摘要:

7 Electro-organic Chemistry* By J. H. P. UTLEY Department of Chemistry Queen Mary College Mile End Road London El 4NS 1 Introduction An important and lengthy review of organic electrochemistry has appeared written from a physical-organic standpoint.' On the electrochemical side an introductory account2 of the application of electroanalytical techniques is available. Volume 5 of the C.S. Specialist Report on Electrochemistry has a~peared.~ The current Report highlights cathodic and anodic reactions followed by a section of stereoselective processes. A recent development in the field is the study of 'paired reactions' i.e. electrolysis in an undivided cell is contrived so that useful products are obtained at both electrodes. A detailed study of one such reaction has been pre~ented.~ The cell is made from a bored graphite block optionally lined with lead and charged with acetonitrile tetra-n-butylammonium iodide (or KI) ethyl acrylate and diethylmalo- nate.The cathodic and anodic products are both obtained in ca. 95% yield their formation being rationalized according to Scheme 1a. An electrochemical synthesis of nitroalkanes in ca. 75% yield from organoboranes also involves' the products of both electrodes (Scheme 1b). 2 Anodic Processes The Anodic Oxidation of Carboxy1ates.-Considerable amounts of aromatic aldehyde are obtained from the Kolbe electrolysis of arylacetates [cf.Ann. Reports (B) 1971 68 3133. It was suggested6 that the aldehyde resulted via peroxides from reaction between benzyl radicals and adventitious oxygen.This suggestion has been verified7 in a careful comparison of the products of anodic oxidation (in the absence and presence of oxygen) of phenylacetate hexanoate and 2-ethylhexanoate ions. For the alkanoates (RCO,-) peroxides of the type ROzR were isolated when oxygen was passed through the electrolyte and for phenylacetate oxidation benzal- dehyde is absent from the products of electrolyses flushed with nitrogen but present if oxygen is bubbled through the solution. 1 L. Eberson and K. Nyberg Adv. Phys. Org. Chem. 1976 12,1. D. Pletcher Chem. SOC. Rev. 1975,4471. 0.R.Brown in 'Electrochemistry' ed. H. R. Thirsk (SpeciulistPen'odicaIReports),The Chemical Society London 1975 Vol. 5 p. 220. M. M. Baizer and R. C. Hallcher J.Electrochem. SOC. 1976 123,809. Y.Takahashi M. Tokuda M. itoh and A. Suzuki Synthesis 1976 616. 6 J. P. Coleman R.Lines J. H. P. Utley and B. C. L. Weedon J.C.S. Perkin U,1974 1064. J. E. Barry M. Finkelstein E. A. Mayeda and S.D. Ross J. Amer. Chem. SOC. 1976 98 8098. * This Report was compiled with the help of a current awareness service run by Ruth Hayden of Queen Mary College library. 137 138 J. H.P. Utley Cathode (a) 2CH2CHC02Et -%Et02CCH(CH2)2CHC02Et Anode 12 ,-2e 21-1 EtOZC(CH2)dCOzEt+ 2(EtO*C)2CH (Et02C)2CHCH(C02Et)2 -Pt electrodes RCH2N02 (b) R3B MeN02/R:NX ' (X = Br Cl) Cathode Anode O~NCH~ RB -,-A ~H~+o~NCH~-RX & ~x,Z-x-1 02NCH2R+ X-Scheme 1 As part of an attempt to functionalize pyridine in the 3-position the reactivity of anodically generated methyl and trifluoromethyl radicals have been compared.' The methyl radical is nucleophilic and for attack on the pyridinium ion the a:y ratio is 3 :1which is also the ratio found for attack by alkyl radicals generated by persulphate oxidation of carboxylates.Methyl attack on pyridine is more efficient (CQ. 20%)but less selective. The trifluoromethyl radical attacks all three positions of the pyridine and the pyridinium ion; the @-position is preferred (ca. 40-60%) but the overall yield of substitution products is low (ca. 5%). There can now be little doubt that alkyl radicals formed in the Kolbe reaction are essentially 'free'. Complete racemization (299.5% ) of several anodically generated chiral radicals has been demonstrated' [cf.Ann. Reports (B) 1973 70 3021. However this would also result from radicals involved in a dynamic adsorption- desorption equilibrium. That for saturated radicals the maximum energy of adsorp- tion is negligible is shown" by the completely random coupling of alkyl-substituted cyclohexyl radicals; if adsorption were important diastereoisomeric radicals would be differently stabilized which would lead to different energies of activation for coupling and thereby stereoselection. Aryl-substituted cyclohexyl radicals behave differently; further oxidation to carbenium ions is encouraged even though substitu- tion is remote and this appears to be a surface effect consistent with the known propensity for aryl groups to adsorb at the anode.Anodic acetamidation which involves the trapping of anodically generated car- benium ions has been used to demonstrate the anodic production" of vinyl cations (Scheme 2). The product mixture is complex the overall yield is 10%and of that less * J. H. P. Utley and R. J. Holman Electrochim. Acta 1976 21 987. L. Eberson K. Nyberg R. Servin and I. Wennerbeck Acta Chem. Scand. 1976,830,186; L. Eberson K. Nyberg and R. Servin ibid. p. 906. lo G. E. Hawkes J. H. P. Utley and G. B. Yates J.C.S. Perkin ZI,1976 1709. l1 E. Laurent and M. Thomalla Compt. rend. 1976 C282,441. Electro -organic Chemistry 139 COCH3 -2e -C02 MeCN/H20 / + CH2:C(Me)C02-[CH2:CMe] -Me2CHCON \C(Me):CHZ + COCHS / CH2:C(Me)CON \ C(Me):CH2 Scheme 2 than half consists of the amides shown.It is suggested that cathodic hydrogenation accounts for the unexpected saturation of one of the isopropenyl groups. Oxidative decarboxylation continues to be of use but a claim" that it is 'tedious inconvenient and limited to small quantities' has led to the development of a chemical alternative which involves heating the dicarboxylic acid at 185 "C for 36 h in a brew containing cuprous oxide 2,2'-dipyridyl quinoline and powdered glass. Yields for three methods of bis-decarboxylation are given in Scheme 3. Anodic (2e) 62% CuzO 40% Pt anode CO,H Scheme 3 removal of a single carboxylate group is a key in a synthesis of cubebol (Scheme 4a). In this case formation of a carbenium ion is involved with subsequent quenching by acetate ion.However for similar electrolysis of a series of easily oxidized substituted tetrahydroisoquinoline-1-carboxylicacids electron-transfer OCCU~S'~at -0.28 V (us s.c.e.); cf. ca. 2.0 V for Kolbe oxidation which suggests oxidation of the aromatic ring with subsequent loss of C02 in a pseudo-Kolbe reaction [cf. Ann. Reports (B) 1971 68 3131. The products are certainly radical- derived (Scheme 4b). The Anodic Oxidation of Neutral Organic Compounds.-The synthetic uses of anodic substitution reactions is the subject of an important wide-ranging and practically oriented review.I5 The interest in indirect methods of oxidation appear to have revived. Anodic acetamidation of relatively inert compounds e.g.alkanes and saturated long chain carboxylates probably proceeds via the formation of a radical by electrolyte oxidation with subsequent abstraction from carbon-hydrogen bonds. Further oxida- tion can then take place (Scheme 5). Good evidence for all this comes from a studyI6 '2 R.A. Snow C. R. Degenhardt and L. A. Paquette Tetrahedron Letters 1976 4447. '3 S. Torii T. Okamoto G. Tanida H. Hino and Y. Kitsuya,J. Org. Chern. 1976,41 166. l4 J. M. Bobbitt and T. Y. Cheng J. Org. Chem. 1976 1,443. 15 L. Eberson and K. Nyberg (Tetrahedron Report No. 21) Tetrahedron 1976,32,2185. 16 L. L. Miller and M. Katz J. Electroanalyt. Chem. Interfacial Electrochem. 1976,72 329. 140 J. H.P.Utley (72%) ( -) cubebol Reagents i Pt electrodes AcOH-BU'OH-E~~N,undivided cell b) ;:zQNR4 -e "'"aNR4-H?; ""WNR4 R20 \ R20 \ R3 C02H R3 CO,H R3 R3 H Scheme 4 electrolyteanion 3 X.RH R. 3 Rf Scheme 5 of the anodic oxidation of methyl hexanoate in acetonitrile in the presence of electrolytes containing C1- C102 C104- and BF4-. In each case the 2-and 3-acetamido products are obtained and in similar proportions. The oxidation of carboxylic acids may be achieved" directly and indirectly in fluorosulphuric acid [cfi Ann.Reports (B) 1975 72 1511. Peroxydisulphuryl difluoride [(FSO,),] may be prepared by the constant current anodic oxidation of K03SF(1M) in anhydrous FS03H. The anolyte may be used directly for the oxidation and lactonization of carboxylic acids (Scheme 6). Similar results are obtained if the acid is present R'R2CH(CH2),C02H + FS03H FS03-+ R'R2CH(CH2),C02H2+ (FS03)2 1 R 'R3C?>O e R'R2C(CH2),C02H2++FS03H I (CH,) + 1 OSOZF Scheme 6 throughout the oxidation although in this case work-up immediately after elec- trolysis is desirable because of subsequent rearrangement reactions.l7 C. J. Myall D. Pletcher and C. Z. Smith,J.C.S. Perkin I 1976 2035. Electro -organic Chemistry Electrochemically generated iodine (I) probably formed in acetonitrile as CH3C& is a powerful electrophile.'8 Typically a solution of the iodine (I)species is formed by electrolysis of iodine at +1.9 V (us. Ag/Ag+) in acetonitrile solution containing lithium perchlorate. This reaction may be carried out on a 10g scale and the aromatic compound to be iodinated is added to the preformed pale yellow solution of the electrophile.Some representative results are given in Table 1. Table 1 Iodination of substituted benzenes (PhX) with iodine (I)18 X OMe CH3 c1 CO2Et COCH3 NO2 Yield ("/o) 90 93 80 65 15 0 Large-scale anodic acetoxylation and methoxylation using the cells described earlier [Ann. Reports (B) 1975 72 1511 has provided"" a route to cyclic N-acylenamines reactive intermediates which have not previously been used in synthesis because of the lack of preparative methods.lgb The sequence of reactions is exemplified in Scheme 7. (92%) Reagents i C anode 8.4 F mol-* MeOH; ii NH4Br 140"C Scheme 7 Anodic aromatic substitution continues to produce surprises. A significant pro- duct2' of the anodic oxidation under acetoxylating conditions of the methoxyl- substituted indene (1)is the dimer (2).This is formally a 27r + 27r cycloaddition but electricity is required for the reaction. The result has therefore been rationalized in terms of Scheme 8. Another unexpected result follows the attempted" nuclear (1) -2-p (1)+ -%-+ (2)t -%(1)t+(2) Scheme 8 L. L. Miller and B. F. Watkins J. Amer. Chem. SOC. 1976,98,1515. l9 (a)K.Nyberg and R. Servin,Acra Chem. Scand. 1976 B30.640; (b)K.Nyberg Synthesis 1976,545. 2o L.Cedheim and L. Eberson Acra Chem. Scand. 1976,B30,527. K. Nyberg and L. G. Wistrand J.C.S. Chem. Comm. 1976 898. 142 J. H.P.Utley acetoxylation of 2-and 4-fluoroanisole. The corresponding chloro- and bromo- compounds yield straightforward products of anodic nuclear acetoxylation.For the fluoro-compounds fluorine is displaced and acetoxylation takes place almost entirely at the position previously occupied by the fluorine substituent. This displacement occurs with high current efficiency (70-80°/~)at low conversions; at high conver- sions the product is oxidized further. The mechanism is not clear but a plausible explanation is given in Scheme 9a. In contrast the introduction of fluorine by anodic substitution provideszz a method of preparation of fluoro-organosilanes (Scheme 9b). The reaction consumes 1F mol-' and the detection of products derived from alkyl or benzyl radicals is good evidence for the mechanism given in the Scheme. (a) ArF -5[FArOAc]. -F-+[ArOAc]+ OAc L -1 Scheme 9 Anodic methoxylation provides an entryz3 into a series of useful easily metallated vinyl halides (Scheme 10).The halide intermediates can be produced electrochemi- cally on a 3040 g scale and metallation is accomplished using the butyl-lithium in THF at -70 "C.The reaction also works well for relatively complex polyfunctional molecules e.g. (3) is produced in 80% isolated yield. Me0 OMe Br Me0 Me0 I 1 Reagents i MeOH-KOH(l%) Pt anode Scheme 10 From the many electrochemical studies of phenols and phenolic ethers it has often seemed that phenols are more easily oxidized than the corresponding ethers. This is contrary to the order expected from the relative electron releasing effects of OH and OR. A careful investigationz4 reveals that indeed the expectation from inductive effects is correct and the apparent anomaly is due to special structural features of the phenols previously studied.The results summarized in Table 2 show clearly that in acidic solution phenol oxidation becomes reversible and a valid comparison of the 22 I. Y. Alyev I. N. Rozhkov and I. L. Knunyants Tetrahedron Letters 1976 2469. 23 M. J. Manning P. W. Raynolds and J. S. Swenton J. Amer. Chem. SOC.,1976,98 5008. 24 0.Hammerich V. D. Parker and A. Ronlan Acfa Chem. Scand. 1976 B30 89. Electro -organic Chemistry Table 2 Peak potentials for phenol and phenolic ether E,/V(vs. s.c.e.) -50°C Substrate CH2C12 CH2C12-FS03H (10% VOl/VOl) 4-Me0.C6H4-OH 1.20 (irr) 1.49 (rev) 1,4-(Me0)2C6H4 1.38 (rev) 1.39 (rev) 4-Ph.C6H4OH 1.48 (irr) 1.59 (rev) 5-Ph.C6H40Me 1.55 (rev) 1.56 (rev) oxidation peak potentials with those for reversible oxidation of the ethers can be made.The same group has reported fully25 on the anodic intramolecular coupling of a series of phenolic diarylkanes (Scheme 11). The dienones are produced in high (for n = 3) Reagents i Pt anode CH&N Scheme 11 yield (75-85%) for n = 3; no cyclization is found for n = 2 or 4. It is almost certain that the favoured pathway is formation of a phenoxonium ion which attacks the adjacent aromatic ring in an electrophilic substitution step. A remarkably slow anodic coupling reaction has been studied.26 The metacyclophane (4)gives on cyclic voltammetry a quasi-reversible oxidation-reduction couple at 0.65 V (us.Ag/Ag') in acetonitrile. Controlled potential electrolysis at the potential at which the dication is formed (1.05V) gives (5) in 90%yield. The slowness of coupling relative to the 25 U. Palmquist A. Nilsson V. D. Parker and A. Ronlan J. Amer. Chem. Soc. 1976 98 2571. 26 J. Y. Becker L. L. Miller V. Boekelheide and T. Morgan Tetrahedron Letters 1976 2939. 144 J. H. P. Utley singly bridged compound is probably due to steric strain in the relevant intermediate (6). Similar anodic cyclizationz7 allows the efficient conversion of diarylamides such as (7) into dibenzazocines e.g. (8). Me0 OMe Me6 Me0 Me0 (6) (7) (8) The electrochemical production of ortho-quinones in the presence of 1,3-dicarbonyl compounds providesz8 a convenient and high-yield method for the preparation of certain oxygen heterocycles (e.g.Scheme 12).?H -4e -4Hf aoH OH +ao 0 Reagents i 1.1V (us. s.c.e.) C anode Pt cathode undivided cell H20-NaOAc (0.15M) Scheme 12 Another example of anodic cleavage with loss of acylium ion has been reportedz9 [cf. Ann. Reports (B) 1973 70 681. The electro-oxidation of N-acetyldiazines results in the production of the corresponding diazines with the consumption of 2F mol-'. The implied mechanism is given for one of the examples studied (Scheme 13). Ac Ac I I Ac Ac Ac Scheme 13 Attempts to trap the acylium ion failed presumably because the heterocyclic product is more nucleophilic than the aromatic trapping species.An important approach to specific functionalization is foreshadowed by what is probably a template-directed electrochemical chlorination of a ster~id.~' The ester 27 M. Sainsbury and J. Wyatt J.C.S. Perkin I 1976 661. 28 2.Grujic I. Tabakovic and M. Trkovnik Tetrahedron Letters 1976,4823. 29 P. Martigny H. Lund and J. Simonet Electrochim. Acta 1976 21 345. 30 R. Breslow and R. Goodin Tetrahedron Letters 1976 2675. Electro -organic Chemistry 145 (9) shows on cyclic voltammetry an oxidation peak (E,) at +2.6 V (us. Ag wire). Oxidation in acetonitrile solution in the presence of chloride ion (E ca. 1.0 V) was performed at two potentials. At 1.8V in the dark chlorine was evolved but the steroid molecule was not chlorinated; at 2.7 V conversion into (10) was achieved.After saponification 35-7 1YO isolated yields of the corresponding cholestan-3a -01 were obtained. These results are interpreted as shown in Scheme 14 i.e. in terms of (9) X =H (10) x=c1 Scheme 14 an electrochemically initiated chain reaction sustained by the anodic production of chlorine. Consistent with this is the suppression of the reaction by the addition of 02 NO or Br2. It would be interesting to see if the reaction could be sustained by short pulses at +2.7 V followed by longer pulses at +1.8 V. 3 Cathodic Processes The Cathodic Reduction of Organic Cations.-Some years ago quaternary ammonium amalgams with strongly reducing properties were prepared by the cathodic discharge of quaternary ammonium ions at mercury [Ann.Reports (B) 1968,65 2501. It now appears that the discharge of quaternary ammonium ions at graphite also produces an association which has reducing propertie~.~~ The cathode in question was constructed by glueing a small crystal of graphite to a vitreous carbon electrode. When used for cyclic voltammetry it was found that in DMF solution a number of tetra-alkylammonium salts gave reuersible reduction at ca. -1.5 V (us. Ag/AgI). Approximately 95*/o of the charge is recoverable e.g. subsequent addition 31 J. Simonet and H. Lund J. Electroanalyt. Chem. Interfacial Electrochem. 1977,75 719. 146 J. H.P.Utley of fluorenone results in formation of fluorenone radical anion. The efficiency of charging depends on the size of the quaternary ammonium cation; for the larger cations the cathode disintegrates.For the time being a suitable representation of the species involved is [graphite-&N]"-. The best direct route to the aporphine structure [e.g. (12)in Scheme 151 a high-yield cathodic cyclization (Scheme 15). Voltammetry suggests that two discrete le steps are involved hence the mechanism- given in the Scheme. It is not clear however why the intermediate (1 1) is formed with the stereochemistry required for cyclization. e R=HorMeO e. -1-1 Me ~~lPt0~ R Rjy RIy R Scheme 15 The Cathodic Reduction of Neutral Organic Compounds.-A significant advantage of the electrochemical method has been found for the hydr~genation~~ of cyclo-octatetraene tricarbonyl iron (13).Chemical methods which involve alkali-metal reduction and protonation on work-up operate on a time scale which allows disproportionation of intermediate radical-anions and thereby imposes a maximum of 50% for the yield. Cathodic reduction in the presence of trimethylamine hydrobromide as proton donor results in quantitative hydrogenation to (14). Other 32 R. Gottlieb and J. L. Neumeyer J. Amer. Chem. SOC.,1976,98 7108. 33 N. El Muir M. Riveccie and E. Laviron Tetrahedron Letters 1976,3339. Electro -organic Chemistry FdCO) FdCO1 (13) (14) cathodic hydrogenations are dealt with in the final section on stereoselective reactions. For cyclic ketones however a marked change of behaviour is associated with hindrance to the carbonyl For the series (15) to (17) 2e cathodic reduction to alcohol is found for carvomenthone (15),4e reduction to hydrocarbon is found for menthone (16)’ and camphor (17)can only be reduced (2e)under ‘solvated (15) (16) (17) electron’ conditions.The best electrolytes for the 4e reduction are ethanol contain- ing Li’ Mg2+ or Zn2’ i.e. conditions which encourage the formation of ion-pairs. Charge dispersal in an ion-pair is also helpful to further reduction. These observa- tions are accommodated in the proposed mechanism (Scheme 16). The ‘solvated Scheme 16 electron’ reduction of camphor to a mixture containing (*)-borne01 (84% ) and (It)-isoborneol (16%) is the most convenient and effective way of carrying out this transformation; chemical reductions are either unreliable or tend to give isoborneol as the major product.Cathodic substitution is becoming a useful preparative method. Two examples are discussed here in which products are accessible which are difficult to obtain by other methods. It has proved difficult to prepare 3-t-butylpyrene (18) by Friedel-Crafts alkylation or by a route involving metallation. The radical-anion of pyrene is however formed at a readily accessible potential [-1.5 V (vs. Ag/AgI)] and its in 34 R.J. Holman and J. H.P.Utley J.C.S. Perkin ZZ 1976 884. 148 J. H.P.Utley situ reaction in DMF with t-butyl gives (18) in 52% isolated yield. The carotenoid dione canthaxanthin (19) is also easily reduced36 and at preparative scale concentrations (2 x moll-’) the reactive intermediate is probably the highly stabilized retro-dianion (20).In the presence of acid anhydrides 0-acylation occurs and the corresponding retro-diacylates are formed. Electrolyte conditions may be chosen in which the diacylates hydrolyse readily [e.g. LiC104(0.2m) in 1 1 CH3CN-CH2C12] and S,S-dihydrocanthaxanthin (2 1) is formed almost quantitatively. This is the product of kinetic control treatment with base converts it entirely into an isomer 7,7’-dihydrocanthaxanthin(22). 0 0 -0 0 0 An unexpected coupling reaction resulted from the attempted cathodic cyclic hydr~dimerization~’ of dimethyl benzene- 1,2-diacrylate (23) (Scheme 17). A par-ticularly interesting implication of this work is that should steric factors dictate a-coupling may occur.The same observation has been made3* and put to prepara- tive use in the cathodic pinacolization of the a-and @-ionones [to give (24) and (25)] and of vitamin A aldehyde [to give (26)]. An early report that at the cathode crotonaldehyde gave mainly a -coupling to the glycol has been corrected.” The major product (56%) is the furan (27). 35 R. E. Hansen A. Berg and H. Lund. Actu Chem. Scund. 1976 B30,267. 36 E. A. H. Hall G. P. Moss J. H. P. Utley and B. C. L. Weedon J.C.S. Chem. Comm. 1976 586. 37 J. Anderson and L. Eberson J.C.S. Chem. Comm. 1976 565. 38 R. E. Sioda B. Terem J. H. P. Utley and B. C. L. Weedon J.C.S. Perkin I 1976 561. 39 J. C. Johnston J. D. Faulkner L. Mandell and R. A. Day J. Org. Chem. 1976,41 2611. Electro -organic Chemistry C0,Me M cc02Ee i,g C 0 2 e C0,Me ’’C02Me ” I (23) \ C0,Me Reagents i -1.25 V (vs.s.c.e.),Hg cathode 1.1F mol-’ DMF-HzO (4%) Scheme 17 (26) (27) Interest continues in the products of cathodic reduction of sulphur and selenium compounds. The reduction of ethylene trithiocarbonate (28) gives rise4’ to an interesting transformation (Scheme 18). The loss of ethylene is confirmed by addition of bromine to form lY2-dibromoethane. The involvement of the dianion (29) is suggested because when lY2-dibromo- or 1,2-di-iodo-ethane is used in the alkylation step the bicyclic compound (30) is obtained. The cathodic reduction of _ii @-+ cs e scs,-S-[p- ss (30) (29) Reagents i -1.4 V (us. s.c.e.) Pt cathode 0.98F mol-’ DMF-Bu4NBr; ii XCHZCH~X X=Br I Scheme 18 carbon diselenide with subsequent methylation has been used to prepare41 an intermediate (31) which can be coupled to prepare a tetraselenafulvalene (32) 40 F.J. Goodman and J. Q. Chambers J. Org. Chem. 1976,41 626. 41 E. M. Engler D. C. Green and J. Q. Chambers J.C.S. Chem. Comm. 1976 148. 150 J. H.P.Utley (Scheme 19). Although in similar conditions carbon disulphide gives a methylated reduction product [Ann. Reports (B) 14:4 71 2281 coupling to the fulvalene analogue does not take place. 97 MeseE"i-s. ii+MeSe CSez i IsgseIseMe MeSe Se MeSe Se Se SeMe (31) (32) Reagents i -1.35 v (DS. s.c.e.) Pt cathode DMF; ii (Me0)3P C6H6 80 "c Scheme 19 Deoxygenation by cathodic cleavage can be a mild and selective method.In this way the highly sensitive hydrocarbon axerophtene (33a) has been prepared42 from vitamin A acetate (33b). For vicinal acetates in which one of the acetate groups may (33a) X = H; (33b) X= OAc be cleaved cathodically a rapid elimination is induced (Scheme 20). Thus another sensitive compound hitherto obtained with difficulty 3,4,3',4'-tetrahydro-P- carotene (35) is obtained from the reduction of crustaxanthin tetra-acetate (34). OAc OAc AcO OAc Scheme 20 42 J. G. Gourcy M. Hodler B. Terem and J. H. P. Utley J.C.S. Chem. Comm. 1976 779. Electro-organic Chemistry 151 According to the mechanism implied in Scheme 20 alkynes should be obtainable from alkene diacetates; the reported formation43 of diphenylacetylene by cathodic reduction of a,a’-diacetoxystilbene (36) is consistent with this.A slightly different reductive elimination results from work designed to involve oxyphosphirane species Ph \OAC AcO Ph (36) such as (38). This type of intermediate has been implicated in other reactions. The products obtained from cathodic reduction44 of a,a’-dihalogenophosphinates(37) together with the known propensity of 1,3-dihalogeno-systems to cyclize strongly confirm the intermediacy of (38) (Scheme 21). Cathodic cleavage of halides in 0 0 0 II -II II PhCH(Br)P(OMe)CH(Br)Ph 2PhCPCH(Br)Ph 5(PhCH&POMe I (37) OMe 24’!’ Ph Ph (38) Reagents i 0 V (us.Ag/AgBr) Hg cathode 2F mol-’ DMSO-Et4NBr; ii Hf,2e H+ Scheme 21 aprotic solvents is also the basis of an efficient ~reparation~~ of hexamethyldisilane (Me3Si-SiMe3) from chloro-trimethylsilane.Presumably a silicon anion formed by 2e cleavage can displace halogen from a second molecule of chlorotrimethylsilane. The cathodic removal of both chlorine atoms from NN-dichloroto1uene-p-sulphonamide (39)gives in principle a nitrene (40). When cleavage was carried in the presence of dioxan the product expected from the well-known insertion reaction of nitrenes (41)is found in up to 32% yield. The other major product is the amine (42) and these results suggest strongly the pathway given in Scheme 22. An increasing number of studies are being reported of the electrochemistry of biologically important molecules and redox systems. In many of these investigations the systems are so complex or so poorly understood that meaningful progress is unlikely.An important exception is the rigorous and comprehensive treatment given4’ to the oxidoreduction mechanism of the vitamin B12r-B12ssystem. 43 P. Martigny. M. A. Michel and J. Simonet J. Electroanalyt. Chem. Interfacial Electrochem. 1976 73 373. 44 A. J. Fry and L. L. Chung Tetrahedron Letters 1976 645. 45 E. Hengge and G. Litscher Angew. Chem. 1976,88,414. 46 T. Fuchigami T. Nonaka and K. Iwata J.C.S. Chem. Comm. 1976,95 1. 47 D. Lexa and J. M. Saveant J. Amer. Chem. Soc. 1976,98,2652. 152 J. H.P. Utley TsNC12 -& [TsN:] 4TsNH i) (39) y+ (40) (41) ke. 2H+ TsNH~ (42) Reagents i Pt Cathode 1.8A dm-2 2F mol-' MeCN-dioxan-LEI04 Scheme 22 Electrochemical techniques have been applied particularly with a view to ascertain- ing the role of cobalt co-ordination by the 5,6-dimethylbenzimidazolemolecule at the end of the nucleotide side chain.This is clearly dependent upon pH and in principle three species are in equilibrium for each oxidation state (Scheme 23). N N 'NH Base on Base off Protonated base off Scheme 23 Saveant's main conclusion is that vitamin BIzris largely reduced by two pathways (i) reduction of the 'base-off' species with de-co-ordination of the cobalt being rate- limiting at pH >2.9; (ii) reduction at more negative potentials of the 'base-on' form with rate-limiting electron-transfer. 4 Stereoselectivity Asymmetric reduction of 2- and 4-acetylpyridine to the corresponding alcohol may be achieved in the presence of chiral electrolytes or at chiral electrodes [cf.Ann. Reports (B) 1975 72 1641. It is proving to be a good system for the detailed investigation of stereoselective cathodic reduction. For reduction in the presence of strychnine conditions have been optimized.48 Optical yields of 47% with current yields of 70-80% may be obtained using relatively small amounts of strychnine in an acetate buffered catholyte. It is important to minimize contamination of the mercury pool and therefore short electrolysis times at a large electrode favour stereoselectivity. Using similar conditions but in the presence of (+)-quinidine the optically active alcohol (30% optical yield) is obtained from 2-a~etylpyridine.~' Reduction of the 4-isomer is stereoselective in the presence of strychnine but it yields only racemic alcohol in the presence of (+)-quinidine.The 3-isomer has not been asymmetrically reduced under any conditions. The factor distinguishing the 48 J. Hermolin J. Kopilov and E. Gileadi J. Electroanalyt. Chem. Interfacial Electrochem. 1976,71,245. 49 J. Kopilov S. Shatzmiller and E. Kariv Electrochim. Actu 1976 21,535. Electro -organic Chemistry 153 behaviour of the three isomers is believed to be the relatively slow protonation of the stabilized intermediate [(43) in Scheme 241. It is envisaged that the proton donor effective at the cathode is the conjugate acid of the added alkaloid; slow protonation can occur therefore via diastereoisomeric transition states leading to stereoselection.Homogeneous asymmetric reduction of 2-acetylpyridine has also been eff ected5* Scheme 24 using the chiral reagent (44). In this case the presence of magnesium perchlorate is required. By analogy with the electrochemical work it is tempting to speculate that proton transfer is slowed by co-ordination between 2-acetylpyridine (or an inter- mediate) and magnesium ion. &CON H CH(Me)Ph (44) For graphite electrodes modified with phenylalanine methyl ester [Ann.Reports (B) 1975 72 1641 it is now clear that it is the edge surface which is made ~hiral.~' Using highly ordered pyrolytic graphite one modified electrode was deployed with its edge masked by silicon rubber and one was deployed with the basal surface masked.Asymmetric reduction (of 4-acetylpyridine) was observed only when using the electrode with an exposed edge. Two examples of anodic asymmetric oxidation have been provided. An enan- tiomeric excess (2.5%) of the sulphoxide (45) was obtained by oxidation5' of the (45) corresponding sulphide at a graphite anode modified with phenylalanine methyl ester. Less easily understood is the highly stereoselective anodic depicted in Scheme 25. It is claimed that the absence of the RS-dimer following coupling of the racemic starting material is due to a surface effect but this suggestion needs testing by comparing the results with those from homogeneous coiipling. The involvement of electrolyte cations in directing stereoselective electro- reduction through ion-pairing has been discussed previously [Ann.Reports (B) so Y. Ohnishi and T. Namakunai Tetrahedron Letters 1976,2699. 51 B. E. Firth L. L. Miller M. Mitani T. Rogers J. Lennox and R. W. Murray J. Amer. Chem. SOC.,1976 98 827 1. 52 J. M. Bobbitt I. Noguchi H. Yagi and K. A. Weisgraber J. Org. Chem. 1976 41 845. 154 J. H.P.Utley Me HO Me Me Me Me0 OH / Me Reagents i C felt anode +O. 16 V (0s. s.c.e.) CH3CN-H20-Et4NC104-NaOMe Scheme 25 1974 71,227 2291. A full report is now available on experiments showing the importance of ion-pairing in the stereoselective reduction of cyclic The cathodic cleavage of (*)-PhCH(Br)CH(Br)Ph which yields a mixture of cis -and trans-stilbene has also proveds4 to be a useful system for the systematic study of electrolyte effects on stereoselectivity.The cis:trans ratio can for comparable conditions be changed from 0.18 (0.012M-LiBr) to 1.27 [0.1M-(CBH17)4NBr]. It is suggested that the stereochemistry of reduction is described by Scheme 26 and that small cations neutralize charge and cause slow rotation in the carbanion inter- mediate. H cgt Ph H cit Ph (*)-PhCH(Br)CH(Br)Ph -b ph FH + H.vPh Br Br 1 I Ph Ph Ph w -Ph Reagents i -0.95 V (us. s.c.e.) Hg cathode DMF Scheme 26 53 J. P. Coleman R. J. Holman and J. H. P. Utley J.C.S.Perkin ZZ,1976 879. 54 H. Lund and E.Hobolth. Acta Gem. Scand. 1976 B30,895.

ISSN:0069-3030    

DOI:10.1039/OC9767300137

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

8 Photochemistry By H. A. J. CARLESS Department of Chemistry Birkbeck College Malet Street London WClE 7HX Photochemistry is the subject of a well-established annual Specialist Periodical Report the most recent volume (Vol. 7) of which contains over 1300 references to papers on organic photochemistry. Consequently the present report is highly selective. The main processes already observed on direct irradiation of simple alkenes are cis-trans isomerization [2 + 21 cycloaddition and carbene formation. Kropp and co-workers’ have added yet another possibility to this list by their observation of a 1,34gmatropic hydrogen shift in alkenes [e.g. (1)to (2)]. Migration is intramolecu- lar as shown by the lack of incorporation of deuterium in the isomer (2) on irradiation of (1) in [2H12]cyclohexane,and by the specific rearrangement of the deuteriated alkylidenecyclopentane (3).The photochemical cyclisation of allyl Grignard reagents such as (4) leads to cyclopropyl Grignards (5) in good yield.’ This interesting example of the photo- chemical closure of an allyl anion to a cyclopropyl anion might be expected to be a disrotatory process but unfortunately the authors could not establish the stereochemistry of the ring closure. An investigation of the stereochemistry of the acetone-sensitized photorearrangement of allylic chlorides to chlorocyclopropanes has shown that this triplet process is stereoselective but certainly not stereo~pecific.~ R (1) (2) (3) (4) a; R=H (5) b; R=Ph Kropp and Poindexter4 have previously reported that the irradiation of alkyl iodides in solution is a method for the generation of carbocations which are probably formed via homolytic C-I bond cleavage followed by electron transfer to produce cation and iodide ion.Kropp and McNeely’ have now used the photolysis of vinyl iodides in solution as a simple method for the generation of vinyl cations. The reaction appears especially useful for the generation of cyclic vinyl cations otherwise P. J. Kropp H. G. Fravel and T. R. Fields J. Arner. Chem. SOC.,1976,98 840. S. Cohen and A. Yogev J. Amer. Chem. SOC.,1976,98,2013. S. J. Cristoi and C. S. Ilenda Tetrahedron Letters 1976 3681. G. S. Poindexter and P. J. Kropp J. Amer. Chem. SOC.,1974 % 7142. S. A. McNeely and P. J. Kropp J. Amer.Chem. SOC.,1976,98,4319. 155 156 H. A.J.Carless accessible with difficulty. Thus irradiation of 1-iodocyclohexene in methanol or dichloromethane solution gives products (65-87% yield) arising from nucleophilic trapping of the 1-cyclohexenyl cation. A vinyl cation may also be generated on irradiation of the dianisylvinyl bromides (6a-c) which produce anisyl-group- migrated products (7a-~).~ Interestingly the less electron-rich diphenylvinyl bromide (6d) does not rearrange in this manner. (6) a; R=p-OMe (7) b; R=m-OMe c; R=o-OMe d; R=H The belief that production of a twisted trans -like cyclohexene intermediate occurs on irradiation of cyclohexenes in methanol has received support. Laser flash photolysis of 1-phenylcyclohexene in methanol produces a transient species (absorp- tion maximum 380nm lifetime 9ps) which is quenched by hydrogen ions and is assigned the structure trans-1-phenylcy~lohexene.~ Morrison and Nylund' report that along with triplet di-n-methane rearrangement products an unusual anti- Markovnikov addition occurs to the double bond of alkene (8)on irradiation in acidic methanol yielding the ether (9).The technique of adding xenon' to quench the production of (9)suggests that a singlet excited state is the species responsible for the above reaction. CH,OMe A further example of the photochemical di-n-methane rearrangement now provides the first case in which reaction proceeds in one direction on direct irradiationlo*" and in the other direction on sensitized irradiation.lo Thus direct irradiation of the diene (10) (cis-trans mixture) in hexane ether or dioxan produces predominantly the chrysanthemate (11) whereas sensitized irradiation in acetone or benzene produces (12). Hou~'~,~~ has presented a molecular orbital method to 6 T. Suzuki T. Sonoda S.Kobayashi and H. Taniguchi J.C.S. Chem. Comm. 1976 180. R. Bonneau J. Joussot-Dubien L. Salem and A. J. Yarwood J. Amer. Chem. SOC.,1976 98,4329. 8 H. Morrison and T. Nylund J.C.S. Chem. Comm. 1976 785. 9 H. Morrison T. Nylund and F. Palensky J.C.S. Chem. Comm. 1976 4. 10 P. Baeckstrom J.C.S. Chem. Comm. 1976,476. 11 M. J. Bullivant and G. Pattenden J.C.S. Perkin I 1976 256. C. Santiago and K. N. Houk J. Amer. Chem. SOC.,1976,98 3380. C. Santiago K. N. Houk,R.A. Snow and L. A. Paquette J. Amer. Chem. SOC.,1976,98 7443. Photochemistry 157 explain regiospecificity in the di-rr -methane rearrangements of benzonorbor-nadienes recently observed by Paq~ette,'~ but there is evidence from deuterium labelling studies that the rearrangement of 2-cyanobenzobarralene to 1-cyanobenzosemibullvalene does not proceed by Houk's predicted pathway. l5 Irradiation of o-divinylbenzenes such as (13a) is known to lead to benzobicyc- lohexenes [e.g. (14a)l which are formed by [4+2] addition followed by rearrange- ment.16 The [2+2] cycloaddition products [e.g. (15a)l normally found for hexa-1,5- dienes are not formed. However it is now reported that 2-vinylstilbene (13b) gives [2+2] cycloaddition to yield (15b) as the major process on irradiation and the alternative product (14b) is absent from the reaction mixture." The effect of the phenyl group in determining the conformational preference of the vinylstilbene (13b) probably lies at the root of this marked difference in behaviour between (13a) and (13b).Hixson" has measured rate constants for the photochemical 1,2- migration of hydrogen methyl and phenyl in the isomerization of substituted styrenes to arylcyclopropanes. An investigation of the photorearrangement of optically active 2-phenyl-3-methylmethylenecyclopropaneshows that chirality is maintained during rearrangement. l9 Although the results are somewhat equivocal on this point there does seem to be an inversion of configuration at the migrating centre similar to that observed in the thermal methylenecyclopropane rearrangement.Certainly the present results exclude the formation of a planar trimethylenemethane intermediate on photolysis. (13) a; R=H b; R=Ph The photocyclization of stilbenes to phenanthrenes involves the well-known processes of trans to cis isomerization followed by cyclization and oxidation of an unstable dihydrophenanthrene intermediate; such intermediates have been observed spectroscopically but never isolated. Filipescu et ul.*O have now obtained the first stable dihydrophenanthrene from diethylstilbestrol(l6) photocyclization in 14 L. A. Paquette D. M. Cottrell R. A. Snow K. B. Gifkins and J. Clardy J. Amer. Chem. Soc. 1975,97 3275. 15 C. 0.Bender and E. H. King-Brown J.C.S.Chem. Comm. 1976,878. 16 M. Pomerantz J. Amer. Chem. Soc. 1967,89,694;J. Meinwald and P. H. Mazzochi ibid. 1967,89,696. M. Sindler-Kulyk and W. H. Laarhoven J. Amer. Chem. Soc. 1976,98 1052. S. S. Hixson J. Amer. Chem. SOC.,1976,98 1271. 19 W. A. Gros T. Luo and J. C. Gilbert J. Amer. Chem. SOC.,1976,98,2019. to T. D. Doyle W. R. Benson and N. Filipescu J. Amer. Chem. Soc. 1976,98 3262. H.A.J. Carless which it appears that the extra stability results from the double tautomerism of the dienol to a keto-structure (17). (16) (17) 1,5-Hydrogen shifts have been noted in alkene photochemistry. For example an intramolecular hydrogen abstraction (similar to that observed in carbonyl com- pounds) occurs on irradiation of 1-0-tolyl-1-phenylethylene leading to an o -xylylene intermediate (18) which may be trapped in a Diels-Alder reaction by cyclohexene.21 However the author does not mention the similar trapping experi- ments recently carried out by Pratt.22 The predominant products formed on photolysis of cis-cyclo-octene vapour appear to arise by intramolecular hydrogen abstraction of the vibrationally excited triplet state of the alke~~e.~~ The epoxy-diene (19) undergoes a novel photoreaction on irradiation (254 nm) in pentane producing the cyclopropenyl ketone (20) in 90% yield.24 A mechanism is proposed which involves homolytic C-0 bond-breaking of the epoxide ring as the initial step.(18) (19) (20) This year has seen some very interesting examples of reactions which ensue because of the conformational mobility of the biradicals generated by a-cleavage of cyclic ketones.Weiss and ~o-workers~~ have noted a stereospecific decarbonylation in the photolysis of the bicyclic ketone (21) to produce the ester (22) in which the stereochemistry of the methoxycarbonyl group is changed from ex0 to endo. This unusual inversion process is thought to reflect a radical substitution reaction whereby the LY -cleaved alkyl acyl biradical changes conformation allowing the alkyl radical to assist displacement of carbon monoxide from the acyl radical centre. The biradical (23) generated by photolysis of bicyclo[3,2,l]octan-6-one(24) disproportionates almost entirely to the unsaturated aldehyde (25).26 From a study of the rearrange- ment on photolysis of two specifically deuteriated isomers of (24) it is concluded that 21 J.M. Hornback Tetrahedron Letters 1976 3389. 22 A. C. Pratt J.C.S. Chem. Comm. 1974 183. 23 Y. Inoue K. Moritsugu S. Takamuku and H. Sakurai J.C.S. Perkin II. 1976 569. 24 A. P. Alder H. R. Wolf and 0.Jeger Helu. Chim. Acta 1976,59,907. 25 D. S. Weiss M. Haslanger and R. G. Lawton J. Amer. Chem. SOC.,1976,98 1050. 26 W. C. Agosta and S. Wolff J. Amer. Chem. SOC.,1976,98,4182. Photochemistry 159 the transfer of axial hydrogen in the biradical(23) is about 20 times more favoured than the transfer of equatorial hydrogen.27 H 0 eCH2CH0 - (23) (24) (25) The Norrish Type I1 reaction of aryl alkyl ketones such as (26a) generally leads via a 1,4-biradical to predominant elimination with a small amount of cyclization to cyclobutanol.Wagner and Thomas28find that a-fluorine substitution in the ketones (26b) and (26c) leads to a striking enhancement of cyclobutanol formation so that cyclobutanol is the only significant product formed from ketone (26c). An explana-0 I1 Ph-C-CXYCH,CH,Me (26) a; X=Y=H b; X=H,Y=F c; X=Y=F tion which will need further substantiation is given whereby fluorine substitution alters the preferred conformation of the 1,4-biradical to prevent C-C bond cleavage. In ester photochemistry although similar examples of elimination to alkene and carboxylic acid are well known there have been no reports of the cyclization to yield oxetanols. Marron and Gan~~~ now present this unobserved process as responsible for the photochemical conversion of adamant-2-yl trifluoroacetate (27) into the isomer (28) and they propose this reaction as a convenient high-yield route to various 1,2-disubstituted adamantanes.(27) (28) Double decarboxylation by irradiation of the diester (29) in methanol provides an ingenious route to [2,2]paracyclophane (30) in yields of up to 70% .30 Kaupp3' has observed three new examples of [6+61photocleavage of [2,2]cyclophanes including 27 W. C. Agosta and S. Wolff J. Amer. Chem. SOC.,1976,98 4316. 28 P. J. Wagner and M. J. Thomas J. Amer. Chem. SOC.,1976,98 241. 29 N. A. Marron and J. E. Gano J. Amer. Chem. Soc. 1976,98,4653. 30 M. L. Kaplan and E. A. Truesdale Tetrahedron Letters 1976 3665. 31 G. Kaupp Angew.Chem. Internat. Edn. 1976,15 442. 160 H. A. J. Carless the formation of the tetraene (31) on irradiation of the cyclophane (30) at low temperatures. (29) (30) (31) Irradiation of cyclobutanones in solution generally leads to ring expansion decarbonylation and cycloelimination reactions. However Jones and M~Donnell~~ describe a novel pathway from the photolysis in methanol solution of chlorocyc- lobutanones such as (32a) which produces the ring-contraction products (33) in competition with cycloelimination to form (34a). The ratio of ring contraction to (32) a; R1=Me,R2=C1 (33) (34) b; R1=C1 R2=Me elimination depends on the stereochemistry and conformation adopted by the particular bicyclic ketone. Theoretical considerations suggest that the photo- chemistry of cyclobutanones may differ so markedly from that of unstrained cycloal- kanones because of the ability of the former to generate a linear rather than bent acyl radical by cu-~leavage.~~ Attempts have been made to cause bis-decarbonylation (loss of C20,)by photo- lysis of cyclic unsaturated a-diketones.A more careful study of this reaction has now shown that bicyclic a-diketones such as (35) do not bis-decarbonylate but instead rearrange via a 1,3-shift to form cyclobutanediones [e.g. (36)].34 It is these latter compounds which give rise to the observed photochemical decarbonylations previ- ously ascribed to their bridged precursors. The overall reaction presents a useful synthetic route from the benzonorbornenedione (37) to the highly reactive isoindene (38).35 Photoenolization which has been reviewed by Samme~,~~ has provided some significant results this year.Ullman and Tseng3' have shown that the photoenoliza- 32 G. Jones and L. P. McDonnell J.C.S. Chem. Comm. 1976 18; J. Amer. Chem. SOC.,1976,98,6203. 33 N.J. Turro W. E. Farneth and A. Devaquet J. Amer. Chem. SOC.,1976,98 7425. 34 M. B.Rubin M. Weiner and H.-D. Scharf J. Amer. Chem. SOC.,1976,98 5699. 35 R.N.Warrener R. A. Russell and T. S. Lee Tetrahedron Letters 1977,49. 36 P.G.Sammes Tetrahedron,1976,32 405. 37 S.-S. Tseng and E. F. Ullrnan J. Amer. Chem. SOC.,1976 98 541. Photochemistry 161 (35) (36) (37) (38) tion of o-alkylbenzophenones such as (39) can be followed by efficient elimination reactions to produce o-vinylbenzophenone.Wagner and Chen3' report quenching studies which implicate both short-lived (0.2 ns) and long-lived (30 ns) triplets in the photoenolization of o-methylacetophenone (40). The long-lived triplets are thought to be anti-isomers [derived from anti-(40)] that rearrange to short-lived enolizable syn-isomers [also derivable from syn-(40)]. There does also appear to be singlet- state photoenolization. In a series of o -alkyl-phenyl alkyl ketones the authors3* present evidence that the measured apparent rate constant for enolization is independent of CFH bond strength so that they interpret this rate (ca. lo7 s-') instead as that of rotation of the anti-triplet to the syn-conformation. Ph 0A (39) anti -(40) syn -(40) Enone photochemistry remains a controversial subject.Hou~~~ has reviewed comprehensively the photochemistry of By -unsaturated carbonyl compounds much of which is dominated by 1,2-shifts (oxa-di-.n-methane rearrangements) occurring from excited triplet states and 1,3-shifts occurring from excited singlet states. This latter generalization is questioned in independent paper^.^^.^^ Dalton et aL41prop-ose on the basis of enone fluorescence quantum yields and lifetimes that some of the 1,3-acyl shifts observed on irradiation of alkyl py-enones may be occurring from the triplet nr*(T,) state rather than from the accepted singlet n.n*(S1) state. Such arguments would certainly help to explain some of the sensitized 1,3-acyl shifts 2f py-enones mentioned in last year's Report and also those recently observed by Parker and In principle the study of a triplet oxa-di-wmethane rearrangement of an optically active enone should allow a choice between the various radical and concerted pathways available for the 1,2-~hift.~~ Two group^^^,^^ have studied such a rearrangement but the results are not clear-cut.Schaffner and co-worker~~~ report that irradiation of the optically active enone (41) produces the two diastereoisomers (42)and (43) each essentially retaining the optical purity of the starting enone; in this example both a radical (a-cleavage) mechanism and a fully concerted [,2 +,2,] route are ruled out. However the optically active enone (44) 38 P. J. Wagner and C.-P. Chen J. Amer. Chem. SOC.,1976,98 239.39 K. N. Houk Chem. Rev. 1976,76 1. 4O K. Schaffner Tetrahedron 1976 32 641. 41 J. C. Dalton M. Shen and J. J. Snyder J. Amer. Chem. SOC.,1976,98 5023. 42 S. D. Parker and N. A. J. Rogers Tetrahedron Letters 1976,4389. 43 R. L. Coffin R. S. Givens and R. G. Carlson J. Amer. Chem. Soc. 1974 96 7554. 44 B. Winter and K. Schaffner J. Amer. Chem. SOC.,1976,98 2022. H.A.J. Carless has been photolysed by Dauben et QI.,~~ and in this case both oxa-di-rr-methane diastereoisomers formed are optically active but only about 10%optically pure. In conclusion the acyl-shifted biradical [e.g. (45)]is the intermediate most consistent with all these observations but its formation and selectivity of ring closure may depend very much on the substitution pattern of the &-enone from which it is derived.(41) R =CH(OMe)* (42) (43) (44) (45) In another example of the photochemical rearrangements of optically active ketones Schuster and have investigated the cyclohexenones (46).In each case the bicyclic ketones (47)and (48)are formed without any detectable loss of (46) a; R=Pr” (47) (48) b; R=Ph optical purity and the absolute stereochemistry of the products has been determined. The results prove that these cyclohexenone rearrangements proceed with inversion at the chiral centre (as expected for a concerted [,2 +,2,] process) and show that a biradical mechanism is not permissible. Photolysis of 6-hydroxycyclohexenones gives the first examples of products derived from a-cleavage of the cyclohexenone ring.47 There are very few molecules known where an upper excited state has a lifetime long enough to show different chemical reactions to those of the lowest excited state.Thiones are amongst such molecules and de Mayo has presented clear examples showing how two excited states can differ in their chemistry.48 Thus irradiation into the S2(?r?r*)band of aryl alkyl thiones such as (49)containing a 6-Chydrogen atom in the alkyl chain produces the cyclopentanethiol (50) from 6-hydrogen abstrac- ti~n.~~ Irradiation of (49)in the long-wavelength band [Sl(n.rr*)],however produces different unidentified products with an efficiency reduced by a factor of lo3. Likewise adamantanethione undergoes [2 +21 photocycloaddition to alkenes;” on irradiation in the Sz band addition is stereospecific but not regiospecific whereas irradiation in the S1band leads to regiospecific but not stereospecific reaction.These 45 W. G. Dauben G. Lodder and J. D. Robbins J. Amer. Chem. Soc. 1976,98 3030. 46 D. I. Schuster and R. H. Brown J.C.S. Chem. Cornm. 1976 28. 47 M. Jeffares and T. B. H. McMurry J.C.S. Gem. Comm. 1976 793. 48 P. de Mayo Accounts Chem. Res. 1976,9 52. 49 A. Couture K. Ho M. Hoshino P. de Mayo R. Suau and W. R. Ware J. Amer. Chem. Soc. 1976,98 6218. SO A. H. Lawrence C. C. Liao P. de Mayo and V. Ramamurthy,J. Amer. Chem. Soc. 1976,98,2219,3572. Photochemistry 163 differences are reminiscent of the singlet and triplet cycloadditions observed by Lewis and Hirsch’l (see below) and suggest that the reactive excited states are Sz (TT*) and TI (n?r*) respectively.Aryl alkyl ketones having an activated /3-C hydrogen such as (51) cyclize on irradiation in the S1 band to produce cyclo- propanethiols (52) in high yield.52 (49) (50) (51) a; R=Ph (52) b; R = 2-naphthyl c; R=SMe Fluorine substitution seems to exert a powerful effect in determining the orienta- tion of photochemical addition of alkenes to 5-fluorouracil (53),53 in contrast to the normally rather unselective [2 +21 additions of enones to alkenes which have been observed. For example isobutene reacts with (53) to form the adduct (54) as the exclusive photoproduct. Treatment of such adducts with base converts them into potentially useful 5-substituted uracil~.~~ (53) (54) Lewis and Hirsch” report a detailed investigation of the [2 +21 photocycloaddi-tion of diphenylvinylene carbonate (55) with conjugated dienes which gives much information on the role of the singlet and triplet excited states of (55) in the reaction.H Ph Ph (55) The singlet reaction occurs oiu an observable ex~iplex,~~ with complete retention of diene stereochemistry but only modest regioselectivity in attack at an unsymmetrical diene. In contrast the triplet cycloaddition occurs with substantial loss of diene stereochemistry but with high regioselectivity at the less substituted terminus of the diene. The important fact emerges that this high triplet regioselectivity is due to preferential collapse of the more substituted 1,4-biradical intermediate rather than to selective bonding to the less substituted diene terminus.Koch and co-workers 51 F. D. Lewis and R. H. Hirsch J. Amer. Chem. Soc. 1976,98 5914. 52 A. Couture M. Hoshino and P. de Mayo J.C.S. Chem. Comm. 1976 131. 53 A.Wexler and J. S. Swenton J. Amer. Chem. SOC.,1976,9& 1602. s4 Cf. A. Wexler R. J. Balchunis and J. S. Swenton J.C.S. Chem. Comm. 1975 601. 55 F.D.Lewis and C. E. Hoyle J. Amer. Chern. SOC.,1976,98,4338. 164 H.A. J.Carless have found further uncommon examples of the reactivity of the carbon-nitrogen double bond towards photocycloaddition in the reactions of 3-ethoxyisoindolone (56)56 and 2-oxazolin-4-ones (57)57with alkenes. (56) (57) Photocycloaddition reactions of the nitrile group are rare. Cant~eIl~~ has suggested a 1-azetine (58a) as an intermediate in the photoaddition of benzonitrile with 2,3-dimethylbut-2-ehe to yield the azadiene (59a).Yang and co-w~rkers~~ have now been able to isolate such 1-azetines (58a-c) from [2+21 photoadditions of A Ar * Ar $ (58) a; Ar=Ph (59) b; Ar =1-naphthyl c; Ar =2-naphthyl the corresponding aromatic nitriles to the same alkene. For the naphthonitriles [2+2] addition between the aromatic ring and the alkene also forms a competing reaction.60 A very different route to azadienes (60) is provided by the irradiation of derivatives of 2-hydroxymethylazirines (6 1) containing good leaving groups.6' A mechanism is proposed which involves photochemical generation of a nitrile ylide (62) followed by its 1,4-substituent shift to yield the azadiene (60).*-(60) a; X=C1 (61) b; X=Br c; X=OCOMe d; X=OCOPh Photo-oxidations are generally carried out by the use of light a dye photosen- sitizer and ground-state oxygen (30,) to generate the reactive species singlet oxygen ('0,). Amines are sometimes used to test for the participation of '0 in such dye-sensitized reactions although Davidson and Trethewey6 now point out that caution must be used in interpreting such experiments because amines (and also 56 K. A. Howard and T. H. Koch J. Amer. Chem. SOC.,1975,97 7288. 57 R. M. Rodehorst and T. H. Koch J. Amer. Chem. SOC., 1975,97,7298. 58 T. S. Cantrell J. Amer. Chem. SOC.,1972 94 5929. 59 N. C. Yang B. Kim W. Chiang and T. Hamada J.C.S. Chem. Comm. 1976,729.60 J. J. McCullough R. C. Miller D. Fung and W.-S. Wu J. Amer. Chem. SOC.,1975 97 5942. 61 A. Padwa J. K. Rasmussen and A. Tremper J.C.S. Chem. Comm. 1976 10. 62 R. S. Davidson and K. R. Trethewey J. Amer. Chem. SOC.,1976,98 4008. Photochemistry p-carotene) quench not only '0,but also the singlet excited state of the dye. Cyclic conjugated dienes generally react with '0, in a [4 +21 addition reaction to yield 1,4-endo-peroxides. In an alternative route Barton and co-~orkers~~ have used the triphenylmethyl cation and other electrophiles as catalysts in the photo-oxygenation of ergosteryl acetate to the peroxide excitation of a diene-catalyst complex allows the formally spin-forbidden reaction of 302with cisoid dienes to yield endo- peroxides.The oxidation of the strained acetylene (63)with triplet oxygen is another example of a reaction involving the conversion of 302 into singlet Attack by '0,on (63)is also feasible and low-temperature reaction produces evidence to suggest a dioxeten intermediate (64),which decomposes with fluorescence above ca. -30"Cto the corresponding a-diketone. One synthetic use of photo-oxidation is the recently reported conversion in high yield of ketones into LY -diketones uia the formation of enamino-ketones and their reaction with 0-0 (63) (64) The role of exciplex formation in the photochemical cycloadditions of aromatic molecules continues to evoke interest. 9,lO-Dicyanoanthracene and methyl-1,2- diphenylcyclopropene-3-carboxylate form an emitting exciplex in benzene solution and irradiation under these conditions leads to formation of the [4 + 21 adduct (65).66 In contrast different products are observed on irradiation in acetonitrile solution and no exciplex emission is seen.As in other example^,^' polar solvents are believed to assist electron transfer in the exciplex producing radical ions. Yang6' presents evidence that the two adducts arising from photocycloaddition of 9-cyanoanthracene to cycloheptatriene are formed by different reaction pathways uiz. a [4+4]con-certed route and a [4 + 21 biradical pathway. The first example of what purports to be an allowed photochemical [m4+,2 +,2] cycloaddition has been reported in the formation of compound (66) (along with anthracene photodimer) by irradiation of anthracene in benzene solution in the presence of q~adricyclane.~~ Exciplex forma- tion is again important in the photochemical behaviour of octafluoronaphthalene (65) (66) 63 D.H. R. Barton R. K. Haynes G. Leclerc P. D. Magnus andI. D. Menzies J.C.S. Perkinl. 1975,2055. 64 N. J. Turro V. Ramamurthy K.-C. Liu A. Krebs and R. Kemper J. Amer. Chem. SOC.,1976,98,6758. 65 H. H. Wasserman and J. L. Ives J. Amer. Chem. SOC.,1976,98 7868. 66 S. Farid and K. A. Brown,J.C.S. Chem. Comm. 1976 564. 67 A. Weller Pure Appl. Chem. 1968,16 11.5. 68 N. C. Yang and K. Srinivasachar J.C.S. Chem. Comm. 1976 48. b9 T. Sasaki K. Kanematsu I. Ando and 0.Yamashita J. Amer. Chem. Soc. 1976,98 2686. 166 H. A.J. Carless towards conjugated diene~.~’ In non-polar solvents (e.g.cyclohexane) 1 :1 adducts of aromatic with diene are formed whereas in polar solvents (e.g.acetonitrile) the yield of adducts is reduced and the formation of diene dimers becomes an important reaction. There is strong evidence that the diene dimers do not result from enhanced intersystem crossing of the exciplex. In contrast with the complex cycloaddition products formed on irradiation of hexafluorobenzene in the presence of cis-cyclo- ~ctene,~~ the photoaddition of hexafluorobenzene in cyclohexane solution to indene or 1,2-dihydronaphthalene results in the stereospecific formation of a single adduct (67) in each case.72 &GF HFF F (67) a; n = 1 b; n=2 Notable examples of aromatic substitution include the first instances of photo- chemical cine-substitution in the reactions of primary and secondary amines with aryl fluoride~’~ and the use of crown ethers and potassium cyanide in acetonitrile for the photochemical cyanation of aromatic^.^^ Two groups have succeeded in intercepting a zwitterionic intermediate in the photorearrangement of 4-pyrones to 2-pyrones by nucleophilic trapping with trifluoroethan01.~~”~ Thus the 4-pyrone (68)leads to the adduct (69) uia trapping of the zwitterion (70).Additionally Barltrop and co-w~rkers~~ have trapped the same species (70) by cycloaddition to furan. In protonated form the zwitterion (70) is also involved in the photorearrangement of hydroxypyrylium cations and can be trapped by sulphuric ac as the cyclic ~ulphate.~~ The first photochemical rearrangement of homotropyliuw cations has been noted in the conversion of the hydroxy-derivative id (71) on irradiation in fluorosulphonic acid at -70 “C into the cation (72).78The 0 0-(68) (69) (70) (71) (72) stereospecific nature of such cyclopropyl migrations around the periphery of the ring is in accord with orbital symmetry predictions.70 J. Libman J.C.S. Chem. Comm. 1976 361 and 363. 71 D. Bryce-Smith A. Gilbert and B. H. Orger Chem. Comm. 1969 800. 72 B. Sket and M. Zupan J.C.S. Chem. Comm. 1976 1053. 73 D. Bryce-Smith A. Gilbert and S. Krestonosich J.C.S. Chem. Comm. 1976,405. 74 R. Beugelmans M.-T. Le Goff J. Pusset and G. Roussi J.C.S. Chem. Comm. 1976 377; Tetrahedron Letters 1976 2305. 75 J.W. Pavlik and L. T. Pauliukonis Tetrahedron Letters 1976 1939. 76 J. A. Barltrop A. C. Day and C. J. Samuel J.C.S. Chem. Comm. 1976,822. 77 J. A. Barltrop A. C. Day and C. J. Samuel J.C.S. Chem. Comm. 1976 823. 7* R. F. Childs and C. V. Rogerson J. Amer. Chem. Soc. 1976,98 6391.

