摘要:

7 Photochemistry ByA. COX Department of Chemistry and Molecular Sciences University of Wawick Coventry CV4 7AL 1 Introduction Reviews have appeared on a number of topics including photosensitization in organic synthesis,’ phototransformations of heterohexa-l,3,5-trienes,*and of mag- netic field and magnetic isotope effects in organic photochemical reaction^.^ A three-volume work on rearrangements in ground and excited states has also been p~blished.~ 2 Alkenes A study has been reported’ of the photobehaviour of some 3-(o-alkylphenyl)- substituted cyclopropenes that contain a benzylic hydrogen in the y-position of the side chain. The results of this investigation which is aimed at providing more information about the reactivity of excited olefins towards hydrogen abstraction show that triplet states of tetra-substituted cyclopropenes possessing y-hydrogens readily undergo intramolecular hydrogen transfer.For 1,2-diphenyl-substituted cyclopropenes the primary isotope effect is significantly higher than previously observed for H-transfer to an excited state. Irradiation of alkyl-substituted hexa- 1,5 -dienes induces6 allylcyclopropane formation and rearrangement to an isomeric hexa-1,5-diene. These products arise via competing [1,2]-and [1,3]-sigmatropic allyl shifts. Other products which are characteristic of the photochemical behaviour of isolated double bonds are also formed. It is suggested that on direct irradiation the sigmatropic allyl migrations occur from an excited state which arises when the diene has a conformation in which an orbital interaction exists between the two double bonds and the central C-3 -C-4 bond.Some substituted cycloheptatrienes are known to undergo regioselective [1,7]-sigmatropic shifts as well as electrocycliz- ations from singlet states and a model has been suggested’ that accounts for the reactivity and selectivity trends as well as for some wavelength-dependent photo- reactions. Regioselectivities are explained as a function of substituents with electron ’ A. Albini Synthesis 1981 249. M. V. George A. Mitra and K. B. Sukumaran Angew. Chem. Int. Ed. Engl. 1980,19,973. N. J. Turro and B. Kraeutler Acc. Chem. Res. 1980 13 369. Organic Chemistry Vol. 42-3 ‘Rearrangements in Ground and Excited States’ ed. P. de Mayo Academic Press New York 1980.’ A. Padwa C. S. Chou R. J. Rosenthal and B. Rubin J. Am. Chem. Soc. 1981,103 3057. T. D. R. Manning and P. J. Kropp J. Am. Chem. Soc. 1981,103,889. ’T. Tezuka 0.Kikuchi K. N. Houk M. N. Paddon-Row C. M. Santiago N. G. Rondan J. C. Williams and R. W. Gandour J. Am. Chem. SOC.,1981,103 1367. 133 134 A. Cox donors favouring electrocyclizations and electron acceptors promoting sigmatropic rearrangements. The model involves an excited singlet state in which there is 90" rotation about one terminal double bond accompanied by 'sudden polarization' to form a zwitterionic species. Using an ene reaction an intermediate has been trapped' in the photosensitized electron-transfer dimerization of 1,l-diphenylethylene and in the cross-cyclo- addition of 1,1-diphenylethylene with methylpropene (Scheme 1).The products of Ph H R sens.Ph H R H (a) R = Ph Scheme 1 the ene reaction are not readily available by alternative routes and consequently the transformation may be useful in synthesis. Photochemical reduction of carbon- carbon and carbon-nitrogen double bonds has been achieved using benzene- selen01.~ For example irradiation of @-aryl-cup-unsaturated carbonyl compounds and of some imino-derivatives of benzaldehyde in the presence of benzeneselenol leads to the formation of the corresponding saturated compounds. These reactions seem to occur either by an SH2displacement of the benzylic radicals from the selenium by PhSe or by direct photolysis of the benzyl-Se bond.3 Aromatics Photoionization techniques have been used to produce a number of novel species trapped in an argon matrix including cycloheptatriene benzyl bromide and toluene cations. The behaviour of the cycloheptatriene cation under photolysis has been examined" and excitation at 470 nm was found to be most effective in promoting rearrangement to the toluene cation. Photolysis of the benzyl cation brings about rearrangement to the tropylium cation and photochemical interconversion of these two species has also been demonstrated." An investigation of the photoreduction of chlorobenzene and of chloroanisoles in methanol under conditions in which photosubstitution also occurs has shown'* that the solvent behaves both as a hydrogen donor and as a nucleophile.The key step is thought to be formation of D. R. Arnold R. M. Borg and A. Albini J. Chem. SOC., Chem. Commun. 1981 138. M. J. Perkins B. V. Smith and E. S. Turner J. Chem. SOC.,Chem. Commun. 1981,977. lo L. Andrews and B. W. Keelan J. Am. Chem. SOC., 1980,102,5732. l1 L. Andrews and B. W. Keelan J. Am. Chem. SOC.,1981,103 99. l2 J. Ph. Soumillion and B. De Wolf J. Chem. SOC., Chem. Commun. 1981,436. Photochemistry 'ArCl* homolytic rupture 1 lNU 1 ArCl Substitution Reduction product product via H-abstraction Scheme 2 a pair of radical ions via a triplet excimer of which the radical cation leads to the substitution product (Scheme 2). A number of other interesting photosubstitutions have been reported.An examin-ation of the photocyanation of anisole in the presence and absence of electron acceptors such as terephthalonitrile has shownI3 that polyethylene glycol (PEG) can supplant a crown ether in the photoinduced replacement of the methoxy-group using KCN in CH2C12. The success of the reaction is ascribed to the ability of PEG to complex with K' as do crown ethers with the consequent activation of the CN- ion in an aprotic solvent. Addition of the electron acceptor improves both the yield of photocyanation products and also the specificity of the substitution and these observations are rationalized in terms of charge-transfer complex formation between substrate and added electron acceptor. Enolate anions derived from simple ketones and esters have been rep~rted'~ to undergo an efficient photo-S,,l reaction.However 2-lithio-1,3-dithianes give low yields as do dialkyl-substituted ketone and ester enolates. This is because of hydrogen atom transfer from a carbon situated adjacent to the enolate anion to the transient phenyl radical. Intramolecular reaction of enolate anions with aryl halides can also be very efficient and if @-hydrogen transfer is blocked the cyclization can proceed with yields of 70-90% even for eight-membered rings. A report has appeared" of the photo-Birch reduction of some arenes with NaBH in the presence of rn-or p-dicyanobenzene. Thus irradiation of phenanthrene and of anthracene leads to the corresponding 9,1O-dihydroarenes and naphthalene and some substituted naphthalenes are exclusively reduced at C-1 and C-4.The mechan- ism involves electron transfer from the excited singlet-state of the arenes to dicyanobenzene followed by nucleophilic attack of borohydride on the arene radical cation. The reaction may be of wide applicability to the reduction of electron donating arenes. l3 N. Suzuki K. Shimazu T. Ito and Y. Izawa J. Chem. SOC.,Chem. Commun. 1980 1253. l4 M.F.Semmelhack and T. Bangar J. Am. Chem. SOC.,1980,102,7765. '' M.Yasuda C. Pac and H. Sakurai J. Org. Chem. 1981,46,788. 136 A. Cox The addition of nonsymmetrical tertiary amines to photoexcited trans-stilbene in its singlet state has been discussed.'6 It is shown that addition of highly branched amines is selective for formation of the least substituted a-amino-radical and that less highly branched amines are relatively non-selective in this process.The product selectivity is determined by the orientation during the deprotonation of the aminium radical by the stilbene radical anion and the oxidation selectivity of amines is a consequence of a stereoelectronic effect which depends on branching in at least one alkyl group. The bis(crown ether) (1)has been synthesized" and on irradiation undergoes trans-cis isomerization as expected; reversion to the original geometry then occurs thermally. A stable 1 1 sandwich-type complex is formed between cis-(1) and large alkali-metal cations and this enables ion extraction and ion transport through a liquid membrane to be controlled by light. (1) The photochemistry of the tetraphenylcyclopentadienylanion and of the fluorenyl anion has been examined.18 Although there is no reaction in homogeneous aprotic media if the photolysis is carried out at the surface of a potentiostated (0.0 eV us.Ag) n-Ti02 electrode both alkylation and dimerization occur. These new routes for carbon-carbon bond formation may be of value in synthesis and a possible mechanism for the photoinduced oxidative dimerization is shown in Scheme 3. The photoconversion of aryl vinyl ethers to dihydrofurans has been shownIg to occur via the triplet states of educts and zwitterionic ground-state intermediates followed by mono- or bimolecular 1,4-hydrogen shifts. This photocyclization is Photoanodic reaction Dark cathodic reaction Scheme 3 l6 F.D. Lewis T.-Ing. Ho and J. T. Simpson J. Org. Chem. 1981 46 1077. *' S.Shinkai T. Nakaji T. Ogawa K. Shigematsu and 0.Manabe J. Am. Chem. Soc. 1981 103 111. M. A. Foxe and R. C. Owen J. Am. Chem. Soc. 1980,102,6559. l9 T.Wolff J. Org. Chem. 1981,46,978. Photochemistry similar to that of aryl vinyl sulphides and of aromatic enamines and favourable conditions are suggested for the reaction on the basis of the results obtained. A new pathway to multibridged cyclophanes has been published” which avoids the laborious conventional routes and which depends upon an efficient stereochemically controlled photoreaction. Irradiation of (E,E,E)-1,3,5-tristyrylbenzene leads via a loose singlet excimer to a product (2; R = Ph) having c3h symmetry.Because of the involvement of this singlet excimer precursor it is believed that it is this product which is formed rather than the alternative structure having Dfhsymmetry and arising from threefold stereospecific head-to-tail cycloaddition. (2) 4 Carbonyl Compounds Picosecond absorption experiments have been carried out on the photoreduction of benzophenone by triethylamine.” These have enabled direct observation to be made of the charge-transfer complex (3) tl12 10 f 5 ps A,, 610 and of the intermediate amine radical (4) tII2 15 f 5 ps A,, 545 to which it decays. The intrinsic rate of electron transfer kIR,and the rate of proton transfer kH,have 0 \ *-\ +./ A(Ti)+ /CH-N( -% A + /CH-N \ (3) 0 \ OH \ A(&) ../ I\+ ../ + CH-N k-~ / \ /\ (4) Scheme 4 also been measured and the quantum yield for net hydrogen-transfer is shown to be one.In some related workz2 the quenching of excited benzophenone has been studied by a range of aliphatic amines. The results suggest that quenching normally occurs by H abstraction from N and/or a-Cwith radical formation. However this 20 J. Juriew T. Skorochodowa J. Merkuschew W. Winter and H. Meier Angew. Chem. Int. Ed. Engl. 1981,20,269. 21 C. G. Shaefer and K. S. Peters J. Am. Chem. SOC.,1980 102 7566. 22 S. Inbar H. Linschitz and S. G. Cohen I.Am. Chem. SOC., 1981,103,1048. 138 A. Cox is not true for quenching with DABCO in the case of which a triplet amine charge-transfer complex or radical-ion pair is formed. Photoexcited acetophenone (AH,) and photoexcited trifluoroacetophenone (AF,) are both known to attack p-cymene to yield a mixture of primary and tertiary radicals and it has now been reportedz3 that the primary/tertiary ratio varies as a function of ring substitution.Electron-withdrawing substituents increase this ratio and electron-donating substituents decrease it the magnitude of the effect being greater in AF than in AH,. These effects can be related qualitatively to the degree of positive charge on the p-cymene in the exciplex formed between the p-cymene as donor and the triplet ketone and this provides a unique probe for determining the extent of charge transfer in exciplexes generally. An examination of the photoreduction of acetophenone by 1-phenylethanol has revealedz4 that half of the ketone triplets are quenched by an OH bond.This finding has led to a reinvestigation of an early reportz5 that ketones photosensitize the oxidative cleavage of pinacols. Mechanistically the transformation probably involves hydrogen abstraction by the ketone triplet possibly via an exciplex to give an alkoxy-radical which undergoes p-scission very rapidly. This observation leads to the conclusion that in-cage disproportionation of the a-hydroxy-alkoxy radical pair is highly efficient. From a study of the reaction between xanthone triplets and propan-2-01 as a function of solvent composition,z6 the degree of solvent-hydrogen bonding is found to dominate the photochemistry. Clear evidence of this is provided by the values of the bimolecular rate constant for reaction of the triplet state which in propan-2- Ol-cCl4 and neat propan-2-01 are 1.1 x lo8 M-' s-' and 2.2 x lo5 M-' s-' respec-tively.This implies an inversion of the ,(n T*) and '(T T*)states and although the effect is well known its size is without precedent. The triplet lifetimes of hindered 4'-substituted-2,4,6-tri-isopropylbenzophenones have been to be influenced by substituents in a manner which is precisely opposite to that expected from the rate of intermolecular hydrogen abstraction reactions of unhindered benzophenones. A Hammett plot of log T~/T,against u+ gave a reasonably good correlation with p = -0.35 yet for unhindered benzo- phenones a similar plot gave p = +0.6,clearly suggesting a strong effect of the bulky isopropyl group at the ortho-position.This may be ascribable to the effect of hindered rotation about the C-C single bond between the carbonyl group and the tri-isopropylphenyl group on the lifetime of the triplet excited-state. Irradiation of both a-allylbutyrophenone and y-cyclopropylbutyrophenone gives 1,4-biradicals that undergo typical radical rearrangements in competition with conventional Norrish Type I1 reactions. An analysis of product distributions has shown28 that rearrangements of these biradicals occur with rates characteristic of analogous monoradicals. 23 P. J. Wagner and A. E. Puchalski J. Am. Chem. SOC., 1980,102,6177. 24 P. J. Wagner and A. E. Puchalski J. Am. Chem. SOC., 1980,102 7138. *' A. Schonberg and A. Mustafa J.Chem. SOC.,1944,67. 26 J. C. Scaiano J. Am. Chem. SOC., 1980,102,7747. 27 Y. Ito Y. Umehara Y. Yamada and T. Matsuura J. Chem. SOC.,Chem. Commun. 1980,1160. 28 P. J. Wagner K.-C. Liu and Y. Noguchi J. Am. Chem. SOC.,1981,103 3837. Photochemistry 139 The CIDNP technique has been usedz9 to study the reaction between excited benzophenone and phenols and the results show that the triplet state of the ketone abstracts H' from the phenol to give PhO'. However in [*H6]benzene the reactants form a complex leading to a predominantly singlet-state reaction. The same method has also been used to study the 1,4-biradical generated in the Norrish Type I1 reactions of valerophen~ne.~' Two intersystem-crossing mechanisms operate for this species one of which involves hyperfine coupling of the odd electron with the protons and a second which is product-selective and involves spin-orbit coupling.A new method of photoreducing ketones and aldehydes in yields varying between 70 and 80% and using hydrogen selenide in THF has been rep~rted.~' At the wavelengths used H,Se in THF has no absorption band and in the presence of triplet quenchers the photoreduction proceeds much more slowly than in their absence. These observations suggest the involvement of the triplet state of the carbonyl compound. Irradiation of biacetyl in the presence of alkenes such as indene 2,3-dimethylbut-2-ene furan and 1,2-dimethoxyethene promotes photo- addition via biacetyl triplets as well as the Paterno-Buchi rea~tion.~' In the case of biacetyl and 1,2-dimethoxyethene the photoaddition is non-stereospecific and isomerization of the starting alkene is observed to accompany oxetan formation.Biacetyl-alkene exciplexes are the primary photochemical intermediates. Hydrogen abstraction also features importantly in a newly developed33 synthesis of (&)-oestrone which has as its key step the photoinduced cyclization (5) -B (7). Excita-tion of (5) promotes photoenolization to the kinetically unstable o-quinodimethane (6),which undergoes intramolecular [4 + 21-cycloaddition to (7). This can be readily converted into (&)-oestrone (Scheme 5). 0 Scheme 5 29 M. L. M. Schilling J. Am. Chem. SOC.,1981,103 3077. 30 R. Kaptein F. J. J. de Kanter and G. H. Rist J. Chem. SOC.,Chem.Commun. 1981,499. 31 N. Kambe K. Kondo S. Murai and N. Sonoda Angew. Chem. Int. Ed. Engl. 1980,19,1008. 32 G. Jbnes M. Santhanam and S.-H. Chiang J. Am. Chem. SOC.,1980 102,6088. 33 G. Quinkert W.-D. Weber U. Schwartz and G. Durner Angew. Chem. In?. Ed. Engl. 1980,19,1027. 140 A. Cox In ether solution photochemical conversion of the spirodiketone 2,3-benzo- spiro[4.5]deca-2,6-diene-1,8-dione (8) into 3,4-dihydro-9-hydroxy-2( 1H)-anthracenone (10) has been reported34 to proceed uia 3,4-dihydro-2,9( lH 10H)- anthracenedione (9).This is the first example of the isolation of the ketone tautomer of a naphthol. Conversion of (9)into (10) is a thermal process and the photoinduced rearrangement of (8) into (9) may be an example of the oxa-di-7r-methane rearrangement of py-enones.hohu & -b II \ \ \/ (8) (9) H (10) Two interesting papers have appeared on the mechanistic photochemistry of acylsilanes. In propan-2-01 as solvent irradiation of acetyltrimethylsilane (11) at 366 nm leads3’ to the acetal(l2) as sole photoproduct in 80-90% yield. Excitation of the acylsilane to its triplet state induces a rapid migration of silicon from carbon to oxygen to generate a nucleophilic siloxycarbene (13) which is capable of 0 OCHMez II 1 Me -C -SiMe3 Me -CH -OSiMe3 Me-C-OSiMe3 (11) (12) (13) intermolecular reaction with a variety of reagents. In this particular case reaction with the alcohol solvent gives (12). It has also been that in some instances at least photoreaction of the acylsilane (11)with electron deficient olefins such as @)-dimethyl butendioate results from direct reaction of the ester with S1 and TI states of the acylsilane to give a substituted cyclopropane.An ‘umpolung’ of the excited state has been revealed3’ in the photolysis of sterically hindered dialkylketenes. Thus irradiation of (14) gives the typical C-H insertion product of a carbene (15). However on irradiation of (14) in methanol at -60 “C,an equimolar mixture of (15) and (16) is produced (Scheme 6). These (16) Scheme 6 34 M. Kimura and S. Morosawa J. Am.Chem. SOC.,1981,103,2433. ” R. A. Bourque P. D. Davis and J. C. Dalton J. Am. Chem. SOC., 1981,103 698. 36 J. C. Dalton and R. A. Bourque J. Am. Chem. SOC., 1981,103,699. 37 W. Kirmse and Walter Spaleck Angew.Chem. Int. Ed. Engl. 1981 20 776. Photochemistry 141 observations constitute experimental verification of the quantum mechanical sug- gestion that the carbonyl carbon of the ketene carries a positive charge in the ground state and a partial negative charge in the excited state. Aromatic ketones have been used to photosensitize the dissociation of di-t-butyl per~xide.~' No evidence has been found for the intermediacy of an exciplex and energy transfer seems to populate a repulsive state of the peroxide. It is suggested that if the sensitizer does not meet the energy requirements at the equilibrium 0-0 bond distance then energy transfer occurs by vertical excitation at non- equilibrium distances. Photoirradiation has been reported3' to lead to an increase Me I o=c 4-0-0 N=N trans-( 17) cis-( 17) 'shallow cavity' Scheme 7 'deep cavity' in the rate of hydrolysis of P-nitrophenyl acetate catalysed by azobenzene-capped P-cyclodextrin (17).The maximum value of the rate enhancement klight/kdark is 5.5 and the observed catalysis has its origin in a photoinduced cis-trans isomeriz- ation (Scheme 7). Two opposing considerations seem to be relevant. In trans-(17) the substrate is better placed for achieving the maximum rate-constant but in cis-(17) the deeper cavity results in enhanced binding. It appears that the second consideration is the more important. An interesting use of an intramolecular photochemical cycloaddition is in the synthesis of derivatives of tricyclo[4.2.0.0'*4]octane ([4.4.4]fenestrane) a member of the class of structures known as broken-windo-w (Scheme 8).5 Singlet Oxygen The mechanism of the ene reaction between singlet oxygen and olefins has been re~iewed.~' The behaviour of singlet oxygen towards trans-cyclo-octene has been reported42 to be very different from that towards the corresponding cis-isomer. Some of the 38 J. C. Scaiano and G. G. Wubbels J. Am. Chem. SOC.,1981,103,640. 39 A.Ueno K. Takahashi and T. Osa J. Chem. SOC.,Chem. Commun. 1981,94. 40 S. Wolff and W. C. Agosta J. Chem. SOC., Chem. Commun. 1981 118. 41 L. M.Stephenson M. J. Grdina and M. Orfanopoulos Acc. Chem. Res. 1980 13,419. ** Y.Inoue and N. J. Turro Tetrahedron Lett. 1980 21,4327. 142 A.Cox iSeveral steps Scheme 8 trans-alkene reacts stereospecifically in a [2 + 21 cycloaddition to form significant amounts of an unstable trans-fused bicyclic dioxetan. Differing yields of allylic hydroperoxides are obtained from the two isomers and this may be a consequence of oxidation pathways open to the trans-isomer which do not involve singlet oxygen. Dye-sensitized photo-oxygenation of (2,Z)-octadeca-9,12-dienoic 'acid methyl ester (methyl linoleate) gives rise43 to the monhydroperoxides (18) and (19) which are formed by a stereoselective alkenylperoxy radical cyclization. The cyclization of &-unsaturated lipid hydroperoxides to cis-1,2-dioxolanes could be general and such a transformation may be involved in prostaglandin biosynthesis. 0-0 0-0 R U P R R W R OOH I OOH (18) R = (CH2)7C02Me R' = (CH2)3Me R = (CH2)4Me R' = (CH2)&02Me The oxazole-triamide rearrangement has application in a general lactone synthesis for ring sizes from five-membered to macrocycles (Scheme 9).This transformation employs 2-methyl-4,5-diphenyloxazoleas a protected carboxy- function from which the carboxylate is generated under the mild conditions of photo-oxidation. The utility of this sequence of reactions is demonstrated by synthesis of recifeiolide. A re-investigation of the Methylene Blue-sensitized photo-oxygenation of trans- stilbene in MeCN has suggested4' that contrary to earlier reports,"6 the major pathway does not involve singlet oxygen but rather that the reaction proceeds by transfer of an electron from stilbene to the dye in its singlet excited-state.Other reactions sensitized by Methylene Blue e.g. the photo-oxidation of 2-methoxynor- bornene in MeOH could also occur by this mechanism and if so this is especially significant because the results from these experiments have been used as support for a zwitterionic peroxide intermediate in singlet oxygen chemistry. 43 E. D. Mihelich J. Am. Chem. SOC.,1980,102,7141. 44 H. H. Wasserman R. J. Gamble and M. J. Pulwer Tetrahedron Lett. 1981 1737. 45 L.E.Manring J. Eriksen and C. S. Foote J. Am. Chem. Suc. 1980 102,4275. 46 G.Rio and J. Bertholet Bull. SOC.Chim. Fr. 1969 3609. Photochemistry 143 Ph t 13-tridecanolide Scheme 9 6 Heterocycles 1-Azatriptycene is a di-?r-methane system carrying a heteroatom at the methane position and has been investigated photochemically under a variety of condition^.^' In addition to indenoacridine a product already known48 to occur in this process a number of new products have been found and these implicate a singlet nitrene- intermediate which arises from the excited singlet-state of the starting material.Carbenes however do not appear to be involved. The high bridging regioselectivity evident in this transformation may result from the C-N bond being shorter than the bridgehead-to-benzene C-C bond present in many triptycenes. Alternatively the determining consideration could be the greater electronegativity of nitrogen as compared with carbon which may stabilise the aziridine-2,3-dicarbinyldiradical with respect to the cyclopropylcarbinyl radical.(20) (21) (22) (23) Certain azoalkanes for example (20)-(23) all of which contain six-membered rings and which resist denitrogenation (& < 0.05) at 350 nm have been reported49 to undergo denitrogenation to the corresponding hydrocarbon at 185 nm probably as a result of n + T* and/or ?r -* T*excitation. Similar investigations involving the bichromophoric substrate 3,3,5,5-tetramethylpyrazolin-4-one have also been carried out and these suggest that denitrogenation of reluctant azoalkanes at 185 nm may be a general phen~menon.’~ The first report of the photochemistry of a l,l-diazene a group isoelectronic with the carbonyl function has appeared.’l Thus n -* T* excitation of N-(2,2,5,5-47 T.Sugawara and H. Iwamura J. Am. Chem. SOC.,1980,102,7134. 48 G.Wittig and G. Steinhoff Annalen 1964,676 21. 49 W. Adam and F. Mazenod J. Am. Chem. SOC.,1980,102,7131. ’’ W. Adam A. Fuss F. P. Mazenod and H. Quast J. Am. Chem. SOC.,1981,103,998. 51 P.G.Schultz and P. B. Dervan J. Am. Chem. Soc. 1981,103 1563. 144 A. Cox L Scheme 10 tetramethylpyrrolidiny1)nitrene in CFC13 at -78 "C leads to the fragmentations shown (Scheme 10). Both the S1and TI states are product precursors and in addition the S1 state may also be deactivated by fluorescence. Photochemical cyclization of an azimine to an aziridine has been achieveds2 and is the first reported example of a triaziridine. Thus irradiation of the acylazimines (24) obtained by addition of ethoxycarbonyl-nitrene to an excess of (E)-or (2)-azoisopropane gave l-ethoxycarbonyl-trans-2,3-di-isopropyltriaziridine(25).At room temperature this reverts thermally to (24a) and (24b) with a half life of 3.5 days (Scheme 11). v I I 0 EtO,C-N+ N\\N -\)_N."? v A f-o .A (24) a; 22 b; 2E Scheme 11 Evidence has been presented5 to suggest that in propan-2-01 5-bromouracil is reduced to uracil by a radical pathway in the singlet manifold and by an ion-radical pathway in the triplet manifold. The transformation probably occurs by an electron transfer from the solvent to the triplet state of the bromouracil somewhat analogously to the photo-oxidation of alcohols with one-electron photo-oxidizing agents.54 A study has been made of the effects of CN and CF substituents on pyrazole photo~hemistry.~~ Cyano-substituted pyrazoles undergo phototransposition by two 52 C.Leuenberger L. Hoesch and A. S. Dreiding J. Chem. SOC.,Chem. Commun. 1980 1197. '' B.J. Swanson J. C. Kutzer and T. H. Koch J. Am. Chem. SOC.,1981,103,1274. 54 A.Ledwith P. J. Russell and L. H. Sutcliffe Proc. R.SOC.London Ser. A 1973,332,151. 55 J. A. Barltrop A. C. Day A. G. Mack A. Shahrisa and S. Wakamatsu J. Chem. SOC.,Chem. Commun. 1981.604. Photochemistry 145 concurrent pathways namely 1,5-interchange and 2,3-interchange but by contrast phototransposition of 1,5-dimethyl-3-trifluoromethylpyrazoleoccurs only by the former pathway. Irradiation of a number of 2-(4-pyridylvinyl)-4H-chromen-4-ones in oxygenated benzene induce^'^ photocyclization to 12H-[ l]benzopyrano[2,3- h Jisoquinolin-12-one in 70% yield.This transformation which is also successful for a number of related substrates provides a synthetically convenient route to benzopyranoisoquinolines and benzopyranoquinolines. s6 I. Yokoe K. Higuchi Y. Shirataki and M. Komatsu J. Chem. SOC.,Chem. Commun. 1981,442.

ISSN:0069-3030    

DOI:10.1039/OC9817800133

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

8 Aliphatic Compounds Part (i) Hydrocarbons By D. F. EWlNG Department of Chemistry The University of Hull Hull HU6 7RX 1 Alkanes Although the reduction of primary and secondary alkyl halides to the corresponding hydrocarbon can be readily achieved by a variety of metal hydrides the analogous reduction of tertiary compounds has often proved troublesome. The lithium ate- complex (l),derived from 9-butyl-9-borabicyclo[3.3.llnonane and butyl-lithium is capable of selective removal of the halogen atom from tertiary alkyl benzyl and allylic halides in excellent yields (60-100%).' There is a very marked reduction in the reactivity of (1)towards secondary and primary alkyl halides and this high selectivity when combined with the mild reaction conditions for tertiary systems (3 hours at 20 "C) makes (1)a reagent of some utility.Benzylic and allylic halides are also easily reduced by (l),in keeping with a mechanism involving formation of a carbo-cation. (Alky1azo)diphenylmethanols (2) are a good source of alkyl radicals and hence can be used to hydroalkylate alkenes such as norbornene acrylonitrile and crotonaldehyde.* The regiochemistry is consistent with initial attack by alkyl radical (primary or secondary) e.g. H,C=CHCN gives RCHzCH2CN (R = Me Et or Pri) but the yields are not high enough (35% for hydroethylation) for this to be a useful method of generating alkanes except in special cases. Another intriguing report3 concerns the reaction of alcohols with iodine and hydrogen at 7MPa and 300"C. Under these conditions the corresponding iodide is formed initially and subsequent hydrogenolysis gives the corresponding alkane or a rearranged product.For example n-butanol gives n-butane (%YO) isobutane (20%) and propane H. Toi Y. Yamamoto A. Sonoda and S.-I. Murahashi Tetrahedron 1981,37 2261. * D. W. K. Yeung and J. Warkentin Can. J. Chem. 1980 58,2386. W. W. Paudler and T. E. Walton I. Org. Chem. 1981,46,4306. 147 148 D. F. Ewing (15%). It is noteworthy that this reduction by molecular hydrogen does not require a noble-metal catalyst and further exploration of this reaction may lead to inexpensive procedures that are of synthetic value. 2 Alkenes Synthesis.-From Alkynes. Specifically modified palladium catalysts have been developed4 which permit rapid stereosFlective transfer reduction of alkynes to alkenes.The best hydrogen donor is sodium phosphinate which is insoluble in organic solvents; hence benzyltriethylammonium chloride was used as a phase- transfer catalyst. Palladium metal is too reactive but suitable poisoning of Pd on charcoal could be achieved by precipitation of mercury or lead (by the reduction of an aqueous solution of an appropriate salt with NaBH,). Catalysts prepared in this fashion can be stored indefinitely. Yields of 70-97% have been achieved for the reduction of alkynes such as R'C=CR2(R' = H R2 = Ph cyclohexenyl or 4-N02C6H4COOCH,; R' = R2 = Ph; R' = Me R2 = Ph). A nitro-group is reduced to an amino-group but other functional groups are unaffected.The addition of vinyl cuprates to @-unsaturated sulphones offers promise as a novel stereoselective route to 2-olefins.' Vinyl cuprates are generated from alkyl cuprates and acetylene in the usual way (Scheme 1)and the addition to the alkenyl sulphone proceeds without loss of the 2 stereochemistry of the vinyl group. Mild reductive desulphonation affords the 2-alkene (3). The coupling of vinyl cuprates with aryl iodides has also been achieved6 efficiently using a palladium complex as catalyst (Scheme 1).Both phenyl- and thienyl-ethenes can be prepared in 65-80% yield. (R\_j];uLi + R' \=/CR2R3CH,S0 Ph RiCuLi + 2HCzzCH --) R'9Y iii 1 X Reagents i PhS0,CH=CR2R3; ii H'; iii 6% Na-Hg at 25 OC; iv ZnBr, THF 5% [Pd(PPh,),] IPhX Scheme 1 Carbometallation reactions of propargyl and homopropargyl derivatives usually display the opposite regioselectivity to that found for simple alkynes or they are non-selective.In contrast the recently developed zirconium-catalysed carboalumi- nation of alkynes shows' an unexpected regioselectivity with propargyl and homopropargyl derivatives (4; n = 1 or 2) that contain OH OSiMe2But,SPh or R. A. W. Johnstone and A. H. Wilby Tetrahedron 1981,37 3667. ' G. De Chirico V. Fiandanese G. Marchese F. Naso and 0.Sciacovelli J. Chem. SOC.,Chem. Commun. 1981,523. N. Jabri A.Alexakis and J. F. Normant TetrahedronLett. 1981 22 3851. C. L.Rand D. E. Van Horn M. W. Moore and E. Negishi J. Org. Chem. 1981 46,4093. Aliphatic Compounds -Part (i) Hydrocarbons iodo groups.The regioselectivity is very high (over 98% in many cases) and in all cases it results in alkylation at the substituted carbon (Scheme 2). The intermediate alane can be readily converted into a wide variety of synthons by established methods with overall yields in the range 60-90%. A x(cH2)nt=(" X(CH,),C CH Me AIMe -!L x(cH2)n>_(H z Me (4) X = OH OSiMe2Bu',SPh or I n = lor2 Reagents i Me,Al Cl,ZrCp, at 20 "C;ii H20 (Z = H) or I (Z = I) Scheme 2 Synthesisof AikenesfromCarbonyl Compounds. Olefination of carbonyl compounds by using stabilized ylides is not always fully stereospecific and the separation of the isomeric olefins may be difficult. Using Ph2P0 as the stabilizing group has the advantage that the reaction with aldehydes stops at the alcohol stage.' Isolation and purification of the alcohol permits subsequent conversion into a pure Z-alkene.The reaction of the ylide with an ester affords the P-keto-phosphinate which is readily reduced (by NaBHJ to the other diastereoisomeric alcohol; this in turn affords the pure E-olefin.* Aromatic aldehydes are not very reactive toward phos- phonate-stabilized anions and the high reaction temperatures that are necessary result in indifferent yields. However addition of a catalytic amount of a crown ether so greatly enhances the nucleophilicity of the carbanion that stilbenes can be obtained in nearly quantitative yields corresponding to a rate increase of several hundred-fold.g A 'one-pot' conversion of esters or lactones (e.g. R'C02Me) into the corresponding olefin (R'CH=CR2R3) has been described in some studies of natural products." The carbonyl species is reduced to the hemiacetal with Bui2A1H at -65 "Cbefore its reaction with a conventional Wittig reagent.An alternative to the Wittig procedure for the formation of substituted vinyl bromides involves the reaction of carbonyl compounds with dibromomethyl- lithium," followed by reductive elimination of HOBr. Yields are good (70-95%) but stereocontrol is poor with only a slight preference for the E-form. (Trimethyl- silylacety1)trimethylsilane (5) contains both a-and 0-ketosilane structures and is the starting point for a novel synthetic route to functionalized trisubstituted olefins (Scheme 3).'* Groups R' and R2 are introduced via successive alkylation of the lithium enolate with an alkyl halide (R' = Me Et allyl or benzyl) and an aldehyde (R2 = alkyl alkenyl or alkynyl).Step v proceeds spontaneously to afford essentially pure E-olefin with overall yields of 72-92% Synthesis of Alkenes by Elimination. There has been much interest in recent years in the formation of olefins by the oxidative syn-elimination of PhSeOH from alkyl A. D. Buss and S. Warren J. Chem. SOC.,Chem. Commun. 1981 100. R. Baker and R. J. Sims Synthesis 1981 117. lo W. Boland P. Ney and L. Jaenicke Synthesis 1980 1015. l1 D. R. Williams K. Nishitani W. Bennett and S. Y. Sit Tetrahedron Lett. 1981 22 3745. l2 J. A. Miller and G. Zweifel J. Am. Chem. SOC.,1981 103 6217. 150 D. F. Ewing Me3Si OLi 1 \/ Me3SiCH2C//O -b (5) \ SiMe3 H/c=c \SiMe3 Reagents i Lithium di-isopropylamide (LDA) THF at -78 "C; ii alkyl halide R'X at -25 "C in THF; iii LDA at 0-5 "C; iv R'CHO at -78 "C; v at -78 'C; vi H,O, OH-Scheme 3 phenyl selenides and this reaction is rep~rted'~ to afford nitroalkenes in 55-85% yield (Scheme 4).The nitro-selenides (6) are somewhat unstable and are oxidized without isolation. R'CH2CHR2I SePhIR'CH2CR2 A R'CH2CR2 -%R'CH=CR2 II I I NO2 NO; NO2 NO2 Reagents i Bu"Li THF at 0 "C; ii PhSeBr; iii 35% H,O Scheme 4 A new reagent for the 'reductive' elimination of -hydroxylated phenylselenides phenylsulphides and iodides is Me3SiC1 and NaI in acetonitrile.'* The exact mechanism is unknown but yields of 70-90% were achieved without loss of stereochemistry.In cases where low yields are found with phenyl selenoxide eliminations the analogous pyridylselenium derivative may be more effective." The PySe moiety is a better leaving group but can be readily introduced by nucleophilic substitution with sodium pyridine selenate. An efficient method of generating double-bonds by the elimination of telluroxide has not been found to date. This difficulty can be circumvented'6 by treatment of the telluride with chloramine-T in refluxing THF to afford olefins in 66-93% yield (for C8 to C13 terminal olefins). Presumably the intermediate tellurium(v) species RCH2CH2Te(Ph)=NTosyl is formed and then eliminated as the N-tosyltel- l3 T. Sakakibara I. Takai E. Ohara and R. Sudoh J. Chem. Soc.Chem. Commun. 1981,261. '' D. L. J. Clive and V. N. KBB,J. Org. Chem. 1981 46 231. '' A. Toshimitsu H. Owada S. Uemura and M. Okano Tetrahedron Lett. 1980 21 5037. l6 T. Otsubo F. Ogura H. Yarnaguchi H. Higuchi Y. Sakata and S.Misumi Chem. Lett. 1981,447. Aliphatic Compounds -Part (i) Hydrocarbons luramide. Anodic oxidation of carboxylic acids that have a p -trimethylsilyl group gives exclusively the terminal olefin (7) (Scheme 5).17 These acids are conveniently prepared by a malonic acid synthesis with Me,SiCH2Cl and RC1. A 'one-pot' conversion of a-chlorocarbonyl compounds R'R2CClCOX (X = H alkyl C1 or alkoxy) into the alkenes R'R2C=CR3 by reaction with a Grignard reagent has been described.18 RCHCH2SiMe3 aRCH=CH2 I C02Na Reagents i RCH,CH,NH,; ii triphenylpyridine at 150"C Scheme 5 A milder alternative to the Hofmann elimination of quaternary amines is shown in Scheme 5.The pyrylium salt (8)reacts readily" with primary amines to give the corresponding pyridinium species which undergoes elimination at 150"C in the presence of a non-nucleophilic base. Yields are good (80-97% for C5to C12alkenes) but the product is not pure terminal alkene some 25% being the isomeric 2-enes. Synthesis of Alkenes by Alkylation of Vinyl Compounds. A drawback to the use of organoboranes for the alkylation of a lithium vinyl derivative is the fact that only one of the alkyl groups of the borane is utilized. The 'throwaway' group i.e. 9-borabicyclo[3.3. llnonane which was developed earlier is readily alkylated on boron and it shows no tendency to compete with the alkyl group in transfer to a vinyl compound in a normal coupling reaction.20 Yields are in the range 40-80%.Alkenyl-zirconium complexes have been usedz1 to alkenylate steroids at C-18 or at C-20. The general synthetic utility of this reaction has not been explored but since it invokes attack at palladium in a r-ally1 complex it may have wider application. Reactions of A1kenes.-A number of interesting addition reactions of alkenes have been studied (Scheme 6). Methanethiolsulphinate MeS(O)SMe reacts with trifluoracetic anhydride at -10 "C in carbon tetrachloride to afford an unstable sulphenyl ester (reagent i) which adds to simple olefins in a regiospecific (Markownikoff) and stereospecific (trans) manner [Scheme 6; reaction (a)]." l7 T.Shond H. Ohmizu and N. Kise Chem. Lett. 1980 1517. J. Barluenga M. Yus J. M. Concellon and P. Bernad J. Org. Chem. 1981,46,2721. l9 A. R. Katritzky and A. M. El-Mowafy J. Chem. SOC.,Chem. Commun. 1981 96. 2o A.B.Levy R. Angelastro and E. R. Marinelli Synthesis 1980 945. 21 J. S.Temple and J. Schwartz J. Am. Chem. SOC.,1980,102 7381. 22 T.Morishita N. Furukawa and S. Oae Tetrahedron 1981,37 2539. 152 D. F. Ewing Products from a variety of sulphenyl trifluoroacetates and olefins were investigated yields being in the range 60-90%. An interesting route to vinyl sulphones (9) is presented in Scheme 6 [reaction (b)]. Addition of selenosulphonates (PhSeS0,Ar) to olefins in the presence of BF etherate proceeds with trans-stereochemistry and in most cases with exclusively Markownikoff ~rientation;'~ selenoxide elimination gives the sulphone in good yield.If the reactants are heated in the absence of a Lewis base free-radical addition occurs to give the anti-Markownikoff product. Two methods of introducing an amino-group into a double-bond are shown in reactions (c) and (d) in Scheme6. The amidation reactionz4 is an example of nucleophilic addition by the widely applied mercuriation-demercuriation pro-cedure. Simultaneous introduction of bromo- and amino-groups into an alkyl residue is conveniently achieved" by the reaction of an alkene with NN-dibromophosphoramidic acid followed by reduction of the N-brominated intermediate and hydrolysis to the amine salt (10).The regio-control is anti-Markownikoff ; this is consistent with a radical-chain mechanism for this reaction which offers a convenient route to aziridines. OCOCF3 IR'CH-CH~ SO2Ph R' AH-CHZSePh -% PhS02CR1=CH2 (9) R'CH-CH2HgN03INHCOR' INHCOR~ h R'CH-CH3 R'CH=CH2 (c) R'CH-CH,NHP(OEt),I1 0 IBr % R'CH-CHzkH3 I Br (10) C1- R'CH2-CH2BR22 -% R'CH2CH2Br Reagents i MeSOCOCF,; ii PhSeSO'Ar BF * Et20;iii 3-C1C,H4COOOH; iv R'CONH, Hg(NO,),; v NaBH,; vi NN-dibromophosphoramidicacid NaHSO,; vii HCl in benzene; viii R2 BH; ix Br Scheme 6 A facile conversion of terminal alkenes into the corresponding. primary alkyl bromide is possible via an organoborane reaction (e) as shown in Scheme6.26 This procedure is ideal for functionally substituted alkyl bromides for which substitu- tion reactions would be ruled out.The oxidation of an olefin to an a-glycol or an a-ketol by permanganate is a very old and much studied reaction but the precise relationship between the two mechanistic pathways has remained obscure. It has now been established that for reactions starting with simple alkenes the cyclic hypomanganate ester (11) (see Scheme 7) can be hydrolysed to the glycol at pH 9 but in neutral media this Mn" 23 T. G. Back and S. Collins J. Org. Chem. 1981,46 3249. 24 J. Barluenga C. JimCnez C. Nhjera and M. Yus J. Chem. SOC.,Chem. Commun. 1981,670. 2s S. Zawadzki and A. Zwierzak Tetrahedron 1981,37,2675. 26 G.W. Kabalka K. A. R. Sastry H. C. Hsu and M. D. Hylarides J. Org. Chem. 1981 46 3113.Aliphatic Compounds -Part (i) Hydrocarbons I I CHOH CHOH CHOH Scheme 7 ester is rapidly transformed into the MnV1 ester (12) by oxidation with excess permanganate. Careful studies with deuteriated ethene indicated that (12) is conver- ted into a Mn'" ester of the ketol by oxidative decomposition; the free ketol is liberated by subsequent hydroly~is.~' These studies will assist in the selection of conditions for optimum discrimination between the two types of products in the case of more complex substituted alkenes. A very efficient catalytic procedure has been described2* for the oxidation of terminal olefins to methyl ketones. The addition of hydrogen peroxide to the solution of the olefin in Bu'OH in the presence of a catalytic amount of palladium acetate results in 90% conversion into ketones with a 75-80% selectivity for the 2-keto-derivative.There appears to be negligible oxidation at C-1 and only minor oxidation at other sites. A further very extensive study has appeared29 of the Pdo-catalysed reaction of vinyl bromides with cup-unsaturated compounds in the presence of an amine (Scheme 8). The active catalyst was not characterized but is likely to be a bisphos- phine palladium(0) complex which reacts initially with the vinyl halide. In the presence of a secondary amine acrolein or methacrolein acetal reacts with the palladium vinyl species to give [reaction (a)] either a diene acetal (13) or the amino-acetal (14) the relative proportions varying in a complex way with the structure of the alkene.With cup-unsaturated acids (or esters amides or nitriles) the dienoic acid is formed in good yield [reaction (b)]. This procedure obviously has wide synthetic scope for conversion of alkenes into functionalized dienes although the rate of reaction and the yields of products depend upon the nature of the substituents on the alkene (H or alk~l).~~ The reaction of the complex [Zr(Cp),(isoprene)] with alk-1 -enes and alk-2-enes results exclusively in the coupling of C-4 of the isoprene moiety with C-2 of the alkene.30 This regiospecificity is 98-99% with respect to both alkene and diene. In the analogous reaction with alkynes the high specificity for C-4 of isoprene is maintained but for instance in pent-2-yne coupling occurs equally readily at C-2 and C-3.Aryl-acetylenes exhibit different behaviour (vide infru). '' S. Wolfe C. F. Ingold and R. U. Lemieux J. Am. Chem. Soc. 1981,103,938. 28 M. Roussel and H. Minoun J. Org. Chem. 1980,45,5387. *' B. A.Patel J.-I. I. Kim D. B. Bender L.-C. Kao and R. F. Heck J. Org. Chem. 1981 46 1061; J.-I. I. Kim B. A. Patel and R. F. Heck ibid. p. 1067. 30 H. Yasuda Y. Kajihara K. Nagasuna K. Mashima and A. Nakamura Chem. Letr. 1981 719. 154 D. F.Ewing R' + R:NH -& R,< R2 Br CH(OMe)2 CH(OMe)2 (13) + R;NCR1 R2CR3=CHCHzCH(OMe)2 (14) CO H X = COZH COZMe CONHz or CN Reagents i Pd(OAc), tri-o-tolylphosphine Scheme 8 The catalyst WC1,/SnMe4/EtOAc has been reported31 to be effective in the metathesis of a-olefins to long-chain internal olefins (Scheme 9).Although both geometric isomers are formed and the yields are somewhat variable (30-50% of pure trans-isomer was isolated) the product is largely free from contamination by the next lower homologue. Hydrozirconation with [(Cp)ZrHCl] {generated in situ from [(Cp),ZrClz]) results in moving the functionality to the end of the chain and appropriate treatment of the alkyl-zirconium species can lead to halides alcohols aldehydes or carboxylic acids. Alkyl iodides that contain up to 42 carbon atoms may be prepared31 by this method. Isomerization of olefins using CnHZn+l CH=CHz A CnHZn+l CEI=CHCnHzn+1 )i CZnH4n+l CHZCHZZr(Cp)ZCl w CZnH4n+1CHZCHZI CZ~H~~+ICHZCH~OH Reagents i WCl, SnMe, EtOAc; ii [(Cp),ZrCl,] NaAIH,(OCH,CH,OMe),; iii I,; iv 0 Scheme 9 [RUC~~(PP~~)~] as a homogeneous catalyst has been known for some time.This catalyst has now been incorporated into a polystyryldiphenylphosphineresin and the resulting supported heterogeneous catalyst can be used with very little loss of catalytic activity for hundreds of cycles of the isomerization of 3-phenylpropene to cis-and trans- 1-phenylpr~pene.~' Similar properties are observed for analogous supported iridium and rhodium catalysts. The conversion of alkenes into cyclopropanes continues to be of widespread interest and several new synthetic methods have been described. Dibromomalonic ester condenses with olefins in the presence of copper powder providing a novel '' T. Gibson and L.Tulich J. Org. Chem. 1981,46 1821. 32 A. Zoran Y. Sasson and J. Blum J. Org. Chem. 1981 46 255. Aliphatic Compounds -Part (i) Hydrocarbons 155 route to derivatives of gem -dialkoxycarbonylcyclopropane.33 The reaction is appli- cable to a wide range of olefins and proceeds smoothly at moderate temperature to give fairly good yields particularly in polar solvents. It is unlikely that free carbene [i.e.:C(CO,Et),] is involved since no evidence of C-H insertion was found. Radical attack by CBr(CO,Et) followed by elimination of Br is consistent with the complete lack of stereospecificityin the reaction with P-methylstyrenes. In a later the same workers have investigated the use of cuprous bromide as an alternative to copper and have extended the reaction to the use of dibromomalononitrile.Styrenes lead to higher yields of cyclopropane derivatives than do alkenes but the same lack of stereospecificity is ~bserved.'~ The use of di-iodomethane for the photocyclopropanization of olefins has been studied in detail.35 It has been found to be a synthetically useful procedure for about twenty alkenes and cycloalkenes and shows significantly less sensitivity to steric effects than does the traditional Simmons-Smith method. This is evident in the increasing relative rate for increased substitution about the double-bond. Although this is a photochemical reaction the methylene-transfer species is thought to be the a-iodo-cation CH21+. N,=CHCO,Et (15) Diazoacetates (15) have been used with rhodium and copper catalysts to effect the cyclopropanization of olefins presumably via a metal-carbene complex.However the synthetic utility of this reaction is limited by extensive competition from attack of the carbene on the diazo-compound and it has been usual to have the olefin reactant in large excess. It has now been that careful control of the rate of addition of the diazo reactant (i.e.low rates for low catalyst concentration and a reduction in the rate as the reaction proceeds) leads to yields of product as high as 90%. Of the two rhodium catalysts R~,(OAC)~ and Rh,(CO),, the acetate is the more effective although there is little difference in the control of the stereochemistry of the product. Both cationic and neutral ferrate complexes have been utilized in the alkylidation of alkenes (Scheme 10).The highly electrophilic carbene complex (16)reacts rapidly Alkene + [Cp(CO)#eCHPh]PF6 (16) Alkene + Cp(CO)2FeCHSPh Me Reagents i at -78 "C;ii FSO,Me at 25 "C Scheme 10 33 N.Kawabata and M. Tanimoto Tetrahedron 1980 36 3517. 34 N. Kawabata S. Yano J. Hashimoto and J. Yoshida Bull. Chem. SOC.Jpn. 1981,54,2539. 35 P. J. Kropp N. J. Pienta J. A. Sawyer and R. P. Polniaszek Tetrahedron 1981,37 3229. 36 M. P. Doyle D. Van Leusen and W. H. Tamblyn Synthesis 1981 787. 156 D. F. Ewing with unactivated alkenes at -78 "C[reaction (a)] to effect efficient transfer of the benzylidene ligand,37 giving phenylcyclopropanes (18;X = Ph). This reaction has two notable features. It is highly stereoselective in favour of the less stable isomer and is almost insensitive to steric effects with tetrasubstituted alkenes.In the presence of FSO,Me the sulphide complex (17) is converted into the analogous methylsulphonlum species which reacts with alkenes [reaction (b)] to afford methyl- cyclopropanes (18; X = Me).,' The active species is probably the ethylidene com- plex cation analogous to that in (16) but no evidence of the corresponding ethene complex was found. Ene-complexes can be formed from ylidene-complexes by proton shift.38 This may prove to be a general route for the alkylidation of alkenes. 3 Dienes Synthesis.-Coupling of alkenyl cuprates with alkenyl halides is not usually very successful because even with the available catalysts the required reaction tem- perature is high enough to result in serious decomposition of the cuprate to give the symmetrical diene (19) (see Scheme 11).It has now been discovered39 that -& R'>-\ + "i= R2 ZnBr R2 CuLiBr (21) ii 1 1 R' R' RZ)y2 RZQ' R' (19) Reagents i ZnBr,; ii Pd 4PPh3 R3R4C=CHI Scheme 11 the addition of one equivalent of zinc bromide raises the yield of the required diene (20) to over 90%. Furthermore the stereochemical purity is extremely high [typi- cally 99% of (20; R' and R3 are trans) and 1% of (20; R' and R3 are cis)]. These interesting results are due to the formation of the relatively stable alkenylzinc species (21).In cross-coupling reactions with alkenyl bromides an alternative to alkenyl cuprates is an alk-1-enylborane (22) (see Scheme 12) and it has now been shown4' that 2-alkenylboranes (22; R' = H R2= alkyl or siamyl) give rise to 2,E-or 2,Z-dienes of very high isomeric purity.This reaction complements earlier work with E-alkenylboranes which provide a route to E,E- and E,Z-dienes. Although yields are not always very high all four isomeric dienes can be obtained via organoboranes. 37 M. Brookhart M. B. Humphrey H. J. Kratzer and G. 0.Nelson J. Am.Chem. SOC.,1980,102,7802. 38 K. A. M. Kremer P. Helquist and R. C. Kerber J. Am. Chem. Soc. 1981,103 1862. 39 N. Jabri A. Alexakis and J. F. Normant Tetrahedron Lett. 1981 22 959. 40 N. Miyaura H. Suginome and A. Suzuki Tetrahedron Lett. 1981 22 127. Aliphatic Compounds -Part (i) Hydrocarbons R' R4 R' R2 BX R3 RS R2 (22) R3 RS Reagents i Pd(PPh,), 2EtONa Scheme 12 A convenient route to 2-alkyl-1,3-dienes involves the reaction of the correspond- ing dienyl Grignard reagent with an alkenyl iodide in the presence of transition-metal catalysts.Thus direct alkylation is effected at -30 "Cin THF in the presence of cuprous iodide and arylation occurs in the presence of [Pd(PPh3)4].41 Grignard alkylation (Scheme 13) has also been used as a route to allenes (23; R4 = H).42 R' R2*R4 CI \ R' R2 *R4 R3 (24) Reagents i PdC12 NeSO,(neophyl); ii dimethylglyoxime MeOH Scheme 13 Both propargylic and allenic halides are alkylated at the terminal carbon the reaction proceeding via the corresponding allenic palladium complex.The alkylated propargyl compound (24) is not formed to any significant extent. Similar preference for allene formation is shown in the vinylation of propargyl tosylates (25)(see Scheme 13) with a vinyl c~prate.~~ The vinyl group is introduced at the opposite end of the incipient allenic species to give (23; R4 = vinyl R' = R2= H). The synthesis of terminal conjugated dienes via a Pdo .rr-allylic complex has been extended to the formation of analogous p01yenes.~~ For example (2E,4E)-hexa-2,4- diene acetate was refluxed with palladium acetate in the presence of excess triphenylphosphine to give an 87% yield of hexa-1,3,5-triene which was at least 97% the E-isomer. (3E,5E)-Octa-1,3,5,7-tetraene was obtained in 48% yield in 41 S.Nunomoto Y. Kawakami and Y. Yamashita Bull. Chem. SOC. Jpn. 1981 54 2831. 42 T. Jeffery-Luong and G. Linstrumelle Tetrahedron Lett. 1980 21 5019. 43 R. Baudouy and J. GorC J. Chem. Res. 1981 (S),278; (M),3081. 44 K. Yamamoto S. Suzuki and J. Tsuji Bull Chem. SOC.Jpn. 1981,54 2541. 158 D. F. Ewing a similar fashion. Whilst the formal 1,w-elimination of acetic acid obviously occurs stereoselectively in these cases 1,2-elirnination from 1-vinylbut-3-enyl acetate gave an E/Z mixture of hexatriene~.~~ Reagents i T13+ MeOH Scheme 14 Reactions of Dienes.-The reaction of conjugated dienes such as buta- 1,3-diene 2,3-dimethylbuta-1,3-diene,and cyclohexa-l,3-diene with thallium(II1) acetate in acetic acid at 10-65 OC for 0.5 to 15 hours gives a mixture of the corresponding 1,2- and 1,4-diacetoxy-alkenes in 10-92Oh yield.In most cases 1,2-addition predominate^.^^ This reaction is assumed to proceed by initial acetoxythallation followed by sequential or synchronous dethallation and attack by an acetoxy-group. In contrast to the above reaction the major products in the oxidation of conjugated dienes by thallium(II1) nitrate are those resulting from vinyl migration (Scheme 14). For example 2,3-dimethylbutadiene is converted (in 35% yield) into 4-methylpen- tenone (26).46 With more complex dienes a variety of products are formid. Migration of the vinyl group probably proceeds via a cyclopropylium cation. In another study of the oxidation of butadiene it has been shown4' that tellurium oxide in acetic acid in the presence of a 3- to 5-fold excess of LiBr gives the 1,4-diacetoxy-derivative almost exclusively.This very high selectivity for 1,4- addition is unusual; other halide salts (e.g.NaCl and LiCl) were less selective. The formation of a six-membered ring via concerted cycloaddition reactions of butadiene is a well-established procedure. The generation of a cyclopentene ring is more unusual and often shows poor lack of stereo- and regio-control since it requires addition of a carbene followed by thermal rearrangement (cf. Scheme 15). It has now been dem~nstrated~~ that very high stereoselectivity is possible by using an alkoxy-carbene largely because the conditions required for the concerted [1,3] I R4 OCH2CH,CI Reagents i CHOCH,CI; ii Bu"Li (excess) THF at 50 "C,for 1-2 hours Scheme 15 45 S.Uemura H. Miyoshi A. Tabata and M. Okano Tetrahedron 1981 37 291. 46 M. Murakami and S. Nishida Chem. Lett. 1981,997. 4' S. Uemura S. Fukuzawa and M. Okano Tetrahedron Lett. 1981,22 5331. 48 R. L. Danheiser C. Martinez-Davila R. J. Auchus and J. T. Kadonaga J. Am. Chem. SOC. 1981 103,2443. Aliphatic Compounds -Part (i) Hydrocarbons sigmatropic shift are significantly milder than is usually the case (Scheme 15). Stereochemically cyclopentenols are accessible by this procedure in 45-80% overall yield. Another cycloaddition which has received attention is the reaction of dienes with aromatic sulphonyl azides although the intermediate cyclic addition products were not isolated.49 With non-conjugated dienes (e.g.hexa-1,5-diene) a sulphonimide is the initial product hydrolysis giving the corresponding unsaturated ketone (e.g. hex-5-en-2-one). More complex results are obtained with conjugated dienes since the initial product an enamine is hydrolysed by pathways correspond- ing to migration of both hydrogen and a vinyl group. Reactions of 7r-allylpalladium species that are derived from conjugated dienes [e.g. (27); see Scheme 161 generally lead to E-olefins as might be expected from thermodynamic considerations. However if the complex is treated with dimethyl- glyoxime in methanol/pyridine inversion of configuration around the allylic moiety occurs leading to 2-olefins of high stereochemical purity. This interesting conver- sion has been employed5’ to convert the complexes from anti-Markownikoff sulphonylpalladiation of dienes into 2-olefins as shown in Scheme 16.Both regio-isomers are formed and the stereochemistry of the products (27) and (28) is independent of the starting diene (cis-trans mixtures were usually used). R2 R3 RZ R3 R’ S0,Ne PdCI, (Ne = neophyl) Reagents i PdCI, NeSO,(neophyl); ii dimethylglyoxime MeOH Scheme 16 A two-volume work on ketenes allenes and related compounds has appeared” in the ‘Chemistry of Functional Groups’ series edited by Patai. It covers the fifteen years since the first volume on alkene chemistry appeared and will be an invaluable reference work in this field. Iodination of 1,l-dimethylallene in the presence of mercuric acetate in methanol is known to involve addition at the substituted double-bond to give a tertiary alcohol that is iodinated on the vinyl group i.e.Me2C(OH)CICH2. In the absence of metallic salts however the regioselectivity is reversed.’* Hence with iodine in 49 R. A. Abramovitch M. Ortiz andS. P. McManus J. Org. Chem. 1981 46 330. ’ ” Y. Tamaru M. Kagotani R. Suzuki and Z. Yoshida J. Org. Chem.. 1981,46,3314. ’’ ‘The Chemistry of Ketenes Allenes and Related Compounds’ ed. S. Patai J. Wiley and Sons,New York 1980. 52 C. Georgoulis W. Srnadja and J. M. Valery Synthesis 1981 572. 160 D. F.Ewing chloroform followed by treatment with an alkoxide the isomeric primary alcohol Me2CCICH20His formed. An interesting class of compounds a@-unsaturatedhydroxy-ketones (29) has been identified53as the major product from the treatment of allenes with dicobalt octacarbonyl methyl iodide and carbon monoxide in the presence of a phase-transfer catalyst (cetyltrimethylammonium bromide) in a two-phase system (5M-NaOH/benzene).Carbonylation is presumed to occur by addition of acetylcobalt tetracarbonyl (generated in situ) to the allene followed by attack of hydroxide ion. Yields of (29) are low (23-43%) and a dienone (30)is a by-product in most cases. Reactions carried out in the absence of a phase-transfer catalyst gave only this latter type of product. IIR’R~C ,c C II C R3/ ‘H CH3 OH 0 OH I II I R‘R~C‘c/ C \c/ CR’R~ II II C0\ ~3’ ‘H H R3 R’R~C /c \c,~~i~2 C (29) (30) A very detailed study has been made54of the reaction of arenesulphenyl halides with allenes.Both steric and electronic effects are generally of minimal importance in the rate-determining step (SN2attack on sulphur to form an alkylidenethiiranium ion intermediate) but some steric influence is apparent in the final step (addition of halide ion) particularly if the arene moiety possesses two bulky ortho-groups. The analogous addition reaction with areneselenyl halides is more complex. Product distributions reflect changes in chemoselectivity and configurational selectivity in accord with two different types of steric interaction in the product-determining step. The most likely intermediate is thought to be an alkylidene-episelenurane which subsequently isomerizes to an alkylideneseleniranium ion but a complete understanding of all the subtleties of these addition reactions of allenes is not achieved.4 Alkynes Synthesis.-An improved synthesis of alkynes from vicinal dibromides has been reported,56 involving the use of a phase-transfer catalyst. Typically 0.1 mole of dibromide and 1mmole of tetraoctylammonium bromide in a hydrocarbon solvent is stirred with 0.25 mole of solid KOH for six hours at 90 “C to give the. alkyne in 85-95% yield. This catalytic method is simpler and cheaper than using potassium t-butoxide with 18-crown-6. A novel route to alkynes is shown in Scheme 17. The keten adduct of anthracene (31) is readily alkylated via its lithium enolate to give (32; R’= alkyl or benzyl). The dialkylated species (33)is accessible by two routes (see reagents in the Scheme) ’’ S.Gambarotta and H. Alper J. Org. Chem. 1981 46 2142. 54 D. G. Garratt and P. L. Beaulieu Can. J. Chem. 1980,58,2737. 55 D. G. Garratt P. L. Beaulieu V. M. Morisset and M. Ujjainwalla Can. J. Chem. 1980,58 2745. 56 E. V. Dehmlow and M. Lissel Tetrahedron 1981 37 1653. Aliphatic Compounds -Part (i) Hydrocarbons pi R’C~CR’ Reagents i Bun Li R’Br ;ii either R’MgX TsOH in benzene or tri-isopropylbenzenesulphonylhydrazide Bu“Li R’X; iii heat Scheme 17 and thermal elimination provides the alk~ne.~’ With yields in the range 60-loo% this reaction may be specially attractive in some cases. Several workers have investigated methods for the synthesis of aryl-acetylenes. The decarbonylation of diaryl-cyclopropenones has been noted in the past but this reaction has now been made into a general preparative method for diaryl-acetyl- enes.’* Thermal decomposition of the cyclopropenones in the presence of alumina gives the alkynes in high yield usually >go%.Six established methods for the generation of alkynes have been sur~eyed,~’ and the best methods can now be specified for ArCZCH and ArCECR depending on the nature of the group R and the type of substituent in the aryl ring. The extent to which these guidelines can be usefully applied to other systems (e.g. heteroaryl-alkynes) is uncertain. An attractive extension to the reaction involving coupling between a protected acetyl- ene and an aryl halide has been described.60 Treatment of trimethylsilylacetylene with a substituted aryl bromide in triethylamine in the presence of palladium acetate and triphenylphosphine affords the corresponding protected aryl-acetylene in good yield.The basic solvent acts as a scavenger for the hydrogen bromide that is generated. The trimethylsilyl protecting group is smoothly removed with potassium carbonate at ambient temperature. This mild procedure tolerates sensitive aryl substituents such as CHO NH2,and C02Me and hence usefully extends the range of accessible ethynylated benzene derivatives. The reaction of an aryl-lithium species with 1,l-difluoro-2,2-dichloroethene followed by treatment with two equivalents of n-butyl-lithium provides access to the corresponding ethynyl-arene (Scheme 18).This approach has now been applied successfully6’ to the synthesis of 2,5diethynylthiophen and 2,Sdiethynylfuran and related derivatives.A ‘one-pot’ procedure for the synthesis of 1,4-enynes has been ArLi ArCF=CC12 -% ArCECLi -% ArC=CH Reagents i F,C=CCI,; ii BunLi; iii H,O Scheme 18 57 B. Tarnchompoo Y. Thebtaranonth and S. Utamapanya Chem. Lett. 1981 1241. j8 D. H. Wadsworth and B. A. Donatelli Synthesis 1981 285. 59 D. Mesnard F. Bernadou and L. Miginiac J. Chem. Res. 1981 (S),270; (M),3216. 6o W. B. Austin N. Bilow W. J. Kelleghan and K. S. Y. Lau J. Org. Chem. 1981,46 2280. K. Okuhara Bull. Chem. SOC.Jpn. 1981 54 2045. 162 D. F. Ewing (H2C=C-CH2)3B + 3EtOCECH I R li (H2C=C -CH2 -C=CH)3B -L H,C=C -CH;? -C=CHAlEt I I I I R OEt R OEt (34) Reagents i at -70 "C; ii Et,AI; iii at 180 "C Scheme 19 described.62 The strategy is to obtain an alkoxy-alkene which will undergo 1,2- elimination to generate a triple bond and this is achieved as shown in Scheme 19.Although the (alkoxy-viny1)borane (34) is obtained quantitatively from the alkoxy- acetylene direct 1,2-elimination could not be effected with normal reagents (acids or base) but conversion into a vinylaluminium species in situ gives the desired lability and facile transformation into the enyne. Reactions of A1kynes.-A new catalyst for the hydrogenation of alkynes has been de~eloped.~~ Chloromethylated cross-linked polystyrene beads were treated with anthranilic acid and then palladium chloride to give a catalyst which converted phenylacetylene (30 p.s.i.g.H for 7.3 hours) into styrene 82% and ethylbenzene (14%). Several disubstituted alkynes were converted into cis-alkenes (60-90%) and alkanes (4-20%). This is clearly less selective than the Lindlar catalyst but it has the advantage of being stable in air and of remaining active indefinitely if stored at ambient temperature. The alkylation of terminal alkynes with organoaluminium compounds in the presence of zirconocene has been thought to proceed via Al-assisted carbozirconation. However it has now been unequivocably established64 that in the typical cases examined this reaction proceeds via Zr- assisted carboalumination. This improved understanding of the role of the zirconium species allows a reagent system to be selected which prevents the competing hydrometallation reaction (which requires an alkyl-zirconium species).For example Prn2A1C1/ZrC12Cp2 shows no ligand exchange and with hept-1-yne it affords 2-n-propylhept-1-ene (76%) and (E)dec-4-ene (21%) with negligible formation of hept-1 -ene. In contrast a trialkyl-aluminium does exchange with ZrC12Cp2 and that catalyst system would produce some hept-1-ene in the above reaction. The alkylation of but-2-yne with the diene complex [ZrCp,(isoprene)] is highly stereo- specific giving 99% alkylation at C-2 but approximately equal amounts of alkyl- ation at C-2 and C-3 occur with ~ent-2-yne.~' In both cases the isoprene unit couples only at C-4. Phenyl- and diphenyl-acetylene react differently giving the 62 Yu.N. Bubnov A. V. Tysban and B. M. Mikhailov Synthesis 1980,904 63 N. L. Holy and S. R. Shelton Tetrahedron 1981,37 25. 64 T. Yoshida and E.-I. Negishi J. Am. Chem. SOC., 1981 103,4985. Aliphatic Compounds -Part (i) Hydrocarbons 163 corresponding dihydro-dimers (1,4-diphenyl- and 1,2,3,4-tetraphenyl-buta-1,3-diene) without any coupling to isoprene. The addition of a carboxylic acid to a triple-bond catalysed by silver salts has been investigated6' for several compounds (35) (see Scheme20). For (35; R' R2 = CH20COMe CH2COMe or C02Me) yields are in the range 50-95% but aryl- and alkyl-acetylenes (35;R'R2 = Ph Et or H) give much poorer yields (O-28%). Silver carbonate was the best catalyst and stereospecificity was good in most cases the isomer ratios being between 4 1 and 9 :1.The most likely mechanism is initial formation of a silver r-complex followed by attack by the carboxylate anion. R'CGCR~ + R'C=CR~ -+R'C=CHR' '-,+ ,/' I (35) Ag OCOR~ Reagents i Ag salt; ii R'C0,H Scheme 20 Interest in metallation reactions of alkynes continues to increase and several interesting reports have appeared. Phenylselenol reacts slowly with alkynes at ambient temperature in the absence of a base to give the 2-vinylselenide but the stereospecificity is reduced at higher temperatures (Scheme 2 1).66Aryl-acetyl-enes react more rapidly to give the product that is expected from initial formation of the more stable carbanion but for alkyl-acetylenes the site of attack by PhSe- is governed by steric effects.Pure E-vinylselenides were obtained by hydrogenation of seleno-alkynes [reaction (b) in Scheme211. A different regio- and stereo- chemistry is found for the addition of benzeneselenyl chloride to propargyl alcohols (36) [reaction (c)] consistent with an initial step involving electrophilic The addition is invariably anti but the regioselectivity is structure-dependent. For alkynes with small substituents geminal to the hydroxy-group e.g. (36;R2 = R3 = Me Et Pr' or Ph) rapid formation of the thermodynamically favoured Markownikoff product occurs but for large substituents e.g. (36;R2 = R3 = Bu') the reaction is slow and leads to the anti-Markownikoff product. There are a number of complex subtleties to the steric control of this reaction and the product distribution may reflect the relative rates of addition and is~rnerization.~~ Hydromagnesiation of disubstituted acetylenes with Bu'MgBr in the presence of Cp2TiC12 has been shown68 to occur with high stereoselectivity to afford E-alkenyl- R'CZCR2 (5 R'CH=CR2SePh * R'CGCSePh (b) R' c1 R' SePh Reagents i PhSeH at 20 "C; ii LiAlH,; iii PhSeCl Scheme 21 65 Y.Ishino I. Nishiguchi S.Nakao and T. Hirashima Chem. Lett. 1981 641. 66 J. V. Comasseto J. T. B. Ferreira and N. Petragnani J. Organomet. Chem. 1981,216 287. 67 D. G. Garratt P. L. Beaulieu and V. M. Morisset Can. J. Chem. 1981 59 927. F. Sato H. Ishikawa and M. Sato Tetrahedron Lett. 1981 22 85. 164 D. F. Ewing magnesium bromides. The regioselectivity is also high for aryl-acetylenes the magnesium atom being attached to the carbon adjacent to the phenyl group.Not unexpectedly unsymmetrical alkynes show negligible regioselectivity. For silyl- acetylene magnesiation also occurs at the carbon that is a to the silyl group. Such regio-control is consistent with initial attack on the alkyne by a hydride species [probably (CP)~T~H] followed by transmetallation to magnesium. A full report has now appeared69 concerning the silylcupration of acetylenes using the reagent (Me,PhSi),CuLi.LiCN. At 0 "C (or even at -78 "C) terminal alkynes silylate selec- tively on the terminal carbon with the result that the final products are 2,2-disubstituted vinylsilanes. The reactions between the syn -adducts of various acety- lenes with the above reagent and electrophiles such as iodine acyl and alkyl halides enones and epoxides are described.Silylcupration of acetylenes is clearly a powerful method for the synthesis of a wide range of vinylsilanes. In connection with some work on the synthesis of p-lactam antibiotics it has been suggested" that hydro- stannation of internal alkynes may offer a useful method for the regioselective formation of ketones (Scheme 22). The alkenyl-stannane (37) was the dominant isomer when R was a p-lactam group but selectivity is not high (2:l) and the extent to which the group R co-ordinates to tin and directs the addition is not established. If the methyl group is replaced by CHOHMe the regioselectivity is reversed owing to the co-ordinating effect of the OH group.A more general exploration of this reaction is required if its general usefulness is to be assessed. RCH2, \ RCH2CGCNie A C=CHMe -RCH2COCH2Me Bu3Sn' Reagents i 1.5 equivalents of Bu",SnH at 90 "C;ii 3-chloroperoxybenzoic acid; iii excess HCO,H at r.t.; iv LiOH in aqueous THF Scheme 22 Extensive use has been made of the reactions of propargylic halides esters and tosylates (38) with alkyl-copper species to give either alkylated acetylenes (by direct substitution) or allenes (by 1,3-substitution) (see Scheme 23). A very thorough study has now been made of the various factors that might influence the course of this reaction. The results show that a large steric effect at the acetylenic site [R' in (38)] or at the propargylic site [R2 in (38)] shifts the balance of the reaction to the other site to give (40) and (39) respectively; very large groups such as Me3C almost exclude substitution at a given site.Leaving-group effects were examined by varying R3in (38;R' = cyclohexyl,R2 = H). In terms of the pK of the conjugate acid R3H,no clear trends were apparent for R3 = OTos OAc and OC02Me. The acetate produced mainly the alcohol (41) in this case and in the case of several other variations in R' and R2. Products of the type (42) were rarely observed. The most dominant factor in determining the site selectivity was the nature of the organocopper reagent. The species Me2CuLi usually gave a mixture of (39) and (40)together with some (41) whereas MeCuMgBrI exhibited a high ratio of alkyne 69 I.Fleming T. W. Newton and F. Roessler J. Chem. SOC., Perkin Trans. 1 1981 2527. 'O A. Nishida M. Shibasaki and S. Ikegami Tetrahedron Lett. 1981,22 4819. Aliphatic Compounds -Part (i) Hydrocarbons to allene with no formation of (41). Virtually exclusive formation of allene was observed with MeCuLiBreMgBrI in THF suggesting that a distinctly different reactive species is involved in this case. A number of other less important facets of this reaction are covered in the 33 experiments reported in this work.” R’CzCCR2C5H11 + R1CrCCR2C5Hll+ R1C~CCR2C5H11 I I Me OH GR3\ I (39) (41) R’ R2 R’ R2 \ / \ / /c=c=c \ + /c=c=c \ Me C5Hll C5Hll (40) (42) Scheme 23 Olefination of the carbonyl group in aldehydes and ketones is achieved efficiently by their reaction with the ambident anion (44)that is derived by metallation of 1,3-bistrimethylsilylpropyne(43;R = Me) [reaction (a) in Scheme 24].72In the case of aldehydes stereo-control is achieved by increasing the size of the substituent on the silicon at the carbanionic site.For example the enynes from hexanal have a Z/E ratio of 3 :1 for R = Me but a ratio of 31 :1 is observed if R = But. A steric effect in the transition state is responsible for this enhancement of the proportion of the 2-isomer. Less obvious is the reason for a two-fold increase in the Z/E ratio when the carbanion (44)is effectively a Grignard reagent (M = MgBr) rather than a lithio-derivative (M = Li). A greater tendency to form (45)may lead to a cyclic transition state thus enhancing the steric interaction.Several reactions of propargyltrimethylsilane (46) have been explored73 [reaction (b) in Scheme 241. M’ RMe2SiCH -CrCSiMe3 (44) RMe2SiCH2C=CSiMe3 I* 1L 5R’CH=CHCZCSiMe (a) M (43) RMe2SiCH=C=C / \ SiMe3 (45) RC-C-SiMe3 __* RCX=C=CH2 (b) (46) (47) Reagents i Bu‘Li then MgBr, if required; ii R’CHO Scheme 24 71 T. L. Macdonald D. R. Reagan and R. S. Brinkmeyer J. Org. Chem. 1980,45,4740. ” Y.Yamakado M. Ishiguro N. Ikeda and H. Yamamoto J. Am. Chem. Soc. 1981,103,5568. 73 T.Floor and P. E. Paterson J. Org. Chem. 1980,45,5006. 166 D. F. Ewing Electrophilic reagents such as trifluoroacetic acid Br, I, and acetyl chloride/AlCl afford the corresponding 3-substituted allene.This is a convenient route to several compounds (47; X = H Br or I). Treatment of (46) with base gives a mixture of the products from 3-substitution i.e. the allene (47; X = H) and l-substitution i.e. the methylacetylene. Homolytic chlorination of six acetylenes with sulphuryl chloride in benzene gave mixtures of the corresponding E-and Z-dichloro-alkenes in good yield.74 The isomer ratio depends very markedly on the substituents on the alkyne the proportion of Z-isomer increasing with the size of these groups. An interesting route to naphthoquinones is shown in Scheme 25. A wide range of alkynes from electron-rich alkyl-acetylenes to electron-deficient alkynyl esters (48) Reagents i MeCN in a sealed tube at 100 "C Scheme 25 react with a cyclic iron complex [48; M = Fe(CO),] to result in the formation of a quinone ring in high yield (70-100%).75 The analogous cobalt complex [48; M = CoCl(PPh,),] requires the presence of AgBF to induce the formation of the quinone but is superior to the iron complex for sterically hindered alkynes.Extensions of this approach could lead to a fruitful development of reactions for ring formation by incorporation of a two-carbon acetylenic unit. Another potentially interesting development is the addition of a carbene to alkynes with the complex [Cp(CO),FeCHR]' PF6-. A simple alkyne but-2-yne shows a surprisingly high reactivity towards this reagent leading to the formation of dimethylphenyl-cyclopropenium ion (49). The chemistry of this reaction is largely unexplored as yet.37 Ph 74 S.Eumura C. Masaki A. Toshimitsu and S. Sawada Bull. Chem. SOC.Jpn. 1981 54,2843 '' L.S.Liebeskind S. L. Baysdon and M. S. South J. Am. Chem. Soc. 1980,102,7397.

