摘要:

8 Photochemistry By H. A. J. CARLESS Department of Chemistry Birkbeck College Malet Street London WClE 7HX Interest in photochemistry continues unabated and the most recent volume of Specialist Periodical Report’ suggests that more than 1400 papers on organic photochemistry are appearing each year. The present review is of necessity highly selective but overall there is a clear trend towards the use of photochemistry as a routine synthetic method. Alkene photochemistry is an area of research where much effort continues to be expended both in intramolecular photochemical reactions of alkenes and in [2 + 21 photocycloaddition reactions in which an alkene plays a role. An interesting review has summarized the numerous intramolecular photochemical rearrangements and fragmentations undergone by alkenes and polyenes.* Srinivasan and his group have begun a series of investigations into the photo- chemistry of alkene~~.~ in pentane solution using high-energy and cyclopropane~~ light (185 nm 6.7 eV).Notable features include the rearrangement of cycloalkenes such as cyclohexene to (1) (@=0.05)and (2) (@=Oo.07).3Experiments using 3,3,6,6-[*H4]cyclohexenesuggest that both carbenes (3)and (4)are involved arising 6860 from C-C and C-H bond migration in the excited cyclohexene. These results amplify the previous observations by Kropp and co-workers6 that a carbene may be an intermediate in the rearrangement of alkenes caused by direct irradiation. Curiously these rearrangements are not reported in the irradiation of cyclo-octene at 185 nm where cis-trans photoisomerization OCCU~S.~The sum of the quantum yields of cis -+ trans and trans +cis isomerization is ca.2 which indicates that common intermediate is not reached. The excited species responsible for ‘Photochemistry’ a Specialist Periodical Report ed. D. Bryce-Smith. The Chemical Society London 1978,Vol. 9. G.Kaupp Angew. Chem. Internat. Edn. 1978,17 150. (a)R. Srinivasan and K. H. Brown J. Amer. Chem. SOC.,1978,100,4602;(6)Tetrahedron Letters 1978 3645. R. Srinivasan and K. H. Brown J. Amer. Chem. Soc. 1978,100 2589. R. Srinivasan and J. A. On J. Amer. Chem. SOC.,1978,100,7089. (a)T.R.Fields and P. J. Kropp J Amer. Chem. Soc. 1974,% 7559; (b)P. J. Kropp Mol. Photochem. 1978-9.9 39. 147 H.A. J. Carless isomerization cannot therefore be the TT*state but could be a Rydberg state of the cycloalkene. Another approach to the photochemistry of alkenes which does not involve vacuum U.V. excitation is that of irradiation of the copper(1) complexes of alkenes at 254 nm. Thus irradiation of the copper(1) trifluoromethanesulphonate (triflate) complexes of methylenecyclopropanes yields an array of rearrangement products which suggests a copper(1) carbenium ion as an intermediate.' Irradiation of copper(1)-cyclohexene or -cycloheptene complexes produces copper(1)-trans- cycloalkene isomers which may lead to dimerization may be trapped in a Diels- Alder reaction by dienes,8a or (at lower concentrations) rearrange to products analogous to (1)and (2).86 A reaction which might have synthetic potential is the use of copper(1) triflate to promote [2 +21 photocycloadditions such as those of norbor- nenes to ally1 alc~hol.~ Aromatic esters act as sensitizers for the cis-trans isomerization of cyclo-octene probably uia a singlet excited complex.The use of chiral aromatic esters can thus induce optical activity in the trans- cyclo-octene produced (enantiomeric excess up to 4%)." The rather surprising fact that photolysis of the tricyclic azo-compound (5) (5) gives cis,trans- cyclo-octa- 1,5 -diene as the major product becomes understandable when account is taken of the conformational preference of the 1,4-biradical inter- mediate.'' Excited states of phenylalkenes are known to have hydrogen-abstracting ability and Padwa et u1.12 have provided an interesting example of this process in the triplet-sensitized conversion of the cyclopropene (6)into (8) and (9).The products arise by hydrogen abstraction of the triplet cyclopropene from a cyclopropenyl y-hydrogen atom followed by coupling or disproportionation of the biradical(7) in a Ph Ph Ph Ph Ph Ph (6) (7) (8) (9) process which bears some resemblance to the Norrish Type 11reaction of carbonyl compounds. Electron transfer reactions are playing an increasingly important role in alkene photochemistry. Irradiation of cyanoaromatic sensitizers in the presence of phenyl- R. G. Salomon A. Sinha and M. F. Salomon J. Amer. Chem. SOC.,1978,100,520. (a) J. Th.M. Evers and A. Mackor Tetrahedron Letters 1978 2317; (b)ibid.,1978,2321.R. G. Salomon and A. Sinha Tetrahedron Letters 1978 1367. lo Y. Inoue Y. Kunitomi S. Takamuku and H. Sakurai J.C.S. Chem. Comm. 1978,1024. H.-D. Martin B. Heiser and M. Kunze Angew. Chem. Internat. Edn. 1978,17,696. l2 A. Padwa U. Chiacchio and N. Hatanaka J. Amer. Chem. Soc. 1978 100,3928. Photochemistry alkenes leads by electron transfer to alkene radical cations. For example irradiation of 1,l -diphenylethylene (10) and potassium cyanide in acetonitrile-2,2,2-trifluoro-ethanol solution in the presence of 1-cyanonaphthalene yields the anti-Markovnikov addition product (1l),via the alkene radical cation.13 Conversely the 1,l-diphenyl- ethylene radical anion can be produced by the use of electron-donating sensitizers as in the conversion of (10)under the conditions shown into the Markovnikov addition product (12)in a mild non-acidic route.14 Generation of an alkene radical cation in 1 -cyanonaphthalene 1 -methoxynaphthalene hv hw Ph2CHCH2CN-KCN Ph2C=CH2 -+ Ph2C-Me KCN I CHKN-CHKN-CN CF3CH20H CF3CH2OH the manner described can lead to interesting reactions such as photoaddition of phenylalkenes to furans,” and it also serves to explain the anti-Markovnikov addition of methanol to homoconjugated arylalkenes such as methyl-enebenzonorbornene.16 A related process of photocyanation occurs on irradiation of pyrroles in methanolic sodium cyanide solution using 1,4-dicyanobenzene as sensitizer.” A new type of photosensitized cyclobutane cleavage can be induced by an electron-transfer route.Thus selective excitation of phenanthrene in the presence of 1,4-dicyanobenzene and indene dimers results in cleavage of indene dimers to indene via a radical chain mechanism (ad 8.2).’* A novel route to medium-ring and macrocyclic compounds depends upon such electron transfer. Irradiation of N-alkenyl-phthalimides in alcohols results in cyclization with incorporation of ~olvent,~’ as in the conversion of (13)into (14).lga 0 0 0 (13) A satisfactory mechanism would involve electron transfer from the alkene as donor to the phthalimido group producing the alkene radical cation which is trapped by alcohol and then undergoes radical coupling to give the cyclized product (14). Similar l3 A. J.Maroulis Y. Shigemitsu and D. R. Arnold J. Amer. Chem. SOC.,1978,100 535. l4 D. R. Arnold and A. J. Maroulis J. Amer. Chem. SOC., 1977,99,7355. ’’ K. Mizuno R. Kaji H. Okada and Y. Otsuji J.C.S. Chem. Comm. 1978,594. l6 (a)D.D. Neidigk and H. Morrison J.C.S. Chem. Comm. 1978,600;(6)T.Nylund and H. Morrison J. Amer. Chem. SOC.,1978,100,7364. ” K. Yoshida J.C.S. Chem. Comm. 1978 1108. Is T.Majima C. Pac A. Nakasone and H. Sakurai J.C.S. Chem. Comm. 1978,490. l9 (a)K. Maruyama and Y. Kubo J. Amer. Chem. Soc.,1978,100,7772;(b)K. Maruyama Y. Kubo M. Machida K. Oda Y. Kanaoka and K. Fukuyama J. Org. Chem. 1978,43,2303. H. A. J. Carless electron transfer could be responsible for the unusual 6-hydrogen abstraction and cyclization found on photolysis of cycloalkanone 2-carbo~amides.~' Michl and co-workers2' have published a full account of the reactions in which irradiation at long wavelength of a cyclobutene [e.g.(15)I2l" converts it into a butadiene [e.g. pleiadene (16)] at 77 K by a mechanism which involves successive (15) (16) absorption of two photons with triplet cyclobutene as the intermediate. The implication of this work is that the possible involvement of higher excited states in solution photochemical processes should not be overlooked. [2 +21 Photocycloadditions are well known but there has been a resurgence of interest into possible synthetic conversions of the resulting cyclobutanes. For example the photoaddition of an enolized P-diketone to alkenes can be followed by a retro-aldol reaction to produce a 1,5-dicarbonyl compound.22 An intramolecular version of this transformation has allowed Oppolzer and G0de1~~ to provide an interesting alternative synthesis of longifolene (20) by [2 +21 photocycloaddition of the enol derivative (17),followed by retro-aldol reaction of (18)to yield (19) and subsequent conversion to (20).Pattenden and co-w~rkers~~ have also used this (19) X=H,Y=Z=O (20) X=Me Y =(Me)2 Z =CH2 approach in an ingenious route to the bicyclo[3,2,l]octane system of the gibberellins by irradiation of the enol acetates derived from 4-(prop-2-enyl)cyclopentane-1,3-diones followed by retro-aldol reaction. Cyclobutene-1-carboxylicacid2' and its methyl ester26 have been used in [2 +21 photocycloadditions to give functionalized bicyclo[2,2,0]hexanes.Treatment of the bicyclohexane with lithium in liquid ammonia produces cis-fused cyclohexanes,26 2o T. Hasegawa M. Inoue H. Aoyama and Y. Omote 1. Org. Chem. 1978,43 1005. 21 (a)A.Castellan J. Kolc,andJ.Michl J. Amer. Chem.Soc. 1978,100,6687; (b)M. A. Souto J. Kolc,and J. Michl ibid. 1978,100 6692. 22 P. de Mayo Acc. Chem. Res. 1971,4,41. 23 W. Oppolzer and T. Godel J. Amer. Chem. Soc.. 1978,100,2583. 24 M. Mellor D. A. Otieno and G. Pattenden J.C.S. Chem. Comm.. 1978 138. 25 G. L. Lange and F. C. McCarthy Tetrahedron Letters 1978,4749. 26 P. A. Wender and J. C. Lechleiter I. Amer. Chem. SOC.,1978,100 4321. Photoehemistry whilst heating transforms the bicyclohexanes into derivatives having the germacrane or cadine ring ~ystems.~’ The carbon skeleton of the ring system found in hirsutic acid and related sesquiterpenes can be produced by [2+21 photocycloaddition of dicyclopent-1-enylmethanessuch as (21) in methanol to give the cis,syn cis-tricyclic derivatives[e.g.(22)]which are presumably formed by in situ addition of methanol to (21) (22) the intermediate bicycl0[2,1,0]pentanes.~~Two new routes to propellanes which have appeared involve the intermolecular [2+21photocycloadditions of diphenyl- acetylene or trans-stilbene to bicyclic alkenes,28 and the intramolecular cyclization of an alkenylcyclohexenone (23) to give a tricyclic ketone (24) followed by its unusual acid-catalysed conversion into (25).29 (23) (24) (25) There have been several other notable advances in the field of intermolecular [2+21 photocycloadditions.Lewis and Johnson3* claim to have observed different addition reactions from excited singlet stilbene monomer and excimer with dimethyl fumarate; the monomer reaction leads to a cyclobutane whilst the excimer yields oxetans. Cantrel13’ has clearly shown the features which control the site of attack of alkenes on benzonitrile yielding cycloaddition either at the nitrile group or at the aromatic ring. Irradiation of thiocarbonyl compounds in the presence of alkynes has been shown by two groups32 to give the first stable examples of [2 +21 cycloaddition products thietes. The regioselectivity of rearrangement of a divinylmethane depends on the substi- tution att tern;^^,^^ for example the cyano or methoxy substituents in (26) ensure exclusive photorearrangement to quite different products (27)and (28) respec-ti~ely.~~ The stereochemistry of two of the three major types of di-wmethane rearrangement has already been established.Whereas the divinylmethane re- arrangement gives inversion of configuration at the methane carbon atom the 27 J. S. H. Kueh M. Mellor and G. Pattenden J.C.S. Chem. Comm. 1978 5. 28 G. Kaupp and M. Stark Angew.Chem. Internut. Edn. 1978,17,758. 29 R. L. Cargill J. R. Dalton S. O’Connor and D. G. Michels Tetrahedron Letters 1978,4465. F. D. Lewis and D. E. Johnson J. Amer. Chem. Soc. 1978,100,983. 31 T. S. Cantrell J. Org. Chem. 1977,42,4238. 32 (a)H. Gotthardt and 0.M. Huss Tetrahedron Lelters 1978,3617; (b)A.C. Brouwer A. V. E. George D. Seykens and H. J. T. Bos. ibid. 1978,4839. 33 D. W. Alexander A. C. Pratt D. H. Rowley and A. E. Tipping J.C.S. Chem. Comm. 1978,101. 34 H. E. Zimmerman and R. T. Klun Tetrahedron,1978,34,1775. H.A. J. Carless oxa-di-vmethane case leads to a loss of stereochemistry. Zimmerman and co- worker~~~ have now determined the stereochemistry of the third type involving an arylvinylmethane(29) in which it rearranges to (30)and (31)with complete inversion (29) (30) (31) at the methane carbon atom. However the fast rate of photoracemization of the cyclopropanes meant that rearrangement had to be extrapolated to zero conversion to establish this stereospecificity. Zimmerman's continued detailed study of the rates and regioselectivities of rearrangement of a variety of aryl~inylmethanes~~ and tetra-aryl substituted di~inylmethanes~~ has led him to propose a theory which is capable of explaining such reactions using SCF-CI calculation^.^^ Briefly AP for each pair of orbitals is the change in bond order of the excited state compared to the ground state and the constructionof a 'APmatrix' gives an idea of how excitation energy is partitioned in a molecule.The extension of the concept to cover the kind of molecular motions likely to convert electronic into vibrational energy can be applied to a wide variety of photochemical reactions.39 One of the most remarkable syntheses reported this year must be that of tetra-t-butyltetrahedrane (32). Whilst matrix irradiation of the trisubstituted cyclopentadienone (33) has been shown to produce the [2 +21 cycloadduct 'housenone' (35),,' the addition of an extra t-butyl group as in (34) causes exclusive [2 +21 criss-cross addition on matrix isolation to give tricyclopentanone (36).,l Bu' n R B;' 'H Bu' Bu' (33) R=H (35) (34) R=Bu' 35 H.E. Zimmerman,T. P. Gannett apd G. E. Keck J. Amer. Chem. Soc. 1978,100 323. 36 H. E. Zimmerman M. G. Steinmetz and C. L. Kreil J. Amer. Chem. Soc. 1978,100,4146. 37 (a)H. E. Zimmerman and W. T. Gruenbaum,J.Org. Chem. 1978,43,1997; (b)H. E. Zimmerman and T. R. Welter J. Amer. Chem. SOC.,1978,100,4131. 38 H. E. Zimmerman W. T. Gruenbaum R. T. Klun M. G. Steinrnetz and T. R. Welter J.C.S. Chem. Comm..1978,228. 39 H. E. Zimmerman and M. G. Steinmetz J.C.S. Chem. Comm. 1978,230. 40 G. Maier U. Schiifer W. Sauer H. Hartan R. Matusch and J. F. M. Oth Tetrahedron Letters 1978 1837. 41 G. Maier S. Pfriem U. Schafer and R. Matusch Angew. Chem. Internat. Edn. 1978,17,520. Photochemistry 153 Irradiation of this latter material in diethyl ether at -100 "Cgives decarbonylation to yield the tetrahedrane (32) which is sufficiently stable that it can be made to isomerize to tetra-t-butylcyclobutadieneonly by heating above 130 "C. The Norrish Type 11 photoelimination reaction of carbonyl compounds is well known to occur uia a l,4-biradical. A competing process which is available to the 1,4-biradical(38) from 6-substituted valerophenones (37) is the radical loss of X'to produce a yS-unsaturated ketone (39).Wagner's group4* have examined the competition between formation of Type I1 products and (39) for a variety of &substituted ketones which allows a calculation of the relative rates of radical p-cleavage in these biradicals. Amongst the halogens the radical leaving abilities are I > Br > C1 to the extent that (39) becomes the only product detected from irradiation of (37; X = I). (37) PhCOCHZCHzCH = CHz (39) Scaiano's group4345 have continued to find applications for their important technique in which 1,4-biradical lifetimes are measured by trapping with paraquat dication (l,l'-dimethyl-4,4'-bipyridylium)and following the production of the coloured paraquat radical cation Lifetimes of triplet biradicals from phenyl alkyl ketones (typically -100 ns) are surprisingly insensitive to changes in temperature substitution pattern and solvent suggesting a process like intersystem crossing (to singlet) as the main deactivation pathway.43 In contrast an aliphatic aldehyde such as valeraldehyde gives rise to a much longer lived 1,4-biradical (2 ps in water-a~etonitrile).~~ In the photoenolization of o-methylacetophenone Small and Scai- an045 have found evidence for only one biradical intermediate (lifetime 300 ns) which helps to clarify the mechanisms proposed for this complex and controversial photochemical reaction.One of the usual assumptions about photochemical processes is that they are independent of temperature wavelength and light intensity.Each of these assump- tions has been shown in certain circumstances to be invalid for carbonyl compounds especially when radical intermediates may be involved in such photochemical processes. Thus the ratio of products from the photoaddition of aldehydes to bicyclo[2,2,2]octan-2,3-dionedepends strongly on light intensity,46 and acenaph- thoquinone appears to undergo wavelength-dependent processes of photoaddition and photo-oxidation in ~olution.~' Citral (40) is predominantly converted into '' (a)P. J. Wagner J. H. Sedon and M. J. Lindstrom J. Amer. Chem. SOC.,1978 100 2579; (b)P.J. Wagner and J. H. Sedon Tetrahedron Letters 1978 1927. 43 R. D. Small and J. C. Scaiano J. Phys. Chem. 1977,81 2126. O4 M.V.Encinas and J. C. Scaiano J. Amer.Chem. Soc. 1978,100 7108. " R.D.Small and J. C. Scaiano J. Amer. Chem. SOC.,1977,99,7713. " M.B.Rubin and S. Inbar J. Amer. Chem. Soc. 1978,100,2266. 47 T.-S. Fang and L. A. Singer J. Amer. Chem. SOC.,1978,100,6276. H.A. J. Carless aldehydes (41) and (42) on irradiation at high temperature (165-190 "C),perhaps via a 1,2-formyl shift whereas these products are not seen at all on irradiation at room temperat~re.~' CHO hv 280"C e (40) (41) R' = Me R2=CHO (42) R' = CHO R2=Me The much-studied ring expansion of cyclobutanones to cyclic acetals which occurs on irradiation in alcohols has been exploited in a synthesis of the prostaglandin precursor (44) by irradiation of the bicycloheptanone (43).49 Yields of (44) are .. .I I.0 0 increased to 42% in the presence of sodium bicarbonate and 2,5-dimethylhexa-2,4- diene though the function of this latter triplet quencher in increasing the yield is not obvious. Photolytic rearrangement of 2,3-epoxycyclohexa- 1,4-diones such as (45) occurs on irradiation in acetone to yield the y-alkylidene butyrolactones (46),"" R-Go U= 1;:. 0 H CHO (45) (46) which may in turn be used to provide a route to the y-alkylidene-A"*'-butenolide structures found in a variety of natural Working to a plan conceived nearly 15 years ago Quinkert Barton and co- workersS' have now completed a three-step synthesis of dimethyl crocetin (49). The key step involves the photochemical ring opening of a bis-cyclohexadienone (47) to a bis-ketene (48).F. Barany S. Wolff and W. C. Agosta J. Amer. Chem. SOC.,1978,100 1946. O9 N. M. Crossland S. M. Roberts and R. F. Newton,J.C.S. Chem. Cornm. 1978,661. 50 (a)T. Kitamura T. Imagawa and M. Kawanisi Tetrahedron Letters 1978 3443; (6)T.Kitarnura Y. Kawakami T. Irnagawa and M. Kawanisi Tetrahedron Letters 1978,4297. 51 G. Quinkert K. R. Schmieder G.Durner K. Hache. A. Stegk and D. H. R. Barton Chem. Ber. 1977 110,3582. Photochemistry 155 (49) Most py-unsaturated ketones give two characteristic photoreactions triplet sensitized oxa-di-m-methane rearrangement [e.g.(50)+ (5l)] from the lowest (50) (51) triplet mr* state or a 1,3-acyl shift [e.g. (50)-+ (52)] on direct irradiation that has been variously ascribed to a singlet nw* or a second triplet nr* state.In an interesting attempt to show the state responsible for this latter reaction Schaffner et al.52have generated the triplet n7zX state of the enone (50) by thermolysis of the dioxetan (53) comparing the product distribution with that obtained from direct and O-O OMe 4 x’. 0 (52) (53) sensitized photolyses. There is certainly evidence that the 1’3-acyl shift on irradia-tion of (50)can occur from the triplet nn* state although the additional involvement of the singlet n7r* state cannot be excluded. CIDNP Studies during irradiation of y-methyl substituted acyclic py-unsaturated ketones also suggest that the 1,3-acyl shift occurs mainly from a triplet excited Photolysis in micelles can have a very important effect on the fate of radical intermediates.For example irradiation of p-tolyl benzyl ketone in a micelle (at low ketone to micelle ratios) yields only 1-p-tolyl-2-phenylethane (ArCH2CH2Ph) with none of the cross-coupled products (PhCH2CH2Ph or ArCH2CH2Ar) which are found on irradiation under normal solution condition^.^^ Under the intriguing title of ‘sunlight and soap for the efficient separation of I3Cand ’*Cisotopes’ Turro and ’’ M. J. Mirbach A. Henne and K. Schaffner,J. Amer. Chem. Soc. 1978,100,7127. s3 A.J. A. van der Weerdt H. Cerfontain J. P. M. van der Ploeg and J. A. den Hollander J.C.S. Perkin IZ 1978,155. N. J. Turro and W. R. Cherry J. Amer. Chem. Soc. 1978,100,7431. H.A. J. Carless KraeutlerS5 describe how the irradiation of dibenzyl ketone in micelles can lead to a process of high isotope enrichment at the carbonyl group of the unreacted ketone by means of a magnetic isotope effect.Another example of the importance of environment in photochemistry is provided by the irradiation of 16-0x0- 16-p- tolylhexadecanoic acid where Type I1 elimination is enhanced in micelles compared to solutions but effectively prevented in monolayer Crown ethers have inevitably found their ways into photochemistry with reports which range from dramatic changes in photophysical properties of a crown ether naphthalene derivative on complexation with a caesium cation,” to catalysis by potassium ions of the Type I1 elimination process on irradiation of the valerophenone derivative prepared from dibenzo-18-crown-6.’* Lithium ions can stabilize the 12-crown-4 product formed by intramolecular photochemical cycloaddition of two anthracene residues linked by a polyoxyethylene chain although they do not appear to increase the efficiency of the cy~lization.~’ Since last year’s Report,60 more evidence has accumulated for the possibility that attack of singlet oxygen (lo2) on electron-rich alkenes occurs by way of a zwitterionic peroxide intermediate,61 rather than in a concerted process.The reaction of ‘02with norbornenyl ethers in methanol leads to zwitterion trapping by the whilst reaction of lo2with the norbornadiene (54) gives intramolecular trapping of the zwitterion by the remaining double bond to yield peroxide (55).61b There is 0-0 increasing recognition that photosensitized oxidation does not need to involve lo2 but may instead proceed through formation of the superoxide radical anion (02‘-) in an electron-transfer reaction.62 Research in this area may be assisted by the publication of a photochemical method for the generation of superoxide ion in aqueous Schultz et al.have applied the photocyclization of aryl vinyl and sulphides6’ to the synthesis of dihydrofurans and dihydrothiophens respectively. These reactions can provide a useful arylation process exemplified in the total ” N. J. Turro and B. Kraeutler J. Amer. Chem. SOC.,1978,100,7432. 56 P.R. Worsham D. W. Eaker and D. G. Whitten J. Amer. Chem. SOC.,1978,100,7091. ” J. M.Larson and L. R. Sousa J. Amer. Chem. SOC.,1978,100,1943.’* R. R. Hautala and R. H. Hastings J. Amer. Chem. SOC., 1978,100,648. 59 J.-P. Desvergne and H. Bouas-Laurent J.C.S. Chem. Comm. 1978,403. 6o H. A.J. Carless Ann. Reports 1977,74 165. (a)C. W. Jefford and C. G. Rimbault J. Amer. Chem. Soc.,1978,100,6437;(b)ibid.,1978,100,6515. 62 (a)C. W. Jefford and A. F. Boschung Helv. Chim. Acta 1977,60,2673;(b)J.Eriksen C. S. Foote and T. L. Parker J. Amer. Chem. SOC.,1977 99,6455; (c)J. P.McCormick and T. Thomason. ibid.,1978 100 312; (d)V.S.Srinivasan D. Podolski N. J. Westrick and D. C. Neckers ibid. 1978,100 6513. 63 R. A. Holroyd and B. H. J. Bielski J. Amer. Chem. SOC.,1978 100 5796. A. G. Schultz R. D. Lucci W. Y. Fu M. H. Berger J. Erhardt and W. K. Hagmann J. Amer. Chem. SOC. 1978,100,2150. Photochemistry 157 synthesis of the alkaloid lycoramine by the photocyclization of (56) to the dihy- drofuran (57).Irradiation of phenethyl vinyl ether (PhCH2CH20CH=CH2) in solution gives the unusual intramolecular cycloadduct (58),resulting from attack of the vinyl group on the 2,5-positions of the aromatic ring.66 qyyj C0,Me R C0,Me (56) R = CH2CH2NHC02Me (57) (58) Photorearrangement of five-membered ring heterocycles continues to provide results of mechanistic interest. The phototransposition of 2-cyanopyrroles to 3-cyanopyrroles has been proposed to occur by 2,5-bonding and 'walk' of the aziridine nitrogen atom as shown in Scheme 1. Conclusive evidence for (59) as an inter- Scheme 1 mediate in 2-cyano-N-methylpyrrole rearrangement results from its trapping by irradiation in methanol or f~ran.~' The related 1,3-phototransposition of an indene provides no evidence for a bicyclopentene intermediate but seems more in accord with a concerted di-.rr-methane mechanism;68 inversion occurs cleanly at the migrat- ing centre as for the arylvinylmethane rearrangement.35 Another pathway for photochemical rearrangement in five-membered ring heterocycles is that of the dihydrofuran (60)to acylcyclopropane (61),being a reaction used as an entry to the chrysanthemum monocarboxylic acids.69 szMe po2Me COMe (60) (61) " A.G. Schultz W. Y. Fu R.D. Lucci,B. G. Kurr K. M. Lo and M. Boxer J. Amer. Chem. Soc. 1978,100 2140. '' A. Gilbert and G. Taylor J.C.S. Chem. Comm. 1978 129. '' J. A.Barltrop A. C. Day and R. W. Ward J.C.S. Chem. Comm. 1978 131. 68 D. Giacherio and H. Morrison J. Amer. Chem. Soc. 1978,100,7109. 69 K. Ohkata T. Isako and T. Hanafusa Chem. and Ind. 1978 274. H. A. J. Carless Ring expansion of aryl azides to 3H-azepines on irradiation in the presence of nucleophiles is a well-known reaction examples of which are found in the recently- observed reactions of 0-azidobenzoic acid derivatives70a and azidoquin~lines.~~~ The reaction has been assumed for the last 20 years to involve an azirine intermediate (62) formed from phenylnitrene (63). However Chapman and Le Roux71 have shown that irradiation of phenyl azide in a matrix at 8 K leads to a product (vmu 1895 cm-l) assigned the ketenimine structure (64). Reaction of the keteni- mine with nucleophile (e.g.R,NH) would lead to 1H-azepine (65) followed by isomerization to 3H-azepine (66) which is the normal end-product. Recent e.s.r. studies also suggest that 2-pyridylmethylene (67)may be formed by irradiation of the (62) (63) (64) (65) (66) (67) ketenimine (64).72 When all else fails another means of providing evidence for intermediates in such ring-expansion reactions may come from the observation of isotope effects such as those found in the conversion of 1-iminopyridinium ylides into 1,2-diazepine~.~~ One of the most useful methods for the preparation of cyclophanes involves the extrusion of sulphur or sulphur dioxide from bis-sulphides or bis-sulphones respec- tively. Givens and W~lie~~ report that the efficient extrusion of sulphur dioxide by photolysis of bis-sulphones suspended in benzene represents a reasonable alter- native to pyrolysis.The extrusion of sulphur is an important method for C-C coupling in macrocyclic systems often carried out by photolysis of sulphides in the presence of trialkyl phosphites. This latter reaction has allowed the preparation of triple-layered paracy~lophanes,’~ and of the extraordinarily insoluble hydrocarbon Kekulene with its cyclic fused system of 12 benzenoid rings.76 A new method for the cyclopropanation of alkenes involves photolysis of di-iodomethane in the presence of an alkene and it has the advantage over the Simmons-Smith reaction in being little affected by steric constraints.” The absence of C-H insertion products suggests that methylene itself is not involved.70 (a) R. Purvis R. K. Smalley W. A. Strachan and H. Suschitzky J.C.S. Perkin I 1978 191; (6)F. Hollywood E. F. V. Scriven H. Suschitzky D. R. Thomas and R. Hull J.C.S.Chem. Comm. 1978,806. 71 0.L. Chapman and J.-P. Le Roux 1Amer. Chem. SOC.,1978,100,282. 72 0.L.Chapman R. S. Sheridan and J.-P. Le Roux J. Amer. Chem. SOC.,1978 100,6245. 73 (a)H.Kwart D. A. Benko J. Streith D. J. Harris and J. L. Schuppiser J. Amer. Chem. SOC.,1978,100 6501;(6)H.Kwart D. A. Benko J. Streith and J. L. Schuppiser ibid. 1978 100 6502. 74 R. S. Givens and P. L. Wylie Tetrahedron Lztters 1978 865. ” T. Otsubo T. Kohda and S. Misumi Tetrahedron Letters 1978 2507. 76 F.Diederich and H. A. Staab Angew. Chem. Internat. Edn. 1978,17,372. 77 N.J. Pienta and P. J. Kropp J. Amer. Chem. SOC.,1978,100,655.

ISSN:0069-3030    

DOI:10.1039/OC9787500147

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

9 Aliphatic Compounds Part (i) Hydrocarbons ~~~~ ~ By K.J. TOYNE Department of Chemistry The University of Hull Hull HU6 7RX 1 Alkanes Two similar methods for the deoxygenation of alcohols to alkanes have been reported. Tertiary alcohols and sterically hindered secondary alcohols can be deoxygenated by reaction of their acetates with lithium in ethylaminel and esters of primary secondary or tertiary alcohols are reduced by sodium in hexamethyl- phosphoric triamide (HMPA) containing t-butyl alcohol2 (Scheme 1). The only significant side reaction in these convenient procedures is the regeneration of the initial alcohol. 0 0-R'OH -+ R~-C R2-C ' -+ R1. -+ R1H 'OR' 0-R' 1' R'O-+ R'OH Reagents i Li-EtNH or Na-HMPA-Bu'OH Scheme 1 The debromination of uic- dibromoalkanes to alkanes has been achieved using sodium hydrogen telluride prepared in situ (Scheme 2).3 The reaction proceeds via the alkene4 and sodium hydrogen telluride may therefore prove to be a useful reagent both for debromination of vic-dibromides and for the hydrogenation of alkenes.R1CHBrCHBrR22R'CH=CHR2 R'CH2CH2R2 Reagents i and ii Te-NaBH.,-EtOH Scheme 2 The transformation of aldehydes and ketones into alkanes can be achieved indirectly by reduction of the tosylhydrazones in various ways and now sodium borohydride-acetic acid has been shown to be a convenient alternative reagent R. B. Boar L. Joukhadar J. F. McGhie S. C. Misra A. G. M. Barrett D. H. R. Barton,and P. A. Prokopiou J.C.S. Chem. Comm. 1978,68. 'H.Deshayes and J.-P. Pete J.C.S. Chem. Comm. 1978 567. K. Ramasamy S. K. Kalyanasundaram and P. Shanmugam Synthesis 1978,545. K. Ramasamy S.K. Kalyanasundaram and P. Shanmugam Synthesis 1978,311. 159 160 K. J. Toyne which offers the advantage that migration of the double bond in &-unsaturated tosylhydrazones does not occur.' The use of sodium borohydride in polar aprotic solvents to achieve selective reductions of halides sulphonate esters tertiary amines and NN-disulphonimides has been summarized and a method is given for the preparation of hydrocarbons from alcohols by the conversion of alcohols into iodides followed by reduction in situe6 2 Alkenes Synthesis.-Several attractive routes have been reported for the synthesis of substi- tuted alkenes from alkynes.Terminal and internal alkynes react with organoalanes- zirconocene dichloride complexes [R32A1-C12Zr(C5H5)] to produce alkenyl metals (1) by stereospecific cis-addition (Scheme 3).' The Pd- or Ni-catalysed coupling MLn = A1R22or ClZr(C5H5)2 Reagents i RZ Al-C1zZr(C5H5)z; ii H'; iii R3X-Pd or Ni phosphine complex-ZnClz Scheme 3 reactions of (1)with alkenyl aryl or alkynyl halides are significantly promoted by metal salts such as zinc chloride and this discovery provides for the first time a general procedure for the synthesis of trisubstituted alkenes [(2);H(R') =HI.' With suitable choice of R3X a method is therefore available for the stereoselective and regioselective 'one-flask' conversion of terminal alkynes into conjugated dienes (R3=alkenyl) and enynes (R3=alkynyl).The 2-methylalkenylalanes (3)formed in these reactions from terminal alkynes and Me3AI-C12Zr(C5Hs)2 can be functional- ized in a variety of ways (Scheme 4),9 and this procedure offers a simple selective route to some terpenoids as illustrated by the synthesis of geraniol and ethyl geranate. The reaction of alkynes with trimethylalane-titanocene dichloride has also been reported but the reactions with internal and terminal alkynes have ' R. 0.Hutchins and N. R. Natale J. Org. Chem. 1978,43,2299. R. 0.Hutchins D. Kandasamy F. Dux C. A. Maryanoff D. Rotstein B. Goldsmith W. Burgoyne F. Cistone J. Dalessandro and J. Puglis J. Org. Chem. 1978,43 2259. D. E. Van Horn and E. Negishi J. Amer. Chem.Soc. 1978,100,2252. * E. Negishi N. Okukado A. 0.King D. E. Van Horn and B. I. Spiegel J. Amer. Chem. SOC.,1978,100 2254. N. Okukado and E. Negishi Tetrahedron Letters 1978,2357. A liphatic Compounds R H R H R H i\/ ii \ / \c=c / t c=c + c=c /\ / \-Me/ \C02CH2Me Me Al(Me)2 Me A1(Me)2Bun )i (3) R H a X=CH20H \/ b. X=C02H Me/c=c\x c X=CH20Me Reagents i ClCO,CH,Me; ii BunLi;iii (CH,O) or CO or ClCH,OMe Scheme 4 their limitations because of dehydrometallation or polymerization." However carbometallations of metal-substituted alkynes (e.g. RCzCZnC1) with Me3A1-Cl2Ti(C5H5) and subsequent hydrolysis gives the terminal alkene R(Me)C=CH,. Another convenient stereospecific route to tri-substituted alkenes involves suc- cessive reaction of a terminal alkyne with a Grignard reagent and a trialkylborane (Scheme 5)." The intermediate alkenyl iodide (4) can also be stereospecifically R H R H R H iii-v \C=C / -A \c=c / ___ \c=c / I/* RCECH R H \c=c / Reagents i R'MgBr-CuBr,Me,S; ii I,; iii Bu"Li; iv R23B; v I,; vi RZMgX,Pd(PPhJ4; vii electrophiles Scheme 5 cross-coupled in a palladium-catalysed reaction with a variety of Grignard reagents to give tri-substituted alkenes (by using alkylmagnesium halides) or 1,3-dienes (by using alkenyl magnesium halides).I2 When methylmagnesium bromide was used in the first stage of the sequence the product was hydrolysed to a terminal alkene [(S); R' = MeE =HI or was treated with ally1 bromide or acetyl chloride to produce 1,4-dienes or a@-unsaturated ketones re~pectively.'~ Terminal and internal alkynes have been reduced stereoselectively by MgHz-CuI or MgH2-CuOBu' to terminal alkenes and cis-alkenes respectively without formation of alkane or tr~ns-alkene.'~ cis-Alkenes have also been obtained from lo D.E. Van Horn L. F. Valente M. J. Idacavage and E. Negishi J.Orgunometullic Chem. 1978,156,C20. N. J. LaLima and A. B. Levy J. Org. Chem. 1978,43,1279. l2 H. P. Dang and G. Linstrumelle Tetrahedron Letters 1978 191. l3 A.Marfat P. R. McGuirk and P. Helquist Tetrahedron Letters 1978 1363. l4 E.C.Ashby J. J. Lin and A. B. Goel. J. Org. Chem. 1978 43,757. 162 K. J. Toyne internal alkynes by reaction with a dialkylborane followed by palladium diacetate- catalysed protonolysis of the intermediate alkenyldialkylborane (Scheme 6 ;X = R’).’’ In this sequence terminal alkynes behave in a completely different manner to give trans-alkenes.The reduction of alkynes and alkenes with lithium aluminium hydride mixed with transition metal halides in catalytic or equimolar amounts has been studied in detail and the reagent LiA1H4-NiCl2 (1:0.1) is particularly usefu1.16 Alkynes can be reduced quantitatively to alkanes or using milder reaction condi- tions to alkenes. R H \/ R H/c=c\R i\ /x RCZCX-C=C H/ \BR22 a R R’ \/ X=HorR’ c=c H/\H Reagents i R2,BH; ii Pd(OAc),-Et,N-THF; iii Pd(OAc),-THF Scheme 6 Several syntheses of alkenes based on ketone precursors have been reported. Titanium metal freshly prepared from anhydrous titanium(II1) chloride by reduction with magnesium or potassium in anhydrous THF reduces enol phosphates to alkenes and so provides a regioselective conversion of ketones (not conjugated to aromatic rings) into a1kenes.l’ This method of reduction gives higher yields than that using Li-EtNH and the method may be particularly useful for the synthesis of 1,3-dienes from ap-unsaturated ketones.The lithium derivative of the intermediate formed from the reaction of an a-chloroketone and a Grignard reagent decomposes to give an alkene (Scheme 7). This sequence therefore provides a convenient ‘one-flask’ synthesis of alkenes and with a double bond present in the Grignard reagent it should allow the synthesis of dienes with the double bonds in predetermined positions.l8 Is H. Yatagai Y. Yamamoto and K. Maruyama J.C.S. Chem. Comm. 1978,702. l6 E. C. Ashby and J. J. Lin J. Org. Chem. 1978,43,2567. ’’S. C. Welch and M. E. Walters J. Org. Chem. 1978,43,2715. J. Barluenga M. Yus. and P. Bernad J.C.S. Chem. Comm. 1978 847. Aliphatic Compounds 163 @-Hydroxysulphides (RCHSPh.CHOHR') readily prepared from carbonyl compounds and a-lithiosulphides undergo reductive trans-elimination on treatment with 1-ethyl-2-fluoropyridiniumtetrafluoroborate and lithium iodide to give alkenes (RCH=CHR') under mild condition^.'^ The synthesis of terminal alkenes by an elimination reaction is frequently complicated by the simultaneous formation of substitution products and isomeric alkenes.A novel regiospecific route to obviate these problems uses the trityl carbonium ion to abstract a hydride ion from the @-carbonof an alkyl-iron compound {prepared by reaction of a bromide or tosylate with [CSH5Fe(CO),]-Na') and subsequent liberation of the alkene from the complex (Scheme 8)." v5-CSHSF~(CO)~CHRCHR~[v5-CSH5Fe(C0)2(RCH=CR2)]+BF4-'kRCH=CRz Reagents i Ph,C+BF,-; ii NaI-Me,CO Scheme 8 Terminal alkenes can also be converted into terminal alkenes with the carbon chain increased by three atoms in an attractively simple and general method based on hydroalumination (Scheme 9).21 Hydroalumination of alkenes gives organo- aluminium compounds which can be coupled by an SN2' pathway with allylic halides in a copper(1) halide catalysed reaction.All four alkyl groups on aluminium can participate and when 3-haloprop-1 -ene is used the chain-lengthening procedure shown in Scheme 9 (Reactions i and ii) is possible. Dienes react selectively at the less RCH~CHZCH~CH=CH~ /2-/ * RCHzCHzCH2CrCH RCH=CHz 4 (RCHzCH2)4A1Li RCH2CH2CH=C=CHz RCHZCHzHal Reagents i LiAlH,-TiCl,? ii CH,=CHCH2Hal-CuC1; iii CH,=C=CHBr-CuCl; iv CHrCCH2Br- CuCl; v CuCl or CuBr Scheme 9 substituted double bond and so in conjunction with substituted allylic halides the route may prove very useful for the synthesis of complex molecules. This procedure can be regarded as an extension of an important synthetic method for alkenes which is based on the regio- and stereo-selective coupling reactions of various allyl alcohol derivatives with Grignard reagents.However in the latter reactions complications frequently arise from allyl transpositions. A highly regioselective coupling of certain Grignard reagents with allyl 2-pyridyl ethers in the presence of magnesium bromide is now possible.22 It is suggested that the intermediate complex (6)is involved and most simple primary allyl pyridyl ethers in THF are alkylated selectively without rearrangement (Path A for unhindered ethers) whereas secondary and tertiary allyl l9 T. Mukaiyama and M. Imaoka Chem. Letters 1978,413. 2o D.E.Laycock and M. C. Baird Tetrahedron Letters 1978 3307. 21 F.Sato H. Kodama and M. Sato J. Organometallic Chem. 1978,157,C30. 22 T. Mukaiyama M. Yamaguchi and K.Narasaka Chem. Letters 1978,689. 164 K.J. Toyne (6) ethers in benzene react regioselectively with rearrangement (Path B). Direct alkyl- ation of allylic alcohols can be achieved with RCu:BF3 and this represents the first direct displacement of a hydroxyl group by an alkyl group using an organocopper reagent.23 The major product arises from allylic rearrangement. Several examples have been reported of the use of titanium derivatives in alkene-forming reductions. Reduction with titanium(II1) chloride and potassium lithium or a zinc-copper couple gives active titanium metal which is an efficient reagent for coupling ketones and aldehydes to produce alkenes [2RR'(H)CO + RR'(H)C=CRR'(H>].*" Intermolecular coupling works best with identical carbonyl groups but certain mixed products can be prepared e.g.with a diary1 ketone and another carbonyl system. Intramolecular coupling of dicarbonyls works well and rings of 4-16 and 22 carbon atoms have been prepared in high yield. The reaction involves a pinacol dianion intermediate and therefore active titanium metal can also be used for the deoxygenation of 1,2-diols. A titanium(II1) chloride-zinc powder induced coupling of pinacolone yields the new alkene trans-2,2,3,4,5,5- hexamethylhex-3-ene; some unusual chemical and physical properties of the compound have been rep~rted.'~ Titanium(II1) chloride-lithium aluminium hydride reductively couples allylic or benzylic alcohols and reduces epoxides and bromohydrins non-stereospecifically to alkenes.26 However two procedures for the stereospecific generation of alkenes from epoxides have appeared.In one method the epoxide is treated with methyl- triphenoxyphosphonium iodide in the presence of boron trifluoride ethe~ate,~' and in the second method trifluoroacetyl iodide and sodium iodide are used.28 Both procedures may involve an intermediate (7) which directly or via the intermediacy of an iodonium ion reacts with iodide ion to give the alkene. ox -.. I :' ;c-7LI (7) X = (Ph0)3PMe or CF3C0 A review of the usefulness of the intramolecular ene reaction in synthesis has been p~blished.~' 23 Y.Yamamoto and K. Maruyama J. Organometallic Chem. 1978,156 C9. 24 J. E.McMurry M. P. Fleming K. L. Kees and L. R. Krepski J. Org. Chem. 1978,43,3255. 25 D.Lenoir Chem. Ber. 1978 111,411.26 J. E.McMurry M. G. Silvestri M. P. Fleming T. Hoz and M. W. Grayston J. Org. Chem. 1978 43 3249. 27 K.Yamada S.Goto H. Nagase Y. Kyotani and Y. Hirata J. Org. Chem. 1978,43 2076. 28 P.E.Sonnet J. Org. Chem. 1978,43 1841. 29 W.Oppolzer and V. Snieckus Angew. Chem. Internat. Edn. 1978,17,476. Aliphatic Compounds Reactions.-Anti-Markovnikov hydrohalogenation of alkenes has been achieved in two ways. The readily available lithium tetra-alkylaluminiums from alk-1-enes react with copper(I1) chloride or bromide to give the corresponding 1-haloalkanes in good yield (Scheme 9; Reactions i and v).~’ Terminal alkenes react more readily than internal alkenes in the hydroalumination stage and so the method is parti- cularly useful for the preparation of 1-haloalkenes from non-conjugated dienes.The other procedure uses alkylpentafluorosilicates derived from hydrosilylation of an alk-1 -ene (Scheme lo).” Whereas tetraco-ordinated alkylsilanes are completely inert towards halogenolysis alkylpentafluorosilicatesreact extremely rapidly with halogens to produce the alkyl halide in good yield. iii RCH=CH2 4 RCH2CH2SiC13 K2[RCH2CH2SiF5]-RCH2CH2Hal Reagents i HSiC1,-H,PtCl,; ii KF; iii Hal Scheme 10 Several papers have developed the idea of allylic functionalization of alkenes by the formation of a C-C bond -a reaction which has its analogy with alkylation a to a carbonyl group. T-Allylpalladium complexes have been prepared from alkene~~~ and when their electrophilicity is increased by the addition of Iigands they react with ‘soft’ nucieophiles to give reaction at the ally1 position (Scheme 11).33,34The PdCl X = CHzCOzMe CHzCOR CHZSO~R CH2R CH2CH=CH2 \t WCO,Me Reagents i NaC1-PdC1,-NaOAc-HOAc-CuC12;ii phosphines or phosphites nucleophile Scheme 11 regioselectivity of the reaction depends on the nature of the attacking nucleophile and the structure of the m-ally1 complex but a preference normally exists for reaction at the less substituted carbon.Whereas methyl-lithium methylmagnesium iodide and lithium dimethylcuprate fail to give alkylation products successful alkylations have been achieved with the anions derived from malonate esters p-keto sulphones P-keto sulphoxides and P-keto sulphides and the types of alkylation shown in Scheme 11have been achieved.A new prenylation sequence has been devised which 30 F. Sato Y. Mori and M. Sato Chem. Letters 1978,833. 31 K. Tamao J. Yoshida M. Takahashi H. Yamamoto T. Kakui H. Matsumoto A. Kurita and M. Kumada J. Amer. Chem. SOC.,1978,100,290. 32 B. M.Trost P. E. Strege L. Weber T. J. Fullerton andT. J. Dietsche J. Amer. Chem. SOC.,1978,100 3407. 33 B. M. Trost L. Weber P. E. Strege T. J. Fullerton andT. J. Dietsche J. Amer. Chem. SOC.,1978,100 3416. B. M. Trost L. Weber P. E. Strege T. J. Fullerton and T. J. Dietsche J. Amer. Chem. SOC.,1978,100 3426. 166 K. J. Toyne allows the direct conversion of lower terpenes into higher terpenes by using the anion (8). Alkylation of a T-ally1,palladium complex followed by decarbomethoxylation and desulphonylation gives the prenylation product.Ultimately catalytic alkylation processes would be desirable but at least the transformation of the palladium chloride into palladium black allows the metal to be recycled. SO2Ph (8) Allylic functionalization has also been achieved by the three-step synthesis of allylic malonates from alkenes (Scheme 12).35The ene reaction of alkenes with hexafluorothioacetone generated in situ followed by reaction with dicar-bomethoxycarbene gives ylide (9) which rearranges and is then reduced to give the product. Reagents i [(CF,),CS]; ii N,C(CO,CH,),-CuSO,; iii Na-Hg Scheme 12 1-Phenylselenoalkan-2-ones(10)are readily prepared in high yield from terminal alkenes and are useful because they permit regiospecific alkylation at C-1 (Scheme 13,reactions i and ii).36 Reductive and oxidative removal of the phenylseleno-group SePh i-iii I RCH=CH2 -RCOCH2SePh 5RCOCHCH2R' /RCoCH2CH2R1 \ /(10) (11) \ RCOCH=CHR' [RCH(OSnBu&3€$SePh] Reagents i PhSeBr-EtOH; ii NaI0,-aq.MeOH; iii heat; iv Bu'OK-R'CH,X; v Et,N-PhSH; vi NaI0,-aq. MeOH; vii (PhSe)2-Br,-(Bu,Sn),0 Scheme 13 from (11) gives saturated ketones and ap-unsaturated ketones respectively (see Scheme 24 for a similar synthesis of ap-unsaturated ketones). The formation of (10) is thought to proceed via (12),which on oxidation and heating gives the vinyl ether (13). The eliminated phenylselenenic acid (PhSeOH) adds to (13) to give a hemi- acetal which is hydrolysed to (10).a-Phenylseleno carbonyl compounds (10) have '' B. B. Snider and L. Fuzesi Tetrahedron Letters 1978 877. 36 T. Takahashi H. Nagashima and J. Tsuji Tetrahedron Lettsrs 1978 799. Aliphatic Compounds OEt OEt I I RCHCH2SePh RC=CH2 (12) (13) also been prepared in a one-step process by using diphenyl diselenide bromine and hexabutyldistannoxane (Scheme 13; Reaction v)37 but the disadvantage of this approach is that appreciable amounts of the a-phenylseleno-aldehyde [RCH(SePh)CHO] are also produced. Phenylselenenic acid (PhSeOH) has been produced in situ from phenylseleninic acid (PhSe02H) and diphenyl diselenide (PhSeSePh) and reacts with trisubstituted alkenes by Markownikoff addition (Scheme 14).38 Oxidation of the p-hydroxy 0 OH SePh I R'R2C=CHCH2R3 A R'R2&-CHCH2R3 A (14) OH R' R2&CH=CHR3 Reagents i (PhSe),-H,02-MgS0,; ii Bu'OOH Scheme 14 phenylselenide (14)gives the unstable selenoxide which decomposes to the allylic alcohol and the complete 'one-flask' sequence represents a route from alkenes to rearranged allylic alcohols.The use of t-butyl hydroperoxide to oxidize (14) avoids the secondary epoxidation of the alkene product which can occur when hydrogen peroxide is used. Alkenes and alkynes are hydrometallated by magnesium hydride in the presence of a titanium catalyst [e.g. C12Ti(C5H5)]. The reaction is most satisfactory for monosubstituted alkenes which give nearly quantitative yields of the alkane after hydr~lysis;~~ (see also ref. 14). The formation of methyl ketones from terminal alkenes by oxidation with rhodium dioxygen complexes4o or combinations of rhodium trichloride and cupric perchlorate or nitrate41 has been reported and several papers and a book have appeared on the ozonolysis of alkene~.~~ Several workers have tried to distinguish between bridged and acyclic transition states for electrophilic additions to alkenes and alkynes.One approach uses the addition of arenesulphenyl chloride to alkenes and the hydration of alkenes as model 37 I. Kuwajima and M. Shimizu Tetrahedron Letters 1978 1277. 38 T.Hori and K.B. Sharpless J. Org. Chem. 1978,43,1689. 39 E.C.Ashby and T. Smith J.C.S. Chem. Comm. 1978,30. 40 F.Igersheim and H. Mimoun J.C.S. Chem. Comm. 1978,559. 41 H. Mimoun.M. M. P. Machirant and I. S. de Roch J. Amer. Chem. SOC.,1978,100. 5437. 42 (a)P.S. Bailey T. M. Ferrell A. Rustaiyan S. Seyhan and L. E. Unruh J. Amer. Chem. SOC.,1978,100 894;(b)P. S.Bailey and T. M. Ferrell J. Amer. Chem. Soc.,1978,100,899; (c) B.Mile and G.M. Morris J.C.S. Chem. Comm. 1978,263; (d) P.S. Bailey 'Ozonation in Organic Chemistry' Academic press New York 1978. 168 K. J. Toyne reactions involving bridged and acyclic rate-determining transition states respec- tively. These reactions are standards against which the structure-reactivity rela-tionship of other electrophilic addition reactions can be compared. The similarity in the structure-reactivity profiles of the addition of bromine and arenesulphenyl chloride indicates a bridged rate-determining transition state for both Another approach uses a series of compounds RMeC=CH2 and RHC=CMe2 (R=Me Et Pr" PhCH2 MeC02CH2 or CICH2) in an attempt to distinguish between a bridged and a carbonium ion-like transition state by internal comparison of the series and without resorting to external structure scales.The rate constants for bromination also lead to the conclusion that a bromonium ion pathway is The competitive nucleophilic attack of methanol and bromide ion on the inter- mediate bromonium ion has been used to study quantitatively the rapid second step in the bromination of alkene~.~'A series of methyl substituted ethylenebromonium ions give a mixture of bromomethoxyalkane and dibromoalkane in each case and the regio-selectivity and chemo-selectivity of the reaction can be correlated with charge distributions.The addition of bromine chloride to hex-1-ene and hex-1-yne in carbon tetra- chloride and methanol has been studied and an attempt has been made to distinguish between the bridged bromonium ion (15) the weakly bridged ion (16) and the open vinyl cation (17)in additions to hex-l-~ne.~~ A symmetrically bridged intermediate is believed to exist in the reactions of hex-1-ene and on the basis of small amounts of anti-Markownikoff products (in CCI,) or absence of cis-product (in MeOH) the reaction of hex-1-yne probably involves a very weakly bridged bromonium ion (16). (15) (16) (17) The acid-catalysed hydration of several isomeric Z/E-alkenes has been Surprisingly the value of the k(Z)/k(E)ratio for 1,2-di-t-butylethylene is much less than the values for additions involving bridged intermediates whereas one might have anticipated that the formation of the open ion in hydration would more effectively relieve strain present in the 2-isomer.However it is suggested that during protonation there is significant double bond character remaining and only in the fully formed intermediate is sufficient rotation possible to reduce the repulsion of the substituents. For reactions involving bridged transition states steric approach control is the decisive rate-determining factor. 3 Dienes Terminal 1,3-dienes can be prepared in a simple palladium-catalysed elimination of acetic acid or phenol from the readily available allylic acetates and allylic phenyl 43 G.H. Schmid and T. T. Tidwell J. Org. Chem. 1978,43,460. 44 E. Bienvenue-Goetz and J.-E. Dubois Tetrahedron 1978,34,2021. 45 J.-E. Dubois and J. R. Chrktien J. Amer. Chem. Soc. 1978,100,3506. 46 V. L. Heasley D. F. Shellhamer J. A. Iskikian D. L. Street and G. E. Heasley J. Org. Chem.. 1978,43 3139. 47 W. K. Chwang and T. T. Tidwell J. Org. Chern. 1978,43 1904. Alipha tic Compounds ethers re~pectively.~~ The allylic isomers give the same product in the same yield via a w-allylic complex (Scheme 15). R'CH2CH=CHCH20R (or R'CH2CHORCH=CH2) A R'CH=CH-CH=CH2 R = Ph or MeCO Reagents i Pd(OAc),-PPh Scheme 15 A method4' has been developed for the preparation of terminal 1,3-dienes which is similar in outline to that shown in Scheme 28 for allenes.1-Trimethylsilylallyl carbanion reacts with aldehydes and ketones to give a mixture of a-and y-products with the a-isomer predominating (Scheme 16). The crude mixture can be worked up in two ways to give the 1,3-diene. i,ii,iii HCH CH2=CHCH2SiMe3 -+ CH2 Reagents i Bu'Li; ii MgBr,; iii R'RZ(H)CO; iv SOCl,; v MeCOCI; vi Et4NF-MeCN Scheme 16 The importance of organometallic compounds in synthesis is well illustrated by the use of three different metals in distinct and very attractive stereospecific syntheses of substituted 1,3-dienes. The first involves the palladium-catalysed coupling of (E)-1-alkenylzirconium derivatives with alkenyl halides to give dienes of 297'/o isomeric purity (Scheme 17)." The second procedure involves the formation of a lithium dialkyl(trans-1-alkenyl)( 1-alkyny1)borate which on treatment with either boron trifluoride etherate or tri-n-butyltin chloride results in the preferential migration of the alkenyl group from boron to the adjacent alkynyl carbon atom.Protonolysis of the intermediate produced gives the 1'4-disubstituted (E,2)-buta- 1,3-dienes in good yields (Scheme 18; R2 must not be a tertiary alkyl gro~p).~' The method therefore offers a way of linking together two terminal alkynes in a predetermined way and should prove useful in natural product syntheses. Vinylmercurials are used in the third method (Scheme 19)52 to provide a route for the 'head-to-tail' dimeriza- tion of alkynes which complements an earlier procedure for the symmetrical 48 J.Tsuji T. Yamakawa M. Kaito and T. Mandai Tetrahedron Letters 1978,2075. 49 P. W. K. Lau and T. H. Chan Tetrahedron Letters 1978,2383. N. Okukado D.E. Van Horn W. L. Klima and E. Negishi Tetrahedron Letters 1978 1027. " G.Zweifel and S. J. Backluntl J. Organometallic Chem. 1978,156,159. '' R.C. Larock and B. Riefling J. Org. Chem. 1978,43 1468. 170 K. J. Toyne X R3 Reagents i H(Cl)Zr(C,H,),; ii 'C=C' (X = Br or I)-C12Pd(PPh3)z-Bui2AlH H/ 'R2 Scheme 17 R' H H R' iii iv \/ \c=c / Li+ L \c=c R2 /\ / \c=c / H \BR2-CrCR2 H c=c BR2 -.[". 1 H' \H Reagents i R,BH; ii R2C=CLi; iii BF3-ether or Bu3SnC1;iv MeCOzH Scheme 18 Reagents i catecholborane; Hg(OAc),; aq.NaC1; ii PdC12-Et3N-C6H6 Scheme 19 dimerization of vinylmercurials.The best results were obtained with 0.5 equivalents of palladium chloride but catalytic amounts can be used if anhydrous copper(r1) chloride is present as a reoxidant. @Unsaturated ketones react with dilithium carboxylates to give hydroxyacids which undergo decarboxylative dehydration under very mild conditions with dimethylformamide dimethylacetal and so provide a useful regiospecific route to lY3-dienes (Scheme 20).53 Even the unstable 1,3-diaryl-1,3-butadienescan be prepared by this method. Alkenylpentafluorosilicates,formed from terminal alkynes couple with allylic halides under the influence of a palladium catalyst to provide the regio- and stereo-isomerically pure (E)-1,4-diene (Scheme 21)54 (see also ref. 31).53 J. Mulzer U. Kiihl and G. Briintrup Tetrahedron Letters 1978,2953. 54 J. Yoshida K. Tamao M. Takahashi and M. Kumada Tetrahedron Letters 1978,2161. 171 Aliphatic Compounds R2 H R2 H R2 H -\/ i\/ ii \/ c=c +c=c c=c /\ H H/\CR’OH.CHR3C02H H/\C=CHR3 R’ /c=o R’/ Reagents i R3CH=C(OLi) from R3CH2C0,H-Pr’,NLi; ii Me,N.CH(OMe) Scheme 20 R RCECH A ‘C=C H / H iii R H \/ H/ H \CH2CH=CH2 Reagents i HSiCl,-H,PtCb; ii KF; iii CH,=CHCH,CI-Pd(OAc) Scheme 21 Two allylic groups have been linked regioselectively to produce the ‘head-to-tail’ 1,5 -dienes.” An allylic halide (R’CH=CHCH,Hal) regioselectively couples with a lithium ally1 boron ate complex (RCH=CHCH2BR32Li’) to form the 1,5-diene (R1CH=CHCH2CHRCH=CH2). 4 Alkynes Synthesis.-Alkynes are frequently prepared by alkylation of acetylene or alk-l- ynes or by elimination reactions but the methods are generally poor for alkynes with secondary tertiary or P-branched primary groups.A survey is reported of eight standard syntheses of internal or terminal alkynes containing one branched group and the best methods have been ~pecified.~~ A new synthesis which may be worth considering in conjunction with those discussed in the survey achieves the alkylation of terminal alkynes indirectly. The alkynes are converted into 1-bromoalk-1-ynes (R’C-CBr) which have been shown to react rapidly with trialkylalanes (R3Al) in the presence of catalytic amounts of bis(N- methylsalycila1dimine)nickel[Ni(me~al)~] to give the internal alkyne (R’CECR).’’ A method for increasing the chain length of terminal alkenes was shown in Scheme 9 (Reactions i and ii).21 Basically the same simple procedure can be modified to provide a general ‘one-flask’ route from alk-1 -enes to terminal alkynes containing three more carbon atoms (Scheme 9; Reactions i and iii).” The hydroalumination product of the alkene is coupled by an SN2‘pathway with bromopropadiene in the presence of catalytic amounts of copper(1) chloride to give terminal alkynes and it is possible to introduce the alkyne moiety selectively to one of the double bonds of a diene.Two new similar procedures for the preparation of mono- and di-substituted alkynes under mild conditions are based on the use of p-keto-sulphones which can 55 Y.Yamamoto and K. Maruyama J. Amcr. Chem. SOC.,1978,100,6282. 56 F. Bernadou. D. Mesnard and L. Miginiac J. Chem. Research (S),1978,106; J. Chem. Research (M) 1978,1501. ”G. Giacomelli and L. Lardicci TetrahedronLarters 1978,2831. 58 F. Sato H. Kodama and M. Sato Chem. Letters 1978,789. 172 K. J. Toyne be prepared in several ways.59,60 For example the lithium derivative of an alkyl aryl sulphone will react with a carboxylic acid derivative so that each reactant provides part of the ultimate alkyne (Scheme 22) or the P-keto-sulphone can be obtained Reagents i Bu"Li-RC0,Me or RCOCl; ii NaH-(EtO),POCI-THF-HMPA;iii Na-liq. NH or Na/Hg-THF-DMSO Scheme 22 from a ketone (RCOCH2R1) by enolate sulphenylation (or sulphinylation) followed by oxidation.The p-keto-sulphone is then converted into an enol phosphate from which the alkyne is produced by reductive elimination. The sequence has also been used for the preparation of conjugated enynenes (R = R' =alkenyl) and highly stereoselective routes to central-cis- and central-trans-conjugated trienes are now available.60 Another new synthesis of alkynes also starts with a carboxylic acid derivative (Scheme 23)6' and has superficial similarities to the sequence described above. NNHTos II MeLi RC02Li+R'CHLiSMe + RCOCHR'SMe + R-C-CHR'SMe RCrCR' Scheme 23 Reaction of a lithium carboxylate with a (methy1thio)methyl-lithiumderivative gives an a-sulphenylated ketone the toluene-p-sulphonylhydrazone of which decom- poses on treatment with methyl-lithium to give the alkyne.(Methy1thio)methyl- lithium (Scheme 23; R'=H) is used to give terminal alkynes in most of the published examples but the method should be suitable for the formation of a variety of alkynes. Reactions.-The reactions of alkynes and their derivatives frequently form the basis for the synthesis of alkenes and allenes (see appropriate section). In this part of the report other significant reactions of alkynes are considered. A mild regiospecific synthesis of trans-a$?-unsaturated ketones uses the reaction of trialkylalkynylborate salts with benzeneselenenyl chloride (Scheme 24).62Selec-tive oxidation at boron and subsequent oxidation at selenium gives (19) whereas oxidation of (18)with hydrogen peroxide gives the internal alkyne (RC=CCH,R').Homoallylic alcohols bearing tri-substituted olefinic groups can be prepared stereoselectively from the reaction of epoxides and a vinylcopper (Scheme 25).63 59 P.A. Bartlett F. R. Green and E. H. Rose J. Amer. Chem. Soc. 1978 100,4852. 6o B. Lythgoe and I. Waterhouse Tetrahedron Letters 1978,2625. 61 S. Kano T. Yokomatsu and S. Shibuya J. Org. Chem. 1978,43,4366. 62 J. Hooz and R. D. Mortimer Canad. J. Chem. 1978,56,2786. P. R. McCuirk A. Marfat and P. Helquist Tetrahedron Letters 1978 2465. Aliphatic Compounds R2B SePh 0 SePh [R3BC~CCH2R']Li+ '\/ -% \C-CH / R /'='\CH2R1 R / 'CH2R' (18) liii RCOCH=CHR' (19) Reagents i PhSeCl; ii H,O-Me,NO; iii H,Oz Scheme 24 R3 OH R*C=CH i -+ R' Cu(Me2S)MgBr:! R1 \CH-CH \ / ii-iv \ / H -/c=c\R2/C=C\H R2 / \R4 Reagents i R'MgBr-CuBr(Me,S); ii PrC-CLi; ,O\iii R3CH-CHR4; iv NH4Cl Scheme 25 Normally the reaction is slow but the vinylcopper can be activated by the addition of a lithium acetylide and with monoalkylated epoxides the only product results from reaction at the less substituted position.The use of phase-transfer reagents in the potassium permanganate oxidations of alkynes permits the formation of a-diones from internal alkynes; carboxylic acids are formed by oxidative cleavage of terminal alkyne~.~~ An improved method for the hydration of alkynes to ketones uses a mercury impregnated resin sulphonic acid catalyst which can be recovered and ~e-used.~' 5 Allenes A series of papers has clarified the confused area of the reactions of propargylic chlorides with Grignard reagents and dialkylcuprates.6648 In the absence of tran- sition metal impurities terminal propargylic chlorides (R12 CClCECH) react with Grignard reagents (RMgX) to form an allene carbene-ztvitterion intermediate (20) by proton abstraction of the acetylenic hydrogen by the Grignard reagent R12t-C% R12C=C=C: f* (20) followed by loss of chloride ion.66 Nucleophilic attack on this intermediate by a second molecule of Grignard reagent at either the propargyl or the allenyl carbon and subsequent hydrolysis produces a mixture of two alkynes (R',RCC=CH R',CH-CrCR) and an allene (R',C=C=CHR).D. G. Lee and V.S. Chang Synthesis 1978,462. " G. A. Olah and D. Meidar Synthesis 1978,671. ''D.J. Pasto R H. Shults J. A. McGrath and A. Waterhouse J. Org. Chem. 1978 43 1382. 174 K.J. Toyne However in the presence of catalytic quantities of transition metal salts (e.g. FeC13) Grignard reagents react with propargyl chlorides to produce allenes (Scheme 26).67The proposed mechanism involves the reaction of the Grignard reagent with 2RMgX+FeC13 + R2FeCl -P Fe'CI+R2 FeCI2 R / / + R',C=C=C /FeCIR + R'zC=C=C /R12C=C=C 'R2 \R2 \R2 R' CCICrCR2 + FeCl \ ii ii (21) R1,C(FeCI,)C~CR2 + R12C(FeCIR)CrCR2+ R1,RCC-CR2 Scheme 26 the metal salt to produce a low-valence state metal species which undergoes insertion into the carbon-chlorine bond of the propargyl chloride. Displacement of the chlorine bonded to the metal by an alkyl group from the Grignard reagent produces a species which undergoes thermal decomposition to produce the allene and regenerate Fe'CI.With primary and secondary alkyl Grignard reagents the allene is formed exclusively and only when the alkyl group of the Grignard reagent is methyl and the propargyl chloride is non-terminal is an appreciable amount of the alkyne formed. t-Butylmagnesium bromide is totally unreactive and this is probably due to steric hindrance in the formation of (21) and/or (22). The final paper of the series however presents a procedure by which t-butyl- allenes could be prepared.68 Dialkylcuprates react with propargyl chlorides to form allenes which arise by alkyl transfer from copper to the propargyl halide in a tr-complex (Scheme 27).The mixed n-butylmethyl- and t-butylmethyl-cuprates react to transfer preferentially the n-butyl and t-butyl groups respectively. R' Scheme 27 Three useful methods have been published for the synthesis of terminal allenes. In one of these the hydroalumination product of a terminal alkene is treated with 67 D. J. Pasto S.-K. Chou A. Waterhouse R. H. Shults and G. F. Hennion J. Org. Chem. 1978,43,1385. D.J. Pasto S.-K. Chou,E. Fritzen R. H. Shults A. Waterhouse andG. F. Hennion J. Org. Chem. 1978 43,1389. Aliphatic Compounds 175 3-bromoprop-1-yne in the presence of a catalytic amount of copper(1) chloride (Scheme 9; Reactions i and i~).~' This reaction represents a simple general method for the addition of an allene moiety to an alkene double bond and even sterically hindered alk-1 -enes react satisfactorily.Aldehydes and ketones can be converted into terminal allenes as shown in Scheme 28.70 The vinyl carbanion formed from a-bromovinyltriphenylsilane or a-bromo- vinyltrimethylsilane by metal-halogen exchange reacts with aldehydes or ketones to give (23). This hydroxy compound and other P-functionalized vinylsilanes [(24)and (25)] are surprisingly resistant to elimination but fluoride ion on (24) or (25) promotes elimination under mild conditions to give the allene uncontaminated with alkyne. The reaction via the chlorides is only suitable for aldehydes or diary1 ketones and the route via the trifluoroacetates is more suitable for aliphatic ketones. R'\ C-c=CH + isomeric /I I chlorides R2(H)C1 SiR k R'\ (24) R' \ C-C=CH / RZ[H)'~~ iiR3\ R2W) C=C (23) R' \ C-C=CH R2' I I OCOCF SiRJ (25) Reagents i SOCI,; ii (CF,CO),O-pyridine; iii F-in DMSO or MeCN Scheme 28 The third synthesis of terminal allenes also starts with a carbonyl group which is reacted with lithium diethyl phenylsulphinylmethylphosphonate to give the 1-alkenyl sulphoxide (26) (Scheme 29).71Methylation of the vinyl hydrogen of (26) gives (27),and the lithium derivative of (27) generates the allene.R'R2C=0 &R'R2C=CHSOPh AR'R2C=CMeSOPh (26) (27) 1 R' R2C=C=CH2 Reagents i (EtO),POCH,SOPh-BuLi; ii Pr',NLi-MeI; iii lithium 2,2,6,6-tetramethylpiperidide; iv NH4Cl Scheme 29 69 F.Sato K.Oguro and M. Sato Chem. Letters 1978,805.'O T. H. Chan W. Mychajlowskij B. S. Ong and D. N. Harpp J. Org. Chem. 1978,43 1526. "G.H.Posner P.-W. Tang and J. P. Mallamo Tetrahedron Letters 1978,3995;G.H. Posner and P.-W. Tang I. Org. Chem. 1978,43,4131. 176 K. J. Toyne Three further syntheses of allenes use propargyl ketones or propargyl alcohols as their starting material. The reduction of tosylhydrazones of @unsaturated ketones by catecholborane occurs with regiospecific migration of the double bond. With tosylhydrazones of conjugated acetylenic ketones the migration also occurs to produce allenes in good yield (Scheme 30).72 NNHTos II RC~C-CR' 4RCH=C=CHR' I1 Reagents i catecholborane; ii NaOAc,3H20 Scheme 30 In 1975 an efficient synthesis of allenes from prop-2-ynyl tosylates and organo- copper(1) compounds was reported which had the disadvantage that direct synthesis of tosylates from the tertiary alcohols is unsatisfactory.However sulphinic esters are readily available and it has now been shown that the sulphinate group can be substituted by organocopper(r) reagents (Scheme 3 1).73 The stereochemistry of the reaction in one example was shown to be syn-1,3-substitution arising from a stereospecific substitution by the copper species followed by a 1,2-shift of the alkyl group on copper with retention of configuration (Scheme 31). R'C=CCR2R30H -I* R'CrCCR2R30S(0)Me RR'C=C=CR2R3 Reagents i MeSOCl; ii (RCuBr)MgX-LiBr-THF R3 R' R3 (RCuBrj-\ \ R' CzC -C' / ' 1 'R2 R R2 0s(0)Me R-CU Scheme 31 A procedure which is similar in principle to the one shown in Scheme 31 uses the substituted pyridinoxy group as the leaving group.The 2-propargyloxypyridinium salt formed in situ from propargyl alcohols reacts with Grignard reagents in the presence of catalytic amounts of copper(1) iodide to produce the allene in high yield (Scheme 32).74 R'CfCCHOHR2 A [R1CGCCHR20py] 2R'R3C=C=CHR2 Reagents i pyF-NEt,; ii R'MgBr-CuI. py = Me Scheme 32 72 G. W. Kabalka R. J. Newton J. H. Chandler and D. T. C. Yang J.C.S. Chem. Cbmm. 1978,726. 73 P. Vermeer H. Westmijze H. Kleijn and L. A. van Dijck Rec. Truu. chim. 1978,97 56. 74 T. Mukaiyama and K. Kawata Chem. Letters 1978 785.