ISSN:0069-3030    

DOI:10.1039/OC9767300155

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

9 Aliphatic Compounds Part (i) Hydrocarbons By D. R. TAYLOR Department of Chemistry University of Manchester institute of Science & Techhology Manchester M60 IOD 1 Acetylenes Useful reviews have appeared which deal with synthetic applications of ynamines,' the present state of knowledge of palladium-catalysed oligomerizations,* and the synthesis of alkynes via organoborane~.~ An interesting method for improving one of the older methods for alkyne synthesis dehydrohalogenation recommends the use of an excess of a phase- transfer catalyst a technique termed ion-pair extraction. Mono- and di-aryl- acetylenes were readily prepared as well as examples less easy to obtain by a conventional dehydrohalogenation technique (Scheme l).4 (EtO),CHCH=CCI (EtO),CHCrCCl (2)-RCH=CBrCOMe RCrCCOMe Reagents i 50% aq.NaOH Bu4"N+HS04- (excess) C5H12-CHzC12; ii PhCHZNMe3+OH- (excess) C6H6-CH2C12 (R = PhCEC cc12=ccl efc.) Scheme 1 Further reports testify to the usefulness of alkynylborates for mono- and di-yne synthesis. The lithium lithioethynylborate (l),for example can be selectively alkylated at carbon so providing an alternative approach to unsymmetrical alkynes (Scheme 2).5 Problems which arose when the alkynylborate route to symmetrical [R',BCzCH]Li -&[R',BCrCLi]Li 4[R',BC_CR2]Li -% R'CGCR2 (1) e.g. R' = n-C5H11 R2= (2)-MeCH=CHCH2 Reagents i Bu"Li; ii R2Hal; iii I2 Scheme2 diynes was applied to unsymmetrical diynes have been overcome in two ways. The first relies on steric hindrance at boron to prevent side reactions such as the formation J.Ficini Tetrahedron 1976,32 1449. P. M. Maitlis Accounts &m. Res. 1976 9 93. J. Weill-Raynal Synthesis 1976 633. A. Gorgues and A. Le Coq Bull. Soc. chim. France 1976 125; Tetrahedron Letters 1976,4723. K. Utimoto Y. Yabuki K. Okada and H.Nozaki Tetrahedron Letters 1976,3969. 167 168 D. R. Taylor of symmetrical dialkynylborates,6 while the other relies on reversible complexation to lower the reactivity of intermediate alkynylborane~.~ The two routes are com- pared in Scheme 3. R',BSMe [R1,B(SMe)CrCR2]Li R1,BC=CR2 Li c R2Cr CCr CR' Reagents i R2C-CLi; ii R3CrCLi; iii I2 Scheme3 The recently discovered chain extension of alkynes uia dilithiation of terminal acetylenes has been shown to accommodate chain-branching (Scheme 4).8 Suitable electrophiles with which to capture the intermediate lithium acetylides (2) are proton alkyl halides aldehydes ketones and halogens (E= H R3 CH20H CR3*OH,or I respectively).R'CH,C_CH --b R'CHLiC_CLi -kR'R'CHCeCLi 4R'R'CHCr CE (2) Reagents i 2 x Bu"Li; ii R2Br; iii electrophiles (E; see text) Scheme4 Their susceptibility to both nucleophilic substitution and nucleophilically trig- gered dehalogenation has led to the use of l,l-dichloro-2-fluoroalkenesas alkyne- synthons by the sequence' 2RLi repeat CF2=CCI2 5RCF=CC12 -RCrCLi B RCzCCF=CCI +RCzCC=CLi which may be terminated by electrophilic quenching in the same way as Scheme 4. Other new-looking routes to acetylenes involve the conversion of 1,2-disilyloxyalkenes into thiocarbonates (3) which are decomposed by phosphites," S I1 */c\g \I c =c R/\ R (3) J.A. Sinclair and H. C. Brown J. Org. Chem. 1976,41 1078. A. Pelter R. Hughes K. Smith and M. Tabata Tetrahedron Letters 1976 4385. * A. J. G. Sagar and F. Scheinmann Synthesis 1976 321; S. Bhanu E. A. Khan and F. Scheinmann J.C.S. Perkin I 1976 1609. K. Okuhara J. Org. Chem. 1976,41 1487. lo D. P. Bauer and R. S. Macomber J. Org. Chem. 1976,41,2640. Aliphatic Compounds-Part (i) Hydrocarbons and cathodic coupling reaction of monosubstituted alkynes with alkyl halides in which the triple bond survives.11 There i.s further news of the so-called acetylene-zipper potassium 3-amino- propylamjde which leads to extremely rapid migration of a triple bond from an internal to a terminal position.Internal acetylenes with a terminal hydroxy-group isomerize in good yield though somewhat less rapidly than the parent hydrocarbons to w -hydroxyalk- 1-ynes an observation of promise for lipid chemists. 12~13 Either pr~tonation'~ of alkynes in the absence of nucleophiles as in or alkylati~n'~ S02-SbF5 or Magic Acid can yield stable solutions of allylic cations by simultaneous Wagner-Meerwein rearrangement (Scheme 5). Intermediate vinyl cations were not Me,CCrCH 6[Me,C?=CH,] [Me2C-CMe-CH2]+ MeCrCMe -% [(CD,),CCMe=cMe] -% [(CD,),C-C(CD,)-CMe2]+ Reagents i H+ from superacid; ii Me-[ 1,2] shift; iii (CD3)3C+from (CD3)3CCI-SbFs-S02 at -78 "C; iv Me- and CD3-[ 1,2] shifts Scheme5 detectable spectroscopically but related work shows that in the presence of nucleophiles 1 1adducts are obtained the predominantly E-geometry of which is consistent with attack upon open vinyl cations from the less hindered side and more rapidly than Wagner-Meerwein shifts.l6 Non-terminal alkynes can be converted into either mainly 2-dichlorides with antimony pentachloride" or mainly E-dichlorides with iodobenzene dichloride.l8 The unusual halogenating agent MeIF2 formed from iodomethane and xenon difluoride (sic),converts alkynes initially into synaadducts which may easily be isomerized if desired (Scheme ,).Ig An electro- Ph But Ph I Reagents i MeIF,; ii MeI-HF Scheme 6 philic addition to alkynes which certainly seems to proceed via a bridged inter- mediate cation is that of an arenesulphenyl chloride at least to judge by the results of a study of steric and electronic effects of alkyne substituents upon the rate and regioselectivi ty of addition .20 M.Tokuda T. Taguchi 0.Nishio and M. Itoh J.C.S. Chem. Comm. 1976,606. l2 C. A. Brown and A. Yamashita,J. Amer. Chem. SOC. 1975,97,891;J.C.S. Chem. Comm. 1976,959. l3 J. C. Lindhoudt G. L. van Mourik and H. J. J. Pabon Tetrahedron Letters 1976 2565. l4 G. A. Olah and H. Mayr J. Amer. Chem. Soc. 1976,98,7333. Is G. Capozzi V.Lucchini F. Marcuzzi and G. Melloni Tetrahedron Lars 1976 717. l6 F. Marcuzzi and G. Melloni J. Amer. Chem. Soc.,1976,98 3295; J.C.S. Perkin ZZ 1976 1517. S. Uemura A. Onoe and M.Okano J.C.S. Chem. Comm. 1976 145. A. Debon S. Masson and A. Thuillier Bull. Soc.chim. France 1976 2493. l9 M. Zupan Synthesis 1976,473. 2o G. H. Schmid A. Modro F. Lenz D. G. Garratt and K. Yates 1. Org. Chem. 1976,41 2331. 170 D.R. Taylor Useful new methods for the conversion of alkynes into olefins and dienes with excellent stereochemical control are based upon the addition of di-iso-butylaluminium hydride followed by treatment with butyl-lithium and electro- philes (Scheme 7).21*22Note that either E-or 2-isomers of the intermediate R' R2 R' R2 \c=c /A1Bui2 ii& R' R3\c=c / H/ \R2 H/ \R2 244) Reagents i BU~~AIH-C~H,, or +,H16; ii RLi (e.g. R =Me or Bu"); iii R3Hal (e.g. R3=Me allyl PhCH, or HCGCCH,); iv Bu',AlH-C6Hl4-N-methylpyrrolidine or -C,H,,-Et,O Scheme 7 vinylalanes (4) are obtainable by adjusting the reaction conditions and starting with a silylalkyne (R2 = Alk3Si).22 Vinylalanes can also be coupled with vinyl halides giving conjugated dienes of known Rather similar results have been reported using vinyl mercurials produced by mercuration of alkyne~,~~ a procedure which is claimed to have a greater degree of tolerance for other functionality within the molecule than either hydroalanation or hydroboration.A recent example of the well known trimerization of alkynes to arenes featured the conversion of dicyclopropylacetylene into (9,a molecule which should be extremely susceptible to photochemical conversion into a Dewar-ben~ene.~~ Another ingeni- ous application of this trimerization is the [CpC~(CO)~]-cataIysed generation of 21 E.Negishi S. Baba and A. 0.King J.C.S. Chem. Comm. 1976,17; S. Baba D. E. Van Horn and E. Negishi Tetrahedron Letters 1976 1927. 22 J. J. Eisch and G. A. Damasevitz J. Org. Chem. 1976,41,2214; K. Uchida K. Utimoto and H. Nozaki ibid. p. 2215. 23 S. Baba and E. Negishi J. Amer. Chern.Soc.,1976,98 6729. 24 R. C. Larock J. Org. Chem. 1976,41,2241; R. C. Larock and B. Reifling Tetrahedron Letters 1976 4661. 25 V. Usieli R. Victor and S. Sarel Tetrahedron Letters 1976 2705. Aliphatic Compounds-Part (i)Hydrocarbons o-xylylenes such as (6) setting up an elegant approach to naturally occurring polycycles from diynes (Scheme 8).26 x-Y r Xnd (X=0,Y =CH,; X= CH, Y =CH,orO) Reagents:i RCGCR (R =Me$) [CpCo(CO),]; ii CF,CO,H-CCI Scheme8 Further details have appeared of the interesting work on alkyne-ozonolysis intermediates which may be used to epoxidize alkenes.Suggested species are (7)-(9) all of which are presumed to require prior formation of (lo).*' Other workers have now shown that a thermally unstable intermediate (half-life 35 min at -42 "C)is formed when ozone attacks tolan. The intermediate is reduced to benzil by diphenyl sulphide and leads to chemiluminescence when treated with singlet acceptors its structure was suggested to be (1l) and it was supposed to arise via the sequence (7)+(1O)+(11).*' 0' '0H R R O,-,OC-COR /R RCO-0,H 0-b/ IIRC-COR 0-0 PhWPh 0 (7) (8) (9) (10) (1 1) 2 Alkanes New methods for alkane synthesis are fairly rare.One such is a new technique for reduction of alkyl halides which makes use of the ready transfer of hydride ion from a trialkylsilane to a carbenium ion.29 Fully developed carbenium ions are not essential to the success of the method since the reaction proceeds readily with methyl iodide and ethyl bromide but functional groups such as NOz or CN which could co-ordinate strongly to the catalyst must be absent (Scheme 9). 26 R L. Funk and K. P. C. Vollhardt J. Amer. Gem. Soc.,1976,98,6755. 27 R. E. Keay and G. A. Hamilton,J. Amer. Chem. Soc. 1976,98,6578; see also ibid. 1975,97,6876. 28 S. Jackson and L. A. Hull J. Org. Chem. 1976,41 3340. Z9 M. P. Doyle C. C. McOsker and C. T. West J. Org. am. 1976,41 1393.172 D.R. Taylor Me(CH,),Br [Me(CH2),6HCH,] -bMe(CH,),CHDCH Reagents i anhydrous AICI (catalytic); ii Et,SiD Scheme9 Protonated ozone inserts electrophilically into the 0-bonds of alkanes in superacid The products obtained are not consistent with initial protolysis of the alkane followed by reaction of ozone with alkylcarbenium ions this is clearly shown by the behaviour of n-butane which is oxygenated at C-2 and gives only small amounts of the product formed by treating t-butyl cation with ozone (the rearrange- ment of s-butyl cation to t-butyl cation is very rapid) (Scheme 10). 6H II MeCH,CH,Me MeCCH,Me +MeCH=bEt (main products) Me,CH 4 -% [M;:-O-O,H] [Me,C--::roz~ Me,CCl -% [Me,C+] Me,C=bMe Reagents i 0,,FS0,H-SbF,-SO,CIF -78 "C; ii -H+; iii H+,-H,O, Me-[1,2] shift; iv SbFS-SOZCIF -78 "C -C1 ;v 0, -02,Me-[1,2] shift Scheme 10 The novel superacid system HF-TaF5 has been found to be highly efficient for converting methane-ethylene mixtures into propane with 99% ~electivity.~~ Since n-butane not isobutane was the sole product of ethane-ethylene reactions in this system no intermediate butyl cation can have been formed.A polymer catalyst with superacid properties has been formed; aluminium chloride was complexed with a cross-linked polystyrenesulphonic acid and the resulting beads were shown to have excellent capability for alkane catalytic cracking and isomerization at only 85 0C.32If catalyst activity can be regenerated simply the implications for refinery processes seem very important.Direct amination of acyclic alkanes has been effected by the combined effect of trichloramine and aluminium chloride at -20 to +20°C. Typical carbenium ion fragmentations and rearrangements occur so that mixtures of alkylamines fre- quently 3 AUenes Two long-standing methods for preparing allenes have received fresh impetus from recent discoveries. The first is Zakharova's method which involves a Grignard- 30 G. A. Olah N. Yoneda and D. G. Parker J. Amer. Chem. Soc.,1976,98,5261. M. Siskin J. Amer. Chem. Soc. 1976 98 5413. 32 V. L. Magnotta B. C. Gates and G. C. A. Schuit J.C.S. Chem. Comm. 1976 342. 33 T. A. Wunk S. S. Chaudhary and P. Kovacic J. Amer. Chem. Soc. 1976,98 5678. ,-&+ Aliphatic Compounds-Part (i) Hydrocarbons 173 initiated propargyl rearrangement with substitution I I -CZC-C-X I i-RMgX __* RC=C=C / \ I I + RC-C=C- The main disadvantage of this method is the concurrent formation of variable often large amounts of isomers such as alkyne or conjugated diene.A number of recent publications show that high selectivity for allene formation can be achieved using catalytic amounts of ferric cobaltous ~hloride,~’ or cuprous or just an excess of magnesium halide:37 yields are excellent (Scheme 11). The closely related reaction between propargyl esters and organocuprates has also been made more selective for allene formation by modifications in technique.38 Me,C=C=CHC,H, I Me,C-CzCR RjH+ Me,C=C=CHBu Me,C=C=CMePh R=Me Reagents i n-CBHl7MgI-MgBr2 (X = OAc); ii BunMgBr-FeC13 (catalytic; X = Cl); iii PhMgBr-CuBr (catalytic; X = OMe) Scheme 11 The second method to receive more modern treatment is that of Hartzler which involves trapping allenylcarbenes with olefins to give alkenylidenecyclopropanes.Phase-transfer catalysis which permits a simple two-phase technique first reported in 1974 has now been further improved by the use of crown ethers (e.g. Scheme 12).39Instead of aqueous alkali powdered KOH may now be used at sub-ambient temperatures enabling rather labile carbene traps to be employed. The unmodified Hartzler technique was quite successfully applied recently to vinyl-substituted allenic carbenes though yields of trapped products were Me,CClCECH [Me,C=C=C] A >C a Reagents:i aq.KOH-dicyclohexyl 18-crown-6,25“C;ii Me,C=CHCH=CMe,-C,H Scheme 12 Lithiation of propadiene followed by alkylation was cited in last year’s Report; it has now been extended to encompass the preparation of allenic organocuprates and 34 D. J. Pasto G. F. Hennion R. H. Shults A. Waterhouse and S.-K. Chou,J. Org. Chem. 1976,41,3496. 35 F. Coulomb-Delbecq J. Gort and M.-L. Roumestant Bull. Soc.chim. France 1976 533. 36 J.-L. Moreau and M. Gaudemar J. OrganometallicChem. 1976,108 159. 37 F. Delbecq and J. Gort Angew. Gem. Internat. Edn. 1976,15496. 38 P. Crabbt E. Barreiro J.-M. Dollat and J.-L. Luche J.C.S. Chem. Comm. 1976 183. 39 T. Sasaki S. Eguchi M. Ohno and F. Nakata J. Org. Chem. 1976,41 2408. 40 A. Doutheau and J. Gort Bull.Soc. chim. France 1976 1189. 174 D.R. Taylor (RCH=C=CH),CuLi / H' \CO,Me (12) Reagents i Bu"Li; ii RBr (R =n-C,H,,); iii Bu'Li; iv CuI v HCrCC0,Me Scheme 13 hence of more complex molecules such as the insect pheromone (12) (Scheme 13).41 Lithiation of propynylcyclopropane (13; R' =R2=H) is followed by alkylation adjacent to the cyclopropyl ring giving allenes but similar treatment of higher homologues such as (13; R'=R2=Me) gives mainly acetylenic isomers by ring alkylation (Scheme 14).42Dilithiation was apparently not detectable. 1"' [)--CrCCHR'Me bCR3=C=CH2 ji PCEcCHR'Me Reagents i Bu"Li (R' = R2=H); ii R3Hal (eg.R3= Et or Me$); iii Bu"Li (R' =Me R2= H or Me) Scheme 14 Two fresh instances of the application of Skattebol's allene synthesis to the preparation of higher cumulenes have been reported.43v44 Also noted were two new methods for the synthesis of higher cumulenes (Scheme 15) the first of which BU'C~CHi,BU'CH=C=C=CHBU* + CH~CH2=C=C=C=CH2 Reagents i [Ru(H),CO(Ph,P),-C,H, 100"C; ii 700 "C low pressure Scheme 15 41 D.Michelot and G. Linstrumelle Tetrahedron Letters 1976 275. 42 D. Bauer and G. Kobrich Gem. Ber. 1976,109,2185. 43 J. C. Jochims and G. Karich Tetrahedron Letters 1976 1395. W. R. Roth and H.-D. Exner Gem. Ber. 1976,109 1158. Aliphatic Compounds-Part (i) Hydrocarbons appears to be of general application it involves the catalytic coupling of two terminal alkyne m01ecules.~~ The other embodied a thermal retro-Diels-Alder reaction and provides the first synthesis of pentatetraene CH2=C=C=C=CH2.46 The hy- drocarbon proved to be relatively stable in solution (half-life 20 min at +40"C) but rapidly polymerized when pure.The energy barrier to double-bond rotation in substituted pentatetraenes has been measured experimentally and the value obtained agrees with theoretical prediction^.^^ 1,2,3,5Hexatetraene otherwise called vinylbutatriene which is a benzene isomer has been synthesized and is also stable in solution though at sub-ambient temperature. It undergoes a Diels-Alder reaction with tetracyanoethylene even at -78 0C.47 Solvation plays an important role in determining the regioselectivity of elec- trophilic additions to allenes. This conclusion emerged from work aimed at resolving conflicting reports in the literature concerning the orientation of hydrogen bromide addition to cy~lononadiene.~~ In glacial acetic acid protonation by HBr occurs almost exclusively at the central carbon of the allene function but if the solvent is diluted with a less polar liquid such as diethyl ether or petroleum ether the orientation is reversed and protonation at the terminal carbon occurs preferentially (Scheme 16).Acyclic monoalkyl- and 1,3-dialkyI-allenes protonate terminally Reagents i HBr-AcOH-Et,O (X =CH,CH or CH=CH); ii HBr-AcOH (X =CH,CH,) Scheme 16 whether or not a non-polar co-solvent is added which indicates a preference for incipient vinyl cation formation except in the cyclic allene in a polar solvent. These observations are particularly interesting in view of results obtained in the gas phase by ion cyclotron resonance; these appear to show conclusively that the cation obtained by protonation of propadiene in the gas phase is not allyl but has the + structure MeC=CH2.The same vinylic cation is formed by protanation of gaseous pr~pyne.~~ In contrast with the above results a classical physical-organic study of relative rates of iodination of 1,3-diarylallenes provided clear evidence for the formation of transition states which resemble 2-iodoallyl cations (14). Rates of addition corre- lated well with Hammett c+values for substituents in the aryl groups and concurrent racemization of optically active allenes proceeded at the same rate as additi~n.~' 45 H.Yamazake,J.C.S. Chem. Comm. 1976,841. 46 J. L. Ripoll J.C.S. Gem. Comm. 1976 235. 47 H. Maurer and H. Hopf Angew Chem. Zntemat. Edn. 1976,15,628. 48 M. S. Baird and C. B. Reese Synthesis 1976 385. 49 D. H. Aue W. R. Davidson and M. T. Bowers J. Amer. Chem. Soc. 1976,98,6700. A. J. G. van Rossum and R. J. F. Nivard J.C.S. Perkin ZZ 1976 1322. 176 D.R. Taylor I I I I H Ar HH (14) The chemistry of alkenylidenecyclopropanes (15) and (16) has been the subject of an extensive ~tudy.~' Electrophiles such as proton AcOHg' and PhS' attack (15) selectively at the exocyclic C=C bond yielding ring-opened diene adducts (Scheme 17). The tetramethylcyclopropylideneallene(16) is attacked in the same way as (15) I if Reagents:i AcOH 115 "C (E = H X =OAc); ii (AcO),Hg-AcOH (E=AcOHg X = OAc); iii PhSCI-CH,CI (E = PhS X =Cl); iv X Scheme 17 by the acetoxymercuri-cation but proton and phenylsulphenyl cation attack the remote C=C bond and hence produce acetylenic adducts after ring-opening (Scheme 18).Free-radical addition of benzenethiol to (15) and (16) gives adducts derived by addition only to the exocyclic C=C bond and without ring-opening. if XCMezCMezCECCMe2E + CH2=CMeCMezC=CCMezE Reagents i AcOH-TsOH 25 "C (E = H X = OAc); ii PhSCI-CHzCI2 0 "C (E= PhS X =C1); iii X-and -H+ Scheme18 51 D. J. Pasto and M. F. Miles J. Org. Chem. 1976,41 425; ibid. p. 2068. Aliphatic Compounds-Part (i) Hydrocarbons These results were explained in terms of the relative hardness and softness of the electrophiles and the electronic interactions in the intermediate cations or free radicals.An intriguing preliminary communication reveals e.s.r. evidence for the formation of non -planar ally1 free-radicals (17) by reaction of tetramethylallene with thiyl silyl and stannyl radicals which selectively attack the central carbon atom of such a highly substituted allene. The evidence against rotation of the singly occupied orbital into coplanarity with the remaining rr-bond which had always been supposed to occur instantaneously is that all twelve hydrogen atoms in the four methyl groups are magnetically equivalent a result incompatible with a planar allylic radical (1 8) which has two different types of methyl gro~p.’~ II 1 Me Me Me Me (17) R = MeS CF3S Me3Si,or Me3Sn The tendency for rearrangements to occur during 1,3-dipolar cycloadditions to allenes has been explored.Azomethine oxides with N-aryl groups yield pyr- rolidones whereas N-alkyl-azomethine oxides unexpectedly produce piperidones (Scheme 19).53 Further evidence for intermediate bis-ally1 biradicals in allene Ph fIPh I R Reagents i PhCH=N(O)R; ii R= Ph or C6Hll;iii PhCH=N(O)R if R=Me or Et; iv -RNO Scheme19 cyclodimerizations has been reported. Thermal dimerization of 1,l-dimethylallene and thermal or photochemical extrusion of nitrogen from (19)are reactions which all yield the same mixture of dimers (Scheme 20) a result best explained by the formation of a common intermediate biradical (20).’4 The photoelectron spectra and I3Cn.m.r.chemical shifts of a considerable number of allenes have been rep~rted.~~’~~ 52 W. H. Davis and J. K. Kochi Tetrahedron Letters 1976 1761. 53 G. Cum G. Sindona and N. Uccella J.C.S. Perkin Z 1976 719. 54 T. J. Levek and E. F. Kiefer J. Amer. Chem. Soc. 1976 98 1875. 55 D. J. Pasto T. P. Fehlner M. E. Schwartz and H. F. Baney J. Amer. Gem. Soc. 1976,98,530; D. J. Pasto and J. K. Borchardt J. Org. Chem. 1976,41 1061. 56 M. J. S. Dewar G. J. Fonken T. B. Jones and D. E. Minter J.C.S. Perkin ZZ 1976 764. 178 D.R. Taylor II + II Scheme20 4 Olefins and Dienes Substantive reviews have appeared on the following topics the kinetics and orienta- tion of free-radical additions to 01efins;~' biomimetic cationic polyene cyclizati~ns;~~ hydrogenation of alkenes over metal oxide catalysts;59 and olefin metathesis.60 Organic chemists are currently very interested in developing new methods for olefin and diene synthesis to judge by the plethora of publications in this area.Two new routes are now available for preparing trialkyl-P -hydroxysilanes which are precursors for the Peterson synthesis and so give access to specific geometrical isomers of trisubstituted olefins.61762 Highly ingenious is the one which involves two successive nucleophilic displacements at selenium in organoselenides (Scheme 21).61 (MeSe),CHR '' b MeSeCHRSiEt3 Et,SiCHRC(OH)PhCH,Ph H Ph Reagents i Bu"Li;ii Et,SiCI; iii PhCOCH,Ph -78 "C; iv H,O+ Scheme 21 However it is not necessary to introduce silicon at all since P-hydroxyselenides undergo the same type of acid-catalysed trans-elimination with a high degree of stereo~pecificity.~~ For example phenyl hydroselenide and aldehydes are sufficient precursors for preparing 2-dialkyl-olefins (Scheme 22).The final elimination can be 57 J. M.Tedder and J. C. Walton Accounts Chem. Res. 1976,9 183. 58 W. S. Johnson Angew. Chem. Internat. Edn. 1976,15 9. 59 Kh. M. Minachev Yu. S. Khodakov and V. S. Nakhshunov Russ. Chem. Rev. 1976,45 142. 60 N. Calderon E. A. Ofstead and W. A. Judy Angew. Chem. Internat. Edn. 1976,15,401. W. Dumont and A. Krief Angew. chem. Internat. Edn. 1976,15 161. 62 K. Utimoto M. Obayashi and H. Nozaki J. Org. Chem. 1976,41 2940. J. Remion W.Dumont and A. Krief Tetrahedron Letters 1976 1385; J. Rtmion and A. Krief ibid. p. 3743. Aliphatic Compounds-Part (i)Hydrocarbons H H R'CH0'-R'CH(SePh)2 -% R'CH-CHR2 -% \C=C I I R' ' / \R2 SePh OH Reagents i PhSeH; ii Bu"Li-R'CHO; iii TsOH C,H, or HCIO, Et,O or (CF,CO),O (or SOCI,) CH,CI,-Et,N. Scheme22 triggered by toluenesulphonic acid perchloric acid trifluoroacetic anhydride or thionyl chloride. New routes to chosen isomers of alkenylsilanes which may also be used as precursors for the Peterson reaction or for more direct oiefin synthesis by eiectrophilic displacement of silicon have also appeared recently.6M6 Some very elegant conversions of acetylenes into olefins and dienes can now be achieved (see also Section 1). One technique which is used with increasing frequency is the addition of an organocopper to an alkyne which proceeds exclusively syn followed by stereospecific displacement of copper e.g.Scheme 23.67In this version R' H R' H R' H 1. H H \/ c=c R2/ \Cu(SPh)Li Reagents i R2Cu (e.g. R' = Me RZ = Et); ii I, -20 "C; iii Bu"Li -60 OC;+iv electrophile (e.g. CO2 or CH20); v R2Cu(SPh)Li (R' = H); vi HC=CCO,Et; vii aq. NH Scheme 23 of the method the choice of solvent is important if alkylation of the alkenyl-lithium (21) by liberated idobutane is not to occur. The usual range of reactions of an organolithium reagent could be achieved with (21)without loss of stereochemical integrity provided that the temperature was kept low enough. Alkynylborates continue to provide new techniques for stereoseiective olefin syntheses some of which are illustrated in Scheme 24.68*69 64 K.Uchida K. Utimoto and H. Nozaki J. Org. Chern. 1976,41 2941. 65 T. H. Chan A. Baldassarre and D. Massuda Synthesis 1976,801; W. Mychajlowskij and T. H. Chan Tetrahedron Letters 1976,4439. 66 R. F. Cunico and F. J. Clayton J. Org. Chem.,1976,41 1480. 67 G. Cahiez D. Bernard and J. F. Normant Synthesis 1976 245; A. Alexakis J. F. Normant and J. VilliCras Tetrahedron Letters 1976 346 1. 6.9 J. Hooz and R. Mortimer Tetrahedron Letters 1976,805. 69 R. Kiister and L. A. Hagelee Synthesis 1976 118. 180 D.R. Taylor R'~B SnBu3 R' 2BCH2 SnBu3 -\/ ii iii \/ [R',BC_CR2]Li c=c c=c R' /\R2 R' /\R2 p P R12B SiMe3 \/ H3C\/ H c=c c=c R' /\ R3 Reagents i Bu",SnCl; ii MeSCH,Li; iii MeI; iv HC0,H; v R3Hal (R2=SiMe,) Scheme24 1,4-Dienescan be obtained from alkynes by addition of chloroborane followed by methylcopper-induced coupling of the stereospecifically formed dialkenyl-chloroborane (22; R =Bun) with ally1 bromide.If the blue solution obtained by treating the chloroborane (22;R =H) with methylcopper is successively treated with a phosphite or with PhSLi and then with an alkyl halide E-disubstituted olefins are obtained (Scheme 25).70 Bun R Bu"C=CR 4 \/ H Bun H/\CH2CH=CH2 Reagents i H,BCI; ii MeCu -30°C; iii (R =Bun) CH,=CHCH,Br; iv (R =H) MeI-(EtO),P Scheme 25 A stereospecific synthesis of conjugated dienes has been devised which involves stereoselective migration of the Ph2P(0) group in Wittig-Horner reaction inter- mediates (Scheme 26).The overall effect is to build up the diene from two aldehydes and an alkyl halide.'l Phase-transfer catalysis of the Wittig olefin synthesis has been found to be very effective when 18-crown-6 is However the Wittig-Horner reaction works well in a two-phase system even without any phase-transfer catalyst provided that a phosphonate containing a very acidic methylene group is used as the substrate such as (Et0)2P(0)CH2C0,H which presumably catalyses phase transfer it~elf.~~,~~ 70 Y. Yamamoto H. Yatagai A. Sonoda and S.-I. Murahashi J.C.S. Chem. Comm. 1976 452. 71 A. H. Davidson and S. Warren J.C.S. Perkin I 1976,639; J.C.S. Chem. Comm. 1976 181. 72 R.M. Boden Synthesis 1976 784. 73 M. Mikolajnyk S. Grzejszczak W. Midura and A. Zatorski Synthesis 1976 396. 74 C. Piechucki Synthesis 1976 187. Aliphatic Compounds-Part (i)Hydrocarbons R'CH2CHBrCH iof ji P Ph2P(0)CHMeCH2R1 iii '" b Ph2P(0)CMeCH2R' I R*CHOH Reagents i Ph,P then aq. NaOH; ii Mg-Et,O then Ph,P(O)CI; iii Bu"Li; iv R*CHO; v TsOH; vi R3CH0 and separation of diastereoisomers; vii NaH-DMF Scheme26 Polymer-supported peracids suitable for the epoxidation of di- and tri-substituted olefins under mild conditions have been developed and are sufficiently stable for practical application^.^^ Several reports testify to the capabilities of polymer- supported hydrogenation catalysts and this is an area which may be expected to expand rapidly since the materials offer numerous An attempt has been made to provide a new and unifying theory of catalytic hydrogenation mechanisms on metal ~urfaces,'~ the essence of which is that hydrogen is transferred to adsorbed olefin from an adsorbed hydrocarbon species designated M-C,H,.This original idea removes the necessity for dependence of energy barhers upon the nature of the metal or for correlations with physical properties of surfaces except insofar as these factors influence the formation and stability of the M-C,H centres. Certainly the theory seems well worthy of experimental testing. Further support for the Criegee mechanism of ozonolysis has come from work intended to test the accuracy of the methods used to locate the site of I8O incorporation into ozonides.Hitherto this has been achieved by mass spectrometric analysis of the ozonides produced in the presence of I80-labelled aldehyde and the results indicated that l80 entered the ozonide in both the ether and the peroxide positions as in (23). An alternative method claimed to be more reliable has been based upon triphenylphosphine reduction of the ozonide; within the experimental error the results showed that l8Oentered exlusively the ether moiety as in (24).79 There is therefore no need to invoke a mechanism which requires scrambling of a label (see 1975Report). Spectroscopic evidence for pre-zwitterion rr-complexes has been obtained at very low temperature for non-aromatic terminal olefins.'' 75 C. R. Harrison and P. Hodge J.C.S.Perkin Z 1976 605. 76 E. S. Chandrasekaren R. H. Grubbs and C. H. Brubaker J. Organometallic Chem. 1976,120,49. 77 K. G. Allum R. D. Hancock I. V. Howell T. E. Lester S. McKenzie R. C. Pitkethly and P. J. Robinson J. Organometallic Chem. 1976 107 393. 78 S. J. Thomson and G. Webb J.C.S. Chem. Comm. 1976,526. 79 D. P. Higley and R. W. Murray J. Amer. Gem. Soc. 1976,98,4526. so W. G. Alcock and B. Mile J.C.S. Chem. Comm. 1976 5. 182 D.R. Taylor Chloramine-T has found a new use in the presence of catalytic amounts of osmium tetroxide it converts olefins into hydroxytosylamides (25) by a syn -addition mechanism (Scheme 27).8' Terminal olefins mainly produce 1-amido-2-hydroxy- I Reagents i TsNCINa 3H,O (Chloramine-T) 1% OsO, Bu'OH; ii Na-NH,; iii Mel-RO-Scheme27 alkanes.Osmium tetroxide also catalyses vicinal cis-hydroxylation of olefins by t-butyl hydroperoxide under alkaline conditions.82 Other interesting or potentially useful new reagents for olefin conversions include the selenium di-imide TsN=Se=NTs which 1,2-diaminates conjugated diene~~~ and aminates mono- olefins at the allylic (this reaction is also effected by TsN=S=NTs8') the new enophile TsN=CHC02R which converts olefins into precursors of yS -unsaturated a-amino-acids;86 and MeIF2 which regioselectively and stereospecifi- cally iodofluorinates aryl o1efins8' (corresponding bromofluorination is achieved by the less exotic combination of hydrogen fluoride pyridine and N-bromosuccinimide") . A detailed comparative study has been made of ionic chlorination of 1,3-dienes by molecular chlorine iodobenzene dichloride and antimony penta~hloride.~~ 1,4-Chlorination of a 1,3-diene by molecular chlorine is predominantly syn but less stereoselective than is bromination.The other reagents give substantial amounts of anti-adducts. 1,2-DichIorination by chlorine is rather non-stereospecific though it may give mainly syn -or mainly anti -adducts according to diene structure. Iodoben- zene dichloride gives relatively large proportions of anti- 1,2-dichlorides. These results can be rationalized by consideration of the sizes of the counteranions PhICl- and [SbCI6]- are much larger than chloride and are therefore constrained towards anti -addition. A physical-organic study of medium and ring-strain effects on acid-catalysed hydration of dienes has been completed.90 The results emphasize the incomplete- K.B. Sharpless A. 0.Chong and K. Oshima J. Org. Chem. 1976,41 177. 82 K. B. Sharpless and K. Akashi J. Amer. Chem. SOC.,1976,98 1986. K. B. Sharpless and S. P. Singer J. Org. Chem. 1976,41 2504. K. B. Sharpless T. Hori L. K. Truesdale and C. 0.Dietrich,J. Amer. Chem. Soc.,1976,98,269. 85 K. B. Sharpless and T. Hori J. Org. Chem. 1976,41 176. 86 0.Achmatowicz and M. Pietraszkiewicz J.C.S. Chem. Comm. 1976 484. 87 M. Zupan and A. Pollack J.C.S. Perkin I 1976 1745; J. Org. Chem. 1976,41 2179. M. Zupan and A. Pollack J.C.S. Perkin I 1976 971. 89 G. E. Heasley D. C. Hayse G. R. McClung and D. K. Strickland,J. Org. Chem. 1976,41,334;V.L. Heasley K. D. Rold D. B. McKee and G. E. Heasley ibid. p. 1287. 90 J. L. Jensen and V. Uaprasert,J. Org. Chem. 1976,41,649;J. L. Jensen V. Uaprasert and C. R. Fujii ibid. p. 1675. A liphatic Compounds -Part (i)Hydrocarbons 183 ness of proton transfer in the transition state and the greater importance of conjugative interactions during acid-catalysed hydration of dienes compared with reactions of mono-olefins. Two promising methods for the cyclization of a,@-dienes have been reported. One employs a catalytic amount of a dialkylaluminium hydride and produces methylenecy~loalkanes.~~ The other gives cycloalkanes by silver ion-catalysed coupling of diborane adducts (Scheme 28).92 Reagents i Bu~ AlH (catalytic); ii B,H,-THF 0 "C; iii KOH-MeOH then aq.AgNO Scheme28 Of the many active areas of research in diene chemistry the development of new versatile dienes for use as Diels-Alder substrates seems to have been one of the most productive this year. For example the diene (26) obtainable from cyclobutanone contains a 2-thiyl substituent which not only controls the regioselectivity of the cycloaddition but also activates its site of attachment to substitution (Scheme 29).93 Meox i,MeOoCHO ii..v PhS PhS PhS ' (26) vl p3Tocoph AcO Reagents i CH2=CMeCHO; ii NaBH4-MeOH; iii PhCOC1-py; iv 50 1 MeCN aq.HC104; V Pb(OAc)4 Scheme 29 In a similar vein another diene (27) of potential contains a silyl ether group which activates its Diels-Alder adducts to electrophilic attack (Scheme 30).94 Trimethylsilyl-substituted dienes have been put to similar use.95 Several examples of a little-studied class of dienes amido-dienes have been prepared and their Diels-Alder reactions in~estigated.~~ Whereas the 1-substituted trichloro-acetamido-diene (28) is relatively unreactive the corresponding 2-amido-diene (29) is reactive and undergoes cycloaddition regiospecifically.91 P. W. Chum and S. E. Wilson Tetrahedron Letters 1976 1257. 92 R. Murphy and R. H. Prager Tetrahedron Letters 1976,463. 93 B. M.Trost and A. J. Bridges J. Amer. Chem. Soc. 1976,98,5017. 94 M. E. Jung and C. A. McCombs Tetrahedron Letters 1976,2935. 95 M.J. Carterand I. Fleming,J.C.S. Gem. Comm. 1976,679;I. Flemingand A. Percival ibid. p. 681. 96 L.E.Overman and L. A. Clizbe J.Amer. Chem. Soc.,1976,98,2352; L. E. Overman,G. F. Taylor and P. J. Jessup Tetrahedron Utters 1976 3089. 184 D.R. Taylor Ph C0,Me 'C0,Me C0,Me IV Me,SiO 'C0,Me 0 'CO Me (27) \ ","i Hozl/yCo2Me Reagents i (E)-MeO,CCH=CHCO,Me; ii PhCHO-TiCl,-CH,Cl,; iii H,O+; iv MeOH-CF,CO,H; v m -CIC,H,CO,H-C,H,,; vi ion-exchange column Scheme30 -NHCOCCI VBu NHCOCCI (28) (29) The formation of A3-sulpholenes from sulphur dioxide and dienes is a well known [4 +21 cheletropic reaction. It has recently been shown to be accelerated by bulky electron-releasing substituents at the 2-position and retarded by 1-alkyl groups in a similar way to the Diels-Alder rea~tion.~' More novel is an ingenious suggestion for the use of the reaction to remove sulphur dioxide from effluents based upon the preparation of polymer-supported dienes which react reversibly with sulphur Although fewer than expected cases of Lewis Acid-catalyzed Diels-Alder reac- tions were noted (e.g.ref. 99) the study of acid catalysis of the ene reaction seems to be gaining momentum. The use of Lewis Acids such as aluminium trichloride is particularly valuable for promoting ene reactions between olefins and less reactive enophiles such as acry1atesloo and propiolateslol at or below ambient temperature. Contrary to an earlier report,lo2 [2 +21 cycloaddition is not a serious problem in such catalysed ene reactions of acrylates,lOO but the formation of four-membered ring compounds certainly occurs in some cases becoming the main pathway in compar- able reactions of propiolateslol and electron-rich acetylenes.'03 Prediction of the outcome is not easy but for substantial yields of ene-adducts the ene-component seems to require a minimum of 1,l-disubstitution (Scheme 31).Hitherto few synthetic routes have been based upon ene reactions an exception is that shown in Scheme 32.l" 97 N. S. Isaacs and A. A. R. Laila Tetrahedron Letters 1976 715.. 98 Th.J. Niewstad A. P. G. Kieboorn A. J. Breijer J. van der Linden and H. van Bekkum Rec. Truu. chim. 1976 95 225. 99 P. M. Mdurry and R. K. Singh J.C.S. Chem. Comm. 1976,59. loo H. Greuter and D. BelluS Synth. Comm. 1976,6,409. lol B. B. Snider J. Org. Chem. 1976,41 3061; see also B. B. Snider ibid.1974 39 255. lo2 R. D. Sands Synth. Cbmm. 1973 3 81. lo3 J. H. Lukas F. Baardman and A. P. Kouwenhoven,Angew. Chem. Internat. Edn. 1976 15 369. lo4 G. Stork and G. Kraus J. Amer. Chem. SOC.,1976,98,6747. Aliphatic Compounds-Part (i)Hydrocarbons (R= H) (R = Me) I I \ \ C02Et C02Et C02Me Reagents i HC~CCO,Et-AICl,-C,H,; ii CH,=CHCO,Me-CH,CICH,Cl-MeN0,-AICI,; iii spon-taneous (AlCI,) Scheme 31 yR3 ?H 0R2 OR2 Reagents i ButMe,SiCI; ii HCZCCHO kinetic aldol; iii Me3SiCN-KCN-dicyclohexyl-18-crown-6-CCI,; iv 250°C; v HCI-aq. THF; vi Ac,O-py; vii NaBH,-MeOH; viii Bu'Me,SiCI; ix K,CO,-aq. MeOH; x Jones oxidation Scheme32 Several new methods have been reported for the interconversion of E-and 2-isomers of olefins.Arenesulphuric acids catalyse the rapid equilibration of internal isomers without detectable double-bond migration,lo5 but methods which provide access to pure geometrical isomers are more useful such as those based upon stereospecific formation and ring-opening reactions of epoxides.106~107Very simple and ingenious is a two-step procedure which involves halogenation of an olefin by chlorine or BrCl followed by an apparently syn -elimination effected by sodium iodide:"* apparently syn because the reality is that SN2substitution by iodide precedes stereospecific anti-elimination (Scheme 33). lo5 T. W. Gibson and P. Strassburger,J. Org. Chem. 1976,41,791. lo6 P. E. Sonnet and J. E. Oliver J. Org. Chem. 1976,41 3279. Io7 M. T. Reetz and M. Plachky Synthesis 1976 199.P. E. Sonnet and J. E. Oliver J. Org. Chem. 1976 41 3284. 186 D.R. Taylor Scheme33 It is roughly ten years since the first reports appeared in the patent literature of the reaction of magnesium with diene hydrocarbons. Two groups now describe a 'myrcene-magnesium' complex (30) evidently a useful reagent since it undergoes electrophilic attack at the 2-and 3-positions in a manner typical of a Grignard reagent (Scheme 34).1099'10 Similar complexes of butadiene"' and 1,4-diphenylbutadiene' lo have also been studied. +Mg2+ ii-iv a CRZOH CRzOH CHZCHROH + 6+ 5? QHzCHRoH II 0 \ Reagents i Mg-THF; ii BF,,OEr,; iii HO,-; iv H,O'; v R,CO-H,O'; vi RCf;-CH,-H,O+ Scheme34 A substantial programme of investigation into the conformations of normal and congested 1'3-dienes and mono-olefins is proceeding.Apart from ab initio calcula-tions' 12,113 and the older forms of spectroscopy,' 14*' '' photoelectron spectra are providing useful data in this area."5y"6 S. Akutagawa and S. Otsuka J. Amer. Chem. Soc. 1976,98,7420. R. Baker R. C. Cookson and A. D. Saunders J.C.S.Perkin Z 1809 1815. l1I K. Fujita Y. Ohnuma H. Yasuda and H. Tani J. Organometallic Chem. 1976,113 201. A. J. P. Devaquet R. E. Townshend and W. J. Hehre J. Amer. Chem. Soc. 1976,98,4068. S. Skaarup J. E. Boggs and P. N. Skancke Tetrahedron 1976,32 1179. D. A. C. Compton W. 0.George and W. F. Maddams J.C.S. Perkin ZZ 1976 1666. 115 P. D. Mollere K. N. Houk D. S. Bomse and T. H. Morton J. Amer.Gem. Soc. 1976,98,4732. K. B. Wiberg G. B. Ellison J. J. Wendolowski C. R. Brundle and N. A. Kuebler J. Amer. Chem. Soc. 1976,98,7179.

ISSN:0069-3030    

DOI:10.1039/OC9767300167

出版商:RSC    

年代:1976

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 Swansea SA2 8PP The following areas of current activity in aliphatic chemistry may be highlighted (i) stereospecific rearrangements of optically active amine oxides and glycidic esters; (ii) the isomerization and chiral oxidation of N-alkylimines; (iii) the generation of specific enolates of unsymmetrical ketones and reactions of enolate anion equival- ents; (iv) the stereochemistry of nucleophilic displacement at tervalent phosphorus and sulphinyl sulphur; (v) asymmetric syntheses of a-substituted ketones and amino-acids. 1 Amines and Imines The thermally allowed [2,3]-sigmatropic rearrangement of the optically active amine oxide (1) to the hydroxylamine (2) proceeds with almost complete conservation of chirality.By determining the absolute configuration of the starting material and the product it has been shown that the reaction proceeds through a five-membered cyclic transition state by a concerted mechanism.'= The related reaction (3) 3(4) involv-ing transfer of chirality from a tetrahedral carbon atom to a trigonal carbon atom has also been investigated.lb Me Me I * I Tol-NTCH2CH=CHMe + CH,=CHCH-0-N-To1 I I 0-Me (1) (2) H I PhCH=CH-C-CH3 + PhzH-CH=CHMe I I +NMe2 0 -0/ "Me* (3) (4) A well-known procedure for converting primary amines into isothiocyanates involves treating the amine with carbon disulphide followed by condensation with ethyl chloroformate and thermal decomposition of the product.An analogous (a) M.Moriwaki Y. Yamamoto J. Oda and Y. Inouye J. Org. Chem.,1976,41,300;(b)Y. Yamamoto J. Oda and Y. Inouye ibid. p. 303. 187 8 Aliphatic Compounds-Part (ii) Other Aliphatic Compounds Ar C-+ c-"\ R2 trans (+)-PCA Scheme 2 tionalized p -lactam.' Similarly the reactions of azidoketen with iminodithiocarbo- nate esters yield p -1actams containing an orthoester functionality.* 2 Alcohols and Ethers The protecting p -methoxyethoxymethyl(MEM) group can be introduced by treat- ing the sodium or lithium salt of the alcohol with MEM chloride or by treating the alcohol with MEM chloride in the presence of di-isopropylamine.' The protecting group can be removed by treating the ether with a mild Lewis acid such as ZnBrz or TiCL.The methylthiomethyl (TMT) group can be introduced by treating the alcohol with dimethyl sulphoxide and acetic anhydride in the presence of acetic acid." This group can be removed by treating the ether with methyl iodide in moist acetone. The use of the tetrahydrofuranyl (THF)group for protecting alcohols has hitherto been precluded by the lack of a general method for preparing THFethers. It has now been shown that such ethers can be conveniently prepared by treating the alcohol with sulphuryl chloride in THF in the presence of triethylamine." The allyl group also constitutes a useful protecting group for alcohols. Cleavage of allyl ethers is usually effected by isomerization to the corresponding enol ether followed by hydrolysis or oxidative cleavage catalysed by H' or Hg2+.Palladium on activated charcoal catalyses this process and the allyl group can be selectively removed in the presence of other protecting groups e.g.(7)+(8)." OCH2Ph OCH2Ph MeOH-H30+ tOCH2Ph tOCH2Ph Trichloroacetaldehyde on alumina can be used to transform structurally diverse secondary alcohols into ketones by an Oppenauer type of rea~ti0n.l~ The same H. W. Moore L. Hernandez and A. Sing J. Amer. Chem. Soc. 1976,98,3728. D. F. Sullivan,D. I. C. Scopes A. F. Kluge and J. A. Edwards J. Org. Chem. 1976,41 1112. E. J. Corey J. L. Gras,and P. Ulrich Tetrahedron Letters 1976,809. K. Yamada K. Kato H. Nagase and Y. Hirata Tetrahedron Letters 1976 65; P.M. Pojer and S. J. Angyal ibid. p. 3067. C. G. Kruse N. L. J. M. Broekhof and A. van der Gen Tetrahedron Letters 1976,1725. ** R. Boss and R. Scheffold Angew. Chem. Internat. Edn. 1976,15 558. l3 G. H. Posner R. B. Perfetti and A. W. Runquist Tetrahedron Letters 1976 3499. 190 R. S. Ward reagent will also selectively convert some diols into keto-alcohols. Selective oxida- tion of secondary alcohols can also be achieved using bromine and distanno~ane,'~~ a halogen and HMPA,'4b or a triphenylcarbenium salt. 14c I R' R' R2 R' R3 I H -H~O h+ \/ R'-C-O?H -+ R~-C-O -+ c=o+ I I R3 R3 R3/ Scheme 3 The reactions of tertiary alkyl hydroperoxides with 'magic acid' have been st~died.'~" By varying the amount of acid used both of the pathways shown in Scheme 3 can be observed.Moreover the use of superacid media allows direct observation of the carbocation intermediates involved with the result that the mechanismsof the reactions can be unequivocally established. Similar products can be obtained by treating the corresponding tertiary alcohols with hydrogen peroxide and 'magic acid' or by treating the alkylcarbenium ions with ozone.15b A new method for converting dialkyl ethers into trialkyloxonium salts has been reported.16 The method is based upon the well-known cleavage of ethers by acyl halides leading to carboxylic esters and alkyl halides. Acyldialkyl oxonium salts (9) are believed to be intermediates in this process and at low temperatures in the presence of excess ether trialkyloxonium salts are formed.7+ /R s* PhC02R+RCl+SbC15 PhCOCl R20 sba,-Ph-C-0 \R PhC02R+ R30+SbCI6-* (9) The synthesis and chemistry of macrocyclic polyethers continue to attract con- siderable interest. Recent developments have centred on the chromatographic resolution of a-amino-acid and ester salts by a chiral host covalently bound to a polystyrene resin and the stereoselective catalysis of reactions leading to enantio- meric The ally1 siloxyvinyl ether modification of the Claisen rearrangement provides the key step in a stereoselective synthesis of methylsantolinate (1 1a).18 Heating the enol l4 (a)Y.Ueno and M. Okawara Tetrahedron Letters 1976,4597; (b)M. Al-Neirabeyeh J. C. Ziegler B. Gross and P. Caubere Synthesis 1976,811; (c)M.E. Jung and L. M. Speltz J. Amer. Chem. Soc. 1976 98 7882. Is (a)G. A. Olah D. G. Parker N. Yoneda and F. Pelizza J. Amer. Chem. Soc.,1976,98,2245; (b)G. A. Olah N. Yoneda and D. G. Parker ibid. p. 2251. R. Szymanski H. Wienorek P. Kubisa and S. Penczek J.C.S. Gem. Comm. 1976 33. l7 Y. Chao and D. J. Cram J. Amer. Gem. SOC.,1976,98 1015; G. D. Y. Sogah and D. J. Cram ibid. p. 3038; K. E. Koenig R. C. Helgeson and D. J. Cram ibid. p. 4018. J. Boyd W. Epstein and G. Frater J.C.S.Chem. Comm. 1976,380; see also R. E. Ireland R. H. Mueller and A. K. Willard J. Amer. Chem. SOC.,1976,98 2868. A lip h a tic Cornpounds -Part (ii ) Other Alipha tic Compounds ether (10) at 65°C for 3 h affords the rearrangement products (llb) and (12b). Hydrolysis followed by methylation then gives the monoterpene (lla) and its epimer (12a).(11) a; R=Me b; R = SiMe2Bu' 3 Aldehydes and Ketones Several methods are available for the regiospecific generation of enolates of unsym-metrical ketones. Thus specific enolates of methyl ketones can be generated even in the presence of aldehydes by using a sterically hindered base such as lithium 1,l- bis(trimethylsilyl)-3-methylbutoxide.19 The enolates react with aldehydes in a regiospecific manner to give a high yield of the corresponding aldol e.g. (13) -+(14). The alternative approach involving the use of masked carbonyl compounds to generate specific enolate anion equivalents is illustrated by the use of metallated derivatives of NN-dimethylhydrazones e.g.(15)-+(16).20 OH I n-C5Hl lCHO +MeCOCH2CHMe2-+ n-C5Hl lCHCH2COCH2CHMe2 (13) (14) "Me2 "Me OH II i BuLi II I n-C3 H7 -C- Me B n-C3H7-C-CH,CHCH=CHMe ii MeCH=CHCHO (15) (16) The alkylation of a metallated dialkylhydrazone also forms the basis of an asymmetric synthesis of cy -substituted ketones.21 This involves conversion of the ketone (17) into a chiral hydrazone (18) followed by alkylation to give (19) and liberation of the alkylated ketone (20). In a similar manner a chiral imine has been used to bring about asymmetric alkylation of cyclohexanone,22 and 1,4-addition of Grignard reagents to chiral cup -unsaturated imines provides an asymmetric synthesis of /3 -substituted aldehydes.23 (-)-N-Dodecyl-N-methylephedrinium bromide is an efficient phase-transfer catalyst in the borohydride reduction of carbonyl compounds and also brings about asymmetric indu~tion.~~ Alternatively reduction of the prochiral ketone with a chiral a1koxyaluminohydride gives a good optical yield of the corresponding 19 I.Kuwajima,T. Sato,M. Arai and N. Minami Tetrahedron Leners 1976 1817; see also I. Kuwajima N. Minami and T. Sato ibid. p. 2253. 20 E. J. Corey and D. Enders Tetrahedron Letters 1976,3,7 11; see also T. Cuvigny J. F. Le Borgne M. Larcheveque and H. Normant Synthesis 1976,237,238. 21 D. Enders and H. Eichenauer Angew. Gem. Internat. Edn. 1976,15,549. 22 A. I. Meyers D. R. Williams and M. Druelinger J. Amer. Chern. SOC.,1976,98,3032. 23 S. Hashimoto S. Yamada and K. Koga J. Amer. Chem. Soc.,1976,98 7450.24 J. Balcells S. Colonna and R. Fornasier Synthesis 1976 266. 192 R. S. Ward (17) (18) (19) (20) secondary alcohol and alkylation with a chiral alkoxytributylaluminate gives an optically active tertiary alcoh01.’~ The chiral lithium enolate derived from (+ )-S-3-methylpentan-2-one reacts with electrophiles to give optically active ketones.26 The carbinolamine intermediate resulting from nucleophilic addition of hydroxyl- amine to acetaldehyde in aqueous solution has been detected by n.m.r. spectroscopy using flowing liquids and its rate of dehydration has been measured as a function of pH and buffer c~ncentration.~’ In the pH range 6.5-8.5 hydroxylamine adds to the ketone group of ethyl acetoacetate to form a carbinolamine intermediate which subsequently dehydrates to give the syn- and anti-oximes.28 The syn-isomer cyclizes to form 3-methyl-isoxazolone.Conversion of the anti-isomer into the isoxazolone proceeds more slowly and presumably involves isomerization. In the analogous reaction with acetylacetone addition and cyclization occur rapidly without the intermediacy of a long-lived oxime. 4 CarboxylicAcids The gas-phase acidities of a-halogenoacetic acids (XCH,CO,H) follow the order Br >C1> F which is exactly the reverse of the order in aqueous ~olution.’~ Hence the observed order in aqueous solution cannot be attributed to the increasing inductive effect of the halogen but must be due to a solvation effect. It has been shown that the differences between the gas-phase and aqueous acidities arise mainly from differences in the hydration enthalpies of the halogenoacetate ions.a/3-Unsaturated carboxylic acids can undergo alkylation at either the a-or y -position. Alkylation of the dianion derived from but-2-ynoic acid affords mainly the y -alkylated whereas alkylation of the dianion derived from 3-methylbut-2-enoic acid affords three products (21)-(23) in the ratio1 :4 11. The (21) (22) (23) ratio of a-to y-alkylation is markedly changed by addition of cuprous iodide to the reaction mixture. The y-selective alkylation of copper dienolates provides a very convenient method for the synthesis of isoprenoid natural 25 G. Boireau D. Abenhaim J. Bourdais and E. H. Basch Tetrahedron Letters 1976,4781; J. P. Vigneron and 1.Jacquet Tetrahedron,1976,32,939. 26 D. Seebach V. Ehrig and M. Teschner Annalen 1976 1357. 27 M. Cocivera C. Fyfe A. Effio H. E. Chen and S. Vaish J. Amer. Chem. SOC.,1976,98 1573. 28 M. Cocivera A. Effio,H. E. Chen and S. Vaish,J. Amer. Chem. SOC.,1976,98 7362; M. Cocivera and K. W. Woo,ibid. p. 7366; M. Cocivera and A. Effio ibid. p. 7371. 29 P. Haberfield and A. K. Rakshit,J. Amer. Chem. SOC.,1976,98,4393. 30 B. S. Pitzele J. S. Baran and D. H. Steinman Tetrahedron,1976,32 1347. 31 J. A. Katzenellenbogen and A. L. Crumrine J. Amer. Chem. SOC.,1976,98,4925. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds 193 In a related study of the reactions of the dianion derived from 3-methylbut-2- enoic acid with aldehydes it has been shown that the regioselectivity depends upon the nature of the counterion the proportion of y-attack increasing with the ionic character of the organometallic intermediate.32 At reflux temperatures electrophilic attack at the a-position is reversible and exclusive formation of the y-substituted product occurs.An asymmetric synthesis of a-substituted alkanoic acids involving alkylation of a rigid oxazoline derivative has been An efficient asymmetric synthesis of a-substituted amino-acids has also been devised which involves alkylation of a chiral Schiff base prepared from glycine t-butyl ester (Scheme 4).34 . $fN-CH40Bu, OLi @CH 2C02Bu' LiNPr; H2NCHRC02Bu' Scheme 4 The mechanism of Corey's method for the lactonization of hydroxy-acids has been further in~estigated,~~" and a number of new methods for lactone formation have been 5 Esters and Lactones MO calculations indicate that the preferred conformations of vinyl formate and vinyl acetate have the planar cis -trans structure (24).36Measurements of dipole moments and Kerr constants suggest that this is indeed the preferred conformation in solution.Ethyl cyanoformate ethyl chloroformate and ethyl trifluoroacetate display low- resolution microwave spectra which suggest that in the gaseous state the preferred conformations are the cis-trans and cis-gauche forms (25) and (26).37 R X X (24) (25) (26) The rearrangement of an alkoxycarbonyl group to an electron-deficient centre is of interest because the migrating carbon should itself possess a partial positive charge 32 G.Cardillo M. Orena and S. Sandri Tetrahedron 1976,32 107. 33 A. I. Meyers G. Knaus K. Kamata and M. E. Ford J. Amer. Chem. Soc. 1976,98 567. 34 S. Yamada T. Oguri and T. Shioiri J.C.S. Chem. Comm. 1976 136. 35 (a)E. J. Corey D. J. Brunelle and P. J. Stork Tetrahedron Letters 1976,3405,3409; (b)see for example T. Kurihara Y. Nakajima and I. Mitsunobu ibid. p. 2455. 36 M. J. Aroney E. A. W. BNCX I. G. John L. Radom and G. L. D. Ritchie Austral. J. Chem. 1976,29 581. 37 N. S. True and R. K. Bohn J. Amer. Chem. Soc.,1976.98 1188. 194 R.S. Ward due to the normal polarization of the carbonyl group.3g The BF,-induced rearrange- ment of ethyl (+)-3-methyl-3-phenylglycidate (27) to ethyl (-)-2-formyl-2- methylphenylacetate (28) occurs with complete inversion of configuration at the migration The related transformation of thiol glycidates to p -oxothiol esters is the first non-biochemical example of the migration of a thiol ester A reversible anionic rearrangement of an ethoxycarbonyl group has also been reported in which the position of the equilibrium (29) $ (30)is dependent upon the nature of the c~unterion.~~ COZEt CO2Et I-M=Na PhzC-NPh ’M=Li Ph2C-APh (29) (30) A 13C n.m.r.analysis of the mixed butene isomers obtained by pyrolysis of threu and erythru methyl 2-deuterio- 1-methylpropenylcarbonateshows that the reaction involves syn eliminati~n.~~ Full details have also appeared of the stereospecific conversion of diastereoisomeric p -1actones into E-and Z-alkene~.~~ The alkaloid gentiocrucine has been synthesized by reaction of the dianion of an enaminoketo-ester with formaldehyde (Scheme 5).“ The synthesis unambiguously confirms the revised structure and affords a simple new approach to substituted 3-keto-S -valerolactones.Scheme 5 Bromobutenolides are useful synthons for a variety of natural products containing an unsaturated y -butyrolactone moiety. A number of brominated butenolides have been synthe~ized,~’ and one such molecule has been used in a new synthesis of the Witchweed seed germination stimulant (+)-strigol and its 4’-e~imer.~~ 38 J. Kagan D. A. Agdeppa S. P. Singh D. A. Mayers C. Boyajian C. Poorker and B. E. Firth J. Amer. Chem. SOC.,1976,98,4581. s9 J. M.Domagala R. D. Bach and J. Wemple J. Amer. Chem. Soc. 1976 98 1975. 40 R. A. Gorski D. J. Dagli and J. Wemple J. Amer. Chem. SOC.,1976,98,4588. 41 J. G. Smith and J. M. Sheepy J.C.S. Gem. Comm. 1976 339. 42 D. B. Bigley C. Brown and R. H. Weatherhead J.C.S. Perkin II 1976 701. (3 S. Mageswaran and M. U. S. Sultanbawa J.C.S. Perkin I 1976 884. 44 B. Ganem J. Amer. Gem. SOC.,1976,98,224. 45 C. B. Chapleo K. L. Svanholt R. Martin and A. S. Dreiding Helv. Chim. Acfu 1976,59 100 2724. 46 J. B. Heather R. S. D. Mittal and C. J. Sih J. Amer. Chem. Soc. 1976,98 3661. 195 Aliphatic Compounds-Part (ii) Other Aliphatic Compounds The widespread occurrence of the a -alkylidene y -butyrolactone unit in biologi- cally active compounds has stimulated considerable interest in devising new methods for the introduction of an a-alkylidene unit.Some of these reactions are shown in Scheme 6.47 yMe2 Scheme 6 6 Amides and Lactams A 15N and I3Cn.m.r. study of the conformations of amides and lactams has shown that whereas small-ring lactams must of necessity adopt the cis -conformation large-ring lactams and acyclic N-monosubstituted amides prefer to adopt the tr~ns-conforrnation.~~ The cross-over point occurs at the nine-membered lactam which exists as an equilibrium mixture of the cis-and trans-conformers the relative amounts of each depending upon the solvent and temperature. From the coales- cence temperature of the carbonyl peaks the free energy of activation for intercon- version of the conformers was determined (71.6 kJ mol-').A 'H and 13Cn.m.r. study has shown that in the conformational equilibria of t-butoxycarbonyl deriva- tives of a-amino-acids the Z-rotamer predominate^.^^ Addition of E~(fod)~ increases the amount of the E-rotamer present since complexation increases the effective size of the carbonyl group. The a-carbanions derived from NN-disubstituted amides can be prepared by treatment with very powerful bases. These anions react with various electrophiles to give a-substituted amides." At low temperatures t-butyl-lithium abstracts a proton from bis(isopropy1)formamide to give LiCONPri which reacts with carbonyl com- pounds to give Q -hydroxyamide~.~' The thermolysis of N-chloroamides affords a convenient route to aliphatic y-lactones.The reaction has been used to prepare the flavour and scent material y-Z-6-dodecenolactone (32) from N-propyl-6-dodecenamide (3l).52 The isolation of clavulanic acid (33) a potent new /3 -1actamase inhibitor produced by Streptomyces cluuuligerus and its conversion into isoclavulanic acid (34) by benzylation followed by irradiation have been 47 S. F. Martin and D. R. Moore Tetrahedron Letters 1976,4459;P. A. Grieco M. Nishkawa S. D. Burke and N. Marinovic J. Amer. Chem. Soc. 1976,98,1612;S. Danishefsky T. Kitahara R. McKee andP. F. Schuda ibid. p. 6715; see also R. E. Damon and R. H. Schlessinger Tetrahedron Letrers 1976 1561. 48 K. L. Williamson and J. D. Roberts J. Amer. Chem. Soc.,1976,98 5082. 49 H. Kessler and M. Molter J. Amer. Chem. Soc.1976,98,5969. P. Hullot T. Cuvigny M. Larcheveque and H. Normant Cad. J. Chem. 1976,54 1098. 51 K. Smith and K. Swaminathan J.C.S. Chem. Comm. 1976 387. 52 M. Benn and K. N. Vohra Canad. J. Chem. 1976.54136. 53 T. T. Howarth A. G. Brown and T. J. King J.C.S. Chem. Comm. 1976 266; A. G. Brown T. T. Howarth I. Stirling and T. J. King Tetrahedron Letters 1976,4203. 196 R.S. Ward H NHPr RUO 5It-(%" (3 1) (32) R =(2)-2'-octenyl 7 Anhydrides and Imides It is known that metal hydride reduction of unsymmetrical cyclic anhydrides usually occurs at the more hindered carbonyl group e.g. (35)+(36). However when 2,2-dimethylsuccinic anhydride (35) is hydrogenated in the presence of [RuCI,(Ph,P),] as catalyst the major product is (37).54 The anion derived from acetophenone reacts with citraconic anhydride (38)at the more hindered carbonyl group to give (39),55and reduction of the anhydride (40) with lithium aluminium hydride gives (41).56The latter reaction forms part of a total synthesis of two permethylated pulvinic acid pigments.do phc0cH2~ .dOH 0 CH,COPh The reaction of N-protected succinimides with a-1ithiated acetic acid derivatives at -78 "Cyields either the y-hydroxylactam or the tautomeric y-~xoamide.~~ 54 P. Morand and M. Kayser J.C.S. Chem. Comm. 1976 314. Ss G. M.Strunz and P. I. Kazinoti Canad. J. Chem. 1976,54415. 56 D.W.Knight and G. Pattenden J.C.S. Chem. Comm. 1976 660. s7 A.Gossauer W. Hirsch and R. Kutschan Angew. Chem. Intentat. Edn. 1976,15,626. Aliphaic Compounds-Part (ii) Other Aliphatic Compounds 8 Phosphorus Compounds The 'H n.m.r.spectra of optically active phosphinic amides exhibit distinct signals due to the P-methyl groups of the R -and S-enantiomers. This phenomenon may be explained by formation of diastereoisomeric dimers (42) and (43) in which the associated amide molecules have the same or opposite configuration^.^^ Assuming that there is no marked preference for association of molecules of like or opposite configuration the major enantiomer in an unequal mixture will usually be paired with a molecule of like configuration whereas the minor enantiomer will usually be paired with a molecule of opposite configuration. The two enantiomers give rise to different n.m.r. spectra and hence the composition of an optically active sample can be determined without recourse to optically active reagents or solvents.The addition of lithium dimethylcuprate to the allenic phosphine oxide (44) gives after protonation a mixture of two isomeric adducts (45) and (46).59 Compound (45) is the major product but treatment with one equivalent of n-butyl-lithium converts this into (46) which is presumably the thermodynamically more stable product. The first stage of the reaction involves 1,2-rather than 1,4-addition and the reaction is therefore very similar to the corresponding reaction of allenic ketones. 0 0 11CH2=C=CH-PPh2 Me 0 Me i LiCuMe2 I II -CH2=CCH2PPh2+ 'c=C' 11 NH4CI II PPh2 / Me \€-I (44) (45) (46) Nucleophilic displacement at tervalent phosphorus proceeds with inversion of configuration (Scheme 7).60The available data indicate that the reaction can best be regarded as a classical SN2-type process.I MeLi I P .,*' A\ .*' A\ '* Et Ph Me Et Ph Scheme 7 s8 M. J. P. Harger J.C.S. Chem. Comm. 1976,555. 59 J. Berlan J. P. Battioni and K. Koosha Tetrahedron Letters 1976 3351. 60 J. Omelanczuk and M. M. Mikolajczyk J.C.S. Chem. Comm. 1976 1025; E. P. Kyba J. Amer. Chem. Soc. 1976,98,4805. 198 R.S. Ward 9 Sulphur Compounds Optically stable thiosulphinate S-esters have been prepared by the asymmetric condensation of sulphinyl chlorides with achiral thiols in the presence of optically active tertiary amines (Scheme 8). They can be converted into optically active sulphoxides sulphinamides and sulphinates.61 * * R'-S-CI+R~SH Me2NR R' -S-SR~ II II 0 0 Scheme 8 The reaction of sulphinamides with alcohols in the presence of strong acids leading to sulphinates has been shown to proceed with inversion of configuration at the sulphinyl centre.The stereospecificity of the reaction is dependent upon the structure of the alcohol used (Scheme 9).62 Scheme 9 Although a wide variety of substituted sulphines is known the parent compound (CH,=S=O) has only recently been reported. It has been generated by flash vacuum pyrolysis of a number of readily available precursors including thietan-S oxide and 1,3-dithietan 1-oxide which decomposed cleanly in the gas phase at 600 and 300 "C respectively. Microwave spectroscopy has shown that sulphine is a planar molecule having a dipole moment of 2.994 D.The gas-phase i.r. spectrum exhibits two strong bands at 1170 and 760 cm-' the former frequency being characteristic of the C=S=O group. The photoelectron spectrum of sulphine has also been The reactions of sulphimides with electrophilic acetylenes have been used to prepare a series of stable sulphonium imido-ylides which react with a further mole of the acetylene to give pyrroles (Scheme Scheme 10 Several simple methods for determining the absolute configuration of chiral alcohols and amines have been reported. It has now been shown that dia- 6' M. Mikolajayk and J. Drabowin J.C.S. Chem. Comm. 1976 220. 62 M. Mikolajnyk J. Drabowin and B. Bujmicki J.C.S.Chem. Comm. 1976 568. 63 E. Block R. E. Penn R. J. Olsen and P. F. Sherwin,J. Amer. Ckm. Soc. 1976,98,1264;E. Block H. Bock S. Mohrnand P. Rasmus and B. Solouki Angew. Gem. Znternat. Edn. 1976,15,383. @ P. Barraclough M. Edwards T. L. Gilchrist and C. J. Harris J.C.S. Perkin Z 1976 716. Aliphatic Compounds-Part (ii)Other Aliphatic Compounds 199 stereoisomeric thiol esters of hydratropic acid show differences in their 'H n.m.r. spectra which enable the relative configuration of the thiol ester and hence the absolute configuration of the thiol to be determined.65 In summary a chiral thiol possesses the absolute configuration (47) if the signal due to R' in (48) comes farther downfield than that of R' in (49) or if the signal due to R2 in (48) comes farther upfield than that of R2 in (49).Ph R ' (R)-HTA R (5')-HTA -HS-H -H-Ph R2 R2 Me0 R2 (48) (47) (49) The [1,3]-phenylthio-shift of substituted allyl phenyl sulphides can take place by thermal photochemical and (in some cases) acid-catalysed pathways. Crossover experiments suggest that the thermal and photochemical reactions occur by a radical mechanism whereas the acid-catalysed reaction involves an allyl cation.66 10 Halogen Compounds An n.m.r. study of the conformational equilibria in monohalogenobutanes with methyl substituents has shown that in the gauche conformer of Me,CHCFMe2 there is an unusually large attractive interaction involving the fluorine which more than balances the unfavourable gauche -methyl-methyl interaction^.^' Hindered alkyl iodides may be prepared by treating the corresponding chlorides with sodium iodide in carbon disulphide in the presence of an inorganic catalyst such as ZnC12.68 These reactions appear to involve electrophilic catalysis and in situ trapping of a carbenium species by iodide ion.The oxidation of alcohols by chromic acid very probably proceeds via decomposi-tion of the corresponding chromate ester. The reaction between alkyl halides and potassium chromate in HMPA (or chromic acid on an anion-exchange resin) provides another route from alkyl halides to aldehydes (Scheme 1l).69 0 H 0 II II RCH,+KO-Cr-OK -+ RC!-O Cr-OK -+ RCHO II -11 0 0 Scheme 11 Sodium dithionite is an effective debrominating agent." Thus meso-1,2-dibromo- 1,2-diphenylethane is converted into trans -stilbene in almost quantitative yield and trans -1,2-dibromocyclohexane affords cyclohexene.The reaction is not stereospecific however since both meso and racemic 2,3-dibromobutane give a 1:1 mixture of cis-and trans-but-2-ene. 65 G. Helmchen and R. Schmierer Angew. Chem. Internat. Edn. 1976,15 703. 66 P. Brownbridge and S. Warren J.C.S. Perkin I 1976 2125. 67 J. E. Anderson C. W. Doecke and H. Pearson J.C.S. Perkin IZ 1976 336. J. A. Miller and M. J. Nunn J.C.S. Perkin Z 1976,416. 69 G.Cardilio M. Orena andS. Sandri J.C.S. Chem. Comm. 1976,190; Tetrahedronktters 1976,3985. 70 T. Kempe T. Norin and R. Caputo Acta Chem. Scand. (B),1976,30,366.