ISSN:0069-3030    

DOI:10.1039/OC9817800147

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

8 Aliphatic Compounds Part (ii)Other Aliphatic Compounds By A. R. TATCHELL School of Chemistry Thames Polytechnic Wellington St. London SE18 6PF 1 Alcohols and Ethers The search for chiral stationary phases for the resolution of racemates by h.p.1.c. techniques continues. An ionically-bonded chiral stationary phase prepared by passage of a solution of (R)-N-(33-dinitrobenzoyl)phenylglycine through a pre- packed y-aminopropyl silanized column of silica has been shown successfully to resolve racemates having a wide diversity of functionality.'" A model for chiral recognition by the stationary phase leading both to a prediction of elution order and assignment of absolute configuration of arylalkylcarbinols is proposed.'* Fur- thermore the resolution of various racemic 2,2'-disubstituted-l l'-binaphthyls on a preparative scale," previously possible only by classical means should enable the use of these compounds in other stereochemical studies to be exploited further (see refs.13 15 and 29). Low molecular weight (+)-poly(triphenylmethy1 metha-crylate) coated onto silanized silica gel also successfully resolves a similar range of racemic binaphthyls. Optically pure a-[1-(9-anthryl)-2,2,2-trifluoroethoxy]acetic acid has been synthesized from either enantiomer of 2,2,2-trifluoro-1-(9-anthryl)ethanol and used as a chiral derivatization agent for racemic alcohols amines and thiols (R'R2CHX; X = OH NH2,or SH).2The diastereoisomeric esters amides and thioesters exhibit n.m.r. spectra in which chemical shift differences are noted for diastereotopic nuclei notably R' and R2.The proposed preferred conformation for the derivatives [(l) (1) X = O,NH,S,orNR * (a)W. H. Pirkle J. M. Finn J. L. Schreiner and B. C. Hamper J. Am. Chem. Soc. 1981 103 3964; (b)W. H. Pirkle and J. M. Finn J. Org. Chem. 1981 46 2935; (c) W. H. Pirkle and J. L. Schreiner ibid. 1981 46 4988; (d)S. Honda S. Murata R. Noyori Y. Okamoto I. Okamoto H. Takaya and H. Yuki J. Am. Chem. Soc. 1981,103,6971. W. H. Pirkle and K. A. Simmons J. Org. Chem. 1981 46 3239. 167 168 A. R. Tatchell illustrates one diastereoisomer] upon which the n.m.r. interpretation is based is carefully argued and these conformations appear to be stable highly populated even at room temperature unperturbed by strong interactions of R' and R2with the anthryl system and largely unaffected by changes in solvent polarity.Primary alcohols may be acetylated using ethyl acetate in the presence of commercially available Woelm alumina.3a This simple and convenient met hod is also specific in that application to primary-secondary diols results in the formation of primary monoacetates. The methodology has been successfully extended to primary hydroxyalkylphenols and arylamines (phenols and aliphatic amines are unaff e~ted)~' and to carbohydrate^.^' The cleavage of a-diols with sodium metaperiodate supported on silica gel offers a method of promising ver~atility,~ as does the procedure employing triphenyl- bismuth in catalytic amounts with N-bromosuccinimide in moist acetonitrile in the presence of potassium carbonate.A cautionary note has been published with regard to asymmetric syntheses carried out using phase-transfer techniques wherein P-hydroxyammonium compounds (e.g. ephedrine) are used as chiral quaternary ammonium catalysts.6 A careful survey of a range of such reactions is reported including chiral epoxidation processes where artefact formation from the catalyst can cause spurious results. The formation of (R)-1,2-epoxyoctane from oct-1-ene has been achieved in higher yields than hitherto and with enantiomeric excess of >70% using media inoculated with P.oleovorans. The two-phase technique that was developed involved successive transfer of the organic phase to a fresh batch of inoculated media to overcome the problems of cell and enzyme damage.' The asymmetric epoxidation of prochiral allylic alcohols reported last year using t-butyl hydroperoxide with titanium(1v) isopropoxide in the presence of tartrate esters has been further exploited and procedures have been improved to overcome the previous limitation resulting from more water-soluble products.' Similar epoxi- dation processes with racemic allylic alcohols [e.g.(2) Scheme 11when allowed to proceed to 50% conversion revealed that recovered untreated alcohol had a remarkably high enantiomeric purity (frequently >96Y0).~ The success of this kinetic resolution process resides in the reaction-rate difference of the two enantiomeric allylic alcohols being in the region of 100 although relative rate differences of 5-10 can still at a 50% conversion lead to e.e.values of recovered alcohol being in the region of 70-90%. It was also noted that the isolated epoxy alcohol had e.e. >96% arising of course from the faster epoxidation of the (S)-enantiomer in the racemic mixture. (a) G. H. Posner S. S. Okada K. A. Babiak K. Miura and R. K. Rose Synthesis 1981 789; (6) G. H. Posner and M. Oda Tetrahedron Letr. 1981 22 5003; (c) S. S. Rana J. J. Barlow and K. L. Matta ibid. 1981 22 5007. D. N. Gupta P. Hodge and J. E. Davies J. Chem. SOC.,Perkin Trans. 1 1Y81 2Y70. D. H. R. Barton W. B. Motherwell and A. Stobie J. Chem. SOC.,Chem. Commun. 1981,1232. E. V. Dehmlow P. Singh and J. Heider J. Chem. Res. (S),1981,292.M.-J. de Smet B. Witholt and H. Wynberg J. Org. Chem. 1981 46 3128. B. E. Rossiter T. Katsuki and K. B. Sharpless J. Am. Chem. SOC.,1981 103,464. V. S. Martin S. S. Woodard T. Katsuki Y. Yamanda M. Ikeda and K. B. Sharpless J. Am. Chem. SOC.,1981 103,6237. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 6)- (2) threo-(2:98) erythro-slow (R)-(2)___* ihreo-(62:38) erythro-Scheme 1 2 Aldehydes and Ketones Convenient and efficient procedures have been reported for the synthesis of [l-2Hl]aldehydes10 and of [1-"O]aldehydes or ketones," and for deuterium exchange of acidic hydrogens in ketones in compounds having active methylenic hydrogens and in hydrocarbons.'* The alkylation of aldehydes the reduction of ketones and a-ketoaldehydes and the a-alkylation of acyclic and cyclic ketones under conditions which induce chirality in the products has been the subject of an unusually high number of publications.The most significant examples of the wide range of chiral-inducing catalysts that have been employed have been derived from the compounds (3)-(11). The most satisfying feature about most of the reactions reported is the rationalization of the X 3 \ X NHR (3) (4) Bu-N Me OH (7) lo I. Degani R. Fochi and V. Regondi Tetrahedron Lett. 1981,22 1821. B. T. Golding and A. K. Wong Angew. Chem. Int. Ed. Engl. 1981 20 89. G.W. Kabalka R. M. Pagni P. Bridwell E. Walsh and H. M. Hassaneen J. Org. Chem. 1981,46 1513. 170 A. R. Tatchell Me Z = OCN? H CH SC6H4Me-p I (9) enantiomeric excesses obtained on the basis of alternative diastereoisomeric transi- tion-states.Some selected relevant results are now summarized. For example the binaphthyl (3; X = CH,Br) when treated with N,N-dimethyl-l,2-diaminoethane gave a bridged derivative [3; X,X = CH2.N(CHzCHzNMez)CH2], which on reac- tion first with alkyl lithiums and then with aldehydes gave secondary alcohols having e.e. 22-5590 .13 The lithio-derivative of the diaminoalcohol (5) when present in reactions between alkyl lithiums and aldehydes results in e.e. in the secondary alcohols of 40-95% .14 Modified LAH complexes from the binaphthyl(3; X = OH) were found to reduce a range of alkyl alkynyl ketones in selectivities ranging from 57 to 96Y0.l’ Similar complexes from the diamine (4),14 the 1,2-aminodiols (7),16 and alkoxy-amine-borane complexes from (6),” were found to effect reduction of prochiral alkyl aryl ketones to give e.e.of 86-95% 44-57% and 37-60% respectively. The 1,4-dihydropyridine system contained within the chiral macrocycle (8)in the presence of magnesium perchlorate effected reduction of prochiral ketones and a-ketoesters to the extent of e.e. 10-90% ,I8 and the bis-1,4-dihydropyridine (9) was effective with similar substrates to the extent of e.e. 18-98Y0.’~ The methoxy-derivative of the amino-alcohol (6; R = CH2Ph) gave with a range of aliphatic ketones a chiral imine [e.g. (12) Scheme 21; according to the conditions used after the lithiation reaction either the (2)-or (E)-lithioenamine could be generated in high stereoselectivity.The former was the kinetically controlled and the latter the thermodynamically controlled product and both retained their stereo- integrity for the subsequent alkylation process.2o Highest e.e. (77-94%) was obtained when the (E)-isomer was alkylated. The studies have also been extended to the alkylation of cyclic ketones. l3 J.-P. Mazaleyrat and D. J. Gram J. Am. Chem. Soc. 1981,103,4585. l4 T.Mukaiyama Tetrahedron 1981,37 4111. l5 M.Nishizawa M. Yamada and R. Noyori Tetrahedron Lett. 1981 22 247. l6 J. D.Morrison E. R. Grandbois S. I. Howard and G. R. Weissmann Tetrahedron Lett. 1981,22,2619. l7 A.Hirao S. Itsuno S. Nakahama and N. Yamazaki J. Chem. SOC.,Chem. Commun. 1981,315.*’ P. Jouin C. B. Troostwijk and R. M. Kellogg J. Am. Chem. SOC.,1981 103,2091. l9 M. Seki N. Baba J. Oda and Y. Inouye J. Am. Chem. Soc. 1981,103,4613. *’ A.I. Meyers D. R. Williams S. White and G. W. Erickson J. Am. Chem. SOC.,1981,103 3081. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds (2) (E) iii \ Jiii 25% /e.e. 94Yoe.e. 0 Reagents i LiNPri THF -20 "C; ii reflux 1 h; iii MeI -78 "C Scheme 2 The conformationally rigid 1,3-0xathiane (10) prepared from (+) -pulegone pro- vides a chiral adjuvant which exerts better stereocontrol than the corresponding derivatives reported in earlier years.21a This new reagent has been used for the synthesis of (R)-2-ethyl-2-hydroxypentanal, which was then converted into (R)-3-methylhexan-3-01 having 93% optical purity.Using the same chiral adjuvant (-)-(R)-mevalolactone of 87% optical purity has been synthesized (Scheme 3).216 Reagents i BuLi MeCHO; ii DMSO (CF,CO),O; iii THF MgCl, CH,:CHMgBr; iv N-chloro- succinirnide AgN03 v LAH; vi TsCI; vii KCN; viii BH,-THF; ix H,O,-NaOH; x NaOHaq H,O+ Scheme 3 Finally the sulphoxide (11) has been used for the asymmetric synthesis of a-methoxyaldehydes (Scheme 4).22 " (a9 E. L. Eliel J. E. Lynch and W. R. Kenan jun. Tetrahedron Lett. 1981 22 2855; (b) E. L. Eliel K.Soai and W. R. Kenan jun. ibid. p. 2859. 22 L. Colombo C. Gennari G. Guanti E. Narisano and C. Scolastico J. Chem. Soc. Perkin Trans. 1 1981 1278. 172 A. R. Tatchell Reagents i BuLi THF -78 "C RCHO; ii Bu4NOH-Me2S0,-H20-CH,C1,; iii R = Ph NaI-I,-PPh,; R = CH,Ph NaI-I,-HMPA; iv I,-NaHC0,-H,O dioxan Scheme 4 3 Carboxylic Acids In connection with biosynthetic studies on the inhibitory action of an active fluorocitric acid (1R,2S)- and (lS,2S)-fluorocitric acids [(15a) and (15b) respec- tively] have been synthesized from methyl 4,6-0-benzylidene-2-deoxy-~-erythro-hexopyranosid-3-ulose (13)via a Reformatsky reaction with ethyl bromofluoroace- tate.23 In this reaction (Scheme 5) equatorial attack on the carbonyl carbon was unequivocally demonstrated to give the intermediates (14a) and (14b).H0,C (154 CO,H (13) (14a) X = CO,Et,Y = H (14b) X = H Y = C0,Et H C02H Reagents i Zn CHFBr.CO,Et; ii H,O'; iii KMnO, -OH; iv H30f Wb) Scheme 5 Oxazoline derivatives continue to be used as intermediates in the synthesis of achiral- and chiral-substituted carboxylic acids.For example a-substituted acrylic acids have been formed from saturated unbranched acids (Scheme 6);24alkylation of 2,4-dimethyl-4-(hydroxymethyl)-2-oxazoline(16),when attached to a cross- linked polystyrene via the hydroxy-function yields 2-alkyl- and 2,2-dialkylalkanoic acids. The use of the chiral oxazoline (17) in the polymer provides a promising reagent for asymmetric alk yla tion. 25 Optically pure a,P-ethylenic sulphoxides (18) have been shown to be useful substrates for the synthesis of either enantiomer of chiral 3-alkylalkanoic acids (e.e. 59-65Y0);~~ the reaction (Scheme 7) proceeds via a-lithiation (which was shown to result in neither racemization at sulphur nor E,Z-equilibration) followed by carboxylation and esterification to yield the optically pure a-(methoxycar-bony1)alkenyl sulphoxides (19).Subsequent reactions with dialkylcopper-lithium 23 S. Brandange 0.Dahlman and L. Morch J. Am. Chem. Soc. 1981,103,4452. 24 S. Serota J. R. Simon E. B. Murray and W. M. Linfield J. Org. Chem. 1981 46,4147. " A. R. Colwell L. R. Duckwall R. Brooks and S. P. McManus J. Org. Chem. 1981,46 3097. 173 Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 0 RCH,CO,H RCH,CONHCMe,CH20H -% RCH2<N]Me2 0 0 It N 1 RCHC0,H RC< Me RyH<N)Me, II CH2 CH HOCH Reagents i H,NC(Me,)CH,OH 150 "C;ii 180 "C; iii HCHO; iv 180 "C; v H30+ Scheme 6 Me phhcH ,OH OyN Et (17) reagents were rationalized on the basis of the approximately planar metal chelate (20) and nucleophilic addition from the side opposite to that of the aryl group.26 The method has also been applied to the synthesis of chiral3-alkylcyclopentanones and to 11-oxoequilenin methyl ether.High e.e. values (79-99%) have been obtained in the Michael addition reaction of Grignard reagents to a$-unsaturated acid amides derived from ~-ephedrine;~' the method offers a useful alternative to the oxazoline routes previously published.28 Ph \ Ph :FC02Me Ph Ph -(-:..]-R2 so \ i-iii \ %[ R2 Met:,'. R' R' C0,Me -0 1v,vi R' Me0 (18) (19) Reagents LiNPri2(2equiv.) THF -78°C; ii CO, -78°C; lii MeI HMPA; iv RZCuLi -15°C; v AI/Hg EtOH-H20; vi NaOHaq Scheme 7 The synthesis of a range of macrocycles incorporating only one chiral unit namely a 2,2'-disubstituted-l,l'-binaphthylsystem has been described and their effective- ness as chiral recognition hosts towards the perchlorate salts of amino-acids and 26 G.H. Posner J. P. Mallamo and K. Miura J.Am. Chem. SOC., 1981 103,2886. 2' '* T. Mukaiyama and N. Iwasawa Chem. Lett. 1981 22 913. A. I. Meyers R. K. Smith and C. E. Whitten J. Org. Chem. 1979 44 2250. 174 A. R.Tatchell their methyl esters e~amined.~' The publication provides a valuable summary of the current state of the art in this sphere and shows that the highest chiral recognition is attained between the macrocycle (21) and the perchlorate salt of phenylglycine.The more stable diastereoisomer is that wherein host/guest is (S)/(S),i.e. (22). a-Amino-acids have been used to form diaza-18-crown-6 derivatives (23) which show chiral recognition towards racemic primary alkylammonium thi~cyanates.~' /O R R" ,-R3 (23) R' = H CHMe2 or CHzPh R2= HorPh R3= Me or CH2Ph The amino-acid constituent of the antitumour antibiotic bleomycin (2S,3S,4R)- 4-amino-3-hydroxy-2-methylpentanoicacid has been synthesized from L-rham- nose;31 (+)-avenic acid A and (-)-2'-deoxymugineic noted in last year's report as iron chelators excreted from the roots of various cereals have been synthesized using pathways that establish the configurations at the chiral 4 Lactones and Macrolides The antitumour properties of various plant lignans has prompted interest in a novel lignan recently isolated from the urine of certain mammals.Two syntheses of this lignan (24) and its corresponding diol have been reported this year. One route33 involves a two-stage Stobbe reaction between diethyl succinate and 3-benzyloxy- benzaldehyde to yield bis-(3'-benzyloxybenzylidene)sucFinic acid which was then converted into (24) by standard procedures. The other involved a Michael 29 D. S. Lingenfelter R. C. Helgeson and D. J. Cram J. Org. Chem. 1981 46 393. 30 D. J. Chadwick I. A. Cliffe I. 0. Sutherland and R. F. Newton J. Chem. Soc. Chem. Commun. 1981,992. 31 T. Ohgi and S.M. Hecht J. Org. Chem. 1981,46,1232. 32 Y.Ohfune and K. Nomoto Chem. Len. 1981,827; S. Fushiya Y.Sato S. Nakatsuyama N.Kanuma and S. Nozoe ibid. 1981,909;Y.Ohfune M. Tomita and K. Nomoto J. Am. Chem. Soc. 1981 103 2409. 33 G. Cooley R. D. Farrant D. N. Kirk and S. Wynn Tetrahedron Lett. 1981 22 349. 34 A. Pelter P. Satyanarayana and R. S. Ward Tetrahedron Lett. 1981 22 1549. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 175 addition of the anion derived from 3-methoxyphenyldiphenylthiomethane to butenolide (27;R' = R2 = R3 = H) and the intermediate trapped with a sub- stituted benzyl bromide; subsequently the thioacetal group was removed reduc- tively. There has been interest in more general synthetic pathways to P-hydroxy-a- methylene- y-butyrolactones (25)and to a-alkylidene-P-hydroxy- y-butyrolactones (26)because of their physiological activity.The compound (25)(R' = R2 = H) occurs in tuliposide B which has been isolated from tulip bulbs and its prepar- ati01-1~~~ from a-methylene phosphonate (28)356was achieved using the sequence (24) Ar = rn-HOC6HdCH2 (25) (26) (27) generalized in Scheme 8. Here the conversion of (28)into (30)proceeds through the betaine (29)(Homer-Emmons reaction type) and the rearrangement (31)to (32)is the sulphoxide-sulphenate conversion of Mislow and Evans. The P-acetoxy derivative (33) was readily converted with base into (25). PhS ~~O(OEt)2 PhSycozR _* CR'R, R 1R c'A I I OAc -OAc (30) Tco2R 1v _iv F'hiyco2R HRZ PhSO CR'R' 0 CR~R~ AcO R1 I I OAc OAc (33) (32) (31) Reagents i PhSNa; ii R'R'C(0Ac)CHO; iii m-CPBA; iv P(OMe),; v p-TsOH Scheme 8 The series of Lauraceae lactones (26)possess all possible combinations of stereoisomerism at the a-alkylidene residue; they may also have at the y-position either a methylene group or a single methyl group which may be cis or trans related to the P-hydro~y-group.~~ Generalized methods for the formation of some of these lactones are shown in Scheme 9.35 (a)J.-P. Corbet and C. Benezra J. Org. Chem. 1981 46 1141; (b) C. H.Heathcock and W. A. Kleschick ibid. 1978,43 1256. 36 S. W. Rollinson R. A. Amos and J. A. Katzenellenbogen J. Am. Chem. Suc. 1981 103,4114. 176 A. R. Tatchell 1- R3CH2CH2C02Me Li ii . ... 1,111,v R3CH2CHC02Me i'iv'v SePh I 1 1 vi-viii Jvi.ix vi,ix R3 0 R3 0 HO Me HO Me HO HO Reagents i LiNPri THF -78 "C; ii PhSeBr THF -78 "C; iii CH,:CHCHO -78 "C; iv HC:CCHO -78 "C; v H,O, H,O 25 "C; vi KOH H,O-MeOH; vii PhSeC1 CH,Cl, 25 "C; viii Bu,SnH PhH A; ix Hg(CF,CO,), CH,Cl, 0 "C Scheme 9 Viable routes to variously substituted butenolides (27) have been reported this year and the essential features of the reaction sequences involved are shown in Scheme Scheme 11,38 Scheme 12,39and Scheme 13.40In Scheme 10 the a-(pheny1thio)ketones are formed either from bis(pheny1thio)acetals or from a-halogenoketones In Scheme 11 the formation of the unsaturated ester of pre- dominantly (2)-configuration requires the use of hindered a-silyl esters.In Scheme 12 the photochemical conversion of furfural into 4-alkoxybutenolide has been previously doc~mented.~~ In Scheme 13 the Grignard reagents from primary alkyl halides yield 4,4-dialkylbutenolides from secondary alkyl halides they yield 4- alkylbutenolides and from primary am-alkyl dihalides they yield the corresponding spiro-4-bicyclobutenolides.COzH / H2C 0 iii R' -3 R' PhS R2 PhS R2 PhS ~2 R3 R2 Reagents i NaH THF 20 "C; ii ICH,CO,Na THF; iii R'MgX (2equiv.); iv NaIO,; v A Scheme 10 37 P. Brownbridge E. Egert P. G. Hunt 0. Kennard and S. Warren J. Chem. SOC.,Perkin Trans. 1 1981,2751. 38 M. Larcheveque Ch. Legueut A. Debal and J. Y. Lallemand Tetrahedron Lett. 1981 22 1595. 39 F. W. Machado-Araujo and J. Gore Tetrahedron Lett. 1981 22 1969. 40 P. Canonne M. Akssira and G. Lemay Tetrahedron Lett.1981 22 2611. 41 M. A. Stevens U.S.P. 2 859 218; Chem. Abstr. 1959 53 10 061. 177 Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Reagents i [Me,SiCHCO,Bu']Li' -78 "C; ii NH,Cl-H,O; iii Si0,-H,S04; iv NaBH Scheme 11 \OR \OH \R Reagents i 02,ROH hv; ii H,O'; iii RLi THF -70 "C Scheme 12 Scheme 13 Carbohydrate derivatives have been further exploited as chiral sources for other natural products. Thus L-glucose is proposed for (SS)-hydroxy-(2S)-methyl-hexanoic acid lactone (the pheromone of the ~arpenter-bee).~~ (+)-Prelog-Djerassi lactone [(+)-(37)] has been prepared from 4,6-O-benzylidene-~-allal,~~ from methyl c~-D-glucopyranoside,~~ Two reports have appeared and from ~-glucal.~' on the formation of (*)-(37)utilizing a cyclic stereoselective hydroboronation process of the 1,5-diene (34)followed by appropriate oxidation procedures [Scheme 14,(34)+ (37)].46An alternative method47 involves the reaction of crotyltrialkyltin with the aldehydic carbonyl group in (38) in the presence of boron trifluoride etherate; the latter reagent chelates the two carbonyl oxygens and induces the crown conformation (39).This conformation ensures that the stereoselective direction of attack of the reagent is in the direction shown to give (40).The most dramatic synthetic achievements of the current year are the asymmetric total synthesis of erythrom~cin~~ and the total synthesis of rifamycin S.49 Both 42 S. Hanessian G. Demailly Y. Chapleur and S. Leger J. Chem. Soc. Chem. Commun.1981,1125. 43 R. E. Ireland and J. P. Daub J. Org. Chem. 1981 46 479. 44 S. Jarosz and B. Fraser-Reid Tetrahedron Lett. 1981 22 2533. 45 M. Isobe Y. Ichikawa and T. Goto Tetrahedron Lett. 1981 22 4287. 46 D. J. Morgan jun. Tetrahedron Lett. 1981,22 3721; W. C. Still and K. R. Shaw ibid. 1981,22,3725. 47 K. Maruyama Y. Ishihara and Y. Yamamoto Tetrahedron $eft. 1981 22 4235. 48 R. B. Woodward E. Logusch K. P. Nambiar K. Sakan and D. E. Ward J. Am. Chem. SOC., 1981 103 3210 3213 3215. Forty-four other authors are cited. 49 N. Nagaoka W. Rutsch G. Schmid H. Iio M. R. Johnson and Y:Kishi J. Am. Chem. Soc. 1980 102 7962; H. Iio H. Nagaoka and Y. Kishi ibid. p. 7965; H. Nagaoka G. Schmid H. Iio and Y. Kishi Tetrahedron Lett. 1981 22 899 2451; H. Nagaoka and Y.Kishi Tetrahedron 1981 37 3873. 178 A. R. Tatchell ROX -+ Meb le (34) R = SiMe2Bu' (35) CHO CO,Me Me uMe Scheme 14 impressive contributions originate from Harvard University and no summary could in any way do justice to the crispness and clarity of the accounts. 5 Lactams An interesting fused p-lactam system (41; R = Et) has been isolated in high yield (80%)from the photolytic reaction of N-ethoxycarbonylmethylene-2-pyridone.50 Modifications of functionality have been effected; for example hydrogenation of the carbon-carbon double bond epoxidation or conversion into the corresponding bromohydrin (42).Photolytic conversion of the isoxazolidine (43),obtainable by a 1,3-dipolar cycloaddition between the nitrone (44)and the nitro-substituted alkene (43 results in the formation of the trans-p-lactam (46).5'In contrast when (43) was heated in methanol it gave the cis-p-lactam (47),which is regarded as the thermodynamically more stable system in this case.When an N-methyl analogue HO (44) 0.. + ,Ph CO,R COiR Bu (41) (42) (43) (45) W. J. Begley G. Lowe A. K. Cheetham and 3. M. Newsam J. Chem. SOC.,Perkin Trans. 1 1981,2620. A. Padwa K. F. Koehler and A. Rodriguez J. Am. Chem. SOC., 1981,103,4975. Aliphatic Cornpounds -Part (ii) Other Aliphatic Compounds NC NC Bu’ of (43) was used in this reaction series the trans-p-lactam analogue was demon- strated to be the more stable. Other methods for p-lactam synthesis have been described that involve (a) C-2-N bond formation and (b) C-4-N bond formation from appropriate acyclic precursors.The concepts for these cyclizations are not new but the procedures offer useful extensions to existing methods. Thus p-amino-acids may be cyclized by a PTC method using methanesulphonyl chloride in a chloroform-water system and tetrabutylammonium hydrogen sulphate as (R)-and (S)-4-[(methoxycarbonyl)methyl]-2-azetidone[(53) and (52) respectively] have both been synthesized from dimethyl P-aminoglutartrate (48) (Scheme 15).s3 This chemico-enzymic method utilizes the specificity ofpig-liver esterase in the hydrolysis of the unprotected (48) to (50) and protected (49) diester to (51),and cyclization by use of Mukaiyama’s reagent in acetonitrile.iii I_ HO,C C02Me H2x 1i,iv Me02C C02H H (51) (52) Reagents i pig-liver esterase; ii Ph3P-MeCN; iii PhCH20COCl Et,N; iv H2 Pd/C Scheme 15 An interesting method for C-4-N bond formation leading to the synthesis of 3-methylene-azetidin-2-ones (57; Scheme 16)involves the cyclization of substituted acrylamides (56) which are formed by the reaction of secondary a-ketoamide 2,4,6-tri-isopropylbenzenesulphonylhydrazones (54) with excess butyl-lithium and trapping of the intermediate dianion (55) with aldehyde^.^^ ” Y. Watunabe and T. Mukaiyama Chem. Lett. 1981,443. 53 M. Ohno S. Kobayashi T. Iimori Y.-F. Wang andT. Izawa J. Am. Chem. SOC.,1981,103,2405,2406. 54 R. M. Adlington M. J. Betts A. G. M. Barrett P. Quayle and A. Walker J.Chem. SOC.,Chem. Commun. 1981 404; R. M. Adlington and A. G. M. Barrett ibid. p. 65. 180 A. R. Tatchell R’ (57) Reagents i BuLi 3.3equiv. -78°C; 25°C in DME; ii R’CHO -78°C; 25°C; iii H,O; iv BuLi 2 equiv.; v TsCl -78 “C; 25 “C 10 min; vi 25 “C 15 h Scheme 16 6 Amines The method of H. C. Brown for the conversion of trialkylboranes into primary amines has been developed into one of greater convenience by the in situ generation of chloramine from aqueous ammonia and sodium hypochlorite at 0 0C.55(E)-Allylamines have been formed in high stereoselectivity (91-100%) by a chain- elongation process involving an aldehyde vinyltributylphosphonium bromide phthalimide and sodium hydride; the intermediate N-allylphthalimide was decom- posed into the required allylamine with for example hydrazine in high yield.56 In those cases where some (2)-isomer was formed it could be readily removed by recrystallization.Interestingly far lower stereoselectivity was found when vinyltriphenylphosphoniumbromide was used. Two new protecting groups for the primary amino-function have been reported. In one case the reagent is 1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene(58) which is readily available owing to its use as a cross-linking agent in polymer chemistry.” Primary aliphatic and aromatic amines and amino-acid esters give adducts (59) which are however unstable to aqueous acid and alkali although the conversion of the latter into lithio-derivatives and subsequent reaction with elec- trophiles was usefully demonstrated.An acid- and alkali-stable protecting group arises from the reaction of the primary amine (or amino-acid ester) with allyl bromide in the presence of a tertiary amir~e.~* The N,N-diallyl protecting group may be removed with Wilkinson’s catalyst [(Ph,P),RhCl] which effects an allyl- propenyl isomerization and this is followed by an in situ enamine hydrolysis. The usefulness of this protecting group in which the amino-nitrogen exhibits little or no nucleophilic character has been exploited in the synthesis of (+) -anticapsin (60) in about 20% e.e. from L-0-methyltyrosine. ’’ G. W. Kabalka K. A. R. Sastry G. W. McCollurn and H. Yoshioka J. Org. Chem. 1981 46 4296. 56 A. I. Meyers J. P. Lawson and D. R. Carver J. Org. Chem. 1981,46 3119.’’S. Djuric J. Venit and P. Magnus Tetrahedron Lett. 1981 22 1787. B. C. Laguzza and B. Ganem Tetrahedron €ett. 1981 22 1483. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds Reaction of primary amines with the polycyclic pyrylium triflate (61) gives the corresponding N-alkylacridinium triflate in high yield; pyrolysis at 150"C in the presence of triphenylpyridine affords the terminal alkene.59 7 Other Nitrogen-containing Compounds Carbamates generated from allylic alcohols (62) and the corresponding alkyl or phenyl isocyanates when converted into their dilithiated derivatives undergo reaction with a range of electrophiles (Scheme 17). The overall reaction shows the carbamate to be a readily accessible propanal-d3 equivalent.60 N,N-Dialkylcarba- mates yield a monoanion which reacts with aldehydes and ketones to give S-hydroxyenolcarbamates.of iii,iv ,E~ R' R1 CH,:CHCHOHR~ -@+ 0 NR2 OCONHR~ y- (62) 0 lv ECH ,CH ,COR Reagents i R'NCO; ii BuLi 2.1 equiv. THF TMEDA -78°C; iii EX = RX Me,SiCl (MeS), MeOCO,Me or HNPr;; iv g.1.c or 1.c.; v H,O+ Scheme 17 The use of nitroalkanes as precursors for aldehydes has received impetus from two new approaches to their synthesis. Thus as their nitronate anions nitromethane nitroethane and 2-nitropropane may be C-alkylated with l-alkyl-2,4,6-triphenyl-pyridinium salts generated from primary amines and 2,4,6-triphenylpyrylium tetrafluoroborate.61 In a second route,62 a tertiary nitroalkane (63; Scheme 18) when treated with nitromethane and sodium hydride in DMSO solution and the reaction mixture irradiated gives the primary nitroalkane (64) by an electron -transfer chain-substitution mechanism.Subsequently the nitroalkane may be con- verted into the corresponding aldehyde (65) by an improved oxidative procedure 59 A. R. Katritzky and A. M. El-Mowafy J. Chem. SOC.,Chem. Commun. 1981,96. 6o R. Hanko and D. Hoppe Angew Chem. Znr. Ed. Engl. 1981 20 127; D. Hoppe R. Hanko A. Bronneke and F. Lichtenberg ibid. p. 1024; D. Seebach Angew. Chem. Int. Ed. Engl. 1979 18 239. 61 A. R. Katritzky G. De Ville and R. C. Patel Tetrahedron 1981 37 Supplement No. 9 25. " N. Kornblum and A. S. Erickson J. Org. Chem. 1981,46 1037. 182 A. R. Tatchell R'R2R3CN02 + R'R2R3CCH2N02-+ R'R2R3CCH0 Scheme 18 employing potassium permanganate.62 An alternative reaction for this conversion uses a MooS-pyridine-HMPA reagent.63 8 Sulphur Compounds Photoelectron spectroscopy which was effectively used with /3-dicarbonyl com- pounds to substantiate the existence of two rapidly interconverting enol structures rather than a single electron delocalized form has been applied to p-thioxoketone~.~~ These sulphur compounds may exist as an enethiol-(66)-enol-(67) equilibrium.In agreement with previous results obtained from 'H n.m.r. i.r. and U.V. spectra the photoelectron spectra clearly substantiated the view that thioacetyl- acetone (66; R'=R2 = Me) has comparable amounts of both forms present at equilibrium that 2-acetylcyclohexanethioneexists predominantly as the enethiol (68) and 2-thioacetylcyclohexanone is predominantly the enol (69).The assign- ments of the ionization energies are supported by semiempirical MO calculations. (66) (67) (68) (69) Alkylation of the dianion of secondary thioamides (70) which are generated for example by reaction with 2.2 equivalents of butyl-lithium has been shown to take place at the a-carbon atom rather than at the sulphur which might have been expected on the hard-soft acid-base prin~iple.~' A range of alkyl and aryl halides were used as the electrophilic species. In the case of the monoanions of secondary thioamides (2)-enolate geometry was presumed as subsequent reaction with aldehydes gave pronounced erythro-stereoselection (73; Scheme 19). Here the formation of the preferred enolate was seen to arise from the proton abstraction from the more stable conformer (71)of the thioamide and stereoselection from the more favoured chair transition-state (72).66 Secondary amides do not show such stereoselectivity.A wide range of sulphur-containing macrocycles have been prepared in much higher yields than previous literature reports. The methodology is based upon the ready formation of caesium thiolates from aw-dithiols and caesium carbonate in DMF solution and ring formation by subsequent reaction with aw-dibrornide~.~' M. R. Galobardes and H. W. Pinnick Tetrahedron Lett. 1981 22 5235. 64 F. S. J0rgensen;L. Carlsen and F. Duus,J. Am. Chem. SOC.,1981,103 1350. " Y. Tamaru M. Kagotani Y.Furukawa Y. Amino and Z.Yoshida Tetrahedron Lett. 1981 22 3413. 66 Y. Tamara T. Harada S.Nishi M. Mizutani T. Hioki Z. Yoshida J. Am. Chem. SOC.,1980,102,7806. " J. Buter and R. M. Kellogg J. Org Chem 1981,46 4481. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Reagents i BuLi THF -78 "C; ii R'CHO; iii H30+ Scheme 19 The high polarizability of the large caesium cation leading to tight ion-pairs in DMF is thought to be responsible for the success of this reaction; smaller cations (K+ Na+ or Li') lead to poorer or negligible yields. 9 Phosphorus Compounds A range of allenic phosphonates [e.g. (74)] having additional carbon-carbon bond unsaturation have been prepared by the route outlined in Scheme 20. The sub- sequent rearrangements on heating were dependent upon the nature of the sub- stituent groups and the length of the saturated carbon-chain.Thus (75) underwent a Cope rearrangement which resulted in the formation of (76) and (77) in a 1:4 ratio; the compound (78) on heating gave first diethyl 3,5-dimethylhexa-1,3,5- trienylphosphonate via a [1,5]-hydride shift which then cyclized to the correspond- ing cyclohexadiene.68 R1= (CH*),CH:CHR'R Reagents i HC i CNa; ii (EtO),PCI NR Scheme 20 /*@PO(OEt), c 3 PO(OEt) (75) (76) (77) (78) 6R D. Cooper and S. Trippett J. Chem. SOC.,Perkin Trans. I 1981 2127. 184 A. R. Tatchell 10 Miscellaneous Two reviews have appeared describing recent developments in the chemistry of carbodi-imide~.~~.~~ Other reviews include the use of halogenated ketenes in the formation of four-membered rings by cycloaddition processes leading to cyclic ketones lactones lactam and squaric acid derivative^,^^ and the preparation structure and synthetic applications of nitroenamine~.~~ The use of a selection of polymers containing functional groups either for effecting a simple chemical trans- formation of a substrate or for providing a protecting group for a substrate while functional group modification processes are carried out at a remote site has been Reviews have also appeared on the use of chiral organoboranes for asymmetric hydroboration of alkenes and for the asymmetric reduction of carbonyl on homogeneous asymmetric hydr~genation,~’ and on the use of sulphoxides as chiral inducing agent^.^^*^' The conformational preferences of macrocyclic ketones and lactones have been assessed and the product ratios arising from for example C-alkylation determined; a consistent argument has been presen- ted wherein the high kinetic diastereoselection is seen to result from control of the asymmetric induction processes by these preferred conformations and the preferred direction of reagent attack.78 Stereoselection in acyclic systems has been the subject of numerous publications including contributions from the work of D.A. Evans,79 C. H. Heathcock,80 R. W. Hoffman,81S. Masamwe,** and Y. Yarnam~to.~~ 69 M. Mikolajczyk and P. Kielbasinski Tetrahedron 1981 37 233. 70 A. Williams and I. T. Ibrahim Chem. Reu. 1981,81,589. 71 W. T. Brady Tetrahedron 1981 37 2949.72 S. Rajappa Tetrahedron 1981 37 1453. 73 J. M. J. Frichet Tetrahedron 1981 37 663. 74 H. C. Brown P. K. Jadhav and A. K. Mandal Tetrahedron 1981 37 3547. 7s V. Ciplar G. Cornisso and V. SunjiC Synthesis 1981 85. 76 G. SolladiC Synthesis 1981,185. 77 S. Colonna R. Annunziata and M. Cinquini Phosphorus Sulfur 1981 10 197. 78 W. C. Still and I. Galynker Tetrahedron 1981 37 3981. 79 D. A. Evans J. Bartroli and T. L. Shih J. Am. Chem. SOC.,1981,103 2127; D. A. Evans and L. R. McGee ibid. p. 2876; D. A. Evans J. V. Nelson E. Vogel and T. R. Taber ibid. p. 3099. C. T. White and C. H. Heathcock J. Org. Chem. 1981,46 191; C. H. Heathcock C. T. White J. J. Morrison and D. VanDerveer ibid. p. 1296; C. H. Heathcock M. C. Pirrung J. Lampe C. T.Buse and S. D. Young ibid. p. 2290; C. H. Heathcock M. C. Pirrung S. H. Montgomery and J. Lampe Tetrahedron 1981 37 4087; C. H. Heathcock J. P. Hagen E. T. Jarvi M. C. Pirrung and S. D. Young J. Am. Chem. SOC.,1981,103,4972. R. W. Hoffman and T. Herold Chem. Ber. 1981 114 375; R. W. Hoffman and H.-J. Zeiss J. Org. Chem. 1981,46,1309;R. W. Hoffman and B. Kemper Tetrahedron Lett. 1981,22,5263. 82 S. Masamune W. Choy F. A. J. Kerdesky and B. Imperiali J. Am. Chem. SOC.,1981 103 1566; I. Masamune M. Hirama S. Mori S. A. Ali and D. S. Garvey ibid. p. 1568; W. Choy P. Ma and S. Masamune Tetrahedron Lett. 1981 22 3555. Y. Yamamoto H. Yatagai and K. Maruyama J. Chem. SOC.,Chem. Commun. 1981 162; J. Am. Chem. SOC.,1981 103 3229; Y. Yamamoto and K. Maruyama Tetrahedron Lett.1981 22,2895.