ISSN:0069-3030    

DOI:10.1039/OC9787500159

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

9 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By R. S. WARD Department of Chemistry University College of Swansea Singleton Park Swansea SA2 8PP Since this is now the third Report on this subject by the present author an attempt has been made wherever possible to include reference to any similar or related work which has been reported in the previous two years.' In some instances this amounts to little more than a cross-referencing exercise while in others it represents a genuine attempt to place the work in its true context with respect to recent work on related topics. 1 Amines and Imines Primary amines can be efficiently converted into secondary amines by alkylation of the corresponding trifluoroacetamide (RNHCOCF,) using potassium hydride and a crown ether.2 Subsequent deacylation of the dialkylamide is achieved by treatment with potassium hydroxide in methanol at room temperature.This approach to the synthesis of secondary amines should be compared with the double alkylation of diphenylphosphinic amide which was highlighted in last year's Report. lb A tremendous amount of recent interest has been focused on attempts to extend or reverse normal functional group reactivity. The use of a-metallated isocyanides as a-metallated primary amine equivalents may be considered to be an example of this approach.lb An alternative method for activating the a-carbon atoms of primary amines involves converting them into the corresponding sulphinylamine (RCH2NSO) by treatment with thionyl chloride followed by alkylation and finally hydr~lysis.~ A new method for preparing primary enamines of P-dicarbonyl compounds involves treating the P-dicarbonyl compound with N-trimethylsilyliminotriphenyl-phosphorane in the presence of a molar equivalent of isopropanol and a catalytic amount of toluene-p-sulphonic acid (Scheme l)." Scheme 1 ' See R.S. Ward Ann. Reports (B)(a)1976 73,187; (6) 1977,74,194. 'J. E. Nordlander D. B. Catalane T. H. Eberlein L. V. Farkas R. S. Howe R. M. Stevens N. A. Tripoulas R. E. Stansfield J. L. Cox M.J. Payne and A. Viehbeck Tetrahedron Letters 1978 4987. F. M. Schell J. P. Carter and C. Wiau-bar J. Amer. Chem. Soc. 1978,100,2894. 'J. A. Kloek and K.L. Leschinsky,J. Org. Chem. 1978,43 1460. 177 178 R. S.Ward A useful route to cyclopentenones and butenolides makes use of the P-alkoxy- carbonylvinyl lithium reagent (2) generated from ethyl p-(1 -pyrrolidinyl) acrylate (1)under kinetically controlled conditions.' Reaction of (2) with a@-unsaturated carbonyl compounds leads to functionalised cyclopent-2-enones (3) while alde- hydes and esters give functionalised but-2-enolides (4).These reactions are analo- gous to those of p-(l-pyrrolidinyl)acrylonitrile,'b and extend the usefulness of metallated enamine derivatives. Bu'Li -1OOOC -R2N H 0 (4) Further reports have appeared of asymmetric syntheses of a-alkylated aldehydes and ketones by alkylation of metalloenamines generated by deprotonation of chiral imines.6 However the generation of metalloenamines by deprotonation of imines suffers from the limitation that it occurs preferentially (or exclusively) at the less substituted a-position.This limitation can be circumvented by regiospecific generation of metalloenamines from &unsaturated imines (Scheme 2),' a process which resem- bles the regiospecific generation of ketone enolates from enones. ,-CHPh Scheme 2 The dipolar tautomers (6) of a-amino-acid ester imines (5) undergo 1,3-dipolar cycloaddition reactions8 Imines themselves undergo 1,3-dipolar cycloaddition by thioketene S-oxides to give 1,2,4-oxathiazolidines (7) which undergo rearrangement to 1,3-oxazolidinethiones (8).9 R. R. Schmidt and J. Talbiersky Angew. Chem. Internat. Edn.. 1978,17,204. A. I. Meyers G. S. Poindexter.and Z. Brich J. Org. Chem. 1978 43 892; A. I. Meyers and D. R. Williams ibid. p. 3245. 'P. A. Wender and M. A. Eissenstat J. Amer. Chem. SOC..1978,100,292; P. A. Wenderand J. M. Schaus 1. Org. Chem.. 1978,43,782. R. Grigg J. Kemp G. Sheldrick and J. Trotter J.C.S. Chem. Comm. 1978 109. E. Schaumann,J. Ehlers and U. Behrens Angew. Chem. Infernat. Edn. 1978,17,455. Aliphatic Compounds (X= 0 or NPh) R' >&S, RZ ;;H;J"'qs O--P R4 -0 R4 R3-N< W R3/ H (7) (8) The hydrogenation of chiral imines has proved useful for the asymmetric synthesis of amino-acids (Scheme 3)." The effects of the alkyl residue and the solvent on the Scheme 3 course of this reaction have been studied. When the alkyl residue is small the substrate undergoes hydrogenation from the re face forming (S)-alanine but increasing the size of the alkyl residue reduces the optical purity of the product.The use of a more polar solvent also increases the amount of (R)-alanine obtained. These effects may be explained in terms of the structure of the substrate-catalyst complex. The asymmetric reduction of imines using a lithium aluminium hydride-3-O- benzoyl-1,2-0-cyclohexylidene-a-D-glucofuranose complex gives optically active secondary amines. '* Reduction of the iminium salts (9) by the Hantzsch ester (10) proceeds stereo- specifically to give the axial product (1l).l2 In contrast sodium borohydride gives lo K. Harada and Y. Kataoka Tetrahedron Letters 1978,2103. " S. R.Landor 0.0.Sonola and A.R. Tatchell J.C.S. Perkin I 1978,605. '' M.J. de Nie-Sarink and U. K. Pandit Tetrahedron Letters 1978,1335. 180 R. S. Ward mainly the equatorial product (12). It must be concluded that the steric requirements of the dihydropyridine reagent play a vital role in determining the overall stereo- chemical course of the reaction. X C0,Et XY Eto2cQH Me , Me (10) I CI0,-(9) The energy barriers for E-2 isomerisation in a series of N-sulphenylimines (R'R2C=NSR3) have been measured and interpreted in terms of hyperconjugation involving the nitrogen lone pair in an inversion me~hanism.'~ 2 Other Nitrogen Compounds Methanesulphonate methyl ether and methyl thiomethyl ether derivatives of vicinal cyanohydrins undergo reductive-elimination by dissolving metals to give alkenes.14 The related reaction of methyl thiomethyl ether sulphones with sodium napthalenide has been shown to proceed with syn stereochemistry (Scheme 4).Scheme 4 Medium and large ring enediones can be prepared by intramolecular coupling of (YW-bisdiazoketones using bis(acety1acetonato)copperas catalyst (Scheme 5).15 The enediones can be converted into fused ring cyclopentenones by reduction with sodium dithionite followed by treatment with sodium hydroxide. COCHN, / Cu(acac), (cH<co~H (i) Na2S204 (Cyz)" (CH,)"4 COCHN 'CO H = 0 n =4,7,8,9,10,12,or 16 Scheme 5 Nitroalkanes are becoming increasingly important as organic reagents due in part to the ease with which they can be converted into other functional groups.lb Ethyl P-nitropropionate functions as a P-acyl vinyl anion and has been used to synthesise the macrocyclic antibiotic pyrenophorin,16 while nitroethane acts as an acyl anion equivalent in the synthesis of jasmone (Scheme 6)." l3 C.Brown R. F.Hudson and B. T. Grayson J.C.S. Chem. Comm. 1978 156. l4 J. A. Marshall and L. J. Karas J. Amer. Chem. SOC.,1978,100,3615. Is S. Kulkowit and M. A. McKervey J.C.S. Chem. Comm. 1978 1069. l6 P. Bakuzis M. L. F. Bakuzis and T. F. Weingartner Tetrahedron Letters 1978 2371. l7 P. Dubs and R. Stussi Helu. Chim. Acta. 1978 61,990; 998. Aliphatic Cornpoun ds (i) CH,CHNO (ii) NaOH/H2S04(Nef) 0 (iii) NaOH 0 Scheme 6 Fluoride ion catalysed reactions of nitro compounds are also of increasing importance.Thus potassium fluoride catalyses the reactions of nitromethane with aldehydes which af€ord a convenient route to higher nitroa1kanes,l8 and tetrabutyl- ammonium fluoride catalyses the reactions of silyl nitronates with aldehydes which afford a useful synthesis of 2-aminoalcohols (Scheme 7)." OH 18-crown-6 Scheme 7 Seebach has shown that nitroalkane dianions can be generated from allylic and homoallylic nitro compounds.20 The dianion (14)derived from 4-nitrobut- 1-ene (13) is a dienolate equivalent which unlike normal dienolates normally reacts preferentially at the S position. 3 Alcohols and Ethers The reactions of prochiral cations with chiral reagents were mentioned in last year's Report.lb It has now been shown that reduction of the 2-phenyl-2-butyl cation (15) generated from the corresponding alcohol or alkene by a chiral organosilane gives an optically active alkane.2* When the (R)-enantiomer of the organosilicon reagent is used the (R)-enantiomer of the product (16)predominates.This implies that the (R)-enantiomer of the reagent preferentially delivers hydride to the si face of the carbenium ion. Ph CH y 3 \ /C' (R)-(+)NpPhMeSiH + Ph-C-H I C2H5 C2HS (15) (14) R. H. Wollenberg and S. J. Miller Tetrahedron Letters 1978 3219. l9 E. W. Colvin and D. Seebach J.C.S. Gem. Comm. 1978,689. 2o D.Seebach R. Henning and F. Lehr Angew. Chem. Internat. Edn.. 1978,17,458. J. L. Fry and M. G. Adlington J. Amer. Chem. SOC.,1978 100,7641. 182 R. S.Ward Several new reagents for oxidising primary and secondary alcohols to carbonyl compounds have been investigated. 22-24 Probably the most interesting is ben- zeneseleninic anhydride which can be used under essentially neutral conditions. The mechanism is believed to involve the fragmentation of an intermediate seleninic ester. NN-Dimethylformamide dimethyl acetal reacts with vicinal diols to give cyclic derivatives which can be cleaved as shown to give alkene~.~' These reactions therefore afford a mild and stereospecific method for converting diols into alkenes (Scheme 8). C02Et C0,Et C0,Et Me,NCH(OMe) (i) Me1 'OlOH -ex:Me2(G f! C0,Et C0,Et C0,Et Scheme 8 An attempt has been made to estimate the contribution of ring strain to the reactivity of the epoxide (17)by comparing its rate of reaction in ethanolic sodium ethoxide with that of the acyclic ether (18).26Ring strain accelerates the reaction to EtO-EtS0,-EtO; EtS0,y EtS0,-OMe (18) such an extent that elimination occurs 2.46 X lo6 times faster than in the acyclic analogue and it is estimated that about one third of the strain energy of the epoxide is translated into a reduced energy of activation for the reaction.Two stereocontrolled syntheses of epoxides have been reported.27 Epoxidation of the unsaturated alcohol (19) gives predominantly one stereoisomer (20),but asym- "'?Me vo(aca& R2?Me R3 HOAC R3 __* Et BU'OOH Et I R1 OH R' OH Me H H Et OH 22 H. Firouzabadi and E. Ghaderi Tetrahedron Letters 1978 839.23 D.Fletcher and S. J. D. Tait Tetrahedron Letters. 1978 1601. 24 D.H.R. Barton A. G. Brewster R. A. H. F. Hui D. J. Lester S. V. Ley and T. G. Back J.C.S. Chem. Comm. 1978,952.cf D.H. R. Barton J. P. Kitchen and W. B. Motherwell ibid. p. 1099. 25 S. Hanessian A. Bargiotti and M. LaRue Tetruhedron Letters 1978,737. 26 R.J. Palmer and C. J. M. Stirling J.C.S. Chem. Comm. 1978 338. 27 T. Fukuyama B. Vranesic D. P. Negri and Y. Kishi Tetrahedron Letters 1978,2741;T. Nakata and Y. Kishi ibid. p. 2745. Aliphatic Compounds 183 metric reduction of the epoxyketone (21) using a chiral lithium aluminium hydride- amine complex gives predominantly the other stereoisomer (22). Both reactions (21) (22) proceed with a high degree of stereospecificity as do the subsequent cyclization reactions.The latter sequence has been used to synthesise the polyether antibiotic lasolocid A. The Lewis acid catalysed migration of acyl groups in optically active epoxides has been studied in some detail in recent years.la The 1,2-migration of an ethoxycar- bony1 group is known to involve a highly concerted process. It has now been shown that the 1,2-migration of a benzoyl group (23 + 24) proceeds with 100°/~ inversion 0 Me CHO Me-/Lf-COPh BF3* ,i-( Ph H Ph COPh (23) (24) of configuration at the migration terminus.28 This establishes that the acyl migration is completely stereospecific and excludes the possibility of a long-lived freely rotating carbenium ion intermediate. It does not however rule out the possible involvement of a short-lived carbenium ion in which acyl migration occurs more rapidly than bond rotation.G.1.c. can be used to measure the enantiomeric purity of chiral epoxides by using an optically active stationary phase consisting of nickel(11)bis-(3-trifluoroacetyl-1R-camphorate) or (3-heptafluorobutyryl-1R-camphorate) in ~qualene.~’ 4 Aldehydes and Ketones The asymmetric reduction of carbonyl compounds by chiral NADH model compounds attracts continued interest. The reduction of methyl benzoylformate by either diastereoisomer of the dihydropyridine (25) affords a single enantiomer of the Me OH I PhCOCO Me (25) + PhCHC0,Me hydroxy ester in 97% optical yield.” The high stereospecificity of this reaction is attributed to the close proximity of the chiral centre to the reaction site.The second J. M. Domagala and R. D. Bach J. Amer. Chem. Soc. 1978,100,1605. 29 V. Schurig and W. Burkle Angew. Chem. Internat. Edn. 1978,17,132;V.Schurig B.Koppenhofer and W.Burkle ibid. p. 937. ’O A. Ohno M. Ikeguchi T. Kimura and S. Oka I.C.S. Chem. Comm.. 1978,328. 184 R. S.Ward chiral centre in the side chain exerts only a very minor influence on the stereochemi- cal course of the reaction. The allylic Grignard reagent (26)exists almost exclusively in the primary form but reacts with unhindered carbonyl compounds to give the a-methallyl product (27). However as the steric requirements of the carbonyl compound increase more of the crotyl product (28) is formed and with di-t-butyl ketone this is the sole product obtained.It is suggested that the crotyl products are formed both by isomerisation of the initially formed a-methallyl adduct and by direct four-centre addition of the Grignard reagent.31 R2COMgBr I CH3CHCH=CH2 CH&H=CHCHzMgBr (27) (26) -% R2COMgBr I CH2CH=CHCH3 (28) The addition of lithium P-lithiopropionate to aldehydes and ketones affords y-hydroxyacids which can be readily cyclised to give y-lactones. In a similar manner aldehydes and ketones react with lithium P-lithioacrylates (29) to give butenolides (30) Li R3 R2 R'/\ R2 (29) (30) One problem which bedevils the detailed study of enolate reactions is the difficulty of generating enolates of known configuration. However by using ethyl tri- methylsilylacetate it is possible to prepare Z-enol silyl ethers which can in turn be converted into Z-enolates.Since the E-enolates can be obtained directly from the ketone by using lithium 2,2,6,6-tetramethyl-piperidide (LiTMP) two complemen- tary methods are available for preparing the 2 and E enolates stereospecifically (Scheme 9).33 Scheme 9 31 R.A. Benkeser M. P. Siklosi and E. C. Mozdzen J. Amer. Chem. Soc. 1978,100,2134. 32 D.Caine and A. S. Frobese Tetrahedron Letters 1978,883; 5167. 33 E.Nakamura K. Hashimoto and I. Kuwajima Tetrahedron Lerters 1978 2079. Aliphatic Compounds Although a-alkylation of carbonyl compounds is one of the most important carbon-carbon bond forming reactions it invariably fails when tertiary alkyl groups are involved.However by treating the silyl enol ether with a tertiary alkyl halide in the presence of a Lewis acid the desired tertiary alkyl derivative can be obtained in good yield.34 The cyclisation of regiospecifically generated metal enolates of o-bromo-ketones has been In almost all cases the terminal lithium enolates of 6-bromo-ketones undergo intramolecular C-alkylation to give cyclohexanone derivatives. Lithium dienolates normally undergo alkylation at the a-position (cf.Section 2). However lithium dienolates derived from some P-alkoxy a@-unsaturated ketones surprisinglx undergo exclusively y-alkylati~n.~~ A more general solution to the problem achieving y-alkylation of @unsaturated compounds involves the temporary incorporation of a y-arylsulphonyl group which directs the incoming alkyl group to the y-position and can be subsequently removed after alkylation to give the y-substituted The formation of alkenes from tosylhydrazones on treatment with two equivalents of an alkyl lithium reagent (or lithium di-isopropylamide) is known to proceed via the syn dianion and exhibits a high degree of regio~pecificity.~' The dianions can be trapped by aldehydes or ketones to afford dianions of P-hydroxytosylhydrazones which are converted into homoallylic alcohols upon further treatment with an alkyl lithium reagent (Scheme H ,NHSO,ArN 2Bu"Li ,NSO,ArN R 'CH ,'CH R2 (ii) Bu"Li Scheme 10 2,4,6-Tri-isopropylbenzenesulphonylhydrazonesserve as a convenient source of vinyl lithium reagents since treatment with two equivalents of an alkyl lithium reagent at -78 "C followed by warming to 0 "C generates the corresponding vinyl anions which can be trapped by a wide variety of electrophiles yielding ally1 alcohols and a@-unsaturated acids or aldehydes as possible products (Scheme 1l).40The two ,NHSO,Ar N,NSO,Ar 2Bu"Li 0"C E __3 -E+ -780c C6HIACH2 C6Hl 3ACH2 Scheme11 aforementioned reactions have been elegantly combined to afford a 'one-pot' synthesis of a-methylene y-lactones (Scheme 12)41 " M.T. Reetz and W. F. Maier Angew. Chem. Internat. Edn.. 1978,17,48. '' H. 0.House,W. V. Phillips,T. S. B. Sayer and C.4. Yan J. Org. Chem. 1978,43,700. 36 A. B. Smith and R. M. Scarborough Tetrahedron Letters 1978,4193.37 P.T. Lansbury and R. W. Erwin Tetrahedron Letters 1978,2675; C.N. Lam J. M. Mellor P. Picard and J. H. A. Stibbard ibid. p. 4103. 38 K. J. Kolonko and R. H. Shapiro J. Org. Chem. 1978,43 1404. 39 M. F. Lipton and R. H. Shapiro,J. Org. Chern. 1978,43,1409. ''A. R. Chamberlin J. E. Stemke andF. T. Bond J. Org. Chem. 1978,43 147. " R. M. Adlington and A. G. Barrett J.C.S. Chem. Comm. 1978,1071. 186 R. S. Ward NS0,Ar N' ,NHSO,Ar (i) 2Bu"Li ____, (ii) R,CO 1 Scheme 12 Chiral hydrazones have been previously used in a number of syntheses of optically active a-alkylated aldehydes and ketones.' The same reagents have now been shown to undergo stereoselective aldol condensations which further enhance their utility as precursors for chiral synthesis?2 5 Carboxylic Acids The homogeneous hydrogenation of dehydroamino-acid derivatives by rhodiurn(1) catalysts has been widely studied as a route to optically active amino-acids Chiral catalysts which incorporate bidentate diphosphine ligands capable of forming rigid chelate rings give high optical yields.Some insight into the mechanisms of these reactions can be obtained by varying the substituent groups on the substrate and the However more fundamental information about the mechanism and stereochemistryof the reaction can be obtained by analysing the 31Pn.m.r. spectra of the various intermediate^,^^ and by using deuterium instead of hydr~gen.~' The latter method is particularly useful for studying the extent of E-2 isomerisation during the reaction.Of practical interest is the observation that the use of benzene as solvent reduces the amount of isomerisation and significantly increases the optical purity of the products obtained from E-isomers. Several new reagents for bringing about the esterification of carboxylic acids under mild conditions have been reported. The use of dicyclohexylcarbodi-imidealong with an acylation catalyst such as 4-dimethylamino- or 4-pyrrolidino-pyridine brings about esterification at room temperature under almost neutral conditions?6 The same method can also be used to prepare thiolesters. Another method for bringing about mild esterification involves the use of pyridine and either phenyl dichlorophosphate or NN-dimethylphosphoramidedi~hloride.~' In last year's Reportlb the lactonisation of unsaturated carboxylic acids by phenyl selenenyl and phenyl sulphenyl halides was described.Iodolactonisation is an alternative method for bringing about the same kind of conversion and when followed by methanolysis of the iodolactone it can be used to bring about stereoselective epoxidation of unsaturated acids (Scheme 13).48 42 H. Eichenauer E. Friedrich W. Lutz and D. Enders Angew. Chem. Internat. Edn. 1978,17,206. 43 R.Glaser,S. Geresh,J. Blurnenfeld and M. Twaik Tetrahedron 1978,34,2405;R. Glaser,S.Geresh M. Twaik and L. Benoiton ibid. 3617. * J. M. Brown and P. A. Chaloner,J.C.S. Chem. Comm. 1978,321;Tetrahedron Letters 1978 1877. " C. Detellier G.Gelbard and H. B. Kagan J. Amer. Chem. Soc.. 1978,100,7556;K.E.Koenig and W. S. Knowles ibid. p. 7561. 46 A. Hassner and V. Alexanian TetrahedronLetters 1978,4475;B. Neisesand W. Steglich,Angew. Chem. Internat. Edn. 1978,17 522. 47 H.-J. Liu W. H. Chan and S. P. Lee Tetrahedron Letters 1978,4461. 48 P. A. Bartlett and J. Myerson J. Amer. Chem. Soc. 1978,100 3950. Aliphatic Compounds 0 H Scheme 13 Although macrolides are among the most chemically important and therapeutic- ally useful natural products very few methods are available for the lactonisation of o-hydroxy acids. la However in the presence of silver perchlorate o-hydroxy thiol- esters formed by reaction with 2-amino-4-mercapto-6-methylpyrimidine, give good yields of the corresponding lactones on refluxing in ben~ene.~’ N-Acylamino acids can be used as acyl anion equivalents by converting them first into 2-oxazolinones which will then react with various electrophilic reagents (Scheme 14).” Subsequent hydrolysis releases the a-substituted N-acylamino acid which can be readily converted into the corresponding ketone by oxidation with lead-(Iv) acetate.Aldehydes can also be prepared in a similar manner starting from hippuric acid (N-benzoylglycine). I R’-jl,. R3 R ‘CHCO2H A~,O R3X R~-C-CO~H I NHCOR2 -H,o’ NHCOR’ I Nyo NyO Pb(OAc), R2 RZ 1 R’COR3 Scheme 14 A useful synthesis of (2R)-[2H,3H] acetic acid starting from (2R)-[2H]glycine has been devised.’l The sequence of reactions involves converting the labelled glycine (31)into the a-bromoacetic acid (32),followed by reduction with lithium aluminium tritide and finally oxidation to give the chirally labelled acetic acid (34).H H D LiAIT4 cr20:; H--I-C02H D-J-co~H HNO b D--CO2H -H-!-CT*OH P I KBr I Nh2 Br T T 6 Esters and Lactones Intramolecular Diels-Alder reactions provide a versatile method for the stereo- controlled synthesis of polycyclic structures including bicyclic lactones (Scheme 15).52 The initial adduct in this case is formed by exo addition but if the correspond- ing carboxylic acid is used instead of the ester the endo adduct is formed. 49 J. S. Nimitz and R. H. Wollenberg Tetrahedron Lerrers 1978,3523. R. Lobmar and W. Steglich Angew. Chem. Internat. Edn. 1978,17,450. ’’ M. Kajiwara S.-F.Lee,A. I. Scott M. Akhtar C. R.Jones and P. M. Jordan J.C.S. Chem. G-imm.. 1978 967. 52 J. D.White B. G. Sheldon B. A. Solheim and J. Clardy Tetrahedron Letters 1978 5189. 188 R. S.Ward Me0,C Me0,C ,Me Me0,C ,Me OAHMe* 0-NaOMe ;&o / \ \ H H Scheme 15 The stereochemistry of SN2‘ displacement reactions of allylic esters has been studied. The reaction of the acyclic ester (35)with (S)-a-methyl-benzylamine (36) reveals that syn stereochemistry is preferred but only by a factor of 1.4-1.8.53 ArCO D ‘Ph (35) (36) Me/ * Ph Although this result is in agreement with that obtained in carbocyclic systems it suggests that competition between the syn and anti mechanisms may be more finely balanced than had been previously assumed. y-Acetoxy p-ketoesters (37) react with 1*/o alcoholic hydrogen chloride to give 4-alkoxyfuran-2-ones but react with 50% sulphuric acid to give the tetronic acids (38).54 R,&,CO,Et HO OAc H2S04_ R00 (37) (38) In contrast to its reactions with aromatic aldehydes which give 1:1adducts (39) the aldol condensation reactions of /3-tetronic acid with aliphatic aldehydes give 2 :1 adducts (40).55 R I (39) (40) Two stereoselective syntheses of (+) and (-) tetrahydro-cerulenin have been carried out and have lead to a revision of the absolute configuration of the naturally occurring The syntheses of both compounds start from D-glUcoSe or D-xylose and involve cleavage of an epoxylactone (e.g.41) by ammonia followed by oxidation of the hydroxyamide so formed. These reactions illustrate the value of carbohydrates as starting materials for the asymmetric synthesis of natural products.53 T. Oritani and K. H. Overton J.C.S. Chem. Comm. 1978,454. ’‘ P. Pollet and S. Gelin. Tetrahedron 1978,34 1453. ’’ H. Zimmer W. W. Hillstrom J. C. Schmidt,P. D. Seemuth and R.Vogeli,J. Org. Chem.. 1978,43,1541. s6 H. Ohrui and S. Emoto Tetrahedron Lstters 1978 2095; J.-R. Pougny and P. Sinay ibid. p. 3301. Aliphatic Cdmpounds (41) (+) The enantiomeric purity of a chiral lactone can be determined by reaction with methyl lithium and then examining the n.m.r. spectrum of the resulting diols in the presence of a chiral shift reagent.” An alternative method based on the g.1.c. analysis of diastereoisomeric ortho esters was reported last year.lb Alkyl lithium reagents react with thioesters at carbon to give negatively charged intermediates which can be converted into monothioacetals by reaction with alkyl halides.The same intermediates can also be converted into thioenolates and thereby alkylated to give vinyl sulphides (Scheme 16).58However Grignard reagents react S SLi SMe It RICH Li I Me1 I R-C-OEt 2R-C-OEt -R-C-OEt I I CH~R’ CH2R’ S MeS I1 LiNPri2 R-C-CH2R’ RJ \R1 H S SEt 0 I1 E+ II R-C-SEt EtMgI I -R-C-SEt -R-C-E I HgCIz MgI Scheme 16 with the sulphur atom of dithioesters to give metallated dithio-acetals.” These function as acyl anion equivalents and react with electrophiles to give dithioketals which can be subsequently converted into carbonyl compounds.In contrast allylic Grignard reagents apparently react with dithioesters at the carbon atom leading to dithioketals of py-unsaturated ketones on alkylation.60 Thioenolate anions of dithioesters can be prepared by treatment with lithium di-isopropylamide. Alkylation gives a ketene dithioacetal whereas reaction with a carbonyl compound gives a p-hydroxydithioester (Scheme 17).” On treatment with organolithium reagents sterically protected thioesters (42) give dipole stabilized carbanions (43),which react with electrophiles in the expected manner (cf. Section 7).61 57 I. J. Jakovac and J. B. Jones J.C.S. Chem. Comm. 1978,722. L. Narasimhan R. Sanitra and J. S. Swenton J.C.S. Chem. Comm. 1978,719. 59 A. I. Meyers T. A. Tait and D. L.Comins Tetrahedron Letters 1978,4657. 6o P. Gosselin S. Masson and A. Thuillier Tetrahedron Letters 1978 2717. 61 D. B. Reitz P. Beak R. F. Farney and L. S. Helmick J. Amer. Chem. Soc.,1978,100,5428. 190 R. S. Ward S SLi SMe II LiNPr‘ I Me1 / CH3-C-SEt 2CH*=C--SEt -CH2=C ‘SEt I RCHO OH S I II RCHCHZCSEt Scheme 17 7 Amides and Lactams Several independent pieces of evidence suggest that the contribution from polar resonance structures is greater in the case of thioamides than amides.’* In agreement with this conclusion ”N n.m.r. spectroscopy shows that base-catalysed NH proton exchange in a thiolactam occurs 1500 times faster than in the cor- responding lactam.62 In a related study it has also been shown that base-catalysed NH proton exchange in the cis isomer of 1-aza-2-cyclononanone occurs 25 times faster than in the trans isomer.Metallated derivatives of NN-disubstituted ap-unsaturated amides undergo a-substitution with ele~trophiles.~~ y-Regioselectivity is enhanced by using the cor- responding cuprate reagents (Scheme 18). Dianions derived from NN-dimethyl Scheme 18 6-ketoamides afford a useful alternative to those derived from p-ketoesters and have the advantage that nucleophilic attack on the amide group is inhibited by resonance.64 By sterically protecting the carbonyl group of an amide as in (44a) it is possible to generate a carbanion a to the nitrogen atom which reacts with electrophiles leading 62 I. Yavari and J. D. Roberts TetrahedronLetters 1978,2491; J.Amer. Chem. Soc. 1978,100,5217. 63 J. A. Oakleaf M. T. Thomas A. Wu and V. Snieckus Tetrahedron Letters 1978 1645. 64 J. S. Hubbard and T. M. Harris Tetrahedron Letters 1978,4601. Aliphatic Compounds to extension of the amine residue,65 Since steric protection of the carbonyl group also makes hydrolysis of the amide group more difficult the use of the triphenylacetic acid derivative (44b) or the NN-dimethylcarbamate (44c) is to be preferred since they can be easily cleaved by lithium aluminium hydride reduction. (44) (45) b;X=Ph& c; X = ArO The reactions of isoimidium salts derived from NN-disubstituted monoamides of dicarboxylic acids have been studied.66 Those derived from the monoamide of succinic acid for example react with primary and secondary amines to give NN-tri- or tetra-substituted succinamides (Scheme 19).c'o CO COzH ;z4r c10,-RzNH* CONR2 0 Scheme 19 a-Methylene &lactams can be prepared by cyclization of 3-bromo-2-(bromo-methy1)propionamides using a phase transfer The a-methylene @-lactams undergo addition by nucleophilic reagents at the exocyclic carbon atom (Scheme 20). a-Methylene @-lactams can also be prepared by cycloaddition of 40%NaOH Me,NH Br methyl(pheny1thio)keteneto imines followed by elimination of the oxidised phenyl- thio group.68 D. Seebach and T. Hassel Angew. Chem. Internat. Edn. 1978,17,274. 66 G. V. Boyd and R. L. Monteil J.C.S. Perkin I 1978 1338. ''S. R.Fletcher and I. T. Kay J.C.S. Chem. Comm. 1978,903. T.Minami M.Ishida and T. Agawa J.C.S. Chem. Comm. 1978,12. 192 R. S. Ward General methods for the preparation of 3-acyl tetramic acids include (a) acylation of pyrrolidine-2,4-diones and (b) intramolecular Claisen condensation (Scheme 21).69*70In addition a new route (c) involving the rearrangement of a-[N-(acyl-acety1)amino)imides has also been rep~rted.~~ 13C n.m.r. spectroscopy reveals that the major tautomer of simple 3-acyl tetramic acids is the one indicated in Scheme 21.71 R I I I R' R' R' R Scheme 21 8 Anhydrides and Imides Bis(thioacy1)sulphides are obtained along with bis(acyl)sulphides by base-catalysed disproportionation of acyl thioacyl sulphides (Scheme 22).72 As previously reported acyl thioacyl sulphides can themselves be prepared by treating sodium or piperi-dinium dithiocarboxylates with acetyl chloride.lb ss 00 II I1 RzXLi II II II I1 so -R-C-S-C-R+ 2R-C-S-C-R' R'-C-S-C-R' (x=O or S) Scheme 22 Previously inaccessible acid anhydrides can be prepared by ozonolysis of enol Thus ozonolysis of diketene yields malonic anhydride whereas dehy- dration of malonic acid affords carbon suboxide rather than the anhydride. Methyl- eneketene (CH2=C=C=O) can be generated by flash thermolysis of acrylic anhydride at 510-560 0C.74 Reactions of nucleophilic reagents with unsymmetrical cyclic anhydrides have been included in previous reports.'" The reactions of Grignard reagents with the '' V. J. Lee A. R. Branfman T. R. Herrin and K. L. Rinehart. J. Amer. Chem. SOC.,1978..100,4225; D. Cartwright V. J. lee and K. L. Rinehart ibid. p. 4237. 'O R. C. F. Jones and S. Sumaria Tetrahedron Letters 1978 3173; Tetrahedron 1978 34 223. 'I' P. S. Steyn and P. L. Wessels Tetrahedron Letters 1978,4707. 72 S. Kato K. Sugino M. Mizuta. andT. Katada. Angew. Chem. Znternat. Edn.. 1978,17.675. 73 C. L. Perrin and T. Arrhenius J. Amer. Chern. Soc. 1978,100,5249. 'I4 G. L. Blackman R. D. Brown R. F. C. Brown F. W. Eastwood G. McMullen and M. L. Robertson Austral. J. Chem. 1978 31 209. Aliphatic Compounds anhydride (46) involve nucleophilic attack on the most reactive carbonyl The reactions of organometallic azides with the anhydride (47) however apparently involve nucleophilic attack at the most hindered carbonyl group.76 It is suggested that the reagent forms a complex with the less hindered carbonyl group which is then attacked by azide at the other carbonyl group.The latter reactions afford a useful synthesis of 4-methyl-oxazinediones (48). 2-Methoxy-3-pentylmaleic anhydride (49) reacts with carbomethoxymethylene-triphenylphosphoraneto give a mixture of the 2and E methyl esters \>MgBr fi 00 OH n.cLiu,"' (46) Me Me Me 0-NH (47) (48) MeO,CCH=PPh; 00 Me0,CCH (49) (50) 9 Phosphorus Compounds Many reactions of phosphates have been postulated to involve metaphosphate intermediates. It has now been shown that monomeric methyl metaphosphate (51) can be generated in solution by fragmentation of p-bromo-pho~phonates.~~ When methyl hydrogen 1-phenyl-1,Z-dibromopropylphosphonate(52) is heated to 70 "C C6H5 -CBr-CHBrCH3 C6H5CBr=CHCH3 I 70 'C -+ [MeOPOz]+ Br-in diethylaniline or tetraethyl rn-phenylenediamine in the presence of acetonitrile and water the products obtained include those to be expected from electrophilic substitution of the methyl metaphosphate onto the aromatic amine.75 C.-L. Yeh W. T. Colwell and J. I. DeGraw Tetrahedron Letters 1978,3987. 76 S. S. Washburne and H. Lee J. Org. Chem.. 1978,43.2719. 77 M. J. Begley D. R. Gedge and G. Pattenden J.C.S. Chem. Comm. 1978,60. A. C. Satterthwaite and F. H.Westheher J. Amer. Chem. SOC.,1978,100,3197. 194 R. S.Ward Two elegant syntheses of chirally labelled phosphate monoesters have been reported (Schemes 23 and 24).".'O They are the first examples of phosphorus compounds in which the optical activity is due solely to the chiral disposition of three oxygen isotopes and their synthesis opens the way to detailed study of the mechanisms of enzyme-catalysed phosphoryl transfer reactions.A method for determining the absolute configuration of phosphate monoesters has also been devised." 1 Scheme 23 Scheme 24 10 Sulphur Compounds Simple sulphenic acids have eluded isolation because of their reactivity and their facile conversion into thiosulphinate esters. However methane-sulphenic acid has now been generated by flash thermolysis of t-butyl methyl sulphoxide.'* It has been characterised by microwave spectroscopy and shown to possess structure (53) rather than the isomeric structure (54).79 P. M.Cullis and G. Lowe J.C.S. Chem. Comm. 1978,512. 8o S. J. Abbott S. R. Jones S. A. Weinman and J. R. Knowles J. Amer. Chem. SOC.,1978,100,2558. R. E. Penn E. Block and L. K.Revelle. J. Amer. Chem. Soc. 1978,100,3622. Aliphatic Compounds CH3-S-0-H CH3-S-H (53) (54) It is instructive to compare the orientation of 1,2-elimination from the bis- sulphide (55) and the bis-sulphone (56). In the former case the elimination is Ph PhS LSPh EtO-_ phsK (55) Ph PhSO &,SO,Ph Ph+SO,ph (56) directed by the phenyl group to give the alkene derived by more rapid deprotonation at the site of phenyl substitution whereas in the second case the opposite orientation is accounted for by steric repression of deprotonation at the site of phenyl substitu-tion.82 The chiral 1,3-oxathiane (57) has been used as the key reagent in a highly efficient asymmetric synthesis of S-( +)-atrolactic acid methyl ether (58).83 H Me&sq BSi H H MekSfCOPh MeMgI,Me1 H H~~kL&~r~ (ii) PhCHO0 (iii) DMSO Me (CF,CO)T/Et3N (57) Me 0 Me (i) hydrolysis (ii) oxidationI HO,C Ph Me'OMe Optically active sulphinyl compounds are usually prepared by reactions of diastereoisomeric sulphinates and sulphinamides with organometallic reagents.Thus chiral thioacetal monosulphoxides (60) can be prepared by reaction of the optically active sulphinate (59) with alkylthiomethyl lithium reagent^.'^ Reaction 0 0 I\ RSCH,Li II .$\ OMenthyl RSCti,+ p-to1 p-to1 (59) (60) 82 P.J. Thomas and C. J. M. Stirling J.C.S. Chem. Comm. 1978,975. 83 E.L.Eliel J. K. Koskimies and B. Lohri J. Amer. Chem. Soc. 1978,100,1614. '' L.Colombo C. Gennari and E. Narisano Tetrahedron Letters 1978.3861. 196 R. S. Ward proceeds with complete inversion of configuration at the sulphur atom. The resolu- tion of chiral sulphoxides sulphinates and thiosulphinate esters as their P-cyclo- dextrin inclusion complexes has also been rep~rted.~' A new method for preparing selenoacetals involves treating the aldehyde or ketone with tris(phenylse1eno)borane in the presence of a small amount of trifluoroacetic acid.86 Phenylselenides (prepared by treating primary alcohols with PhSeCN and Bu",P) and selenoacetals (prepared as above) can be reduced by triphenyl tin hydride to give the corresponding hydrocarbons (Scheme 25).PhSeCN RCH20H + RCH2SePh Ph,SnH RCHj SePh R2CO (PhSe),B Ph,SnH * R2C/ ' RzCH2 CF3COZH 'SePh Scheme 25 A study has been made of the reactions of phenyl vinyl selenide with organo- lithium reagents8' Depending upon the reaction conditions a wide variety of products are obtained (Scheme 26). RCHO CH2=CHSeBu + PhLi +RCH(OH)Ph BU'LAHF Li RCHOH I RCHO I PhSeCH=CH2 2;:; BuCH2CHSePh -BuCH2CHSePh ,iNpr\ RCHO CH2=CSePh -CH2=CSePh I I Li RCHOH Scheme 26 11 Halogen Compounds The oxidative-elimination of alkyl iodides bearing strongly electron-withdrawing substituents proceeds with syn stereochemistry (Scheme 27).88 (X= S02Ph orC02Et) Scheme 27 " M.Mikolajczyk and J.Drabowicz J. Amer. Chem. SOC.,1978,100 2510. '' D. L. J. Clive and S. M. Menchen J.C.S. Chem. Comm. 1978,356; D. L. J. Clive G. Chittattu and C. K. Wong,ibid. p. 41. '' M. Sevrin J. N. Denis and A. Krief Angew. Chem. Internat. Edn.. 1978,17,526. H. J. Reich and S. L. Peake J. Amer. Chem. Soc. 1978,100,4888. Aliphatic Compounds 2-2-Ethoxyvinyl bromide (61) undergoes halogen/metal exchange with butyl lithium to give 2-2-ethoxyvinyl lithium (62).89 However the E-isomer (63) under- goes hydrogen/metal exchange to give E-1-bromo-2-ethoxyvinyl lithium (64). The E-2-ethoxyvinyl lithium (65) can be obtained by using lithium dihydrobiphenylide but it cannot be intercepted by electrophiles since at -80 "C it decomposes to give lithium ethoxide and ethyne.In contrast the 2-isomer (62)is stable up to -50 "C in ether and up to -30°C in tetrahydrofuran or dimethoxyethane. It reacts with aldehydes and ketones to give the expected adducts (66). HH HH R,CO )=-( =+)+ A)+ Br OEt Li OEt R,COH OEt Br H Li MH BrHH BuLi -M H OEt Li OEt H OEt (63) (64) (65) 89 K.S. Y.Lau and M.Schlosser J. Org. Chem. 1978,43 1595.