ISSN:0069-3030    

DOI:10.1039/OC9767300187

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

10 Aromatic Compounds 13 By R. G. COOMBES Department of Chemistry The City University St. John Street London EC7 V 4PB 1 Introduction It has been shown' by one-electron MO theory that the greater stability of a Huckel aromatic cyclic molecule relative to its non-aromatic non-cyclic analogue is only partly the result of maximization of stabilizing orbital interactions and that overlap repulsion contrary to intuitive expectation can destabilize the cyclic form less than the non-cyclic one. A new approach to Dewar-type resonance energies for a wide range of cyclic conjugated molecules has been developed using graph theory.* Direct support for the accepted theoretical basis for paratropism is forthcoming from a 'H n.m.r. study3 of a series of 9-arylmethylenecyclo-octatrienyl anions in liquid ammonia at -6O"C which indicated that the ring-current effect is primarily a function of the HOMO-LUMO energy difference.A series of semi-empirical MO calculations of varying degrees of sophistication have been applied4 to paracylene (cyclopenta[fg]acenaphthylene). All methods predict a net 'London' m-electron paratropism for the molecule as 'H n.m.r. spectral studies have suggested. However the differences observed make the prediction of the overall diatropic or paratropic nature of polycyclic hydrocarbons on inspection of their structures a hazardous undertaking a conclusion which echoes that reached on a different basis by C. F. Wilcox et al. [see Ann. Reports (B) 1975 72 2151. C N.m.r. spectroscopy has been used in the evaluation of ring-current effect^.^ The spectra of paracylene and some related molecules also confirmed that the former molecule exhibits paratropism and a simple additive procedure for comparison of the effects was developed.The preparation of the 8,9- benzobicyclo[5,2,0]nonatetraenyl anion (l) the first (4n + 2)m-electron analogue of biphenylene has been reported.6 It behaved as both a benzannelated peripheral (4n + 2)~electron system and as a local 4nm-electron system and it seemed that the four-membered ring was in the dimethylenecyclobutene form. The cyclo- octa[def]fluorenyl anion (2) has also been synthesized,' and appears to be the first example of a species that behaves as a perturbed paratropic [lSIannulenyl anion. 7 I. Willner and M. Rabinovitz Tetrahedron .Letters 1976 1223.The electrochemical reduction of 2,3,6,7-dibenzobicyclo[6,2,O]deca-2,6,8-trien-4- * N. D. Epiotis and R. L. Yates J. Amer. Chem. SOC. 1976,98 461. J.-I. Aihara J . Amer. Chem. Soc. 1976,98,2750. S . W. Staley and G. E. Linkowski J. Amer. Chem. Soc. 1976,98 5010. C. A. Coulson and R. B. Mallion J. Amer. Chem. SOC. 1976,98 592. B. M. Trost and W. B. Herdle J. Amer. Chem. SOC. 1976,98,4080. S . W. Staley F. Heinrich and A. W. Orvedal J. Amer. Chem. SOC. 1976,98 2681. 201 R. G. Coombes 202 yne-9,lO-dione to the dianion (3) occurred so easily that it was concluded' that fusion of the two 4nr-electron rings in (3) the core of which is a cyclobutadienocyclo-octatetraene ?r-system resulted in stabilization. Benzyl halides have been shown' to adopt low-energy conformations in which the C-halogen bond lies either in a plane perpendicular to the aromatic ring plane (Cl Br or I) or in the plane (F).The two-fold barrier to internal rotation rises from -0.25 kcal mo1-l for benzyl fluoride to -2 kcal mol-' for benzyl chloride in agree- ment with MO calculations. Two conformational isomers of o-tolyldi-t- butylcarbinol have been reported,loU the more stable of which has the hydroxy- group in close proximity to the o-methyl substituent. The activation energy for conversion of the less stable conformer into the more stable one is 26 kcal mol-l. The rotational barrier for interconversion of the two rotamers of l,8-di-0- tolylnaphthalene (AG* = 24 kcal mol-') is about 8 kcal mol-' higher than that for the analogue lacking the o-methyl groups and the cis- and trans-isomers have been isolated.lob Values of the angle a! and its variation with the substituent X in substituted benzenes (4) have been presented," on the assumption that the magnitude of a is independent of the presence of para -substituents. Correlations suggest that the 0-inductive effect of X is a dominant factor influencing the magnitude of a and these values may have relevance to the rationalization of the as yet unexplained anomalies of I9F n.m.r. chemical shifts [Ann. Reports (B) 1975 72 2161. Arguments have been presented'* that the inductive substituent effect is transmitted into the para- position of the benzene nucleus more effectively than into the mefa-position in the ratio 1.13(j~O.O3) 1.This effect cannot be attributed to preferential solvation and literature values of < 1 1 appear to be due to a defect in the statistical procedure used in their determination. The exaltation of the para-substituent effect for ?r-donor X H. N. C. Wong F. Sondheimer R. Goodwin and R. Breslow Tetrahedron Letters 1976 2715. T. Schaefer J. B. Rowbotham W. J. E. Parr K. Marat and A. F. Janzen Canad. J. Chem. 1976,54 1322; T. Schaefer L. J. Kruczynski and W. J. E. Parr ibid. p. 3210. ( a ) J. S. Lomas and J.-E. Dubois J. Org. Chem. 1976,41,3033; ( b ) R. L. Clough and J. D. Roberts J. Amer. G e m . SOC. 1976,98 1018. A. Domenicano P. Mazzeo and A. Vaciago Tetrahedron Letters 1976 1029. l2 0. Exner and K. Kalfus Coll.Czech. Chem. Comm. 1976,41 569. 203 Aromatic Compounds substituents on the base strength of anilines decreases regularly when conjugation of the reaction centre with the aromatic ring is increasingly sterically inhibited and the substituent has its normal U-value when inhibition is complete. This was inter- preted13 in terms of decreasing resonance saturation. A comprehensive study of the substituent effects in the naphthalene ring system by 19F n.m.r. has been de~cribed,'~" and the shifts from the 6p and 7p orientations can be confidently interpreted in terms of chemical reactivity parameters. These positions seem to have a number of advantages over the meta and para dispositions of fluorobenzene for estimating aI and a values for substituents. A study of data on the electronic effect of the tricyanomethyl group by this method the alternating induced charge model rather than the classical c+-inductive model and reassessment of the effect of the trifluoromethyl substituent then leads to results in agreement with last year's ESCA study [Ann.Reports (B) 1975 72 2161. Preliminary 19F n.m.r. data for a new model system (l-substituted-4-p-fluorophenylbicycIo[2,2,2]octanes) offer a definitive estimate of the effects of remote polar groups on the "F chemical shifts of aryl fluorides1& and unambiguously contradict the majority viewpoint hitherto that the field effect is relatively unimportant (but see ref. 14d). C Substituent chemical shifts of meta-carbon atoms are correlated well by substituent electronegativities rather than by a-parameters a result to be expected if paramagnetic shielding is a dominant f a ~ t 0 r .l ~ ~ Studies*5b of shifts in disubstituted benzenes have shown that these are not additive and that this is particularly so when the substituents are in the para-orientation. Solvent effects were also described. 13 An interesting contribution'6 to the selectivity-reactivity debate which may have relevance to aromatic systems suggests that the constant selectivity observed in the N relationship may be due to the cancellation of two opposing effects. A reactive electrophile is strongly solvated a factor tending to increase selectivity but the transition state for a reactive electrophile is early resulting in a decrease in selectivity.Such an approach supports the reactivity-selectivity principle but suggests that solvation effects may mask its general applicability. An account of the solution chemistry of arene oxides has appeared." 2 Benzene Isomers Oxides and Homobenzenes A gas-phase electron diffraction study of Dewar-benzene has been reported,'* and the results are in good agreement with previous studies of substituted compounds. Perfluorohexamethylbicyclopropenyl the final member of the first complete set of benzene valence isomers has been prepared'' by coupling of iodoperfluoro- 1,2,3- trimethylcyclopropene. This thermodynamically least stable member of the series is l3 A. J. Hoefnagel M. A. Hoefnagel and B. M. Wepster J. Amer. Chem. Soc. 1976,98,6194. l4 ( a ) W. Adcock J. Alste S.Q. A. Rizvi and M. Aurangzeb J. Amer. a m . Soc. 1976,98,1701; ( b ) W. Adcock and D. P. Cox Tetrahedron Letters 1976,27 19; ( c ) W. Adcock and T. C. Khor ibid. p- 3063; ( d ) W. F. Reynolds and G. K. Hamer J. Amer. Chem. Soc. 1976,98,7296. Is ( a ) N. Inamoto S . Masuda K. Tokumaru K. Tori M. Yoshida and Y. Yoshimura Tetrahedron Letters 1976,3707,3711; ( b ) J . Bromilow R. T. C. Brownlee R. D. Topsom and R. W. Taft. J. Amer. Chem. Soc. 1976,98,2020. lC A. Pross J. Amer. Chem. Soc. 1976,98 776. T. C. Bruice and P. Y. Bruice Accounts Chem. Res. 1976,9 378. l 8 E. A. McNeil and F. R. Scholer J. Mol. Structure 1976,31,65. l9 M. W. Grayston and D. M. Lemal J. Amer. Chem. SOC. 1976,98 1278. 204 R. G. Coombes by a wide margin the ost 'stable' kinetically.Studies2'" of the thermal aromatiza- tion of the diastereomers (5a) and (5b) provide strong evidence that opening of a m cyclopropene ring is h e initial critical step in the formation of the established Dewar-benzene intermediates. This evidence seems to rule out the recently post- ulated tricyclic biradical mechanism [Ann. Reports (B) 1975,72 2181 at least for thermal processes. Hexaferrocenylbicyclopropenyl aromatizes with ease at room temperature 2ob and the thermal rearrangement of hexamethyl-Dewar-benzene is strongly accelerated by extreme pressure.*" X ( 5 ) a;X=H,Y=Me b; X= Me Y = H An alternative synthesisz1 of Dewar-benzene in 45% yield results from the photolysis of the tetracyclic azo-compound (6) in the absence of oxygen. 1,4- Pentamethylene-Dewar-benzene has been prepared22a from 9,12-dithia[5,3,3]- propellane and has interest as a possible precursor of [5]paracyclophanes.1,2- Tetramethylene-Dewar-benzene derivatives may be formedzzb from the aluminium trichloride complexes of substituted cyclobutadienes (Scheme l) and the method may be extended to simultaneous formation of 1,2- and 3,4-polymethylene bridges. Q ~ ~ ~ ~ 3 .__ Reagents i Dimethyl acetylenedicarboxylate . i i i & I 1 0 2 ~ e C02Me }in CH2ClZ at -40 "C ii DMSO Scheme 1 A method to bridge the 5,6-positions was also described. The reaction of hexamethyl-Dewar-benzene with tetracyanoethylene did indeed give mainly the adduct (7) but the reaction was more complicated than a typical Diels-Alder reaction of a homoconjugated diene; a zwitterionic mechanism has been The mechanism of the synthesis of benzvalene by the reaction of cyclopentadienyl- lithium with dichloromethane in the presence of methyl-lithium has been described.24 It involves the initial formation of one new C-C bond in a substitution and P.Plieninger Tetrahedron 1976,32 2335. N . J. Turro C. A. Renner W. H. Waddell and T. J. Katz J. Amer. Chem. SOC. 1976,98,4320. 22 ( a ) K. Weinges and K. Klessing G e m . Ber. 1976,109,793; (b) D. S. B. Grace G. Hogeveen and P. A. 20 ( a ) J. H. Davis K. J. Shea and R. G. Bergman Angew. Chem. Infernat. EdH. 1976,15,232; (b) A. J. Fry R. L. Krieger I. Agranat and E. Aharon-Shalom Tetrahedron Letters 1976,4803; ( c ) R. Miindnich Wade Tetrahedron Letters 1976 123.23 H. Iwamura Y. Tanabe and H. Kobayashi Tetrahedron Letters 1976 1987. 24 U. Burger and F. Mazenod Tetrahedron Letters 1976 2881. 205 reaction producing the carbene precursor followed by internal addition. It has been that the fact that the thermal aromatization of benzvalene is not chemiluminescent may be due to the fact that the electrons of the double bond participate in the ring opening making it a six-electron allowed process. A (7) X=C(CN)2 deuterium-labelling study of the copper- and silver-catalysed isomerizations of benzvalene to the fulvene and the arene respectively has been reported and mechanisms have been With copper catalysis 1-deuteriobenzvalene yields fulvene labelled at all positions. The general applicability of the Diels-Alder addition of dienes to hexakis(trifluoromethy1)benzvalene has been investigated,26" and studies of the furan adduct indicate that it has the ex0 structure.This benzvalene also undergoes [2 + 21 photochemical cycloaddition to alkynes (e.g. but-2-yne) in the presence of a sensitizer to yield adducts [e.g. (S)].""" The trioxa-hexa-cr/w-homobenzenes (9a and b) have been ~ynthesized,~'" and are stable up to 400 "C. The formation and reactions of some aza- and oxa-bis- and -tris- cr-homobenzenes have also been The approach involved addition of diazomethane to for example benzene oxide and photolysis of the resulting adducts. V x&x (10) R = C02Me Y 4 9 d Y (9) a; X = CH2 Y = 0 b; X=O Y=CH2 3 Benzene and its Derivatives Aromatic Compounds 2545; ( b ) 1976,2703.R wR Carbocyclic syn -bishomobenzenes have been prepared for the first time.28 Com- pound (10) was prepared directly by the reaction of cyclo-octatetraenyldilithium carbon dioxide and diazomethane. Its unhindered double bond endows it with considerable potential as a synthetic reagent. General.-The first partz9 of an important review of the photochemistry of benzene is largely concerned with photoisomerization reactions but includes also orbital 25 ( a ) N . J. Turro C. A. Renner T. .I. Katz K. B. Wiberg and H. A. Connon Tetrahedron Letters 1976 4133; ( b ) U. Burger and F. Mazenod ibid. p. 2885. 26 Y. Kobayashi I. Kumadaki A. Ohsawa Y. Hanzawa and M. Honda Tetrahedron Letters ( a ) 1976 27 ( a ) H. Prinzbach V. Wessely and H.Fritz Tetrahedron Letters 1976 2765; ( 6 ) H. Prinzbach D. Stusche M. Breuninger and J. Markert Chem. Ber. 1976 109 2823; H. Prinzbach D. Stusche J. Markert and H.-H. Limbach ibid. p. 3505. G. Kaupp and K. Rijsch Angew. Chem. Internat. Edn. 1976,15 163. 29 D. Bryce-Smith and A. Gilbert Tetruhedron 1976,32 1309. 206 R. G. Coombes symmetry aspects of photoadditions. The scope and synthetic potential of the photoenolization of aromatic carbonyl compounds has also been re~iewed.~' The photochemical reaction of tetracyanoethylene with toluene in the presence of methanol a novel 1,2-addition to give 3-phenylpropane- 1,1,2,2- tetracarbonitrile via charge-transfer excitation. The irradiation of a mixture of anisole and acrylonitrile in solvents methanol and acetonitrile gave o- and p - cyanoethylated products and [2 + 21 cycloadducts re~pectively.~'~ In contrast with the usual course from o-divinylbenzenes irradiation of 2-vinylstilbene involved3* a (ll) a result ascribed in part to conformational effects.[2 + 21 cycloaddition to give mainly exo-5-phenylbenzobicyclo[2,1,l]hex-2-ene Recent methods for the synthesis of polyfluoro-aromatic compounds have been reviewed.33 An effective new aryl annelation method has been which involves the cycloelimination of carbonyl compounds from the adducts obtained by cycloaddition of acetylenic dienophiles to 2H-pyrans (e.g. Scheme 2). A convenient method for the benzannelation of a ketone containing an adjacent methylene group Scheme 2 has been de~cribed.~' It involves formation of a diene by a vinyl Grignard route and subsequent Diels-Alder addition of dimethyl acetylenedicarboxylate dehydrogena- tion saponification and decarboxylation.1-Ethyl-2-propylbenzene was formed from heptan-4-one by this route. A general method for the construction of benzene rings involves the dehydrohalogenation of halogeno+ -1actones [e.g. (12)] by a 30 P. G. Sammes Tetrahedron 1976,32,405. 31 ( a ) M. Ohashi S. Suwa and K. Tsujimoto J.C.S. Chem. Comm. 1976,404; ( b ) M. Ohashi Y . Tanaka andS. Yamada ibid. p. 800. 32 M. Sindler-Kulyk and W. H. Laarhoven J. Amer. Chem. Soc. 1976,98 1052. 33 G. G. Yakobson and V. M. Vlasov Synthesis 1976,652. 34 R. G. Salomon J. R. Burns and W. J. Dominic J. Org. Chem. 1976,41 2918. 35 L. A. Paquette W.P. Melega and J. D. Kramer Tetrahedron Letters 1976,4033. 207 Aromatic Compounds non-nucleophilic base to give a presumed p -1actone intermediate which rapidly extrudes carbon This mild procedure should have applications in arene oxide synthesis. Hexacyclopropylbenzene has been synthesized" by the cyclo- trimerization of dicyclopropylacetylene on heating with Fe3(CO)12 and the data suggest that for this molecule at room temperature in solution no particular conformation is favoured. The photochemical reactions of some azo-compounds leading inter alia to benzocyclopropenes have been The first reported halogeno- benzocy~lopropene~~" is indeed39* the 3- and not the 2-chloro-compound as was to be expected from its synthesis by treatment of 3,4,7,7-tetra- chlorobicyclo[4,1,0]heptane with an excess of potassium t-butoxide in DMSO.The selective halogen-lithium exchange in l-bromo-2-(2-bromoethyl)benzene has led to a new convenient synthesis of benzocy~lobutene.~~ The necessity for synthesis of benzocyclobutenes as precursors to complex natural products is circumvented and the overall procedure much simplified by a one-step synthesis41 of polycycles involving in situ generation and intramolecular trapping of o -xylylenes by cobalt- catalysed acetylene co-oligomerizations (Scheme 3). Benzo[ 1,2 3,4]dicyclobutene x-Y Reagents i bis(trimethylsilyl)acetylene-CpCo(CO)2 Scheme 3 (13) has been ~ynthesized,~~ the key step involving Diels-Alder addition of 1- vinylcyclobutene to dimethyl cyclobutene- 1,2-dicarboxyIate.Surprisingly the non- equivalent benzylic protons have coincidental chemical shifts. The reaction of 1,5,9-cyclododecatriene with dimethyl maleate leads to (14) presumably by the intermediate generation of the elusive 1,2 3,4 5,6-tricy~lobutabenzene.~~ Some aryl- and benzoyloxy-cyclohexadienyl radicals 1,3,5-Tris(trimethylsiloxy)benzene forms cyclohexadienyl radicals which are sufficiently long-lived to be observable by e.s.r. spectroscopy on reaction with a series of radical species.44a Other organosilyl radicals including ips0 -substituted ones have been have been trapped by nitrosodurene as the corresponding duryl nitroxides on 3 ~ i G. W. Holbert L. B. Weiss and B. Ganem Tetrahedron Letters 1976,4435. 3? V. Usieli R. Victor and S.Sarel Tetrahedron L.e#ers 1976 2705. 313 H. Schmitz A. C. Ranade and H. Diirr Tetrahedron Letters 1976,4317. 39 ( a ) A. Kumar S . R. Tayal and D. Devabhakara Tetrahedron Letters 1976,863; ( 6 ) P. J. Garratt and W. Koller ibid. p. 4177. 40 W. E. Parham L. D. Jones and Y. A. Sayed J. Org. Chem. 1976,41,1184. 41 R. L. Funk and K. P. C. Vollhardt J. Amer. Chem. Soc. 1976,98,6755. 42 R. P. Thummel J. Amer. Chem. SOC. 1976,98,628. 43 A. J. Barkovich and K. P. C. Vollhardt J. Amer. Chem. Soc. 1976,98,2667. 44 ( a ) P. G. Cookson A. G. Davies and B. P. Roberts J.C.S. Chem. Comm. 1976,289; ( 6 ) H. Sakurai I. Nozoe and A. Hosomi J. Amer. Chem. Soc. 1976,98,8279; Chem. Letters 1976 129. \ P Me0,C Meo2cw 208 generation of the precursor radicals in benzene Some radicals of rele- vance are discussed in a review on persistent carbon-centred radicals.46 Last year [Ann.Reports (B) 1975 72 2215 the results of a study of the phenylation of 46 47 48 dichlorobenzenes were interpreted in terms of reversible formation of cyclohexa- dienyl radicals. However comparison with data from the phenylation of 4- methylpyridine has now led to the proposal4’ of an alternative explanation in terms of radical dimerization. The photobromination of halogeno-benzenes particularly in the presence of N-bromosuccinimide gives predominantly meta -orientation.48” The reaction of dihalogeno-benzenes gave ‘unexpectedly large amounts of ortho - substitution and in some cases the extensive replacement of the original chloro- substituent.It has been pointed that these latter observations are suggestive of ips0 -attack. The proposed mechanism of phenylation of polyfluoro-aromatic compounds has been ~onfirmed.~’ Several advantageous routes from amides have been reported. The reaction of Vilsmeier complexes of tertiary aromatic amides with zinc dust affords the corre- sponding aldehydes in high yields,50” and reduction of Vilsmeier complexes with sodium borohydride gives the corresponding amine.”’ The N-tosyl imines from aromatic aldehydes and toluene-p -sulphonamide reacted with cyanide ion in hexa- methylphosphoramide to give good yields of corresponding nit rile^.'^ The presence of the remote aromatic rings in exo-3,4-benzo- tricyclo[4,2 1,02.5]nona-3,7-diene and the exo -anthracene-norbornadiene adduct leads to an enhancement of the Birch reduction of the norbornene double bonds by factors of ca.200; this extraordinary effect has been explained in terms of orbital interactions through bondss2 4s T. Suehiro M. Kamimori K. Tokumaru and M. Yoshida Chem. Letters 1976 531; T. Suehiro M. Kamimori H. Sakuragi M. Yoshida and K. Tokurnaru Bull. Chem. SOC. Japan 1976,49,2594. D. Griller and K. U. Ingold Accounts G e m . Res. 1976,9 13. S . Vidal J. Court and J. M. Bonnier Tetrahedron Letters 1976 2023. ( a ) P. Gouverneur and J. P. Soumillion Tetrahedron Letters 1976 133; ( b ) J. G. Traynham ibid. p. 2213. 49 R. Bolton W. K. A. Moss J. P. B. Sandall and G. H. Williams J. Fluorine Chem. 1976,7 597. so ( a ) Atta-ur-Rahman and A.Basha J.C.S. G e m . Comm. 1976,594; ( b ) Atta-ur-Rahman A. Basha N. v C O M e C0,Me Waheed and S. Ahmed Tetrahedron Letters 1976,219. 51 R. S . Glass and R. C. Hoy Tetrahedron Letters 1976 1781. 52 M. N. Paddon-Row R. Hartcher and R. N. Warrener J.C.S. Chem. Comm. 1976,305. R. G. Coombes \ 209 Aromatic Compounds Electrophilic Substitution.-Full details of the gas-phase reaction of the t-butyl cation with the xylenes have been given,53o and in the case of m-xylene the results have been discussed in terms of reversible t-butylation at the positions ortho to one methyl group. In the cases of phenol and anisole predominant 0-alkylation giving t-butylated oxonium ions as the major reaction intermediates. Reaction at oxygen perhaps via an intermediate 7r-complex is also in a study of the gas-phase acetylation of some substituted anisoles.Rates for the latter reaction of a series of alkylbenzenes have also been Substituent effects on the proton affinity of benzene calculated by the STO-3G method may be correlated with v+ parameters and such calculations on electrophilic aromatic substitutions afford a method complementing gas-phase experimental results for distinguishing solvation effects from internal electronic eff e c t ~ . ~ ’ It is clear that a new reaction path for nitrous-acid-catalysed nitrations has been identified in the ob~ervation~~ that the nitration of the NN-dimethylanilinium ion by nitric acid in sulphuric acid is catalysed by nitrous acid under conditions when C-nitrosation is very slow.The proceedings of a 1975 symposium on nitration reactions have been publi~hed.~’” Two general reviews by G. A. Olah and L. M. Stock contrast informatively and a number of papers are concerned with ipso- substitution a topic which has also been reviewed el~ewhere.~’~ A further contribu- tion provides more evidence in support of Bamberger’s hypothesis that the nitration of aromatic amines as the free bases occurs initially at the amino nitrogen. The effects of remote double bonds and cyclopropane rings on the nitration of aromatic rings have been studieds8 and the results interpreted in terms of competing homoconjugative hyperconjugative and inductive effects. The inertness of the ips0 - and a -positions of benzonorbornadiene and em- and endo-benzo- tricyclo[3,2,1,02**] octenes (15) was attributed principally to inductive electron withdrawal.Nitrations of N-acyl derivatives of aniline and 0-acyl derivatives of phenol have been st~died.~’ Acetyl and methanesulphonyl derivatives are exclusively ortho - and para-directing whereas phosphorylated compounds give a considerable proportion of meta-orientation. 53 (a) P. Giacomello and F. Cacace J. Amer. Chem. Soc. 1976 98 1823; (6) M. Attina F. Cacace G. Ciranni and P. Giacomello J.C.S. Chem. Comm. 1976,466. 54 D. A. Chatfield and M. M. Bursey ( a ) J. Amer. Chem. SOC. 1976,98,6492; (6) J.C.S. Faraday I 1976 72 417. 55 J. M. McKelvey S. Alexandratos A. Streitwieser J.-L. M. Abboud and W. J. Hehre J. Amer. Chem. SOC. 1976,98 244. 56 J. C. Giffney D.J. Mills and J. H. Ridd J.C.S. Chem. Comm. 1976 19. 57 ( a ) ‘Laboratory and Industrial Nitrations’ A.C.S. Symposium Series No. 22 ed. L. F. Albright and C. Hanson American Chemical Society Washington 1976; (6) R. B. Moodie and K. Schofield Accounts Chem. Res. 1976,9,287. s8 M. W. Galley and R. C. Hahn J. Org. Chem. 1976,41 2006. 59 T. A. Modro and J. Pioch Canad. J. Chem. 1976,54 560. 210 R. G. Coombes Nitrodebromination was a major outcome of the nitration of several para- substituted bromobenzenes in aqueous sulphuric acid.60" The appropriate Wheland intermediates were either debrominated or rearranged by nitro-group migration. For p-bromotoluene ipso-attack at C(Me) also occurred and was followed by nucleophilic capture by water and by nitro-group migration in proportions which varied with acidity.Studies of the acidolysis of 3,4-dimethyl-4-nitrocyclohexadienyl acetate have showdo' that below 50-55'/0 sulphuric acid the major route of reaction initially involves nitrous acid elimination but that above 55% acid an AAll mechanism generating the ips0 Wheland intermediate which is also formed in the nitration of o-xylene applies and in this latter region the results are indeed relevant to the outcome of the nitration. Nitration of the tetramethylbenzenes in acetic anhydride at € -50 "C gave6'= the now expected acetoxy-nitro-adducts [e.g. (16) from durene] normal nitro-derivatives and in addition nitritonitro-adducts side- chain nitrates and phenylnitromethanes. Rearomatization of the tertiary acetoxy- adducts [e.g.(1 6)] gave aryl acetates nitro-arenes and side-chain derivatives depending on the solvent acidity. The acid-catalysed methanolysis and basic hy- drolysis and rearomatization of the acetoxy-nitro-adducts of p-cymene have also been studied.616 An acetoxy-adduct was also reported from the reaction of cop- per(@ nitrate with o-xylene in acetic anhydride at low temperatures.62 The addition-elimination mechanism accepted for the formation of acetates under normal nitration conditions in acetic anhydride also applies63 to the reaction of o -xylene and hemimellitene with aroyl nitrates to give dimethylphenylbenzoates. Aryl thallium(III) compounds may be into nitro-arenes on reaction with sodium nitrite in trifluoroacetic acid by a route involving ipso-nitrosation and oxidation complementing that reported last year [Ann.Reports (B) 1975,72,224]. The direct oxidation of 4-substituted phenols to 4,4-disubstituted cyclohexa-2,5- dienones by thallium(Ir1) nitrate is postulated65 to proceed by ips0 -thallation fol- lowed by nucleophilic displacement of the thallium. Application66 of the transition-state activity-coefficient approach to the proto- dealkylation of some derivatives of phenol and anisole in perchloric acid indicates that for protodetritylation proton transfer is rate-determining in a conventional A -SE2 process but that for protode-t-butylation the formation of the t-butyl cation from the Wheland intermediate is rate-determining. Full details of the protodetritia- tion of a series of cycloalkyl- and secondary alkyl-benzenes have been rep~rted,~' and the apparently constant logfJlogf ratios for these and other substrates which correspond with those predicted for the charge distribution in a Wheland inter- mediate allow the assignment of a,',h constants for application to electrophilic substitutions.60 ( a ) R. B. Moodie K. Schofield and J. B. Weston J.C.S. Perkin ZZ 1976 1089; ( b ) H. W. Gibbs R. B. Moodie and K. Schofield J.C.S. G e m . Comm. 1976,492 61 ( a ) A. Fischer and D. R. A. Leonard Canad. J. Chem. 1976,54 1795; (b) A. Fischer and R. Rijderer ibid. p. 423. 62 J. Yamashita S. Shishido Y. Hayatsu and H. Hashimoto Nippon Kaguku Kaishi 1976 642. 63 M. E. Kurz and E. S. Woodby J. Org. Chem. 1976,41,2443. 64 S . Uemura A.Toshimitsu and M. Okanu Bull. Chem. SOC. Japan 1976,49 2582. 65 A. McKillop D. H. Perry M. Edwards S. Antus L. Farkas M. Nbgrhdi and E. C. Taylor J. Org. Chem. 1976 41 282. 66 T. A. Modro and K. Yates J. Amer. Chem. SOC. 1976,98 4247. 67 M. M. J. Le Guen and R. Taylor J.C.S. Perkin ZZ 1976 559. Aroma tic Compounds 211 Studies68" of aromatic hydrogendeuterium exchange of (17) show that the positive centte surprisingly deactivates both rings to a similar extent despite the fact that the distances from the centres of the rings are very unequal. The rate retardations in nitration and bromination reactions due to the bridging on going from substrates of type (18) to those of type (19) have been determined686 and attributed + + + (18) X = NH, NMe3 or h e 2 (1 9) X = &H2 l?Mez or ;Me to the change in the form of the molecular cavity together with when n > 1 the change in distance of the positive centres from the aromatic ring.An assessment of the results of these and earlier papers on inductive and field effects of positive pole substituents in aromatic substitution that the deactivation of the meta-position in a ring is more consistent with the operation of a field effect than of an inductive effect but that the transmission of the effect in some cases occurs almost entirely through the molecular cavity. A conjugative effect also influences + + + orientation of substitution in the ions Ph(CH2),X (X = NR3 SR2 or PR,) and differences in the importance of this effect may have some part in the different + + substituent behaviour of NR3 and PR,.Three reports of special regioselectivity in halogenations have appeared.69 Treat- ment of a phenol with thallium(1) acetate and iodine gives selective ortho- iodinatior~.~~" Chlorination of 2-methylphenol containing catalytic amounts of aluminium chloride and diphenyl sulphide with sulphuryl chloride at 15 "C gave substitution para to the hydroxy-gr~up.~~~ Studies on the selective chlorination of anisole by hypochlorous acid catalysed by cyclodextrins have been and the use of dodecamethyl-cr -cyclodextrin or an 0-alkylated polymer prepared from a -cyclodextrin and epichlorohydrin gave >99% para -substitution. A study7'" of the molecular chlorination of acetoxybenzenes has led to the first u+ values for the 68 ( a ) J.H. Rees and J. H. Ridd,J.C.S. Perkin II,1976,285; ( b ) R. Danieli A. Ricci and J. H. Ridd ibid. p. 290; ( c ) J. H. Rees J. H. Ridd and A. Ricci ibid. p. 294. 69 (a) R. C. Carnbie P. S. Rutledge T. Smith-Palmer and P. D. Woodgate,J.C.S.PerkinZZ 1976,1161; ( b ) W. D. Watson TetruhedronLetters 1976,2591; ( c ) R. Breslow H. Kohn and B. Siegel ibid. p. 1645. ' O (a) P. B. D. de la Mare N. S. Isaacs and M. J. McGlone J.C.S. PerkinII 1976,784; ( b ) P. B. D. de la Mare B. N. B. Hannan and N. S. Isaacs ibid. p. 1389; ( c ) P. B. D. de la Mare N. S. Isaacs and P. D. McIntyre Tetrahedron Letters 1976,4835. 212 R. G. Coombes acetoxy-substituent and the fact that the chlorination of 4-substituted acetanilides gives a much lower p value than the corresponding reaction of substit ted benzenes has been discussed in terms of the modification of the conjugative elec$on release of the acetamido-group by the 4-substituent.The (esults of the study 01 the extent of abnormal reaction paths probably via ips0 -substitution of aryl acetates have also appeared in The formation of an ips0 -substituted cyclohexadienone from the bromination of 3,4-dimethylphenol has been e~tablished,~~‘ and possible pathways from related species have been discussed. In contrast with which suggested that peroxydisulphate-initiated copper-mediated aromatic halogenation involved cation radical intermediates it has now been reported7” that the mechan- ism involves molecular chlorination and that the role of copper(r1) is to mitigate the otherwise preponderant side-chain halogenation.The Friedel-Crafts alkylations of benzene and p-xylene by 2- and 3- chloropentane and 2- and 3-chlorohexane are accompanied by simultaneous isomerization of the chloroalkanes and rearrangement of the product arylalkanes the latter dominating at room temperat~re.~~ Friedel-Crafts benzoylation of the dichlorobenzenes involves chloronium ion migration and secondary protodechlori- nation in addition to normal s~bstitution.’~ It has been dem~nstrated~~ that the type and extent of sulphur complexation of thioanisole with Lewis acids can markedly affect the rate and products of both acetylation and chloromethylation. The trans- t-butylation of arenes with 2,4-di-t-butylanisole in the presence of aluminium chloride has been studied,75 and it is the t-butyl group ortho to the methoxy-group which is transferred.Labelling with deuterium has shown that in the alkylation of arenes by homologues of cyclopropane classical carbonium ions which undergo isomerization and fragmentation are intermediate^.^^ It has been suggested that the reaction of arenes with styrene in the presence of palladium(I1) acetate to give substituted stilbenes involves initial electrophilic metallation to give a a - c ~ m p l e x . ~ ~ The overall spread of reactivity is however very small. A review of the recent uses of positional protective groups in selective substitution reactions to form phenols diphenylmethanes and biphenyls has appeared.78 Nucleophilic Substitution.-Reactions involving displacement of hydrogen by nu- cleophiles in arenes and quinones have been reviewed.79 In contrast with the reaction of aliphatic substrates the nucleophilic substitution of suitably activated aryl halides by the superoxide ion from the K02-crown ether complex in benzene proceeds via an intermediate anion radicaLgO The synthetic scope of the photo- stimulated SRNl reaction of ketone enolate ions with aryl halides has been 71 ( a ) A.Ledwith and P. J. Russell J.C.S. Chem. Comm. 1974,291,959; ( b ) R. Filler and R. C. Rickert ibid. 1976 133. 72 R. M. Roberts S. E. McGuire and J. R. Baker J. Org. Chem. 1976,41,659. 7 3 M. Godfrey P. A. Goodman and P. H. Gore Tetrahedron 1976,32 843. 74 S. H. Pines J. Org. Chem. 1976,41 884. 75 K. Shimada Bull. Chem.SOC. Japan 1976,49 1375. 76 V. A. Isidorov B. V. Stolyarov and B. V. Ioffe J. Org. Chem. (U.S.S.R.) 1976,12 323. 77 Y. Fujiwara R. Asano I. Moritani and S. Teranishi J. Org. Chem. 1976,41 1681. 78 M. Tashiro and G. Fukata Org. Prep. Proced. Internat. 1976,8 51. 79 0. N. Chupakhin and I. Ya. Postovskii Russ. Chem. Rev. 1976,45,454. A. Frimer and I. Rosenthal Tetrahedron Letters 1976 2809. 213 F The first stable gem -difluoro-Meisenheimer complex (2 1 ; X = F) has been detectedg3= by n.m.r. spectroscopy from the addition of picryl fluoride to a mixture of 18-crown-6 ether and potassium fluoride in acetonitrile. Further evidence for (21 ; X=H) which was detected last year by visible spectroscopy [Ann. Reports (B) 1975 72 2261 was however not forthcoming.The spectra of gem-diamino- complexes formed by the reaction of amide ion and nitro-anilines have also been Kinetic and equilibrium data on the formation of the spiro-complexes (22a) and (22b) have been given,84 and it has been found that opening of the dithiolan ring is much less susceptible to acid catalysis than is that of the dioxalan (22c). Homologue (23c) has also been prepared although (23a) is ~nstable.~’ Both of these species gave an intramolecular displacement of the o -nitro-group on treatment with triethylamine. Temperature- jump experiments have showng6 that protc transfer is rate-limiting in the formation of (24a) from catechol2,4,6-trinitrophet$ ether not a;X=Y=S I . < c; X = Y = O Z / / X Y O z N O N o 2 b; X = S Y = 0 .. _ NO2 ( a ) J. F. Bunnett and J. E. Sundberg J. Org. Chem. 1976,41,1702; ( b ) J. F. Bunnett R. G. Scamehorn and R. P. Traber ibid. p. 3677. Aroma tic Cum po u nds examined,81a and ketone dimer formation was identified as a yield-limiting and rate-depressing side-reaction. A survey of solvents suitable for aromatic SRNl reactions has also been carried out.81b Photosubstitution of aryl fluorides by primary and secondary amines has been reported to give both conventional and for the first time cine‘-substitution probably by an addition-elimination mechanism.82 ortho - Photoadducts are usually also formed but p-difluorobenzene gives the para -adduct (20) with diet hylamine. F 81 83 84 85 N. Drozd J. Org. G e m . (U.S.S.R.) 1976,12 846.82 D. Bryce-Smith A. Gilbert and S. Krestonosich J.C.S. G e m . Comm. 1976 405. ( a ) G. Ah-Kow M.-J. Pouet and M.-P. Simonnin Tetrahedron Letters 1976 227; ( b ) S. Ohsawa Nippon Kagaku Kaishi 1976,456. M. R. Crampton and M. J. Willison J.C.S. Perkin ZZ 1976 901. R. Cabrino E. Farina and F. D. Cima J.C.S. Perkin I 1976,2214; V . N. Knyazev V. M. Minov and V. 86 C. F. Bernasconi and H.-C. Wang J. Amer. Chem. Soc. 1976,98,6265. 214 R. G. Coombes because of an abnormally slow protein transfer but because of the rate of nucleo- philic attack on the aromatic carbon which is the highest yet recorded for such a process. The ambident nature of phenolate ions in the formation of 0-complexes with 1,3,5trinitrobenzene has been discussed8’” and the carbon-bonded (+-complex is The protonation undergoes with - 1 phenol pK unit stronger than picric of the p-nitro-group displacement to give of a methoxide nitronic acid from which the trinitrobenzene-methoxide (+-complex by aromatic amines occurs by a dissociative mechanism.88 The greater susceptibility to base catalysis of aromatic substitutions by secondary amines than by primary amines of similar pK may be a consequence of intramolecu- lar hydrogen bonding by ortho -nitro-substituents and new kinetic data support this interpretati~n.~~ Two uses of hexamethylphosphoramide as a solvent have appeared.” Unactivated aryl halides react with sodium methoxide in this solvent to give unusually good yields of methyl ethers.”“ The mechanism involves bimolecular displacement product distributions not being consistent with aryne intermediacy.Nitrobenzenes carrying a range of electron-withdrawing substituents readily undergo nucleophilic displacement of the nitro-group at room temperature in the solvent in excellent yields.”’ 4-Alkoxy12,3-dinitroanilines undergo a novel cink- substitution in secondary amines which enter at the 6-position with displacement of the 3-nitro-substi tuent . 91 Organo-copper compounds have been shown9* not to be intermediates in the halide-exchange reaction between aryl halides and anions of copper salts from a study of 2-iodo-NN-dimethylaniline and the copper-assisted nucleophilic displace- ment mechanism involving a four-centre transition state or intermediate was favoured.Further studyg3“ of the copper(I1)-catalysed replacement of bromine by chloride ion in substituted 2-bromonitrobenzenes also disfavours aryl-copper inter- mediates and it seems that steric effects are the most important consequences of substituents in the 3-position. Any reductive dehalogenation probably proceeds as does the copper(1)-promoted reduction of the nitro-group by a photochemically induced side-reaction involving electron transfer to the nitro-c~rnpound.~~~ Biaryls.-The lamellar potassium-graphite compound KC8 forms a well-defined lamellar complex with benzene and THF and causes conversion of benzene into biphenyl at room temperat~re.~~ Arylmercury(I1) salts are converted into biaryls in high yield and under mild reaction conditions on treatment with copper and a catalytic amount of palladium chloride in ~yridine.’~ The electrochemical oxidation method of coupling aryl alkyl ethers has been extended96 to the intramolecular (a) S .M. Shein 0. G. Byval’kevich and A. D. Khmelinskaya J. Org. G e m . (U.S.S.R.) 1976,12 130; (b) E. Buncel and W. Eggimann Canad. J. Chern. 1976,54,2436. E. Buncel and J. G. K. Webb Tetrahedron Letters 1976,4417. 89 C. F. Bernasconi and R. H. de Rossi J. Org. Chem. 1976,41,44. 90 ( a ) J. E. Shaw D. C. Kunerth and S. B. Swanson J. Org. Chem. 1976,41,732; (b) N . Kornblum L. Cheng R. C. Kerber M. M. Kestner B. N. Newton H. W. Pinnick R. G. Smith and P. A. Wade ibid. p. 1560. 91 K. G. Barnett J. P. Dickens and D. E. West J.C.S. Chern. Cornm.1976 849. 92 G. van Koten J. T. B. H. Jastrzebski and J. G. Noltes Tetrahedron Letters 1976 223. 93 B. Liedholm Acra Chem. Scand. (B) (a) 1976,30 141; ( b ) 1976,30 165. 94 F. Btguin and R. Setton J.C.S. Chem. Comm. 1976,611. 95 R. A. Kretchmer and R. Glowinski J. Org. Chem. 1976,41 2661. 96 M. Sainsbury and J. Wyatt J.C.S. Perkin I 1976 661. Aromatic Compounds 215 coupling of diary1 amides and the scope and limitations of the process have been discussed. The kinetics of the homogeneous copper(1)-induced Ullmann coupling of o -bromonitrobenzene is consistent97a with a mechanism involving reversible oxida- tive addition of the C-Br bond to copper(1) to form an organo-copper(@ inter- mediate which may either displace a'bromide ion from A second aryl bromide molecule or become protonated by the medium.A mild method for the homogene- ous Ullmann coupling of ortho -halogenated arylimines has also been Trimethylsilyl groups have been used suc~essfully~~ to protect both hydroxy- and amino-groups substituted in aryl halides during coupling reactions under standard Ullmann conditions. The anomalously high value for the 0rtho:pura ratio for the homogeneous nitration of biphenyl by nitric acid in aqueous sulphuric acid has been ~onfirmed,'~ and the data render an explanation involving ips0 -attack and rearrangement most unlikely. A studyloo of the acidities of a series of 2-substituted fluorenes afforded a rather poor Hammett plot with both strongly conjugatively electron-donating and -withdrawing substituents showing deviations.Further substitution by some sub- stituents exhibited saturation effects which in the absence of steric effects were attributed to the consequences of changes in electron distribution in the anion caused by resonance delocalization. Polar saturation effects were of little or no importance. The considerable solvent effect on the rotamer equilibria and on barriers to rotation in the 9-arylfluoren-9-01 derivative (25) was attributed"'" to M e 0 hydrogen-bonding effects on the 9-hydroxy-group. The barriers to rotation in 1-(9- fluorenyl)-2-naphthyl aroates were with the presence of charge- transfer interaction between the fluozenyl group and nitro-substituted aroyl groups. The topic of restricted rotations in these and other systems has been reviewed."'' Quinones and Related Compounds.-Species (26) a nucleophilic quinone synthon can be prepared by anodic oxidation of 2-bromo- 1,4-dimethoxybenzene followed by metallation in THF at -70°C. The first stage of this sequence is applicable to complex systems of synthetic interest. lo* The utility of the reagent diphenylseleninic 97 ( a ) T . Cohen and I. Cristea J. Amer. Chem. Soc. 1976,98,748; (6)F. E. Ziegler K. W. Fowler and S. Kanfer ibid. p. 8282. 98 F. D. King and D. R. M. Walton Synthesis 1976,40. 99 R. G. Coombes and J. G. Golding Tetrahedron Letters 1976,771. loo F. G. Bordwell and G. J. McCollum J.-Org. Chem. 1976,41 2391. lo' (f) M. Nakamura H. Kihara and M. Oki Tetrahedron Letters 1976 1207; (6) M. Nakamura and M. Oki Chem. Letters 1976,651; (c) M. Oki Angew. Chem. Internat. Edn. 1976,15,87. Io2 M- J. Manning P. W. Raynolds and J. S. Swenton J. Amer. Chem. Soc. 1976,98 5008.