ISSN:0069-3030    

DOI:10.1039/OC9817800167

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

9 Alicycl ic Chemistry ByJ. M. MELLOR Department of Chemistry The University Southampton SO95NH 1 Introduction The dominant theme in alicyclic chemistry continues to be the synthesis of natural products or their analogues which are expected to show important biological activity. The challenge to develop new synthetic methods parallels the discovery of novel skeletons. So a fresh challenge is provided by the discovery’ of for example naturally occurring cyclopropenone derivatives (1)and (2). An older challenge the synthesis of steroids can still be reawakened by a fresh insight. The recent studies based on the Kametani approach of an intramolecular Diels-Alder reaction using benzocyclobutene intermediates have been reviewed.2 The special position of the Diels-Alder reaction containing six-membered rings is emphasized by later examples and by a review3 describing the many possibilities of both inter- and intra-molecular reactions of heterosubstituted 1,3-dienes.A further review4 con- cerns both intramolecular cycloadditions and ene-reactions. Ring formation by cyclizations involving radical intermediates has been little used in target synthesis but a recent review5 emphasizing the regio- and stereo-selectivity of such cyclizations suggests an under-used potential. No naturally occurring benzvalenes have been reported but their easy synthesis has permitted the development of an extensive chemistry which is now reviewed.6 The first half’ of a ‘Symposium in print’ on ‘Perspectives in Small Ring Chemistry’ has appeared.‘ F. Bohlmann J. Jakupovic L. Muller and A. Schuster Angew. Chem. Znt. Ed. Engl. 1981 20 292. * T. Kametani and H. Nemoto Tetrahedron 1981 37 3. M. Petrzilka and J. I. Grayson Synthesis 1981 753. W. Oppolzer Pure Appl. Chem. 1981 53 1181. A. L. 3. Beckwith Tetrahedron 1981,37,3073. M. Christl Angew. Chem. Znt. Ed. Engl. 1981 20 529. ’ Israel1 Chem. 1981 21 95. 185 186 J. M. Mellor 2 Synthesis Monocyclic Compounds.-A gap in the methodology for cyclopropanation of alkenes has been an efficient procedure for introduction of a methyl carbene or dimethyl carbene equivalent. Now ethylidenations have been developed based on stable iron complexes. Thus treatment' of the stable complex (3)with trimethylsilyl triflate gives the triflate salt of the ethylidene complex (4).When (4) is generated in the presence of an alkene high yields of methyl cyclopropanes are obtained. The applicability of this method to the synthesis of a variety of alkylcyclopropanes seems probable but has yet to be demonstrated. In an alternative procedure' stable complex (5) with methyl fluorosulphonate gives an unstable sulphonium salt (6) which acts as an efficient agent for ethylidene transfer (Scheme 1).By generation Ph CP(CO)~F~CH(SP~)M~ +/ A Cp(C0)2FeCH(Me)S \ Reagents i Me,SiOSO,CF, CH,Cl, -78 "C; ii FSO,Me CH,CI, 25 "C Scheme 1 of dimethylcarbene at -70 "C low yields of cyclopropanation products" are obtained from 2,2-dibromopropane and n-butyl-lithium. Photolysis of di-iodomethane" has only modest advantages in certain cases over the conventional Simmons-Smith method but the selectivity observed with dienesI2 is very different using diazomethane and palladium(I1) acetate.Attack is selectively at the less hindered site and yields are excellent. A novel cyclopropane ~ynthesis'~ proceeds stereoselectively by an intramolecular ene-reaction (Scheme 2) termed 'an oxy- homodienyl hydrogen shift'. Acceleration by metallation of the hydroxy-group by analogy with the anionic oxy-Cope rearrangement has yet to be proved. CHZOH Gas phase 263 ' 85% Scheme 2 Photochemical routes to substituted cyclobutanes are extended by observation that 1,3-diacetylimidazolin-2-one(7) adds to alker~es'~ and to enol silyl ether^:'^ M.Brookhart J. R. Tucker and G. R. Husk J. Am. Chem. SOC.,1981,103,979. K. A. M.Kremer P. Helquist and R. C. Kerber J. Am. Chem. Soc. 1981,103 1862. lo P. Fischer and G. Schaefer Angew. Chem. Znt. Ed. Engl. 1981,20,863. P. J. Kropp N. J. Pienta J. A. Sawyer and R. P. Polniaszek Tetrahedron 1981,37 3229. M.Suda Synthesis 1981 714. F.-G. Klarner W.Rungeler and W. Maifield Angew. Chem. Znt. Ed. Engl. 1981,20 595. l4 K.-H. Scholz J. Hinz H.-G. Heine and W. Hartmann Liebigs Ann. Chem. 1981 248. Is R. A.Whitney Can. J. Chem. 1981,59,2650. Alicyclic Chemistry Ac I Ac (7) Hydrolysis of the former adducts leads to cyclobutane-cis -1,2-diamines and elabor- ation of a suitable adduct with an enol ether permits a short synthesis of biotin.The importance of keteneiminium salts in the synthesis of cyclobutanones by thermal addition has been recogriized for some time. Now improved procedures (Scheme 3) permit the efficient synthesis’6 of both cyclobutanones and cyclo- butenones. Further the remarkable reactivity of these salts is shown’’ by their ability to add to a,p-unsaturated carbonyl compounds. CF3S03-Ph 77% Ph o CF SO3-Ph’ ‘ 80O/O 0 ZnC1,-57% Reagents i (CF,SO,),O; ii PhCH=CH,; iii PhCGCPh; iv CH,=CHCO,Me Scheme 3 The ‘three-phase test’ the use of a polymer-bound reagent to release an unstable intermediate able to migrate through solution to be trapped by a second polymer- bound reagent has been used to investigate the chemistry of fleeting intermediates.Cyclopentadienone can be generated18 in this way and can be trapped by insoluble reagents via Diels-Alder additions in which the cyclopentadienone can act either as diene or dienophile. Substituted cyclopentadienones are possible synthetic pre- cursors of substituted cyclo-butadienes and -tetrahedranes. Elegant new syntheses are shown in Scheme 4. Although disubstituted (8) is readily dimerized flash J.-B. Falmagne J. Escudero S. Taleb-Sahraoui and L. Ghosez Angew. Chem. Znt. Ed. Engl. 1981 20,879. ” H.-G. Heine and W. Hartmann Angew. Chem. Int. Ed. Engl. 1981 20 782. ’* F.Gavina A. M. Costero P. Gil B. Palazon and S. V. Luis J. Am. Chem. SOC.,1981,103,1797. 188 J. M. Mellor C 3C-/ SiMe SiMe SiMe \(CH )4 CEC-SiMe SiMe Ref. 19 SiMe SiMe Me,Si-CCCH A pM:, + Me,sipo co Ref.19 pj 53% Me,St ,SiMe Me,%\ iii __* M (9) (10) Reagents i hv,THF [(q5-CsH,)Co(CO),]. -20 "C; ii MeCN n-CsH12 (NH,),Ce(NO,),; iii hv Scheme 4 pyroly~is'~ of the dimer of (8) at 550 "Cquantitatively regenerates the monomer. The trisubstituted (9) and (10) are more stable and have been used2' as prekursors of the tetrasubstituted (11) (Scheme 5). However in contrast to the photolysis2' of tetra-t-butylcyclopentadienone,which gives a tetrahedrane photolysis of (1 1) only gives2' a cumulene tetrakis(trimethylsily1) butatriene via an intermediate allenyl ketene. Tetramethylcyclopentadienone can be obtained by photolysis of l9 E. R. F. Gesing J. P. Tane and K.P. C. Vollhardt Angew.Chem. Int. Ed. Engl. 1980,19,1023. 2o G.Maier H. W. Lage and H. P. Reisenauer Angew. Chem. Int. Ed. Engl. 1981,20,976. *' G. Maier S. Pfriem U. Schafer K.-D. Malsch and R. Matusch Chem. Ber. 1981,114,3965. Alicyclic Chemistry SiMe SiMe 0 0 (10) (11) Reagents i Pyridinium perbromide n-C5HI2 -78 OC; ii 1,5-diazabicyclo[5.4.O]undec-S-ene;iii LiSiMe, CuI Scheme 5 cyclobutene dicarboxylic anhydride and in turn on photolysis givesz2 tetramethyl- cyclobutadiene. Silyl-substituted cyclopentadienones (9) and (10) are similarly prepared. Two features of the vinyloxycyclopropane rearrangement to give 3-cyclopen- tenols are likely to stimulate further studies. In contrast to typical vinylcyclopropane rearrangements requiring high temperatures as shown in Scheme 6 Reagents i *CHOCH,CH,Cl; ii n-BuLi Scheme 6 proceeds efficiently at 25 "C.Further and again in contrast to the conventional rearrangement reaction proceeds with high stereoselectivity.Trimethylsilylal- lene~*~ can act as a three-carbon unit which with a,@-unsaturated ketones affords regioselectively for example (12) from methyl vinyl ketone. Target synthesis of cyclopentanoid anti-tumour antibiotics is fashionable. These highly functionalized antibiotics are very unstable and must be generated under mild conditions. The key steps of some recent syntheses are shown in Scheme 7. Interest in new syntheses of prostacyclins and prostaglandins continues. Full details 22 G. Maier and H. P. Reisenauer Chem. Ber. 1981 114 3959.23 R.L.Danheiser C. Martinez-Davila and J. M. Morin J. Org. Chem. 1980,45 1340; R. L. Danheiser C. Martinez-Davila R. J. Auchus and J. T. Kadonaga J. Am. Chem. SOC., 1981,103,2443. 24 R. L. Danheiser D. J. Carini and A. Basak J. Am. Chem. SOC., 1981 103 1604. 25 A. J. H. Klunder W. Bos and B. Zwanenburg Tetrahedron Lett. 1981,22 4557. 26 Y.Kobayashi and J. Tsuji Tetrahedron Lett. 1981,4295. 27 Y.Takahashi K. Isobe H. Hagiwara H. Kosugi and H. Uda J. Chem. SOC.,Chem. Commun. 1981 714. 28 D. Boschelli R. M. Scarborough and A. B. Smith Tetrahedron Lert. 1981 19. 190 J. M. Mellor Ref. 25 %o 0 fterrein C0,Me sarkomycin vi Li Ref. 27 PhSxco2Me methylenomycin A 0 0 *%+ CO,CH CH SiMe 1vii Ref. 28 viii ix CO,H CO H desepoxydidehydro-methylenomycin A Reagents i 420°C; ii H,O'; iii [Pd(OAc),] PPh,; iv 7 steps; v CH,=CHCO,Me; vi 7 steps; vii AcCI Me,SiCH,CH,OH; viii 5% Na,CO,; ix H30+ Scheme 7 are published2' of the Salford/Glaxo route to a variety of prostaglandins by homoconjugate addition of organocuprates to (13) and of the Australian route3' to prostaglandins via (14) which is available from phenol in five steps.The highly stereoselective addition31 of carbomethoxychloroketene to cyclopentadiene to give 29 R. J. Cave R. F. Newton D. P. Reynolds and S. M. Roberts J. Chem. SOC.,Perkin Trans. 1 1981 646;J. Davies S.M. Roberts D. P. Reynolds and R. F. Newton ibid. p. 1317;M. A. W. Finch S. M. Roberts G. T. Woolley and R. F. Newton ibid. p. 1725;R.F. Newton D. P. Reynolds C. F. Webb andS. M. Roberts ibid, p. 2055. 30 M. Gill and R. W. Rickards Aust. J. Chem. 1981,34,1063;R. M. Christie M. Gill and R. W. Rickards J. Chem. SOC., Perkin Trans. 1 1981,593;M. Gill and R. W. Rickards ibid. p. 599. 31 S. Goldstein P. Vannes C. Houge A. M. Frisque-Hesbain C. Wiaux-Zamar L. Ghosez G. Germain J. P. Declercq M:Van Meerssche and J. M. Arrieta J. Am. Chem. SOC.,1981,103,4616. 191 AlicycEic Chemistry 0 X OSiMe2Bu' H (13) X = Br or SiMe2Bu' /CCo2R (16) (17) (15) makes (16) available from cyclopentadiene in only four steps. A similarly economical synthesis results32 from an improved methodology of organocuprate addition to the monoepoxide of cyclopentadiene. Although prostacyclin (PGI,) (17; Re= H) an inhibitor of blood platelet aggregation is extremely unstable analogues lacking the enol-ether functionality can have a similar profile of phar- macological activity.Hence in addition to a new of (17; R = Me) there will be considerable interest in the full details of the synthed4 of 6-thia-analogues and in the synthesis3' of 6-carba-analogues as both series show interesting activity. In spite of the many detailed studies of the Diels-Alder reaction improvements continue to be made in this remarkably useful reaction. The intramolecular version has recently led to many short syntheses of natural products and has been re~iewed.~ Jung and Hal~eg~~ provide a further example where the stereochemical control stems from the conrotatory opening of a cyclobutene intermediate (Scheme 8) in the synthesis of coronafacic acid (18).Lewis-acid catalysis of the Diels-Alder reaction has frequently been used to advantage but efficient catalysis of cases where both diene and dienophile are hydrocarbons has proved difficult. Aminium cation radicals3' may prove to be effective catalysts. Dimerization of cyclohexa- 1,3-diene at 200 "Cfor 20 h gives (19) in only 30% yield but an aminium salt permits much higher yield (70%)to be obtained at 0 "Cafter only 15min. Earlier studies of asymmetric induction in the Diels-Alder reaction have been frustrated by the inability to obtain high enantiomeric excesses easily. Rationally designed chiral acrylate esters3* and chiral dienes3' give sufficiently high enantiomeric 32 J.P. Marino and M. G. Kelly J. Org. Chem. 1981 46 4389. 33 R. F. Newton S. M. Roberts B. J. Wakefield and G. T. Woolley J. Chem. Suc. Chem. Commun. 1981,922. 34 K. C. Nicolaou W. E. Barnette and R. L. Magolda J. Am. Chem. Suc. 1981,103 3472. " W. Skuballa and H. Vorbruggen Angew. Chem. Int. Ed. Engl. 1981,20 1046. 36 M. E. Jung and K. M. Halweg Tetrahedron Lett. 1981,2735. 37 D.J. Belville D. D. Wirth and N. L. Bauld J. Am. Chem. Soc. 1981,103 718. W. Oppolzer M. Kurth D. Reichlin C. Chapuis M. Mohnhaupt and F. Moffatt Helv. Chim. Acta 1981,64 2802; W. Oppolzer M. Kurth D. Reichlin and F. Moffatt Tetrahedron Lett. 1981 2545. 39 B. M. Trost D. O'Krongly and J. Belletire J. Am. Chem. Suc. 1981,103,7595. 192 J. M. Mellor I C0,Et C02Et C0,Et Reagents i 100"C; ii 180"C; iii HCI Scheme 8 (19) endo :ex0 ratio 5 :1 excesses to suggest that Diels-Alder reactions with asymmetric induction will soon become important in target synthesis.Use of a disymmetric dienophile derived from a sugar alternatively permits highly selective formation of norbornene deriva- tive~~' that can easily be degraded to optically pure cyclopentane derivatives. A more recently discovered reaction now shown to have wide synthetic applica- tions is the oxyanionic Cope and related rearrangements (Scheme 9). Wender's permits a ring enlargement by an 8-carbon unit. The stereocontrol has been crucial in synthesis of the natural product m~ltifidene.~' Although (20; R = allyl) readily undergoes an oxyanionic Cope rearrangement (20; R = Me) with KH suffers dehydration to give (21) and (22).Crucial evidence45 that (21) arises by electrocyclization of a trienyl anion is the observation that (21)is exclusively formed when 18-crown-6 is added. Bicyclic Compounds.-Spirocyclization procedures are still limited. Welcome addi- tions are the regiospecific intramolecular alkylation of enolates generated by mild halide-ion-induced decarb~xylation~~ of w-halogeno-P-keto-esters used in the 40 D. Horton and T. Machinami J. Chem. SOC.,Chem. Commun. 1981,88. 41 P. A.Wender S. McN. Sieburth J. Petraitis and S. K. Singh Tetrahedron 1981,37 3967. 42 G.D.Crouse and L. A. Paquette J. Org. Chem. 1981,46,4272. O3 S. G.Levine and R. L. McDaniel J. Org. Chem. 1981 46 2199.44 S.L.Schreiber and C. Santini TetrahedronLett. 1981,4651. 45 L.A.Paquette and G. D. Crouse J. Am. Chem. SOC., 1981,103,6235. 46 R. G.Eilerman and B. J. Willis J. Chem. SOC.,Chem. Commun. 1981 30. Alicyclic Chemistry Ref. 41 Ref. 42 viii X ___) -* Ref. 44 Reagents i 9 steps; ii KH THF; iii NH4Cl; iv LiCH=CH-CH=CH,; v RMgX; vi Me,SiCl; vii 4 steps; viii 2 steps; ix KH 18-crownd; x 180 "C Scheme 9 (20) (21) (22) synthesis of P-vetivone a reductive cleavage4' of (23) obtained via photocycliz-ation to give (24) and a closure48 based on vinylsilanes (25) +(26). Yields49of spirolactones from treatment of cyclic anhydrides with a,odiGrignard reagents are surprisingly high (typically 75%) but the procedure is limited by lack of 47 W.Oppolzer L. Gorrichon and T. G. C. Bird Hefv. Chim. Actu 1981,64 186. 48 S. D. Burke C. W. Murtiashaw M. S. Dike S. M. S.Strickland and J. 0.Saunders J. Org. Chem. 1981,46,2400. 49 P. Canonne D. Belanger G. Lemay and G. B. Foscolos J. Org. Chem. 1981,46 3091. 194 J. M. Mellor (23) (24) (25) (26) stereoselectivity. Such selectivity5’ is the merit of acylation of ynamines by enol lactones. Syntheses of bicyclopentanoid and polycyclopentanoid natural products have been a focus of attention and are the subject of a symposium in print.5’ An important general procedure is the highly regioselective addition” of an organopalladium Reagents i [(Ph,P),Pd] Ph,P; ii TsOH CDCI, 50 “C Scheme 10 intermediate to a,&unsaturated ketones (Scheme lo) and the use of chiral phos- phines to effect the intramolecular Wittig reactions3 of (27) to give (28) in high (27) (28) (29) enantiomeric excess suggests a developing importance for such asymmetric induc- tions.Intramolecular ene-reactionsS4 and cyclization of acetylenic ketone^'^^^^ have been elegantly used in the synthesis of the propellane natural product modhephene (29) (Scheme 11). Bridged and PolycyclicCompounds.-Successive cyclizationsof ketone (30)aff ~rd~~ the propellane (31) which is readily converted into the triepoxides (32) and (33). Remarkably both epoxides are smoothly rearrangeds8 by BF3 to give a trioxa- J. Ficini G. Revial and J. P. Genet Tetrahedron Lett. 1981 629. ” ‘Recent Developments in Polycyclopentanoid Chemistry’ ed.L. A. Paquette Tetrahedron 1981 37 4357. ’* B. M. Trost and D. M. T. Chan J. Am. Chem. SOC.,1981,103,5972. ” B. M. Trost and D. P. Curran Tetrahedron Lett. 1981,4929. 54 W. Oppolzer and F. Marazza Helv. Chim. Acta 1981 64 1575; W. Oppolzer and K. Battig ibid. p. 2489. ’’ H. Schostarez and L. A. Paquette J. Am. Chem. SOC.,1981,103,722. ’‘ M. Karpf and A. S. Dreiding Helv. Chim. Acta 1981 64 1123. ’’ J. Drouin F. Leyendecker and J. M. Conia Tetrahedron 1980 36 1203. ’* L. A. Paquette and M. Vazeux Tetrahedron Lett. 1981 291; S. A. Benner J. E. Maggio and H. E. Simmons J. Am. Chem. SOC.,1981,103 1580. Alicyclic Chemistry A _* Ref. 54 Ref. 55 Ref. 56 Scheme 11 analogue of a hexaquinane (34).Conversion of (31) into (35) gives a racemate. 'H n.m.r. establishes that at +147 "C interconversion of the enantiomers occurs probably by a stepwise inversion. (33) (34) (35) (36) (37) 59 J. E. Maggio H. E. Simmons and J. K. Kouba J. Am. Chem. SOC.,1981,103,1578. 196 J. M. Mellor (38) (39) The synthesis of the much sought pentaprismane (36) has been achieved6’ at last. The key transformation is generation of the pentaprismane skeleton by Favor- skii rearrangement of (37). Although fenestrane (38)has not yet been synthesized some hope of a possible synthesis is given by the relative stability of (39)61and related62 broken window compounds. The details of the synthesis and valence isomerization of tetra-t-b~tyltetrahedrane~l.~~ to give the corresponding cyclo- butadiene have been published but it is proving diffic~lt~**~~ either to synthesize or to show unambiguously the transient generation of other substituted tetra- hedranes.Highly strained alkenes continue to evoke interest. The diene (40) having two double bonds that are both highly strained and constrained by their geometry into interaction has been by dimerization of (41) (Scheme 12). At 80°C I (42) (40) Scheme 12 (40) is equilibrated with (42) via a Cope rearrangement. Not surprisingly (40) is highly reactive. For example oxygen gives a bis-epoxide. Force-field calculations66 suggest that in some anti-Bredt alkenes the localization of the double bond at a bridgehead position may lead to extra stability relative to their positional isomers.In such cases -‘hyperstable’ alkenes -a lower reactivity can be expected. 6o P. E. Eaton Y.S. Or and S. J. Branca J. Am. Chem. SOC.,1981,103,2134. 61 K. B. Wiberg L. K. Olli N. Golembeski and R. D. Adams J. Am. Chem. SOC.,1980,102,7467. 62 S. Wolff and W. C. Agosta J. Chem. SOC., Chem. Commun. 1981 118. 63 G. Maier S. Pfriern K. D. Malsch H.-0. Kalinowski and K. Dehnicke Chem. Ber. 1981 114 3965. 64 E. H. White R. E. K. Winter R. Graeve U. Zirngibl E. W. Friend H. Maskill U. Mende G. Kreiling H. P. Reisenauer and G. Maier Chem. Ber. 1981 114 3906; G. Maier and H. P. Reisenauer ibid. p. 3916; G. Maier M. Schneider G. Kreiling and W. Mayer ibid. p. 3922; G. Maier W. Mayer H.-A. Freitag H. P. Reisenauer and R. Askani ibid.,p.3935. 6s K. B. Wiberg M. Matturro and R. Adams J. Am. Chem. SOC., 1981,103,1600. 66 W. F. Maier and P. Von R. Schleyer J. Am. Chem. SOC., 1981,103 1891. Alicyclic Chemistry 197 3 Structural Aspects Studies of Conformation.-Nuclear Overhauser experiments and in particular the study of conformational equilibria using kinetic nuclear Overhauser effects have not been greatly used in conformational analysis. In a study showing the potential of kinetic n.0.e.67 the preferred conformation of (43)was established [as shown in (43)].High-resolution solid-state I3C n.m.r. spectroscopy is yet another new technique with great potential. Rapid equilibration6' of enantiomeric conformers of (44)and other cis-fused diones has been established by means of this method.J-J) 0 (43) (44) Better spectra obtained in infrared studies of matrix-trapped cyclohexane the earlier observations and assignment of a minor component as the twist-boat form of cyclohexane. Synthesis7' of (45)permits X-ray characterization of a compound having a six-membered ring rigidly constrained to a twist-boat. (45) Photosensitized is~merization~' of cis-cycloheptene at -78 "C affords trans-cyclo- heptene. In methanol solution the strained alkene readily adds methanol to give methoxycycloheptane but in the absence of added acid thermal trans-cis isomeriz- ation also occurs. In neutral methanol at 0 "C trans-cycloheptene has a lifetime of several minutes. X-Ray diffraction studies e~tablish'~ the planarity of the central eight-membered ring in (46).The enhanced diamagnetism suggests double-bond delocalization of the 87r system.(46) 67 J. D. Mersh and J. K. M. Sanders Tetrahedron Lett. 1981 4029. C. A. McDowell A. Naito J. R. Scheffer and Y.-F. Wong Tetrahedron Lett. 1981 4779. 69 J. L.Offenbach L. Fredin and H. L. Strauss J.Am. Chem. SOC.,1981,103 1001. 70 D. J. Herbert J. R. Scheffer A. S. Secco and J. Trotter Tetrahedron Lett. 1981 2941. 71 Y. Inoue T. Ueoka T. Kuroda and T. Hakushi J. Chem. Soc. Chem. Commun. 1981 1031. 72 F. W.B. Einstein A. C. Willis W. R. Cullen and R. L. Soulen J. Chem. Soc. Chem. Commun. 1981 526. 198 J. M. Mellor Stereocontrolled development of chiral centres remote from other centres of chirality in acyclic systems is very difficult.One solution is the use of macrocyclic compounds in which first the ratios of diastereoisomers may be controlled leaving a problem then of generation of the acyclic system for example via Baeyer-Villiger oxidation. Such a strategy requires a better knowledge of the conformational demands of the different macrocyclic systems. Promising (Scheme 13) show that even a single methyl substituent provides enough control of possible conformers to permit highly stereoselective formation of new chiral centres. Reagents and Yields i Me,CuLi 72% (>99% trans);ii LiNiPr', MeI >go% (98% cis); iii Me,CuLi 82% (99% cis); iv Me,CuLi 95% (>99% cis) Scheme 13 Intramolecular hydrogen bonding to wsystems is often suggested. An X-ray now shows that in (47) the conformation of the hydroxyl-group is such that interaction occurs in the crystal.1.r. studies show that this interaction persists in solution. Bu" I (47) 73 W. C. Still and I. Galynker Tetrahedron 1981 37 3981. 74 W. B. Schweizer J. D. Dunitz R. A. F'fund G. M. R. Tombo and C. Ganter Helu. Chim.Acta 1981 64 2738. A licyclic Chemistry 4 Chemistry Neutral Species.-Flash techniques75 permit the sensitized photogeneration of the lowest triplet state of a cyclobutadiene (48). Thermolysis of either (49) or (50) generates a common product assigned to be (51) on the basis of the mode of formation and the photoelectron spectrum. It is suggested76 that (51) is formed via monothiobenzoquinone (52). (48) (49) The effective distinction between an unsaturated carbene and an allene [for example (53)and (54)] can be very difficult.The possibility of equilibration depends not only on their relative energies but also on the magnitude of the kinetic barrier separating them. An MNDO analysis77 predicts that (54) is substantially the more stable. Ph~togeneration~~ of (53) rather confirms that (53)behaves as a nucleophile with respect to alcohols whereas (55) behaves as an electrophile. The possible intermediacy of (54) in the chemistry of (53) has not been excluded. Dehydrobr~mination~~ of (56) gives (57) which can be trapped by 1,3-diphenyl- benzofuran. Isolation of an optically active adduct from optically active (56)strongly suggests the intermediacy of chiral (57).Similarly examination8' of the dehydro- bromination of (58) suggests that the twisted allene (59) is formed. Trapping 75 J. Wirz A. Krebs H. Schmalstieg and H. Angliker Angew. Chem. In?. Ed. Engl. 1981 20 192. 76 R.Schulz and A. Schweig Angew. Chem. Znt. Ed. Engl. 1981 20 570. 77 E. E. Waali J. Am. Chem. SOC.,1981,103,3604. 78 W.Kirrnse K. Loosen and H.-D. Sluma J. Am. Chem. SOC.,1981,103,5935. 79 M.Balci and W. M. Jones J. Am. Chem. SOC.,1980,102,7607. M. Balci and W. M. Jones J. Am. Chem. SOC.,1981,103 2874. 200 J. M. Mellur (60) (61) (62) experimentss1 suggest that reaction of (60) with potassium fluoride in DMSO leads first to the highly strained alkene (61) which then can rearrange to the cyclic triene (62). Diphenylbenzofuran traps both (61) and (62); the ratio of trapped adducts depends upon the concentration of the isobenzofuran.Carbenium Ions.-The detailed description of the 2-norbornyl cation continues to evoke interest. The group of Grob have summarizeds2 their extensive studies of the solvolysis of 6-substituted-2-exu- and -2-endu-norbornyl sulphonates. Solvoly- sis rates are clearly very sensitive to 6-ex0 substitution and indicate substantial 1,3-bridging. Donor substituents favour formation of 2-exu products and acceptor substituents facilitate formation of 2-endu products. The results rule out steric effects as the major factor causing high exu-endu product ratios. A further interest- ing test of the origin of high exu-endu rate ratios is providedS3 by the constrained epimeric sulphonates (63) and (64) and the epimeric benzoates (65) and (66).In &OTs QOTs hopNB contrast to the unconstrained 2-norbornyl system where a high exo-endu-rate ratio is observed only low rate ratios are observed for the epimeric pairs (63) and (64). The difference is attributed to the inability in (63) and (64) because of geometric constraints of a bridging stabilization to permit acceleration of the exu solvolysis. In sharp contrast high exu-endu-rate ratios are observed in (65)-(67) implying a common steric factor relatively facilitating solvolysis of the exu isomer. The successful application of the Saunders technique of deuterium-induced perturbation of 13C n.m.r. chemical shifts to the problem of the 2-norbornyl cation (Annu.Rep. Prog. Chern. Sect. B 1980 77 154) has highlighted a major new technique in the study of possibly equilibrating cations. Further successful uses of H.-G. Zoch G. Szeimies R. Romer and R. Schmitt Angew. Chem. Int. Ed. Engl. 1981,20,877. '* W. Fischer C. A. Grob R. Hanreich G. Von Sprecher and A. Waldner Helv. Chim. Acra 1981 64,2298;C. A. Grob B. Gunther and R. Hanreich ibid. p. 2312. 83 J. E.Nordlander J. R. Neff W. B. Moore Y. Apeloig D. Arad S. A. Godlesk and P. von R. Schleyer Tetrahedron Lett. 1981,4921. Alicyclic Chemistry 201 the method establish the symmetrys4 of the dication (68) the absence” of equilibra-tion and hence the necessity of hydride bridging in the cation (69) and the structures6 of the 9-barbaralyl cation (70).I Radical Species.-Low-temperature photolysis8’ of the aluminium halide com- plexes of tetramethylcyclobutadiene affords the monomeric tetramethylcyclo- butadiene radical cation. Details of the photolysis of pentamethylcyclopenta- diene88 giving the pentamethylcyclopentadienyl radical are reported. Radical cations with one electron situated between two bridgehead carbon atoms of a bridged system have been generated. y-RadiolysisS9 of [3,3,3]propellane (7 1) in carbon tetrachloride at 77 K affords a species to which the cation radical structure can be unambiguously assigned from the e.s.r. spectrum. Observation of such a radical cation in fluid solution has yet to be demonstrated. However formation of (72)from photolysisgO of (73) is suggested to involve the intermediacy of the cation radical (74).CF3 X- & &’ X- (74) Alkene cation radicals are typically highly reactive. Although the cation radical of adamantylideneadamantane (75) has previously been reported it is now that anodic oxidation of (75) affords via the intermediacy of the cation radical the dioxetane (76). Chemical of (75) by one-electron transfer 84 H. Hogeveen and E. M. G. A. Van Kruchten J. Org. Chem. 1981,46 1350. ” R. P. Kirchen K. Ranganayakulu A. Rauk B. P. Singh and T. S. Sorensen J. Am. Chem. SOC.,1981 103 588. 86 P. Ahlberg C. Engdahl and G. Jonsull J. Am. Chem. SOC.,1981 103 1583. ’’ Q. P. Broxterman H. Hogeveen and D. M. Kok Terrahedron Left. 1981 173. A. G. Davies and J. Lusztyk J. Chem.SOC.,Perkin Trans. 2 1981 692. 89 R. W. Alder R. B. Sessions and M. C. R. Symons J. Chem. Res. 1981,82. 90 P. Golitz and A. de Meijere Angew. Chem. Inf. Ed. Engl. 1981,20 298. 91 E. L. Clennan W. Simmons and C. W. Almgren J. Am. Chem. SOC.,1981,103,2098. 92 S. F. Nelsen and R. Akaba J. Am. Chem. SOC.,1981,103,2096. 202 J. M. Mellor (75) (77) oxidants can lead to epoxide (77) and ketone (78) via an at present obscure mechanism. The range of relatively stable cation radicals of sterically hindered alkenes has been extended by obser~ation~~ that (79; n = 1,2 and 3) are character- ized by reversible cyclic voltammograms with removal of a single electron from (79). Although the thermal isomerization and photoisomerization of substituted cyclo- propanes are well documented there has been no clear evidence of a catalysed thermal isomerization proceeding via the intermediacy of anion radicals.Isomeriz- ati~n~~ of (80)occurs at 20 "Cin the presence of a sodium-potassium alloy showing that arylcyclopropanes are readily isomerized. Carbanions.-Stable car bani on^^^ have been generated by reaction of 7-substituted cycloheptatrienes with KNHz in liquid ammonia. For example 7-carbomethoxy- cycloheptatriene gives anion (8l),which is assigned the non-planar structure on the basis of the 'H and I3C data. However this assignment seems to conflict with the observation of some paratropic character in (8l),implying delocalization of an 87~system. MNDO and ab initio calculations suggest that anion (82),initially considered to be the classic example of anionic homoaromaticity should not be considered as a Me 93 F.Gerson J. Lopez A. Krebs and W. Ruger Angew. Chem. Znt. Ed. Engl. 1981,20,95. 94 G. Boche and H. Wintermayr Angew. Chem. Znt. Ed. Engl. 1981,20,874. " A.W.Zwaard and H. Kloosterziel Red. Trav. Chim. Pays-Bas 1981,100,126. Alicyclic Chemistry homoaromatic system. Confirming recent doubts homoaromatic stabilization in carbanions is found96 to be unimportant. 5 Stereoselectivity of Attack at sp2 Centres The view has developed that the stereochemical outcome of nucleophilic addition at the carbonyl centre of substituted cyclohexanones is partly controlled by factors other than repulsive steric interactions in the transition state.A detailed present- ati~n~~ extends this view by the suggestion that in addition to a stericfactor favouring equatorial approach of a nucleophile in 4-t-butylcyclohexanone an axial approach is assisted by a transition-state stabilization. However in contrast to the earlier view98 that an axial transition state is stabilized by interaction of u* antibonding orbitals of axial C-H bonds this alternative view emphasizes an interaction with vicinal-occupied orbitals with the antibonding orbital of the developing bond. Stereoselection for the two possible modes of attack at an alkene has been explained by a view similar to that of Anh and Ei~enstein~~ for attack at carbonyl centres. Hence the structural relationship of allylic substituents controls the observed mode of attack.With this analysis99 ex0 attack on norbornenes and the relative rate of additions to cyclopentenes and to cyclohexenes are rationalized. 96 J. B. Grutzner and W. L. Jorgensen J. Am. Chem. SOC. 1981,103 1372; E. Kaufmann H. Mayr J. Chandrasekhar and P. von R. Schleyer ibid.,p. 1375. ’’ A. S. Cieplak J. Am. Chem. SOC.,1981 103,4540. 98 N. T. Anh and 0.Eisenstein Nouu. J. Chim. 1977 1,61. 99 P. Caramella N. G. Rondan M. N. Paddon-Row and K. N. Houk J. Am. Chem. Soc. 1981,103,2438.