ISSN:0069-3030    

DOI:10.1039/OC9787500177

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

10 Aromatic Compounds By W. CARRUTHERS Department of Chemistry The University Stocker Road Exeter 1 Introduction Reviews on naturally occurring compounds of the shikimic acid pathway’ and on the biosynthesis of aromatic hemiterpenes2 have been published. Resonance energies of conjugated compounds in the electronically excited states have been calculated and the ‘allowedness’ of some pericyclic reactions predicted using these resonance energies. The predictions based on the difference in resonance energy between the pericyclic transition state and the reactants were in general agreement with e~periment.~ Qualitative potential energy surfaces for electrophilic photoelectrophilic nucleophilic and photonucleophilic aromatic substitutions have been constructed and selection rules derived.The regiochemistry of electrophilic and photonucleophilic aromatic substitution is predicted to be controlled by the electron density of the highest occupied molecular orbital of the aromatic substrate while the regiochemistry of nucleophilic and photoelectrophilic substititution is controlled by the electron density of the lowest unoccupied molecu- lar orbital of the aromatic ~ubstrate.~ The benzene radical anion is of interest in experimental organic chemistry as the species formed in the first stage of the Birch reduction of benzene. Ab initio MO calculations have been carried out for the radical anions of benzene and fluoroben- zene. In accordance with the Jahn-Teller theorem benzene radical anion is predic- ted to be distorted from regular hexagonal (&h) symmetry to structures of DZh symmetry having either four longer and two shorter carbon-carbon bonds or two longer and four shorter carbon-carbon bonds.’ An MO study of the effect of substituents in benzene radical ions has been reported.The effects of various types of substituent (OH CH3 CN SiH,) in benzene radical cations were investigated using INDO-SCF computations with and without consideration of n-conjugation between the substituents and the adjacent substrate.6 Experimental data for 1,2- and 1,4-dihydroxybenzene and 1,2,4-trihydroxybenzene correlate well with the results of INDO calculations of proton hyperfine coupling constants of free radicals from some hydroxybenzenes.’ Theoretical geometries and relative energies are ’ B.Ganem Tetrahedron 1978,343353. * M.F.Grundon Tetrahedron 1978,34,143. J. Aihara Bull. Chem. SOC.Japan 1978,Sl. 1788. ‘N.D.Epiotis and S. Shaik J. Amer. Chem. SOC.,1978,100 29. A. L. Hinde D. Poppinger and L. Radon J. Amer. Chem. SOC.,1978,100,4681. F. Bernardi M.Guerra and G. D. Pedulli Tetrahedron. 1978,34,2141. Y. Shinagawa and Y. Shinagawa J. Amer. Chem. Soc.. 1978,100.67. 199 200 W. Carruthers reported for aliphatic and aromatic diazonium ions. Open structures are preferred for both with NGN bond lengths in both cases similar to that in molecular nitrogen.' Further studies have been made of quantum mechanical tunnelling in the iso- merization of sterically hindered aryl radicals. The isomerization of 2,4,6-tri-t- butylphenyl (1) to (2) which occurs by quantum-mechanical tunnelling of a (cH3)3cyJcH3)3 (CH3)3c~c(cH3)2cH2* C(CH3)3 C(CH313 (1) (2) hydrogen atom from an ortho-t-butyl group occurs at the same rate in matrices as formerly found for solutions.The rate of this process has been measured at temperatures down to 28 K; at such low temperatures the rate is virtually indepen- dent of temperature. A number of less hindered aryls decay by intermolecular abstraction of hydrogen from the surrounding medium.' The benzenium (3) naphthalenium and meso-anthracenium cations have been prepared and studied by 'H and I3C n.m.r. spectroscopy. The pattern of delocal- ization of positive charge in (3)suggests approximate Cz symmetry for this species Q +' ,-.I .,* HH (3) and the absence of antihomoaromatic character in this potentially anti-Hiickel system." The dianions of phenanthrene and 1,2,3,4-dibenzocyclo-octatetraene have been prepared by metal reduction of the neutral compounds.A descriptionof the charge distribution can be achieved which is consistent with both MO models and the spin-density distribution of the corresponding radical anions. Thus the dianion of 1,2,3,4-dibenzocyclo-octatetraene appears as a 7r-bond-delocalized species with the excess of charge concentrated in the eight-membered ring.lla The charge distribution in the dianion of pyrene as revealed by 'H n.m.r. spectroscopy suggests that it can be regarded as essentially a 4nr perimeter an approach'which is satisfactorily rationalized by simple MO models and supported by e.s.r.measure- ments of the spin density in the corresponding radical anion.'lb Ionization reactions of anti-9-chloro-9-methoxybicyclo[4.2.l]nona-2,4,7-triene (4) proceed without skeletal rearrangement. From the relatively low reaction rate of the triene it is concluded that the cation is destabilized by homoantiaromatic interaction between the cationic centre and the butadiene moiety. The 'H and 13C n.m.r. spectra point to an interaction of the cationic centre with one of the double H. A. Vincent and L. Radom J. Amer. Chem. SOC..1978,100,3306. G. Brunton J. A. Gray D. Griller L. R. C. Barclay and K. U. Ingold J. Amer. Chem. Soc.,1978,100 4197. lo G. A. Olah J. S. Staral G. Asencio G.Liang D. A. Forsyth and G. D. Mateescu,J. Arner. Chem. SOC. 1978,100,6299. (a)K.Miillen Helv. Chim. Am 1978 61 1296; (b)ibid p. 2307. Aromatic Compounds (4) bonds of the butadiene moiety. The mode of conjugative interaction is obviously controlled by orbital symmetry.12 In a series of eighteen papers J. Michl and his co-workers have considered the magnetic circular dichroism of a number of benzenes naphthalenes and anthracenes some aza derivatives of these some polycyclic aromatic hydrocarbons azulene and benzazulene. A general classification of chromophores with a (4n+2) T-electron perimeter is proposed and rules for the effects of substituents on magnetic circular dichroism spectra of such T systems are derived. In many cases excellent agreement between experiment and theory was found.13 A detailed analysis of the electronic structure of p,p’-dibenzene (5) and related molecules based on quantitative perturbational MO treatment reveals that through-bond coupling of the four w systems is responsible for an elongation of the (T bonds which mediate the intera~tion.’~ (5) ‘Is antiaromaticity absolute?’ it has been asked.In reply it is said that theoretical and experimental evidence do not support the idea of absolute antiaromaticity at least in the monocyclic series. Relative antiaromaticity is affirmed but only for the three smallest monocyclic systems; cyclopropenide cyclobutadiene and cyclo- pentadienylium.l5 2 Benzene Isomers Oxides and Homobenzenes Reaction of l,2,5,6-tetramethyl-3,4-dimethylenetricyclo[3.l.0.02*6]hexane(6)with reactive dienophiles gives derivatives of benzvalene benzene or homofulvene depending on the dienophile and the reaction conditions.16 With tetracyanoethylene the benzvalene derivative (7) is obtained but with maleic anhydride and 4-phenyl- I I (6) (7) P.Schipper and H. M. Buck J. Amer. Chem. Soc. 1978,100,5507. l3 J. Michl etal.,J. Amer. Chem. Sac. 1978,100,6801,6812,6819,6824,6828,6834.6838,6844,6853 6857,6861,6867,6872,6877,6882,6884,6887,6892. l4 I).A. Dougherty H. B. Schlegel and K. Mislow Tetrahedron 1978,34,1441. Is N. L. Bauld T. L. Welsher J. Cessac and R. L. Holloway J. Amer. Chem. Soc. 1978 100,6920. l6 H. Hogeveen and W. F. J. Huurdeman,I. Amer. Chem. Soc. 1978,100,860. 202 W.Carruthers 1,2,4-triazoline-3,5-dione reaction leads directly to the corresponding homofulvene derivative (as 8) probably by way of the benzvalene. Acid-catalysed (Ag’) re-arrangement of (7)leads to the corresponding benzene derivative (9). Similarly reaction of (6) with maleic anydride and with the triazolinedione in presence of Ag’ gives not the homof ulvene but the corresponding benzene derivative. Less reactive dienophiles such as methyl acrylate do not react with (6) under ordinary conditions but in the presence of silver perchlorate benzene derivatives are formed in high yield. Both the acid lability as well as the preferred pathway of rearrangement of benzvalene derivatives appear to depend on the nature of the substituents. ‘Isobenzvalene’ (lo) a highly strained molecule generated transiently by action of lithium bases on l-chlorotricyclo[3.1 .0.02*6]hexane has now been trapped as the Diels-Alder adduct with anthracene (11).The structure of the adduct was established by X-ray crystallography. l7 n Attempts to prepare the bicyclohexatriene (12) (m-benzyne) by elimination of hydrogen bromide from 4,6-dibromobicyclo[3.1.0]hex-2-ene did not lead to the desired product. Depending on the base employed either bromobenzene or a 6-substituted fulvene was obtained. Labelling experiments suggest that the fulvenes may be formed by way of the triene (12).’* 2-Methoxycarbonyloxepin-benzene oxide (13;R = CH3) and the corresponding carboxylic acid have been synthesized and their aromatization reactions studied.l9 The results obtained support the suggestion that 1,2-oxides of benzoic acids may be ” U. Szeimies-Seebach J. Harnish G. Szeimies M. van Meerssche. G. Germain and J.-P. Declerq Angew. Chem. Internat. Edn. 1978,17,848. l8 W. N. Washburn R. Zahler and I. Chen J. Amer. Chem. Soc. 1978,100,5863. l9 D. R. Boyd and G. A. Berchtold J. Amer. Chem. Soc. 1978,100,3958. 203 Aromatic Compounds ooo2R (13) intermediatesin biological oxidative decarboxylations and that the acid (13; R =H) may be an intermediate in the ortho-hydroxylation of benzoic acid. The ester (14) rearranges quantitatively in trifluoroacetic acid to methyl salicylate with 50% retention of deuterium; a reaction pathway which involves migration of the methoxycarbonyl group is suggested (Scheme 1).1 1 CO,Me Scheme 1 A novel route to 3-substituted benzene oxides which involves consecutive elimination (under mild conditions) of hydrogen bromide and carbon dioxide from bromocyclohexane &lactone epoxides has been applied” to the synthesis of the oxide (15) as shown in Scheme 2. The oxide (15) has been proposed as an intermediate in the biosynthesis of senepoxide (16) one of a number of highly oxygenated cyclohexane epoxides with tumour-inhibitory anti-leukaemic and antibiotic activity and it was successfully converted into (16) in the laboratory. 4,5-Dimethyloxepin (17) is converted into the syn-oxepin epoxides (19) and (20) by a sequence involving Diels-Alder addition of bis(trichloroethy1) azodicarboxylate to the benzene form of (17) followed by epoxidation to give (18).Extrusion of nitrogen from (18) at ambient temperature in deuteriochloroform monitored by n.m.r. spectroscopy gave transiently the oxepin epoxide (29,which was quan- titatively converted into the aldehyde (21).’l 2,7-Dimethyloxepin behaves differently towards the azodicarboxylic ester giving a cyclopropane derivative by initial addition to the oxepin form.’lb 2o B. Ganem G. W. Holbert L. B. Weiss and K. Ishizumi J. Amer. Chem Soc. 1978,100,6483; G. W. Holbert and B. Ganem ibid 1978,100,352. 21 (a)W. H. Rastetter and T. J. Richard Tetrahedron Letters 1978,2995; (b) ibid p. 2999. 204 W. Carruthers n n :OC,H (mainly) (16) (15) Reagents i Brz NaHCO,; ii C,H,COCI-pyridine; iii CF,CO,H Na,HPO,; iv 13-diazabicycloC5.4.Olundec-5-ene(DBU);v reffux in benzene Scheme 2 Me Me Me Me Me 1 "eQe -MeQetMeQMe H CHO 0 (21) (20) (19) A remarkably simple synthesis of anti-benzene dioxide and anti- benzene trioxide from benzoquinone has been reported22 and is outlined in Scheme 3.cis-Benzene dioxide was also made. There is continuing interest in oxides derived from polycyclic aromatic hydro-carbons because of their r61e in carcinogenesis. Biphenyl 2,3-oxide obtained2j by the conventional route from 1-phenyl- 1,4-dihydrobenzene is not stable but a tetrachloro derivative of biphenyl 3,4-oxide one of a number recently prepared,24 is exceptionally stable. The reaction of the 2-3-oxide with water gave 2-phenyl- and 3-phenyl-phenol in the ratio 49 :1.A synthesisof a trans- 1,2-dihydroxy-3,4-epoxy-z2 H. J. Altenbach H. Stegelmeier and E. Vogel Tetrahedron Letters 1978,3333. " M.P. Serve and D. M. Jerina J. Org. Chem. 1978,43,2711. 24 H. J. Reich I. L. Reich and S. Wollowitz J. Amer. Chem. SOC.,1978,100 5981. Aromatic Compounds +&r __+ I,. I1 .. iii 6 fj Br -+) 0 OH Reagents i Br,; ii NaBH,; iii. KOH-ether; iv m-CIC,H,CO,H Scheme 3 1,2,3,4-tetrahydrochrysene has been reported.25 The rates of acid-catalysed solvolysis of and of nucleophilic attack on some polycyclic arene oxides and their variation with the structures of the oxides have been studied.26 A review of homoaromatic ions has been p~blished.~' By analogy with the homoaromatic homocyclopropenyl and homotropylium cations cyclohexadienyl anions might have been expected to be non-planar homoaromatic species.However study of the 'H and 13Cn.m.r. spectra of several such anions indicated that they were planar and not homoaromatic. MIND0/3 calculations on the parent cyclo- hexadienyl anion found the planar form in a shallow energy minimum.28 Analysis of the photoelectron spectrum of nortriquinacene (22) and its 2- methylene and 2-isopropylidene derivatives confirms that the exocyclic double bond in the last two compounds does not interact with the endocyclic w-bonds. These findings agree well with chemical and spectroscopic evidence of the lack of homoaromaticity in these compounds.29 The interesting CI6-hexaquinacene (23) has been synthesized in nine steps from sodium ~yclopentadienide.~'" It is apparent from its 'H and 13C n.m.r.spectra that it does not exist as a highly delocalized ground *' P. P. Fu and R. G. Harvey,J.C.S. Chem. Comm. 1978,585. 26 A. R. Becker J. M. Janusz D. 2.Rogers and T. C. Bruice J. Amer. Chem. SOC.,1978,100,3244. 21 L. A. Paquette. Angew. Chem. Internat.Edn. 1978,17,106. G. A. Olah G. Asensio H. Map and P. von R. Schleyer,J. Amer. Chem. SOC.,1978,100,4347. 29 L. N. Domelsmith K. N. Houk,C. R. Degenhardt and L. A. Paquette J. Amer. Chem. SOC.,1978,100 100. 30 (a)L. A. Paquette R. A. Snow J. L. Muthard andT. Cynkowski J. Amer. Chem. Soc.. 1978. la.1600; (b)G. G. Christoph J. L. Muthard L. A. Paquette M. C. Bohm and R. Gleiter ibid p. 7782. 206 W.Carruthers state. X-Ray crystallographic analysis shows that although the geometry is favour- able the interatomic distances rule out an effective aoverlap of the w-orbitals of the double Thermolysis of trans-tris-a-homobenzene (24) at 380-400 "C in a flow system leads to trans- bicyclo[4.3.0]nona-3,7-diene(26). Studies of the reaction pathway using labelled material established that cis,truns,trans- 1,4,7-~yclononatriene (25) is (24) (25) (26) an intermediate.31" This contrasts with the behaviour of cis-analogues of tris-a-homobenzene which give cis,cis,cis-cyclononatrienesat 60-200 "C. A theoretical study of the rearrangements of tris-o-homobenzenes by MIND0/3 has been carried out.3 3 Benzene and Its Derivatives General.-The orientation of the products formed by meta photocycloaddition of olefins to substituted benzenes can depend critically on the nature of the olefin.The 1-position in the metu-adducts from methylbenzenes does not always bear a methyl group and deactivation of positions metu to the methyl substituent in toluene reported by some workers is not always observed. There is a preference for endu stereochemistry but this also is not in~ariable.~~ The photo-addition of maleimide to anisole has been studied with the object of discovering whether the charge- transfer mechanism found with benzene and substituted benzenes and maleic anhydride as addend but not with maleimide could be induced to oceur with maleimide by choice of a relatively more nucleophilic substituted benzene.In the event irradiation in the maleimide-anisole charge-transfer band gave three isomeric 2 1 adducts resulting formally from initial 1,2- 2,3- and 3,4-addition to the aromatic ring followed by Diels-Alder addition of a second molecule of maleimide.33 Photo-addition of ethylenes and acetylenes to hexafluorobenzene shows some points of resemblance to the corresponding processes with benzene but some differences were noted.34 Both cis-and trans-cyclo-octene gave various 1:1-cycloadducts which arise via 1,2- and 1,3-addition and subsequent isomerization of the initial adducts; no products formed by 1,4-addition to the aromatic ring were detected. In contrast 2,3-dimethylbut-2-ene gave mainly a 1:1adduct formed by substitutive addition. Propyne and but-2-yne gave cyclo-octatetraene derivatives.Two routes to derivatives of resorcinol have been described. Substituted resor- cinol monomethyl ethers are obtained by Diels-Alder reaction of 1,l-dimethoxy-3- trimethylsilyloxy-l,3-butadienewith acetylenic dienophiles or with the readily '' (a) W. Spielmann D. Kaufmann and A. de Meijere Angew. Chem. Internat. Edn.. 1978,17,440;(b) J. Spanget-Larsen and R. Gleiter Angew. Chem. Internat. Edn. 1978,17,441. 32 D.Bryce-Smith W. M. Dadson A. Gilbert B. H. Orger and H. M. Tyrrell Tetrahedron Letters. 1978 1093. 33 D. Bryce-Smith A. Gilbert and B. Halton J.C.S. Perkin I 1978 1172. 34 D. Bryce-Smith A. Gilbert B. H. Orger and P. J. Twitchett J.C.S. Perkin I 1978 232. Aroma tic Compounds available methyl trans-& nitroacrylate.With the latter dienophile the orientation of the addition is controlled by the nitro-group and after elimination of nitrous acid the resorcinol derivative obtained has a different orientation from that formed in the reaction of the diene with methyl acetylenecarboxylate (Scheme 4).35 E-CO,Me TMSO Scheme 4 A route to 5-substituted resorcinols is exemplified in Scheme 5 by the synthesis of 5-phenylresorcinol. The formation of the resorcinol is envisaged as proceeding by base-catalysed Michael addition of the sulphoxide to the double bond followed by cyclization and thermal elimination of phenylsulphenic acid. Olivetol a naturally occurring 5-alkyl-resorcinol was synthesized by this method.36 Reagents i Mg(OMe),-MeOH; ii reflux in benzene Scheme 5 2,3-Bis(trimethylsilyloxy)-173-butadiene is a useful diene in the Diels-Alder reaction.It adds to a variety of olefinic and acetylenic dienophiles giving adducts which may be converted into derivatives of catech01.~' The synthesis and chemistry of cyclopropabenzenes have been reviewed.38 Cyclo- propa[3,4]benzocyclobutene (27),the second isomer to be reported in which a benzene ring is annelated with a three- and a four-membered ring has been '' S. Danishefsky R. K. Singh and R. B. Gammill J. 0%.Chem. 1978,43 379; S. Danishefsky M. P. Prisbylla and S. Hiner J. Amer. Chem. SOC.,1978,100,2918. " A. A. Jaxa-Chamiec P. G. Sammes and P. D. Kennewell J.C.S. Chem. Comm. 1978,118. '' D. R.Anderson and T. H. Koch. I. Org.Chem. 1978,43,2726. '* W.E.Billups Accounts Chem. Res. 1978,ll.245. 208 W. Carruthers synthesizedJg from (28)by reaction with potassium t-butoxide in dimethyl sulphox- ide. The isomer (29) could not be converted into (27) and it is thought that this may be related to the position of the double bond in (29). Benzo[l,2 :4,5]dicyclobutene (30; R = H) and two derivatives (30;R = CH,or Br) have been obtained by pyrolysis of the appropriate cy,a'-dichlor~durenes,~~" and a number of other benzocyclobutenes have been prepared by the same method; pyrolysis of o-methylbenzyl chlorides provides a straightforward route to compounds of this class.4o6 As with benzocyclobutene itself electrophilic substitu- tion of (30) occurs exclusively by ips0 attack giving the corresponding ring-opened products in high yield.For example chloromethylation using paraformaldehyde and hydrogen chloride gave 4-chloromethyl-5-(2-chloroethyl)benzocyclobutene. (30) Pyrolysis of the trisulphone (31) gave not the expected benzo[l,2 3,4 5,6]-tricyclobutene but hexaradialene (32),4' previously obtained by pyrolysis of 1,5,9-cyclododecatriyne. It is most conveniently obtained by pyrolysis of commercially available 1,3,5-tri~hloromethylmesitylene.~~ The 13Cn.m.r. spectrum of hexaradi-alene provides no evidence for a diamagnetic ring current in the six-membered ring. With dimethyl acetylenedicarboxylate it forms the adduct (33). qO,Me C0,Me (33) 39 D. Davahan P. J. Garratt and M. M. Mansuri J. Amer. Chem. SOC.,1978,100,980.*O (a)R. Gray L. G. Harruff J. Krymowski J. Peterson and V. Boekelheide J. Amer. Chem. Soc.,1978 100 2892; (b)P. Schiess M. Heitnnann S. Rutschmann and R. Staheli Tetrahedron Letters 1978 4569. 41 L. G. Harruff M. Brown and V. Boekelheide,J. Amer. Chem. Soc. 1978,100,2893; see also P. Schiess and M. Heitzmann Helv. Chim. Actu 1978,61 844. Aromatic Compounds Naphtho[a]cyclobutene and naphtho[b]cyclobutene have been obtained by reac- tion of benzene with vinylcyclobutene and 1,2-dimethylenecyclobutanerespec-tively followed by dehydrogenation of the initial adducts. Similar reaction of 2,3-dehydronaphthalene with the two dienes gave adducts which could be converted into anthra[a]- and anthra[b]-cy~lobutene.~*It is suggested that the apparent instability of anthra[b]cyclopropene may indicate a higher degree of bond fixation in this compound than in naphtho[b]cyclopropene.1,l-Difluorobenzocyclopropene and 1-chloro-1-fluorobenzocyclopropene have been prepared from butadiene and the appropriate 1,2-dichloro-3,3- dihalogeno- cy~lopropene.~~" The corresponding 2,s -diphenyl derivatives have also been made.436 On ionization in cold fluorosulphonic acid 1,l-difluorobenzocyclo-propene gives fluorobenzocyclopropeniumion. It is well known that aryl halides react readily with olefins in the presence of tertiary amines and palladium catalysts to form vinylic substitution products but attempts to extend the reaction to aryl bromides containing strongly electron- donating substituents such as hydroxyl and amino were generally unsuccessful.It is now found that significant improvements in yield are often obtained when tri-o- tolylphosphine is used in place of triphenylphosphine as the palladium ligand or even better by using the corresponding aryl iodide instead of the bromide when palladium acetate without a phosphine ligand can be employed as the The reaction has been applied to the preparation of 2-arylethylamines by reaction of aryl bromides or iodides with N-~inylamides.~~~ Additional methods for specific ortho-substitution of benzene derivatives have been reported. 0-(1-Hydroxybenzyl)- and 0-(1-hydroxyalkyl)-anilines are obtained specifically by reaction of aldehydes with secondary anilinodichloroboranes them- selves prepared in situ from N-alkylanilines and boron trichloride.Reaction with nitriles leads to the valuable 2-acyl-N-substituted aniline~.~' Another sequence makes use of the new reagents lithium o-lithiobenzyl oxides (34) which are easily obtained from 1-phenylalkanols and butyl-lithium in the presence of tetramethyl- ethylenediamine. They react readily with electrophiles to give derivatives of type (35).46 R R Phenyl isocyanide also undergoes ortho-lithiation when treated with t-butyl- lithium and tetramethylethylenediamine. The resulting o-lithio lithiumaldimines 42 R. P. Thurnrnel W. E. Cravey and W. Nutakul J. Org. Chem. 1978,43,2473. 43 (a) P. Miiller. J. F'fyffer E. Wentrup-Byrne and U. Burger Helu. Chim. Ada 1978 61 2081. P. Muller R. Etienne J. Pfyffer.N. Pineda and M. Schipoff Tetrahedron Letters 1978 3151; (b)P. Miiller R. Etienne J. Pfyffer N. Pineda and M. Schipoff Helu. Chim. Acta 1978,61 2482. 44 (a)C. B. Ziegler and R. F. Heck J. Org. Chern. 1978,43,2941; J. E. Plevyak and R. F. Heck J. Org. Chem. 1978,43,2454; (b)C. B. Ziegler and R. F. Heck J. Org. Chem. 1978,43,2949. *' T. Sugasawa. T. Toyoda M. Adachi and K. Sasakura,J. Org. Chem. 1978,43,4842. 46 N. Meyer and D. Seebach Angew. Chem. Internat. Edn. 1978.17.521. 210 W. Carruthers (36) react with a variety of electrophiles to form ortho-substituted anilines and with metal dihalides they give novel heterocyclic sy~tems.~’ R / \ Li (36) A method for alkylating aromatic rings which provides 1,2,3-trisubstituted ben- zene derivatives conveniently and in high yield has been described.48 Following- earlier work by other workers the bis-oxazolinylbenzene (37) which is readily available from isophthalic acid gave the lithio derivative (38) on treatment with lithium di-isopropylamide in the presence of tetramethylethylenediamine.Alkyl-ation with methyl iodide followed by hydrolysis gave the methylisophthalic acid (40; R = CH3).Further lithiation of (39),reaction with ethyl iodide and hydrolysis gave (40; R =C&) (see Scheme 6).R (40) Reagents i LiNPri2-MezNCH2CH2NMe2;ii MeI; iii aqueous HCI Scheme 6 Following on his earlier work [cf. Ann. Reports (B),1977,74,235] Gassman has developed a method for specific ortho-benzylation formylation and vinylation of anilines involving [2,3]sigmatropic rearrangement of ylides derived from azasul- phonium salts (Scheme 7).49“ A similar principle was used to make o-alkyl- and o-formyl-phen~ls.~~~ A useful synthesis of a variety of ortho-substituted phenyl- acetic esters by [3,3]sigmatropic rkarrangement of benzyl vinyl ethers derived from derivatives of ethyl mandelate and orthoesters has been de~cribed.~’ 4’ H.M. Walborsky and P. Ronman J.Org. Chem. 1978,43,731. 48 T.D.Harris B. Neuschwander and V. Boekelheide J. Oig. Chem. 1978,43,727. 49 (a)P.G. Gassrnan and H. R. Drewes J. Amer. Chem. Soc. 1978,100,7600;(b)P.G. Gassrnan and D. R. Arnick ibid 1978 100 7611. S.Raucher and A. S.-T. Liu J. Amer. Chem. Soc. 1978,100,4902. Aromatic Compounds 211 CI-ns Reagents i Bu'OCI; ii U;iii NaOMe; iv hydrolysis Scheme 7 Oxidative cleavage of aromatic rings is widespread in Nature.Typically the enzyme pyrocatechase catalyses the oxidative cleavage of catechol to &,cis-muconic acid with incorporation of a molecule of oxygen into the muconic acid. Pyro-catechase and related enzymes are known to require either copper or iron for maximum activity. It is now found that smooth oxidative cleavage of catechol to a mono-ester of cis&-muconic acid takes place with copper(1) chloride and molecular oxygen in pyridine at room temperature. Phenol was similarly oxidized although in poorer yield. The reactions have synthetic utility because of the high yields and mild reaction condition^.^^ Further experiments aimed at mimicking the action of the mono-oxygenase group of enzymes by irradiation of derivatives of pyridine N-oxide carrying 2-benzyl 2-phenylethyl and 2-phenoxy substituents have been rep~rted.~' In the presence of boron trifluoride migration of oxygen round the pyridine ring is inhibited resulting in increased nuclear hydroxylation of the 2-substituent.An oxenoid mechanism (i.e. transfer of atomic oxygen) involving transient formation of benzene oxides is proposed. Three reactions have been reported which lead to direct introduction of a hydroxyl substituent into the benzene ring. Reaction of benzene alkylbenzenes and halo- benzenes with hydrogen peroxide in superacidic media at low temperatures gives high yields of monohydroxylated products. The phenols formed are protonated in the superacid and thus are deactivated against further electrophilic attack or secondary oxidation.In some cases 1,2-shifts of methyl substituents occur and it is suggested that benzene oxides may be intermediates in the ~xidations.~' In another reaction peroxydisulphate in the presence of suitable metal ion oxidants notably Cu" brought about ring hydroxylation of a number of benzene derivative~.~~ Hydroxylated products have also been obtained by attack of oxygen ('P) atoms generated by y-radiolysis of liquid carbon dioxide on alk~lbenzenes.~~ " J. Tsuji and H. Tokayanagi Tetrahedron 1978,34 641. '* P.G.Sammes G. Serra-Errante and A. C. Tinker J.C.S. Perkin I 1978,853. s3 G.A.Olah and R. Ohnishi J. Org. Chem. 1978,43,865. " C.Walling D. M. Carnaioni and Sung So0 Kim J. Amer. Ckem. Soc. 1978,100,4814. 55 A Hori H. Matsumoto S. Takamuku and H. Sakurai J.C.S. Chem. Comm. 1978 16. 212 W. Carruthers Anodic oxidation in methanol of a series of alkylanisoles and hydroquinone ethers and of p-xylene leads initially to the corresponding cation radicals Under appropriate conditions reaction then may give either nuclear methoxylated products or in the case of p-alkylanisoles or p-xylene benzyl ethers or benzaldehyde dimethyl acetal~.~~ Anodic oxidation of hexamethylbenzene in acetonitrile with Bu4NBF4as electrolyte at a platinum anode gave mainly 1,3-bis(acetarnidomethy1)2,4,5,6-tetramethylben~ene.~’ Aminocyclohexadienes containing either conjugated or unconjugated double bonds are readily available by metal-ammonia reduction of aniline derivatives.Their reactions as enamines make them of synthetic interest and this is increased if the starting amines contain methoxy substituents for the products of reduction then contain masked carbonyl groups. In an investigation of the potential of this scheme the reduction of N-(m-and o-methoxypheny1)morpholine by metal and liquid ammonia has been studied and some cyclo-addition reactions with the resulting dienamines have been attempted.58 For example reduction of rn-morpholinoanisole gave the 2,5-dihydro-compound which on distillation iso- merized to the conjugated diene (Scheme 8). Scheme 8 ElectrophilicSubstitution.-Previous studies have suggested that tritiation of alkyl- benzenes with Lewis acid and a tritium source occurs randomly in the benzene ring and is confined to the aromatic protons.New work using 3Hn.m.r. spectroscopy now shows that exchange can follow the normal electrophilic substitution pattern and may not be confined to the aromatic proton~.’~ In order to ascertain the extent to which hydrogen exchange may be hindered in very crowded molecules the rates of protodetritiation and protodesilylation of each position in tri- and tetra-phenyl- methane were determined in trifluoroacetic acid. In both reactions tetraphenyl- methane was more reactive than expected possibly due at least in part to steric enhancement of neighbouring group participation.60 Electrophilic aromatic substitution by vinyl triflates is thought61 to proceed by way of vinyl cations and a number of other aromatic substitutions with unsaturated progenitors such as vinyl halides and alkynes may also proceed by way of vinyl cations.Surprisingly Friedel-Crafts benzylation of 2,6-dimethylphenol under a variety of conditions gave approximately 40% of the rneta-substitution product. s6 A. Nilsson U. Palmquist T. Pettersson and A. Ronlan J.C.S. Perkin I 1978 708. ” A. Bewick G. J. Edwards and J. M. Mellor Annalen 1978,41. A. J. Birch and S. F. Dyke Austral. J. Chem. 1978.31 1625. ” M. A. Long J. L. Garratt and J. C. West Tetrahedron Letters 1978,4171. H. V. Ansell and R. Taylor J.C.S. Perkin 11 1978,751. “ P. G. Stang and A. G. Anderson J. Amer. Chem. SOC.,1978,100,1520. Aroma tic Compounds 213 With 2,6-dimethylanisole and isopropyl 2,6-dimethylphenyl ether the metu benzyl derivatives were the main products.It is believed that these products are formed by direct attack at the meta position and not by initial ortho or para attack.62a Unexpectedly high yields of rneta-substitution products were also observed in Friedel-Crafts allylation of 2,6-dimethylphenol and 2,6-dimethylani~ole.~~~ Reac-tion of a variety of benzene derivatives with nitroniethane and manganese(II1) acetate gave nitromethyl derivatives; substitution by nitromethyl radicals is pro- Metal acetates including manganese(rI1) acetate have also been used to obtain diarylmethanes from alkylben~enes.~~ Treatment of aromatic hydrocarbons with sodium nitrite in trifluoroacetic acid is reported to give nitroarenes in high yield.65 Nitrosodemetallation at the ips0 position occurs to give nitrosoarenes by similar treatment of arylmetal compounds.The former reaction proceeds through attack by NO2+,while NO' or its carrier N203is the attacking species in the latter reaction. Rate profiles for nitration of rn-xylene and several other reactive benzene derivatives in aqueous perchloric acid are all closely similar and probably reflect the rate of encounter between nitronium ions and the aromatic compound in these media.66 Study of the aromatization of 4-methyl-4-nitrocyclohexadienonesto o-nitro- phenols which takes place in a wide variety of solvents by a formal 1,3-shift of the nitro-group strongly suggests that it proceeds by a radical dissociation-recom- bination pathway (Scheme 9).67 47 + *NO 1 Scheme 9 Migration of the nitro-group in 1,2-dimethyl- 1-nitro-[3,5-2H2]cyclohexadienyl cation (41b) obtained by solvolysis in 85% sulphuric acid of the cyclohexadienol (41a) gave equal amounts of 1,2-dimethy1-3-nitr0-[4,6-~H~]benzene (formed by a single 1,2-migration of the nitro-group) and 1,2-dimethyl-3-nitr0-[5-~H~]benzene 62 (u) M.P. McLaughlin V. Creedon and B. Miller Tetrahedron Letters 1978 3537; (b)B. Miller and M. P. McLaughlin ibid p. 3541. M. E. King and T. R. Chen J. Org. Chem. 1978,43,239. S. Tanaka S. Uemura and M. Okano J.C.S. Perkin Z 1978,431. 63 64 63 S. Uemura,A. Toshimitsu and M. Okano J.C.S.Perkin Z 1978 1076.R. B. Moodie K.Schofield and P. N. Thomas,LCS. Perkin ZZ 1978,318. '' C. E. Barnes and P. C. Myhre J. Amer. Chem. SOC.,1978,100,973; see also R. G. Coombes and J. G. Golding. Tetrahedron Letters 1978,3583. 214 W. Carruthers Me NO Me NO D H' 'OH (414 (4 1 b) (formed by two successive ly2-migrations via the neighbouring ips0 position). No 1,2-dimethy1-4-nitrobenzenewas detected. It can be estimated from these data that the rate of a ly2-shift of a nitro-group to an unsubstituted position is about one fiftieth the rate of migration to an equivalent ips0 position.68 The absence of lY2-dimethyl- 4-nitrobenzene from the reaction products is difficult to reconcile with Perrin's suggestion[cf.Ann. Reports (B),1977,74,224] that migration of nitro-groups occurs uia an aromatic cation-radical pair.Perrin's suggestion is also not supported by the observation that the composition of the product from reactions of the cation radical of mesitylene differs from that found in direct nitration of mesitylene even when the cation radical is generated in the nitrating medium and in the presence of added dinitrogen tetr~xide.~' The behaviour of the nitro Wheland intermediates formed by solvolysis of 4-methyl-4-nitrocyclohexa-2,5-dienyl acetate and some of its homo- logues has also been studied7' and confirms earlier views of the results of nitrating methylbenzenes in aqueous sulphuric acid. Nitration of a series of benzene derivatives with nitric acid in acetic anhydride has been studied;71 a series of ipso-nitration products were isolated and their re-aromatization was examined.A number of reactions other than nitration which appear to involve ipso-attack on an aromatic substrate have been reported. Thus kinetic suggest that oxidation of NN-dimethylaniline with peroxydisulphate to give the o-aminoaryl sulphate takes place by ipso-attack of reagent followed by rearrangement and cyclization of suitably labelled 7-1-naphthylbutyric acid with boron trifluoride etherate shows that this also involves some ip~o-reaction.~~ Several examples of free-radical substitution which appear to proceed by ipso-attack have been re- ported.74" Thus photo-chlorination of p-nitrobromobenzene gave among other products some 3-bromo-4-chloronitrobenzene and some 2,4-dichloronitroben- zene.74 The sulphonation of 1-methylnaphthalene and polymethylbenzenes has been The mechanistic conclusion that sulphonation with H3S04+has a later transition state than this with H2S2O7 is in agreement with the results of Huckel MO calculations.Sulphonation of a number of biphenyl derivatives containing de- activating substituents with concentrated sulphuric acid at 25 "Ctakes place in the C. E. Barnes and P. C. Myhre J. Amer. Chem. SOC.,1978,100,975. 69 M. R. Draper and J. H. Ridd J.C.S. Chem. Comm. 1978,445. 70 H.W.Gibbs R. B. Moodie and K. Schofield J.C.S. Perkin I 1978 1145. " A.Fischer and Khay Chuan Teo Canad. J. Chem. 1978,56,258,1758; A.Fischer and C. C. Greig ibid p. 1863;A. Fischer and S. S. Seyan ibid p. 1348;A. Fischer G.N.Henderson and R. J. Thompson, Austral. J. Chem. 1978 31 1241. '2 E. J. Behrman and I).M. Behrman J. Org. Chem. 1978,43,4551. 73 A.H.Jackson P. V. R. Shannon and P. W. Taylor J.C.S. Chem. Comm. 1978,734. 74 (a) L.Benati P. C. Montevecchi and A. Tundo J.C.S. Chem. Comm. 1978,530; L. Testaferri U. Tiecco M. Tingoli M. Fiorentino and L. Troisi ibid 1978,93;(6)C. R.Everly and J. G. Traynham J. Amer. Chem. SOC.,1978,100,4316. 75 K. Lammertsma C. J. Verlaan and H. Cerfontain J.C.S. Perkin IZ 1978 719. Aromatic Compounds 215 unsubstituted ring predominantly at the 4’-po~ition.~~” At 180“Cin 75% aqueous sulphuric acid all biphenyldisulphonic acids are eventually converted into the 3,4’- isomer.76b NucleophilicSubstitution.-A review of nucleophilic substitution of aromatic nitro- groups has been p~blished,’~ and aromatic substitution by the SRN1mechanism i.e.a radical chain mechanism of nucleophilic substitution has been reviewed.” Nucleophilic attack on aromatic nitro-compounds by nucleophiles which them- selves contain substituents able to leave as anions results in substitution products resulting from formal displacement of hydride ion. The leaving group departs in the form of an anion and at the same time hydride ion migrates to the carbon atom of the nucleophile vacated by the leaving group. Hence the whole process could be considered as a nucleophilic substitution of a hydride ion in the aromatic ring whereas actually the leaving group is present in the nucleophilic agent.The term ‘vicarious substitution’ has been coined to designate the process (Scheme 10).The tendency for substitution of hydride is so strong that reaction of p-chloro-nitrobenzene as in Scheme 10gave mainly the product formed by replacement of an ortho hydrogen without notable substitution of the chlorine in the aromatic ring.” + CICH,SO2C,H f c1-NO2 Scheme 10 Nucleophilic displacement of aryl fluorides is well known to occur readily in the presence of strong electron-withdrawing substituents. It is now shown that o-fluoroaryl-oxazolines which are readily obtained from the corresponding benzoic acids react readily with Grignard or organolithium reagents or with lithium amides (all designated RM in Scheme 1l),with replacement of the fluorine substituent.800 o-Methoxyaryl-oxazolines undergo similar displacement of the methoxy substitu- ent.”’ Hydrolysis of the products affords the corresponding benzoic acid derivatives (Scheme 11).Aromatic nitro-compounds also may be alkylated in the ortho and para positions by reaction with alkyl-lithium or alkyl Grignard reagents.81 The formation of an anion radical in the nucleophilic displacement of one nitro- group of p-dinitrobenzene by hydroxide ion in aqueous dimethyl sulphoxide has been demonstrated by visible and e.s.r.spectroscopy. The formation of the anion radical seems to be due to direct electron transfer from hydroxide ion to 76 (a) T. A. Kortekas H. Cerfontain and J. M. Gall J.C.S. Perkin 11 1978,445; (b)T. A. Kortekas and H. Cerfontain ibid 1978 742.77 J. R. Beck Tetrahedron 1978,34 2057. ’18 J. F. Bunnett Accounts Chem. Res. 1978 11,413. 79 J. Golinski and M. Makosza Tetrahedron Letters 1978 3495. 80 (a) A. I. Meyers and B. E. Williams Tetrahedron Letters 1978,223,227; (6)A. I. Meyers R. Gabel and E. D. MiheIich J. Org. Chem. 1978 43 1372. 81 F. Kienzle Helu. Chim. Acta 1978 61,449. 216 W Carruthers Reagents i SOCl,; ii HzN<OH ;iii RM; iv H,O' Scheme 11 p-dinitrobenzene. Kinetic studies suggest that the anion radical is a precursor in the substitution react ion. 82 Dediazoniations of arenediazonium ions are generally considered to be the only nucleophilic aromatic substitutions which proceed by an SN1-like mechanism. Results of further study of the dediazoniation of benzene- and of 2,4,6-tri-methylbenzene-diazonium tetrafluoroborate in solvents of low nucleophilicity and comparison with results in 2,2,2-trifluoroethanol suggest that two reaction inter- mediates are involved a tight nitrogen-aryl cation molecule-ion pair and a (solvated) aryl cation free of or solvent-separated from ArN; S [Ar'N,] +Ar' + N2+ products.Experiments on the scope and mechanism of photostimulated reactions of aryl iodides with diethyl phosphite ion continue [cf.,Ann. Reports (B),1977,74,227]. In SRN 1 reactions of dihalobenzenes with nucleophiles whether one or two halogen atoms are replaced depends on the nucleophile and the halogen involved and on their ~rientation.'~" Results of interrupted photostimulated reaction of diethyl phosphite ion with rn-bromoiodobenzene in liquid ammonia are compatible with the SR,1 mechanism but exclude alternative mechanisms.846 The reaction of rn-bromo-iodobenzene and rn-chloroiodobenzene with diethyl phosphite gives mixtures of a monosubstitution product in which only iodine is replaced and a disubstitution product in which both halogens are replaced.As expected from the SRN1 radical chain mechanism the ratio of monosubstitution to disubstitution product from either substrate increases linearly with increasing concentration of sub~trate.'~' Biary1s.-A new synthesis of unsymmetrical biphenyls proceeds (see Scheme 12) from the Diels-Alder adducts of arylmaleic anhydrides and substituted butadienes." Ar 0 Ar 'OzH (i)Pb(OAc) R'OAr R2 \ 4-CO,H (ii)DDQ' R2 "I$ 0-::a 0 Scheme 12 *' T.Abe and Y. Ikegami Bull. Chem. SOC.Japan 1978,51,196. 83 I. Szell and H. Zollinger J. Amer. Chem. SOC. 1978,100,2811;Y.Hashida R.G. M.Landells G. E. Lewis 1. Szele and H. Zollinger ibid p. 2816. 84 (a)J. F. Bunnett and R. B. Traber J. Org. Chem. 1978,43,1867;(6)J. F.Bunnett and S. J. Shafer ibid p. 1873;(c) ibid p. 1877. '' L. A. Levy J. Org. Chem. 1978,43 3068. Aromatic Compounds Among naturally occurring biphenyl derivatives the lignan (f)-schizandrin (42)86 and the anti-tumour compound (f)-steganacins7 (43) have been synthesized. r-0 Me0 -Me Me0Meow:/ Me0 OMe OMe (42) (43) A number of non-planar polycyclic aromatic compounds including some heli- cenes have been resolved by high-performance liquid chromatography using the chiral cyclic atropisomeric binaphthyl-2,2'-diyl hydrogen phosphate linked to silica gel (44) as stationary phase." (44) Continuing their work on host-guest complexation Cram and his co-workers describes9" the chiral recognition properties of a+series of hosts (45) based on 1,l'-binaphthyl towards guests of the type LMSCNH3 X-,where L M,and S are large medium and small groups respectively.Total optical resolution of three amine or amine ester salt racemates was achieved by chromatography using (45; X=Y = -CHz-O-CHz-).s9b ~6 E. Ghera and Y. Ben-David J.C.S.Chem. Comm. 1978,480. F. E. Ziegler K. W. Fowler and N. D. Sinha Tetrahedron Letters 1978 2767. F. Mikts and G.Boshart J.C.S. Chem. Comm. 1978,173. 89 (a)E. P. Kyba. J. M. Timko,L. J. Kaplan F. de Jong G. W. Gokel and D. J. Cram,J. Amer. Chern. Soc. 1978,100,4555; (b)L. R. Sousa G. D. Y. Sogah D. H. Hoffmann and D. J. Cram ibid p. 4569. 218 W.Carruthers 4 Quinones and Related Compounds Anodic oxidation of 2-bromo- 1,4-dimethoxybenzenes in 1-2% methanolic potas- sium hydroxide affords the bromoquinone bisketal. Metallation of these bromo- bisketals at low temperatures with an alkyl-lithium reagent followed by reaction of the lithiated derivatives with electrophiles provides a convenient route to functionalized quinone bi~ketals.~' An investigation of the anodic methoxylation of phenols and the use of this reaction for the synthesis of quinones quinone hemi- acetals 4-alkyl-4-me thoxycyclohexa-2,5 -dienones and 2-alkyl-2 -met hoxycyclo- hexa-3,5-dienones has been de~cribed.~' The reaction of n-allylnickel bromide complexes with p-quinones which usually leads to 2-allylhydroquinones has been showng2 to proceed through relatively unstable allylquinol intermediates which rearrange to the allylhydroquinones.Some interesting and synthetically useful reactions of p-quinone monoketals leading to p-quinonemethide ketals and thence to benzene derivatives derived formally by nucleophilic aromatic substitution have been de~cribed.'~ Thus the dimethyl ketal (46) reacted with the anion of the trimethylsilylacetamide (47) to give the p-quinone methide ketal (48) converted with boron trifluoride into (49) (Scheme 13).Me0 OMe Me0 OMe CH,SiMe + 0 0 0 (47) (48) 1ii Reagents i LiNPr',; ii BF Scheme 13 The Diels-Alder reaction of o-benzoquinones with acyclic dienes has been used to make derivatives of 9,IO-phenanthraq~inone.~~ Thus reaction of 2,3-dimethyl-butadiene with 3-substituted catechols in the presence of an oxidizing agent (Ag20 Mn02) gave tetrahydrophenanthraquinoneswhich were easily converted into 9,lO- 90 J. S. Swenton,D. K. Jackson M. J. Manning andP. W. Raynolds,J. Amer. Chem. SOC.,1978,100,6182. 91 A. Nilsson U. Palmquist T. Pettenson and A. Ronlan J.C.S. Perkin I 1978,696. 92 L.S.Hegedus and B. R. Evans J. Amer. Chem. SOC.,1978,100,3461. 93 D.J. Hart,P. A. Cain and D. A. Evans J. Amer. Chem. Soc. 1978,100 1548. 94 R. Al-Hamdany and B.Ali J.C.S. Chem. Comm. 1978,397. Aromatic Compounds phenanthraquinones. The addition of 1,l-dialkoxyethenes to 1,4-benzoquinones and 1,4-naphthoquinones has been re-e~amined.’~ Reaction of 1,4-benzoquinones with 1,l-dialkoxyethenes in dimethyl sulphoxide gives high yields of 1,4-naph-thoquinones by 1:2 addition. In boiling hydrocarbon solvents however reaction with 1,4-benzoquinones leads chiefly to 1:1adducts.(Scheme 14). By 1:2 addition to 0 EtO OEt Me + DMSO OEt HO+ EtoyoEt Me6-M~ 25°C / OEt OEt 0 0 0 Scheme 14 naphthoquinones in dimethyl sulphoxide anthraquinones are obtained. Juglone for example gave 1,3-diethoxy-8-hydroxyanthraquinone,and 2-acetylemodin was synthesized from 1,l-diethoxyethene and stypandr~ne.~~ The reaction pathway shown in Scheme 15 is proposed.{6’ PAOR OR OR 0 0 0 X = H or Halogen 1 1 OH OR OR 0 OR 1 1 1 :1 products 1:2 products Scheme 15 95 D. W. Cameron and M. J. Crossley,Austral. J. Chem.. 1978,31 1353. D.W.Cameron M. J. Crossley, G. I. Feutrill and P. G. Griffiths ibid p. 1335. 96 D.W.Cameron M. J. Crossley G. I. Feutrill and P. G. Griffiths Austral.J. Chem. 1978,31,1363;see also D.W. Cameron G. I. Feutrill P. G. Grifiths and D. J. Hodder J.C.S. Chem. Comm. 1978.688. 220 W. Carruthers Several other approaches to anthraquinones involving Diels-Alder additions to naphthoquinones have been reported some of them prompted by synthetic interest in the anthracycline antibiotics. Thus reaction of 6-methoxy-4-methylpyran-2-one with naphthoquinone followed by oxidation and demethylation gave pachybasin 2-methyl-4-hydroxyanthraquinone,in 64% yieldg7 and the synthesis of several methoxylated anthraquinones including two coccid pigments by the Diels-Alder addition of 1,1,4-trimethoxy-3-trimethylsilyloxybutadiene,1,l -dimethoxy-3-tri- methylsilyloxyocta-l,3-diene,and 2-acetyl-l,l-dimethoxy-3-methylbutadiene to appropriate naphthoquinones has been described.98 A related route to tetrahydro- naphthacenequinones which has been extended to the synthesis of 4-demethoxy- daunomycinone proceeds by Diels-Alder addition of a,a'-dibromo-o-quinodi-methane to the appropriate naphthoq~inone.~~ One of the main difficulties in the synthesis of anthracyclines is posed by the dissymmetric arrangement of the substituents in the two terminal rings and in several synthetic approaches this resolves itself into the problem of how to achieve regioselective substitution at C-2or C-3 in an anthraquinone in which there is a substituent at C-5.A possible way round this difficulty lies in the observation'00 that under the appropriate conditions the leuco compound (50) prepared in situ by reduction of 5 -hydroxyquinizarin with alkaline dithionite reacts with aldehydes specifically at C-2or C-3 to give (51) or (52)(Scheme 16).An intramolecular (52) Reagents i C,H,CHO-OH-; ii C2H5CH0 isopropanol piperidinium acetate Scheme 16 version of this procedure has been used to prepare a tetracyclic system.1o' A different approach to this problem exploits the regioselective lithiation of appro- priately substituted benzene derivatives.Thus lithiation of N-phenyl-rn-anis- amide takes place exclusively at the position ortho to both substituents. Reaction of " M.E. Jung and J. A. Lowe J.C.S. Chem. Comm. 1978,95. '' J.-L. Grandmaison and P. Brassard J. Org. Chem. 1978,43 1435; G. Roberge and P. Brassard,J.C.S. Perkin I 1978 1041; K. Krohn and A. Rosner Tetrahedron Letters 1978 353; K. Krohn and K. Tolkiehn Tetrahedron Letters 1978,4023. 99 J. R. Wiseman N. I. French R. K. Hallmark and K. G. Cheong Tetrahedron Letters 1978,3765; see also F. A. J. Kerdesky and M. P. Cava J. Amer. Chem. Soc. 1978,100,3635. loo L. M. Harwood L. C. Hodgkinson and J. K. Sutherland J.C.S. Chem. Comm.1978,712. lo' F. Suzuki S. Trenbeath R. D. Glein and C. J. Sih J. Amer. Chem. Soc. 1978,100 2272. Aromatic Compounds the resulting lithio derivative with an aromatic aldehyde gives a phthalide which can be elaborated to an anthraquinone. Appropriate choice of starting materials pro- vides an unsymmetrically substituted anthraquinone suitable as a precursor for synthesis of anthracyclines102 (Scheme 17) OLi n @NHc6H5 OMe OCH,C,H Reagents i 2 mols. BuLi; ii I ;iii H,O* 0.H. OMe Scheme 17 Interest in the synthesis of anthracyclines has led to some interesting work on the regioselectivity of Diels-Alder addition of dienes to peri-hydroxylated naph- thoquinones. It has long been known that the nature of the oxygen function in 5-hydroxy- and 5-acetoxy- 1,4-naphthoquinone profoundly influences the regio- chemistry of the cycloaddition with 1-acetoxybutadiene and this general trend has been noted more recently for a variety of diene system^."^ The reaction is catalysed by Lewis acids but remarkably with peri-hydroxylated naphthoquinones the regioselectivity varies dramatically with the nature of the catalyst (Scheme lS).'" no catalyst 75 25 BF,.Et,O >99 <1 MgI2 15 85 Scheme 18 J.E. Baldwin and K. W. Blair Tetrahedron Letters 1978,2559; see also I. Forbes R. A. Pratt and R. A. Raphael ibid p. 3965. for example T. R. Kelly,J. Gillard,R. Goemer and J. Lyding J. Amer. Chem. Soc. 1977,99,5513;T. R. Kelly Tetrahedron Letters 1978 1387. '04 T. R.Kelly and M. Montury Tetrahedron Letters 1978.4311.222 W. Carruthers The explanation suggested for the effect in the uncatalysed reaction at any rate is based on the concept that the strong hydrogen bond in 5-hydroxy-1,4-naph- thoquinone serves as an internal Lewis acid polarizing the unsaturated system so that the C-4 carbonyl group controls the direction of cycloaddition. In the cor- responding acetate or methyl ether on the other hand electron donation by the substituent is held to dominate leading to reversal of the direction of addition. It has been suggested however that this picture is oversimplified and that for high regiocontrol the proper choice of the diene might be more crucial.1o5 Phenanthraquinones are obtained in good yield by photocyclization of 1,2-diarylvinylidene carbonates themselves available from benzoins by treatment with phosgene.lo6 A polychloro pigment isolated from certain green soils has been assigned the novel structure (53).lo' 5 Cyclophanes The observed splitting of the first two photoelectron bands and the calculated strain energies of the [n]paracyclophanes are attributed to deformation of the benzene ring.Calculated energies suggest that the aromatic character of the benzene nucleus in [n]paracyclophanes has been largely lost for n =6 and completely lost for n = 5.'08 Diels-Alder reactions of benzene derivatives are rare However sterically strained benzene rings such as that in (54) can act as dienes; 1:l addition of reactive dienophiles leads to bridged ba-rrelenes (55;n =7or 8; R = CF3or CN)."' Insertion of a chromium atom between the benzene rings of [2,2]paracyclophane has been accomplished by condensation of the hydrocarbon with chromium atoms at -196"C.The novel complex can be sublimed and survives eight days in hydrochloric acid."' R (54) (55) R. K. Boeckman T. M. Dolak and K. 0.Culos J. Amer. Chem. Soc. 1978,100,7098. '06 I. Lantes Tetrahedron Letters 1978,2761. lo' D. W.Cameron and M. D. Sidell Austral. J. Chem. 1978,31 1323. 'pa H. Schmidt A. Schweig W. Thiel and M. Jones Chem. Ber. 1978 111 1958. K.-L. Noble H. Hopf M. Jones and S.L. Kammula Angew. Chem. Internat. Edn. 1978,17 602. C. Elschenbroich R.Miickel and M. Zenneck Angew. Chem. Znfernar. Edn. 1978,17,531. Aromatic Compounds The long-sought [2](4,4')orthoterphenylophane (56) has been prepared."' Particular interest attaches to such cyclophanes in which benzene rings are held orthogonal to each other.N.m.r. and U.V. spectroscopic data for (56) suggest that there is very little if any interaction between the ?r-electron clouds of the orthogonal benzene rings. (56) Cyclic sulphones have again shown their worth as precursors of cyclophanes. By vacuum pyrolysis of the appropriate cyclic sulphones a series of sterically hindered [1,n]paracyclophanes some of them not accessible by other methods was obtained in excellent yield,"*" and several [2,2]cyclophanes were obtained by photo- extrusion of sulphur dioxide from the bis-sulphones of 2,ll -dithia[3,3]paracyclo- phanes."*' Tetrasubstituted [2,2]paracyclophanes are formed by cycloaddition of ace tylenic dienophiles to 1,2,4,5 -hexat e traene .I A new route to [4,2]paracyclophanes with unsaturation in the larger bridge proceeds by condensation of vinyl p-xylylene with other xylylene-type inter- mediate~.~~~ Thus pyrolysis of (57) with (58) gave (59) and (60) as well as [2,2]paracyclophane (Scheme 19).+ Scheme 19 ''I N. Jacobson and V. Boekelheide Angew. Chem. Intentat. Edn. 1978.17,46. 'I2 (a) A. Ruland and H. A. Staab Chem. Ber. 1978 111 2997; (b) R.S. Givens and P. L. Wylie Tetrahedron Letters 1978,865. I. Bohm H. Herrmann. K. Menke and H. Hopf Chem. Ber. 1978,111,523. 'I* P. S. Hammond and D. T. Longone Tetrahedron Letters 1978 415. 224 W. Carruthers In the naphthalenoparacyclophane (61)the upfield shift of the internal protons Hi confirms the expected stepped structure in which the para-disubstituted benzene ring is tilted towards the naphthalene ring.'" The variable-temperature 'H n.m.r.spectrum of [2,2](2,6,2',7')naphthalenophan-l,ll-dieneindicates that it undergoes conformational flipping in X-Ray crystallography shows that the furanonaphthalenophane (62) exists in the anti conformation. The non-bridged portion of the naphthalene ring is planar but the bridged ring is puckered and boat-shaped.' l7 In [2,2]anthracenophane also there is slight distortion of the bridged benzene moieties.'" (61) (62) Further examples of highly strained cyclophanes which have two benzene rings held with three or more ethano-bridges have been synthesized.[2,2,2]- (1,2,4)(1,2,5)-and [2,2,2](1,2,4)(1,3,5)-cyclophanes the first examples of [2,2,2}cyclophanes in which the benzene rings are held together in an unsymmetrical manner by three ethano bridges were obtained by the sulphone pyrolysis route. Their U.V. and n.m.r. spectra suggest highly strained structure^."^ The novel triply clamped biphenylophanes (63) and (64) have also been made by the sulphur- @ V (63) (64) (65) extrusion route. Their n.m.r. and U.V. spectra reveal transannular steric and elec- tronic effects.12' The cyclophane (65)has been synthesized. On pyrolysis it gave hexaradialene (cf.p. 208) and not the hoped for [2,2,2,2,2,2]( 1,2,3,4,5,6)cyclophane with six ethano bridges.'*' Nevertheless it appears that direct dimerization of o-xylylenes does provide a convenient route to some multibridged cyclophanes.J. R. Davy M. N. Iskander and J. A. Reiss Tetrahedron Letters 1978 4085. M. N. Iskander and J. A. Reiss Tetrahedron 1978,34 2343. M. Corson B. M. Foxman and P. M. Keehn Tetrahedron 1978,34,1641. T. Toyoda and S. Misumi Tetrahedron Letters 1978,1479. 'I9 M. Nakazaki K. Yamamoto and Y. Miura J. Org. Chem. 1978,43 1041. ''O F. Vogtle and G. Steinhagen Chem. Ber. 1978 111,205. ''I R. Gray L. G. Harruff J. Krymowski,J. Peterson and V. Boekelheide J. Amer. Chem. Soc. 1978,100 2892. L. G. Harruff,M. Brown and V. Boekelheide ibid 1978,100,2893. Aromatic Compounds Thus thermal dimerization of the bis-o-xylylene (66) gave the cyclophane (67) (Scheme 20).122Formation of multibridged paracyclophanes in this way has a bearing on the mechanism of dimerization of o-xylylenes to dibenzocyclo-octa- 1,s-dienes.+ / Scheme 20 Multilayered cyclophanes proliferate and their chemistry has been reviewed. 123 In triple-layered [2,2]metacyclophanes the isomers in which a benzene ring is forced to take up a boat conformation are more stable by at least 17kJ mol-' than the isomers with a benzene ring in the chair conformation. SCF MO calculations confirm that distortion of a benzene ring to a boat is preferred to that to a Using the standard method of ring-contraction with extrusion of sulphur the triple-layered anti-[2,2]metacyclophanes (68; R = H) and (68; R =CH,) have been synthesized --Me\ /R />M;.( ) (68) and shown to have a staircase-type geometry.125 A series of triple-layered [m,m]- [n,n]paracyclophanes has been synthesized.'26 There is continuing interest in paracyclophane quinhydrones. Intramolecular fixation of donor-acceptor systems in the rigid skeleton of cyclophanes provides information on the dependence of charge-transfer interactions on orientation and V. Boekelheide and G. Ewing Tetrahedron Letters 1978,4245. S. Misumi and T. Otsubo Accounts Chem. Res. 1978,11,251. IZ4 H. Iwamura H. Kihara S. Misumi Y. Sakata and T. Umemoto Tetrahedron 1978,34,3427. T. Otsubo D. Stusche and V. Boekelheide J. Org. Chem. 1978 43 3466; D. Kmp and V. Boekelheide ibid 1978,43 3470. T.Otsubo T.Kohda and S. Misumi. Tetrahedron Letters 1978 2507.226 W. Carruthers separation which is inaccessible by the study of intermolecular complexes. The quinhydrone (69)derived from [2,2,2,2 ]( 1,2,4,5)cyclophane is of particular interest in this connection. It shows a broad intense charge-transfer band which is surpris-ingly similar in line shape and position to that of pseudogeminal[2,2]paracyclophane quinhydrone surprising in view of the shorter transannular distances and the completely rigid arrangement of the donor and acceptor units in (69).127Charge-transfer spectra have been observed in triple-and quadruple-layered cyclophanes in which respectively one and two benzene rings are sandwiched between the quinone and hydroquinone rings.'*' The triptycene derivative (70)shows strong transannular & 0 I oqj 0 OH interaction in spite of the apparently disadvantageous molecular framework.'H n.m.r. and U.V. absorption studies and electrolytic reduction clearly indicate that the electron donor-acceptor interaction between the hydroquinone and p-benzo-quinone chromophores in the triptycene is almost as strong as that in quinhydrone itself. A simple through-space interaction between donor and acceptor rings held at 120" to each other is considered not to account for the strong interaction observed and a through-bond homoconjugative interaction between donor and acceptor rings is The use of cyclophanes as components of the host in host-guest compounds is discussed in a review,l3' and the synthesis and characterization of a number of stereoisomeric macrocyclic polyethers (hosts) containing rigid chiral a,a'-binaph-thy1 units for study of chiral recognition in molecular complexation with racemic alkylammonium salts is rep~rted.'~' 6 Condensed Systems A novel route to condensed polycyclic aromatic compounds by intramolecular cyclization of benzynes and heteroarynes has been reviewed,'32 and so has the dehydrogenation of polycyclic hydroaromatic compounds.133 H.A. Staab and V.Schwendemann Angew. Chem. Internat. Edn. 1978,17,756. 12* H. A. Staab U. Zapf and A. Gurke Angew. Chem. Internat. Edn. 1977,16,801;H.Machida, H.Tatemitsu Y. Sakata and S. Misumi Tetrahedron Letters 1978,915; H.A.Staab and U. Zapf Angew. Chem. Internat. Edn. 1978,17 757. 129 H. Iwamura and K.Makino J.C.S. Chem. Comm.. 1978,720. I3O D.J. Cram and J. M. Cram Accounts Chem. Res. 1978,11,8. 13' D.J. Cram,R. C. Helgeson S. C. Peacock L. J. Kaplan L. A. Domeier P. Moreau K. Koga J. M. Mayer Y. Chao M. G. Siegel D. H. Hoffman and G. D. Y. Sogah J. Org-Chem. 1978,43,1930. S. V.Kessar Accounts Chem. Res. 1978,11,283. 133 P.P.Fu and R. V. Harvey Chem. Rev. 1978,78,317. 12' Aromatic Compounds 227 It has been found that the outcome of the reduction and reductive alkylation of many aromatic compounds with an alkali metal and liquid ammonia depends on secondary reactions which occur on quenching and different products are obtained in many instances by using an inverse quench proced~re.'~~ A number of new syntheses of naphthalene derivatives have been described.Michael addition of the anion derived from phthalide to electrophilic olefins under aprotic conditions leads to cyclic products which on dehydration afford substituted naphthols (Scheme 21),13' and in another route naphthalene derivatives are obtained by reaction of phthalide ortho esters with acetylenic and olefinic dien0phi1es.l~~ 00 @C02Me m\ M eMe \ /Me OH Reagents i LiNPriz;ii MeCH=CHCO,Me; iii CF,COZH or BF,. Et,O Scheme 21 Another route by condensation of the anion of 2-ethoxycarbonylbenzyl phenyl sulphone with @unsaturated esters and ketones gives 1-hydroxy-2,3-disubstituted naphthalenes and by suitable modification 1,4-dihydroxy-2,3 -disu bsti tuted nap h-thalene~.'~'A closely similar procedure leads to naphthalene derivatives from ortho-substituted benzyl sulphones and Michael ac~eptors.'~~ Naphtho[b,e]dicyclo-butene (71) has been synthesized by a sequence involving two Diels-Alder reactions with dimethyl cyclobutene- 1,2-dicarboxylate.Preliminary X-ray crystallographic analysis reveals a symmetrical carbon framework. 13' (71) A 180" rotation about a phenyl-naphthyl bond is expected to be effectively blocked for derivatives of the peri-diphenylnaphthalenes.However surprisingly low P. W. Rabideau and E. G. Burkholder J. Org. Chem. 1978,43,4283. 13' N. J. P. Broom and P. G. Sammes J.C.S. Chem. Comm. 1978 162. '" L. Contreras C. E. Slemon and D. B. Maclean TetrahedronLetters 1978,4237. 13' F. M. Hauser and R. P. Rhee J. Org. Chem. 1978,43 179.J. Wildeman P. C. Borgen H Pluim P. H. F. M. Rouwette and A. M. van Leusen TefruhedronLetrers 1978,2213. 139 R. P. Thummel and W. Nutakul J. Amer. Chem. Soc. 1978,100,6171. 228 W. Carruthers rotational energy barriers have been found. For a 3'-substituted derivative of the highly crowded 1,4,5,8-tetraphenylnaphthalenethe barrier to rotation (63 kJ mol-') is even smaller than that (69 kJ mol-') for 1,8-diphenylnaphthalene and consider- ably less than that (141 kJ mol-') of the stereotopically similar [3,4]paracyclophane. The differences are discussed in terms of a rotational transition state with large deformations of the naphthalene ring. 140 Chirality and conformational changes in 4-phenylphenanthrenes and 1-phenylbenzo[c]phenanthrenes have been studied.l4' N.m.r.data for several methyl-substituted 4-phenylphenanthrenes revealed that the crowding in these compounds does not lead to chirality at temperatures as low as -90 "C. The easy rotation of the phenyl substituent observed by n.m.r. spectroscopy implies that although the phenanthrene moiety on average is planar the phenyl group does not experience steric hindrance. With 1-phenylbenzo[c]phenanthrene however some restriction to rotation of the phenyl group was observed. The photocyclization of a series of 2-(P-arylvinyl)biphenyls to 9-aryl-9,1 O-dihy- drophenanthrenes has been studied and quantum yields have been measured. The p ho toreaction consists of a stereoselective probably concerted conro tatory cycliza- tion from the S state of both the cis-and trans-arylvinylbiphenyl to a 9-aryl-8a,9- dihydrophenanthrene derivative followed by a fast thermal suprafacial [1,5]sig-matropic hydrogen shift (Scheme 22).142Photocyclization of stilbene derivatives to Scheme 22 phenanthrenes continues to be of interest.Dicyclobuta[b glphenanthrene and dicyclobuta[b,h]phenanthrene have been made in this way from the appropriate stilbene and a number of 4,4'-dihydroxystilbenes (72),constrained in the cis configuration cyclized on irradiation to the corresponding 4a,4b-dihydro- phenanthrenes which were stabilized by isomerization to the corresponding enones (73) (Scheme 23).144 W. H. Laarhoven W. H. M. Peters and A. H. A. Tinnemans Tetrahedron 1978,34,769. P. H. G. op het Veld and W.H. Laarhoven J.C.S. Perkin ZZ 1978 915. 0 hv -* Me (73) Scheme 23 140 R. L. Clough and J. D. Roberts J. Org. Chem. 1978,43,1328. 143 P. Perkins and K. P. C. Vollhardt Angew. Chem. Internat. Edn. 1978,17,615. 144 M. Maienthal W. R. Benson E. B. Sheinin T. D. Doyle and N. Filipescu J. Org. Chem.. 1978,43,972. 14' Aromatic Compounds 229 Anthracene photo-oxide on thermolysis undergoes changes resulting eventually in the formation of the di-ether (74) uia the diepoxide (75). With naphthacene won / \ / \ 0 0 photo-oxide a similar di-epoxide is formed but subsequent reactions are more complex and a mixture of products results.145a Mixtures were also obtained by photo-rearrangement of the endoperoxides of 9,lO-diphenylanthra~ene’~~~ and of 7,12-dimethylbenz[a Ianthracene.146 The complex triphenylmethyl radical (76) has been prepared by reduction (Na or K mirror in benzene) of the cation. E.s.r. results indicate clearly that it is ~1anar.l~’ A novel route to the benz[a]anthracene ring system by Diels-Alder reaction of 1,4-phenanthraquinone and 1-methoxy- 1,3-~yclohexadiene followed by thermal extrusion of ethylene led to a mixture of 8-and 11-methoxybenz[a]anthra-quinone.14’ A dicarboxylic anhydride of benz[a]pyrene was obtained by photo- addition of maleic anhydride to chrysene in presence of air.’49 Dibenz[a,c]anthracene is conveniently and directly obtained from 2-(9’-phenanth- roy1)benzoic acid with boiling hydriodic acid and red phosphorus.150 The unexpec- ted ease of cyclization of the benzoic acid in comparison with that of analogous keto-acids is ascribed to the relatively high olefinic character of the phenanthrene 9,lO-bond in this compound. Reaction with hydriodic acid and phosphorus of 0-(1-naphthoy1)benzoic acid which lacks such a bond furnished only the product of reduction of the carbonyl group 0-(1-naphthylmethyl)benzoic acid. Dihydro-diols of polycyclic aromatic hydrocarbons have become important because of their r61e in the causation of cancer by some of the hydrocarbons and 14’ (a)J. Rigaudy J. Baranne-Lafont A. Defoin and N. K. Cuong Tetrahedron 1978,34,73; J. Rigaudy and D. Sparfei ibid 113,226; (6)J. Rigaudy C. Breliere and P. Scribe Tetrahedron Letters 1978,687. 146 M.K. Logand W. A. Austin and R. E. Davis Tetrahedron Letters 1978,511. 14’ F. A. Neugebauer D. Hellwinkel and G. Aulmich Tetrahedron Letters 1978,4871. 14’ S. W. Wunderly and W. P. Weber J. Org. Chem.. 1978,43 2277. H. Karpf and 0.E. Polansky Tetrahedron Letters 1978 2069. 1so R. G. Harvey C. Leyba M. Konieczny P. P. Fu and K. B. Sukumaran J. Org. Chem. 1978,43,3423. 230 W. Carruthers several derived from ~hrysene,'~' ben~o[eJpyrene,'~~ have and ben~o[a]pyrene'~~ been synthesized for biological study. The absolute stereochemistry of the cis-l,2- trans- 1,2- and cis- 3,4-dihydro-diol metabolites of phenanthrene has been deter- mined. 154 Several 'bay-region' diol epoxides of phenanthrene and chrysene have been prepared and the rates and products of their hydrolysis compared with those observed for corresponding derivatives of ben~o[a]pyrene.'~~ (77) (78) (79) Heating concentrated ' solutions of 1,3,14,16-tetramethylhexahelicene(77) at 180-300 "C results in the formation of the two spiro compounds (78)and (79);dilute solutions only racemize.Similar behaviour is shown by the 1,16- but not by the 1,3- or 1,14-dimethyl compounds. Presumably the carbon skeleton of the pyrene moiety arises via a sigmatropic hydrogen shift from the C1-CH3 to C19 followed by an electrocyclic reaction.'56 Irradiation of 2-~tyrylbenzo[c]phenanthrene in eleven different chiral solvents led to non-racemic hexahelicene in optical yields of 0.2-2.0%. The r61e of the chiral solvents is ascribed to their influence on the equilibrium between enantiomeric conformations of the cis-styrene.157 Methyl substituents at C-1 and C-16 of hexahelicene lead to a large increase in the free energy of activation in the thermal racemization compared with hexahelicene but methyl substituents in other positions have little effect.ls8 A new helical molecular skeleton (80)has been constr~cted.'~~ The temperature- dependent 'H n.m.r. spectrum shows that the molecule is helical at low tempera- U (80) 15' P. P. Fu and R. G. Harvey J.C.S. Chem. Comm. 1978,585. 152 R. E.Lehr C. W. Taylor S. Kumar H. D. Mah and D. M. Jerina J. Org. Chem. 1978,43 3462. 15' D.R.Boyd G. S. Gadaginamath R. Hamilton H.Yagi and D. M. Jerina Tetrahedron Letters 1978 248. 154 M. Koreeda M. N. Akhtar D. R.Boyd J. D. Neill D. T. Gibson and D. M. Jerina J. Org. Chem. 1978 43 1023. 155 D. L. Whalen A. M. Ross H. Yagi J. M. Karle and D. M. Jerina J. Amer. Chem. Soc. 1978,100,5218. J. H.Borkent P. H. F. M. Rouwette and W. H. Laarhoven Tetrahedron 1978,34,2569. 15' W. H.Laarhoven and T. J. H. M. Cuppen J.C.S. Perkin ZI 1978,315. ''* J. H.Borkent and W. H. Laarhoven Tetrahedron 1978,34,2565. 159 F. Vogtle and E. Hammerschmidt Angew. Chem. Internat. Edn. 1978.11 268. 15' Aromatic Compounds 231 tures; the signals of the benzylic protons appear as singlets at room temperature but display considerable broadening on cooling. 7 Non-benzene Systems Three- and Four-membered Rings.-The first example of an electrophilic substitu- tion in the cyclopropenylium ion has been reported.160a The compound (81; X = H) when treated with D2S04,is converted into the deuteriated analogue (83) presum-ably by way of the a-complex (82).In the same system the synthetically useful lithium derivative (81; X=Li) is obtained by action of butyl-lithium on (81; x = C1)?Ob The results of ab initio SCFand CI calculations for the low-lying singlet and triplet states of cyclobutadiene imply that the square form is the lowest energy intermediate for interconversion of rectangular singlets. 16' Experimental evidence for a rec- tangxiar structure for the ground state of cyclobutadiene comes from a careful infrared study. This rules out the possibility that cyclobutadiene is square and sugpgsts that it is very likely rectangular.'62 X-Ray crystallographic analysis of the benzocyclobutadiene derivative (84) shows that the benzocyclobutadiene moiety is planar and that the bond in the four-membered ring carrying the substituents is as short as an isolated carbon=carbon double bond.The measured bond lengths rule out any contribution from the resonance structure (86),and the ground state is best described in terms of the two resonance structures (84) and (85).163 Hiickel molecular orbital theory predicts the aromatic 2welectron cyclobutadiene dication to have a square-planar ground state. Results of more recent calculations suggest however that the parent dication as well as the tetramethyl derivative is not planar but is puckered.'64 The dianion of dimethyl cyclobut-3-ene-1,2-dicar-boxylate has been prepared.Spectroscopic and chemical evidence suggest that it does not benefit from aromatic delo~alization.'~~ 160 (a)R.Weiss and C. Priesner Angew. Chem. Internat. Edn. 1978,17,445;(b)R.Weiss C. Priesner and H. Wolf ibid 1978 17,446. 161 J. A.Jafri and M. D. Newton J. Amer. Chem. Soc. 1978,100,5012. 162 S. Masamune F.A. Souto-Bachiller T. Machiguchi and J. E. Bertie J. Amer. Chem. Soc. 1978,100 4889;cf. also H.Kollmara and V. Staemmler ibid 1978,100,4304. 163 W. Winter and H. Straub Angew. Chem. Internat. Edn. 1978 17 127. 164 K. Krogh-Jespersen P.von R.Schleyer J. A.Pople and D. Cremer J. Amer. Chem. Soc. 1978,100 4301. 165 P.J. Garratt and R. Zahler J. Amer. Chem. SOC..1978,100,7753. 232 W. Carruthers Five- and Seven-membered Rings.-The highly strained 6,6-dimethylenefulvene (88)has been generated by gas-phase pyrolysis of (87).It is stable at low tempera- tures as a crystalline solid or in dilute solution in deoxygenated hydrocarbon solvents but the neat liquid polymerizes explosively at room temperature.'66 The [6 + 4Jcycloaddition of 1-dialkylaminobutadiene to fulvenes provides an efficient new synthesis of hydroazulenes and with suitable starting materials of azulenes as well.167 A fresh study confirms that the [6+ 41adduct (89) is probably the initial product from reaction of tropone with monocyclic fulvenes.'68 (89) The heat of formation of the tropyl cation is estimated at 882 f8.4kJ mol-' from the helium(1) photoelectron spectrum of the tropyl ~adical.'~' This value is in good agreement with that estimated by ab initiu MO calculations (873 kJ mol-') though it is considerably above the MIND0/3 estimate (822 kJ mol-').All nucleophiles so far investigated react with benzotropylium ion to give mixtures of the 5H-and 7H-benzocycloheptatriene in approximately equal amounts. With the 5-and 7-methoxybenzotropylium ions however the position of attack varies with the nu~leophile.'~~ Nucleophilic capture of cation (90) by methoxide ion yields 9-methoxyfluorene instead of the expected product. This rearrangement of derivatives of 4bH-benzo[3,4]cyclobuta[ 1,2]cycloheptene to derivatives of fluorene appears to be gene~a1.l~~ (90) Tropone and tropolone do not undergo Friedel-Crafts acylation.The tropone- irontricarbonyl complex on the other hand is easily acylated with acetyl chloride and aluminium chloride to a mixture of tautomeric acetyltropone complexes in high yield. The reaction was used in syntheses of P-thujaplicin and P-dolabrin (Scheme 24).172 A new approach to the synthesis of tropolones by rearrangement of appro-166 R. D. Miller and D. Kaufmann J.C.S. Chem. Comm. 1978,496. 16' L. C.Dunn and K. N. Houk Tetrahedron Letters 1978 3411. 16* 1.-M. Tegmo-Larrson and K. N. Houk Tetrahedron Letters 1978,941. 16' T. Koenig and J. C. Chang J. Amer. Chem. Soc. 1978,100,2240. ''* B. Fiihlisch C.Fischer and W. Rogler Chem. Ber. 1978,111 213. 17' L.Lombard0 and D. Wege Austral. J. Chem. 1978,31 1569. 172 M. Franck-Neumann F. Brion and D.Martina Tetrahedron Letters 1978 5033. Aromatic Cornpounds 0 OH Reagents i MeCOCI-AlCI,; ii Me2CN2 Scheme 24 priately substituted bicyclo[4.l.0)hept-3-en-2-ones has been de~cribed.”~ Thus P-dolabrin (91)was obtained as shown in Scheme 25. The ring expansion is viewed as proceeding by electrocyclic ring opening of the enolate of the enone. The sequence has been applied in a promising route to the ring system of colchicine. Me0 4 Me00 0 OSiMe 0 (91) Reagents i KH-THF;ii Me,SiCl; iii chloranil; iv BBr Scheme 25 Oxyallyl species generated from a,a‘-dibromoketones and iron carbonyls react with open-chain and cyclic 1,3-dienes in a 3+4+7 manner giving 4-cyclo- heptenones. Dehydrogenation of these by bromination-dehydrobromination gives substituted tropones.The procedure can be modified to give y-tropolones 43- homotropones and hydroxyhomo trop ylium ions 74 The rearrangement of cycloheptatrienylidene to phenylcarbene in solution has been studied.’” Simple dilution and increase in temperature to 240°C were not sufficient for the rearrangement of the parent cycloheptatrienylidene to be competi- tive with dimerization to heptafulvalene but rearrangement was observed when dimerization was retarded by the presence of substituents at C-2 and C-7. The 173 D. A. Evans D. J. Hart and P. M. Koelsch 1.Amer. Chem. Soc. 1978,100,4593. 174 H. Takaya Y. Hayakawa S. Mikino and R. Noyori J. Amer. Chem. Soc. 1978,100 1765 1778. C. Mayor and W. M. Jones J. Org. Chem. 1978,43,4498. 234 W.Carruthers preparation of several 8,8-dimethylhomotropyliumcations has been reported. They undergo a variety of molecular rearrangements including circumambu- lation. 176 Annulen-.-MIND0 methods are unsuccessful in predicting correct geometries or enthalpies of formation (when geometries are known) for the larger annulenes. One cause of this could be neglect of the correlation energy. The dependence of this energy on the size of the 7r system the symmetry of the molecule and the number of the considered doubly excited configurations has been investigated and some simple rules for estimating the importance of the correlation energy of a Tsystem have been put f0r~ard.l~~ The reaction of 9-anti-methoxy- or 9-anti-chloro-cis-bicyclo[6.l.O]nona-2,4,6-triene with alkali metals in tetrahydrofuran leads stereoselectively to the aromatic cis,cis,cis,trans-[9]annuleneanion which can be isolated as crystalline salts.The isomeric 9-syn-methoxy- and 9-syn-chloro-cis-bicyclo[6.1.O]nona-2,4,6-trienes on the other hand gave the all-cis anion.’78a The topomerization and isomerization of the cis,cis,cis,trans-anion have been A derivative (92) of 1,5-methano[ 10Iannulene has been prepared. Its n.m.r. spectrum suggests that it sustains as large a diamagnetic ring current as 1,6- methano[ lO]ann~lene.’~~ Two aza derivatives of 1,6-methano[ 101annulene have been prepared. Both show evidence of a diamagnetic ring current in their n.m.r. spectra. 180 Experimental evidence has been presented that other things being equal the possibility or not of equivalent ‘Kekult’ structures can have a profound effect on the diatropicity (aromaticity) of an annulene.lgl The two bridged annulenes (93) and (94)were synthesized.Compound (93) for which two equivalent ‘KekulC’ structures can be drawn showed a much more strongly pronounced diamagnetic ring current \ I / I OMe \ @ 176 R. F. Childs and C. V. Rogerson J. Amer. Chem. Soc. 1978,100,649. 177 H. Baumann J. Amer. Chem. SOC..1978,100,7196. 178 (a) G. Boche H. Weber D. Martens and A. Bieberbach Chem. Ber. 1978,111,2480; (6)G.Boche H. Weber and A. Bieberbach ibid 1978,111 2833. G. Boche and A. Bieberbach ibid 1978,111 2850. 179 T. Scott and W. R. Brunsvold J. Amer. Chem.SOC.,1978 100,4320. 180 W. J. Lipa H. T. Crawford P. C. Radlick and G. K. Helmkamp J. Org. Chem. 1978 43 3813. M. Schaffer-Riddler A. Wagner M. Schwarmborn H. Schreiner E. Devrant and E. Vogel Angew. Chem. Internat. Edn. 1978 17 853. H.-J. Goiz J. M. Muchowski and M. L. Maddox ibid 1978 17 855. 181 R. H. Mitchell R. J. Carruthers andL. Mazuch J. Amer. Chem. Soc. 1978,100 1007. Aroma tic Compounds as shown by 'Hand 13Cn.m.r. than did (94) which does not have two equivalent KekulC structures. The hexahydrocoronene (95) has been obtained in solution by photocyclization of [2,2,2]paracyclophan-1,9,17-triene (Scheme 26). It shows a (95) Scheme 26 pronounced diamagnetic ring current and is readily oxidized by oxygen to coronene. A quantitative analysis of the ring current in (95)has been made following Haddon's procedure.The large value of 0.87found for the fraction of maximum calculated ring current for (95) is strong evidence that there is no significant trend toward bond alternation at the ring size of an [18]ann~lene.'~~ The corresponding benzo- and dibenzo-analogues (96) and (97)were also made. The dibenzo analogue (97) shows a larger ring-current contribution to chemical shifts than does the monobenzo analogue (96). This is held to illustrate the important r61e of symmetry in ring- current contributions to chemical shifts. The analogues (98) also show n.m.r. X=H,H; -CH2-CH2-; -S-; or -CH=CH-18' T. Otsubo R. Gray and V. Boekelheide J. Amer. Chem. Soc. 1978,100.2449. 236 W.Carruthers characteristics to be expected for bridged [18]annulenes with a strong diamagnetic ring c~rrent."~ The pentatridecafulvalene (99) has been made as well as a vinylogous pentatridecafulvalene. As in other cases the protons of the cyclo- pentadiene ring of (99)give a singlet in the 'H n.m.r. spectrum; there is no evidence for a ring current.lg4 w (99) The photoelectron and ultraviolet absorption spectra of octamethylcyclododeca- 1,3,7,9-tetrayne (100)have been measured and interpreted with the aid of ab initio Me Me$; -Me ;yML -_-Me Me (100) molecular orbital calculations. The p.e. spectrum gave clear evidence of through- space interaction between the two conjugated diacetylene units situated essentially face-to-face across the twelve-membered ring.The molecule has both in-plane and out-of-plane antiaromatic 8n-electron systems which promote bending of the acetylenic linkages.'*' Kekulene (101) a kind of 'super-benzene' has been synthesized. Its 'H n.m.r. spectrum supports the benzenoid (101a) rather than the annulenoid (101 b) form.186 In continuationof earlier work lO-methylbenzo[d1-6,8- (101a) (101b) 183 R. B. Du Vernet 0.Wennerstrom,J. Lawson T. Otsubo and V. Boekelheide J. Amer. Chem. SOC. 1978,100,2457. 184 P. D. Howes and F. Sondheimer I. Org. Chem. 1978,43,2158. 185 C. Santiago K. N. Houk G. J. De Acco,and L. T. Scott J. Amer. Chem. SOC.,1978,100,692. 186 F. Diederich and H.-A. Staab Angew. Chem. Internat. Edn.. 1978.17,372. Aromatic Compounds bisdehydro[ 1Slannulenone and 12-methylbenzo[fl-8,l0-bisdehydro[ 1Slannul-enone have been synthesized.The 'Hn.m.r. spectra show that the protonated annulenones are diatropic. 18' Cycloheptadecaoctaene has been synthesized from the dimer of cyclo-octatetraene and converted into [17lannulenyl anion by treat- ment with base. The 'H n.m.r. spectrum of the anion shows the presence of a strong diamagnetic ring current.'88 The aromatic character of the annuleno-annulenes has been examined theoreti- cally and found to be dominated by the aromaticity of the two fused rings rather than by that of the molecular peri~hery.'~' The synthesis of the trisdehydroannuleno- annulene (102) has been described. Features of the 'H n.m.r. spectrum are explained in terms of an independent ring current in each ring.'" 18' J.Ojima and Y. Shiroishi Bull. Chem. Soc. Japan 1978 51 1204. lS8 P. Hildenbrand G. Plinke J. F. M. Oth and G. Schroder Chem. Ber. 1978,111 107. lS9 B. A. Hess L. J. Schaad and I. Agranat J. Amer. Chem. Soc. 1978,100,5268. 190 S. Nakatsuji S. Akiyama and M. Nakagawa Tetrahedron Letters 1978,1483.