ISSN:0069-3030    

DOI:10.1039/OC9767300201

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

11 Heterocyclic Chemistry By 0. METH-COHN and R. K. SMALLEY The Ramage Laboratories University of Salford Salford M5 4Wl 1 General An intriguing set of 'Rules for Ring Closure' has been formulated by Baldwin.'" Several examples which are covered by these rules have been highlighted including some involving heterocyclic ring formation (Scheme l).'* Only time will decide whether these dictates are to become an integral part of modern organic chemistry. 5 -exo-Trig 0 (favoured) / HlY,.. NH* Scheme 1 Also of a general nature is a highly critical rejoinder by Huisgen2 on the concerted nature of 1'3-dipolar cycloadditions us. the question of biradical intermediates the latter view being consistently championed over the past few years by Fire~tone.~ Presumably this debate will continue particularly since Padwa and Carl~en~~ have reported what appears to be an intramolecular stepwise 173-dipolar cycloaddition in an allylazirine system.Evidence is presented in favour of a biradical intermediate with partial dipolar character. 2 Three-membered Ring Compounds In addition to the allylazirine reaction mentioned above more examples of the thermal rearrangement of 3-allyl-2H-azirines to 3-azabicyclo[3,l,0]hex-2-enes mentioned last year,' have been reported.4b Further instances5 (e.g. Scheme 2) of (a)J. E. Baldwin,J.C.S. Chem. Comm. 1976,734; (6) J. E. Baldwin J. Cutting W. Dupont L. Kruse L. Silberman and R. C. Thomas ibid.,p. 736; see also Chapter 13 Section 13 of this volume. * R. Huisgen J.Org. Chem. 1976 41 403. R. A. Firestone J. Org. Chem. 1968,33 2285; 1972 37 2181; J. Chem. Soc. (A),1970 1570. A. Padwa and P. H. J. Carlsen (a)J.Amet. Chem. Soc. 1976,98,2006; (b)J. Org.Chem. 1976,41,180. Ann. Reports (B),1975,72,249. 239 240 0. Meth -Cohn and R.K.Smalley N=CHAr I N=CHAr Scheme 2 cycloadditions involving the carbenoid mesomer of nitrile ylides have emerged.6 Surprisingly the nitrile ylide (l),derived either from an azirine or by base-catalysed dehydrohalogenation of the corresponding a-chlorobenzaldehyde imine in the absence of added dipolarophile reacts as shown in preference to an intramolecular 1,3-dipolar cycloaddi tion. Extension of the thermally induced intramolecular rearrangement of 2H-azirines bearing unsaturated side-chains5 has led to the synthesis of pyrazoles or 3H-azepines from (2; X = NCHzCH=CH2 or CHCH=CHC02Me).' Another useful high-yield (95'10)route' to azabutadienes [PhC(X)=NCH=CH,] employs the photochemical rearrangement of azirines (3; X = halogen OAc or OBz).Apparently X has to be a good leaving group or other products are formed. For example when X = OH the oxazoline (4) is obtained. Ph Ph CH=X CH,X (2) (3) (4) Thermal C-C bond cleavage as opposed to thermal C-N or photolytic C-C bond cleavage of 2H-azirines is a rare event. Of interest therefore is the first unequivocal example of this type whereby imino-carbene (5)(Scheme3) is formed.' The derived azabutadiene (6) may be isolated whereas its valence tautomer (7) undergoes slow decomposition to nitrile (RCN) and styrene.However if R =Me A. Padwa A. Ku,A. Mazzu and S. 1. Wetmore jun. 1.Amer. Chem. Soc. 1976,98 1048. A. Padwa J. Smolanoff and A. Tremper J. Org. Chem. 1976 41 543. A. Padwa J. K. Rasmussen and A. Tremper J.C.S. Chem. Comm. 1976 10. L. A. Wendling and R.G. Bergman J. Org. Chem. 1976,41,831. Heterocyclic Chemistry 241 then 3-methyl-3,4-dihydroisoquinoline(9) results uia a novel transformation of the azahexatriene (8) followed by a 1,5-H shift. The products from the metal-carbonyl-induced dimerization of 2H-azirines appear to be metal dependent. Whereas Group VI metal carbonylsl' yield pyrazines Fe2(CO) induces 2,5-diarylpyrrole formation,' lb and [Rh(CO),C12] yields 2-styrylindoles.' '' Aziridine-imine (10; R' = Pr'; X = NR R2= C02Me) is formed in high yield (70%) by the action of afkyl diazo-acetates on N,N-di-isopropyl carbodi-imides in the presence of cupric triflate or rhodium(I1) acetate." Apparently unlike earlier similar reactions triazolines are not intermediates in this reaction.Thermal isomeri- zation of vinyl aziridines available by Wittig reaction on 2-a~ylaziridines,'~" has been to yield either A'-or A3-pyrrolines depending on the nature of the 2-and 3-substituents. C-C bond cleavage of aziridines to give azomethine ylides is well known. However the generation and trapping of a 1,3-dipolar species (ll) derived from an aziridone (10; X = 0)(Scheme 4) has now been reported.14 Scheme 4 Wentrup" has demonstrated that iminocyclohexadienylidenes(12)-( 12a) in the gas-phase interconvert quantitatively via the elusive lH-benzazirine species (13) prior to ring-contraction by Wolff rearrangement to the isolable cyanocyclopenta- diene (14).The first example of the intermediacy of diazoalkanes in the thermally as opposed to photolytically induced decomposition of diazirines has been described. l6 Diaziridinyls cyclic analogues of hydrazyls have been detected and characterized by e.s.r. spectroscopy.l7 Ann. Reports (B),1975,72 250. l1 H. Alper and J. E. Prickett J.C.S. Chem. Comm. 1976 (a)p. 983; (b)p. 191; (c) p. 483. l2 A. J. Hubert A. Feron R. Warin and P. Teyssie Tetrahedron Letters 1976 1317. D. Borel Y. Gelas-Mialhe and R. Vessiere Canad. J. Chem. 1976,54 (a)p.1582; (b)p. 1590. M. Kakimoto S. Kajigaeshi and S. Kanemasa Chem. Letters 1976 47. I5 C. Thitaz and C. Wentrup 1.Amer. Chem. SOC.,1976.98 1258. l6 B. M. Jennings and M. T. H. Liu J. Amer. Chem. SOC.,1976,98,6416. A. R. Forrester and J. S. Sadd Tetrahedron Letters 1976 4205. 0.Meth-Cohn and R.K.Smalley syn-Naphthalene- 1,2;3,4-dioxide (17)has been prepared by the annexed route (Scheme 5) and displays surprising stability.'* The synthesis is of interest in that intermediates (16) and (16a) appear to be the first examples of the hitherto hypothetical benzene imine unsubstituted at nitrogen. A synthesis of the anti-dioxide has also been reported. Exhaustive photo-oxidation of peroxide (16)yields what is thought to be the syn,syn,syn,syn -1,2;3,4;5,6;7,8-ant-9,lO-naphthalene pentoxide (18) and similar treatment of imino-annulene (15) yields a 1,2;3,4;5,6;7,8-tetroxide of as yet unknown configuration.0 / 2); qvJ -L+go NH NH NH (15) (16) Scheme 5 The first practicable synthesis of an a-metallated epoxide a potentially useful synthon has been achieved. l9 The process involves regiospecific lithiation of ethylsilanes at -78 "C.Lithio-derivatives,e.g. (19),are obtained exclusively and in high yield with retention of stereochemical and structural integrity. ph3si9 Li (19) A full report on the synthesis of chiral and achiral thiirans and alkenes by reaction or lithiated 2-alkylthio-2-oxazolines with carbonyl compounds has appeared.20a.b Preliminary attempts21 to prepare ylidic heterobicyclobutanes of general formula (20;X =0or S) have led to the isolation of tetramethylallene episulphide (21) (40-65%) possibly by way of ylide (20;X =S) although carbene (22)is a viable (20) (21) (22) l8 E.Vogel H-H. Klug and M. Schafer-Ridder,Angew. Chem. Internat. Edn. 1976,15,229. l9 J. J. Eisch and J. E. Galle J. Amer. Chem. Soc. 1976,98 4646. 2o (u)Ann. Reports (B)1975,72 253; (b)A. I. Meyers and M. E. Ford J. Org. Chem. 1976.41 1735. 21 A. G. Hortmann and A. Bhattacharayya,J. Amer. Chem. SOC.,1976,98,7081. Heterocyclic Chemistry alternative. Synthetic efforts towards the oxygen analogue (20; X =0)yielded only vinyl ketone (23) probably viu oxeten derivative (24). Me>=(Me Me&Me Me COMe Me 0 (23) (24) Two reports which claim the preparation of the hitherto undescribed silacyclo- propenes have appeared.The first method22 uses the addition of dimethylsilene (Me2Si:) to dimethylacetylene at 600 "C giving silacyclopropene (25; R =Me) in 50% yield. The second method23 involves treatment of hexamethyl-l-silacyclopropane with Me,SiC=CSiMe, and gives trimethyhilyl derivative (25; R =Me3Si) as a stable (inert atmosphere) isolable product. RwR Si /\ Me Me (25) 3 Four-membered Ring Compounds Photolysis (300 nm) appears to be superior to flash vacuum pyrolysis24 as a method of generating benzazetes (27; R =Ar) from 4-ary1benzo-l72,3-triazin~s (26; R = Ar).25u At -80 "C the benzazete can be trapped by various dienes and 1,3-dipoles whereas at room temperature dimers (28) identical with those obtained previously by thermolysis are formed.In c~ntrast,~~' when R =alkyl the benzazete (27) is much less stable and is non-isolable even at -197 "C.However low yields of dimer and 'trapped' products may be obtained when R =But. Contrary to earlier reports,26 1-azetines e.g. (29; Ar =a-naphthyl) are available in reasonable yield (30-40%) by photolytically induced (2 +2) cycloadditions between alkenes and naphthyl cyanide.*' Benzonitrile behaves similarly. The azeto-isoxazole (30) thought2' to be produced by reaction of keto-acid (31) with 22 R. T. Conlin and P. P. Gaspar J. Amer. Chem. Soc. 1976,98,3715. 23 D.Seyferth D. C. Annarelli and S. C. Vick J. Amer. Chem. Soc. 1976,98,6382. 24 Ann. Reports (B),1973,70,478.C. W. Rees R. C. Storr and P. J. Whittle (a)J.C.S. Chem. Comm. 1976,411;(b) TetruhedronLCttcrs 1976 4647; (c) ibid. p. 3931. 26 J. J. McCullough R. C. Miller D. Fung and W.-S. Wu J. Amer. Chem. Soc. 1975,97 5942. 27 N.C.Yang B. Kim W. Chiang and T. Hamada J.C.S. am. Comm. 1976,729. 28 T.Kurihara and M. Mori TetrahedronLetters 1976,1825. 244 0. Meth -Cohnand R.K. Smalley MeBMe / q Ar Ar Me hydroxylamine hydrochloride has been shown 25c to possess the more mundane isoxazole structure (32). COC02H Ar CN ArCH=C / 0 Me 5 'COMe N (31) (32) Two new p-lactam syntheses are worthy of mention. The first2' involves treat-ment of the readily available azetidine-2-carboxylic acid with lithium di-(isopropy1)amide and then reaction of the resulting carbanion with O2at -78 "C.Treatment with acid followed by decomposition of hydroperoxide (33) yields azetidinone (34) (50-60%)(Scheme 6). The second route,30more complicated but i 0,. -78 "C rPCO-'@H acoO- 0' jj,H+* N \ jj,H+ N\\ -qo \ 'RR R 'RR (33) (34) Scheme 6 nevertheless of interest starts from the commercially available mucochloric acid (35; X =0,R =C1). Treatment with azide ion followed by thermal decomposition of resulting aide (35; X =0,R =N3),results in loss of nitrogen and methyl formate to give chlorocyanoketen which readily adds to dicyclohexylcarbodi-imide,giving p-lactam (36). p-Lactams e.g. (37) are also produced by direct thermolysis of azidopyrrolinones e.g.(35; X =NMe R =N3). H' 'OMe CN OMe (35) (36) (37) The first synthesis of the 2H-1-benzothiete ring system has been achieved31by Wolff rearrangement (39)+(40) of keto-carbene (39) obtained by photolysis of diazoketone(38). Addition of methanol to keten (40) yields benzothiete (41) in 30% 29 H. H. Wasserman and B. H. Lipshutz Tetrahedron Letters 1976,4613. 30 H. W. Moore L. Hernandez and A. Sing J. Amer. Chem. Soc.,1976,98,3728. 31 E. Voight and H. Meier Angew. Chem.Internal. Edn. 1976 15 117. Heterocyclic Chemistry yield. Predictably (41) is more stable than thiete since ring-opening to its valence tautomer (42),which would involve loss of aromaticity in the benzene ring is not observed. (42) (4 1) Another3*“* higher yield synthesis of 2H-benzojblthiete 1,l-dioxide (43)has been announced (Scheme 7).33 (stepwise halogenation) /m (43) Scheme 7 The non-stereospecific photolytically (400nm) induced cycloaddition of cis-and trans-alkenes to thione (44)to give thietans (45)suggests that a triplet (C-S) species is More intriguing are the reactions of (44)with alkynes under similar conditions e.g.Scheme 8.346 A full report on the synthesis and reactions of naphtho[ 1,8-bc]thiete (46;X = S) noted previo~sly,~~ has appeared.36 The silicon analogue (46;X = SiEt,) has been synthesized (43% yield) by treating 1,8-dilithionaphthaIene with dichlorodiethyl- silane in diethyl ether at O°C.37The parent 1,3-dithietan system (47)has been prepared for the first time by sodium sulphide treatment of 1,l’-dichlorodimethyl sulphoxide in the presence of a phase-transfer catalyst followed by diborane-induced deoxygenation of the resulting dithietan By judicious choice 32 (a)D.C. Dittmer and F. A. Davis J. Org. Chem. 1967,32 3872; (b) B.Lamm and J. Simonet Acta Chem. Scund. (B),1974,28 147. 33 D. C. Dittmer and T. R. Nelsen J. Org. Chem. 1976,41 3044. 34 H.Gotthardt and S. Nieberl (a) Tetrahedron Letters 1976,3563;(b)Chem. Ber. 1976,109,2871. 35 Ann. Reports (B),1974,71,326. 36 J. Meinwald S. Knapp S. K. Obendorf and R. E. Hughes J. Amer. Chem. SOC.,1976,98 6643. 37 L.S.Yang and H. Shecter J.C.S. Chem. Comm. 1976,775. 38 (a)E.Block E. R. Corey R. E. Penn T. L. Renken and P. F. Sherwin J. Amer. Chem. Soc. 1976,98 5715;(b) E.Block,R.E. Penn R. J. Olsen and P. F. Sherwin ibid. p. 1264. 246 0.Meth -Cohn and R. K.Srnalley 0 Me 0 Me OEt Scheme 8 of reaction conditions and oxidizing agent all possible mono- di- tri- and tetra-S- oxides of (47) can be prepared. Flash vacuum pyrolysis of thietan S-oxide or of 1,3-dithietan 1-oxide generates the hitherto unknown sulphine (thioformaldehyde S-oxide) (CH,=S=O); the structure was confirmed by microwave The 1,3-oxazetidines(48) formed by treating imines with acetyl chloride and triethylamine have been shown4’ to have the isomeric 1,3-oxazin-4-one structures (49). 4 Five-membered Ring Compounds The versatile Boulton-Katritzky rearrangement (Scheme 9) does not proceed with carbon as the central atom (E),and recent experiments support the intermediacy of a bicyclic transition state (50)in a concerted process.41 New routes to pyrroles include 39 H.Iwamura M. Tsuchimoto and S. Nishimura TetrahedronLelters 1975 1405. 40 A. Maujean and J. Chuche TetrahedronLetters 1976,2905. *1 A. S. Afridi A. R. Katritzky and C. A. Ramsden J.C.S. Perkin I 1976 315. Heterocyclic Chemistry (50) Scheme 9 an interesting approach to 3,4-dimethy1pyrrole4' (a useful porphyrin precursor) (Scheme and the interaction of 'TosMIC' analogues (51) with chalcones Me MeENH (62%) \ Me *o Me Me Scheme 10 (Scheme 1l).43Use of aldehydes or imines instead of chalcones results in oxazoles and imidazole~.~~ Ar ArCH=X T~CH,-N=( R ArCH=CHCOPh + (QCOPh A ~ K I R Y H X = 0or NAr' (51) R =Me Ph OMe or SMe Y = C1,OMe or SMe Scheme 11 Pyrrole-2-aldehyde undergoes an interesting series of reactions with the bis- phosphonium salt (52) to give finally a pyrroloazacyclazine (Scheme 12) uiu an isolable intermediate (53).45 (52) (53) Scheme 12 42 K.Ichimura S. Ichikawa and K. Imamura Bull. Gem. SOC.Japan 1976,49 1157. 43 Ann. Reports (B),1974,71,333. 44 H.A. Mouwing J. Wildeman and A. M. Van Leusen Tetrahedron Letters 1976 143. 45 W.Flitsch and E. R. Gesing Tetrahedron Letters 1976 1997. Meth -Cohn and R.K. Smalley 248 0. 1976 has again been a vintage year for indole syntheses. It now appears that the classical Fischer indole reaction does succeed with acetaldehyde phenylhydrazone so long as the indole produced is flushed out of the reaction mixture with a stream of nitrogen.This prevents the tar-forming action of the intermediate hydrazone and yields 36% ind01e.~~ Several groups have reported useful indole syntheses based on allylanilines. Thus N-allylanilines rearrange to o-allylanilines with acid which may subsequently be cyclized to indolines ph~tolytically.~~ o-Chloro-N-allylanilines cyclize to 3-methylindoles on treatment with a zerovalent nickel derivative by way of halogen-metal exchange. Alternatively the use of a Grignard reagent (RMgBr) together with the nickel complex yields 3-RCHz-substituted indoles and replace- ment of the ally1 by an acryloyl group yields ~xindoles.~~ A related approach commencing with o-bromoanilines and v-allylnickel bromide involves cyclization of the resulting o-allylanilines to indoles with palladium ~hloride.~’ N-Benzyl-N-propynylanilines on successive treatment with rn -chloroperbenzoic acid (making the N-oxide) and a nucleophile e.g.CN- give 1-benzyl-3-cyanomethylindolesin a one-pot Azide or phenylthiolate may be used in place of cyanide with equal success. A novel indole synthesis involves (2+2) cycloaddition of a chloroketen to a Schiff base followed by capture of the pendant chlorine to give a fused B-lactam (54).” This may be transformed into an indole by thermal or alkali treatment (Scheme 13). CICH,COCI A NEt EtOH 6”’=NAr -Scheme 13 Another new source of N-methylindoles (as well as of benzo-furans and benzothiophens) involves generation of an o-substituted phenylvinyl cation (55) (Scheme 14).The intermediate (56; X = NMe) may be isolated.” 46 M. Nakazaki and K. Yamamoto J. Org. Chem. 1976,41 1877. 47 K. Krowicki N. Paillous M. Riviere and A. Lattes J. Heterocyclic Chem. 1976 13 555. 48 M. Mori and Y. Ban Tetrahedron Letters 1976 1803 1807. 49 L. S. Hegedus G. F. Allen and E. L. Waterman J. Amer. Gem. Soc. 1976,98 2674. Y. Makisumi and S. Takeda Chem. and Pharm. BUN. (Japan) 1976,24,770. 5’ R. L. Bentley and H. Suschitzky J.C.S. Perkin I 1976 1725. 52 T. Sonoda M.Kawakami,T. Ikeda,S. Kobayashi,andH. Taniguchi J.C.S. Chem. Cornm. 1976,612. 249 Heterocyclic Chemistry Ar' NaOH-EtOP 120°C. 8 h CAr \ I Me I Me . (55) X = NMe 0,or S (Upto 100%) Scheme 14 The sulphonium salt resulting from N-chlorosuccinimide and a dialkyl sulphide readily attacks indole by electrophilic substitution to give 3-alkylthioind0le.~~ When an allylic sulphide is used the product is a 2-allyl-3-allylthioindole by rearrangement of the intermediate.This offers a convenient route to 2-alkyl- and 2- allyl-indoles by subsequent desulphurization. Last year5* the products from iodine azide and N-acylindoles were noted. 2,3-Dimethyl- and 2-aryl-3-substituted (Me or Ph) indoles react with this reagent to give the azides (57) and (58),respectively in high yield whereas (59) is obtained from 2-methy1-3-(2-hydro~yethyl)indole.~~ The azides (58; R = Me and Ph) give 2-phenyl-4-methylquinazoline and 2,3-diphenylquinoxaline respectively on thermolysis.(57) (58) (59) N-Acetylisatin condenses with two moles of hydroxylamine to yield the quinazolinylhydroxamic acid (60)56and not the isatin dioxime as originally formu- lated.57 This has required the reformulation of much chemistry based on the supposed dioxime such as the dehydration product (61) [not (62)Is8 and its isomer from alkali treatment (63) [not (64)].58 Further Gordian knots based on isatin have been unravelled this year. Isamic acid derived from the action of ammonia on isatin after 134years of argument has finally been given the structure (65) in a beautifully lucid piece of work by C~rnforth,~~ who also solved the long-standing riddle of the action of moist air on 0-methylisatin. The product methylisatoid is now formu- lated as another dihydroquinazoline (66).Further strong support for the singlet s3 K. Tomita A. Terade and R. Tachikawa Heterocycles 1976,4 (a)p. 729; (6)p. 733. 54 Ann. Reports (B) 1975,72,259. ss M. Ikeda F. Tabusa Y. Nishimura S. Kwon and Y. Tamura Tetrahedron Letters 1976 2347. s6 J. Bergman R. Carlsson and J. 0.Lindstrom Tetrahedron Letters 1976 361 1 3615. s7 E. Scheinck and L. Marchlewski Ber. 1896,29 194. s8 M. Takahashi Bull. Gem. SOC. Japan 1970 43 2986. 59 J. W. Cornforth J.C.S. Perkin I 1976 2004. 0.Meth -Cohn and R.K. Smalley CONHOH 0 H (65) nitrene origin of carbazoles6' from 2-aminobiphenyls stems from the thermal and photolytic decomposition of 2-azido-2'-methylbiphenyl. Under triplet nitrene- promoting conditions the formation of phenanthridine competes efficiently with carbazole formation.61 NN-Diallylamides of conjugated dienoic acids are readily cyclized by way of intramolecular Diels-Alder reactions.Among numerous examples are the two shown in Scheme 15.62 Criss-cross intramolecular 173-dipolar cycloaddition has also been reported bis(o -propynyloxybenzal)azine for example forming the pentacycle (67).63 1-Hydroxyimidazole 3-oxides are readily prepared by the interaction of an aldehyde an a-diketone and two equivalents of hydroxylamine. Alternatively any combination of the preformed oximes in the same proportion gives the same result.64 Isoindazoles (68) are conveniently synthesized as well as the interesting products (69) and (70).65 6o Ann.Reports (B),1975,72 259. 61 J. M.Lindlay I. M. McRobbie 0.Meth-Cohn and H. Suschitzky Tetrahedron Letters 1976,4513. 62 G. Frater Tetrahedron Letters 1976 4517. 63 S.S.Mathur and H. Suschitzky J.C.S. Perkin I 1975 2479. 64 B.Krieg and W. Wohlleben Chem. Ber. 1975,108,3900. 6s G.S.Zenchoff A. Walser and R. I. Fryer J. Heterocyclic Chem. 1976,13 33. Heterocyclic Chemistry 25 1 H (3 isomers) N-N R' R2 R' R2 R' RZ NH AcZO 1103 R' R2 R' R2 O E N A C [ENAcI2 + (69) (70) The hitherto unknown bendcd]indazole has been prepared by photolysis of 1,8-diazidonaphthalene at 77K in a rigid matrix.66 The photo-conversion of 2,3-dimethylindazole into 1,2-dimethylbenzimidazoleis now shown to proceed via the isolable intermediate (71) by irradiation (300 nm) at -60 0C.67 Full details and mechanistic rationalizations have been published on the photo- rearrangements of 1-(2-nitrophenyl)-pyrazoles and -imidazoles whereby benzo- triazole 1-oxides and benzimidazoles are produced respectively by fission of the 66 A.Yak K. Honda S. Oikawa and M. Tsuda Chem. Letters 1976,823. 67 W. Heinzelmann M.Marky and P. Gilgen Helv. aim. Acfa 1976,59 1512. 0.Meth -Cbhn and R. K.Smalley (71) initial heterocycle and incorporation of the nitro-group into the new one.68 A related process has been recorded for 2-(2-nitrophenyl)oxazoles,which are trans- formed into 2-acylquinazolin-4-ones on phot~lysis.~~ By generation of nitrenes specifically in the singlet or triplet state alternative syntheses of two heterocycles are available." Thus pyrazolobenzotriazoles or pyrazoloquinoxalines are derived from 2-nitrenophenylpyrazoles (Scheme 16) and application of the principle to other systems has been rep~rted.~~ Me Me via Me via singlet triplet ' 6": X X x Sctleme 16 In the presence of potassium carbonate TosMIC?~ liberates a 1,3-dipole capable of converting diazonium salts into l-aryl-3-tosyl- 1,2,4-triazole~.~~ Although the reaction does not take place with nitriles in place of diazonium salts a (3 +2) anionic cycloaddition of 'son of TosMIC' (72) with nitriles offers a useful synthesis of 2-unsubstituted imidazoles (73) the arylthio-group being removable by desulphuri- at ion.^^ N-Benzoyltetrazole has been recommended as a mild benzoylating agent for nucle~sides.'~ The countdown on remaining new meso-ionic heterocycles con- tinues with another seven systems (74) being reported by the Ollis group.75 R' .("@Ay-'N H (73) (74)X = S,Y =0,S,NAr or C(CN), X =NAr Y =S or C(CN)* X=O,Y=S 6s P.Bouchet C. Coquelet J. Elguero and R. Jacquier Bull. Soc.chim. France 1976 184 192. 69 I. A. Silberg R. Macarovici and N. Palibroda Tetrahedron Letters 1976 1321. 70 I. M. McRobbie 0.Meth-Cohn and H. Suschitzky Tetrahedron Letters 1976 925. 71 I. M. McRobbie 0.Meth-Cohn and H. Suschitzky Tetrahedron Letters 1976 929. 72 A. M. Van Leusen B. E. Hoogenboom and H. A. Houwing J. Org. CAem. 1976,41,711. 73 A. M. van Leusen and J. Shut Tetrahedron Letters 1976,285.74 J. Stawinski T. Hozumi and S. A. Narang J.C.S. Chem. Comm. 1976,243. 75 R. N. Hanley W. D. Ollis and C. A. Ramsden J.C.S. Chem. Comm. 1976 306 307. Heterocyclic Chemistry 253 Although the nitro-group has been previously noted as a photo-l,3-dipolar species (being an aza-ozone derivative) its reaction in thermal cycloaddition has not been accomplished. However nitrobenzenes react with strained olefins for example cyclo-octadiene (79 at ambient temperatures to give 1,3,2-dioxazolidines (76) which are stable in aprotic The O,a-C-dilithio derivatives of alkyl ketoximes react readily with aldehydes or ketones (R'R2CO) to give 2-isoxazolines (77).77 Two possible pathways for the photofragmentation of the meso-ionic system )-=-Ri2 '"0 (75) (76) (77) (78) have been previously observed but the cause for the dichotomy is unexplained.It now appears that at 10K in solid nitrogen photolysis of the isolated molecules gives only the keten (79) whereas aggregation brought about by melting and recooling the system leads to the other 0 -0 (79) (78) Mukaiyama has continued7' to demonstrate the prolific synthetic capabilities of quaternized halogenoheterocycles,* and recommends 1-ethyl-2-fluorobenzo-thiazolium borofluoride as a reagent of choice for conversion of alcohols into alkyl halides.80 SN2 replacement of the 2-oxybenzothiazoiium group by halide ion proceeds readily and in high yield and is especially effective with optically active alcohols. Sulphuryl chloride effects the ring expansion of 2-alkylbenzothiazolines to benzo- 1,4-thiazines by way of a ring-opened sulphenyl chloride (Scheme 17).8' An Scheme 17 unexpected route to the diazathiathiophthen (80) system occurs by the action of sodium thiocyanate on dichloromethyl alkyl disulphides,82 and the interesting 76 J.Leitich Angew. Chem. Internat. Edn. 1976,15,372. 77 C. A.Park C. F. Beam E. M. Kaiser and R. J. Kaufman J. Heterocyclic Chem. 1976,13,449. 7s I. R.Dunkin M. Poliakoff J. J. Turner N. Harrit and A. Holm Tetrahedron Letters 1976,873. 79 Ann. Reports (B),1975,72,336. K. Hojo and T. Mukaiyama Chem. Letters 1976,619. B1 F. Chioccara R. A. Nicolaus E. Novellino and G. Prota Chimica e fndustria,1976,58.546. 82 J. Goerdeler H. Hohage and I. aid Chem. Bet. 1976 109 3108.* ke also Section 5. 254 0.Meth -Cohn and R.K. Smalley S-S-S (80) system (8 1)has been made by stepwise annulation from benz0-2,1,3-thiadiazole.'~ Isoselenazolium salts (82) have been reported for the first time,84 as have benzo- 1,2,3-diselenazolium salts." (81) (82) Acetyl toluene-p-sulphonate efficiently acylates furans and thiophens at room temperature.86 3-Lithiothiophens are well known to ring-open to give vinyl- acetylene derivatives but the corresponding furans appeared generally to be stable. However 2,5-diaryl-3-bromofurans react with butyl-lithium to give a mixture of an allene and acetylene in good yield (Scheme 18)by way of the corresponding lithium enolate." The latter may be trapped by the action of either acetic anhydride giving an enol acetate or by an aromatic aldehyde by conjugate addition to the acetylene giving finally (83).Pyrroles do not ring-open although 2,5-diphenyl-4-bromo-oxazole does. Ar BuLi pCICAr Ar + fiBr hexane ' Ar 0 Ar 6570°C Ar ArCO Ar CO Scheme 18 Isobenzofurans continue to attract interest. They may be generated and sometimes isolated from 2-bromomethylbenzophenone and intercepted with dienophiles giving finally a-naphthols." 1-Methyl and 1,3-dimethyl-isobenzofuran exist totally as such but 1-benzylisobenzofuran (84) prefers the 1-benzalphthalan tautomer (85) though it can be made to react with dienophiles. Flash vacuum pyrolysis at 600 "C of the system (86) (made by hydrogenation of the benzyne adduct of 2-benzylfuran) quantitatively yields 1-benzylisobenzofuran (84) which only slowly (4 h in CHCl,) reverts to the phthalan (85).The tautomerism is acid-catalysed.'' 83 A P. Komin and M. Carmack J. Heterocyclic Chern. 1975,12,829. 84 J. Liebscher and H. Hartmann Synthesis 1976 273. A. M. Erdokimov Y. I. Akulin B. K. Strelets and L. S. Efros Khim. geterotsikl. Soedinenii 1975,1429. 86 S. I. Pennanen Heterocycles 1976,4 1021. 87 T.L. Gilchrist and D. P. J. Pearson J.C.S. Perkin I 1976 989. 88 R.Faragher and T. L. Gilchrist J.C.S. Perkin I 1976 336. 89 E. Chacko D. J. Sardella and J. Bornstein Tetrahedron Letters 1976 2507. Heterocyclic Chemistry Qlqy-$ @ \' \ \ CH Ph CHPh CH,Ph (84) (85) (86) 2-Mercaptophenol gives benzoxathiolium salts with carboxylic acid chlorides which are readily reduced to the dihydro-analogues with sodium borohydride thereby offering a useful source of aldehydes in good yield by hydrolysis with aqueous mercuric chloride.Use of sodium borodeuteride yields the corresponding deuterioaldehyde." A new approach to thiophens uses the 1,3-dipolar character of meso-ionic 1,3- dithiolones (87) (easily prepared from arylacetic acids) whereby interaction with acetylenes with subsequent elimination of carbonyl sulphide gives the thiophens (88).91 The elusive 2,3-thiophyne seems to have been convincingly created by flash 0-R2 C (87) (88) R2=mono-or di-C02R Ph or COPh pyrolysis of thiophen-2,3-dicarboxylicanhydride as demonstrated by careful pro- duct analysis and trapping experiment^.^^ 3-Chlorothiophens are surprisingly difficult to obtain.A simple method applicable to 2- 3- di- tri- or tetra-chloro- thiophen synthesis in excellent yield involves heating the corresponding bromothiophens with cuprous chloride in dimethylformamide solution for 12- 16 h.93 Despite its appearance in 'Organic Syntheses' the action of N-bromosuccinimide on 3-methylthiophen is a temperamental reaction. However by adding the thiophen to the NBS in refluxing carbon tetrachloride with a trace of azobis(isobutyronitri1e) as initiator consistent yields of 3-(bromomethy1)thiophen are claimed (70-75 Thiophen sulphoxide has been successfully trapped for the first time by its formation from thiophen with a peracid at 0 "Cin the presence of benzoquinone.The adducts may be converted into naphtho- 1,4-quinones also available from the more stable thiophen s~lphone.~~ The attempted t-butylation of 2,5octamethylenethiophen results in a deep-seated rearrangement to t-butylated 3,4-octamethylenethiophens(Scheme 19),in line with other curious results arising from t-butylation of sterically congested heterocycle^.^^'^' The ring-expansion of 3-pyrrolidinothiophen on treatment with dimethyl acetylenedicarboxylate (DMAD) in benzene by way of a thiepin to a benzene derivative (89) follows the course already established. If methanol is the solvent formation of polar intermediates is 90 I. Degani and R. Fochi J.C.S. Perkin I 1976 323. y1 H. Gotthardt M. C. Weisshuhn and B. Christe Chem. Ber. 1976 109 740 753. y2 M.G. Reinecke and J. G. Newsom J. Amer. Gem. SOC. 1976,98,3021. 93 S. Conde C. Corral R. Madronero and A. S. Alvarez-Insua Synthesis 1976 412. 94 S. Gronowitz and T. Frejd Synthetic Comm. 1976,6 475. 9s K. Torssell Acfa Chem. Scand. (B) 1976,30 353. 96 Ann. Reports (B),1975,72 264. 97 R. Helder and H. Wynberg Tetrahedron 1975,31 2551. 0.Meth -Cohn and R. K. Smalley Scheme 19 promoted and the reaction takes a totally different course (Scheme 20); solvents of intermediate polarity e.g. CHC13,give 0 N (89) E=C02Me CfYE E Scheme 20 Thiosuccinic anhydride (the stable tautomer of 2,5-dihydroxythiophen) under- goes a Wittig-type reaction allowing synthesis of the useful thiophen-2,5-diacetic esters and -diacetonitriles (Scheme 21).Surprisingly the latter compound exists Ph,P=CHR RCH2OCH,R NCCHOCHCN (90) Scheme 21 mainly as the non-aromatic tautomer (90).99 Ethyl 2-aminothiophen-3-carboxylates rearrange to 3-cyanothiolen-2-ones on treatment with base (Scheme 22) highlighting the great difference between aminothiophens and anilines. loo A new type of non-classical thiophen (91) has been synthesized and the deep-violet product behaves only as a thiocarbonyl ylide and not as a thiocarbonyl imine with 98 D. N. Rheinhoudt,W. P. Trompenaars and J. Geevers Tetrahedron Letters 1976,4777. 99 W.Flitsch J. Schwieger and U. Strunk Annulen 1975 1967. loo K. Gewald H. Jablokoff and M. Hentschel J. prukf. Chem. 1975,317,861. Heterocyclic Chemistry CO2Et C02Et CN 2 Scheme 22 (91) 1,3-dipolarophiles.lo' Thiolactones undergo an interesting condensative trimeriza- tion when subjected to high pressures and temperatures (Scheme 23).lo2 Scheme 23 The search for an organic 'super-metal' continues with avidity,lo3 a recent notable example1o4 being charge-transfer complex (92) having an ambient conductivity of 600 0cm-'.2-Phenyl-selenophen and -tellurophen lose selenium and tellurium respectively to give phenylvinylacetylene on irradiation in ether solution. Deuterium labelling showed that hydrogen abstraction from the solvent occurred during the fragmentati~n."~ NC s~sei-<"e~o Se Se NC CN (92) lol H. Gotthardt and F. Reiter Tetrahedron Letters 1976 2163. lo2 R. Proetzsch D. Bieniek and F.Korte 2. Naturforsch. 1976,31b 529. lo3 Ann. Reports (B),1975,72 267. lo4 C. Berg K. Bechgaard,J. R. Andersen and C. S. Jacobsen Tetrahedron Letters 1976 1719. Io5 T. J. Barton C. R. Tully and R. W. Roth J. OrganometallicChem.,1976,108 183. Meth -Cohnand R. K. Smalley 258 0. The phosphole (93)performs some surprising jugglery with DMAD with products and pathways as suggested in Scheme 24.'06 Bu 1 Bu E Scheme 24 5 Six-membered Ring Compounds New and modified syntheses of the pyridine ring system are still being discovered and several are worthy of mention. 3,5-Diphenylpyridine is available in 36% yield by heating phenylacetaldehyde morpholine enamine (2 mol) with N-formylidene-t- butylamine (Bu'N=CH2) in benzene at 200 "C for 9 h.Substitution of the imine by N-(t-buty1)oxaziridine permits use of a lower reaction temperature (80 "C) but the reaction time is longer (18 h) and yields are lower (24%).'07 Fully substituted pyridines e.g. (94) result from reaction of the cyclobutadiene-aluminium chloride cr-complex (95) with ethyl cyanoformate at 0-20 0C.108Possibly the reaction proceeds via a Dewar-pyridine intermediate. CUP -Unsaturated ketoximes cyclize in the presence of the palladium complex PdC12(PPh3)2to isoxazoles.109a Extension of this reaction e.g. (96)-+(97),to Py and 78-,and aPy8-unsaturated ketoximes constitutes a new pyridine ~ynthe~is.'~~~ lO6 A. N. Hughes K. Amornraksa S. Phisithkul and V. Reutrakul J. Heterocyclic Chem. 1976,13 65. *07 M. Komatsu H. Ohgishi Y.Ohshiro and T. Agawa Tetrahedron Letters 1976,4589. lo* P. B. J. Driessen D. S. B. Grace H. Hogeveen and H. Jorritsma Tetrahedron Letters 1976 2263. lo9 (a)K. Maeda T. Hosokawa S.-I. Murahashi and I. Moritani Tetrahedron Letters 1973 5075; (6)T. Hosokawa N. Shimo K.Maeda A. Sonoda and S.-I. Murahashi ibid. 1976 383. Heterocyclic Chemistry R2 R3 (96) (97) Cobaltocene appears to be superior to other cobalt compounds '10a7b as a catalyst for the formation of pyridines from alkynes and nitriles.llof A synthesis for N-alkyl- 1,2-dihydropyridines (99) apparently rare species with- out stabilizing electron-withdrawing groups has been reported (Scheme 25). ''' The successof the method lies in synthesizing the valence isomer (98; R = H) of the as yet unknown 1,2-dihydropyridine (99; R = H).This tautomer lacks the highly reactive dienamine functionality of its monocyclic tautomer but can be readily alkylated and thermally rearranged to substituted 1,2-dihydropyridines (99; R = alkyl). i MeLi -15 "C ii H,O Scheme 25 N-Substituted 3-formylpyridine-2-thiones are obtainable in good yield by treat- ment of glutacondialdehyde anion with isothiocyanates.'12 Selective ortho-acylation of 2-alkylpyridines is possible by [2,3]-sigmatropic (Sommelet-Hauser) rearrange- ment of Q -pyrrolidinyl-2-alkylpyridine sulphonates (loo) prepared by treating the parent base with cyanomethylbenzene sulphonate (PhS020CH2CN)."3 Acid hydrolysis of the rearranged product yields 3-formyl-2-methylpyridine (101)(50%) (Scheme 26).Methylation of (loo) using NaH-MeI prior to hydrolysis allows formation of 3-acetyl-2-methylpyridine (78%). CN 110 (a)Ann. Reports (B) 1973 70 501;(b) ibid. 1974 71 341; (c) Y. Wakatsuki and H. Yamazaki Synthesis 1976 26. 111 J. N.Bonfiglio I. Hasan J. J. Piwinski B. Weinstein and F. W. Fowler J.Amer. Chem. Soc. 1976,98 2344. 112 J. Becher and E. G. Frandsen Tetrahedron Letters 1976,3347. 113 E.B. Sanders H. V. Secor and J. I. Seeman J. Org. Gem. 1976,41,2658. 0.Meth-Cbhn and R. K.Smalley Sulphuric acid (72%) is advocated114 as the reaction medium for the selective chlorination of 2-aminopyridine at the 5-position; yields of 98% are claimed accompanied by only 2% of the 3,5-dichloro-derivative.Regioselective mono- cyclopropylation of pyridine at the 2-position can be achieved using preformed cyclopropylmagnesium bromide.' '' Reaction in situ either with cyclopropyl bromide and magnesium or with cyclopropyl-lithium results in non-selective pol ycyclopropylation . The high reactivity of quaternized 2-halogenopyridines particularly the 2-fluoro- compound has led to their exploitation as synthons for alkyl iodides,'lh ketones,"66 acyl fluorides,'16' ~ulphinimides.'~' N-acyl-lactams,'18" and carboxylic thiol esters."8b Selected examples are outlined in Scheme 27. OF '::> \+ nF 4 no -t RCOF N N OCOR N Me I I Me TsO-Me ( 102) 0 R*,NH I1 "?3 t R'-S-NR; + (102) N Qc, Me OSOR' I-Me Scheme 27 Azidomono- and azidodi-azine N-oxide chemistry' 19r*6 continues to flourish.2-Azidopyridine N-oxides lacking a 3-substituent undergo ring-contraction in hot benzene apparently by a concerted non-nitrene mechanism to give 2-cyano- 1-hydroxypyrroles,e.g. (103) in high yield. '*O' 2-Azidopyrazine N-oxide by analogy OH (103) on photolysis yields 2-cyano-1-hydroxyimidazole.The presence of a 3-substituent however alters dramatically the reaction products. For example 2-azido-3- 114 T. J. Kress L. L. Moore and S. M. Costantino J Org. Chem. 1976,41 93. ILS W. Kurtz am. Ber. 1975,108,3415. 116 (a)S. Kobayashi M. Tsutsui and T. Mukaiyama Chem.Letters 1976,373; (6)S. Kobayashi M. Tsutsui. and T.Mukaiyama ibid. p. 381; (c)T. Mukaiyama and T. Tanaka ibid. p. 303. 117 M. Furukawa and T.Okawara Synthesis 1976,339. 118 (a)A. Ishida,T. Bando andT. Mukaiyama Chem.Letters 1976,711;(b)Y.Watanabe S. Shoda andT. Mukaiyama ibid. p. 741. 119 (a)Ann.Reports (B),1975,72,272; (b) ibid. 1973,70,505. 120 (a)R. A. Abramovitch and B. W. Cue jun. J. Amer. Chem. Soc.,1976 98 1478; (b) R. A. Abramovitch I. Shinkai B. W. Cue jun. F. A. Ragan and J. L. Atwood J. HeterocyclicChem. 1976 13,415. Heterocyclic Chemistry methylpyridine N-oxide on thermolysis in benzene gives the novel pyrrole N-oxide (104) (89%),120awhereas 3-halogeno-substituents promote oxazinone formation e.g. (1O5).l2Ob -0 (104 (105) Many papers concerning the multifarious reactions of 3-oxidopyridinium betaines e.g. (106; R =Ph) have appeared.l2laSb Dealt with are the 2,6-cycloadditions of (106) with benzyne,122a and with cis-and trans-alkenes giving tropones.122b'C Also reported is the double cycloaddition of betaine (106; R = CH2COPh) with acrylonitrile to form (107).122dA molecular orbital based rationali- zation of the general reactivity of oxidobetaines and the regio- and stereo-selectivity of their dimerization further examples of which have come to light,123u has been put forward.123b Frontier molecular orbital theory successfully explains the regio- and stereo-selectivity of their cycloadditions to a variety of dipolarophiles.123c The versatility of these dipolar species is further expressed in their reaction with dichloroketen with which they undergo an (8+2) cycloaddition to give after loss of HCl adduct ( and in the intramolecular cycloadditions of for example [106; R =(CH2)3CH=CH2] which yields the novel heterocycle (109).12' NR+ H CN R 0 (106) (107) (108) (109) 3-Oxidobetaines of other heterocycles e.g.isoquinoline"*' and phthalazine. 1246*c have also been prepared. The former undergo similar reactions to the pyridinium betaines whereas the phthalazinium betaines show some as yet unexplained abnormal cycloadditions. 2,4-Bis(dimethylamino)quinoline is available by a new quinoline synthesis involv- ing reaction of cyanine (110)with aniillie in high dilution,126 and also by condensa- 121 (a) Ann. Reports (B),1974,71,343; (b) ibhlml975,72,269. (a)N. Dennis A. R. Katritzky and S. K. Parton J.C.S. Perkin I 1976 2285; (b)N. Dennis A. R. Katritzky S.K. Parton Y. Nomura Y. Takahashi and Y. Takeuchi,ibid.,p. 2289;(c) N. Dennis A. R. Katritzky and R. Rittner ibid. p. 2329; (d)N. Dennis A. R. Katritzky and S. K. Parton am. and Pharm.Bull. (Japan),1975,23,2904;(e)N.Dennis A. R.Katritzky and S. K. Parton ibid.,p.2899. 123 (a)N. Dennis A. R. Katritzky and H. Wilde,J.C.S.Perkin I 1976,2338;(b)N. Dennis B. Ibrahim and A. R. Katritzky ibid. p. 2296; (c) N. Dennis B. Ibrahim and A. R. Katritzky ibid. p. 2307. lz4 (a)N. Dennis A. R. Katritzky and G. J. Sabounji TetrahedronLetters 1976,p. 2959; (b) N. Dennis A. R. Katritzky E. Lunt M. Ramaiah,R. L. Harlow and S. H. Simonsen ibid.,p. 1569;(c) N. Dennis A. R. Katritzky and M. Ramaiah J.C.S. Perkin I 1976,p. 2281. 125 P. G.Sammes and R. A. Watt J.C.S. Chem. Comm.1976,367. H. G. Viehe G. J. Devoghel and F. Smets Chimiu (Swirz.) 1976,30 191. 0.Meth -Cohn and R.K. Smalley + c1-MezN\*NMe2 CI c1 (110) tion of aniline with diethyl malonate in hot HMPA. 127a The latter is a variation ofa reaction previously 2,3-Disubstituted quinolines and quinolines e.g. (11l) which are useful as precursors of more complex tricyclic systems result from the one-step condensation of o-amino-ketones and -esters respectively with ketenthioacetals e.g. (MeS)2C=CHN02.'28 Ketenthioacetals and related species e.g. (MeShC=NTs have also been used in cycloadditions with isoquinolinium ylides to prepare a variety of tricyclic systems e.g. (1i2).129 GNo2 NHAr qNxco2Et N SMe (111) (112) Improved yields of 3-halogenoquinolines (bromo- and chloro-) are claimed by the use of phase-transfer catalysts in the well-known dihalogenocarbene-induced ring-expansion of in dole^.'^' The hitherto unreported 3-(lithioalkyl)quinolines are now available by treatment of 3-methylquinoline with lithium di-isopropylamide in THF-HMPA at -78 0C.131 Condensation of 3-bromo-4-nitroquinoline N-oxide with a variety of aldehyde and ketone enamines constitutes a facile one-step general synthesis of fur0[3,2-b]quinolines.'~~ Further examples of the use of /3 -(o-thiocyanatopheny1)acrylaldehydes (obtained by ring-opening of quinolines with thi~phosgene)'~~" for the synthesis of novel heterocycles have been recorded.'336 An interesting study on the thermolysis of all possible isomeric 1-(isoquinoly1)acetates has led to the first quantitative assay ofthe relative reactivity of the positions in the neutral isoquinoline molecule towards electrophilic substitution.The following order of reactivity relative to a phenyl nucleus is proposed 4> (phenyl)> 5 = 7 > 8> 6 > 3 > 1 The study indicates that each position is less reactive than the corresponding position in naphthalene but more reactive than that in pyridine. (4 + 2) Cycloaddition followed by rapid [3,3]-sigmatropic rearrangement ofendo -adduct (1 13) (Scheme 28) explains the formation of pyridazines and oxazines (1 14; X = NAr and 0)from furans and nitroso- and azo-alkenes re~pectively.~~' 127 (a)E. B. Pedersen Acta Chem. Scund. (B),1976,30 133; (b) Ann. Reports (B),1975,72,271.lZ8 H. Schafer K. Gewald and M. Seifert J. prukt. Chem. 1976,318 39. H. Fujito Y. Tominaga Y. Matsuda and G. Kobayashi Heterocycles 1976 939. I3O S. Kwon Y. Nishimura M. Ikeda and Y. Tamura Synthesis 1976 249. E. M. Kaiser and J. D. Petty J. Org. Chem. 1976 41 716. 132 H. Noda T. Yamamori M. Yoshida and M. Hamana Heterocycles 1976,4 453. 133 (a)Ann. Reports (B)1975 72 272; (6)R. Hull and M. L. Swain J.C.S. Perkin I 1976 653. 134 E. Glyde and R. Taylor J.C.S. Perkin 11 1975 1783. lJ5 R. Faragher and T. L. Gilchrist,J.C.S. Gem. Comm. 1976,581. Heterocyclic Chemistry 263 (113) Scheme28 Alkylation of pyridazines at room temperature is now possible using nitroalkanes in DMSO-K2C03.’36 Condensation of ureas with propiolic acid in the presence of polyphosphoric or concentrated sulphuric acid yields uracils (60-70% ),13’ which are also available by treating cup -unsaturated acyl ureas e.g.(1 15) with lithium chl~ropalladite.’~~”~~ A new pyrimidine synthesis e.g. (1 16)+(1 17) employs the acid cyclization of a-cyanoamides (1 16) obtained by reaction of a-cyano-esters with sodium cyanamide.139 Non-regioselective (2 +2) photochemical cycloadditions of alkenes to various heterocyclic systems e.g. uracils thymine are well established. A report now indicates however that 5-fluoro-substituents confer complete regioselectivity on photo-induced cycloadditions of type (118)-+(1 19).l4’ Quaternary diazines of various types have been involved in several interesting transformations.Pyrimidine N-oxide (120; R =Ph or But) on photolysis in methanol suffers uncommon attack at C-2 to give oxaziridine (121) which subse- quently ring-contracts to pyrazole (i22).141 136 M. Yanai S. Takeda and M. Nishikawa Heterocycles 1976 4 1331. 137 K. Harada and S. Suzuki Tetrahedron Letters 1976 2321. 13* (a)A. Kasahara and N. Fukuda Chem.and Id. 1976,485; (b)Ann. Reports (B),1975,72,269. 139 T. Hirayama M. Kamada H. Tsurumi and M. Mimura Chem. and Pharrn. Bull. (Japan) 1976,24,26. I4O A. Wexler and J. S. Swenton J. Amer. Gem. Soc. 1976,98 1602. 14* F. Roeterdink and H. C. van der Plas J.C.S. Perkin I 1976 1202. 0.Meth -Cohn and R. K. Smalley R R R k?JR OR 3 'I 0' -0 (120) (121) (122) Pyrazoles are also formed in the photolysis of pyrazinium ylides (Scheme 29).142 By analogy with pyridinium ylides reaction probably goes via the as yet uncharac- terized 1,2,5-triazepine system (123) followed by electrocyclic ring-contraction and loss of R'CN.R hv -Me,CO +I -NCO,Et I C0,Et c- I I C02Et CO,Et Scheme29 Even more exotic is the sodium hydroxide-induced polar cycloaddition of pyrazinium fluorosulphonate (124) which yields the cage-like structure (125; X = 0) (70-80°/0).'43 Sulphur and nitrogen analogues (125; X = S or NH) are formed if NaSH and NH3 respectively are used in place of NaOH. Me Me I / 0 c>o FS020-Me X Me (1 24) (125) The first example of the participation of the base DBN (diazabicyclononene) as a nucleophile has been rep0~ted.l~~ Formation of o-amino-benzamides and -benzanilides by ring-opening of isatoic anhydride with an appropriate base can be a troublesome procedure.However it has now been claimed145 that high and consistent yields of amino-amides are 142 T. Tsuchiya J. Kurita and K. Ogawa J.C.S. Chem. Cumm. 1976 250. 143 G. W. Reader and J. Rokach Tetrahedron Letters 1976,17. 144 D. C. Palmer and M. J. Strauss TetrahedronLetters 1976 1431. 145 C. H. Foster and E. V. Elam J. Org. Chem. 1976,41,2646. Heterocyclic Chemistry obtained if the reaction is carried out in DMF this process being the first step in a new one-pot synthesis of biologically active 4-aminoquinazolines. Formation of quinazolinones from benzo-3,l-oxazin-4-ones, e.g.(126) and amines is well estab- lished and has long been thought to involve o-acylamido-anilide intermediates e.g. (127). Recent ~tudies,~~~~,~ however have shown that initial nucleophilic attack takes place at the carboimino centre i.e. C-2 giving N-arylamidine (128) rather than at C-4 as was previously supposed. Me A new pteridine synthesis has been claimed for the reaction of 6-amino-5- nitrosouracils with phenacylidene triphenylphosphoranes (RCOCH=PPh,) (Scheme 30).“’ Scheme 30 Aza-heterocycles particularly quinazoline in the presence of trifluoroacetic acid behave as electrophilic heteroarylating agents (4-position) towards ‘activated’ sub- strates e.g. resorcinol indole thiophen anthracene and other polycyclic aromatic hydrocarbons.14* ANRORC reactions149 continue to be exploited 150a3b as do other novel reactions of aza-heterocycles in liquid ammonia.15oc For example the tele -substitution of 1,7-naphthyridine (Scheme 3l).151 A unique cyclization of a diazonium cation onto an ortho-cyano-group to yield benzothieno[3,2-d]-vic -triazine (130) (77%) has been observed during normal diazotization of amino-nitrile (129).15*The tentative suggestion has been made that stabilization by sulphur of an as yet undefined intermediate may be responsible for cyclization since the benzorblfuran analogue and o-aminobenzonitrile fail to undergo analogous cyclization.146 (a)L. A. Errede J. Org. Chem. 1976,41,1763; (b)L. A. Errede J. J. McBrady and H. T. Oien ibid. p. 1765. 14’ K. Senga H. Kanazawa and S.Nishigaki,J.C.S. Chem.Comm. 1976 588. 148 W. Girke Tetrahedron Letters 1976,3557. 149 Ann. Reports (B),1974,71 347; ibid. 1975,72 275. (a) G. Simig H. C.van der Plas and C. A. Landheer Rec. Trau. chim. 1976,95 113; (b)G. Simig and H. C. van der Plas ibid. p. 125; (c)A. Nagel and H. C. van der Plas Chem. and Phmm. Bull. (Jupun) 1975,23,2678. lS1 H. C. van der Plas M. Woznick and A. van Veldhuizen Tetrahedron Letters 1976 2087. lS2 J. R. Beck and J. A. Yahner J. Org. Chem. 1976,41,1733. 0.Meth -Cohn and R.K. Smalley 7N mH "".bP N\ N -N NH N NH C! CI C1 H 1 J NH Scheme 31 (129) (130) The oxyallyl zwitterion (13 l) obtained on photolysis of 3,5-dimethyl-y-pyrone in 2,2,2-trifluoroethanol can be trapped as the furan adduct (132).153u Alternatively (131)can undergo nucleopbilic substitution by solvent to give (133) or can rearrange to 3,6-dimethyl-a! -pyrone.The photochemical conversion of 4-hydroxy-3,5-dimethylpyrylium in concentrated sulphuric acid into the 2-hydroxy-3,6- dimethyl isomer has been shown to involve the cyclic sulphate intermediate (134). 536 MebMe qp OCH,CF 0 Me Mea>S02 0 Me OH I 0 (131) (132) (133) (134) There is continuing interest in the photochemistry of enol tautomers and besides the full report on the photoisomerism of 3-substituted isochr~manones,'~~~ mentioned last year,lS4* this year has been a similar study on 4-substituted-3- chromanones. Diels-Alder cycloaddition of a-pyrans has been achieved for the first time and unlike the behaviour of reactions with a!-pyrones a high degree of regiospecificity is ob~erved."~ The process is useful in that it provides a new aryl annelation method.153 J. A.Barltrop A. C. Day and C. J. Samuel J.C.S. Chem. Comm. 1976 (a)p. 822;(b)p. 823. 1s (a)Ann. Reports (b) 1975,72,273;(b)ibid. p. 276. 155 (a)A. Padwa and A. Au J. Amer. Gem. Soc.,1976,98,5581; (b)A.Padwa A. Au G. A. Lee and W. Owens ibid. p. 3555. 156 R. G. Salomon J. R. Burns and W. J. Dominic J. Org. Gem. 1976,41,2918. Heterocyclic Chemistry p -Arylacrylates e.g. (139 undergo photoisomerism to the cis-isomer followed by photo-cycloelimination of chlorine to give coumarins e.g. (136).”’ The reaction which apparently proceeds viu the singlet state is useful but limited in that two ortho-substituents one of which must be chlorine are required for coumarin formation.R R 0 &co2R Me \ a.@=”” CO,Et (135) (137) A single-stage high-yield synthesis of chromones (Scheme 32),lS8 and a novel transformation of chromene-3-aldehyde (in the presence of ethyl acetoacetate and ethanolic piperidine) to the o-hydroxybenzophenone (1 37)159 have been announced. CH2R2 i DMF BF3 EtzO HO HO Scheme 32 Unlike anthracene and higher members of the acene series naphthalene shows little tendency to form the 1,4-endo-peroxide (140) with singlet oxygen. However (140) is now obtainable’60 from 1,6-imino-[ 10)annulene (138) viu the nitroso- compound (139; R = NO) as shown in Scheme 33. N N H R Moderate yields of xanthones thioxanthones and acridones (142; X = 0,S or NH) are formed in the photo-Friedel-Craf ts reaction of the corresponding thio-esters (141).16’ R.Arad-Yellin B. S. Green and K. A. Muszkat,J.C.S. Gem. Comm. 1976 14. ISB R. J. Bass,J.C.S. Chem. Comm. 1976 78. Is9 W. D. Jones and W. L. Albrecht J. Org. Chem.,1976,41 706. I6O M. Schafer-Ridder U. Brocker and E. Vogel Angew. Gem. Internat. Edn. 1976,15,228. J. Martens K. Praefcke and U. Schulze Synthesis 1976 532. 0.Meth-Cohn and R.K.Smalky 0 XAr (141) (142) Practicable yields of acridones are also obtainable by a new base-promoted (NaH) intramolecular cyclization of 2-amino-2'-methoxybenzophenonesin dimethyl sul- phoxide.16* Heterodienes of type X=CHCH=Y (X =0,Y =NR) rarely undergo (4 +2) cycloadditions with alkenes and alkynes.Of interest therefore is the cycloaddition of the bis-copper(I1) complex (143) with DMAD to give 1,4-benzoxazine (144).'63 Cycloaddition is not observed with o-benzoquinone-rnonoxime and it is thought that the copper not only helps to polarize electron density towards the termini of the heterodiene system but also creates a favourable reaction template. A new simple to 2H-1,3-benzothiadiazines(145) involves heating a mixture of thiophenol formaldehyde and amide (RCONH,) in pyridine and phos- phorus oxychloride. (143) (144) E =COzMe (145) 1,3-Oxazin-6-ones (147) are formed by thermal (300 "C) rearrangement accom- panied by loss of CO and EtOH of 2-oxazolin-5-ones (146; R2=C02Et).'"'" In contrast the allyloxazolinones (146; R2=CH=CH,) at 230 "C undergo rearrange- ment with loss of C02to yield 2,Sdisubstituted pyridines.16" 2H-1,3-0xazin-2-ones (149) a new heterocyclic system result from the spon- taneous electrocyclic ring-closure of p -carbamoyl isocyanates (148) the latter being obtained by Curtius rearrangement of the corresponding acid azide.166 16'bromomethylsaccharin derivatives (Scheme 34).ofring-expansion Ph Ph (146) (147) (148) (149) 1,2-Benzothiazin-4(3H)-one1,l-dioxides (1 50) arise from a novel base-induced 162 J. H. Adam P. Gupta M. S. Khan J. R. Lewis and R. A. Watt J.C.S. Perkin I 1976 2089. 163 A. McKillop and T. S. B. Sayer J. Org. Chem. 1976,41 1079. I64 J. Szabo L. Fodor I. Varga and P. Sohar Acru aim.Acud. Sci. Hung. 1976,88 149. lbS (a) S. Gotze and W. Steglich Chem.Ber. 1976,109,2327; (b)S. Gotze,B. Kubel and W. Steglich ibid. p. 2331. 166 A. E. Baydar and G. V. Boyd J.C.S. Chem. Comm. 1976,718. 167 R.A. Abramovitch K. M. More I. Shinkai and P. Srinivasan,J.C.S. Chem. Comm. 1976 771. Heterocyclic Chemistry 269 Scheme 34 1,4,5,8-TetrathiatetraIin(15 l) which is isomeric with tetrathiafulvene a valuable n-donor in organometal systems,'68a'b has been synthesized (Scheme 35),16' but (45%) (37%) (151) Scheme 35 shows little potential as a conducting system since it is not easily oxidized to a charge-transfer complex by tetracyanoquinodimethane. Compound (15 1) is poten- tially a 14n aromatic system but exhibits only alkene absorptions in its 'Hn.m.r.spectrum suggesting a non-planar ring system such as prevails in the parent p-dithiin. Quantitative annelation of dihydro- 1,4-dithiins is possible e.g. (152)+(153) by oxidation with peroxy-acid (MCPBA) of the spiro-1,3-dithiolan (152) followed by acid-catalysed ring-expansion of the resulting S-mon~xide.'~~ Reaction is successful for n =4,5,6,11 or 14 but fails for n =3. Several heterocyclic systems involving the less-common elements have been synthesized this year including the previously unknown 1,3-selenazinium salts (1 54) prepared from selenoureas and fl -chloropropenylidene immonium salts (C1C=CCH=N-),l7' and the diphosphabenzene (155).17* 168 (4)Ann. Reports (B), 1974,71 340; (6) ibid. p 267. 169 M. Mizuno M.P. Cava and A. F. Garito J. Org. Chem. 1976,41 1484. 170 C. H. Chen and B. A. Donatelli J. Org. Chem. 1976,41 3053. 171 J. Liebscher and H. Hartmann TetrahedronLetters 1976,2005. Y. Kobayashi I. Kurnadaki H. Ohsawa and H. Hamana TetrahedronLetters 1976,3715. 0.Meth -Cohn and R. K. Smalley F3cxp1cF3 F,C P CF3 c104-(154) (155) Bismabenzene (156) a system hitherto'73" known only as a 'trappable' reaction intermediate (with hexafluorobutyne) has now been synthesized (Scheme 36) although only as a transient and its 'H n.m.r. spectrum re~0rded.l~~~ I CI (156) DBU =diazabicycloundecene Scheme 36 6 Seven-membered Ring Compounds Chlorosulphonyl isocyanate reacts with homoconjugated olefins e.g. (157) (Scheme 37) to give hydroazepinones possibly in a stepwise manner.174 A new approach to arylnitrenes by thermolysis of NO-bis(trimethylsily1) phenylhydroxylamine gives almost quantitative yields of 3H-azepines when conducted in the presence of an amine (Scheme 38).17' Scheme 38 173 (a) A.J. Ashe and M. D. Gordon J. Amer. Chem. Soc. 1972,94,7596; (6)A. J. Ashe Tetrahedron Letters 1976,415. 174 S. Sarel A. Felzenstein and J. Yovell Tetrahedron Letters 1976,451. 1's F. P. Tsui Y. H. Chang,T. M. Vogel and G. Zon J. Org. Chem. 1976,41 3381. Heterocyclic Chemistry 271 Another interesting synthesis (Scheme 39) uses the phenol oxidative dimers (158) which react with primary amines to produce azepinones in high yield. The latter undergo further useful cyclizations on oxidation or irradiati~n.'~~ '$R3y c:R3 R@NHR3+ R' I--Ar R2 --0 R1 R2 Ar R2 (158) Scheme 39 In 1974 we reported the remarkable photocyclization of the N-chloroacetyl derivative of rn -methoxyphenethylamine attack occurring either ortho to the side- chain or on the methoxy-group depending upon the s01vent.l~~ The same workers 2,4-17'examined the reaction using the corresponding o-methoxy- have now dime t hoxy -,"'2,5 -dimet hoxy- and m -and p-dimethylamino-analogues,'sOwith fascinating results (Schemes 40 and 4 1).The reactions demonstrate how delicately dependent many reactions are on small changes in electronic steric and solvent effects and other reaction parameters. 1,2-Diazepines (160) have been isolated by thermolysis of a 1,5-diazabicycIo[3,3,0]octen-2-ene (159),*'l and a related photo-reversion (161)+(162) has been reported.'82 The product (163) from cycloaddition of a cyclopropene to a 1,2,4,5-tetrazine undergoes thermal or photo-electrocyclic ring expansion to a 1,2-diazepine (164) which on longer irradiation is successively Scheme 40 H.-D.Becker and K. Gustafsson Tetrahedron Letters 1976 1705. 177 Ann. Reports (B).1974,71,354. 178 Y. Okuno and 0.Yonernitsu Heterocycles 1976 4 1371. 179 Y. Okuno M. Kawarnori,K. Hirao and 0.Yonernitsu G'hem. and Pham. Bull. (Japan),1975,2584. lB0 N. Nurnao and 0.Yonemitsu Heterocycles 1976,4,1095. K. Burger and H. Schickaneder Tetrahedron Lttters 1976,4255. 182 C. D. Anderson J. T. Sharp E. Stefaniuk and R. S. Strathdee Tetrahedron Letters 1976 305.0.Meth -Cohn and R. K. Smalley 8\ 3-NMe2 Me2NpTH 4\ ' hu 5 COCH zC1 CI -NH b4+41 + 0 (original benzenoid rings are bold) Scheme 41 (159) (160) (161) (162) converted into a diazabicycloheptadiene and finally into a 1,4-diazepine (as exem- plified in Scheme 42).lg3 A supposed 1,4-benzodiazepinone (165) prepared by successive treatment of anthranilic acid with chloral phenylhydrazine and acetic anhydride has been shown to be an oxazinone (166) thus requiring each of the intermediates also to be reformulated. lg4 sym-Oxepin oxide (167) has been made in high yield and 'Hn.m.r. studies indicate its degeneracy."' The benzoxepin valence tautomer (169) has been made by brief treatment of the dibromocarbene adduct (168) with butyl-lithium.Aswith the sulphur analogue,lS6 it reverts to benzoxepin on treatment with transition-metal catalysts and gives the fused benzofuran (170) on thermolysis probably by way of the oxepin. **' Benzoxepinones are conveniently available by treatment of 2-acylaryl H. Kolbinger G. Reissenweber and J. Sauer Tetrahedron Letters 1976,4321. N.W.Gilman J. F. Blount and R. I. Fryer J. Org. Chem. 1976,41 737. ls5 W. H. Rastetter J. Amer. Gem. SOC.,1976,98 6350. IS6 Ann. Reports (B), 1974,71 353. M. Uyegaki S. Ito Y. Sugihara and I. Murata Tetrahedron Letters 1976,4473. Heterocyclic Chemistry y$ph N Aorhv* walk Ph Ph . Scheme 42 f 0t-O& 25°C 0 0 274 0.Meth -Cohn and R. K. Smalley propargyl ethers with base (Scheme 43).Further base treatment causes the products to ring-contract giving finally in suitable cases (R2=H) naphthoquinones.188A related high-yield bpproach giving 3-hydroxy-2,3,4,5-tetrahydro-1-benzoxepins derives from the action of the same base on o-hydroxyphenethyl alkyl ketones whereby a dimethylsulphoxonium methylide carbon is incorporated into the ring.189 NaH ~ DMSO R,& \ 0 R2 R2 0 Scheme 43 Unlike 1-benzoxepin mentioned above 1-benzothiepin collapses to naphthalene with extrusion of sulphur at ambient temperature.186 However by X-ray structure analysis at -140°C the hetero-ring has now been shown to take up a boat conformation thus diminishing anti-aromatic delocalization.lgO The potentially low dithiepin anion (171) is a deep-red compound with n.m.r.chemical shifts of uncertain significance as to its aromaticity. The high-field absorption of the proton at position 2 is suggested to be due to involvement of d-orbitals conferring planarity and thus aromaticity on the ring.lgl However the reporters feel that a localized C-2 anion is equally likely. The dibenzodiazocine (172) has sufficient conformational stability (=154 kJ mol-' racemization barrier) to allow resolution of its derivatives (e.g. -4.20 7 (171) (172) X =CHO).19* The arsatranes (173) easily made from diethanolamines and bis(dimethylamino)arsines,have been shown by X-ray analysis to exist in the N-As IE8 M. Jackson-Mully,J. Zsindely and H. Schmid Helv. Chim. Acta 1976 59,664.la9 P. Bravo C. Tiwzzi and D. Ma& J.C.S. Chem. Comm. 1976 789. 190 N. Yasuoka Y. Kai N. Kasai T. Tatsuoka and 1. Murata,Angew. Gem. Internat. Edn. 1976,15,297. 191 C. L. Semmelhack I.-C. Chiu and K. G. Grohmann Tetrahedron Letters 1976 1251. j9* D. OlliCro J. M. Ruxer A. Solladit-Cavallo and G. SolladiC J.C.S. Chem. Comm. 1976 276. Heterocyclic Chemistry 275 bonded tonformation shown in which the oxygens are n~n-linear.'~~ Related silicon derivatives,e.g. (174) have been made from trialkanolamines and orthosilicate~.'~~ (173) (174) ha-and oxa-[l3]annulenes (175) and (176) have been ingeniously prepared (Scheme 44) by the action of ethoxycarbonylnitrene or epoxidation of a cyclo-octatetraene derivative. Low-temperature photolysis of these precursors gives heteroannulenes of uncertain configuration which may be hydrolysed as shown.lg5 (175) X = NC02Et (176)X=O Scheme 44 The presence of polystyrene beads has a surprisingly useful effect on the Iactoniza- tion of long-chain o-hydroxycarboxylic acids with boron trifluoride etherate giving 41-78% yields with the series containing 13-19 carbon^.''^ Corey's excellent 193 P. Maroni M. Holernan J. G. Wolf L. Ricard and J. Fischer TetrahedronL.et&rs. 1976 1193. 19* E. Lukevits I. I. Solomennikova and G. I. Zelchan Zhur. obshchei. Khim. 1976,46134. Ig5 (a)G. Frank and G. Schroder Chem. Ber. 1975,108,3736; (6) W. Henne G.Plinke and G.Schroder ibid. p. 3753. L. T. Scott and J. 0.Naples Synthesis 1976,738. 0.Meth-Cohn and R.K. Smalley 'double activation' method'97 for the synthesis of macrocyclic lactones by cyclization of w -hydroxycarboxylic acids by way of their 2-pyridyl thioesters has been shown to follow the appended mechanism (Scheme 45),198 and 2,2'-bis-(4-t-butyl-l-isopropylimidazolyl) disulphide has proved to be the substrate of choice for this reaction being 100 times more effective than 2-pyridyl disulphide. 199 Scheme 45 Two non-high-dilution methods for the synthesis of 'crown' amines have been reported one using tosylamides and tosyl esters as the two reactants2" and the other employing (YO-diamines and aw -diesters.201The use of chiral crown ethers for the resolution of amino-acids and their esters continues to make dramatic reading."* Other useful complexing agents include the water-soluble crown sulpho~ides~'~ and bridged mono- di- and tri-meric benzimidaz~lones.~'~ One such example (177) is specific for calcium ions.7 Reviews The synthetic application of 2-0xazolines,~'~ six-membered heteroaromatic betaines,206crown and benzofuroxans (for heteroaromatic N-oxide synth- esis)208 have been reviewed and routes to p -lactam~,~'~ tetrathia- and tetraselena- 19' Ann. Reports (B),1974,71 444. 198 E. J. Corey D. J. Brunelle and P. J. Stork Tetrahedron Letters 1976 3405. 199 E. J. Corey D. J. Brunelle and P. J. Stork Tetrahedron Letters 1976 3409. W. Rasshofer W. Wehner and F. Vogtle Annalen 1976,916. 201 I. Tabushi H.Okino and Y. Kuroda Tetrahedron Letters 1976,4339. 202 S.C. Peacock and D. J. Cram J.C.S. Gem Comm. 1976 282. 203 E. Weber and F. Vogtle Annalen 1976 891. 2oa M. M. Htay and 0.Meth-Cohn Tetrahedron Letters 1976 79,469. 205 A. I. Meyers and E. D. Mihelich Angew. Chem. Internat. Edn. 1976,15,270. =06 N. Dennis A. R. Katritzky and Y. Takeuchi Angew. Chem. Internat. Edn. 1976,15 1. 207 G. W. Gokel and H. D. Durst Synthesis 1976 168. 208 M. J. Haddadin and C. H. Issidorides Heterocycles 1976,4 767. 209 N. S. Isaacs Chem. Soc. Reu. 1976,5 181. Heterocyclic Chemistry 277 fu1valenes,210- pyrroles and pyrrolenines,2’ ’ indolizines,212 and pyridines and ~ligopyridines~’~ have been appraised. The conformational analysis of 1,3-dioxans214 and geometry of 4-ylideneo~azolones~~~ have been evaluated.Reviews have appeared of the chemistry of azirines arene thiirans,2’8 p-lactam antibi~tics,~” 1,2,4-0xadiazoles,~~~ meso-ionic com-pounds,221 1,2,3,4-thiatriazole~,~~~ thienothiophen~,~~~ condensed tetrazole~,~’~ 1,2,3- tria~ines,~” 1,2-diazepine~,~~~ unsaturated lac tone^,^^' and cycloimmonium ylides.228 Other subjects that have been collated include the utility of heterocyclic diazo-compo~nds~~~ and bis-Wittig in synthesis and the rearrangement of heteroaromatic N-oxides to accomplish aromatic the nomencla- ture of the application of the Hammett equation to heterocyclic and the role of covalent hydration in nitrogen The photochemistry of heteroaromatic N-oxide~,’~~ and the synthesis of heterocycles through nucleophilic additions to acetylenic as well as cycloadditions of azines and anil~,~~~ of the intramolecular 1,3-dipolar type,238 and of azomethine carbonyl and thiocarbonyl ylide~,’~~ have been examined.210 M. Narita and C. U. Pittman jun. Synthesis 1976,489. 211 J. M. Patterson Synthesis 1976 281. 212 T. Uchida and K. Matsumoto Synthesis 1976 209. 213 F. Krohnke Synthesis 1976 1. 214 M. J. 0.Anteunis D. Tavernier and F. Borremans Heterocycles 1976,4,293. 215 Y. S. Rao and R. Filler Synthesis 1975 749. 216 A. Padwa Accounts Chem. Res. 1976,9,371. 217 T. C. Bruice and P. Y. Bruice Accounts Chem. Res. 1976,9,378. 218 A. V. Fokhin and A. F. Kolomiets Rws. Chem. Rev. 1976,45 25. 219 P. G. Sammes am. Rev. 1976.76 113. 220 L. B. Clapp Ado. Heterocyclic Chem. 1976,20 66. 221 W.D.Ollis and C. A. Ramsden Adv. Heterocyclic Chem. 1976,19,3. 222 A. Holm Adv. Heterocyclic Chem. 1976,20 145. 223 V. Ya. Pochinok L. F. Avramenko T. F. Grigorenko and V. N. Skopenko Russ. Chem. Rev. 1976,45 183. 224 V. P. Litvinov and Ya. L. Goldfarb Adv. Heterocyclic Chem. 1976,19 124. 225 R. J. Kobylecki and A. McKillop Ado. Hefermyclic Chem. 1976 19 216. 226 M.Nastasi Heterocycles 1976,4 1509. 227 Y. S. Rao Chem. Rev. 1976,76,625. z28 G.Surpateanu,J. P. Catteau P. Karafiloglou and A. Lablache-Combier Tetrahedron 1976,32,2647. 229 M. Tisler and B. Stanovnik Heterocycles 1976,4 1115. 230 K.P. C. Vollhardt Synthesis 1975 765. 231 R. A. Abramovitch and I. Shinkai Accounts Chem. Res. 1976 9 192. 232 A. D. McNaught Adv. Heterocyclic Chem. 1976,20 176.233 P. Tomasik and C. D. Johnson Adv. Heterocyclic Chem. 1976,20 1. 234 A. Albert Adv. Heterocyclic Chem. 1976 20 117. 235 F. Bellamy and J. Streith Heterocycles 1976,4 1391. 236 M. V. George S.K. Khetan and R. K.Gupta Adv. Heterocyclic Chem. 1976 19 279. 237 T. Wagner-Jauregg Synthesis 1976,349. 238 A. Padwa Angew. Chem. Internat. Edn. 1976,15 123. 239 R. M. Kellogg Terrahedron,1976 32 2165.