ISSN:0069-3030    

DOI:10.1039/OC9817800185

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

10 Aromatic Compounds By R. BOLTON Department of Chemistry Bedford College London NW14NS 1 General and Theoretical Considerations Calculations by ab initio methods are the basis of a discussion' of the stabilities of the isomeric CloHlo annulene systems. Similarly ab initio modelling of substituent effects in the Hammett LFER correlation is the basis of an important contribution from Streitwieser's school.' An equally useful contribution extending the relation- ship is the hyperbolic modification suggested by Lewis Shen and More O'Ferrall in a paper that deserves study.3 In this context the introduction of a new substituent constant uc+, is relevant. Derived by Brown by methods that parallel those used to obtain the most successful u+fun~tion,~" it applies to 13Cn.m.r.spectroscopic chemical shifts in carbocations and is based upon the a,a-dimethylbenzyl ('t-cumyl') system The parameters fit well with the result of measurements in the 2-butyl- 2-phenyl and 4-heptyl-4-phenyl carbocationic and also have been applied with similar success to the 3-aryl-3-pentyl and 2-aryl-2-adamantyl analogues.4c The significance of these new parameters and the breadth of their application are still to be determined. The M function has been reconsidered and improved by Marziano and his colleagues5 and awaits an exhaustive study of its potentialities. MIND0/3 calculations of the structure fragmentation and scrambling of phenyl carbocations have been reported6 and so have studies of the protonation of ethylene and of benzene.These calculations7" follow an earlier assessment of the relative importances of u-and 1.r-complexes in the protonation of benzene7' and suggest that while the heat of reaction is reduced by proton solvation the desolvation of the proton is not complete until well after the transition state; considering the very high solvation energy of H' in comparison with activation energies of processes that readily occur at ordinary temperatures this conclusion might have been expected from thermodynamic considerations alone. Twist in 2,4,6-trialkyl-L. Farnell J. Kao L. Radom and H. F. Schaefer tert. J. Am. Chem. SOC.,1981,103,2147. E.R. Vorpagel A. Streitwieser jun. and S. D. Alexandratos J. Am. Chem. SOC.,1981 103 3777. E.S. Lewis C. C. Shen and R. A. More O'Ferrall J.Chem. Soc. Perkin Trans. 2 1981 1084. '(a)H. C. Brown and Y. Okamoto J.Am. Chem. SOC.,1958,80,4979;(b)H.C.Brown M. Periasamy and K.-T. Liu J. Org. Chem. 1981 46 1646; (c) D.P. Kelly M. J. Jenkins and R. A. Mantello J. Org. Chem. 1981,46 1650. N. C.Marziano A. Tomasin and P. G. Traverso J. Chem. SOC.,Perkin Trans. 2 1981 1070. M. Tasaka M. Ogata and H. Ichikawa J. Am. Chem. SOC.,1981,103 1885. '(a)T. Sordo M. Arumi and J. Bertran J. Chem. SOC.,Perkin Trans. 2 1981 708; (b)T.Sordo J. Bertran and E. Canadell J. Chem. SOC.,Perkin Trans. 2 1979 1486. 205 206 R. Bolton biphenyls8 and in 2,4,6-trisubstituted benzophenones' has been studied by dynamic n.m.r. spectroscopic methods; the rotation about the central bond in 9,9'-bifluorenyl has similarly been investigated." Two interesting systems have come under study recently.The first is the iodonium derivative (l),"' the synthesis of which had been claimed by both the present authorslla and by Beringer and his group.llb The instability of the system both towards decomposition and towards the collapse of ion pairs to covalently bonded isomers complicated its identification; however salts with BPh,- and with SbC16- counter-ions were isolated"' despite the formal similarity with the cyclopentadienyl carbocation. Part of this stability may well depend upon the phenyl substituents. The second structure of interest is that of arsabenzene (2). Although the details of the mechanisms of reaction have not been conclusively demonstrated the system undergoes hydrogen exchange with trifluoroacetic acid in dichloromethane as well as Friedel-Crafts acetylation by acetyl chloride-aluminium chloride (CH2C12 -78 "C)and nitration (HN03-A~20).'2 Both the mild reaction conditions and the orientation of attack (ortho and para to the hetero-atom) contrast sharply with those of pyridine and further studies of (2) will be of interest.2 Benzene Derivatives Electrophilic Substitution.-The recent p~blication'~ of studies in the gas phase of the interaction between Me+ NO' NO2+ and 02NCH2+ with benzene fluoro- or chloro-benzene anisole toluene or benzotrifluoride shows that here no Wheland- type intermediates predominate but that charge transfer is the main process. The obvious differences between these processes and a number of classical electrophilic reactions show clearly the role of the solvent in determining the course of the reaction so that theoretical calculations of electrophilic substitution reactions must take account of solvation to be valid.Each of the main schools has contributed to aspects of nitration. Ridd and his colleagues14 have confirmed and extended their earlier report of the course of the nitration of derivatives of "aimethylaniline by nitric acid in 70% sulphuric acid. The formation of (3)requires nitrous acid and the previously proposed mechanism * G. Hafelinger and M. Beyer Chem. Ber. 1981,114,109. Y. Ito Y. Umehara K. Nakamura Y. Yamada T. Matsuura and F. Imashiro J. Org. Chem. 1981 46,4359. lo G.A. Olah L. D. Field M. I. Watkins and R. Malhotra J. Org. Chem. 1981,46 1761. (a) G. R. Buske and V. R. Sandel Abstr. 6th Great Lakes Regional Meeting Am. Chem. SOC. Houghton MI U.S.A. June 22-23 1972; (6)F.M.Beringer P. Ganis G. Avitabile and H. Jaffe J. Org. Chem. 1972,37,879;(c)V.R. Sandel G. R. Buske S. G. Maroldo D. K. Bates D. Whitman and G. Sypniewski J. Org. Chem. 1981,46,4069. l2 A. J. Ashe tert. W.-T. Chan T. W. Smith and K. M. Taba J. Org. Chem. 1981,46 881. l3 J. D.Morrison K. Stanney and J. Tedder J. Chem. SOC.,Perkin Trans. 2 1981,838,967. l4 F. Al-Omran K. Fujiwara J. C. Giffney J. H. Ridd and S. R. Robinson J. Chem. SOC.,Perkin Trans. 2,1981 518. Aromatic Compounds LJ R was strengthened by the identification of the cation radical (4) [reaction (l)].Rearrangement of (3)gives the o-nitroaniline derivative (5); the m-isomer is thought to arise by direct electrophilic attack. These conclusions were justified by a study of the enhancement of the ”N n.m.r. signal in the course of the nitration of NNdimethylaniline by H1’NO3 in 85-90’/0 sulphuric acid. p-Nitro-NN-dimethyl- aniline but not the m-isomer nor the nitric acid reagent showed an enhanced emission signal that subsequently reverted to a weaker absorption signal. l5 The enhancement and the change of phase were consistent with the formation of a radical pair such as (6) arising not from electron transfer within a caged system but from the random association of NO,’ and ArHt and so suggested a mechanism for the formation of the p-nitro product different from that of the m-isomer (formation of which showed no radical component).The formation and isolation of (3; R = Me) had already been reported,16 but it was significant that enhancement of the ‘’N n.m.r. signal (‘CIDNP’) was again observed during the exchange of the nitro group between isotopically different (3) and nitric acid; in both cases the signal from the (3) present was enhanced whether it was the reagent or the product but here both signals were absorption and not emission phenomena.” Draper and Ridd have also studied the nitration of some quaternary anilinium derivatives in 63.7-100% nitric acid at 25 “Cand have coupled this with a study of the nitration of a number of activated aromatic compounds (usually phenolic ethers) in which a first-order contribution competed with a zeroth-order component in the kinetic form.18 The latter process reflected the formation of nitronium ions as a kinetically limiting step and demonstrated the rate-determining formation of an encounter pair.In 83-98% H3P04 phenol and anisole may show a zeroth-order kinetic form in their nitration by a deficiency of nitric acid. The reaction rate may also under certain conditions show a first-order dependence upon the concen- tration of the arene but be independent of its nature. Such behaviour was consistent with an encounter-controlled nitration.” The nitration of durene l5 J. H. Ridd and J. P. B. Sandall J. Chem. SOC.,Chem. Commun. 19111,402. l6 P. Helsby J. H. Ridd and J.P. B. Sandall J. Chem. SOC.,Chem. Commun. 1981 825. ’’ P. Helsby and J. H. Ridd J. Chem. SOC.,Chem. Commun. 1980 926. l8 M.Draper and J. H. Ridd J. Chem. SOC.,Perkin Trans. 2 1981 94. l9 H. W. Gibbs L. Main R. B. Moodie and K. Schofield J. Chem. SOC.,Perkin Trans. 2 1981 848. 208 R. Bolton (1,2,4,5 -tetramethylbenzene) in aqueous sulphuric acid occurs under encounter- controlled conditions whereas that of 3-nitrodurene proceeds at one-twentieth of the rate; the corresponding reactions of prehnitene (1,2,3,4-tetramethylbenzene) occur at 41 times the rate of the nitro-derivative and there is an impressive parallel between such results and those found using a theoretical mixing-reaction model with NO2+PF6- in nitromethane attacking nitromethylbenzenes.20 A more complicated situation was found in the nitration of styrene derivatives (PhCH=CHX) in sulphuric acid; electron-withdrawing groups are necessary to prevent or minimize the competing electrophilic addition to the olefinic bond but even in cases where this has been successful the interpretation of the results in terms of classical electronic effects is difficult.The comparison between the behaviour of such systems and the corresponding PhX structure seems to be a valuable test of the various mechanisms proposed to explain the orientation of electrophilic attack; the difficulties of interpretation perhaps explain the general lack of work in this field.21 Suzuki and his colleagues have demonstrated that the nitration of monoacyl- and 1,3-diacyl-polymethylbenzenesto give side-chain nitration products occurs preferentially at the most crowded carbon atom in the latter case at the site between the two acyl groups.22 They have also extended their studies of anomalous nitration to the thiophen systems and showed that 2,s-dimethylthiophen undergoes nitration with copper nitrate and acetic anhydride to give some benzyl nitrate analogues and that 3,4-dibromo-2,5-dimethylthiophen shows similar behaviour on treatment with nitric acid in di~hloromethane.~~ Fischer and his group have continued their studies of the ips0 adducts with a report of the stereochemistry of the 1,4-dimethyl-4- nitrocyclohexa-2,5-dienolsand their acetates and methyl and a report of the complex behaviour of the diastereoisomers resulting from the addition of nitronium acetate to p-ethyltoluene.Aluminium hydride cleaves these species stereospecifically to give diols which may undergo methylation. Re-aromatization of these reduction products depended on its direction upon the substituent (NO2 OH OMe OAc) attached to the cyclohexadiene carb~cation.~’ The nitration of more fully substituted aromatic systems provides readily isolable adducts; thus 2,4-dibromo-3,6-dimethylphenolgives (7a)26 and 2,4,5-tribromo-3,6-dimethyl-phenol gives the analogous compound (7b). Compound (7b) undergoes ring- contraction on treatment with aqueous sodium carbonate (Scheme 1)to give (8) which is the major product obtained under aqueous nitration condition^.^^ Olah has reportedz8 the use of silver nitrate-boron trifluoride as a nitration agent in acetonitrile including a study of the mechanism of the reaction; he has also ” A.K. Manglik R. B. Moodie K. Schofield E. Dedeoglu A. Dutly and P. Rys J. Chem. SOC.,Perkin Trans. 2 1981 1358. R. B.Moodie K. Schofield P. G. Taylor and P. G. Baillie J. Chem. Soc. Perkin Trans. 2 1981,842. 22 H. Suzuki M. Hashihama and T. Mishina Buff. Chem. SOC.Jpn. 1981,54 1186. 23 H.Suzuki I. Hidaka A. Iwasa and T. Mishina Bull. Chem. SOC.Jpn. 1981 54,771. 24 A.Fischer G. N. Henderson T. A. Smyth F. W. B. Einstein and R. E. Cobbledick Can. J. Chem. 1981,59 584. ’’ A. Fischer and G. N. Henderson Can. J. Chem. 1981,59,2314. 26 M. P. Hartshorn H. T. Ing K. E. Richards and W. T. Robinson J. Chem. Soc. Chem. Commun. 1981,225. *’ P.A. Bates E. J. Ditzel M. P. Hartshorn H. T. Ing,K. E. Richards and W. T. Robinson Terrahedron Lett. 1981,22,2325. 28 G. A. Olah A. P. Fung S. C. Narang and J. A. Olah J. Org. Chem. 1981,46,3533. Aromatic compounds 209 Br I Me (7) 111 a; X=H b; X = Br Reagents i HN0,-HOAc; ii Na,CO (aq); iii HN0,-HOAc-H,O Note Reactions (ii) and (iii) occur only with X = Br Scheme 1 extended the range of N-nitro heterocyclic compounds able to behave as sources of nitronium ion to include N-nitropyrazole which in the presence of Lewis or Bronsted acids acts as a rather unselective nitrating agent. Like the corresponding reagents reported previously this N-nitro derivative shows little relationship between substrate and positional reactivity in its attack upon alkylben~enes.~~ In view of the variety of mechanisms of aromatic nitration which have recently been discovered a study of the displacement of 3-substituents in indole to give 3-nitroindole might have offered valuable support to the more unusual proposals.However this ips0 displacement although it took place with either nitrous or nitric acid in acetic acid does not allow an assured interpretation because of the somewhat forcing conditions employed. The authors consider NO’ or NO2+to be the respon- sible reagents but the formation of dinitrogen tetraoxide (a necessary consequence of oxidation when nitrous acid is used) allows a number of alternative Halogenation studies have concentrated upon the addition products.de la Mare’s school have continued their careful identification and characterization of addition compounds formed during the attack upon aromatic systems with reports of the tetrachlorotetrahydro-2-methyl naphthalene^^' and an analysis of the 13C n.m.r. spectra of these and the corresponding derivatives of na~hthalene.~~ They have also investigated the properties of the bromination products of the isomeric cresols including dienone structures and their thermal and photochemical reactions. The action of hydriodic acid (55% HI) upon polybromophenols offers a route to 3,5-disubstituted phenols that are otherwise not easily prepared; thus 5-bromo-3- methylphenol 3-bromo- and 3,5-dibromo-4-methylphenol, and 3-bromo- 5-bromo- and 3,5-dibromo-2-methylphenolmay all be obtained from the corres- ponding cresols through their polybrominated derivative^.^^ The difficulties of distinguishing the contribution of r-complexes to the course of electrophilic substi- tution reactions have been referred and the argument may be given new 29 G.A. Olah S. C. Narang and A. P. Fung J. Org. Chem. 1981,46,2706. 30 M. Colonna L. Greci and M. Poloni J. Chem. SOC. Perkin Trans. 2 1981 628. ” P. B. D. de la Mare and B. C. J. McKellar J. Chem. SOC. Perkin Trans. 2 1981,42. 32 G. A. Bowmaker D. Calvert P. B. D. de la Mare and B. C. J. McKellar J. Chem. SOC. Perkin Trans. 2 1981 1015. 33 J. M. Brittain P. B. D. de la Mare and P. Newman J. Chem. SOC. Perkin Trans. 2 1981 32. 34 R. Bolton Annu. Rep. Prog. Chem. Sect. B 1979 186.210 R. Bolton impetus by Fukuzumi and Kochi’s report,35 in which they claim the first systematic and general study of charge-transfer complexes between arenes and chlorine bromine or mercury(I1) trifluoroacetate. Me0 \ Me0 The bromination of 6,7-dimethoxy-l-phenyl-1,2,3,4-tetrahydronaphthalene (9) in acetic acid with pyridine showed concomitant acetoxylation at C-8; the corres- ponding reaction of 3,4-dimethoxy-di- or -tri-phenylmethanes (10)showed acetoxy- lation at C-2 but l-(3’,4‘-dimethoxyphenyl)-1,2,3,4-tetrahydronaphthalene (11) gave no such The authors interpret their observations in terms of a ‘doubly benzylic’ carbocation though it is unclear to the Reporter why an addition- elimination mechanism was rejected. Friedel-Crafts alkylation processes were involved in the catalysed (A12Br6-HBr) rearrangement of [l-’3C]toluene in which the methyl group was shown to undergo 1,2-shifts about the ring.The formation of doubly labelled diethylbenzene from ethylbenzene occurred at the same rate as 13Cappeared at the para position so that transalkylation-dealkylationwas found to proceed intermolecularly under these c~nditions.~~ It has been observed that treatment of benzene with aluminium chloride alone gives alkylbenzenes and biphenyl38” and that the presence of carbon monoxide and hydrogen is not necessary nor are the isotopes incorporated in these arenes when 13C0 or 2H2is present. From these findings the earlier of the influence of transition-metal carbonyls upon these reactions must be viewed with reserve.A study of the variation of the isomer distribution in the acetylation of naph- thalene in 1,2-dichloroethane at 20 “Cinterprets the results in terms of a separate third-order process by which the a-isomer is formed and a second-order process that produces the The mathematical analysis for the successful separ- ation of these two contributions is necessarily complicated and is applicable only with some assumptions that limit the range of results for which the treatment is valid. Although good agreement was found between the experimental results and the parameters derived from them the absolute values of these parameters are conditioned by the limits of the mathematical analysis one requirement of which is that both the time of reaction and the extent of formation of the &isomer are small; in some cases it is not certain that the second condition is met adequately ’’ S.Fukuzumi and J. K. Kochi J. Org. Chem. 1981,46,4116. 36 W. M. Bandaranayake and N. V. Riggs Aust. J. Chem. 1981,34,115. ’’ R. M. Roberts and S. Roengsumran J. Org. Chem. 1981,46 3689. ’* (a) L. S. Benner Y.-H. Lai and K. P. C. Vollhardt J. Am. Chem. SOC.,1981 103 3609; (6) G. Henrici-Olive and S. Olive Angew. Chem. Int. Ed. Engl. 1979 18 77. 39 A. D. Andreou R. V. Bulbulian P. H. Gore F. S. Kamounah A. Y. Miri and D. N. Waters J. Chem. Soc. Perkin Trans.2 1981 376. Aromatic Cornpo u nds 211 and an iterative computer simulation method might provide numerical values somewhat different from the rate constants.It has also been shown4' that the acetyl-group exchange which occurs on treatment of acetomesitylene (2,4,6- trimethylacetophenone) or acetodurene (2,3,5,6-tetramethylacetophenone)with [14C]acetyl chloride-aluminium chloride involves ips0 attack at C-1 for there was no detectable displacement of deuterium when 3,5-dideuterioacetomesitylenewas used. The reaction must not therefore involve diacylation as a necessary precursor to exchange and the reaction is not therefore reversible in the classical sense (Scheme 2). MeOC COMe COMe M e 8 M e o.,._- e MeoMe Me Me Me COMe Me Reagents i Me'"C0CI; ii -MeCOCI Scheme 2 Nucleophilic Substitution.-Comparatively little new material has been reported during the last year the literature containing mainly extensions or confirmations of known reactions.Thus a further report of the nucleophilic displacement reactions of halogenobenzene complexes to metal-carbonyl systems consolidates earlier reported The rate of reaction of chloro-2,4-dinitrobenzeneis reported with a number of derivatives of 4-aminothiane (12) in 80% aqueous di~xan;~' here the interest lies not with the mechanism of the displacement but rather with the properties of the primary amines. Bamkole Hirst and 0nyid0~~ have reported a study of the reaction of fluoro-or chloro-2,4-dinitrobenzene with 2,2,2-trifluoroethylamine. No base catalysis is found here; it occurs in the corresponding displacement reaction of 1,3,5-trinitrobenzene but only in acetonitrile and not in dimethyl sulphoxide.The reaction of aniline with 1,3,5-trinitrobenzene shows base catalysis by DABCO (diazabicyclo-octane) in both solvents. Such a capricious catalysis admits a number of explanations but the ready formation of Meisenheimer 40 A. D. Andreou R. V. Bulbulian P. H. Gore D. F. C. Morris and E. L. Short J. Chem. SOC.,Perkin Trans. 2 1981 98. "'A. C. Knipe S. J. McGuinness and W. E. Watts J. Chem. SOC.,Perkin Trans. 2 1981 193. 42 P. L. Subramanian K. Ramalingam N. Satyamurthy and K. D. Berlin J. Org. Chem. 1981,46,4384. 43 T. 0.Bamkole J. Hirst and I. Onyido J. Chem. SOC.,Perkin Trans. 2 1981 1201. 212 R. Bolton complexes from this trinitrobenzene under very similar conditions suggests a poss- ible mechanism. Among a number of contributions to more detailed knowledge of such complexes Crampton and Gibson44 have reported that in the reaction of 1,3,5-trinitrobenzene with n-butylamine benzylamine isopropylamine or piperidine in dimethyl sulphoxide proton transfer becomes kinetically significant.The possible contribution which the stability of the Meisenheimer complex may make to the observed kinetics is shown in a study of the nucleophilic attack by tetramethylammonium hydroxide in aqueous t-butanol upon some polynitroben- zene derivatives. 1,3,5-Trinitrobenzene gives the cr-adduct ;chloro-2,4-dinitroben-zene gives 2,4-dinitrophenol. The rates of these two processes fall when the amount of water in the solvent is increased. In contrast picryl chloride gives picric acid at a rate which increases with increasing concentration of water in the solvent mixture and this behaviour is ascribed to the necessary formation of the 3-hydroxy add~ct.~~ The number of a-complexes possible increases considerably when more than one reaction centre is available as shown by the behaviour of 2,4,6-trinitrobenzyl chloride and of 2,4,6-trinitrotoluene with the latter compound continues to provide a rich source of Meisenheimer adducts.The SNAr mechanism has been associated with some of the more successful applications of the Hammett equation. This year the Nigerian workers have reported the effect of substituents at the 2- and 2,5-positions of aniline upon the rate of displacement of chlorine from picryl chloride in acetonitrile. Additivity was found only to a limited extent.47 In the 2-bromo-3-nitro-5-X-thiophen system (X = Br CONHz COMe SO,Me CN or NOz) an inconsistency was found with the expectations of the structure-reactivity relati~nship.~~ The authors might take comfort from a recent review49 of the limitations of predictions based upon this relationship.Aminodemethoxylation of 5-acetyl-2-methoxy-3-nitrothiophenand of 5-carbomethoxy-2-methoxy-3-nitrothiophenby piperidine shows catalysis by both piperidine and methoxide ion; loss of the methoxy group is also reported to show general acid catalysis.50 Nucleophilic attack of 2,4- and 2,6-dinitroanisole by piperidine or N-methylpiperidine shows the duality of reaction which a number of such systems undergo. Thus methylation competes with dinitroarylation.The authors seem surpri~ed,~' but Miller and Moran5' recently reported a similar reaction and indeed allied processes have been long known.53 The synthesis of l,3,5-trifluoro-2,4,6-trinitrobenzenes4" has led to a study of some of its nucleophilic displacement reactions. The combination of electron-withdrawing groups promotes 44 M. R. Crampton and B. Gibson J. Chem. SOC., Perkin Trans. 2 1981 533. 45 A. D. A. AlAruri and M. R. Crampton J. Chem. SOC., Perkin Trans. 2 1981 807. 46 D. N. Brooke M. R. Crampton G. C. Corfield P. Golding and G. F. Hayes J. Chem. SOC., Perkin Trans. 2 1981 526. 47 T. A. Emokpae J. M. Nwaedozie and J. Hirst J. Chem. SOC., Perkin Trans. 2 1981 883. 48 G. Consiglio C. Arnone D. Spinelli R.Noto and V. Frenna J. Chem. Soc. Perkin Trans. 2 1981 388. 49 C. D. Brown Tetrahedron 1980 36 3641. G. Consiglio C. Arnone D. Spinelli and R. Noto J. Chem. SOC.,Perkin Trans. 2 1981,642. N. S. Nudelman and D. Palleros J. Chem. Soc. Perkin Trans. 2 1981,995. 52 J. Miller and P. J. S. Moran J. Chem. Res. 1980 (S) 62 (M)0501. 53 M. Kohn and F. Grauer Monatsh. Chem. 1913,34 1751. 54 (a)W. M. Koppes M. E. Sitzmann and H. G. Adolph U.S.P. 4 173 591 (Chem. Absrr. 1979 91 39 112); (6) W. M. Koppes G. W. Lawrence M. E. Sitzmann and H. G. Adolph J. Chem. Soc. Perkin Trans. 1 1981 1815. Aromatic Compounds 213 some remarkably easy reactions such as the displacement of fluorine by bromide ion in acetonitrile at room temperature and the hydroxydefluorination of 5-fluoro-2,4,6-trinitro-1,3-diaminobenzeneby 15 h boiling in 96% aqueous acetic The acid-catalysed hydrolysis of 2-fluoropyridine and of a number of analogously substituted derivatives of methylpyridine quinoline and pyrimidine occurs in aqueous hydrochloric acid at a rate which follows ho at low acidities but then shows maxima at higher acid concentrations.The application of various functions such as w w” and the Bunnett-Olsen equation led to the conclusion that the hydrolysis of the pyrimidine derivatives involved the slow attack by water upon the cation and that the slower substrates showed additional contributions by proton transfer to water Perchloroindane has been showns6 to react with ethoxide ion to give first the 5-ethoxy derivative and then the 1,1,5-triethoxy analogue.Errors in the literature were corrected and a number of interesting reactions are described. The ring-opening of pyrylium ions by primary amines is reported to be fast with strong bases and base-catalysed with the weaker amines. The subsequent ring- closure to form the pyridine system is acid-catalysed and apparently suffers from steric hindrance and concomitant electronic effects while the effect of solvents as might be predicted from such a multi-stage reaction is ~ornplex.~’ Katritzky and his colleagues have reported the kinetics of decomposition of N-benzyl-2,4,6- triphenylpyridinium ions,58a the effect of pyridine substituents in the decomposition of N-benzylpyridinium ions (in which the rate variations are most simply tied to the steric effects of the leaving group),586 and a study of the result of introducing substituents into the phenyl system of N-benzyl-2,4,6-triphenylpyridiniumion when the different degrees of contribution of SNl and sN2 processes were associated with the nucleophiles involved.The rates of displacement were dependent upon the ionic strength of the medium when anionic nucleophiles were used but not surprisingly with neutral The mechanism continues to attract attention and a report of some further reactions of 2-chloropyrimidine 4-chloro- 2,6-dimethoxypyrimidine,3-chloro-6-methoxypyridazine,and 2-chloropyrazine with enolates in liquid ammonia extended the range of the process.59 An elegant and much needed demonstration of a chain process similar to this SRNl mechanism was made by Eberson and Jonnson60 who reasoned that as bis(pentafluorobenzoy1) peroxide attacked chlorobenzene at the ips0 position,61 p-fluoroanisole should undergo attack by benzoyl peroxide to lose fluorine.The logic was not flaw- less for fluorobenzene undergoes much less selective attack by bis(pentafluor0- benzoyl) peroxide than does either chloro- or bromo-benzene and much less ester ” H. R. Clark L. D. Beth R. M. Burton D. L. Garret A. L. Miller and 0. J. Muscio jun. J. Org. Chem. 1981,46,4363. 56 M. Ballester J. Riera L. Julia J. Castaner and F. Ros J. Chem. Soc. Perkin Trans. 1 1981 1690. s7 A. R. Katritzky and R. H. Manzo J. Chem. SOC.,Perkin Trans.2 1981 571. (a) A. R. Katritzky G. Musumarra K. Sakizadeh and M.Misic-Vukovic J. Org. Chem. 1981 46 3820;(6)A.R.Katritzky A. M. El-Mowafy G. Musumarra K. Sakizadeh C. Sana-Ullah S. M. M. El-Shafie and S. S. Thind J. Org. Chem. 1981 46 3823; (c) A.R.Katritzky G. Musummara and K. Sakizadeh J. Org. Chem. 1981,46,3831. 59 D. R. Carver A. P. Komin J. S. Hubbard and J. F. Wolfe J. Org. Chem. 1981,46,294. 6o L.Eberson and L. Jonsson J. Chem. SOC.,Chem. Commun. 1981,133. P. H. Oldham and G. H. Williams J. Chem. SOC.(C),1970 1260. 214 R.Bolton is produced;62" nor is benzoyloxydehalogenation common in the reaction of benzoyl peroxide with polyfluorobenzenes.62b Nevertheless in solutions of potassium acetate in acetic acid a chain reaction was set up in which fluorine in p-fluoroanisole was displaced mainly by acetate ion the ratio of acetate to benzoate attack being between 2.6 and 7.3 to 1and demonstrating thereby the chain process.Diazonium ion studies have been limited to a detailed study of the association of crown ethers with these ions in which the earlier was confirmed,63b and to an attempt to show the two-stage nature of the Sandmeyer reaction. The Ko~hi~~ mechanism allowed two essential roles to the copper catalyst and it was intended to replace copper in the second process by adding another metal salt (Scheme 3). Of the additives chosen only iron(II1) showed a little catalytic efficacy PhN2+ + X-+ Cu' + Ph*+ N2 + X-+ Cu2+ Ph*+ CuX2 + PhX + CuX (X = Bror C1) Scheme 3 in the absence of copper(1) chloride but in its presence iron(@ salts ferrocene and tin@) chloride all showed the ability to promote the Sandmeyer reaction although the best yields with these additives were only marginally better (68%) than without (63°h).65Sandmeyer's discovery was as he reported,66 a happy accident but Hodgson6' has made a thorough study of the effect of a number of metal salts upon promoting this decomposition of diazonium salts in hydrochloric acid media; he also found iron(II1) chloride to be as weakly efficient as the present author finds it and this aspect of the work is confirmed well by the earlier study.It seems however that the demonstration of a two-stage mechanism by this latest method65 relies upon the assumption that where copper(1) has been oxidized to copper(I1) in the first step it cannot be subsequently reformed by iron(II) ferrocene or tin(I1).Oxidation potentials appear to allow such a process although it may be too slow to occur under the reaction conditions; until this point has been demon- strated the two-stage mechanism cannot be regarded as proved by these particular experiments. The arguments against an earlier mechanism and based upon the expected reactions of [ArI]' might also be criticized. Homolytic Aromatic Substitution.-The use of 'CIDNP' in demonstrating free- radical processes has been extended to the decomposition of azosulphones (ArN=NS02Ar') whose homolysis has been shown68 to be associated with anomalies in the 'H and 13Cn.m.r. spectra. The photolysis of p-toluoyl peroxide of p-tolyl sulphide sulphoxide or sulphone or of p-iodotoluene in mixtures of pyridine and pentadeuteriopyridine shows only slight isotope eff e~ts.~~ This con- trasted with the considerable isotope effects that have been found specifically in 62 (a)M.W. Coleman Ph.D. Thesis University of London 1972; (b) R. Bolton J. P. B. Sandall and G. H. Williams J. Fluorine Chem. 1978 11,591. (a) R. A. Bartsch and P. N. Juri J. Org. Chem. 1980 45 1011; (b)H. Nakazumi I. Szele and H. Zollinger Tetrahedron Lett. 1981 22 3053. 64 J. K. Kochi J. Am. Chem. SOC.,1957 79 2942; Tetrahedron 1962,483. " C. Galli J. Chem. SOC., Perkin Trans. 2 1981 1459. 66 T. Sandmeyer Ber. 1884 17 1633. 67 H. H. Hodgson S. Birtwell and J. Walker J. Chem. SOC.,1942 720; jbid. 1944 18. 68 M. Yoshida N. Furuta and M.Kobayashi Bull. Chem. SOC.Jpn. 1981,54,2354. 69 T. Nakabayashi T. Horii S. Kawamura and Y. Abe Bull. Chem. SOC. Jpn. 1981,54 2535. Aromatic Compounds 215 phenylation of 4-methylpyridine at the 2-position (kH/kD,3.7)by the thermolysis of benzoyl per~xide.~’ The discrepancy may reflect differences in the source and energy of the attacking radicals but raises some doubts about mechanistic interpreta- tions which the generalization from the earlier work allows. A confirmation of earlier work was found in a careful study of the phenylation of some simple arenes by the thermolysis of benzoyl peroxide at 80 “C. Earlier measurements of substituent effects and isomer distributions had relied upon the measurement of yields of biaryls that were often far short of those calculated; the assumption was often made that isomer ratios and even relative yields of competition products between arenes were not changed in consequence.The use of oxidation catalysts improved the biaryl yields to much nearer those expected from the stoicheiometry of reaction (2):71 ArH + RCOOOCOR = ArR + RC02H + COz (2) Measurements of the rates of thermolysis of dibenzylmercury derivatives in octane were used as a basis of substituent constants that are appropriate to homolytic processes (a’).” However the relatively small effects of substituents in homolytic processes mean a correspondingly large sensitivity to polar contributions whether derived from solvent interactions or reagent-substrate interactions. These are not constant and are not properties of the substituent alone; they must vitiate the general applicability of such a’values.3 Synthetic Aspects Mercuration of 1,2,4-trichlorobenzene by mercury(@ trifluoroacetate at the boiling point gives bis(2,3,6-trichlorophenyl)mercury (13).73 The corresponding 2,4,5- trichlorophenyl derivative is obtained using trifluoroacetic acid as solvent; at higher temperatures the 2,4,5-isomer rearranges so that the formation of these two organomercurials apparently reflects the imposition of thermodynamic or of kinetic control. The general difficulties of preparing 1,2,3,4-tetrasubstituted benzenes makes this synthesis important. r CI i Xenon(I1) fluoride in dichloromethane has been reported to give monofluorinated arenes with aromatic hydro~arbons;~~ thus 1-fluoro- and 2-fluoro-9,lO-dihydroan-thracene are obtained in the ratio 2 :3 from 9,lO-dihydroanthracene.In the presence of boron trifluoride xenon(I1) fluoride adds fluorine to pentafluorobenzene deriva- tives (C6F,X; X = H c1,Br or C6F5) to give l-X-heptafluorocyclohexa-1,4-dienes 70 S. Vidal J. Court and J. M. Bonnier J. Chem. SOC.,Perkin Trans. 2 1976,497. ’*R. Bolton B. N. Dailly K. Hirakubo K. H. Lee and G. H. Williams J. Chem. Soc. Perkin Trans. 2 1981 1109. 72 S. Dincturk R. A. Jackson M. Townson H. Agirbas N. C. Billingham and G. March J. Chem. Soc. Perkin Trans. 2 1981 112 1. ” G. B. Deacon and B. S. F. Taylor Aust. J. Chem. 1981 34,301. 74 B. Sket and M. Zupan Bull. Chem. SOC.Jpn. 1981,54,279. 216 R.Bolton (14) (14),75in a manner similar to that of KC OF,.^^ Ethers such as PriOC6Fs give a slightly more complex reaction to provide hexafluorocyclohexa-2,4-and -2,5-dienones [reactions (3)and (4)].Fluorine can also be introduced into phenol anisole toluene and biphenyl by the fluoroxysulphate ion (FSO,-) in acetonitrile. The mechanism of the substitution is uncertain but fluorine is found attached to sites ortho and guru to the substituent. On the other hand toluene also gives benzyl fluoride which suggests a radical component to the reaction that might otherwise seem to have electrophilic chara~ter.~~ Naphthalene is also attacked by this reagent.78 A particular application of such reactions might be the preparation of radio-labelled fluorocarbons containing 18F.Two further reports of syntheses of such materials have appeared this year. The first relies upon the cleavage of C-Sn bonds by molecular fluorine at -78°C [reaction (S)].Even at this temperature molecular fluorine is used as a 1% mixture in neon; radiochemical yields of 8% (R = Ph) and 37% (R = Bu; theoretical maximum 50%) are rep~rted.~' -78 "C,CFCI PhSnR3 + [18F]F2 Ph18F Alternatively fluorine may be introduced into the aromatic system through conventional diazonium ion chemistry. Although the Balz-Schiemann reaction is usually used to prepare such aryl fluorides it is wasteful of radio-label since three-quarters of the inorganic fluorine is lost as boron trifluoride. Ng Katzenellen- bogen and Kilbourn" successfully used the original Wallach" process in which a triazene (15)is decomposed by hydrogen fluoride.A second process in which the decomposition of an aryl azide (16)gives p-fluoroaniline was found to be less useful since the reaction required about three times the half-life of the radioisotope." Photocyanation of naphthalene or biphenyl occurs with potassium cyanide in aqueous acetonitrile or with sodium cyanide in methanol though in yields only in the range 12-27% .82 Aryl nitriles were found to act as necessary electron acceptors '' S. Stauber and M. Zupan J. Org. Chem. 1981,46 300. 76 I. W. Parsons J. Fluorine Chem. 1972-3 2 63. 77 D. P. Ip G. D. Arthur R. E. Winans and E. H. Appleman J. Am. Chem. Soc. 1981,103,1964. 70 S. Stauber and M. Zupan J. Chem. Soc.Chem. Commun. 1981,148. 79 M. J. Adam B. D. Pate T. J. Ruth J. M. Berry and L. D. Hall J. Chem. SOC.,Chem. Commun. 1981,733. 80 J. S. Ng J. A. Katzenellenbogen and M. R. Kilbourn J. Org. Chem. 1981 46 2520. 0. Wallach Liebigs Ann. Chem. 1886 235 255; 0.Wallach and F. Heusler Liebigs Ann. Chem. 1888,243,219. N. J. Bunce J. P. Bergsma and J. L. Schmidt J. Chem. SOC.,Perkin Trans. 2 1981,713. Aromatic Compounds +-Ar-N=N-N 3 Ar-N=N=N (15) (16) so that sodium cyanide in aqueous acetonitrile photocyanated phenanthrene naph- thalene methoxynaphthalene or rn-dimethoxybenzene usually in 50-70% yield but with only 30-50% conversi~n.~~ Lapin and KurzS4 report the photochemical cyanomethylation of electron-rich aromatic systems over 22 h irradiation; yields are poor (16% for pdimethoxybenzene) although the conversion is somewhat higher.Nitromethylation of arenes has already been reported.85a A mechanistic study of the hydrogen isotope effect showed k,/k 4.0-4.2 for deuterionitromethane (D,CNO,) but 1.05 for hexadeuteriobenzene compared with C6H6.It followed that the Mn"' acetate used was involved kinetically with the formation of the reagent and that hydrogen loss from the intermediate in the aromatic substitution is not rate-limiting.85b Cerium(1v) as cerium ammonium nitrate is effective also but concomitant nitration occurs. The orientation of attack (55% ortho attack of toluene) is considered consistent with a homolytic aromatic substitution mechanism and is similar to that shown by phenyl radicals.85c Electrolytic (anodic) nuclear acetoxylation of alkylarenes is brought about by a non-divided cell containing palladized The purpose of the catalyst is to promote hydrogenolysis at the cathode of the side-chain acetoxylation products thus allowing the phenol esters to accumulate.The attack of carboethoxycarbene upon arenes which gives cycloheptatrienecar- boxylate esters in which the polyene system is not conjugated with the ester function is catalysed by rhodium(r1) salts such as the trifluoroacetate [strictly tetrakis(perfluoroalkylcarboxylato)dirhodium(~~)].Even hexafluorobenzene is attacked in a reaction with considerable synthetic potential." March and Engenito" have attempted to improve the yield of amidation products by the process given in reaction (6) ArH + MeCONH(0H) ArNHCOMe (6) but could not realize more than ca.50% yields with aromatic ethers which seem to have been the only substrates studied. Potassium metal in a mixture of polyglycol methyl ethers causes ethylene to alkylate aromatic hydrocarbons of the general formula ArR." Attack takes place at the benzylic positions and at sites ortho and meta (but not para) to the alkyl 83 M. Yasuda C. Pac and H. Sakurai J. Chem. Soc. Perkin Trans. 1 1981 746. 84 S. Lapin and M. E. Kurz J. Chem. Soc. Chem. Commun.. 1981,817. 85 (a) M. E. Kurz and T. Y. R. Chen J. Org. Chem. 1978 43 239; (b)M. E. Kurz P. Ngoviwatchai and T. Tantrarant J. Org. Chem. 1981,46,4668; (c)M. E. Kurz and P. Ngoviwatchai J. Org. Chem. 1981,46.4612.86 L. Eberson and E. Oberrauch Acta Chem. Scand. Ser. B 1981,35,193. 87 A. J. Anciaux A Demonceau A. F. Noels A. J. Hubert R. Warin and P. Teyssie J. Org. Chem. 1981,46,873. nn J. March and J. S. Engenito jun. J. Org. Chem. 1981,46,4304. 89 W. E. Russey and M. W. Haenel Tetrahedron Lett. 1981,22,4065. 218 R. Bolton I+ethylated reduction products Scheme 4 group; the reaction products are themselves unstable towards further hydrogenation under these conditions (Scheme 4). In the absence of ethylene these products if they are formed at all arise in lower yields and in different ratios -presumably through cleavage of the solvent. A kinetic study of the hydroxylation of benzene or of toluene by potassium peroxydiphosphate in aqueous acid (0.05-1 .OM) in the presence of copper(I1) showed the general similarity between this reagent and the peroxydis~lphate.~~" This latter reagent gives phenol biphenyl and 0-and p-nitrophenols in its reaction with a mixture of benzene and nitrobenzene (water 80°C).90b In the absence of benzene or when it is replaced by toluene or by anisole no nitrophenols are formed.Since the anisole radical cation is said to add water and toluene preferen- tially gives material derived from the benzyl radical the mechanism (Scheme 5) is H/'OH proposed in which the benzene radical cation (17) undergoes hydrolysis to give (18) from which hydroxyl radicals may be generated. The application of this suggestion to synthetic uses will be interesting.Phenols also arise from the photolysis of a-azohydroperoxides in mixtures of arenes and acetonitrile. The isomer distribu- tion changes when oxygen and not argon is present and this was held to show a change of mechanism away from the formation of aryl radicals and so a distinction from Fenton's reagent or radiolytic sources of hydroxyl radical." In this context it may be appropriate to report that Mishra and Symons9* demonstrated the inter- mediacy of u* radicals (in which the electron is localized to the C-halogen CT* orbital rather than the usual expectation of a v* orbital) in the irradiation of halogenobenzenes (y 6oCosource ca. 1Mrad 77 K). Electrophilic attack of alkylbenzenes by hydrogen peroxide with HF-BF occurs at -60 to -78 "C. Further attack is presumably minimized by the low temperatures 90 (a) K.Tomizawa and Y. Ogata J. Org. Chem. 1981,46 2107; (b)M. K. Eberhardt J. Am. Chem. SOC.,1981,103,3876. 91 T. Tezuka N. Narita W. Ando and S. Oae J. Am. Chem. SOC.,1981,103 3045. 92 S. P. Mishra and M. C. R. Symons J. Chem. SOC.,Perkin Trans. 2 1981 185. Aromatic Compounds 219 and highly acidic condition^.'^ Under circumstances where oxidation may occur quinones may arise from attempts to nitrate phenols by nitrate salts in trifluoroacetic anh~dride,’~ and a variety of interesting products may be obtained under special conditions Thus oxidation of 2-bromo-4,6-di-t-butylphenol (19a) with potassium hexacyanoferrate(II1) in benzene gives 1,4-dihydro-4-bromo-2,4,6,8-tetra-t-butyl-1-0xodibenzofuran (20a) which with methanol or ethanol gives the 4-alkoxy analogues (20b) but with isopropanol provides the fully aromatic derivative (2 1) (Scheme 6) presumably through the 4-isopropoxy species (20c).On the other hand 2-chloro-4,6-di-t-butylphenol (19b) gives 6,6’-bis(2,4-di-t-butyl-6-chloro-cyclohexa-2,5-dienone) (22) and 2,4-di-t-butyl-4-chloro-6-(2,4-di-t-butyl-6-chlorophenoxy)cyclohexa-2,5-dienone(23) the fluorine analogue of which is the sole product of oxidation of 2-fluoro-4,6-di-t-butylphenol by hexacyanofer- rate(111).~’ Benzene seleninic anhydride [(PhSe=O),O] oxidizes phenols specifically giving the o-quinone. Both naphthols afford 1,2-naphthoquinone 2,4- di-t-butylphenol provides 4,6-di-t-butyl-o-benzoquinone, and carvacrol and thymol both give 3-methyl-6-isopropyl-o-benzoquinone.96 The limits of the method are still to be assessed but some substrates such as 2,4-dimethylphenol and o-nitro- phenol do not undergo the reaction.Oxidative cleavage by 30% hydrogen per- oxide of p-cycloalkenyl groups provides hydroquinones from such para-substituted phenols in high (60-90%) yields and may be an appropriate synthetic method.97 Methods to obtain a-naphthols have also been reported. The condensation of diphenylacetaldehyde with diethyl malonate or with P-keto-esters provides the expected a$-unsaturated ester. However the presence of molecular sieves encouraged cyclization to give derivatives of 4-phenyl-1-naphthol [reaction (7); X = C02Et COMe or COPh]:98 Ph2CHCHO + CH,XCO,Et + Ph,CHCH=C(X)CO,Et +@Jx / (7) Ph 1-Aryl-2-benzoylcyclopropanes(24) cyclize under the influence of Lewis acids to give 4-aryltetralones but apparently only under conditions in which the aryl group and usually the benzoyl fragment as well has hydroxyl or alkoxyl sub- ~tituents.’~A method which appears to have more general synthetic potential involves the Michael addition of lithium phthalide to a variety of olefins.The 4-hydroxytetralones which are formed readily undergo acid-catalysed dehydration to form a-naphthols.”’ In the presence of both aluminium chloride and boron ArvcoPh (24) 93 G. A. Olah A. P. Fung and T. Keumi J. Org. Chem. 1981,46,4305. 94 J. V. Crivello J. Org. Chem. 1981 46 3056. 95 M. Tashiro H. Yoshiya and G. Fukata J. Org.Chem. 1981 46 3784. 96 D. H. R. Barton A. G. Brewster S. V. Ley C. M. Read and M. N. Rosenfeld J. Chem. SOC.,Perkin Trans. 1 1981 1473. 9’ D. V. Rao and F. A. Stuber Tetrahedron Lett. 1981 22 2337. G. A. Taylor J. Chem. SOC.,Perkin Trans. 1 1981 3132. 99 W. S. Murphy and S. Wattanasin J. Chem. SOC.,Perkin Trans. 1 1981 2920. loo N. J. P. Broom and P. G. Sammes J. Chem. SOC.,Perkin Trans. 1 1981,465. 220 R. Bolton trifluoride chloromethyl cyanide (chloracetonitrile) attacks phenols to give o-chloroacetylphenols exclusively.'o' The authors make the point that although the reaction conditions seem very similar to those of the Houben-Hoesch reaction under the latter conditions only the p-hydroxyketone is found. It is perhaps worth recalling that the orientation of the Houben-Hoesch reaction like that of the Fries rearrangement may be altered by changing the temperature at which the reaction occurs so that the contribution useful though it is might be most useful in the preparation of thermally unstable hydroxyacetophenones.(19) a; X == Br (20) a; X = Br b; X == C1 b; X = MeOor EtO c X = OPr' (19b) A + Reagent i K,Fe(CN),-C,H Scheme 6 Mixed acid anhydrides are obtained by the decomposition of diazonium borofluorides in acetonitrile in the presence of carbon monoxide sodium carboxy- late and a palladium(0) catalyst [reaction (S)] lo* ArN2+ + CO + RC02-+ ArCOOCOR + N2 (8) Palladium(I1) acetate is important in the synthesis of ortho-substituted aniline derivatives. Acetanilide and rn-and p-substituted analogues form derivatives of (25) which undergo reactions at multiple bonds that involve cleavage of the C-Pd bond and formation of a new carbon-carbon bond (Scheme 7).'03 2-Bromoacetanilide can also provide anthranilic acid derivatives through palladium complexation and subsequent attack by carbon monoxide; yields range between 70% and 90%.104 lo' T.Toyoda K. Sasakura and T. Sugasawa J. Org. Chem. 1981 46 189. lo' K. Kikukawa K. Kono K. Nagira F. Wada and T. Matsuda J. Org. Chem. 1981 46 4413. lo3 H. Horino and N. Inoue J. Org. Chem. 1981,46,4416. D. Valentine jun. J. W. Tilley and R. A. Le Mahieu J. Org. Chem. 1981,46,4614. Aromatic Compounds 221 ~NHCOR CH=CHCOMe Scheme 7 Potassium amide gives o-hydroxyphenylamidines upon reaction with either o-or m-halogenobenzamides and these products on heating give benzoxazoles.The ring-closure occurs as a second stage in this synthetically useful reaction because of the instability of the benzoxazole system to amide ion.'O5 o-Bromo- or o-iodo- styrene oxide with n-butyl-lithium at -78 "Cprovides a preparation of l-hydroxy- benzocyclobutene.106 A new synthesis of benzo( 1,2;4,5)dicyclobutene by reaction of n-butyl-lithium with 2,2',2',5-tetrabromo-p-diethylbenzene(26)has been repor- ted"' and the useful intermediate 1-bromobenzocyclobutene (27) is obtained in 2045% yield from the interaction of bromoform potassium carbonate and cycloheptatriene in the presence of 18-crown-6 ether.lo8 CH,CH ,Br BrQ Br m-,Br CH ,CH ,Br (26) (27) Oxidation of a side-chain as in p-ethylanisole by copper(I1) sulphate and sodium peroxydisulphate in aqueous acetonitrile seems to be a promising route to aldehydes and ketones; in certain systems such as &methoxytetralin aromatization is also Benzhydrol derivatives may be made from benzaldehydes with -I substituents through their reaction with aryltrimethylsilanes in dimethylformamide in the presence of potassium t-butoxide.Labile ethers such as Ar,CHOSiMe are first formed and they cleave to give the alcohol [reaction (9)]:"' KOBut in HCONMe2 ArAr'CHOSiMe3 + ArCHOHAr' ArCHO + Ar'SiMe3 lo' M. I. El-Shiekh A. Marks and E. R. Biehl J. Org. Chem. 1981 46 3256. E. Akgun M. B. Glinski K. L. Dhawan and T. Durst J. Org.Chem. 1981,46,2730. lo' C. K. Bradsher and D. A. Hunt J. Org. Chem. 1981,46,4608. lo* M.R.de Camp and L. A. Viscogliosi J. Org. Chem. 1981,46 3918. lo9 M.V. Bhatt and P. T. Perumal Tetrahedron Lett. 1981,22,2605. 'lo F.Effenberger and W. Spiegler Angew. Chem.,Znt. Ed. Engl. 1981 20,265. 222 R. Bolton The preparation of 2,4-dinitrobenzenesulphonic acid from chloro-2,4-dinitrobenzene and potassium metabisulphite has been studied; the abstract however confuses the product with 2,4-dinitrobenzoic acid.' l1 A condensation between two three-carbon fragments affords a new synthesis of 2,6-disubstituted aniline derivatives. Yields are usually low (30%) but may reach 50% in special instances.l12 The preparation of 1,2,3,4-tetra-t-butylbenzene,and of 2,3,4,5-tetra-t-butyl- biphenyl as well as the analogously substituted furan and pyridine systems has been achieved through the Diels-Alder reaction of (28) with triple-bond systems such as RC=CCO2Me (R = H or Ph) and Me02CCN which provides a Dewar- benzene structure (or Dewar-pyridine structure) from which these compounds may be ~btained."~ (28) Oxidative coupling of arenes to obtain symmetrically substituted biaryls has remained popular since the first commercial synthesis of biphenyl by the thermal dehydrogenation of benzene.Thallium(II1) trifluoroacetate with 10% palladium(@ acetate is reported to be more effective in combination than either reagent is alone; the yields claimed114 certainly make this method of preparing some biaryls very attractive.A peculiar but preparatively useful reaction involves the rearrangement of arylhydrazines of derivatives of benzophenone by polyphosphoric acid. The process seems to have resemblances to the Benzidine Rearrangement so that (29) provides (30) (reaction (lo)].' Benzophenones and acetophenones having a p-hydroxyl function correspondingly give biaryl ethers. *lS6 PPA_ (30) The synthesis of some hydroxy-9,lO-dihydrophenanthrenesrecently reported' l6 relies upon the nucleophilic properties of the carbanions formed during the Birch reduction. Thus the dianion from the reduction of 2,5dimethoxybenzoic acid is alkylated by 2-(3',5'-dimethoxypheny1)ethyl iodide to give 1,4-dihydro-2,5-dimethoxy-l-(3',5'-dimethoxyphenyl)benzoicacid which affords a mixture of "' M.Gisler and H. Zollinger Angew. Chem. Int. Ed. Engl. 1981,20 203. '" P.Camps C. Jaime and J. Molas Tetrahedron Lett. 1981 22 2487. '13 A.Krebs E. Franken and S. Muller Tetrahedron Lett. 1981 22 1675. 'I4 A.D.Ryabov S. A. Deiko A. K. Yatsimirsky and I. V. Berezin Tetrahedron Lett. 1981 22 3793. 'I5 (a)R. Fusco and F. Sannicolo J. Org. Chem. 1981,46,83;(6)ibid. p. 90. K.-D. Krautwurst and W. Tochtermann Chem. Ber. 1981,114,214. Aroma tic Compounds hexahydro-5,7-dimethoxy-2-phenanthrones(31) [reaction (1l)]. Aromatization of (31) to give derivatives of 9,1O-dihydrophenanthr-2-01is achieved with pyridinium perbromide followed by treatment with n-butyl-lithium (Scheme 8). Allyltrimethylsilyl-lithium reacts with keto-acetals to give species from which by treatment with titanium(1v) chloride new benzene rings may be obtained.This promises to be a good general route to derivatives of biphenyl and of 9,lO- dihydrophenanthrene.' l7 CH2CH21 I M&OMe C02H -M&o ' MeOoOMe Me0 / Me0 (31) Reagents i D;o2-;ii Py+W; Me0 Scheme 8 4 Polybenzenoid and Non-benzenoid Systems Polybenzenoid Systems.-The ready loss of iodine and subsequent dimerization by some derivatives of naphthalene such as (32)are solid-state phenomena said1'* to arise from charge-transfer interaction between adjacent molecules in the crystal layers so that the ease of reaction reflects the packing efficiency; substituent effects are the result of influences upon this close packing rather than being electronic in character.The formation of 1,2,3,4-tetrahydrophenanthrenemay occur in the cyclization (BF3-Et20) of either isomer of 4-(naphthy1)butanol. The high susceptibility of the a-position to attack is reflected by a second mechanism unique to 4-(1'-naph-thyl)butanol in which ips0 attack followed by rearrangement is a minor (16%) contributor. 'I9 11' M. A. Tius TetrahedronLett. 1981 22 3335. D. W. Cameron G. I. Feutrell L. J. H. Pannan C. L. Raston B. W. Skelton and A. H. White J. Chem. SOC.,Perkin Trans. 2 1981 610. A. H. Jackson P. V. R. Shannon and P. W. Taylor J. Chem. SOC.,Perkin Trans. 2 1981,286. 224 R. Bolton Reagents i CHGCLi; ii reduction; iii HI or POCI Scheme 9 The unstable 2,3-naphthoquinone has been trapped by cyclopentadiene during its formation from 2,3-dihydro~ynaphthalene.’~’ The synthesis of anthraquinones by the use of isobenzofulvalene (33) analogous to the behaviour of isobenzofuran is described,121 and oquinones (e.g.phenanthraquinone) afford a good general annelation reaction through the formation of the diacetylene diol (34) and ring- closure of the derived diallyl diol (35) (Scheme 9).12* Amongst new and interesting systems Paquette and his colleague^^^^^ have reported the preparation of three derivatives of 114sopropylidenedibenzonorbor-nadiene in which the two benzene rings are dissimilarly substituted. The syntheses themselves are interesting and the influence of the two different aromatic systems upon the orientation of electrophilic attack (epoxidation) of the olefinic bond may have considerable significance in understanding mechanisms of electrophilic addi- tion and considering recent observations in free-radical chemistry (36) (37) ‘Iptycene’ is the suggested generic name of systems such as triptycene p-pentipty- cene {5,7,12,14-tetrahydro- 5,14[ 1’,2‘] 7,12[ 1”,2”]-dibenzopentacene (36)} the o-analogue and the tris-derivative (37).They may be made by methods that exactly parallel the synthesis of triptycene from o-dihalogenobenzenes n-butyl-lithium and anthracene but use ‘diaryne intermediates’ from 1,2,3,4- and 1,2,4,5-tetra- bromobenzene or 2,3,6,7-tetrabromonaphthalenederivative^.'^^ ‘’O V. Horak F. V. Foster R. de Levie J. W. Jones and P. Svoronos TetrahedronLett. 1981 22 3577. R.A. Russell E. G. Vikingur and R. N. Warrener Aust. J. Chem. 1981 34 131. K. B. Sukumaran and R. G. Harvey J. Org. Chem. 1981,46,2740. (a) L. A. Paquette F. Kilnger and L. W. Hertel J. Ore. Chem. 1981 46 4403; (b) R. Bolton J. P. B. Saridall and G. H. Williams J. Fluorine Chem. 1978 11 591; J. Chem. Res. 1977 (S) 24 (M)0373. H. Hart S. Shamouilian and Y. Takehira J. Org. Chem. 1981,46 4427. Aromatic Compounds The addition of tetranitroethylene to anthracene gives 11,11,12,12-tetranitro- 9,1O-dihydro-9,10-ethanoanthracene(38). Hexanitroethane loses dinitrogen tetraoxide readily to form the reagent; (38)analogously gives 11,12-dinitro-9,10- dihydro-9,10-ethenoanthracene, whose chemistry is interesting and will repay fur- ther study.Addition expectedly occurs with cyclopentadiene but nucleophilic displacement by benzylamine gives a zwitterionic product with loss of one nitro group.12' (38) Halogenated derivatives of diphenyl ether have been found among the com- ponents of some Western Australian sea sponges.'26 Although this is not a unique occurrence the incidence of tetrabromo compounds (39) allied to the teratogen (40)suggests a possible natural source of such materials or perhaps the accumula- tion of particular pollutants by the organism. A study of the i.r. spectra of some derivatives of pyrene has led the authors to conclude that some of the more common substitution patterns may be easily recognized by this method.'27 Such a clear distinction is not available by 220MHz n.m.r.studies although 1,6- and 1,8- disubstituted systems could be recognized with difficulty'28" and older methods relied upon empirical and poorly based rules-of-thumb.'286 (39) (40) The synthesis of a klavinone (41 )129a--cand of an allied has been accomplished. The studies of electrophilic substitution of 4H-cyclo- penta[d,e,f]phenanthrene now include sulph~nation,'~~ which was predictably more complicated than bromination or Friedel-Crafts acylation and a study of protiodetritiation which deserves praise because of the small scale of the detailed studie~.'~' The deductions from this second report were somewhat less satisfactory '" K. Baum and T. S. Griffin J. Org. Chem. 1981,46,4811. R. Capon E. L. Ghisalberti P. R. Jefferies B.W. Skelton and A. H. White J. Chem. SOC.,Perkin Trans. 1 1981 2464. '" P. E. Hansen and A. Berg Acta Chem. Scand. Ser. B 1981 35 131. 12* (a)J. Grimshaw and J. Trocha-Grimshaw J. Chem. SOC.,Perkin Trans. 1 1972,1622; (6)H. Vollmann H. Becker M. Corell and H. Streeck Liebigs Ann. Chem. 1937 531 11 ('Da .. . alle 3,8-Derivative hoher schmelzen als die entsprechenden 3,lO-Derivative . ..'). (a) A. S. Kende and J. P. Rizzi J. Am. Chem. SOC.,1981 103 4247; (6) B. A. Pearlman J. M. McNamara I. Hasan S. Hatakeyama H. Sekizaki and Y. Kishi J. Am. Chem. Soc. 1981 103,4248; (c) P. N. Confalone and G. Pizzolato J. Am. Chem. SOC.,1981,103 4251; (d)Z. Ahmed and M. P. Cava Tetrahedron Lett. 1981 22 5239. 130 M. Yoshida M. Kobayashi M. Minabe and K. Suzuki Bull. Chem.SOC.Jpn. 1981 54. 1186. 13' W. J. Archer and R. Taylor J. Chem. SOC.,Perkin Trans. 2 1981,.1153. 226 R. Bolton (41) for there was a clear agreement between the isomer distribution predicted by calculation and those found in hydrogen exchange and in attack by nitric acid in acetic anhydride (where the incidence of addition oxidation and nitrous acid catalysis made the mechanism less certain) but not acylation and bromination which are generally found to be more representative electrophilic processes. Non-benzenoid Systems.-The synthesis of the [101annulene derivative (42) from the previously reported bis-aldeh~de'~~" has been achieved;'32b and trans-15,16-dimethyl-1,4:8,1 l-ethanediylidene[l4]annulene(43) has been prepared and under- goes nitration with copper nitrate and acetic anhydride at the 6-po~ition.l~~ (42) (43) Conventional syntheses of tetrakisdehydro[ 16]annuleno[ 18]ann~lene'~~~ and of the [18][20]'346 and [14][20]134c analogues are reported.Dicyclobuta[a,c]anthracene was obtained by a cyclization between the dianion of dimethylcyclohexene-4,5-dicarboxylic acid and the appropriate derivative of 1,2-bis (bromome t h yl) benzene ; the reaction is presumably general and therefore a useful annelation reaction. 135 Photochemical dimerization of methyl naphthalene-2-carboxylategives (44) from which by removal of the carbomethoxy groups and rearrangement of the (44) X = C02Me Br or H 13' (a)T. L. Gilchrist C. W. Rees D. Tuddenham and D. J. Williams J. Chem. SOC., Chem.Commun. 1980 691; (6)T. L.Gilchrist D. Tuddenham R. McCague C. J. Moody and C. W. Rees J. Chem. SOC., Chem. Commun. 1981,657. 133 W. Huber J. Lex T. Meul and K. Mullen Angew. Chem. Int. Ed. Engl. 1981,20 391. 134 (a) K. Sakano T. Makagawa M. Iyoda and M. Nakagawa Tetrahedron Lett. 1981 22 2655; (6) Y. Yoshikawa M. Iyoda and M. Nakagawa Tetrahedron Lett. 1981,22,2659;(c)Y. Yoshikawa M. Iyoda and M. Nakagawa Tetrahedron Lett. 1981 22 1989. 13' C. W. Doecke and P. J. Garratt J. Chem. SOC.,Chem. Commun. 1981,873. Aromatic Compou nds carbon skeleton through formation of the rhodium complex p,p’dinaphthalene [5,6,11,12-tetrahydro-5,12:6,11-diethenodibenzo[~,e]cyc1o-octene (45)] is obtained after removal of rhodium by tripheny1pho~phine.l~~ At room temperature (45) in turn provides 1,2:7,8-dibenzo-4a,4b,8a,8b-tetrahydrobiphenylene.(45) The synthesis of naphtho[l,8-a,b:4,5-a’,b’]diazulene from [2,2](1,3)-azulenophane was brought about by iodine followed by chloranil. The electronic spectrum shows considerable absorption (E ca. lo2)past 1400 nm further into the red than either the dihydro intermediate or the starting material. The authors concluded from this that the newly formed central bond must contribute to the delocalization although in their argument they seem to come close to confusing resonance structures and tautomer~.~~’ 1,4-Dihydro-l,4-ethenobenzotropylium ion (46) has been obtained through the oxidation of 1-amino-1H-cycloheptatriazol-6-one in the presence of the oxepin (47); the adduct (48) then provides (46) by conventional methods (Scheme N 1 + -* u- 0 (47) Reagent i Pb(OAc) Scheme 10 Carcinogenic Hydrocarbons.-Mechanisms of carcinogenesis by polybenzenoid aromatic hydrocarbons now focus attention upon the arene oxides the dihydro- diols and the epoxides derived from these.Thus the aromatization of 1-(trimethyl- sily1)benzene 1,2-oxide provides phenol and 0-(trimethylsily1)phenol at a rate which is linked to the pH of the system. The subtleties of the process are evident when deuterium labelling is The aromatization of toluene 1,2-oxide and 2,3- oxide are also re~0rted.l~~’ The mechanism of formation of these intermediates seems to have received less attention; the detailed study of the parallel process in Y.Tobe F. Hirata K. Nishida H. Fujita K. Kimura and Y. Odaira J. Chem. SOC.,Chem. Commun. 1981,786. 13’ Y. Fukazawa M. Aoyagi and S. Ho Tetrahedron Lett. 1981 22 3879. ”* T. Nakazawa K. Kubo and I. Murata Angew. Chem. Znt. Ed. Engl. 1981 20 189. (a) J. E. Van Epp jun. D. R. Boyd and G. A. Berchtold J. Org. Chem. 1981 46 1817; (b) H. J. Org. Chem. 1981,46 1948. S.-I. Chao G. A. Berchtold D. R. Boyd J. N. Dynak J. E. Tomaszewski H. Yagi and D. M. Jerina 228 R.Bolton a cyclophane system and the catalysis which cobalt mesotetraphenylporphyrin brings may well be significant. Benz[a]anthracene oxides have now been made optically pure. Thus the (-)-enantiomer of the 8,9-oxide a major initial metabolite was shown to be [8S,9R] by correlation with (+)-trans-9S-bromo-8S(menthyloxyacetoxy)-8,9,10,11-tetrahydr~benz[a]anthracene.'~' The (+)-enantiomer of the 10,11-oxide was found to be (lOS,llR) and that of the 5,6-oxide was (5S,6R).'42The synthesis of the dihydrodiols of benzo-[b]- -[j]- and -[k]-fluoranthenes was achieved by a stereo- specific route from the appropriate tetrahydroketones through reduction dehydra- tion the Prevost reaction allylic bromination dehydrobromination and finally hydrolysis; the route was intended to provide solely trans-diol~.'~~ In contrast Lee and who have used epoxidation of the bay region dihydrodiols of dibenz[a,h]anthracene and of 7-methylbenz[a]anthracene to give syn-diol epoxides were perturbed by the unexpected cis-directing effect of the benzylic hydroxy groups.Both cis-and trans-3,4-dihydroxy-1,2,3,4-tetrahydrophenan-threne have been obtained optically pure the trans-isomer having the (-)-(3R,4R) configuration and the cis-enantiomer being (+)-(3S,4R).'45 Halogenated biphenyl oxides show increased stability towards both acids and bases upon increased extent of halogen sub~titution.'~~ Arene 1,4-oxides which arise from cycloadditions involv- ing furan or benzo[~]furan,'~~~ may be deoxygenated by low-valent forms of iron tungsten or titanium formed from the reaction of the metallic halide with n-butyl- lithium at -78 "C.The single-step process usually gives good yields; 1,4,5,8,9,10- hexamethylanthracene has been prepared by this method.'476 A detailed study of the bonding between polybenzenoid hydrocarbons and DNA that occurs on irradiation (regardless of the intermediates that seem likely to be involved) has taken the pragmatic approach of measuring the uptake of radiolabelled aromatic The application of Longuet-Higgins' calculations'49a to measure the reactivity of various sites in the bay regions of polybenzenoid car- cinogens towards addition has been used to rationalize the orientation of attack and the subsequent reactions of these Those factors which make epoxidation preferred by allowing delocalization of charge also encourage the formation of benzylic carbocations in the subsequent ring-cleavage.The anodic fluorination of benz[a]anthracene involves attack mainly at C-7 with a little of the 12-fluoro isomer and some 7,12-difl~oro-arene.~~~ 3-Methylcholanthrene has been I.Erden P. Golitz R. Nader and A. de Meijere Angew. Chem. Int. Ed. Engl. 1981 20 583. 14' D. R. Boyd K. A. Dawson G. S. Gadaginamath J. G. Hamilton J. F. Malone and N. D. Sharma J. Chem. SOC. Perkin Trans. 1 1981 94. D. R. Boyd G. S. Gadaginamath N. D. Sharma A. F. Drake S. F. Mason and D. M. Jerina J. Chem. SOC. Perkin Trans. 1 1981 2233. 143 S. Amin V. Bedenko E. LaVoie S. S. Hecht and D. Hoffman J. Org. Chem. 1981,46,2573. H. Lee and R. G. Harvey Tetrahedron Left.,1981,22 1657. D. R. Boyd R. M. E. Greene J. D. Neill M. E. Stubbs H. Yagi and D. M. Jerina J. Chem. SOC. Perkin Trans. 1 1981 1477. I. L. Reich and H. J. Reich J. Org. Chem. 1981,46 3721. (a)W. Friedrichsen Adv. Heterocyclic Chem.1980 26 142 182; (6) H. Hart and G. Nwokogu J. Org. Chem. 1981,46,1251. G. M. Blackburn A. J. Flavell L. Orgee J. P. Will and G. M. Williams J. Chem. SOC.,Perkin Trans. 1 1981,3196. (a) H. Longuet-Higgins J. Chem. Phys. 1950 18 265 et seq.; (6) J. P. Lowe and B. D. Silverman J. Am. Chem. SOC. 1981,103,2852. R. F. O'Malley H. A. Mariani D. R. Buhier and D. M. Jerina J. Org. Chem. 1981,46 2816. 14' Aromatic Compounds obtained from the Elbs reaction of l-naphthyl-7-methylindan-4-ylketone; the intermediate 7-methylindane-4-carboxylic acid was prepared from the Diels-Alder adduct of sorbonitrile and cyclopentanone pyrrolidine enarnine by aromatization. 15’ 5 Cyclophanes The recent publications in this field have included some elegant synthetic work.Cyclophane systems are now being extended through their heterocyclic analogues to include macrocyclic ethers and amines which are more properly akin to the crown ethers and whose properties are more correctly discussed in this light. A second direction of expansion is towards metallocene systems. For example ruthenocenophane and ruthenocenoferrocenophane derivatives have been repor- ted. Examples are [3,3](l,l’)ruthenocenophane-2,14-dien-l,l6-dione(49) and [5,5](l,l’)ruthenocenophane-2,14,17,29-tetraen-l, 16-dione (50) which arise from the simple Claisen-Schmidt condensation of ketones (acetone or other methyl ketones) and the metallocene-1,l’-dialdehyde[reactions (12) and (13)]:15* OCHO 2 Ru + 2MeCOMe + Ru Ru (13) oCH0 oCH=CH-co-cH= cHJJ (50) [2.2.2]Paracyclophane [‘T-prismand’ (5 l)]was prepared from p-xylylene chlor- ide in a Wurst-type synthesis.Its major interest at present is the size of the cavity which complexes silver ions very well (K = ca. 200; cf. K = ca. 2 for simple arene~).’~~ Gas-phase pyrolysis has led to the synthesis of 4,16- and 4,13-diaza- [2.2.2.2](1,2,4,5)cyclophane (52) and (53) re~pectively,’~~ and this process was used .by Boekelheide and Sekine successfully in the preparation of c2.2.2.2.2.21-(1,2,3,4,5,6)cyclophane [‘superphane’ (54)]. 155 Staab and Appel have also reported the synthesis and properties of some 4,7-diaza(2,2)para~yclophanes,’~~ and Bock- mann and Vogtle’57 have investigated the synlanti interactions that may be seen in the proton n.m.r.spectra of some dithia[3,3]metacyclophanes.Such temperature 15* P. W. Tang and C. A. Maggiulli J. Org. Chem. 1981,46 3429. 152 S. Kamiyama A. Kasahara T. Izumi I. Shimizu and H. Watanabe Bull. Chem. SOC.Jpn. 1981,54 2079. lS3 J.-L. Pierre P. Baret P. Chautemps and M. Armand J. Am. Chem. SOC.,1981 103,2986. lS4 H.C.Kang and V. Boekelheide Angew. Chem. Int. Ed. Engl. 1981,20 571. 155 Y.Sekine and V. Boekelheide J. Am. Chem. SOC.,1981 103 1777. lS6 H.A. Staab and W. K. Appel Liebigs Ann. Chem. 1981 1065. K. Bockmann and F. Vogtle Chem. Ber. 1981 114 1065. 230 R. Bolton @ / (51) (52) (53) (54) dependence of the ‘H n.m.r. spectrum also occurs with 8,16,24,32-tetraphenyl[2,2,2,2]metacyclophane (55).158 (55) In general the conformation changes occurring with change of temperature and seen in the altered n.m.r.spectrum are the main reason for preparing cyclophanes once the synthetic challenge has been met; however Th~lin”~ has made three new [2,]-p- [4,-,]cyclophane systems and studied their cyclic voltammetric behaviour. The radical anion derived from [2.2.2.2](1,2,4,5)cyclophane has also been investi- gated by Gerson Lopez and Boekelheide,16’ who showed two species to be present. These differed in their extent of association with the gegen-ion (IC), the distinction arising from the different degrees of symmetry of the two systems and the consequent differences in spectroscopic behaviour. (56) Among the more remarkable systems that have been synthesized are the paddle- wheel system (56),[2,2]-4,4’-tran~-stilbenophane (57) and the series of compounds K.Bockmann and F. Vogtle Chem. Ber. 1981 114 1048. B. Thulin J. Chem. SOC.,Perkin Trans. 1 1981,664. 160 F. Gerson J. Lopez and V. Boekelheide J. Chem. SOC.,Perkin Trans. 2 1981 1298. Aromatic Compounds 231 (57) based upon p-terphenyl and exemplified by (58). The photodimerization of (E,E,E)-1,3,5 -tristyrylbenzene produces (56),whose structure was determined by n.m.r. and confirmed by X-ray crystallography. Iodine blocks the course of the dimeriz- ation and gives instead the dicyclobutapyrene derivative (59).16' Conventional syntheses from bibenzyl-4,4'-dialdehyde produced (57) which isomerized to the cis,cis product presumably through a cis,trans isomer.'62 The synthesis of deriva- tives such as [58] allowed interesting changes of the 'H n.m.r.spectrum to be observed with changes of temperature since the substituents in the bridge systems are in an unusually anisotropic en~ir0nment.l~~ Similar n.m.r. studies have been made of [2.2.2.2]cyclophanes with ethylene bridges,'64 of their [2.2.2.2.2.21cyclophane analogues 165 and of [5.S]paracyclophanetetraenessuch as (60).166 [3.3]-Other workers have investigated [3.31(2,6)naphthalenophane~,'~~ (1,5)(2,6)naphthalenophane~,'~~ and [3.2](1,4)naphthalen0phane.'~~Somewhat Ph Ph (59) J. Juriew T. Skorochodowa J. Merkuschew W. Winter and H. Meier Angew. Chem. Int. Ed. Engl. 1981 20 269. D. Tanner and 0.Wennerstrom Tetrahedron Lett.1981 22 2313. K. Bockmann and F. V6gtle. Liebigs Ann. Chem. 1981 467. 164 T. Olsson D. Tanner B.Thulin 0.Wennerstrom and T. Liliefors Tetrahedron 1981 37 3473. 16' T. Olsson D. Tanner B. Thulin and 0.Wennerstrom Tetrahedron 1981 37 3485. T. Olsson,D. Tanner B. Thulin and 0.Wennerstrom Tetrahedron 1981 37 3491. N. E. Blank and M. W. Haenel Chem. Ber. 1981,114,1520. 16' N. E. Blank and M. W. Haenel Chem. Ber. 1981,114,1531. 232 R. Bolton less imaginative synthetic routes led to 1,8,19,26-tetraoxo[8.8](2,6)-naphthalenophane-3,5,2 1,23 -tet~aynel~~ and to 6,21-dioxo-5,22-diaza[ 10.101- para~yclophane,'~' although the interest in the former heterocycle was based upon the unusually large (6.5 A) cavity. Calixarenes continue to be st~died,'~' but the reported properties are disappointing considering their apparent potential.(61) A new system (61) has been obtained by conventional though arduous methods; few resonance interactions are found,17* although this comes as no surprise. Allied to this last system are the triangulenes for which n.m.r. studies suggested a pyramidal structure (62; n = 0 or 1)until sufficiently flexible to form a mobile helical system (62; n = 2).173 OMe and (64) In a section dealing with perseverance in the face of synthetic difficulties one must record studies of the 13C n.m.r. spectra of pre~atenanes,'~~ the synthesis of the [2]prerotaxane (63),17' and the recognition of the distinguishible isomeric [3]catenanes which may be represented by (64).176 169 B.J. Whitlock E. T. Jarvi and H. W. Whitlock J. Org. Chem. 1981.46 1832. 170 H. Okamoto J. Kikuchi and J. Sunamoto J. Chem. Soc. Perkin Trans. I 1981 3125. 17' C. D. Gutsche B. Dhawan K. H. No and R. Muthukrishnan J. Am. Chem. SOC.,1981 103 3782. M. Nakazaki K. Yamamoto andT. Toya J. Org. Chem. 1981,46 1611. 173 D. Hellwinkel A. Gerhard and M. Melan Chem. Ber. 1981 114 86. 174 E. bgemann K. Rissler G. Schill and H. Fritz Chem. Eer. 1981,114,2245. 17' G. Schill and H. Ortlieb Chem. Ber. 1981,114,877. G. Schill K. Rissler H. Fritz and W. Vetter Angew. Chem. hr. Ed. Engl. 1981 20 187.

ISSN:0069-3030    

DOI:10.1039/OC9817800205

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

11 Heterocyclic Compounds By T. M. CRESP Department of Chemistry University College London 20 Gordon Street London WC7 OAJ 1 Introduction The review on heterocyclic compounds for 1981follows the format established last year. It is necessarily highly selective and by design is slanted towards the synthetic aspects of the subject. There can be little doubt that the most significant contribution to the secondary literature of heterocyclic chemistry this year is the Printers Dispute Delayed Specialist Periodical Reports on Heterocyclic Chemistry.’ Its contents will already be familiar to all interested in the field. No author has published more work on heterocyclic compounds than Professor Tetsuji Kametani and two special issues of Heterocycles* mark the occasion of his retirement.2 Three-memberedrings The utility of 2-chloro-oxiranes as the synthetic equivalents of 2-chloroketones has been demonstrated by their reactions with monodentate3 and bidentate4 nucleophiles (Scheme 1). X = SorSe H*N Reagents i Nu-; ii />-R3 X Alkyl-lithiums’ and diethylaluminium benzenethiolate6 both add to vinyl oxiranes (1)with regio- and stereo-control to afford the 1,4-adducts (2) and (3)respectively. ‘Heterocyclic Chemistry’ a Specialist Periodical Report ed. H. Suschitzky and 0.Meth-Cohn The Royal Society of Chemistry London 1980,Vol. 1. Heterocycles 1981,15,special issues Nos. 1 and 2. J. Gasteiger and C. Herzig Angew. Chem. Znt. Ed. Eng. 1981 20 868. J. Gasteiger and C. Herzig Tetrahedron 1981,37 2607.M. Tamura and G. Suzukano Tetrahedron Lett. 1981,22 577. A.Yasuda M.Takakashi and H. Takaya Tetrahedron Lett. 1981,22,2413. 233 234 T.M. Cresp (2) (3) R3 = SPh A kinetic study of the thermal rearrangement of N-pyridino-2-vinylaziridines' leads to the conclusion that the ring expansion (see Annu. Rep. Prog. Chern. Sect. B 1980,77,181) proceeds via a [3.3] sigmatropic rearrangement. With electrophilic acetylenes and olefins the vinylaziridine (5) gives azepine derivatives paralleling the well established ring closure of cis-1,2-divinylcyclopropanesto seven-membered rings For example reaction of (5) with dimethyl acetylenedicarboxylate affords the dihydroazepine (6).' However the adduct (4) from reaction of (5) with p-nitrostyrene undergoes an intramolecular ene reaction below 100 "Cto yield the nitroenamine (7).' Ph Ph YC0,Me (5) /-C0,Me HO 0 (4) (6) 1 Palladium(0)-catalysed carbonylation of the aziridine (8) affords the bicyclic p-lactam (10).The condensation presumably involves attack by the T-ally1 complex (9) onto the aziridine (8) followed by ring closure (Scheme 2).' Vacuum pyrolysis of the lithium salt of the hydrazone (11) yields the thiiranoradialene (12) as a relatively stable crystalline solid." As would be expected (12) is more stable than the other known heteroradialene furanoradialene (13)." The electrochemically generated radical anions from 1,2-diphenylthiiren dioxide (14) and the monoxide (15) decompose at least 3 x lo3times as fast as the radical anion from the acyclic sulphone (16).12 The non-Huckel character of the radical anions of (14) and (15) is suggested to account for at least some of their relative 'H.P. Figeys and R. Jammar Tetrahedron Lett. 1981,22,637. A. Hassner R. D'Costa A. T. McPhail and W. Butler Tetrahedron Lett. 1981 22 3691. H. Alper C. P. Perera and F. R. Ahmed J. Am. Chem. SOC.,1981,103 1289. lo W. Ando Y. Hariu and T. Takata Tetrahedron Lett. 1981 22 4815. l1 J. Julien J. M. Pechine F. Perez and J. J. Piade Tetrahedron Letr. 1980 21 611. l2 A. J. Fry K. Ankner and V. K. Handa J. Chem. SOC.,Chem. Cornmun. 1981 120. Heterocyclic Compounds Reagents i Pd(Ph,P), CO; ii (8) Scheme 2 instability. The contribution from relief of ring strain however remains to be assessed.(14) X = SO2 (16) (17) (15) X = SO 2-Arenesulphonyl-3-aryloxaziridines (17),an increasingly useful class of oxygen- transfer reagents have been shown13 to effect epoxidation of olefins in good yield. Sterically crowded thiaziridines (18) can be isolated at low temperatures from the addition of diazoalkanes to N-sulphonylamines. On warming they decompose to sulphur dioxide and aldimines (Scheme 3).14 R' R2 = But adamantyl I 1 SO + R14N0R2 Scheme 3 l3 F. A. Davis N. F. Abdul-Malik S.B. Awad M. E. Harakal Tetrahedron Lett. 1981 22,917 l4 H. Quast and F. Kees Chem. Ber. 1981,114 774. 236 T.M. Cresp 3 Four-membered Rings General.-Large amounts of azetidine can be obtained by thermal ring closure of the azido-alcohol (19) itself readily pre2ared from acrolein (Scheme 4).*' Dehy-drohalogenation of N-chloroazetidine gives 1-azetine. A colourless liquid at -70 "C iii I Reagents i NaN, HOAc; ii NaBH,; iii Ph,P; iv heat Scheme 4 l-azetine polymerizes at ambient temperatures and on flash vacuum pyrolysis ring-opens to 2-a~abutadiene.'~ A detailed study of the chemistry of the photo- chemically generated Dewar 4-pyrimidones (20) has been rep~rted.'~ P-Ladams.-Volume 4 of 'Topics in Antibiotic Chemistry' concentrates on the synthetic chemistry of p-lactams." It will prove valuable to those already in the field and essential reading to the ever increasing numbers of new disciples. A number of monocyclic p-lactams have been i~olated'~ from bacteria and join the norcaradicins as naturally occurring examples of 'monobactams'.The commercially attractive antibacterial activity of the carbapenems notably thienamycin PS-5,and the olivanic acids continues to catalyse interest in this group of 8-lactams. An otherwise satisfactory synthesis of PS-5p-nitrobenzyl ester (21) is marred by the low yield (16%) of the intermediate (23) from treatment of the 4-acetoxyazetidin-2-one (22) with ethyl 2-lithioa~etate.~' Carbon-carbon bond formation at C-4 by replacement of an acetoxy-group can be effected more satisfac- Is J. Szmuszkovicz M. P.Kane L. G. Laurian C. G. Chidester and T. A. Scahill J. Org. Chem. 1981 46 3562. l6 J. C. Guillemin J. M. Denis and A. Lablache-Combier J. Am. Chem.SOC.,1981 103,468. S. Hirokami T. Takahashi M. Nagata Y. Hirai and T. Yamazaki J. Org. Chem. 1981,46 1769. Topics in Antibiotic Chemistry Vol. 4 The Chemistry and Antimicrobial Activity of New Synthetic @-Lactam Antibiotics ed. P. Sammes John Wiley and Sons (Halstead Press) New York 1980. I9 A. Imada K. Kitano M. Muroi and M. Asai Nature 1981 289 590; R. B. Sykes C. M. Cimarusti D. P. Bonner K. Bush D. M. Floyd N. H. Georgiopapadakou N. H. Koster W. C. Liu W. L. Parker P. A. Principe M. L. Rathaum W. A. Slusarchyk W. H. Trejo and J. S. Wells ibid.,p. 489. T. Kametani T. Hondo A. Nakayama Y. Sasakai T. Mochizuki and K. Fukumoto J. Chem. SOC. Perkin Trans. 1 1981 2228. Heterocyclic Compounds 237 CO,PNB (21) PNB = p-nitrobenzyl (22) NaH,THF 0 "C 0JiAc + PhCH,O,C 0qo C0,Na (27) torily by using nucleophiles such as Zn-free A1 eno1ates,21 tertiary carbanions,22 or silyl enol For example the key intermediate (26) in the synthesis of 1-carbadethia-2-oxocephem4-carboxylate (27) was prepared in high yield (83 YO) by condensation of the sodium salt of the malonate (25) with 4-acetoxy-2- azetidinone (24).24 Displacement of the acetoxy-group from (24) with carboxylate2' and nucleophiles has also been studied.Approaches to the carba-1-penem system include C-1-C-2 bond formation by intramolecular Wittig rea~tion,~' aldol condensation,28 and Horner-Wittig reac-tion*' (Scheme 5). The double bond isomer (28) of thienamycin has negligible antibacterial a~tivity.~' The phosphorane (29) has been prepared and shown to be a versatile intermediate which is readily convertible using the methodology developed by the Woodward group into a number of 2-penems (30) (Scheme 6).31The 2-aza-1-thiacephem (31) undergoes smooth desulphurization to the relatively unstable (attempted hydrogenolysis of the p-nitrobenzyl ester led only to decomposition) azapenem (32).32 The achiral zwitterionic species (33) is proposed as an intermediate in the ring contraction.The aza analogues (34) of clavulinic acid in which the enamine C. W. Greengrass and M. S. Nobbs Tetrahedron Lett. 1981,22 5339. 22 C.W.Greengrass and D. W. T. Hoople Tetrahedron Lett. 1981 22 1161. 23 A.G. M. Barrett and P. Quayle J. Chem. SOC.,Chem. Commun. 1981 1076. 24 C. W. Greengrass and D.W. T. Hoople Tetrahedron Lett. 1981,22 5335. '' M. M. Carnbell and V. J. Jasys Heterocycles 1981,16 1487. K.Prasad H. Hamberger P. Stutz and G. Schulz Heterocycles 1981,16,243. 27 R.Sharma and R.J. Stoodley Tetrahedron Lett. 1981 22,2025. H. Hirai K. Fujimoto Y. Iwano T. Hiraoka T. Hata and C.Tamura Tetrahedron Lert. 1981,22,1021. 29 B.Venugopalan A. B. Hamlet and T. Durst Tetrahedron Lett. 1981 22 191. 30 D. H. Shih and R. W. Ratcliffe J. Med. Chem. 1981 24. 639. 31 A.Longo,P. Lombardi C. Gandolfi and G. Franceschi Tetrahedron Lett. 1981 22 355. 32 G.Johnson and B. C. Ross J. Chem. SOC., Chem. Commun. 1981,1269. 238 T.M. Cresp . .. ... 1 11 111 mC0,Et 0 C02Bu‘ C02Bu‘ C0,PNB PNBOzC PNB0,C v 0q.’ R’ Reagents i O,,CH2C12-CF3C02H; ii Me$; iii NaHCO,; iv C,H,,N-AcOH; v NaH THF Scheme 5 CO H (28) is stabilized by forming part of a triazole ring have been synthesized by intramolecular cycloaddition of the azides (35).33 Et*qsa i,ii ~ 0 0 CO,R’ CO R’ iii (29) \r//”h3 C0,R’ (30) Reagents i AgNO,; ii R’COCl; iii toluene reflux Scheme 6 33 D.Davies and M. J. Pearson J. Chem. SOC.,Perkin Trans 1 1981 2539. Heterocyclic Compounds 239 Replacement of the sulphur of the cephem nucleus by oxygen results in 1-oxacephalosporins with increased antibacterial activity and reduced resistance to p-lactamase~.~~ An elegant method for the preparation of the 1-oxacephalosporin (36) from the cephem (37) uses the 2-methoxy-group to facilitate opening of the dihydrothiazine ring of (37).Subsequent ring closure is directed by the 7a-amido- group to the p-face of the azetidinone ring.35 Ph I C0,PNB C0,PNB C0,PNB (33) ggR 0 (34) (35) H PhH ,CCON __ CO CH Ph z (37) A number of new synthetic approaches to p-lactams have been reported. Allene dianions (38) resulting from a Shapiro reaction condense with aldehydes to provide the amides (39) which can be readily converted into the a-methylene-p-lactams (40) (Scheme 7).36 1,3-Dipolar cycloaddition of nitrones (41) with trans-1-cyano- 2-nitroethylene gives the two isomeric isoxazolidines (42) and (43). Phptolysis of (42) yields the trans-p-lactam (44) which can be isomerized to a 1:1 mixture of (44) and the thermodynamically more stable cis-isomer (45) by prolonged irradi- ation (Scheme Q3’ Cleavage of the cyclobutene ring of the photoisomer (46) of 4-methyl-2-pyridone gives the p-lactam (47) which has the same ring stereochemistry as the olivanic acids (Scheme 9).38 4 Five-membered Rings 3-Methoxyfuran readily undergoes cycloaddition reactions with electron deficient dienophiles with regio- and stereo-control to give endo-adducts (Scheme 34 K.Murakami M. Takasuka K. Motokawa and T. Yoshida J. Med. Chem. 1981,24,88. 3s J. L. Pfeil S.Kukolija and L. A. Paquette J. Org. Chem. 1981 46 827. 36 R. M. Adlington A. G. M. Barrett P. Quayle and A. Walker J. Chem. SOC.,Chem. Commun. 1981 404. 37 A. Padwa K.F. Koehler and A. Rodriguez J. Am.Chem. SOC.,1981,103,4974. J. Brennan J. Chem. SOC.,Chem. Commun. 1981 880; W. J. Begley. G. Lowe A. K. Cheetham and J. M. Newsam J. Chem. SOC.,Perkin Trans. 1 1981,2620. 39 A. Murai K. Takahashi H. Taketsuru and T. Masamune J. Chem. SOC.,Chem. Commun. 1981,221. 240 T.M. Cresp NR' A H2C=C=C / (38) 'O-?H Reagents i Bu"Li DME;ii R'CHO; iii Bu"Li THF; iv TsCl Scheme 7 Bu' But H Bu' I I Ph 0-+ ph=P NO2 CN But \ iii 4 7 Ph Reagents i ; ii MeOH hv;iii hu NO* Scheme 8 Me Me A H-&.H -+ ii iii OH M:w 0 H 0 (46) (47) Reagents i hv;ii Oj MeOH -78°C; iii NaBH Scheme 9 Heterocyclic Compounds 241 Me0 Y = COR or CN Reagents i. Et,O 0-20 "C Scheme 10 Intramolecular cycloadditions involving furans demonstrates the ability of furan to act either as a dienophile by reactions with electron deficient dienes4' or as a diene in the intramolecular trapping of benzyne~.~' The improved yields of the tetramer (48) obtained from the condensation of acetone and furan resulting from addition of metal salts has been attributed to pH changes rather than a metal template eff e~t.~~ Oxidation of the furan rings of the tetramer (48) with m-chloroperoxyben- zoic acid proceeds in remarkably high yield (87%) to afford the octaketone (49).Hydrogenation gives the highly symmetrical macrocycle (50). The hexamer corresponding to (48) can be converted by the same method into a dode~aketone.~~ Acid catalysed addition of methoxyurethanes (51) to furan gives aminofurans (52).44*45 A two-step preparation of pyridoxine (54)from the aminofuran (53)demon-strates the synthetic utility of this reaction."" (48) (49) R' 40'' I SN/R \ 2 C0,Me C0,Me (51) R' (53) (54) *O H.Kotsuki A. Kawamura and M. &hi Chcm. Lea 1981,917. *' W. M. Best and D. Wege TetrahedronLett. 1981,4877. 42 M. De Sousa Healy and A. J. Rest J. Chem. Soc. Chem. Commun. 1981,149. *' P. D. Williams and E. LeGoff J. Org. Chcrn. 1981,46,4143. T. Shono Y. Matsumura K. Tsubata and J. Takata Chem. Lett. 1981 1121. 242 T.M. Cresp cis-2,5-Disubstituted tetrahydrofurans can be prepared with a high degree of stereocontrol by the iodocyclization of y,S-unsaturated ethers when the ether contains a group R (see Scheme 11) that is sufficiently bulky to disfavour the oxonium intermediates (53 but not so large as to prevent cyclization.The 2,6-dichlorobenzyl group was found to be the most sati~factory.~~ R2+i3 -R2&i3 I Reagents i Iz MeCN 0 “C Scheme 11 Di- and tri-t-butylpyrroles on reaction with tetrafluoroboric acid yield the first examples of stable protonated pyrr01es.~~ Azoalkenes derived from dichloroacetal- dehyde-methoxycarbonylhydrazonegive addition elimination products (56) with 1,3-dicarbonyl compounds. Conjugate addition to (56) occurs in the presence of excess 1,3-dicarbonyl compound and the resultant 2:1adducts (57) can be cyclized to N-aminopyrroles (58).48 Other pyrrole syntheses include the deoxygenation of 4H-1,2-oxazines with iron carbony1s4’ and the rearrangement of N-benzyl-N-(2-benzylaminocyclopropyl)-N-benzylideneammoniumions.” NMe2 (59) 45 V.Asher C. Becu M. J. 0.Anteunis and R. Callens TetrahedronLett. 1981 22 141. 46 S.D.Rychnovsky and P. A. Bartlett J. Am. Chem. SOC., 1981,103 3963. 47 R.Gassner E. Krunbholz and F. W. Steuber,Justus Leibigs Ann. Chem. 1981 789. T. L. Gilchrist B. Parton and J. A. Stevens Tetrahedron Lett. 1981,22 1059. 49 S. Nakanishi Y. Shirai K. Takahoshi and Y. Otsuji Chem.Lett. 1981,869. so H.Quast W. van der Saal and J. Stawitz Angew. Chem. Int. Ed. Eng. 1981,20 588. Heterocyclic Compounds N-(N,N-Dimethy1amino)pyrrolecan be lithiated at C-2 and the derived Grignard reagent (59) condensed with pyridinethiol esters to provide after removal of the amino protecting group 2-acylpyrroles.” The amino protecting group will undoubtedly prove useful in other applications however protection has been shown to be unnecessary in the aforementioned reaction.52 Alkylation of l-methyl-2- pyrrolyl-magnesium bromide and -zinc chloride with aromatic halides proceeds in good yield in the presence of palladium-phosphine complexes as catalyst~.’~ Electrophilic substitution of pyrrole in the gas phase gives predominantly 3 -substitution indicating that the usually observed 2-substitution of pyrrole is in part a result of medium eff e~ts.~~ N-Phenylsulphonylpyrroleundergoes Friedel-Crafts acylation exclusively at the 3-position.The phenylsulphonyl group is readily removed thus providing a convenient synthesis of 3-acylated pyrr~les.~’ For electrophilic substitution via metalation at the 2-position of pyrroles and indoles N-protection with the t-butoxycarbonyl group appears to offer advantages over use of the benzenesulphonyl gro~p.’~ A study of the acid-mediated rearrangement of acylpyrroles suggests that the mechanism may involve the 1,2-acyl shift of C-protonated pyrr01es.~’ Condensation of the dianions (60) from 2-bromoanilines with biselectrophiles provides an indole synthesis with complete regio-control.For example condensa- tion of (61)with 2-chlorocyclohexanone affords the indole (62).” Under hydrofor- mylation conditions using supported rhodium as catalyst 2-nitrostyrene is conver- ted into 3-methylindole in high yield.59 The synthesis of 4-substituted indoles and R (60) M = Li (62) (61) M = Li X = OMe R = COCF3 200 “C 51 G.R. Martinez P. A. Grieco and C. V. Srinvasan J. Org. Chem. 1981.46 3760. 52 K. C.Nicoloau D. A. Claremon and D. P. Papahatjis Tetrahedron Lett. 1981,22,4647. 53 A. Minato K. Tamao T. Hayashi K. Suzuki and M. Kumada Tetrahedron Lett. 1981,22,5319. 54 M. Speranza J. Chem. SOC.,Chem. Commun. 1981,1177. 55 R. X.Xu H. J. Anderson N. J. Gogan C. E. Loader and R. McDonald Tetrahedron Lett. 1981 22,4899;J. Rokach P. Hamel and M. Kakushima ibid. p. 4901. 56 I. Hasan E. R. Marinelli L. C. Lin F. W. Fowler and A. B. Levy I. Org. Chem. 1981,46 157. 57 J. R.Carson and N. M. Davis I. Org. Chem. 1981,46 839. 58 P. A. Wender and A.W. White Tetrahedron Lett. 1981,22 1475. 59 E.Ucciani and A. Bonfand J. Chem. SOC.,Chem. Commun. 1981,82. 244 T. M.Cresp their elaboration to the ergot alkaloids (see Annu. Rep. Prog. Chem. Sect. B 1980 77 188) has been reviewed.60 The key step in an extremely elegant synthesis of lysergic acid6* is thermolysis of the indole (63) to give the tetracyclic intermediate (64) by intramolecular cycloaddition 0; the in situ diene generated by a retro-Diels- Alder reaction. It is noteworthy that the methodology allows the indole nucleus to be kept intact throughout the synthesis. Flash vacuum-pyrolysis of the product (65) from the condensation of pyrrole-2-carboxaldehyde with Meldrum’s acid constitutes a high yielding and convenient preparation of the interesting heterocycle pyrrolizin-3-one (66).62 l-Pyrroline (68) G oOY 1;:;:;rr Q H 0 0 (65) (66) THF CICOR reflux A 0’ R can be obtained in solution extremely easily by distillation of a tetrahydrofuran solution of the trimer (67).At -78 “Ctrimerization is slow and (68) can be trapped for example by acylating agents to yield N-a~yl-2-pyrrolines.~~ The claima that the 2H-imidazole (69) is a product of the reaction between benzilmonohydrazone (70)and S4Nwas always suspect in view of the alleged thermal stability of (69). It has now6’ been shown that the product is the mixed azine (71). The mechanism of the formation of benzo[b]thiophens from the reaction of benzyne with thiophens appears somewhat surprisingly to involve a 1,3-cycloaddi- tion.66 A full and detailed account of the formation of the two didehydrothiophens (72) and (73) from the flash vacuum-thermolysis of the appropriate thiophen anhydrides has been rep~rted.~’ Oxidation of the bishydrazone (74) in the presence 6o A.P. Kozikowski Heterocycles 1981,16 267. W. Oppolzer E. Francotte and K.Battig Helv. Chem. Actu 1981,64478. 62 H. McNab I. Org. Chem. 1981,46,2809. G. A. Kraus and K. Neuenschwander J. Org. Chem. 1981,46,4791. 64 M. Tashiro and S. Mataka Heterocycles 1976 4 1243. 65 S. T. A. K. Daley and C. W. Rees Tetrahedron Lerr. 1981,22,1759. 66 D. D. Mazza and M. G. Reinecke J. Chem. SOC.,Chem. Commun. 1981,124. 67 M. G. Reinecke J. G. Newsom and L.-J. Chen. J. Am.Chem. Soc. 1981,103,2760. Heterocyclic Compounds CH,Ph Ph Ph Ph Ph I \F-=( (79) (80) (81) of trapping agents indicates that the strained acetylene (75) has a finite lifetime.68 Heating the 3-azidothiophen (76) in refluxing xylene gives rise to two interesting and not often observed modes of reaction.Coupling of the azide groups of (76) followed by nitrogen extrusion gives the pyridazine (77) whereas decomposition of the vinyl azide to a vinyl nitrene followed by loss of the thiophen aromaticity and consequent elimination of acetylene leads to formation of the isothiazole (78).69 Sensitized photocycloaddition of benzo[b]thiophens to dimethyl acetylenedicar- boxylate gives different products depending on the frequency of the irradiating light.70 Analogous cycloadditions with benzisothiazoles have also been studied." It has previously been suggested that alkali-metal reduction of the silacyclopen- tadiene (79) gives the tetra-anion (80).13C-n.m.r. data has now been produced that provides convincing evidence for the formation of this highly charged heter~cycle.~' Condensation of the organoaluminium reagents derived from the reaction between trimethylaluminium and 1,2-diaminoethane 1,2-diaminobenzene or 2-mercaptoaniline with esters provides a high yielding preparation of 2-imidazolines benzimidazoles and benzothiazoles (Scheme 12).72 Comparatively little work has been reported on the chemistry of anions derived from the important 2-imidazoline system. The successful alkylation with a variety of electrophile~'~ of the anion 68 J.M. Bolster and R. M. Kellog. J. Am. Chem. Soc. 1981,103 2868. 69 C. J. Moody C. W. Rees and S. C. Tsoi J. Chem. SOC.,Chem. Commun. 1981,550. 'O S. R. Ditto P. D. Davis and D. C. Necken Tecruahedron Len. 1981 22 521; M. Sindler-Kulyk and D. C. Neckers ibid. pp. 525 and 529; M. Sindler-Kulyk D. C. Neckers and J. R. Blount Tetrahedron '' D. 1981,37,3377. H. OBrien and D. L. Breeden J. Am. Chem. Soc. 1981,103,3237. 72 G. Neef V. Eder and G. Sauer I. Org.'Chem. 1981,46,2824. l3 M. W. Anderson R. C. F. Jones and J. Saunders Tetrahedron Lett. 1981,22.261. 246 T.M. Cresp i,ii ~ T2R3<Nr:l R 2* X X = NH:! or SH Reagents i Me,Al; ii R*CO,Me Scheme 12 derived from the imidazoline (81) should arouse interest in the synthetic potential of this system.Imidazole and benzimidazole react with vinyl chloroformate and phenyl chloroformate to give the expected Bamberger cleavage products which undergo subsequent ring-cleavage to the corresponding 2(3H)-imida~olones.~~ 43-Dihalo-2(3H)-imidazolones (82) are available from trihaloimidazoles by alkyla- tion on both nitrogens and base treatment of the resultant imidazolium salts (Scheme 13).75 The chemistry of benzimidazoles and their derivatives has been reviewed in the Weissberger-Taylor series.76 n (82) X = ? Reagents i RiSO,; ii (R$O)’BF;; iii NaOH Scheme 13 A report describing the synthesis of the diaza-azulenes (87) by the condensation of the bis-sulphoxides (83) with the amino-fulvene (84) has been found to be in error.77 The starting materials are actually the sulphones (85) the expected products of peroxide oxidation of 1,3,4-thiadiazoles and the products are the fulvenes (86) and not the previously reported diazo-azulenes (87).Reaction of 3-diazo-4-methyl-5-phenylpyrazole(88) with electron-rich olefins proceeds by an initial 1,3-cycloaddition followed by rearrangement. For example reaction of (88) with 1,l-dimethoxyethene gives the 1,3-dipolar cycloadduct (89) which rearranges slowly and loses methanol to yield the pyrazolotriazine (90).78 Electrolysis of CHNMe N-N N-N R\SXSAS/R 6 RO2SXs~SO2R II 02 0 (84) (85) (83) 74 R. F. Pratt and K. K. Kraus Tetrahedron Lerr. 1981,22,2431. 75 H. Wamhoff W. Kleimann G. Kunz and C. H. Theis Angew. Chem. Int.Ed Eng. 1981 20 612. 76 ‘Benzimidazoles and Congeneric Tricyclic Compounds’ P. N. Preston M. F. G. Stevens and G. Tennant (Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’) Wiley-Interscience New York 1981 VoI. 40 parts 1 and 2. 77 A. J. Boulton and A. K. A. Chong J. Chem. Soc. Chem. Commun. 1981,736. ’’ A. Padawa and T. Kumagai Tetrahedron Lett. 1981,22 1199. Heterocyclic Compounds Me2NS0 RSO N* + Me#y"'7 OMe J=-N Ph urazoles (9 1) provides a simple and efficient preparation of 1,2,4-triazoline-3,5- diones (92).79 The method allows for the isolation of the triazolinediones (92) free from by-products and if desired they can be trapped as Diels-Alder adducts in situ. NA Rf:x,. R'yR' %iN-R00 NYo 0 R3 Ph LNP Me 0 (95) Both gas-phase thermolysis" and photolysis'l of 2-oxazoline-5-ones (93) induces decarbonylation to afford acetimides (94).On thermolysis the ally1 oxazolinone (95) undergoes a 1,3-sigmatropic rearrangement to (96) prior to decarbonylation." Photolysis of (96) regenerates (95) via a 1,2-~igmatropic rearrangement. The chemistry of 2-oxazoline-5-ones has been reviewed.82 Metalation and alkylation of 3,5-dimethylisoxazole occurs on the 5-methyl group. A second metalation- alkylation sequence results in regiospecific alkylation or the 3-methyl group and subsequent hydrogenation of the isoxazole ring completes the introduction of a useful 1,3-diketone equivalent (Scheme 14).83 The chemistry and pharmacology of 79 H. Wamhoff and G.Kunz Angew. Chem. Inr. Ed. Engl. 1981,20,797. S. Jendrzejewski and W. Steglich Chem. Ber. 1981,114 1337. A. Padawa M. Akiba L. A. Cohen and J. G. MacDonald Tetrahedron Lett. 1981,22,2435. A. K.Mukerjie and P. Kumar Heterocycles,1981,16,1995. 83 D. J. Brunelle Tetrahedron Letr. 1981 22 3699. 248 T.M.Cresp 0 i 0-N ii. iii 0-N ,Ed Reagents i NH,OH; ii Bu"Li; THF -78 "C; iii E'; iv Bu'Li Et,O -78 "C; v E"; vi [HI Scheme 14 the well known psychoactive isoxazole muscimol(97) is the subject of an authorita- tive reviews4 and a new synthesis of (97) in three steps from propargyl chloride has appeared.*' (97) (98) (99) (100) (101) Under acidic conditions the oxime from the ketone (98) is converted into the 4,5-dihydroisoxazole (99); the protonated triazole ring of the oxime from (98) providing a good leaving group.In the absence of a good leaving group as in the oxime from the unsaturated ketone (loo) protonation on the cyclopropane ring leads to formation of the oxazine (101).86 1,2-Oxathiolan (102) has been isolated for the first time. N-(3-hydroxypropy1thio)phthalimide (103) gives a non-volatile compound probably a cyclic oligmer which on standing yields (102).87 The use of acyl-amidines to prepare (102) R (104) " P. Krosgaard-Lanen L. Brehm and K. Schumburg Acfa Chem. Scad. Ser. B,1981,35,311. B. E. McCarry and M. Savard TetrahedronLett. 1981,22,5153. 86 C. N. Rentzea Angew. Chcm. Inr. Ed. En& 1981,20,885. " A. P. Davis and G. H. Whitham I. Chem. Soc. Chem. Commun.1981,741; L. Carlsen H. Egsgaard, G. H. Whitham and D. N. Harpp ibid. p. 742. Heterocyclic Compounds 249 C02Et R’ NHCH< >N+< R2 SMe CN R’ (1Ob) (107) (110) five-membered heterocycles (see Annu. Rep. Prog. Chem. Sect. By1980,77 192) has been extended to the synthesis of triazolo[l,5-a]pyridines (104) and the triazolo[ 1,s -a]isoquinoline (105).” Cyclization of the isothiosemicarbazones (106) provides a facile entry into the triazolo[ lY5-c]pyrimidines (107).89 A detailed review describes the progress since 1961 in the chemistry and in the understanding of the biological properties of 2- 4- and S-thiazolidinone~.~~ A potentially general route to 1,3,4-thiazolines (110) involves the condensation of the diazabutadienes (109) with the thiones The novel heterocycle (112) containing a silicon-carbon double bond is an intermediate in the reaction of (111) with hindered bases.The tricyclic product (113) resulting from dimerization of (112) is isolated from the reaction.92 5 Six-membered Rings Metalation occurs at the 4-position of 3-methoxy-5-(pivoloylamino)pyridine(114)93 and 3-aminocarbonylpyridines(115)94*9’ and at the 3-position of 2-aminocarbonyl-pyridines (116).95 These results together with a number of others reported recently make direct metalation of the pyridine ring a useful method for the preparation 88 Y.-I. Lin and S. A. Lang Jr. J. Org. Chem. 1981,46 3123. 89 C. Yamazaki J. Org. Chem. 1981,46,3956. 90 S. P. Singh S. S. Parmar K. Raman and V. I.Stenberg Chem. Reo. 1981,81 175. 91 S. H. Askari S. F. Moss,and D. R. Taylor J. Chem.SOC.,Perkin Trans. 1 1981.360. 92 W. Clegg U. Klingebiel G. M. Sheldrick and P. Werner Angew. Chem. Int. Ed. Engl. 1981,20,384. 93 Y. Tamura M. Fujita L.-C. Chen M. Inoue and Y. Kita J. Org. Chem. 1981 46 3564. 94 J. Epsztajn Z. Berski J. Z. Brzezihski and A. J6iwiak Tetrahedron Lett. 1980,21,4739. 95 A. R. Katritzky S. Rahimi-Rastgoo and N. K. Ponkshe Synthesis 1981 127. 250 T. M. Cresp of substituted pyridines. They show that addition of organometallic reagents across the C=N bond need not be the major reaction when the carbon anion is stabilized. Acid catalysed rearrangement of the dihydro-oxazine (117) in the presence of alcohols leads to the pyridine-1-oxide (118).96 This method is one of the few useful alternatives to the usual method of N-oxidation of pyridines.N 0N WN COBu‘ N0 The 2-chloroquinoline-3-carbaldehyde(119) and related compounds easily pre- pared from N-arylacetamides under Vilsmeier formylation conditions have been shown to possess considerable potential for the synthesis of fused q~inolines.~’ The first part of an authoritative four-part series of monographs on isoquinolines covers the properties and reactions of simple isoquinolines synthetic and natural sources of the isoquinoline nucleus the biosynthesis of the isoquinoline alkaloids and the synthesis and reactions of quaternary isoquinolinium salts.’* Electrophilic substitu- tion at C-1of isoquinolines and reduced isoquinolines is usually achieved through stabilized anions in the Reissert reaction.The poor nucleophilicity of these anions limits the usefulness of this reaction. Surprisingly electrophilic substitution can be readily achieved in high yield with a wide range of electrophiles with the anion from the pivalylamide (l2O).” Arsabenzene undergoes electrophilic substitution in the 2-and 4-positions the electropositive heteroatom being comparable to that of an activating ortho-para group on a benzene ring.”’ 1,2,3-Triazine (121) has been prepared for the first time by nickel peroxide oxidation of N-aminopyrazole.”’ Although the extent of .rr-electron delocalization 96 T. L. Gilchrist G. M. Iskander and A. K. Yagoub J. Chem. SOC.,Chem. Commun. 1981,696. 97 0.Meth-Cohn B.Narine B. Tarnowski R. Hayes A. Kayzad S. Rhouati and A. Robinson J. Chem. SQC.,Perkin Trans. 1 1981,2509. 98 ‘Isoquinolines’ Part 1 ed. G. Grethe (Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’) Wiley-Interscience New York 1981 Vol. 38. 99 J.-J. Lohmann D. Seebach M. A. Syfrig and M. Yoshifuji Angew. Chem. Int. Ed. Engl. 1981 20 128. 100 A. J. Ashe 111 W.-T. Chan T. W. Smith and K. M. Taba I. Org. Chem. 1981,46,881. 101 A. Ohsawa H. Arai H. Ohnishi and H. Igeta J. Chem. SOC.,Chem. Commun. 1981 1174. Heterocyclic Compounds 251 N-CN -* (122) (123) (124) and the chemistry of (121) remains to be evaluated it is as expected a stable compound. The condensation of N-cyanocarbamimidates (122) with chloromethyl- eneiminium salts (123) gives substituted 1,3,5-triazines (124) in excellent yields and represents an attractive route to this class of compounds.’02 4-0xo-5,6-dihydro-1,2(4H)-oxazines (125) can be readily prepared from 1,3- diketones.On heating in refluxing xylene they undergo an interesting rearrangement to 3-0x0- 1-pyrroline-1-oxides (Scheme 15). ‘03 2-Imino-2,3-dihydro- 1,3 -thiazines (128) can be prepared by condensation of azabutadienes (126) with isothiocyanates (127).lo4 (125) Reagents i NaNO, AcOH; ii toluene reflux Scheme 15 (128) The utility of 1-azabutadienes in the synthesis of six-membered-ring heterocycles (see Annu. Rep. Prog. Chem. Sect. B 1979,76,238) has been further demonstrated by a synthesis of 1,2,6-thiadiazine~,’~~ The 2,3-dihydro-1,2-thiazine(129) one of the products resulting from the addition of (Z)-3-bromoacrylic acid to the thiazine CO,Et 0...,N C02Et (130) C02Et (129) (131) lo’ R. L. N. Harris Synthesis 1981 907. lo3 C. Deshayes and S. Gelin Tetrahedron Lett. 1981,22,2557. ‘04 Y. Oshiro T. Hirao N. Yamada and T. Agawa Synthesis 1981 896. J. Barluenga. J. F. L6pez-Ortiz M. Tomis and V. Gotor J. Chem. SOC.,Perkin Trans. 1 1981 1891. 252 T.M. Cresp (130).'06 undergoes photorearrangement to the fused cyclopropathiazolidine (131).'07 Metal acetylacetonates catalyse the reaction of 1,3-diketones with dicyanogen to provide an efficient route to substituted pyrimidines (Scheme 16).'08 R 00 A Me*coNH2 C2N2 + UR "YN H2N%R COMe Reagent i M(acac) Scheme 16 6 Seven-membered and Larger Rings Few areas of organic chemistry can have become so popular as quickly as crown ethers.A comprehensive review of the contributions to the area in 1980 would have covered in excess of 250 papers. Under the title of 'Host Guest Complex Chemistry' much of the field up to 1980 has been authoritatively reviewed. The areas covered include the concept of 109a and structural requirements f ~ r ~ complexation in naturally occurring and synthetic ionophores a discussion of the complexation of uncharged molecules and anions by crown-type host the dynamic aspects of ionophore mediated membrane transport,"" and a dis- cussion of ligand complexes as model systems for enzyme catalysis."0c Full details of the interesting photoresponsive crown ethers have appeared"' and the area is one important direction this field will take.Crown ethers containing 1'4-dihy- dropyridines continue to be developed as synthetic equivalents of NAD(P)H for asymmetric reductions.'12 5H-Dibenz[c,e]azepine not unexpectedly exists in the imine form (132) rather than the amine form (133).'13 Detosylation of the N-tosyl azepine (134) yields the stable 1H-azepine (135)' which is stabilized by intramolecular hydrogen bonding. '14 A review on thiepin chemistry covers the major advances since 1970."' Benzamidine reacts with sulphur dichloride under basic conditions to give the 3,7-diphenyl-1,5-dithia-2,4,6,8-tetrazocine(136).'16 '06 R. W. McCabe D. W. Young and G.M. Davies J. Chem. SOC.,Chem. Commun. 1981,395. lo' P. B. Hitchcock R. W. McCabe D. W. Young and G. M. Davies I. Chem. SOC.,Chem. Commun. 1981,608. lo* R. Koster and G. Seidel Angew. Chem. Int. Ed. Engl. 1981,20,972. (a) D.J. Cram and K. N. Trueblood Top. Cum Chem. 1981 98 43; (b)F. Vogtle H. Sieger and W. M. Miiller ibid. p. 111. 'lo (a) R. Hilgenfeld and W. Saenger Top. Cum. Chem. 1981 101 1; (6) G.R. Painter and B. C. Pressman ibid. p. 83;(c) R. M. Kellog ibid. p. 111. 'I' S.Shinkai T. Nakaji T. Ogawa K. Shigematsu and 0.Manabe J. Am. Chem. SOC.,1981,103 111. 'I2 P.Jouin C. B. Troostwijk and R. M. Kellog J. Am. Chem. SOC.,1981,103,2091. '13 R.Kreher and W. Gerhardt Justus Liebigs Ann. Chem. 1981,240. l'' N. R. Ayyangar A. K.Purohit and B.D. Tilak J. Chem. SOC.,Chem. Commun. 1981,399. ''' I. Murata and K. Nakasuji Top. Cum. Chem. 1981,97,33. '16 .I. Ernest W. Holick G. Rihs D. Schomburg G. Shoham D. Wenkert and R. B. Woodward J. Am. Chem. SOC.,1981,103 1540. Heterocyclic Compounds 253 C0,Me Q-. I gN C0,Me / (133) (134) R = 02SC6H4pMe (135) R = H NN’\N R4 ‘>-R N\‘S’ ,N (136) R = Ph (137) R = NMez The crystal structure of (136)reveals that the eight-membered ring is perfectly planar with all S-N bond lengths equal and all C-N bond lengths equal. The corresponding 3,7-bis(dimethylamino)-ly5-dithia-2,4,6,8-tetrazocine (137)has the same equality of bond lengths as (136) but is markedly non-planar.