ISSN:0069-3030    

DOI:10.1039/OC9787500199

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

11 Heterocyclic Chemistry By A. J. BOULTON School of Chemical Sciences University of East Anglia Norwich NR4 7TJ 1 Heterocycles in Functional Group Transformations The 4,4-dimethyl-2-oxazoline substituent already established as a versatile protec- tive group and reaction intermediate continues to assert its value. As a typical electron-withdrawing group in a benzene ring it activates an ortho-fluorine atom to nucleophilic displacement by carbon nucleophiles (e.g. Grignard reagents) as well as amide ions.’ As a 4-substituent in pyridine (l),it allows metallation (MeLi) at the 3-position forming (2) and leading to a variety of 3-substituted isonicotinic acid derivatives2 A similar directive effect of metallation occurs at the thiophene 3- position in (3).3 On the other hand the nicotinic acid derivative in ether adds alkyl lithium (RLi) to produce unusually stable 1,4-dihydropyridines (4) on a~idification.~ (1) R=H (2) R=Li Acylamino-acids can be cyclised to azlactones [oxazolinones; (5)] the anions of which may be alkylated at C-4 hydrolysed and oxidatively degraded to ketones.The alkylidene azlactones (6) undergo conjugate addition of organocuprates and the products can be converted into aldehydes (Scheme l).’Asymmetric induction by the (S)-l-phenylethyl substituent on alkylation of the lithium salts of the imidazol- inones (7)leads to amino-acids (8) in good chemical and optical yields after hydrolysis.6 As a rival to the oxazoline the 2-benzothiazolyl substituent shows promise as revealed in an interesting set of preliminary notes,’ which are sum- marised in Chapter 13 of these Reports.A. I. Meyers and B. E. Williams Tetrahedron Letters 1978,223. * A. I. Meyers and R. A. Gabel Tetrahedron Letters 1978,227. L.DellaVecchia and I. Vlattas J. Org. Chem. 1977,42,2649. C. S.Giam and A. E. Hauck J.C.S. Chem. Comm. 1978,615. R. Lohmar and W. Steglich Angew. Chem. Internat. Edn. 1978,17,450. U.Schollkopf H. H. Hausberg 1. Hoppe M. Segal and U. Reiter Angew. Chem. Intemat. Edn. 1978 17 117. ’ E.J. Corey and D. L. Boger Tetrahedron Letters 1978,5,9 13. 239 240 A. J. Boulton Li(PhSCuBu) R' R-C*-C02H I I NH2 R,R'= alkyl aralkyl (7)R=H (8) A reagent for directing lithiation and at the same time introducing chirality is the N-aminopyrrolidine (9).The aldol product is liberated from (10) by oxidative cleavage (MeOH/H202 or photo-oxidation).* ___* CH,OMe PzH2OMe R'COCH pH I I iii Me,SiCI I OSiMe, I NH NYCH3 R' (9) (10) The conversion RCH2NH2 +RCHO is achieved using the quaternary triazolium salt (11). An imine is formed which is a-oxidised using diethyl azodiformate and the product is hydrolysed by acid to the aldeh~de.~ The reagent (11) is also applicable to condensation reaction^,^ cf. the halo-substituted quaternary salts reviewed in this Section last year. Another condensation reagent for peptide coupling is the tetramethyluronium salt (12) which is reported to have the advan- tage of good shelf stability." The formamidopyridine (13) is found to be an excellent reagent for effecting the conversion RMgX +RCHO." H.Eichenauer E. Friedrich W. Lutz and D. Enders Angew. Chem. Internat. Edn. 1978,17,206. G. Doleschall Tetrahedron Letters 1978,2131. lo V.Dourtoglu. J. C. Ziegler and B. Gross,Tetrahedron Letters 1978 1269. " D. Comins and A. I. Meyers Synthesis 1978,403. Heterocyclic Chemistry 241 2 General Heterocyclic Synthesis Reactions and Properties 0-Acylanilines starting materials for a wide variety of heterocycles are not easy to prepare by direct substitution of the anilines. However a reasonably efficient procedure has been described using nitriles as the acylating agents and boron trichloride with or without aluminium chloride as catalyst. The boron is suggested to direct the attacking reagent by its complexation with the amino-group.Aldehydes and ketones in place of nitriles introduce hydroxyalkyl substituents.” More details are available on the thioacetal procedure for ortho-functionalisation of anilines which has been mentioned in previous re~orts.’~ Details of some cine-substitution reactions of o-dinitro-heterocycles have been published. The relative proportions of the direct (14) and cine (15) substitution products of the reaction of piperidine with 6,7-dinitroquinoxaline are variable the cine-product predominates at high base concentration the normal at low. It is suggested that the cine-substitution reaction is second order in base and the direct substitution is first ~rder.’~ 1-Methyl-3,4-dinitropyrrole with methoxide forms the 2-methoxy compound (16); the dihydropyrrole (17) has been isolated from this reaction and its formation was found to be accelerated by excess of methoxide.” The mechanism in this case is suggested to involve SN2-displacement of nitrite ion by methoxide in (18) and to be different overall from that which occurs in the superficially similar reaction of 3,4-dinitrothiophen with thiolates.I6 H OzNaI> X\ Y Me H (14) X =piperidino Y =H (15) X =H Y = piperidino OMe T.Sugasawa T. Toyoda M. Adachi and K. Sasakura,J. Amer. Chem. Soc. 1978,100,4842. l3 P. G. Gassman and H. R.Drewes J. Amer. Chem. Soc. 1978,100,7600. l4 R.Nasielski-Hinkens D. Pauwels and J. Nasielski Tetrahedron Letters 1978 2125.’’ P. Mencarelli and F. Stegel J.C.S. Chem. Comm. 1978,564. l6 C.Dell’Erba D. Spinelli and C. Leandri Guzzettu 1969,99 535. 242 A. J. Boulton Longer-range cine-displacements are sometimes termed tele-substitutions. An example has been found. in the 1,2,4-triazoIo[4,3-a]pyrazines:the 5-bromo compound (19) with methoxide yields a mixture of the 5-and 8-methoxy deriva- tive~.~’ The bicyclic ‘Dewar’ isomers of both five- and six-membered rings have been known for many years to be involved in photochemical ring interconversion reac- tions and a number of these species have been isolated. The scope and detailed mechanism of these reactions continue to attract attention and 1978 saw a number of interesting publications in this area.2-Picolines carrying electron-withdrawing a-substituents [e.g. (20)] are photochemically converted into anilines (21) with scrambling of the ring substituents as indicated by the suggested mechanism of Scheme 2. ’*2,6-Di-t-butyl-4-pyrone forms 4,6-di-t-butyl-2-pyrone on irradiation _3 HN CHCN Scheme 2 in sulphuric acid,lg implying a Dewar-pyrylium salt intermediate rather than an ‘oxygen walk’ mechanism which is the process usually favoured in this typt of compound.20 Steric hindrance to the formation of the 2,6-bond is suggested to be the reason for the change in mechanism. In five-membered rings the ‘Dewar intermediate’ and ‘heteroatom-walk’ mechanisms amount to the same thing. Irradiation of 2-cyanopyrroles (22) and (23) in methanol and in furan gives adducts formed by trapping of the intermediate bicyclic cup-unsaturated nitrile (24) produced by a one-step nitrogen walk.The furan adduct (25; R = H R’= Me) on heating reverts to the azabicyclopentene (24); at the pyrolysis temperature the nitrogen atom walks freely about the ring eventually ’’ J. Bradac Z. Furek D. Janezic S. Molan I. Smerkolj B. Stanovnik M. Tisler and B. Vercek J. Org. Chem. 1977,42,4197. Is Y. Ogata and K. Takagi J. Org. Chem.. 1978,43,944. l9 J. W. Pavlik and R. M. Dunn Tetrahedron Letters 1978 5071. 2o I$ Ann. Reports (B),1975 72 167 257. Heterocyclic Chemistry producing all four isomeric pyrroles. A footnote to this paper reports that the permutation pattern has been uniquely established by deuterium labelling of one of the two ring hydrogen atoms.21 (Scheme 3) R'OCN %R1 CN A wgc~A furan RNm +-a N H N R' R R' CN (24) (22) R =H R' = Me (25) (23) R=Me,R=H t 11.\ A/ R N -OMe R,QNR A -H RN 4 CN CN Scheme 3 In seven-membered eight r-electron systems 'walk' processes are preceded by thermally-allowed cyclisation; this is possibly what happens with the 1,2-diazepine (26),although the acetoxy-group seems to be necessary and a further intermediate (27) is proposed on the way to the pyridine (28) and the 1,3-diazepine (29) which are formed at 110 "C(Scheme 4).*' M2OAc MP COPh -N phf-jAc H N -NCOPh COPh (27) Scheme 4 The products of methylation (with MeOS02F) of a number of prototropic tau- tomeric systems many of them heterocyclic have been investigated.Naive expec- tation would be that alkylation of the union would give mainly the product of methylation at the site which usually carries the mobile proton but reaction of the neutral species (as here) would favour alkylation at the alternative site. In general. *' J. A. Barltrop A. C. Day and R. W. Ward J.C.S. Chem. Comm.. 1978,131. J. A. Moore,W. J. Freeman R. C. Gearhart and H. B. Yokelson J. Org. Chem. 1978,43,787. 244 A. J. Boulton this seems to be borne out in practice; cases (e.g. 4-pyridone) where the isolated product does not follow this general rule are neatly explained.23 The question of sulphur d-orbital participation seems to be as controversial as ever.In a series of diazoles of structure (30)the thiadiazole had the highest-field ”N chemical shift. It was suggested that structure (31) is an important resonance contributor. Comparison was also made with the sulphur di-imides (32) and (33) which have still higher shifts.24 On the other hand the photoelectron spectroscopy of (33) and (34) has led another group25 to the conclusion that quadrivalent sulphur structures with d-orbital participation are of no importance in the thiadiaz- ine case. Also relevant to this question is the novel heterocycle (33 the protons of which resonate at S 4.45 surely justifying its description as ‘of ambiguous aromatic character’.26 (30) X = 0,S Se (31) (32) (33) x=s (35) (34) X=NMe Nitrogen elimination from cyclic azo-compounds has received a fair share of attention in 1978.Theoretical calculations on the reaction were reported,*’ and many practical results were obtained. When the fragment left after the N2 has departed is a stable molecule the reaction usually proceeds thermally with ease; the azoxy-compounds are then much more stable.28 The meso-and dl-1,2-azetines (36) prepared by stereospecific routes decompose stereospecifically the meso giving the cis- and the dl the trans-olefin. The decomposition is theoretically energetic enough to produce the TIlevel of the olefin but this does not appear to be formed; neither is the [2 (olefin)+ 2 (N2)]retro-addition pathway followed.29 More vigorous conditions of temperature or irradiation are needed for those compounds where removal of nitrogen leaves a biradical.Some of these triplet species have been identified spectroscopically for instance those formed on irradiation in glassy matrices at 77 Kof (37)30 and (38).3’ Another precursor to a related species is (39).32 The cage structure (40) is thermally very stable and being efficiently fluorescent requires special conditions (Xe-Hg radiation at 80-90 “C,in vapour phase) for its successful photoly~is.~~ The 1,l-diazene (41) is reported to form a purple solution 23 P. Beak J. K. Lee and B. G. McKinnie J. Org. Chem. 1978,43 1367. ” I. Yavari R. E. Botto and J. D. Roberts J. Org. Chem. 1978,43 2542. ” R. Bartetzko and R. Gleiter Angew. Chem. Internat. Edn. 1978 17,468. 26 R. C. Haddon M. L. Kaplan and J. H. Marshall J.Amer. Chem. Soc. 1978,100 1235. ” B. Bigot A. Sevin and A. Devaquet I.Amer. Chem. Soc. 1978,100,2639. ’* J. P. Snyder and H. Olsen J. Amer. Chem. SOC.,1978 100 2566. ’’ D. K. White and F. D. Greene J. Amer. Chem. Soc. 1978,100,6760. 30 H. Quast L. Bieber and W. C. Danen J. Arner. Chem. Soc. 1978,100 1306. 31 N. J. Turro M.J.Mirbach,N. Harrit,J. A. Berson and M. J. Platz J. Amer. Chem. SOC.,1978,100,7653. 32 R. J. Busby and M. D. Pollard. Tetrahedron Letters 1978 3855 3859. 33 N. J. Turro K. C. Liu W. Cherry J. M. Liu and B. Jacobson Tetrahedron Letters 1978 555. Heterocyclic Chemistry 245 when the corresponding hydrazine is oxidised (t-butyl hypochlorite in NEt3/Et20).34 3 Three-memberedRings A careful study of the thermal decomposition of the P-benzoylvinyl azide (42) has shown that the benzoylazirine (43)is an important intermediate in the pathway to the heterocyclic products (44)and (45).The oxazole is formed by a base-catalysed process as shown by labelling experiments; the isoxazole is produced by thermal rearrangement of (43). The P-ketonitrile (46) is also formed independently (Scheme 5). When a substituent is present 0-to the azide group an oxazole can still be formed by an alternative acid-catalysed mechanism.35 0 Me (45) Scheme 5 The azomethine ylide (47) which is in thermal equilibrium with the aziridine (48),is stabilised by lithium perchlorate. The complex (49)reacts with bromomalononitrile anion to form the azetidine Some steroidal N-nitroaziridines have been prepared by cyclisation of P-hal~nitramines.~’ Oxidation of N-aminoaziridines gives besides bisaziridinodiazenes by dimerisation some (not much) olefin by extrusion of NZ and when the opportunity is presented nitrene insertion products for instance the interesting example (51).38 34 W.D. Hinsberg and P. B. Dervan J. Amer. Chem. Soc. 1978,100,1608. 35 K.Isomura Y. Hirose H. Shuyama ,Q ’.5e,G.-I. Ayabe and H. Taniguchi,Heterocycles,1978,9,1207. 36 M.Vaultier and R. CarriC Tetrahedron Letters 1978 1195. ’’M.J. Haire and G. A. Boswell J. Org. Chem. 1977,42 4251. L. Hoesch N. Egger,and A. S. Dreiding Helv. Chim. Acta 1978,61,795. 246 A. J. Boulton MeO PhCH C=O, PhCH-C(CO,Me) -PhCH C(CO,Me) LiCI04 \ \\+ / . \/ 7 \\+/ N-C-'ti + N N Ph Ph (+) Ph/\c=o'' Me0/ (47) (49) The photolysis of various 1,2,3-thiadiazoles at 8 K in Ar matrix gives i.r.bands attributable to thiirene~.~~ Details of similar work reported last year4' are criticised but it is clear that the same species was observed. Thiazirines are claimed as intermediates in the formation of nitrile sulphides from various ring systems (e.g. Scheme 6) by irradiation at 10-15 K,in PVC film.4' Substituents which stabilise diazomethane usually tend to destabilise diazirene and vice-versa. So the photoisomerisation of a-carbonyl diazoalkanes has not often led to the isolation of the corresponding cyclic isomers although instances of adiazoamide conversion were noted in these Reports earlier.42 Now examples (e.g. 52+53) in the a-diazoketone field have been and the Meldrum's acid derivative (54) has been prepared.44 Theoretical ab initio SCF calculations have been made on the photochemical diazomethane-diazirine interconversion and also on their decomposition to N2and CH2.45 39 M.Torres. A. Clement 3. E. Bertie. H. E. Gunning and 0.P. Strausz J. Org.Chem. 1978,43,2490. 40 Ann. Reports (B),1977,14253. 41 A. Holm N. Harrit and I. Trabjerg J.C.S. Perkin I 1978 746; A. Holm and N. H. Toubro,ibid. p. 1445. *' cf-Ann. Reports (B),1975,72.252. " T. Miyashi T. Nakajo and T. Mukai J.C.S. Chem. Comm. 1978,442. 44 T. Livinghouse and R. V. Stevens J. Amer. Chem. Soc.,1978,100,6479. 45 B. Bigot R. Ponec A. Sevin. and A. Devaquet J. Amer. Chem. SOC.,1978,100,6575. Heterocyclic Chemistry 247 A report noted in this Section last year46 has turned out to be incorrect X-ray crystallography has shown that the reaction between methanesulphonyl azide and dimethyl N-arylketenimines produces a five- (55) rather than a three-membered NAr Me,C=C=NAr + Me2<I NAr 0NS~3Me2 -+ Me.SO,N NS0,Me /o Me (55) ring.47 X-ray evidence has however confirmed the structure of the adduct (-N2)of tosyl isothiocyanate and diphenyldiazomethane as a stable thiiranimine (56).48 The S-C(sp3) distance is long (1.94A) and on standing for some time in chloroform the compound forms the benzothiophene (57) quantitatively it is suggested uia the zwitterion (or trimethylene-methane analogue) (58).48 (56) (58) (57) Allene episulphide (59)seems to be much more stable than its cyclopropanethione isomer (60); (59) generated in a variety of ways was fully characterised by microwave spectroscopy.No unambiguous evidence for (60) was found but the -cs C2H S (59) (60) formation of ethylene suggested it as an intermediate.49 Some kinetic data on the rearrangement of the optically-active trimethylsilyl methyleneaziridine (61) are available (Scheme 7). The cyclopropane product (62) retains much of the SiMe k values (x lo5) K (sec-’1 at 120 oc NMe (62) Scheme 7 46 Ann. Reports (B),1977,74 256. 47 G. L‘abbC C. C. Yu J.-P. Declercq G. Germain and M. Van Meerssche Angew. Chem. Internut. Edn. 1978,17,352. 48 G. L’abbk J.-P. Dekerk J.-P. Declercq G. Germain and M.Van Meensche Angew. Chem. Inrernur. Edn. 1978,17 195. 49 E.Block,R.E. Penn. M. D. Ennis T. A. Owens and S. L. Yu J. Amer. Chem. SOC..1978,100,7436. 248 A. J. Boulton dissymmetry the rearrangement. of (61) to (62) must be at least partly stereospecific.50 Three-membered rings containing unusual heteroatoms are becoming more common. Silirene chemistry is vigorously investigated in several laboratories. Photochemical addition of nitriles to the derivative (63) results in 2 :1 compounds (64) probably via (65) then (4 + 2)-cycloaddition of another molecule of (63). Acrylonitrile however gives (66) by an alternative (2+2) addition to (65; R= vinyl).’l Siliranes likewise undergo insertion reactions into a ring C-Si bond giving products of type (67) along with ope?-chain compounds (when X =C Y = O).’*The tri-t-butyl phosphirane oxide (68) has been rep~rted.’~ A diphosphaborirane (69) [from (Bu‘P)& +Pr:N.BC12] is said on n.m.r.evidence to have a rapidly-equili- brating structure above -100 “C,with the boron atom n~n-planar;~~ to the Reporter this seems rather strange. The crystal structure of the bridged triarsirane (70) has been determined.” PhkSiMe + RCN Me,Si (65) (63)(R=vinyl) i Ph fPh 4 Four-membered Rings A number of benzo-fused heterocycles undergo ring transformations under the vigorous conditions of flash vacuum pyrolysis to bring a nitrogen atom from a @position to an a-,adjacent to the benzene ring. Examples are the rearrangements H. Quast and C. A. Weise Velez Angew.Chem. Internat. Edn. 1978,17,213. 51 H. Sakwai Y. Karnikama and Y. Nakadaira J.C.S. Chem. Comm. 1978,80. 52 D.Seyferth and D. P. Duncan J. Amer. Chem. Soc. 1978,100,7734. 53 H.Quast and M. Heuschmann Angew. Chem. Internat. Edn. 1978,17,867. 54 M.Baudler A. Marx and J. Hahn 2.Naturforsch. 1978,33b 355. 55 G.Thiele G. Zoubek H. A. Lindner and J. Ellerman Angew. Chem. Internat. Edn. 1978,17,135. Heterocyclic Chemistry (71 -+ 72) of indoxazenes (X = 0),benzisothiazole dioxides (X = SO,) and 2,3-benzoxazin-1-ones (X = COO). Spiro-azirene intermediates of type (73) are suggested to account for this. However in the FVP preparation of 2-phenyl- benzazete (74) from 4-phenyl-1,2,3-benzotriazine,no such transposition takes place as was shown by substituent labelling in the benzo-fused ring.56 2-Phenyl- benzazete adds to diarylnitrilimines with rearrangement finally giving 1,3,5-benzo- triazepines (73,’’ in a way quite analogous to its reaction with nitrile oxides which was reported earlier.The diazomethane adduct (76),which could be isolated forms 2-azido-a-phenylstyrene (77) on mild heating while chromatography on silica results in rearrangement mainly to 2-phenylind0le.~~ A few years ago some malonic anhydrides were reported as formed by carbo- di-imide cyclisation of the acids.’* This claim has now been disputed,” on the grounds that the published5’ properties did not agree with those of compounds formed by ozonolysis of p-lactone ketene dimers (78) and assigned the anhydride structures (79).The compounds were not isolated being very unstable contrary to =~ the earlier claims. The Y~ frequency (only one observed) was in the region of 1820 ~m.-’.~~ Clearly since no alternative explanation for the earlier results was suggested the matter cannot be regarded as closed. The malonimide and related systems (80) have been reported from penicillin sulphoxide precursors.6o The synthesis of ‘penems’ (81) unsaturated and even more unstable analogues of penicillins (penams) has been reported.61 r Ph 1 0 0 (78) X=CR2 (80) X=O S (76) (77) (79) x=o CMe2,CHMe s6 K. L. Davies R. C. Storr and P. J. Whittle J.C.S. Chem. Comm. 1978 9. 57 P. W. Manley R. Sornanathan D. L. R. Reeves and R. C. Storr J.C.S. Chem. Comm. 1978,396; cf.Ann. Reports (B),1975,72 255. ” G. Resofzki M. Huhn B. Hegediis P. Dvorak and K. Kaloy Tetrahedron Letters 1975,3091. 59 C. L. Perrin and T. Arrhenius I. Amer. Chem. Soc. 1978,100,5250. M. D. Bachi 0.Goldberg and A. Gross Tetrahedron Letters 1978 4167. I. Ernest J. Gosteli C. W. Greengrass W. Holick D. E. Jackrnan H. R. Pfaendler and R. B. Woodward J. Amer. Chem. Soc. 1978,100,8214. 250 A. J. Boulton (81) R=H Me Irradiation of 2-cyano- 1-pyrroline- 1-oxides leads via the oxaziridines to ring- contraction forming N-(cyanoformy1)azetidines (82).62Photo-adducts from various heterocyclic thiones and acetylenes have been shown by X-ray crystallography to be spiro-thietes [e.g. (83)],63not thiopyrans as earlier Another thiete (84) is found to be in equilibrium with its open-chain isomer (85).Both forms have been isolated in the solid phase but the equilibration is fairly rapid in solution according to n.m.r. evidence.65 The cycloadduct formed from thiobenzophenone and diphenylketene is shown by 13Cn.m.r. spectroscopy to be the thietan-2-one (86).66 0 SMe & / 030 '0' '0 (84) (85) (86) Other sulphur-containing four-membered rings of note are the oxathietanone S-oxide (87),formed by irradiation of a mixture of SO and CH,CO at 10 K in an argon matri~,~' and the sulphone (88),which has been investigated as a precursor to a trimethylenemethane derivati~e.~~ Flash vacuum pyrolysis of allylsilanes leads to loss of propene in some cases with rearrangement of the residue as in the example (89-+90) which produces a siletene.68 '* D.StC. Black N. A. Blackman and A. B. Boscacci Tetrahedron Letters 1978 175. H. Gotthardt and 0.M. Huss,Tetrahedron Lerters 1978 3617. cfAnn. Reports (B) 1976,73,245. " A. C. Brouwer A. V. E. George D. Seykens and H.J. T. Bos Tetrahedron Letters 1978,4839. H. Kohn P. Charumilind and Y. Gopichand J. Org. Chem. 1978 43,4961. " 1. R. Dunkin and J. G. MacDonald J.C.S. Chem. Comm. 1978 1020. '* E. Block and L. K. Revelle J. Amer. Chem. SOC.,1978,100,1630. Heterocyclic Chemistry 25 1 Cyclic phosphinimines (91) form adducts with i~ocyanates,~~~ isothi~cyanates,~~~ and ketones.69c The ketone adducts are formed reversibly but decompose irrever- sibly to split the four-membered ring in the opposite sense.The isothiocyanate adducts can be formed by addition across the C=S or C=N bonds and in solution rearrangement between isomers was observed. (Scheme 8) I; syNR' E E E Scheme 8 5 Five-membered Rings It has been known for some years that the nitrone tautomers of oximes can be trapped by their reactions with dipolarophiles forming isoxa~ol(id)ines.~~ Ben-zylidene derivatives of a-amino-acids and their esters have now been found to behave in a similar way to generate azomethine ylides which in turn produce a variety of pyrrolidines and 3-pyrrolines with olefins and acetylene~,'l-~~ and aryl- hydrazones similarly give pyrazolines and pyra~olidines.~~*~' Among more con- ventional 1,3-dipole reactions the nitrone cycloaddition to olefins forming isox- azolidines has led to a neat stereospecific synthesis of and to 4-phenylquinolizidin-2-ones (not stereo~pecifically).~~ The reaction of enamines [e.g.(92)] with dimethyl acetylenedicarboxylate (DMAD) in polar solvents (e.g. methanol) follows the pattern of the 3-pyr- rolidinothiophene described here in 1976.78The enamino-ester (93) with phenyl- diazonium fluroborate produces a phenylhydrazone (94) which on heating with a base cyclises with elimination of aniline to give the fused imidazole (95).79Both of 69 (a) A. Schmidpeter and T. von Criegern J.C.S. Chem. Comm. 1978 470; (b) Angew. Chem. Internat. Edn. 1978,17,443;(c) ibid. p. 55. 'O M. Ochiai M. Obayashi and K. Morita Tetrahedron 1967,23 2641;A.Lablache-Combier M.L.Villaume. and R. Jaquesy Tetrahedron Letters 1967,4959;Tetrahedron 1968,246951. 71 R. Grigg J. Kemp G. Sheldrick and J. Trotter J.C.S.Chem. Comm. 1978,109. 72 R. Grigg and J. Kemp Tetrahedron Letters 1978,2823. 73 M.Joucla and J. Hamelin Tetrahedron Letters 1978 2885. 74 R.Grigg J. Kemp and N. Thompson Tetrahedron Letters 1978,2827. " G. Le Fevre and J. Hamelin Tetrahedron Letters 1978,4503. 76 J. J. Tufariello J. J. Tegeler S. C. Wong and S. Asrof Ali Tetrahedron Letters 1978 1733. '' J. J. Tufariello and R. C. Gatrone Tetrahedron Letters 1978 2753. '* D.N.Reinhoudt J. Geevers and W. P. Trompenaars Tetrahedron Letters 1978 1351. 79 C. B.Kanner and U. K. Pandit Heterocycles 1978,9,757. 252 A. J. Boulton these reactions seem to involve electro-cyclisation of conjugated azomethine ylides (96) and (97) respectively to account for the involvement of the pyrrolidine a-positions.0 3 N H,E 9 E (93) b,+ 1 NEt, N ___+ eNaNHPh E (94) (97) (95) E =C02Me or C02Et Cyclisation of 1,5-dipoles remains the theme for the next few papers to be considered. The rate of formation of tetrazoles (98)from azides (99)appears to be N=CHAr’ I Ar’ N=CHArZ Ar lrN\N N3 N.$ N3)=” N=CHAr2 [Ar$N/ (99) (98) controlled by the syn-anti isomerisation rate of the mine group which is very sensitive to the effect of substituents on the remote (Ar2) ring conjugative inter- action of type (100) is said to explain the rate-increasing effect of electron- withdrawing substituents.** A full paper on the cyclisation of azidoximes to 1-hydroxytetrazoles (101) has appeared.81 Evidence (from substituent and kinetic isotope effects) has been presented which suggests that the first step in the thermal decomposition of phenyl 172,3,4-thiatriazole is ring-opening to thiobenzoyl azide.82 For the photochemical decomposition see Section 3.A. F. Hegarty K. Brady and M. Mullane J.C.S. Chern. Cornm. 1978,871. ’* J. Plenkiewin Tetrahedron,1978 34,2961. ’* A. Holm L. Carlsen and E. Larsen J. Org. Chern. 1978,43,4816. Heterocyclic Chemistry 253 Four papers were noted which widen the range of substitution possibilities into the indole nucleus. Lithiation at the 2-position followed by addition to a trialkylborane leads to 2-indolyltrialkylborate ions which are decomposed by iodine introducing a 2-alkyl group into 1-methyl or 1-phenylsulphonyl ind01e.~~ Meldrum's acid an aldehyde and indole undergo a triple condensation to yield a product (102) which may be ethanolysed to an a-substituted indole-3-propionic Indole can be converted directly into the 3-malonic ester using a 2,5-dichloro-1-thiophenium ~lide.~~ The chromium tricarbonyl activation method allows introduction of some nucleophilic substituents into the indole 7-position (103); the scope in terms of R and Nu is still rather limited however.86 P-Nitrostyrenes have been cyclised to oxindoles (104) using acetyl chloride and ferric ~hloride.~' a T aH R J O M e 2 Cr(CO),07t R 03;H Nu (102) (103) (104) 2,3-Dimethylbenzofuran under Friedel-Crafts conditions gives a mixture of the 6-acetyl compound and the rearranged product (105 in which the ethyl group is formed by migration of the 2-methyl onto a 3-methylene group of a dihydro- intermediate.88 a7jMe + ' AcCl ' 'Me SnCI oT)cH2Me 'Ac (105) Thiophene reacts with maleic anhydride in a variety of organic solvents at 100 "C and 15 kbar pressure to form the exo-Diels-Alder adduct (106).No reaction was observed with a number of other common dien~philes.~~ A crystal structure '0 (106) '' A. B. Levy J. Org. Chem. 1978,43,4684. 84 Y.Oikawa H. Hirasawa and 0.Yonemitsu Tetrahedron Letters 1978 1759. 85 R. J. Gillespie and A. E. A. Porter J.C.S. Chem. Comrn. 1979 53. " A. P. Kozikowski and K.Isobe,J.C.S. Chem. Comm. 1978,1076. '' P. Demerseman J. Guillaumel J. M. Clavel and R. Royer Tetrahedron Letters 1978 2011. 88 E. Baciocchi A. Cipiciani S. Clementi and G. V. Sebastiani. J.C.S. Chem. Comrn. 1978 597. 89 H. Kotsuki S. Kitagawa H. Nishizawa and T. Tokoroyama J. Org. Chem. 1978.43 1471. 254 A. J. Boulton determination has been carried out on the thiophenium ylide (107).90 It was made by Rh(OAc)2-catalysed addition of dimethyl diazomalonate to thiophen and on heat- ing it rearranged to the 2-thienylmalonic ester ( 108).91 Although this rearrangement was found to be intramolecular the 2,5-dichloro-derivative of (107) transferred its ylide grouping to cyclopropanate 01efins~~ and substitute activated aromatic rings.85 Bisallenyl sulphide (109) prepared by base-catalysed isomerisation of dipropargyl sulphide forms the dimer (110) when heated (at 50 “Cin CHCl,) presumably via the ‘non-classical’ dimethylene-thiophen (111)(or its equivalent biradical) which can be trapped by 302 [forming (112)] or maleic anhydride.93 Solvent and deuterium- isotope effects on the rate of rearrangement of the selenium analogue (113) to the selenophene (114) are small the first step is probably a rate-determining cyclisation to (115) followed by rapid H-migrati~n.~~ 5) A S(CH=C=CH,) +[sm’”]-CHZ CMe CMe2H Se(CH=C=CMe,) [Sex ] % Se(>x ,,CHZ CMe C I The isoindole structure (116) exists as such rather than in alternative tautomeric forms without NH groups.It is however sensitive to oxygen and gives a 1 2 adduct with N-phenylrnaleimide.9s The pyrroloquinoxaline (117) adds dienophiles across the 1,3-positions.It is made by oxidation of its 1,3-dihydro derivative by Mn02 or of its 4,9-dihydro derivative by 02.96 H b N H a:xNBul (116) (117) 9o R. J. Gillespie J. Murray-Rust P. Murray-Rust and A. E. A. Porter J.C.S. Chem. Comm. 1978 83. 91 R. J. Gillespie A. E. A. Porter and W. E. Willmott J.C.S. Chem. Comrn. 1978,85. ’* J. Cuffe R. J. Gillespie and A. E. A. Porter J.C.S. Chem. Comm. 1978,641. 93 Y. S. P. Cheng E. Dominguez P. J. Garratt and S. B. Neoh Tetrahedron Letters 1978,691. 94 S. Braverman and Y. Duar Tetrahedron Letters 1978,1493. ’’ R. Kreher and K. J. Herd Angew. Chem. Znternat. Edn. 1978 17 68. 96 R.Kreher and G. Use. Tetrahedron Letters 1978,4671. Heterocyclic Chemistry Light was shed on some long-standing puzzles in the year under review. Hector's base an oxidation product of N-phenylthiourea has been known for many years to be a diphenyl diamino-1,2,4-thiadiazole,but the precise location of the two phenyl groups and two mobile protons was not known with certainty. It is now clear that at least in the crystal structure (118) prevail^.^' The structure of its adduct with CS2 is also c~rrected.~~ The products of the action of sodium sulphite on o-diazonioben- zophenones which were originally supposed to be 2-hydroxyindazoles are the 3-hydroxy isomers (119).99Hydrazine and indigo react to form a variety of products. Ph PhNHcNyNH N-s (118) (119) One the so-called desoxyindigo is assigned the complex spirocyclic indoxyl struc- ture (120) while the same reactants under anhydrous conditions produce the very unusual quinazoline derivative (12 1) at low temperatures and its des-imino ana- logue at high temperatures.100 As was briefly mentioned last year the oxidation product of 2,4-di-t-butylphenol which was previously thought to be a spiro-benzo- xete has been found by X-ray crystallography to have the oxepinobenzofuran structure (122).'O' (122) A 2 :1adduct is formed between acetylenic esters and pyrazolo[l,2-~]pyrazoles both with the parent and with the much more stable 1-benzoyl-2-phenyl derivative.Crystallographic confirmation is desirable for the novel cyclophane structures (123) and (124) suggested.It is proposed that they are formed by proton shifts and ring-opening of the cyclazine intermediates (125) and (126) respectively.lo2 The 97 A. R. Butler C. Glidewell and D. C. Liles J.C.S. Chem. Comm. 1978 653; Acta Cryst. 1978,34b 3241. 98 A. R. Butler C. Glidewell and D. C. Liles Acra Cryst. 1978,34B,2570. 99 A.J. Boulton J. S. Khosrowshahi and "hoe K. W. J.C.S. Chem. Comm. 1978 1052. loo J. Bergman B. Egestad and N. Eklund Tetrahedron Letters 1978,3147. lo' H.Meier H.-P. Schneider A. Ricker and P. B. Hitchcock Angew. Chem. Infernut. Edn. 1978,17,121. lo2 K.Matsumoto and T. Uchida Chem Letters 1978. 1093. 256 A. J. Boulton (123) (124) substituted pyrazolopyrazole had earlier been reported to form a 1:1adduct with oxidation,lo3 in a way quite analogous to that which has now been found with the pyrazolo[ 1,2-a][ 1,2,3]triazoles (127) giving the cyclazines (128).The heterocycles (127) are made (R = Ph) by amination of 1-phenacylpyrazole or (R =Me) from C N H,NOSO,H I CH ,COPh E R (127) (128) 1-aminopyrazole by reaction with 3-chloropentane-2,4-dione,followed by dea~etylation.~’~ Another novel cyclazine is the blue polyaza compound (129) formed by decomposition of the tetrazolopyrimidine (130).lo’ Some interesting results have been obtained from the photolysis and pyrolysis of 8-azido-1-arylazonaphthalenes(131). The known naphthotriazine system (132) was observed in only one case and as a minor product and it photo-rearranged to the red-violet azimine isomer (133) which was the main product in all of the reactions.lo6 lo3 V.Boekelheide and N. A. Fedoruk Proc. Nut. Acad. Sci U.S.A.,1966,55,1385 (Chem. Abs. 196665 13 683). lo4 H. Koga M. Hirobe and T. Okamoto Tetrahedron Letters 1978 1291. lo’ A. Konnecke E. Lippmann R. Dorre and P. Lepom Tetrahedron Letters 1978 3687. ‘06 P. Spagnolo A. Tundo and P. Zanirato J. Org. Chem. 1978 43 2508. Heterocyclic Chemistry 257 A number of o-azidobenzoic acid derivatives (134) were photolysed in methanol to produce the azepines (135); in no case was any of the anthranil(l36) dete~ted.~”The amino-compound (136; X=NH2) and the N-H tautomer of the hydroxy- compound (X= OH) are known but the 3-chloro- -alkoxy- -aryloxy- and alkyl- thio-anthranils have proved remarkably resistant to isolation.Possibly these anthranils thermally form the nitrenes rather too easily. Even the 3-styryl derivative (137) rearranges (at 245 OC) the product is (138),rather than the 2-phenylquinolone which might have been expected. The suggested mechanism is outlined in Scheme 9. At lower temperatures (155 “C)(and in a more basic solvent) the indogenide (139) is formed.lo’ Ar X =OMe OPh OH OCOPh SPh NH2 NHPh Ar 1 A new synthesis of pyrazolo[ 1,2-~]pyrazolediones involves treatment of 4- chloropyrazoles with base. It is suggested that the pyrazolones (140) are formed lo’ R. Purvis R. K. Srnalley W. A. Strachan and H. Suschitzky J.C.S. Perkin I 1978 191. R. K. Srnalley R. H. Smith and H. Suschitzky Tetrahedron Letters 1978 2309.258 A. J. Boulton which react with their open-chain tautomers (141) as indicated. Both 1,5-and 1,7-dione (142) isomers are produced in the reaction."' The tetrone (143) (R = R' = H) is reported to exist in the CH form in tetrahydrofuran but as an enol in sulphuric acid,"' and to be an even stronger acid (pK <-1) than the disic acids."' N-NH L (143) (142) A modification of an earlier procedure for acylating dilithiated oximes which uses NN-dimethyl amides instead of esters provides a regiospecific synthesis of isox- azoles in generally good yields. The amide carbonyl becomes the isoxazole C-5."' Flash vacuum pyrolysis of isoxazolin-5-one derivatives has led to some interesting systems. The stable molecules CO and Me-(or Ph)CN are lost leaving an unsaturated carbene [from (144)] which rearranges to an acetylene (R'CECH).* l3 The imines (145) produce isonitriles and a wide range of these were formed,'14 while the readily-available hydrazones (146) give fulminic amide derivatives (ArNH.NC)."' (144) R =Me X = CHR' (145) R =Ph X = NR' (146) R =Me X = NNHAr The A1CI3-catalysed addition of a-diazoketones to nitriles results in an efficient oxazole synthesis."6 The oxazole (147) on heating undergoes intramolecular cyclo- addition of the acetylene to the ring followed by loss of acetonitrile. The furan (148) is hydrolysed to the butenolide (149) by acid."7 E. M. Kosower B. Pazhenchevsky and E. Herschkowitz J. Amer. Chem. Soc. 1978,100,6516. D. S.Kemp J.C. Chabala and S. A. Marson Tetrahedron Letters 1978 543. G. Zvilichovsky Trtrahedron 1975,31 1861;cf.Ann. Reports (B),1975 72 261. 'I2 G. N. Barber and R. A. Olofson J. Org. Chem. 1978,43,3015. C. Wentrup and H. W. Winter Angew. Chem. Internat.-Edn. 1978 17,609. 114 C. Wentrup U.Stutz and H. J. Wollweber Angew. Chem. Internal. Edn. 1978,17,688. 115 W. Reichen and C. Wentrup Helv. Chim. Actu 1976,59,2618. M. P. Doyle M. Oppenhuizen R. C. Elliott and M. R. Boelkins Tetrahedron Letters 1978 2247; T. Ibata and R. Sato Chem. Letters 1978 1129. P.A.Jacobi and T. Craig J. Amer. Chem. Soc. 1978,100,7748. Heterocyclic Chemistry M~OCH,-C~C-~H-OM~ L (147) J-M~CN Benzoxazoles are reduced by diborane in glyme followed by acid work-up to o-aminophenols.The reaction has been followed by "B n.m.r. and three inter- mediates were detected. One was the benzoxazaborole (150) which could be isolated in excellent yield by omitting the hydrolysis step. Another was assigned the tricyclic structure (151) on account of the boron signal splitting (a triplet) and chemical shift. The earliest detectable intermediate is the borane adduct (152). Similar reactions were observed for benzothiazole 2-methylbenzothiazole and 2-methylbenzoselenazole.1 l8 (150) The zoanthoxanthins remarkable coral pigments containing two imidazole rings fused to a seven-membered ring have yielded to a neat synthesis the key step of which is a [4 +6lcycloaddition of two moieties formed by dehydration of 4-hydr-oxyethylimidazoles thus the two precursors as shown in (153) eventually form pseudozoanthoxanthin.Inthe course of this work an unprecedented rearrangement was discovered. The imidazoles were produced by a known rearrangement from 1,2,4-0xadiazoles (Scheme 10,Path a). However in addition a pyrazole by-product (154) was found for the formation of which the very strange mechanism of Path b was suggested. Path b operates when R = H and steric effects involving R and the "* K. K. Knapp P. C. Keller and J. V. Rund J.C.S. Chem. Comm. 1978 971. 260 A. J. Boulton Me 1 J Scheme 10 N-Na group (or ion-pair) are invoked to explain the preference for Path a otherwise.' l9 Mesoionic heterocycles have as usual received a considerable amount of attention. The electric dipole moments of derivatives of fourteen classes of mesoionic compound (32 compounds altogether) have been measured.The values found are usually quite large (some <40,but most >5 and some >9D),which the authors state is consistent with their assigned mesoionic structures (drawn as 155).lZ0 It was not altogether clear how low a moment would have to be before it would be regarded as inconsistent with such a structure. An extensive paper describes the photochemistry of sydnones (156) and 1,3,4-oxadiazolin-2-ones (157).I2l The unusual sydnone (158)on irradiation forms a photoisomer which was shown by X-ray crystallography to have the interesting structure (159).lZ2 The unstable 1,3,4-oxadiazolines (160) are formed by cycloaddition of aryl-diazomethanes to perfluoroketones.This addition is in the opposite sense to that found in reactions between diazomethane and normal ketones (in which a new C-C M. Braun G. Biichi and D. F. Bushey J. Amer. Chem. Soc. 1978,100,4208. R. N. Hanley W. D. Ollis C. A. Ramsden G. Rowlands and L. E. Sutton J.C.S. Perkin I 1978,600. lZ1 M. MGky H. Meier A.'Wunderli H. Heimgartner H. Schmid and H. J. Hansen Helu. Chim. Acra 1978,61 1477. 12* H. Gotthardt F. Reiter A. Gieren and V. Lamm Tetrahedron Letters 1978 2331. Heterocyclic Chemistry 26 1 bond is formed) but is in accord with its reactions with C=S and C=N It is however not necessary to postulate that diazomethane (or its substituted derivatives) adopts any particular one of its resonance canonical forms in order to react as appears to be suggested to account for the formation of (161)from (162).'24 N-N RJ=p N-\ CH,N, [p-];=s -N_\ b-(J Ar 0 RF (160) (162) (161) R = Ar or Me RF= CF3 or CF2H The azidoquinoxaline dioxide (163)on heating gives two products both with o-quinonoid benzene rings.The first is a violet solid (164),which on further heating rearranges to an amber oil (165).'25 Benzyne and 2,1,3-benzoselenadiazoleform the benzisoselenazole (166) by addition of the two reactants in the sense as indicated.lZ6 Furoxans are thermally 0-0-[ak:e] 05;:0-a;x: I I 0-0-(163) (164) (166) (165) cleaved to nitrile oxides. Unless the ring is strained as for instance by fusion to a five-membered ring this reaction requires high temperatures when the nitrile oxide groups are isomerised to isocyanates.This potentially useful isocyanate-forming lZ3 N. Shimizu and P. D. Bartlett J. Amer. Chem. Soc. 1978,100,4260. lZ4 A.Martvon L. Floch and S. Sekretar Tetrahedron 1978,34 453. J. P. Dirlam B. W. Cue and K. J. Gombatz J. Org. Chem. 1978,43 76. '*' C. D. Campbell C. W. Rees M. R. Boyce M. I).Cooke P. Hanson and J. M. Vernon J.C.S. Perkin I 1978,1006. 262 A. J. Boulton reaction can be brought about at lower temperatures by sulphur dioxide catalysis when cycloaddition of SOz,and its elimination creates a more favourable pathway for the group ~earrangernent.~~’ Thioketone S-imides react with 1,3-dienes to give [2 + 4]cycloadducts (167) but with enol ethers [3 + 2]cycloadducts (168) are formed.The precise location of the substituents in the products is not known with certainty.128 Thioketene S-oxides form [3 + 2]cycloadducts (169) with imines which in some cases thermally rearrange to oxazolidinethiones (170).12’ Bistrifluoromethylthioketene reacts with mesityl azide to form the thiatriazoline (171). This loses nitrogen on heating perhaps transiently forming a thioketene S-imine but the product which is isolated is the 2,1-benzisothiazole (172); the fate of the lost methyl group was not determined.13’ (171) ( 172) When the dithiazole (173) is oxidised with rn-chloroperbenzoic acid (MCPBA) two products (174) and (175) are obtained in approximately equal amounts one of which has lost a t-butyl group. In this case it is suggested that the departing residue deposits 0 N-S HN-S; // 0’1MCPBA .Ic;.To + e’ / / / t t t (173) (174) (175) 12’ J.F. Barnes R. M. Paton P. L. Ashcroft R. Bradbury J. Crosby C. J. Joyce D. R. Homes and J. A. Milner J.C.S. Chem. Comm.. 1978 113. 12* T. Saito and S. Motoki Chem. Letters 1978 591. E. Schaumann J. Ehlers and U. Behrens Angew. Chem. Znternat. Edn. 1978,17,455. 130 M. S. Raasch J. Org. Chem. 1978,43,2500. Heterocyclic Chemistry a proton on the nitrogen atom as it 1ea~es.l~' The system of (175) is that formed on partial hydrolysis of Herz Another alkyl leaving group whose fate was determined is that in the aromatisation of the pyrazoline (176). On heating in xylene with triethylamine catalysis methane was evolved while the lithium salt [from (176) with BuLi] on heating eliminates methyl lithium.A similar dealkylation was involved in the aromatisation of the spiro-pyrazolidines (177).75 Me0,C H MeO,? - HUX (176) h177) X =H or CO2Me Many interesting developments were noted in the field of five-membered phos- phorus heterocycles. The phosphacymantrene (178)133 and pho~phaferrocene'~~ are claimed to be 'the first carbon-phosphorus 5eterocycles with a true aromatic chemistry'; certainly (178) undergoes conventional Friedel-Crafts acylation. 133 1,3-Benzazaphospholes (179) are formed from o-aminophenylphosphine and imin- oether hydrochlorides. Oddly P-phenyl and P-ethyl derivatives of the phosphine also produce the same compounds by loss of ROMe from the intermediate benz- azap hospholines.135 + R (178) (179) A series of tri- and tetra-azacycloalkanes with bridges of two and three CH groups between the N atoms has been prepared and reaction with hexamethyl phosphorous triamide studied. Whether or not compounds of type (180) or (181) are formed or whether in the case of the tetra-aza rings compoun.? (182) predominates depends on the sizes of the rings formed.'36 A hydroxyphosphorane with a P-H 13' Y. Inagaki R. Okazaki and N. Inamoto Chem. Letters 1978 1095. "* L. D. Huestis M. L. Walsh and N. Hahn J. Org. Chem. 1965,30,2763. 133 F. Mathey. A. Mitschler and R. Weiss J. Amer. Chem. SOC. 1978,100 5748; F. Mathey Tetrahedron Letters 1976,4155. 134 F. Mathey A. Mitschler and R.Weiss J. Amer. Chem. Soc. 1977 99 3537; F. Mathey J. Organo-metallic Chem. 1977,139 77. K. Isslieb R. Vollmer H. Oehme and H. Meyer Terruhedron Lerters 1978,441. (a) T.J. Atkins Tetrahedron Letters 1978,4331; (6)J. E. Richman and T.J. Atkins ibid.,p. 4333; (c)T. J. Atkins and J. E. Richman ibid. p. 5149. 264 A. J. Boulton bond -the covalent hydrate (183)-has been rep~rted.'~' A 'phosphoranoxide anion' (184)'38and a 'phosphoranide anion' (185)'39 have been described. Both tautomers (186)and (187)of the neutral molecule are observed by 31Pn.m.r. but the anion (184)is ~ymmetrical.'~~ With CF3S03H the phosphonium salt (188)is formed; this can be reduced (LiAlH4) to the anion (185) probably viu the intermediate phosphorane (189) which is also formed on protonation of (185).139 P3S03H The optically active spirosulphurane (190)was found to be configurationally very stable to racemisation not losing its activity even after 1hr at 210 "C.On oxidation it gave the corresponding sulphurane oxide which was reported to racemise very readily (AG' 46 kJ m~l-').'~~ Sulphuranes of type (191) have been prepared by cyclisation of 2-arylsulphinylisophthalic acids. The compounds with CH20H instead of COOH do not ~yclise.'~' Sulphurane anions (192)14*and (193)'43have been made. Methylation of (193)produces both 0-and S-alkylated products (194; R = Me) and (195).143 13' D. Houalla M. Sanchez R. Wolf and F. H. Osman Tetrahedron Letters 1978,4675. 138 1. Granoth and J. C. Martin J.Amer. Chem. SOC.,19?8,100 5229. 139 I. Granoth and J. C. Martin J. Amer. Chem. Soc. 1978,100 7434. P. Huszthy I. Kapovitz A. Kucsman and L. Radics Tetrahedron Letters 1978 1853. W. Walter B. Krische and J. Voss J. Chem. Res. 1978 (S) 332; (M) 4101. 14* W. Walter B. Krische G. Adiwijaja and J. Voss Chem. Ber. 1978,111 1685. P. H. W. Lau and J. C. Martin J. Amer. Chem. Soc. 1978,100,7077. Heterocyclic Chemistry +q;z +o ql-K0 + (194) (193) (195) Phenylene orthosulphite (196; R = H) has been looked at again,144 by "C and 'H n.m.r. At low temperatures the apparent symmetry is lost (below -80 "Cfor the 13C spectrum) an activation energy of ca. 38 kJ mol-' was estimated for the inversion process and ca. 46 kJ mol-' for a similar process in the 3-methylcatechol derivative (196; R=Me) (an 'unusually pure sample'!) which seems to exist in two isomeric forms (cis and trans),each undergoing fluxional processes.A trigonal bipyramidal geometry about the sulphur atom was suggested to explain the A related S'" heterocycle is the sulphurane (197).146The fused dithiolium salt (198) on (196) (197) (198) reduction formed a very stable and persistent free radical which showed no tendency to dimerise in The iodine heterocycles (199) and (200) have been as have the silicon and phosphorus compounds (201)149 and (202).''' Finally in this Section we have this year's Puzzle Corner. Maleic anhydride is refluxed in acetic acid with 2-aminopyridine followed by hydrolysis (reflux in 2M H2S04),to produce dimethyl-maleic anhydride in good yield.The imide (203) is the intermediate which is hydrolysed giving the anhydride according to the 144 cf Ann. Reports (B),1977,74 262. 145 B. A.Belkind D. B. Denney D. Z.Denney Y. F. Hsu and G. E. Wilson J. Amer. Chem. SOC.,1978 100,6327. 146 T.Kitazume and J. M. Schreeve J. Amer. Chem. SOC.,1978,100 985. 147 R.C. Haddon F. Wudl M. L. Kaplan J. H. Marshall R. E. Cais and F. B. Bramwell J.C.S. Chem. Comm. 1978,429;J. Amer. Chem. SOC.,1978,100,7629. 148 R.L.Amey and J. C. Martin J. Amer. Chem. Soc. 1978,100,300. 149 H.Watanabe K. Higuchi M. Kobayashi and Y. Nagai J.C.S. Chem. Comm. 1978,1029. 150 M.Baudler and E. Tolls 2. Narurforsch. 1978,33b 691. 266 A. J. Boulton (199) X=ICl (201) R =Ph X = SiMez (200) X=IFg (202) R =H X =PMe 0 0 0 (203) stoicheiometry required by the equation and regenerating the amine.The curious but impatient reader may find an elegant explanation for these results in ref. 151. 6 Six-membered Rings The kinetics of conformational inversion processes in saturated heterocyclic six- membered rings has been the subject of numerous reports and enlivened by occasional controversy. Ring-inversion and nitrogen-inversion commonly occur together and when an inverting nitrogen is adjacent to an oxygen atom its barrier is increased so that it is comparable with that of the ring-inversion. Compounds of this type e.g. 2-methyl-perhydro- 1,4,2-dioxazine (204) have been studied pre- vi~usly;’~~ however the conclusion that the Winversion barrier is lower than the ring-inversion is now challenged by another group.153 Nitrogen barriers comparable with or even higher than ring barriers are found for the novel perhydro-1,2,4- and 1,2,5-oxadiazine derivatives (205)’54 and (206).ls5 13C n.m.r. is now probably the M~N-X M~N? I 0-NMe (204) X=O (206) (205) X=NMe most powerful tool for conformational study being particularly useful when low barriers are involved as in the perhydro-l,2,5-oxadiazinesand -tria~ines,’~~ and a detailed account of its application to bridgehead diazadecalins has appeared. 157 Information on hexahydropyridazines from a more unusual source has been pro- vided by low-temperature cyclic voltammetry which is suggested to be a probe for M.E. Baumann and H. Bosshard Helv. Chim. Acra 1978,61 2751. R. A.Y.Jones A. R. Katritzky A. R. Martin and S. Saba J.C.S. Perkin ZI 1974 1561. F.G.Riddell M. H. Berry and E. S. Turner Tetrahedron 1978,34 1415. F.G.Riddell and E. S. Turner J. Chem. Research 1978,(S)476. Is’ A. R. Katritzky and R. C. Patel Heterocycles 1978,9,263;F. G. Riddell and E. S. Turner ibid. p. 267. V.J. Baker I. J. Ferguson A. R. Katritzky R. C. Patel and S. Rahimi-Rastgoo J.C.S. Perkin TI 1978 377. Is’ S. F. Nelsen and E. L.Clennan J. Amer. Chem. Soc. 1978,100,4004. Heterocyclic Chemistry 267 conformational measurements since the various conformers behave differently on electron-removal.15* From conformational equilibrium studies on the dithioacetals (207) and (208) (X=SMe and OMe) it has been concluded that there is a repulsive interaction between S and 0,and between S and S.In (209) however there is a net 0-0 attra~tion."~ The inversion at phosphorus is well known to be many orders of magnitude slower than that at nitrogen. The kinetics of the isomerisation of the cis and trans isomers of (210) have been followed the reaction parameters show an X .? Ph (210) unexpectedly large entropy of activation (AG* 147 kJ mol-' AS*193 J K-'mol-' at 164"C) with a modest preference for the Ph-equatorial (trans) isomer (AGO 1.2 kJ mol-') as expected.16* Although experimental evidence has shown that in non-polar solvents the 2- hydroxypyridine-2-pyridonetautomeric equilibrium swings somewhat towards the hydroxy-form comparison with results in the vapour phase (in which the hydroxy- form heavily predominates) suggested that the pyridone proportion is still anomalously high.It now appears that this is due to the effect of self-association of the pyridone in the condensed phase. Even in very dilute chloroform solutions the pyridone is very heavily self -associated. "' It seems likely that other equilibrium constants determined by apparently direct and reliable spectral methods may bear little relation to the simple monomer-monomer equilibria which they were thought to represent. In another study of 2- and 3-hydroxypyridines in acetonitrile-water mixtures the lactam or zwitterion proportions were found to increase with the water concentration which was attributed to preferential stabilisation of these tautomers by hydration.'62 Cope rearrangements in dihydropyran systems have been investigated.The thione (211) produces (212),'63 but the imines (213) on heatingappear to react in the enamine forms because the rearrangement products are the cyclohexenes (214).'64 Thermal rearrangement of 1-alkyl- 1,2-dihydropyridines generated from their azabicyclohexene valence bond isomers proceeds by electrocyclic ring-opening and 1,7-H-shift followed by recyclisation as illustrated for the 1-ethyl compound (215).16' S. F. Nelsen E. L. Clennan. and D. H. Evans J. Amer. Chem. Soc. 1978,100,4012. E. L. Eliel and E. Juaristi J. Amer. Chem. SOC.,1978,100,6114. I6O G. D. Macdonell K. D. Berlin J. R. Baker S. E. Ealick D. van der Helm and K.L. Marsi J. Amer. Chem. SOC.,1978,100,4535. '" P. Beak J. B. Covington and J. M. Zeigler J. Org. Chem. 1978,43 177. 0.B ensaude M. Chewier and J. E. Dubois Tetrahedron Letters 1978 2221. K. B. Lipkowitz and B. P. Mundy Tetrahedron Letters 1977 3417. lWB. P. Mundy and W. G. Bormann Tetraheifron Letters 1978,957. 165 I. Hasan and F. W. Fowler J. Amer. Chem. SOC.,1978 100 6696. Mecoo A. J. Boulton Mea M e aC,Hs Me NHR X I A 200°C 1 The 1,3-dipolar activity of 3-oxidopyridinium betaines has featured in these Reports on an earlier occasion.'66 The 5-methoxy analogues (216)have proved to be particularly reactive examples of this class of compound and they form adducts (across the 2,6-positions)with a wide variety of dipolarophiles.Singlet oxygen for instance gives the primary adduct (217) with (216; R = Ph) but with (216; R =H) the quinone (218) is obtained.167Flash vacuum pyrolysis allows valence isomers of 6-dialkylamino-1,3-0xazin-2-ones (219) to be isolated. These isocyanates (220) slowly revert to the heterocycles at room temperature.'68 A convenieot synthesis of 3-hydroxyisoquinolines and 2-substituted isoquinolin-3-ones (221) is by the cyclisation (H2S04)of N-benzyl-diethoxyacetarnide~.'~~ The bridged peroxide (222)decomposes on refluxingin oxygen-free benzene to generate the yellow unstable species (223) which can be trapped by maleic anhydride; otherwise it collapses to odibenzoylbenzene.I7' A new synthesis of 2,3,1-diazaborines has been reported by cyclising aldehyde tosylhydrazones with boron trichloride or tribromide (at 50-80 OC in CCl,) 166 Ann.Reports (B),1976,73 261.Y. Tamura M. Akita H. Kiyokawa L. C. Chen and H. Ishibashi TetrahedronLetters 1978 1751. P. W. Manley R. C. Storr A. E. Baydar and G. V. Boyd J.C.S. Chem. Comm. 1978,902. H. Fukumi and H. Kurihara Heterocycles 1978,9 1197. ''O 3. P. Smith and G. B. Schuster,J. Amer. Chem. Soc. 1978 100 2564. Heterocyclic Chemistry followed by hydrolysis. The example illustrated (224) is produced from 0-naph- thaldehyde with cyclisation in an unexpected dire~tion.'~' a-Lithiated nitrosamines if allowed to stand for some days form interesting tetrazine structures e.g. (225) from lithio-dirnethylnitro~amine.'~~ Diphenylthi-irene dioxide and azide ion react to form the thiatriazine dioxide (226).'73 The structures of these last two products were established by X-ray analysis and the molecular dimensions of the compounds (227) and (228) have been determined ~imi1arly.l~~ Me COMeMeQ*\ I Me PIl% Ph Me (226) (227) X=CH (228) X=N Cyclic sulphimides (229) have been prepared by reaction of amidines (230) with sulphenyl halides and N-chlorosuccinimide (NCS).With 4,4'-thiobismorpholine instead of the sulphenyl halide the product is (229; R=morpholino) which on heating gives the benzothiadiazine (23 1).'75 (230) (229) (231) Some interesting new cyclazines were reported from the bispyridinium salts (232) and (233). Dimethyl acetylenedicarboxylate (DMAD) when in excess condenses with (232) in the presence of sodium hydride to form (234) while acetic anhydride and (233) form (235).When (232) DMAD and NaH react in a 1 1:1 ratio a mixture of the red quinolizine (236) and its colourless valence isomer (237) are produced. 176 17' B. W. Miiller Helv. Chim. Acta 1978,61 325. D. Seebach R. Dach D. Enders B. Renger M. Jansen and G. Brachtel Helv. Chim. Acta 1978,61 1622. 173 B. B. Jarvis G. P. Stahly and H. L. Ammon Tetrahedron Letters 1978,3781. 174 T. Fujiwara T. Hombo K. Tomita Y. Tamura and M. Ikeda J.C.S. Chem. Comm. 1978 197. T. L. Gilchrist C. W. Rees and D. Vaughan J.C.S. Chem. Comm. 1978,1049. 176 G. G. Abbot D. Leaver and K. C. Mathur J. Chem. Res. 1978 (S)224; (MI 2850. 270 A. J. Boulton (232) R=H (234) R =R'= C02Me (233) R=Me (235) R =Me R1=H The diene (238)has been prepared as part of an attempt to produce the phosphorus analogue (239)of a nitro-compound.A Diels-Alder adduct was formed between (238)and an acetylenic ester but on pyrolysis the hoped-for fragment proved too unstable and polymerised at once.177 Another unsuccessful try was one to force a C=P bond into existence by Diels-Alder addition of (CF&C2 to 3-methyl-2-phosphanaphthalene;however the product (240)was too labile and lost MeCP which polymerised. 17' (238) (239) (240) There have been further interesting developments in arsenin (asabenzene) chem- istry. The rearrangement of 1-phenylarsenin-4-one noted kt year,'79 when ap- plied to the corresponding oxime (241)proceeds with an unexpected reduction to form the diacetylamine (242).18*Radical substitution (Ph2Hg heat) into 2-aryl-4- hydroxyarsenin gave the 1-phenyl derivative.This rearranges (Ac20/H') to the 2,6-diaryl-4-acetoxy-compound,hydrolysis of which gives a product which appears NOH fi3 H+ As I Ph (241) (242) 177 I. Segal and L. hew J. Amer. Chem. SOC.,1978,100,6394. T.C.Klebach L. A. M. Turkenburg and F. Bickelhaupt Tetrahedron Letters 1978 1099. 179 Ann.Reports (B),1977,74,277. G. Mark1 and J. B. Rampal Tetrahedron Letters 1978 1175. 17' Heterocyclic Chemistry 27 1 to contain both tautomers (243) and (244) in EtOH and CHCI,.'" Friedel-Crafts acylation (AcC1/AlCl3 -70 "C in CH2C12) of arsenin gave a 4 1mixture of the 4-and 2-acetyl derivatives.This is in striking contrast to the behaviour of pyridine in that the heteroatom here behaves effectively as a powerful activating opdirecting substituent.'82 n H (243) (244) Silabenzenes continue to evade isolation but the evidence for their transient formation must now convince all but the most sceptical. The method of thermal elimination of an ally1 group68 has been applied to compound (245) providing an intermediate which is in all probability (246) since it could be trapped by acetylenes to form (247).'83 7 Seven-membered and Larger Rings Matrix isolation experiments (in Ar at 8 K) have shown that on ultraviolet irradia- tion of various phenylnitrene and 2-pyridylcarbene precursors the aza- 1,2,4,6- cycloheptatetraene structure (248) is to be preferred to the aza-norcaratriene (249) in the schemes involving reactions of these species.184 Similarly 4-pyridyl- diazomethane forms 5-aza-l,2,4,6-~ycloheptatetraene(250).18' The evidence is based mainly on strong i.r. bands near 1895cm-'. Azatropolones (251) and (252) have been prepared from the photo-adduct (253) of phenylacetylene and 3-ethoxycarbonyl-2-phenyl-2-pyrroline-4,5-dione, by heating with or without prior photoisomerisation. Diazomethane produces a single 0-methyl ether from (25l),which has been examined by X-ray crystallography; (252) forms two isomeric ethers. The compounds readily rearrange in methanol to pyridine-2-carboxylic acid derivatives. 186 G. Mark1 and J. B. Rampal Tetruhedron Leffers 1978 1471."* A. J. Ashe W. T. Chan and T. W. Smith Tetrahedron Letfers 1978,2537. T.J. Barton and G. T. Burns J. Amer. Chem. SOC. 1978,100 5246. 0.L.Chapman and J. P.LeRowt J. Amer. Chem. SOC. 1978,100,282. ''' 0.L.Chapman R. S.Sheridan and J. P. LeRoux J. Amer. Chem. SOC.,1978,100,6245. lab T.Sano Y. Horiguchi and Y. Tsuda Heterocycles 1978.9,731. 272 A. J. Boulton (251) R=Ph,R=CO,Et (253) (252) R=CO,Et R=Ph The thienodiazepine (254) on heating forms the thienylpyrazole (255) probably via an initial 1,5-H-shift and rearrangement. On irradiation (254) forms a thieno- pyrazole (256) by biradical cleavage (of the 2,3-bond) and recombination. The mechanisms were studied by deuterium-labelling.'87 (255) (254) (256) The Cope rearrangement of the isomeric oxepin oxides (257) and (258) has been studied.The azo-compound (259) forms (257) specifically and this can be detected although it rapidly rearranges to the more stabie (258). In the presence of a catalytic trace of acid (257) forms the pyran (260) faster than it rearranges to (258) which with acid gives (261).lS8 The relief of strain which occurs on forming the azepine (262) from the cyclo- propane (263) is almost completely counterbalanced by the loss of imidate resonance at equilibrium ca. 75% of (262) is pre~ent."~ Imidate resonance is also important in determining the site of cyclopropanation (by CH2C12) of 2-methoxy- azocine dianions [e.g. (264)l:190.191 the products (265) and (266) all retain this structural element which is also present in the compounds (267) and (268) which T.Tsuchiya M. Enkaku and H. Sawanishi J.C.S. Chem. Comm. 1978,568. 18' W. H. Raststetter and T. J. Richard Tetrahedron Letters 1978 2995. lS9 L. A. Paquette and G. D. Ewing J. Amer. Chem. SOC.,1978,100 2908. 190 L. A. Paquette G. D. Ewing S. V. Ley H. C. Berk and S. G. Traynor J. Org. Chem. 1978,43,4712. 19' G. D. Ewing S.V. Ley and L. A. Paquette J. Amer. Chem. SOC.,1978,100,2909. 18' Heterocyclic Chemistry + Me MeQ M e OMe N-OMe (264) (265) (266) 1. 1 Me &e N-OMe MQMe OMe (267) (268) they form on thermal rearrangement although transiently lost in the monocyclic azonine intermediate^."^ The optical and kinetics of racemi~ation'~~ of the (non-planar) dibenzodiazocine (269) have been reported.The kinetics were followed by an (269) unusual method applicable to very small quantities of material involving periodic measurements on the pitch of spiral optical phenomena observed in cholesteric liquid crystal droplets. Several groups have reported the preparation of ma-analogues of the 1,5-methano-bridged cyclodecapentaenes. The key step in the synthesis of (270) is the cyclisation of (271) to (272).'94The isomeric system (273) has also been made with an alkoxy-group (OMe or OEt) present as indi~ated.'~~-''~ A variety of new synthetic techniques have been applied to the preparation of medium- and large-ring polyamines. Diborane reduction of the tetraketopyrazolo- pyrazoles (143) leads to cleavage of the N-N bond and formation of perhydro-diazocines.'" With suitable substituents R in (143) further aza-bridging could be J.M. Ruxer and G. SolladiC J. Chem. Res. 1978 (S)409; (M)4944. 193 J. M. Ruxer G. SolladiC and S. Candau J. Chem. Res. 1978 (S)82. 194 M. Schafer-Ridder A. Wagner M. Schwamborn H. Schreiner E. Devrout and E. Vogel Angew. Chem. Internat. Edn. 1978,17 853. 19' H.-J. Golz J. M. Muchowski and M. L. Maddox Angew. Chem. Internat. Edn. 1978,17,855. 196 W. J. Lipa H. T. Crawford P. J. Radlick and G. K. Helmkamp J. Org. Chem. 1978 43 3813. 274 A. J. Boulton -[ao] H (273) (272) introduced to form for instance (274)with three mutually bridged eight-membered rings.19' A rather spectacular macrocycle formation is the so-called 'zip reaction' in which the nitrogen of a lactam group is exchanged for another four atoms further along a chain under the influence of a strong base.198 When the amide carbonyl group of (275) fiinally reaches the terminal NH2 group the salt of the amide (276) is produced so the reaction stops at the bottom of its thermodynamic energy trough.'99 n (274) (275) Having displayed considerable versatility with cations crown ethers and cryptates have now turned their attention to anions.The bicyclic compound (277) when hexaprotonated forms stable complexes with linear triatomic anions such as N3-.200 Other anion receptors include macrocyclic guanidium salts with two and three cationic units.20* The polyamine cryptand (278) has a particular interest in heavy metal cations (Hg2+ Cd2+ and Pb2') which has led to the suggestion that compounds of this type may become of importance in therapeutic and environmental nn (277) (278) lg7 D.S. Kemp R. V. Punzar and J. C. Chabala Tetrahedron Letters 1978 547. 19* U. Kramer A. Guggisberg,M. Hesse a.nd H. Schmid Helo. Chim. Acta 1978,61 1342. 199 U. Kramer A. Guggisberg M. Hesse and H. Schmid Angew. Chem. Internat. Edn. 1978,17 200. J. M. Lehn E. Sonveaux and A. K. Willard. J. Amer. Chem. Soc. 1978,100,4914. '01 B. Dietrich T. M. Fyles J. M. Lehn L. G. Pease and D. L. Fyles J.C.S. Chem. Comm. 1978,934. Heterocyclic Chemistry 275 detoxification.202 The ability of tri- and tetra-aza-cycloalkanes with rings of 9-16 members to encircle a P"' atom has beeh referred to earlier136 (Section 5) and the synthesisof N-substituted derivatives of this type of compound has been The introduction of elements of dissymmetry and the question of 'chiral recog- nition' in crown ether complexes have been studied in several laboratorie~.~~-~~~ Polyether-bridged compounds have been prepared with chiral 1,l'-binaphthyl components.206 The importance of conformation in the association of crown ether (18-crown-6) derivatives with t-butylamine thiocyanate and with alkali metal chlorides has been An ion-selective crown ether azo-dye has been described.208 The porphyrin N-oxide (279) has been made by oxidation of octaethylporphyrin with hypofluorous acid.The oxygen atom is rather labile.209 The 'stretched porphy- rin' (280) has been synthesised.210 An interesting quinquedentate ligand (281) forms complexes of unusual geometry with transition metal ions.211 Me N \ N-N-3 N' Me (281) 'O' J.M. Lehn and F. Montavon Helv. Chim. Acra 1978,61 67. '03 M. Hediger and T. A. Kaden J.C.S. Chem. Comm. 1978,14. 2cu J. M.Lehn and C. Sirlin J.C.S. Chem. Comm. 1978 949. 'OS S. C. Peacock L. A. Domeier F. C. A. Gaeta R. G. Helgeson J. M. Timko and D. J. Cram J. Amer. Chem. Soc. 1978,100,8190. 206 E. P. Kyba G. W. Gokel F. de Jong K. Koga L. R. Sousa M. G. Siegel L. Kaplan G. D. Y.Sogah and D. J. Cram J. Org. Chem. 1977.42,4173. 'O' A. C. Coxon D. A. Laidler R. B. Pettman and J. F. Stoddart J. Amer. Gem. Soc. 1978,100,8260. '08 J. P. Dix and F. Vogtle Angew.Chem. Internat. Edn. 1978,17 857. '09 R. Bonnett R. J. Ridge and E. H. Appelman J.C.S. Chem. Comm. 1978,310. 'lo R. A. Berger and E. LeGoff Tetrahedron Letters 1978.4225. 211 M. M. Bishop J. Lewis T. D. O'Donoghue and P. R. Raithby J.C.S. Chem. Comm. 1978,476; M. M. Bishop J. Lewis T. D. O'Donoghue P. R. Raithby. and J. N. Ramsden. ibid. p. 828. 276 A. J. Boulton 8 Reviews Several valuable monographs have recently been published. Studies on 1-benzo-pyran systems,’12 on six-membered rings with three or more nitrogen atorn~,’’~ and the first part of a multi-volume work on quin01ines”~ are new additions to a well-known series. A volume on heterocyclic photochemistry has appeared,215 and also three more volumes on six-membered ring heterocycles.216 Specific ring systems which have been reviewed generally include the iso- benzofuran~,~’ pyrrol0[3,4-b]quinolines,”~ the indolizines,21 the 1,3-oxazine~,’’~ phenanthrolines,221 the quinoxalines,”’ and P-lactam~.’’~ Of interest to indole chemists is a review on ‘the spiroindolenine intermediate’ (in the Pictet-Spengler condensation and one on isatogens and in do lone^,"^ and one on the synthesis of pyrrolo[ 1,2-~]indoles.’’~ Other special aspects of specific ring systems include the 13Cn.m.r.of quinoli~idines,~’~ and ‘ring-modifying reactions of pyridines containing a quaternary nitrogen’,228 the latter including some interesting hitherto unpublished work of the Wageningen group. Personal accounts of studies on the conformation of hexahydropyrida~ines,’’~and on asymmetric C-C bond formation from chiral oxazoline~,~~~ have appeared.Reviews in which several ring systems are treated under a general heading include one on eight-membered rings with ten or more tr-electrons (‘tr-excessive heteroan- n~lenes’),~~’ and one which another concerned with the ‘aromatic a~apentalenes’,~~’ deals with cyclazines and related N-bridged ann~lenes.~~~ Heterocycles containing P-N-N linkages,234 and the Group V heterobenzene~,~~’ have been covered as have heterocyclic v-complexes of the transition metals.236 Further accounts of ”’ ‘Chromenes Chromanones and Chromones’ ed. G. P. Ellis (Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’) J. Wiley and Sons,London 1977,vol. 31.’13 H. Neunhoeffer and P. F. Wiley ‘The Chemistry of 1,2,3-Triazines 1,2,4-Triazines Tetrazines and Pentazines’ (Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’) Wiley -Inter-science New York 1978,vol. 33. 214 ‘Quinolines’ Part I ed. G. Jones (Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’) Wiley -Interscience New York 1977,vol. 32. ‘15 ‘Photochemistry of Heterocyclic Compounds’ ed. 0.Buchardt J. Wiley and Sons,New York 1976. ‘16 ‘Rodd’s Chemistry of Carbon Compounds’ 2nd Ed. ed. S.Coffey Elsevier Amsterdam and New York 1977,vol. IV part E; 1978,vol. IV part G part H. ’17 M. J. Haddadin Heterocycles 1978,9,865. ”* F.J. Swinbourne J. H. Hunt and G. Klinkert Adu. Heterocyclic Chem. 1978,23 103. 219 Z.Eckstein and T.Urbanski Ado. Heterocyclic Chem. 1978,23,1. 220 M. A. Khan and J. F. da Rocha Heterocycles 1978 9 1059. 221 L.A. Summers Adu. Heterocyclic Chem. 1978 22 1. 222 G.W. H. Cheeseman and E. S. G. Werstiuk Adv. Heterocyclic Chem. 1978 22 367. 223 A. K. Mukerjee and A. K. Singh Tetrahedron 1978,34 1731. 224 F.Ungemach and J. M. Cook Heterocycles 1978,9 1089. 225 S.P.Hiremath and M. Hooper Adu. Heterocyclic Chem. 1978,22,123. 226 T.Kametani and K.Takahashi Heterocycles 1978,9,293. 227 D.Tourw6 and G. Van Binst Heterocycles 1978,9,507. ’” H.C. van der Plas Heterocycles 1978 9 33. 229 S.F.Nelsen Accounts Chem. Res. 1978 11 14. 230 A. I. Meyers Accounts Chem. Res. 1978,11 375. 231 A. G.Anastassiou and H. S. Kasmai Adu. Heterocyclic Chem. 1978 23 55. 232 J.Elguero R. M. CIaramunt and A. J. H. Summers Ado. Heterocyclic Chem. 1978 22 183. 233 W. Flitsch and U. Kramer Ado. Heterocyclic Chem. 1978 22 321. 234 J. P. Majoral Synthesis 1978 557. 235 A. J. Ashe Accounts Chem. Res. 1978,11,153. 236 K.H. Pannell B. L. Kalsotra and C. Parkanyi J. Heterocyclic Chem. 1978 15 1057. Heterocyclic Chemistry personal research treat the chemistry of cryptate ligand~,’~~ and the design of macrocycles in the study of host-guest complexes.238 Reviews on aspects of heterocyclic reactivity include a very extensive account of the reactions of acetylenic esters with nitrogen-containing a consi- deration of quantitative aspects of the quaternisation of heteroaromatic and a study on the S,(ANRORC) me~hanism.~~’ There is also a detailed account of the ‘anil reaction’ whereby olefins are prepared by condensation of aldimines with heterocyclic (and other) methyl A review on the synthetic applications of malononitrile is of considerable interest to heterocyclic An obituary review of the chemical work of H.Schmid who died in 1976 takes pride of place in the Helvetica Chimica His posthumous papers still enrich the pages of that journal contributing largely to its heterocyclic content. 237 J. M. Lehn Accounts Chem. Res. 1978,11,49. 238 D. J. Cram and J. M. Cram Accounts Chem. Res. 1978,11,446. 239 R. M.Acheson and N. F. Elmore Ado. Heterocyclic Chem. 1978,23,263. 240 J. A. Zoltewicz and L. W. Deady Ado. Heterocyclic Chem. 1978 22 71. 241 H. C. van der Plas Accounts Chem.Res. 1978,11,462. 242 I. J. Fletcher and A. E. Siegrist Adv. Heterocyclic Chem. 1978 23 171. A. Fatiadi Synthesis 1978 165 241. 244 H. J. Hansen M. Hesse and W. von Philipsborn Helv. Chim. Actu 1978,61 1.