ISSN:0069-3030    

DOI:10.1039/OC9767300239

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

12 Alicyclic Chernistry ByA. COX Department of Molecular Sciences Universityof Warwick Coventry8 CV4 7AL 1Introduction This year has seen the publication of a further volume of ‘Organic Syntheses’’ and also the Cumulative Indices2 to Collective Volumes 1-5. A survey of the 1974 literature on mechanisms has appeared3 as has another volume4 of ‘Organic Reac- tions’ together with several supplements to R~dd.~ Reviews have been published on the chemistry of rings of various sizes,6 bridgehead carbonium ions,7 bridgehead olefins’ and the chemistry of the prostaglandins.’ Finally a set of rules have been announced” which predict the relative ease of ring formation. 2 Synthesis Three- and Four-membered Rings.-A number of syntheses of cyclopropanes by routes involving carbenes have appeared.In particular it has been found” that reaction of olefins with organic gem-dihalides and copper proceeds smoothly at moderate temperature to give cyclopropanes in good yields. The cis-isomer is obtained predominantly from terminal olefins such as hex-1-ene. gem-Difluorocyclopropanes are formed’* in high yields from chlorodifluoromethane alkanolate ions and reactive alkenes provided that the concentration of alkanolate is small. Alkanolates of the necessary small concentration are found in a solution of halide ions in epoxides such as oxiran and (chloromethy1)oxiran. The first successful cyclopropanations using zinc chloride-catalysed decompositions of diphenyl-diazomethane have been rep~rted.’~ Conjugated dienes and electron-rich olefins 1 ‘Organic Syntheses’ ed.S. Masamune Wiley New York 1976 Vol. 55. 2 ‘Organic Syntheses Collective Volumes 1-5 Cumulative Indices’ Wiley New York 1976. 3 ‘Organic Reaction Mechanisms’ ed. A. R. Butler and M. J. Perkins Interscience London 1974. 4 ‘Organic Reactions’ Wiley New York 1976 Vol. 23. 5 Rodd’s Chemistry of Carbon Compounds 2 Supplements A B C D and E Elsevier Amsterdam 1974. 6 (a)S. A. Math. in ‘Alicyclic Chemistry’ ed. W. Parker (Specialist Periodical Reports) The Chemical Society London 1976 Vol. 4 p. 1; (6)D. G. Morris ibid. p. 196; (c) E. J. Thomas ibid. p. 278. 7 J. Carnduff in ‘Alicyclic Chemistry’ ed. W. Parker (Specialist Periodical Reports) The Chemical Society London 1976 Vol. 4 p. 345. 8 R. Keese Angew.Chem.1975,87 568. 9 G.Pattenden in ‘Aliphatic Chemistry’ ed. A. McKillop (Specialist Periodical Reports) The Chemical Society London 1976 Vol. 4 p. 243. 10 J. E. Baldwin J.C.S. Chem. Comm. 1976 734 736 738. 11 N. Kawabata M. Naka and S. Yamashita J. Amer. Chem. SOC.,1976,98 2676. 12 M. Kamel W. Kimpenhaus and J. Buddrus Chem. Ber. 1976,109,2351. 13 D. S. Crumrine T. J. Haberkamp and D. J. Suther J. Org. Chem. 1975,40,2274. 279 280 A. Cox were found to be good substrates and the relatively high yields ease of isolation and ease of scaling-up compared with the carbene route make this the preferred method for synthesizing 6,6-diarylbicyclo[ 3,l ,O]hex-2-enes. Mechanistic studies suggest that the results are best explained by a diphenylcarbenoid intermediate which reacts competitively with the olefin to produce the cyclopropane product.A series of papers on various aspects of metal salt-catalysed synthesis of carbenoids has appeared.I4 The synthesis and some chemistry of perfluorohexamethylbicyclo-propenyl the final member of the first complete set of benzene valence isomers has been described." The synthetic strategy (Scheme 1)entailed coupling of a suitably F3cbCF3 I ,Iv Reagents i OC1- C1- DMSO H20; ii F~CCEZCCF,,A; iii NaI MeCN; iv hv Hg. Scheme 1 functionalized perfluoro- 1,2,3-trimethylcyclopropene, prepared in turn via addition of a carbene to perfluorobut-2-yne. The thermal stability of perfluorohexamethyl- bicyclopropenyl is remarkable in that it aromatizes cleanly with 2h at 360 "C.Hence the thermodynamically least-stable member of the valence isomer set is by a wide margin the most stable kinetically. The Favorskii-type reaction of 2-dialkylamino-3-halogenocycloalkenes,which provides an elegant entry into bicy- clopropane chemistry has now been extended16 to the synthesis of simpler systems. For example when enamine (l),AgBF4 and dimethylamine react in a 1 1 2 molar ratio in ether the bisamine (2) is formed almost quantitatively. Me AgBFq c MezNH CH2Cl2 ' Me2NGz2 Me 20% Me (1) (2) The first light-induced cyclization of allylmagnesium halides to cyclopropylmag-nesium halides has been rep~rted.'~ This transformation which proceeds in good 14 (a)D. S. Wulfman Tetrahedron,1976,32 1231; (6)D. S. Wulfman R.S. McDaniel and B. W. Peace ibid.,p. 1241; (c) D. S. Wulfman B. W. Peace and R. S. McDaniel ibid. p. 1251; (d)D.S. Wulfman B. G. McGibboney E. K. Steffen N. V. Thinh R. S. McDaniel and B. W. Peace ibid.,p. 1257. 15 M. W. Grayston and D. M. Lemal J. Amer. Chem. SOC.,1976,98,1278. 16 E. Jongejan H. Steinberg and Th. J. de Boer Tetrahedron Leffers 1976 397. 17 S. Cohen and A. Yogev J. Amer. Chem. SOC.,1976,98,2013. Alicyclic Chemistry 28 1 yield is of interest because since allylmagnesium halides are known to exist in solution as aggregates of tight anion-cation pairs the reaction formally amounts to a light-induced interconversion of ally1 carbanions into cyclopropanyl carbanions. Although the degree of selectivity could not be established theoretical considera- tions suggest a disrotatory course for the transformation.A number of new substituted cyclopropanes have been prepared'* by trapping various metallated alkyl-substituted cyclopropanes. Although a recent p~blication'~ indicates that iodocyclopropenes are expected to be very unstable this year has brought2' the syntheses of l-chloro-2-iodo-3,3-difluorocyclopropeneand of 1,2-di-iodo-3,3-difluorocyclopropene. The interest in these compounds stems from their potential use in copper coupling reactions. These studies are still in progress. A method of cyclization of dienes based on the silver-ion-induced oxidation of organoboranes has been reported (Scheme 2).21 For example 2,3-dimethylbuta- R3B [R-Ag] -B R' % R-R Scheme2 1,3-diene is cyclized to trans-dimethylcyclobutane in 79% yield on reaction of the diene with diborane followed by alkaline AgNO,.The transformation has been shown to be applicable up to eight-membered rings. A typical procedure is given. Reactions of anhydrous hydrogen chloride with mixtures of propyne and but- 1-yne and of propyne and pent-1-yne produce22 the corresponding 1,3-dialkyl- 1,3- dichlorocyclobutane cross-cyclization products together with the addition and cy- clodimerization products of the individual acetylenes. The amounts of the total (i.e. homo-and cross-)cyclization products range from 9 to 35%. 1,l-Dipyrrolidinocyclopropanes are known to react with ketones to form addition products. It has now been that these aminals undergo ready alkylation with nitromethane and the reduction products of this process yield primary amines which may serve as substrates for the Tiff eneau-Demjanov ring enlargement forming fused-ring cyclobutanones (Scheme 3).A new and general method for the synthesis a,n=l b,n=O a n =l;X= N3 b,n=O;X=N Scheme3 18 D. Bauer and G. Kobrich Chem. Ber. 1976,109,2185. l9 D. C. F. Law S. W. Tobey and R. West J. Org. Chem. 1973,38,768. 20 J. Sepiol and R. L. Soulen J. Org. Chem. 1975,40 3791. 21 R. Murphy and R. H. Prager Tetrahedron Letters 1976,463. 22 K. Griesbaum and W. Seiter J. Org. Chem. 1976 41 937. 23 H. H. Wasserman M. J. Hearn B. Haveaux and M. Thyes J. Org. Chem. 1976,41 153. 282 A. Cox of 1-substituted cyclobutenes has been described24 and its utility illustrated by synthesis of a natural product.The method (Scheme 4) involves metallation of RLi +El fE + TMEDA Scheme 4 methylenecyclobutane followed by reaction with electrophiles of the ambident anion sogenerated. Suitable variation of the reaction parameters make it possible to adjust the regiomer ratio from 0 100 to 61 :39 in favour of the desired product. A high yield synthetic procedure (Scheme 5) has now been announcedz5 leading to ben- a; R1=OMe; R2=H b; R' =R2= OMe c; R' R2 = OCHzO Scheme 5 zocyclobutene itself and also to the same system bearing oxygen substituents on the aryl ring. The experimental procedure involves sublimation of isochromanones in a stream of nitrogen at 3 Torr over a nichrome wire at 500°C and collection of the pyrolysate in a cold trap at -78°C.The intramolecular reductive coupling of 1,4-dicarbonyl compounds using TiC1,-LiAlH forms the basis of a one-step prep- aration of 1,2-diphenylcyclob~tene.~~ This transformation which proceeds in -50% yield can also be adapted to the synthesis of 1,2-diphenylcyclohexene from a 1,6-dicarbonyl compound. A synthesis of the short-lived tetrafluorocyclobutadiene has been Irradiation of tetrafluorocyclobutene-3,4-dicarboxylic anhy-dride at 253.7 nm in the presence of -100 m mol of furan yielded in addition to octafluorocyclo-octatetraene a compound having the composition of a 1:1adduct of furan with tetrafluorocyclobutadiene. These observations are summarized in Scheme 6. Five- Six- Seven- and Eight-membered Rings.-A method of cyclopentanone formation using the recently developed reagent 1-1ithiocyclopropyl phenyl sulphide has been reported.'* The overall transformation which proceeds with high stereoselectivity is illustrated in Scheme 7.Closely related is the cyclopentane annelation represented in Scheme 8 and brought about under the agency of lithium phenylthio(~yclopropy1)cuprate.~~ 24 S. R. Wilson and L. R. Phillips Tetrahedron Letters 1975 3047. 25 R. J. Spangler and B. G. Beckmann Tetrahedron Letters 1976 2517. z6 A. L. Baumstark E. J. H. Bechara and M. J. Semigran Tetrahedron Letters 1976 3265. M. J. Gerace D. M. Lemal and H. Erti J. Amer. Chem. SOC.,1975,97,5584. 28 B. M. Trost and D. E. Keeley J. Amer. Chem. Soc. 1976,98 248. 29 E. Piers C.K. Lau,and I. Nagakura Tetrahedron Letters 1976 3233. 2' Alicyclic Chemistry ‘0 1 “qa* co’‘irionrJ 1 F8 FF FF Scbeme 6 Reagent i PhS Scbeme7 Reagent i LiCu+PhS q)2 Scbemell The stoicheiometric reaction of dialkyl- or diaryl-acetylenes with tetracarbonyl- nickel in the presence of HCI aff ords3’ tetrasubstituted cyclopentenones in yields ranging from 25-70%. A dependence of cyclopentenone formation on acidity has been found and a mechanism suggested to account for this. The thiazolium ion- catalysed dimerization of aldehydes to acyloins has been used3’ to cyclize pentane- dials and hexanediols in the presence of triethylamine using acetonitrile as solvent. Oxidation gives 2-hydroxy-2-enones several of which are important flavouring materials.30 W. Best B.Fell and G. Schmitt Chem. Ber. 1976 109 2914. 3l R. C. Cookson and R. M. Lane J.C.S. Chem. Comm. 1976,804. 284 A. Cox A preliminary report3* shows that the reaction of P-iodo-cY,&unsaturated ketones with lithium phenylthio(2-vinylcyclopropyl)cuprate followed by thermal rearrange- ment of the resulting ~-(2-vinylcyclopropyl)enones,provides a short efficient synthesis of cycloheptatriene systems. This conversion (Scheme 9) constitutes a \ A I Scheme 9 seven-membered ring annelation. The synthesis and properties of 2-hydroxycyclo-octa-2,4,6-trienone(3) and 2-hydroxycyclo-octa-2,4,7-trienone(4) have been It is concluded that (3)seems to have some 7r-interaction and hence may be called a 1,7-7r-homotropolone and similarly that (4)has some homoconjugation and likewise may be called a 5,7-7r-homotropolone.8x5 \/ (3) (4) Medium and Large Rings.-A new method has been for the preparation of medium-ring cycloalkynes. These compounds are strained and therefore excep- tionally reactive. Consequently mild conditions are demanded €or their synthesis. The reaction sequence is as outlined in Scheme 10. Reaction of the bicyclic system c"3 Br gg* OMe Me0 Scheme 10 (5) for 2 h with a slight excess of silver tosylate in refluxing acetonitrile has been found36 to be a highly stereoselective method of generating tosylated medium-sized rings in excellent yields. The interesting hydrocarbon cyclododeca- 1,5,9-triyne (6) has been ~ynthesized.~~ Although aspects of the electronic spectrum of (6)point to 32 E.Piers and 1. Nagakura Tetrahedron Leners 1976,3237. 33 Y. Kitahara M. Oda and S. Miyakoshi Tetrahedron Letters 1976,4141. 34 Y. Kitahara M. Oda S. Miyakoshi and S. Nakanishi Tetrahedron Letters 1976,4145. 35 C. B. Reese and A. Shaw J.C.S. Perkin I 1976,890. 36 H. J. J. Loozen W. M. M. Robben T. L. Richter and H. M. Buck J. Org. Chem. 1976.41.384. 37 A. J. Barkovich and K. P. C. Vollhardt J. Amer. Chem. SOC.,1976,98,2667. Alicyclic Chemistry 285 (5) n = 1,2,or3 effective interaction of the three acetylene groups proof of tlle triacetylene structure is provided by the i.r. spectrum and l3C-H coupling constant which appears normal for propargylic moieties. This rules out the possibility of structures such as (7a) and (7b).The 24-w-electron system 3,11,16,24-tetra-t-butyl-1,12-24-trisdehydro-0 Bra _.__I, 1.3Brz.CC14 2.3NaOEt. EtOH \ NaOMe-MeOH H20 I Br ve(/j$z (yj A 7 (7b) (74 (6) [24]annulene has been ~ynthesized.~~ Its n.m.r. spectrum clearly indicates it to be strongly paratropic and its essentially temperature-independent nature demon- strates it to have high conformational stability. A group of papers on the synthesis and properties of dehydroannulenes has also appea~ed.~’ Amongst the conclusions is that the tetramethyltetrakisdehydro[18lannulene (8) sustains a strong diamagnetic ring current and has high conformational stability. Me-Melil II Polycyclic Systems.-A communication has appeared4’ in which the first successful synthesis of a compound 1,2-diphenyltricyclo[2,2,0,02~5]hexan-2-ol (1l),containing S.Nakatsuji S. Akiyama and M. Nakagawa Tetrahedron Letters 1976 2623. 39 (a)T. Nomoto K. Fukui and M. Nakagawa Bull. Chem.Soc.Japan 1976,49,305; (b)T.Katakami K. Fukui T. Okamoto and M. Nakagawa ibid.,p. 297; (c)S. Tomita and M. Nakagawa,ibid.,p. 302; (d)J. Ojima T. Katakami G. Nakaminami and M. Nakagawa ibid. p. 292. 40 E. C. Alexander and J. Uliana J. Amer. Chem. SOC.,1976,98,4324. 286 A.Cox the hitherto unknown tricycl0[2,2,O,O~*~]hexane ring system is announced. The synthesis which proceeds in five stages from 2-phenylbicyclo[ 1,l,l]pentan-2-01 contains the interesting mandelate ester photodecarboxylation (9) -+ (10).The (9) Ph (1 1) syntheses of a number of monosubstituted and 1,4-disubstituted cubanes have been de~cribed,~' together with the measurement and analysis of their 100 MHz 'H n.m.r. spectra. Typical coupling constants observed are quoted and a simple additivity rule is described whereby chemical shifts in CDC13 can be predicted. The derived correlations allow quick and effective identification of cubane derivatives from their 'Hn.m.r. spectra and also aid in the interpretations of the more complex spectra of less symmetrical cage molecules. A second paper4* by the same authors reports that aromatic solvent-induced shifts have been measured for a number of substituted cubanes in benzene and pyridine and an additivity rule again derived which allows accurate prediction of these shifts.These arise from independent transient 1:1 associations of solvent molecules with the electron-deficient sites of all local dipoles in the solute. On exposure to n-butyl-lithium 1,2-di-iodoadamantane yields43 a highly reactive intermediate which can be intercepted in a Diels-Alder reaction with butadiene at -78 "Cand which in the absence of butadiene dimerizes spontaneously in a [2 + 21 fashion. This intermediate is believed to be adamantene the tricyclic analogue of trans-cyclohexene. As such it represents a much more extreme case of a highly inflexible system in which the opportunity for distributing the large angle strain over several bonds is at a minimum. Of the theoretically possible 2486 tetracycloun- decanes empirical force field calculations that 2,4-ethanonorademantane (13) and 2,8-ethanonoradamantane (14) should be the most stable and should have comparable stability.It has been found that AIBr rearrangement of tetracyclo[6,3,0,02*6,05~g]undecane (12) gives (13)and (14) in the ratio 97 :3,thus identifying (13)as the thermodynamically more stable isomer. A description of the synthesis of 3-oxobicyclo[3,3,l]nonan-6-ylmethyl methanesulphonate and its cycli- 41 J. T. Edward P. G. Farrell and G. E. Langford J. Amer. Chem. SOC.,1976,98,3075. 42 J. T.Edward P. G. Farrell. and G. E. Langford J. Amer. Chem. SOC.,1976,98,3085. 43 W.Burns D. Grant M. A. McKervey and G. Step J.C.S. Perkin Z,1976 234. 44 S.A.Godleski P. von R. Schleyer and E.Osawa J.C.S. Chem. Comm. 1976 38. Alicyclic Chemistry zation to twistan-4-one has been rep~rted.~’ This synthesis illustrates the remaining single -single bond process for constructing the twistane skeleton and along with the detailed analysis of the structure of twistane exemplifies the analytical approach to synthesis as expounded by Corey. Two papers have a~peared,~~.~’ which make contributions to the dodecahedrane skeleton as a synthetic goal. The first reports the synthesis of chiral triquinacene-2-carboxylic acid and (+)-2,3-dihydrotriquinacen-2-one (15) together with the first configurational assignments to members of the triquinacene family for which configurational assignments are available. The second paper reports conversion of hexahydrotriquinacen-2-one into the pentaseco- dodecahedrane (16)for which system the name ‘meso-bivalvane’ has been suggested.3 Stereochemistry A theoretical analysis has been of the effects of geometry optimization upon computed barriers to rotation and pyramidal inversion from which it appears that if AE is the true energy difference between the energy minimum and the transition state for a particular conformational process then (barrier using the optimized geometry of the lower state) >AE> (barrier using the optimized geometry of the higher state). The effect of carbonyl substitution on ring planarity and ring-puckering vibration has been analy~ed~~ for cyclobutane in terms of a one-dimensional potential model incorporating a ‘torsional strain’ parameter in addition to the contributions of ring angle deformations and unstrained torsions about the ring bonds.The potential constants determined indicate that the increased planarity is due mainly to reduction in torsional repulsion. An investigation has been undertaken” of the effect of the t-butyl group on the cyclopentane ring and values of Av(Av = v(OH)free-Y(OH)bnded) measured for a series of 1,2-disubstituted-4-t-butylcyclopentanes of structural type (17). Comparison of the Av values reveals a pronounced effect of the t-butyl group on the dihedral angle of the substituents in 45 D. P. G. Hamon and R. N. Young Austral. J. Chem. 1976 29 145. 46 L. A.Paquette W. B. Farnham and S. V. Ley J. Amer. Chem. SOC.,1976,97,7273. 47 L.A.Paquette I.Itoh and W. B. Farnham J. Amer. Chem. SOC.,1976,97 7280. 48 J. P. Colpa H. B. Schlegel and S. Wolfe Canad. J. Chem. 1976,54 526. 49 A.L.Meinzer and W. C. Pringle J. Phys. Chem. 1976,80 1178. 50 G.Bernath and L. Gera Tetrahedron Letters 1976 1615. 288 A. Cox I Bu‘ (17) positions 1and 2. The results of an investigation of the geometry of four conforma- tions of cyclohexane chair (D3d),boat (&) half-chair (Q and planar (06) by means of the FSGO model are reported.’l There are four coplanar carbon atoms in the half-chair conformation and this gives rise to considerable eclipsing of the hydrogens of neighbouring methylene groups. The FSGO model calculations indicate that some of these eclipsing interactions are relieved by a slight ‘rocking’ of these methylene groups.However although the relative energies of the various conformations are given their expected ordering the energy differences between the chair and the other conformations are larger than those previously reported. A study has been presenteds2 determining the steric role of 7r-electrons on conformational equilibria. Whereas an em-methylene group alters the polar character of the molecule only slightly it is found to have an enormous influence on the conforma- tional preference of substituents at the 3-position. Moreover the results show the ‘steric effect’ of the 7r-electrons to be either attractive or repulsive in comparison to a cyclohexane axial-axial interaction depending on the nature of the interacting substituent and of the solvent.By measuring53 the low-temperature pulse Fourier transform 13C n.m.r. spectrum of rnethylcyclohexane enriched with 13C in the methyl substituent the ratio of the major to the minor conformation has been shown to be 164 :1. This corresponds to a conformational free energy difference at 172 K of 7.30k0.25 kJ mol-’. Work has also been reporteds4 in support of the view that the standard kinetic method of conformational analysis using 4-t-butyl derivatives is unreliable when atom-1 is directly involved in the reaction. These results derive from measurements of the combined rate constants for ethoxy exchange in 1,l-disubstituted cyclohexane ethyl carboxylates. Proton-decoupled 31P n.m.r. spectra have been for cyclohexyl cis-and truns-4-methylcyclohexyl and cis-and trans-4-t-butylcyclohexyl derivatives of a number of different phosphorus functions and the 31P shifts for the conformationally rigid t-butyl derivatives found to reveal a strong dependence on the steric disposition of the group.By the principle of additivity of group conformational free energies the first A values for phosphorus functions were obtained and these were found to be larger than for comparable nitrogen and sulphur functions. ‘H n.m.r. studies of dimethylcycloheptanones at low temperatures together with conformational calculations using the PCILO approach indicates6 that the most stable conformations are twist chairs with the carbonyl group 51 T. D. Davis and A. A. Frost J. Amer. Chem. SOC., 1975,97,7410. 52 J.B. Lambert and R. R. Clikeman J. Amer. Chem. SOC.,1976,98,4203. 53 H. Booth and J. R. Everett J.C.S. Chem. Comm. 1976 278. 54 D. R. Brown P. G. Leviston J. McKenna J. M. McKenna R. A. Melia J. C. Pratt and B. G. Hutley J.C.S. Perkin ZZ 1976 838. 55 M. D. Gordon and L. D. Quin J. Amer. Chem. SOC.,1976,98 15. 56 M. St.-Jacques C. Vaziri D. A. Frenette A. Goursot and S. Fliszar J. Amer. Chem. SOC.,1976,98 5759. Alicyclic Chemistry located at position 2 i.e. (18) (19) and (20) in accord with a greater competitive conformational preference for the carbonyl group relative to the gem-dimethyl group. Cyclo-octa-1,3-diene and the 1,4- and 1,5-isomers have been studied" by (18) (19) (20) the force field method. The former is calculated to be a mixture of two conforma- tions of which one (21) has a C axis and one (22) is irregular (Cl).For the 1,4-isomer there are two conformations a boat-boat (23) and a boat-chair (24) both (21) (22) (23) (24) of which have C symmetry. The 1,4-isomer is substantially all in the boat-chair conformation whereas the 1,5-isomer is known to be preferentially a twist-boat (C,) conformation. The calculations indicate the 1,3-isomer to be much more stable followed in turn by the 1,4- and the 1,5-isomer. Another force-field study of &,cis- cyclo-octa-1,5-diene has also been the results of which although corn- patible with work of Anet,59 is less so with that reported by Alli~~ger.~' Three potential energy minima and four transition states have been found to be relevant for a description of the conformational properties of cyclo-octa- 1,5-diene and the seven calculated conformations are essentially characterized by different distributions of angle and torsion strain.It is concluded that the most favourable calculated conformation of cis,cis-cyclo-octa- 1,5-diene is a twist-boat structure of symmetry C2(C-CH2-CH,-C torsion angles of 52.5") in agreement with Anet's experi- mental evidence. "C-n.m.r. has been used6' to show that cyclonona- 1,2,6-triene exists in an unsymmetrical twist-boat-chair conformation (25) that can undergo a (25) hindered pseudorotation (barrier height 53 kJ mol-') to achieve a C time-averaged symmetry. A conformational analysis of 3,4-homotropilidene has been carried out6* by means of 'H n.m.r.spectroscopy and if compared with cyclohepta-1,3,5-triene having the three-membered ring in the ex0 position (trans-conformation) the s7 N. L. Allinger J. F. Viskocil U. Burkert and Y. Yuh Tetrahedron,1976,32 33. s8 0.Ermer J. Amer. Chem. SOC., 1976,98 3964. 59 F. A. L. Anet and L. Kozerski J. Amer. Chem. SOC.,1973,95 3407. 60 F. A. L. Anet and I. Yavari J.C.S. Chem. Comm. 1975 927. 61 H. Giinther and J. Ulmen Chem. Ber. 1975,108 3132. 290 A. Cox molecule has been shown to exist in a flattened boat conformation. Polycyclic annulenes are among the molecules which show .rr-systems highly deformed from planarity. A simplified force-field has been discussed62 for such compounds and the ratios of the twist and out-of-plane bending force constants involved are derived from structural data.4 Structural Properties and Orbital Interactions Theoretical studies have been of the planar (26) and twisted (27) forms of vinylmethylene together with the corresponding calculation on cyclopropene. The calculated parameters are of sufficient accuracy to be compared directly with the experimental results. The calculations show that it is the 1,3-biradical singlet state ('A ") rather than the methylene-like singlet ('A ') which correlates well with cyclo- propene and the suggestion is made that (lA") (26) is the state most important in the H H H (26a) (26b) (27) isomerization. Ab inifioMO theory has been to study the relative energies of various isomers of C3H3+. The cyclopropenium ion is found to be the most stable C3H3+ isomer with a resonance energy >247 kJ mol-'.The propargyl cation is the next most stable form with an energy 140 kJ mol-' above the cyclopropenium cation. Results of similar calculations have also been reported for two acyclic C3H' systems. Single determinant ab initio MO theory has also been applied6' to the study of the structures and relative energies of all possible singlet and triplet isomers of formula C3H2. Within the manifold of closed shell singlets cyclopropenylidene is found to be the most stable being some 70 kJ mol-' below vinylidenecarbene. Comparison is drawn between the relative energies of the most stable of each of the singlet and triplet manifolds and it has been estimated that the lowest energy singlet isomer cyclopropylidene is ca.54kJ mol-' more stable than the best triplet form propar- gylene. A series of cyclobutenyl cations has been prepared66 and studied by 13C and 'H n.m.r. spectroscopy. The data for the 1,3-diphenyl-2,4-diR-cyclobutenyl cations (28) are characteristic of alkenyl (allyl) cations with undetectably small contribu- tions from 1,3~overlap. Exclusive methyl substitution as in the 1,3-dimethylcyclobutenyl cation (29) and the 1,2,3,4-tetramethylcyclobutenylcation (30) lead to decreased importance of allylic delocalization and accordingly greater 1,3~-overlapand homoaromatic charge delocalization. The series culminates in the parent cyclobutenyl cation which exhibits truly aromatic delocalization. However results6' of an ab inifiocalculation do not appear to be in entire agreement with these experimental conclusions for it is claimed that the calculated geometry of the H.B. Burgi and E. Shefter Tetrahedron 1975 31,2976. 63 J. H. Davis W. A. Goddard and R. G. Bergman J. Amer. Chem. SOC.,1976,98,4015. 64 L. Radom P. C. Hariharan J. A. Pople and P. von R. Schleyer J. Amer. Chem. SOC.,1976,98 10. 65 W. J. Hehre J. A. Pople W. A. Lathan L. Radom E. Wasserman and Z. R. Wasserman J. Amer. Chem. SOC.,1976,98,4378. 66 G.A. Olah J. S. Staral R. J. Spear and G. Liang J. Amer. Chem. SOC.,1975 97 5489. 67 W. J. Hehre and A. J. P. Devaquet J. Amer. Chem. SOC.,1976,98,4370. Alicyclic Chemistry 291 R)-fR Ph Me Me Me Ph H Me (28) R = Ph Me or But (29) (30) R =H D or CI homocyclopropenyl cation is closer to that expected of an open ‘cyclobutenyl’ ;.ucture than a tightly bridged bicyclic form.The lowest energy form on the C4H5+ potential surface is a methyl derivative of the 27r electron aromatic cyclopropenyl Y cation. A series of remarkably stable 1-methoxy-2-R-3,4,4-trifluorocyclobutenyl cations (R = F Cl or OMe) has been prepared and studied68 by ‘H and 19F n.m.r. in sdution each cation is found to exist as an equilibrating pair of isomers which differ only by the 1-methoxy-group conformation. The n.m.r. data establish the impor- tance of 1,3~-overlap and also from a complete lineshape analysis a series of AG’ values was obtained. The generalized cyclobutene anion radical/butadiene anion radical electrocyclic reaction has been explored69 experimentally and theoretically and its preferred stereochemical course found to be conrotation.Among the theoretical approaches evaluated the HOMO method alone was found to be un-satisfactory. A number of papers have appeared once again on the structure of cyclobutadiene. Ab initio MO theory finds7’ singlet cyclobutadiene to be a rectangular molecule in contrast with the square geometry assumed by the triplet species. Neither state of cyclobutadiene is as stable as another cyclic form on the C4H4 potential surface namely methylenecyclopropene but both are lower in energy than yet another possibility tetrahedrane. Another paper71 on the geometry of cyclobutadiene concludes that when the important effects of electron repulsion in open-shell systems are considered a square or effectively square singlet can be the ground state of cyclobutadiene.Repulsion between the two electrons in the non- bonding MOs of cyclobutadiene is considered to be minimized in a square geometry resulting in a flat curve for rectangular distortion in the lowest singlet state. Experimental evidence however seems to favour the conclusions reached in ref. 71 for it is now that cyclobutadiene has a strong propensity to form a charge-transfer complex whenever a species possessing acceptor properties is availa- ble. Consequently it is probable that CO generated in the photolysis of (31) or (32) interacts weakly with cyclobutadiene and causes a weak splitting of the band associated with the degenerate bending vibration.0 0 B. E. Smart and G. S. Reddy J. Amer. Chem. SOC.,1976,98,5593. 69 N. L. Bauld J. Cessac C.4. Chang F. R. Farr and R. Holloway J. Amer. Chem. Soc. 1976,98,4561. 7O W. J. Hehre and J. A. Pople J. Amer. Chem. SOC.,1975,97,6941. 71 W. T. Borden J. Amer. Chem. SOC.,1975,97 5968. 72 S. Masamune Y. Sugihara K. Morio and J. E. Bertie Canad. J. Chem. 1976 54 2679. 73 G. Maier H.-G. Hartan and T. Sayrac Angew. Chem. Internat. Edn. 1976,15 226. 292 A.Cox The results of a kinetic study of the reaction of substituted alkenylidenecyclo- propanes with 4-phenyl- 1,2,4-triazoline-3,5-dione (PTAD) have been and discussed in terms of the ionization potentials of the HOMOSand the results of CNDO calculations and frontier MO theory. The detailed analysis of the cycloaddi- tion leads to the conclusion that it is concerted and occurs uia a very early transition state which is orbitally controlled (Scheme 11).A second paper under the same R3 Scheme 11 authorship reports7' details of an investigation using He(1) photoelectron spectro- scopy and CNDO calculations of the electronic structure and bonding in alkenylidenecyclopropanes.The nature and magnitude of the interactions between the Walsh orbitals of the three-membered ring and the two 7r-bonds of the allene chromophore are analysed and the forms of the five highest energy MOs are outlined. In addition to the interaction of the cr-type in-plane Walsh orbital with the terminal allene double bond the analysis indicates that one of the lower-lying degenerate pz 7r-type orbitals interacts significantly with the exocyclic double bond.Tworeviews have in the field of non-classical carbonium ions both of which are mainly concerned with the 2-norbornyl cation. In a more general arti~le,~' Hogeveen discusses pyramidal mono- and di-cations. Structural data for the geometries of the l-triquinacenyl cation (33) and the 10-triquinacenyl cation (34) and for the corresponding radicals have been obtained7' by a MIND0/3 calculation. This reveals that the cation (33) is ca. 95 kJ mol-' more stable than (34) and the upper limit of the activation energy for the transformation of + (33) (34) (34) into (33) is calculated to be 37 kJ mol-'. The three chlorides (35)-(37) have been prepared" and allowed to react with antimony pentafluoride in S0,FCl at -78 "C and the 'H and 13Cn.m.r.spectra of the reaction mixture measured. Only the monocations were found to be present in each case their kinetic stability 74 D. J. Pasto J. K. Borchardt T. P. Fehlner H. F. Baney and M. E. Schwartz,J. Amer. Chem. SOC.,1976 98 526. 75 D. J. Pasto T. P. Fehlner M. E. Schwartz and H. F. Baney J. Amer. Chem. Soc. 1976,98 530. 76 G. A. Olah Accounts Chem. Res. 1976,9 41. 77 H. C. Brown Tetrahedron 1976 32 179. H. Hogeveen and P. W. Kwant Accounts Chem. Res. 1975,8,413. 79 P. Bischof Angew. Chem. Internat. Edn. 1976,15,556. Bo D. Bosse and A. de Meijere Angew. Chem. Internat. Edn. 1976 15 557. 293 Alicyclic Chemistry c1 c1 @z$ (35) (36) (37) increasing with chlorine substitution.The ‘H and I3C n.m.r. spectroscopic data for the free carbenium ions show that almost planar divinylcarbenium ion units are present in these species. The He(1) photoelectron spectra of a series of nine cycloalkenes have been reported.8’ Along with the calculated coefficients for the frontier orbitals of these species measurement or estimation of experimental vertical IPSor EAs has made possible determination of reactivity indices. The behaviour of cycloalkenes toward ‘one-bond’ and ‘two-bond’ nucleophiles is quite different so that a theoretical criterion for concertedness in cycloaddition is established. In another papers2 on cycloadditions it is shown that orbital interaction between antisymmetric MOs can furnish cyclic additions with concerted character.The density analysis locates a clear-cut distinction of the consequence of the interaction between two antisymmetric MOs from that of the interaction between two symmet- ric MOs in cyclic additions. According to the analysis concerted formation of two bonds can be expected only if the dominant orbital interaction is the one between two antisymmetricMOs. 5 Reactions Metal-promoted Reactions.-A review containing 132 references on the transition- metal-catalysed rearrangement of small-ring organic compounds has appearedeS3 The rhodium-catalysed addition of CO to reactive dienes and enones with the formation of five-membered rings has been For example reaction of diene (38) with [Rh(C0)2C1J2 leads to 4,5,6,7,-tetramethylindan-2-one, besides the products resulting from the rearrangement of the bicyclobutane moiety.It is probable that the mechanistic route proceeds via intermediate (39) which may [Rh(CO),C112 co + I I CI-Rh-CO + (38) (39) ‘Rh(C0)CI’ possibly exist in polymeric form. An interesting paper has appeared8’ describing the nickel(0)-catalysed reaction of a 1,8-bishomocubane. The ease with which the isomerization occurs is profoundly influenced by the catalyst system employed and in the case of certain ligands at least it appears that formation of soluble 81 K. N. Houk and L. L. Munchausen J. Amer. Chem. SOC.,1976,98,937. 82 H. Fujimoto S. Inagaki and K. Fukui J. Amer. Chem. Soc. 1976,98 2670. 83 K. C. Bishop Chem. Rev. 1976,76,461. 84 R. F.Heldeweg and H. Hogeveen J. Amer. Chem. Soc. 1976,98,6040. 85 R. Noyori M. Yamakawa and H. Takaya J. Amer. Chem. SOC.,1976,98,1471 294 A. Cbx co-ordinatively unsaturated nickel(0) complexes is crucial. The catalytic two-bond cleavage of (40) is considered to proceed by a mechanism involving the C-2-C-5 edge-on co-ordination complex and the possibility of a concerted process through C0,Me C0,Me (40) face-on metal co-ordination is ruled out. The synthesis of the bipyridylnickelocyc- lopentane derivatives (41)-(43) and their displacement reactions with ring-strained (41) (42) (43) olefins have been reported.86 These metallo-cyclopentane complexes are thought to be relevant for the cyclodimerizations shown in Scheme 12. Scheme12 A number of examples of silver-ion-promoted rearrangements of strained polycyclic systems have appeared.Dehydronoriceane (44),for example has been shown” to rearrange to 2,4-ethenonoradamantane.However on the basis of calculations presented it appears that rationalization of the observed relative reactivity of (44)and bicyclopentane (45)towards Ag’ ion has to be founded on considerations other than strain. It is suggested that an intermediate resulting from 86 M.J. Doyle J. McMeeking and P. Binger J.C.S. Chem. Comm. 1976 376. 87 T. Katsushima R. Yamaguchi and M. Kawanisi J.C.S. Chem. Comm. 1976 39. Alicyclic Chemistry (44) (45) breaking of the central bond a is stabilized by the hyperconjugative effect of the three C-C bonds connecting the bicyclopentane portion to the cyclohexane ring [see (44) bold lines].Homopentaprismane (46a) has been synthesized;88 it is not rearranged to the less strained undecanes by silver salts. Comparison of the hypothetical course of this unobserved conversion of homopentaprismane with examples of known conversions in the cubane series leads the authors to conclude that the rate-determining step in these silver-ion-catalysed rearrangements is the bond migration b-+c (Scheme 13). -2 cyclobutanes (-2 cyclobutanes) [+ 1cyclopropane] (+1cyclopropane) bb bd a X = zero bridge :cubane d cuneane a X = -CH2-:homocubane d homocuneane (norsnoutane) a X = -CH2CH2-:1,8-bishomocubane d snoutane a X = no bridge :secocubane d secocuneane (46a) (-2 cyclobutanes) (no ring loss) (46c) (+1 cyclopropane) (46b) -’(46d) Scheme 13 A review has been published8’ of olefin metathesis.Treatment of 1-methylcyclobutene with (dipheny1carbene)pentacarbonyltungsten leads” to polymer the structure of which enables the preference for alternating sequences of monomeric units to be measured and in which the stereochemistry of trisubstituted olefin metathesis can be determined. The selectivity was found to be small compared with that for other additions or for metatheses of terminal olefins and the stereochemistry was interpreted as that for 1,2-disubstituted olefins The first report has appeared’’ of the conversion of a structure possessing two non-conjugated 88 P. E. Eaton L. Cassar R. A. Hudson and D. R. Hwang J. Org. Chem.1976 4X 1445. 89 N. Calderon E. A. Ofstead and W. A. Judy Angew. Chem. Internat. Edn. 1976,15,401. 90 T. J. Katz J. McGinnis and C. Altus J. Amer. Chem. SOC.,1976 98 606. 91 P. G. Gassman and T. H. Johnson,J. Amer. Chem. SOC.,1976,98 861. 296 A. Cox olefinic groups (47)into (48) by a commonly accepted metathesis catalyst. Experi- mental evidence has been announced92 showing that some olefin metatheses involve formation of metal-carbene complexes from non-carbenoid precursors. This prem- ise is based on the selective trapping of such carbenes by Michael acceptors e.g. ethyl (CH2)8 - $(cH2)$; H' - CF3 CF3 CF3 CF3 (47) (48) acrylate. Indeed in certain cases they appear to be so efficient that a complete quenching of the metathesis can occur.The well-established olefin metathesis catalyst derived from phenyltungsten trichloride and aluminium trichloride has been found93 to be successful in promoting retrocarbene additions from certain simple cyclopropanes under mild conditions. In the light of this knowledge a cyclopropane-olefin cross metathesis reaction has been acc~mplished~~ (Scheme 14) in the presence of catalysts formed from the reaction of phenyltungsten trichloride with either aluminium trichloride or ethylaluminium dichloride. 4"' kR2 +CH2=CHR2 -+CH2=CHR'+ H H Scheme14 Thermally Induced Reactions.-A paper has appeared9' which is aimed at studying the overall reaction isomerization of cyclopropane by means of a complete potential energy surface including simultaneously all the important geometrical degrees of freedom of the molecule.Among the conclusions drawn are that the initial methylene vibrational energy for a trajectory to be reactive is much greater than generally expected and that also for most reactive trajectories a single rotation of 180"of one or both terminal CH2groups occurs within the radical species before ring closure. Berson has inve~tigated~~ the thermal stereomutation of phenyl cyclo- propanes. Analysis of the kinetics leads to results which are expected if the stereomutation pathway passes over a 0,O-trimethylene ('wcyclopropane'). The accelerating effect of a 2-dimethylamino-substituent on the thermal 1,3-sigmatropic rearrangement of vinylcyclopropane to cyclopentene has been measured and found9' to exceed even the large effect of a 2-methoxyl substituent.This rate enhancement is attributed to stabilization of a developing radical centre at C2-by the 2-dimethylamino-group. The optically active 2-E-benzylidene-4-t-butyl-4-cyano-3-phenylcyclobutanone (49) has been to rearrange thermally to the 2-2-benzylidene isomer (50) by a [1,3]-sigmatropic shift with inversion of the 92 P. G. Gassman and T. H. Johnson J. Amer. Chem. SOC., 1976,98,6055. 93 P. G. Gassman and T. H. Johnson J. Amer. Chem. Soc. 1976 98,6057. 94 P. G. Gassman and T. H. Johnson J. Amer. Chem. SOC., 1976,98 6058. 95 X. Chapuisat and Y. Jean J. Amer. Chem. SOC.,1975 97,6325. 96 J. A. Berson L. D. Pedersen and B. K. Carpenter J. Amer. Chem. SOC., 1976 98 122. 97 H.G. Richey and D. W. Shull Tetrahedron Letters 1976 575. 98 H. A. Bampfield P. R. Brook and K. Hunt J.C.S. Chem. Comm. 1976 146. 297 Alicyclic Chemistry R Rkc2 XdR X Y Y Y (49) X=Y=Ph X=CN;Y=Bu' migrating centre. A planar and hence achiral intermediate is excluded by the results which allow a twisted conformation as transition state or intermediate in the rearrangement. The thermal dimerization of 1,l-dimethylallene gives99 three different substituted cyclobutanes and thermal decomposition of 4,5-dimethylene-3,3,6,6-tetramethyl-3,4,5,6-tetrahydropyridazinegives the same products in the same ratios. The results are interpreted in terms of the 2,2'-bis-( 1,l-dimethylallyl) biradical being a common intermediate (Scheme 15).5-Alkylpentakis(methoxycarbonyl)cyclopentadienes \ Scheme 15 equilibrate loo at 100"Cwith 1-alkyl-pentakis(methoxycarbony1)cyclopentadienes uia [ 1,5]-sigmatropic ester shifts. At higher temperatures a further ester shift is observed leading to 2-alkyl-pentakis(methoxycarbonyl)cyclopentadienes. The intramolecular character of the rearrangement is demonstrated by crossover experi- ments. Trisection has been undertaken'" of the thermal automerization of 4-vinylcyclohexene. In an attempt to provide information bearing on the question of the temporal succession of bond breaking and bond formation as represented by the three extreme cases of transition states (5 1)-(53) several 2,6-disubstituted homo- (.\U Initial bond bond formation step breaking (51) (53) tropilidenes have been synthesized and their rearrangements studied'" by 'H n.m.r.spectroscopy. Evidence is cited attesting to the conclusion that in (bridged) homo- tropilidenes the transition state is like (54)or (55). A related study has been 99 T. J. Levek and E. F. Kiefer J. Amer. Chem. Soc. 1976,98 1875. 100 R. W. Hoffmann P. Schmidt and J. Backes Chem. Ber. 1976,109,1918. 101 W. von. E. Doering and D. M. Brenner Terruhedron Letters 1976 899. 102 H. Kessler and W. Ott J. Amer. Chem. Soc. 1976,98 5014. 298 A. Cox (54) (55) ~ndertaken"~ as a model system. It is using the tricyclo[3,3 1,02*8]nona-3,6-dienes concluded that heteroatoms such as chlorine and oxygen seem to cause little if any perturbation of the barbaralane framework provided that they are attached to C-3 and C-7.This negligible effect contrasts with the rate-enhancing influence of oxygen in the 3-hydroxy Cope rearrangement of hexa-1,5-dienes and especially in the 3-oxido Cope rearrangement. The activation parameters of the Cope rearrange- ment of 1,2,3,4,5,6,7,7'-octadeuterio-3,4-homotropilidene have been deter-minedlM between -20 and +102"C by a complete lineshape analysis of the temperature-dependent 'H n.m.r. spectrum. In addition it was found that the isomer with the CH2 group at the three-membered ring is more stable than the isomer with the diallylic CH2 group by ca. 1kJ mol-l. A Cope rearrangement has also been imp1icatedlo5 in the transformation of (56) into (57). The reaction which is important synthetically in regiospecific quinone isoprenylation is an exceptionally ready allyl-p-quinol Cope rearrangement.It should be viewed as good precedent for the possible reinterpretation of the mechanism of other ally1 quinol rearrangements together with related transformations. Vapour-phase pyrolysis of pentacyclo[5,5,0,02"2,06'8,O3~9]dodeca-4,10-diene has been shownlo6 not to give detectable amounts of any other (CH2)12isomer. Instead the starting material fragments to benzene at temperatures above 160 "C. Experimental support is cited to account for this behaviour in terms of Scheme 16. For pericyclic reactions it has Scheme16 103 A. Busch and H. M. R. Hoffmann Tetrahedron Letters 1976 2379. 104 H.Giinther J.-B. Pawliczek J. Ulmen and W.Grimrne Chem. Ber. 1975,108,3141. 105 D.A. Evans and J. M. Hoffman,J. Amer. Chem. SOC.,1976,98,1983. 106 E.Vedejs and R. A. Shepherd,J. Org. Chem. 1976,41,742. Alicyclic Chemistry 299 been suggested that substitution of one component with electron-releasing groups (raising the MOs of that component) and of the other component with electron- withdrawing substituents (lowering the MOs) effectively reduces the energy barrier for disallowed processes. In this context the thermal [a2,+ ds]ring-opening of substituted 1,4,5-endo-6-endo-tetramethylbicyclo[2,2,O]hex-2-enes(58) to give (59),has been investigated.'" In each case the product expected for [dS+dr] Me Me Me I Me ... 1 (58) R' = R2= Me (59) R' = C02Me R2= Me R' = R2= C02Me R1= C02Me R2 = Ph cycloreversion was selectively formed.Approximate values of activation parameters are given. In solution at 180"Cor on passage through a hot tube (>370"C 18s residence time) as-homobasketene has been observed'08 to fragment cleanly to benzene and cyclopentadiene. Evidence is presented supporting the view that fragmentation of as-homobasketene starts with a (2+ 4)-cycloreversion to syn-tricyclo[5,4,0,02~6]undeca-3,8,10-triene. Classification of the second step as a (2 + 2) or a (4 + 4)process cannot be made at this stage. A report has appeared"' on the butadienylcyclopropane rearrangement in tricyclo[5,3,0,02*'0]deca-3,5-diene (60) the cisoid geometry of which is fixed by the ethano bridge. Detection of the rearrangement was accomplished with the 2H,-labelled compound.The free energy of activation was found to be CQ. 21 kJ mol-' higher than in (61).Bearing in mind that (61)must first be transformed into its higher energy transoid conformer (62),the energy difference for the pericyclic reaction itself in the cisoid as against the transoid transition state should be taken as AAG' a25 kJ mol-'. (60) (61) (62) Photochemically Induced Reactions.-A study has been made''' of the stereochem- ical fate upon rearrangement of the optically active 2-phenyl-3-methylenecyclopropane when reaction has been induced either thermally or photo- chemically. The results clearly demonstrate that chirality is maintained during the course of the transformation whether thermally or photochemically induced and also exclude the development of the planar geometry calculated to be favoured for triplet 10' F.van Rantwijk and H. van Bekkum Tetrahedron Letters 1976.3341. W. Mauer and W. Grimme Tetrahedron Letters 1976,1835. 109 K.Heger and W. Grimme Angew. Chem. Infernat.Edn. 1976,15,53. 110 W.A.Gros T. Luo,and J. C. Giibert J. Amr. Chem. SOC.,1976,98,2019. 300 A. Cox trimethylenemethane. Irradiation of a series of tetrasubstituted olefins leads"' to positional migration of the double bond e.g. (63)+(64),and labelling studies have (63) (64) indicated that the migration process is intramolecular and is therefore a [1,3]-sigmatropic shift of hydrogen. That the migration process is apparent in cyclopen- tenes may be due at least in part to the emergence of the .np* state as the lowest-lying singlet excited state.An investigation of the photoreactions of methyl cis-and trans-4,4,6-trimethylhepta-2,5-dienoatehas provided"* the first example of a di-.n-methane rearrangement where the ring-opening goes in one direction on direct irradiation and in the other direction when a sensitizer is used (Scheme 17). 0 0 3oo nm Acetone Scheme 17 The results show that vinylcyclopropane formation competes with triplet energy dissipation by the free-rotor effect and which products are formed depends only on relative rates. The stereoselective photochemical photodimerization of liquid but-2- ene has been in~estigated."~ The experimentally observed distribution of the four isomers as a function of the cisltrans ratio in liquid but-2-ene has been quantitatively reproduced by calculation.The calculations were based on theoretical rate expres- 111 P.J. Kropp H. G. Fravel and T. R. Fields J. Amer. Chem. SOC.,1976,98 840. 112 P. Baeckstrom J.C.S. Chem. Comm. 1976,476. lf3 H. Yamazaki R. J. Cvetanovic and R. S. Irwin J. Amer. Chem. SOC.,1976,98 2198. Alicyclic Chemistry sions derived from a reaction mechanism which considers the statistical probability of encounters between the electronically excited and the ground-state cis-and trans-but-2-ene molecules. The products and mechanisms of the reaction of O(3P)atoms with inter alia 1:methylcyclohexene have been investigated. '14 A general mechan- ism is discussed for this oxidation which is of interest not only from the fundamental grounds of structure and reactivity but also because of its significance for atmos- pheric pollution.Experimental evidence has been pr~duced"~ for a twisted form of 1-phenylcyclohexene presenting a double bond past orthogonality and commonly called trans-1-phenylcyclohexene. Laser photolysis of 1-phenylcyclohexene in methanol at room temperature forms a transient absorbing in the range 300- 430 nm with a maximum near 380 nm and having a lifetime of 9 ps. 114 J. S. Gaffney R. Atkinson and J. N. Pitts J. Arner. Chem. SOC.,1976,98 1828. 1x5 R. Bonneau J. Joussot-Dubien L. Salem and A. J. Yarwood J. Amer. Chern. SOC.,1976,98,4329.