ISSN:0069-3030    

DOI:10.1039/OC9817800233

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

12 Organometallic Chemistry Part (i)The Transition Elements By M. BOCHMANN and R. A. HEAD ICl New Science Group The Heath Runcorn Cheshire WA7 4QE and M. D. JOHNSON Department of Chemistry University College London 20 Gordon Street London WClH OAJ 1 Introduction The year 1981 saw the publication of an excellent textbook on organometallic chemistry’ that refers substantially to the chemistry of q -complexes. Monographs include surveys of organic synthesis with palladium complexes’ and aspects of homogeneous cataly~is.~ The following reviews refer to organic chemistry or to the reactions of organic ligands; phase-transfer catalysis in organometallic ~hemistry,~ homogeneous asymmetric hydr~genation,”~ the reactions of ClRh(Ph3P)37 and of HCO(CO)~,* heterolytic activation of hydrogen by transition metal^,^ titanocene and vanadocene,” q5-cyclopentadienyl and q6-arenes as protecting ligands towards platinum metal complexes,” and redistribution reactions of silicon catalysed by transition metals1* The literature on the use of transition metals in organic synthesis for 1979 has been reviewed in detail13 and the principal proceedings of the 1st International Symposium on Organometallic Chemistry Directed Towards Organic Synthesis have been p~b1ished.l~ The latter includes papers on palladium-catalysed synthesis of conjugated polyenes bimetallic catalytic systems containing Ti Zr Ni and Pd ’ J.P. Collman and L. S. Hegedus ‘Principles and Applications of Organotransition Metal Chemistry’ University Science Books California 1981.’J. Tsuji ‘Organic Synthesis with Palladium Compounds’ Springer-Verlag Berlin 1980. ’ ‘Aspects of Homogenous Catalysis’ ed. R. Ugo D. Reidel Dordrecht 1981. H. Alper Ado. Organornet. Chem. 1981,19 183. U. Mateoli P. Frediani M. Bianchi C. Botteghi and S. Gladiali J. Mol. Catal. 1981 12. 265. V. G. Comisso V. Caplar and V. Sunjic Synthesis 1981 85. F. H.Jardine Prog. Inorg. Chem. 1981,28.63. M. Orchin Acc. Chem. Res. 1981 14 259. P. J. Brothers Bog. Inorg. Chem. 1981 28 1. G.P. Pez and J. N. Armor Adv. Organomet. Chem. 1981,19,2. l1 P. M. Maitlis Chem. SOC.Rev. 1981 10 1. ’’ M. D.Curtis and P. S. Epstein Adv. Organomet. Chem. 1981,19 213. l3 L.S.Hegedus J. Organornet. Chem. 1981,207 185. Seven contributions in Pure Appi.Chem. 1981,53 2323-2419. 25 5 M.Bochrnann R. A. Head andM. D. Johnson and their application to selective organic synthesis transition-metal templates for selectivity in organic synthesis palladium catalysis in natural product synthesis nucleophilic addition to diene and arene metal complexes the activation of molecular oxygen and selective oxidation of olefins catalysed by Group VIII transition-metal complexes and control in transition-metal-catalysed organic syntheses. Of fundamental interest is the determination of a series of metal-(sp3)carbon metal-(sp2)carbon,metal-hydrogen and metal-oxygen bond dissociation energies for a series of first-row transition-metal complexes MX' (X = CH3 CH2 H or 0)derived from ion-beam experiments." The bond energies correlate with the differences in energy between the metal ion ground-state and the lowest state derived from the 3d"-14s1configuration.This correlation suggests that the forma-tion of the first metal-to-ligand CT-bond involves mainly the 4s orbital on the metal. 2 Reactions of Co-ordinated Ligands Several papers have appeared in which various ligands are reduced and combined into more complex ligands. Thus treatment of a yellow solution of Me2Zr(~-CsHs)2 with H2W(q-C5Hs)2in C6D6 in the presence of carbon monoxide leads to the formation via (3) of (5)which slowly changesinto a mixture of (7)and (8); (Scheme 1). Using 13C0 it is evident that one carbon monoxide has been incorporated R RH co / CPZWH~ /\ CpzZrR +CpzZr ' Cp2Zr (1) R = Me O&C-R 0+wRcp2 I (2)R = Ph (3) R = Me (4) Ph /:$1 R = Me R = Ph %CP,Zm2O + CP2W(V-C*H4) Cp2W=CHPh (7) (8) Cp v-C~HS Scheme 1 because the complex (8) contains the ligand "CH213CH2.The initially formed bimetallic complex (6) from the diphenyl complex (2) is more stable than (5) and can be converted under forcing conditions into the green carbene complex (7-CSH5)2W=CHPh,the structure of which has been confirmed by an X-ray study.16 In the reduction of the cation (9) with NaBH3CN in alcoholic solvents two of the carbon monoxide ligands are converted into two-carbon ligands and subsequently into organic molecules (Scheme 2)." 1s P. B. Armentrout L. F. Halle and J. L. Beauchamp J. Am.Chem.Soc. 1981,103,6501. l6 J. A. Marsella F. Folting J. C. Huffman and K. G. Caulton J. Am.Chem. Soc. 1981,103 5596. '' T. Bodnar G.Coman S. La Croce C. Lambert K. Menard and A. R. Cutler J. Am. Chem. Soc. 1981,103,2471. Organometallic Chemistry -Part (i) The Transition Elements 0 [c~Fe(C0)~]'i,CpFe(C0)2CH20R-% CpFe(CO)(L)C// (9) 'CH20R / I H+ CpFe( CO) (L)CH2CH0 & CpFe( CO) (L)C / CpFe(CO)(L)CH2C02R lH+ CH3CHO CpFe( CO)(L)Et CH3C02R Reagents i NaBH,CN-ROH; ii Ph,P or (MeO),P; iii RiO'; iv R,BH-; v BH; Scheme 2 Just as carbene and q2-alkene complexes are formed in the above reactions so the formation of both types of complex from a single precursor has been postulated to account for the production of the q2-complex (12) and the cation (13) in the reaction of the vinyl complex (11)with acid or of the methoxyethyl complex (10) with acid or the trityl cation (Scheme 3).18The formation of the q2-ethene complex (15) on treatment of (q-C5H5),WMe2'PFz with trityl radicals followed by saturated /OMe \ CpFe(CO)(L)C-H 'Me Ph,C+ (10) [CpFe( CO)( L) =CHMe]+ + [CpFe( CO)(L)(q- CzHJ]+ (12) CpFe(CO)(L)CH=CH2 Y-(11) CpFe(CO)(L)CH26HCH(Me)Fe(CO)(L)Cp (13) (L = Ph3Por CO) Scheme 3 aqueous KOH has been ascribed to the hydrogen-atom abstraction from one of the methyl groups to give the diamagnetic carbene complex (14) which can then undergo insertion of the methylidene ligand into the carbon-tungsten bond.This gives an ethyltungsten cation which is in equilibrium with a hydrido(q2-ethene) cation from which the proton is removed by base to give (15).The intermediate carbene complex can be trapped by PMe2Ph and the equilibrium between the two cationic species was evident from the reaction of (q-C5H5)2W(CD3)2 in protic media (Scheme 4)." In the reaction of the complex (16) with alkylacetylenes the complex formed contains in sequence a carbonyl ligand the acetylene and the carbene ligand. Oxidation of (17)with Ag20 liberates the quinone (Scheme 5); a reaction which Is T. Bodnar and A. R. Cutler J. Organume?. Chem. 1981,213,C31. l9 J. C. Hayes G. D. N. Pearson and N. J. Coope J. Am. Chem. Suc. 1981,103,4648. M. Bochmann R. A. Head and M. D. Johnson H Scheme 4 Ph/\C=Cr(CO) +RCECMe -+ I @:r(co)3 Me0 (16) OMe (17) R = CH2CH=CHCHMeCH2(CH2CH2CHMeCH2)2CH2CH2CHMe2 li aR Me 0 Reagent i Ag,O or CH,C02H-HN03 Scheme 5 is applicable to vitamin K chemistry.'' Carbon dioxide incorporation into a ligand can take place if a negatively charged centre can be generated on that ligand by reversible dissociation of that ligand from the metal.The incorporation shown in reaction (1)is reversible.21 The mechanism of incorporation of carbon dioxide into 2o K. H. Dotz and I. Pruskill J. Orgunomet. Chem. 1981 209 C4. " P.Braunstein D. Matt Y. Dusausoy J. Fisch D. Mischler and L. Richard J. Am. Chem. Soc. 1981 103,5115. Organometallic Chemistry -Part (i) The Transition Elements 259 the titanium complex (18) is not clear but the enoate complex (19) is readily cleaved on hydrolysis to the enoic acid.(Scheme 6). The same reaction has been carried out using chiral cyclopentadienyl ligands and the resulting enoic acid is formed in substantial enantiomeric excess.22 As the titanium(1v) precursor is formed on oxidative hydrolysis in the presence of chloride ion and molecular oxygen the system can be made regenerative (Scheme 6). Cp' = 77-C5H5 or Scheme 6 The reaction of (7-C5H5)2Ti(C0)2 with acetylenes in dry non-polar solvents normally leads to the formation of a metallocycle. However when the reaction is carried out in the presence of a two-fold excess of water (or D20)a hydrogen from the water is incorporated in the formation of the poxobis(dicyc1open-tadienyl)alkenyltitanium(Iv) product (20) in 95%yield [reaction (2)].On hydrolysis the cis-olefin is formed in good yield.23 R2 R' R' RZ Cp2Ti(CO)2+ 2R'CECR' + HzO + HMTi/o\Ti+-(H (2) /\ /\ CP CP CP CP (20) Large ring metallocycles are intermediates in the coupling of ligands on zir- conium(diene) complexes such as (21).Thus (21) reacts with aliphatic aldehydes ketones and nitriles regioselectively at C- 1 to give 2-oxa- or 2-aza-metallocycles which on hydrolysis release the corresponding alcohols or ketone^.'^ Complex (21) also reacts with the terminal or internal alkenes to give highly regiospecific C-C bond formation between C-2 of the terminal olefin and C-4 of the isoprene ligand.Hydrolysis of the intermediate metallocycle liberates the free alkene.The 22 F. Sato S. Iilima and M. Sato J. Chem. SOC.,Chem. Commun. 1981 180. 23 B. Demersman and P. H. Dixneuf J. Chem. SOC.,Chem. Commun. 1981,665. '* H. Yasuda Y. Kajihara K. Mashima K. Nagasura and A. Nakamura Chem. Lett. 1981 671. 260 M.Bochmann R. A. Head and M. D. Johnson \ R 1 II CH,=CHEt E..4 Et Scheme 7 use of an excess of isoprene allows the formation of tail-to-tail dimer~.~~ These diene complexes and the corresponding hafnium analogues are believed from n.m.r. spectroscopy,26 to resemble a metallocyclopent-3-ene as drawn for (21) in Scheme 7. The use of metal complexes to control the course of organic reactions has been elegantly exploited in the oxidative cyclisation of cyclohexadiene(tricarbony1)iron complexes such as (22) having appropriately placed intramolecular hydroxy-groups capable of attacking the transient dienyl cation,27 (Scheme 8)in the cobalt-mediated eo~ M Fe(CO) HO b % Meogoc *OQ Me CO2Me (CO),Fe Me CO&e Me COzMe (22) (23) (24) Reagents i Ac,O-HBF,; ii Ce4' Scheme 8 (2 + 2 + 2)-cycloaddition of a,&-enzynes and alkynes2* and in the cobalt-mediated cycloaddition of several enediynes of the'type shown in Scheme 9.29In each of these cases the organic product a 4,4-disubstituted cyclohexa-2,5-dienone (24) from (23) and the diene (26) from (25) is liberated in high yield by oxidation with cerium(1v).3 StereoselectiveSynthesis The chromium(I1)-mediated reaction between various aldehydes and cis-and trans-1-bromobut-2-ene gives homoallyl alcohols with remarkable threo-selectivity [reac- *' H.Yasuda Y. Kajihara K. Nagasura K. Mashima and A. Nakamura Chem. Lett. 1981 719. 26 H.Yasuda Y. Kajihara K. Mashima K. Lee and A. Nakamura Chem. Lett. 1981,519. " A. J. Pearson and C. W. Ong J. Chem. SOC.,Perkin Trans. 1,1981 1614. '* C.-A. Chang J. A. Kim and K. P. C. Vollhardt J. Chem. SOC.,Chem. Commun. 1981,53. 29 T. R.Gadek and K.P. C. Vollhardt,'Angew. Chem. Int. Ed. Engl. 1981,20,802. Organometallic Chemistry -Part (i) The Transition Elements 261 i - 8% ii/ (26) Reagents CpCo(CO),-A/hv; ii Ce4' Scheme 9 tion A solvent effect also operates with THF giving virjually exclusively the threo-product whereas in N,N-dimethylformamide up to 63% erythro- selectivity is achieved.Preferential erythro -alcohol is obtained regardless of solvent with sterically hindered aldehydes. To account for the pronounced threo-selectivity the chair form of transition state (27) is proposed in which the R-Me interaction is minimized. Epoxidation of the homoallylic alcohols with t-BuO,H gives mainly the erythro-epoxide (28) [(28) (29) = 76 241 using VO(acac), whereas the threo-epoxide predominates [(28) (29) = 18 821 using A~(OBU')~. RCHO +- Br CrC'z '("+ (3) OH OH threo erythro I Me' The important intermediate in the synthesis of Cecropia juvenile hormones (2)-4-methylhex-3-enol is obtained in a single step and under very mild conditions from hex-3-ynol and TiCl,-AlMe3. The reaction is thought to involve methylation at titanium followed by an intramolecular syn-carbotitanation of the yne group to give (30) as the only product on protonolysis (Scheme An interesting stereospecific intramolecular free-radical addition to an alkene occurs in the cyclization of N-methylhex-4-enyl-N- chloramines to 6-functionalized pyrrolidines [reaction (4)].32Whereas several metal salts promote the cyclization only with CuC1-CuC12 is high yield and diastereoisomeric purity combined.30 T. Hiyama K. Kimura and H. Nozaki Tetrahedron Lett. 1981 22 1037. M. D. Schiavelli J. J. Plunkett and D. W. Thompson J. Org. Chem. 1981 46 807. 32 J.-L. Bougeois L. Stella and J.-M. Surzur Tetrahedron Lerr. 1981 22 61. M. Bochmann R. A. Head and M. D. Johnson OH A1 /\ Scheme 10 Vinylsilanes continue to be useful synthetic intermediates and have now been shown to react with acetals to give penta-1,4-diene derivative^.^^ In the presence of Lewis acids especially MoC15 (E)-P-styryltrimethylsilane affords only (E,E)-pentadienes whereas with the (Z)-vinylsilane the (E,Z)-isomer is iso1ate.d.CIC.U7-CI \ 4 Asymmetric Hydrogenation Chiral lactones are from prochiral cyclic anhydrides using Ru2C14(diop) in the presence of triethylamine. For instance 3-methylglutaric anhydride gives (R)-3-methyl-S-lactone under relatively mild conditions (100"C 10 atm. H2). Commercial hydrogenation of invert sugar a 1 1 mixture of D-glucose and D-fructose gives D-mannitol in 25-28'/0 yield. Since D-mannitol is only derived from D-fructose the addition of glucose isomerase (g.i.) increases D-mannitol formation but at the expense of catalyst activity.It has now been found that activities can be increased by at least an order of magnitude using ruthenium- exchanged Y-type zeolite in conjunction with g.i. The enhancement is attributed to both the sieving properties of the zeolite in preventing cell debris from poisoning the catalyst and also an improved dispersion of ruthenium.35 Optically active ditertiary bisphosphines are prepared through a series of high yield steps from the amino-acids (S)-phenylalanine and (S)-valine. Rhodium com- plexes containing these ligand~~~ give excellent optical yields (384%) in the hydro- genation of (Z)-a-acylaminoacrylic acids to the corresponding saturated N-acyl-a-amino-acids.A full paper on the bis(dimethylglyoximato)cobalt(II)-chiral amine alcohol hydro- genation has explained the function of the amino-alcohol and the beneficial effect of adding achiral bases. Under very mild reaction conditions (30 "C 1atm. H,) asymmetric hydrogenation of a-diketones a-ketocarboxylates and 33 T. Hirao S. Kohno J. Enda Y. Ohshiro and T. Agawa Tetrahedron Lett. 1981 22 3633. 34 K. Osakada M. Obana T. Ikariya M. Saburi and S. Yoshikawa Tetrahedron Lett. 1981 22 4297. '' J. F. Ruddlesden and A. Stewart J. Chem. Res. (S),1981 378. 36 W. Bergstein A. Kleemann and J. Martens Synthesis 1981 76. 37 (a) Y. Ohgo S. Takeuchi Y. Natori and J. Yoshimura Bull. Chem. Soc. Jpn 1981 54 2124. (b) S. Takeuchi and Y.Ohgo Bull. Chem. SOC.Jpn 1981 54,2136. Organometallic Chemistry -Part (i) The Transition Elements olefinic compounds gives increased optical yields in less polar solvents and at lower temperatures. A certain amount of preferential hydrogenation is also observed; for instance methyl phenyl diketone affords 88% (S)-a-hydroxy-a-phenylacetone in 56%optical yield. At higher substrate :Co ratios reductively coupled compounds become significant products [reaction (5)]. The new co-catalysts a-aminocar-boxamides (31)and P-aminocarboxamides (32) give poorer optical yields3" in the hydrogenation of benzil and methyl N-acetylaminoacrylate than were found in previous studies. OH C0,Et NMe2 NMe2 I I R'-C-H PhCHCH(0R)CONHCHPh I I CONHCH( R2)Ph Me (31) (32) 5 Nucleophilic Additions Involving r) '-Allyl Complexes The reactions of nucleophiles with 773-allylcomplexes present either in stoicheiometric amounts or as members of catalytic cycles has proved to be an extremely versatile tool for the formation of C-C C-0 and C-N bonds.With palladium complexes in particular the reactions proceed generally under mild conditions and often with a high degree of regio- and stereo-specificity. The palladium-catalysed substitution of allylic substrates often with acetate as a leaving group has found widespread application. An interesting example is provided by the synthesis of 5- 6- and 8-membered azaspirocycles via intramolecular ring closure (Scheme 1l).38Quantitative cyclization is achieved by 5 mol.% Pd(Ph3P) under mild conditions (2 h 70 "C)in the presence of base.This reaction promises to be useful in several natural product syntheses. PdLl OAc-' -2L /H (CH,),-NHR (CH,)" -N R. (L = PPh3 R = CHZPh n = 3 or 4) Scheme 11 38 S.A. Godleski J. A. Meinhart D. J. Miller and S.van Wallendael Tetrahedron Lett. 1981 22 2247. M. Bochmann R. A. Head andM. D. Johnson In some cases it is advantageous to maintain a neutral reaction medium. Since the reaction of allyl halides with alkylating agents such as pentane-2,4-dione liberates acid that may lead to side reactions allylic alcohols and ethers are preferable replacements. Various allylic alcohols have been treated with pentane- 2,4-dione in the presence of a Pd(acac)*-Ph3P catalyst to give good yields of mono- and di-allylated products (Scheme 12).39Benzyl alcohol can also be alkylated but requires more severe conditions.The products include those following a dispropor- tionation of the alcohol into benzaldehyde and toluene. Anhydrous cobalt chloride can replace palladium in these reaction^.^' The cobalt catalyst allows alkylation of benzylic substrates like diphenylcarbinol and bis(diphenylmethy1)ether more smoothly than allyl alcohol. The antibiotics grifolin and neogrifolin have been synthesized in this way. \ H LO R p O H + R' H )=O + 'lz: R/ R.' Scheme 12 Nucleophilic attack of q3-allyl palladium complexes takes place usually on the face of the allyl ligand away from the metal a feature that was elegantly demon- strated in the stereocontrolled synthesis of the side-chain of Vitamin E (35).4' Sodium malonate reacts with complex (33) to give diastereoisomerically pure (34) [5% Pd(Ph3P)4-THF,95%] (Scheme 13).-*-y&OR H RO H N-+ Me \ Me H+ H Pd 0 L' L (33) [N = CH(COOMe)2,L= PPh3] Scheme 13 39 M. Moreno-Maiias and A. Trius Tetrahedron 1981,37 3009. 40 J. Marquet and M. Moreno-Mafias Chem. Lett. 1981 173. '' B.M. Trost and T. P.Klein J. Am.Chem. SOC.,1981,103,1864. Organometallic Chemistry -Part (i) The Transition Elements The presence of palladium catalysts ensures a high degree of regioselectivity in the reactions of 1,3-diene monoepoxides (36) with various nu~leophiles.~~ 3,4-Epoxy-1-alkenes give products of type (37) exclusively whereas 1,2-epoxy-3- alkenes also form minor amounts of 1,2-addition product (38) (Scheme 14).pdLm + R &R1 R &R1 \ (36) PdL N (37) Scheme 14 The cycloaddition of an activated olefin such as cyclopentenone to substituted trimethylenemethyl palladium complexes proceeds with remarkably high regio~electivity.~~ The zwitterionic complexes (40) and (42) are generated from the isomeric precursors (39) and (43) with catalytic amounts of Pd(Ph3P),. Both give an identical addition product (41) with the olefin but different products on proton- ation with dimethylmalonate showing that protonation is faster than equilibration which itself is faster than cycloaddition (Scheme 15). The conversion of (41) into (44) (E = COOMe) Scheme 15 42 J.Tsuji H. Kataoka and Y. Kobayashi Tetruhedron Lett. 1981,22,2575. 43 B. M. Trost and D. M. T. Chan J. Am. Chern.SOC.,1981,103,5972. M. Bochmann R. A. Head and M. D. Johnson (44) demonstrates the value of the method in significantly reducing the number of steps leading to (44) compared with a previous synthesis. Identical trimethylene- methyl intermediates are involved in the reactions of methylenecyclopropanes with olefins in the presence of nickel or palladium catalysts to give mainly methylene- cy~lopentanes.~~ Vinylsilanes are formed regioselectively in the reactions of the allyl acetates (45) and (46) with sodium diethyl mal~nate.~~ No allyl silanes are observed (Scheme 16). (E/Z 22 :78) SiMe (46) Scheme 16 The regiochemistry of the reaction of allyl ethers with Grignard reagents as nucleophiles can be influenced by the choice of metal catalyst (nickel or palladium) and ligand.46 Bis(dipheny1phosphino)ferrocene [47) as ligand gave particularly effective control.The nickel complex of this phosphine generates predominantly (49) whereas palladium leads to (48) (Scheme 17). Ligand control of regioselec- tivity is also apparent in the palladium-catalysed reactions of allylic halides with Me- +PhMgBr 5 Me- Me (48) (E + 2) catalyst Me (49) (47).NiC1212 :88 (47).PdC1296 4 Fe Scheme 17 alkenylzirconium c~mplexes.~’ The use of a phosphine-free catalyst precursor (q3-crotyl)palladium chloride dimer allowed a study of the influence of non-phosphine ligands such as maleic anhydride which promotes coupling at the 44 P.Binger and U. Schuchardt Chem. Ber. 1981 114 3313; P.Binger and P. Bentz J. Organomet. Chem. 1981,221,C33. 45 T. Hirao J. Enda Y. Ohshiro and T. Agawa Tetrahedron Lett. 1981 22 3079. 46 T. Hayashi M. Konishi K.Yokata and M. Kumada J. Chem. SOC.,Chem. Commun. 1981,313. 47 Y. Hayasi M. Riediker J. S. Temple and J. Schwartz Tetrahedron Lett. 1981 22 2629. Organometallic Chemistry -Part (i) The Transition Elements 267 sterically less hindered terminus of the allylic fragment whereas Ph,P has the opposite effect. Maleic anhydride displays a far better selectivity. The- rate-deter- mining step in the catalytic cycle appears to be the oxidative addition of the allylic halide to the Pd(0) intermediate (Scheme 18).This reaction has been applied to the synthesis of 20-(R)-and 20-(S)-cholestan-3-one.J R’ R’ R3 Scheme 18 The attack by nucleophile on a q3-allylmetal complex can occur either cis or trans to the metal. A surprisingly simple method for selecting the stereochemistry of the attack was found in the diacetoxylation of cyclohexa- 1,3-diene.48 The reaction of the diene with HOAc-LiOAc in the presence of benzoquinone (bq) and a palladium catalyst gives trans-(50),but addition of LiCl to the mixture inverts the stereochemistry to give essentially pure cis-(50) (Scheme 19). The reaction was shown to be general for a range of conjugated dienes. HOAc-LiOAc (’ AcO 0- bq-LiC1 cis-(50) Scheme 19 The examples described above deal with the generation of single bonds.Carbon- carbon double bonds are formed in the reaction of aldehydes with allylic alcohols and triphenylphosphine in the presence of a palladium catalyst (Scheme 20).49The equilibrium is shifted by removing water with molecular sieves. The method is quite general and mimics in effect the Wittig reaction. 48 J. E. Backvall and R. E. Nordberg J. Am. Chem. Soc. 1981,103,4959. 49 .M. Moreno-Mafias and A. Trius Tetrahedron Lett. 1981,22 3109. M.Bochmann R. A. Head andM. D. Johnson OH Pdbcac) R'CH=CHCH=CHR2 or + R'CHo + PPh3 dioxanreflux ' + Ph3p=0 + H20 OH (R' = aryl or alkyl; R2 = alkyl) Scheme 20 6 C-C Coupling via Metal-Carbon @-Bonds The facile oxidative addition to low-valent transition-metal complexes by certain organic compounds RX such as vinyl or aryl halides via the generation of intermediates with reactive carbon-metal bonds is now well documented.Reaction of these intermediates can follow two paths both leading to C-C bond formation the first part of this section provides examples of coupling reactions of these intermediates with reagents such as alkenes alkynes and acyl halides and the second part deals with reactions of metal-alkyl-type nucleophiles. Coupling Reactions with Alkenes Alkynes and Acyl Halides.-Con jugated dienals can be prepared by reaction of various vinyl halides with acrolein acetals and amines in the presence of palladium catalysts. With secondary amines 5 -amino-3-enal acetals may also be formed (Scheme 21).Acrylic or maleic acid and their esters &"' -%-& /R1 + HPdLzX H-Pd-L I X 1 OR OR WCHO Scheme 21 Organometallic Chemistry -Part (i) The Transition Elements give the corresponding 2,4-dienoic acid derivative^.^' The reaction of vinyl halides with alkali salts of 3-butenoic acids leads to the regioselective formation of 3,5-dienoic acids. The catalysts are RhCI(Ph,P) or Ni(Ph,P)3 [reaction (6) where RCH=CHBr + CH2=CHCH2COOK c8t,RCH=CHCH=CHCH2COOH + KBr (6) R = Ph or HI. The same product is obtained from phenylacetylene and 3-butenoic acid; the nickel catalyst is inactive in this case.'l The reactive vinyl halide may be part of a wring system as exemplified by the reaction of 2-chlorotropone with styrene [reaction (7)]and Pd(Ph3P)4 as catalyst.The Pd intermediate chloro(2- troponyl)bis(triphenylphosphine)palladium was prepared separately. It reacts with CO in methanol to give 2-methoxycarbonyltropone.52 0 0 The method can be extended to the synthesis of substituted heterocycles. Various N-heterocycles for example 2-bromopyridine react with the commercially avail- able 2-methylbut-3-yn-2-01 as a protected acetylene starting material to give after treatment with NaOH 2-ethynylpyridine. A PdC12(Ph3P)2-CuI catalyst was used.53 The alkylation of halogen-free substrates requires oxidative conditions if the reaction is to be catalytic. Furan and thiophen are alkenylated in their activated 2-positions by electron-deficient olefins such as acrylonitrile and methyl acrylate in the presence of catalytic amounts of Pd(OAc)* and an excess of Cu(OAc) in air.Mono- and di-substituted heterocycles are produced [reaction N-Aroylpyrrole will even react with benzene under these conditions to give mono- and di-phenylated + (8) (X= 0 or S; R = CN Ph or C02Me) The alkylation of orthopalladated compounds with nucleophiles is well known. However it has now been found that complexes of the type (51) also undergo reactions with electrophiles such as acetyl chloride to give ortho-substituted aryl ketones [reaction (9)JS6 'O B. A. Patel J. I. Kim D. D. Bender L. C. Kao and R. F. Heck J. Org. Chem. 1981,46 1061; J. I. Kim B. A. Patel and R. F. Heck. ibid. p. 1067. G. P. Chiusoli G.Salerno. W. Giroldini and L. Pallini I. Orgunornet. Chem. 1981,219 C16. " H. Horino N. Inoue and T. Asao Tetrahedron Lett. 1981,22,741. " D. E. Ames D. Bull and C. Takundwa Synthesis 1981,364. " Y. Fujiwara 0.Maruyama M. Yoshidomi and H. Taniguchi J. Org. Chem. 1981,46,851. " T. Itahara J. Chem. Soc. Chem. Commun. 1981,254. " R. A. Holton and K. J. Natalie Tetrahedron Lett. 1981 22,267. 270 M. Bochmann R. A. Head and M.D. Johnson + CH,COCl -+ + PdC12 (9) 0 Coupling Reactions with Metal-alkyl-type Nucleophi1es.-Palladium phosphine complexes promote the reaction of organic halides with metal hydrocarbyls to give cross-coupling products. The same allylarenes are obtained in a stereo- and regio- selective manner by treating either benzylzinc compounds with vinyl halides or alkenylaluminium compounds with benzyl halides (Scheme 22).Ni(Ph3P) is also an active catalyst but tends to isomerize the ally1 group. No homocoupling was observed. The reaction does not proceed in the absence of Ni or Pd catalysts under comparable c~nditions.~’ The alkenylaluminium compounds of the type used above R’ R2 ArCH,ZnX + X R3 R’ R2 ArCH,X + R2Al R3 (X = halogen) 1 R’ R2 )=.( ArCH R3 Scheme 22 are easily accessible uia the zirconium-catalysed carboalumination of terminal alkynes. Over 90% regioselectivity to the @)-isomer has been achieved and a variety of functional groups can be tolerated [reaction (lO)].” T.t. Z(CH,),CrCH + MeJAl Cp2ZrC1 * Z(CH2)nHH Me AlMe (Z = OH OSiMeBu‘ SPh or I n = 1 or 2) 1,2-And 1,3-transpositions of keto-groups with and without alkylation of the substrate are possible by reaction of enol phosphates with trialkylaluminium in the presence of a palladium catalyst [reactions (11)-(13)].Triethyl- and tri-isobutyl- aluminium give mixtures of alkylated and hydrogenated product~.~’ The modification of nucleic acids and their monomeric units is of interest in the study of enzyme mechanisms. For example 5-arylpyrimidines have been synthe- sized from the 5-chloromercuric derivative and aryl iodides have been synthesized ” E. Negishi H. Matsushita and N. Okukado Tetrahedron Lett. 1981 22 2715. C. L. Rand D. L. van Horn M. W. Moore and E. Negishi J. Org. Chem. 1981,46,4096. 59 M. Sato K. Takai K. Oshima and H.Nozaki Tetrahedron Lett. 1981 22 1609. Organometallic Chemistry -Part (i) The Transition Elements 27 1 AIMe, & +~ 'MSPh' Medph Ph Ph Pd (12) Ph Ph 0 SPh AIMe Phb*+Ph+ 7 X = -OP(OPh)z H II 0 by stoicheiometric transmetallation with Li2PdC14. The yields are generally low [e.g. reaction (14)].60The related 5-allylation of pyrimidine nucleosides has also been reported.61 g'Li,PdCI -HN oAN (14) R I I R (X = H or NO2) The cross-coupling reaction could be significantly simplified if the metal-alkyl component from one of the two organic halides was generated selectively and in situ. This was achieved in the syntheses of benzyl ketones from benzyl bromide and acyl chlorides in the presence of zinc powder and a palladium catalyst.62 The reaction proceeds within 20 minutes at ambient temperature and relies on the preferential oxidative addition of the acyl halide to the palladium catalyst whereas benzyl bromide reacts more readily with zinc to give benzylzinc bromide (Scheme 23).Dibenzyl is the by-product usually in minor amounts. PdLZC12 PdL2 RCoC1+ R-C-PdLC1 ArCH2Br + Zn It 0 / 1 BrZnCH2Ar R-C-CH2Ar + PdLz e R-C-PdL2(CH2Ar) II II 0 0 (R = alkyl or aryl Ar = Ph p-MeC6H4- or p-ClC6H4- L = PPh3) Scheme 23 6o C. F. Bigge and M. P. Mertes J. Org. Chem. 1981,46 1994 D. E. Bergstrom J. L. Ruth and P. Warwick J. Org. Chem. 1981,46 1432. T. Sato K. Naruse M. Enokiya and T. Fujisawa Chem. Lett.. 1981 1135. M.Bochmann R.A.Head and M.D. Johnson 7 Carbonylation In the first example of cyanocarbonylation aromatic iodides are smoothly carbonyl- ated in the presence of potassium cyanide to give good yields of aroyl cyanides (Scheme 24).63" The reaction is conveniently carried out at 100 "C with 20 atm. I CN / / + Pdo + \ Scheme 24 CO pressure in THF with a palladium catalyst and only traces of nitriles are formed as by-products. In contrast when organic chlorides are used the THF acts as a reagent and chlorohydrin esters are formed in 15-35'/0 yield [reaction (15)].63b Yields are greater for smaller cyclic ethers and though higher temperatures (130 "C) are required than for cyanocarbonylation the reaction has been effected at 1atm. CO. The rhodium carbonyl-catalysed synthesis of 5-allyl-2(5H)furanones has been achieved by the carbonylation of alkynes in the presence of an alkene and a hydrogen donor such as ethan01.~~" Reaction (16) using diphenylacetylene at 150- 200 "C 20 atm.ethene and 30 atm. CO gave isolated yields of (52) of 60-73%. Similar products are formed but in lower yield from propene and methyl acrylate R'CECR* + 2CO + R3CH=CH2 + 2[H] R3 63 (a)M.Tanaka Bull. Chem. SOC.Jpn 1981,54,637. (b)M.Tanaka M. Koyanagi and T. Kobayashi Tetrahedron Lett. 1981,22 3875. 64 (a)P. Hong T. Mise,and H. Yamazaki Chem. Lett. 1981,989. (b)T. Mise,P. Hong and H. Yamazaki Chem. Lett. 1981,993. Organometallic Chemistry -Part (i) The Transition Elements whereas with terminal alkynes no furanones are obtained.Interestingly at tem- peratures below 150 "C ethanol rather than the alkene becomes incorporated into the product affording low yields (13% at 100°C) of (53) which can be increased phG: Ph H OEt (53) to 87% in the presence of bases such as sodium The reaction is thought to occur via nucleophilic attack of alkoxide on co-ordinated carbon monoxide to give an alkoxycarbonyl intermediate. Stepwise insertion of the acetylene and CO into the Rh-C bond gives the lactone complex (54) [reaction (17)] from which the furanone is obtained by protonolysis. The carbonylation of methanol to acetic acid using a homogeneous rhodium catalyst has recently been commercialized. It is now found6' that nickel supported on carbon is highly efficient for the vapour-phase carbonylation of methanol principally to acetic acid at 320 "C and 1atm.CO in the presence of an organic halogen compound such as methyl iodide. The catalyst exhibits long life and shows higher selectivity than the supported rhodium analogue and is in addition far less expensive. The high yield synthesis of a,& unsaturated carboxylic esters has been achieved66 by carbonylation of 1-alkenylboranes in the presence of alcoholic sodium acetate under very mild conditions (25 "C 1atm. CO). The reaction proceeds with retention of configuration with respect to the alkenylborane. Thus from (E)-hex-1-enyl-1,3,2-benzodioxaborole methyl (E)-hept-2-enoate (55) was obtained in 92% (g.1.c) yield [reaction (18)]. CH H H )=(-/O* CO-MeOH-PdCI,-NaOAc H 8 Chemistry of Synthesis Gas An interesting approach to synthesis gas chemistry is the use of Lewis acids as solvent media.In a NaC1-AlCl melt Ir4(CO),2 converts synthesis gas (170-180 "C 1atm. CO-H2 1 1 ratio) into a mixture of hydrocarbon^^^" with propane and " T. Inui H. Matsuda and Y. Takegami J. Chem. SOC.,Chem. Commun. 1981,906. '' N. Miyaura and A. Suzuki Chem. Lett. 1981,879. " (a) H. K. Wang H. W. Choi and E. L. Muetterties Inorg. Chem. 1981 20 2661. (6) H. W. Choi and E. L. Muetterties Inorg. Chem. 1981 20 2664. M. Bochmann R. A. Head and M. D. Johnson isobutane as major constituents. Cycloalkanes are also produced with this and with the NaBr-AlBr3 melt although catalyst activities are rather poor. Using the liquid Lewis acid BBr3 and OS~(CO)~~ as catalyst both alkyl bromides and acyclic hydro- carbons are The formation of alkyl halides directly from synthesis gas is quite unique but only occurs with BBr3 and under certain conditions methyl bromide selectivities of up to 69% are observed.Previous studies with homogeneous ruthenium catalysts have shown them to be rather inactive for the conversion of CO-H2 into methanol and methyl formate. Halide promoters are now found6' to give a much faster rate with methanol ethanol and ethane-1,2-diol being formed under more severe conditions (230 "C 850 atm. CO-H2 1:1ratio). While all halides show a beneficial effect over the unpromoted system with iodide ion the effect is particularly pronounced regardless of the cation.Homologation of carboxyfic acids has recently been achieved69 using a soluble ruthenium catalyst promoted by iodide ion. Selectivities to homologated acids are typically 40% with significant amounts of undesirable alkane by-product. The reaction is thought to proceed through acyl iodide formed rapidly in situ which reacts with the catalyst to give an acyl complex. Hydrogenation carbon monoxide insertion followed by attack of water affords the homologated acid (Scheme 25). [Ru] + MeCOI + [Ru]-CMe % [Rul-CH2Me II -HzO 0 HOCCH2Me @ [Rul-CCHzMe I1 II 0 0 Scheme 25 Acetate esters are obtained7' in the absence of iodide ion from CO-H2 in glacial acetic acid. In addition to methyl and ethyl acetates both mono- and di-acetate esters of ethane-1,2-diol are major products.The presence of large cations e.g. Bu,P' both increases the conversion of acetic acid as well as the selectivity to glycol esters. Tracer experiments using Me13C02H have unambiguously identified the source of carbon in the glycol-forming reaction [equation (19)]. 0 II 2CO + 3Hz + 2Me*C02H [Ru? yH20* CMe CH20*CMe II 0 A reinvestigation of benzene alkylation by CO-H2 with transition-metal carbonyls and AlC13 has shown7* that the alkyl group is derived from Lewis acid fragmentation of the arene and that there is no involvement of CO-H or the metal carbonyl. B. D. Dornbek,.L Am. Chem. SOC.,198f 103,6508. ''J. F.Knifton J. Chem. SOC.,Chem. Commun. 1981,41. '' J. F.Knifton J. Chem. SOC.,Chsm. Commun. 1981,188. " L.S.Benner Y.H. Lai and K. P. C. Vollhardt J. Am. Chem. SOC.,1981,103,3609. Organometallic Chemistry -Part (i) The Transition Elements 275 9 Catalysis by Metal Clusters The catalytic behaviour of metal clusters has been reviewed.72 Although there is often little evidence that the active species is a cluster and that no fragmentation has occurred Rh6(C0)16 is found to be exceptionally active for the room-temperature cyclopropanation of alkenes by ethyl diazoacetate [reaction (20)].73 With 2,5-dimethylhexa-2,4-diene~90% isolated yield of ethyl chrysanthemate is obtained which represents turnovers in excess of 2000 per cluster molecule. In addition to higher activities and yields compared with the more conventional Cu and Pd catalysts side reactions are severely reduced.The evidence for Rh6(CO)16 being the actual catalyst comes from its quantitative recovery when the reactions are performed under an atmosphere of carbon monoxide. The recovered cluster shows no loss of activity on re-use. R' R'R~ EtOOCCHN + )=(R3 -N2 b EtOOCq R3R4 (20) R2 R" The same cluster also catalyses the reduction of nitrobenzene to aniline using water as the source of hydrogen.74 Under typical conditions (80°C 1atm. CO) with amine promoters especially 4-dimethylaminopyridine and N,N,N',N'-tetramethyl- 1,3-diaminopropane quantitative formation of aniline and conversion of nitrobenzene occurs. While the same system is also active for the water-gas shift (wgs) reaction (CO + H20 + CO + H2) this is not the source of hydrogen in nitrobenzene reduction.Proof of this is that amines that promote the wgs reaction are virtually inactive for nitrobenzene reduction. Experiments using deuterium oxide give high 2H incorporation in the aniline produced and supports water as the reducing agent. A simple synthesis of from alcohols using Ru3(C0)12 operates by an initial hydrogen transfer from the alcohol to a hydrogen acceptor such as diphenylacetyl- ene. The resulting aldehyde combines with more alcohol to give the ester by a second hydrogen-transfer step. Despite the low activity of the catalyst (turnovers -65) the yields of ester are high (SO%) [equation (21)]. 2RCH20H + 2Phcz~CPh1470c) R-C-OCH2R + 2PhCH=CHPh (21) I1 0 10 Heterocyclic Chemistry Substituted furans are valuable synthetic intermediates but attempts to prepare them by Friedelcrafts alkylation of furan generally result in low yields (-10%) and a significant degree of resinification.A convenient alkylation procedure has 72 E. L. Muetterties Card Rev. Sci. Eng. 1981 23 69; R. Whyman in 'Transition Metal Clusters' ed. B. F. G. Johnson Wiley London 1980 Ch. 8; S. D. Jackson P. B. Wells R. Whyman and P. Worthington in 'Catalysis',ed. C. Kemball and D. A. Dowden (Specialist Periodical Reports) The Royal Society of Chemistry London 1981,Vol. 4,p. 75. 73 M. P. Doyle W. H. Tamblyn W. E. Buhro and R. L. Dorrow Tetrahedron Letr. 1981,22 1783. 74 K. Kaneda M. Hiraki T. Imanaka and S. Teranishi J. Mol. Card. 1981 12 385. 75 Y.Blum D. Reshef and Y. Shvo Tetruhedron Lett.1981,22 1541. M. Bochmann R. A. Head and M. D. Johnson now been using arenemolybdenumtricarbonyl and t-butyl chloride which at 130 "C,affords 2-t-butylfuran with turnovers approaching 153 per molybdenum. Increasing the catalyst concentration increases the amount of 2,5-disubstituted furan at the expense of turnover [reaction (22)]. Substituted pyrroles are in high yield directly from 1-aminoalk-3-yn-2-ols which are themselves synthesized from the conjugated ynone (56) (Scheme 26). In a closely related reaction a range of pyrroles are prepared7' by 1,4- cycloamination of 1,3-dienes in acetic acid (Scheme 27). In the absence of amine high yields of the q3-intermediate (57) are obtained. Nucleophilic attack by the amine on (57) gives the aminoacetate (58).The pyrroline (59) is obtained by intramolecular cyclization of (58) and is oxidized to the pyrrole by Pd" or Cu". 0 OH II (i) Me3SiCN R1-C-C~C-R* -R4-CrC-R2 (ii) LiAIHi I (56) CH2-NH;! I H Scheme 26 (58) Me (57) (59) Scheme 27 An interesting extension to studies on the N-alkylation of amines by alcohols is the synthesis of pyrrolidines from diols and amines [reaction (23)];79 high yields (82%g.1.c.) are obtained. 11 Pyrethroid Synthesis Pyrethroids structurally derived from vinylcyclopropylcarboxylic acid (60),are the most powerful insecticides known to date. The synthesis of the building block has 76 D. J. Milner J. Orgunomet. Chem. 1981 217 199. 77 K. Utimoto H. Miwa and H. Nozaki Tetrahedron Lett. 1981,22,4277.78 Backvall and J.-E. Nystrom J. Chem. Sor. Chem. Cornmun. 1981 59. J.-E. 79 R. Grigg T. R. B. Mitchell S. Sutthivaiyakit and N. Tongpenyai J. Chem. Soc.. Chem. Commun. 1981,611. Organometallic Chemistry -Part (i) The Transition Elements been attempted from very different starting points and synthetic approaches without the aid of transition metals have been reviewed.80 X COOH (60) Cy clopropanation of substituted dienes (61) with diazoacetate gives a mixture of four isomers the ratio of which is influenced by the use of copper complexes of chiral Schiffs bases.'l Cyclopropanation of the diene precursor (62) gives a lower yield but increases the selectivity for the favourable cis-(1R)-isomer (Scheme 28). CI N,CHCOOR cu (61) COOR T COOR Scheme 28 An elegant synthesis of cis- chrysanthemonitrile (63) takes advantage of the high stereo- and regio-selectivity of the palladium-catalysed allylic substitution.82 Alkyla- tion of the allylic acetate (64) occurs at the more highly substituted carbon and gives compound (65) with exclusive E-double bond stereochemistry (Scheme 29; A = COOR or CN; X = COOR S02R' or CN).The stereochemistry of the subsequent ring-closure depends on the nature of the substituents A and X. In the case of A = CN and X = S02Ph only one isomer (66a) is isolated in high yield. The ratio of (66a) :(66b) can be strongly influenced by the presence of a catalyst. If A = CN X = COOEt the presence of Pd(PPh& during the cyclopropanation increases the amount of (66a) from 50 to 95% of the total product.D. Arlt M. Jautelat and R. Lantzsch Angew. Chem. 1981,93,719. " D. Holland D. A. Laidler and D. J. Milner J. Mol. Cutul. 1981 11,119. 82 J. P. Genet and F. Piau J. Org. Chem. 1981,46 2414. M. Bochmann R. A. Head and M. D. Johnson HO Me + NaCHAX PdPPh,) Me>cHAx OH OAc Me Me )=yxVA + Me 'Me Me 'Me Me-Me (A = CN X = SOZPh) Scheme 29 The highly strained bicyclo[ 1.1.O]butane reacts with electron-deficient olefins in the presence of nickel(0) to give allylcyclopropane derivative^.'^ Deuteriation and substitution studies suggest that two geminal u-bonds of the bicycle are cleaved and a nickelallylcarbene complex is formed which cyclopropanates methyl acrylate with retention of the stereochemistry of the olefin (Scheme 30).With bis(1,S-cyclo- octadiene)nickel(O) as catalyst the reaction proceeds smoothly in high yield even at 0 "C.Non-activated olefins do not react. % + 9 O O R D COOR H H Scheme 30 83 H. Takaya T. Suzuki Y. Kumagai M. Hosoya H. Kawauchi and R. Noyori J. Org. Chem. 1981 46,2854. Organometallic Chemistry -Part (i) The Transition Elements (68) (R = H Ph or C02Et) Protection of double bonds can be achieved with iron complexes. Thus the chiral iron complex (67) is cyclopropanated by diazomethane on the unco-ordinated double bond to give after oxidation with Ce4' a cyclopropane with 90% enan-tiomeric excess.84 In contrast the carbene-iron complex (68) reacts with diazo- alkanes to give the diene complex (69) [reaction (24)].85 A.Montpert J. Martelli R. Grke and R. Carrie TetruhedronLett. 1981,22 1961. T.Mitsudo H.Watanabe K. Watanabe Y. Watanabe and Y. Takeganu J. Orgunornet. Chem. 1981 21487.