ISSN:0069-3030    

DOI:10.1039/OC9787500239

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

12 Alicyclic Chemistry By A. COX DepalZment of Chemistry and Molecular Sciences University of Warwick Coventry CV# 7AL 1 Introduction Reviews have been published on preparative aspects of vinyl cation chemistry with particular reference to their application to the synthesis of some cycloalkanones,' the preparative chemistry of cyclobutenedione and derivative~,~'~ the synthesis of carbocyclic spiro compound^,^ spiroc~njugation,~ conformational analysis of cyclo- hexa-l,4-diene~,~ metal-induced rearrangements of cyclopropyl olefins,' nucleo- philic eliminative ring fission' and aspects of prostaglandin chemistry.' 2 Synthesis Electrochemical reduction of aa'-dibromoalkanedioates containing alkoxycarbonyl groups at both termini has been shown" to lead to three- to seven-membered ring cycloalkane-l,2-dicarboxylicacid esters.Although the detailed mechanism has not yet been elucidated in the case of the dibromoglutaric ester the ratio of trans to cis isomers is affected considerably by solvent cathode material and electrolysis poten- tial. Three-membered Rings.-A highly enantioselective synthesis of cyclopro-pane derivatives has been reported' involving carbenoid type reactions between olefins and diazoalkanes and catalysed by bis[( -)-camphorquinone-a-dioxi-mato]cobalt(~~). Enantioselectivities of 88% optical yield and chemical yields of 90-95% have been recorded. The results suggest the intermediacy of a cobalt- carbene complex. A mechanistic study12 reveals an interesting sequence of reactions consisting of carbene complex formation enantioselective attack upon the olefin and epimerization during the cyclization.It has also been shown that a correlation ' M. Hanack Angew. Chem. Internat. Edn. 1978,17,333. 'A. H. Schmidt and W. Ried Synthesis 1978. 1. H.Knorr and W. Ried Synthesis 1978,649. A. P.Krapcho Synthesis 1978 77. H.Diirrand R. Gleiter Angew. Chem. Infernat.Edn. 1978,17,559. 'P. W. Rabideau AccountsChem. Res. 1978,11 141. S. Sarel Accounts Chem. Res.. 1978,11 204. * C.J. M. Stirling Chem. Rev. 1978 78 517. K. H. Gibson Chem. SOC.Rev. 1977,6,489. S. Satoh M.Itoh and M. Tokuda J.C.S. Chem. Comm. 1978 481. A. Nakamura A. Konishi Y. Tatsuno and S. Otsuka J. Amer. Chem. SOC.1978,100,3443. I' A. Nakamura A. Konishi R.Tsujitani M.-A. Kudo and S. Otsuka J. Amer. Chem. SOC.,1978,100. 3449. 279 280 A. Cox exists between the chirality of cyclopropane products and catalyst structure enabling selective production of the desired enantiomer. An extension has been made13 to the scope of the addition of carbenes to allenes to produce a variety of substituted methylenecyclopropanes. Both photolytically generated carboethoxycarbene as well as the copper carbenoid species have been studied and the intervention of perpendicular trimethylenemethane intermediates is discussed. Use has been made14 of the addition reactions of various carbanions of ketones and nitriles to chloromethyloxirane as a convenient synthesis of bifunctional vicinal cyclopropanes. Good yields are reported involving translcis ratios varying from 95 :5 to 10:90 depending on the substituents.The synthesis has been described” of a new class of compounds silylcyclopropyl ketones (Scheme 1). Methyl-Me,Si Me,SiCH=SMe, yo-R R Scheme 1 thiomethyltrimethylsilane is converted into its methiodide and following depro- tonation this gives an ylide treatment of which with a variety of ap-unsaturated carbonyl systems leads to the desired silylcyclopropyl ketones. In view of the ability of the Si atom to stabilize a P-carbonium ion these ketones may find use synthetic- ally. High yields are reported16 for the synthesis of activated cyclopropanes by the phase-transfer catalysed condensation of diethyl bromomalonate with suitable Michael acceptors.16 Although these syntheses appear to be of limited scope only products of 1,4-addition are formed.Reaction of methyl 4-bromocrotonate with lithium s-butyl- or t-butyl-mercaptide leads17 to the trans-cyclopropane (1). The R = s-butyl or t-butyl (1) course of the reaction is found to be critically dependent upon both solvent and mercaptide gegenion. The reaction occurs by Michael addition of mercaptide to methyl 4-bromocrotonate. It is suggested that the Li metal is co-ordinated to both S and ester carbonyl oxygen thereby holding the attacking S atom in close proximity to the @-carbon. The stability of this complex is solvent dependent and also dependent on the ability of the metal to co-ordinate effectively with the oxygen atom allowing more access to the &carbon.l3 X. Creary J. Org. Chem. 1978 43 1777. l4 G. Mouzin H. Cousse and B. Bonnaud Synthesis 1978 304. ’’ F. Cooke P. Magnus and G. L. Bundy J.C.S. Chem. Comm. 1978,714. J. M. McIntosh and H. Khalil Canad. J. Chem. 1978,56 2134. l7 R. D. Little and J. R. Dawson J. Amer. Chem. SOC.,1978 100 4607. Alicyclic Chemistry An interesting variation of a recent route to cyclopropanes has been announced" and involves electroreductive as opposed to metallic reductive elimination. For example electrochemical reduction of a citral derivative (Scheme 2) yields a mixture of the cyclopropane and acyclic hydrocarbon (85 :15in 8 1o/o yield). Any decrease in the amount of proton donors promotes enhancement of the formation of cyclo- propane at the expense of undesired acyclic compounds.Scheme 2 The photochemistry of gem-di-iodides has been investigated. l9 Irradiation of CH212in the presence of cyclohexene or other alkenes gives the corresponding cyclopropanes. This convenient method complements the familiar Simmons-Smith procedure but does not suffer from the disadvantageous sensitivity to steric effects; the transformation probably occurs via a H2C :I2 complex. A report has appeared2' describing the use of some rhodium carboxylates as catalysts for cyclopropanation of acetylenes (Scheme 3). Although the reaction fails for R' = CF3 and Ph yields of H CO,CH R'C=CR2 +N2CHC02CH3 Rhz(02CR3) +N, ' A R' R2 Scheme 3 86% are recorded for R' = C4H9. The results are consistent with a bimolecular carbenoid mechanism involving competitive cyclopropanation and insertion reac- tions.The intramolecular reductive coupling of dibenzoylalkanes with TiC13- LiA1H4 gives21 cyclopropenes in yields of between 40 and 60%. Four- Five- and Six-membered Rings.-A synthesis has been reported22 of a-methylenecyclobutanones involving the reaction with olefins of methyl(pheny1thio)- keten generated in situ by dehydrochlorination of a-(pheny1thio)propanoyl chloride with triethylamine. All of the cyclobutanones formed contained an endo-phenylthio group suggesting a concerted [2 +21 cycloaddition mechanism. Silyl ethers are found to react23 readily with dichloroketene a compound generated from trichloroacetyl chloride and activated zinc to afford good yields of cyclobutanones (Scheme 4).Mild acid hydrolysis of the siloxycyclobutanones leads to the corresponding 3-hydroxydichlorocyclobutanones. T. Shono Y.Matsumura S. Kashimura and H. Kyutoku Tetrahedron Letters 1978 1205. l9 N. J. Pienta and P. J. Kropp J. Amer. Chem. SOC.,1978,100,655. 2o N. Petiniot A. J. Anciaux A. F. Noels A. J. Hubert and Ph. Teyssie Tetrahedron Letters 1978,1239. 21 A. K. Baumstark C. J. McCloskey and K. E. Witt J. Org. Chem. 1978 43 3609. 22 T. Minami M. Ishida and T. Agawa J.C.S. Chem. Comm. 1978 12. 23 L.R. Krepski and A. Hassner J. Org. Chem. 1978,43,3173. 282 A. Cox Scheme 4 Continued interest is shown in the use of oxycyclopropanones in synthesis. In particular (*)-grandisol(2) has been from 4-methoxy-3,6,6-tri-methylcyclohexa-2,4-dienone by a procedure involving regiospecific cyclo- propanation of the dienone acid-catalysed hydrolytic rearrangement of the product and opening of the five-membered ring of the resultant bicyclo[3,2,0]heptanone system.A three step synthetic sequence of a cyclopentenone has been described25 (Scheme 5) also involving a p-oxycyclopropyl ketone and this has been used to -0 Scheme 5 prepare a number of natural products including a prostanoid intermediate (&)-a-cuparenone and (*) -p-vetivone. It is reported26 that epoxysulphones 0 /\ PhS02(CH2),CH-CH2 (n= 1or 2) react with CH3MgI in THF to give 3-phenyl- sulphonylcyclobutanols and 3-phenylsulphonylcyclopentanols.Yields are often in excess of 90% and oxidation of the product by the Jones reagent followed by treatment with triethylamine leads to 3-substituted cyclobutenones and cyclopent-2- enones.A new facile route to functionally substituted cyclopentenones has been described2' which starts from ethyl p-(1-pyrrolidiny1)acrylate (Scheme 6). By use of t-butyl-lithium this is almost quantitatively transformed into the P-alkoxycar- 24 E. Wenkert D. A. Berges and N. F. Golob J. Amer. Chem. Soc. 1978,100 1263. 25 E. Wenkert B. L. Buckwalter A. A. Craveiro E. L. Sanchez and S. S. Sathe J. Amer. Chem. Soc. 1978 100,1267. 26 B.Corbel J. M. Decesare and T. Durst Canad. J Chem. 1978,56,505. 27 R.R.Schmidt and J. Talbiersky Angew. Chem. Internat. Edn. 1978,17 204. Alicyclic Chemistry 0 Scheme 6 bonylvinyl-lithium reaction of which with @-unsaturated carbonyl compounds leads to functionalized cyclopent-2-en-1 -ones.Electrolysis of the anion of 3-methoxycarbonyl-7-oxabicyclo[2,2,l]heptane-2-carboxylic acids gives2* the 7-oxabicyclo[2,2,l]heptyl-2-cation,a species otherwise difficult to obtain (Scheme 7). Wagner-Meerwein rearrangement into the 2-oxabi- cyclo[2,2,l]heptyl-3-cation occurs by virtue of the participation of the oxygen atom 0 0 &C02CH3coy -2c0,-2e+ fiC0*CH R R -co I R Scheme 7 (R= H or Me) T. Akiyama T. Fujii H. Ishiwari T. Imagawa and M. Kawanishi TetrahedronLetters 1978 2165. 284 A. Cox and this sequence provides a novel stereoselective synthesis of 1,2,3-trisubstituted cyclopentanes.A significant feature of this route is that each substituent is present in a different oxidation state.Reaction of a diethyl alkylidenemalonate with an alkynyl bromide and zinc followed by heating and subsequently by hydrolysis leads2' to a good yield of a dialkyl cyclopent-2-ene-l,l-dicarboxylate(Scheme 8). It is possible that the product arises by thermal cyclization of the intermediate (3)for which supportive i.r. evidence is available. R' C0,Et R2)!?(C02Et (3) Scheme 8 A new method has been reported3* for the preparation of 2,2-dialkylcyclo- pentane-1,3-dione. The procedure uses intramolecular oxidative coupling of di- lithium enolates of 3,3-dialkylpentane-2,4-dioneby CU(OSO~CF~)~ and is charac- terized by the ready availability of the starting materials and experimental simplicity.Functionalized spiro [4 n]ring systems can also be elaborated by this method. Reaction of ketones with 1,l-dichloroallyl-lithium leads to the dichlorohomoallyl alcohol (4) which following acid dehydration and solvolysis gives the chloro- pentadienyl cation (5). Thermal conrotatory ring closure of this cation proceeds in excellent yield (Scheme 9). This method3' is applicable to both cyclic and acyclic ketones and is of particular use for cyclopentenone annulation; some regioselectivity seems to occur. It is reported3* that epoxy ketone (6) on treatment with hydrazine in methanol undergoes cyclization to the hydrindenol (7) in 85% yield. Substitution on the side-chain double bond does not appear to be crucial and the cyclization is also successful with acyclic systems (Scheme 10).This method can be modified for the preparation ofsix-membered rings as demonstrated by the cyclization of epoxide (8). Two serious mechanistic possibilities have been suggested concerted collapse of the vinyldiazene (9) and decomposition of the diazene to give a radical (lo) which then adds to the double bond. Eight-membered Rings.-Treatment of benzocyclo-octene with one mole of bromine results in the known 5,6-dibromide which on reaction with 10 molar equivalents of KOBu' leads to 67% of 7-t-butoxybenzocyclo-octene. This implies the intermediacy of 6,7-didehydrobenzocyclo-octene,a cumulene which has however proved to be too unstable for isolation or independent trapping.33 29 B.Bellassoued Y. Frangin and M. Gaudemar Synthesis 1978 150. 30 Y. Kobayashi T. Taguchi and T. Morikawa Tetrahedron Letters 1978 3555. 31 T. Hiyama M. Shinoda and H. Nozaki Tetrahedron Letters 1978 771. 32 G. Stork and P. G. Williard J. Amer. Chem. SOC., 1977,99 7067. 33 H. N. C. Wong T.-L. Chan and F. Sondheimer Tetrahedron Letters 1978,667. Alicyclic Chemistry 'yo LiCCI,CH=CH; R2 R2 Scheme 9 (8) OH OH v-HC < H (10) (9) Scheme 10 286 A. Cox A new annulating procedure has been announced34 involving the electrophilic addition of dichloromethyl methyl ether to dienes. Lewis acid catalysed conden- sation with 2,5-dimethylhexa-1,5-dienefollowed by treatment with base leads to a mixture of dimethylcycloheptatrienes.A related condensation with cyclo-octa- 13-diene yields a stereoisomeric mixture of dichloro-9-methoxybicyclo[3,3,1] nonanes. In an improved synthesis3’ of cyclo-octyne treatment of 4,5,6,7,8,9-hexahydro-cyclo-octa-1,2,3-thiadiazolor 4,5,6,7,8,9-hexahydrocyclo-octa-1,2,3-selenadiazol with butyl-lithium at low temperature results in up to 85% of the cyclo-octyne. A similar thermolysis of 1,2,3-~elenadiazoles has been to prepare cyclo-oct- 1-en-3-yne. Comparison of the 13C-n.m.r. chemical shifts with those of the unstrained cyclododecyne shows that ring strain causes an overall downfield shift of the signals. In this series the A6 values of the sp carbons appear to be capable of serving as a direct experimental measure of ring strain.Medium Ring Compounds.-It has been reported3’ that photolysis of the tri- cyclodecanone (11) leads to a mixture of dienes cis,cis-cyclonona-l,4-dieneand the previously unknown cis,trans-cyclonona-1,4-diene.Although the structural con- straints of (11)disfavour concerted processes they do permit a biradical mechanism to operate with selective formation of the trans double bond. This mechanism is based on stereoelectronic controlled fragmentation of an intermediate acyl cyclo- propyl radical to the isomeric trans-homoallylic species. A new synthesis of medium ring cycloalkene-1-carboxylic acids has been announced.38 The E isomers of cyclodecene-1-carboxylicacid and the E and 2 isomers of cycloundecene-1-carboxylic acid and cyclododecene- 1-carboxylic acid have been synthesized by aqueous alkaline hydrolysis of the corresponding 4-chloro- 3,4-poly(methylene)-2-pyrazolin-5-ones.Although the 2 isomer predominates determination of thermodynamic data show that for isomerization of the E/Z-cycloundecene-1-carboxylicacid the E isomer is the more stable.Annu1enes.-A synthesis has been reported3’ of the cis,cis,cis,trans-[ 9lannulene anion by reaction of 9-anfi-chloro-cis-bicyclo[6,l,O]nona-2,4,6-triene with alkali metals in THF. The conformational mobility of the compound has been investi- gated4’ and at three different temperatures by deuterium equilibration saturation transfer and dynamic n.m.r. spectroscopy. Almost identical activation enthalpies ” C. F. Garbers H. S. C. Spies H. E. Visagie J. C.A. Boeyens and A. A. Chalrners Tetrahedron Letters 1978 81. ’’ H. Biihl H. Gugel H. Kolshorn and M. Meier Synthesis 1978 536. 36 H. Petersen H. Kolshorn and H. Meier Angew. Chem. Internat. Edn. 1978,17 461. ’’ I. M. Takakis and W. C. Agosta Tetrahedron Letters 1978 2387. 38 A. Silveira Y. R. Mehra and W. A. Atwell J. Org. Chem. 1977 42 3892. 39 G. Boche H. Weber D. Martens and A. Bieberbach Chem. Ber. 1978,111 2480. 40 G. Boche H. Weber and A. Bieberbach Chem. Ber. 1978,111 2833. Alicyclic Chemistry 287 were found. It is concluded that the mechanism of topomerization probably doesnot involve reversible valence isomerizations of the corresponding all trans-anion. The isomerization of the cis-cis,cis,trans-[9]annulene anion into the thermodynamically more stable all-cis-[9lannulene anion has been studied41 kinetically under different conditions.It is catalysed by acids and also by alkali metals and a lower limit of 145.6 kJ mol-' found for the thermal isomerization. Dienyne ketones such as 2,2-dimethyl-7-t-butylnona-4,6-dien-8-yn-3-one give4* the corresponding tetrasubstituted 14-membered cyclic glycols on treatment with KOH in liquid NH3. Reaction of the cyclic glycols with tin(I1) chloride in organic solvents saturated with HCl affords the strongly diatropic tetrasubstituted bis- dehydro[ 14lannulenes. Using an already published method43 naphtho[2,3-i]-5,14-dimethyl-1,3-bisde-hydro[ 141annulene and nap h tho[ 1,2- i]- 5,14-dime thyl- 1,3-bisdehydro[ 14lannulene have been ~ynthesized.~~ These compounds are both analogues of anthracene and phenanthrene in which a terminal 6r-ring has in a formal sense been expanded to a 14r ring.Inspection of the 'H n.m.r. parameters of these two naphthodimethylbis- dehydro[ 14lannulenes reveals that the phenanthrene analogue is more diatropic than the anthracene analogue. This can be explained simply on the basis of KekulC structures. The synthesis of 1,6-methanofluorene and 9-methyl-1,6-methanofluorene and their anions has been acc~mplished.~~ By use of 'H n.m.r. the anions were shown to be delocalized aromatic systems existing in the 'cyclo- heptatriene' rather than norcaradiene form. Thus the anions exhibited electron delocalization over the entire r-system but a decided downfield shift of bridge protons relative to those in the methanoindenyl anion.The synthesis of 3-methoxy-1,5-methano[ 101annulene has been achieved46 and its 'Hn.m.r. spectrum measured. Comparison with the 'H n.m.r. spectrum of 1$-methano[ 101annulene reveals striking similarities and argues against any significant difference in the ability of the two r-systems to support an induced diamagnetic ring current. It is therefore,-concluded that both ring systems are of comparable aromatic character. A study of the molecular structure of 5,8,16,19-tetra-t-butyl-6,17,23-trisdehydro[ 10,10,2][ 14]annuleno[ 14lannulene has been ~ndertaken~~ to deter- mine if the r-electron delocalization in this compound is located within two separate 14-carbon ring systems or whether it embraces the entire 22-carbon ring.Measure- ment of bond distances show the former to be the correct model. Related work describes4* the preparation of trisdehydro[ 14,10,2][ 14]annuleno[ 18lannu- lene a compound consisting of two different (4n +2)-membered rings. The n.m.r. parameters of this compound reveal that it is strongly diatropic. Interestingly there is a gradual high-field shift of outer protons with increasing distance from the bridge and the same trend is observed with the inner protons of the 18-membered ring. 41 G. Boche and A. Bieberbach Chem. Ber. 1978,111,2850. 42 K. Fukui T. Nomoto S. Nakatsuji S. Akiyama and M. Nakagawa Bull. Chem. SOC.Japan 1977,SO 2758. 43 N. Darby T. M. Crisp and F. Sondheimer J. Org. Chem. 1977,42 1960. 44 T.C.Walsgrove and F.Sondheimer Tetrahedron Letters 1978,2719. 45 R. J. Hunadi and G. K. Helmkamp J. Org. Chem. 1978,43,1586. 46 L.T.Scott and W. R. Brunsvold J. Amer. Chem. SOC.,1978,100,4320. 47 Y. Kai N. Yasuoka N. Kasai S. Akiyama and M. Nakagawa Tetrahedron Letters 1978 1703. 48 S. Nakatsuji S. Akiyama and M. Nakagawa Tetrahedron Letters 1978 3723. 288 A. Cox These observations are difficult to understand if the ring current is confined to the periphery. Another trisdehydro[4tn +2]annuleno[4n‘ +21 annulene which has been s~nthesized~~ and examined spectroscopically is trisdehydro[ 18,10,2][ 14lannu- leno[22]annulene. As with the [18]annulene discussed above the signals of both the inner and outer protons in the 22-membered ring move to higher field as the distance from the common bond is increased.This can be explained in terms of an indepen- dent current being induced in each ring as is assumed in polycondensed benzenoid systems. Trisdehydro[ 14,14,2][ 18]annuleno[ 18lannulene has been reported” to be fairly stable and the electronic spectrum of this 30~-electron system found to show a close similarity with the analogous trisdehydror 10,10,2][ 14]annuleno[ 14lannulene. The n.m.r. spectrum reveals a strong diatropicity and once again displays the remarkable characteristic of a gradual high-field shift of all signals with increasing distance from the bridge. The synthesis and properties of l0-methylbenzo[d]-6,8-bisdehydro[151-annulenone (12) and 12-methylbenzo[ f]-8,1O-bisdehydro[ 1Slannulenone (13) have been ann~unced.~~ The electron absorption spectra are similar to one another OH OH indicating that the position of the benzene ring has little effect on the conjugation between the benzene nucleus and the bisdehydro[ 1Slannulenone skeleton.The n.m.r. shows that both compounds are atropic but similar measurements on the analogous protonated species show them to be diatropic and that they can be represented by delocalized formulae. Aromaticity in annulenoannulenes has been studied5*by several different theoretical approaches. The main conclusion is that the aromaticity is determined by the nature of the fused rings rather than by the size of the periphery. Po1ycyclics.-The preparation and properties of the highly strained olefin bicy- clo[2,2,0]hex-l(4)-ene have been rep~rted,’~ Controlled current electroreduction of the bromochloride (14) in DMF at -14°C gives volatile effluents which were Br 49 S.Nakatsuji S. Akiyama and M. Nakagawa Tetrahedron Letters 1978 1483. 50 M. Osuka Y. Yoshikawa S. Akiyama and M. Nakagawa Tetrahedron Letters 1977 3719. 51 J. Ojima and Y. Shiroishi Bull. Chem. SOC.Japan 1978 51 1204. ” B. A. Hess L. J. Schaad and I. Agranat J. Amer. Chem. SOC.,1978,100,5268. 53 J. Casanova J. Bragin and F. D. Cottrell J. Amer. Chem. SOC.,1978,100 2264. Alicyclic Chemistry 289 fractionally collected in cold traps. The substance obtained at -95 "C is the desired product and is found to be extremely reactive having t~< 10 s at -23 "C.Although the olefin reacts with cyclopentadiene at temperatures below those necessary for polymerization it fails to undergo cycloaddition with 2,3-dimethylbuta-1,3-dienein CD2C12 solution.The 13C n.m.r. displays an unusual downfield shift of the olefinic carbon suggesting a tendency toward allene-like sp character. Unlike 2,3,4-tri-t-butylcyclopentadienone,which on irradiation cyclizes to 'housenone' irradiation of tetra-t-butylcyclopentadienone(A = 254 nm) does not undergo C-2/C-5 bridge formation but rather leads to tricyclopentanone the criss-cross addition product (15). On prolonged irradiation this leadss4 to a hydro- carbon whose spectroscopic properties are in complete agreement with those expected for tetra-t-butyltetrahedrane (Scheme 11).The stability of this compound hu +++ 0 0 (15) Scheme 11 is attributed to the fact that any attempt at bond lengthening as a precursory step to bond cleavage is resisted because movement apart of any two t-butyl groups is opposed by the others.A tetrahedral structure permits the four substituent groups to adopt a regular spherical distribution and hence a maximum separation. Scheme 12 Model calculations have been described" discussing the possible collapse of bicyclobutan-2,4-diyl to tetrahedrane and allied experimental works6 shows that irradiation of some bicyclobutane derivatives offers little hope of access to tetra- hedrane. A report has been presented" summarizing both the theoretical and experimental approaches towards a synthesis of tetralithiotetrahedrane.Irradiation of dilithioacetylene in liquid NH3 at -45 "C leads to a compound having a 13C n.m.r. displaying a singlet (8 57.2) consistent with the expected sp3 hybridization of the tetrahedrane carbon and evaporation of the NH3 yields a product which by field desorption mass spectrometry is concluded to be C4Li4. Ab initio MO calculations indicate that face-centred tetralithiotetrahedrane (16) is 273 kJ mol-' more stable than the corresponding structure bearing the Li atoms at the vertices and this is " G. Maier S. Pfriem U. Schiifer and R. Matusch Angew. Chem. Internat. Edn. 1978,17,520. 55 M. C.Bohm and R. Gleiter Tetrahedron Letters 1978 1179. 56 G.Maier H. P. Reisenaure and H.-A. Freitag Tetrahedron Letters 1978 121. " G.Rauscher T. Clark D. Poppinger and P.von R. Schleyer Angew Chem. Internat. Edn. 1978,17 276. 290 A. Cox Li attributed to stabilization of the tetrahedrane 'bent bond' orbitals by Li. The nature of the photochemical process involving C2Li2 is at present unclear. Stimulated by the isolation of spiro[4,5]decanes possessing interesting biological activity a new general method (Scheme 13) for preparing this system has been anno~nced.~' Although yields are only moderate the reaction appears to be especially suited for the synthesis of 2-alkyl spiro[4,5]decane sesquiterpenes. For example when the sodium salt of a-formycyclohexanone (17) and (18)are allowed to react in (Me2N),P0 a spiro keto ester is produced as the major non-phosphorous- containing compound. The reaction has been applied to the total synthesis of (+)-P-vetivone (+)-p-vetispirene and (+)-a-vetispirene.,CO,Et BF,- - C0,Et+Q (17) (18) Scheme 13 A novel synthesis of spiro[4,5]deca-6,9-dien-2,8-dionehas been reported59 involving the intramolecular cyclization of phenolic a-diazoketones in the presence of copper(1) halides (Scheme 14). Evidence is presented to show that catalytic decomposition proceeds uit 3 norcaradiene. 0 ?H OH 0 li 8-RR R 0 "OQ L Scheme 14 (R=H or Me) W. G. Dauben and D. J. Hart J. Amer. Chem. SOC.,1977,99,7307. 59 C. Iwata M. Yamada Y. Shinoo K. Kobayashi and H. Okada J.C.S. Chem. Cornrn. 1977,888. Alicyclic Chemistry 291 As part of a programme to synthesize a molecule displaying neutral homoaroma- ticity the synthesis of elassovalene 2a,8b-dihydrocyclopent[cd]azulene (19) its Cr(C0)3 complex and its 5-and 6-methoxy derivatives was undertaken.60 Measurements of the ‘H- 13C-n.m.r.U.V. and p.e. spectra together with the diamagnetic susceptibility reveal that at least some small degree of homoaromaticity is present in the bridged cycloheptatriene part of their structure. A full paper has appeared6’ describing the use of multiple Diels-Alder cycloaddition reactions (of the domino or pincer type) in the construction of highly condensed alicyclic frameworks such as hexahydro-3,4,7-methenocyclopenta[a]pentalene (20) octahydro-3,6-dimethylenedicyclopenta-[cd,ghlpentalene (21) triquinacene(22) and a number of previously unknown (CH), isomers.The results suggest that there is considerable potential for the synthesis of highly condensed carbocyclic structures by the use of multistage cycloaddition reactions of 0-coupled cyclopolyolefins. The synthesis has been described6* of a tetracyclo[5,5,1 ,04.13,010,*3]tride~ane-tetraone (23) for which the generic name ‘staurene’ has been proposed. Generality has been an aim of the work with the immediate objective being the synthesis of the diketo-acid (24) by means of the reaction between 3-ketoglutarate and 1,2-dicar- bony1 compounds. H02CvC0,H H 6o L. A. Paquette C. C. Liao R. L. Burson R. E. Wingard,jun. C. N. Shih J. Fayos and J. Clardy,J. Amer. Chem. SOC.,1977,99,6935. L. A. Paquette M. J. Wyvratt H. C. Berk and R. E. Moerck J. Amer.Chem. SOC.,1978,100,5845. 62 R.Mitschka J. M. Cook,and U. Weiss J. Amer. Chem. SOC.,1978,100,3973. 0-0 292 A. Cox A new simple route to the [4,l,l]propellane system has been De-hydrohalogenation of. 1-chlorotricyclo[4,1 ,0,02*7]heptane in the presence of anthracene using lithium 2,2,6,6-tetramethylpiperidide leads to 9,10-dihydro-9,10- (1,7-tricyc10[4,1,0,02*7]heptano)anthracene. Between 160 and 180 "C this cleanly rearranges to 9,10-dihydro-9,10-[2,7-(3-methylenecyclohex-l-eno)]anthracene. The thermal rearrangement probably proceeds uia a retro-carbene ring opening of the bicyclo[ 1,l ,O]butane unit. Two hitherto unknown members of the tricyclic C10H16 cage compounds anti-and syn-tricycl0[4,2,1 ,12qdecane have been ~ynthesized.~~ These compounds are of interest because of their structural relationship to adamantane.A new approach to the synthesis of diamondoid hydrocarbons has been de~cribed.~' The method which may serve as either a single or double homologation has been used to synthesize anti-tetramantane but it may be applicable generally to higher members of the series. The sequence employs a keto-carbenoid insertion reaction to attach one or two cyclopentane rings to the diamantane periphery and this is followed by an unusual gas phase rearrangement-cyclization on a platinum-silica catalyst. 3 Stereochemistry An improved force field for molecular mechanics calculations of the structures and energies of hydrocarbons has been reported.66 With the aid of one-fold and two-fold rotational barriers a solution was achieved to the problem of obtaining a sufficiently large gauche butane interaction energy while keeping the hydrogens small enough for good structural predictions.For a varied list of hydrocarbons the results compared favourably with those obtained experimentally. Based upon MO cal-culations an analysis has been pre~ented~~ of l,3(non-bonded) carbon-carbon interactions in the cyclobutane series. The results suggest that this effect is dominant and that along with Baeyer strain these are the main factors determining the total strain of cyclobutanes and account for many of their exceptional properties. In a study6' of the conformational analysis of tertiary cycloalkyl (c6 c7 c,) carbocations it has been shown that tertiary cyclohexyl cations have a twist-boat ground state which is 2 kJ mol-' more stable than the chair.The tertiary cycloheptyl cation is fluxionally mobile but the methoxycyclo-octyl cation has an unsymmetrical chair-twist-boat conformation. Other cations are also discussed. A report has been made6' of the use of the lanthanide-induced shift reagent Eu(fod) in the direct determination of the solution structure of the conformationally mobile system cyclohexanecarbonitrile. The results show that the conformation with an equatorial cyano group exists to an extent of 54% in good agreement with earlier w~rk.~~,'~ 63 U. Szeimies-Seebach and G. Szeimies J. Amer. Chem. SOC. 1978,100 3966. 6A B. Ernst and C. Ganter Helu. Chim. Acta 1978,61 1107. 65 W.Burns M. A. McKervey T. R. B. Mitchell and J. J. Rooney J.Amer. Chem. SOC. 1978,100,906. 66 N. L. Allinger J. Amer. Chem. SOC.,1977,99 8127. 67 N. L. Bauld J. Cessac and R. L. Holloway J. Amer. Chem. SOC., 1977,99 8140. " R. P. Kirchen and T. S. Sorensen J. Amer. Chem. SOC., 1978 100 1487. 69 D. J. Raber M. D. Johnston and M. A. Schwalke J. Amer. Chem. SOC. 1977,99 7671. 'O J. A. Hirsch Topics in Stereochem. 1967,1 199. 71 For example B. Rickborn and F. R. Jensen J. Org. Chem. 1962,27,4606. Alicyclic Chemistry 293 In an investigation of the temperature dependence of the e.s.r. spectrum of the cyclohexadienyl radicals (25) generated by hydrogen abstraction from the cor- responding cyclohexa- 1,4-dienes it is shown7* that the cyclohexadienyl radical is planar but that it vibrates between bent structures.The vibrational spectrum of cycloheptanone has been examined73 and the results of the analysis show that cycloheptanone is a non-rigid pseudorotating molecule having a twist-chair struc- ture. Calculation of the pseudorotation energy surface indicates that the symmetric twist-chair conformer and the two adjacent twist chairs have almost the same energy. The other twist chair forms are separated by barriers of different heights. H (25) a; R=H b; R=SiMe3 Molecular mechanics calculations have been performed74 to fit the vibrational and rotational spectra of cyclo-octanone. In this way the lowest energy conformation was shown to be the boat-chair with the carbonyl in the 3-position (position 1 is the symmetric position at the chair end).The p.e. surface of this molecule emerged as being very complex and the various boat-chairs shown to interconvert by pseudoro- tation with barriers of about 33.5 kJmol-’. Use has been made” of dynamic n.m.r. spectroscopy and iterative strain energy calculations to determine the confor- mational properties of cis,cis-cyclo-octa- 1,4-diene. This work shows that the compound exists as a mixture of twist-boat (flexible) and boat-chair (relatively rigid) conformations having nearly the same energies. The calculated barrier to intercon- version is 37.6 kJ mol-’. It is of interest to note that since the interaction of the r-orbitals of the double bonds is mainly through space in the boat-chair and largely by hyperconjugative interaction via 3-methylene in the twist-boat this should have significance for the interpretation of the photoelectron spectrum.The same investigative techniques have been applied76 to probe the confor- mational features of cyclonona-1,2-diene cycl~nona-1,2,6-triene (26) and cyclo- deca-1,2,6,7-tetraene. The first compound exists in solution as a mixture of two conformations and undergoes two conformational processes a ring pseudorotation of the major conformation leading to time-average Czsymmetry and interconversion of the major conformation with the minor (symmetrical) conformation. The second compound exists as an unsymmetrical conformation that can undergo a strongly hindered ring pseudorotation (Scheme 15). The ground-state conformation of (*)-cyclodeca-1,2,6,7-tetraene is found to have a ‘non-intersecting’ two-fold axis of symmetry which is not maintained during conformational interconversions.72 M. Kira and H. Sakurai J. Amer. Chem. SOC.,1977,99,3892. 73 D. F. Bocian and H. L. Strauss J. Chem. Phys. 1977,67 1071. 74 T. C. Rounds and H. L. Strauss J. Chem. Phys. 1978,69,268. ’’ F. A. L. Anet and 1. Yavari J. Amer. Chem. SOC.,1977,99,6986. 76 F. A. L. Anet and I. Yavari J. Amer. Chem. SOC.,1977,99 7640. 294 A. Cox (26) Scheme 15 A study has been made77 of the conformational changes induced by europium shift reagents in medium ring 3-methoxycycloalkanones. The H2-H3 coupling constants which are approximately equal for trans and cis protons in the free cyclo-octanone show a marked change on addition of shift reagent consequent on bidentate co-ordination of the shift reagent.Reduction in ring size (c8+C7-+C,) induces a series of spectral changes consistent with a reduction of bidentate co-ordination. Molecular mechanics calculations have been to assess the relative stabilities of the conformers of humulene. The results show that the CT and CC conformations (27) and (28) are significantly more stable than the others. An investigation of the conformational interconversions of truns7truns,truns-cyc1ododeca-1,5,9-triene by 'H n.m.r. measured between -5 to -180 "C reveals79 a dynamic effect associated with a conformational process having a free energy of activation of 36.0 kJ mol-' and consistent with a single conformation with D3 symmetry for the triene.The conformational energy surface for ring inversion of the D3conformation to its mirror image has been investigated by iterative force-field calculations and the strain energy barrier for the best path is calculated to be 39.7 kJ mol-' in good agreement with the value from n.m.r. data. By use of line shape analysis of the temperature-dependent n.m.r. spectrum the isodynamical interconversion between the quasiplanar equilibrium conformers 77 E. Dunkelblum and H. Hart J. Org. Chem. 1977,42 3958. H. Shirahama E. bsawa and T. Matsumoto Tetrahedron Letters 1978 1987. 79 F.A. L. Anet and T. N. Rawdah J. Amer. Chem. SOC.,1978,100,5003. Alicyclic Chemistry (29b) and (29c) of 1,5-bisdehydro[l2]annulene has been found to involve" AG* = 18.8kO.84kJ mol-' (120 K).The magnitude of this barrier is consistent with the energy needed to disrupt the cyclic T-conjugation on transformation to the non- planar transition state (29a).Scheme 16 4 Structural Properties and Orbital Interactions Cyclobutadiene continues to excite considerable interest. A theoretical study has been undertaken" involving ab initio calculations both on the SCF level and with electronic correlation for both the square singlet and triplet and also the rectangular singlet states of the planar molecule. The square singlet is more stable than the corresponding triplet by about 29 kJ mol-' and the energy difference between the rectangular and square singlets is about 58.5 kJ mol-'. It is concluded that cyclo- butadiene should have a rectangular singlet ground state with very long C-C single bonds (1.57w).These resuIts are confirmed by other authorsg2 whose CI cal- culations additionally suggest that the square is the lowest energy intermediate for interconversion of rectangular singlets. This is supported in related workg3 from which it emerges that a square geometry represents a transition state for bond flipping in singlet cyclobutadiene. Theoretical determination of the i.r. spectrum of cyclobutadiene using ab initio SCF calculations of the vibration frequzncies and intensities of the i.r. active vibrations have showns4 that the observed i.r. spectrum is compatible with a rectangular structure and that the band at 1240cm-' is an in-plane CCH bending deformation of cyclobutadiene.In a study designed to elucidate the orbital interactions present between two and three linked cyclopropane rings as a function of dihedral angles the p.e. spectra of syn-and anti-bishomocyclohepta-3,f-trieneand syn,syn- anti,anti- and anti,syn-8o R. Gygax J. Wirz J. T. Sprague and N. L. Allinger Helv. Chim. Acra 1977,60 2522. 81 H. Kollmar and V. Staemmler J. Amer. Chem. SOC., 1977,99 3583. 82 J. A. Jafri and M. D. Newton J. Amer. Chem. SOC.,1978 100 5012. 83 W. T. Borden E. R. Davidson and P. Hart J. Amer. Chem. SOC.,1978,100 388. 84 H. Kollmar and V. Staemmler J. Amer. Chem. Soc. 1978,100,4304. 296 A. Cox trishomocycloheptatriene have been meas~red.'~ Satisfactory agreement between the p.e.measurements and model calculations could however only be achieved if 'radially' oriented components were mixed into the highest occupied 'tangential' Walsh orbitals. The p.e. spectra of 1,1,3,3-tetramethyl-2-vinyl-,3-ethynyl-1,l-dimethyl- and 2-ethynyl-1,1,3,3-tetramethyl-cyclobutanehave been measured.86 An interaction term of HRs= -52 kJ mol-' was used to describe the conjugation and from the spectra it appears that this interaction does not depend on conformation. The influence of the cyclobutane ring on the r-system is comparable to that of an alkyl substituent but may be considerably enhanced by alkyl substitution of the ring which lowers the energy difference between cyclobutane and r-orbitals. For a selected number of systems a comparison has been mades7 between the through-bond interaction of two mutually perpendicular r-systems and spirocon- jugation.Such systems can interact quite effectively via the c+-bonds of the four- membered ring as a consequence of the strong interaction of the Walsh orbitals of the cyclobutane ring and the r-orbitals. In some cases the HOMO or LUMO is influenced resulting in changes in both energy and symmetry. This should have consequences for reactivity. Dispiro[2,2,2,2]deca-4,9-dienehas been synthesized and its properties and reac- tions investigated." The compound exhibits a relatively large bathochromic shift of the absorption maximum (222nm) and a lowering of the ionization potential (698 kJ mol-') as compared to cis-1,2-dicyclopropylethylene.However no cyclic conjugation appears to be present as shown by n.m.r.A paper has appearedsg discussing the electronic properties and the spectra of cyclobutanone and its derivatives spiro[2,3]hexan-4-one spiro[2,3]hexan-5-one dispiro[2,1,2,l]octan-4-one and dispiro[2,0,2,2]octan-7-one. The theoretical approach used is an all-valence electron semiempirical method and the results are discussed in terms of charge-donation and charge-transfer from the 3-ring hypsochromic and bathochromic shifts of electronic transitions related to the carbonyl direct substituent effects on the carbonyl stretching frequency and the across-ring interaction in cyclobutanone. Single determinant ab initio MO theory has been usedgo to study equilibrium geometries enthalpies strain energies and spiro interactions for spiropentane spiropentene spiropentadiene spiro[2,4]hepta- 4,6-diene spiro[2,4]heptatriene and spiro[4,4]nonatetraene.The calculated values are in good agreement with experimental results. Spiro interaction is also apparent in other calculated molecular properties such as dipole moments and ionization potentials. In a paperg1 concerned with the dependence of transmission of con-jugation through a cyclopropane ring into a vinyl group the chemical consequences resulting from placement of substituents of high electron demand on the cyclo- propane ring in spiro-vinylcyclopropaneson the reactivity of the vinyl group toward electrophilic olefins are discussed. A %5 J. Spanget-Larsen,R. Gleiter M. R. Detty and L. A. Paquette J. Amer.Chem. Soc. 1978,100,3005. 86 P. Bruckmann and M. Klessinger Chem. Ber. 1978 111 944. *' P. Bischof R. Gleiter and R. Haider J. Amer. Chem. Soc. 1978 100 1036. T. Tsuji T. Shibata Y. Hienuki and S. Nishida J. Amer. Chem. Soc. 1978 100 1806. 'I. Y. Meyer and R. Pasternak Theoret. Chim. Acta 1978,47 27. 90 J. Kao and L. Radom J. Amer. Chem. Soc. 1978,100,760. 91 M. Langbeheim and S. Sarel Tetrahedron Letters 1978 1219. 13' Alicyclic Chemistry The a,.rr-electron system in (30) is shown to be highly sensitive to substitution effects and the cyclopropane ring to be capable of effectively transmitting con- jugation from the polar substituent through the ring into the vinyl group. The first (30) X = CN or C02CH3 theoretical calculations that reproduce the observed U.V.spectrum of barrelene are reported.92 Both through-space interaction which determines the ordering of the orbitals and is predominantly T,and through-bond interaction which mixes cr with .rr and inserts antibonding (T among antibonding T are present. The lowest energy transition (>200nm) is assigned as T-+(T* and the first excitation which is essentially .rr -+ .rr* is predicted at about 180 nm. The effect of substituents on the reactivity of the double bond in (31) towards [,4 + ,2,] and epoxidation reactions has been in~estigated.~~ The observed rate sequence is (31c) > (31a)> (31b) in both Me2S0 and CHCI3,and this is interpreted (31) a; X=Y=H b; X,Y=O c; X=OMe,Y=H in terms of orbital interactions through space operating between the substituents and the double bond.An examination has been made,94 using a series of CND0/2 semiempirical MO calculations of substituent effects on model exchange reactions of 4-substituted bicyclo[2,2,2]octylcarbinyl and cubylcarbinyl chlorides. The trends produced in both sets of compounds are similar in magnitude and probably in mechanism. Should through-bond coupling via framework orbitals be important it cannot be appreci- ably charge-transfer in character. The present results do not allow estimation of the relative importance of polarization and of the electrostatic effect. A theoretical study has been made95 of the cubane molecule using ab initio STO-3G SCF-X, MIND013 and INDO methods and the p.e. ionization energies calculated from the above by Koopman’s theorem.Utilizing the concept of interactions between symmetry-adapted combinations of localized CC and CH orbitals an analysis of the MO energy splitting pattern has been made. 92 A. Y. Meyer and R. Pasternak Tetrahedron 1977,33 3239. 93 M. N. Paddon-Row H. K. Patney and R. N. Warrener J.C.S. Chem. Comm. 1978,296. 94 R. B. Davidson and C. R. Williams J. Amer. Chem. SOC.,1978,100,2017. ’’ J. M. Schulman C. R. Fischer P. Solomon and T. J. Venanzi J. Amer. Chem. SOC.,1978,100,2949. 298 A. Cox 5 Reactions Metal-promoted Reactions.-It is that reaction of cyclopropene with ( qS-C5H5),NbCl leads to a new complex (q'-C5H5)NbC1(C3H4) which has been fully characterized spectroscopically. Treatment of this complex with HCl yields almost pure cyclopropane (>90°/0) and represents the first reported reduction of cyclopropene via an isolable metal complex.An investigation9' of the permethyl substituted A1Cl3 u complex (Scheme 17) has shown that a dynamic process is occurring consisting of consecutive 1-2 shifts of the Tl T1 ;;-#-AlC1,-AlCl; Scheme 17 AlC13 group. Complexes having an oligomethylene chain in some cases give struc- tures involving an AlC13 residue bonded exclusively to the bridgehead and in others a mixture having either this feature or one involving the AlC13 at some other position. The rates of cleavage of (32) and (33) by an equivalent of Rh(N0R)acac areg8 1.3x 1mol-' s-l and 1.3 x 1mol-' s-' respectively; introduction of a second endomethyl group (34) stops the reaction altogether (Scheme 18).The fgj-[Rh(NOR)CI]z '\ /' (32) R= R' -H \/ (33) R=H,R'=CH3 Rh (34) R = R'= CH~ NaBH,/CH,OH 1 Scheme 18 (NOR = norbornadiene) 96 S. Fredericks and J. L. Thomas J. Amer. Chem. Soc. 1978,100,350. 97 P.B.J. Driessen and H. Hogeveen J. Amer. Chem. Soc. 1978,100,1193. 98 P.E.Eaton and D. R. Patterson,I.Amer. Chem. Soc. 1978,100,2573. Alicyclic Chemistry remarkable effect resulting from introduction of a methyl group so far from the reaction site probably arises from steric interference to the internuclear movements which accompany opening of the cage. The first example of a six-electron Rh-catalysed isomerization of a dicyclopropyl compound has appeared.* Thus syn-l,3-bishomocycloheptatriene(35) leads to a 59 :41 mixture of bicyclo[6,l,0]nona-2,5-diene (36) and cis,cis,cis-cyclonona- 1,3,6-triene.An investigation is reported'00 of the effect of 1-trimethylsilyl and l-tri-methylgermyl substitution on the outcome of Ag+- and €3'-catalysed rearrange-ments in tricyclo[4,1,0,0,02*7] heptanes. The results can be interpreted in terms of the dependence of an electrophilic attack at a given edge bicyclobutane bond upon the position of the alkyl substituent and the hyperconjugative and homoconjugative stabilizationof cationic intermediates by C-Si and C-Ge. The binding of unsaturated propellanes to transition metals has been studied. lo' Among the group six metal carbonyls investigated the specific catalytic effectiveness correlates directly with metal-carbon bond strengths (Cr >W >Mo) and the order of wback donation (W-C >Cr-C >Mo-C).Isotopic labelling studieslo2 have established that in the Mo(CO),-promoted isomerizations the induced [1,5]-carbon shifts involve specific co-ordination of the unsaturated propellane to Mo with suprafacial migration operating under the control of the transition metal. Thermalv Promoted.-Thermal isomerization of phenylcyclopropane leads'03 to trans-and cis-p-methylstyrene and alkylbenzene. From kinetic and labelling studies it has been shown that there is synchronous stereomutation of the phenyl-bearing carbon and also of Cz and C3. The MO method PRDDO has been used'" to investigate the surface for the degenerate thermal rearrangement of methyl-enecyclopropane.The calculated activation energy is in agreement with that determined experimentally and the barrier to ring closure found to be c7.84 kJ mol-'. The rate of interconversion of endo-and exo-2-methyl-6-methylenebicyclo[3,1 ,O]hexane is c~rnparable'~~ with that for cis to trans isomeriz-ation of the 2,3-dimethylenecyclopropanes,suggesting the intermediacy of a planar trimethylenemethane singlet. Tracer experiments suggest exo methylene rotation succeeds rate-determining formation of a planar trimethylenemethane biradical. Mainly orthogonal and to a lesser extent planar or bisorthogonal trimethylene 99 L. A. Paquette and M. R. Detty Tetrahedron Letters 1978,713. loo R. T. Taylor and L. A. Paquette J. Ore.Chem. 1978,43,242. lo' L. A. Paquette J. M. Photis and R. P. Micheli J. Amer. Chem. SOC., 1977,99 7899. lo2 L. A. Paquette R. P. Micheli and J. M. Photis J. Amer. Chem. SOC.,1977,99 7911. lo3 J. T. Wood J. S. Amey D. Cortes and J. A. Berson J. Amer. Chem. Soc. 1978,100,3855. D. A. Dixon R. Foster T. A. Halgren and W. N. Lipscomb J. Amer. Chem. SOC.,1978,100 1359. lo' J. J. Gajewski and S. K. Chou J. Amer. Chem. Soc.. 1977,99,5696. 300 A. Cox biradicals are involved in the pyrolysis of both cis- and trans-2,3-dimethyl- me thylenecyclopropanes. An investigation'06 of the Cope rearrangement of allyl-substituted cyclopropenes in particular 1,2-diphenyl-3-allyl-3-methylcyclopropene, has shown that the reac- tion proceeds via an intermediate analogous to the ly4-cyclohexylene biradical; a pericyclic process does not therefore appear to be implicated.cis-Divinylcyclo- propane has been synthesized"' by Wittig reaction of cis-2-vinylcyclopropanecar-boxaldehyde with methylenetriphenylphosphorane,despite earlier reports of its reactivity. The compound is stable at low temperatures rearranging quantitatively to cyclohepta-1,4-diene with ti = 11min at 288.5 K. Complexes involving hexafluoroacetylacetonatorhodium are discussed. The thermal reactions of cis-1-aryl-2-vinylcyclopropaneshave been reported"' and have provided unequivocal evidence for the participation of an aromatic double bond in the Cope rearrangement. For 4-phenylbut-l-ene AH' is estimated as 125.52 kJ mol-' and for replacement of a double bond by a phenyl ring in the Cope rearrangement 4HA-41.8 kJ mol-'.By using the semiempirical MIND0/2 method the potential surface for the thermal reaction of methylenecyclobutane has been e~aluated.''~ Electronic factors are shown to be the least likely cause of the observed stereospecificity and strong support is provided for Gajewski's views"' that the ring opening pathway is similar to that of other cyclobutane derivatives and that a flat energy profile exists in the region of the transition state. An investigation has been begun'" of the largely unexplored area of the Chem- istry of the bis- and tris-homocycloheptatrienes. In particular a study of 7,7-diduterio-anti-1,5-bishomocycloheptatriene has revealed that the thermal reor- ganization of this system occurs via a two-fold 1,5-homodienyl rearrangement the second stage of which involves prior conformational ring inversion and geminal hydrogen interchange.Results have been reported112 of the first homogeneous gas phase thermolysis study of the 1,2,4-trideuterio derivative of bicyclo[2,2,0]hexa- 2,5-diene (Dewar benzene). These reveal that there is no single step pericyclic alternative to disrotatory cyclodissociation and that potential multistep mechanisms are limited to those that would require rate limiting formation of either trans cis cis-cyclohexa- 1,3,5-triene or trans-Dewar benzene. Gas phase pyrolysis of (+)-[3-2H]bicyclo[3,2,1]oct-2-en-7-one in a degenerate rearrangement to (-)-[ 1-2H]bicyclo[3,2,1]oct-2-en-7-one as observed by 'H-and 13C-n.m.r.spectroscopy and by polarimetry. It is however presently unclear whether the rearrangement is a concerted [1,3] sigmatropic acyl shift or a stepwise reaction passing over an allylic-acyl biradical intermediate derived by cleavage of the C1-C7 bond. An investigation of the automerization of (-)-[3-2H,9-'3C]-6-methylene-bicyclo[3,2,l]oct-2-ene has been shown114 to proceed via a non-random mixed A. PadwaandT. J. Blacklock J. Amer. Chem. SOC.,1978,100 1321. lo' J. M. Brown B. T. Golding and J. J. Stofko J.C.S. Perkin I. 1978,436. lo* E. N. Marvel1 and C. Lin J. Amer. Chem. Soc. 1978,100 877. lo9 W. W. Schoeller J. Amer. Chem. SOC.,1978,99 5919. 'lo J. J. Gajewski J. Amer. Chem. SOC.,1976 98 5254. 'I1 M. R. Detty and L. A. Paquette J.C.S.Chem. Comm. 1978 365. M. J. Goldstein and R. S. Leight J. Amer. Chem. SOC.,1977 99 8113. '13 J. M. Janusz L. J. Gardiner and J. J. Berson,J. Amer. Chem. SOC.,1977,99 8509. J. M. Janusz and J. A. Berson J. Amer. Chem. SOC.,1978 100 2237. Alicyclic Chemistry 301 mechanism consisting of (37)*(38) and (37)dequal amounts of (39) and (40) of which the major component is the Cope rearrangement. Detailed interpretation of the minor component depends on the relative values of the two [1,3]sigmatropic rate constants k and k7. . 2 .D (37) 11 11 .= (38) 13C (39) Activation parameters of spironorcaradiene-spirocycloheptatrieneequilibria (Scheme 19) have been determined1I5 by line shape analysis of 'H and I3C n.m.r. R' = R2= C1 or R' R2= benzo R3=HorCF3 Scheme 19 spectra.The results reveal that whereas the values obtained for the dibenzo- spironorcaradienes are comparable with the data of simple norcaradiene derivatives the tetrachloroderivatives show considerable differences. M. Kausch and H.Diirr Chem. Ber. 1978 111 1.