ISSN:0069-3030    

DOI:10.1039/OC9767300279

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

13 Synthetic Methods By G. PATTENDEN DeparCment of Chemistry The University Nottingham NG7 2RD 1 Alkanes Organosilanes are extremely useful hydride-ion donors in all types of ‘ionic hydrogenation’ reactions. Their use in the reduction of alcohols to alkanes however has been limited because of the frequent side reactions which occur between the silane and the strong acid conditions necessary to generate the required carbocation intermediates (Scheme 1). Fry and his colleagues have now demonstrated that in BF- + ROH -+ R G,OH 3RH Scheme 1 these cases it is expedient to use an organosilane-BF system for the ionic hydrogen- ation.’ This system permits even the reduction of simple alcohols to the correspond- ing hydrocarbons in acceptable yields (50-80%).In closely similar investigations it has been shown that alkyl halides are reduced readily to hydrocarbons by organosilanes when catalytic amounts of either BF or AICl are Toluene-p-sulphonate esters of both cyclic and acyclic alcohols whether hindered or not are most efficiently reduced to the corresponding hydrocarbons with lithium triethylb~rohydride.~ An alternative method which does not use metal hydride agents simply involves treating the tosylate (or mesylate) with sodium iodide and zinc in hot glyme;’ the reaction proceeds oia the corresponding iodide. Synthetic methods based on organoselenium intermediates are presently attract- ing considerable attention. Krief and his co-workers6 have developed a new procedure for the conversion of ketones into the corresponding methylene com- pounds which involves cleavage with base of one C-Se bond in the corresponding seleno-acetal (l),followed by quenching to the selenide (3) and cleavage of the second C-Se bond using Li-EtNH2 or Raney Ni (Scheme 2).A feature of the method is that the a-selenocarbanion intermediate (2) can be alkylated producing a new selenide which is then transformed into a substituted hydrocarbon. The technique of catalytic transfer hydrogenation has hitherto not been widely applied in synthesis. It is now reported that aromatic carbonyl compounds can be M.G. Adlington M.Orfanopoulos and J. L. Fry,Tetrahedron Letters 1976,2995. M. P. Doyle C. T. West S.J. Donnelly and C.C. McOsker J. Organometallic Chem. 1976,117,129. M.P. Doyle C. C. McOsker and C. T. West J. Org. Chem. 1976,41 1393. S. Krishnamurthy and H. C. Brown J. Org. Chem. 1976,41,3064. Y.Fujimoto and T. Tatsuno Tetrahedron Letters 1976,3325. M.Sevrin D. Van Ende and A. Krief Tetrahedron Letters 1976 2643. 303 304 G.Pattenden R2C0 -R2C(SeR')2 R2c-SeR1 4R2CH-SeR' (1) (2) (3) jii Jv R2CH & R2C-SeR' R2CH2 I I R2 R2 Reagents i Bu"Li; ii HzO; iii R2X; iv Li-EtNH2 Scheme2 reduced to the corresponding hydrocarbons by this method in good yields using cyclohexene or limonene as the donor molecule Pd-C as catalyst and in the presence of catalytic amounts of Lewis acids such as FeCI,.' In one of the few demonstrations of the synthetic utility of organometallic electrochemistry Jennings et aZ.* have shown that transition-metal complexes such as [Ni(acac),] or [Fe(acac)J can be induced to react in an electrochemical system with alkyl halides leading to good yields of coupled hydrocarbon products.2 Alkenes Olefination reactions with phosphonates can be carried out in two-phase systems in the presence of tetrabutylammonium iodide as catalyst,' although Mikolajczyk et aZ." in similar studies have shown that a phase-transfer catalyst is not entirely essential; the authors suggest that the phosphonate itself is able to catalyse its own two-phase reaction. The synthesis of ally1 phosphine oxides by phosphinolyl migration in a substituted alcohol [uiz. (4)-+ (5)] is totally regioselective giving only the phosphine oxide (5) with the more substituted double bond." Furthermore the synthesis is stereoselec- tive leading largely to the E-a@-unsaturated phosphine oxide useful in the synthesis of conjugated dienes of defined geometry.12.13 Interestingly the least substituted phosphine oxide (7) is produced when the alcohol containing a trimethylsilyl group [uiz.(6)] is treated similarly with acid.14 The successful outcome of this last reaction is due to the general observation that the C-Si bond is more easy to break heterolytically than the corresponding C-H bond (Scheme 3). The potential for cis-a@-unsaturated phosphoranylides and cis -ap-unsaturated aldehydes in the preparation of all-cis-conjugated isoprenoids is well illustrated by the synthesis of the all-cis-pentaene (10) from (8) and (9).15 The utility of vinylsilanes in the stereospecific synthesis of olefins via a@-epoxysilanes and @-hydroxysilanes has been elegantly demonstrated by Hudrlik and his co-workers.In procedures which greatly expand the scope of this olefination sequence [Ann.Reports (B) 1975 72 3113 several groups of workers have now G. Brieger and T. H. Fu J.C.S. Chem Comm. 1976,757. P. W. Jennings D. G. Pillsburg J. L. Hall and V. T. Brice J. Org. Chem. 1976,41 719. C. Piechucki Synthesis 1976 187. lo M. Mikolajnyk S. Grzejsznak W. Midura and A. Zatorski Synthesis 1976 396. It A. H. Davidson and S. Warren J.C.S. Chem. Cbmm. 1976 181. B. Lythgoe T. A. Moran M. E. M. Nambuding and S. Ruston J.C.S. Perkin Z 1976 2386. A. H. Davidson and S. Warren J.C.S. Perkin Z 1976,639.l4 I. Fleming A. Pearce and R. L. Snowden J.C.S. Chem. Comm. 1976 182. L. Barlow and G. Pattenden J.C.S. Perkin Z 1976 1029. 305 Synthetic Methods (4) Scheme 3 -t (10) outlined new methods for the stereoselective syntheses of E-and 2-vinylsilanes via the reductive alkylation of appropriate l-alkynylsilanes.'6-18 Thus in one method direct hydroalumination of the alkynylsilane (1 1)followed by complexation of the resulting vinylalane with MeLi and alkylation led to E-vinylsilane (12); in the presence of a Lewis base hydroalumination gave the corresponding 2-vinylalane (13) which produced 2-vinylsilane (14) on alkylation (Scheme 4).16 iii iv //r R-fSiMe3 R-fSiMe3 AlBu; R' R-Cr CSiMe (12) Reagents i BuiAlH; ii BuiAIH-Lewis base; iii MeLi; iv R'X Scheme 4 I6 J.J. Eisch and G. A. Damasevitz J. Org. Chem. 1976 41 2214. K. Uchida K. Utimoto and H. Nozaki J. Org. Chem. 1976,41 2215. l8 K. Uchida K. Utimoto and H. Nozaki J. Org. Chem. 1976,41 2941. 306 G. Pattenden In an alternative stereoselective approach to vinylsilanes Chan and his co-worker~~~ have shown that chlorination of the carbinol (15) produced from a-trimethylsilylvinyl-lithium and aldehydes leads predominantly (-90%) to the Z-isomer of the ally1 chloride which by reaction with organocopper lithium reagents leads to 2-vinylsilanes (16).,' The isomeric vinylsilane (18) can also be prepared from (15) following acetylation to (17) and reaction with organocopper lithium reagents (Scheme 5).An equally attractive route to vinylsilanes is from carbonyl compounds via base treatment and silylation of their benzenesulphonylhyd- razones.21 SiMe (17) (18) Reagents:i RCHO; ii SOCI,; iii R',CuLi; iv acetylation Scheme 5 /3-Hydroxysilane intermediates [viz.(19)] can also be prepared by nucleophilic additions to appropriate /3 -ketosilanes. These reactions produce predominantly one diastereoisomer of the two possible P-hydroxysilanes which under basic conditions undergoes syn-and under acid conditions anti-elimination leading to efficient stereoselective syntheses of trisubstituted alkenes2 The more obvious and indeed the first systematically investigated route to /3-hydroxysilanes is by nucleophilic addition of a-silyl carbanions to carbonyl compounds.A new and useful synthesis of a-silyl carbanions offering several advantages over classical procedures has been described by Dumont and Krief23 which involves simply treating monosubstituted methyl a-silymethyl selenides with BuLi at 0°C. Only the C-Se bond is cleaved under these conditions and the resulting carbanions are then treated directly with carbonyl compounds (Scheme 6). In a closely similar approach to the stereoselective synthesis of alkenes via hydroxysilane intermediates two groups have shown independently that nu-cleophilic silicon reagents such as Me3SiK and Ph(Me)2SiLi react with epoxides to produce /3 -alkoxysilane intermediates which spontaneously break down stereo- l9 T. H. Chan W. Mychajlowski B. s. Ong and D. N.Harpp J. Organometallic Chem. 1976,107 C1. 2o W. Mychajlowskij and T. H. Chan Tetrahedron Letters 1976,4439. 21 T. H. Chan A. Baldassarre and D. Massuda Synthesis 1976 801. 22 K. Utimoto M. Obayashi and H. Nozaki J. Org. Chem. 1976,41,2940. 23 W. Dumont and A. Krief Angew. Gem. Internat. Edn. 1976,15 161. 307 Synthetic Methods R4 Iv R2 RzSi-CH-SeMeIR’ -% IR’ R$iCH Reagents i R4Li; ii base; iii acid; iv BuLi; v R’COR4 Scheme6 specificallysyn,leading to alkenes with inversion of stereochemistry (Scheme 7).24p25 The deoxygenation of epoxides to olefins with retention of stereochemistry can be accomplished with 3-methyl-2-selenobenzothiazole in the presence of trifluoroace- tic acid26 or simply by using metal atoms produced by resistive heating of coated tungsten rods in an appropriate reactor.” Scheme7 In view of the current interest in P-hydroxysilane intermediates for the synthesis of alkenes it is perhaps inevitable that P-hydroxyselenides should also be investigated.Krief and his co-~orkers~~~~ have developed several methods for the synthesis of P-hydroxyselenides based on trcms-opening of epoxides with alkylselenols addition reactions of a-selenocarbanions to carbonyl compounds and reduction of a-selenocarbonyl compounds. The trans-elimination of the elements of alkylselenic acid from the P-hydroxyselenides using SOC12-Et3N then completes a new synthe- tic approach to alkenes which the authors suggest in some instances is competitive with the Wittig reaction; we shall have to wait and see! Several more important demonstrations of the use of McMurry’s reagent (TiC1,- LiAlH4) in the reductive coupling of carbonyl compounds to alkenes have been published.The intramolecular coupling of the 174-dione (20) to give the strained cyclobutene (21) is quite remarkable and the general method has also been 24 P. B. Dervan and M. A. Shippey J. Amer. am. Soc. 1976,98 1265. 25 M. T. Reetz and M. Plachky Synthesis 1976 199. 26 V.Calo L. Lopez,A. Mincuzzi and G. Pesce Synthesis 1976,200. 27 J. A. Gladys J. G. Fulcher and S. Togashi J. Org. Gem. 1976,41 3647. 28 J. Remion W. Dumont and A. Krief Tetrahedron Letters 1976 1385. 29 A. M.Leonard-Coppens and A. Krief Tetrahedron Letters 1976.3227. 30 J. Remion and A. Krief Tetrahedron Letters 1976 3743.308 G.Pattenden Ph-?C)SPh -a 00 Ph Ph (20) (21) employed in the synthesis of cyclopentenes and cyclohexenes from appropriate 13-and 1,6-dione prec~rsors.~~’~~ Using 4-methoxy-2,6-dimethylacetophenonethe highly hindered stilbene (22) has also been ~ynthesized.~~ In view of some erratic (22) results reported in the literature using the TiC13-LiA1H4 ‘reagent’ McMurray and Fleming32 have suggested that a better method of carrying out these reactions is to use the active Tiometal powder prepared by treating a slurry of TiC13 in THF under nitrogen with potassium metal. The stereoselective synthesis of alkenes from trialkylalkynylborates via vinyl- boranes is limited by the often unpredictable nature of the migratory aptitudes of the ligands attached to boron.Hooz and M~rtimer~~ have now shown that reaction of borates (23) with Bu3SnC1 produces only the isomer (24) in which the migrating SnBw (23) (24) group and entering electrophile are trans to each other. Hydrolysis in formic acid then leads to a simple cis-olefin. Although boronic esters [viz.(25)] have not enjoyed widespread use in synthesis they feature in a useful synthesis of the prostaglandin precursor (27) described this year whereby the alkeneboronic ester (26) was shown to rearrange in MeOH-THF (2 :1)in the presence of NaOMe leading to (27) in 75% overall yield from (25).35 In a simple and efficient ‘one-pot’ procedure for the stereoselective synthesis of E-glkenes a monosubstituted acetylene is treated sequentially with di-isobutylaluminium hydride and BuLi and the resulting trans-alkenyl-trialkylaluminate is then treated with an alkyl halide or s~lphonate.~~ The cross- coupling of dialkylchloroboranes prepared from disubstituted acetylenes and BH2Cl with alkyl halides leads to trisubstituted alkenes with >99’/0 stereochemical purity.37 31 A.L. Baumstark E. J. H. Bechara and M. J. Semigran Tehuhedron Letters 1976 3265. 32 J. E. McMurry and M. P. Fleming J. Org. Chem. 1976 41 896. ’’B. G. James G. Pattenden and L. Barlow J.C.S. Perkin I 1976 1466. 34 J. Hooz and R. Mortimer Tetrahedron Letters 1976,805. 3s D. A. Evans R. C. Thomas and J. A. Walker Tetruhedron Letters 1976 1427. 36 S. Baba D. E. van Horn and E. Negishi Tetrahedron Leners 1976 1927.37 Y. Yamamoto H. Yatagai A. Sonoda and S. Murahashi J.C.S. Chem. Comm. 1976 452. Synthetic Methods Earlier work established that the reduction of enol phosphonates of ketones with Li-Bu‘OH provides an exceptionally ready route to alkenes. Reduction of the enol phosphonate with a dialkylcuprate has now been shown to lead to the corresponding trisubstituted alkene (Scheme 8).38 0 ?PO(OPh) t + + Reagents i LDA; ii CIPO(OPh),; iii R2CuLi. Scheme8 Homogenous hydrogenations in the presence of cationic rhodium complexes of the type [Rh(norbornadiene) (PPhMe2)3]’C104- offer several advantages over the Lindlar-type heterogenous hydrogenation for the synthesis of cis-alkenes from alkyne~.~’ Provided that attention is given to experimental detail the reduction of alkynes to alkenes by LiAlH4 in the presence of TiC14 can also be controlled to produce largely the ~is-alkene.~’ A useful procedure for converting an alkyne into the corresponding trans-alkene is by reaction of the corresponding 1,2-diorganoborane with alkaline silver nitrate.41 There have been several beautiful illustrations of the synthetic potential of the intermolecular variant of the ‘ene’ reaction in the past few years.Stork and Krauss4* have now demonstrated that the reaction is particularly useful for the synthesis of the methylenecyclopentane system (29) (an intermediate in prostaglandin synthesis) from cyclization of the enyne (28) and Corey and co-w~rkers~~ have developed a synthesis of the terpenoid isopulegone (31) from treatment of citronellol with pyridine chlorochromate which proceeds via ‘ene’ transformation of the inter- mediate citronella1 (30).38 L. Blaszczak J. Winkler and S. O’Kuhn Tetrahedron Letters 1976. 4405. 39 R. R. Schrock and J. A. Osborn J. Amer. Chem. Soc. 1976,98 2143. 40 P. W. Chum and S. E. Wilson Tetrahedron Letters 1976 15. 41 K. Avasthi S. S. Ghosh and D. Devaprabhakara Tetrahedron Letters 1976 4871. 42 G. Stork and G. Kraus J. Amer. Chem. Soc. 1976,98,6747. 43 E. J. Corey H. E. Ensley and J. W. Suggs J. Org. Chem. 1976,41 380. 3 10 G.Pattenden (30) (31) Twofurther illustrations of the scope provided by the intramolecular Diels-Alder reaction in synthesis are the preparation of polycyclic y-lactams from an appropriate unsaturated N-allylamide (32) -+ (33),44 and the synthesis of the bridged tropanoid derivative (35)from the betaine (34).45 (32) (33) (34) (35) An interesting approach to the cyclodeca-1,5-diene system found in the germa- cranolide group of terpenoids has been described by Lange et (~1.~~ The approach outlined in Scheme 9 is based on photoaddition of a substituted cyclobutene to a cyclohex-2-enone followed by thermolysis of the resulting tricyclic system (36).dcozMe \ C02Me 0 + x) Scheme 9 Gy. Frater Tetrahedron Letters 1976,4517. 45 P. G. Sammes and R. A. Watt,J.C.S. Chem. Comm. 1976,367. 46 G. L. Lange M.-A. Huggins and E. Neidert Tetrahedron Lemers 1976,4409. Synthetic Methods 3 Akynes Enynes and AUenes Acetylenes are obtained from /3-keto-esters by conversion into the corresponding 4-halogeno-2-pyrazolin-5-onefollowed by treatment with aqueous NaOH in the presence of K3Fe(CN) (Scheme They are also obtained from 1,2-diones by treatment of the corresponding thiocarbonates with (EtO),P although yields of alkyne products are not as high as via oxidation of bis-hydrazones of 1,2-diones with HgO or P~(OAC),.~’ Reagents i NHzNH2; ii PyHBR3-HOAc; iii NaOH-K3Fe(CN)6.Scheme 10 Pelter and Smith and co-workers have extended their studies of the synthesis of diynes from alkynylborates and now show that unsymmetrical dialkynyldicy- clohexylborates can be prepared by stepwise addition of two different lithium alkynes to dicyclohe~ylmethylthioborane.~~ Reaction of these borates with iodine then leads to the unsymmetrical conjugated diyne (Scheme 11).In contemporane- R = cyclohexyl LiCECR’1 R’C=C-C_CRZ R2B-(CrCR’)(CrCR2)Li+ Scheme 11 ous studies Sinclair and Brown” have outlined a closely identical procedure for obtaining unsymmetrical conjugated diynes. An easy route to lithium trialkylal- kynylboratesis by alkylation of lithium lithioethynylborate~,~’ and a timely review of the application of these and other important organoborates in synthesis has been p~blished.~’ An efficient and stereoselective synthesis of a terminal cis-enyne unit (38) is by selective hydrogenation of the unsilylated triple bond of a diyne (37) prepared by oxidative coupling of an acetylene with trimethylsilylacetylene (Scheme l2).53A mixture of cis- and trans-a-substituted terminal enynes has been obtained by Cope rearrangement of dienynols prepared from the acetylenic Grignard reagent (39) and a~rolein,’~whereas trans-enynes of type (40) are obtained by treating a-cyclopropylacetylenic carbinols with a mixture of HBr and ZnBr in the presence of 47 P.J. Kocienski J. M. Ansell and B. E. Norcross,J. Org. Chem. 1976,41,3650. 48 D. P. Bauer and R. S. Macomber J. Org. Chem. 1976,41,2640. 49 A Pelter R. Hughes K. Smith and M. Tabata Tetrahedron Letters 1976,4385. so J. A. Sinclair and H. C. Brown J. Org. Chem. 1976,41 1078. 51 K. Utimoto Y. Yabuki K. Okada and H. Nozaki Tetrahedron Letters 1976,3969. 52 E.-I. Negishi J. Organometallic Chem. 1976 108 281.53 A. B. Holmes R. A. Raphael and N. K. Wellard Tetrahedron Letters 1976 1539. 54 M. L. Roumestant P. Place and J. Gore Tetrahedron Letters 1976 677. 312 G.Pattenden R-r + R-CrC-CrCSiMe -+ Ill Ill (37) SiMe (38) Scheme12 -BrMg-=C =-egBr -R2 octacarbonyldicobalt; in the absence of the octacarbonyl the latter transformation is less selective and leads to a mixture of cis-and fr~ns-enynes.~~ The potential for allenic lithiums and allenic cuprates in synthesis is well illustrated by a simple synthesis of the allenic pheromone (41)of the Dried Bean beetle (Scheme 13).56 HI 7c6 LC-=c= i ii ,=C=-C8HI7 'll-" + C0,Me (41) Reagents i BuLi; ii n-C8H17Br; iii Bu Li; iv CuI; v E-CO2Me. Scheme 13 4 Alkyl Halides In still further illustrations of the novel and diverse applications of organo-selenium compounds in synthesis Krief and his co-~orkers~~*~~ have shown that alkyl halides can be obtained from both selenides and selenoxides by treatment with appropriate halogenating agents (Br2 HBr NBS).Since selenides and selenoxides are most conveniently prepared by alkylation of a-seleno- and a-selenoxy-carbanions respec- tively the overall processes permit an effective method for the homologation of halides (Scheme 14). 5s C. Descoins and D. Samain Tetrahedron Letters 1976 745. 56 D. Michelot and G. Linstrumelle Tetruhedron Letters 1976 275. *' M. Sevrin W. Dumont L. Hevesi and A. Krief Tetrahedron Letters 1976 2647. 58 L. Hevesi M. Sevrin and A. Krief Tetrahedron Letters 1976 2651.Synthetic Methods -191RCH-SePh MeBr+ RCH-SePh +RCH-Br IMe IMe Scheme14 Although thionyl chloride is a common reagent for the preparation of alkyl chlorides from alcohols the method can also lead to products resulting from rearrangement. Rearrangements of this type are almost completely avoided how- ever by conducting the chlorinations in the presence of either DMF or HMPA.s9 Excellent yields in the well known anti-Markovnikov hydroiodination of alkenes via organoboranes using iodine and a base are realized using NaOMe rather than NaOH as the base.60 5 Alcohols Sodium hydride is much used in synthesis for the production of enolate anions from carbonyl compounds. It has little tendency to reduce carbonyl compounds.Exceptions can be found amongst certain non-enolizable ketones although vigor- ous reaction conditions are required. In contrast Fujisawa et aL61 have now shown that 'normal' carbonyl groups are reduced by NaH when the carbonyl compound is added to a yellow suspension generated by addition of FeCI3 to NaH (ratio 1 3) in THF and the resulting mixture is stirred for 24 h at 25 "C; similar reductions of aliphatic carbonyl compounds can be accomplished using FeCl in place of FeCl,. Reductions with sodium borohydride are normally carried out in polar solvents since the reagent is insufficiently soluble in non-polar solvents. A solution to this problem has been to employ in place of NaBH4 tetrabutylammonium borohydride which is very soluble in solvents such as CH2C12.62 Masse and Parayre6' have provided an alternative method by demonstrating that typical reductions with NaBH can be carried out out by phase-transfer catalysis in a H20-ClCH,CH2Cl system catalysed by ephedrinium surfactants.Developments in the hydroboratian area have made available a number of hindered trialkylboranes which can be converted into the corresponding trialkyl- borohydrides useful in the stereoselective reduction of carbonyl compounds. To add to this growing list of reagents is lithium trisiamylborohydride a highly hindered reagent which reduces cyclic ketones with exceptional steric e.g. 3-methylcyclohexanone is converted into trans-3-methylcyclohexanol in >99.5% isomeric purity. Asymmetric reductions of carbonyl groups can be effected using the chiral reagent produced from LiAIBu" and ( -)-N-methylephedrin (optical yields 8-31 Solutionsof a-amino-ester boranes in the presence of Lewis acids have also shown promise for 'asymmetric' conversions.66 59 H.R. Hudson and G. R. de Spinoza JCS Perkin I 1976 105. 6o N. R. De Lue and H. C. Brown Synthesis 1976 114. 61 T. Fujisawa K. Sugirnoto and H. Ohta J. Org. Chem. 1976 41 1667. 62 D. J. Raber and W. C. Guida J. Org. Chem. 1976,41,690. 63 J. P. Masse and E. R. Parayre J.C.S. Chem. Comm. 1976,438. 64 S. Krishnamurthy and H. C. Brown J. Amer. Chem. Soc. 1976,98 3383. 65 G. Boireau D. Abenhaim J. Bourdais and E. Henry-Basch Tetrahedron Letters 1976 4781. 66 M. F. Grundon D. G. McCleery and J. W. Wilson Tetrahedron Letters 1976 295.314 G. Pattenden A timely full account of the use of 9-borabicyclo[3,3,1] nonane (9BBN) as a selective reducing agent for representative functional groups has been published by Brown and his co-w~rkers.~~ Last year it was shown that the lithium di-n-butyl ‘ate’ complex of 9BBN is a useful reagent for the selective reduction of tertiary alkyl halides to hydrocarbons. This year Yamamoto and his group have also found that the reagent also has considerable potential for the stereo- and regio-selective reductions of carbonyl groups.68 Thus 4-methylcyclohexanone in MeOH is reduced to cis-4-methylcyclohexanol (84%) whereas in MeOLi it is reduced largely to the trans-alcohol (goo/,). In addition the reagent discriminates admirably between the carbonyl groups of aldehydes and ketones [equation (l)]and even between two + J 5YO ketone carbonyl groups [equation (2)J The reagent even reduces aryl and aliphatic epoxides in a discriminatory manner;69 thus aryl epoxides are reduced at the most A+&-& 91% + & 9Yo sterically hindered positions leading to carbinols (42) whereas aliphatic epoxides are reduced at the least hindered positions [leading to (43)] (Scheme 15).It is clear that we are going to hear more about 9-BBN ‘ate’ and related reagents in synthesis. They offer considerable scope for the chemo- regio- and stereo-selective reduc- tions of many functional groups. Ally1 silanes are known to react with electrophiles to produce substitution products with loss of the trimethylsilyl group and a shift of the double bond.In illustrations of the synthetic utility of this transposition Hosomi and Sakurai7’ have developed a ready synthesis of 76-unsaturated alcohols via condensation with carbonyl compounds in the presence of a Lewis acid [viz.(44) +(45)] and Carter and Fleming’l have shown that treatment of the ally1 silane (46) with peracetic acid produces the corresponding allylic alcohol (47). 67 H. C. Brown S. Krishnamurthy and N. M. Yoon J. Org. Chem. 1976,41 1778. Y. Yamamoto H. Toi A. Sonoda and S. 1. Murahashi J. Amer. Chem. Soc. 1976,98 1965. 69 Y. Yamamoto H. Toi A. Sonoda and S. I. Murahashi J.C.S. Chem. Comm. 1976 672. 70 A. Hosomi and H. Sakurai Tetrahedron Letters 1976 1295. 71 M. J. Carter and I.Fleming J.C.S. Chem. Comm. 1976 679. Synthetic Methods 3 15 OH Bu -,Bu B Scheme 15 .COR R1 -HoyJ.coR (44) (47) A useful 1,3-transposition of ally1 alcohols can be accomplished via sequential epoxidation and mesylation to an epoxy-mesylate (48) followed by reductive elimination (Scheme 16).72 i.ii RwMs OH OH (48) Reagents i [V0(aca~)~)-Bu'OH; ii Et3N-MeS02CI; iii Na-NH3; iv NH4CI. Scheme 16 The method of preparation of cis-1,2-diols via catalytic osmylation of alkenes using chlorate or H202to regenerate the osmium tetroxide suffers from the disad- vantage that further oxidation to an a-ketol is frequently encountered. Two new procedures which avoid the a-ketol by-products use either tertiary amine or t-butyl hydroperoxide under alkaline as the oxidant.In systematic studies of the pinacolic coupling of ketones and aldehydes Corey and his co-worker~~~ have shown that the three titanium-based reagents MgCl-TiC14 cyclopentadienyl-TiC13-LiAll% and the hexamethylbenzene complex of 72 A. Yasuda H. Yamamoto and H. Nozaki TetrahedronLetters 1976,2621. 73 V. VanRheenen R. C. Kelly and D. Y.Cha TetrahedronLetters,1976 1973. 74 K. B. Sharpless and K. Akashi J. Amer. Chem. Soc. 1976.98 1986. 75 E. J. Corey R. L. Danheiser and S. Chandrasikaren,J. Org. Chem. 1976,41 260. 3 16 G.Pattenden Ti(CI,AICI,) are consistently the most effective reagents for carrying out both inter- and intra-molecular couplings. The scope for the reaction is illustrated by the synthesis of the tricyclic system (50)by intramolecular coupling of the keto-aldehyde (49).H H (55%) (49) (50) A new protecting group for primary secondary and tertiary alcohols is the P-methoxyethoxymethyl (MEM) group MeOCH2CH20CH,. It is stable to base and mild acid and its removal is accomplished under aprotic conditions with mild .~~ Lewis acids (ZnBr, Yamada et ~1 have established that the methyl- thiomethyl protecting group is equally effective for tertiary alcohols as for primary and secondary alcohols. 6 Ethers The synthesis of epoxides by treatment of olefinic substrates with peracids is a common enough procedure but not without its dangers. Meyers and S~hwartzman~~ emphasize that special precautions should be taken when effecting epoxidations of olefinic alcohols protected as their tetrahydropyranyl ethers.They found that epoxidation of (51)using 40% peracetic acid gave not only the epoxide (52) but also sensitive peroxides produced from the tetrahydropyranyl protecting group which detonated violently after purification of (52) by distillation. A similar explosion resulted when the hydroboration product of the tetrahydropyranyl ether (53) was routinely oxidized using alkaline H202. (53) Anions derived from N-to~ylsulphilimines,~~ and a-seleno-carbanions8' are useful alkylidine transfer reagents for the synthesis of epoxides from carbonyl compounds. The addition of a-seleno-carbanions to enones followed by methylation of the intermediate selenide (54) and treatment with base provides a particularly valuable 76 E.J. Corey J.-L. Gras and P. Ulrich Tetrahedron Letters 1976 809. 77 K. Yamada K. Kato H. Nagase and Y. Hirata Tetrahedron Letters 1976 65. 78 A. I. Meyers and S. Schwartzman Tetrahedron Letters 1976,2417. 79 Y. Tamura H. Matsushima and M. Ikeda Synthesis 1976 35. 8o D. Van Ende and A. Krief TetrahedronLetters 1976,457. Synthetic Methods synthesis of ap-unsaturated epoxides (Scheme 17). The procedure is a useful complement to those involving alkylidene transfer from sulphur ylides to enones which are of wide application only in the methylene case. Reagents i MeSeCR2; ii Mel; iii BuO. Scheme 17 Reactions of either stabilized phosphoranylides of type (55)or partly stabilized ylides of the benzyl type with formates produce vinyl ethers in high overall yield; the more reactive alkyl phosphoranylides on the other hand give rise to the acylated products [viz.(56)]instead." Me02CCH=PPh3 4MeO,CCH=CHOEt (55) -EtCHPPh 4EtCH=PPh, 1 CHO (56) Good methods for the de-0-methylation of primary and secondary alkyl methyl ethers are limited.A method which shows some promise is by use of BF etherate in the presence of thiols. A feature of the method is that alcohols derived from secondary alkyl methyl ethers can be secured with retention of configuration." High-yield methylenations of catechols with dihalogenomethane can be realized in the presence of an excess of KF or CsF in DMF A non-photochemical route to oxirans involves base treatment of 3,4-epoxy- alcohols in DMSO [viz.(57)-+ (58)].R4The cyclization of trans-epoxy allyl ethers of type (59) in base is also shown to produce oxirans.8s The dienal (61) resulting from a homo-[4,5] sigmatropic change is one of the interesting products produced in the Wittig rearrangement of allyl vinylcyclopropyl- methyl ether (60).86 V. Subramanyam E. H. Silver and A. H. Soloway J. Org. Chem. 1976,41 1272 M. Node H. Hori and E. Fujita J.C.S.Perkin I 1976 2237. 83 J. H. Clark H. L. Holland and J. M. Miller Tetrahedron Letters 1976 3361. 84 A. Murai M. Ono and T. Masamune J. C. S. Chem. Comm. 1976 864. 85 W. C. Still Tetrahedron Letters 1976 2115. 86 L. Crombie G. Darnbrough and G. Pattenden J.C.S. Chem. Comm. 1976 684. 3 18 G.Pattenden 7 Amines The 'reagent' sodium trifluoroacetoxyborohydride prepared in situ from NaBH and CF3C02H,can be added to the long list already available for the reduction of nitriles and amides to amines." Another new procedure for the conversion of amides into amines is by reduction of the corresponding Vilsmeier complexes (62)of the amide with NaBI-€+88 c1 POC13 I+ H-R'CH2CONR22 b R'CHC=NR22 -R1CH2CH2NRZ2 (62) A useful asymmetric synthesis of amines has been accomplished by transamination of the amino-group from an optically active amino-acid to a ketone according to Scheme 18.89Hydrogenation of the Schiff base (63) prepared from the ketone and R' R' \C=N -L 'CH-NH I R2/ R3dHC02R4 R2/ R3CHC02R4 (63) (44) Reagents i H2-PdlC; ii Bu'OCI; iii NaOEt; iv HzC04.Scheme18 N. Umino. T. Iwakuma and N. Itoh Tetrahedron Letters 1976 763 2875. A. Rahman A. Basha N. Waheed and S. Ahmed TetrahedronLetters 1976,219. S. Yamada N. Ikota and K. Achiwa TetrahedronLetters 1976 1001. Synthetic Methods 319 the amino-acid leads first to a mixture of diastereoisomers of the N-alkylated amino-acid ester (64). Treatment of this ester with Bu'OCl and NaOEt then leads to the new Schiff base (65) which is hydrolysed to the optically active amine. Overman has developed a new synthesis of amines based on thermolysis of ally1 alcohol trichloroacetimidic esters to give by overall 1,3-transposition amides (66) which are hydrolysed in base.90 R R R R COCCI, NH 8 Aldehydes and Ketones Posner and his colleaguesg1 have extended their studies of the use of alumina as a 'reagent' in synthesis and shown that the oxidation of secondary alcohols can be performed heterogeneously within the micropores of the solid alumina.After investigating various carbonyl compounds as hydride acceptors they found tri- chloroacetaldehyde to be the most suitable oxidant. Oxidations are simply per- formed by stirring mixtures of equivalent amounts of alcohol and CC1,CHO in CCl in the presence of Woelm W-200 neutral dehydrated alumina at room temperature for 24 h. The general method also permits the selective oxidation of some diols into the corresponding keto-alcohols e.g. MeCH(OH)(CH2)8 CH,OH -+MeCO(CH2)8CH20H (65%). Contrary to some earlier reports trifluoroacetydimethylsulphonium trifluoro-acetate prepared in situ from DMSO and TFAA below -50 "C reacts with alcohols to give a sulphonium salt intermediate which produces carbonyl compounds on treatment with Et3N.92 Although the method complements previous reagents based on DMSO it appears to be more efficient (yields 80-100%) and is applicable to sterically hindered alcohols.93 Several useful procedures for the oxidation of alcohols to carbonyl compounds via the corresponding 0-trialkylstannyl (using NO' Br, or NBS)94-97 or 0-trimethylsilyl (using Ph3C+ or derivatives have emerged.Two particularly effective methods for carrying out the conversion R2CHOH-+R2C0 are by phase-transfer catalysis with aqueous NaOClg9 and by N-methylmorpholine-N-oxidein acetone in the presence of a ruthenium catalyst e.g.LRuC12( Ph3),]. loo The number of 'methods' for the oxidation of alcohols to carbonyl compounds based on chromic acid seems endless. This year Cardillo and his co-workers have shown that chromic acid in HMPA is particularly effective for the oxidation of 90 L. E. Overman J. Amer. Chem. SOC.,1976,98 2901. 91 G. H. Posner R. B. Perfitti and A. W. Runquist Tetrahedron Letters 1976 3499. 92 K. Omura A. K. Sharma and D. Swern J. Org. Chem. 1976,41,957. 93 S. L. Huang K. Omura and D. Swern J. Org. Chem. 1976,41 3329. 94 G. A. Olah and T. L. Ho Synthesis 1976 609. 95 Y. Ueno and M. Okawara Tetrahedron Letters 1976,4597. 96 K. Saigo A. Morikawa and T. Mukaiyama Bull. Chem. SOC.Japan 1976,49 1656. 97 T. Ogawa and M.Matsui J. Amer. Chem. SOC.,1976,98 1629. 98 M. E. Jung J. Org. Chem. 1976,41 1479. 99 G. A. Lee and H. H. Freedman Tetrahedron Letters 1976 1641. loo K.B. Sharpless K. Akashi and K. Oshima Tetrahedron Letters 1976,2503. 320 G.Pattenden alcohols containing acid-sensitive groups.lof They also report the use of CrO on anion-exchange resins where the oxidations can be carried out by a batch technique simply by stirring an excess of the CrO,H- resin with the alcohol in a suitable refluxing solvent followed by isolation of the product by filtration evaporation and distiIlati~n.'~~*'~~ Cardillo et al. have also found that alkyl halides are converted into aldehydes by chromate ion in HMPA in the presence of crown ethers;lo4 this reaction is apparently without precedent.In a procedure complementary to the use of aqueous TiC13 Kirchhoff lo5 has shown that nitro-compounds are smoothly converted at low pH into the corresponding carbonyl compounds by VCl in DMF. Carbonyl compounds can be obtained from nitriles by hydride reduction and subsequent hydrolysis of the 1,3-benzoxanthiolium tetrafluoroborates produced by reaction between the nitrile and 0-mercaptophenol in the presence of tetrafluoroboric acid.lo6 There have been several improvements and modifications to the Rosenmund method of reduction of acid chlorides to aldehydes in the past few years. A new and particularly convenient modification leading to high yields of aldehyde products involves hydrogenation in THF in the presence of one equivalent of 2,6-dimethylpyridine and Pd on BaS04 as cata1y~t.l~~ The reduction of esters by sodium bis-(2-methoxyethoxy)aluminium hydride modified by the addition of one equival- ent of N-methylpiperazine leads to higher yields of aldehyde products than proce- dures based on diaminoaluminium hydride reducing agents."' Habeeb and Tuck show that ketones can be produced by electrochemical abstraction of halogen from mixtures of acid chlorides and alkyl halides at a cadmium anode.lo9 Alternatively organocopper(1) ate complexes of Grignard reagents and methylcopper(1) can be used with advantage over the usual methods for the synthesis of ketones from acid chlorides.' lo Phenylselenoethyltrimethylsilane(67) prepared from diphenyl sulphide by reac- tion with NaBH and chloromethyltrimethylsilane is an exceptionally useful reagent for the synthesis of aldehydes from alkyl halides (Scheme 19).'" Treatment of (67) Me,SiCH2SePh -+ Me,SiCH RCH2Br B Me3SiCHCH2R -+ OHCCH2R I 1 SePh SePh with a lithium dialkylamide (LDA) generates the anion (68) which functions as a protected formyl anion.Subsequent reaction with the alkyl halide then leads to the Iol G. Cardillo M. Orena and S. Sandri Synrhesis 1976 394. lo* G. Cainelli G. Cardillo M. Orena and S. Sandri J. Amer. Chem. SOC.,1976,98 6737. Io3 G. Cardillo M. Orena and S. Sandri Tetrahedron Letters 1976 3985. Io4 G. Cardillo M. Orena and S. Sandri J.C.S. Chem. Comm. 1976 190. Io5 R. Kirchhoff Tetrahedron Letters 1976 2533. Io6 1. Degani and R. Fochi Synthesis 1976 757.lo7 A. W. Burgstahler L. 0.Weigel and C. G. Shaefer Synthesis 1976 767. Io8 R. Kanazawa and T. Tokoroyama Synthesis 1976 526. Io9 J. J. Habeeb and D. G. Tuck J.C.S. Chem. Comm. 1976 696. 'lo D. E. Bergbreiter and J. M. Killough J. Org. Chem. 1976 41 2750. K. Sachdev and H. S. Sachdev Tetrahedron Letters 1976,4223. Synthetic Methods alkylation product (69),which with peroxide directly affords the aldehyde; the last stage of this reaction is envisaged as proceding uia decomposition of a p-h ydrox yselenide intermediate. A useful-looking sequence for converting a terminal alkene into an aldehyde involves transformation into the phenyl alkyl sulphide by free-radical addition of thiophenol followed by oxidation with NCS and hydrolysis;"2 the method provides a useful alternative to those based on hydroboration-oxidation (Scheme 20).Scheme 20 Nitrile oxides are known to add very easily in a 1,3-dipolar manner to olefins giving rise to substituted A'-isoxazolines. The ease with which this reaction can be effected has been exploited by Kalvoda and Kaufmann1I3 in the development of a new procedure for the 'non-oxidative' cleavage of double bonds (Scheme 21). In A R'CHO R2CH2CN Scheme21 their method the isoxazoline (70)prepared from the olefin substrate and ethoxycar- bonylformonitrile oxide is simply hydrolysed and the resulting free acid is then decarboxylated to produce a carbonyl compound and a nitrile. In an alternative sequence U.V. irradiation of the corresponding isoxazolines formed from triphenylacetonitrile oxides leads to the same cleavage products.Hydrazones feature prominently this year in a number of synthetically useful transformations [see p. 333 (Sect. 12. Alkylation)]. Although the efficient regen- eration of carbonyl compounds from hydrazones has been a problem in the past studies show that the hydrolyses can be accomplished smoothly using either cupric- ion catalysis,114 oxidatively with NaIO, MoC12 MoF6 WF6 and Na202,115*116 or with nitronium and nitrosonium salts.117 A new method for the protection of the carbonyl function is by conversion into the 5,5-dibromo- 1,3-dioxan derivative using crystalline 2,2-dibromopropane- 1,3- diol;"8 the protecting group is easily removed with Zn-Ag couple at 25 "C in THF containing HOAc.Il2 P. Bakuzis M. L. F. Bakuzis C. C. Fortes and R. Santos J. Org. Chem. 1976 41 2769. Il3 H. Kaufrnann and J. Kalvoda J.C.S. Chern. Cornm. 1976 209 210. 114 E. J. Corey and S. Knapp Tetrahedron Letters 1976,3667. ILs G. A. Olah J. Welch G. K. S. Prakash and T. L. Ho Synthesis 1976 807. T. L. Ho and G. A. Olah Synthesis 1976 611. G. A. Olah and T. L. Ho Synthesis 1976 610. 11* E. J. Corey E. J. Trybulski and J. W. Suggs Tetrahedron Letters 1976 4577. 322 G. Pattenden Functionalized Aldehydes and Ketones.-Although most organo-mercuric com- pounds are completely unreactive towards acid halides vinyl-mercury derivatives have been shown to react within minutes with acid chlorides in the presence of AlCl to give excellent yields of a@-unsaturated ketones.’” Since the vinyl mercurials are easily available by a variety of acetylene addition reactions this method becomes an attractive synthesis of enones.An equally attractive synthesis of ap-unsaturated aldehydes is from tosylhydrazones of type (71) following metalation to (72) trapping of the intermediate alkenyl-lithium species (73) with DMF and hydrolysis.’20 (73) 2-Isoxazolines (74) which are easily accessible by 1,3-dipolar cycloadditions of nitrile oxides to alkenes fragment on treatment with LDA to produce oximes which are smoothly cleaved with TiCl to the corresponding enones (Scheme 22).’” The Scheme 22 commercially important rearrangement of t-propargylic alcohols to &@-unsaturated aldehydes [uit.(75)+(76)] is cleanly effected in the presence of polymeric organosilyl vanadates (R,SiO),VO. ‘22*123 u*- OH \ ‘0 (75) (76) A simple yet highly effective route to a@-unsaturated aldehydes is by a new ‘directed aldol’ condensation using silyl aldehyde dimethylhydrazones as key inter- mediates (Scheme 23).124 In the method the aldehyde hydrazone is first metalated and then treated with Me,SiCI leading to the silylated hydrazone (77). Further treatment with LDA and reaction with a ketone followed by acid treatment then lI9 R. C. Larcock and J. C. Bernhardt Tetrahedron Letters 1976,3097. lZo P. C. Traas H. Boelens and H. J. Takken Tetrahedron Letters 1976 2287. lz1 V. Jager and H. Grund Angew. Chem. Internat. Edn. 1976 15 50. 122 M. B. Erman 1.S. Aul’chenko L. A. Kheifits V. G. Dulova J. N. Novikov and M. E. Vol’pin Tetrahedron Letters 1976 2981. lZ3 H. Pauling D. A. Andrews and N. C. Hindley Hefu.Chim.Acta 1976,59 1233. 124 E. J. Corey D. Enders and M. G. Bock Tetrahedron Letters 1976 7. Synthetic Methods SiMe3 R ’. .I n Reagents i LDA; ii Me3SiC1; iii R’COR2; iv H+ Scheme23 completes the synthesis of the enal. In an alternative sequence the corresponding silyl aldimine is used in place of the silyl hydrazone. Methods for effecting ‘directed aldol’ condensations not involving masked car- bony1 compound intermediates are limited. Sometime ago Stork and his co-workers reported the ‘kinetic’ generation of enolates from ketones and a demonstration of the potential for this approach in synthesis is provided by a new synthesis of the aldol (79)’a naturally occurring pungent principle of ginger (Scheme 24) starting from the MeOe M e O e0 RO ‘ 4 RO ‘ (75) 0 OH Reagents i (Me3Si),NLi; ii Me(CH2)dCHO; iii H+ Scheme24 ketone (78).12’ Kuwajima et ~1.’~~ have shown that the specific enolate of a methyl ketone can also be generated effectively in the presence of a hindered base such as lithium l,l-bis(trimethylsilyl)-3-methylbutoxide.Even more interesting is the generation of the specific enolate in the presence of an aldehyde which leads to high yields (70-80%) of aldols. Active enolates of ketones are produced in a regioselec- tive manner by the reduction of 2,2,2-trichloroethyl esters of a-substituted 0-keto- acids with zinc (Scheme 25).12’ A flexible synthesis of vinylogous aldols has been described by Stork and his co-workers128 whereby the methyl ether of an acylic 1’3-dione is converted under Iz5 P.Denniff and D.A. Whiting J.C.S.Chem. Comm. 1976 712. I. Kuwajima T. Sato M. Arai and N. Minami Tefruhedron Letters 1976 1817. T. Mukaiyama T. Sato S. Suzuki T. Inoue and N. Hakamura Chem. Letters 1976 95. G. Stork and G. A. Kraus J. Amer. Chem. Soc. 1976,98 235. 324 G.Pattenden 00 R'CHO-Z" R-OCH,CCI ___* R Scheme25 kinetic control into the enolate (80) which by reaction with a carbonyl compound produces (8 1);reduction of (8 1)and mild acid treatment then leads to the vinylogous aldol. 0 OMe The most commonly used methods for reducing enones to the corresponding saturated carbonyl compounds are either by catalytic hydrogenation or by sodium in liquid ammonia.Some recently described alternative methods of accomplishing this type of reduction include the LiAIH,-based cocktails LiAlH,-CuI and LiAIH4- TiC13129and the hydride complexes Na[HFe2(C0),]130 and Na[HCr2(CO)lo].'31 The transposition of cyclic enones to their most stable a@-unsaturated enones via migration of the double bond about the rings is conveniently carried out at 100"C in a sealed tube in the presence of RuC1,,3H20 as catalyst [e.g. (82) -+ (83)].'32 W+Q 0 Bu 0 Bu (82) (83) Organozirconium intermediates feature in a new synthesis of yhnsaturated aldehydes from 1,3-dienes (Scheme 26). It is found that the hydride [(q5-Scheme26 129 E.C. Ashby J. J. Lin and R. Kovar J. Org. Chem. 1976,41 1939. 13" J. P. Collman R. G. Finke P. L. Matlock R. Wahren and J. I. Brauman,J. Amer. Chern. Soc. 1976,98 4685. IJ1 G. P. Boldrini and A. Umani-Ronchi Synthesis 1976 596. 132 P. A. Grieco M. Nichizawa N. Marinovic and W. J. Ehmann J. Amer. Chem. Soc. 1976,98 7102. Synthetic Methods C5H5)2Zr(H)C1]reacts with the dienes via 1’2-addition to the sterically less hindered olefinic bond to give y6-unsaturated complexes which when treated with CO Y produce the corresponding acyl species (84) which is easily hydrolysed to the unsaturated aldehyde. 133 In an approach to the asymmetric synthesis of 3-substituted aldehydes it has been shown that the chiral a@-unsaturated aldimines (85)’ prepared from optically active a-amino-acid t-butyl esters undergo conjugate addition with Grignard reagents producing intermediates of the type (86) which on hydrolysis furnish the 3-substituted derivatives with ca-91-98% optical This approach to asymmetric synthesis is closely similar to those made by Meyer and his co-workers using lithiated chiral oxazolines.Pr’ Pr’ H R-Ni :pri R’M~B~ H20p Rho OBu‘ R’ OBu‘ R’ BrMg (85) Trimethylsilyl enol ethers and epoxysilanes were highlighted separately last year as reagents of considerable potential in synthesis. In a ‘marriage’ between the two reagents it is now shown that epoxysilanes undergo rearrangements to the isomiric silyl enol ethers thermally,’35”36 or in some instances in the presence of magnesium bromide ethe~ate.~~~ Another method for the2ynthesis of silyl enol ethers is by retro-Diels-Alder reaction of silyl ethers of type (87) prepared from dehydronor- &7) ~amph0r.I~~ An instructive demonstration of the use of silyl en01 ethers in synthesis is a new method of preparation of 1,4-diones based on Michael addition of the silyl ether to a nitro-olefin catalysed by Lewi acids (Scheme 27).13’ In an alternative new synthesis of 1,4-diones Tsuji et aZ.14’ have shown that a-allyl-ketones can be oxidized with palladium chloride-cuprous chloride in DMF under an oxygen Scheme27 133 C.A. Bertelo and J. Schwartz J. Amer. Chem. Soc. 1976,98 262. 134 .%-I. Hashimoto. S.-I. Yamada and K. Koga J. Amer. Chem. Soc.1976,98 7450. 135 P. F. Hudrlik C. N. Wan and G. P. Withers Tetrahedron Letters 1976 1449. 136 A. R. Bassindale A. G. Brook P. Chen and J. Lemon J. Organometallic Chem. 1976,94 C21. P. F. Hudrlik R. N. Misra G. P. Withers A. M. Hudrlik R. J. Rona and J. P. Arcdeo Tetrahedron Letters 1976 1453. 13* J. Haslouin and R. Rouessac Bull. SOC.chim. France 1976 1122. 13y M. Miyashita T. Yanami and A. Yoshikoshi J. Amer. Chem. SOC.,1976,98,4679. I4O J. Tsuji I. Shimizu and K. Yamamoto Tetrahedron Letters 1976 2975. 326 G.Pattenden atmosphere. 1,4-Diones are pivotal intermediates in a large number of syntheses of cyclopent-2-enones and new reviews of their methods of synthesis are A generally useful synthesis of fused polycyclic cyclobutane derivatives which provides a valuable complement to the use of dichloroketen involves as a first stage acyloin condensation of an appropriate ‘succinate’ (88) followed by hydrolysis acetylation [to (fig)] and reduction with zinc dust.’43 The ring-opening of activated OSiMe OSiMe OAc bicyclo[3,1 ,O]hexane intermediates by nucleophiles has provided a useful strategy for the synthesis of the prostaglandin intermediate (90),’44 and also for the stereocontrolled creation of the C,-side-chain of steroids (Scheme 28).14’ Scheme28 The utilization of ‘masked’ functionality has emerged as a powerful tool in design of synthesis during the past few years and the whole area of ‘methods’ for inversion of carbonyl reactivity (carbonyl umpolung) has been excellently reviewed by Lever.146 Although dithian anion remains the most valuable acyl anion equivalent currently used in synthesis Warren and co-worker~~~~ have demonstrated that the correspondingbis(pheny1thio)-carbanion (91)offers some advantages over dithians in the synthesis of ketones of the type R’COCHR2R3 from alkyl halides R’X and carbonyl compounds R2R3C0 (Scheme 29).I4l S. Nimgirawath E. Ritchie and W. C. Taylor Austral. J. Chem. 1976,29 339. 142 G. Rio and A. Lecas-Nawrocka Bull. SOC.chim. France 1976,317. 143 R. D. Miller D. L. Dolce and V. Y. Merritt J. Org. Chem. 1976,41 1221. K. Kondo E. Hiro and D. Tunemoto Tetrahedron Letters 1976,4489. 145 B. M. Trost D. F. Taber and J. B. Alper Tetrahedron Letters 1976 3857. 146 0.W. Lever Tetrahedron 1976,32 1943.147 P. Blatcher J. 1. Grayson and S. Warren J.C.S. Chem. Comm. 1976 547. Synthetic Methods (ai \ R' H OH n Reagents:i BuLi; ii R2R3CO;iii TFA. Scheme29 9 Carboxylic Acids and Amino-acids Meyers and his co-~orkers~~~ have now published full details of their elegant studies of the use of the readily available chiral oxazolines (92) for the asymmetric synthesis of a-alkylalkanoic acids. In a new illustration of the utility of (92; R = H) in asymmetric synthesis Meyers and Whitter~'~~ have described a preparation of w-methoxy-P-substituted acids (93) which can be transformed into chiral valerolac- tones (Scheme 30). OMe OMe (92) jii-v c- vi meow^^,^ H Bu Reagents:i MeOCH2CH2CHO;ii TFA; iii BuLi; iv MeOH;v Hf; vi BBr3.Scheme 30 Superoxide was highlighted last year as a potent and synthetically useful oxygen nucleophile. It is now shown that superoxide also reacts with a-keto- a-hydroxy- and a-halogeno-ketones -esters and -carboxylic acids in the presence of 18-crown- 6 resulting in the oxidative cleavage of these compounds to carboxylic acids.lso Yamada et al. have described two new approaches towards the asymmetric synthesis of amino-acids. In one approach (Scheme 31) use is made of the chiral Schiff base (94) from glycine t-butyl ester and (lS,2S,SS)-2-hydroxypinan-2-0ne and the derived chiral carbanion (95).lS1Another asymmetric synthesis is achieved by transamination of the amino-group from an existing optically active amino-acid to an a-keto-e~ter.'~~ Alkylation of the trianion produced from hippuric acid or the dianion obtained from ethyl hippurate is shown to lead to C-alkylated products (96) which are 148 A.I. Meyers G. Knaus K. Kamata and M. E. Ford J. Amer. Chem. Soc. 1976,98 567. 149 A. I. Meyers and C. E. Whitten TetrahedronLetters 1976 1947. 150 J. San Filippo C. I. Chern and J. S. Valentine,J. Org. Chem. 1976,41 1077. S. I. Yamada T. Oguri and T. Shioiri J.C.S. Chem. Comm. 1976 136. Is* S. I. Yamada and S. I. Hashimoto Tetrahedron Letters 1976 997. 328 G.Pattenden H+ H,N H X @>C02Bu1 + R C0,Bu' Scheme31 PhCONHCH2CO2H + PhCON-CHC02-+ PhCONHCHC02H I R (96) hydrolysable to amino-acids 153 and Tabushi et al.ls4have shown that amino-acids are obtained directly from a-keto-acids and ammonia in the presence of sodium hydrosulphite as a reducing agent.The total optical resolution of a-amino-acids and ester salts has been accom- plished by Cram and his group15s using a resin-bound host (RR)-(97)produced from covalent attachment of the chiral cyclic pol yether to macroreticular cross-linked pol ystyrene-p-divin ylbenzene. 10 Exters and Functionalized Esters A simple stereoselective synthesis of trans-cup-unsaturated esters is achieved by treatment of vinyl alanes derived from 1-alkynes with methyl chloroformate fol-lowed by hydrolysis. lS6 a-Hydroxy-esters are produced when the anion obtained from the ortho-ester (98) is treated with carbonyl and a useful Is3 A. P. Krapcho and E. A. Dundulis Tetrahedron Leners 1976 2205.ls4 I. Tabushi Y. Yabushita and T. Nakajima Tetrahedron Letters 1976 4343. lSs G. Dotsevi Y. Sogah and D. J. Cram J. Amer. Chem. Soc. 1976,98,3038;cf. S. C. Peacock and D. J. Cram J.C.S. Chem. Comm. 1976 282. G. Zweifel and R. A. Lynd Synthesis 1976 625. Is7 W. D. Woessner Chem. Letters 1976 43. Synthetic Methods MeS MeS 'r OH (98) method for the homologation of aldehydes to a-halogeno-esters proceeds via the intermediate a-trimethylsilyl vinyl sulphide (99) (Scheme 32).'" The Lewis acid-PMe3 RCHO+(Me3Si)2CSR' + RCH=C .-& RCHC0,Et I 'SR' c1 (99) Reagents i NCS-EtOH. Scheme32 catalysed reaction between an olefin and acrylate previously reported to produce cyclobutanes actually leads to &unsaturated esters (100)via an ene rea~tion."~ H (100) Lactones.-Metal hydride reductions of unsymmetrical cyclic anhydrides to y-lactones usually occur at the more hindered carbonyl group (i.e.(102) +(101)l.The interesting observation has now been made that this highly regioselective reduction is reversed (i.e. (102)-+ (103)] when the anhydride is hydrogenated in the presence of [RuC~,(PP~,)~] as catalyst.16' An alternative and novel method of obtaining (103) and related lactones is by selective oxidation of the corresponding p-allenic alcohol (104) with H2O2-benzonitrile;the reaction is depicted as proceeding via isomerization of the intermediate allene oxide (105).16' / t: - t e = (104) (10-5) ls8 B. T. Grobel and R.Burstinghaus Synthesis 1976 121. lS9 H. Greuter and D. Bellus Synth. Cumm. 1976,6 409. lb0 P. Morand and M. Kayser J.C.S. Chem. Comm. 1976 314. 16l M. Bertrand J. P. Dulcere G. Gil J. Grimaldi and P. Sylvestre-Panthet Tetrahedron Letters 1976 3305. 330 G.Pattenden Activated cyclopropanes of the type (106) can be converted smoothly into y-lactones with inversion of configuration by solvolysis in acetone.162 Dimethylaminomethylation of the lactone (107) which is best effected with the specific Mannich agent CH2=NfMe21-,163 followed by conversion into the methiodide and base treatment then completes a useful synthesis of the a-methylenebutyrolacetone ring system from a cyclopropane (Scheme 33).164 Scheme 33 A refreshing new approach towards the synthesis of the a-methylenebutyrolacetone system involves the simultaneous construction of a car- bocyclic ring and the fused lactone from an acyclic 2-bromo-aldehyde [viz.(lOS)] under mild conditions with a Zn-Cu couple at 25 OC.16’ (108) Macro1ides.-Without doubt the more useful synthetic routes to macrolides have proceeded via lactonizations of appropriate hydroxy-acid precursors. The key features of design in this approach have been choice of protecting groups for the terminal OH and COIH functions during the construction and the development of ‘methodology’ for the final intramolecular lactonization process. The most widely exploited method for the lactonization process has been the thermal cyclization of an ester of pyridine-2-thiol with the hydroxy-acid.This year has seen further illustra- tions of the utility of this particular method166168 and details of the reaction 162 R. K. Singh and S. Danishefsky,J. Org. Chern. 1976,41 1668. 163 G. Kinast and L. F. Feitz Angew. Chern. Infernat. Edn. 1976,15,239. S. Danishefsky T. Kitahara R. McKee and P. F. Schuda J. Arner. Chem. Soc. 1976,98,6715. 165 M. F. Semmelhack and E. S. C. Wu J. Amer. Chem. SOC.,1976,98 3384. E. J. Corey P. Ulrich and J. M. Fitzpatrick J. Amer. Chem. SOC.,1976,98 222. 16’ H. Gerlach K. Oertle and A. Thalmann Helv. Chim. Acta 1976,59 755. (a) J. Gombos E. Haslinger H. Zak and U. Schmidt TetrahedronLe#ers 1975,3391; (b)H. Gerlach K. Oertle A. Thalmann and S. Semi Helv. Chirn. Acta 1975 58 2036. Synthetic Methods 331 mechanism have been pre~ented.'~' Despite the satisfactory results with pyridine-2- thiol esters however Corey and his co-workers have extended their investigations of macrolide synthesis to other thiol esters and report significant advances based on the use of various bis-2-imidazoyl sulphides as reagents in place of 2,2'-dipyridyl di~ulphide.'~' In particular the imidazoyl sulphide (109) is the superior reagent for lactonization of long-chain hydroxy-acids.(109) R=Me or Pr' In their elegant synthesis of the macrolide antibiotic pyrenophorin (1lo) Colvin et ~1.'~~ employed di-imidazol-1-yl ketone as a lactonizing agent. Other methods which have been used successfully in the cyclization of long-chain hydroxy-acids are 1-methyl-2-chloropyridiniumiodide in the presence of trieth~larnine,'~~ BF ether-ate in the presence of unfunctionalized polystyrene beads as and several cocktails based on triphenylphosphine and azodicarboxylate.174 0 An entirely different approach to macrolide synthesis has been outlined by Mahajan,17' based on an intramolecular reverse Dieckmann reaction of an approp- riately substituted cycloalkane-1,3-dione [viz. (1 1 l)]. 169 E. J. Grey D. J. Bruneile and P. J. Stork Tetrahedron Letters 1976 3405. I7O E. J. Corey and D. J. Brunelle Tetrahedron Letters 1976 3409. E. W. Colvin T. A. Purcell and R. A. Raphael J.C.S. PerkinZ 1976 1718. 172 T. Mukaiyama M. Usui and K. Saigo Gem. Leners 1976,49. 173 L. T. Scott and J. 0.Naples Synthesis 1976 738.174 T. Kurihara Y. Nakagima and 0.Mitsunobu Tetrahedron Letters 1976 2455. 17s J. R. Mahajan Synthesis. 1976 110. 332 G.Pattenden 11 Amides and Nitriles 2-Chloro-N-methylbenzothiazolium trifluoromethanesulphonateacts as an efficient condensation agent in the preparation of amides from carboxylic acids and amine~.'~~ have shown that In a new synthetic route to amides Yamashita et di7' acyl tetracarbonyl ferrates (0) act as both reducing and acylating reagents in reactions with nitro-compounds producing amides of type (1 12) in excellent yields. RN02+ R'COFe(C0)4-+ RCONHR' (112) Formamide anions free from the presence of extraneous nucleophiles are produced when di-isopropyl formamide is treated with Bu'Lu at -95°C in a THF-ether- pentane mixture.The anions then react with carbonyl compounds producing a-hydroxy-amides in good yields. 178 Although several methods are available for converting an aldehyde into the corresponding nitrile a useful procedure is by metalation of the corresponding hydrazone followed by hydrolysis (Scheme 34).179 Triflic anhydride is highly recom- mended for the dehydration of aldoximes to nitriles,'" and a-oximino-acids are converted into nitriles by reaction with phenyl isocyanate.'81 The conjugate addition of cuprous methyltrialkylborates to acrylonitrile provides a very convenient route to alkyl nitriles.182 LDA-HMPA R2CHCH=NNMe2 ---+ R2CH-C!N &Me2 -+ R2CHCN Scheme34 A new method for 'remote functionalization' along an alkyl chain based on photolysis of a-peracetoxynitrile intermediates has been publi~hed."~ In this method a nitrile is treated with base and then oxygen to give after acylation the a-peracetoxynitrile (1 13).Photolysis of (1 13) then leads to migration of the nitrile group to the fourth carbon along the chain (Scheme 35). 12 Alkylation Hydrazones have featured prominently in a number of valuable synthetic operations during the period covered by this Report. Corey and his co-workers for exam- ple,1847185 have shown that dimethylhydrazones of enolizable aldehydes and ketones are metalated selectively at the less alkylated carbon producing lithium derivatives [uiz. (114)] which can be aklylated with alkyl halides epoxides and carbonyl compounds (Scheme 36). At the end of the sequence the dimethylhydrazone group is F.Souto-Bachiller G. S. Bates and S. Masarnune J.S.C. Chem. Comm. 1976 719. 177 M. Yamashita Y. Watanabe T. Misudo and Y. Takegarni Tetrahedron Letters 1976 1585. 178 K. Smith and K. Swaminathan J.C.S. Chem. Comm. 1976 387. T. Cuvigny J. F. LeBorgne M. Larcheveque and H. Normant Synthesis 1976 237 238. J. B. Hendrickson K. W. Bair and P. M. Keehn Tetrahedron Letters 1976,603. A. Ahmad Synthesis 1976,418. 182 N. Miyaura M. Itoh and A. Suzuki Tetrahedron Letters 1976 255. 183 D. S. Watt J. Amer. Chem. SOC.,1976,98 271. 184 E. J. Corey and D. Enders Tetrahedron Letters 1976 3. 185 E. J. Corey and D. Enders Tetrahedron Letters 1976 11. Synthetic Methods Ac I Scheme 35 / /N\ 1. 1Y N I Li I 0 Reagents i LDA; ii RX; iii CuC12-H20-THF; iv fi;V RCHO; vi CuI-Pri2S; vii Scheme 36 easily removed with aqueous NaI04 or with cupric ion.The a-lithiated hydrazones undergo 1,2-addition to a@-unsaturated ketones but they can be converted first into the copper derivatives which then undergo 1,4-additition to the enones. Reaction between the metalated hydrazone (114) and dimethyl disulphide leads to the methylthiodimethylhydrazone(1 15) which can be made to react seemingly via an acyl carbonium ion; thus treatment of (115) with mercuric ion in HOAc followed by CuCl hydrolysis led to (116)in the sequence providing a new method of introducing an acetoxy-group at a carbon centre a-to a ketonic carbony1.186 In closely related studies Sachs and Fuchsls7 have demonstrated that the tosylazohydrazones of a-bromo-ketones can be converted into the synthetic equivalent of enol cations [uiz.(117)] which by reaction with organo-copper reagents lead to a-alkyl-ketones. E. J. Corey and S. Knapp Tetrahedron Letters 1976 4687. C. E. Sachs and P. L. Fuchs J. Amer. Chem. SOC. 1975,97,7372. 334 G.Pattenden (114) + NHTs N Ts NHTs / / N N4 N Br Na2C03 0- Two versatile methods for the regio- and enantio-selective a-alkylation of ketones have emerged. In one method the ketone is first converted into the chiral hydrazone (118) which is then metalated with LDA leading to an anion with the chelate structure (119). Alkylation of this anion followed by regeneration of the new substituted ketone then gives (120) with 45435% optical purity.la8 In the second method due to Meyer etal.,the optically active amine (121),which is used in place of a hydrazine is converted into a chiral imine.Metalation alkylation and hydrolysis in a similar manner then lead to the alkylated ketone with 82-95%0 optical Ph &/R2Ci,+pl- < R2R' 4 OMe Rl%- ~ R2 i + ~0 Me R' Pr H2NTH OMe (1 18) (119) (120) (121) In a different illustration of the use of hydrazones in synthesis Stork and PonaraslgO have shown that an alkyl group can be introduced at the a-carbon of an a@-unsaturated ketone by first converting the corresponding dimethylhydrazone into the epoxy-derivative (122) followed by reaction with a Grignard reagent hydrolysis and dehydration according to Scheme 37.The selective mono-a- alkylation of a@-unsaturated aldehydes e.g. crotonaldehyde is smoothly accom- plished via the corresponding imine;lgl direct alkylation of the anion produced from D. Enders and H. Eichenauer Angew. Chem. Internat. Edn. 1976,15,549. Is9 A. I. Meyers D. R. Williams and M. Druelinger J. Amer. Chem. Soc. 1976,98 3032. 190 G. Stork and A. A. Ponaras,J. Org. Chem. 1976,41,2937. 191 G. R. Kieczykowski R. H. Schlessinger and R. B. Sulsky Tetrahedron Lerters 1976 597. Synthetic Methods Scheme37 crotonaldehyde itself has earlier been shown to lead to complex mixtures of mono- and di-a -and y-alkylated products in low yields. Treatment of a@-unsaturated aldehydes and ketones with triphenyl thioborate provides 1,3-bis(phenylthio)alkene derivatives whose anions [uiz.(123)] function as highly effective P-acyl-vinyl anion equivalents.192 Thus alkylation of the anion (123) followed by hydrolysis produces the ketone product (124) corresponding to 6-6-6-6 R SPh SPh (1 23) (124) @-alkylationof the starting carbonyl compound. Pitzele ef and have shown that to achieve selective y-alkylation of dienolate anions derived from ap-unsaturated acids it is expedient to prepare the cuprate complex of the dianion before alkylation. Thus alkylation of the dianion (125) with dimethylallyl bromide in the presence of CuI leads to a 2 :1mixture of (126) and (127) whereas in the absence of CuI the ratio favours (127). 12-13 Ring Synthesis Based largely on considerations of the preferred angle at which a nucleophile attacks u-and -bonds Baldwin’” has been able to develop a useful set of rules which permit one to predict whether any of the ring closures in Scheme 38 leading to three- to seven-membered rings are likely to occur or not.The ‘rules’ which are 192 T. &hen D. A. Bennett and A. J. Mura J. Org. Chem. 1976,41 2507. 193 B. S. Pitzele J. S. Baran and D. H. Steinman Tetrahedron 1976 1347. 194 J. A. Katzenellenbogen and A. L. Crumtine J. Amer. Chem. Soc. 1976,98,4925. 195 J. E. Baldwin J.C.S. Chem. Comm. 1976 734 738. 336 G.Pattenden n Qy 3-7-Ring favoured 5 or 6-Ring disfavoured 3-7-Ring favoured n G-k Y 3-5-Ring disfavoured 3 or 4-Ring disfavoured 3-7-Ring favoured 6 or 7-Ring favoured 5-7-Ring favoured Scheme 38 summarized on the diagrams show why for example the alcohol (129) with base is cleanly converted into the lactone (130) with no trace of (128).'96 The overall ideas reflected in the 'rules' are clearly of immense value to chemists planning syntheses.C0,Me -0Me a+-+-cx, 0 do / OMe Trost and his co-worker~'~' have extended their studies on the synthesis of cyclopentanes based on thermolysis of (siloxy)vinylcyclopropanes and show that it is expedient to use the recently developed 1-lithiocyclopropyl phenyl sulphide (13 1) for the preparation of the appropriate vinylcyclopropane precursor (133). Thus addition of (131) to a ketone followed by dehydration of the hydroxy-sulphide (132) with S0Cl2,led to the vinylcyclopropane (133) which on thermolysis and hydrolysis gave cyclopentanone (134).In closely related studies Piers et~Z.,'~~ and also Marino and have shown that vinylcyclopropanes of type (135) can be constructed uiu reaction between lithium cyclopropylcuprates and P-halogeno-cup-unsaturated ketones (Scheme 39). Furthermore by using the 2-vinyIcyclopropyl-lithium and 196 J. E. Baldwin J. Cutting W. Dupont L. Kruse L. Silberman and R. C. Thomas J.C.S. Chem. Comm. 1976,736. lY7B. M. Trost and D. E. Keeley,J. Amer. Chem. SOC.,1976,98,248;cf. R. D. Miller,J.C.S. Chem. Comm. 1976,277. 198 E. Piers C. K. Lau and I. Nagakura Tetrahedron Letters 1976 3233. Iy9 J. P. Marino and L. J. Browne J. Org. Chem.. 1976 41 3629. Synthetic Methods Scheme 39 copper reagents both these groups of workers200*z0' and othersZo2 have established that the general method can be developed for the synthesis of the corresponding cycloheptadiene system according to Scheme 40.Scheme40 Raphael in his synthesis of the germination stimulant strigol applied an interest- ing known cyclopentane annelation reaction which is based on acid transformation of an appropriate yne-diol of type (136).'03 The facility with which this transforma- tion is effected has now been exploited in a new synthesis of the 15-membered-ring ketone muscone from a 12-membered-ring ketone precursor (Scheme 41).204 Robinson annelation first described some 40 years ago has remained one of the most widely used methods for six-membered ring synthesis.There have been several E. Piers and I. Nagakura Tetrahedron Letters 1976,3237. 201 J. P. Marino and L. J. Browne Tetrrahedron Letters 1976 3241 3245. 202 P. A. Wender and M. P. Filosa J. Org. Chem. 1976,41 3490. 203 G. A. MacAlpine R. A. Raphael A. Shaw A. W. Taylor and H. J. Wild J.C.S. Perkin I 1976,411. 204 M. Baumann W. Hoffmann and N. Muller Tetrahedron Jktters 1976,3585. 338 G.Pattenden variants and modifications of the original procedure and this year two excellent reviews of the reaction and its variants have appeared.zos~zm In a sequence which actually represents an ‘anomalous’ Robinson annelation Konst et ul. have shown that enamines of either (137) or (139) are alkylated by methyl vinyl ketone at the most substituted a-positions affording bicyclic enones (138) and (140) respectively in yields of up to 70%.’07 14 General The deirelopment of computational methods as aids in the strategy and design of synthesis remains a fertile area of investigation.208-211A new book containing useful advice for the design of synthesis is highly recommended,212 and a review by Ernest under the heading ‘strategy and reality’ provides a fascinating and candid account of the ideas behind the prostaglandin synthesis developed in the Woodward Research Institute at Excellent reviews of synthetic ynamine photo-en~Iization,~~~ and the applications of catecholborane in synthesis216 are included amongst the recently introduced Tetrahedron Reports and a number of reviews of procedures for oxidation and reduction have a~peared.~~’-~~’ Other reviews of immediate interest to the synthetic chemist include one by Meyers et aLZz1on the applications of 2-oxazolines in synthesis another on crown ether chemistry,z22 and one by Crowley and Raporport on solid-phase organic ~ynthesis.”~ 205 R.E. Gawley Synthesis 1976 777. xm M. E. Jung A Review of Annelation Tetrahedron 1976,32 3. 207 W. M. B. Konst J. G. Witteveen and H. Boelens Tetrahedron 1976,32 1415. 208 E. J. Corey and W. L. Jorgensen J. Amer. Chem. Soc. 1976,98 189 203. 209 E. J. Corey and H. W. Orf and D. A. Pensak J. Amer. Chem. Soc.,1976,98,210. 210 P. E. Blower jun. and H. W. Whitlock jun. J. Amer. Chem. Soc.,1976,98 1499. H. W. Whitlock J. Amer. Chem. Soc. 1976,98,3225.212 S. Turner ‘The Design of Organic Synthesis’ Elsevier Amsterdam 1976. 213 I. Ernest Angew. Chem. Internat. Edn. 1976 15 207. 214 J. Ficini Tetrahedron 1976,32 1449. 215 P. G. Sammes Tetrahedron 1976,32 405. *I6 C. F. Lane and G. W. Kabalka Tetrahedron 1976,32 981. 217 A. H. Haines Chem. and Znd. 1976,883. 218 A. Pelter Chem. and Znd. 1976 888. 219 K. A. Korinek Chem. andZnd. 1976 931. R. H. Thompson Chem. and Znd. 1976,936. 221 A. I. Meyers and E. D. Michelich Angew. Chem. Internat. Edn. 1976.15 270. 222 H. D. Durst and G. W. Gokel Synthesis 1976 168. 223 J. I. Crowley and H. Rapport Accounts Chem. Res. 1976,9 135.