ISSN:0069-3030    

DOI:10.1039/OC9817800255

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

12 Organometallic Chemistry Part (ii) Main-Group Elements By J. L. WARDELL Department of Chemistry University of Aberdeen Meston Walk Old Aberdeen AB9 2UE 1 Introduction Reviews on various aspects of organometallic chemistry were published in 1981. Amongst these were the following (i) the formation of Grignard reagents from chemically activated magnesium,' (ii) uses of silicon compounds in organic syn- thesis, (iii) organotin compounds in ~ynthesis,~ (iv) photochemistry of organopoly- ~ilanes,~ (v) organic compounds of divalent tin and lead,5 and (vi) calculations of electronic structures of main-group organometallics.6 Two volumes on organo- antimony(1Ir) compounds have appeared in the Gmelin series.' 2 General One significant growth area in recent years has been cross-coupling reactions of in particular magnesium zinc aluminium mercury and tin compounds.These reactions most frequently catalysed by nickel or platinum complexes were abun- dantly reported in 1981. The synthesis of allyl-arenes from either PhCH2ZnBr and vinylic halides or vinylic alanes and PhCH2X (see Scheme l),described by Negishi et al. can be added to the established reactions which lead to aryl-benzyl alkenyl-allyl and aryl-ally1 coupled compounds.8 From another study,g the reactivity of allyl-X in couplings to alkenyl- and aryl-metals (metal = A1 or Zn) was found to decrease in the sequence X = halogen OAc > OAlR > OPO(OR) > OSiR3. The regioselectivity in catalysed reactions of (E)-RCH=CHCH2X or H,C=CHCHRX (R = Me or Pr; X = C1 OH or OR) with Grignard reagents apparently depends on the metal catalyst used." Scheme 2 shows examples of the effect of the catalyst.Y. H. Lai Synthesis 1981 585. * I. Fleming Chem. SOC.Rev. 1981,10 83. M. Pereyre and J. P. Quintard Pure Appl. Chem. 1981 53 2401. M. Ishikawa gnd M. Kumada Adv. Organomet. Chem. 1981,19 51. J. W. Connolly and C. Hoff,Adv. Organomet. Chem. 1981,19,123. D. R. Armstrong and P. E. Perkins Coord. Chem. Rev. 1981,38 139. 'M. Wieber Organoantimony Compounds Parts I and 11 Gmelin Handbook of Inorganic Chemistry Springer-Verlag Berlin 1981. E. I. Negishi H. Matsushita and N. Okukado Tetrahedron Lett. 1981 22 2715. E. I. Negishi S. Chatterjee and H. Matsushita Tetrahedron Left. 1981 22 3737. lo T. Hayashi M.Konishi K. I. Yokota and M. Kumada J. Chem. Soc. Chem. Commun. 1981 313. 281 282 J. L. Wardell Scheme 1 Me OSiEt PhMgBr 4yPh + pPh + Me-Ph -Catalyst ’ (1) Me (4) Me or (3) (5) Compound Catalyst Proportion (3):(4) :(5) (1) “iClz(dppf)l 88 :11:1 (1) [PdCl2(dPPf)l 4:92:4 (2) “iCb(dppf)l 81 :10:9 (2) [PdCl* (dPPf)l 9:75:16 (dppf = 1,1‘-bisdiphenylphosphinoferrocene) Scheme 2 Predominant inversion of configuration occurs“ in the reaction of (+)-(S)-but-l-en-3-01 and PhMgC1. Use of NiC12 complexes of chiral phosphines e.g. (S)-Pr’CH(NMe2)CH2PPh2 and (-)-norphos in coupling reactions of vinyl bromide to racemic alkyl-Grignard reagents,I2 e.g. PhMeCH(CH2),MgX (n = 1 or 2) and norborn-2-ylmagnesium halides leads to some asymmetric induction e.g.reac-tion (1). NiCl ‘PPh,’ H2C=CHBr + MeCHPhMgX + H2C=CHCHPhMe (1) 9’5”/0chemical yield [67% optical yield of (S)-isomer] A general cross-coupling reaction has been established with organomercurials. A wide range of alkyl- alkenyl- and aryl-mercurials readily react with primary and secondary alkyl- and alkenyl-cup rate^,'^ e.g. reaction (2). H. Felkin M. Joly-Goudket and S. G. Davies Tetrahedron Lett. 1981 22 1157. l2 T. Hayashi K. Kanehira T. Hioki and M. Kumada Tetrahedron Lett. 1981,22,137; H. Brunner and M. Probster J. Organornet. Chem. 1981 209 C1. I3 R. C. Larock and D. R. Leach Tefrahedron Lett. 1981,22,3435. Organometallic Chemistry -Part (ii) Main-Group Elements The biaryl cross-coupling of 1-methyl-2-pyrrolyl-MgBr (or -ZnBr) with aryl halides catalysed by [PdC12(Ph2PCH2CH2CH2CH2PPh2)]{ = [PdCl2(dppb)]} has also been rep~rted,'~ and is shown in Scheme 3.Me Me Me [87%] [73Yo] Reagents i (M = MgBr) PhBr THF heat for 1h [PdCl,(dppb)]; ii (M = ZnCl) QB THF heat for 1 h [PdCl,(dppb)] Scheme 3 Organotin compounds RSnMe3 (R = alkyl aryl indenyl or fluorenyl) react with ArX (Ar = Ph or nitrophenyl) at 120-130°C in the presence of Pd compounds in ClCH2CH2Cl solution to give good yields of RAr." Other interesting cross- coupling reactions16 produce p y-ethylene esters from vinylic halides and Refor- matsky reagents [reaction (3)] and allenic derivatives [reaction (4)]. RCH=CHBr + BrZnCH2C02Et HMPT'rPd(PPh3)41b RCH=CHCH,CO,Et (3) ,, Bt 45 .,c H2C=C=CHX or HCEC-CH~Y RZnBr*THF P H2C=C=CHR (4) [Pd(PPh&I [>80Yo] (X= Br or I Y = Br or Ac) (R = Ar vin 1, alkynyl or algnyl) An interesting aryl-coupling reaction of ArMgBr takes place in Et20 in the presence of ClCH,C=CCH,Cl (or ClCH,CH=CHCH,Cl); high yields (>70%)of Ar are obtained for meta-or para-(but not ortho-) substituted Ar gro~ps.'~ There have been several on the formation and detection of organometallic radical complexes [(R,ML)'] e.g.[RMg(phen)] [RMg(bipy)] [EtZn(Bu'NCHCHNBu')] [R2Al(bipy)] [R,M(thioketone)] (M = Si Ge or Sn) l4 A. Minato K. Tamao T. Hayashi K. Suzuki and M. Kumada Tetrahedron Left. 1981 22 5319. Is A. N. Kashin I. G. Bumagina N. A. Bumagin and I. P. Beletskaya J. Org.Chem. USSR (Engl. TrunsL),1981 17 18. K. Ruitenberg H. Kleijn C. J. Elsevier J. Meijer and P. Vermeer Tetrahedron Left. 1981 22 1451; J. F. Fauvarque and A. Jutand J. Orgunornet. Chem. 1981,209,109. l7 S. K. Taylor S.G. Bennett K. J. Heinz and L. K. Lashley J. Org. Chem. 1981 46 2194. E. C. Ashby and A. B. Goel J. Orgunomef. Chem. 1981,221 C15. l9 J. T. B. H. Jastrzebski J. M. Klerks G. van Koten and K. Vrieze J. Orgunornet. Chem. 1981 210 c49. *' W. Kaim J. Orgunornet. Chem. 1981 222 C17; A. Alberti P. F. Colonna M. Guerra B. F. Bonini G. Mazzanti Z. Dinya and G. F. Pedulli ibid. 1981 221 47; A. Alberti A. Hudson A. Maccioni G. Podda and G. F. Pedulli J. Chem. Soc. Perkin Trans. 2 1981 1274. 284 J. L. Wardell Rn+lM + L + [(RnML)'] and [R2M(benzo[2,1-b ; 3,4-b']dithiophen-4,5-dione)](M = As,'Sb or Bi).These complexes were prepared by the reaction of the appropriate organometallic com- pound with the chelating ligand L. In addition to these radical cation complexes of aluminium were also obtained21 [reaction (5)]. AlMez A new theoretical approach to nucleophilic addition to carbonyl groups has been put forward.** This involves charge-transfer stabilization of transition states. The feature of the transition state critical for stereoselectivity of the reaction is the existence of a low-lying vacant orbital UT associated with the u-bond that is being formed in the reaction. Electron delocalization into the u$ orbital will stabilize the transition state and may thereby enhance the reaction rate.The stereochemistry of nucleophilic addition to cyclohexanones is determined by two factors (i) steric hindrance which favours equatorial approach and (ii) electron donation from the ucc and uCH bonds of cyclohexanone into the ur orbital which favours the axial approach since the carbon-hydrogen bonds are better donors of electrons. 3 Group1 The use of ultrasound in organic synthesis has been further illustrated by the formation of R-R from equimolar amounts of lithium (in the form of a wire) and RX (R = aryl benzyl acyl or alkyl) in THF solution.23n This report comple- ments an earlier finding23b that good yields of RLi are obtained from lithium (4 equivalents) and RBr (e.g. R = Pr Bu or Ph) using ordinary ultrasound laboratory cleaners.7-Lithionorbornadiene has been prepared for the first time from 7-chloronorbornadiene and (p-Bu'C6H4C6H4Bu'-p)' Li' (6). The restated the advantages of using (6) (rather than sodium naphthalene) as the metallating agent as being that electron transfer is favoured over radical combination owing to the greater steric hindrance in (6) and that lithium as a counter-ion results in a lower degree of carbanionic character in the radical anion. &Substituted organo-sodium and -potassium compounds have been obtainedz5 by mercury-alkali-metal exchange reactions of organomercurial compounds [reac- tion (6)]. A study ab initio was conducted on the relative energies of R- and RLi. A close relationship (attentuation factor = 0.71) was found between the relative energies '' W.Kaim J. Organomet. Chem. 1981,215,325,337. *' A.S.Cieplak J. Am. Chem. SOC.,1981 103,4540. 23 B. Han and P. Boudjouk Tetrahedron Lett. 1981 22 2757; J. L.Luche and J. C. Damiano J. Am. Chem. SOC.,1980,102,7926. 24 J. Stapersma and G. W. Klumpp Tetrahedron 1981 37 187. " J. Barluenga F. J. Fananas and M. Yus,J. Org. Chem. 1981,46,1281. Organometallic Chemistry -Part (ii)Main-Group Elements 285 (i) PhM R-CH-CH2HgBr (ii) M b R-CH-CH2M’ (6) I I ZH ZM (R = H or Ph; Z = 0 or PhN; M = Li Na or K; M’ = Na or K) of the carbanion (R-) and those of the corresponding lithium compounds RLi (R = alkyl alkynyl cycloalkyl or cycloalkenyl).26 It thus appears quite reasonable to equate the carbanion with the corresponding organometallic compound.von R. Schleyer and co-workers have also continued their theoretical studies on the structures of organolithium compounds and have reported on further non-classical structures e.g. of LiCH2X (X = OH or NH2) [the structures of lowest energy i.e. (7) contain bridging HO or NH2 groups] LiCH2CH2Li (partially bridged structure) and (2,6-x2C6H3Li) (8; X = H or OH). The structure for (8)that has X H.. / \ ‘C-Li (7) X = OHorNH2 the lowest energy calculated by the MNDO method contains planar tetraco- ordinate bridging carbon Extended aromatic n-delocalization the stability of multi-centre cr-bonds involving lithium and intramolecular solvation were con- sidered to be responsible for this arrangement. MNDO calculations on the dimeric disolvate (PhLi.H20)2 however pointed to tetrahedral bridging carbon atoms in the most stable structure.The change from planar to tetrahedral bridging carbon atoms is a consequence of lithium becoming a poorer 0-donor and n-acceptor on intermolecular complexation. It is interesting that the closest species to (PhLi.H20)2 to have its structure determined by X-ray crystallography28 was (P~L~sTMED)~ which does contain tetrahedral bridging carbons. The X-ray structure of (2,6-MeOC6H3Li)6.Li20 (9)has been ~btained.~’ Perhaps because of the presence of the Li20 moiety the structure of (9) is far removed from that predicted by von R. Schleyer et al. for [2,6-(H0)2C6H3Li]2. In (9) there is a Li80 cluster which is composed of two Li pyramids each of which is connected to the oxygen via its Li base.The remaining six Li faces are occupied by aryl groups. There is considerable interest in polylithiated species. While it is possible to prepare CLi4 CH2Li2 etc. it has been difficult to characterize them owing to poor solubility thermal instability [e.g.see reactions (7)and (S)] and lack of appreciable vapour pressure up to 650°C. However it now appears that polylithiated species may survive for short distances on flash vacuum thermolysis; e.g. 90% CH2Li2 successfully negotiated a distance of lOcm under vacuum on being heated from 26 P. von R. Schleyer J. Chandrasekhar A. J. Kos T.Clark and G. W. Spitznagel J. Chem. SOC., Chem. Commun. 1981,882. 27 J. Chandrasekhar and P. von R. Schleyer J. Chem. SOC. Chem.Commun. 1981 260; A. J. Kos E. D. Jemmis P. von R. Schleyer R. Gleiter U. Fischbach and J. A. Pople J. Am. Chem. Sac. 1981 103,4996; T. Clark P. von R. Schleyer K. N. Houk,and N. G. Rondan J. Chem. SOC.,Chem. Commun. 1981,579. 28 D. Thoennes and E. Weiss Chem. Ber. 1978,111,3157. 29 H. Dietrich and D. Rewicki J. Orgunornet. Chem. 1981 205 281. 286 J. L. Wardell CL~~ B CLL + ~2~i4 + ~ yi; + ~3~i4 2 ~ i ~ (7) [20°/0] [3OYo] [40°/o J [lOYo] CL~~ :iLi + C2Li2 [100 Yo ] room temperature to 1500 "C in less than 3 seconds. The ion (CH2Li2),,+ (n = 1-5) was detected.,' Lithiation of terminal mono- or di-alkenes has been achieved" by using lithium in the presence of 1,5-diphenyl-l,6,aA 4-trithiapentalene (10) and ZnC12 or FeCl,; e.g.reactions (9) and (10). In contrast RCH=CH2 is lithiated by lithium in the presence of (10)and PdCl to give allyl-lithiums. s-s-s P h w Ph RCH=CH2 + Li (10) b (E)-RCH=CHLi (9) ZnCI or FeCI Several chiral ligands have been used in asymmetric addition of RLi to carbonyl the chelating compound (1 1) proved particularly effective resulting in 95% e.e. in the reaction of BuLi with PhCHO in Et20 at -120 "C. (11) New syntheses of aldehydes33 and ketones34 have been reported [reactions (11) and (12)]. 4 Group2 A new procedure for the preparation of highly reactive zinc or magnesium metal powders involves reduction of the metal chlorides in glyme by lithium with a 30 L. A. Shimp J. A. Morrison J. A. Gurak J. W. Chinn Jr. and R. J. Lagow J. Am.Chem. SOC. 1981,103,5951. " B. Bogdanovic and B. Wermeckes Angew. Chem. Int. Ed. Engl. 1981,20,684. 32 J. K. Whitesell and B. R. Jaw J. Org. Chem. 1981 46 2798; J. P. Mazaleyrat and D. J. Cram J. Am. Chem. SOC.,1981,103,4585. 33 G. A. Olah and M. Arvanaghi. Angew. Chem. Int. Ed. Engl. 1981 20,878. 34 S. Nahm and S. M. Weinreb Tetrahedron Lett. 1981,22 3815. 287 Organometallic Chemistry -Part (ii)Main-Group Elements (i) RLi or RMgX + RCHO+ Q (ii) H,O+ CHO H [e.g. R = Ph; 94%] 0IIR'C-N MeOMe (i) R2Li or R2MgX R' 'c=o (ii) H,O+ R2' [R' = Ph R2 = Me; 93%] catalytic amount of naphthalene present as an electron carrier. The zinc powder so formed is particularly reactive more so than that obtained from reduction with it reacts with PhBr (to give a 73% yield after refluxing for one hour) and C1CH2C02Et.Magnesium slurries obtained by evaporation of Mg in a rotating- solution reactor reacted with cyclopropylmethyl bromide in THF and with benzo- cyclobutenylmethyl bromide at low temperatures to give high yields of unre-arranged Grignard reagents as shown by trapping with COz or PhCHO. Normal methods of forming Grignard reagents provide very much more ring-opened prod- uct~,~~ e.g. as shown in Scheme 4. Polar aprotic sulphonamides in particular [Sole product] [Sole product] Reagents i Mg slurry Et20 at -50 "C; ii C02,H20; iii Mg (granulated) THF,at 30 "C Scheme 4 (Et2N)2S02 have been shown to be useful solvents for Grignard reaction~.~~ Solutions of RMgBr (R =Et Pr" Pr' or Ph) in (Et2N)2S02 prepared in high yields e.g.of 87% in Pr'MgC1 at ambient temperature are stable for weeks. Solutions in hexane (25%) of ZnEt and 2 equivalents of (Et2N)2S02are also stable. Whitesides3* has reported further on the mechanism of formation of a Grignard reagent. The forms of the dependence on the rate of reaction of cyclopentyl bromide with a rotating disk of magnesium in Et20 on the angular velocity and on other factors are all those that would be expected for mass-transfer-limited reactions. Additions of RMgX to alkynes catalysed by [(Cp),TiC12] selectively produce (E)-alkenyl Grignard reagents in almost quantitative yields,39 e.g. Scheme 5. Ashby has reported further4* on Grignard additions to carbonyl compounds. When a Grignard reagent reacts with a diary1 ketone Ar2C0 a radical anion- '' R.D. Rieke P. T. J. Li T. P. Burns and s.T. Uhm J. Org. Chem. 1981,46,4323. 36 E. P. Kundig and C. Perret Helu. Chim. Actu 1981,64 2606. 37 H. G. Richey Jr. R. D. Smith B. A. King T. C. Kester and E. P. Squiller J. Org. Chem. 1981 46 2823. 38 K. S. Root J. Deutch and G. M. Whitesides J. Am. Chem. SOC.,1981,103,5475. 39 F. Sato H. Ishikawa and M. Sato Tetrahedron Lett. 1981,22 85. 40 E. C. Ashby and J. R. Bowers J. Am. Chem. Soc. 1981,103,2242. 288 J. L. Wardell Ph PhCGCMe + Bu'MgBr A \ /Me Ph \ /Me /c=c\HBrMg + /c=c 'MgBr [90Yo ] [loo/,] ii 1 PhCMe=CMeH + PhCH=CMe2 90 10 Reagents i [(Cp),TiCl,] ii Me1 Scheme 5 radical cation pair is formed. This can collapse to the 1,2-addition product or dissociate to a radical anion and a free radical within the solvent cage.Further reactions can lead to the 1,2-addition product or a conjugate (e.g. 1,6-) addition product or the radicals can escape from the solvent cage to form pinacol. The 1,2-addition products show free-radical character as indicated by the cyclized addition product from the reaction of Ph2C0 with a tertiary Grignard reagent [e.g. H2C=CH(CH2)3CMe2MgCl in THF] or a primary Grignard reagent [e.g. H2C=CH(CHz)2CMe2CH2MgBr in Et20]. The 1,6-addition process also shows some free-radical character (Scheme 6). R RMgX + Ph2C=0 + Ph2C=O--Mg/ $ [Ph2C-0- RMgXt] (a-complex) \ "J 1 R' + PhzC-OMgX -[PhzC-OMgX R'] + PhzCOMgX I R 11 RH Ph2C-OMgX H -1 (1,2-adduct) etc.PhzCI -0MgX Roc:;Mgx (1,6-adduct) Scheme 6 Ashby4' has also obtained the first direct evidence for the involvement of the s.e.t. mechanism in reductions of Ar,C=O e.g. (mesityl),?C=O (see Scheme 7) using RMgX where R is a primary secondary or tertiary alkyl group. The rate of electron transfer [step (a) in Scheme 71 does not depend on the stability of R. radical and is in the sequence R = But > Pr' > Bus > Et > hexenyl > Bu' > PhCH = ButCH2> Me while the rates of transfer of P-hydrogen [step (b)] are in the order Et > hexenyl > Pr' > Bus > Bu' >> But. Combination of the two steps renders Bu"MgBr a useful reducing agent. The reaction of (CF&Hg and Me2Cd in donor solvents (L = THF glyme diglyme or py) pr wided (CF3)2Cd.L,.These complexes are generally more reactive than (CF,),Hg; e.g. products derived from a carbene ( CF2) can be obtained at lower temperature^.^^ '* E. C. Ashby and A. B. Goel J. Am. Chem. SOC.,1981,103,4983. 42 L.J. Krause and J. A. Morrison J. Am. Chem. SOC.,1981,103,2995. Organometallic Chemistry -Part (ii) Main-Group Elements X / (mesityl)2C=O + RMgX $ (me~ityl)~C=O--Mg a,[(mesityl)&-~ RMgXt] 'R (a-complex) (A,, ca. 575 nm) Scheme 7 The role of charge-transfer (C/T) complexes of mercury salts and arenes in mercuriation reactions has been investigated. Absorption maxima for the complexes Hg(OCOCF3)2.ArH in solution in CH2C12 are at 267(PhC1) 273(PhH) and 288 nm ArH + HgX2 + ArHgX (mesitylene) re~pectively.~~ The second-order rate constants for the disappearance of these C/T absorptions coincide with the rate-constants (k) for mercuriation of the arenes.The relative reactivities (log k/ko)of arenes in mercuriation are linearly related to the relative charge-transfer energies (Ahva) using PhH as the reference arene. Thus the transition state for mercuriation can be linked to the charge-transfer excited state [ArHt Hg(OCOCF3)27]$. Kochi and Fukuzumi have also considered oxymerc~riations.~~ A significant finding was that while there are quite distinct R'CH=CH2 + HgXz + R20H + R'CHOR2CH2HgX patterns of reactivities in brominations and oxymercuriations of alkenes the reac- tivities of the alkenes appear identical when the differences between the steric effects in the transition states for bromination and oxymercuriation are explicitly taken into account.Barluenga et al. have reported on amidomercuriation and sulphonamidomercuri- ati~n;~' these reactions were coupled with subsequent demercuriations (Scheme 8). R3CONHCHR'CHR2HgN03 3 R3CONHCR'CH2R2 R'CH=CHR~ TsNHCHR'CHR2HgN03 -% TsNHCHR'CH2R2 (Ts = p-MeC6H4S02) Reagents i Hg(NO,), CH,CI, reflux; ii R3CONH,; iii NaBH,; iv TsNH Scheme 8 Hydroxymercuriations of mono- or di-substituted alkenes occur in high yield and with very high regioselectivity (Markownikov) when HgX2 (X = OAc 43 S. Fukuzumi and J. K. Kochi J. Phys. Chem. 1981 85 648; J. Am. Chem. SOC.,1981 103 7240; J. Org. Chem. 1981,46,4117. 44 S. Fukuzumi and J.K. Kochi J. Am. Chem. SOC.,1981,103,2783. J. Barluenga C. Jimenez C. Najera and M. Yus J. Chem. SOC.,Chem. Commun. 1981,670 1178. 290 J. L. Wardell i ii RO Ro RO RO (R=PhCH;?) OH Reagents i Hg(OAc), THF at 20°C; ii aq. KCl; iii Et,BuN+ C1- OH- NaBH, CH,Cl,; iv 0,. NaBH, Me,NCHO Scheme 9 OCOCF3,NO3,or 03SMe) is used. In marked contrast only Hg(OAc) was effective in the Markownikov hydration of 1,1-di-,tri- and tetra-substituted alkene~.~~ Use of the oxymercuriation-demercuriation of alkenes has been made in a carbohy- drate4’ synthesis (e.g. Scheme 9). Reduction of organomercurials RHgX including oxymercuriated species to RH has been achieved using N-benzyl-1,4-dihydroni~otinamide.~~ In addition Bu3SnH has proved to be superior to NaBH4 in reductions of peroxymercurials prepared from non-terminal alkene~.~’ Giese et al.” have reported on further synthetic uses of radicals that were generated by the reduction of RHgX using borohydride reagents; a good illustration is the one-pot coupling of dienes and electron-deficient alkenes (Scheme 10).H2C=CHCH=CH2 H2C=CHCH(OMe)CH2HgOAc ii 1 iii iv H2C=CHCH(OMe)CH2CH2CYZH t-[H2C=CHCH(OMe)CH2.] Reagents i Hg(OAc), MeOH; ii NaBH(OMe),; iii H,C=CYZ (Y= H Me or C1; Z = CN COMe or C0,Me); iv hydrogen abstraction Scheme 10 5 Group3 The mechanism of the zirconium-catalysed carboalumination of alkynes has been further examined. These reactions are indeed direct carboaluminations assisted by zirconium-containing species (rather than carbozirconations assisted by an alane).’l The reaction of hept-1-yne and Et,Al in the presence of MeClZr(Cp) [reaction 46 H.C. Brown P. J. Geoghegan Jr. and J. T. Kurek J. Org. Chem. 1981,46,3810. 47 J. R. Pougny M. A. M. Nassr and P. Sinay J. Chem. SOC.,Chem. Commun. 1981 375. 48 H. Kurosawa H. Okada and T. Hattori Tetrahedron Lett. 1981 22 4495. 49 A. J. Bloodworth and J. L. ‘Courtneidge J. Chern. SOC.,Chem. Commun. 1981 1117. B. Giese and K. Heuck Chem. Ber. 1981 114 1572; B. Giese K. Heuck and U. Lunig Tetrahedron Lett. 1981 22 2155. ” T. Yoshida and E. I. Negishi J. Am. Chem. SOC., 1981,103,4985. Organometallic Chemistry -Part (ii)Main-Group Elements 291 n-C5H11 H (i) MeClZr(Cp) \c=c/ + n-C5HI1C=CH +Et3Al (ii) H,O Et' \H 70 L93% total yield J (13)] gave only traces of methylated alkenes.Rapid Me/Cl exchanges occur in the Me3A1/C12Zr(Cp) system but not in any other Me,A1C13-,/Me,C12-,Zr(Cp)2 mixtures; however all systems undergo carbometallation reactions of hept- 1-yne. Negishi also recommended51 that to limit the extent of hydroaluminations that occur when using branched-chain alkyl-alanes the combination R2A1Cl/Cl2Zr(Cp), rather than R,Al/Cl,Zr(Cp), should be employed. Carbo- aluminations of propargyl or homopropargyl derivatives5 that contain OH OSiMe2Bu' SPh or I by Me3Al proceed in a highly stereo- and regio-selective manner to give the corresponding (E)-(2-methyl-alkeny1)dimethylalanes(12). This high regioselectivity is in marked contrast to other known carbometallations.Cleavage of the C-A1 bond in (12) can lead52 to a variety of difunctionally substituted alkenes (e.g. see Scheme 11). Z(CH&CrCH Z(CH2) H -%Z(CH2) H \/ \/ Me /C=C\AlMe2 Me/c=c \C02Me (12) (Z =OH OSiMe2Bu' SPh or I; n =1or 2) Reagents i Me,Al Cl,Zr(Cp), at r.t. ClCH,CH,Cl; ii ClC0,Me Scheme 11 The reactions of R3Al (R =Me Et or Bu) with diary1 ketones or Ph,CCl were shown to proceed via s.e.t. mechani~rns;~~ (mesityl),CH was obtained from (mesityl),CO and Et,Al in THF. Reactions of isobutylaluminium halides with Pr'COPh have been investigated in Et20 solution at 0 "C. Di-isobutylaluminium halides rapidly reduce the ketone to Pr'CHOHPh but BuiAlX2 and Bu3'A12X3 give rise to Pr'CHXPh and Me2C=CHPh in addition to the carbinol.When chiral (2-methylbuty1)aluminium derivatives are employed both Pr'CHOHPh and Pr'CHXPh are optically active.53 Addition reactions of various organo-aluminium compounds R21A1Y (Y =OR2 SR2 SeR' or NR22) have been reported; 1,4-addition of R2A1SPh or of R2AlSeMe to @-unsaturated carbonyl compounds occurs; the reaction of the aluminium enolates with aldehydes provides aldol add~cts;~~ e.g. see reaction (14). Aminolysis of epoxides occurs readily if Et2AlNR2is [reaction (15)]. The compound 4-Me-2,6-Bu2'C6H20A1Bu2' has been shown to be a most useful 52 C. L. Rand D. E. van Horn M. W. Moore and E. I. Negishi J. Org. Chem. 1981,46,4093. "G. Giacomelli and L. Lardicci J. Org. Chem. 1981,46 3116. 54 A. Itoh S. Ozawa K. Oshima and H.Nozaki Buff.Chem. Soc. Jpn. 1981,54 274. "L. E. Overman and F. A. Flippin Tetrahedron Lett. 1981 22 195. 292 J. L. Wardell reductant in prostaglandin syntheses e.g. for reducing PGE methyl ester to PGFz methyl ester in 95% chemical yield and with 100% selectivity.’6 The compound Me(CHz)3CH(OMe)CH2Tl(OAc)2, prepared from hex-l-ene and Tl(OAc) in MeOH is stable for a week. By contrast the methoxythalliation adduct obtained from Tl(OCOCF3)3 undergoes rapid oxidative dethalliation (ca. 85YO dethalliation after 1 hour) to give 1,Z-dimethoxyhexane and 2-metho~yhexanol.~~ The Me0 and HO groups in these products were considered to arise by easy exchange of ligands at the thallium centre followed by transfer of these Me0 or HO groups from thallium to C-1 in a SNiprocess.6 Group4 Further work has been carried out on silenes. Dimethylsilene (MezSi :) generated from Me12Si6 by photolysis adds regiospecifically to allylic methyl ethers and allylic methyl s~lphides;~~ e.g. see reaction (16). MelzSi6 -% MeZSi Me,C=CHCH,OMe b H2C=CHCMezSiMezOMe Insertion of (Me,Si)PhSi :[produced from (Me3Si)3SiPh] into a variety of carbon- chlorine bonds of RCI has been reported” (R = allyl alkyl or vinyl; e.g. see Scheme 12). (Me3Si)3SiPh -% (Me3Si)PhSi (Me3Si)PhSi + R2C=CHX RzC-CHX + [ >/ ]Ph hMe3 RzC=CH X \//St+ Ph SiMe3 X = C1,R = H X = Br,R = Me Scheme 12 56 S. Iguchi H. Nakai M. Hayashi H. Yamamoto and K. Maruoka. Bull. Chem. SOC.Jpn. 1981,54,3033. ’’ A.J. Bloodworth and D. J.Lapham J. Chem. SOC.,Perkin Trans. I 1981,3265. ’* A.Chini and W. P. Weber Inorg. Chem. 1981,20 2822;D.Tzeng and W. P. Weber J. Org. Chem. 1981 46,693. ’’ M. Ishikawa K. I. Nakagawa and M. Kumada J. Organomet. Chem. 1981 214 277; M.Ishikawa K. 1. Nakagawa S. Katayama and M. Kurnada ibid. 1981 216 C48;J. Am. Chem. Soc. 1981,103 4170. Organometallic Chemistry -Part (ii)Main-Group Elements 293 The spirosilane (13) has been produced by the reaction of butadiene6' with the cyclic silene (14) (Scheme 13). The spirosilane was also obtained from the con- densation of silicon vapour with butadiene in a Timms 'freeze-fry' metal- evaporation apparatus (a temperature of ca. 1600 "C was required).60 (310°C) . H2C=CHCH=CH2, Si I / Meo'3 GiD Me& (14) (13) Scheme 13 Dimethylgermylene (MezGe :) generated61 from 7-germabenzonorbornadienes (15) added stereospecifically (as expected for a singlet species) to (E,E),4-diphenylbutadiene and to diallenes (Scheme 14).Only the (Z,Z)-and (E,E)-pairs Me Me \/ R A [Me2Ge:] -!!+ PhoPh Ph H /ce\'H ki R Me Me (15) /\ MC Me (16) R' = Me,R2 = Ph R' = Ph,R2 = Me Reagents i heat at 70-150 "C; ii (E,E)-PhCH=CHCH=CHPh; iii meso-PhMeC=C=C=C=C=CMePh Scheme 14 of isomers of (16) were obtained from meso-diallene. This is as anticipated for a thermal [2 + 41 cheletropic reaction of the Me2Ge The X-ray structures of (Cp),Sn and (MeSC=J2Pb have been determinedq6' Each compound is monomeric and has pentahapto-bonded rings; for (Cp),Sn d(Sn-C) is 2.56-2.85 A the angles (ring centroid)-Sn-(ring centroid) being 148.8 and 143.70'; for (Me,C,),Pb d(Pb-C) is 2.69-2.90 A and the angle (ring centroid)-Pb-(ring centroid) is 151".The divalent Pd" species (17) is monomeric and soluble in such as THF MezN-CH; (17) 60 P. P. Gaspar Y.S. Chen A. P. Helfer S. Konieczny E. C. L. Ma and S. H. Mo J. Am. Chem. Soc. 1981,103,7344. 61 M.Schriewer and W. P.Neumann Angew. Chem. Znt. Ed. Engl, 198120 1019. 62 J. L. Atwood W. E. Hunter A. H. Cowley R. A. Jones and C. A. Stewart J. Chem. SOC.,Chem. Commun. 1981,925. 63 P.P. de Wit H. 0.van der Kooi and J. Wolters J. Organomef. Chem. 1981 216 C9. 294 J.L.Wardell CHC13 or PhH [reaction (1 7)].Reversible thermal decomp~sition~~ of R3SnSnR3 to the radical R3Sn' occurs in compounds having bulky R groups; for (2,4,6-R3C6H2)3SnSn(2,4,6-R3C6H2)3, the dissociation temperatures are 180 100 and 20 "C for R =Me Et and Pr'.The silaethene (18) (m.pt 95 "C) was obtained by photolysis of the acyl-silane (19); compound (18) was characterized by i,r. n.m.r. and mass spectra.65 On standing in solution (18) reverts to (19). 0 II (Me3Si)3Si-C-C10HI5 (Me&)zSi=C ,OSiMe3 \ ClOHl5 (18) v(Si=C) = 1135 cm-' S[29Si(sp2)]=41.8 p.p.m. S['3C(spZ)] =214.2 p.p.m. 3 Silaethenes (21)have been synthesized by retro-diene cleavages of (20),under flash vacuum pyrolysis (Scheme 15) and trapped in argon matrices at 10 K. The i.r. and U.V. spectra of (21) were recorded.66 Six, /I (20) Y =CF3 or (X =H D or C1) COZMe Reagents i YCzCY; ii flash vacuum pyrolysis (650"C; lop4Torr) Scheme 15 Evidence was found for the isomerization of 2-silapropene (MeSiH=CH2) and dimethylsilylene (Me2Si :).Dimethylsilylene photolytically generated from Me12Si6 in an argon matrix at 10 K or a hydrocarbon matrix at 77 K is converted into MeSiH=CH by visible light.Annealing of argon matrices of MeSiH=CH2 at 50 K provides the dimer (Scheme 16); however at a higher temperature and in a hydrocarbon matrix rapid reversion to MezSi :OCCU~S.~'From the low-pressure pyrolysis of 1-methylsilacyclobutane at 625"C in a flow system both MeSiH=CH2 hr Me H (450nm) Ar matrix \n/ Me,Si:= MeSiH=CH Si Si EtCHMeEt /v\ matrix H Me at 100K Scheme 16 64 H.U. Buschhaus W. P. Neumann and T. Apoussidis Liebigs Ann. Chem. 1981 1190. 65 A. G. Brook F. Abdesaken B. Gutekunst G. Gutekunst and R. K. Kallury J. Chem. Soc. Chem. Commun. 1981,191. 66 G. Maier G. Mihtn and H. P. Reisenauer Angew. Chem. Znt. Ed. Engl.. 1981,20,597. 67 T. J. Drahnak J. Michl and R. West J. Am. Chem. Soc. 1981,103,1845;R. T.Conlin and D. L. Wood ibid. p. 1843. Organometallic Chemistry -Part (ii)Main-Group Elements and Mez% :could be separately trapped by butadiene and Me,SiH respectively in yields greater than 60%. Thermolysis and photolysis of (22) provide different products,68 as illustrated in Scheme 17. It was reported that photointerconversion of (22) and (23) occurs at Conditions i heat; ii hv Scheme 17 all temperatures studied.In solution loss of MezSi=SiMez and isomerization to (23) are competing decomposition pathways of (22). In argon or 3-methylpentane matrices loss of MezSi=SiMez from (22) is prevented and so only photoisomeriz- ation occurs. Trapping of MezSi=SiMe2 by anthracene or cyclopentadiene was also reported. Amongst the products of the flash vacuum pyrolysis of (24) is the dimer of 1-methylsilatoluene (25),69 which suggests the intermediacy of the silatoluene formed as shown in Scheme 18. Conditions i heat at 600 “C (1,3-rearrangement); ii elimination of Me,SiOMe Scheme 18 Three distinct routes to carbon-metal-bonded compounds from metal-metal compounds have been reported. These are reactions of (i) Me3SiSiMe3 and dihalogenonitrobenzenes in the presence’’ of [Pd(PPh,),] [reaction (18)] (ii) R,MM‘ and alkyl alkenyl or aryl halides” (M = Ge Sn or Pb; M’ = Li or Na) HMPT for 3 h Me3SiSiMe3+ 2,5-C12C6H3N02-2-NoZ-5-ClC6H3SiMe3 (18) (2 equiv.) [(Ph,P),PdI 68 Y.Nakadaira T.Otsuka and H. Sakurai Tetrahedron Letf. 1981 22 2417 2421; J. D. Rich T. J. Drahnak R. West and J. Michl J. Organomet. Chem. 1981 212 C1. 69 T. J. Barton and M. Vuper J. Am. Chem. SOC. 1981,103,6788. ’O H. Matsumoto K. Shono and Y.Nagai J. Organomet. Chem. 1981,208 145. ” M. S. Alnajjar and H. G. Kuivila J. Org. Chem. 1981 46 1053; J. san Filippo and J. Silbermann J. Am. Chem. SOC. 1981,103,5588; V.S. Zaugorodnii N. D. Grigor’eva and A. A. Petrov Zh. Obshch. Khim. 1981,51,2155; W.Kitching H. Onszowy and K.Harvey J. Org. Chem. 1981,46,2423. 296 J. L. Wardell and (iii) alkyne~~~ and cuprates e.g. (PhMezSi)zCuLior (R3SnCuX)Li which provide alkenyl-metal compounds. Organosilylated hydroxylamines R:Si -N(OR2)X (X = Et02C ArCO ArS02 or Me) have been shown to be nitrene [reaction (19)]. The OR2 RtSiN ’ -B R$iOR2 + [ :N-X] (19) ‘x stereochemistry of nucleophilic substitutions at chiral germanium centres e.g. (25) has been extensively studied. The stereochemical results are similar to those found for silicon O-Me Ge / ‘*.\ X Me (25) X = C1 OR SR NRz or PR2 7 Group5 Arsabenzene (26) undergoes electrophilic substitutions mainly at the 2-and 4- positions; e.g. the ratio of rates of acetylation at -78 “C are 40 :(1):300 for the 2- 3- and 4-positions respectively.Arsabenzene is lo3-lo4 times more reactive than PhH. Other substitutions that have been studied by Ashe were nitration and proton-deuteron exchange as well as protodesilylation of 2-and 4-trimethylsilyl- ar~abenzenes;~~ in the proton-deuteron exchanges and protodesilylations the 2-positions were more reactive than the 4-positions which is the opposite of the finding for acetylation and nitration. Several interesting heterocyclic arsenic species have been synthesized; these included some fourteen-membered quadridentate cyclic ligands (27) prepared by high-dilution [reaction (20)]. The stereochemistry was assigned from the n.m.r. spectra. (20) (X = AsMeorPPh) Y = 0,L = OMes Y = S L = OMes Y = AsMe L = C1 72 E.Piers J. M. Chong and H. E. Morton Tetrahedron Lett. 1981 22,4905; I. Fleming T. W. Newton and F. Roessler J. Chem. SOC.,Perkin Trans. 1 1981 2527; D. E. Seitz and S. H. Lee Tetrahedron Lett. 1981 22,4909. 73 Y. H. Chang F. T. Chiu and G. Zon J. Org. Chem. 1981,46,342. 74 J. Dubac J. Cavezzan A. Laporterie and P. Mazerolles J. Organomet. Chem. 1981,209 25. ” A. J. Ashe 111 W. T. Chan T. W. Smith and K. M. Taba J. Org. Chem. 1981,46 881. 76 E. P. Kyba and S. S. P. Chou J. Org. Chem. 1981,46,860. Organometallic Chemistry -Part (ii)Main-Group Elements The first monocyclic three-membered arsenic ring compound (Bu'As) (28) has been obtained from the reaction of KBu'AsAsBu'K and Bu'AsC12 at -78°C. Compound (28) is table'^ in the dark and in the absence of air at -3O"C but it oligomerizes to (Bu'As) at room temperature.Another interesting cyclic arsenic derivative77 is But6Ass (29) which is the major product of the reaction between Bu'AsCl, AsC13 and Mg. Bu' Bu' Bu'As -AsBu' 'A! Bu'As AsBu' Bu' 'As' \A! Bu' Bu' 2,2',5,5'-Tetramethyldistibolyl (30) is a thermochromic compound. In reflected light (30) is iridescent purple-blue while in transmitted light it is bright red. In CSbLi CSb-SFJ Me Me Me (30) solution in CC1 or PhMe and in the melt it is pale- The crystal structure has some interesting features. The molecule adopts a staggered trans configuration about the Sb-Sb axis with the rings in approximately parallel planes perpendicular to this axis. All the Sb atoms are aligned in collinear chains along the b crystal axis; the Sb * -Sb intermolecular distance of 3.625(2) 8 should be compared with a van der Waals separation of 4.4 8,.The C-Sb-C bond angles are ca.90" indicating that p-orbitals of Sb are used in bonding. ". KN(SiM(,Iz n-C,H,,CHO + Ph&CH,CH,,BF THF n-c,H~,gc'J~ (21) 10% HMPT Me [loo% trans] Reactions of unstabilized arsonium ylides prepared in situ with aldehydes79 provide epoxides; e.g. reaction (21). Some routes to Ph2R'AsCH2R2 BF, which are used in these reactions are given in Scheme 19. Ph3As 5Ph3kH2Prn BF4-Ph3AsMe,BF4-Ph2AsLi -%Ph2AsCH2Pri " ii + Ph2Bu'&CH2Pri,BF4-Reagents i BuOH (CF,SO,),O py; ii Na'BF,-; iii PrI KN(SiMe,),; iv Pr'CHJ THF; v Bu'CI AICI Scheme 19 77 M.Baudler and P. Bachmann Angew. Chem. Int. Ed. Engf. 1981,20 123; M. Baudler J. Hellmann P. Bachmann K. F. Tebbe R. Frohlich and M. Feher ibid. p. 406. 78 A. J. Ashe 111 W. Butler and T. R. Diephouse J. Am. Chern. Soc. 1981,103 207. 79 W. C. Still and V. J. Novack J. Am. Chem. SOC.,1981,103 1283. 298 J. L. Wardell 0 0 0 iii 1 Reagents i Ph,BiCO (92%); ii PhSBi (72%); iii Ph,BiOCOCF (58%) Scheme 20 Further uses of phenylbismuth(v) compounds'' in organic synthesis have been reported. The compound Ph4BiOCOCF3 is a useful reagent for selective formation of phenyl-oxygen bonds. Comparisons with other phenylbismuth species are shown in Scheme 20. D. H. R. Barton J. C. Blazejewski B. Charpiot and W. B. Motherwell J. Chern.Soc.Chem. Commun. 1981 503; D. H. R. Barton J. P. Kitchen D. J. Lester W. B. Motherwell and M. T. B. Papoula Tetrahedron 1981.37 Suppl. No. 9 p. 73.