ISSN:0069-3030    

DOI:10.1039/OC9787500279

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

13 Synthetic Methods By R. BRETTLE Department of Chemistry The University Sheffield S3 7HF 1 Alkanes Primary amines can be directly deaminated a process not really possible hitherto by treatment with hydroxylamine O-sulphonic acid and alkali. An important paper covering reductive displacements by tetrahydridoborate in polar aprotic solvents gives full details of the reductive amination of primary amines via NN-disulphoni-mides.2 Sterically hindered acetates of secondary and tertiary alcohols are predominantly deoxygenated by lithium in eth~lamine;~ 3~,5a-diacetoxycholestanegives 5a-cholestan-36-01. Reduction of 0-(NN-dimethylsulphamoyl) derivatives of secon-dary alcohols with sodium in liquid ammonia likewise effects smooth deoxy- genati~n.~ The cyclopentadienylvanadium tricarbonylhydride anion transfers hydrogen faster than tributyltin hydride so that for example very little cyclization occurs in the reductive debromination of 6-bromohex-1 -ene.’ 2 Alkenes The Silver Jubilee volume of Organic Reactions deals with two important olefin syntheses the use of condensations of carbonyl compounds with phosphoryl- stabilized anions,6 and the Ramberg-Backlund rearrangement starting from a-halos~lphones.~ Another review deals with the synthetic uses of the intramolecular ene reaction; a recent example of the commonest reaction of this type is shown in Scheme 1.8 MeJ-jJ 3oo”c1 Me0,C Scheme 1 C0,Me G.A. Doldouras and J. Kollonitsch J. Amer. Chem. Soc.. 1978 100 341. * R. D. Hutchins D. Kandasamy F.Dax C. A. Maryanoff D. Rotstein B. Goldsmith W. Burgoyne F. Cistone J. Dalessandro and J. hglis J. Org. Chem. 1978,43 2259. R. B. Boar L. Joukhadar J. F. McGhie S. C. Misra A. G. M. Barrett D. H. R. Barton and P. A. Prokopiou J.C.S. Chem. Comm. 1978,68. T. Tsuchiya I. Watanabe M. Yoshida F. Nakamura T. Usui M. Kitamura and S. Umezawa Tetrahedron Letters 1978 3365. R. J. Kinney W. D. Jones and R. G. Bergman J. Amer. Chem. SOC. 1978,100,635. ‘W. S. Wadsworth jun.,Org. Reactions 1977,25,73. L. A. Paquette Org. Reactions 1977,25 1. W. Oppolzer and V. Snieckus Angew. Chem. Internat. Edn. 1978,17,476. 303 304 R.Brettle A new synthesis' of trans-alkenes which is an attractive alternative to the Wittig reaction is particularly useful for the reaction of the carbonyl group with a secondary centre (Scheme 2).An improvement on methylenation with methyl-enetriphenylphosphorane is to use di-iodomethane-zinc-trimethylaluminium or dibromomethane-zinc-titanium tetrachloride." v SO Ph * ;4 i ii Reagents i BuLi; ii PhCOCl; iii Na/Hg; MeOH/EtOAc. Scheme 2 Modifications to the selenoxide elimination route," making it for example useful for primary alkyl aryl selenides have been reported.'* Either a-or y-alkylation of a primary alkyl benzothiazolyl sulphide can be achieved by using a Grignard reagent in the presence of copper(1) iodide and choice of a particular reaction medium (Scheme 3).13 'Et20 THF qR Et,O-RI-R R' Scheme 3 A general method for the syn-carbometallation of alkynes both internal and terminal now seems to have been found in which the alkyne is treated with zirconocene dichloride and a trialkylaluminium.l4 The metal-alkenyl can then be converted into both simple and functionalized alkenes by well-established 'P. J. Kocienski B. Lythgoe and S. Ruston J.C.S. Perkin 1 1978 829. lo K. Takai Y. Hotta K. Oshima and H. Nozaki Tetrahedron Letters 1978 2417. l1 cf. D. L. J. Clive Tetrahedron 1978 34 1049. l2 D. Labar L. Hevesi W. Dumont and A. Krief Tetrahedron Letters 1978 1141; H. J. Reich S. Wollowitz,J. E. Trend F. Chow and D. F. Wendelborn J. Org. Chem. 1978,43 1697. l3 P. Barsanti V. Calo L. Lopez G. Marchese F. Naso and G. Pesce J.C.S. Chem. Comm. 1978 1085. l4 D. E. Van Horn and E.-i. Negishi J. Amer. Chem.Soc. 1978,100 2252. Synthetic Methods method^.'^ This procedure can be used to introduce a methyl group,14 although earlier difficulties in the use of methylcopper reagents have now largely been overcome.l6 Another advance shows that methylmagnesium bromide can be added to silylacetylenes in the presence of a nickel catalyst." Cycloalkenes are produced by the reduction of vicinal cyanohydrin mesylates (l) derivable from imino-nitriles formed by the Thorpe-Ziegler cyclisation." Reduc-tion of specific enol phosphates can now be best accomplished by the use of freshly formed titanium metal; the method" can be used to generate 1,3-dienes [e.g. (2)] which are not reduced under these conditions. Interest continues in other syntheses of 1,3-dienes.The reaction of l-alkenyl-zirconium derivatives (see above) with alkenyl halides with palladium catalysis provides a highly stereo- and regio-selective synthesis2' which is also applicable to more highly substituted alkenylzirconium chloride derivatives provided that the coupling is further promoted by zinc chloride2' (Scheme 4). Et Et Et Et \/ Et-C=C-Et & \C=C / /c=c\ /Me H /' \ZrCp2C1 H H/c=c \C02Me Br Me Reagents i Me,AI/Cp,ZrCl,; ii 'CS ,Pd(PPh& ZnC1 H / 'C0,Me Scheme 4 An equally good method is the palladium-catalysed coupling of alkenylmagnesium halides with alkenyl iodides.22 1,3-Dienes can also be prepared from alkynes through the palladium-catalysed condensation of the derived alkenyl-mercury Is N. Okukado and E.-i.Negishi Tetrahedron Letters 1978 2357. l6 A. Marfat P. R. McGuirk and P. Helquist Tetrahedron Letters 1978 1363. l7 B. B. Snider M. Karras and R. S. E. Conn J. Amer. Chem. SOC.,1978 100,4624. '* J. A. Marshall and L. J. Karas Synth. Comm. 1978 8 65. l9 S. C. Welch and M. E. Walters J. Org. Chem. 1978,43 2715. 2o N. Okukado D. E. Van Horn W. L. Klima and E.-I. Negishi Tetrahedron Letters 1978 1027. 21 E.-i. Negishi N. Okukado A. 0.King D. E. Van Horn and B. I. Spiegel J. Amer. Chem. SOC.,1978 100,2254. '* H. P. Dang and G. Linstrumelle Tetrahedron Letters 1978 191. 306 R. Brettle derivatives which leads to the head-to-tail dimer~.~~ A new regiospecific 1,3-diene synthesis starting from ally1 involves the intermediacy of allylic sulphox- ides produced by a [2,3] sigmatropic rearrangement (Scheme 5).Ar Reagents i ArSCI Et,N; ii A Ar = 2,4-dinitrophenyl. Scheme 5 1,4-Dienes can be prepared by the palladium-catalysed allylation of alkenyl pentafluorosilicates (3)which are available from the hydrosilylation of alkynes. An ester group survives the operations as in the preparation of methyl dodeca-8,ll- dienoate from methyl nor1-8-ynoate.~~ 3 Alkynes Disubstituted alkynes need not be made from alk-1-ynes. They can be prepared also by the reductive elimination of enol-phosphates of a-phenylsulphonyl ketones with sodium in liquid ammonia or sodium amalgam in aprotic solvents; the procedure26 has been applied to the preparation of medium ring cycloalkynes and conjugated enynenes (Scheme 6).Cyclic amidines uniquely permit the condensation of alk-l-ynes with primary halides in the presence of copper(1) halide.27 Reagents i LiN(Pr’),; ii CIPO(OEt),; iii Na/Hg THF DMSO Scheme 6 cui HOCH,C-CH + CH2=CHCH2Br DSV; HOCH2CzC-CH2CH=CH2 * DBU = 1,5-diazabicyclo[5,4,O]undec-5-ene *’ R. C. Larock and B. Riefling J. Org. Chem. 1978,43 1468. 24 H.J. Reich I. L. Reich and S. Woilowitz J. Amer. Chem. SOC.,1978 100 5981. ’’J.-I. Yoshida K. Tamao M. Takahashi. and M. Kumada Tetrahedron Letters 1978 2161. 26 B.Lythgoe and I. Waterhouse Tetrahedron Letters 1978,2625;P.A.Bartlett F. R. Green and E. H. Rose J. Amer. Chem. SOC.,1978 100,4852. 27 K.Eiter F.Lieb H. Disselnkotter and H. Oediger Annalen 1978 658. Synthetic Methods 4 Halides The anti-Markovnikov addition of hydrogen halide to an alkene can be achieved through the alkyl pentafluorosilicate derived by hydrosilylation.Preferential addi- tion to a terminal double bond in the presence of a more highly substituted double bond is observed and the method can also be applied to (3) to give the alkenyl halide.28 Oxidation of the intermediate alkyl pentafluorosilicate with meta-chloro- perbenzoic acid gives the corresponding alcohol providing a competitive method of anti-Markovnikov hydration.29 Although alk-1-ynes are reduced to alkanes by di-imide 1-iodoalkynes are reduced to alkenyl iodides.30 RCH(0H) \ I \/ RCH(OH)C=CI -* /c=c\H H 5 Alcohols Many routes to allylic alcohols have been discussed this year.Several use the reaction of aldehydes or ketones with the carbometallation products of alkynes15-” (see above). Warren who has reviewed organic syntheses using the migrating functional groups Ph,PO and PhS,31 has introduced a versatile synthesis in which the adducts of aldehydes to the anions of ally1 phosphine oxides are reduced with loss of phosphorus and regiospecific and stereoselective transposition of the double bond.32 In the example shown (Scheme 7) an endocyclic double bond moves to an exocyclic Scheme 7 location. Trisubstituted alkenes with ‘phenylselenenic acid’ give selenohydrins which on oxidation with t-butyl hydroperoxide in the presence of magnesium sulphate give the tertiary allylic The reagent is prepared from either diphenylselenide or hypophosphorous acid and phenylseleninic acid.Alternatively selenohydrins can be prepared from formaldehyde and the anions produced by the action of butyl-lithium on selenoacetal~.~~ The analogous P-hydroxysulphoxides give allylic alcohols on refluxing in xylene containing suspended sodium arbo on ate.^^ K.Tamao J.-I. Yoshida M. Takahashi H. Yamamoto T. Kakui H. Matsumoto A. Kuriba and M. Kumada J. Amer. Chem. SOC.,1978,100 290; J.-I. Yoshida K. Tamao K. Kurita and M. Kumada Tetrahedron Letters 1978 1809. 29 K. Tamao T. Kakui and M. Kumada J. Amer. Chem. Soc. 1978,100,2268. 30 C. Luthy P. Konstantin and K. G. Untch J. Amer. Chem. SOC.,1978,100,6211. 31 S. Warren Accounts Chem. Res. 1978 11,401. 32 R. R. Arndt and S. Warren Tetrahedron Letters 1978,4089.33 T. Hori and K.B. Sharpless J. Org. Chem. 1978 43 1689; D. Labor A. Krief and L. Hevesi Tetrahedron Letters 1978 3967. 34 D. Labor W. Dumont L. Hevesi and A. Krief Tetrahedron Letters 1978 1145. 35 J. Nokami K.&La dlld R. Okaware Tetrahedron Letters 1978,4903. 308 R. Brettle The stereo- and regio-selective rearrangement [e.g. (4) + (5)] of oxirans to allylic alcohols by organoaluminium compounds has been reviewed;36 in hexamethyl- phosphoric amide lithium di-isopropylamide achieves the same end.37 ap-Olefinic (4) (5) ketones give almost exclusively the allylic alcohols on reduction with borohydride in methanolic cerium tri~hloride,~~ while the corresponding aldehydes are similarly reduced on treatment with hydridoiridium sulphoxide complexes in propan-2-01.~’ The 1,3-transposition of primary allylic alcohols [e.g.(6)-+(7)] can be achieved through selenium intermediates under mild condition^.^' (TOH -OOH (6) (7) A highly stereoselective synthesis of homoallylic alcohols containing a Z-tri- substituted double bond invoives a pseudoaxially-substituted transition state in a [2,3] sigmatropic rearrangement;41 it is illustrated (Scheme 8)for the synthesis of a natural sex-attractant (8). (8) Reagents i KH; ii Bu,SnCH,I; iii BuLi Scheme 8 A major improvement in the osmium-catalysed vicinal hydroxylation of alkenes by t-butyl hydroperoxide makes this the most economic catalytic method although it is still not successful with hindered and highly substituted alkene~.~* anti-Hy-droxyphenylsulphenylationof an alkene can be effected by treatment with diphenyl disulphide lead tetra-acetate and trifluoracetic acid followed by a basic work-~p.~~ Oxyamination of alkenes is considered in Section 7.’‘ H. Yamamoto and H. Nozaki Angew. Chem. Internat. Edn. 1978,17 169. 37 M. Apparu and M. Barrelle Tetrahedron 1978 34 1541. J.-L. Luche J. Amer. Chem. SOC.,1978 100,2226. 39 B. R. James and R. H. Morris J.C.S. Chem. Comm. 1978,929. 40 D. L. J. Clive G. Chittattu N. J. Curtis and S. M. Menchen J.C.S. Chem. Comm. 1978 770. 41 W. C. Still and A. Mitra J. Amer. Chem. Soc. 1978,100 1927. 42 K. Akashi R. E. Palermo and K. B. Sharpless J. Org. Chem. 1978 43 2063. 43 B. M. Trost M. Ochiai and P. C. McDougal J. Amer.Chem. SOC.,1978,100 7103. Synthetic Methods 6 Nitro-compounds Corey has described a new synthesis of conjugated nitro-cycloalkenes (Scheme 9) and has summarized their many synthetic transformation^.^^ The method is also Reagents i HgCI,; ii NaNO,; iii NaOH Scheme 9 applicable to acyclic alkenes. Various helpful modifications to the alternative nitro-aldol reaction have also been reported.45 Condensation of a phenyl ester with a nitronate anion leads to an a-nitroketone under mild condition^;^^ an application in the biotin field is illustrated (Scheme 10). Reagent i C,HSCHMeNH Scheme 10 7 Amines Propane- 1,3-dithiol is an extremely selective reagent for the reduction of functionalized alkyl and aryl azides to the corresponding primary amine~.~~ Alkyl-lithium type reagents react with NN-dialkyl- 0-arylsulphonylhydroxylaminesto give tertiary amines and in this way some amines which were hitherto unobtainable [e.g.(9)] have finally been ~repared.~’ Certain highly hindered primary amines can be (9) 44 E. J. Corey and H. Estreicher J. Amer. Chem. SOC.,1978 100,6294. ” (a)E. W. Colvin and D. Seebach J.C.S. Chem. Comm. 1978,689;(b)R. H. Wollenberg and S.J. Miller Tetrahedron Letters 1978,3219. 46 J. Vasilevskis,J. A. Gualtieri S. D. Hutchings R. C. West J. W. Scott D. R. Parish F. T. Bizzarro and G. F. Field J. Amer. Chem. SOC.,1979,100 7423. 47 H. Bayley D. N. Standring and J. R. Knowles Tetrahedron Letters 1978.3633;J. V.Staros H. Bauley D. N. Standring and J. R. Knowles Biochem.Biophys. Res. Comm. 1978,80 568. 48 G. Boche N. Mayer M. Bernheim and K. Wagner Angew. Chem. Internat. Edn. 1978 17,687. 310 R. Brettle made by the a-allylation of N-sulphinylamines themselves readily available from primary amines (Scheme 1l).49Treatment of diphenyl disulphide with chloramine T NH -!+ NH Reagents i SOCl,; ii Ph,CLi’; iii h C Scheme 11 affords reagents which react with alkenes to give adducts which on reduction with borohydride give vicinal phenylsulphenyl N-toluenesulphonamides; cyclohexene for example gives (1O).” Raney nickel desulphurization gives the N-toluenesul- phonamides. The corresponding hydroxy-N-toluenesulphonamidesand hydroxy- N-tertiary alkylamines had been made previously using osmium-based processes.OSPh ‘NHTOS (10) However in all these cases liberation of a primary amino-group is scarcely possible. A modified process in which alkenes undergo an osmium-catalysed vicinal oxy- amination through the agency of N-chloro-N-argentocarbamatesnow permits the introduction of nitrogen in a conventionally protected urethane form5’ (Scheme 12). (11) Reagents i AgNO,; ii 1% OsO,; iii MeCN/H20 Scbeme 12 The process works satisfactorily with electron-deficient alkenes and the regioselec- tivity is greater than in the other catalytic processes. A warning is given about the instability in quantity of the N-chlorosodiocarbamates (11)used as reagents. Vicinal ditertiary amines can be obtained by an aminopalladation-oxidation sequence,” with overall syn-addition an alternative to routes using osmium-based reagents or via aziridines.Two preliminary reports on metallo-oxaziridines have appea~ed.’~ They were expected to show ‘nitrenoid’ behaviour but with alkenes the products are 49 F. M.Schell J. P. Carter and C. Wiaux-Zamar J. Amer. Chem. SOC.,1978 100,2894. 50 D. H. R. Barton M.R. Britten-Kelly and D. Ferreira J.C.S.Perkin 1 1978 1090 or 1682. 51 E. Herranz S. A. Biller and K. B. Sharpless J. Amer. Chem. SOC.,1978 100 3596. ” J.-E. Backvall Tetrahedron Letters 1978 163. ’’ L. S. Liebeskind K.B. Sharpless R.D. Wilson and J. A. Ibers J. Amer. Chem. Soc. 1978,100,7061;D. A. Muccigrosso S. E. Jacobson P. A. Apgar and F. Mores J. Amer. Chem. Soc. 1978 100,7063. Synthetic Methods 311 allylamines formed by transposition of the double bond as in an ‘ene’ reaction and not aziridines (Scheme 13).NHAr 0 L,II 0 Reagent i Mo I L’/ \ NPh LL Scheme 13 8 Aldehydes and Ketones The search for new reagents for the preparation of aldehydes and ketones by the oxidation of alcohols has continued. Tetrabutylammonium permanganate seems an attractive po~sibility,’~ but a strong warning has been given about the inherent instability of the crystalline reagent following a fire.” Barium manganate worked well in several casess6 and an operationally simple procedure based on phase transfer catalysis of oxidation by dichromate has been reported.” Chromic acid adsorbed on silica gels8 and polyEvinylpyridinium chlorochr~mate]~~ are two other useful reagents which have been investigated; in these cases there is the well recognised advantage with insoluble reagents of ease of workup.Oxalyl chloride should be added to the list of generally effective activators of dimethyl sulphoxide in alcohol oxidations.60 Benzeneseleninic anhydride gives high yields in the oxidation of various alcohols under essentially neutral conditions.61 For steroids with a hydroxyl group at C-3 the oxidation is accompanied by dehydrogenation of ring A as exemplified in Scheme 14.62 p-0x0-bis(chlorotripheny1bismuth)is another mild oxidant,63 particularly useful for the oxidation of allylic alcohols e.g. vitamin A alcohol. Scheme 14 54 T. Sala and M. V. Sargent J.C.S. Chem. Comm. 1978 253. 55 J. A. Morris and D.C. Mills Chem. Brit. 1978,326. 5‘ H. Firouzabadi and E. Ghaderi Tetrahedron Letters 1978 839. ” D. Pletcher and S.J. D. Tait Tetrahedron Letters 1978 1601. ’’ E. Santanielle F. Ponti and A. Manzocchi Synthesis 1978 534. 59 J. M. J. Frechet J. Warnock and M. J. Fowall J. Org. Chem. 1978,43 2618. “ K. Omura and D. Swern Tetrahedron 1978,34 1651. “ D. H. R. Barton A. G. Brewster R. A. H. F. Hui D. J. Lester S. V. Ley and T. G. Back J.C.S.Chem Comm. 1978,952. 62 D. H. R. Barton D. J. Lester and S. V. Ley J.C.S. Chem. Comm. 1978 130. ” D. H. R. Barton 3.P. Kitchin and W. B. Motherwell J.C.S. Chem. Comm. 1978. 1099. 312 R. Brettle Aldehydes and ketones can be prepared conveniently on occasion by the reduction of the corresponding ap-olefinic compounds and this can be done rather simply by their palladium-catalysed reduction with triethylammonium f~rmate.~~ The reduction of an acid chloride to an aldehyde has always caused some difficulty but it has now been shown that this can be done by sodium borohydride provided that it is used in dimethylformamide containing cadmium or by bis(tri- phenylphosphine)copper(1)borohydride in acetone.66 The McFadyen and Stevens synthesis of aromatic aldehydes has been modified so that it now works well for aliphatic aldehydes too.Vacuum pyrolysis of the dry alkali-metal salts of 1-acyl-2-arylsulphonylhydrazines achieves this.67 An efficient formylation of Grignard reagents leading directly to the aldehyde,68 uses N-formyl- N-methyl-2-aminopyridineas the reagent in a manner reminiscent of the earlier Mukaiyama ketone synthesis.Vinyl chlorides can be hydrolysed to ketones under mild conditions by a combination of-mercury(I1) acetate and boron trifluoride etherate; this method was successful where previously recommended methods f ailed.69 The 1,2-transposition of a keto-group is an important part of synthetic methodology. Paquette has now introduced a method based on vinylsilanes (Scheme 15) which complements earlier methods and is rapid despite the several OH Reagents i ArSO,NHNH,; ii R'Li; iii Me,SiCI; iv m-C1C6H,CO0,H; v LiAIH,; vi CrO, Et,O H20 HzS04 Scheme 15 steps inv01ved.'~ It is regioselective since the deprotonation of the ketone aryl- sulponylhydrazone in the Shapiro reaction normally occurs at the lesser-substituted of the a-positions; thus cholestan-3-one goes to cholestan-2-one.An earlier method due to Trost began with a-sulphenylation. If the Shapiro alkene synthesis is applied to the resultant a-sulphenyl-ketone the product is a vinyl sulphide which en hydrolysis gives the transposed ketone.71 Alternatively a methylative trans- position can be achieved by Wittig methylenation of the a-sulphenyl ketone followed by alkyl-lithium-catalysed isomerisation of the resultant alkyl sulphide to the vinyl ~ulphide.~~ Deprotection is often a vital step in the synthesis of aldehydes and ketones. Treatment of thioacetals with pentyl nitrite followed by hydrolysis provides a mild route to the carbonyl compound; selective cleavage of a fully protected ketoaldehyde 64 N.A. Cortese and R. F. Heck J. Org. Chem. 1978,43,3985. 65 R. A. W. Johnstone and R. P. Telford J.C.S. Chem. Comm. 1978 354. G.W. J. Fleet C.J. Fuller and P. J. C. Harding Tetrahedron Letters 1978 1437; T. N.Sorrel1 and R. J. Spillane Tetrahedron Letters 1978 2473. 67 M. Nair and H. Shechter J.C.S. Chem. Comm. 1978 793. " D.Cornins and A. I. Meyers Synthesis 1978,403. 69 S. F. Martin and T. Chou J. Org. Chem. 1978 1027. 70 W.E.Fristad T. R. Bailey and L. A. Paquette J. Org. Chem. 1978 43 1620. " S.Kano T. Yokomatsu T. Ono S. Hibino and S. Shibuya J.C.S. Chem. Comm. 1978 414. Synthetic Methods 313 to free the aldehyde group has been demonstrated with this The utility of wet silica gel for dea~etalization,~~ particularly to produce acid-sensitive cup-olefinic carbonyl compounds was quickly recognised.Olefinic Aldehydes and Ketones.-Imaginative syntheses of ap-olefinic aldehydes and ketones continue to appear. Hooz has developed a synthesis from alkynes (Scheme 16)which is notable for the selective oxidation of boron in the presence of iii RCH2C=CLi R:BC=CCH,R Li+ A R:BHSePh _+ RlqSePh R' CH,R CH,R Reagents i. R:B; ii PhSeCI; iii H20 Me,&-O; iv H202 Scheme 16 selenium by trimethylamine N-o~ide.~~ Vinylmercurials accessible by the hy- drozirconation of alkynes give ap-olefinic ketones in a stereospecific fashion on treatment with acid chlorides in the presence of aluminium cup-Olefinic ketones can be prepared in a very high yield by the regiospecific desaturation of the saturated ketones brought about by the treatment of a specific enol trimethylsilyl ether with palladium(I1) acetate.76 Photo-oxygenation of enol methyl ethers avail- Pd(0Ac) OSiMe able by the Wittig route by singlet oxygen gives intermediates (11)which are readily transformed into ap-olefinic aldehydes (Scheme 17).77An earlier method for the o-,i_ \ OMe A ROMe 2% Q,/ II OOH 0 (11) Reagents i Ph36-cHOMe; ii lo2; iii Ph3P Scheme 17 72 K.Fuji K.Ichikawa and E.Fujita Tetrahedron Letters 1978 3561. 73 F. Huet A. Lechevallier M. Pellet and J. M. Conia Synthesis 1978 63. 74 J. Hooz and R. D. Mortimer Canad. J. Chem. 1978,562786. 75 R. C. Larock and J. C. Bernhardt J. Org. Chem. 1978,43,710. 76 Y. Ito T. Hirao and T.Saegusa J. Org. Chem. 1978,43 1011. 77 G. Rousseau P. Le Perchec and J. M.Conia Synthesis 1978 67. 3 14 R. Brettle conversion of a ketone into the ap-olefinic aldehyde with two more carbon atoms has been improved by the introduction of a more accessible ~eagent.'~ A modification of the Mannich route uses trioxan and N-methylanilinium trifluoroacetate and is widely applicable to the synthesis of a-methylene-substituted and vinyl ketones." The p-acylenamines (12) obtained by the action of dimethyl- formamide acetals with ketones react with alkyl-lithiums to give ap-olefinic (12) Routes to cup-olefinic ketones based on 1-methoxyallene are illustrated in Scheme 18.81Thiolcarbamates already known as precursors of ap-olefinic aldehydes [see -.-/ OMe i v vi =*q: MeS-0 RZ II I 111 1i; i! o ki Me0 RZL.<OMe -\r-u"' R1 R RZ p Reagents i BuLi; ii R'X; iii R'X; iv H,O'; v R'R'CO; vi MeSOCI Et,N; vii [RCuBrIMgX LiBr Scheme 18 Ann.Reports (B) 1977 74 p 3281 have now been used to prepare a@-olefinic ketones8' and so have olefinic dithioesters for which a new synthesis has been reporteds3 (Scheme 19). L~~~uSMe i,ii,iii MeS SMe Reagents i PhNCS; ii MeI; iii H,S; iv Me,CzCHCH,Br; v AgN03 CdCO, H,O; vi base Scheme 19 '' A. I. Meyers K. Tomioka and M. P. Fleming J. Org. Chem. 1978,43 3788. 79 J.-L. Gras Tetrahedron Letters 1978 211 1 and 2955. R. F. Abdulla and K. H. Fuhr J. Org. Chem. 1978,43,4248. H. Kleijn H. Westmijze and P. Vermeer Tetrahedron Letters 1978 1133; J.C. Clinet and G. Linstrumelle Tetrahedron Letters 1978 1137. T. Nakai T. Mimura and T. Kurokawa Tetrahedron Letters 1978 2895. 83 P. Gosselin S.Masson and A. Thuiller Tetrahedron Letters 1978 2715 and 2717. Synthetic Methods 315 Two sequences (Scheme 20) based on selenium intermediates construct a& olefinic ketones from ketones and o~iranes~~ and from alkenes and halo alkane^^^ respectively. R' R'bo i,ii R' FSeR A A hR2 R' R' 2 R R' 0 Reagents i RSeH/ZnCI,; ii BuLi; iii CH,-CHR2; iv CrO,/Me,CO; v PhSeBr/EtOH; vi NaIO,; vii heat; viii R'CH,X Scheme 20 Cookson has developed versatile syntheses of enones dienones and dienals using a sulphur based methodology the principal features of which are summarized in Scheme 21.86 R' >L.-/~~~ R 'CH iii,iv v ,"y.cb,-RZ?'"i R2 R2 R3 R3 0 Fi OH RICH2 R'cH,+-& )=.& SOAr iii,vi RICH2 SOAr .RICH SAr b )=4A G.4 R2 R2 R2 R3 R2 R3 f (13) Jvii R' R3 R5 R'CH SOAr R'CH2 ix R2+~4 tR'vR3 0 OXR6 \ R2+?rR3 0 R6 R4 R5 viii R6 R4 /JSPh o+ EOgR6d-Ho<R6 R4 R5 R5 R4 R5 (14) Reagents i p-MeC6H4SCI; ii PzSs CsHsN; iii BuLi; iv R3CHO; v HCI/H,O/MeCN m-C1C6H4CO02H; heat; vi R3X; vii HgCI,/H,O/MeCN; viii (13)/NaH; ix ZnCO, distil; x PhSCrC-Na'; xi m-CIC,H,COO,H; xii (14)/NaH %heme 21 '* M. Sevrin and A. Krief Tetrahedron Letters 1978 187. 85 T. Takahashi H. Nagashima and J. Tsuji Tetrahedron Letters 1978,799. 86 R. C. Cookson and R. Gopalan J.C.S. Chem. Comm. 1978 608 and 924; R.C. Cookson and P. J. Parsons J.C.S. Chem. Comm. 1978,821 and 822. 316 R. Brettle Fleming has shown that P-silylated ketones act as masked cup-olefinic ketones into which they can be converted by bromination-desilylbromination. This is demon- strated by the use of the P-keto-ester (15)as a synthon for olefinic ketones of the type (16)and by the sequence shown in Scheme 22.'' MeCOCHC02Me MekR I CH2SiMe3 CH2 (15) (16) Some other routes to aldehydes and ketones based on the alkylation of anion equivalents are discussed in Section 10. Reagents i LiSiMe,Ph CuI; ii R'X; iii CuBr, base Scheme 22 9 Carboxylic Acids and Derivatives Carboxylic acids can be prepared directly from organoboranes by reaction with the dianion from phenoxyacetic acid.88 A selective functionalization of a diene is illustrated by Scheme 23.A new high yielding version of the ester Claisen rear- Reagents i 9-BBN*; ii PhOCHCO;; iii H+/*9-BBN = 9-Borabicyclo[3,3,1]nonane Scheme 23 rangement employing selenium intermediates has been described" and is shown in Scheme 24. 0 Reagents i PhSeBr; ii,'h ; iii NaIO,; iv C6H13NH2 139 "C OH Scheme 24 '' I. Fleming and J. Goldhill J.C.S. Chem. Comm. 1978 176; D. J. Ager and I. Fleming J.C.S. Chem. Comm. 1978,177. S. Hara K. Kishimura and A. Suzuki Tetrahedron Letters 1978 2891. 89 M. Petrzilka Helv. Chim. Acta 1978 61 2286. Synthetic Methods 317 The use of reagents like 4-dimethylaminopyridine (DMAP) and 4-pyrrolidinyl- pyridine (PPY) as highly active acylation catalysts has been reviewed.” They are now used routinely to catalyse the acylation of alcohols using acid anhydrides and it has now also been shown that a direct room temperature esterification of carboxylic acids by alcohols and thiols is possible using dicyclohexylcarbodi-imideas the acti- vator and DMAP or PPY as a catalyst.9* Several other new mild procedures for the direct esterification of acids by alcohols have been recommended based on the use of cyclic amidines (DBU),92 dimethylformamide imide~hloride,~~ NN-dimethyl-phosphoramidic di~hloride,~~ Each of them like the or phenyl dichlor~phosphate.~~ previous procedure” offers advantages for thermally sensitive sterically hindered or chiral reactants.The carboxyl group in amino- hydroxy- and mercapto-carboxylic acids can be specifically activated by 4-dimethylamino-3-butyn-2-one (17) and the resultant enol-ester (18) can then for example be treated with a thiol to give the thiolester (Scheme 25).95 Dimethylaluminium methylselenolate (from tri-methylaluminium and selenium) converts alkyl esters into methylselenol esters which are very promising acyl transfer reagents; for example they react with amines in the presence of mercury(r1) chloride and calcium carbonate to give amide~.~~ Me,N I .Me2NKOCOR Me2N“i.. -% RCOSR’ I IllI CH H\ COMe COMe OCOR (17) (18) Reagents i RC0,H; ii spontaneous at 0 “C; iii R’SH Scheme 25 Acids can also be activated by reaction with catecholborane; an amine then reacts to give the amide.This method9’ hi-is some disadvantages for the preparation of medium ring lactams due to solubility problems but the reaction of the tetrabutyl- ammonium salts of w-amino-acids with B-chlorocatecholborane in pyridine gives better yields of the lactams under homogeneous condition^.^^ Corey’s first total synthesis of a maytansenoid macrocyclic lactam9* employs a characteristically effective new lactamization procedure in which a benzene solution of the tetrabutyl- ammonium salt of the w-amino-acid is added by syringe to a solution of excess mesitylsulphonyl chloride and di-isopropylethylamine in benzene. In the macrolide field 4,4’-bis(2-amino-6-methylpyrimidyl) disulphide has some advantage over 2,2’- bipyridyl disulphide in the activation of w-hydroxy-acids as thiol esters prior to their silver ion catalysed lact~nization.~~ 90 G.Holfe W. Steglich and H. Vorbriiggen Angew. Chem. Internat. Edn. 1978 17,569. 91 A. Hassner and V. Alexaman Tetrahedron Letters 1978 4475; B. Neises and W. Steglich Angew. Chem. Internat. Edn. 1978 17 522. 92 N. Ono T. Yamada T. Saito K. Tanaka and A. Kaji Bull. Chem. SOC.Japan 1978,51,2401. 93 P. A. Stadler Helv. Chim. Acta 1978,61 1675. 94 H.-J. Liu W. H. Chan and S. P. Lee Tetrahedron Letters 1978 4461. 95 H.-J. Gais and T. Lied Angew. Chem. Internat. Edn. 1978,17 267. 96 A. P. Kozikowski and A. Ames J. Org. Chem. 1978,43 2735. 97 D. B. Collum S.-C. Chen and B. Ganem J. Org. Chem. 1978,43,4393. 98 E. J. Corey L. 0.Weigel D. Floyd and M.G. Bock J. Amer. Chem. SOC.,1978 100,2917. 99 J. S. Nimitz and R. H. Wollenberg Tetrahedron Letters 1978 3523. 318 R. Brettle In a quite different type of macrolide Synthesis"' (Scheme 26) an o-hydroxy- iodide is converted into its (phenylsulpheny1)acetyl derivative the anion from which can then displace the iodine; the sulphur substituent permits the optional intro- duction of a conjugated olefinic bond. Reagents i PhSCH,COCI; ii (Me,Si),NK Scheme 26 10 Nitriles The hydrocyanation of conjugated carbonyl compounds has been covered by Organic Acetylenic alcohols [e.g. (191 can be reductively hy- drocyanated to give P-hydroxynitriles [e.g. (20)] by aqueous pentacyanocobaltate(I1) and hydrogen at atmospheric pressure.lo2 Aldoximes can be dehydrated to give nitriles by triethylamine-sulphur dioxide lo3 or by selenium dioxide.lo4 11 Alkylation A bewildering variety of carbanions is now used in synthesis. They are frequently based on the 'Urnpolung' reversed polarity principle so that they are the masked equivalents of hypothetical anions. Many reactions of this type employed to synthesise primarily one particular class of compound have been dealt with in earlier sections. The reactions of other with a wide variety of electrophilic alkylating reagents including halides epoxides aldehydes and ketones and conjugated carbo- nyl systems are discussed in this section. Acyl carbanion equivalents continue to appear. A cyanohydrin ether cannot be used as a masked formaldehyde equivalent but NN-diethylamino acetonitrile can be used instead,"' and in some cases is preferable to 1,3-dithiane.The carbonyl function in the products can be unmasked by copper(r1)-assisted hydrolysis.'06 loo T. Takahashi S. Hashiguchi K. Kasuga and J. Tsuji J. Amer. Chem. Soc. 1978,100,7424. lo' W. Nagata and M. Yoshioka Org. Reactions 1977,25 255. Io2 T. Kunabiki Y. Yamazaki and K. Tarama 112s.Chem. Comm. 1978,63. lo3 G. A. Olah and Y. D. Vankar Synthesis 1978 702. Io4 G. Sosnovsky and J. A. Krogh Synthesis 1978,703. lo' G. Stork A. A. Ozario and A. Y. W. Leong Tetrahedron Letters 1978 5175. G. Buchi P.H. Liang and H. Wuest Tetrahedron Letters 1978 2763. Synthetic Methods Other convenient acyl carbanion equivalents are 2-substituted I,3-benzo-dithiole~,'~~ 1-phenylselenoalkenes,lo8 and bis(phenylseleno)acetals;'08 the selenium based reagents require potassium diisopropylamide-lithium-butoxidefor their deprotonation.The reagent (21) derived from a dithioester by the action of lithium diisopropylamide is the equivalent of the acyl dianion (CHz-C=O) a hitherto unreported specie^.'^' Its application in synthesis is shown in Scheme 27. Et Reagents i RCHO; ii H20; iii EtOCH=CH, H'; iv EtMgX; v E' Scheme 27 R Masked enolate anions continue to be reported and full details have appeared of Corey's earlier work with metallated dimethylhydrazones.' lo Corey has more recently done extensive work in the use of alkenylbenzothiazoles which are readily synthesized from ketones in carbanion chemistry.''* Reduction and metallation gives an enolate anion equivalent (22) which can be alkylated and the carbonyl function then unmasked (Scheme 28a). On the other hand metallation of the alkenylbenzothiazole gives the equivalent of a vinylogous enolate anion (23) which undergoes exclusively a-alkylation; unmasking of the carbonyl group leads to the by-olefinic aldehyde with no isomerization of the double bond (Scheme 28b). (22) major product BT BT BT CH,Ph OHC CH,Ph BT= us> N Reagents i HJPdC; ii BuLi; iii mBr; iv MeOS0,F; v NaBH,; vi MeOS0,F; K2C03 H20; vii LiN(Pr'),; viii PhCH2Br; ix AgNO, H,O; Et3N Scheme 28 lo' S. Ncube A. Pelter K. Smith P. Blutcher and S. Warren Tetrahedron Letters 1978 2345. lo* S.Raucher and G. A. Koolpe J.Org Chem. 1978,43 3794. lW A. 1. Meyers T. A. Tant and D. L. Comins Tetrahedron Letters 1978,4657. 'lo E. J. Corey and D. Enders Chem. Ber. 1978,111 1337 and 1362. E. J. Corey and D. L. Boger Tetrahedron Letters 1978,5,9.and 13. 320 R. Brettle Regiospecifically generated lithioenamines (24) which are available from various precursors can be used as enolate equivalents (Scheme 29),'12 and so can 2-2- ethoxyvinyl-lithi~n;''~the analogous vinylogous anion equivalent 4-ethoxybuta- 193-dienyl-lithium has also been reported.' l4 CHPh CHPh BuCHPh BuCHPh It II I 1 N EtO,RARl -b P R' R' EtO' Reagents i R3COCH2R2; ii BuLi; iii E; iv H,O'; v K'Bu'O-Scheme 29 An a-formylvinyl anion equivalent is available' '' in 1-bromo-2-ethoxycyclo-propyl-lithium (Scheme 30) and the anion (25) is one of several a-ketoanion equivalents now reported116 (Scheme 31).OEt OEt 11 &-i &.(OH). 3OHC OH Br Br Reagents i RCHO; ii EtOH K2C0,; iii H30+ Scheme 30 Reagents i BuLi; ii E; iii (C0,H)2 H20 Scheme 31 "* P. A. Wender and M. A. Eissenstat J.Amer. Chem. SOC.,1978,100,292;P. A. Wender and J. M. Schaus J. Org. Chem. 1978 43 782; S. F. Martin and G. W. Phillips J. Org. Chem. 1978 43 3792. 'I3 K. S. Y. Lau and M. Schlosser I. Org. Chem. 1978,43 1594. 'I4 R. H. Wollenberg Tetrahedron Letters 1978 717. 'I5 T. Hiyama A. Kanakura H. Yamamoto and H. Nozaki Tetrahedron Letters 1978,3047; and 3051. 'I6 M. A. Guaciaro P. M. Wookulich and A. B. Smith Tetrahedron Letters 1978,4661;S. f. Branca and A.B. Smith J. Amer. Chem. Soc. 1978 100,7767. Synthetic Methods Homoenolate anion equivalents are available in the form of a-silyloxyallyl-~ilanes,~"and the anions from Bdiphenylphosphinoyl acetals.118 The former react with acyl halides to give yketoaldehydes and the latter with aldehydes and ketones to give intermediates (26)which can be converted into By-olefinic a~etals"~ (Scheme 32). Lithium p-lithiopropionate reacts with aldehydes and ketones as a homo- enolate dianion thus providing a route to yy-disubstituted y-lactones. Reagents i BuLi; ii R3R4CO; iii NaH THF Scheme 32 Two routes to a-methylene-substituted esters make use of the anions of methyl P-dimethylaminopropionatelzo and ethyl acetoacetate"' as substituted vinyl anion equivalents (Scheme 33).The second of these sequences is just one example of a -C02R C02R Me2N Me2N -f CH3COCH2CO2R2CH3COCHCO2R i,vi.vii vCO2R RI R' Reagents i. LiN(Pr'),; ii R'X; iii MeI; iv DBU*; v NaOR/ROH; vi (CH,O), ;vii heat *DBU = 13-diazobicyclo[5,4,0]undec-5-ene Scheme 33 more general deacylative condensation which is applicable to other active methylkne compounds. A substituted vinyl anion also figures in a new a-methylene-lactone synthesis (Scheme 34);lz2in this work the mesitylsulphonylhydrazone was used but NHS0,Ar NS0,Ar . ... 1. 111 iv v i ii 3R2 R2 5R2 -Reagents i BuLi; ii R1R2CO; iii -70 "C +-3 "C +-70 "C; iv CO,; v CF,CO,H Scheme 34 'I7 A. Hosomi H. Hashimoto and H. Sakurai J. Org. Chem. 1978,43 2551.''' A.Bell A. H. Davidson C. Earnshaw H. K. Norrish R. S. Torr and S.Warren J.C.S. Chem. Comm. 1978,988. 'I9 D. Caine and A. S. Frobese Tetrahedron Letters 1978 883. L.-C. Yu and P. Helquist Tetrahedron Letters 1978 3423. Y. Ueno H. Setoi and M. Okawara Tetrahedron Letters 1978 3753. R. M.Adlington and A. G. M.Barrett J.C.S. Chem. Comm. 1978 1071. 12' 322 R. Brettle the 2,4,6-tri-isopropylsulphonylhydrazone has been recommended recently for this Shapiro-type of vinyl anion generation. lZ3 Carbinyl anion equivalents e.g. (27)124and those of type (28),'25which are readily prepared from aldehydes using tin intermediates have been reported and shown to react with halides and carbonyl compounds to give the protected forms of alcohols and diols respectively.(27) (28) Michael reactions and many other kinds of base-catalysed reactions are well known to be catalysed by fluoride ion in non-protic media. It has now been shown that this catalyst can conveniently be used either immobilized on a polymer or bound to silica gel with the usual advantages of such systems.'26 Several acylanion equivalents have been used as Michael donors. A synthesis of dienones uses the addition of a cyanohydrin ether to a dienylic ~ulphoxide'~~ and a synthesis of y-keto-aldehydes uses the addition of tris(pheny1thio)methyl-lithiumto an a@-olefinic ketone; the aldehyde group is produced by reduction of the adduct by chromium(I1) chloride to the thioacetal which is then unrnasked.l2' A hetero-cuprate derived from acetone NN-dimethylhydrazone has been added to an ap-olefinic ester to give after unmasking a 6-keto-e~ter,'~' and the corresponding lithium salt was added to an alkenyl benzothiazole to give an intermediate which could be converted into a 6-keto-aldehyde; 1-methoxyvinyl-lithium similarly added to give a protected yketo-aldehyde.The Michael addition of ethyl P-nitropropionate to an ap-olefinic ketone intro- duces an acrylic ester residue since the first formed p-nitroester eliminates nitrous acid. This p-acylvinyl anion equivalent has also been used in aldol-type conden- sations. The Michael addition can also be applied to the introduction of an ap-olefinic ketone unit provided that the acetal is used to prevent premature elimination of the nitro group.These Michael additions are illustrated in Scheme 35.130A rather similar result can be achieved by the use of a P-chloroacrylate ester as a Michael acceptor and a preformed ketone enolate as the donor.'31 C02Me WCO2Me 123 A. R. Chamberlin,J. F. Stenke and F. T. Bond J. Org. Chem. 1978,43 147. 124 P.Beak M. Baillargeon and L. G. Carter J. Org. Chem. 1978,43 4255. "'W.C.Still J. Amer. Chem. Sac. 1978,100,1481. J. M. Miller K.-H. So and J. H. Clark J.C.S. Chem. Comm. 1978 466; J. H.Clark J.C.S. Chem. Comm. 1978,789. '" E. Guittet and S. Julia Tetrahedron Letters 1978 1155. '" T.Cohen and S. M. Nolan Tetrahedron Letters 1978 3533. E. J. Corey and D. L. Boger Tetrahedron Letters 1978,4597. P.Bakuzis M.L. F. Bakuzis and T.F. Weingartner Tetrahedron Letters 1978 2371. G.Dionne and Ch. R. Engel Canad. J. Chem. 1978,56,419. Synthetic Methods 0 0 Reagents i Et0,CCH2CH,N0,; ii K' Bu'O-; iii MeOH; iv RC(OMe),CH,CH,NO,; v PriNH; vi H,O+ Scheme 35 The 1,4-addition of the enolate anion from ethyl acetate to an cup-olefinic ketone cannot be achieved directly but two ways of surmounting this difficulty have recently been reported. In the thiolester anion is used (Scheme 36)and in the which is only applicable to disubstituted olefinic ketones the decarboxylative addition of magnesium ethyl malonate gives the desired product directly. COSR COSR CO R I 111 0-Li + Reagents i CH,COSR/LiN(Pr'),; ii R'X or (R'= H),H,O'; iii Hg" Scheme 36 Shono has developed a versatile method for the alkylation of alkenes activated by conjugation to an electron-withdrawing substituent.Reaction with a halide in the presence of zinc leads to an anion which is then trapped by an electrophile for example an aldehyde or ketone or acetic anhydride (Scheme 37). Cyclization can occur with an appropriate halogen-substituted carbonyl compound. 134 The reactions of organocuprates may not be as restricted as earlier reports suggested. Two noteworthy prostanoid syntheses feature a high yield conjugate addition of a vinylcuproate to a y-acyloxy-ap-olefinic aldehyde without loss of the acyloxy group or 1,2-additi0n,'~~ and a facile oxiran ring opening with a mixed cuprate reagent. 136 Corey has developed (3-methyl-3-methoxy-1-butyny1)copper as R'X + R2CH=CR3Y + R4R5C0 M-R'R2CHCYR3C(OH)R4R5 Y = CN or COzMe Scheme 37 132 H.Gerlach and P. Kiinzler Helv. Chim. Acta 1978,61,2503. J. E. McMuny W. A. Andrus and J. H. Musser Synth. Comm. 1978,8 53. T. Shono I. Nishimuchi and M. Sasaki J. Amer. Chem. SOC.,1978 100,4314. 135 B.M.Trost J. M. Timko and J. L. Stanton J.C.S. Chem. Comm. 1978,436. 136 R. F.Newton C. C. Howard D. P. Reynolds A. H. Wadsworth N. M. Crossland and S. M. Roberts J.C.S. Chem. Comm. 1978,663. 324 R. Brettle a superior reagent for the generation of mixed cuprates due to their increased solubility in THF and used it in the preparation of a key intermediate for maytansine synthesis.13' Several other conjugate additions not achievable by organocuprates can now be accomplished in other ways.Conjugate addition to highly-substituted ap-olefinic esters and to ap-olefinic acids can be achieved by using the copper-boron reagents formed from alkyl-lithium copper(1) iodide and boron trifluoride. 13* Conjugate alkynylations can be achieved by the use of a nickel-catalysed reaction with an organoaluminium alkyne; ethynylation requires the use of tri-methylsilylethyne with subsequent deprotection. 139 cup-Olefinic amides perform unsatisfactorily in attempted conjugated addition reactions but the corresponding thioamides undergo 1,4-addition with organolithium and organomagnesium reagents and the products can readily be converted into their oxygen analogue^.'^^ 12 Ring Synthesis Corey has developed two new extremely versatile routes to cyclic systems.The basic reactions have been described in earlier Sections. l1 Addition reactions with alkenyl benzothiazoles make available a variety of dicarbonyl compounds which can then be cyclized by intramolecular aldol reactions to give annelated cup-olefinic ketones. This method is particularly suitable for spiroannelations; one of the many examples is shown in Scheme 38. Corey's 6-keto-ester synthe~is'~' provides an intermediate from which a wide selection of oxygenated decalins can be constructed. Reagents i BTLi; ii P,O,/MeSO,H 60 "C; iii MeLi; iv BrCH,CrCH; v MeOS0,F; vi NaBH,; vii K,CO,/H,O; viii H,SO,; Hg"; ix NaOH/EtOH Scheme 38 The Robinson annelation involves the reaction of a cyclic ketone with an acyclic ap-olefinic ketone.An example of the reverse process has now been re~0rted.l~' It leads to functionalized 9-methyl-& -decalins related structurally to natural sesqui- terpenes (Scheme 39). Much use has been made of the intramolecular versions of reactions better known in their intermolecular modes. For example the first example of an intramolecular De Mayo reaction has been reported as part of a clever total synthesis of longifolene 13' E. J. Corey D. Floyd and B. H. Lipshutz J. Org. Chem. 1978,43,3418; E. J. Corey M. G. Bock A. P. Kozikowski A. V. Rama Rao D. Floyd and B. H. Lipshutz Tetrahedron Letters 1978 1051. Y. Yamamoto and K. Maruyama J. Amer. Chem. SOC.,1978,100 3240. 139 R. T. Hansen D. B. Carr and J. Schwartz 1.Amer. Chern. Soc. 1978,100,2244.Y. Tamura T. Harada H. Iwamoto and 2.4.Yoshida J. Amer. Chem. SOC.,1978 100 5221. H. Irie J. Katakawa Y. Mizuno S. Udaka T. Taga and K. Osaki J.C.S. Chem. Comm. 1978 717. Synthetic Methods C0,Me Me C0,Me O&.+ F- O e O H C0,Me C0,Me H Scheme 39 (Scheme 40).14*Examples of the intramolecular Diels-Alder reaction include the first application to the synthesis of an anti-Bredt ~lefin'~~ (Scheme 41). 0 eoCH 0 Ph O<OCH *Ph .. ... 11 111 0 Reagents i hv; ii Hz,Pd/C; iii spontaneous retroaldolization Scheme 40 Conditions 8 s at 405 "C. Yield 16% Scheme 41 A splendid example of the intermolecular Diels-Alder reaction is provided in Stork's synthesis of Cytochalasin B the major synthetic triumph of 1978,'44in which the reduced iso-indoline unit was constructed by the reaction shown in Scheme 42.The dienophile added to the expected diene component of the triene system and the addition had the expected regioselectivity >80% of the product having the orien- tation shown. Me g$ / H + H OAc Ph 'N Ph H Ac Me 0x0 Scheme 42 W.Oppolzer and T. Godel J. Arner. Chem. Soc. 1978,100,2583. 143 K. J. Shea and S.Wise J. Amer. Chem. S~C., 1978,100,6519. 144 G. Stork Y. Nakahara Y. Nakahara and W. J. Greenlee J. Amer. Chem. Soc. 1978,100,7775. 14' 326 R. Brettle The regioselectivities of several intermolecular Diels-Alder reactions with hetero- substituted dienes have been investigated with a view to obtaining otherwise difficultly available substitution patterns.The nitrogen-substituted diene (29)gives predominantly the 'ortho'-isomer with considerable endo-selectivity (Scheme 43).145The 'rneta'-isomer (30),not accessible using an acetylenic dienophile can be < -cJ:;; i'/CHO NHC0,Et NHC0,Et (29) Scheme 43 obtained by the route shown (Scheme 44)by using methyl P-nitroacrylate where the nitro-group exercises the regiochemical control. 146 In the diene (31)the regioselec- tivity is controlled by the trimethylsilyloxy group;147 the adduct is a protected form of C02Me OMe OMe OMe (30) Reagent i DBU = 1,5-diazabicyclo[5,4,O]undec-5-ene Scheme 44 the ap-olefinic ketone (32) into which it can be converted by standard methods87 (Scheme 45).Phenyl vinyl sulphoxide acts as an acetylene equivalent in the Diels-Alder rea~ti0n.l~~ Me,Si Me,Si 0' i,ii Me,SiO d + MeKCo2Me * Me,SiO C0,Me -odco2Me (31) (32) Reagents i N-brornosuccinimide; ii Me,SO Scheme 45 145 L. E. Overrnan G. F. Taylor K. N. Houk and L. N. Domelsmith,J. Amer. Chem. SOC.,1978,100,3182; L. E. Overman and P. J. Jessup J. Amer. Chem. Soc. 1978 100 5179. 146 S. Danishefsky M. P. Prisbylla and S. Hiner J. Amer. Chem. SOC.,1978 100,2918. 147 I. Fleming and A. Percival J.C.S. Chem. Comm. 1978 178. 14' L. A. Paquette R. E. Moerck B. Harichian and P. D. Magnus J. Amer. Chem. Soc. 1978,100 1597. Synthetic Methods Yamamoto’s modified aldol condensation has been applied intramolecularly to an ap-olefinic aldehyde;14’ only 1,2-addition occurred (Scheme 46).Medium and large B0’ L! Reagents i Et,AICI; ii Zn Scheme 46 ring cycloalk-2-ene- 1,4-diones predominantly with the trans-configuration can be prepared by the intramolecular coupling of aw-bisdiazoketones (Scheme 47). 150 Reagents i Cu(AcAc), C,H, 60 “C Scheme 47 149 J. Tsuji and T.Mandai Tetrahedron Letters 1978 1817. S. Kulkowit and M. A. McKervey J.C.S. Chem. Comm. 1978,1069.