ISSN:0069-3030    

DOI:10.1039/OC9767300303

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

14 Biological Chemistry Part (i) Peptides and Proteins By P. M. HARDY Departmentof Chemistry University of Exeter Stocker Road Exeter EX4 4QD 1 Introduction In this Report peptides are given more attention than proteins but conformational studies and methods of sequencing are omitted and new syntheses (as opposed to methods) cyclic peptides and compounds containing non-protein amino-acids receive scant mention. Sequences of peptides containing more than 20 amino-acid residues are not given; these are of less interest to the general reader and wasteful of space. Such coverage of proteins as is possible has largely been devoted to those of smaller size. 2 Peptide Syntbesis Protecting Groups.-As far as the classical urethane type of N-protection is concerned a common feature of the new variations being explored is the presence of a heteroatom in the group.This may function both to facilitate selective regenera- tion of the amino-function and to help in the purification of protected intermediates. The 5-benzisoxazolylmethyleneoxycarbonyl(Bioc) group (1)can be introduced uiu the corresponding oily chloroformate and like its parent the benzyloxycarbonyl group can be cleaved by hydrogenolysis or hydrogen bromide in acetic acid; it is more stable to trifluoroacetic acid than is benzyloxycarbonyl. The novelty lies in its efficient removal by a two-step sequence of treatment with aprotic base in a dipolar aprotic solvent followed by solvolysis in water at pH 7(Scheme1).Sulphite is added 0 oKNH-2 equivs.NEt,-DMF 30min / 0- I + 04c\ 0 NH--me 1 339 340 P. M.Hardy to trap the quinonemethide liberated as it will further react with free amino-groups in the aqueous medium employed. The basic conditions encountered in standard methods of peptide synthesis e.g. extraction into and recovery from aqueous sodium hydrogen carbonate mixed anhydride couplings and dicyclohexylcarbodi- imide-1-hydroxybenzotriazole couplings are compatible with the Bioc group as long as triethylamine in excess is avoided. The 'H n.m.r. signal of the Bioc isoxazole proton at 68.8 is convenient for monitoring purposes. The peptide Bioc-Arg(N02)- Val-Tyr-Ile-His-Pro-Ala-ONb* was prepared from Bioc-Arg(N02)-Val-Tyr-NHNH2 by an aide coupling and deprotected in 91YOyield.' The 2-(triphenylphosphonio)ethoxycarbonyl (Peoc) group (2) is also introduced through the chloroformate which is in this case crystalline but amino-acids must be protected as their methyl or ethyl esters.Since the group is extremely stable to acid but is decomposed by mild basic conditions the free N-Peoc amino-acids must be derived by hydrolysis in acetic acid with catalysis by hydrogen bromide. Direct synthesis of these derivatives is however possible by acylation of N-trimethylsilyl amino-acid trimethylsilyl esters typically in 80-95% yield. Preferred conditions for deprotection are either solvolysis in liquid ammonia or treatment with 0.1M-sodium hydroxide in aqueous methanol; in the latter case quantitative removal occurs in only one minute.The heteroatom in this case besides activating Peoc- derivatives to elimination (Scheme 2) also exerts a water-solubilizing influence.2 + 1 9-Ph3P-CH=CH2 +O=C-NH-Scheme 2 Another base-sensitive N-protecting group has been used independently in three laboratories The methylsulphonylethoxycarbonyl (Msoc) group based on the earlier use of 2-methylsulphonylethyl esters for C-pr~tection,~ can be introduced directly using the mixed carbonate with p -nitrophenol or 1-hydroxysuccinimide4 or prepared by hydrogen peroxide-catalysed oxidation3 of the base-stable precursor group 2-(methylthio)etho~ycarbonyl.~The latter can be introduced by using 2-(methy1thio)ethyl p-nitrophenyl ~arbonate.~ The influence of the sulphone hetero- D. S. Kemp and D.C. Roberts Tetrahedron Letters 1975,4625. H. Kunz Chem. Ber. 1976,101,2670. P. M.Hardy H. N. Rydon and R.C. Thompson Tetrahedron Letters 1968,2525. G. I. Tesser and I. C. Balbert-Geers Internat. J. Protein Res. 1975,7,295. H. Kunz Chem. Ber. 1976,109,3693. * ONb =pnitrobenzyl ester. Biological Chemistry -Part (i)Peptides and Proteins 341 group is once again to favour p-elimination but hydrogenolytic removal is pre- ~ented.~ The utility of the Msoc group has been proved in its use to protect the E-NH of lysine in syntheses of a-melanotropin and some of its analogues. The group proved stable to liquid hydrogen fluoride.6 It has also proved successful in protecting amino-groups in insulin (Gly- A1 and Lys-B29). Protein recovered after deprotection showed full activity.' Polystyrene resins substituted on the aromatic rings with 2-hydroxyethylsulphonylmethyl groups have also shown potential as solid-phase synthesis carriers.Cleavage of 2-Ala-Phe-Leu-Gly-OH at the end of a synthesis using this ester for linkage to the polymer was complete in 45s using a dioxan-methanol-4M-NaOH (30:9 :1)mixture; C-terminal asparagine however is not compatible with removal by base owing to the formation of aminosuccinimide derivatives under these conditions.' Removal of the peptide from the resin can however also be effected using anhydrous tetramethylammonium fluoride in DMF (40°C,1.5 h) the unsolvated fluoride ion being a strong base. The absence of methanol precludes concomitant transe~terification.~ The heteroatom in the p-dihydroxyborylbenzyloxycarbonyl(Dobz) group (3) fulfils two functions." It can act as a 'handle' for purification because Dobz-peptides form complexes with chromotropic acid (1,8-dihydroxynaphthalene-3,6-disulphonic acid) which are water soluble and are thus selectively extractable from other peptide derivatives e.g.Dobz-Lys (e-2)-Ala-Val-OEt can be recovered in 98% yield from the aqueous phase after organic solvent extraction the complex decomposing at pH 1-2. Dobz-peptides can also be made more lipophilic by complexation with e.g. N-octadecyldiethanolamine. In its reactivity towards deprotection the Dobz-group closely resembles the benzyioxycarbonyl group; it can in fact be converted into the latter by [Ag(NH,),]' at pH 8 in aqueous ethanol.In addition however it can be selectively removed by hydrogen peroxide at pH 9.5 the phenolic intermediate (Scheme 3) decomposing to liberate the quinonemethide HO' (3) Scheme3 which is prevented from causing side-reactions by the use of sulphite as a scavenger. This form of protection is compatible with the presence of the oxidation-sensitive A. Eberle J.-L. Fauchkre G. I. Tesser and R. Schwyzer Helv. aim. Acta 1975,58 2106. R. Geiger R. Obermeier and G. I. Tesser Chem. Ber. 1975,108 2758. * G. I. Tesser J. T. Buis E. Th. M. Wolters and E. G. BothC-Helmes Tetrahedron 1976,32 1069. G. Teutsch Tetrahedron 1976,32 1071. lo D. S. Kemp and D. C. Roberts Tetrahedron Letters 1975,4629. 342 P.M.Hardy amino-aci methionine and tryptophan; these are oxidized 4 X lo2and 1X lo5times more slowly respectively than the boronic acid." The introduction of tertiary amino-substituents into the aromatic rings of the diphenylmethoxycarbonyl and a,a-dimethylbenzyloxycarbonyl N-protecting groups[e.g.(4) and (5)] both facilitates the isolation of their derivatives and increases the stability towards acidolysis without impairing hydrogenolytic removal; (4) is N~CMe20-CO-(4) stable to 45% hydrogen bromide in acetic acid (20 "C 48 h). The incorporation of dimethylcarbamoyl substituents into urethanes [e.g. (6) and (7)]improves the CH20-CO-Me2NCOCH2CH2CMe20-CO- CONMe2 (6) (7) solubility of protected peptides in DMF.The insolubility of fully protected peptide fragments is increasingly being recognized as a limiting factor in peptide synthesis so any attempt to alleviate the situation is welcome." Phosphorus has also found use in N-protection in the form of diphenylphos- phinamides (8).The remarkable acid-lability of these derivatives is ascribed to the Ph0'-'NH-(8) fact that the nitrogen geometry is a flattened tetrahedron in which the lone pair is almost in the N-P-0 plane whereas in the amide bond the lone pair of electrons on the trigonal nitrogen is orthogonal to the N-C-0 plane. Acidolysis is slightly faster than that of the standard t-butoxycarbonyl group with e.g. 80% trifluoro-acetic acid. Resistance to racemization parallels urethane groups rather than acyl groups such as benzoyl. Since no reactive intermediate of the carbonium-ion type is formed during its cleavage scavengers are not needed and side-reactions are thus minimized.The protected C-terminal tetrapeptide of gastrin was successfully synthesized using this group for N-protection whereas difficulty had previously been encountered in analogues having Bpoc* or o-nitrophenylsulphenyl N-a -protection.'* S. Coyle 0.Kelier and G. T. Young J.C.S. Chem. Comm. 1975,939. l2 G. W. Kenner G. A. Moore and R. Ramage Tetrahedron Lctters 1976,3623. * Bpoc =2-(p-biphenyi)isopropoxycarbonyl. Biological Chemistry -Part (i) Peptides and Proteins The specificity of trypsin has been used in a different type of strategy for N-protection. Amino-acids are added to a peptide chain in the form of the p-nitrophenyl esters of their N-benzyloxycarbonyl-L-arginylderivatives usually as the nicely crystalline picrates.Incubation with trypsin removes the Z-arginyl protecting group. The alternation of the guanido-function of arginine with the a! -amino-group of the deprotected peptide suggests that the pK difference between guanidinium and ammonium ions can be utilized in ion-exchange purification at each stage. Any D-amino-acid produced by racemization during coupling is deprotected only very slowly by trypsin. The relatively long synthesis of the dipeptide derivative and the necessity for the peptide to be water-soluble suggest that the method may find its greatest use in semi-synthesis. A hexapeptide was successfully prepared from Z- Arg-Gln- Asn-Cys-Pro-Leu-Gly-NH2 however by enzymic deprotection.Other trypsin-sensitive residues must not of course be present in the peptide chain.13 Two new approaches to the protection of the sulphydryl group of cysteine have been reported. The diphenyl-4-pyridylmethyl group an acid-stable analogue of the trityl group can be used to mask the imidazole-nitrogen of histidine as well as thiols. The nitrogen atom can function also as a basic handle and confers acid-stability presumably by 'distracting' the attacking proton to a non-productive site. Removal is by reductive methods and thiols can also be regenerated by mercury(I1) acetate and iodine.I4 The S-carboxymethylsulphenyl (Scm) group is stable to most of the conditions normally encountered in peptide synthesis and only on treatment with a thiol will it form a disulphide (Scheme 4).It is thus more selective in its reactivity S-S-C02Me S-S-R I I + COS+ MeOH +RSH -cys-. -cys-Scheme4 with sulphur nucleophiles than sulphenyl thiocyanates or sulphenyl iodides and can be used for protection during assembly of a peptide chain yet simply converted in the last stage into an unsymmetrical cystine peptide. The Scm group is introduced using carboxymethylsulphenyl chloride and the formation of methyl esters from free carboxy-groups or transesterification can be prevented by working at 0 "Cor by the addition of calcium carbonate.'* High yields of the y-esters of glutamic acid and the p-esters of aspartic acid can now be simply obtained by a copper-catalysed hydrolysis of their diesters.Aqueous copper sulphate at pH 8is used and after a reaction period of about an hour the pH is lowered to 3.0 the precipitate of the copper complex of the /3 -or y-ester filtered of€ and the free amino-ester subsequently released with edta. Methyl ethyl benzyl p-nitrobenzyl and p -chlorobenzyl esters can all be satisfactorily prepared in this way. This convenient method is likely to prove very useful as it circumvents the hitherto rather lengthy methods needed to prepare such compounds especially as far as the benzyl-type esters are concerned.'6 l3 C. Meyers and J. D. Glass Proc.Nat. Acad. Sci. U.S.A.,1975,72,2193. l4 S. Coyle and G. T. Young J.C.S. Chern. Comm. 1976 980. R. G. Hiskey N. Muthukumaraswamy and R. R. Vunnam J. Org. am. 1975,40,950.R. L. Prestidge D. R. K. Harding J. E. Battersby and W. S. Hancock,J. Org. Chern. 1975,40,3287. 344 P.M.Hardy Another metal ion albeit in the form of a complex is involved in a new selective way of cleaving /3 -halogenated alkyl esters and urethanes. The 'supernucleophile' cobalt (I) phthalocyanine (9)will deprotect for example 2,2,2-trichloroethyl esters of peptides in methanol at 20 "C in 0.1 moll-' solution using Li' or Na' as counterion in less than one minute (Scheme 5). Apart from base-catalysed and C1 H -CI Cl3CCH203CR+ N Co N + N Co"' N (9) / CI H +-O,CR+ \C=C CI' / \H Scheme5 reductive cleavage these esters are otherwise inert towards common deblocking agents." Metal-ion catalysed reactions however may not always be synthetically productive.An attempted preparation of the complex [Cu(Gly-Gly-L-His) J from copper(r1 hydroxide and Gly-L-His gave a compound (10) which X-ray analysis indicated had undergone oxidative decarboxylation the product having the antici- pated square-planar co-ordination around the copper (11) centre. The complex is very stable and can be recrystallized from boiling water.'* Formation of the Peptide Bond.-The development of coupling agents containing phosphorus continues to be vigorously pursued. Intermediates previously suggested as participating in the hexamethylphosphoramide-toluene-p-sulphonic anhydride- mediated reaction have now been isolated. Simple mixture of these two reagents at H. Eckert and 1. Ugi Angew. Chem. In&mat.Edn. 1976,15,681. P.De Meester and D. J. Hodgson J. Amer. Chem. Soc.,1976 98 7086. Biological Chemistry -Part (i)Peptides and Proteins H 20 "C precipitates (11) within 5-20 min. Further reaction (55 "C 3 h) forms the ditosylate (12) dissolution and reprecipitation occurring. The use of a non-hygroscopic although moisture-sensitive salt of (12) p-0x0-bis[tris- + + + (Me2N)3P-O-S02 O M . (Me2N) 3P-O-P( N Me2)3 2TsO- (11) (12) (dimethylamino)phosphonium]bistetrafluoroborate (Bates' reagent) has been found to compare favourably with established methods in the coupling of peptide frag- ments related to lysozyme. The joining of Bpoc-Orn(Adoc)-Thr(0Bu')-Pro-Gly-OH* to H-Ser(0Bu')-Ala-Asn-Gly-OPh, for example gave a crystalline product directly whereas dicyclohexylcarbodi-imide-1-hydroxybenzotriazolegave material requiring extensive purification.When racemization is possible (and the Bates reagent causes more than was earlier thought) additives are effective in suppressing it.l9 A structurally similar reagent benzotriazolyloxytris(dimethy1amino)-phosphonium hexafluorophosphate (1 3) most simply prepared using phosgene2' (Scheme 6) has the advantage as a coupling reagent that it does not cause dehydra- (Me2N)3P=0 + COC12 -'02 P (Me2N)3kl-PFg-" c1-I. O-g(NMe,), I 0-P (13) Reagents i 1 -hydroxybenzotriazole-NEt,; ii KPF,. Scheme 6 l9 A. J. Bates I. J. Galpin A. Hallett D. Hudson G. W. Kenner R. Ramage and R. C. Sheppard Hefu. aim. Acta 1975,58,688. *O B. Castro J.-R.Dormoy B. Dourtoglov G. Evin C. Selve and J. C. Ziegler Synrhesis 1976 751. * Adoc = adamantyloxycarbonyl. 346 P.M.Hardy tion of asparagine residues; racemization however is nearly total in the Young test and 6% in the Anderson test.” Diethyl phosphorocyanidate (DPC) prepared by the Arbuzov reaction of triethyl phosphite with cyanogen bromide can be used as a peptide bond-forming agent in the presence of triethylamine. Acyl cyanides are thought to be formed as transient intermediates; benzoic acid for example is converted by DPC into (14) and benzoyl cyanide is known to be subject to base-catalysed dimerization. Little racemization is seen in the Young test but synthetic applications so far have been restricted to derivatives of ampicillin and cephalexin.’’ The phosphorus ester triazolides (15) and (16) which can be prepared from 1-trimethylsilyl- 1,2,4-triazole and the correspond- ing chloro-derivatives of the phosphorus compounds are also mediators for peptide- bond synthesis but unlike many other condensation reagents they can be used in polar solvents to polymerize free amino-acids or peptides.Racemization was not detectable on comparison of optical rotations after hydroly~is.~~ The general application of mixed anhydrides of diphenylphosphinic acid for amide-bond formation has been recommended. Compared with carboxylic anhy- drides superior yields of crystalline products and ease of purification are claimed although the pivalic mixed anhydride remains better for the coupling of N-benzyl- oxycarbonylasparagine.The tendency for nucleophilic attack on diphenylphosphinic-carboxylicmixed anhydrides to be regiospecific is illustrated by the isolation of Bu‘CONHCH2CH2Ph as the sole product from the reaction of Bu‘C02POPh2 with P-~henethylamine.~~ Peptide synthesis using active esters has attracted rather less attention recently only three papers showing much novelty. The reaction of the sulphone (17) with phosgene forms 4,6-diphenylthieno[3,4-d][173]dioxol-2-one 5,5-dioxide (1S) a doubly activated cyclic carbonate ester which forms active esters (19) on treatment with carboxylic acids in anydrous aprotic solvents. These active esters are described as excellent acyl transfer agents in the presence of pyridine or triethylamine (Scheme 7) the base preventing retardation of reaction by the liberated acidic sulphone (17).On addition of the amino-component the ester (19) forms the orange-red anion (20) whose disappearance (to pale yellow) indicates completion of the reaction. The sulphone (17) is removable by extraction with aqueous sodium hydrogen carbonate. Reaction is much faster than with the corresponding p-nitrophenyl esters and Z-Val-Val-OMe was obtained in 97% yield. The activity is attributed to the fact that the enolate group in the anion can accelerate the aminolysis by intramolecular base B. Castro J.-R. Dormoy G. Evin and C. Selve Tetrahedron Letters 1975 1219. 22 T.Shioiri Y. Yokoyama Y. Kasai and S. Yamada Tetrahedron 1976,32 2211. 23 H. R. Kricheldorf M. Fehrle and J. Kaschig Angew.Chem. Internat. Edn. 1976,15,305. z4 A. G. Jackson G. W. Kenner G. A. Moore R. Ramage and W. D. Thorp Tetrahedron Letters 1976 3627. 25 0.Hollitzer A. Seewald and W. Steglich Angew. Chem. Internat. Edn. 1976,15,444. Biological Chemistry -Part (i) Peptides and Proteins 0 R'CONHR~+(n) Reagents i COClz-py; ii R'C02H-py; iii R2NH2-base Scheme7 A preliminary report on another heterocyclic active ester involves the use of 2-chloro-N-methylbenzothiazoliumtrifluoromethanesulphonate (2 I) prepared from commercially available 2-chlorobenzothiazole as a non-hygroscopic crystalline reagent which on treatment with carboxylic acids and triethylamine at 0 "Cforms the active ester (22). This is subjected to aminolysis without isolation; heating under reflux for 30 min is recommended to complete the reaction.Apparently part of the intermediate N-methylbenzothiazolidone (22) is decomposed to the anhydride of QJkCl 'N pJ:+ 'N Me Me CF3SO3-CF3S03-(21) (22) the carboxy-component.26 Like many other active esters before them however these are unlikely to be widely adopted because whatever their advantages over p-nitrophenyl or the other commonly used esters they lack the simplicity necessary for routine use. Synthetic simulation of non-ribosomal peptide biosynthesis where peptide-bond formation involves alkyl thiolesters however is not open to this objection. Unfortunately in the test-tube such esters aminolyse too slowly to be of practical use. However it has now been found that in the presence of the bifunc- tional catalyst 1-hydroxypyridine the necessary reaction time is reduced to about a day.Racemization has been shown by the Young and Izumiya tests to be minimal. The dual role of the ethylthiolester as protecting group and active ester has been exemplified by the stepwise synthesis of Boc-Trp-Leu-Asp(OBz1)-SEt from F. Souto-Bachiller G. S. Bates and S. Masamune J.C.S. am. Cornm. 1976,719. 348 P.M.Hardy Boc-Asp(OBz1)-SEt and then its coupling with phenylalanine amide to give a tetragastrin derivati~e.~’ The highly unconventional ‘alternative’ approach to peptide synthesis known as the four-component condensation has now been developed into a highly stereoselec- tive process. In the preparation of tetravaline (Scheme 8) from N-formyl-L-valine (R)-1-ferrocenyl-2-methylpropanamine(2-R) 2-methylpropanal and N-(2-isocyanato-3-methylbutanoyl)-~-valine methyl ester the diastereoisomeric deriva- tives (23a) and (23b) are formed in a ratio of 98.5 :1.5.Since acidolysis cleaves the former some 230 times faster than the latter selectivity is even further increased less I CH OCH-N/ \C02H H Me Me Me Me Me Me Me Me ‘CH/ \CH/ \CH/ \CH/ I I I I CH CH CH CH OCH-N / \co-N / \cO-NH / ‘CO-NH ’ \Co2Me H I Me2CH-yH (23) a; S,(R) S. S S b;S,(R),R,S,S I scbeme8 *’ S. Yamada Y. Yokoyama and T. Shiori Experientia 1976,15,967. Biological Chemistry-Part (i) Peptides and Proteins than the detection limit of 0.02% of the S,(R),R,S,S-isomer being present in the resulting N-formyltetravaline methyl ester.*’ Solid-phase Synthesis.-All aspects of peptide synthesis on polymeric carriers have been receiving very critical attention in attempts to alleviate the shortcomings of the method that have been exposed during its widespread use.The tendency of N-alkylation to occur during the acidolytic cleavage of urethane protecting groups under the conditions of solid-phase synthesis has been shown to be slight as far as t-butoxycarbonyl groups are concerned [<O.O5% But-Gly-Lys(& -2)-resin from Boc-Gly-Lys(s -Z)-resin after 14 h in 50% TFA-CH2C12] but Boc-Lys(& -2)resin gave 0.6% H-Lys(& -Bzl)-resin under these conditions. Substitution of the 2,4- dichloro-2 group however reduced alkylation to less than the detectable level.’’ The use of this group for lysine E -protection is desirable in any case in the synthesis of large peptides to minimize the cumulative losses of side-ch$n protection occurring during the repeated N-a-deprotection steps ‘The rearrangement of aspartic acid-containing peptides to the corresponding cyclic aspartoyl imides has been a problem in some solid-phase syntheses when P-benzylaspartyl units in the assembled peptide are exposed to HF during cleavage of the eptide from the carrier resin.Since free P-carboxy-groups show little tendency to cyclize in this way the use of P-phenacyl esters of aspartic acid has been developed. The ester protection is removed prior to HF treatment with 1M-sodium thiophenoxide in DMF.This approach reduced 40-fold the level of cyclic imide by-products in the synthesis of H-Glu-A~p-Gly-Thr-0H.~~ Two groups have proposed similar solutions to the problem of premature loss of peptide from the resin by ester hydrolysis during acid-catalysed N-a-deprotection. These losses which average 1.4% per cycle using the original Merrifield resin are greatly reduced using esters of 4- (h ydrox yme thy1)phenylace t amidoal kyl- polystyrene (24). In the case of (24a) the ester link although still cleavable by HF is 100-fold more stable to acid than the conventional resin. In the synthesis of peptides of 120 residues premature fission of the peptide chain from the polymer would be reduced from 80%to ca. 4% by making this change.32 Using resin (24b) the peptide H-Lys5-Glu3-Leu2-Trp(Nps)-Phe-OH was obtained in 59% yield after purification following HF cleavage; acetyl-L-phenylalanyl resin was cleaved in similar yield.33 (24) a;R2=H b; R2=n-C6HI3 The interpolation of long aliphatic space groups between the polymer and the C-terminal amino-acid of the peptide chain has been found generally beneficial.Use 28 R. Urban G. Eberle D. Marquarding D. Rehn H. Rehn and I. Ugi,Angew. Chem. Inrernut.Edn. 1976 15,627. 29 A. R. Mitchell and R. B. Merrifield J. Org. Chem. 1976,41 2015. 30 B. W. Erickson and R. B. Merrifield,J. Amer. Chern. Soc. 1973,9S 3757. 31 C. C. Yang and R. B. Merrifield J. Org. Chem. 1976,41 1032. 32 A. B. Mitchell B. W. Erickson. M. N. Ryabtsev R. S. Hodges and R. B. Memfield J. Amer am.Soc. 1976,98,7357. 33 J. Blake and C. H. Li J.C.S. Chem. Comm. 1976 504. 350 P.M.Hardy of a p-bromomethylphenylactamido-11-hendecanamido-1l-hendecanamido-methyl-polystyrene (built up as in Scheme 9) gave in the synthesis of a 19-residue Polymer ~CH2NHCO(CH2)l~NH-130c iii c-PolymerOCHzNH iv-vii Reagents i Potassium phthalimide; ii N,H,; iii Boc-NH(CH,),,CO,H-DCCI; iv TFA; v base; vi Repeat coupling; vii Repeat iv and v couple to p-BrCH,C,H,CH,CO,H. Meme 9 peptide fragment of Apolipoprotein C-111 a three-fold improvement in overall yield compared with that from the traditional chloromethylpoly~tyrene.~~ The complete synthesisof this 57-residue protein was subsequently achieved on this modified resin without any of the difficulties in coupling earlier experienced in the first 15 steps using the original Merrifield resin.3s A shorter spacer has been found necessary in a resin derivative (25)designed for cleavage under mild conditions.Here the peptide is H- Arg or Lys-Met-Gly2-OCH2-(JPolymer (25) built up with an additional C-terminal pentapeptide sequence. At the end of the synthesis cyanogen bromide in propionic acid cleaves off peptide Arg- or Lys- homoserine (the diglycine moiety is essential for the unhindered action of this reagent). Subsequent treatment with carboxypeptidase A to remove the homoserine and then with carboxypeptidase B to remove the basic residue liberates the desired peptide. Peptides terminating in basic residues are not compatible with this regime but methionine is acceptable in the peptide chain providing that it has been incorporated as its sulphoxide which is not susceptible to cyanogen Luteinizing hormone-releasing hormone has been synthesized on a 3-nitro-4- aminomethylbenzoylamide resin (26).Removal from the polymer was effected by suspending in methanol and irradiating at 350 nm in the absence of oxygen using a 40% copper sulphate solution to filter out wavelengths below 320nm. The pro- tected decapeptide amide which contains the sensitive tryptophan and tyrosine residues was obtained in an analytically pure form in a 65% yield based on 3 J. T. Sparrow J. Org. Gem. 41 1350. 3s G. F. Sigler A. K. Soutar L. C. Smith A.M. Gotto jun. and J. T. Sparrow,Roc. Nat. Acad. Sci. U.S.A. 1976,73,1422.36 W. S. Hancock and G. R. Marshall J. Amer. am. Soc. 1975 W,7488. Biological Chemistry -Part (i)Peptides and Proteins Tos Bzl Bzl Tos II t Po-&%-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NHCHz/ CONHCH 1 \ Polymer O2N (26) Boc-Gly-resin. Photolytic removal of even hindered residues is very smooth; Boc- Val-resin gives Boc-Val-NHz in quantitative yield. This contrasts with the difficul- ties experience in ammonolyzing valine-resin ester links.37 Incorporation of an extra amino-acid residue at the end of a solid-phase synthesis has been explored by two groups as a means of facilitating isolation of the desired peptide. If lysine is the extra residue it can be used as a handle for carboxymethylcellulose chromatography and subsequently removed by one cycle of the Edman degradation.Successful application to a decapeptide fragment of insulin B-chain is rep~rted.~' Instead of lysine addition of the dipeptide 4-methoxybenzylcysteinylmethioninegives a peptide which after HF cleavage can be reduced and unlike prematurely terminated peptides binds to organomercurial agarose gel. Impurities lacking this affinity can be washed away and subsequent displacement by thiol and cleavage with CNBr will generate the pure des-Cys-Met peptide. The purity of a crude synthetic histone H4 (1-37) fragment was increased six-fold by using this tactic. Unfortunately if the peptide sequence contains cysteine or methionine the method generally fails; many protecting groups for cysteine are removed by mercury reagents and thiols reduce methionine sulphoxide the only useful way of protecting this residue from the action of CNBr.39 In an attempt to overcome a limitation inherent in the use of polystyrene carriers namely that because they are lipophilic whereas peptides in general are hydrophilic maximum accessibility to both is not possible in the same solvent system poly- acrylamide carriers have been thoroughly explored4' and found clearly superior in properties.Copolymerization of dimethylacrylamide NN'-bisacryloylethylene-diamine (cross-Iin king agent) and N-t-butoxycarbon yl-P-alanyl-N'-acryloylhexamethylenediamine(functionalizing agent) gave a carrier which after removal of the N-protecting group was coupled with Boc-leucine as a spacer- internal reference.The first amino-acid in the required peptide is added as an already substituted benzyl ester derivative (Scheme 10). All subsequent reactions are carried out in highly polar organic media in which both peptide and polymer chain are fully solvated. A stringent evaluation test synthesis of the sequence 65-74 of acyl carrier protein (which has proved impossible to prepare satisfactorily using chloromethylated polystyrene resin41) shows the great promise of this appr~ach.~' A classical synthesis of the sequence attributed to rat scotophobin gave inactive peptide. The biological activity of material prepared earlier by a solid-phase method and which has been confirmed seems therefore to be related to impurities 37 D. H. Rich and S. K. Gurwara Tefrahedron Letters 1975 301.38 K.Suzuki Y. Sasaki and N. Endo Chem. and Pharm. Bull. (Jupun) 1976,24,1. 39 D.E. Krieger B. W. Erickson and R. B. Merrifield,Proc. Nut. Acad. Sci. U.S.A. 1976,73 3160. 40 E. Atherton D. L. J. Clive and R. C. Sheppard,J. Amer. Chem. Soc. 1975,97 6584. 41 W.S.Hancock D. J. Prescott P. R. Vagelos and G. R. Marshall J. Org. Chem. 1973,38,774. 352 P. M. Hardy Polymer I Boc-Leu-p-Ala-NH( CH2)6NHCOCHCH2-Polymer i iil Polymer I Boc-AA-OoCH2CH2CO-L,eu-/3-Ala-NH(CH2)6NHCOCHCHz -Polymer w Reagents:i TFA; ii Boc-AA-OCH c1 Scheme 10 present in it and further illustrates one of the problems which can arise using the method.42 3 New Peptide and Protein Structures Small Peptides.-Two interesting biologically active tripeptides have been reported.From cat spinal cord a (selective) neurone inhibitor has been partially characterized as His-(Gly,Lys). The two possible compounds were synthesized but could not be differentiated chromatographically and since both showed activity on bioassay the exact sequence remains From Pseudomonas phaseolicolu a compound causing a disease of beans known as ‘halo blight’ was found to contain the sequence ornithylalanylhomoarginine. However its electrophoretic behaviour showed it to contain a strongly acidic group and the ornithine-8-N was eventually found to be substituted with a phosphosulphamyl group (27) which is readily cleaved off by dilute acid to leave a non-toxic basic tri~eptide.~~ OH NH I II NH-PO-O-SO2NH2 NH-C-NH;? I 1 Me (?H2)4 (YH2)3 I NH2-CH-CONH-CH-CONH-CHC02H (27) The skins of various species of frog continue to attract attention as a rich source of biologically active peptides.A new peptide structurally quite distinct from those hitherto found in amphibian frogs has been isolated from Xenopus Zaevis. This octapeptide (28) xenopsin has hypotensive properties and contracts rat stomach Qu-Gl y-Lys- Arg-Pro-Trp-Ile-Leu-OH (28) strip in vitro. The des-Leu’ analogue is inactive but Arg-Pro-Trp-Ile-Leu is weakly active which is consistent with the observation that tryptic digestion does not completely inactive xenop~in.~~ The nonapeptide litorin (29) from the Australian 42 H. N. Guttman B. Weinstein R. M. Bartschot and P. S. Tam Experientia 1975,31 285.43 C. J. Lote J. P. Gent J. H. Wolstencroft and M. Szelke Nature 1976,264 189. E. E. Mitchell Nafure 1976,260,75. 45 K.Araki S. Tachibana M. Uchiyama T. Nakajima and T. Yasuhara Chem. and Pharm. Bull. (Japan), 1975,23,3132. Biological Chemistry -Part (i)Peptidesand Proteins 353 ~Giu-Gln-Trp-Ala-Val-Gly-His-Phe-Met-NHp (29) speciesLitoria (Hyla)aurea possesses bombesin-like activity but it only differs from ranatensin in its N-terminal amino-acid residue.46 The slightly larger peptide uperolein (30) from other Australian frogs (Uprolia rugosa and U. mamarota) is mu-Pro-Asp-Pro-Asn-Ala-Phe-Tyr-Gly-Leu-Met-NHz (30) again a close relative of known peptides being Pr~~-Ala~-physalaemin.~~ Curiously enough the C-terminal pentapeptide sequence of the newly discovered peptide neurotensin (31) isolated from bovine hypothalami is identical to that of xenopsin.LGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Trp-Ile-Leu-OH (31) Injection of xenopsin into rats was found to cause the cyanosis and hyperglycaemia characteristic of neurotensin the latter differing in activity from other kin in^.^^ A solid-phase synthesis of neurotensin has been rep~rted.~’ Since the isolation of neurotensin might have allowed the hydrolysis of the Gln4 or Leu13 amide groups possible precursors were also prepared. Gln4-neurotensin was indistinguishable from neurotensin on bioassay but neurotensin amide and Gln4-neurotensin amide both showed less than 1%activity. The question of the amidation of residue 4 thus remains unres01ved.~~ Two structurally similar and highly active kinins have been isolated from the venom sacs of the North American offensive stinging insect Vespula maculifrons,the yellow jacket.Both vespulakinins are highly basic and contain the nonapeptide sequence of bradykinin at their carboxy-terminus; the smaller of the two simply lacks the N-terminal dipeptide of the larger which is a heptadecapeptide (32). An H-Thr-Ala-Thr-Thr-Arg-Arg-Arg-Gly-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH 5 10 15 (32) unusual feature is the attachment of carbohydrate chains to both hydroxyls of the threonylthreonine sequence; the precise composition of these remains to be estab- lished but up to five residues of galactose and N-acetylgalactosamine are present.These are the first reported vasoactive gly~opeptides.’~ Also noteworthy is the determination of the structure of the first peptide hormone from an insect neuroen- docrine organ. Adipokinetic hormone (AKH),isolated from locust corpora cardiaca is a blocked decapeptide (33) which causes the release of specific diglycerides from the fat body into the haemolymph for utilization by the flight muscle which it also stimulates. The hormone is important in the maintenance of prolonged flight activity; 46 A. Anastasi V. Erspamer and R. Endean Experientia 1975,31 510. 47 A. Anastasi V. Erspamer and R. Endean Experientia 1975,31,394. 48 R. Carraway and S. E. Leeman J. Biol. &m. 1975,250. 1907. 49 R. Carraway and S. E. Leeman J.Biol. Chem. 1975,250,1912. K. Folkers D. Chang,J. Humphries R. Carraway S. E. Leeman and C. Y. Bowers Roc. Nat. Acad.Sci. U.S.A.,1976,73 3833. 51 H. Yoshida R. B. Geller and J. J. Pisano Biuckmisfry 1976,15 61. 354 P. M. Hardy ~iu-Leu-Asn-Phe-Thr-Pro-Asn-Trp-Gly-Thr-NH2 (33) the initial stages of flight utilize the energy derived from trehalose present in the haern~lymph.~~ There are some structural features common with the red-pigment- concentrating hormone from shrimps (34).53Another hormone from the shrimp =u-Leu-Asn-Phe-Ser-Pro-Gly-Trp-NHZ (34) Pandalus borealis fulfils a light-adapting function. This 18-residue peptide (35) occurs in the eyestalks and enables the crustacean to tolerate brighter light condi- tions by causing the pigment in the distal retinal cells of the eye to move to a more proximal H- Asn-Ser-Gly-Me t-Ile- Asn-Ser-Ile-Leu-Gly- Ile-Pro- Arg-Val-Met-Thr-Glu- Ala-NH 5 10 15 (35) Another peptide isolated from insects lowers the further receptivity of the female of the species if injected.This compound (36) produced in the paragonial gland of H-Asp-Val or Leu-Pro-Ser-Ala-Asn-Ala-Asn-Ala-Asn-Asn-Gln-Arg-Thr-5 10 Ala-Ala-Ala-Lys-Pro-Gln-Ala-Asn-Ala-Glu-Ala-Ser-Ser-OH 15 20 25 (36)Val:Leu =7:3 adult male Drosophila funebris is the first insect peptide capable of influencing mating behaviour to be fully characterized. It contains four Ala-Asn sequences and nine alanine residues in all.55 The tetrapeptide H-Thr-Pro-Arg-Lys-OH isolated from the contents of the oviducal lumen of two-day progravid hamsters has a related activity.If injected subcutaneously into non-bred female hamsters it prevents ovulation. In vivo this small peptide seems to be associated with a An n.m.r. study of alamethicin embarked on for conformational purposes has shown that it is not in fact cyclic but linear. Although the 18-residue sequence earlier proposed is correct there is an extra residue at the N-terminus which is blocked by an acetyl group and a side-chain attached to Glu" (37). Two anomalous peaks in CHzPh I Ac-Mea-Pro-Mea-AIa-Mea-Ala-Gln-Mea-Val-Mea- NHCHCHZOH 5 10 I Gly-Leu-Mea-Pro-Val-Mea-Mea-Glu-Gln-OH 15 (37)Mea =2-methylalanine s2 J. V. Stone W. Mordue K. E. Batley and H. R. Morris Nature 1976 263 207.s3 P. Fernlund Biochim. Biophys. Actu 1974 371 304. 54 P. Fernlund Biochim. Biophys. Acta 1976,439 17. 55 H. Baumann K. J. Wilson P. S. Chen. D. R. E. Humbel European J. Biochem. 1975,52 521. 56 H. A. Kent jun. Biol. Reprod. 1975 12 504. Biological Chemistry -Part (i)Peptides and Proteins 355 the n.m.r. spectrum were identified as belonging to the acetyl CH and the aromatic protons of the pendent phenylalaninol. Partial hydrolysis of alamethicin earlier thought to be opening a peptide bond between the y-carboxyl-group of Glu18 and the amino-group of Pro2 in fact removes N-acetyl-2-methylalanine and phenylalaninol; the latter is not detected on a normal amino-acid analysis prog- ramme.” A further toxic cyclopentapeptide has been isolated from a strain of Aspergillus niger collected from mould-damaged rice.This compound malformin C (38a) is toxic to mammals (LD50in rats = 0.9 mg kg-’) as well as plants; its activity in plants is similar to malformin A (38b).58 Enantio-Val’-malformin has been synthesized but this palindrome peptide did not retain the antibacterial activity found in Val’- malformin itself; it had been hoped to separate this activity from the general toxicity effects.59 s-s I I XX-D-CYS-D-Cys-L-Val-D-Leu 3 4 57 (38) a; XX =L-Leu b; XX =L-Ile The most important of the peptides characterized in the past two years however must undoubtedly be the enkephalins. These pentapeptides (39) of similar activity H-Tyr-Gly-Gly-Phe-Metor Leu-OH (39) were isolated from pig brain occurring in the ratio 34 1 with the methionine peptide predominating.60 (In calf brain the amounts are reversed.61) They constitute endogenous ligands for the opiate receptors in the brain.60 Hopes of compounds of this type being useful as non-addictive analgesics were quickly dashed.When rat brains are continuously perfused with enkephalins they develop withdrawal symp- toms in just the way they do if addicted to morphine. It seems that only its rapid degradation prevents animals from becoming addicted to their own endogenous opiate.62 On a weight basis enkephalin is only ca. 1/20th as active as morphine as an analgesic in tests using intraventricular cannulae in rat brains and is inactive by inje~tion.~~ A conformation of Met’-enkephalin (the more potent of the two) can be constructed which bears a strong resemblance to the (relatively rigid) potent morphine derivative oripavine (40).In particular the tyrosine side-chain the amino-group and the phenylalanine side-chain coincide with the orientations of the phenolic ring of the phenanthrene nucleus the tertiary amino-groups and the phenylethyl substituents respectively of the alkaloids. The methyl thioether of the 57 D. R. Martin and R. J. P. Williams Bimhern.J. 1976 153 181. 58 R. J. Anderegg K. Biemann G. Buchi and M. Cushman J. Amer. Chem. SOC. 1976,98,3365. 59 P. Kurath Helv. Chim. Acta 1976,59 1127. 6o J. Hughes T. W. Smith H. W. Kosterlitz L. A. Fothergill B. A. Morgan and M. R. Morris,Nature 1975 258 577. 61 R.Simanton and S. H. Snyder Roc.Nut. Acad. Sci. U.S.A.,1976,73,2515. 62 A. A. Waterfield J. Hughes and H. W. Kosterlitz Nature 1976,260,624. 63 J. D. Belluzzi N. Grant U. Garsky D. Sarantakis C. D. Wise and L. Stein Nature 1976 260 626. 356 P.M.Hardy OMe HO-C-Me I CH ,CH,Ph methionine also corresponds to the methyl ether in 0ripavine.- Mets-enkephalin amide is about three times as potent as its parent,6s and examination of a series of analogues containing D-amino-acids established [~-Ala~]-enkephalin as the most active (120% in the binding test to opiate receptors 1000% in vas deferens bioassay).66 The sequence of Mets-enkephalin corresponds to the fragment 61-45 of the pituitary hormone /3 -1ipotropin (p -LPH),67 and this brain protein is likely to be its precursor.P-Melanotropin of course comprises the sequence 4 1-58. Whereas /3 -1ipotropin itself has no morphinomimetic activity incubation at neutral pH with the supernatant extracts of rat brain does generate activity.68 From porcine hypothalami three fragments containing the Mets-enkephalin sequence have been isolated (Figure). These have been named the endorphins and all three possess opiate activity. The largest &endorphin (also known as C-fragment) has a much higher affinity for opiate receptors than enke~halin,~' and in vivo tests show it to be 20-30 times more potent an analgesic than morphine on a molar basis.69 Of the P-LPH fragments so far isolated from porcine brain (Figure) only the a-and 1 38 41 58 61 87 90 91 p -LPH LLYS-LYS LYs-Arg I ~ys-~ys-l N-Fragme n t I I I I p-MSH I 1 9 /3 -Endorphin I I I y-LPH I I I I 76 a -Endorphin U77 y -Endorphin I Enkephalin M y-endorphin~~~ are not found by cleavage at the carboxyl side of double base residues.The other products could arise as a result of tryptic-type cleavage (trypsin A. F. Bradbury D. G. Smyth and C. R. Snell Nahue 1976,260 1965. N.Ling and R. Guillemin. Roc.Nut. Acad. Sci. U.S.A.,1976,73,3308. 66 D.H. Coy A. J. Kastin A. V. Schally. 0.Morin N. G. Caron F. Labrie J. M. Walker R. Fertel G. G. Berntson and C. A. Sandman Biochim. Biophys. Res. Cbmm.. 1976.73,632. 67 A.F. Bradbury D. G. Smyth C. R. Snell N. J. M. Birdsall and E. C. Hulme Nature 1976,260 793. 68 L. H. Lazarus N.Ling and R. Guillemin.Roc.Nat. Acad. Sci. U.S.A.,1976,73,2156. 69 M.H.Loh L. F. Tseng E. Wei and C. H. Li Roc.Nat. Acad. Sci. U.S.A. 1976,73,2895. 70 N.Ling R. Burgus and R. Guillemin,Roc.Nut. Acad. Sci. U.S.A.,1976,73 3942. Biological Chemistry -Part (i) Peptides and Proteins 357 itself does not seem to be involved) of P-LPH followed by carboxypeptides B removal of the resulting C-terminal base residue^.^' Proteins.-Sequencing studies on pr~thrombin~~ and factor X,73another blood- clotting protein which has a similar amino-terminal sequence have led to the discovery of y-carboxyglutamic acid (Gla) as a protein constituent. As a malonic acid derivative decarboxylation to glutamic acid occurs under the conditions of acid hydrolysis for amino-acid analy~is.’~ Its presence was originally inferred on the basis of anomalous electrophoretic mobilities; at pH 6.5 more negative charges were present on fragment peptides than were accountable on the basis of the amino-acid content.72 Mass spectrometric studies on these peptides confirmed the presence of Gla.75 It occurs at ten positions in the first 33 residues of the 582-residue pro-thrombin sequence in each case as closely positioned doublets (7,8 15,17 20,21 26,27 and 30,33).Prothrombin binds Ca2’ strongly and two adjacent Gla residues would be expected to make very efficient centres of chelation for calcium ions. The y-carboxylation of glutamic acid is thought to be a post-ribosomal process mediated by Vitamin K; prothrombin from the blood of patients treated with dicoumarol a Vitamin K antagonist does not bind Ca2’ although immunologically identical to normal pr~thrombin.~’ Direct estimation of Gla is possible by amino-acid analysis after alkaline hydrolysis although it gives a low colour yield with ninh~drin.’~ It may also be detected by C3H]diborane reduction in which case 5,5-[3H]dihydroxyleucine is isolated but recovery is low (-30%) owing to peptide-bond reduction.Alterna- tively free carboxy-groups can be coupled to glycine ethyl ester and after acid hydrolysis the extra glycine incorporation can be determined.730 Several syntheses of Gla have been reported. That claimed to be the simplest and most direct is based on an L-serine derivative (Scheme 11). Racemization occurs CHZOH CHZCI I I Z-NHCHCOZBzl 4Z-NHCHCOZBd Bzl= PhCH2 lii CHZCH(COZH)2 iii CH2CH( C02B~l)z 1 4 1 HZNCHCOZH Z-NHCHCOZBzl Reagents i SOCI,; ii NaCH(CO,Bzl),; iii H,-pt.Scheme 11 during the condensation with monosodium dibenzyl mal~nate.~~ Resolution of the useful synthetic derivative DL-N-benzyloxycarbonyl-y-carboxyglutamicacid 71 A. F. Bradbury D. G. Smyth and C. R. Snell Biochim. Biophys. Res. Comm. 1976,69,950. 72 S. Magnussen L. Sottrup-Jensen,T. E. Peterson and H. Claeys Boerhaave Symposium on Prothrombin and Related Coaguiation Factors University Press Leiden 1975 pp. 2546. 73 (a)J. B. Howard and G. L. Nelsestuen Proc. Nar. Acad. Sci. U.S.A. 195,72 1281; (b)D. L. Enfield L. H. Ericsson K. A. Walsh H. Neurath and K. Titani ibid.p. 16. 74 T. H. Zytkovicz and G. L. Nelsestuen J. Biol. Chem. 1975,250 2968. 75 H. R. Morris A. Dell T. E. Peterson,L. Sottrup-Jensen and S. Magnusseo,Biochcm.J. 1976,153,663. 76 P.A. Price,A. S. Otsuka J. W. Poser J. Kristaponis and N. Raman Roc.Nat. Acad. Sci. U.S.A.,1976 73 1447. 77 B. Weinstein K. G. Watrin H. J. Luie and J. C. Martin J. Org. am. 1976,41 3634. 358 P.M. Hardy y -y’-di-t-butyl ester using quinine has been reported.’* A small (49-residue) protein isolated from both calf bone and tooth dentine contains Gla at positions 17 2 1,.and 24; unmodified glutamic acid occurs at positions 31 and 40. This protein binds to hydroxyapatite crystals (although not so tightly as prothrombin to Ca”) but not to amorphous calcium phosphate.Similar proteins probably occur in all calcified tissues (except tooth enamel) including calcified arteries and so are of great medical interest. The protein also inhibits hydroxyapatite crystallization. Its function may be either to regulate mineralization in calcified tissues or to signal a loss of mineral to surrounding tissues. ’’ Of the smaller proteins currently under investigation the sequences of a number of assorted toxins have been unravelled. A basic protein from wheat endosperm P-purothionine (45residues) is toxic to animals (on injection) yeasts and some bacteria. It contains eight cysteine residues and shows considerable homology to the viscotoxin found in the European mistletoe (Viscum album L.).80The main compo- nent of the venom of the snakelocks sea anenome Anenomia sulcafa is of similar size (47residues three disulphide bridges) but shows no significant resemblance to any other known neurotoxin or cardiotoxin; it is the first toxin from this phylum to be sequenced.” The rather larger presynaptic neurotoxin notexin (1 19 residues; all neurotoxins hitherto sequenced have been of the commoner postsynaptic variety) from the Australian Tiger snake shows weak phospholipase activity and there is a high homology with porcine pancreatic phospholipase A at fhe N-and C-terminii but not in the central (569%)segment.Twelve of the fourteen cysteine residues are in alignment; the other two arc deletions. The main fragmentation of notexin was accomplished with a staphylococcal nuclease specific for giutamoyl bonds of which there are four in the The first pollen alle gen structure has also been reported.This molecul from the short ragweed contains four disulphide bonds in its 45 residues. All pollen allergens are thought to be of this order of molecular weight. 83 In addition to bradykinin the kininogen of bovine plasma has been found to release through the action of plasma kallikrein a very basic 41-residue fragment in which histidine glycine and lysine account for more than 70% of the amino-acids there being 1 1 11,and 7 residues of each respectively. Repeating sequences of His- Gly-X and Gly-His-X occur.84 Another unusual protein which is in fact a polyamino-acid is produced by a cyanobacterium and constitutes the subcellular particle known as the cyanophycin granule.It contains a backbone of polyaspartic acid with single arginine residues attached as side-chains but it is not yet clear whether the backbone (>70 residues) is a-or P-linked. Such a product is not of course produced by the usual route of ribosomal protein ~ynthesis.~~ Finally two papers concerning important hormones are worthy of note. Preproparathyroid hormone (PPT) has been isolated after translation of RNA from bovine parathyroid 78 W. Mkki and R. Schwyzer Helv. Chirn.Acta 1976,59,1591. 79 P. A. Price J. W. Power and N. Raman Roc.Nar. Acad. Sci. U.S.A. 1976,73,3374. 8o A. S. Mak and B. L. Jones Canad. J. Biochem. 1976,54,835. 81 G. Wunderer H. Fritz E. Wachter and W. Machleidt European J. Biochem. 1976,68 193.a2 J. Halpert and D. Eaker J. Biol. Chern. 1975,250 6990. 83 L. E. Mole L. Goodfriend C. B. Lapkoff,J. M. Kehoe and J. D. Capra,Biuchemisay 1975,14,1216. 84 Y. H. Han M. Komiya S. Iwanaga and T. Suzuki J. Biochern. (Japan) 1975,77,55. R. D. Simon and P. Weathers Biochim. Biophys. Acra 1976,420 165. Biological Chemistry -Part (i)Peptides and Proteins tissue in a wheatgerm cell-free system. Such systems are known to be sources of precursor proteins not isolable from intact cells because of their ready cleavage. Compared with parathyroid hormone PPT has an extra 25 residues at the N-terminus the sequence Lys-Ser-Val-Lys-Lys-Arg being lost on conversion into the prohormone; there are five methionine residues within the next 14 residues two of them contiguous at the new N-terminus.86 From normal male urine the inhibitor of gastric secretion urogastrone whose existence was first suspected as long ago as 1938 has at last been isolated and sequenced.It contains 53 residues and a protease from Armillaria mellea giving specific bond cleavage on the amino side of lysine proved of particular value in sequencing studies. There are six cysteine residues and 37 of the amino-acids occur in the same positions as in mouse epidermal growth factor. It remains to be seen whether it may be of value as a therapeutic agent in the treatment of duodenal ~lceration.~’ 86 B. Kemper J. F. Habener M. D. Emst J. T. Potts jun. and A. Rich Biochemistry 1976,15 15. 87 H. Gregory Nahtre 1975,257,325.