ISSN:0069-3030    

DOI:10.1039/OC9817800281

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

13 Synthetic Methods By W. CARRUTHERS Department of Chemistry The University Exeter EX4 400 1 Introduction The pace of advance in organic synthesis makes it impossible to include more than a selection of recent methods in this Report. A number of important topics for example oxidation and reduction have been omitted (but not forgotten) and it is hoped that it may be possible to include some of these in next year's Report. 2 Alcohols An extremely simple convenient and selective method for acetylating primary alcohols in the presence of secondary ones has been reported,' and has been applied in the carbohydrate series.* Primary hydroxyalkylphenols are thus converted into acetoxyalkylphenols and primary aromatic amines into the corresponding acetamides.t-Butyldimethylsilyl tri-isopropylsilyl and octadecyldimethylsilyl triflates are useful reagents for silylation of hindered alcohols which react sluggishly with the usual silylating agent^.^ 1,2- and 1,3-diols are conveniently protected by conversion into their di-t-butylsilylene derivatives by reaction with di-t-butyldi- chlorosilane. The protecting group is easily removed by treatment with pyridinium hydr~fluoride.~ The de-oxygenation of secondary alcohols by radical reduction of thiocarbonyl esters has been shown to be a general reaction of value in the synthesis and modification of natural products.' By appropriate modification of experimental conditions the reaction has now been extended to primary alcohols.6 A modified Barton procedure was used to convert ribonucleosides into 2'-deoxyn~cleosides.~ Methods for the inversion of secondary alcohols are valuable in synthesis.Caesium carboxylates in dimethyl formamide are good nucleophiles and are useful for the introduction of hydroxy-substituents by SN2 nucleophilic substitution. In practice the best results were obtained with the propionate. Mesylates of several secondary alcohols were cleanly converted into the propionates of the inverted alcohol in high yield in warm dimethyl formamide. The inversion of (S)-2-octanol ' G. H. Posner and M. Oda Tetrahedron Lett. 1981,22 5003. S. S. Rana J. J. Barlow and K. L. Matta Tetrahedron Lett. 1981 22 5007. E. J. Corey H. Cho C. Rucker and D. H. Hua Tetrahedron Lett. 1981,22,3455. B. M. Trost and C. G. Caldwell Tetrahedron Lett.1981 22,4999. D. H. R. Barton and W. B. Motherwell Pure Appl. Chem.. 1981,53,1081. D. H. R. Barton W. B. Motherwell and A. Stange Synthesis 1981.743. 'M. J. Robins and J. S. Wilson J. Am. Chem. SOC.,1981 103,932. 299 300 W.Carruthers for example to the enantiomerically pure (R)-isomer proceeded in 86 percent yield without detectable elimination a considerable improvement on published procedures.* Kinetic resolution of racemic allylic alcohols by enantioselective epoxi- dation provides a very effective route to optically pure allylic alcohols. (S)-Allylic alcohols are epoxidized by t-butylhydroperoxide much faster than the (R)-isomers in the presence of (+)-L-di-isopropyl tartrate-titanium alkoxide catalyst leaving the (R)-alcohol of high enantiomeric purity.' Methods for the stereoselective and regiospecific synthesis of allylic alcohols continue to be explored.Reaction of alkyl-lithium reagents with isoprene epoxide in the presence of a base such as a tertiary amine or lithium alkoxide gives fly-disubstituted allylic alcohols of predominantly (2)-configuration." A promising method for the specific conversion of propargylic alcohols into (2)-yy-disubstituted allylic alcohols which complements the well known Corey route to the (E)-isomers has been described (Scheme 1). Hydromagnesiation of propargylic alcohols (e.g. 1) by isobutylmagnesium halides in the presence of catalytic amounts of (q5-C5H5)2TiC12 affords the corresponding (E)-alkenylmagnesium halide (as 2) exclus-ively in almost quantitative yield; (2) is readily converted into the iodide (3) or the (2)-3-methyl-2-heptenol (4).Bu CH20H \/ /I/c=c\H Bu CH2OMgCl (3) \/ i c=c ClMg'\H CH20H (2) Me (4) Reagents i 2 Bu'MgCl-(q5-C,H,),TiCl,; ii I, -70 "C;iii MeI-THF 0 "C Scheme 1 A novel route to stereochemically defined 1,3-enynols and 1,2,4-trienols through reaction of the organoboranes (7) and (8) with aldehydes is reported (Scheme 2),12 Reaction of the thexylalkenylchloroborane(5) with two equivalents of lithium chloropropargylide at -78 "C furnished the alkenylallenic boranes via the 'ate' complex (6). Treatment of the reaction mixture containing (7) with an aldehyde afforded the 1,3-enynol (9). However if the organoborane (7) formed initially was brought to room temperature it rearranged in a recognised fashion to (8).Reaction of this with an aldehyde produced the 1,2,4-trienol (10).Reaction of the allenic * W. H. Kruizinga B. Strijtveen and R. M. Kellogg J. Org. Chem. 1981,46,4321. V. S. Martin S. S. Woodard T. Katsuki Y. Yamada M. Ikeda and K. B. Sharpless,J. Am. Chem. SOC. 1981,103,6237. lo M. Tamura and G. Suzukamo Tetrahedron Lett. 1981 22 577. F. Sato H. Ishikawa H. Watanabe T. Miyake andM. Sato J. Chem. SOC.,Chem. Commun. 1981,718. G. Zweifel and N. R. Pearson J. Org. Chem. 1981,46 829. Synthetic Methods R' 1iii,iv 1iii,iv R' R' R& OH (9) (10) Reagents i R-G-R' ii 2 equivs. ClCH,C=CLi-THF -78 "C; iii R'CHO -78 "C; iv H20,-NaOH Scheme 2 and propargylic carbon-boron bonds of (7) and (8)with the carbonyl groups of the aldehydes must proceed with bond transposition.Much recent work has been concerned with the enantioselective synthesis of alcohols and an account of some of this can be found in the section dealing with the aldol condensation. Organoboranes have proved useful in this regard. Monoalkyl and dialkylboranes exhibit high stereo- and regio-selectivity in the hydroboration of alkenes and this property coupled with the capability for asym- metric creation of chiral centres with chiral hydroborating agents makes this reaction a valuable one for asymmetric organic ~ynthesis.'~ A new crystalline chiral hydroborating agent dilongifolylborane readily prepared from (+)-longi- folene and borane-methyl sulphide complex is highly effective for asymmetric hydroboration of alkenes providing alcohols after oxidation of the intermediate organoboranes with high optical purities corresponding to 60-78 percent excess of the (R)-enantiomer in the cases ~tudied.'~ Optically active hydroxycarboxylic acids of the general formula RCHOH(CH2),C02H have been prepared from optically active propargylic alcohols themselves obtained by reduction of propargyl ketones with B-3-pinanyl-9-borabicyclo[3,3,1]nonane'5 (Scheme 3).l3 H. C. Brown P. K. Jadhav and A. K. Mandal Tetrahedron 1981,37,3541. '* P. K. Jadhav and H. C. Brown J. Am. Chem. Soc. 1981,46 2988. M. M. Midland and P. E. Lee J. Org. Chem. 1981 46 3933. 302 W. Carruthers Reagents i BuLi; ii Me,SiCl; iii HCI; iv (C6Hll)$H; v H20,-NaOH; vi Ac@; vii KMnO Scheme 3 It has been shown previously16 that intramolecular cyclic hydroboration of acyclic dienes provides an effective method for the stereoselective synthesis of acyclic molecules having widely separated asymmetric centres.The usefulness of this procedure has now been illustrated by the synthesis of the Prelog-Djerassi lactonic acid (12) from enantiomerically pure (11); (Scheme 4).17 The key hydroboration ButMe2SiO% Me i ii ButMe2sioTHYe + Me" Me' Me (1 1) H liii Reagents i BH,-THF; ii H,O,-NaOH; iii several steps Scheme 4 of (11)proceeded with the desired stereoselection for the p-face of the C-5-C-6 double bond to the extent of >20 :1.The chiral centre in (11)induces all the other chiral centres in a relatively efficient way except that at C-2 which results from the initial stereorandom hydroboration.A novel sequence that may be used to prepare erythru-1,2- or -1,3-diols from allylic or homoallylic alcohols involves initial stereoselective formation of the cyclic iodocarbonates followed by reductive removal of iodine and liberation of the diol with base (Scheme 9.'' A potential route to stereo-enriched 1,2- or 1,3-diols or 1,2,3-triols is provided by the iodolactonization of 3-hydroxy-4-alkenoic acids which leads predominantly to the thermodynamically less stable 3-hydroxy-4-alkyl- y-lactones (13). l6 W. C. Still and K. P. Darst J. Am. Chem. Soc. 1980,102,7385. l7 W. C. Still and K.R.Shaw Tetrahedron Lerr. 1981 22 3725. G. Cardillo M. Orena G. Porzi and S.Sandri,J. Chem. Soc. Chem. Commun. 1981,465. Synthetic Methods R' lv OH OH Reagents i BuLi; ii CO,; iii I,; iv Bu,SnH; v NaOH Scheme 5 Methanolysis of these affords mainly the threo- epoxy-alcohols (14) usefully with the opposite relative configuration of the hydroxy- and epoxy-groups from that obtained by direct epoxidation of the hydroxy-ester by the Sharpless procedure (Scheme 6)." A highly stereoselective synthesis of erythro-a@- epoxy-alcohols by reduction of a@-epoxy-ketones with zinc borohydride is reported.20 High preference for the erythro-isomer remains whatever the substitution pattern of the epoxide in contrast to reduction with sodium borohydride.Reagents i I,-CH,CN; ii -0Me; iii Bu'OOH-VO(acac),-CH,C12 Scheme 6 3 Alkenes Organoboranes continue to find new applications in synthesis. B-(Cycloalkyl-methyl)-9-BBN derivatives which are readily available from cycloalkenesY2' are readily converted into exocyclic methylene compounds by reaction with benzal- dehyde. The method appears to be general and since the synthesis proceeds from a cycloalkene it provides a valuable alternative to the well known methylenation of cyclic ketones by the Wittig and related procedures. 1-Methylcyclopentene for example is converted into 2-methylmethylenecyclopentane in 65% yield.22 The method is readily adapted to the preparation of methylene-d2- cycloalkanes but l9 A.R. Chamberlin M. Dezube and P. Dussault Tetrahedron Lea 1981 22,4611.2o T. Nakata T. Tanaka and T. Onishi Tetrahedron Lett. 1981,22,4723. H. C. Brown T. M.Ford and J. L. Hubbard J. Org. Chem. 1980,45.4067. 22 H. C. Brown and T. M.Ford J. Org. Chem. 1981,46,647. 304 W. Carruthers of course is limited to substrates which hydroborate regioselectively or which are symmetrical. Addition of copper(1) reagents to alkynes has been widely used in the synthesis of alkenes. In a new procedure it is shown that cis-dialkenylcuprates generated by addition of dialkylcuprates to acetylene add to ag-unsaturated sulphones with retention of double-bond geometry to give ?&unsaturated sulphones; these are readily desulphonylated to the corresponding alkene. The overall yields were in the range 70-80% .23 A versatile and selective route to difunctional trisubstituted (E)-alkenes by zirconium-catalysed carboalumination of alkynes has been In contrast to other known carbometallation reactions the zirconium-catalysed carboalumina- tion of alkynes shows high regioselectivity when applied to propargyl and homopropargyl derivatives containing OH OSiMe2Bu' SPh or I substituents.Coupled with known carbon-carbon and carbon-heteroatom bond-forming reac- tions this provides a route for the selective synthesis of difunctional trisubstituted olefins. Thus the iodoalkene (15) was obtained from 3-butynol in 87% yield with >98% stereoselectivity (Scheme 7). Stereochemically pure (E)-and (2)-1,2-disubstituted ethylenes are conveniently obtained by application of the Wittig- Horner modification of the Wittig reaction using diphenylphosphinoyl (Ph2PO) as Z(CH2)n H \/ Z(CH,),C=CH Me /C=C\AIMe2 Z = OH OSiMe2Bu' SPh or I; n = 1,2.Reagents i Me,Al-CI,ZrCp,; ii I,-THF -30 "C; iii Bu'Me,SiCI-Et,N Scheme 7 the anion-stabilizing group and this method has clear advantages over the conven- tional Wittig procedure for the preparation of stereochemically pure alkene~.~~ Pure (2)-alkenes are obtained from the erythro-alcohols (16) formed on addition of anions stabilized by PhzPO to aldehydes (Scheme 8). Acylation of the same anions with esters or lactones and reduction of the ketones (17) with sodium borohydride gives predominantly the threo- alcohols (18) readily purified by flash chromatography. Elimination then affords pure (E)-alkenes.The readily available [(trimethylsilyl)acetyl]trimethylsilane (19) can be used to prepare various trisubstituted olefins of defined stereochemistry by sequential deprotonation-alkylationdeprotonation-aldolizationreactions exemplified in the synthesis of the a@-unsaturated acid (21) and aldehyde (22) (Scheme 9).26A 23 G. De Chirico V. Fiandanese G. Marchese F. Naso and 0. Sciacovelli J. Chem. SOC. Chem. Commun. 1981,523 24 C. L. Rand D. E. Van Horn M. W. Moore and E. Negishi J. Org. Chem. 1981,46,4093. 25 A. D. Buss and S. Warren J. Chem. SOC.,Chem. Commun. 1981 100. " J. A. Miller and G. Zweifel J. Am. Chem. SOC.,1981,103,6217. 305 Synthetic Methods R' R ! (17) (18) Reagents i BuLi-THF -78 "C ii R'CHO; iii NaH-DMF; iv R'C0,Et or CH,(CH,),OC=O; v NaBH Scheme 8 Me$ /OLi Me,SiCH,COSiMe A \c=c 5 Me,SiCHCOSiMe3 (19) H SiMe Me (20) li IF;/\ I k-d>Me \ :osiMe] iii Me,Si /c=c\/OLI LiO SiMe Me SiMe 1 H COSiMe 9-Fco2* \I \xc=c\Me (21) +cHo(22) Reagents i LiN(Pr'),; ii MeI; iii CHO ;iv H20,-NaOH; v Bu,NF-HCO,H 75 "C Scheme 9 limitation is presented by the sluggish reaction of enolate (20) with halides other than methyl or ethyl iodides and ally1 and benzyl bromides.Higher alkyl halides react only slowly. A great deal of work continues on the synthesis of dienes and enynes. A new convenient and highly selective route to 1,4-dienes by palladium-catalysed cross-coupling of alkenylmetals containing aluminium or zirconium with allylic halides 306 W.Carruthers or acetates proceeds with essentially complete retention of the stereo- and regio- chemistry of both alkenyl and allyl groups.27 The corresponding reaction of aryl- metals such as those containing zinc is also markedly promoted by palladium catalysts but that of alkylmetals containing aluminium or zinc does not seem to be. Thus (E)-(2-methyl-1-octeny1)dimethylalane(23) prepared by the zirconium- catalysed carboalumination of 1-octyne with trimethylaluminium reacts with allyl bromide in presence of (Ph3P)4Pd to produce the cross-coupled product (24) in greater than 90% yield (Scheme 10). In the absence of the palladium catalyst the yield of coupled product was negligible. Reagents i e B r ;ii 5mol.% Pd(PPh,),-THF 0"C Scheme 10 A new route to 2-substituted butadi-1,3-enes makes use of the radical reduction of a-(hydroxymethy1)allyl sulphones with tri-n-butyltin hydride.The sulphones themselves are conveniently obtained by alkylation of the anion of allyl tolyl sulphone with alkyl halides followed by hydroxymethylation with paraformal- dehyde*' (Scheme 11). Reagents i BuLi; ii (CH,O) ;iii Bu,SnH-azobisisobutyronitriie-benzene,reflux Scheme 11 (E,Z)- and (2,Z)-1,3-dienes have been obtained stereospecifically by reaction of (2)-1-alkenyldisiamylboranes with (2)-or (E)-1-alkenyl bromides in the presence of a catalytic amount of (Ph,P),Pd and sodium eth~xide.~' The correspond- ing (E,E)-and (2,E)-dienes were obtained equally well by reaction of (E)-1-alkenyl-1,3,2-benzodioxaboroleswith the appropriate (E)-and (2)-1-alkenyl bromides.A similar sequence of reactions was employed in the synthesis of insect sex pheromones containing conjugated diene Several insect pheromones with an (E,E)-1,3-diene system have been synthesized by a novel general stereospecific procedure using a preformed simple 1,3-diene locked in the (E)-configuration by an iron tricarbonyl protecting group. Friedel- 27 H. Matsushita and E. Negishi J. Am. Chem. Soc. 1981,103,2882;see also Y.Hayasi M. Riediker J. S. Temple and J. S. Schwartz Tetrahedron Lett. 1981 22 2629. Y.Ueno H.-Sano S. Aoki and M. Okawara Tetrahedron Lett. 1981 22,2675. 29 N. Miyaura and H. Suginome Tetrahedron Lett. 1981.22 127. 30 R. Rossi A.Carpita and M. G. Quirici Tetrahedron 1981,37 2617. Synthetic Methods 307 Reagents i AIC1,-CICO(CH,),CO,Et; ii LiAIH,-AlCl,; iii Ac,O; iv Me,N +0 Scheme 12 Crafts acylation and further manipulation gave the long-chain diene as in Scheme lT31 Conjugated dienes can also be obtained with high isomeric purity by coupling of alkenyl cuprates and alkenyl halides in the presence of zinc bromide and a catalytic amount of PdoL4.32 The pinacol (E)-1-trilnethylsilyl-l-propene-3-boronate (25) in line with other 2-alkene-1-boronic esters reacts with aldehydes to yield (k)-(R,S) -3-trimethylsilyl-4-hydroxy-1-alkenes which are readily deoxy- silylated to give either (2)-or (E)-terminal dienes of >98% isomeric purity (Scheme 13).33 Reagents i RCHO; ii (HOCH,CH,),N; iii KH-THF; iv H,SO,-THF Scheme 13 The anion derived from bis(t-butyldimethylsily1)propyne reacts regioselectively with carbonyl compounds to give enynes with a preponderance of the (2)-isomers as shown in Scheme 14.Very high yields of the (Z)-isomer are obtained when the lithium counter ion is replaced by magne~iurn.~~ Thus hexanal gave a 65% yield of enyne (26) containing about 98% of the (2)-compound. Enynes of high stereoisomeric purity are obtained in excellent yields by reaction of alkenylcopper Bu'Me2SiCH2CGCSiMezBu' i* ii + Bu'Me2SiCH=C=C-SiMezBu' I 1iii Mg Y Ill I SiMe,Bu' (26) Reagents Bu'Li-THF -78 "C; ii MgBr,-ether; iii wCHO Scheme 14 31 G. R. Know and I. G. Thorn J. Chem. SOC.,Chem. Commun.1981,373. 32 N. Jabri A. Alexakis and J. F.Normant Tetrahedron Lett. 1981,22 959. j3 D.J. S.Tsai and D. S. Matteson Tetrahedron Lett. 1981,22 2751. 34 Y. Yamakado M. Ishiguro N. Ikeda and H. Yamamoto. J. Am. Chem. SOC.,1981,103,5568. 308 W. Carruthers intermediates generated in situ from ‘ate’ complexes of 9-borabicyclo[3,3,1]nonane and cuprous iodide or cuprous bromide-dimethyl sulphide complex with 1-halo-1-alkynes. The stereochemistry of the double bond in the enyne is defined by that of the starting alkenylb~rane.~’ The highly hindered olefin (29)was obtained in 65% yield by reaction of (27) with (28) at 185°C (Scheme 15). The related (30) was prepared by a similar method.36 4 Aldol condensation Work continues apace on stereoselective aldol condensations stimulated by wide- spread interest in using the aldol reaction in the synthesis of naturally occurring \ + Ph3PN-Na/ -* / (27) (28) (29) (30) Scheme 15 macrolide and ionophore antibiotics.There appears to be some uncertainty about the stereochemical nomenclature of aldol products. In the convention used by Heathcock3’ if the main aldol chain is written in an extended zig-zag conformation that diastereomer which has the C substituent and the CBhydroxy-group both extending toward the viewer or away from the view is called the erythro- diastereomer (31) and the other the threo (32) although this is not in agreement with the Fischer convention as it is customarily interpreted. The same system is used by Bartlett38 and Evans3’ Masam~ne,~’ however would apparently call (31) the syn-isomer and Kishi4’ would regard (31) as the threo-isomer.R R’ R’ R’ (31 erythro) (32 threo) Scheme 16 ” H. C. Brown and G. A. Molander J. Org. Chem. 1981,46,645. 36 E.R.Cullen F. S. Guziec M. I. Hollander and C. J. Murphy Tetrahedron Lett. 1981,22 4563. 37 C. H. Heathcock C. T. White J. J. Morrison and D. Van Derveer J. Org. Chem. 1981,46,1296. ’* P. A.Bartlett Tetrahedron 1980 36 2 Tables 7 and 9. 39 D. A.Evans J. Bartroli and T. L. Shih J. Am. Chem. Soc. 1981 103 2127; D. A. Evans J. V. Nelson E. Vogel andT. R. Taber J. Am. Chem. Soc. 1981,103 3099. *O S. Masarnune Sk. A. Ali D. L. Snitrnan and D. S. Garvey. Angew. Chem. Inr. Ed. Engl. 1980 19 557. 41 cf.N. Nagaoka and Y.Kishi Tetrahedron 1981,37 3873. Synthetic Methods 309 Earlier work has led to an understanding of the factors responsible for stereocon- trol in aldol condensations (s~mmarized~~). When carried out in aprotic solvents in the presence of a co-ordinating counter ion the reactions proceed by way of chelated six-centred cyclic transition states. For kinetically controlled reactions the erythro- product (Heathcock sense) is favoured from (Z)-enolates whereas the threo- product usually predominates from (E)-enolates. Under thermodynamic control the threo- product is favoured regardless of the geometry of the starting enolate. Much recent work has been concerned with increasing the selectivity of the reactions even further. Evans and his co-workers have now published4* a full account of their study of the generation of stereochemically homogeneous boron enolates from ketones and carboxylic acid derivatives and their stereoselective aldol reaction with a range of aldehydes.For a range of acyclic ketones consistently good correlation was observed between the geometry of the enolate and the stereochemistry of the aldol products regardless of the structure of the ketone or the boron ligands. For the reaction of the cis-enolate of 3-pentanone with isobutyraldehyde for example the erythro-aldol formed at least 97%of the product the same within experimental error as the proportion of cis-isomer in the enolate (Scheme 17). LL Me Me Scheme 17 Carboxylic acids could also be converted into the dialkylboryl enediolates.The enediolate from propionic acid on condensation with benzaldehyde afforded mainly the threo-2-methyl-3-hydroxycarboxylicacid; with benzyloxyacetic acid the threo-isomer was the exclusive product. The reaction of chiral boron enolates with aldehydes was also studied. Enolates derived from methyl ketones gave only moderate levels of chirality transfer but with the cis-enolate derived from the ethyl ketone (33)the stereochemically homogeneous erythro-aldol (34) was obtained in 57% yield by direct crystallization from the reaction mixture (Scheme 18). 42 D. A. Evans J. V. Nelson E. Vogel and T. R. Taber J. Am.Chem. Soc. 1981,103,3099. 310 W.Carruthers Tos Tos (33) (34) Reagents i LiN(Pr') or L,BOSO,CF,-EtN(Pr'),+ther -78 "C; ii >CHO Scheme 18 Chiral boron enolates have been used in a highly effective enantioselective synthesis of erythro-P- hydroxy-a-methylcarboxylic acids (38) and (41); (Scheme 19).43Reaction of the chiral enol boronates (36)and (40) prepared from the chiral Me OSiMe,Bu' Bu'Me,SiO H HO 1iii iv (38) ".c ii-iv ,R '-OH Me Bu'Me,SiO HO 0 (39) (40) (41) Reagents i R2BOS0,CF,-EtN(Pr'),-CH~Clz -78 "C; ii R'CHO; iii HF-CH,CN; iv NaI0,-MeOH-H,O,r.t.Scheme 19 a-trimethylsilylketones (35) and (39) with a range of aldehydes followed by desilylation and oxidative cleavage with sodium metaperiodate gave the a-alkyl-P- hydroxycarboxylic acid with a high degree of erythro- selectivity. Both pure enan- tiomers of the erythro-products could be obtained by starting with the appropriate dialkylboron enolate derived from (1s)-or (1R)- t-butyldimethylsiloxy-l-cyclo-hexylbutan-2-one.The diastereoselectivity of the new reagents (36) and (40) is greatly superior to that of any reported previously for this sequence. (R)-and 43 S. Masamune W. Choy F. A. J. Kerdesky and B. Imperiali J. Am. Chem. Soc.,1981,103,1566; W. Choy P. Ma and S. Masamune Tetrahedron Lett. 1981,22 3555. (/+ Synthetic Methods (S)-methyl p-hydroxyisobutyrate for example were obtained in greater than 98% optical purity and the control possible in complex cases has been vividly demon- strated in a synthesis of 6-deoxyerythronolide B.44 Another procedure for the enantioselective synthesis of p-hydroxy-cr-alkylcar-boxylic acids of both the erythro-and threo-series makes use of chiral boron azaen~lates,~~ although the enantioselectivity is not as high as that achieved in Masamune's method outlined above.By changing the location and nature of the chiral auxiliary unit the stereochemical course of the aldol process was altered from predominantly threo (77-85% enantiomeric excess) to erythro (40-60% enan- tiomeric excess). Chiral erythro p-hydroxy-a-methylcarboxylic acid derivatives can also be obtained through boron enolates derived from N-propionylimides (42b) and (43b) of the recyclable chiral auxiliaries (42a) and (43a).46 The imides (42b) and (43b) undergo highly stereoselective enolization with either lithium di-isopropylamide (THF -78 "C) or di-n-butylboryl trifluoromethanesulphonate to form the corres- ponding (2)-enolates almost exclusively.Condensation of the boron enolates with several aldehydes and oxidative work-up led to the stereoisomeric aldol adducts (44) and (45); (Scheme 20). For the boron enolate reactions the combined threo-adducts never amounted to more than 0.9% of the product and in all cases the imide (42b) afforded erythro-isomer (44) whereas (43b) gave (45) with the y O\'O (43) a; R = H b; R =1COCHzMe i-iii (44) (45) Reagents i Bu2BOS0,CF,-(P~),NEt-THF,-78 OC; ii R'CHO; iii 30% H202; iv KOH-MeOH Scheme 20 44 S. Masamune M. Hirama S. Mori Sk. A. Ali and D. S. GaNey J. Am. Chem. SOC.,1981,103 1568. 45 A. I. Meyers and Y. Yamamoto J. Am. Chem. SOC.,1981,103,4278.46 D.A.Evans J. Bartroli andT. L. Shih J. Am. Chem. SOC.,1981,103 2127. 312 W. Carruthers opposite sense of asymmetric induction. In contrast condensations using the lithium enolates showed low levels of stereoselectivity. Excellent results have also been obtained with the zirconium enolates (46) and (49) shown in Scheme 2 1. Condensation with aldehydes afforded the erythro- aldols (47) and (50) with high selectivity (96-989'0) and after hydrolysis the erythro-8- hydroxy-a- methylcarboxylic acids (48) and (5 1) of opposite absolute (47) R' = methoxymethylene (48) (49) Reagents i RCHO; ii H30+ Scheme 21 stere~chemistry.~' For reaction of isobutyraldehyde with the enolate (46) the product was 96% the erythro-aldol (47; R = i-C3H7) whereas with enolate (49) 97.5% of (50) was obtained.In contrast the lithium enolates showed low levels of both erythro-threo diastereoselection and enolate diastereoface selection under kinetic conditions in all the cases studied. The aldol condensation of the enolates (46) and (49) with chiral a-substituted aldehydes also showed excellent results. Thus reaction of zirconium enolate (49) with both (S)-(52) and (R)-(52) again gave very high levels of erythro-selection (Scheme 22). Similar results were obtained Me (52) (S,R,S)-erythro :(R,S,R)-erythro :threo 98.7 10.9 0.4 ii Reagents i py bMe ' ;ii H,O+ 0- Scheme 22 " D. A. Evans and L. R. McGee. J. Am. Chem. SOC.,1981,103,2876. Synthetic Methods in condensations of (46) with aldehydes (S)-(52) and (R)-(52).The erythro- specificity of the zirconium enolates is attributed to steric interactions in the transition state between the substituents on the enolate and the bulky cyclopen- tadienyl ligands on the metal. Other metal enolates besides the lithium zirconium and boron derivatives have been employed in the aldol reaction. Previous work has shown that the Lewis-acid mediated addition of both cis-and trans-crotyltrialkyltin to aldehydes leads prefer- entially to erythro- products. It is now found4' that triphenyltin enolates prepared from lithium enolates and triphenyltin chloride in tetrahydrofuran at -78 "C undergo rapid aldol condensation with aldehydes without assistance from Lewis acids to give predominantly the erythro-products regardless of the geometry of the enolate.Erythro-compounds are also the main products from the reaction of silyl enol ethers with aldehydes in the presence of a catalytic amount of tris(diethy1- amino)sulphonium difluorotrimethylsiliconate again irrespective of the configur- ations of the en01ates.~~ Titanium enolates also give rise to erythro- aldols preferen- tially. They provide a means of obtaining erythro- products from cyclic ketones; these have hitherto not been readily available because their formation has required the geometrically inaccessible (Z)-en~lates.'~ The diastereoselection with the titanium enolates is reported to be higher than that available using zirconium or tin enolates. Hitherto threo-aldolization products have not been easy to come by but it has now been found that preformed lithium enolates of certain hindered aryl esters condense with aldehydes to give predominantly threo- aldols thus providing a good preparative route to threo-a-alkyl-P- hydroxycarboxylic acids (Scheme 23)." The propionate (53) for example prepared from 2,6-dimethylphenol reacts with ben- zaldehyde and a-unbranched aliphatic aldehydes to give threo :erythro ratios of about 6.5 1.With aldehydes branched at the a-position the threo-aldols were the (53) >98% threo (54) R' = Me (55) R' = OMe Reagents i LiN(Pr'),-THF -78."C; ii >CHO ; iii KOH-H,O-MeOH 25 "C Scheme 23 '* Y. Yamamoto H. Yatagai and K. Maruyama J. Chem. SOC.,Chem. Commun. 1981 162. '' R.Noyori I. Nishida and J. Sakata J. Am. Chem. SOC.,1981 103 2106. M. T. Reetz and R. Peter Tetrahedron Lett. 1981,22,4691. C. H. Heathcock M. C. Pirrung S. H. Montgomery and J. Lampe Tetrahedron 1981,37,4087. 314 W. Carruthers only products detected. Hydrolysis .afforded the corresponding threo-a-alkyl-P-hydroxycarboxylic acids. The esters (54) and (55) gave only threo-aldols with all aldehydes studied but they could not be hydrolysed without retroaldolization. Aldols from (54) can be reduced with lithium aluminium hydride to the correspond- ing threo-diol and aldols from (55) are converted into the P-hydroxy-acid by oxidation with ceric ammonium nitrate. A general synthesis of erythro-a-alkyl-P- hydroxyketones has been reported. It is well known that ketones having one bulky group attached to the carbonyl group give homogeneous (2)-enolates on treatment with lithium di-isopropylamide which condense with aldehydes to give erythro-aldols.But other ketones give mixtures of (2)-and (E)-enolates which take part in the aldol condensation with varying degrees of kinetic stereoselectivity. The general method (Scheme 24) now Reagents i LiN(Pr’),; ii RCHO; iii H,IO,-MeOH; iv I -H+; v BuLi 0 Scheme 24 put forward is based on a route from the same laboratory to erythro-a- hydroxy-acids [for example (58)]from the ketone (56) by reaction with aldehydes followed by reduction of the carbonyl group of (57) and oxidation with periodic acid.52 It is now showns3 that protection of the hydroxy-group in the aldol (57) reaction with an alkyl-lithium reagent (Grignard reagents are unsuitable) and oxidation affords the erythro-P-hydroxy ketone (59)in high yield.It is to be noted that this sequence not only accomplishes the stereospecific synthesis of aldols derived from a wide range of simple ketones but also allows the preparation of regiospecific aldols. Thus (59) is the aldol from specific attack on 3-heptanone at (2-2. Remarkable examples of mutual kinetic resolution in reactions of racemic chiral a-(trimethylsily1oxy)ketonessuch as (60)with racemic chiral aldehydes have been recorded.54Thus reaction of (60) with isobutyraldehyde gave a mixture of two 52 C. H. Heathcock C. T. Buse W. A. Kleschick M. C. Pirrung J. E. Sohn and J. Lampe J. Org. Chem.1980,45,1066. ” C. T. White and C. H. Heathcock J. Ore. Chem. 1981,46 191. 54 C. H. Heathcock M. C. Pirrung J. Lampe C. T. Buse and S. D. Young J. Org. Chem. 1981 46 2290; see also C. H. Heathcock C. T. White J. J. Morrison and D. Van Derveer J. Org. Chem. 1981,46,1296. Synthetic Methods 7+Me OSiMe (60) (61) erythro-aldols in the ratio 3 :1 the main component of which is believed to be (61); higher ratios were obtained with some other aldehydes. With racemic a-phenylpropionaldehyde a single racemic aldol (62) was formed and on oxidation with periodic acid afforded the racemic acid (63) which was at least 98% diastereomerically pure; the other erythro-diastereomer (64) was not detected (Scheme 25). The diastereoface selection shown by phenylpropionaldehyde in this reaction is >40 :1.Several other chiral aldehydes showed similar high diastereoface selectivity in reactions with (60) and related ketones. OSiMe Me Me OSiMe Ph CHO OH Me PhbC Me 0 H (62)liphJgc02H OH OH (64) (63) Reagent i H,IO,-MeOH Scheme 25 It has previously been shown that reaction of crotyl bromide with aldehydes in the presence of chromous ion provides the threo- condensation products very selec- tively. The threo-acids are then available by cleavage of the double bond (Scheme 26).55But the reaction seemed to be less attractive for control of the stereochemistry of three adjacent positions by reaction with a chiral aldehyde. Nevertheless it has now been found4' in work on the synthesis of rifamycin S' that reaction of either cis- or trans-crotyl iodide with the aldehyde (65) gave the threo-product (66)with a selectivity of >20 1.Manipulation of the functional groups of (66) led to (67) which again reacted with crotyl iodide in the presence of chromous chloride to give the threo-product (68) with high selectivity. threo-cis- Products are also formed predominantly by reaction of a-silyl- or a-stannyl-crotyl-9-borabicyclo[3,3,l]nonanewith aldehydes in the presence of certain bases (pyridine n-butyl-lithium or s-butyl-lithi~m).~~ Further elaboration 55 Y. Okude S. Hirano T. Hiyama and H. Nozaki J. Am. Chem. Soc. 1977,99,3179;T.Hiyama K. Kimura and H. Nozaki Tetrahedron Lett. 1981,22,1037; C.T.Buse and C. H. Heathcock Tetrahedron Lett.1978 1685. 56 Y. Yamamoto H. Yatagi and K. Maruyama J. Am. Chem. SOC., 1981,103 3229. 316 W.Carruthers OH RCHO + BrL R& Me Me Me Hfn Ox0 Me ButPh,SiO $ -vi Bu'Ph,SiO H t OH OX0 (68) (67) Reagents i CrC1,-THF 25 "C; ii 0,;iii H,O,-NaHCO,; iv V B r -CrC12-THF 25 "C; v several steps; vi -1 -CrC12-THF 25 "C Scheme 26 of the cis-alkenyl-silanes or -stannanes thus obtained offers the possibility of stereoselective formation of four contiguous chiral centres (Scheme 27). Me R Me //11-1v WH20H OH M HO -.LRw Y4 Me M = SiMe3or SnMe3 Rwe OH Reagents i RCHO-pyridine; ii BuLi; iii CH,O; iv m-ClC,H,CO,H; v Me1 Scheme 27 Fluoride ion-catalysed reaFtion of silylated aci-nitro derivatives (69) with aldehydes also leads almost exclusively to the threo-diastereomer (70) [Heathcock's nomenclature is used here for consistency; the authors call (70)the erythro-is~mer].~' Catalytic reduction with hydrogen and Raney nickel and desilyla- tion affords the corresponding p-amino-alcohols (Scheme 28).The preferential '' D. Seebach A. K. Beck F. Lehr T. Weller and E. Colvin Angew. Chem. In?.Ed. Engf. 1981,20 397. Synthetic Methods Reagents i R'CHO; ii Bu,NF-THF; iii H,-Ni Scheme 28 formation of one diastereomer here is consistent with the mechanism suggested for the normal aldol reaction. 5 Alkylation Ally1 chlorides are readily converted into their anions with lithium di-isopropyl- amide. These anions are alkylated exclusively at the a-position affording syntheti- cally useful secondary ally1 chlorides in high yield." The enantioselective alkylation of carboxylic acids and ketones has been extensively studied by Meyers and his co-workers and a full account has now been published of their work on the alkylation of cyclic ketones with the aid of chiral metalloenamines.s9 Chiral imines (S)-(72) are readily prepared from cyclic ketones and the chiral methoxyamine (S)-(71).Metalation and alkylation followed by hydrolysis of the imine leads to the 2-alkylcycloalkanones (74)with enantiomeric purities in the range 87-100% (Scheme 29). The chelating effect of the methoxy-group in the intermediate lithio-derivative (73) is crucial to the stereoselectivity achieved. Reagents i cyclohexanone;ii LiN(Pri)2-THF,-20 "C;iii RHal -78 "C;iv H,O' Scheme 29 T.L. MacDonald. B. A. Narayanan and D. E. O'Dell J. Org. Chem. 1981,46,1504. 59 A. I. Meyers D. R. Williams G. W. Erickson S. White and M. Druelinger J. Am. Chem. Soc. 1981,103,3081. 318 W.Carruthers The reaction has been extended to the enantioselective synthesis of a-alkyl macrocyclic and acyclic ketones. Here complications arise because of the possibility of (E)-(2)isomerism in the intermediate lithio-derivatives related to (73). (E)-(Z)-Isomerism does indeed occur but can be exploited to prepare the two enantiomers of the alkylated ketones at will with moderate to excellent isomeric purity.60 Thus metallation and alkylation of chiral imines derived from Cl0 CI2,and C, cyclic ketones gave under kinetic metalation conditions 2-alkylcycloalkanones of absolute configuration opposite to that obtained from thermodynamic metalation.(S)-2-Methylcyclododecanone for example is obtained from cyclododecanone in 60% enantiomeric excess under kinetic conditions whereas the (R)-isomer is reached in 80% enantiomeric excess under thermodynamic control. In a similar fashion acyclic ketones are alkylated enantioselectively via chiral imines such as (79 under both kinetic and thermodynamic conditions. Kinetic metalation of (75) gives exclusively the (2)-lithioenamine (76) converted exclusively into the (E)-isomer on refluxing the solution. Chiral a-alkylated derivatives were obtained in 18-97% enantiomeric excess from a selection of open-chain ketones (Scheme 30).Chiral a-alkylation of carboxylic acids can be effected by way of enolates (E -76) (75) (Z-76) \ iii iv /iii iv Reagents i LiN(Pr'),-THF -30 "C; ii reflux; iii MeI-THF -78 "C; iv H20 Scheme 30 derived from chiral amides.61 In another procedure esters derived from the asym- metric alcohols [(77)-(79)] are used.62 a-Alkylation of the lithium enolates pro- ceeds in very good yields with excellent diastereoselection. The sulphonamides (77b)-(79b) show particularly remarkable properties. Products with inverse configuration are obtained with almost complete asymmetric induction using either tetrahydrofuran or tetrahydrofuran-hexamethylphosphoramide(4 :1) as solvent. Purification of the alkylated esters by chromatography and reduction with lithium aluminium hydride then gives the enantiomerically pure alcohols R'R2CHCH20H in excellent yield.6o A. I. Meyers D. R. Williams S. White and G. W. Erickson J.'Arn.Chern. Soc. 1981 103 3088. D. A. Evans J. M. Takas L. R. McGee M. D. Ennis D. J. Mathre and J. Bartroli Pure Appl. Chem. 1981,53,1109. 62 R. Schmierer G. Grotemeier G. Helmchen and A. Selim Angew. Chem. Int. Ed. Engl. 1981,20,207. Synthetic Methods OR (77) (79) Ph (a) X = -0CON / 'Me Me Scheme 31 ap-Unsaturated acids are alkylated at the y-position by reaction of the copper enolates with ally1 halides but alkyl halides react only sluggishly with little prefer- ence for the y-carbon. Best results are obtained with vinylic epoxides.They undergo allylic transposition and react at the y-carbon of the dienolate with high selectivity to form 1,Sdienes with an oxygenated functional group at each end (Scheme 32).63 Mel + " O Me n COzH Me COZH HO) 86% of product 14%of product Reagents i LiN(Pr'),-THF -78 OC -P 0OC; ii CuJ, -78 "C; iii -0 Scheme 32 Further work has been reported on the specific alkylation of @-unsaturated ketones. Earlier studies had shown that 0-silylated dienolates are useful intermedi- ates for the y-substitution of cup-unsaturated carbonyl although the ya-ratio of alkylation was sensitive to both substrate substitution pattern and the nature of the electrophile. It is now found that a suitably chosen silyl group makes it possible to obtain a high degree of y-alkylation of any enone that can be converted into a linearly conjugated silyl dienol ether.65 1,3-Dithienium fluoroborate gave a high degree of y-alkylation in reaction with a range of 0-trimethylsilylated dieno- lates.66a 0-Trimethylsilyl enolates of aldehydes ketones esters and lactones also can be regiospecifically alkylated by 1,3-dithienium fluoroborate to give a selectively protected P-dicarbonyl compound.The 1,3-dithiane substituent may be hydrolysed to a formyl group or desulphurized to a methyl group.66b " P. M. Savu and J. A. Katzenellenbogen,J. Org. Chem. 1981,46 239. 64 I. Fleming J. Goldhill and I. Paterson Tetrahedron Letr. 1979 3205,3209. " I. Fleming and T. V. Lee Tetrahedron Lett. 1981,22 705. " (a)I. Paterson and L. G. Price Tetrahedron Lett.1981,22 2833;(b)I. Paterson and L. G. Grice ibid. 1981,22 2829. 320 W. Carruthers 0 OSiMe 8. . .. 5oo RQ Reagents i LiN(Pr'),-THF -78 "C; ii Me3SiC1; iii RLi or RMgBr; iv H30'; v R,CuLi Scheme 33 Particular interest attaches to methods for the specific alkylation of cyclo- hexenones. 2-and 6-alkylcyclohexenones and cyclopentenones can be obtained from the corresponding ap-epoxycycloalkanone by reaction of the derived trimethylsilyl enol ethers with an organolithium or Grignard reagent or by allylic attack on the epoxide by a cuprate reagent (Scheme 33).67 A new route to 3- substituted cyclohexenones proceeds from cyclohexane-1,3-diones by reaction of the derived 3-mesyloxy-cyclohex-2-enonewith a nucleophile.68 They are also conveniently obtained from 3-bromocyclohexenones by lithiation of the corre- sponding ethylene ketals with two equivalents of butyl-lithium and reaction of the bis-lithio-derivative with alkylating agent.69 The synthetically awkward 5-substituted cyclohexenones can be prepared from tricarbonyl(3-methoxycyclohexa-2,4-dien-l-yl)iron(l') (80) which in these reactions is equivalent to the 5-cyclohex-2-enone cation (81)." It reacts with various nucleophiles to give 5-substituted cyclohex-2-enones in good yield after removal of the iron tricarbonyl (Scheme 34).OMe OMe OMe 6. (81) Reagents i Nu e.g. WSiMe ;ii Jones reagent or pyridinium chlorochromate Scheme 34 " P.A. Wendler J. M.Erhardt and L. J. Letendre J. Am. Chem. SOC.,1981,103,2114.68 C. J. Kowalski and K. W. Fields J. Org. Chem. 1981,46 197. 69 C. Shih and J. S. Swenton Tetrahedron Lett. 1981,22,4217. 70 L. F. Kelly P.Dahler A. S.Narula and A. J. Birch Tetrahedron Lett. 1981 22 1433. Synthetic Methods The palladium(0)-catalysed alkylation of allylic substrates by nucleophiles has been widely developed (review7') and frequently provides complementary selec- tivity to standard methods (see below). A mechanism which invokes the functional equivalent of a .rr-allylpalladium cationic complex has been put forward71 and questioned,'* but further evidence in support has now been adduced.73 Palladium- catalysed alkylation of allylic substrates by carbon nucleophiles has usually been considered to be restricted to anions derived from carbon acids of pK < 20.Among the conjugate bases of acids of pK > 20 the enolate of acetophenone was the only one reported to alkylate ally1 acetate. Conditions have now been found under which ketone enolates are efficient nucleophiles in this reaction (Scheme 35).74 Lithium enolates of 2-pentanone cyclohexanone acetophenone and mesityl oxide reacted with representative allylic acetates in the presence of a Pd(0) catalyst to form the allylic displacement products in good yield and with retention of configuration. qoAc qH2C0Me ~ Ph Ph OLi I Reagent i CH,-C=CH,-Pd(dba),dppe-THF -78 "C +20 "C Scheme 35 Continuing his earlier extensive work Trost now that 1,3-diesters P-keto esters P-keto sulphides and P-sulphonyl esters are readily converted into allylic alcohols under neutral conditions by alkylation with ap-unsaturated epoxides (vinyl epoxides) in the presence of palladium(0) catalysts.The reactions proceed with attack from the same face as the oxygen of the epoxide group so that epoxide (83) for example gives cleanly the cyclohexenol (84) whereas direct substitution under standard base-catalysed conditions leads with inversion to (82); (Scheme 36). (84) Reagents i 5 mol % Pd(PPh,),-THF; ii NaCH(CO,Et),-EtOH; iii CH2(C02Et),-Pd(PPhJ4-THF Scheme 36 71 B. M. Trost Acc. Chem. Res. 1980,13 385. 'I2 J. C. Fiaud and J.-L. Malleron TerruhedronLett.,1981 22 1399. " B. M. Trost and N. R.Schmuff Tetrahedron Lett. 1981,22,2999. 'I4 J. C. Fiaud and J.-L. Malleron J. Chem.SOC.,Chem. Commun.,1981 1159. 75 B. M. Trost and G. A. Molander J. Am. Chem. SOC.,1981,103,5969. 322 W. Carruthers 6 Annelation There is considerable interest in the development of methods for the construction and annelation of five-membered rings. A novel method for the stereoselective synthesis of cyclopentenols from 1,3-dienes which may also be used for annelation exploits the rearrangement of 2-vinylcyclopropanols.76Formation of cyclopentene derivatives by rearrangement of vinylcyclopropanes although frequently used suffers from some disadvantages occasioned by the high temperatures required. It has recently been however that the lithium salts of 2-vinylcyclopropanols undergo greatly accelerated rearrangements in high yield at only 25 "C.It is now found that the alkoxy-accelerated rearrangements generally proceed with high stereoselectivity thus providing a stereoselective method for conversion of 1,3-dienes into cyclopentene derivatives as shown in Scheme 37.Stereospecific syn-addition of (2-ch1oroethoxy)carbene to 1,3-dienes produces mixtures of vinyl- cyclopropanes (85a) and (85b). Exposure of these to butyl-lithium then effects the (85) a; X' = H X2 = OCH2CH2Cl b; X' = OCHZCH2C1 X2 = H [74%] [73%] Reagents i [:CHOCH,CH,Cl]; ii Bu"Li Scheme 37 cleavage and rearrangement of the resulting salts in one step. The intermediate syn-and anti-2- vinylcyclopropanol salts rearrange by topologically different path- ways to afford in most cases a single cyclopentenol. A conceptually related approach leads to bicyclo[4,3,0]-5-nonenonesby pyrolytic rearrangement of vinyl- cyclopropane derivatives obtained by intramolecular addition of an a-ketocarbene to a 1,3-diene Another route to cyclopentenones and cyclohexenones proceeds by rearrangement of 2-vinylcyclobutanones.79In the presence of acid 2-alkyl-2-vinylcyclobutanonesrearrange mainly by a 1,2-acyl migration to give cyclopentenones.2-Vinylcyclobutanones lacking a 2-alkyl substituent how'ever undergo a 1,3-acyl migration to give cyclohexenones (Scheme 38). The rearrange- '' R. L. Danheiser C. Martinez-Davila R. J. Auchus and J. T. Kadonaga J. Am. Chem. SOC.,1981 103,2443. '' R. L. Danheiser C. Martinez-Davila and J. M. Morin J. Org. Chem. 1980 45 1340. '* T. Hudlicky F. J.Koszyk D. M. Dochwat and G. L. Cantrell J. Org. Chem. 1981,46,2911. 79 J. R. Matz and T. Cohen Tetrahedron Letr. 1981 22 2459. Synthetic Methods 0 (J+ OTI Q-u OH O-H + 0 0 [65%] Reagent i MeS0,H-P,O Scheme 38 ments are not completely exclusive except in the case of spirocyclobutanones where 1,3-migration would violate Bredt's rule; here fused cyclopentenone derivatives are formed exclusively. The required vinylcyclobutanones are conveniently obtained from ketones.80 A novel [3 + 21 approach to cyclopentane derivatives by addition of trimethyl- silylallenes to a@-unsaturated ketones in the presence oftitanium tetrachloride seems useful provided the required allenes are readily accessible (Scheme 39).81The reaction involves initial complexation of the a@-unsaturated ketone and titanium \ R' (86) (87) Reagent i TiC1,-CH,Cl, -78 "C Scheme 39 tetrachloride to generate an alkoxyallylic carbocation.Regiospecific electrophilic substitution of this cation at C-3 of the allene provides a vinyl cation stabilized by interaction with the adjacent C-Si bond. A 1,2-shift of the trimethylsilyl group then affords an isomeric vinyl cation which is intercepted by the titanium enolate to produce a five-membered ring. Cyclic acylic and a@-unsaturated ketones all T. Cohen and J. R. Matz Tetrahedron Lett. 1981 22 2455. R. L. Danheiser D. J. Carini and A. Basak J. Am. Chem. Soc. 1981 103,1604. 324 W. Carruthers participate in the reaction and a-methylene ketones form spiro-compounds.Only some heavily substituted enones failed to react. Annelation of trans-3-penten-2-one and carvone afforded stereoselectively the derivatives (87) and (88). 4aSi,, S0,Ph (90) S02Ph (89) 1 ii Cb S02Ph Reagents i KH-DME; ii Bu,NF-THF Scheme 40 The allylsilane (90) is an excellent alkylating agent towards anions of P-keto sulphones and sulphides but gives only poor yields of alkylated products with thermally unstable enolates. With thermally stable nucleophiles such as the anion from (89) excellent yields of the desired alkylation products are obtained and can be cyclized to cyclopentane derivatives (Scheme 40).82In continuation of earlier work on the cycloaddition reactions of trimethylenemethanepalladium complexes it is now shown in studies on the regiochemistry of the addition that the two derivatives (91)and (92) both react with cyclopentenone to form the same annelated product (93).82a 1-Phenylthio- 1-methylthio- and l-isopropylthio-cyclopropyl-phosphonium fluoroborates (94) have been used as synthetic equivalents of the cyclopropanone zwitterion (95).They react with anions of p-keto esters to form vinyl In sulphides which can be hydrolysed to cyclopentanone deri~atives.~~ a OH xe3 & ‘ I ’ PdL Me3sz H MePdL2 ns$3BF4 rP (91) (92) (93) (94) (95) Scheme 41 different approach cyclopentanone annelation has been effected by reaction of [a-(carbethoxy)vinyl]cuprates with a& unsaturated acid chlorides followed by Nazarov cyclization of the a,a’-dienones produced (Scheme 42).84 m2 B.M.Trost and D. P. Curran Tetrahedron Lett. 1981.22 5023. B.M. Trost and D. M. T. Chan J. Am. Chem.,Soc.,1981,103,5972. R3 J. P.Marino and M.P. Ferro J. Org. Chem. 1981,46,1828. “ J. f.Marino and R.L. Linderman J. Org. Chem. 1981,46 3696. Synthetic Methods li 0 R Reagent i SnC1,-CH,CI, 25 "C Scheme 42 7 Cyclization Reactions Although many known methods of spirocyclization involve intramolecular alkyla- tion there has been need for an operationally simple procedure which avoids the use of a strong base. Such a procedure has now been found in the regiospecific intramolecular alkylation of enolates generated in situ by halide-induced non- hydrolytic decarbalkoxylation of w-halogeno-& keto esters (Scheme 43).The reac- tion has been applied in new syntheses of P-vetivone and P-veti~pirene.~~ A novel 0 n = 1 m = l,64%; n = 3; m = 3,70y0 Reagent LiCI-HMPA 125-140 "C Scheme 43 route to macrocyclic ketones by intramolecular alkylation of protected cyanohydrins has been reported.86 The necessary carbanion is generated with sodium hexamethyl- disilazane and under the conditions employed cyclization is rapid and irreversible so that high dilution conditions are unnecessary. Subsequent mild treatment of the cyclized product with acid and base affords the macrocyclic ketones in good yield. The sequence has been applied to the synthesis of 2-cyclopentadecenone (96) a precursor of muscone and exaltone and the macrolides (f)-zearalenone8' and dihydroxy-trans- resorcylide.88 A synthetically useful alternative to base-catalysed intramolecular t-alkylation of ketones is provided by the stannic chloride-catalysed intramolecular reaction of a double bond with the appropriate p-keto ester or P-diket~ne.'~ Reaction plausibly 13' R.G. Eilerman and B. J. Willis J. Chem. SOC.,Chem. Commun. 1981 30. 86 T.Takahashi T. Nagashima and J. Tsuji Tetrahedron Lett. 1981 22 1359. " T. Takahashi; H. Ikeda and J. Tsuji Tetrahedron Lett. 1981,22 1363. T. Takahashi I. Minami and J. Tsuji Tetrahedron Lett. 1981 22 2651. I. Chatzuosifidis and K. Schwellnus,Angew. Chem. Int. Ed. En& 1981,20,687. 326 W.Carruthers I ii iii + __* R = a-ethoxyethyl Reagents i Hexamethyldisilazane-THF 40 "C;ii 3 N-HCl; iii 5% NaOH Scheme 44 takes place by 0-stannylation of the enolized form of the carbonyl compound; protonation of the olefinic bond is then followed by cyclization of the cation (Scheme 45).1 Reagents i SnC1,-CH,Cl, 0 "C; ii LiI-collidine Scheme 45 To date the carbonyl anion equivalence of the 1,3-dithian function has not been realised in intramolecular additions to carbonyl compounds (aldol or Michael reactions). Any base strong enough to deprotonate a dithian can also react with the carbonyl group either as a base or as a nucleophile. A way round this difficulty has now been found by liberation of the required dithianyl carbanion from the corresponding 2-trimethylsilyl dithian by treatment with fluoride The intramolecular aldol(97) -+ (98) and Michael (99) -+ (100)reactions were effected thus in good yield (Scheme 46).Cationic olefin cyclizations continue to provide access to various ring systems. The high synthetic potential of the cyclization of a-acyliminium ions is again shown in the quantitative conversion of the hydroxylactam (101) into a single stereoisomer of (102) on treatment with hydrogen chloride in methanol. The usual reagent formic acid gave only poor yields in this case. Dehydrochlorination of (102) and reduction of the carbonyl group gave the elaeocarpus alkaloid elaeokanine B 9" D. B. Grotjahn and N. H. Andersen J. Chem. Soc. Chem. Commun. 1981,306. Synthetic Methods OH to ( 100) Reagent i Bu,NF-THF Scheme 46 ( 103).91The vinylogous N-acyliminium ion cyclization (104) -B (105) formed the key step in a synthesis of depentylperhydrogephyr~toxin.~~ The occurrence of an aza-Cope rearrangement accompanying the cyclization of the acyliminium ion (106) was detected by using triethylsilane as an acyliminium ion trap.93 Reagents i HCI-MeOH; ii HC0,H-CH,CI, 0 "C Scheme 47 A promising new method of cyclization involving addition of a vinyl anion generated from a vinylsilane to an iminium ion was used in an elegant chiral synthesis (Scheme 48) of the poison-arrow dendrobatid toxin 251D (107).94 91 B.P.Wijnberg and W. N. Speckamp Tetrahedron Lett. 1981,22 5079. 92 D.J. Hart J. Urg. Chem. 1981,46 367. 93 D.J. Hart and Y.-M. Tsai Tetrahedron Lett. 1981,22 1567. 94 L.E.Overman and K.L. Bell. J. Am. Chem. SOC.,1981,103 1851. 328 W.Carruthers :OH L OH Me (107) Reagents i HCHO-EtOH; ii d-10-camphorsulphonic acid Scheme 48 Intramolecular nucleophilic termination during mercuric ion-initiated diene cyc- lizations has been st~died.~' Carboxylic acids ketones and alcohols are effective trapping nucleophiles leading to lactones cyclic enol ethers and saturated ethers respectively. Intramolecular capture by nitrogen was exploited in a synthesis of trans-2,5-dimethylpyrr01idine~~ (Scheme 49). TFAHg Reagents i Hg(OCOCF,),-MeNO,; ii NaBH,; iii Hg(OAc),-THF; iv HCI-HOAc Scheme 49 Unsaturated substrates carrying internal nucleophiles (NuX = C02H OH SH SAC NHCO,Et or CH2SnMe2) also react smoothly with certain organoselenium reagents to afford cyclic systems according to Scheme 50.These reactions have been re~iewed.~' Selenium can be removed from the initial cyclization products by oxidation and elimination of selenoxide or by reduction to give respectively an unsaturated product or a saturated one and the sequence can be used to prepare 95 T. R. Hoye A. J. Caruso and M. J. Kurth J. Org. Chem. 1981,46,3550. 96 K. E. Harding and S.R. Burks J. Org. Chem. 1981,46,3920. 97 K. C. Nicolaou Tetrahedron 1981 37 4097. Synthetic Methods Reagent i PhSe' Scheme 50 lactones ethers thioethers nitrogen heterocycles and carbocycles (Scheme 5 1). N-Phenylselenophthalimide and N-phenylselenosuccinimide are excellent new reagents for the oxyselenation of olefins and a unique feature is their ability to SePh Reagents i PhSeCl-CH,Cl, -78 "C;ii H,-Raney Ni or Bu,SnH; iii H20z-THF Scheme 51 induce macrolide formation from long-chain unsaturated acids9' at room tem- perature.It is known that alkenyl-substituted p-dicarbonyl compounds can be cyclized by certain selenating agents to give cyclic p-keto esters or cyclic enol ethers the products of the reactions depending on the reaction conditions. It is now found that it is possible to effect similar cyclizations via a rearrangement of alkenyl-substituted a-phenylseleno-p- keto esters in the presence of acidic catalysts.98 In general cyclization to the enol ether is effected by reaction under kinetic conditions with toluenesulphonic acid; cyclization to the p-keto ester is favoured by strong Lewis acids (e.g.SnC14) and longer reaction times. At least one other example of the migration of the phenylseleno-group during a cyclization reaction has been recorded.99 A particularly challenging problem in the synthesis of polyether antibiotics is presented by the need for stereocontrolled construction of the tetrahydrofuran units found in many of these natural products particularly those units in which there is a cis-relationship between substituents at C-2 and C-5. An attractive method for the formation of substituted tetrahydrofurans is electrophilic cyclization of yS-unsaturated alcohols but trans- isomers are usually favoured in this reaction. This difficulty has now been cleverly circumvented by exploiting the two transient trans- 1,2-relationships in the cyclization of olefinic ethers (Scheme 52).loo In 9a W.P. Jackson S. V. Ley and J. A. Morton Tetrahedron Lett. 1981 22 2601. 99 T. Kametani H. Kurobe and H. Nemoto J. Chem. SOC.,Perkin Trans. 1,1981 756. loo S. D. Rychnovsky and P. A. Bartlett J. Am. Chem. SOC.,1981 103,3963. 330 W. Carruthers /-{ Rt/yERIQJs I E Rl minor 0 R'&E R1oE I major R Scheme 52 practice cyclization of y6-olefinic ethers with iodine was found to provide a general highly stereoselective route to cis-2,s-disubstituted tetrahydrofurans. Best results were obtained with the 2,6-dichlorobenzyl ethers. 2,2,5-Trisubstituted tetrahy- drofurans which also appear as subunits in many polyether ionophores are also accessible by this route.cis-Linalyl oxide (109) for example was obtained as the main product on cyclization of the benzyl ether acetate (108) followed by elimination and ester hydrolysis. The corresponding diol gave the trans-isomer on cyclization. \4 21 1 CI Reagents i I,-CH,CN; ii KOBu'; iii -OH Scheme 53 The acid-catalysed decomposition of a-diazoketones with subsequent intramolecular cyclization of the electrophilic species produced has come into prominence recently in the synthesis of polycyclic natural products. A review has been published"' covering the formation of cyclic ketones by acid-promoted decomposition of a-diazoketones in the presence of suitably placed heteroatoms benzene rings or olefinic double bonds.Thus a cyclization of the type (110) -+ (111) was the cornerstone of Mander's elegant synthesis of (*)-gibberellin A1 and gibberellic acid"* and more recently acid-catalysed cyclization of the diazoketone (112) to the tricyclic (113)was used in an approach to the ring A. B. Smith 111and R. K.Dieter Tetrahedron 1981 37,2407. lo* L. Lombardo L. N. Mander and J. V. Turner J. Am.Chem. SOC.,1980,102,6626. Synthetic Methods Reagent i CF,CO,H-CH,Cl, -20 "C Scheme 54 system of aphidicolin and related natural products (Scheme 54).'03 Spiro-compounds have also been made as exemplified in a synthesis of (f)-solavetivone.104 In the presence of suitably placed double bonds intramolecular cationic cyclizations may take place (Scheme 55). With Py-unsaturated diazoketones cyclopentenones [44%] [18°/o] (118) Reagents i BF,.Et20-CH2CI,; ii BF,.Et,O-MeNO, 0-5 "C Scheme 55 K.C. Nicolaou and R. E. Zipkin Angew. Chem. Inf.Ed. Eng. 1981,20,785. lo' C. Iwata T. Fusaka T. Fujiwara K. Tomita and M. Yamada J. Chem. Soc. Chem. Commun.. 1981 463. 332 W.Carruthers are formed'05 and with highly nucleophilic double bonds the initial cyclization may be followed by attack on another suitably placed olefinic bond or benzene ring. Compound (114; R = Me) for example was converted into (115) stereoselec-tively in 31% yield but (114; R = H) did not afford a tricyclic product; instead the benzocycloheptanone (116) was obtained.lo6 With the diazoketone (117) and some analogues Lewis acid-catalysed decomposition gave tricyclic products [for example (118)] with cis-ring junctions exclusively attributed to a stepwise cyclization involving initial complexation of the Lewis acid with the oxygen of the diazoketone.lo' Electrocyclic ring-opening of bromocyclopropane derivatives containing internal nucleophilic hydroxy- and carboxy-groups provides a new route to vinyl lactones tetrahydropyrans and tetrahydrofuranslo8 (Scheme 56). Reaction is brought about by warming the substrate in a non-nucleophilic polar solvent such as trifluoroethanol for the more substituted systems or in other cases by treatment with silver(1) or mercury (11) salts. Various methods are available for the stereoselective synthesis of the required cyclopropanes. CO,H HO 0 Reagents i AgOCOCF,-CF,CH20H 25 OC; ii AgOAc-CF,CH,OH Scheme 56 Dreiding has applied his a-alkynone cyclization reaction as the key step (119) + (121) in a synthesis of the sesquiterpene (*)-modhephene (Scheme 57).lo9The preferred formation of the propellane (121) in this reaction shows that the insertion of the postulated alkylidene carbene intermediate (120) into the tertiary ring C-H bond takes preference over insertion into the secondary C-H bonds.Me (1 19) Reagent i 620 "C [95'/0] Scheme 57 H. C. Brown's 'stitching and rivetting with boron' has not so far been widely used in the synthesis of cyclic compounds but recent examples (Scheme 58) lo' A. B. Smith 111 B. H. Toder S. J. Branca and R. K. Dieter J. Am. Chem. Soc. 1981,103,1996. A.B. Smith 111and R. K.Dieter J. Am. Chem. SOC.,1981,103,2009. lo' A. B. Smith I11 and R. K.Dieter .I. Am. Chem. Soc. 1981,103,2017. lo' R. L. Danheiser J. M. Morin M. Yu,and A. Basak Tetrahedron Lett. 1981 22,4205. log M. Karpf and A. S. Dreiding Helv. Chim. Acta 1981.64 1123. Synthetic Methods 0 i-iii iv-vi;iii ~~3 d p-p Cbz Cbz Reagents i BH,-THF; ii CO;iii H,O,-NaOH; iv H-BH ;v KCN; vi (CF,CO),O Scheme 58 underline its potentialities. Thus hydroboration of the triene (122) followed by carbonylation with carbon monoxide under pressure and oxidation with alkaline hydrogen peroxide afforded the carbinol(l23) as a mixture of isomers.11o A better example is provided by the formation of the ketone (125) from the N-allyl-N-(3- buteny1)amine (124) in 33% yield using the Pelter carbonylation technique."' An interesting synthesis of spermidine alkaloids by boron-templated cyclization of appropriate open-chain precursors has been reported."* In a model sequence the amino-ester (126) was converted into the thirteen-membered lactam (128) in 77% yield by treatment with tris(dimethy1amino)boranein boiling xylene presum- ably by way of the intermediates (127) and (129).Reagent i B(NMe,),-xylene reflux Scheme 59 8 The Diels-Alder Reaction The Diels-Alder reaction remains one of the most widely used reactions in organic synthesis and there have been many examples of its application during the past year but other aspects of the reaction have not been overlooked. 'lo C. F.Reichert W. E. Pye. andT. A. Bryson Tetrahedron 1981,37,2441. 'I' M. E. Garst and J. N. Bonfiglio Tetreedron Lett. 1981 22 2075. '12 H. Yamamoto and K. Maruoka J. Am. Chem. Soc. 1981,103,6133. 334 W. Canuthers Addition of unsymmetrical electron-rich dienes to methoxybenzoquinones or naphthoquinones gives adducts in which the more nucleophilic diene terminus becomes bonded to the non-methoxylated carbon and this observation has led to the generalization that electron-donating substituents deactivate alkenes toward attack by nucleophilic cycloaddends and direct attack to the carbon remote from the sub~tituent."~ This generalization is contrary to predictions based purely on alkene LUMO coefficients and the results are not what would be expected from arguments based on classical resonance theory.A rationale has been ~ffered."~ It is well known that Lewis acids can enhance the reactivity of some dienophiles containing oxygen-bearing functional groups. It is now shown usefully that Diels- Alder reactions involving neutral or electron-rich dienophiles may be catalysed by the stable radical cation salt tris( p-bromopheny1)aminium hexachlorostibnate. Thus the Diels-Alder dimerization of cyclohexa- 1,3-diene has been effected in 30% yield after 20 hours at 200°C. In the presence of the radical cation the dimerization occurs in 70% yield within fifteen minutes at 0 OC.ll' Asymmetric induction during Diels-Alder additions to chiral acrylates has been reinvesti- gated."6 Chiral induction in the conversion (130) -P (131) varied between 47- 93% in favour of the 2-(R)-adducts depending on the auxiliary chiral group and the Lewis acid catalyst (Scheme 60).Stannic chloride and titanium tetrachloride gave the highest enantiomeric excess of the (R)-isomer. In all cases the phenylmen- thy1 group (130; R = C6H5) induced chirality more efficiently than the menthyl group itself although the differences were not so great as in an earlier study of an ene cyclization catalysed by Me2A1C1."' Apparently the first example of control of the orientation of addition in a Diels-Alder reaction by a Lewis acid catalyst was encountered in a step in a synthesis of a-and P-himachelene."* Reagent i cyclopentadiene-Lewis acid Scheme 60 2-(Pheny1thio)cyclopentenone is the synthetic equivalent of cyclopentynone in the Diels-Alder reaction.It reacts readily with substituted butadienes to give adducts which are readily converted into dihydro- 1-indanones by elimination from '13 I.-M. Tegmo-Larsson. M.D. Rozeboom and K. N. Houk. Tetrahedron Lert.. 1981,22,2043. IM I.-M. Tegmo-Larsson M. D. Rozeboom N. G. Rondan and K. N. Houk Tetrahedron Lett. 1981 22,2047. '15 D.J. Belleville D. D. Wirth and N. L. Bauld J. Am. Chem. Soc. 1981,103,718. '16 W.Oppolzer M. Kurth D. Reichlin and F. Moffatt Tetrahedron Lett. 1981 22 2545; G.Helmchen and R. Schmierer Angew. Chem. Int. Ed. Engl. 1981,20,205. 11' W. Oppolzer C. Robbiani and K. Battig Helu. Chim. Acta 1980,63 2015. H.-J. Liu and E. N. C. Browne Can. J. Chem. 1981,59,601. Synthetic Methods 335 the sulphoxide.'19 In Diels-Alder reactions with 3-nitrocycloalkenones the direction of addition is controlled by the nitro-group. Removal of the nitro-group from the adduct gives an ap-unsaturated ketone formed in effect by Diels-Alder addition of an alkynone to the diene (Scheme 61).l2' trans- l-Benzenesulphonyl-2- (trimethylsilyl)ethyleneis another useful acetylene equivalent in the Diels-Alder 0 0 YOsiMe3 + ii iii 1,,,+ i rnSiMe3 -Reagents i toluene 110"C 20h; ii 0.05 N-HCl; iii 1,5-diazabicyclo[4,3,0] non-5-ene-THF. 0 "C. Scheme 61 reaction since treatment of the initial adducts with tetrabutylammonium fluoride leads to elimination of the trimethylsilyl and benzenesulphonyl residues.12' Alkyla- tion of the a-sulphonyl carbanion can be effected before elimination so that the reagent can also be considered as the equivalent of a monosubstituted alkyne dienophile.Again the allenic dienophile (132) has been used as the equivalent of the carbalkoxyketene (134). With furan it gives the adduct (133) used in a synthesis of the antibiotic C-nucleoside dl-showdomycin (135).'22 C0,Et EtO,C-CH=C=CH-CO,Et -h bo2Et 0 Reagent i furan-benzene-AlC13 room temperature Scheme 62 The synthetic value of Diels-Alder reactions involving 1-acylaminobutadienes has been demonstrated recently in the synthesis of several complex nitrogenous natural products including dl-perhydrogephyr~toxin'~~ and dZ-isogabaculine.'24 '19 S.Knapp R. Lis and P. Michna J. Org. Chem. 1981,46,624.E. J. Corey and H. Estreicher Tetrahedron Lett. 1981 22 603. 12' L.A.Paquette and R. V. Williams Tetrahedron Lett. 1981,22,4643. lZ2 A.P.Kozikowsky and A. Ames J. Am. Chem. Soc. 1981,103,3923. lZ3 L.E.Overman and C. Fukaya J. Am. Chem. Soc. 1980,102,1454. lZ4 S.Danishefsky and F. M. Hershenson J. Org. Chem. 1979,44 1180. 336 W. Carruthers Overman and his co-workers have now given details of their pioneering work on this reaction and give a survey of the reactions of eight l-(acylamino)-1,3-dienes with thirteen varied dien0phi1es.l~~ The reactions provide convenient access to diversely substituted amino-cyclohexanes and -octalones. An important feature of value in synthesis is the high regio- and stereo-selectivities shown in reactions of the aminodienes with unsymmetrical dienophiles.The acylamino-group is a power- ful directing group and in many reactions only one regioisomer is detected; formed generally through the endo-transition state. Diels-Alder reaction of 1-trimethylsilylbutadienes with dienophiles provides a good route to cyclic allylsilanes especially if the diene is symmetrical or has other substituents to control the regioselectivity of the addition. The trimethylsilyl group itself reduces the rate of Diels-Alder reactions and has if anything only a weak 'ortho-directing' effect. The allylsilanes thus obtained undergo the expected range of reactions including clean protodesilylation with acid and epoxidation to give ally1 Continuing their work on Diels-Alder reactions with 1,3-bis-oxygenated-buta-1,3-dienes Danishefsky and his co-workers have now prepared optically active arogenate (pretyrosine) (138) from the precursor (137) itself obtained from 1-methoxy-3-trimethylsilyloxybutadieneand the optically active glutamic acid derived dienophile (136) ; (Scheme 63).127 l-Methoxy-2-acetoxy-3-trimethylsilyl-oxybuta-l,3-diene is available by enol silylation of l-methoxy-2-acetoxybut-l-ene-3-one.It reacts readily with various dienophiles addition to acetylenes specifically giving convenient access to catechol derivatives. Heterocyclic com- pounds have been obtained by addition of alkoxy- and trimethylsilyloxy-substituted butadienes to heterodienophiles. A series of C-4-branched pseudoglycals was Cbz Cbz H OMe ow C02CH,Ph ... + 0s) +> OSiMe OV0 -(138) Reagents i benzene reflux; ii AcOH Scheme 63 125 L. E. Overman R. L. Freerks C. B. Petty L. A. Clibe R. K. Ono G. F. Taylor and P. J. Jessup J. Am. Chem. SOC.,1981,103,2816. 126 M. J. Carter I. Fleming and A. Percival J. Chem. Soc. Perkin Trans. 1 1981,2415. S. Danishefsky J. Morris and L. A. Clizbe J. Am. Chem. SOC.,1981,103. 1602. 12* S.Danishefsky and T. A. Craig Tetrahedron 1981 37,4081. 12' Synthetic Methods 337 obtained by reaction of (2,E)-1-methoxybutadienes with diethyl mes~xalate~*~ and reaction of di- and tri-acylimines prepared from aza-Wittig reagents and glyoxalates or keto-malonates with methoxy- and trimethylsilyloxy-butadienes gave tetrahydropiperidine derivatives in synthetically useful ~ie1d.l~' Intermolecular Diels-Alder reactions have also been used in synthetic approaches to anthracycline~'~~ and hydroxyanthraquinones including some naturally occurring examples13* and a reaction involving a 1,2-dihydropyridine derivative as the diene component formed a key step in a synthesis of de~ethy1catharanthine.l~~ However many of the most interesting syntheses of natural products have involved the intramolecular Diels-Alder reaction rather than the intermolecular reaction and although employed in the synthesis of natural products only compara- tively recently it is now finding widespread use in the synthesis of steroids alkaloids and terpenoids.Work on the total synthesis of steroids by intramolecular cycloaddi- tion reactions has been reviewed134 but some more recent advances are summarized here.In a commonly used approach a new six-membered ring is formed by intramolecular cycloaddition to an ortho-quinodimethane generated in one of a number of ways. In a synthesis of (+)-chenodeoxycholic acid for example,'35 the ortho- quinodimethane was formed by thermolysis of a benzocyclobutene (Scheme 64). The cis,anfi,trans-D-aromatic steroid (140) was obtained stereoselectively OAc (139) several steps & I 'OH HO' H OAc (140) Scheme 64 129 W. Abele and R. R. Schmidt Tetrahedron Lett. 1981,22 4807. 130 M.E.Jung K.Shishido L. Light and L. Davis Tetrahedron Lett. 1981 22,4607. 131 J.-P. Gesson J.-C. Jaquesy and M. Mondon Tetrahedron Lett.1981 22 1337; F.A. J. Kerdesky R. J. Ardecky M. V. Lakshmikantham and M. P. Cava J. Am. Chem. SOC., 1981,103,1992. 132 C. Brisson and P. Brassard J. Org. Chem. 1981,46 1810;G.Roberge and P. Brassard J. Org. Chem. 1981,46,4161. 133 C.Marazano J.-L. Fourrey and B. C. Das J. Chem. SOC.,Chem. Commun. 1981,37. lJ4 T. Kametani and H. Nemoto Tetrahedron 1981 37 3. 13' T.Kametani H. Suzuki and H. Nemoto J. Am. Chem. Soc. 1981,103,2890. 338 W.Carruthers through the intermediate (139). A more convenient route to ortho-quinodimeth- anes which requires much milder conditions than that from benzocyclobutenes is by elimination from suitable ortho- silylmethylbenzylammonium salts induced by fluoride ion. The quinodimethane (141) for example generated in the presence of dimethyl fumarate gave the adduct (142) in quantitative yield (Scheme 65).'36 (141) Reagents i Bu,NF-CH,CN 25 "e;ii Me0 C (142) *C02Me Scheme 65 Similarly the precursor (143) gave oestrone methyl ether (144) in 86% yield in a stereoselective reaction (see also ref.137) and in a novel route to 11-oxygenated steroids the 11-ketotestosterone derivative (147) was obtained by ozonization of the tetracyclic precursor (146) itself formed stereoselectively by intramolecular Diels-Alder cycli~ation'~~ of (145). A different route to 11-oxygenated steroids which proceeds through ortho- quinodimethanes has been exemplified in a synthesis of 1la-hydroxyoestrone methyl ether.'39 OH ,Me OSiMe2Bu' (145) (146) (147) Reagents i CsF-CH,CN reflux; ii CF,CO,H -78 "C; iii 0,; iv KOH-MeOH 40"C Scheme 66 136 Y.Ito M.Nakatsuka and T. Saegusa J. Am. Chem. SOC.,1981,103,476. 13' Y.Ito S. Mujata M. Nakatsuka and T. Saegusa J. Am. Chem. SOC.,1981,103,5250. G.Stork G. Clark and C. S. Shiner J. Am. Ch m. SOC.,1981,103,4948. 13' S.Djuric T. Sarkar and P. Magnus J. Am. Chem. SQC.,1980,102,6885. Synthetic Methods 339 In the alkaloid field the indolizidine alkaloid 6-coniceine (150)was synthe~ized'~' by cyclization of the imino-diene (149) followed by reduction of the double bond and the carbonyl group and intramolecular cyclization of an imine was also a feature of a new synthesis of (&)-lysergic acid. 14' An intramolecular Diels-Alder reaction (Scheme 68) using for the first time a trimethylsilyloxydienamidewas the key step in a synthesis.of cis-dihydrolycoricidine triacetate (153)14* and a related sequence involving cyclization of an enamide was employed in a synthesis of racemic 1yc0rine.l~~ In the synthesis of cis-dihydrolycoricidine reaction of (15 1) with chlorotrimethylsilane and triethylamine in refluxing dimethylformamide resulted in spontaneous cyclization of the intermediate trimethylsilyloxydienamide.Removal of the trimethylsilyloxy-group with aqueous acid gave the cyclized alcohol (152) in 6045% yield as a mixture of two isomers. The ortho-quinodimethane route has also been employed in a new approach to the synthesis of indole alka10ids.l~~ (148) (149) Reagents i toluene 370-390 "C; ii H,-Pd; iii BH3-THF Scheme 67 OSiMe CHO 0 N-Ph 0 0 1 OH (153) (152) Reagents i Et,N-Me,SiCl-DMF 160"C; ii H,O' Scheme 68 140 N.A. Khatri H. F. Schmitthenner J. Shringarpure and S.M. Weinreb J Am. Chem. Soc. 1981 103,6387. 141 W. Oppolzer E.Franwtte and K. Battig Helu. Chim. Actu 1981,64,478. 14' G. E.Keck E. Boden and U.Sonnewald Tetrahedron Lett. 1981,22,2615. 143 S.F.Martin and Chih-Yun Tu J. Org. Chem. 1981,46 3763. 144 T.Gallagher and P. Magnus Tetrahedron 1981 37,3889. 340 W. Carruthers Intramolecular cyclization of N-acyl-1 -aza-1,3-dienes although not yet employed in alkaloid synthesis provides another route to nitrogen heterocyclic The aza-dienes may be obtained by gas-phase pyrolysis of N-acyl-0-acetyl-N- allylhydroxylamines.Intramolecular Diels-Alder cyclizations have also been used for the stereospecific synthesis of substituted indane and octalin deriva- tives. For example in experiments aimed at the synthesis of the ionophore antibiotic X-14547A146 the trans- hexahydroindene (155) was obtained specifically in 70% yield from the triene (154) via the sterically favoured endo-transition state and in a closely related sequence (156) was obtained in 7 1'/o yield in a catalysed reaction at room temperature (Scheme 69).147 Similarly the cis-octalone (157) was ~btained'~' by way of the correspond- from 3,ll -dimethyl-l,3,9-dodecatrien-8-one ing endo- transition state. Nevertheless a growing body of evidence supports the view that the Alder endo- rule which governs many intermolecular Diels-Alder reactions is not universally valid for the intramolecular reaction and several cases have been reported in which cyclization has clearly proceeded by way of an em- transition Reagent i toluene 130 "C Scheme 69 Many other cycloadditions that have proved useful in synthesis although strictly speaking not Diels-Alder reactions nevertheless are conceptually related and may conveniently be considered here.The first synthesis of the antitumour neolignan megaphone (160) has been achieved15' using as the key step the elegant Lewis acid-catalysed cycloaddition of the propenylbenzene (158)to the p-benzoquinone monoketal (159); (Scheme 70). In a continuation of earlier work on the synthetic Yea-Shun Cheng F. W. Fowler and A.T. Lupo J. Am. Chem. Soc. 1981,103,2090. K. C. Nicolaou and R.L. Magolda,J. Org. Chem.,1981,46,1506,1509;see also M. P. Edwards,S.V. Ley and S. G. Lister Tetrahedron Lett. 1981 22 361. W. R. Roush and A. G. Myers J. Org. Chem. 1981,46 1509. J.-L. Gras J. Org. Chem. 1981,46 3738. 149 J. D. White and B. G. Sheldon J. Org. Chem. 1981 46 2273; W. R. Roush and S. E. Hall J. Am. Chem. SOC.,1981,103 5200. Is' G. Buchi and Ping-Sun Chu J. Am. Chem. Soc. 1981,103 2718. 14' Synthetic Methods 341 OMe OMe Me0 OMe Reagents i SnC1,-CH,CI, -30 “C; ii several steps Scheme 70 uses of oxyallyls,’” the a-multistriatin analogue (163) has been prepared from the adduct (162) of 2,s-dimethylfuran and the oxyallyl(l61); (Scheme 71). The oxyallyl was obtained by a convenient new route from 2-bromopentan-3-one and silver tetrafluoroborate.The muscarine analogue (165) was obtained in a similar way from the adduct (164) through reduction of the double bond and Beckmann 0 0 Me,&Me & (MeAMe Me -% Me Me Br (161) (162) (163) H ‘ Me02cYYkMe3 Reagents i AgBF,-Et3N-CH3CN; ii MeOMe ;iii several steps 0 Scheme 71 rearrangement of the derived o~irne.~’~ A novel route to the cis,anti,cis-linearly- fused tricyclopentanoid ring system found in several sesquiterpenoids of current interest employs in the key step a regiospecific and highly stereoselective *” J. Mann and A. A. Usmani J. Chem. SOC.,Chem. Commun. 1980,1119. lS2 A.P.Cowling J. Mann and A. A. Usmani J. Chem. SOC.,Perkin Trans.I 1981 2116. 342 W. Carruthers intramolecular addition of a diyl to a carbon-carbon double bond. It has previously been shown that cyclopenta- 1,3-diyls can be trapped by alkenes carrying electron- withdrawing substituents to afford preferentially fused rather than bridged ring cycloadduct~.'~~ An intramolecular version of this reaction was used to construct the hirsutene ring On refluxing the azo-compound (166) in acetonitrile a highly stereoselective cyclization ensued from the intermediate diyl to give the tricyclopentanoid (167) in 85'/o yield subsequently converted into dl-hirsutene (168). The marine sesquiterpene A9"*'-capnellene (169) was synthesized by a similar method (Scheme 72).155 Reagent i CH,CN reflux Scheme 72 9 1,3-Dipolar Cycloaddition Reactions 1,3-Dipolar cycloaddition reactions particularly of nitrones are being employed increasingly in synthesis as in a recent approach to quinolizidine alkaloids'56 and perhydroquin~lizinones.'~~ A good illustration is provided by a chiral synthesis of L-daunosamine (175a) and its C-4 epimer L-acosamine (175b) shown in Scheme 73.'58 The chiral nitrone (172) was prepared from the masked aldehyde (170) and the oxalate salt of (S)-(-)-N-hydroxy-a-methylbenzenemethanamine(171) in a refluxing xylene and under the reaction conditions cyclized to give a mixture of the diastereomers (173) and (174) by a reversal of the normal addition of the nitrone oxygen to the oxygen-bearing carbon of an enol ether or ester.Further manipulation of (174) led to (175a) and (175b).The 1,3-dipolar cycloaddition of azomethine ylides (176) to activated alkenes is a good synthetic route to certain pyrrolidine derivatives but is limited in scope because R and R' have to be aryl or electron-withdrawing substituents as a consequence of the methods needed to generate the ylides (Scheme 74). It is now J. A. Berson Acc. Chem. Res. 1978 11 446. 154 R. D. Little and G.W. Muller J. Am. Chem. SOC.,1981 103 2744. R. D. Little and G. L. Carroll Tetrahedron Left. 1981 22,4389. ''' S. Takano and K.Shishido J. Chem. SOC. Chem. Commun. 1981 940. 157 R. Brambilla R. Friary A. Ganguly M S. Puar B. R. Sunday J. J. Wright K. D. Onan and A. T. McPhail Tetrahedron 1981 37 3615. ''' P. M. Wovkulich and M. R.UskokoviC J. Am. Chem. SOC., 1981,103,3956. Synthetic Methods ' (172) 1 (175) a; R = OH R' = H (175) b; R = H R' = OH (174) 82 12 (173) Reagents i xylene reflux; ii several steps Scheme 73 A = electron-withdrawing group Reagents i 0-25 "C;ii Raney Ni; iii AgNO,; iv NaBH Scheme 14 344 W. Carruthers reported"' that the readily available ylides (177a) and (177b) afford adducts (178) on reaction with activated double bonds; these can be desulphurized and hydrolysed to form the pyrrolidines (179). The ylides (177a) and (177b) here act as synthetic equivalents of the inaccessible azomethine ylides (180). 10 Ene Reaction A review of his recent work on the synthesis of (+)-oestradiol (A)-chanoclavine (*)-isochanoclavine (+)-longifolene '(+)-sativene and the neurophysiologically interesting cyclic amino-diacid (+)-a-allokainic acid (181) has been given by Oppol- zer.l6' The synthesis of (181) included the first example of an ene reaction proceed- ing with high asymmetric induction (Scheme 75).161 -L -I= Reagents i.Et,AlCI -35 "C; ii several steps Scheme 75 Recent examples in synthesis have illustrated the 'hetero-ene' reaction in which a double bond to a hetero-atom is involved. Thus cyclopentenols are obtained from y-allenic aldehydes and with the optically active allene (182) the (S)-cyclopentenol (183) was obtained preferentially (Scheme 76) although it was only 36% optically (182) (183) Reagent i 200 "C Scheme 76 G. A. Kraus and J. 0.Nagy Tetrahedron Lett.1981,22 2727. W.Oppolzer Pure Appl. Chem. 1981.53 1181. W.Oppolzer C.Robbiani and K. Battig Helo. Chim. Actu 1980,63 2015. Synthetic Methods pure indicating reaction through both endo-and exo-transition states.16* In the nitrogen series thermal (120 "C) and catalytic (SnCL BF, AlCl,) ene addition reactions of butyl N-(p-tolylsulphony1)iminoacetate with alkenes gave adducts which could be readily converted into 78-unsaturated a-amino-acid~'~~ (Scheme -(COzBu pC0,Bu 1 NHS0,C6H4Me-p fi' /N Me Me S0,C,H4Me-p Reagents i benzene 120 "C sealed tube or SnCl,-CH2Cl, 0 "C Scheme 77 77). Both inter- and intra-molecular ene reactions of acylnitroso compounds also take place readily affording N-alkyl hydroxamic acids which are smoothly conver- ted into amides by reduction of the corresponding ally1 ethers with sodium amalgam (Scheme 78).164The intramolecular reactions are highly regioselective providing entry into either spiro or fused bicyclic nitrogen ring systems in appropriate cases.Reagents i benzene reflux; ii ABr-K2C03 ;iii Na-Hg-EtOH-Na,HPO Scheme 78 162 M. Bertrand M. L. Roumestant and P.Sylvestre-Panthet Tetrahedron Lett. 1981 22 3589. 163 0.Achmatowia and M. Pietraszkiewin J. Chem.SOC.,Perkin Trans. I 1981 2680. lo4 G. E. Keck R. R. Webb and J. B. Yates Tetrahedron 1981,37,4007.