ISSN:0069-3030    

DOI:10.1039/OC9787500303

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

14 Biological Chemistry Part (i) Biosynthesis By J. R. HANSON School of Molecular Sciences University of Sussex Brighton BN 1 9QJ 1 Introduction This report covers the period since 1975l and is of necessity highly selective. The fourth and fifth volumes of the Chemical Society’s Specialist Periodical Report on Biosynthesis have appeared. The period has been dominated by the application of C n.m.r. whilst examples have also begun to appear using 2H 3H,and ”N n.m.r. However these still complement rather than displace radio-isotopic techniques. Computer methods which have been used2 to generate skeleta based on a limited number of plausible biogenetic reactions illustrate the wide variety of possible skeletal types and the consequent limitations of ‘biogenetic analogy’ in structural reasoning.These methods have also been used3 to predict the distribution of label arising from different plausible biogenetic schemes. In a review lecture Birch has disc~ssed,~ inter alia the possibilities of analogue biosynthesis which is attracting attention in a number of fields (e.g. gibberellins ergot alkaloids gliotoxin). A useful review of the stereospecific synthesis of 3H-labelled organic compounds describes’ the preparation of many biosynthetic intermediates. The preparation of chiral acetic acid from glycine has been described.6 2 Polyketides Deuterium has been as a tracer in a study of terrein (1)biosynthesis. The isotope was located using 2H-’3C coupling patterns. The intact incorporation of the starter CD3C02- group was established from the isotope shift of the 13C resonance in the *H-decoupled spectrum.The superposition of two 13C-13C coupling patterns in R. B. Boar and D. A. Widdowson Ann. Reports (B),1975,72,415. * D. H. Smith and R. E. Carhart Tetrahedron 1976,32,2513. T. H. Varkony D. H. Smith and C. Djerassi Tetrahedron 1978 34 841. A. J. Birch Pure Appl. Chem. 1978,50 1005. D.W. Young in ‘Isotopes in Organic Chemistry’ Vol. 4 ed. E. Buncel and C. C. Lee Elsevier Amsterdam 1978 p. 177. ‘M. Kajiwara S.-F. Lee A. I. Scott M. Akhtar C. R. Jones and P. M. Jordan J.C.S. Chem. Comm. 1978,967. ’ M.J. Garson R. A. Hill and J. Staunton J.C.S. Chem. Comm. 1977,624. M.J. Garson R. A. Hill and J. Staunton J.C.S. Chem. Comm. 1977 921. 329 330 J.R. Hanson the fungal metabolite scytalone (2) biosynthesized from [13C2]acetate impliesg a symmetrical precursor such as (3).A similar effect has been noted" in the biosyn- thesis of secalonic acid A in which the labelling pattern is in accord with a benzophenone intermediate which can reach rotational equilibrium before dimerization. The 2H-'3C isotope shift and coupling pattern was also usedg'" to locate the site of an [2-2H3 2-13C] acetate label in scytalone. OH 0 OH OH HO HOfyJ HOfyJ O"i" OH ' OH ' OH (1) (2) (3) A number of pathways involving either the folding of a polyketide of six acetate units or two separate polyketide residues have been for the biosyn- thesis of the fungal metabolite sclerin (5). However the [13C2]acetate labelling pattern and the incorporation of a sclerotinin A (4) suggestt4 that it is a pentaketide formed by a novel cleavage and recyclization sequence.On the other hand two initial chains may be involved" in the biosynthesis of citromycetin (6). Scheme 1 The biosynthesis of the antibiotic griseofulvin (9) was one of the first examples to be studied by 14C labelling. The incorporation of 13C-labelled acetate via a U. Sankawa H. Shimada T. Sato T. Kinashita and K. Yamasaki Tetrahedron Letters 1977,483; H. Set0 and H. Yonehara ibid. 1977,487. lo I. Kurobane L. C. Vining A. G. McInnes J. A. Walker and J. L. C. Wright Tetrahedron Letters 1978 1379. U. Sankawa H. Shimada and K. Yamasaki Tetrahedron Letters 1978,3375. R. E. Cox and J:S.E. Holker J.C.S. Perkin I 1976 2077. I3 M. Yamazaki Y. Maebayashi and T. Tokoroyama Tetrahedron Letters 1977,489. I4 M. J. Garson and J. Staunton J.C.S. Chem. Comm. 1977,928; 1978 158. G. E. Evans and J. Staunton J.C.S. Chem. Comm. 1976,760. Biological Chemistry 33 1 heptaketide chain has been described.I6 The benzophenone griseophenone B(7)," which possesses two free hydroxyl groups in ring A,has a key role in the oxidative coupling to form normethyldehydrogriseofulvin (8). 2H n.m.r. spectroscopy has been used" to show that griseofulvin is biosynthesized with the 5'a-configura-tion of deuterium from [5'-2H]griseophenone B and 4-demethyl-[5'-2H]de-hydrogriseofulvin. The last reductive step in the biosynthesis takes place with a trans diaxial addition of hydrogen.CI CI (7) The aflatoxins continue to attract attention.' The [13C]acetate labelling pattern implicated" a single polyketide chain in the biosynthesis of aflatoxin B1 whilst evidence has been presented for the formation of averufin versiconal acetate (11),21and versicolorin A (12)22from [13C]acetate and for their role (Scheme 2) together with that of sterigmatocystin in aflatoxin B1(13)biosynthesis. 0 CH3-C02-O -HO ~ ~ ~ ~0 ~ 0 HO 0 HO OH 0 OH (10) / (11) OH 0 OH 00 '' T. J. Simpson and J. S. E. Holker Phytochemistry 1977,16,229. C. M. Harris J. S. Robertson and T. M. Harris J. Amer. Chem. SOC. 1976,98,5380. " Y. Sato T. Oda and H. Saito J.C.S. Chem. Comm. 1977,415; 1978 135. l9 D. P.H. Hsieh R. C. Yao D.L. Fitzell and C. A. Reece J. Amer. Chem. Soc. 1976,98 1020. *' C.P. Gorst-Allman K. G. R. Pachler P. S. Steyn P. L. Wessels andD. BuysScott,J.CS. Chem. Comm. 1976,916;J.C.S. Perkin I 1977,2181. R.H. Cox F. Churchill R. J. Cole and J. W. Dorner J. Amer. Chem. Soc. 1977,99 3159. '* C. P. Gorst-Allman P. S. Steyn P. L. Wessels and D. Buys Scott J.C.S. Perkin I 1978 961 and refs. therein. 332 J. R. Hanson The assembly pattern of acetate units in the phenalenone system of deoxy-herqueinone (14) indicates23 a biosynthesis (Scheme 3)from seven acetate units and an isoprene unit. Malonate feeding results showed a clear acetate starter effect. Amongst many other 13C n.m.r. labelling studies which have been reported are those on the fungal xanthone ravenelin which is biosynthesized purely from acetate rather than shikimate chartreu~in,~~ daunomycin,26 dothi~tromin,~~ lankacidin C," molli~in,~~ and ~anthomegnin.~' (14) Scheme 3 The stereochemistry of incorporation of chirally labelled acetate and malonate into fatty acids has been de~cribed.~~ A higher proportion of label was retained in palmitic acid from the (S)-[2-'4C,2-2H,2-3H]acetyl CoA and (S)-[U-I4C,2-3H]malonyl CoA than from the (R)-epimers.Arachidonic acid (15) forms a key intermediate in the biosyn thesis (Scheme 4) of the prostaglandins prostacyclins and thromboxanes -a subject which has been extensively re~iewed.~' 3 Terpenoids The biosynthesis of 3-hydroxy-3-ethylglutarate and 3-homomevalonic acid precursors of the insect juvenile hormone has been e~tablished~~ in the insect Manduca sexta.The prenyltransferase reaction involving the 1'4-coupling of isoprene units has been extensively and evidence presented for an ionization :condensation :elimination sequence (Scheme 5). Prenyltransferase does not have a very stringent substrate specificity. The coupling of the methylated 23 T. J. Simpson J.C.S. Chem. Comm. 1976,258. 24-A.J. Birch J. Baldas J. R. Hlubucek T. J. Simpson and P. W. Westerman J.C.S. Perkin I 1976,898. 25 P. Canham L. C. Vining A. G. McInnes J. A. Walter and J. L. C. Wright J.C.S. Chem. Comm. 1976 319. 26 R. C. Paulick M. L. Casey and H. W. Whitlock J. Amer. Chem. SOC. 1976,98 3370. 27 G. J. Shaw M. Chick and R. Hodges Phytochemistry 1978,17 1743.28 M. Uramoto N. Otake L. Cary and M. Tanabe J. Amer. Chem. SOC.,1978,100,3616. 29 M. L. Casey R. C. Paulick and H. W. Whitlock J. Amer. Chem. SOC., 1976,98,2636. 30 T. J. Simpson J.C.S. Perkin I 1977 592. 31 B. Sedgwick and J. W. Cornforth EuropeanJ.Biochem. 1977,75,465;B. Sedgwick J. W. Cornforth S. J. French R. T. Gray E. Kelstrup and P. Willadsen European J. Biochem. 1977,75481. 32 see for example K. H. Gibson Chem. SOC. Rev. 1977,6,489. 33 F. C. Baker and D. A. Schooley,J.C.S. Chem. Comm. 1978,292;E.Lee D. A. Schooley M. S. Hall and K. J. Judy ibid.,p. 290. 34 for a review see C. D. Poulter and H. C. Rilling Accounts Chem. Res. 1978 11 307. Biological Chemistry C02H OH OH PGHZ TXAp 0 Hd \?4 CO,H 2aA+- OH OH OH OH PGF2 PGI2 Scheme 4 LOPP -/&/+ R R\ L+OPP OPP 1 OPP (PP =P*o6-) Scheme 5 334 J.R. Hanson analogue (16) of isopentenyl pyrophosphate with dimethylallyl pyrophosphate afforded3’ (4S,8S)-4,8-dimethylfarnesol (17) revealing the latent stereospecificity of this process. CH H CH (16) (17) The biosynthesis of aromatic hemiterpenoids has been reviewed.36 The incorporation of [l3C2]acetate into flavoglaucin has shown that in this case of aromatic isoprenylation there was no change in the stereochemistry of the olefin in the dimethylallyl moiety.37 Cell-free extracts of monoterpenoid-producing plants contain3* ‘salvage’ enzyme systems which convert prenyl pyrophosphates such as isopentenyl pyrophosphate into water-soluble products such as 3-methyl-3,4-oxidobutan-l-ol and the cor- responding triol.The biosynthesis of the thujane skeleton from geraniol and nerol which are interconverted by a redox process has continued to attract attention.39 However tracer from geraniol and nerol was incorp~rated~~ into the irregular monoterpene artemisiaketone (18) with extensive scrambling in contrast to the incorporation into regular monoterpenoids such as isothujone (19). The hydrolysis of the C-0 bond of truns,truns-farnesyl pyrophosphate (20) in Androgruphis tissue culture takes place41 with retention of configuration. Using the cyclization to cyclonerodiol(22) to reveal the stereochemistry the isomerization of farnesyl pyrophosphate to nerolidyl pyrophosphate (21)has been shown to occur42 with a syn (suprafacial) stereochemistry (Scheme 6).[l3C2]Acetate and mevalonate studies have been used to define the folding of farnesyl pyrophosphate in the formation of a number of sesquiterpenoids including f~mannosin,~~ tri~hothecin,~~ and illudin M.45 Examination of the [4,5-13C2]mevalonate coupling and the induced 35 T. Koyama K. Ogura and S. Seto J. Amer. Chem. SOC.,1977,99 1999. 36 M. F.Grundon Tetrahedron 1978,34,143. ’’ J. K. Allen K. D. Barrow A. J. Jones and P. Hanisch J.C.S. Perkin I 1978 152. 38 D.V. Banthorpe G. A. Bucknall J. A. Gutowski and M. G. Rowan Phytochemistry 1977,16,355. 39 D.V. Banthorpe J. Mann and I. Poots Phytochemistry 1977,16,547;D. V. Banthorpe 0.Ekundayo and M. G. Rowan Phytochemistry 1978,17,1111;D.V. Banthorpe B. M. Modawi I. Poots and M. G. Rowan ibid. p. 1115. 40 K.G. Allen D. V. Banthorpe B. V. Charlwood and C. M. Voller Phytochemistry 1977,16,79;D. V. Banthorpe B. V. Charlwood G. M. Greaves and C. M. Voller ibid. p. 1387. 41 H.Mackie and K. H. Overton European J. Biochem. 1977,77 101. 42 D.E.Cane R. Iyengar andM.-S. Shiao J. Amer. Chem. SOC. 1978,100,7122. 43 D.E.Cane and R. B. Nachbar Tetrahedron Letters 1976,2097;J. Amer. Chem. SOC. 1978,100,3208. 44 B. Dockerill J. R. Hanson and M. Siverns Phytochemistry 1978 17 427. 45 A. P.W. Bradshaw J. R. Hanson and M. Siverns J.C.S. Chem. Comm. 1978,303. Biological Chemistry Ill DJ :$OH H OH Scheme 6 couplings between centres enriched by flooding a system with [13C]acetate has been to define the folding of farnesyl pyrophosphate in the biosynthesis of dihydrobotrydial (23).U AcO The application of 2H n.m.r. to the biosynthesis of ovalicin (24) enabled4’ the labels from [5-2H]mevalonate to be located. The fate of mevalonoid hydrogen in ‘OCH 0 (24) 46 A. P. W. Bradshaw J. R. Hanson and M. Siverns,J.C.S. Chem. Comm. 1977,819;J. R. Hanson and R. Nyfeler J.C.S. Chem. Comm. 1976,72. ‘’D. E. Cane and S. L. Buchwald J. Amer. Chem. Soc. 1977,99 6132. 336 J.R. Hanson the biosynthesis of the sesquiterpenoids culmorin cyclonerodiol illudin M tri-chodiene and trichothecin has been determined using 3H:14C ratio In another application of ’H n.m.r. to biosynthetic studies the stereochemistry of the SN2’ process involved in the allylic displacement of the pyrophosphate (25) to form rosenonolactone (26) has been to take place with an overall anti-stereochemistry (Scheme 7).The biosynthesis of the gibberellin plant hormones has H Scheme 7 continued to attract attention in both the chemical and biological literature.” l80 Studies have showns1 that both the oxygen atoms of the 19-carboxylic acid grouping in (27) are incorporated into the 19,lO-y-lactone bridge of the CI9 gibberellins e.g. (28) whilst the C-20 carbon atom is liberateds2 as carbon dioxide. The substrate g-$J moH . HO !H H *PC02HCHZoH CO H (27) (28) specificity of a number of steps in gibberellin biosynthesis has been examined53 using variously substituted including fluorinated kaurenoid substrates.The effect of deuterium on the 13C n.m.r. spectrum has been to distinguish between different hydride shifts in the cyclization of geranylgeranyl pyrophosphate to form fusicoccin. A demonstration that presqualene pyrophosphate is an obligatory intermediate in squalene biosynthesis utilized” the homologous phosphonophosphate analogue as a 48 R. Evans and J. R. Hanson J.C.S. Perkin I 1976,326; J. R. Hanson T. Marten and R. Nyfeler ibid.,p. 876; R. Evans J. R. Hanson. and R. Nyfeler ibid. 1976,1214; R. Evans J. R. Hanson and T. Marten ibid. p. 1212; J. R. Hanson and R. Nyfeler ibid. p. 2471. 49 D. E. Cane and P. P. N. Murthy J. Amer. Chem. SOC.,1977,99,8327. J. R. Bearder and V. M. Sponsel Biochem. Soc. Trans.1977,5,569; P. Hedden J. MacMillan and B. 0. Phinney Ann. Rev. Plant Physiol. 1978 29 149; J. MacMillan Pure Appl. Chem. 1978 50 995. ” J. R. Beader J. MacMillan and B. 0.Phinney J.C.S. Chem. Comm. 1976 834. ’’ B. Dockerill R. Evans and J. R. Hanson J.C.S. Chem. Comm. 1977,919. 53 M. W. Lunnon J. MacMillan and B. 0.Phinney J.C.S. Perkin I 1977,2308;B. M. Fraga J. R. Hanson and M. Hernandez Phytochemistry 1978,17,812;B. E. Cross and A. Erasmuson,J.C.S. Chem. Comm. 1978 1013. s4 A. Banerji R. Hunter G. Mellows K.-Y.Sim and D. H. R. Barton J.C.S. Chem. Comm. 1978,843. ” E. J. Corey and R. P. Volante J. Amer. Chem. SOC., 1976,98 1291. Biological Chemistry competitive inhibitor. In contrast to prenyltransferase squalene synthetase shows a marked substrate specificity.The C-3 methyl groups of farnesyl pyrophosphate are required56 whilst 2-methylfarnesyl pyrophosphate differentiates between the two binding sites of squalene synthetase affording only an 11-monomethylsqualene and not a dirnethylsq~alene.~~ The biosynthesis of sterols in photosynthetic organisms proceeds through cyclo- artenol (29) in contrast to non-photosynthetic organisms which utilize lanosterol (30). The formation of the cyclopropane ring in cycloartenol (29) may occur with inversion or retention of configuration. The use of chiral labelled oxidosqualene and 3Hn.m.r. has that the process involves retention of configuration (Scheme 8). The mechanism of cleavage of the ring has been studieds9 in the formation of obtusifoliol (31) from cycloeucalenol.H HO The removal6' of the 14a-methyl group of lanosterol (30) in cholesterol biosyn- thesis involves the C-32 aldehyde and the loss of the carbon atom as formic acid. Demethylation at C-4 involves the loss firstly of the 4a-methyl group via a P-keto-acid and then the original 4P-methyl group is epimerized to afford a C-4a-monomethyl sterol. The demethylation of this in obtusifoliol(31) results in the axial 4P-hydrogen atom being inverted into the equatorial 4a-position of the 4-desmethyl product poriferasterol.61 The loss of the C-19 group in oestrogen biosynthesis proceeds via the C-19 aldehyde and leads to the liberation of formic acid which acquires an "0label from oxygen gas implicating a Baeyer-VilIiger type 36 P.R. Ortiz de Montellano R. Castillo W. Vinson and J. S. Wei J. Amer. Chem. SOC. 1976,98,3020;W. N. Washburn and R. Kow Tetrahedron Letters 1977 1555. 57 P. R. Ortiz de Montellano R. Castillo W. Vinson and J. S. Wei J. Amer. Chem. SOC. 1976,98,2018. 58 L. J. Altman C. Y. Han A. Bertolino G. Handy D. Laungani W. Muller S. Schwartz D. Shanker W. H. de Wolf and F. Yang J. Amer. Chem. Soc. 1978 100 3235. 59 A. Rahier L. Cattel and P. Benveniste Phytochemistry 1977,16 1187. 60 M. Akhtar K. Alexander R. B. Boar J. F. McGhie and D. H. R. Barton Biochem. J. 1978,169,449. 61 F. F. Knapp L. J. Goad andT. W. Goodwin Phytochemistry 1977,16 1677. 338 J. R. Hanson of mechanism for this step.62 13C n.m.r. studies have been reported on cholesterol biosynthesized from [f3C]mevalonates.The labelling pattern of the side chain (32) indicates that in its formation by reduction of the 24,25-double bond the hydrogen atoms are added from the re The stereochemistry of hydrogen migration from C-24 to C-25 during isofucosterol bio~ynthesis~~ and the sequence involved in the elaboration of the phytosterol side chain6' have been studied. The cyclization of the carotenoid lycopene (33) to zeaxanthin (34) in a Flauobac-terium species grown in 2H20has been shown66 to occur with the initial attack of a proton (deuteron) on the re-faceof the 1,2-double bond. from 3'Me MvA 4 Shikimic Acid Metabolites An extensive review of the shikimic acid pathway has appea~ed.~' The stereo- chemistry of isoflavone reduction during the biosynthesis of the phytoalexin demethylhomopterocarpin (35) has been studied6' by 2H n.m.r.Evidence based69 on the feeding of cinnamic acids shows that various procyanidin dimers are biosyn- thesized from two metabolically distinct units (+)-catechin or (-)-epicatechin and the C-4 carbo-cation derived by protonation of flav-3-en-3-01s. Naturally occurring xanthones are commonly biosynthesized uia benzophenones derived from polyketides in fungi24 and shikimate polyketides in plants. The intact incorporation of a c&3 unit p-coumaric acid (as opposed to c&1 unit) into mangiferin (36) has been demonstrated" in Anemarrhena asphoeliodes. M. Akhtar D. Corina J. Pratt and T. Smith J.C.S. Chem. Comm. 1976 854. 63 G.Popjhk J. Edmond F.A. L. Anet and N. R. Easton J. Amer. Chem. SOC. 1977,W. 931. F.Nicotra F.Ronchetti G. Russo,G. Lugaro and M. Casellato J.C.S. Chem. Comm. 1977 889. " C.Largeau. L. J. Goad and T. W. Goodwin Phyrochemisfry 1977,16 1925. " G.Britton W. J. S. Lockley N. J. Patel T. W. Goodwin and G. Englert J.C.S. Chem. Comm. 1977 655. '' B. Ganem Tetrahedron 1978,34 3353. P. M.Dewick and D. Ward J.C.S. Chem. Comm. 1977,338;Phytochemistry 1978,17,1751. 69 E.Haslam Phytochemistry 1977 16 1625; E.Haslam C. T. Opie and L. J. Parter ibid. p. 99;D. Jacques C. T.Opie L. J. Porter and E. Haslam J.C.S. Perkin I 1977. 1637. 'O M.Fujita and T. Inoue Tetrahedron Letters 1977,4503. Biological Chemistry 339 5 Alkaloid Biosynthesis The mode of incorporation of lysine into securinine (37)has shown7' that the piperidine ring is formed in an unsymmetrical manner.The results of a study7* of the biosynthesis of the lupin alkaloid lupanine suggest that it is formed from lysine via an isotripiperideine. Reticuline (38)is an established precursor of a large number of benzylisoquinoline alkaloids. Although tyrosine contribute^^^ to the formation of both portions dopa & M::J3$Me Me0 ' H OH (37) (38) and dopamine afford the phenylethylamine portion whilst the benzylic portion is derived from 3,4-dihydroxyphenylpyruvicacid. Both enantiomers of reticuline are incorp~rated~~ into the morphinandienone alkaloid sebiferine (39)through the intervention of a redox system which allows the epimerization of the (+) to the (-)-form.Tracer experiments have been on the incorporation of (+)-norprotosinomenine into the abnormal Erythrina alkaloids such as isococculidine. The specific incorporation of phenylalanine into cephalotaxine (40) has shown that the cyclopentene arises76 by the loss of one carbon atom from the aromatic ring of OMe Me0 0 0 phenylalanine. The incorporation of tyrosine cinnamic acid and some later inter- mediates into the mesembrine alkaloids has been Several groups have 71 W. M. Golebiewski P. Horsewood and 1. D. Spenser J.C.S. Chem. Comm. 1976,217. 72 W. M. Golebiewski and I. D. Spenser J. Amer. Chem. SOC.,1976,98,6726. 73 D. S. Bhakuni A. N. Singh S. Tewari and R. S. Kapil J.C.S.Perkin I 1977 1662. 74 D. S. Bhakuni V. M. Mangla A. N. Singh and R.S. Kapil J.C.S. Perkin I 1978 267. 75 D. S. Bhakuni A. N. Singh and R. S. Kapil J.C.S. Chem. Comm. 1977,211. 76 J. N. Schwab M. N. T. Chang and R. J. Parry J. Amer. Chem. SOC.,1977,99,2368. 77 P. W. Jeffs D. B. Johnson N. H. Martin and B. S. Rauckman,J.C.S. Chem. Comm. 1976,82; P. W. Jeffs and J. M. Karle. ibid. 1977,60; P. W. Jeffs J. M. Karle andN. H. Martin Phyrochemistry,1978,17,719. 340 J. R. Hanson shown7' that in contrast to previous work the key precursor of the indole alkaloids which arises from tryptamine and secologanin is (3s)-strictosidine (41) and not its (3R)-epimer. Strictosidine is the common precursor for both the 3a- and 3P-indole alkaloids. The corresponding 3a-isomer in the condensation of dopamine and secologanin acts as the precursor of the Ipecac alkaloid^.^' Cathenamine (42),which accumulates in cell-free preparations from Catharanthus roseus in the absence of NADPH is incorporatedso into ajmalicine.The biosynthesis of the ergot alkaloids has been reviewed.81 6 Other Amino-acid Derived Metabolites The biosynthesis of the p-lactam antibiotics has been thoroughly reviewed.82 The tripeptide 8-(L-a-aminoadipy1)-L-cysteinyl-D-valine is a key intermediate in peni- cillin biosynthesis. Since the configuration at C-3 of penicillin is 'D',an inversion takes place on the incorporation of L-valine. Although the a-hydrogen of L-valine is lost in this process I5N n.m.r. studies have now confirmed83 that the N atom is retained. The feeding of stereospecifically labelled cysteines has shown that the cyclization to give the p-lactam ring of the penicillin^^^ and cephalo~porins~~ proceeds with the loss of the 3-pro-S-hydrogen and the retention of the 3-pro-R- hydrogen of cysteine.Thus there is net retention of stereochemistry in the cycliza- tion. Cyclo-(L-phenylalanyl-L-seryl) has been showns6 to be an intermediate in the biosynthesis of gliotoxin. Cyclo-(L-alanyl-L-phenylalanyl) is efficiently con-verted8' into 3a-deoxygliotoxin in an analogue biosynthesis in Trichoderma uiride. The biosynthesis of the porphyrins was extensively reviewed in last year's Annual Repord8 and hence is only briefly mentioned here. Other reviews have also appea~ed.~~.~~ Further evidenceg1 has been presented showing that the 78 J. Stockigt and M.H. Zenk J.C.S. Chem. Comm. 1977,646;M. Rueffer N. Nagakura and M. H. Zenk Tetrahedron Letters 1978 1593; R. T. Brown J. Leonard and S. K. Sleigh Phytochemistry 1978 17 899; A. H. Heckendorf and C. R. Hutchinson Tetrahedron Letters 1977,4153. 79 A. R. Battersby N. G. Lewis and J. M. Tippett Tetrahedron Letters 1978,4849. J. Stockigt H. P.Husson C. Kan-Fan and M. H. Zenk J.C.S. Chem. Comm. 1977 164. H. G. Floss,Tetrahedron 1976 32 873. D. J. Aberhart Tetrahedron 1977 33 1545. 83 H. Booth B. W. Bycroft C. M. Wels K. Corbett and A. P. Maloney J.C.S. Chem. Comm. 1976 110. 84 D. W. Young D. J. Morecombe and P.K. Sen European J. Biochem. 1977,75,133. J. A. Huddleston E. P.Abraham D. W. Young D. J. Morecombe and P.K. Sen Biochem. J. 1978 169,705. 86 G.W. Kirby G. L. Patrick and D. J. Robins J.C.S. Perkin I 1978 1336. 87 G. W. Kirby and D. J. Robins J.C.S. Chem. Comm. 1976 354. D. G. Buckley Ann. Reports (B) 1977 74 392. 89 A. I. Scott Accounts Chem. Res. 1978 11,29. 90 A. R.Battersby Experientia 1978 34 1. 91 A. R. Battersby C. J. R. Fookes E. McDonald and N. J. Meegan J.C.S. Chem. Comm. 1978,185;A. R.Battersby C. J. R. Fookes G. W. J. Matcham and E. McDonald ibid. p. 1064. Biological Chemistry deaminase :cosynthetase enzyme system ring-closes the unrearranged bilanes far more efficiently than any of the isomeric irregular bilanes. In support of its structure sirohydrochlorin is specifically incorporated into cobyrinic acid.92 The retention of 'sN-'3C coupling in streptonigrin (43) biosynthesized from [2-'3C,1-'5N]tryptophan has been used to show which bonds remain intact during the bio~ynthesis.~~'~~ C-Methylated amino-acids are quite rare.However /3-methyltryptophan has been shown" to be an intermediate in the biosynthesis of streptonigrin. A similar C-methylation occurs in the biosynthesis of indolmycin The use of methionine carrying a chiral methyl group has that this alkylation proceeds with inversion of configuration. The biosynthesis of the firefly luciferin (44) has been ~hown~'.~~ to involve the condensation between p-benzoquinone and two molecules of cysteine. 0 CH,O OCH (43) (44) 7 Miscellaneous Metabolites The conversion of octanoic acid to lipoic acid (45) involves the unusual substitution by sulphur at two saturated carbon atoms.This takes place without the loss of hydrogen from the adjacent centres (C-5 and C-7).99 A similar observation has been made on the incorporation of desthiobiotin into biotin."' s%,o OH (45) The labelling pattern of the antibiotics geldanamycin"' and pactamycin'02 by [6-'3C]glucose methionine and acetate has been described. 92 A. R. Battersby E. McDonald M. Thompson and V. Y. Bykhovsky J.C.S. Chem. Comm. 1978,150. 93 S. J. Gould and C. C. Chang J.Amer. Chem. SOC.,1978,100,1624. 94 S.J. Gould and C. C. Chang J. Amer. Chem. Sac. 1977,99 5496. 95 S. J. Gould and D. S. Darling Tetrahedron Letters 1978 3207. 96 L. Mascaro. R. Horhammer S. Eisenstein L. K. Sellers K. Mascaro and H. G. Floss.J. Amer. Chem. SOC.,1977,99,273.97 K. Okada H. Iio and T. Goto J.C.S. Chem. Comm. 1976 32. 98 F. McCapra and Z. Razavi J.C.S. Chem. Comm. 1976 153. 99 R. J. Parry J. Amer. Chem. SOC.,1977,99 6464. loo R. J. Parry and M. G. Kunitani J. Amer. Chem. SOC.,1976,98,4024. lo' A. Haber R. D. Johnson and K. L. Rinehart J. Amer. Chem. SOC.,1977,99 3541. D. D. Weller and K. L. Rinehart J. Amer. Chem. SOC., 1978 100 6757.

ISSN:0069-3030    

DOI:10.1039/OC9787500329

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

14 Biological Chemistry Part (ii) Organic Peroxides Biological and Synthetic Aspects By W. ADAM" Department of Chemistry University of Puerto Rico Rio Piedras Puerto Rico 00931 USA and A. J. BLOODWORTH Department of Chemistry University College London 20 Gordon Street London WCl HOAJ The current reintensification of interest in the chemistry of organic peroxides stems from the recognition that organic peroxides have an important and varied role in a biological context. The identification of peroxides as key products in biosynthetic pathways has presented organic chemists with new synthetic challenges. These challenges have in turn stimulated the development of new synthetic methodology in the peroxide area. In this review we attempt to highlight these developments.1 Biological Perspective The discovery of ascaridole in 1908 as principal constituent of chenopodium oil and its characterization in 1912 as the endoperoxide structure (1) marks the beginning of (1) the challenging and fruitful era of biologically relevant peroxides.* Thereby it was illustrated that the reaction of biological matter with molecular oxygen or its derivatives (hydrogen peroxide superoxide ion ozone etc.) leads to peroxide- containing products which survive the biological conditions despite the labile nature of the peroxide linkage. a National Institutes of Health Career Development Awardee (1975-80) K.Gollnick and G 0.Schenck in '1,CCycloaddition Reactions' ed. J. Hamer Academic Press 1967 Chap. 10; H. H. Szmant and A.Halpern J. Amer. Chem. Soc. 1949,71,1133. 342 Biologica1 Chemistry Nevertheless it took about half-a-century until full-scale exploration of this important field began. This is indeed rather paradoxical since biological systems must abound with bio-peroxides in view of the fact that molecular oxygen is essential for sustaining life of most organisms. Thus biological matter in cells continuously interacts with molecular oxygen transforming it into hydrogen peroxide superoxide ion etc. all known to degrade cell components by oxidation presumably but not necessarily via the labile peroxides. In part the reason for the delay on the progress of detecting isolating and identifying bio-peroxides can be ascribed to the contro- versial case of ergosterol endoperoxide (2).It was first discovered by Windaus (1928:)’ in connection with his Vitamin D studies but claimed as a ‘natural’ endoperoxide by Wieland and Prelog (1947),3who isolated it from the mycelium Aspergillus fumigatus which was cultured in the dark. However first Schenck’ and more recently Arditti4 suggested that (2) was formed as an adventitious by-product due to photo-sensitized oxygenation of ergosterol. However a careful recent investigation’ clearly established that the endoperoxide (2) is the product of an enzymatic oxygenation. The mechanistic origin of ascaridole (l),which is produced in the leaves of the plant is clearly by way of photosensitized oxygenation in which the chlorophyll serves as sensitizer sunlight as radiation source a-terpinene as substrate and atmospheric oxygen as oxidant.However ergosterol endoperoxide (2) is formed in the dark as the result of enzymatic oxygenation. The biomechanistic details of this interesting process are still not well understood but it is clear that oxygenating enzymes (oxygenases) must be involved. The detection purification and charac- terisation of a number of these important enzymes6 during the last twenty-five years provided impetus in the search for bio-peroxides. The latter must be the initial products of enzymatic oxygenation and consequently their detection isolation and identification form the cornerstone in understanding the action of oxygenases on biological matter. Much progress has been made on bio-peroxides and enzymatic oxygenation especially during the last decade.To summarize this progress exhaus- tively would be difficult since new bio-peroxides are being discovered or postulated daily. However we shall highlight the salient features of this exciting development in the interest of providing an overview and perspective. Stable Peroxides of Marine and Plant Origin.-Let us illustrate the diversity and complexity of stable peroxides that have been isolated and characterized during the A. Windaus and J. Brunken J. Liebig Ann. Chem. 1928,460,225. P. Wieland and V. Prelog Helv. Chim. Acta 1947,30 3272. J. Arditti R. Ernst M. H. Fisch andB. H. Flick J.C.S. Chem. Comm. 1972 1217. M. L. Bates W. W. Reid and J. D. White J.C.S. Chem. Comm. 1976.44. ‘Molecular Mechanisms of Oxygen Activation’ ed.0.Hayaishi Academic Press,1974. W. Adam and A. J. Bloodworth last few years from a variety of natural sources especially of marine origin. An unusual structure is rhodophytin (31 which was isolated from marine algae of the genus Laurencia (Rhodophyta).' The remarkable structural feature of this novel marine natural product is the vinyl peroxide moiety. To date no stable model compound of chemical origin possessing this elusive peroxide functionality is known which underlines the uniqueness of this bio-peroxide. The evidence on which the structure (3) is based is convincing but its thermal stability contradicts chemical experience. An X-ray structure confirmation seems important. From sponge of the Chondrilla genus the stable natural peroxide (4) containing the peroxyketal structure was isolated.8 Again the structural assignment appears convincing except that the HC1-catalysed conversion of (4) into a chloro-enone via a cyclic vinyl peroxide seems unlikely.A simpler and more probable decomposition mode of (4) into chloro-enone would be a Criegee-Hock rearrangement. Another stable bioperoxide derived from the Caribbean sponge Plakortis halichondrioides is plakortin (5).9 Unlike the stable steroidal peroxides possessing the ergosterol endoperoxide structure (2) found in sponges,'o which are derived from adventitious photo-oxygenation (4) and (5) appear to be of enzymatic origin. Both are formed stereospecifically rather than as a mixture of diastereoisomers as in the case of (2).The interesting neoconcinndiol hydroperoxide (6) was recently isolated from the red seaweed Laurencia sugderiae." It is still uncertain whether this unprecedented diterpene hydroperoxide (6) is the result of a dioxygenase biogenic pathway or an artifact of ene-type hydroperoxylation with singlet oxygen. ' W. Fenical J. Amer. Chem. SOC.,1974 96 5580. R. J. Wells Tetrahedron Letters 1976,2637. M. D. Higgs and D. J. Faulkner J. Org. Chem. 1978,43,3454. lo E. Fattorusso S. Magno C. Santacroce and D. Sica Garzetta 1974,104 409; Y. M. Sheikh and C. Djerassi Tetrahedron 1974 30,4095. B. M. Howard W. Fenical J. Finer K. Hirotsu and J. Clardy J. Amer. Chem. SOC.,1977,99,6440. Biological Chemistry (6) Novel natural peroxides of plant origin are (7) and (8),isolated respectively from the leaves of Eucalyptus grandis and from fungi.I3 The hydroxy-1,2-dioxy- cyclohex-4-ene structure (7) represents the ring tautomer of the hydroperoxy isomer (7a) which most likely is the product of a photosensitized ene-type oxygenation in the leaves of Eucalyptus grandis.The fungi peroxides verruculogen (8a) and fumitre- morgin A (8b) are unusual and it is as yet unknown whether they are produced by enzymatic oxygenation. The physiological activity of these stable natural peroxides is as diverse as their varied structural features. Thus the sponge endoperoxide plakortin (5) shows antimicrobial activity,' the Eucalyptus grandis derived peroxide (7) inhibits root formation,'* and the fungus metabolites verruculogen (8a) and fumitremorgin A (8b) are tremorgenic agents.13 (7) CH Ho-o oyo (8b)R= (74 Diepoxide and Furan Metabolites.-Several natural products possess structural units consisting of either cis-diepoxides (10) or furans (11).Some of these are thought to be derived via metabolic transformation of the intermediate endo- peroxides (9) arising from the oxygenation of 1,3-dienes (Scheme 1).Although this biogenetic pathway has not been established for most of the examples that are cited studies of model compounds amply support this supposition. Furthermore bio- mechanistically it constitutes the most expedient rationalization of their formation. One of the earliest cis-diepoxides to be recognized was crotepoxide (12) isolated from the fruits of Croton macrostachys.l4 This novel tumor-inhibitory antibiotic was l2 W.D. Crow W. Nicholls and M. Sterns TetrahedronLetters 1971 1353. 13 (a)J. Fayos. D. Lokensgard,J. Clardy R. J. Cole and J. W. Kirksey J. Amer. Chem. Soc. 1974 % 6785; (b)N. Eickman J. Clardy R. J. Cole and J. W. Kirksey Tetrahedron Letters 1975 1051. 14 S. M. Kupchan R. J. Hemingway P. Coggon A. T. McPhail and G. A. Sim J. Amer. Chem. SOC.,1968 90,2983. W.Adam and A. J. Bloodworth 0 II "OAc recently synthesized" using the pathway in Scheme 1. A structurally related natural diepoxide is the fungal antibiotic (13).16 Also the unusual antileukemic diterpenoid triepoxides triptolide and tripdiolide (14) isolated from the roots of Tripterygium wilfurdii," might have a similar biosynthetic history.The related diterpene diepoxide stemolide (15) from the leaves of Stemodia maritima is not antitumoric.18 (14a) R=H (i4bj R=OH The naturally occurring 3-alkylfurans perillaketone (16) a-clausenane (17) and ipomeamarone (18) were efficiently synthesized from their respective dienes via singlet oxygenation and subsequent dehydration (Scheme l).I9 This constitutes )JJ ,J 0 / 0 (16) (17) (18) Is M. R. Demuth P. E. Garrett and J. D. White J. Arner. Chem. SOC..1976 98,634. l6 D. B. Borders P. Shu and J. E. Lancaster,J. Arner. Chem. Soc. 1972,94,2540; H.-J. Altenbach and E. Vogel Angew. Chern. 1972 84,9. S. M. Kupchan W. A. Court R. G. Dailey jun. C. J. Gilmore and R. F. Bryan J.Amer. Chem. SOC. 1972,94,7194. P. S. Marchand and J. F. Blount Tetrahedron Letters 1976 2489. l9 K. Kondo and M. Matsumoto Tetrahedron Letters 1976,4363. Biological Chemistry therefore a likely pathway for the biogenesis of terpene derived substances. The rather drastic conditions for the dehydrationlg were recently avoided by employing lithium di-isopropylamide and p-toluenesulfonyl chloride” or the biosynthetically more significant ferrous sulfate-catalysed transformation.21 AflatoxinBiogenesis.-These extremely toxic materials produced in peanuts by the fungus Aspergillus fravus are also among the most potent carcinogenic natural products.2’ Their fascinating biosynthetic history involving intermediate peroxide- containing metabolites is still controversial.BUchiz3 first suggested that aflatoxin B1(21) might be derived from the endoperoxide (19) via the established sterig- matocystin (20). At that time no chemical model studies were available to support the proposed rearrangement of endoperoxide (19) and the pyran (22) was proposed as intermediate. This novel biogenetic hypothesis was tested rigorously by experi- ments involving 13C n.m.r. spectroscopy and the results revealed that the naph- thacene endoperoxide (19)could not be the precursor to (21) via (22).23 (Starred positions represent 13C atoms derived from carboxy carbon-labelled acetic acid). OH OH CH ‘OH 0 ‘ti. (22) However recentz4 studies on the decomposition of model endoperoxides (Scheme 2) revive the endoperoxide (19) as a plausible intermediate metabolite in the aflatoxin biogenesis.Application of the mechanistic sequence of Scheme 2 to the endo- peroxide (19) affords aflatoxin B1(21) with the correct labelling pattern. The fact that the Czo-polyketide metabolite averufin (24) leads to aflatoxin B by the action of Aspergillus para~iticus’~ speaks however against the C18-naphthacene 2o B. Harirchian and P. D. Magnus Synthetic Comm. 1977,119. ” J. A. Turner and W. Herz J. Org. Chem. 1977,42 1900. ’’J. A. Miller ‘Toxicants Occurring Naturally in Foods’,National Academy of Sciences Washington D.C. 1973;E. K. Weisburger. Chemistry 1977,50,42 23 P. S. Steyn R. Vleggaar P. L. Wessels and D. B. Scott J.C.S. Chem. Comm. 1975 193. 24 M.K.Logani W.A. Austin and R. E. Davies Tetrahedron Letters 1978,511 ;J. Rigaudy C. Breliere and P. Scribe Tetrahedron Letters 1978 687. 25 D. P. H. Hsieh R. C. Yao D. L. Fitzell and C. A. Reece J. Amer. Chem. SOC.,1976,98 1020. W.Adam and A. J. Bloodworth \ '01 R Scheme 2 endoperoxide (19)intermediate. Since the biosynthetic history of (24)is still obscure and since the ketal (23) which is structurally similar to (24) is an endoperoxide product (Scheme 2) an endoperoxide precursor is still viable in the biogenesis of aflatoxin B1. Prostaglandin Endoperoxide.-The establishment of the intervention of the endo- peroxide (25) in the metabolism of arachidonic acid emphasizes the importance of peroxides in biological oxidations. The labile endoperoxide (25) serves as precursor to the pharmacologically potent hormonal agents PGE (26a) PGF (26b) throm- boxane (26c) and prostacyclin (26d).Fortunately two recent reviews26 spare us the task of summarizing the structural synthetic and physiological aspects of this vast field. R. R= MCOzH; R'= OH 26 K. H. Gibson Chem. SOC.Revs. 1977,6,489;K.C.Nicolaou G. P. Gasic and W. E. Barnette Angew. Chem. Internat. Edn.. 1978,17,293. Biological Chemistry The prostaglandin endoperoxide (25) was first postulated in 1967,27 isolated and characterized in 1973,28 and synthesized from PGF (26b) in 1977.29 Recent work suggests that the prostaglandin endoperoxide synthetase is a glycoprotein with an easily dissociable haem prosthetic group which exhibits both oxygenase and peroxi- dase a~tivity.~’ The ferrous sulphate-catalysed transformation of endoperoxides to y-hydroxyketones was suggested as a chemical model for the biosynthesis of PGE (26a) thromboxane (26c) and prostacyclin (26d).31 Lipid Hydroperoxides.-The pathological consequences especially in ageing of cellular lipid peroxides has been convincingly summarized by Bland32 in a recent review.The labile lipid hydroperoxides (27) formed from linoleic acid by the action of lipoxygenase and molecular oxygen,33 serve as initiators of free radical chain oxidation of cell components. More recently the intriguing hydroperoxy- 1,2-diox- acyclopentanes (28) have been characterized in the enzymatic oxygenation of FH2\ CH3CH2-CH=CH-CH=CH-CH CH-CHfCH&CO,Me \/I 0-0 OOH (28d /CH2\ CH3CH2-CH-CH CH-CH=CH-CH=CHfCH2+C02Me (!)OH ‘0-0’ (28b) methyl lin01enate.~~ Steroids such as cholesterol afford the hydroperoxides (29) as intermediate metabolites on enzymatic ~xygenation.~’ ’’ M.Hamberg and B. Samuelsson J. Biol. Chem. 1967 242 5336. 28 M. Hamberg and B. Samuelsson Proc. Nut. Acad. Sci.. USA 1974,71 345; D.H. Nugteren and E. Hazelhof Biochem. Biophys. Acta 1973 326,448. 29 R. A. Johnson E. G. Nidy L. Baczynskyj and R. R. Gorman J. Amer. Chem. Soc. 1977,99,7738. 30 F. J. van der Ouderaa M. Buytenhek D. H. Nugteren and D. A. van Dorp Biochim. Biophys. Acta 1977,487,315. 31 J. A. Turner and W. Herz Experentia 1977,33 1133. 32 J. Bland J. Chem. Edn. 1978,55 151.33 H. W.-S. Chan V. K. Newby and G. Levett J.C.S. Chem. Comm. 1978,82. 34 M.Roza and A. Francke Biochim. Biophys. Acta 1978,528 119. 35 L.L.Smith M. J. Kulig D. Muller and G. A. S. Ansari J. Amer. Chem. Soc. 1978,100,6206. W.Adam and A. J. Bloodworth c,H17 HOLYP (29) Homogentisic Acid Biogenesis.-On the basis of “0labelling experiments it was that the enzymatic oxygenation of p-hydroxyphenylpyruvic acid leading to homogentisic acid (Scheme 3) trespassed through the quinol hydroperoxide (30). Although this biosynthetic pathway was ~hallenged,~’ more recent studies” of model systems make the intervention of (30) plausible. CO,H CO,H o=c I O=C I 6H HO \/CO H HO‘cI’o* * I II c.o* CO:H* I ?H O* cG* H2cfJ 6 Hz8 0 OH 0 0 OH (30) Scheme 3 Plastoquinone Peroxides.-The photochemical destruction of electron transport quinones such as the plastoquinones and menaquinones has been rationalized in terms of peroxide intermediate^.^^ For example model studies4’ on the photo- oxygenationof plastoquinone-1 afforded the stable 1,2,4-trioxacyclohexane product (31).Similarly the menaquinone-9 hydroperoxide (32) which appears to be responsible for the photo-oxidized degradation of menaq~inone,~~ could originate from the intermediate 1,2,4-trioxacyclohexane (32a).39 36 B. Lindblad G. Linstedt and S. Linstedt J. Amer. Chem. SOC., 1970,92 7446. 37 A.S.Widman A. H. Soloway R. L. Stern and M. M. Bursey Bioorg. Chem. 1973 2 176. 38 I. Saito Y. Chujo H. Shimazu M. Yamane T.Matsuura and H. J. Cahnmann J. Amer. Chem. SOC. 1975,97,5272. 39 R.M.Wilson S. W. Wunderly J. G. Kalmbacher and W. Brabender Ann. New York Acad. Sci.,1976 267,201. 40 D.Creed H. Werbin and E. T. Strom J. Amer. Chem. SOC. 1971 93 502. Biologica1 Chemistry 351 Bilirubin Photo-oxygenation.-The lack of hepatic catabolism of bilirubin and consequently its accumulation in tissue are the cause for jaundice in premature babies. To avoid brain damage the common treatment for neonatal jaundice is near-u.v. irradiation of the infant which promotes bleaching of the bilirubin a yellow pigment presumably through autosensitized photo-oxygenation and subsequent breakdown of the intermediate peroxides into smaller soluble fragments. Chemical model studies suggest that photo-oxygenation of bilirubin probably proceeds through the peroxides (33),which represents an efficient and convenient mechanistic rati~nalization.~~ In fact Similar peroxide products are formed with bili~erdin.~~ the catabolic conversion of haem into biliverdin has been interpreted to proceed via peroxide intermediate^.^^ Me R' Me R2 RZ Me Me R' I H I H I H I H (334 Me R' Me R2 R2 Me Me R' H H H H Formylkynurenine Biosynthesis.-The important class of oxygenase enzymes were discovered in connection with tryptophan metabolism.Without this discovery it would have been difficult to understand biological oxygenations of organic matter.6 Even so it took about a quarter of a century to confirm through studies of model compounds that the tryptophan hydroperoxide (34) is the precursor to formylky- nurenine in the oxygenation of tryptophan (Scheme 4).45 Similar model studies on other model indole derivatives in support of tryptophan 2,3-dioxygenase action have recently been reviewed.46 Aromatic Hydroxylation by mavine Monoxygenase.-Conflicting mechanistic rationalizations of biological hydroxylation of aromatic rings by molecular oxygen 41 C.D. Snyder and H. Rapoport J. Amer. Chem. SOC. 1969,91,731. 42 D. A. Lightner and G. B. Quistad F.E.B.S.Letters 1972,25,94; D. A. Lightner,G. S. Bisacchi and R. D. Norris J. Amer. Chem. SOC. 1976,98 802. 43 I. B. C. Matheson and M. M. Toledo Photochem. Photobiol. 1977,25,243; D. A. Lightner and D. C. Crandall Tetrahedron Letters 1973 953.44 J.-H.Fuhrhop S. Besecke J. Subramanian Chr. Mengersen and D. Riesner J. Amer. Chem. Soc. 1975 97,7141. 45 M. Nakagawa H. Watanabe S. Kodato H. Okajiura T. Hino J. L. Flippen and B. Witkop Proc. Nat. Acad. Sci. USA,1977.744730. 46 I. Saito T. Matsuura M. Nakagawa and T. Hino Accounts Chem. Res. 1977 10 346. W.Adam and A. J. Bloodworth NH-C-H II 0 Scheme 4 with the help of flavine monoxygenase have been presented. A number of inter-mediates derived from the dihydroflavin which are capable of transferring a single oxygen to the aromatic substrate have been So far none have been rigorously established through chemical model studies but all seem to be derived from the dihydroflavin hydroperoxide (35). Recent chemical work lends support to the intervention of 4a-hydroperoxyflavin (35)and similar structures have been suggested in bacterial biolumine~cence.~~ Firefly Bioluminescence.-Another class of bio-peroxides namely the a-peroxy- lactones are the active intermediates in biolumines~ence.~~ The a-peroxylactone structure (36)of firefly luciferin was postulated over ten years ago,” but it took a decade of controversy to confirm through isotopic labelling experiment^,^' its intervention.Although these bio-peroxides are too unstable to permit isolation model compounds have been prepared’* and shown to emit light on thermal decomposition.53 0 (36) 47 G. I. Dmitrienko V. Snieckus and T. Viswanatha Biorg. Chem. 1977 6 421; H. W. Orf and D. Dolphin Proc.Nut. Acad. Sci. U.S.A.,1974 71 2646. 48 C. Kemal T. W. Chan and T. C. Bruice J. Amer. Chem. SOC. 1977 99 7272; C. Kemal and T. C. Bruice J. Amer. Chem. Soc. 1977,99,7064;J. W. Hastings and K. H. Nealson Ann.Rev. Microbiol. 1977,31 549. 49 W. Adam J. Chem. Educ. 1975,51,138;J. W. Hastingsand T. Wilson Photochem. Photobiol. 1976,23 461. T. A. Hopkins H. H. Seliger E. H. White and M. W. Cass J. Amer. Chem. SOC.,1967,89 7148; F. McCapra Y. C. Chang and V. P. Francois J.C.S. Chem. Comm. 1968,22. 0. Shimomura T. Goto,and F. H. Johnson Proc. Nut. Acad. Sci. U.S.A.,1977,74,2799;J. Wannlund M. DeLuca K. Stempel and P. D. Boyer Biochem. Biophys. Res. Comm. 1978 81,987. 52 W. Adam A. AlzCrreca J.-C. Liu and F. Yany J. Amer. Chem. SOC.,1977 99 5768.53 W. Adam 0.Cueto andF. Yany J. Amer. Chem. SOC.,1978,100,2587. Biological Chemistry 353 The multitude and diversity of bio-peroxides that intervene as stable or labile intermediates in the metabolic pathways of all sorts of biological matter is evident from the examples sited here. Undoubtedly future work in this new and exciting field should uncover and confirm many more biologically important peroxides and lead to a greater understanding of biological oxygenations and their physiological consequences. 2 Synthetic Methods Organic peroxides have always presented a considerable synthetic challenge in view of their marked thermal instability and high chemical reactivity. The labile inter- mediates postulated in biological oxidations are thus particularly formidable pre- parative targets that have demanded the development of new synthetic methods of exceptional mildness.The methodology of organic peroxide synthesis as it stood in 1960 is summarized with great clarity in Davies’ m~nograph.’~ Preparative developments during the next decade are well covered in three volumes edited by Swern.” Subsequently a number of significant advances have been made and it is the aim of this Section to highlight these. For the purposes of discussion we shall divide the methods into three categories according to the nature of the reagent that introduces the O2moiety. Thus new modifications to the alkylation and acylation of hydrogen peroxide and related nucleophiles are treated first. Next we summarize the synthetically useful aspects of singlet oxygenation and finally we present some preparatively important develop- ments in triplet oxygenation.Nucleophilic Displacements by Hydrogen Peroxide and Related Species.-The reaction of hydrogen peroxide at electrophilic carbon atoms provides the main route to many simple organic peroxides. Thus alkyl hydroperoxides and dialkyl peroxides are obtained by SNldisplacements at tertiary carbon atoms or SN2displacements at primary and secondary carbon atoms. Strongly acidic or basic media and long reaction times at elevated temperatures are often required and can cause extensive decomposition of the desired product. Modifications aimed at engendering reac- tivity under milder conditions primarily involve using more powerful alkylating agents but include the use of alternative nucleophiles such as the superoxide ion.Silver-salt-assisted Alkylation by Alkyl Halides. The first successful application of this technique appears to have been Kopecky’s well known tetra-alkyldioxetane synthe~is.~~ hydroperoxide upon shaking with Thus 3-bromo-2,3-dimethyl-2-butyl a suspension of silver acetate or benzoate in dichloromethane gave a mixture (Scheme 5) from which tetramethyldioxetane (37)was isolated in 30% yield. The dioxetane of 1,2-dimethylcyclohexene was similarly prepared but use of P-iodoalkyl hydroperoxides was found to give better yields and to be essential in the preparation of the h9~’0-octalin dioxetane. 54 ‘Organic Peroxides’ A. G. Davies Butterworths London 1961.55 ‘Organic Peroxides’ ed. D. Swern Wiley-Interscience 1970 Vol. 1; 1971 Vol. 2; 1972 Vol. 3. 56 K. R. Kopecky J. E. Filby C. Mumford P. A. Lockwood and J. Y. Ding Cunud.J. Chem. 1975,53 1103. W.Adam and A. J. Bloodworth HOO Me I 1 Me-C-C-Me I I Me Br AgOAc ___+ 0-0 I1 Me-C-C-Me 1 1 Me Me OOH I //CH2+ Me-C-C he ‘Me 0 II+ Me,C-C-Me (37) Scheme 5 The intermolecular reaction with silver trifluoroacetate (Scheme 6)57provides a convenient and general preparation of alkyl hydroperoxides and dialkyl peroxides. AgOzC.CF R’OOH +R2X R’OOR2 +AgX+ H02C.CF3 Scheme 6 Alkyl bromides are suitable for making tertiary and secondary derivatives but iodides are required in the preparation of primary peroxides. Seventeen examples with yields of 27-93% were reported.Some di-t-alkyl peroxides (e.g. Me2PriCOOMe2Pri)were obtained for which the conventional method of alcohol sulphuric acid and hydrogen peroxide fails because dehydration of the alcohol or formation of rearranged products prevail. It appears that chlorides are sufficiently reactive to permit the synthesis of allylic hydro peroxide^.^^ Silver nitrate was used in the preparation of cyclohexenyl hydroperoxide but it was necessary to employ the trifluoromethanesulphonate with 3-chloro-2-methoxycyclohexene(Scheme 7) to avoid substantial competitive incorporation of the silver salt’s anion. Ag03SCF3 GOMe + H2°z -Scheme 7 The intramolecular reaction has been extended to y-bromoalkyl hydroperoxides thereby providing syntheses of 1,2-dioxacyclopentanes (Scheme 8)” and of bicyclic peroxides (Scheme 9)60including 2,3-dioxabicyclo[2,2 l]heptane61 (see Section 3).Results to date suggest that the silver salt method is excellent for making dialkyl peroxides both acyclic and (bi)cyclic but is less successful as a hydroperoxide R NBS R 0-0 OOH Scheme 8 57 P. G. Cookson A. G. Davies and B. P. Roberts Chem. Comm. 1976 1022. A. A. Frimer J. Org. Chem. 1977,42 3194. 59 W. Adam A. Birke C. Cidiz S.Diaz and A. Rodriguez J. Org. Chem. 1978,43 1154. 6o A. J. Bloodworth and B. P. Leddy Tetrahedron Letters 1979,729. 61 N. A. Porter and D. W. Gilmore J. Amer. Chem. SOC.,1977,99,3503. 355 Biologica1 Chemistry __+ J3r2 oooH Scheme 9 synthesis. High yields of allylic hydroperoxides were reporteds8 but the method utilized a large excess (10-14 fold) of 98% H202which is potentialty hazardous and should be avoided if possible.It is advisable to carry out the reactions in the dark to avoid possible formation of metallic silver which can catalyse peroxide decom- position; silver trifluoroacetate appears to be the reagent of choice. The alkylation proceeds with predominant inversion of configuration,62 a factor of considerable importance in the design of reactions leading to bicyclic peroxides.60*61 Alkylation by Alkyl Trifuoromethanesulphonates and N-Alkyl-N'-tosylhydrazines. Alkyl trifluoromethanesulphonates are sufficiently powerful to alkylate t-butyl hydroperoxide under non-alkaline conditions. Acceptable yields (33-56%) of secondary alkyl peroxides have been obtained without accompanying elimination and under conditions where the corresponding alkyl methanesulphonates do not react (Scheme Scheme 10 The method has been extended to the synthesis of 1,2-dio~acycloalkanes~~ (Scheme 11; n = 1-4) and 2,3-dioxabicyc10[2,2,l]heptane~~(see Section 3) by using bis(trimethylstanny1) peroxide as the nucleophile; bis(trimethylsily1) peroxide 0-0 Scheme 11 A very promising new method for the preparation of primary and secondary alkyl hydroperoxides involves the oxidation of N-alkyl-N'- tosylhydrazines (Scheme 12).66 H202/Na202 R-NH-NH-TS AROOH Scheme 12 Neopentyl hexadecyl cyclohexyl cis-and trans-2 -methylcyclohexyl and some steroidal hydroperoxides were obtained in yields (by h.p.1.c.analysis) of 87--95% ; " A. G. Davies and A. J. Sotowicz personal communication. 63 M. F. Salomon R. G. Salomon and R. D. Gleim J. Org. Chem. 1976 41 3983. '* M. F. Salomon and R. G. Salomon J. Amer. Chem. SOC.,1977,99,3500. " R. G. Salomon and M. F. Salomon J. Amer. Chem. SOC.,1977,99,3501. '' L. Caglioti F. Gasparrini D. Misiti and G. Palmieri Tefiuhedron 1978 34 135. W.Adam and A. J. Bloodworth yields of isolated products were not quoted. The N-alkyl-N'- tosylhydrazines are obtained by reducing the corresponding tosylhydrazones (from aldehydes or ketones) or N-acyl-N'-tosylhydrazines (from carboxylic acids) and isolation prior to oxidation is unnecessary. A notable advantage of the method is that it employs low strength (30%)H202.Alkylation by Alkenes and Epoxides. As a route to organic peroxides the alkylation of hydrogen peroxide by carbonium ions generated by protonation of alkenes is very limited in scope. Reactions induced by other electrophiles (Scheme 13) are more \/ c-c I c=c \/E+ /\+/\ROOH -H+ 'ROO-C-C-E 1 /\ E I1 Scheme 13 successful. Thus sources of positive halogen such as N-bromosuccinimide and 1,3-di-iodo-5,5-dimethylhydantoinprovide the P-halogenoalkyl hydroperoxides that are used in dioxetane synthesis (Scheme 5).56 Except for the recent demon- stration of a related intramolecular reaction6' and of the extension (with difficulty) to cyclopr~panes,~~~~~ there have been no developments of note since Kopecky's original introduction of the use of N-haloamides a decade ago.68 Peroxymercuration (Scheme 14) where the electrophile is a mercury(I1) salt has been extensively developed since its discovery in 1969 and has proved to be R'CH=CHR2 +ROOH +HgX2 +R1CH(OOR)CH(HgX)R2+HX (38) Scheme 14 extremely versatile.The P-mercurioalkyl peroxides (38)are obtained in high yield and can often be demercurated with sodium borohydride (Scheme 15)or halogens R1CH(OOR)CH(HgX)R2+NaBH,/OH R'CH(OOR)CH2R2 (39) Scheme 15 (Scheme 16) without substantial cleavage of the 0-0 bond; both peroxymer- curation and demercurations occur rapidly under mild conditions. R'CH(OOR)CH(HgX)R2+ R'CH(OOR)CH(Hal)R2 Halz --XHgHal (40) Scheme 16 That secondary alkyl compounds can be obtained in much higher yields than those achieved through conventional nucleophilic displacements and that the method is applicable to the synthesis of acylic cyclic and bicyclic peroxides are the facts of prime importance."L. A. Paquette R. V. C. Carr andF. Bellamy J. Amer. Chem. SOC.,1978,100,6764. K. R. Kopecky J. H. van de Sande and C. Mumford Canad J. Chem. 1968,4625. Biological Chemistry Thus secondary alkyl t-butyl peroxides (39)69 and P-halogenoalkyl t-butyl perox- ides (40)70 have been obtained in yields (based on alkene) of 60-75%. Ketone and ester functions can be tolerated and a wide range of new functionally substituted peroxides of types (41)-(44)7’ have also been prepared. R1R2C(OOBu‘)CH2CO2Me RCH(OOBu‘)CH(Hal)COY (41) (42) (Y = Ph OMe) Me2C(OOBu‘)COY HalCH2CMe(00Bu‘)COY (43)(Y = Me OMe) (44) (Y= Me OMe) By using hydrogen peroxide and suitable dienes mercury-free cyclic secondary alkyl peroxides containing 5-and 6-membered rings have been obtained for the first time and in yields of 50-75% (Scheme 17; n = 1or 2,Z = H or Br).72 Scheme 17 Several other examples some with tertiary carbons next to the peroxide linkage have been obtained similarly and the four diastereoisomers of compound (45) have been isolated by h.p.1~~~ (45) Scheme 18 In these diene reactions the initial peroxymercuration generates an unsaturated hydroperoxide which then cyclizes via a second intramolecular addition.The cycloperoxymercuration can of course be carried out on alkenyl hydroperoxides prepared in other ways.Interestingly such reactions have provided synthesis of 4- and 7-membered peroxide rings (Schemes 1974 and 2075),albeit in low yield. Scheme 19 69 (a) D. H. Ballard and A. J. Bloodworth J. Chem. SOC.C. 1971 945; (6)A. J. Bloodworth and G. S. Bylina J.C.S. Perkin I 1972 2433; (c) A.J. Bloodworth and I. M. Griffin J.C.S. Perkin I 1975 195. 70 A. J. Bloodworth and I. M. Griffin J.C.S. Perkin I 1975 695. 71 (a)A. J. Bloodworth and R. J. Bunce J.C.S. PerkinI 1972,2787;(6)A. J. Bloodworth and I. M. Griffin J.C.S. Perkin I 1974,688. ” A. J. Bloodworth and M. E. Loveitt J.C.S.Perkin I 1978 522. 73 A. J. Bloodworth and J. A. Khan unpublished work. 74 W. Adam and K. Sakanishi J. Amer. Chem. Soc.,1978,100 3935. 75 J. R.Nixon. M.A. Cudd and N. A. Porter J. Org. Chem. 1978,43,4048. W. Adam and A. J. Bloodworth HgX NaBH OH-nOOH 0-0 Scheme 20 To date the synthesis of bicyclic peroxides uia peroxymercuration has been restricted to the [3,3,2]- and [5,2,1]-dioxabicyclodecanes obtained from 1,s-cyclo- octadiene (Scheme 21),76 1,4-cyclo-octadiene (Scheme 22),77 and cyclo-octenyl hydroperoxide.60 H,02 *-NaBH,/OH-2HgX2 01 Br2 Z Z=HorBr Scheme 21 -BZ (23 Z Z =H or Br Scheme 22 Each reaction is regiospecific and it is important to note that the products obtained are isomeric with the [4,2,2]-peroxide available via photo-oxygenation of 1,3-cyclo-octadiene (see later). The choice of mercury(I1) salt can be crucial. Thus whereas mercury(I1) nitrate is extremely good for preparing monocyclic peroxides it fails completely with 1,s-cyclo-octadiene.Mercury(I1) acetate can be used but the trifluoroacetate usually gives cleaner reactions. Reductive demercuration is usually accompanied by some epoxidation or deoxymercuration but bromodemercuration is generally very clean. Related to peroxybromination and peroxymercuration is the perhydrolysis of epoxides under acid conditions (Scheme 13; E = OH). The preparation of three 6-hydroalkyl hydroperoxides by this route (Scheme 23) was recently described'* by RLR3 RLwR3 RZ 0 H + H20 R2+H HOO OH Scheme 23 '' W. Adam A. J. Bloodworth H. J. Eggelte and M. E. Loveitt Angew Chem. Internat Edn. 1978,17 209. 77 A. J. Bloodworth and J. A. Khan Tetrahedron Letters 1978 3075.78 V. Subramanyam C. L. Brizuela and A. H. Soloway J.C.S. Chem. Comm. 1976,508. Biological Chemistry 359 authors who were apparently unaware of an earlier of similar uncatalysed reactions which proceed much more slowly. As expected by analogy with peroxymercuration intramolecular variations of the reaction (e.g. Scheme 24) afford good yields of cyclic peroxides.80 Cat. CCl,CO,H Scheme 24 Acylation (see following Section also). The imidazolide technology developed in the 1960's for mild anhydrous acylations appears to be the currer?t method of choice for preparing diacyl peroxides and has been extended to the synthesis of peroxycar- bonates and peroxycarbamates (Scheme 25; Z = Bu'OO RO or RZN).'* Scheme 25 Rather surprisingly the rival carbodi-imide approach of similar vintage has not been used as widely but the cyclization of a-hydroperoxy acids (Scheme 26; R=cyclahe~yl)~~ is a powerful demonstration of its capabilities and it can be expected to gain in popularity.+ RN=C=NR -780c '.FfH -"W+ (RNH),CO HOO 0-0 Scheme 26 Use of Superoxide Ion. The advent of crown ethers has made available solutions of potassium superoxide in organic solvents. A benzene solution of this reagent has been used to provide dialkyl peroxides in 42-77'/0 yield from primary and secon- dary alkyl bromides or sulphonates.82 Both alkylations proceed with inversion of configuration and the reaction is believed to follow the pathway shown in Scheme 27. Oi-+RX + ROO+X-ROO+O; -+ ROO-+02 ROO-+RX -+ ROOR+X-Scheme 27 '' W.Adam and A. Rios Chem. Comm. 1971,822. N. A. Porter M. 0.Funk,D. Gilmore R. Isaac and J. Nixon J. Amer. Chem. Soc. 1976,98,6000. M. J. Bourgeois C. Filliatre R.Lalande B. Maillard and J. J. Villenave Tetrahedron Letters 1978 3355. (a) R.A. Johnson and E. G. Nidy J. Org. Chem. 1975,40 1680; (6)R. A. Johnson E. G. Nidy and M. V. Merritt J. Amer. Chem. SOC..1978 100,7960. W. Adam and A. J. Bloodworth Choice of solvent is crucial for a similar reaction in dimethyl sulphoxide gave mainly alcohols and no peroxides.83 Subsequently it has been that dimethylsulphoxide is oxidized extremely rapidly by ROO-and thus it seems that this process competes effectively with the desired alkylati~n.~~~ However use of dimethylsulphoxide can be tolerated when the second SN2displacement is an intramolecular process (Scheme 28) for a 1,2-dioxacyclopentane was isolated in 35% yield.” Crown Wph MeSO 0,SMe 0-0 Scheme 28 Good yields of diacyl peroxides can be obtained with superoxide in benzene even in the absence of a crown ether (Scheme 29).86 2RCOCI + 2K02 -+ (RC00)z+2KC1+ 02 Scheme 29 This avoids using the anhydrous ether solutions of hydrogen peroxide that are employed in other non-aqueous routes to diacyl peroxides.Singlet Oxygenation.-The area of peroxide synthesis which has received the greatest attention during the 1970’sis unquestionably that of singlet o~ygenation.~~ In its readily accessible ‘Agstate molecular oxygen reacts with a wide range of unsaturated substrates by one or more of the three modes illustrated in Scheme 30.(48) Scheme 30 83 J. S. Filippo C. I. Chern and J. A. Valentine J. Org. Chem.. 1975 40 1678. 84 (a)M. J. Gibian and T. Ungermann J. Org. Chem. 1976,41,2500; (b)However see C. I. Chern R. Di Cosimo R. De Jesus and J. S. Filippo J. Amer. Chem. SOC.,1978,100,7317. 85 E. J. Corey K. C. Nicolaou M. Shibasaki Y. Machida and C. S. Shiner TetrahedronLetters 1975,3 183. 86 R. A. Johnson Tetrahedron Letters 1976 331. ” (a)D. R. Kearns Chem. Rev. 1971,71,395; (b)R. W. Dennyand A. Nickon Org. Reactions 1973,20 133; (c) W. Adam Chem-Zeit 1975,!39,142; (d)‘Singlet Oxygen. Reaction with organic compounds and polymers’ ed. R. Ranby and J. F. Rabek Wiley-Interscience 1978.Biological Chemistry These equations reveal the minimum structural requirements for each process though it should be added that in route a (Scheme 30) one or both of the double bonds can form part of an aromatic system. Structures (46)-(48) thus represent the basic types of peroxide that can be obtained via singlet oxygenation and an extension to type (49) can be achieved by the recently developed technique of di-imide reduction. There are a variety of ways of carrying out singlet oxygenations but for experi- mental convenience the technique of dye-sensitized photo-~xygenation~~’ is usually chosen. Here a solution of the substrate to be peroxidized together with a small quantity to 10-3M) of a coloured sensitizer such as Rose Bengal or tetra- phenylporphine is irradiated with visible light and simultaneously saturated with oxygen.The dye absorbs light to become electronically excited and the excitation is transferred to oxygen to produce the singlet species. Use of sodium lamp largely eliminates the problem of thermal and u.v.-induced decomposition of the peroxidic products without recourse to elaborate filtering devices. An important feature of the reaction is that it often proceeds satisfactorily at temperatures as low as -78°C thereby facilitating the preservation of sensitive products. Labile peroxides have been postulated as intermediates in the photo-oxygenation of a vast number of substrates including biologically important heterocyclic compo~nds,~~*~~ but we shall be concerned only with systems from which peroxides have been isolated and even here we shall of necessity be highly selective in the examples we quote.Where appropriate we shall try to illustrate the discussion with examples that postdate the many excellent review but we shall not be concerned with the mechanistic controversies such as the question of perepoxide intermediates that continue to stimulate much of the current work. 1,2-DioxacycZohex-4-enes (46). Singlet oxygen reacts with many (a)cyclic con- jugated dienes and aromatic substrates by the Diels-Alder mode of addition. Reactions with various substituted butadienes have been known since 1972 and conditions for making the adduct of butadiene itself in 20%yield have recently been reported.89 Vitamin Dz contains an s-cis diene function and affords a 1 1mixture of the expected epimeric peroxides (50) in 35% yield.” Products from endocyclic dienes date from the 1940’s but the bicyclic peroxide (51) is a recent additi~n.~’ (50) (51) Polycyclic aromatics such as rubrene 9,lO-disubstituted anthracenes and activated naphthalenes afford 1,4-adducts that release singlet oxygen on ther- molysis.Recent interest in aromatic substrates has centred on vinylarenes where the ’* T. Matsuura and I. Saito in ‘Photochemistry of Heterocyclic Compounds’ ed. 0.Buchardt Wiley- Interscience 1976,p. 456. 89 T. Kondo M. Matsumoto and M. Tanimoto Tetrahedron Letters 1978 3819. 90 S. Yomada K. Nakayama and H. Takayama Tetrahedron Letters 1978,4895. 91 Y.Kayama M.Oda and Y. Kitahara Chem. Letters 1974,345. W.Adam and A. J. Bloodworth generated peroxide linkage bridges the olefinic &carbon and the ortho-carbon of the aromatic ring. In reactions with stilbenes P-methylstyrenes and &Pdimethyl- styrenes the first-formed product is trapped by further singlet oxygenation (Scheme 31).92 Related monoperoxides from methoxystyrenes where a cis-methoxy group causes a marked acceleration in the rate of addition were isolated as Diels-Alder adducts with l-pheny1-1,3,4-tria~oline-2,5-dione.~~ The aromatic ring can be heterocyclic and in fact addition onto a thiophene ring is preferred to that onto a naphthalene ring in an internal competition (Scheme 32).94 Scheme 32 AZlyt Hydroperoxides (47).Formation of allylic hydroperoxides is usually the preferred mode of reaction for monoalkenes. Synthetic usefulness is reduced because mixtures of hydroperoxides are commonly formed and so there is much interest in regio- and stereo-selective reactions. It has become apparent that there is a very strong preference for abstraction of hydrogens from a group that is cis to a methoxy substituent. Thus (52)affords a mixture containing 72% of the thermo- dynamically less stable hydroperoxide (54) whereas only (53)is formed from the isomer in which methoxy and methyl groups are cis.95 MeO<2 ";o) (D + Me0Hog 8 HOO (52) (53) (54) Scheme 33 92 (a)M. Matsumoto S. Dobashi and K. Kondo Tetrahedron Letters 1977,2329; (b)M. Matsumoto S. Dobashi and K.Kuroda Tetrahedron Letters 1977 3361. 93 D. Lerdal and C. S. Foote Tetrahedron Letters 1978 3227. 94 M. Matsumoto S. Dobashi and K. Kondo Tetrahedron Letters 1975 4471. 95 G. Rousseau P. Le Perchec and J. M. Conia Tetrahedron Letters 1977 2517. Biological Chemistry Where 1,4-addition can compete with the ene reaction only that process involving the group cis to methoxy takes ~lace.~~.~’ This is illustrated in Scheme 34; the alkene with cis phenyl and methoxy groups affords products derived from 1,4-additi0n.~’ Ph Me0 Ph Scheme 34 The earlier discovery that the Me3Si group can take the place of an allylic hydrogen in the ene reaction has been used to advantage in the preparation of a-hydroperoxy acidss2 and (Scheme 35; R = SiMe or Me).Scheme 35 Other products are also formed if R’and R2contain allylic hydrogens or are phenyl groups. 1,Z-Dioxetunes (48). Where a monoalkene lacks allylic hydrogens but carries alkoxy or amino substituents [e.g. (55)] or where an ene reaction would lead to an allylic hydroperoxide with a strained double bond [e.g. (56)] and in a few other cases singlet oxygenation provides a route to 1,2-dio~efanes.~’ EtO/-OEt -+ (55) EtO OEt The formation of a-peroxylactones from ketenes (Scheme 37)98is an important extension of this technique. Acceptable yields could not be obtained by photo-oxygenation and it was neces- sary to use triphenyl phosphite ozonide as the singlet oxygen source. % W. Adam and J. del Fierro J. Org. Chem. 1978,43 1159.97 W. Adam Adv. Heterocyclic Chem. 1977,21,437. N. J. Turro Y. Ito M.-F. Chow W. Adam 0.Rodriguez and F. Yany J. Amer. Chem. Soc. 1977,99 5836. W.Adam and A. J. Bloodworth Scheme 37 1,2-Dioxacyclohexanes (48). The discovery99 that di-imide reduces the double bond of singlet oxygen-diene adducts (46) while leaving the peroxide linkage intact opened up a general route to saturated bicyclic peroxides that incorporate the 1,2-dioxacyclohexane ring. There seems no reason why the technique should not be extended to the monocyclic series. Normally the reduction is carried out in methanol where the di-imide is generated in situ from dipotassium azodicarboxylate and acetic acid. By this method the compounds (57),99(58) epidioxyergosteryl acetate and 1,2,3,4-tetrahydro-l,4- dimethyl-1,4-epidoxynaphthalene,100and (59)76have been obtained.By changing the reduction medium to dichloromethane and using a deficiency of acetic acid the more labile peroxides (60) (61),1°1a (62),1°1b (63),lo1' and 2,3-dioxabi- cyclo[2,2 l]heptane102 (see Section 3) have been prepared. Triplet Oxygenation.-Ground state triplet oxygenation of organic substrates occurs widely but is often an unattractive preparative route to peroxides because complex mixtures of products are obtained. Hydroperoxides result from hydrogen abstrac- tion by intermediate peroxy radicals but if the substrate contains unsaturation in a suitable position cycloaddition can occur. Such a process is believed to take place during the biosynthesis of prostaglandin endoperoxides.By generating specific peroxy radicals from unsaturated alkyl hydroperoxides controlled cycloaddition has been achieved (Scheme 38);" subsequent reduction afforded cyclic peroxides iden- tical with those obtained (Scheme 24) via the corresponding epoxides. 99 D. J. Coughlin and R. G. Salomon J. Amer. Chem. Soc. 1977,99,655. loo W.Adam and H. J. Eggelte Angew. Chem. Internat. Edn. 1977,16,713. lo' (a)W.Adam and I. Erden Angew. Chem. Internat. Edn. 1978,17,210,211; (b)W.Adam and I. Erden .K Org. Chem. 1978,43,2737;(c)W.Adam and H. J. Eggelte Angew. Chem. Internat. Edn. 1978,17 765. lo* W. Adam and H. J. Eggelte J. Ore. Chem. 1977,42 3987. Biological Chemistry Scheme 38 One of the ways in which regiospecificity can be introduced into autoxidation is to use an organometallic derivative or carbanion.Good yields of hydroperoxd escan be obtained in this way provided that reaction conditions are such (e.g. inverse addition) that there is always a high oxygen-to-substrate ratio. This methodology has been exploited recently in the synthesis of a-hydroperoxy ketones,lo3 and acids (Scheme 39).52v104 Scheme 39 Lithium di-isopropylamide (R =NPr'J was used to lithiate aliphatic acids but was unsuitable for arylacetic acids because the corresponding peroxides are decomposed by even traces of di-isopropylamine. However the greater carbon-acidity of aryl- acetic acids permitted the use of butyl-lithium (R =Bu) without complications from attack on the carbonyl group.Finally we must draw attention to some new triplet oxygenations that are catalyzed by Lewis acids and present an alternative to singlet oxygenation for converting some cyclic conjugated dienes into bicyclic peroxides. lo5 The oxygenation of ergosteryl acetate (Scheme 40) at -78°C was used as a model for testing catalyst efficiency. l7 catalyst + 30 -AcO AcO Scheme 40 The compounds BF3 SnCI, SnBr4 SbF5 SnCL WF6 12 and Phb3F4 require simultaneous irradiation to be effective whereas with VOCI, FeCI, MoCI, WC16 and (4-BrCsH4),gBF4 the reaction proceeds satisfactorily in the dark. The mechanism currently involves electron transfer from the alkene to generate intermediate radical cations. On the basis of this hypothesis the reaction lo3 Y. Sawaki and Y.Ogata J. Amer. Chem. SOC.,1975,97,6983. '04 (a)D. A. Konen L. S. Silbert and P. E. Pfeffer J. Org. Chem. 1975,40,3253;(b)W. Adam 0.Cueto and V. Ehrig J. Org. Chem. 1976,41,370;(c) W. Adam and 0.Cueto I. Org. Chem. 1977,42 38. (a)D. H. R.Barton,R. K. Haynes G. Leclerc P. D. Magnus and I. D. Menzies J.C.S. Perkin I 1975 2055; (6) R. K. Haynes Austral. J. Chem. 1978,31 121 131. lo' R.Tang,H. J. Yue J. F. Wolf and F. Mares J. Amer. Chem. SOC.,1978 100 5248. W:Adam and A. J. Bloodworth has been extended to the synthesis of 3,3,6,6-tetra-aryl-1,2-dioxacyclohexanes (Scheme 41) where yields of 80-90°/~ have been achieved."' A related trans- formation has been carried out intramolecularly with 1,l'-bis( 1-phenylviny1)ferro- cene.'" 2 Ar\ ,C=CH + 30 Ar 0-0 Scheme 41 3 Biologically Significant Syntheses The implication of novel organic peroxides in key biological roles demanded the study of simpler analogues to enable the postulated chemistry to be put on a firm experimental basis.From a synthetic viewpoint some simple but unknown peroxides thus assumed the role of biologically significant target molecules. In this section we describe how the new synthetic methodology has been applied to the synthesis of 2,3-dioxabicyclo[2,2 llheptane the peroxidic nucleus of prostaglandin endoperox- ides and to a-peroxylactones models for the chemienergizers of bioluminescence. The successful preparation of these model compounds has been closely followed by the first synthesis of an actual prostaglandin endoperoxide.2,3-DioxabHcyclo[ 2,2,l]heptane and Prostaglandin Endoperoxides.-In 1977 three independent syntheses of 2,3-dioxabicyclo[2,2,l]heptane(64)were reported (Reac- tions i-iii in Scheme 42) and later a fourth route was added. Scheme 42 lo' R. K. Haynes M. K.S.Probert and I. D. Wilmot Austral. J. Chem. 1978,31,1737. M. Hisatome T. Namiki and K.Yamakawa J. Organometallic Chem. 1976 117 C23. Biologica1 Chemistry 367 Salomon and Sa10mon~~ utilized their combination of trifluoromethanesulphonate leaving group and bis(tributy1stannyl)peroxide nucleophile (Reaction i) but even then it was necessary to carry out the reaction in vacua with rapid transfer of the volatile products to a cold trap to avoid decomposition. Purification was effected by t.1.c.on silica gel at -20 "C and the yield was 13%. The product was characterized by 'H n.m.r. spectroscopy and by catalytic hydrogenation to cis-1,3-cyclo-pentanediol. Porter and Gilmore's method6' was to ring-close trans- 3-bromocyclopentyl hydroperoxide with silver (trifluor0)acetate (Reaction ii). Reaction of a bicyclo- pentane with 98% H202and N-bromosuccinimide in ether at -41 "C afforded a 1:1 mixture of cis- and trans-hydroperoxides which was separated by silica chromato- graphy at -10 "C.Stirring the trans-isomer with silver acetate for 30 min. then gave a quantitative (n.m.r.) yield of (64). Reaction with the cis-isomer was much slower and not clean reflecting the preference for an SN2type of transition state for bromide displacement.62 The peroxide was isolated as a white crystalline solid (m.pt.4243.5"C) after purification by bulb-to-bulb distillation low temperature crystal- lization or sublimation and 13C n.m.r. spectroscopic data were provided as addi- tional characterization. An attractive variation of the method uses the more readily available cis-1,3-~yclopentanediol as starting material. Conversion into the cor- responding dibromide followed by treatment with hydrogen peroxide and silver salt afforded (64) in 3040%yield Adam and Eggelte'02 supplied the third route to (64) by applying their low temperature di-imide reduction in dichloromethane to the singlet oxygen adduct of cyclopentadiene (Reaction iii). After purification by chromatography on silica gel at -20 "C,the yield was 30%.Finally Wilson and Geiserlo9 obtained (64) in an unspecified yield (<25%) by benzophenone-s_ensitized photodecomposition of the corresponding diazo compound and trapping of the resultant triplet biradical with oxygen (Reaction iv). Correct experimental conditions are vital. Inparticular it is essential to irradiate only the benzophenone chromophore for direct excitation of the diazo compound produces a singlet biradical that collapses to bicyclopentane. Oxygen pressure and reaction time must also be carefully regulated to obtain optimum yields of peroxide. The singlet oxygenation and reduction route to 2,3-dioxabicyclo[2,2,l]heptane has the advantage of using the cheapest and most readily available starting material and is for this reason probably the most attractive of the four methods.However if the cis- 1,3-diol is to hand then the silver salt route becomes the method of choice. Furthermore a diol-based synthesis obviously provides an excellent model for the transformation of a prostaglandin F into its endoperoxide and this conversion has now been achieved with the synthesis of prostaglandin H2 methyl ester (66).29,110 First Johnson and his c~-workers*~ reported the preparation of SP,llP-dibrorno- 9,11-dideoxy-PGF2 methyl ester(65) and its conversion into (66) by reaction with crown ether-complexed potassium superoxide in DMF. The yield was only 3% with limited prospects for improvement. Then Porter's group' lo achieved the same conversion with a sevenfold increase in yield by using the silver trifluoroacetate and hydrogen peroxide reaction and isolating the prostaglandin endoperoxide by h.p.1.c.log R. M. Wilson and F. Geiser J. Amer. Chem. SOC.,1978 100 2225. N.A. Porter J. D. Byers,R. C. Mebane D. W. Gilmore and J. R. Nixon J. Org. Chem. 1978,43.2088. W.Adam and A. J. Bloodworth H Br e ZJMe Br OH OH (65) (66) a-Peroxylactones Chemienergizers of Bioluminescence.-The difficulty with these target molecules is their extreme thermal instability. In fact to date no natural a-peroxylactone has been isolated. As already pointed these hyperenergetic molecules (ca. 400 kJ mol-' is released during thermal decarboxylation which is sufficient to generate an electronically excited product) are inferred as reaction intermediates in the enzymatic oxygenation of luciferins through oxygen-1 8 labelling experiments.Their biogenesis is outlined in Scheme 43. Thus a-hydroperoxy acids 0 0 Scheme 43 (67) are key synthetic intermediates. These are chemically very labile substances which readily decarboxylate in the presence of acids and bases to give ketones and water. It was therefore not surprising that the classical methods of hydro-peroxylation under acidic or basic conditions failed to produce (67). Mild and neutral conditions were required. R2 R*0-0 OH 2 H Li Scheme 44 Biological Chemistry In Scheme 44 the successful synthetic routes to a-hydroperoxy acids (67) are A ill~strated.~~ key discovery"' was the reaction between ketene bis(tri-methylsily1)acetals and singlet oxygen which affords the stable trimethylsilylperoxy derivative (Reaction i).This unusual silatropic shift introduces a peroxide function alpha to the carbonyl group under completely neutral and mild conditions and at the same time the trimethylsilyl groups protect the sensitive a-hydroperoxy acid (67) during purification. However the a-hydroperoxy acid (67) can be released quan- titatively by desilylation with methanol at low temperature. An alternative strategy utilized the reactive a-lactones as synthons (reaction ii).'2 In their open dipolar form a-lactones add hydrogen peroxide to produce the desired a-hydroperoxy acids (67). In this way the stable di-t-butylacetolactone prepared by ozonization of the respective ketene afforded the corresponding a-hydroperoxy acid (67)in high yield on treatment with hydrogen peroxide at -70 "C.A convenient method for generating a-lactones in situ is via photo-decarboxylation of malonyl peroxides.' l2 The third method (Reaction iii) employed base-catalysed oxygenation of car- boxylic acid.lo4 This drastic but most direct method can be quite effective if strict control of the critical reaction conditions is exercised. Both the oxygenation of the lithium a-lithiocarboxylate (readily available by direct a-lithiation of the carboxylic acid) and the protonation of the oxygen adduct must be performed at -78 "Cand the product must be isolated swiftly. These three preparative methods for a-hydroperoxy acids (67) are complemen- tary and a large variety of derivatives have been synthesized.The singlet oxy- genation route (Reaction i) has the limitation that the ketene acetal must not have allylic hydrogens to avoid competitive prototropic ene-reactions. The a-lactone route (Reaction ii) is limited to disubstituted derivatives since monosubstituted ones are unstable. The base-catalyzed oxygenation (Reaction iii) potentially the most general method cannot be employed for base-sensitive substrates. The dehydration of the a-hydroperoxy acids (67) to the a-peroxylactones (68) presented a formidable synthetic challenge. Most dehydrating agents failed because the reagents are too basic or acidic or too nucleophilic or electrophilic and thus cause decomposition of the a-hydroperoxy acid and/or a-peroxylactone or they do not exhibit sufficient subambient reactivity To date the most effective and convenient reagents for the conversion of (67) into (68) are the carb~di-imides.~~ Typically dichloromethane solutions of the substrate and the reagent are mixed at -78 "C allowed to warm up to -40°C when the urea is precipitated.Filtration affords a solution of the a-peroxylactone (68) which is then isolated and purified. This review was conceived and written during the tenure of a NATO Research Grant the receipt of which is gratefully acknowledged. '" W. Adam and J.-C. Liu J. Amer. Chem. SOC.,1972,94,2894;G. M. Rubottom and M. Lopez Nieves Tetrahedron Letters 1972 2423. 'I2 W. Adam and R.Rucktaschel J. Org. Chem. 1978 43 3886.