ISSN:0069-3030    

DOI:10.1039/OC9767300339

出版商:RSC    

年代:1976

数据来源: RSC

摘要:

14 Biological Chemistry Part (ii) Enzyme Mechanisms By A. D. B. MALCOLM Department of Biochemistry St. Mary's Hospital Medical School Paddington London W2 1PG and J. R. COGGINS Department of Biochemistry University of Glasgow Glasgow G12 800 1 Introduction During the past two years two enzymologists have been awarded the Nobel Prize for Chemistry. The 1975 Prize was awarded to J. W. Cornforth (jointly with V. Prelog) for his work on the stereochemistry of enzyme-catalysed reactions.' In 1976 the Prize was awarded to W. N. Lipscomb for his work on the boron hydrides,* but more recently Professor Lipscomb has become known for the structure determination of carb~xypeptidase~" and for theoretical studies on and aspartate trans~arbamylase,~~ amino-acids3" and Table 1 Recent three -dimensional structures of enzymes EnzymePepsin Hexokinase Source ox Yeast Resolution(A)2.7 2.7 Ref 6a 66 Lysozyme (triclinic) Lysozyme (triclinic) Thioredoxin-S2 Hen egg Hen egg Escherichia coli 2.5 1.5 2.8 6c 6d 6e Triosephosphate isomerase Chicken muscle 2.5 6f,g,h Phosphorylase a and b Phosphorylase a Carboxypeptidase B @ -Trypsin TrypsinogenTyrosine-tRNA-synthetase Alcohol dehydrogenase Superoxide dismutase Rabbit muscle Rabbit muscle Ox pancreas Ox pancreas Ox pancreas Bacillus Horse liver Ox erythrocyte stearothennophilus 6.0 3.0 2.8 1.8 1.8 2.7 2.4 3.0 61 6k 61 6m 6n 6j * J.W. Cornforth Science 1976,193 121. 2 W.N. Lipscomb Adv. Inorg. Chem. Rudiochem. 1959,1 117. 3 (a)J. A. Hartsuck and W. N. Lipscomb in 'The Enzymes' ed.P. D. Boyer Academic Press New York 1971,Vol. 3,p. 1;(b)B.F. P.Edwards D. R. Evans S. G.Warren H. L. Monaco S. N. Landfear G. Eisele J. L. Crawford D. C. Wiley and W. N. Lipscomb Proc. Nut. Acad. Sci. U.S.A.,1974,71,4437; (c)D.A. Dixon and W. N. Lipscomb I.Biof.Chem. 1976,251,5992;(d)S. Scheiner W. N. Lipscomb and D. A Kleier J. Amer. Chem. SOC.,1976,98,4770. 360 Biological Chemistry -Part (ii)Enzyme Mechanisms 361 The year 1976 saw the centenary of the word ‘edzyme’ and this was celebrated by a useful collection of essays on various aspects of en~ymology.~ A number of new books on enzymes have also a~peared.~ Protein crystallographers were very productive during 1976 and a list of newly published structures is given in Table 1.6 The inhibition of enzymes by transition-state analogues has been reviewed,’ although the quantitative significance of such an approach has been questioned.8” Enzymologists frequently try to deduce the nature of the ionizing group upon which the catalytic activity of an enzyme depends by studying the pH-dependence of its kinetic parameters.A useful and critical evaluation of this approach has appeared.86 The argument about whether enzymes evolve to a high kat which will tend to result in a high K and hence a correspondingly low degree of saturation or vice versa has been neatly answered in a paper’ which shows that the maximum rate enhancement is achieved when K is within an order of magnitude of the substrate concentration to which the enzyme is usually exposed.2 Suicide Inhibitors A new class of affinity labels known as ‘suicide inhibitors’ has been proposed.”” The enzyme commits suicide by converting a substrate into a highly reactive product which then inactivates the enzyme. For example many transaminases may be inactivated by unsaturated amino-acids because the enzyme acts on these to produce @?-unsaturated keto-acids which are highly susceptible to Michael addition and will therefore react with any suitable nucleophile in the vicinity of the enzyme’s active site. 4 EE.B.S. Letters 1976,Supplement to Vol. 62. 5 (a) A. Cornish-Bowden ‘Principles of Enzyme Kinetics’ Butterworths London 1976;(6) ‘The Enzymes’ Vol. 12,Oxidation-Reduction Part B ed. P. D. Boyer Academic Press New York 1976;(c) ‘The Enzymes’ Vol.13 Oxidation-Reduction Part C ed. P. D. Boyer Academic Press New York 1976. 6 (a) N. S. Andreeva A. A. Fedora A. E. Gruchshina N. E. Shutskever R. R. Riskulav and T. V. Volnava Doklady Akad. Nauk. S.S.S.R. 1976 228 480;(b) T. A. Steitz R. J. Fletterick W. F. Anderson and C. M. Anderson J. Mol. Biol. 1976,104 197; (c)J. Moult A. Yonath W. Traub A. Smilansky A. Podjamy D. Rabinovich and A. Saya J. Mol. Biol. 1976,100,179;(d)K. Kurachi L. C. Sieker and L. H. Jensen J.Mol. Biol. 1976,101,ll;(e) A. Holingren B. 0.Soderberg H. Eklund and C. I. Branden Proc. Nut. Acad. Sci. U.S.A. 1975,72,2305;(f)D.W. Banner A. C. Bloomer G. A. Petsko D. C. Phillips C. I. Pogson and I. A. Wilson Nature 1975,255,609;(g) D.W. Banner A. C. Bloomer G. A. Petsko D.C. Phillips and T. A. Wilson Biochem. Biophys. Res. Comm. 1976,72,146; (h)C.A. Browne I. D. Campbell P. A. Kiener D. C. Phillips S. G. Waley and I. A. Wilson J. Mol. Biol. 1976 100,319; (i)R. J. Fletterick J. Sygusch N. Murray N. B. Madsen and C. N. Johnson J. Mol. Biol. 1976 103 1; (j) R. J. Fletterick J. Sygusch H. Semple and N. B. Madsen J. Biol. Chem. 1976,251,6142; (I) H.Fehlhammer (k)M. F. Schmid and J. R. Herriott J. Mol. BWL 1976,103,175; and W. Bode J. Mol. Biol. 1975,98,683,693; (m)W. Bode H. Fehlhammer and R. Huber J. Mol. Biol. 1976,106,325;(n)M. J. Irwin J. Nyborg B. R. Reid and D. M. Blow J. Mol. Biol. 1976,105 577;(0)H. Eklund B. Nordstrom E. Zeppezauer G. Soderlund I. Ohlsson T. Boiwe B. 0.Soderberg 0.Tapia C. I. Branden and A. Akeson J.Mol. Biol. 1976,102,27; (p)H.Eklund C. I. Branden and H. Jornvall J. Mol. Biol. 1976,102 61; (4)J. S. Richardson K. A. Thomas B. H. Rubin and D. C. Richardson Proc. Nat. Acad. Sci. U.S.A. 1975,72 1349. R. Wolfenden Ann. Rev. Biophys. Bioeng. 1976,5 271. (a)A. D.B. Malcolm J. Theoret. Biol. 1976,60,239;(6)J. R. Knowles Crit. Rev. Biochem. 1976,4 165. A. Cornish-Bowden J. Mol. Biol. 1976 101 1. lo (4)R. H. Abeles and A. L. Maycock Accounts Chem. Res. 1976,9,313;(6)S. Tanase and Y. Morino Biochem. Biophys. Res. Comm. 1976,68,1301. 362 A.D.B.Malcolm and J. R. Coggins An interesting example'' is the inhibition of chymotrypsin by the production of carbonium ions at its active site. Compound (1) is hydrolysed by chymotrypsin to give (2) which rapidly breaks down via the diazonium compound to give PhCH2+.Some of this reacts with (and inactivates) the enzyme but apparently some 80% diffuses away before reaction can occur. The use of a cyclic analogue (3)eliminates this side reaction and produces virtually complete inhibition of chymotrypsin. //O N I //O Me0 ' N,~ PhCH2-CH-CO-N-CH2Ph HN-CH2Ph II NH-CO-CHMe2 NI I Meom 0 (1) (2) (3) Several naturally occurring inhibitors appear to act in this way,"' as do some By-unsaturated analogues of ornithine which are potent inhibitors of ornithine decarboxylase. 2b 3 Arginine Modification It is remarkable how many enzymes have been discovered to possess a functional arginine residue since the introduction of cyclohexanedione phenyl glyoxal and butanedione as specific reagents for this arnino-a~id.'~ We described last yearI4 how the kinases appear to have an arginine involved in ATP binding; in the case of phosphoglycerate kinase the preliminary study reported last year has been indepen- dently confirmed." Among other enzymes whose substrates contain a negatively charged phosphate group and whose active sites are now thought to include an arginine are malate dehydrogenase,l6 glutamate dehydrogenase l7 RNA-dependent DNA polymerase (reverse transcriptase),18 aspartate tran~carbarnylase,'~ fructose diphosphatase,20 mitochondria1 ATPase,'' ribonuclease,22 RNA poIymera~e,~~'*~ and ald~lase,~~' dihydrofolate reducta~e.~~' it is thought In the case of aspartate aminotran~ferase~' l1 E.H.White D. F.Roswell J. R. Politzer and B. R. Branchini J. Amer. Chem. Soc. 1975.97,2290. 12 (a)R. R. Rando Accounts Chem. Res. 1975,8,281;(b)N. Relyea and R. R. Rando Biochem. Biophys. Res. Comm. 1975,67,392. Is (a)A. L.Grossberg and D. Pressman,Biochemistry 1968,7,272;(b)J. F.Riordan ibid. 1973,12.3915. A. D. B. Malcolm and J. R. Coggins Ann. Reports (B) 1975,72,378. 15 T.Hjelmgreen L. Strid and L. Arvidsson F.E.B.S. Lerters 1976.68 137. l6 D.M.Bieile M.Foster J. W.Brady and J. H.Harrison J. Biol. Chem. 1975,250,6222. (a) K. M.Blumenthal and E. L. Smith,J. Biol. Chem. 1975,250,6555;(b)M.David I. Rasched and H. Sund F.E.B.S. Lencrs 1976,62,288;(c)P. K. Pal and R. F. Colman EuropeanJ. Biochem. 1976.68. 437. 18 C.L.Borders J. F. Riordan and D.S. Auld Biochcm. Biophys. Res. Comm. 1975,66,490. l9 E.R. Kantrowitz and W.N. Lipscomb,J. Bwl. Chem. 1976,251,2688. 2O F. Marcus Biochemistry 1976,15,3505. 21 F. Marcus S.M.Schuster. and H.A. Lardy J. Biol. Chem. 1976,251,1775. 22 L. Patthy and E. L. Smith J. Biol. Chem. 1975,250 557 565. 23 (a)A. Graham J. Greene P. Lowe and A. D. B. Malcolm Biochem. Soc. Trans. 1976,4,633;(b)V.W. Armstrong H.Sternbach and F. Eckstein F.E.B.S. Letters 1976,70 48. 24 (a) R. R. Lobb A. M.Stokes H. A. 0.Hill and J. R. Riordan European J. Biochem.,1976,70,5 17; (6) G. A. Vehar and J. H. Freisheim. Biochem. Biophys. Res. Comm. 1976,68,937. 25 (a)J. F. Riordan and R. Scandurra Biochem. Biophys. Res. Comm. 1975.66.417;(b)H. F.Gilbert and M.H. O'Leary ibid. 1975,67 198.363 Biological Chemistry -Part (ii)Enzyme Mechanisms that it is the 8-carboxy-group of the aspartate which binds to the essential arginine. It has been suggested that ninhydrin (triketohydrindene) may be a reagent for rever- sible modification of arginine side-~hains.~~ 4 Cross-linking Reagents For some time bifunctional reagents have been used to cross-link different parts of a polypeptide chain274 and for cross-linking between Their use in the investigation of multisubunit enzymes has been considerably advanced by two papers28asb which clearly outline the interchain cross-linking pattern which would be expected for different arrangements of subunits in tetrameric enzymes. Although the theoretical treatments are somewhat different [one uses a probability and the other a kinetic the final conclusions are in broad agreement.Using a series of bis-imido-esters (4) of different lengths it was shown that lactate + + H2N \C-(CH2). -C NH2// Me0/ 'OMe (4) dehydrogenase,28" aldolase,28a*6 catalase,280 fumarase,28" pyruvate kinase,28a glyceraldehyde-3-phosphatedehydrogenase,28" and yeast alcohol dehydrogenase28b all have D2symmetry i.e. each behaves as a dimer of dimers. The method seems to have two limitations. First the chemical reactivity across the binding domains must be sufficiently different to be detectable. Usually this can be simply achieved by changing the chain length of the reagent. Secondly there must be an adequate amount of cross-linking. Only one tetrameric protein p -galactosidase failed to give a satisfactory result because it was found to be very difficult to cross-link.28a Using a range of bis-imido-esters it has been shown that phosphofructokinase has its subunits arranged as ad4,and that within each a4or p4unit the monomers are probably arranged in tetrahedral The use of N-(l-pyrene)maleimide,30 which cross-links cysteine to lysine and which is fluorescent has been reported as has the use of 2-hydroxy-4-maleimidobenzoyl which also cross-links -SH a~ide,~* to -NH2.It is often an advantage to regenerate the monomers from the cross- linked species and this requires the use of cleavable reagents. Thus aldolase and pyruvate dehydrogenase have each been cross-linked with the dimethyl ester of NN'-bis-(2-carboximidoethyl)tartarimide(5),32which may be cleaved with period- ate.Haemoglobin has been cross-linked with dithiobis(succinimidy1 pr~pionate),~~ which can be cleaved with 2-mercaptoethanol and both glutamate dehydrogenase 26 M. F. Chaplin. Biochem. J. 1976 155,457. ''(a)H.Fasold,J. Klappenberger C. Mayer and H. Remold Angew. C7rem. Intemur.Edn. 1971,10,795; (b)G.E. Davies and G. R. Stark hot.Nut. Acad. Ski. U.S.A.,1970,66,651. 2* (u)F.Hucho H. Miillner and H. Sund European J. Biochem. 1975,59,79; (6)J. Hajdu F. Bartha and P. Friedricks ibid. 1976,68 373. 29 G. Kopperschliiger E. Usbeck and E. Hofman Biochem. Biophys. Rcs. Comm. 1976,71,371. 30 C.-W.Wu L. R. Yarbrough. and F. Y.-H. Wu Biochemistry 1976,15,2863. 31 W. E. Trommer. H. Kolkenbrock and G. Pfleiderer 2.physiol.Chem. 1975,356 1455. 32 J. R. Coggins E. A. Hooper and R. N. Perham Biochemistry 1976,15 2527. 33 A. J. Lomant and G. Fairbanks J. Mol. Biol. 1976,104 243. A.D.B.Malcolm and J. R. cbggins + + H2N NH2 'C-(CH&-NH-CO-CHOH-CHOH-CO-NH-(CH2)2-C // Me6 bhle (5 ) and RNA have been cross-linked with (6),which can also be cleaved by 2-mercaptoethanol. The facility to cleave these cross-links is particularly useful in studies of the quaternary structure of enzymes with non-identical subunits as has been shown for RNA p01ymerase.~~ [-S-(CH2k-O-(CH&-C-OMe II 12 NH (6) As can be seen above bis-imido-esters have been widely used to cross-link proteins. They have the advantage of being both highly reactive and specific for only one kind of side-chain the lysine amino-group.Until recently it was thought that the only products were amidines but evidence has now been presented to show that under certain conditions N-alkyl imidates may be formed probably via Scheme 1.36a R'NH2 +MeC=NH2 R'-NH-C-OR2 S NH3 + MeC&HR' I + [ $'I AR2 OR2 L +;y2 R'-NH:c-M~ + R~-OH Scheme 1 Such N-alkyl imidates are probably formed when the monofunctional reagent methyl acetimidate reacts with alcohol dehydr~genase.~~' N-Alkyl imidate forma- tion may also explain the unexpected cross-linking observed when troponin was treated with methyl a~etirnidate.~~' Because a single imido-ester group can cross- link protein subunits all measurements of inter-lysine distances in enzymes with bis- imido-esters should be treated with caution.5 RNA Polymerase The recent interest in the manipulation of genetic material has focused attention on those enzymes which use nucleic acids either as substrates or templates. RNA polymerase (nucleoside triphosphate :RNA nucleotidyl transferase EC 2.7.7.6) from E. coli is a well-studied example. Using the four ribonucleoside 34 H. J. Schramm and T. Diilffer Z. physiol. Chern. 1976,357,477. 35 J. R. Coggins J. Lumsden and A. D. B. Malcolm Biochemistry 1977,16,1111. 36 (4)D. T. Brown and S. B. H. Kent Biochern. Biophys. Res. Comrn. 1975,67,126; (b)D. T. Browne and S. B. H. Kent ibid. p. 133; (c)S. E. Hitchcock Biochemistry 1975,14 5162. Biological Chemistry -Part (ii)Enzyme Mechanisms 365 triphosphates this enzyme produces an RNA copy (a transcript) of a DNA template.The so-called core enzyme consists of four subunits a2ppfand the enzyme is obviously not symmetric. The holo-enzyme has an extra subunit 0; and whereas the core enzyme will transcribe DNA of any sequence the holo-enzyme must recognize specific initiation sequences in the DNA before transcription can occur. The cr subunit is in dynamic equilibrium with core en~yme.~’ Most RNA chains commence with A or G and it has been shown that there are two sites on the enzyme for nucleoside triph~sphates.~~ The so-called initiation site binds only purine ribo- nucleoside triphosphates whereas the elongation site binds both purine and pyrimidine nucleoside triphosphates.It has been suggested that RNA polymerase is an allosteric enzyme39 and that it is different conformations of the enzyme which recognize different ‘promoters’ on the DNA (these are the sequences which the enzyme recognizes and to which it binds prior to the initiation of RNA synthesis). The amino-acid compositions and N-terminal tetrapeptides of all the subunits have been determined.40 Controlled proteolysis by a variety of proteases41 shows that the fragmentation pattern of the isolated subunit may be converted into that of p in the intact enzyme by the addition of the a subunits suggesting that a2p may be an intermediate in the assembly of the enzyme. This is confirmed by work on the assembly of the enzyme42 which also shows that the a)&?’ formed first is inactive (premature core) and is converted into active enzyme by a subsequent conforma- tional change.The existence of such a conformational change had previously been suggested on the basis of renaturation of denatured ~ubunits,~~~,~ and is supported by cross-linking experiment^.^' The conformational change induced in the core enzyme by the v subunit has been observed by labelling the latter with the fluorescent pyrene ~naleimide.~’.~~ A study of the reaction of core with labelled cr by stopped flow shows a biphasic reaction and the second step being first-order is presumed to be a conformational change. The subunits from E. coli are capable of forming hybrid enzymes with the subunits from Micrococcus fute~s~~ but and Serratia marescen~~~ not with the subunits from Anacystis nid~lans.~’ Chemical modification of RNA polymerase with pyridoxa1-5’-phosphate followed by NaBH4 reduction inactivates the enzyme suggesting the presence of an essential ly~ine.~’ Attempts to synthesize the affinity label 5-formyl-UTP (7) were originally complicated owing to unexpected anomerization on the ribose ring49 but the a-and P-anomers have now been separated,” and it has been shown that the a-anomer inhibits the enzyme and 37 A.Travers F.E.B.S. Letters 1975,53 76. 38 C.-W. Wu and D. A. Goldthwait Biochemistry 1969,s. 4458. 39 A.Travers Nature 1976,263 641. 40 H. Fujiki and G. Zurek F.E.B.S. Letters 1975,55 242. 41 P.A. Lowe and A. D. B. Malcolm European J. Biochem. 1976,64,177. 42 (a)M.Taketo and A.Ishihama I. Mol. Biob 1976,102,297;(b)T. Saitoh and A. Ishihama ibid. 1976 104,621. 43 (a) J. D. Harding and S. Beychok Roc. Nat. Acad. Sci. USA. 1974,71,3395;(b)P. Palm A.Heil D. Boyd B. Grampp and W. Zillig European J. Biochem. 1975,53 283. 44 F. Y.-H. Wu L. R. Yarbrough and C.-W. Wu Biochemistry 1976 IS 3254. 45 U.1. Lill E. M. Behrendt and G. R. Hartmann European J. Biochem. 1975,52,411. 46 B. Konze-Thomas and W. Riiger European J. Biochem. 1976,63 321. 47 F. Herzfeld and M. Kiper European J. Biochem. 1976,62 189. 48 P.Bull J. Zaldivar A. Venegas J. Martial and P. Valenzuela Biochem. Biophys. Res. Comm. 1975,64 1153. O9 V. W. Armstrong H. Sternbach and F. Eckstein F.E.B.S. Letters 1974,44 157. V. W.Armstrong H. Sternbach and F.Eckstein Biochemistry 1976,15,2086. A.D.B.Malcolm and J. R. Cogsins 0 IOH OH (JCH2-0-7-0-7-0-7-0-R R ft 0-0-(5-(7) reduction with BH,-results in irreversible inhibition. Using [y-32P]-labelled reag- ent it was shown that a lysine on the p-subunit was labelled although longer incubations did result in more extensive labelling. It seems likely that there is a partial unwinding of the DNA double helix during transcription,” and calculations of the various stacking energies of the nucleotide bases during RNA synthesis have been made.52 The stereochemistry of RNA synthesis-whether there is retention inversion or even racemization at the a-phosphate-is not known. The problem has been tackled using the sulphur analogue (8) of ATP.An optically active starting ?JH* 00s 0-0-0- OH OH (8) material polymerized on a poly-d(AT) template and hydrolysed to the 2’,3’-cyclic phosphorothioate produces a single stereoisomer and hence the possibility of racemization during polymerization can be eliminated.53 Unfortunately the abso- lute stereochemistry of the starting material has not yet been determined and hence the question of retention or inversion is still open. DNA from bacteriophage T,has three early promoters to which RNA polymerase binds. The sequences of the regions of DNA protected by RNA polymerase from digestion by nuclease have been determined.54 By choosing the correct combination of a dinucleoside monophosphate and a nucleoside triphosphate the enzyme can be made to initiate RNA synthesis at one particular Thus the promoter designated Ar will initiate if given CpC+ATP Az will initiate in the presence of CpG +CTP,and A3 will start transcription with ApC +ATP.The effect of tempera- s* (a)C. Escarmis. E. Domingo and R. C. Warner Biochim. Biophys. Acta 1975,402,261 (6) A. D. B. Malcolm. G. J. Mitchell and B. Wasylyk Nucleic Acids Res. 1975,2 537. s2 H. Fujita and C. Nagata J. Theoret. Biol. 1976 57 187. s3 F. Eckstein V. W. Armstrong and H. Sternbach. Roc. Nut. Aced. Sci. U.S.A.,1976.73 2987. s4 (a)D. Pribnow,Ptoc. Nat. Acad. Sci. U.S.A. 1975,72,784; (b)D.Pribnow,I. Mol. Biol. 1975.99.419. ss J.-P. Dausse A. Sentenac and P. Fromageot Eumpean J. Biochem. 1975,57,569. Biological Chemistry -Part (ii)Enzyme Mechanisms 367 ture and ionic strength on initiation at these promoters has been st~died,'~ and although the response to these twoparameters is in general interdependent it can be said that at low temperatures initiation at A3 predominates and Al and AZare gradually activated as the temperature is raised.An amazing piece of spec- trophotometry has allowed these promoter regions of DNA to be titrated with RNA p01ymerase.~~ The difference spectrum of the nucleic acid at 260 nm titrates to an end-point corresponding to a holo-enzyme :DNA molar ratio of 1at 3 "C 2 at 10"C and 3 at temperatures above 25 "C. In the absence of the u-subunit the core enzyme gives no end-points thus confirming that u is responsible for guiding the enzyme to specific promoter regions.As predicted it has proved comparatively easy to purify" and crystallizes9 RNA polymerase from thermophilic bacteria. 6 Ribonuclease Ribonuclease (EC 3.1.4.22) was the first enzyme to have its primary sequence determined and the sequences from gnu,60 pike whale,61 bison,62 dr~medary,~~ guinea-pig chinchilla and coyp~,~~~.~ topi,-' and eland64d have recently been determined. The most remarkable finding is that each sequence varies from any of the others at between 20% and 30% of the positions -a far greater divergence than is observed in most homologous proteins. Although the mechanism of ribonuclease was substantially discovered by a combination of pH effects and chemical modifica- tion the fine details of the mechanism remain to be clarified by techniques such as n.m.r.The proton magnetic resonance spectra at 250 mHz of the histidine residues have been reinve~tigated~~~'~~ and used to study the conformation changes around His-48 induced by pH changes.656 A study of the 'H n.m.r. spectra of His-12 and Hi~-119~'" has enabled a model for their mutual interaction to be proposed. The effect of temperature on the pK values of His-12 His-105 and His-119 has been determined by n.m.r.67 In thermally unfolded ribonuclease (at 69 "C) two histidines 48 and 105 are still in regions retaining their native structure.68 It is well known that totally denatured ribonuclease (with all four S-S bridges broken) will spontaneously refold to give active enzyme in the presence of air. Sulphydryl reagents such as glutathione will catalyse this reaction,69a and ionic strength effects on this catalysis have been 56 J.-P.Dausse A. Sentenac and P. Fromageot European J. Biochem.. 1976,65 387. 57 M.-T. Sarocchi F.E.B.S. Letters 1976,68,83. 58 M. Fabry J. Sumegi and P. Venetianer Biochim. Bwphys. Acta 1976,435,228. 59 S. Tsuji K. Suzuki and K. Imahori Nature 1976,261,725. G. Groen G. W. Welling and J. J. Beintema EE.B.S. Letters 1975,60,300. 61 M. Emmens G. W. Welling and J. J. Beintema Biochem. J. 1976,157 317. 62 F. Muskiet G. W. Welling and J. J. Beintema Internat J. Peptide Protein Res. 1976,8 345. 63 G. W. Welling G. Groen. and J. J. Beintema Biochem. J. 1975,147 505. 64 (a)A. van den Berg and J. J. Beintema. Nafure 1975 253 207; (b) A. van den Berg L.van den Hende-Timmer and J. J. Beintema Biochim. Biophys. Acta 1976,453 400; (c) H. Kuper and J. J. Beintema ibid. 1976 446,337; (d)F. Russchen G. De Vrieze. W. Gastra and J. J. Beintema. ibid. 1976,427,719. 65 (a)J. L. Markley Biochemistry 1975,14,3546; (b)J. L. Markley. ibid.,p. 3554; (c)J. L. Markleyand W. R. Finklestadt. ibid. p. 3562. 66 D. J. Patel L. L. Canuel F. A. Bovey and C. Woodward Biochim. Biophys. Acta 1975,400,275. 67 D. G.Westmoreland C. R. Matthews M. B. Hayes and J. S. Cohen J. Biol. Chem. 1975,250,7456. a C. R. Matthews and D. G. Westmoreland. Biochemistry 1975.14.4532. 69 (a)A. K. Ahmed S. W. Schaffer and D. B. Wetlaufer I. Biol. Chem. 1975 250 8477; (b) S. W. Schaffer A. K. Ahmed. and D. B. Wetlaufer ibid. p. 8483. 368 A.D.B.Malcolm and J.R. Coggins The role of Lys-41 in the ribonuclease reaction has been studied by reaction with o-methylisourea. Reaction of nine out of the ten lysines causes no loss of activity but modification of Lys-41 results in ina~tivation.~’ Acetylation shows that lysines are not involved in binding of the enzyme to the RNA but that at least one of Lys-7 Lys-41 and Lys-66 is required for catalysis.71 Ribonuclease can be cross-linked to its substrate photochemically in the presence of acetone as a By using light of wavelength greater than 300 nm either pCp or pup can be covalently bound to the polypeptide chain between Asn-67 and Arg-85. Denatured ribonuclease does not react. Dimers of ribonuclease cross-linked by dimethyl suberimidate have been pre- pared.Not only do they have an enhanced activity towards p~ly-A-poly-U,~~ but they can also be used as a cytostatic agent.74 Microcalorimetry has shown that the hydrolysis of RNA by ribonuclease is an endothermic reaction (+35.1 J g-’) whereas the hydrolysis of cyclic nucleotides such as 2’3’-cCMP which are commonly used as model substrates is exothermic (-33.9 kJ m~l-’).~~ This presumably reflects the presence of strain in the cyclic ester. To study the recognition process involved in the reconstitution of ribonuclease by the addition of the S-peptide to the S-protein a series of analogues of the S-peptide has been ~ynthesized.’~ This has shown that each one of the first eight residues makes a contribution to the regeneration of activity in the complex.7 Superoxide Dismutase Superoxide dismutase (EC 1.15.1.1) is an extremely unusual enzyme. Its substrate is a free radical which can only be present in minute amounts and the reaction which it catalyses proceeds rapidly even in the absence of enzyme. Nonetheless the enzyme occurs in all aerobic cells and is generally believed to be essential for survival.77 This is because the enzyme is involved in the catalytic scavenging of the superoxide radical which seems to be a common intermediate of oxygen reduction and the principal cause of oxygen The reaction catalysed is the disproportionation or ‘dismutation’ of two superoxide radicals to give oxygen and at neutral pH hydrogen peroxide (Scheme 2). 02’+02’+2H+ + H202f02 Scheme 2 The activity was discovered less than ten years ago7’ and has now been extensively studied.It has never been mentioned in the Enzyme Mechanisms section of Annual Reports although it seems to the Reporters that during the past five years more papers have appeared on superoxide dismutase than on any other single enzyme. The 70 L. R. Brown and J. H. Bradbury European J. Biochem. 1976,68,227. 71 B. Walter and F. Wold Biochemistry 1976,15,304. 72 J. Sperling and A. Havron Biochemistry 1976,15 1489. 73 D.Wang G. Wilson and S. Moore Biochemistry 1976,15,660. 74 J. Bartholeyns and P.Baudhin Arch. Intenat. Physiol. Biochim. 1976,84 139. 75 M. Tribout S.Paredes and J. Lkonis Biochem. J. 1976 153 89. 76 S.Levit and A. Berger J. Biol. Chem. 1976,251 1333.77 I. Fridovich Ann. Rev. Biochem. 1975,44 147. 78 J. M. McCord and I. Fridovich I. Bwl. Chem. 1969,244.6049. Biological Chemistry -Part (ii)Enzyme Mechanisms 369 majority of these have concentrated on biological aspects of the enzyme and many extensive reviews have More recently detailed structural and mechanistic studies have been carried out; early progress in these areas has been reviewed,” and this section will concentrate on subsequent work. The first protein shown to have superoxide dismutase activity was erythrocup- rein,78a a copper-containing protein which had been isolated 30 years earlier*’ and which for a long time was thought to have only a storage function.” Similar superoxide dismutases have now been isolated from the cytosols of a wide range of eukaryotic organisms.77 These enzymes have a molecular weight of 32 000 and are made up of two identical s~bunits.~”~~~ Each subunit contains one Cu2’ and one Zn2’ ion and the activity is inhibited by cyanide but survives treatment with chloroform-ethano177 and other organic In contrast prokaryotes have manganese-or iron-containing superoxide dismutases; these enzymes are not inhibited by cyanide and are usually inactivated by chlor~form-ethanol.~~ Manganese-containing superoxide dismutase has also been found in the mitochon- dria of several eukaryotes and this has prompted interesting speculations on ev01ution.~~~’~~ The iron- and manganese-containing superoxide dismutases contain either two or four subunits and the subunit molecular weight ranges between 19000 and 24 000; there is not more than one metal atom per There seems to be a high degree of homology between these iron- and manganese-superoxide dismutases whether or not they originate from prokaryotes or from the mitochon- dria of e~karyotes.~~*~~ In contrast the copper- and zinc-containing superoxide dismutases seem to form a separate family of enzymes and show no sequence homology with the iron- and manganese-en~ymes.~~”~~~~~~ The structure of Cu2+,Zn2+ superoxide dismutase has been determined at 3 A The dominant structural feature is an 8-stranded barrel of antiparal- lel p-pleated sheet.There is a short helical section and two loops that have no secondary structure. The copper and zinc atoms which are 6 A apart are bound between the loops and one side of the barrel.The copper has four histidine ligands arranged in a slightly distorted square plane and the zinc is bound to three histidines and an aspartate which are approximately tetrahedral in arrangement.64 The imidazole of His-61 is a common ligand for both copper and zinc. The ligand geometries around both metal atoms and the histidine ligand shared between them 79 (a)I. Fridovich Accounts Chem. Res. 1972,5321; (b)J. M. McCord C. 0.Beauchamp S. Groscin H. P. Misra and I. Fridovich in ‘Oxidases and Related Redox Systems’ ed. T. E. King H. S. Mason and M. Morrison University Park Press Baltimore 1973 Vol. 1 p. 51; (c) U. Weser Structure and Bonding 1973 17 1; (d) I. Fridovich in ‘Molecular Mechanisms of Oxygen Activation’ ed.0. Hayaishi Academic Press New York 1974 p. 453; (e) W. Bors M. Saran E. Lengfelder R. Spiittl and C. Michel Current Topics Radiation Res. 1974 9 247; (f) I. Fridovich Adv. Enzymol. 1974 41 35; (g) I. Fridovich Life Sciences 1974,14 819; (h)I. Fridovich in ‘Horizons in Biochemistry and Biophysics’ ed. E. Quagiariello F. Palmieri and T. P. Singer Addison Wesley Reading (Mass.) 1974 Vol. 1 p. 1; (i)1. Fridovich American Scientist 1975,63,54;(j)I. Fridovich in ‘Free Radicals in Biology’ ed. W. A. Pryor Academic Press New York 1976 Vol. 2 p. 239. 8o B. G. Malmstrom L.-E. Andreasson and B. Reinhammar in ‘The Enzymes’ ed. P. D. Boyer Academic Press New York 1975 Vol. 12 p. 507. T. Marm and D. Keilin Proc. Roy. SOC.,1939 B126 303. 82 (a)H.M. Steinman V. R. Naik J. C. Abernethy and R. C. Hill J. Biol. Chem. 1974,249,7326; (b)M. Y. Symonyan and R. M. Nalbandyan Biochim. Biophys. Acta 1976,446,432. 83 J. Lumsden and D. 0.Hall Nature 1975 257 670. 84 H. M. Steinman and R. L. Hill Proc. Nut. Acad. Sci. U.S.A. 1973 70 3725. J. Bridgen J. I. Harris and F. Northrop F.E.B.S. Letters 1975 49 392. 86 J. S. Richardson K. A. Thomas and D. C. Richardson Biochem. Biophys. Res. Comm.,1975,63,986. 370 A. D.B.Malcolm and J. R. Coggins have extremely close analogues in crystal structures of Cu-imidazole and Zn-imidazole complexes."q The two subunits have essentially the same conformation and there is an extensive inter-subunit contact area which involves mainly hydrophobic side-chain interactions.64 The two copper sites of a dimer are 34 A apart.A remarkable feature of the structure of the polypeptide chain backbone of copper,zinc-superoxide dismutase is its great similarity to the backbone of the variable domain of the immunoglobulins.64~87 There is no obvious reason for this close resemblance of folding pattern between two functionally unrelated proteins which have no evident sequence homology. Previously three categories of proteins had been recognized to have similarities in their basic three-dimensional folding patterns. These were (i) proteins which showed clear amino-acid sequence homologies for example the globins the cytochromes and the trypsin-like serine proteases (ii) proteins which contained internally repeated structural folds with or without sequence homology for example the immunoglobulins and the calcium- binding proteins and (iii) proteins which contained functionally related domains but otherwise differed widely from each other for example the dehydrogenases and the kinases.14*87 The structural similarity between copper,zinc-superoxide dismutase and the immunoglobulins is the first example of a fourth categ~ry.'~ The kinetic properties of copper,zinc-superoxide dismutase have been extensively studied." The first workers in the field encountered problems because of the complexity of the indirect assay procedure and because they failed to avoid inactiva- tion of the enzyme by hydrogen peroxide.88 Fortunately the introduction of pulse radiolysis into enzymology provided a direct means of studying the It was found that the rate of reaction between 02pand the enzyme governed t~rnover.~~-~~ For the ox enzyme the second-order rate constant for this reaction was 2 x lo91 mol-' s-' which is close to the value expected for a diffusion-controlled reaction." Direct evidence for this was obtained by adding glycerol to the reaction mixture and observing a decrease in reaction rate with increasing viscosity of the medium.88 Spectral measurements (optical and e.p.r.) of the oxidation state of the copper after exposure to substrate indicated an enzyme mechanism involving alternate copper reduction and re-oxidation." The rate constants for the reduction of native enzyme and the re-oxidation of reduced enzyme by 02?are approxi- mately the same as the turnover number indicating there are no slower steps in the reaction.The simplest mechanism which can account for these data is given in Scheme 3." Early workers failed to find evidence for the formation of a Michaelis complex.8o More recently however some evidence for saturation of the catalytic sites by 02 Enz-Cu2++02T+ Enz-Cu++O2 Enz-Cu' +2Hf +O2 + Enz-Cu2++H202 Scheme 3 87 J. S. Richardson D. C. Richardson K. A. Thomas E. W. Silverton and D. P. Davies J. Mol. Biol. 1976 102,221. 88 E.M.Fielden P. B. Roberts R. C. Bray D. J. Lowe G. N. Mautner G. Rotilio and L. Calabrese Biochem. J. 1974,139,49. 89 D. King J. Rabani and I. Fridovich J. Biol. Chem. 1972,247 4839. 90 G. Rotilio R. C. Bray and E. M. Fielden Biochim. Biophys.Acta 1972 268 685. Biological Chemistry -Part (ii)Enzyme Mechanisms 371 has been obtained." The rate constant of the rate-limiting step is independent of pH in the range 5-10,80 which contrasts with the rate of spontaneous dismutation which varies with pH.92 Below pH 5 the rate of enzyme-catalysed reaction falls off. This indicates that the radical anion 02T rather than HO is the substrate since the pK for H02* is 4.8.92 Superoxide dismutase shows no dueterium isotope effect:' and this together with the lack of a pH effect suggests that proton transfer is not rate limiting. However the overall dismutation reaction in vivo at pH 7 must require two protons (see Scheme 2). It is possible that the product of dismutation is H02-rather than H202 but still one proton must be involved in the catalytic cycle.It has been suggested that the imidazole (His-61) which was observed 6q by the crystallog- raphers to form a bridge between the copper and zinc atoms may function as a proton carrier to facilitate protonation of the 02+ which interacts with the cuprous enzyme in the second half of the catalytic cycle (Scheme 4).93 Im Im I I OT I +I -Zn2+-Im -Cu2+ +-Zn2+-ImH Cu' +O2 I /\+H I /\ Im Im Im Im -Zn2+-Im -+H02-I /\ Im Im Scheme 4 Both azide and cyanide bind to the copper on the enzyme but only cyanide inhibits. This may be because azide occupies a position normally taken by an imidazole ligand but cyanide tends to bind to the site normally occupied by H20 02-,or H,02.93 Specific evidence that there is an open co-ordination position at one of the metal sites in the reduced form of superoxide dismutase has been obtained from an n.m.r.study.94" This work led to a careful reappraisal of the mechanism of copper,zinc-superoxide dismutase. If the reaction is represented by two distinct steps (Scheme 4) the first step is clearly the simpler consisting of the transfer of only one electron from the superoxide radical ion to the cupric ion.94a However the second step cannot be a simple electron transfer because the direct formation of the doubly charged peroxide anion (02,-) is energetically unfavourable. The charge density must be neutralized and this presumably involves placing the superoxide radical ion close to a positive charge prior to electron transfer.It has been proposed that a water rnolecule bound to the intermediate Cu' species can provide this positive charge.94" 91 A. Rigo P. Viglino and G. Rotilio Biochem. Biophys. Res. Comm. 1975,63 1013. 92 J. Rabani and S. 0.Nielsen J. Phys. Chem. 1973,73,3736. 93 E.K.Hodgson and I. Fridovich Biochemistry 1975 14 5294. 94 (a)J. A. Fee and R. C. Ward Biochem. Biophys. Res. Comm. 1976,71,427;(b)A. Rigo P. Viglino L. Calabrese D. Cocco and G. Rotilio Biochem. J. 1977 161 27 31; (c)L.Calabrese D. Cow L. Morpurgo B. Mondavi and G. Rotilio European J. Biochem. 1976 64 456; (d) L.Morpurgo I. Mavelli L. Calabrese A. F. Agro and G. Rotilio Biochem. Biophys. Res. Comm. 1976,70,607;(e)R. Brigelius H. J. Hartmann W. Bors M. Saram E. Lengfelder and U.Weser 2.physiof. Chem. 1975 356,739;(f)L.R. de Alvare K. Goda and T. Kimura Biochem. Biophys. Res. Comm. 1976,69,687. 372 A.D.B. Malcolm and J. R. Coggins A study of samples of copper,zinc-superoxide dismutase containing less than the stoicheiometric amount of copper indicates that the binding of copper is co- The sites for binding the first Cu2' on apo-enzyme are equivalent but occupation of the first site lowers the activation energy for binding the second Cu2'. This shows that the binding of Cu2+to one subunit brings about a conformational change which facilitates Cu2+ binding to the other. The specific activity with respect to copper of enzyme molecules containing only one Cu2+ per dimer appears to be twice as great as that of molecules with two Cu2' ions.946 This supports the hypothesis that there is interaction between the two copper sites during activity; it also implies that only one Cu2' functions in The Zn2' ions of superoxide dismutase can be readily replaced by Co2' ions and the resulting cobalt-substituted enzyme is active and can be studied by optical e.p.r.spe~troscopy.~~~'~ As can also be deduced from the crystallographic data,% the cobalt (zinc) site is far less exposed to solvent water and to attack by cyanide ions than the copper The spectral data suggest that the reaction of cyanide with the copper involves a water molecule bound to the copper;94c this is consistent with the n.m.r. data referred to The histidine bridge between the copper and the cobalt (zinc) sites is unaffected by cyanide treatment although it is disrupted by acid titration presumably because of protonation of this histidine.The exact role of the zinc ions in catalysis is not yet understood although some evidence suggests that the Zn-imidazole group plays an important role in determining the redox potential of the Cu2' ion.94d Two kinds of low molecular weight copper-containing complexes have been shown to have superoxide dismutase activity.94e" Under certain conditions one of these the [C~"(Tyr)~l complex is as effective a scavenger of OZ1as superoxide dismuta~e.~~' An e.p.r. study of the reaction of the other complex bis- (salicylato)Cu2' complex with 02T suggests that it catalyses dismutation in the same way as superoxide dismutase by alternate oxidation and reduction of copper ions but it is considerably less effective as a catalyst than the enzyme.94f Studies of the mechanism of the iron- and manganese-containing superoxide dismutases have been greatly facilitated during the past year by the isolation and characterization of these enzymes from a number of new species iron-containing enzymes have been purified from Spirulina platen~is,~~ Plectonema boryan~m,~~.~~ and Pseudomonas o~alis,~~ while manganese-containing enzymes have been purified and from Rhodopseudomonas ~pheroides,~' yeast mito~hondria,~~"~~Bacillus stearothermophilus."' The preparation of the apo-forms of both the iron-"' and the manganese-enzymes102"03has been described as has their reconstituti~n.'~~-~~~ Co2' Ni2+ and Zn2' could all bind to the metal site of the manganese enzyme but enzyme reconstituted with these metals showed no a~tivity.''~ It is noteworthy that 95 J.Lumsden R. Camrnack and D. 0.Hall Biochim. Biophys. Acta 1976,438,380. 96 K. Asada K. Yoshikawa M. Takahashi Y. Maeda and K. Enmanyi J. Biol.Chem.,1975,250,2801. 9? H. P.Misra and B. B. Keele Biochim. Biophys. Acta 1975,379 418. 98 F.Yakarnura Biochim. Biophys. Acta 1976,422 280. 99 (a)S.D.Ravindrath and J. Fridovich J. Biol. Chem. 1975,250,6107;(6)K. M.Beem J. S. Richardson and D. C. Richardson J. Mol. Biol. 1976,105,327. 100 J. Bridgen J. I. Harris and E. Kolb J. Mol. Biol. 1976,105,333. lol F.Yakamura and K. Suzuki Biochem. Biophys. Res. Comm. 1976,72 1108. 102 C. J. Brock J. I. Harris and S.Sato J. Mol. Biol. 1976 107 175. 103 D.E.Ose and I. Fridovich J. Biol. Chem. 1976 251 1217. Biological Chemistry -Part (ii ) Enzyme Mechanisms 373 the manganese enzyme from Bacillus stearothermophilus appears to have only one manganese atom per dimer. 100~102*104This appears to be shared between the subunits and is released only under conditions which cause dissociation of the dimeric structure.lo2 The iron enzyme from Pseudomonas ovalis also appears to have only one iron atom per dimer.98*101 The manganese enzyme has recently been crystal- lized,99b.100 and detailed structural analysis at high resolution is being ~ndertaken.~~' Knowledge of the active site structure of manganese-superoxide dismutase will be of great interest as it should reveal how this enzyme can achieve the same function as the copper,zinc-enzyme but by using only one metal atom instead of two.Spectral evidence s~~ws'~~,~~~ that the native manganese-enzyme contains Mn3' and some preliminary kinetic studies using the pulse radiolysis technique have been described. lo6 Spectral studies on the iron-enzyme have that it contains Fe3* and kinetic studies involving pulse radiolysis have also been reported.'08a Both the iron- and manganese-enzymes are believed to work by the alternate oxidation and reduction of the catalytic metal atom by the sub- strate. 104,106,108a Recently evidence has been presented that simple complexes of iron'08' and manganese'08'*d can also catalyse superoxide dismutation. Further studies with these model systems108d should prove very useful for the elucidation of the detailed reaction mechanism of the iron- and manganese-enzymes.Detailed studies on enzymes can only proceed when there is a convenient and precise assay. In the case of superoxide dismutase the instability of the substrate has complicated the design of good assays. The commonly used assays depend upon a competition between superoxide dismutase and some indicating scavenger of 02 e.g.cytochrome c or nitroblue tetraz~lium.~~' Superoxide radicals are generated for example enzymatically from mixtures of xanthine and xanthine oxidase and the amount of superoxide dismutase is measured by its ability to inhibit the reaction of the indicating scavenger with OZT.Such an assay will vary in sensitivity depending on the rate of reaction of OZTwith the indicating scavenger.1o9 The complexity of the chemical photochemical or enzymatic methods used to generate 02T may provide undesirable complications in the assay.' 10,11' The preferred method for generating 02?is pulse radioly~is,~~~~~ but the equipment required is not widely available.Simplified methods have therefore been developed for the chemical'" and electroly- tic'" generation of 02:.Two new versions of the conventional assay each employ- ing a new scavenger have been de~cribed,"~*~'~ as have a highly sensitive version of an existing assay'09 and a micro-a~say."~ Some evidence has been presented which suggests that the use of nitroblue tetrazolium as a scavenger for 02T radicals is lo4 B.B. Keele C. Giovagnoli and G. Rotilio Physiol. Chem. Phys. 1975 7 1. 105 J. J. Villafranca F. J. Yost and I. Fridovich J. Biol. Chem. 1974 249 3532. 106 M. Pick J. Rabani F. J. Yost and I. Fridovich J. Amer. Chem. SOC.,1974,96 7329. 107 J. J. Villafranca F.E.B.S. Letters 1976,62 230. 108 (a) F. Lavelle M. E. McAdam E. M. Fielden P. B. Roberts K. Puget and A. M. Michelson Biochem. J. 1977 161 3; (b)B. Halliwell F.E.B.S.Letters 1975 56 34; (c) Y. Kono M. A. Takahashi and K. Asada Arch. Biochem. Biophys. 1976,174,454;(d)J. K. Howie and D.T. Sawyer J. Amer. Chem. SOC. 1976,98,6698. E. K. Hodgson and I. Fridovich Biochim. Biophys. Acra 1976,430 182. 110 J. A. Fee and P. G. Hildenbrand F.E.B.S. Letters 1974. 39 79. 111 L. E. A. Henry B. Halliwell and D.0.Hall F.E.B.S. Letters 1976 66 303. 112 E. F. Elstner and A. Hempel Analyt. Biochem. 1976,70 616. 113 R. A. Heikkila and F. Cabbat Analyt. Biochem. 1976,75 356. 114 W. Bohenkamp and U. Weser 2. physiol. Chem. 1975 356 747. A. D.B. Malcolm and J. R. Coggins ~nreliable."~ None of the new assays referred to is completely satisfactory for kinetic studies; for such studies it is best to use pulse radiolysis and U.V. spectros-copy. l6 There is considerable evidence77 that many biochemical reactions generate 025. Molecular oxygen in its ground state is reduced by stepwise electron reduction. The electronic basis for this preference depends upon a spin re~triction."~ There is doubt about the exact quantity of OZTproduced in a given cell and about the quantitatively most significant source of OZT,but it is generally agreed that all aerobic cells do produce significant quantities of OZr.Superoxide radicals participate in a spontane- ous dismutation reaction in aqueous solution to give H202and 0,. At pH 7.4 the rate constant for the spontaneous dismutation reaction is ca. 2 X lo51mol-' s-'. This is already a very rapid reaction and it is remarkable that there is an enzyme which can accelerate it still further. The rate constant for the reaction of OZ5with superoxide dismutase at pH 7.4 is 2 X lo91 mol-' s-'; this gives the enzyme-catalysed reaction an advantage of lo4over spontaneous dismutation. However there is a second point which gives the enzyme-catalysed reaction a further advantage.The intracellular concentration of enzyme is much greater than the intracellular concentration of 02 so the collision rate of a superoxide radical with enzyme will be much greater than its rate of collision with another 02T.It has been estimated that this gives the enzyme-catalysed dismutation a further advantage of at least 10'. Taken together these two factors suggest that the enzyme-catalysed dismutation reaction occurring inside a living cell is at least lo9 times faster than the spontaneous dismutation reaction. Why should there be such an efficient process for destroying 02T in living cells? The answer is presumably because 02?is toxic or can give rise to toxic products. Among the possible reasons for OZT is its ready conversion into two very reactive species the hydroxyl radical and singlet oxygen.The hydroxyl radical is produced when OZTreacts with H2O2,ll8 and the spontaneous (uncatal- ysed) dismutation of OZTcan give rise to some singlet Superoxide dismutase is presumably present in all aerobic cells to ensure that superoxide radicals are efficiently eliminated and as a result these reactive species are not formed. It was believed that superoxide dismutase could also eliminate singlet ~xygen.''~ The weight of evidence however now suggests that the enzyme does not destroy singlet oxygen but simply acts to prevent singlet oxygen formation by catalysing the disproportionation of O2-to give oxygen in its ground (triplet) ~tate."~"*~ lls M. Younes and U. Weser F.E.B.S. Letters 1976,61 209.116 A. Shafferman and G. Stein Biochim. Biophys. Acta 1975,416 287. H. Taube in 'Oxygen Chemistry Structure and Excited States' Little and Brown Boston 1965. 11* F. Haber and J. Weiss Proc. Roy. SOC.,1934 A147 332. 119 C. S. Foote in 'Free Radicals in Biology' ed. W. A. Pryor Academic Press New York 1976,Vol. 2 p. 85. 120 W. H. Koppenol Nature 1976,262,420.

ISSN:0069-3030    

DOI:10.1039/OC9767300360

出版商:RSC    

年代:1976

数据来源: RSC