ISSN:0069-3030    

DOI:10.1039/OC9787500342

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

14 Biological Chemistry Part (iii) Peptides and Proteins P. M. HARDY Department of Chemistry University of Exeter Stocker Road Exeter EX4 4QD 1 Introduction This section reviews work published in the period 1977-1978 and abuts the section with the same title in Annual Reports (B) for 1976. Some earlier references are given where topics have developed over a number of years and have not been hitherto discussed in earlier Reports. In view of the number of papers published in the span of time considered the choice of material largely reflects the idiosyncracies of the reporter and current growth areas rather than any even coverage of the field. Peptide synthesis is covered more comprehensively than peptide structures; struc- ture determination is omitted as are detailed structures of peptides containing more than about 30 residues.Only a few selected aspects of proteins have been included. It seems appropriate at this point to draw the attention of readers to a recent authoritative review of many aspects of peptide synthesis in the Bakerian lecture 'Towards synthesis of proteins' by the late Professor G. W. Kenner of Liverpool University (Proc.Roy. Suc. 1977 B197,237-253). This account is written with the same clarity and insight that has characterized the many papers on peptide chemistry that he has written over the years. 2 Peptide Synthesis Protecting Groups.-Amino Protection. Despite all the new protecting groups developed in recent years the t-butoxycarbonyl (Boc) group remains the most popular for a-amino masking.Several new reagents are now available for its introduction and these circumvent problems inherent in earlier methods; i.e. the corresponding chloroformate is unstable while the azide is also subject to thermal decomposition is shock-sensitive and the vapour causes severe headaches. (Several reports have been published of the violent detonation of t-butyl azidoformate. ') Two crystalline reagents are now available commercially for attaching the Boc group i.e. t-butoxycarbonylpyrocarbonate (1)2and 2-(t-butoxycarbonylimino)-2-phenyl-acetronitrile (2).3Other acylating agents of a similar type which may be used include t-butyl S-(4,6-dimethylpyrimid-2-yl)thiocarbonate (3)4 and the water-soluble ' e.g. P. Feyer Angew. Chem. Internat. Edn.1977 16 115. L. Moroder A. Hallett E. Wunsch 0.Keller and G. Wersin 2.physiul. Chem. 1976,357 1651. M.Itoh D.Hagiwara andT. Kamiya Bull. Chem. SOC.Japan 1977,50,718. T.Nagasawa K. Kuroiwa K. Narita and Y. Isowa Bull. Chem. SOC.Japan 1973,46 1269. 370 Biologica1 Chemistry 37 1 materials 1-t-butoxycarbonyl-3-ethylimidazoliumfluoroborate (4)5 and N'-t-butoxycarbonyl- 1,2,4-triazole (5).6 CN BU~-O-CO-O-CO-O-BU~ Bu'O-CO-N=C (1) (2) Me 0 II {~-S-C-OBu' 0 II Bu'O-C-N BF,-!\+ N-Etw 0 The t-butoxycarbonyl group of course has long been the parent from which a number of acid-sensitive urethane N-protecting groups have been developed to give a range of derivatives with sometimes rather subtle variations in reactivity. Two recent examples of fine tuning of this sort illustrate the point.The 1-(1-adamanty1)- 1-methylethoxycarbonyl (Adpoc) group prepared from 1-adamantanecarboxylic acid (Scheme 1)is cleaved by acid lo3times faster than the Boc group making it CO,H C-OH I Me liii Me 0 Adpoc-OPh Reagents i PC1,-EtOH; ii MeMgI; iii PhOCOC1-py; iv H,NCHR'CO;[NRt]' Scheme 1 possible to use the Adpoc group selectively in conjunction with Boc but unlike the a,a-dimethylbenzyloxycarbonyl-typeprotecting groups is also stable to hydro- genolysis.' Purification of certain fragment peptides with Boc N-protecting groups by gel filtration in 50% aqueous acetic acid has been found to lead to substantial loss of the protecting group. This observation stimulated the search for an acid-labile protecting group more stable under these conditions.The 1-methyl-cyclobutyloxycarbonyl group (B)(McBoc) has been found to meet these require- ments. After 48 h in 50% aqueous acetic acid more than 99% of McBoc-phenyl- alanine remains unchanged whereas under the same conditions amino-acid was ' E. Guibb-Jampel,G. Braun M. Wakselman and M. Vilkas Synthetic Comm. 1973,3,111. 'G.Brown Tetrahedron Letters 1973,469. H. Kalbacher and W. Voelter Angew. Chem. Internat. Edn. 1978.17 944. 372 P.M. Hardy liberated from Boc-phenylalanine to the extent of 10-15%. Complete removal of McBoc can be effected when required with trifluoroacetic acid at 25 "C. Use of this group for N-protection therefore enables the favourable solvent properties of 50% aqueous acetic acid to be utilized when working with large peptides.8 One of the advantages of the Boc group is its removal to give only volatile by-products.A base-sensitive protecting group the 2-trimethylsilylethoxycarbonyl (Teoc) has now been explored and found to give an analogous stream of gaseous by-products on cleavage. Introduction of this group is best done with the cor- responding azidoformate and removal by reaction with fluoride ion in e.g. acetoni-trile (Scheme 2). The reaction requires 4-5 h at 50 "C with Et,NF in this solvent. The RNHC02CH2CH2SiMe3 *RNH2+C02+CH2=CH2 +Me3SiF Reagents i F-MeCN; ii H20 Scheme 2 Teoc group is stable towards catalytic hydrogenation and common basic reagents but is rapidly decomposed by trifluoroacetic acid.This clean acid-induced cleavage of urethane derived from a primary alcohol is attributed to carbon-metal U-T conjugation involving the p-silyl function.' In a similar way 2-trimethylsilyl (Tmse) esters have been used for carboxyl group protection. These esters are prepared from N-protected amino-acids and are normally not crystallizable. If used in conjunction with N-benzyloxycarbonyl groups the latter may be selectively removed by hydro- genolysis but methanol as solvent should be avoided to prevent transesterification. Hydrogen chloride in organic solvents does attack the Tmse group but sufficiently slowly to allow selective removal of a Boc group. Their removal otherwise parallels that of the Teoc group but it should be noted that cleavage with fluoride ion causes disproportionation of asymmetric disulphides and partial cleavage of aspartyl P-t- butyl esters.loQ The removal of N-benzyloxycarbonyl groups using catalytic transfer hydro- genation has attracted attention in more than one laboratory.If cyclohexene is used as the hydrogen donor in the presence of 10%palladium-charcoal in alcohol under reflux reaction is complete within 1.5-2 h." However 1,4-cyclohexadiene is a more effective donor and its use enables the cleavage to be effected at room temperature. Benzyl ester and tyrosine benzyl ether groups are also removed under * S. F. Brady R. Hirschmann and D. F. Veber J. Org. Chem. 1977,42,43. L. A. Carpino J. H. Tsao H. Ringsdorf E. Fell and G. Hettrich J.C.S. Chem. Comm. 1978 358. Peptides Proceedings of the Fifth American Peptide Symposium University of California San Diego June 20-24th 1977 ed.M. Goodman and J. Meienhofer John Wiley and Sons 1977; (a)P. Sieber R. H. Andreatta K. Eisler B. Kamber B. Riniker and H. Rink p. 543; (6)M. Ueki S. Ikeda and F. Tonegawa p. 546; (c)Y. S. Klausner T. H. Meiri and E. Schneider p. 536. A. E. Jackson and R. A. W. Johnstone Synthesis 1977 685; G. M. Anantharamaiah and K. M. Sivanandaiah J. C. S. Perkin I 1977 490. Biological Chemistry these conditions; serine and threonine benzyl ethers the W"-benzyl group of histidine and the Ng-nitro-group of arginine are better removed in the presence of the more active palladium-black catalyst.I2 A number of P-haloalkoxycarbonyl N-protecting groups have been investigated in recent years but all show some degree of base lability.It has now been found that the 2,2,2-trichloro-t-butyloxycarbonyl group (Tcboc; 7) is much more stable under these conditions. Its potential is illustrated by the observation that it is retained intact during alkaline hydrolysis of methyl esters and also on acidic cleavage of t-butyl esters. Tcboc-amino-acids can be prepared from the stable and distillable chloroformate and are highly crystalline. Removal may be brought about with the 'supernucleophile' cobalt(1) phthalocyanine anion in methanol or acetonitrile [see Ann. Reports (B) 1976 73 3441 or with zinc in glacial acetic acid.I3 The acid lability of the P-N bond has again been utilized in a protecting group.Dime thylphosp hinothioyl (Mpt) chloride prepared from te tramet hylp hosphine disulphide (Scheme 3) may be used to convert amino-acid esters into their Mpt Me 0 I c1~c-c-o-cII I Me (7) ss S S II I1 II MeMgBr + S=PC13 -+ Me2P-PMe2 --bMe2P' -&Me2P-NHCHR1CO2R2 'c1 Reagents i SO,Cl,; ii NH2CHR'C02R2 Scheme 3 derivatives; alkaline hydrolysis furnishes the corresponding acids. This type of protection is recommended for use with tryptophan. A tripeptide of tryptophan was synthesized by the solid-phase method in 86% yield using Mpt-L-tryptophan and 0.2M HC1/0.2 M triphenylphosphine in dichlorornethane for deprotection (30 min 25 "C). The anti-oxidant activity of the triphenylphosphine obviated the need for addition of any scavenger.Coupling was mediated by the oxidation-reduction method [see Ann. Reports (B),1969 66 503].'0h Although the bulk of this section on protection has been largely devoted to variations on old themes novel types of protection are still being explored and reported. The 1,2,4-dithiazolidine-3,5-dione heterocyclic system has been used as the basis of a new type of N-protecting group. Ethylethoxythiocarbonyl derivatives of amino-acid esters react in anhydrous solution with chlorocarbonyl sulphenyl chloride to give an adduct which undergoes ring closure to generate a dithiasuccinoyl (Dts)-protected amino-ester (8; Scheme 4). Direct preparation from the ethyl- ethoxythiocarbonyl-amino-acid is not possible. The Dts group is stable to acid I2 A. M. Felix E. P.Heimer T. L. Lambros C. Tzougraki and J. Meienhofer J. Org. Chem. 1978 43 4194. l3 H. Eckert M. Lid. and I. Ugi Angew. Chem. Inteemat. Edn. 1978,17,361. 374 P.M. Hardy 0 c3s-c-II c1 -+ 0 II ,c-CI S I 0 S Et-O \ + / C=NH-l CI 3Et -4 J 0 I1 SAC\ I N-R S.c' I\ 0 Scheme 4 (enabling the ester group to be removed) and photolysis above 330nm but is removed by mild reductive procedures. Cleavage with thiol for example (Scheme 9,generates the free amine; this reaction is markedly accelerated by addition of tertiary amines. Prolonged treatment with bases such as the a-amino-group of 0 II SC\ I N-R' +2R2SH -* H2N-R'+2COS+R2SSR2 S.p/ L II 0 Scheme 5 amino-acid esters does not cause detectable cleavage but aliphatic amines or strong aqueous alkali yield the mixed urea or free parent amine.14 The inactivation of the peptide hormone oxytocin on allowing it to stand in contact with acetone first observed in 1965,15has stimulated an investigation into the use of the interaction products of peptides and acetone in peptide synthesis.The reaction involves the formation of an imidazolidinone ring system from the N-terminal dipeptide unit (Scheme 6). Free dipeptides in many instances can be converted into R'HC-co I\ ~ HZNCHR' CONHCHR2COR3 HN ,N-CHRZCOR3 + P Me2C0 /"\ Me Me Scheme 6 l4 G. Barony and R. B. Merrifield J. Amer. Chem. SOC.,1977,99,7363. Is D. Yamashiro H. L. Aanning and V. Du Vigneaud Proc. Nat. Acad. Sci. U.S.A.,1965,54 166.Bio logica 1 Chemistry their NN'-isopropylidene derivatives by stirring in the cold or under reflux with acetone. Such N-protected modified dipeptides may be coupled using NN'-dicy- clohexylcarbodi-imide without risk of racemization even in the absence of additives as oxazolone formation is precluded. Deprotection may be effected by heating the neutral aqueous solution at 60-100 "C for a few hours. A heptapeptide has been prepared by successive addition of three dipeptide units to an amino-acid ester but the method lacks generality as some derivatives are difficult to prepare pure and some are too unstable towards hydrolysis. Free dipeptides are also not readily available starting materials.'6 Carboxyl Protection. Although protection of carboxjrl groups perhaps receives rather less attention than amino-groups each year still brings its crop of novelties and improvements.The preparation of esters of Boc-amino-acids from the caesium salt of the corresponding acid and chloromethylated poly(styrene -1YOdivinylbenzene) (solid-phase resin) was found in 1973 to proceed rapidly and quantitatively; the method avoids the production of quaternary ammonium salts and the presence of residual chloromethyl group^.^' This use of caesium salts has now been applied to the synthesis of N-protected amino-acid and peptide esters for use in solution-phase peptide synthesis." Methyl esters and more usefully benzyl esters can be prepared efficiently in this way. Boc-Phe-Phe-OH showed no racemization within the experimental error of the method (Manning and Moore test)." The use of caesium salts is applicable to other types of ester although Z-Ala-OBu' (Z = benzyloxy-carbonyl) could only be prepared from 2-Ala-OH and 2-bromo-2-methylpropane in 14% yield.18 A novel type of carboxyl protection recently described ingeniously utilizes 2-oxymethyleneanthraquinone (Maq) esters.Simple amino-acids and peptides give highly crystalline Maq esters which are readily soluble in organic solvents but stable to the conventional operations of peptide synthesis and catalytic hydrogenation. The ester group can be removed either by treatment with sodium dithionite photolysis (350 nm) in isopropanol containing N-methylmorpholine treatment with 9-hydr- oxyanthrone in DMF containing triethylamine or with polystyrene functionalized with 9,lO-dihydroxy-anthracene residues.The reduction of the quinone gives a highly unstable intermediate (9) which decomposes to a xylylidene derivative (10)as shown in Scheme 7. This latter apparently tautomerizes sufficiently rapidly to obviate the need for the addition of trapping agents. The Maq group has been successfully used in the synthesis of methionine enkephalin (a pentapeptide) and a heptapeptide angiotensin analogue.2o The use of polyethylene glycol (PEG)in peptide synthesis originated in 1971" and has been pursued in a number of papers since that time notably in the past year. This linear polymer was introduced as a solubilizing carboxyl-protecting group in contrast to the solid-phase crosslinked polymer.Its advantage lies in the ease with which the high mol. wt. growing peptide chain may be purified from low mol. wt. reagents as l6 P. M. Hardy and D. J. Samworth,J.C.S. Perkin I 1977 1954. B. F. Gisin Helv. Chim. Acta. 1973,56 1476. S.S.Wang B. F. Gisin D. P. Winter R. Makofske 1. D. Kulska C. Tsougraki and J. Meienhofer J. Org. Chem. 1977,42,1286. l9 J. M. Manning and S. Moore J. Biol. Chem. 1968,243 5591. 2o D.S.Kemp and J. Renek Tetrahedron Letters 1977 1031. *' M.Mutter H. Hagenrnaier and E. Bayer Angew. Chem. Internat. Edn. 1971. 10,811. 376 P.M. Hardy 0 required either by ultrafiltration or by differences in solubility in organic solvents.” Neutral amino-acids may be attached directly to polyethylene glycol without N-protection in the presence of toluene-p-sulphonic acid in benzene by heating under reflux for 2-3 days the condensate returning to the pot through a bed of molecular sieve to remove water.Arginine and histidine can be introduced in this way in the presence of an additional amount of the acid.22 However one disad- vantage of the PEG approach has been the relatively low yield of final peptide often obtained on cleavage from the polymer because of the rather drastic conditions required to split the ester linkage. Interpolation of a photosensitive moiety between the polymer and the peptide chain is one way in which this drawback can be overcome Use of 3-nitro-4-bromomethylbenzoyl-PEG (11)has enabled a tetra- peptide to be built up and removed from the polymer in 98% yield compared with the 69% cleavage from the polystyrene support used in solid phase synthesis.(11) Peptides attached to the photosensitized PEG are soluble in dichloromethane and DMF but insoluble in ether and ethyl a~etate.’~ Cleavage from the polymer requires photolysis (>350nm) in methanol under N2for 10-20 h; in this way four different N-protected heptapeptides were obtained with an average yield of 91Yo.24 Reagents bound to PEG as opposed to the growing peptide chain have some advantages in peptide synthesis. A comparison between the reaction rates of 22 C. S. Pande and J. D. Glass Tetrahedron Letters 1978,4745. 23 F. S. Tjoeng W. Staines S. St.-Pierre and R. S. Hodges Biochim. Biophys. Acta. 1977 490 489. 24 F. S. Tjoeng E.K. Tong and R. S. Hodges J. Org. Chem. 1978,43,4190. Biological Chemistry PEG-bound and low molecular weight active ester derivatives in the peptide bond- forming step indicated that the soluble polymeric group did not appreciably influence the speed of reaction. Excess polymeric active ester reagent can be simply and quantitatively removed by precipitation with negligible loss of the peptide product which remains in solution. In order to attach active ester groups to PEG it was first converted to the corresponding cvw-diamine (Scheme 8)which could then be coupled lii,iii Reagents i TsCI; ii K phthalimide;iii N,H Scheme 8 directly with appropriate carboxylic acids such as (12) and (13) with NN'-dicyclo- hexylcarbodi-imide to give polymeric derivatives of the well-known o-nitrophenyl and 1-hydroxybenzotriazole active esters respectively.A carbodi-imide has been prepared bound to PEG (Scheme 9) to overcome the insolubility of the correspond- ing urea which can be difficult to separate from desired peptide after a carbodi- imide-mediated coupling. The resulting PEG-urea is soluble in dichloromethane and can be recycled back to carbodi-imide.2s i.ii PEG-NH:! -PEG-N=C=N-CHMe Reagents i Me,CHNCO; ii TsCI NEt,. Scheme 9 Another reagent (14)for deblocking the fluoren-9-ylmethoxycarbonyl (Fmoc) group [cf. Ann. Reports (B) 1974 71 5061 has been developed (Scheme 10) to overcome the problem which can occur of separating the adduct (15) formed when piperidine is used to remove the Fmoc group (Scheme 11).On stirring Fmoc- tryptophan with the resin (14)in dichloromethane containing some water to prevent precipitation of the amino-acid on the polymer a 90% yield of deprotected material was obtained on evaporation of the solvent all liberated dibenzofulvene (16) having been scavenged by the polymer.26 25 M. Mutter Tetrahedron Letters 1978 2839 2843. 26 L. A. Carpino,J. R. Williams and A. topusihski J.C.S. Chem. Comm. 1978,450. 378 P. M. Hardy T Q i,ii,iii n CH,CI CH,N NH U chloromethylated polystyrene -1‘/o divinylbenzene n Reagents i HN NBoc -EtNPri; ii HCl; iii NEt, w Scheme 10 CH ,OCONHR CH Reagent i HN3 Scheme 11 Side-chain Protection. Removal of S-protecting groups by heavy metal salts such as silver or mercury is well known e.g.in the cleavage of S-trityl S-acetamidomethyl and S-ethylcarbamoyl groups from cysteine peptides. Recent work however has shown that a number of other S-protecting groups are also susceptible to fission by mercuric acetate in trifluoroacetic acid or mercuric trifluoroacetate in aqueous acetic acid. These include the S-p-methoxybenzyl group hitherto removed by anhydrous strong acids such as HF and the S-t-butyl and adamantyl derivatives; the S-benzyl group however is quite stable towards these reaction conditions. Removal of the S-p-methoxybenzyl group in this way has been exemplified in syntheses of biologic- ally active oxytocin and somatostatin each of which contains two cysteine residues2’ When the phenolic group of tyrosine is protected as its benzyl ether there is the tendency for rearrangement to 3-alkyltyrosine to occur during cleavage of protecting groups with hydrogen fluoride.The introduction of electron-withdrawing substi- tuents such as m-bromobenzyltyrosine28 or 2,6-dichlorobenzyltyrosine29improved selectivity during removal of Boc groups with trifluoroacetic acid and reduced the 3-alkylation side-reaction to about 5%. However even this level is not tolerable for solid-phase synthesis of large peptides containing many tyrosine residues. A study of four secondary alkyl ethers has shown 0-cyclohexyltyrosine to undergo minimal 27 0.Nishimura C. Kitada and M. Fujino Chem. and Pharm. Bull. (Japan),1978,26 1576. 28 D.Yamashiro and C. H. Li J.Org. Chem. 1973,38,591. 29 B.W.Erickson and R. B. Merrifield J. Amer. Chem. SOC.,1973 95,3750. Biological Chemistry 379 rearrangement (0.3%) on cleavage with HF yet on treatment with 50% CF,CO,H-CH,Cl under the conditions for Boc cleavage in solid-phase synthesis only 0.006°/~ loss of alkyl group occurs. It is therefore not as stable to this reagent as the 0-2,6-dichlorobenzyl group but in the solid-phase synthesis of ribonuclease A which contains 6 tyrosine residues it should give a product in which 97.2% of the molecules would have all six tyrosine-protecting groups intact.30 In order to try and prevent the racemization sometimes observed when N-a-alkoxycarbonylhistidine derivatives are coupled specific blockage of the 7r-nitrogen of the imidazole ring has been investigated.Both the N(T)-and N(r)-phenacyl derivatives of 2-L-His-OH were prepared (Scheme 12) and their couplings with ZNHYHC0,Me ZNHYHC0,Me ZNHYHC0,H -" i ii N kN> kN> k:, N H I I CH,COPh CH,COPh liv (17) ZNHCHC0,Me ZN HCHCO,Me kN\;CH2coPhZN HCHCO,H -k;"2coph I I vi iii N H k N ! N v N ~ CPh 3 CPh (18) Reagents i AgNO,; ii PhCOCH,Br-Me,SO; iii NaOH; iv Ph,CCl-CH,CI,; v PhCOCH,Br-Et,O; vi AcOH-H,O 100 "C. 10 min Scheme 12 L-prolinamide using NN'-dicyclohexylcarbodi-imideunder conditions designed to exacerbate the danger of racemization were compared. Material protected on the 7-nitrogen (17) yielded 35% D-isomer but that from the 7r-nitrogen phenacyl derivative (18) was stereochemically homogeneous within experimental error.Similar results have been obtained with the corresponding Boc derivatives. The Nim-phenacyl group is stable to HBr-HAc,CF3C02H or brief exposure to hydro- genolysis conditions but may be removed by Zn dust in acetic acid.31 Coupling of H-Pro-Ser(Bzl)-His-Arg(NO2)-I1e-Ser-OMe with the 1-succinimidyl ester of Boc- Asp( P-Bzl) in the presence of 1-hydroxybenzotriazole has been found to cause significant 0-acylation. This was traced to catalysis of the alcoholysis of the active ester by the imidazole group of the histidine side-chain.' Such a situation can only be completely prevented by further protection of the side-chains involved and the danger of such 0-acylation must obviously be borne in mind when considering the degree of side-chain protection to use in the synthesis of peptides containing these residues.30 M. Engelhard and R. B. Merrifield J. Amer. Chem. SOC.,1978 100,3559. 31 J. H. Jones and W. I. Ramage J.C.S. Chem. Comm. 1978,472. 32 M. Bodanszky M. L. Fink Y. S. Klausner S. Natarajan K. Tatemoto A. E. Yiotakis and A. Bodanszky J. Org. Chem. 1977 42 149. 380 P.M. Hardy Formation of the Peptide Bond.-A new coupling agent for peptide synthesis described as a ‘push-pull’ acetylene (19) has been found to form peptide bonds efficiently with little racemization and it can be used in aqueous solution. Addition of this compound to a solution of N-protected amino-acid or peptide gives a primary non-isolable adduct (20) which rearranges to a crystalline enol ester (21).This active derivative couples selectively with amino-components (Scheme 13). The R:N H Me H RiN-CrCCOMe +R2C02H + \/c=c \/c=c (19) [R2C02/ ‘COM] R2C0,/ ‘CONRi (20) (21) b3NH2 Me H \c=c / R =Me2or -NMe U (22) + RVON HR Scheme 13 NN-dimethylacetoacetamide(22) formed as a by-product is readily soluble in both water and ether. Tyrosine 4-hydroxyproline cysteine histidine and asparagine can all be linked without protection of their side-chain functional groups. Themethod has been tested successfully up to the tetrapeptide level. The acetylene (19) can be prepared from the corresponding olefin by a simple bromination-dehydrobromina-tion sequence (Scheme 14).33*34 The cyclo-adduct 1,3,4-trimethyl-A3-phospholen-I pii Me R~N-CEC-COM~ Reagents i Br,; ii NEt,; iii KOBu‘ Scheme 14 1,l-dichloride (23) of 2,3-dimethylbutadiene and methylphosphorus dichloride has also been examined as a coupling agent.Although the highly sensitive Young test3’ gave 47% racemization coupling of dipeptides with C-terminal valine leucine or 33 M. Neuenschwander H.-P.Falwin and U. Lienhard Helu. Chim. Acta. 1978,61 1609 2437. 34 H.-J. Gais Angew. Chem. Internat. Edn. 1978,17,597. ’’M.W. Williams and G. T. Young,J. Chem. Suc. 1963 881. Biological Chemistry (23) phenylalanine residues to amino-acid esters was apparently racemization-free yields being 86-90°/0. Reactions were carried out in the presence of N-methyl- imida~ole.~~ Of the established coupling agents for peptide synthesis NN’-dicyclohexyl- carbodi-imide (DCC) of course remains by far the most widely used.The use of 1-hydroxybenzotriazole in conjunction with DCC to depress racemization in its coupling of peptides3’ has proved immensely useful. A recent paper however shows that a by-product may be formed by interaction of these compounds. On allowing them to stand in dichloromethane (20“C,24h) 31% of the 1,3-diazetidine (24) was A number of unsymmetrical carbodi-imides have been compared with DCC in respect of their tendency to cause racemization when used to couple peptides in the absence of additives. According to the Young test DCC is worst in this respect and N-ethyl-N’-phenylcarbodi-imidebest (25).The latter compound was also found to cause less N-acylurea formation in the coupling of 2,4-dinitrophenylsulphenylglycineto valine methyl C6H1 lN=C=NC6HI >PhCH,N=C=NEt >p-MeC,H,N=C=NEt >PhN=C=NEt (25) The building up of peptide bonds by means of active esters is still a very popular method and structural variants continue to attract attention.N-Protected amino- acid esters of 3-hydroxyquinazolin-4(3H)-one (26)have been shown to be useful in 0 (26) 36 E. Vilkas M. Vilkas and J. Sainton Tetrahedron Letters 1978 3922. 37 W.Konig and R. Geiger Chem. Ber. 1970 103 788. 38 H.-D. Jakubke and C. Klessen J.prukt. Chem. 1977,319 159. 39 H.Ito N. Takamatsu and I. Ichikizaki Chem. Letters 1977,539. 382 P. M. Hardy this respect and their practicality demonstrated in the stepwise synthesis of the C-terminal hexapeptide of substance P.On coupling CF,CO-Pro-Val-OH to H-Pro-OMe by this method only 2.5% of the L-D-L-tripeptide was formed.40 Introduction of a sulphonic acid group into the well-known o-nitrophenyl ester gives a water-soluble derivative. These o-nitro-p-sulphophenyl esters are best prepared from N-protected amino-acids by the symmetrical anhydride method and are coupled at pH 8-8.5. Acylation is somewhat faster than with the parent o-nitrophenyl ester and 1-hydroxybenzotriazole is an efficient catalyst in aqueous as well as organic solution. The desired product of reaction normally precipitates out. The tetrapeptide Z-Lys(&-Boc)-Pro-Val-Gly-OEt was synthesized by this method even though the lysine active ester was not water-soluble; the suspension soon dissolved and the acylation was rapid."' Another method which involves a largely aqueous reaction medium is the use of enzymes for coupling.There has been a recent resurgence of interest in this approach which was originally investigated back in 193741and has not since been systematically explored using modern protecting groups. Hydrolysis of protected product peptides is low due to their water insolubility and inhibition of secondary hydrolysis of the product if soluble is inhibited by the presence of a high concen- tration of the amino-component nucleophile. Specificity for synthesis is of course very similar to the leaving group specificity in hydrolysis. As acceptor nucleophiles however free amino-acids and their esters are inadequate.Peptide bond formation by enzymes has the great advantage of being highly stereospecific and therefore of potential particularly in fragment condensations. Proteinases of all types can be effective in appropriate cases.42 The rather specific enzyme a-chymotrypsin can be used to couple peptides with C-terminal Phe Tyr or Trp residues and since esterase activity is also present esters can be used as donors. The best result obtained was in the coupling of Z-Ala-Phe-OMe to H-Phe-Leu-OH. A 95% yield of product was obtained in 5 min. in water containing 35% DMF to solubilize the starting ester. By contrast the worst result (43%) was obtained in the reaction of Z-Ala-Phe-OMe with H-G~Y-NH~.~~ More generally useful of course are the proteinases of rather broader specificity.Of three metalloproteinases studied that from Bacillus subtilis var. amyloliquefaciens (Prolisin A) has proved the most promising. Even crude enzyme preparations in the presence of the serine proteinase inhibitor from potatoes to prevent the amidase action of impurities proved reasonably successful. This enzyme may be used to link amino-components with hydrophobic N-terminal amino-acid side-chains. The use of some organic solvents in modest proportion often increased yields; e.g. in the case of Z-Leu-Gln-OH and H-Leu-Val-NH2 dioxan (16%)improved the yield of tetrapeptide from 71 to 87.3%. The use of Boc for N-protection however gave in general poor results; only 20% of the pentapep- tide was obtained in the coupling corresponding to that mentioned above.44 40 H.D.Jakubke C. Klessen and K. Neubert J. prukt. Chem. 1977,319,640. M. Bergmann and H. Fraenkel-Conrat J. Biol. Chem. 1937,119,707. 42 Y. Isowa M. Ohmori T. Ichikawa H. Kurita M. Sato and K. Mori Bull. Chem. SOC.Japan 1977,50 2762. 43 K. Morihara and T. Oka Biochem. J. 1977,163 531. 44 Y. Isowa T. Ichikawa and M. Ohmori Bull. Chem. SOC.Japan 1978 51 271. Biological Chemistry 383 New Peptide Structures.-The myotropic substance proctolin isolated from the cockroach Periplanata americana has been found to be the linear pentapeptide H-Arg-Tyr-Leu-Pro-Thr-OH. This compound is of neural origin occurring in nerves of the viscera and evoking contraction of the visceral musculature at concen- trations down to M.It is thought to function as an excitatory neuromuscular transmitter and probably occurs in a wide variety of insects. The structure has been confirmed by synthesis.45 The most basic angiotensin (27) so far known has been H-Asn-Arg-Val-Tyr-Val-His-Pro-Phe-His-Leu-OH (27) isolated from the goosefish. The basicity is a consequence of the masking of the side-chain of the N-terminal aspartic acid residue as the amide. This appears to be the first natural peptide characterized in which asparagine is N-terminal. Apart from the side-chain amidation of the aspartic acid this decapeptide sequence is identical to that of bovine angiotension I.46 Like all other natural tachykinins the dodecapeptide kassinin (28) derived from the skin of the African amphibian Kassina senegalensis possesses the characteristic H-Asp-Val-Pro-Lys-Ser-Asp-Gln-Phe-Val-Gly-Leu-Met-NH~ 5 10 (28) Gly-Leu-Met-NH2 C-terminal tripeptide sequence but the amino-acids at the other end of the molecule differ sharply from known members of the series Like substance P kassinin exhibits a free amino-group instead of the more usual pyroglutamyl re~idue.~'The peptide has been synthesized using methionine as its sulphoxide to prevent alkylation of this residue on stripping off protecting groups with methanesulphonic acid.As a final step methionine was regenerated from its sulphoxide by treatment with 2-mer~aptoethanol.~~ A peptide of the same size has been found in the skin of the frog Rana rugosa. This compound named granuliberin (29) has a potent mast-cell-degranulating activity and belongs to a new family of active peptides in amphibian skin.The N-terminus is hydrophobic and the C-terminus basic and hydr~philic.~~ H-Phe-Gly-Phe-Leu-Pro-Ile-Tyr-Arg-Arg-Pro-Ala-Ser-NH* 5 10 (29) Details of the structure determination of three new peptides from the venom of the common European honeybee Apis mellifera have been reported. Melittin F proved to be a fragment of the known peptide melittin lacking the N-terminal heptapeptide of the latter. Mast-cell-degranulating peptide (30)shows a similarity to the neuro- toxic venom component apamin both containing a Cys-Asn-Cys-Lys sequence. The third novel peptide secapin (3l),is structurally unrelated to the other basic peptides " A.N. Starratt and B. E. Brown Canad. J. Chem. 1977,55,4238. 46 T.Hayoshi T. Nakayarna,T. Nakajima and H. Sakabe Chem.and Pharm. Bull. (Jupan),1978,26,215. 47 A. Anastasi P. Montecucchi V. Erspamer. and J. Visser Experientiu 1977,33 857. 48 H. Yajima T. Sasaki H. Ogawa N. Fujii T. Segawa and Y. Nakata Chem. and Phurm. Bull. (Japan), 1978,26,1231. 49 T. Nakajirna and Y. Yasuhara Chem. and Pharm. Bull. (Japan) 1977,25,2464. w S S H-Ile-Lys-Cys-Asn-Cys-Lys-Arg-His-Val-I1e-Lys-Pro-His-Ile-Cys-Arg-Lys-Ile-Cys-Gl I I y-Lys-Asn-NH2 P SI 5 10 15 s I 2o (30) S S I I H-Tyr-Ile-Ile-Asp-Val-Pro-Pro-Arg-Cys-Pro-Pro-Gly-Ser-Lys-Phe-Ile-Lys-Asn-Arg-Cys-Arg-Val-Pro-Val-OH 5 10 15 20 (31) Human H-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- Val-Gly-Lys-Lys-Arg-Arg-Pro-Val- Ostrich _--_----Arg---Dogfish _------Met -Arg --Ile-10 20 Lys-Val-Tyr-Pro-Asn-Gly-Ala-Glu-Asp-Glu-Ser-Ala-Glu-Ala- Phe-Pro-Leu-Glu-Phe-OH --_ -Val-Gln-Glu -Thr-Ser -Gly ------Ser-Phe-Glu-Asp -Ser-Val -Asn-Met-Gly-Pro -Leu 30 Figure 1 (-means same as above) Antiamoebin Ac-Phe-Aib-Aib-Aib-Iva-Gly-Leu-Aib-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phol Emericin I11 --Val -----Phol Emericin IV --Val ----Ala-Phol 5 10 15 Figure 2 [Iva =L-isovaline=(S)-a-ethylalanine;Hyp =L-4-hydroxyproline] Biological Chemistry 385 present in bee venom.It contains only one disulphide bridge and a Pro-Pro sequence is repeated twice. This peptide is not toxic and the quantity present in the venom is very ~ariable.~' The first avian corticotropin (ACTH)sequence has been elucidated.Material from the ostrich Struthi0 camelus (Figure 1)shows the invari- ance in the N-terminal dodecapeptide sequence hitherto observed but like dogfish (Squalusacanthias) ACTH shows rather more differences in the rest of the molecule than is seen between mammalian species.'l In 1968 the antibiotic antiamoebin was reported to be a cyclic peptide linked to phenylalaninol (Ph~l).~ A recent reinvestigation of this molecule however shows it to be a linear peptide (Figure 2)much richer in a-aminoisobutyric acid (Aib). It thus falls into a class of peptide antibiotics containing Phol and Aib residues as well as other amino-acids for which the name peptaibophols has been Two antibiotics from Emericillopsis microspora emericins I11 and IV (Figure 2) show a close similarity to antiam~ebin.~~ In all three peptides the presence of the glutamine residue was indicated by the formation of ornithine after dehydration (ethylene chlorophosphite-triethyl phosphite 100"C 24h) reduction (Na-NH,-MeOH) and hydrolysis (6 M HCI 110"C 24h).53*54 CH2CH=CHMe I CHMe2 CHMe I I CH2 Me CHMe2 MeCHOH Et Me I II II I I MeN-CH-CO -N-CH-C-N-CH-CO-N-CH-C-N-CH2 II I I' 'co 0 y 0 I I co MeCHCH2CH I I I NMe NMe H 0 s\ I I II OC-CH-NH-CO-CH-N-CO-CH-N-C-CH-N-CO-CHCH2CHMe2 I I II I Me Me CH2 Me CHMe2 I CHMe2 (32) Cyclosporin A a cyclic undecapeptide metabolite (32)of the fungus Trichoderma polysporum has been found to have a remarkable immunosuppressive activity.55 Its antilymphocytic action has been shown by its greater effectiveness than any other drug in prolonging the survival of heart grafts in pigs.56 This hydrophobic peptide contains the novel amino-acid (2S 3R 4R)-(6E)-methylamino-3-hydroxy-4-methyl-oct-6-enoic acid and its sequence was established by Edman degradation after an acid-induced NO-acyl migration (Scheme 15).The crystal structure of an iodo-derivative has been determined and shows a conformation which is partly 50 J. Gauldie J. M. Hanson R. A. Shipolini and C. A. Vernon European J. Biochem. 1978,83,405. 51 C. H. Li D. Chung W. Oelofsen and R. J. NaudC Biochem. Biophys. Res. Comm. 1978,81,900. 52 M. G. Voidya P. V. Deshmukh and S.N. Chari Hindustan Antibiot. Bull. 1968 11 81. R. C. Pandey H. Meng J. C. Cook and K. L. Rinehart J. Amer. Chem. SOC. 1977,99,5203. 53 54 R. C. Pandey J. C. Cook and K. L. Rinehart J. Amer. Chem. SOC. 1977,99 5205. A. Ruegger M. Kulm H. Lichti H.-R. Loosli R. Huguenin C. Quiquerez and A. von Wartburg Helv. 55 Chim. Acta. 1976,59 1075. 56 A. J. Kostakis D. J. G. White and R. Y. Calne IRCSMed. Sci. Libr. Compend. 1977,5 243. 386 P.M. Hardy Reagents i,MeS0,H-MeOH; ii reflux in dioxan Scheme 15 &pleated sheet and partly open 100p.~~*~’ Cyclosporins B C and D which occur in the same culture contain respectively L-Ala L-Thr and L-Val in place of L-Q-aminobutyric acid. 58 The complete structure of another cyclic peptide antibiotic which is a potent inhibitor of bacterial protein synthesis has also now been determined.Berninamycin A (33) contains five residues of dehydroalanine out of its ten ring amino-acid residues as well as two 5-methyloxazole units and the hitherto unreported thia- zolonaphthyridinium chromophore. The sequence was assigned on the basis of products obtained on trifluoroacetolysis of the antibiotic; two fragments were I NH oc \ JH2 I C C HN’ *CH~ I Me 1 CH I /\ &\ MeCH CO-NH-C ’H I OH N& Me@,N ?Me “-(C-NH HI \ HN-CO H2C co ‘CH’ I Me-C-OH I Me (33) ’’T. J. Petcher H.-P. Weber and A. Ruegger Helv. Ckim. Acta. 1976 59 1480. 58 R. Traber M. Kuhn H. R.Loosli W. Packe and A. von Wartburg Helv. Chim. Acta. 1977,60 1247 1568. Biologica1 Chemistry isolated [the larger one after partial reduction of dehydroalanine residues; arrows in (33)show the break points] which comprise the whole amino-acid sequence.59 Aspects of Protein Structure.-The first synthesis of a functional polypeptide from a chemically synthesized gene was achieved in 1977. Tke gene for somatostatin a tetradecapeptide hormone which inhibits the secretion of a number of other hormones was fused to the Escherichia coli P-galactosidase gene on the plasmid pBR322. After transformation into E. coli the chimaeric plasmid directed the synthesis of a protein containing P-galactosidase linked to somatostatin. In order to enable somatostatin to be separated from the enzyme a methionine codon was included prior to the amino-terminal end of the hormone.Treatment of the protein product with cyanogen bromide specifically cleaved the peptide chain at methionine to yield active somatostatin.60 The use of recombinant DNA methods in this way is only limited by the difficulty of synthesizing the DNA corresponding to the required peptide. It is clear that the idea of using bacteria to synthesize foreign peptides by hiding them in a natural bacterial protein has great potential as an alternative to classical organic synthesis for the production of peptides and proteins of medical interest. Insulin in particular is an attractive target being actively pursued. However it must be remembered that only analogues containing natural amino-acids are accessible by this method.The form in which proteins are initially synthesized by the ribosome continues to be very actively explored and some interesting work has been reported over the past two years in the field. The exotoxin of Pseudomonas aeruginosa has enzyme activity catalysing the transfer of the adenosine diphosphate ribose portion of nicotinamide adenine dinucleotide to eukaryotic elongation factor Z. The exotoxin is synthesized as a pro-enzyme but conversion into the active form does not unusually enough require proteolysis. Diphtheria toxin which catalyses the same reaction does require peptide bond cieavage for activation. In the case of the Pseudomonas toxin activation results from simultaneous treatment with a protein denaturant and a chemical able to split disulphide bonds.It is concluded that such treatment induces a conformational change that exposes the previously buried active site no peptide fragments at all being released.61 Most of the secretory proteins so far examined have been found to be synthesized with an amino-terminal extension of from 15-30 amino-acid residues which is rich in hydrophobic residues. This 'signal' sequence is thought to interact with a specific membrane receptor which directs this 'recognized' protein through the cell membrane. The signal sequence is normally removed before the protein assembly is coinplete but its existence can be shown by using cell-free protein-synthesizing systems lacking membranes and associated proteases in the presence of the appro- priate mRNA.In this way pre-lysozyme was found to have an additional 18residues (34) at its N-terminus 16 of them being hydrophobic.62 There is a 75% identity in the eight amino-acids preceding the cleavage site of pre-lysozyme and another '' J. M. Liesch and K. L. Rinehart J. Amer. Chem. Soc. 1977 99 1645. 6" K. Itakura T. Hirose R. Crea A. D. Riggs M. L. Heyneher F. Bolivar and M. W. Boyer Science 1977 198,1056. '' S. H. Leppla 0.C. Martin and L. A. Muehl Biochem. Biophys. Res. Comm. 1978 81 532 R. D. Palmiter J. Gagnan L. H. Ericsson and K. A. Walsh J. Biol. Chem. 1977 252 6386. 388 P. M. Hardy Y h G x Biologica1 Chemistry egg-white protein pre-ov~mucoid.~~ Pre-lipoprotein from E.coli itself a membrane protein has a twenty-amino-acid N-terminal extension (35);64 like prelysozyme removal of this sequence requires specific cleavage of a C-terminal glycine and in both cases the initiator amino-acid methionine (which is probably N-formylated) has not been lost. Egg-white ovalbumin in contrast to other proteins synthesized in the same cells appears to lack a transient hydrophobic leader sequence. When the growing peptide chain is about 20 residues long the N-terminal initiator methionine is lost and the new N-terminal glycine acetylated when the peptide is 44 residues long. It may be that a signal sequence is located elsewhere in the molecule but the amino-terminal end of ovalbumin shows only a weak resemblance to other hydrophobic signal sequences.One speculation considers the possibility that the transacetylase is itself the receptor.65 Parathyroid hormone (PTH) a single-chain polypeptide regulating the level of calcium in the extracellular fluid is on the other hand formed as a precursor which then undergoes two successive proteolytic cleavages. Like other secretory proteins PTH is synthesized specifically on polyribosomes bound to membranes and conversion of the pre-protein in cell-free systems can be brought about by the addition of microsomal membranes; normally in the endoplasmic reticulum a 25-amino-acid N-terminal fragment is lost within one minute of synthesis and the resulting prohormone takes 15 minutes to be transported to the Golgi apparatus where an N-terminal hexapeptide is removed to give PTH itself .66 Insulin is another protein in which two cleavages occur the second one in this case excizing the central portion of the molecule to leave two separate but disulphide- bridged chains.Partial sequences of pre-proinsulins from the rat6' and two fishes the angler fish and the sea raven,68 have been determined (Figure 3). There is consider- able homology at least with respect to the leucine residues. Since the cleavage site for the conversion of nascent fish pre-proinsulin into nascent proinsulin is recognized correctly by dog pancreas microsomal enzyme and the signal peptide is also recognized by the corresponding microsomal membrane it is thought that mechanisms and information for the transfer of secretory proteins are highly conserved during Two unnatural disulphide bond isomers of human insulin (36) and (37) have been synthe~ized~~ using the strategy earlier developed s-s w s-s s-s I 7 19 7 19 (36) (37) 63 S.N. Thibodeau J. Gagnan and R. D. Palrniter Fed. Proc. 1977,36 656. 64 S. Inouye S. Wang J. Schizawa S. Halegona and M. Inouye Proc. Nut. Acad. Sci. U.S.A.,1977 74 1004. " R. D. Palrniter J. Gagnan and K. A. Walsh Proc. Nut. Acad. Sci. U.S.A.,1978 75 94. J. F.Habener M. Rosenblatt B. Kemp. H. M. Kronenberg A. Rich and J. T. Potts,Proc. Nut. Acad. Sci. U.S.A. 1978 75 2616. 67 S. J. Chan P. Keirn andD. F. Steiner Proc. Nut. Acad. Sci. U.S.A.,1976,73 1964. D.Shields and G. Blobel Proc. Nut. Acad. Sci. U.S.A. 1977,74 2059.''P. Sieber E. Eisler B. Karnber B. Riniker W. Rittel F. Marki and M. de Gasparo J. physiol. Chem. 1978,359,113. 390 P.M. Hardy for the total synthesis of human insulin (38) itself.70 Their biological activities are similar and qualitatively indistinguishable from insulin and for several tests range from 13 to 37% compared to insulin. Chromatographically they can easily be distinguished from insulin but they are significantly less stable and partially iso- merize to insulin. Their perhaps unexpectedly high biological activities would seem to indicate that their tertiary structures may resemble that of insulin in essential features. It is unlikely that their activity is due to enzyme-catalysed isomerization to insulin during biological testing.69 The key intermediate in this synthesis of insulin and its isomers was the compound (39) (side-chain-protecting groups are omitted S for clarity but are all t-butyl esters or ethers).This could be coupled with the BOG(1-1 3) sequence containing a preformed intramolecular disulphide bridge (6-7 7-1 1 or 6-1 1) and an S-acetamidomethyl (Acm) cysteine. Treatment with iodine generated the third disulphide bridge from the S-Acm-cysteines and all protecting groups were stripped off with trifluoroacetic The structure of a 70-residue protein growth factor from human plasma (IGF-1) has now been determined. The molecule contains 3 disulphide crosslinks and displays obvious homology to proinsulin positions 1-29 resembling insulin B chain and 46-62 resembIing insulin A chain.The connecting peptide 30-41 is much smaller than the 30-35 fragment found in proinsulin and there is no homology between them. The C-terminal octapeptide sequence is also not found in the insulins. All the cysteine and glycine and most of the non-polar core residues of the insulin monomer are conserved indicating that its conformation may resemble that of insulin. It has been suggested that duplication of the gene of the common ancestor of IGF-1 and proinsulin occurred before the time of appearance of the vertebrates7* Somatomedin B is a polypeptide found in plasma which is thought to mediate the action of growth hormone. Material from human plasma has now been sequenced and the 44-residue compound shows a relationship to protease inhibitors and phospholipase rather than any known growth factors.Residues 5-8 for example Cys-Lys-Gly-Arg resemble those of basic trypsin inhibitor (Cys-Lys-Ala- Arg). Somatomedin B inhibits trypsin but not plasmin thrombin or kallikrein and its precise biological role remains to be elucidated.’’ 70 P. Sieber B. Kamber A. Hartmann A. Johl B. Riniker and W. Rittel Helv. Chim.Acta. 1977,60,27. ” E. Rinderknecht and R. E. Humbel J. Bid. Chem. 1978,253,2763. 72 L. Frykland and H. Sieverteson F.E.B.S.Letters 1978,87 55.

ISSN:0069-3030    

DOI:10.1039/OC9787500370

出版商:RSC    

年代:1978

数据来源: RSC