ISSN:0069-3030    

DOI:10.1039/OC9817800299

出版商:RSC    

年代:1981

数据来源: RSC

摘要:

14 Biological Chemistry Part (i) Prostaglandins By R. F. NEWT0N”and S. M. ROBERTSb Chemical Research Gepartment Glaxo Group Research Ware Herts. SG 12 ODJ 1 Introduction The field of prostaglandin research has not been the subject of a Report before. We will concentrate on work that has been published in the last two years with reference to earlier studies where necessary. Some aspects of the biological activities of prostaglandins are presented in order to put the chemical data into perspective. 2 History Nomenclature and Occurrence’ The first report describing the biological effects of prostaglandins was published in the 1930’s. The small quantities of material that were available at that time precluded purification and structure elucidation. It was not until twenty years later that Bergstrom isolated the first crystalline samples of prostaglandins and deter- mined their structures.Nine classes of prostaglandins and two classes of thromboxanes have been discovered to date (Figure 1):the classes differ in the substitution pattern about the five- or six-membered ring respectively. Prostaglandins (PGs) and thromboxanes (TXs) possess two side-chains which contain seven and eight carbon atoms and these are called the a-and w-chains respectively. In the series described in Figure 1the side-chains contain two alkene units and this number is included in the name in the form of a subscript. Other series have been isolated in which the side-chains contain one and three alkene units as described for the PG-E class in Figure 2.All the classes of prostaglandin have three members the I-class is the exception to this rule since PG-I has not been found in nature to date. The numbering of the prostaglandins is conventional and is illustrated for PG-E2 in Figure 2. Prostaglandins D2,E2 and F2aare widely distributed in mammalian tissue but they are present in only very low concentrations. The seminal fluids of sheep and man are two of the richest sources and contain ca. 300 pg 1-’. A coral endogenous to the Caribbean Plexaura homomallu contains large quantities of PG-A2 and onions have been shown to contain PG-A,. Recently the alga Grarciluria fichenoides has been shown to contain PG-F2a and PG-E2. a Address correspondence to this author. * Present address Chemical Research Department Glaxo Group Research Ltd.Greenford Middlesex. R. F. Newton and S. M. Roberts in ‘Fats and Oils Chemistry and Technology’ ed. R. J. Hamilton and A. Bhati Applied Science London 1980 p. 109. 347 R. F.Newton and S. M. Roberts 4.1 0 4-R' aQH R (),R2 0 -2 R' R' R' R' PG-C;? PG-D2 PG-AZ PG-B;? OH R' 9" PG-G2 PG-H;? PG-E;? PG-F;?(Y Figure 1 Structures of PGs and TXs e11 Z ) 3 " Z H /* 15 C5H11 OH 13 9 OH PG-E2 OH Figure 2 Structures of PG-El PG-E2 and PG-E3 Biological Chemistry -Part (i) Prostaglandins 3 Biosynthesis and Metabolism of Prostaglandins' The prostaglandins are unusual in that unlike the hormones and the neurohormones there is no mechanism for their storage.They are biosynthesized from the appropri- ate polyenoic acid in response to a stimulus. For the 2-series prostaglandins arachidonie acid is released from membrane- bound phospholipids by the action of a phospholipase. The free acid is then cyclized to form PG-G2 by a cyclo-oxygenase enzyme system (Scheme 1).The hydroperoxide Cyclo-oxygenase enzyme _7 \/ fi2H 2H Other prostaglandins and thromboxanes Arachidonic acid Scheme 1 unit of PG-G2 is reduced by a peroxidase enzyme to give PG-H2. Except for PGF2a which is the product of an enzymic reduction process all the prostaglandins of the 2-series and TX-A2 are obtained from PG-G2 and/or PG-H2 by enzyme catalysed rearrangements. Prostaglandins of the 1-and 3-series are formed from the corresponding tri- and penta-alkenoic acids respectively by analogous routes.PG-I and TX-A2 are unstable under physiological conditions and rapidly hydrolyse to 6-ketoprosta- glandin Fla (1)and TX-B2 respectively. These decomposition products and the rest of the prostaglandin family are subject to extremely efficient metabolic pro- cesses. The first step is an oxidation of the C-15 hydroxy-group by a dehydrogenase enzyme followed by reduction of the C-13 C-14 alkene unit by a hydrogenase system. Two cycles of p-oxidation of the cy -side-chain and oxidation at the terminus of the w-side-chain produce compounds such as the keto-acid (2) which is the major urinary metabolite of PG-E,. 0 nu OH (1) (2) K. H. Gibson in 'Prostaglandins and Thrornboxanes an Introductory Text,' ed R.F. Newton and S. M. Roberts Butterworths London 1982 p.8. R. F. Newton and S. M. Roberts 4 Biological Activity of Prostaglandins and Thromboxanes Most of the early work on the biological activity of prostaglandins was concentrated on prostaglandins E and F. It became quite clear that both classes displayed potent effects on a number of biological systems3 For example PG-F2a is a potent l~teolytic:~ that is it causes regression of the corpus luteum in experimental animals. Since the corpus luteum is responsible for the maintenance of progesterone levels during implantation and development of a fertilized egg the prostaglandin can cause termination of pregnancy at an early stage.Prostaglandins E relax isolated airway smooth muscle and thus are potentially useful as aids to asthmatic patient^.^ Unfortunately the prostaglandins frequently cause severe irritation of the respiratory tract when administered by aerosol to patients. The natural prostaglandins have found very few therapeutic applications in man mainly as a result of their lack of selectivity and oral activity and their short duration of action. For instance an injection of PG-E causes a fall in blood pressure an increase in gut motility diarrhoea uterine stimulation inhibition of acid secretion and sensitization of pain receptors! The discovery of prostaglandins I and thrombodanes renewed hopes that pros- tanoids would be clinically useful. TX-A is produced from PG-H within the blood platelets and acts to increase the level of Ca2’ within the cytoplasm of the cell.This causes the platelet to deform and release TX-A and other aggregating agents into the blood plasma. Further platelets then deform and aggregate to give a thrombus. In addition TX-A is a potent vasoconstrictor so reducing blood flow even more. Prostaglandin I2 is produced from PG-H2 in the epithelial cells of blood vessels (e.g. artery walls) and released into the blood plasma. Besides acting as a potent vasodilator it also acts at a specific receptor on the blood platelet. This causes an increase in cyclic AMP levels within the cytoplasm which in turn leads to a decrease in the concentration of cytoplasmic Ca” levels. Thus the actions of TX-A and PG-I are directly opposed.In a healthy individual these effects are balanced and blood platelet homeostasis is maintained. In the event of damage to the blood vessels e.g. lesions or fat deposits on arterial walls PG-I production will be impaired whilst TX-A production in the vicinity will be undiminished. Blood platelets then adhere to the damaged vessel and clump together. Breakaway of this mass of platelets at a later time could provide a potentially lethal thrombw6 One possible aid to a patient at risk from thrombosis or stroke would be the administration of a chemically and metabolically stable PG-I analogue which would supplement the low concentration of the natural compound. Alternatively blocking E. W. Horton in ‘Chemistry Biochemistry and Pharmacology of Prostanoids’ ed.S. M. Roberts and F. Scheinmann Pergamon Oxford 1979,p.1. E. W.Horton and N. Poyser Physiol. Rev. 1976,56 595. I. Kennedy in ‘Prostaglandins and Thromboxanes an Introductory Text’ ed. R. F. Newton and S. M. Roberts Butterworths London 1982,p. 19;M.Wassermann J. Pharmacol. Exp. Ther. 1980,214,68. S. Moncada and J. R. Vane Pharm. Rev. 1978,30 293;‘Prostaglandins and Cardiovascular Disease’ ed. R. J. Hegyeli Raven Press 1980;R. J. Gryglewski Crit. Rev. Biochem. 1980,7 291. Biological Chemistry -Part (i) Prostaglandins 351 the production of TX-A2 from PG-H (a thromboxane synthetase inhibitor) or blocking the action effected by binding of TX-A to its macromolecular receptor (a thromboxane antagonist) may provide a remedy by reducing the rate of blood- platelet aggregation.Prostaglandins have been implicated in many other biological processes for example regulation of the onset of fever and the transmission of pain,7 the inflamma- tory response,* control of gastric acid secretion,’ regulation of adrenergic trans- mission,1o cancer,” immunology and allergy,’ and in the central nervous ~ystem.’~ 5 Chemical Synthesis of Prostaglandins Thromboxanes and Analogues Many of the points brought out in the above discussion have direct relevance to the synthesis of PGs TXs and analogues. For instance the abundance of PG-A in a Caribbean coral led to this substance being used as a starting material for other prostanoid syntheses by some group^.'^ The preparation of prostanoids designed to be metabolically stable and orally active has been a principal’goal in the field.Moreover the synthesis of prostanoids with enhanced selectivity of biological activity has been the raison d’etre of many research groups. The recent emergence of prostaglandins I and thromboxanes as highly important natural products has led synthetic chemists to focus their attention on these molecules as target structures. Prostaglandin synthesis has led to the discovery of many reactions and the use of some new protecting groups of general interest.” Early strategies (pre-1977) in prostaglandin synthesis have been reviewed in three excellent textbooks.16 A full review of the synthetic chemistry reported in the primary journals between 1977 and mid-1980 is a~ailab1e.I~ Synthesis of Prostaglandins A-F.-New Routes to the Corey Lactone and Congen -ers. The pioneering work of Corey established the lactone (3)as a key intermediate to PG-El PG-E2 PG-E3 PG-Fla PG-F2a and PG-F3a. Since PGs A-C are available from PGs-E’~ this lactone became a focal point for prostaglandin synthesis. ’S. H. Ferreira Nature (London) 1972,240,200; W. Feldberg in ‘Prostaglandin Synthetase Inhibitors’ ed. H. J. Robinson and J. R. Vane Raven Press New York 1974 p.197. J. R. Vane J. Allergy Clin. Immunol. 1976 58,691. A. Robert in ‘Prostaglandins and the Gastrointestinal Tract’ ed. L. R. Johnson Raven Press 1981 p.1407. lo K. V. Malik Fed. Proc. 1978 37,203. ” G. C. Easty and D. M. Easty Cancer Treatment Rev. 1976 3 217. l2 J. Morley J.L. Beats M. A. Bray and W. Paul J. Royal SOC.Med. 1980 73 443; L. M. Pelus and H. R. Strausser LifeSci. 1977 20,903. l3 F. Coceani Arch. Interm. Med. 1974,133 119. l4 G. L. Bundy W. P. Schneider F. H. Lincoln and J. E. Pike J. Am. Chem. SOC. 1972,94 2123; M. B. Floyd R. E. Schaub G. J. Siuta J. S.Skotnicki C. V. Grudzinskas M. J. Weiss F. Dessy and L. Van Humbeeck J. Med. Chem. 1980 23 903; K. M. Maxey and G. L. Bundy Tetrahedron Lett. 1980,445. M. P. L. Caton Tetrahedron 1979 35 2705. l6 J. S. Bindra and R. Bindra ‘Prostaglandin Synthesis’ Academic New York 1977; A. Mitra ‘The Synthesis of Prostaglandin Derivatives’ J. Wiley and Sons,New York 1978; C. Szartay and L. Novak ‘Synthesis of Prostaglandins’ Akademiai Kiado Budapest 1978. ” S. M.Roberts and F. Scheinmann ‘Recent Synthetic Routes to Prostaglandins and Thromboxanes’ Academic London,1982; see also ‘Aliphatic and Related Natural Product Chemistry’ (A Specialist Periodical Report) ed. F. D. Gunstone The Chemical Society London 1979 (Volume 1) and The Royal Society of Chemistry London 1981 (Volume 2). R. F. Newton and S.M. Roberts (3) R' = H or protecting group R2 = one carbon unit e.g. CHO CHpOR' (4) liv o-fo H02C Br&>o 01x-xii (3) xiii-xv+ 9 OR' OH OR2 C,Hl1 OR21xvi OH PG-F2u q xvii OR2 OR2 (7) R' = p-PhC6H4NHC0 R2 = tetrahydropyranyl (THP) Reagents i HC02H HCHO; ii Jones' reagent; iii HBr AcOH; iv HOOA? NaOAc; v HBr AcOH; vi NaHCO, H,O; vii PhSH pyridine DCC; viii Raney Ni; ix (Et0)2P(0)CH2COC5H,I NaH; x K,C03 MeOH; xi p-PhC6H4NC0 Et,N; xii LiBHBu',; xiii LiOH H,O then CIC02Et CO,; xiv dihydropyran (DHP) H'; xv HAIBu',; xvi Ph3PCH(CH2),CO,-; xvii MeCO,H H20 Scheme 2 Biological Chemistry -Part (i) Prostaglandins 353 The Sutherland-I.C.I.synthesis of the Corey lactone is detailed in Scheme 2.'* The initial Prins reaction on norbornadiene formed a key step in setting up the required stereochemistry in the keto-acid (4). This keto-acid was cleaved regio- and stereo-specifically with hydrobromic acid to give the carboxylic acid (5). Baeyer-Villiger oxidation of (5)led to the formation of the 8-lactone (6),which was readily converted into the Corey lactone. Conversion of this lactoqe into PG-F2a followed the original Corey strategy; thus a Wittig reaction appended the w-side-chain and the 15(S) hydroxy-group could be introduced by a stereocontrol- led reduction process.Partial reduction of the lactone unit to a lactol followed by a 'salt-free' Wittig reaction to introduce the Z-alkene moiety gave the PG-F2a derivative (7),which formed PG-F2a on treatment with acid. ?H OH -0Q OH Cl (8) Simple amendment of this pathway gave cloprostenol (8) which 'is marketed under the trade-name Estrumate as a veterinary aid to maximize the efficiency of artificial insemination. l9 Ghosez's elegant syntheses of the Corey lactone begins with a [2 + 21 addition of the keten (9) to cyclopentadiene (Scheme 3).20The four-membered ring of the . .. iii+ :1KCo2Me[C02Me % 0 II 0 0 \CH(OMe) (9) 1vi vii q0 (3; R1= p-PhC6HaC0 R2 = CHO) 4 viii ii BrQ** OH CH(0Me)Z (13) Reagents i cyclopentadiene; ii Bu",SnH AIBN; iii NaBH, MeOH then NaOMe then HCl HC(OMe),; iv NaOH; v KI,; vi diazabicycloundecene (DBU); vii MeCONHBr H,O;viii p-PhC6H,COCl pyridine; ix H' Scheme 3 l8 N.R. A. Beeley R. Peel J. K. Sutherland J. J. Holohan K. B. Mallion and G. J. Sependa Tetrahedron 1981,37(Supplement l) 411. l9 M. Dukes W. Russell and A. L. Walpole Nature 1974,330. 2o S. Goldstein P. Vannes C. Houge A. M. Frisque-Hesbain C. Wiaux-Zamar L. Ghosez G. Germain J. P. Declercq M. Van Meerssche. and J. M. Arrieta J. Am. Chem. SOC.. 1981 103,4616. R. F.Newton and S. M. Roberts bicycloheptenone (10) is readily cleaved to give the ester (11).Saponification and iodolactonization gave the acetal (12). Elimination of hydrogen iodide followed by stereospecific addition of HOBr gave the bromohydrin (13)which was converted in three steps into the Corey lactone. A [2 + 21 cycloaddition is also featured as the first stage in Fleming's route to the Corey lactone.*' Trimethylsilylcyclopentadiene(14)reacted with dichloroketen to give solely the bicycloheptenone (15). Electrophilic substitution of the silyl moiety with concomitant migration of the double bond gave the ether (16),which was converted into the unsaturated lactone (17) and thence into the Corey lactone by a well-defined series of reactions. SiMe ,oq Me Si c1 -Qcl 0VI 4,q0Ssteps (3) 3 Q**' -Zsteps, Q -OMe OMe The Corey lactone has been prepared from readily available cyclo-octa-l,5-diene.This diene was converted into cyclonona-2,4,7-trien-l-ol(18) in six steps this trienol isomerized to the aldehyde (19) in the presence of potassium hydride (Scheme 4).The derived carboxylic acid (which could be resolved) was iodolacton- ized to give (20) and by further transformations the acetal (12). This compound . nu CHO ?-to Pqo 1'1 Reagents i KH THF; ii Ag20 NaOH H,O; iii I, K2C03. THF H20; iv. 0,. MeOH CHZCIz then Me2S; v H' CH(OMe) Scheme 4 I. Fleming and B. W. Au-Yeung Tetrahedron 1981 37 (Supplement l) 13. L. A. Paquette and G. D. Crouse Tetrahedron 1981,37(Supplement l),281. Biological Chemistry -Part (i) Prostaglandins was converted into the Corey lactone (see Scheme 2) and into the enal (21) a precursor of PG-C216 and TX-B2.The enal (21) has also been prepared from the lactone (22) (available in optically active form23). The carbonylation process was accomplished using an intra-molecular a-amido-alkylation reaction as the key step (23) + (24) (Scheme 5).24 Prostaglandin-D3 has recently been added to the list of naturally occurring prostaglandins available from the Corey la~tone.~~ OCOAr ,fy&iv v 6-f‘ o***y i ii -iii ’ (21) NHMe OH -N \ (22) (23) (24) Me Reagents i MeNH,; ii ArCOCl pyridine; iii CH,O MeNO, CF,CO,H; iv HCl; v Bu‘OCl NaOMe then H’ Scheme 5 The Glaxo Syntheses. Prostaglandin A is available from the optically active ketone (-)-(25) using the sequence described in Scheme 6.26The key step involved $r $‘ lvi LiCuC,H7 -C,H 1 1 OR OR R = SiMezBut (29) Reagents i Br, NaHCO, CCl,; ii LiN(SiMe,),; iii (26) CH,CI,; iv m-ClC,H,CO,H; v DBU; vi Me,NCHO heat Scheme 6 23 N.Ishizuka S. Miyamura T. Takeuchi and K. Achiwa Heterocycles 1980,14 1123. ’* T. T. Li P. Lesko R. H. Ellison N. Subramanian and J. H. Fried J. Org. Chem. 1980,46 111. ” Y.Konishi H. Wakatsuka and M. Hayashi Chem. Lett. 1980 377. 26 M. A. W. Finch S. M. Roberts G. T. Woolley and R. F. Newton J. Chem. SOC.,Perkin Trans. 1 1981 1725. 356 R. F. Newton and S. M. Roberts homoconjugate addition of the cuprate reagent (26)to the bromotricycloheptanone (27). The product norbornanone (28)was transformed in three steps into the late-stage PG-A2 precursor (29).The enantiomeric bicycloheptenone (+)-(25)was converted into the same PG-A2 precursor (29)using a different series of reactions (Scheme 7).27The key transforma- tion involved the cuprate reagent (26)and the epoxyester (30) in an SN'anti reaction to give the lactone (29)directly. A small amount of the isomeric lactone (31)was also isolated. Interestingly the SN2'pathway was found not to predominate when the epoxide (30) underwent reaction with other nucleophiles.28 Reagents i MeC0,H; ii N-bromosuccinimide CCI, hu; iii K,CO, MeOH; iv (26) Scheme 7 n I\ (-)-enantiomer (+)-enantiomer OK0 -a.$1 I 3 steps 3 steps e Q -Qo 0,''- 0 0 QR o-fo # 3 steps 2 steps 9, ' ' LC5Hl1 OH C,Hl1 OR OR OH 3 steps 1 1 PG-E2 &H2Lc02H II PG-FZa 4 IV CJI 1 CJI I HO OH OR % PG-D2methyl ester OH (33) Reagents i (26);ii H'; iii hv H,O,MeCN; iv Ph,PCH(CH,),CO; Scheme 8 27 C.B. Chapleo M. A. W. Finch T. V. Lee S. M. Roberts and R. F. Newton J. Chem. SOC.,Perkin Trans. 1 1980 2084. S. M. Roberts G. T. Woolley and R. F. Newton J. Chem. SOC.,Perkin Trans. 1. 1981 1729. Biological Chemistry -Part (i) Prostaglandins ProstaglandinsEZand Fza are also available from both enantiomers of the ketone (25) as shown in Scheme 8.29These enantiocomplementary routes were based on reaction sequences worked out previously on the racemic A noteworthy feature of the route starting from the ketone (+)-(25) is the high yield photochemical conversion of the cyclobutanone (32) into the y-lactol (33).This route represents the shortest synthesis of prostaglandins E2 and F2a reported to date. In order for the above strategy to be viable an efficient resolution of the ketone (25) is required. Reduction of the ketone (25) with actively fermenting bakers' yeast gave two diastereoisomeric alcohols (34) and (35) of high optical purity and in good chemical yield. The alcohols (34) and (35) were easily separated by distillation and were oxidized to the ketones (+)-(25) and (-)-(25) respectively using Jones' conditions the alcohols (34) and (35) gave the bromohydrins (36) and (37) respectively on reaction with N-bromosuccinimide in aqueous di~xan.~' (34) (35) 1 1 Br I Br 0 (36) (37) Another important feature of the Glaxo route is the direct access to PG-D232 and simple derivative^.^^ Conjugate Addition to 4 -Substituted Cyclopentenones.Two approaches have been explored (Scheme 9). The first involves conjugate addition to a 2-alkyl-4-alkoxy cyclopentenone the second involves conjugate addition to a 4-alkoxycyclopen- tenone and trapping of the enolate ion with a moiety which can be readily transfor- med into the C-7 side-chain. Note that direct alkylation by addition of the complete a-side-chain to the enolate anion has not been achieved. In these strategies the stereochemistry at C-4 of the cyclopentenone establishes the whole substitution pattern required for the prostaglandin E class. Thus nucleophilic addition of the C-8 side-chain takes place on the less hindered face 29 J.Davies S. M. Roberts D. P. Reynolds and R. F. Newton J. Chem. SOC.,Perkin Trans. 1,1981 1317. 30 T. V. Lee S. M. Roberts M. J. Dimsdale R. F. Newton D. K. Rainey and C. F. Webb J. Chem. Soc. Perkin Trans. 1 1978 1176; C. Howard R. F. Newton D. P. Reynolds A. H. Wadsworth D. R. Kelly and S. M. Roberts ibid 1980 859; C. Howard R. F. Newton D. P. Reynolds and S. M. Roberts ibid 1981 2049. 3' R. F. Newton J. Paton D. P. Reynolds S. N. Young and S. M. Roberts J. Chem. SOC.,Chem. Commun. 1979,908. 32 R. F. Newton D. P. Reynolds C. F. Webb and S. M. Roberts J. Chem. SOC.,Perkin Trans. 1 1981 2055. 33 R. J. Cave R. F. Newton D. P. Reynolds and S. M.Roberts J. Chem. SOC.,Perkin Trans.1 1981,646. R. F. Newton and S. M. Roberts 6-L T C5H' 1 OR2 OR2 ' 0R3 R' =(cH2)&02Me or CH2CH:CH(CH2)3C02Me R2=R3=protectinggroup R4 =simple C-1 or C-2 unit Scheme 9 of the cyclopentenone and a trans relationship between the a-and w-side-chains is set up by thermodynamic control. In a series of papers,34 Rickards et al. have demonstrated that phenol can be converted into the acid (38) this acid (which can be resolved) was transformed into the 3-chloroenone (39). Conjugate addition of the C-7 unit followed by elimination of chloride ion and carbonyl group transposition furnished the PG-El precursor (40) (Scheme 10). In an alternative process the chloroenone (39) was OR2 (41) (40) R' =SiMe2Bu';R2 =THP Reagents i Pb(OAc),; ii CrCl,; iii CISiMe,Bu' imidazole; iv BrMg(CH,),OR' CuI Scheme 10 34 R.M. Christie M. Gill and R. W. Rickards J. Chem. SOC.,Perkin Trans. 1 1981,593;M. Gill and R. W. Rickards ibid p. 599; M. Gill and R. W. Rickards Aust. J. Chem. 1981,34 1063. Biological Chemistry -Part (i) Prostaglandins transformed into the stannylcyclopentenediol derivative (41) which reacted efficiently with various electrophiles to give after standard functional group manipulation the required enone (40).35 The PG-E2precursor (42)was obtained from the lactone (22) (which is available in optically active form36) by the series of simple transformations described in Scheme 1l.37 qo OH0,.-0,,*~H2)3c02Me -6,.*ucH2) 3c0 2 Me - - (22) 0 (CH2)3C02Me PG-E2 -wH2)3c02Me + OH OTHP (42) Scheme 11 The preparation of simple derivatives of PG-EI and PG-E from (40) and (42) respectively was achieved using a cuprate reagent (26) or a The enone (43) is readily available.It has been prepared in the optically active Stork prepared (43) in racemic form from cyclopentadiene in two steps. Conjugate addition of the appropriate cuprate reagent followed by trapping of the enolate with formaldehyde gave the hydroxyketone (44).The hydroxyketone (44) was transformed into the a-methylene ketone (45). A second conjugate addition gave the PG-E2derivative (46) (Scheme 12).40 Another successful conjugate addition-enolate trapping sequence was described recently by Davis.41 Two features are noteworthy. First the use of the cuprate reagent (47) and the transformation of the 132,15R configuration of the w-side- chain into the required 13E,15sconfiguration using a subtle sulphenate-sulphoxide rearrangement.Secondly the use of keten bis(methy1thio)acetal monoxide as the enolate trapping agent (Scheme 13). Organozirconium reagents in the presence of a low-valence nickel catalyst can be used in place of the more commonly employed cuprate reagent^.^' ” M. Gill H. P. Bainton and R. W. Rickards Tetrahedron Lett. 1981 22 1437. 36 M. Nara S. Terashima and S. Yamada Tetrahedron,1980 36 3161. ” L. Novak Acad. Chim. Acad. Sci. Hungary 1979,102,91. ’* C. J. Sih R. G. Salomon P. Price R. Sood and G. Peruzotti J. Am. Chem. SOC. 1975 97 857; C. J. Sih J. B. Heather R.Sood P. Price G. Peruzzotti L. F. Hsu-Lee and S. S. Lee ibid 1975 97 865; J. B. Heather R. Sood P. Price G. Peruzzotti S. S. Lee L. F. Hsu-Lee and C. J. Sih Tetrahedron Lett. 1973 2313. 39 K. Ogwa M. Yamashita and G. Tsuchihashi Tetrahedron Lett. 1976 759; S. Miura S. Kurozumi T. Tom,T. Tanaka M. Kobayashi S. Matsubura and S. Ishimoto Tetrahedron 1976 32 1896. 40 G. Stork and M. Isobe J. Am. Chem. SOC.,1975,97,6260. 41 R. Davis and K. G. Untch J. Org. Chem. 1979 44,3755. 42 J. Schwartz and Y. Hayasi Tetrahedron Lett. 1980 21 1497. R. F. Newton and S. M. Roberts iii iv 4-i ii -C5H1 1 C5H11 OR' OR' O'R' OR2 OR2 (43) (44) (45) j/ &2)3cH20R3 RZ = CHZOCHzPh R' CMezPh C,Hll OR' OR2 (46) Reagents i LiCu[CH:CHCH(ORZ)C5H1,],; ii CH,O; iii MsCl pyridine; iv Et,N; v LiCu[CH:CH(CH,),CH,0R3] Scheme 12 ))Me LII vi vii CH 5&C5H1 -(33) OR -, OR OH R = SiMezBu' Reagents i L~CU[CH:CHCH(OCM~~OM~)C,H,,]~ (47); ii H,C:C(SMe)S(O)Me; iii PhSCI Et,N; iv P(OMe),; v chromatography; vi L-selectride; vii HCI Scheme 13 MiscellaneousProcedures.Holton has reported a four-stage synthesisof the lactone (53) starting from cyclopentadiene (Scheme 14).43Thus addition of hydrogen chloride gas to cyclopentadieneand treatment of the resultant chloride with anhy-drous dimethylamine furnished the cyclopentenylamine (48). Reaction of this intermediate with lithium tetrachloropalladate and sodio diethyl malonate followed by addition of di-isopropylamine gave the alkene (50) via the complex (49).The alkene (50) was treated with lithium tetrachloropalladate in a mixture of 2-chloroethanol dimethyl sulphoxide (DMSO),and ethyldi-isopropylamine to give the complex (51) which on reaction with oct-1-en-3-one gave the desired enone (52). Conversion of (52) into the lactone (53) was straightforward. A very interesting route to optically active PG-E has been described by Fuchs. The ally1 sulphide (54) is readily available in optically active form44and was 43 R. A. Holton J. Am. Chem. SOC.,1977 99 8084. 44 J. C. Saddler R.E. Donaldson and P. L. Fuchs J. Am. Chem. SOC.,1981,103,2110. Biological Chemistry -Part (i)Prostaglandins L NMe I ,NMe NMe (48) CH(CO,Et) (49) 1iv NMe, I Reagents i HC1; ii Me,NH; iii lithium tetrachloropalladatc NaCH(CO,Et) then EtNPr’, heat; iv lithium tetrachloropalladate Cl(CH,),OH DMSO EtNPr’,; v C,H,,COCH:CH,; vi L-selectride; vii NaCN; viii MeI; ix KOH Scheme 14 converted in four steps into the sulphone (55).This sulphone reacted stereo- specifically with dimethylamine with displacement of the mesyloxy-group to give a tertiary amine. Quaternization of the amine function and an SN’(syn) reaction with more dimethylamine gave the key sulphone (56). Reaction of (56) with the appropriate organolithium reagent gave the stabilized carbanion (57) which was quenched with the ally1 iodide (58)in the same pot (overall yield 67%). The amine (59) was formed and converted into the amino-acid (60) in four steps. The acid (60) was converted into the oxime (61) and thence into PG-E2 (Scheme 15).45 Thus in the Fuchs’ procedure the cyclopentane ring is connected to the two prostaglandin side-chains in one pot this highly desirable ‘triply convergent’ approach has been used to prepare 11-deoxyPG-E from cyclopentenone (vide infra),but fails to provide PG-E from 4-alkoxycyclopentenones (vide supra).Synthesis of Some Analogues of Prostaglandins A-F. -1 1-Deonyprostaglandin E. The 11-deoxyprostaglandin E class is noteworthy for two reasons. First this class of compound is readily prepared from cyclopentenone. Second some members 45 R. E. Donaldson and P. L. Fuchs,J. Am. Chem.Soc. 1981,103,2108. 362 R.F.Newton and S. M. Roberts QH QH -6 GS0,Ph OSPh QS0,Ph ii-i" SOZPh q 0 OR OR (54) (55) 'Fi CH,CH:CH(CH,)3C0,Me & CSH, C5Hl I OR OR OR OR (59) (57) 4 steps Ho\ &i CH,CH:CH(CH,),CO,H -2 steps &:;;;H aPG-E C31 OR OR OR OR (60) (61) R = SiMe2Bu' Reagents i m-CIC6H4C03H; ii DBU; iii ClSiMe,Bu'; imidazole DMF; iv MeSO,Cl Et3N; v Me,NH; vi FS0,Me; vii LiCH:CHCH(OR)CSHI1; viii ICH,CH:CH(CH,),CO,Me (58); ix CH8 BF,.Et,O Me,CO Scheme 15 of this class exhibit interesting biological activity for example the prostanoid (62) is a highly potent and selective anti-ulcer agent.46 Two methods of synthesis of the 11-deoxyPG-E system are available.Either the w-side-chain can be added to cyclopentenone and a derived enolate alkylated directly (see Scheme 16)47 or a 2-substituted cyclopentenone is prepared and reacted 46 A.K. Banerjee B. J. Broughton T. S. Burton M. P. L. Caton A. J. Christmas E. C. J. Coffee K. Crowshaw C. J. Hardy M. A. Heazell M. N. Palfreyman T. Parker L. C. Saunders and K. A. J. Stuttle Prostaglandins,1981 22,167. 47 J. W. Patterson and J. H. Fried J. Org. Chem. 1974 39 2506; see also A. J. Dixon R. J. K. Taylor and R. F. Newton 1.Chem. SOC.,Perkin Trans. I 1981 1407. Biological Chemistry -Part (i) Prostaglandins ,I3CO2Me / C31 / C,Hl I OR OR R = CMezOMe Reagents i LiCu[CH:CHCH(OR)C,H,,] then CISiMe then Li NH,; ii (58) Scheme 16 with the requisite cuprate reagent to give an 11-deoxyPG-E. The required precursor (65) of 11-deoxyPG-El was prepared by reaction of the aldehyde (63) with the enamine (64) and rearrangement of the first formed product48 or by dialkylation (63) (64) 1 1-deoxy-PG-El of diethyl3-oxoglutarate followed by periodate oxidation hydrolysis decarboxyla- tion cyclization and re-e~terification.~’ C0,Et to-(65) ~2k,co~Et O~lhcozEt + Et0,C C0,Et Et0,C C0,Et C02Et 0 0 The precursor (66) of 11-deoxyPG-Ez can be prepared by thiazolium salt cata- lysed addition of the appropriate aldehyde to methylacrylate followed by cyclization partial reduction and dehydration.” RCH2CH0 + CH2:CHCO2Me + RCH2CO(CHz)2C02Me U 11-deoxy-PG-E2 48 A.Barco S. Benetti P. G. Baraldi and D. Sirnoni Synrhesis 1981 199. 4p Y.Naoshima S. Mizobuchi and Wakabayashi Agric. Bid. Chem. 1979,43 1765. 50 L.Novak G.Baan J. Marosfalvi and C. Szantay Chem. Ber. 1980 113 2939. 364 R. F. Newton and S. M. Roberts The Stork synthesis of optically active 11-deoxyPG-E from 2,3-isopropylidene- L-erythrose (67) is elegant but long. The key step involves reaction of the carbonate (68) with the ortho-ester (69) to give the triester (70) through a Claisen rear- rangement.” Me0,C- Me0,C co Me “0 I 5 steps H nCHz)3COzMe040 (67) Me02C(CH2)3CI C(CH2)2C(OMe)3 (69) (70) 5 steps1 Me0,C C02Me 11-deoxy-PG-E2 sH::3c0z Me R = CH(Me)OEt ‘0R F‘luoroprostaglandina 12-Fluoroprostaglandin FZa (73) (and also the correspond- ing 13,14-dihydro-derivative)are biologically interesting because they show a significant separation of antifertility and smooth muscle stimulating activities in the hamster.’* These fluoroprostaglandins are not substrates for the 15-hydroxy PG-dehydrogenase enzyme.The prostanoid (73) was prepared using the Corey-Suther- land-I.C.I. strategy and the fluorobicycloheptane (72). The latter compound is prepared by fluorination of the bromoester (71).53 14-Fluoroprostaglandin-F2ahas been prepared from the ester (72).54 Me0,C Me0,C F Brho-Br&o e2)3c02Me sye; CSHll OH k 02 02 OH (71) (72) (73) + F C0,Me Br&> 0 ’’ G. Stork and S. Raucher J. Am. Chem. Soc. 1976,98 1583. 52 P.A. Grieco and T.Takigawa J. Med. Chem. 1981,24,839. 53 P.A. Grieco W. Owens C.-L. J. Wang E. Williams W. J. Schillinger K. Hirotsu and J. Clardy J. Med. Chem. 1980,23 1072. 54 P. A.Grieco W. J. Schillinger and Y. Yokoyama J. Med. Chem. 1980,23,1077. Biological Chemistry -Part (i) Prostaglandins 10,10-Difluoro-13,14-dehydroprostaglandin F2a(76) has been prepared by Fried (Scheme 17)" using a strategy that had been used earlier to prepare naturally occurring prostaglandins. The reaction of the epoxide (74) and the alane (75) was highly regioselective due to the influence of the neighbouring primary hydroxy- group. d OH 0 OBu' (75) OR Reagents i Bu'OH H'; ii LDA ICH,CH:CH2; iii HCI; iv FCIO, MeOH KHCO,; v KAIHBu',; vi chromatography; vii 0, MeOH; viii KI, Na2C0, H,O; ix (CF,SO),O pyridine; x KOH MeOH; xi CO then 12; xii KOH then H+; xiii LiAIH4; xiv (75) Scheme 17 Azaprostaglandins The most interesting azaprostanoids have an hydantoin system replacing the cyclopentane ring of the natural compounds.For example the hydan- toin (78) shows very potent anti-aggregatory activity on blood platelets. The active compound is very readily prepared from the acyclic aminodiester (77) as shown in Scheme 18." The diester (77) was converted into other series of heteroprostanoids. The structure-activity relationships suggested that a nitrogen atom at position 10 and the prostaglandin configuration at C-8 are vital for maximum biological activity." The compound (79) prepared by a Pfizer group has been shown to be a potent thromboxane synthetase inhibitor,58 while the 13-azaprostanoid (80) synthesized by Collington et al. is a potent thromboxane antag~nist.'~ Whether any of the " J.Fried D. K. Mitra N. Nagarajan and M. M. Mehrotra J. Med. Chem. 1980,23 234. 56 M. A. Brockwell A. G. Caldwell N. Whittaker and M. J. Begley J. Chem. Soc. Perkin Trans. 1 1981,706. 57 P.Barraclough A. G. Caldwell C. J. Harris and N. Whittaker J. Chem. SOC.,Perkin Trans. 1 1981, 2096. '* M. J. Randall M. J. Parry E. Hawkeshead P. E. Cross and R. P. Dickinson Thrombosis Res. 1981, 23 145. '' R.A. Coleman E. W. Collington H. P. Geisou. E. J. Hornby P. T. A. Humphrey I. Kennedy G. P. Levy P. Lumley P. J. Mc€abe and C. J. Wallis Br. J. Pharm. 1981,72 524. 0 OH (78) Reagents i MeCO,H H,O; ii (MeCO),O; iii porcine renal acylase; iv SOCI, EtOH; v CH2:CHCOC6H11; vi NaBH,; vii HCl KCNO EtOH Scheme 18 compounds(78) (79),or (80)can be used to protect a patient at risk from thrombosis or stroke remains to be seen.A number of aza-11-deoxyprostaglandin E analogues have been described. The 8-a~a-(81),~' and 8,lO-diaza-prostanoid (83)62have been prepared 10-a~a-(82),~~ by standard routes. OCH,Ph N'l (79) 6o P. A. Zoretic J. Jardin and R. Angus J. Heferocycl.Chem. 1980,17,1623. " P.A. Zoretic F. Barcelos J. Jardin and C. Bhakta J.Org. Chem. 1980,45,810. '* S. Saijo M. Wada J. Himizu and A. Ishida Chem. Pharm. Bull. 1980.26,1459. Biological Chemistry -Part (i) Prostaglandins OH OH (82) (83) Recently the synthesis and biological profile of aza-analogues of PG-I2 have been reported. Cassidy et al. converted the aminoester (84) into the amidolactone (85) this lactone gave the aza-prostanoid (86).Preliminary biological results suggest that (86) is a potent inhibitor of collagen- and ATP-induced platelet aggregation in human platelet-rich plasma.63 Synthesis of ProstaglandinsG-I. -PG-G2 and PG-H2have been synthesized from PG-F2a. Mukaiyama's reagent (87) is used to replace the hydroxy-groups at C-9 (2-11,and if required C-15 by halogen atoms prior to substitution with peroxide anion (Scheme 19).64Overall yields are low. CQHHI)~CO#~ 2)3COzMe CSHIl C5H11 OH Br ' OR la-iv PG-H2 CI I .... III.LV I +' Et PG-G2 (87) R = SiMe2Bu' Reagents i (87) Et46Br; ii H'; iii hog pancreas lipase; iv AgO,CCF, H202;v PhCH,&Bu,CI- (87) Scheme 19 63 F. Cassidy R. W. Moore G. Wootton K.H. Baggaley G. R. Green L. J. A. Jennings and A. W. R. Tyrrell Tefrahedron Lett. 1981 22 253. 64 N. A. Porter J. D. Byers K. M. Holden and D. B. Menzel 1.Am. Chem. Soc. 1979 101,4319;N. A. Porter J. D. Byers A. E. Ali and T. E. Eling ibid 1980,102. 1184. R. F.Newton and S. M. Roberts 368 Following the structure elucidation of PG-I2a number of research groups reported the preparation of this material from PG-F2cu.A common strategy was employed namely halogeno- (or mercuri-) etherification of the C-5 alkene unit with intramolecular participation of the hydroxy-group at C-9 followed by base catalysed elimination of hydrogen halide. The required 2-geometry about the enol-ether OH ?$~CHZ)W~M~ '~4,-iik / C5H11 C5H11 OH OH OH OH OH OH liii PG-12 Reagents i KI, Na,CO, H,O; ii DBN benzene; iii NaOH MeOH H,O Scheme 20 HO + 'erythro' isomers OR OR OR OR Reagents i \IJ ,pentane -78 "C; ii KI, Na,CO, H20; iii Bu",SnH; iv m-CIC,H,CO,H; v K,CO, MeOH; vi MeSO,Cl pyridine; vii H'; viii chromatography; ix DBN; x NaOH MeOH H20 Scheme 21 Biological Chemistry -Part (i) Prostaglandins moiety was ensured by the stereochemistry of the addition (trans)and elimination (trans)processes (Scheme 20).65 Recently Newton has reported a total synthesis of PG-I,.The key step in this synthesis involved the reaction of the readily available aldehyde (88)and the lithium enolate of cyclopentanone in a stereocontrolled aldol reaction. The two ‘threo’ diastereomers (89) and (90) were isolated in 70% yield and were independently converted into PG-I2 by a series of high yield reactions outlined in Scheme 21.66 Synthesis of Some Analogues of Prostaglandins H and I.-Prostaglandins-G and -H are very important compounds. Not only do they possess biological activity per se but also all other PGs and TXs are derived from them in viuo. A large number of analogues of PG-H2 have been prepared in order to study the biochemistry and pharmacology of the unstable natural materials. Corey et al. prepared the diaza-analogue of PG-H (91) from the mesylate (92; R’ = R2 = H) by a route closely related to that used by Porter to prepare the natural compound (vide supra). In fact Corey prepared the bis-mesylate (92) from (91) (93) PG-A2 rather than from PG-F2a6’ The dithia-analogue (93) was prepared from the bis-mesylate (92; R’ = Me R2 = THP) in a similar manner.67 (&;72H -,py3C02M‘ OH C,Hl L \ I ’ OH OH OTs OH (94) OH (95) 65 B.De N. H. Andersen R. M. Ippolito C. H. Wilson and W. D. Johnson Prostaglandins. 1980 19 221 and references therein. 66 R. F. Newton S. M. Roberts B. J. Wakefield and G. T. Woolley I. Chem. SOC., Chem. Commun. 1981,922. 67 K. C; Nicolaou G. P. Gasic and W. E. Barnette Angew. Chem. Inr. Ed. Engl. 1978 17 293 and references therein. R. F. Newton and S. M. Roberts 11-HomoPG-E (94) is produced on benzophenone sensitized photolysis of PG-A2 in methanol. The 9,ll-epoxymethano-analogue(95)of PG-H was prepared from (94).6' The endoperoxide analogue (97) was prepared from the Diels-Alder adduct of cyclopentadiene and methyl propynoate (96).The cuprate reagent (26) was used to add the w-side-chain to the @-unsaturated ester function in compound (96).6' The corresponding PG-HI analogue has been prepared using a similar strategy.@ OSiMe3Bu' OH (97) (98) A number of the analogues described above inhibit the synthesis of thromboxane; however they all cause platelet aggregation at low concentrations rendering them unsuitable for consideration as potential anti-thrombotic agents.More interesting from the biological viewpoint is the report by the Upjohn group that the analogue (98)prevents thromboxane synthesis but does not affect PG-1 synthesis nor does it cause aggregation of blood platelets in simple test ~ystems.~' 0 /CO,Me 4QOzMe Cco2Me 0,Ph OR OR 0,Ph O'R o,Ph (99) (100) R = THP 0,Ph OH OH (102) (101) Reagents i NaOH then CH,N,; ii CrOCI, HOBu' pyridine; iii LiCH,CO,Me iv H1.Pd-C; v KOBu' benzene; vi HMPA A Scheme 22 68 M.F. Ansell M. P. L. Caton and P. C. North Tetrahedron Lett 1981 22 1723. 69 F. Fitzpatrick R. Gorman G. Bundy T. Honohan J. McGuire and F. Sun Biochim. Biophys. Acra 1979 573,238. Biological Chemistry -Part (i) Prostaglandins 6,9-MethyleneprostaglandinI (Carba-PG-12). Several groups have made use of Corey intermediates to prepare carba-PG-I (102). For example the lactone (99) was converted into the keto-ester (100)and then via a Dieckmann cyclization into the cyclopentanone (101).The w-side-chain was elaborated in the usual manner and the carboxylic acid side-chain was appended using a ’salt-free’ Wittig reaction (Scheme 22).” Aristoff used the late-stage Corey intermediate (103) and a novel Wadsworth- Emmons-Wittig reaction (104) + (105) to furnish after catalytic reduction the ketone (106). The ketone (106) was converted into carba-PG-I using previously described methods.71 bC H I I OR s+C5HlL -CJII I OR OR OR OR OR (104) (105) R = THP 1 OH (106) The key reaction in an alternative route to carba-PG-I2 involves an intramolecular Michael reaction and the diketoester (107). Transformation of the hydroxyester (108) into the desired PG-I2 analogue closely paralleled the routes described above (Scheme 23).72 n ..I. , 111 iv v --* ---* p+ CO,H C02Et QC0,Et 0 0 Reagents i Jones’oxidation; ii (Et0,CCH,C0,-),Mg2’ (imidazole),CO; iii K,CO,; iv 2-methyl-2- ethyl-1,3-dioxolane H’; v NaBH Scheme 23 ’O Y.Konishi M. Kawamura Y. Arai and M. Hayashi Chem. Lett. 1979 1437. ” P. A. Aristoff J. Org. Chem. 1981 46 1954. ’* A. Barco S. Benetti G. P. Pollini P. G. Baraldi and C. Gandolfi J. Org. Chem. 1980 45 4776. 372 R. F. Newton and S. M. Roberts The enone (109) is a key intermediate in the route to carba-PG-I described by Ikegami. Two routes to this intermediate are a~ailable.’~ Reaction of the enone (109) with the cuprate reagent (26) gave the bicyclo-octanone (110) which was transformed in six steps into the carba-PG-I2 precursor (106) (Scheme 24).The ketone (110) was converted also into A6-~arba-PG-12.74 -7 *T -(106) 6 steps &O & / C5HIl OR OR OR (109) (110) R = SiMe2But Reagents i (26),ether -78 “C Scheme 24 6,9-Thiaprostaglandin 12. The PG-F2a derivative (111)was subjected to two SN2 reactions at C-9to introduce a sulphur atom to this position with retention of configuration. Iodine mediated cyclization and base catalysed trans-elimination of HI gave thia-PG-I (112) from which the sulphoxide (113) was produced on treatment with peroxide (Scheme 25).” 5E-Thia-PG-I sulphoxide and sulphone OH SAC *\C5Hl I *+C5Hl 1 OR OH OR OH (111) li OH O’H OH OH OH (113) (112) R = THP Reagents i NaOMe MeOH then 12 CH2CI,; ii DBU iii HOOBu‘ Scheme 25 ’’M.Shibasaki K. Iseki and S. Ikegami Chem. Lea. 1979 1299; Synrh. Commun. 1980,10,545. 74 M.Shibasaki K. Iseki and S. Ikegami Terrahedron Len. 1980 21 169. ” K.C.Nicolaou W. E. Barnette and R. L. Magolda J. Am. Chem. Soc. 1981,103,3472 3486. Biological Chemistry -Part (i)Prostaglandins 373 (114) are available by a similar strategy.75 A6-Thia-PG-I (116) was prepared from the prostanoid (115).76 (114;n = 1or2) (115) (116) Thia-PG-I is chemically more stable than PG-I,. It is a potent inhibitor of blood platelet aggregation; however it is a substrate for prostaglandin 15-hydroxy- dehydrogenase and hence it is rapidly metabolized in vivo. (117) (118) Homoprostaglandin I,. The PG-Iz analogue (118) has been synthesized from the A4-PG-Fla derivative (117) by a cyclization-elimination procedure similar to those described above.77 The isomeric homo-PG-Iz (119) was prepared from the lactone (99) as indicated in Scheme 26.78 2 OAc 6 steps __* a<-;p 1-(CH2)3COzH z C5Hl I OTHP 0,Ph 0,Ph O’Ac OH OH (99) (119) Scheme 26 Prostaglandin Il.Prostaglandin I1 (121) was prepared from PG-Fza by tri-n- butyltin hydride reduction of the iodo- or seleno-ethers (120).79 76 M. Shibasaki Y. Torisawa and S. Ikegami Chem. Lett. 1980 1247. 77 R.A.Johnson and E. G. Nidy J. Org. Chem. 1980,45,3802. ’I8 W.Skubulla Tetrahedron Lett. 1980 21 3261. 79 R. A. Johnson F. H.Lincoln E. G. Nidy W. P. Schneider J. L. Thompson and U.Axen J. Am. Chem.Soc. 1978,100,7690;K.C.Nicolaou W. E. Barnette and R. L. Magolda ibid 1981,103,3480. R. F. Newton and S. M. Roberts (120) X = I Br or SePh (121) R' = R2 = H or protecting group A total synthesis of 6p-PG-II has been reported by Newton et al. The key reaction involves the bis-Grignard reagent (122) which was alkylated and carboxy- lated in one-pot to give the hydroxy-acid (123). The acid (123) was cyclized in the 'reverse' manner i.e. utilizing an hydroxy-group in the side-chain and an endo-cyclic alkene unit (Scheme 27).80 <+< CHO BrMg(CH2)4MgBr C411Jk+(121) (122) OR CJ,l OR OR OR (88) R = SiMe2Bu' (123) Reagents i (122); ii CO,; iii KI, THF H,O; iv HSnBu",; v H' Scheme 27 Synthesis of Thromboxane B2.-A laboratory synthesis of TX-A2 has not been reported to date.TX-B has been prepared from well-established PG-precursors for example an Upjohn group used the lactone (21) to prepare the key intermediate (21) R. F.Newton,M. A. W. Finch and S.M. Roberts J. Chem. SOC.,Perkin I 1981 1312. Biological Chemistry -Part (i) Prostaglandins (124) in ten stepss1 A second group from the Upjohn laboratories prepared the same intermediate (124) from the lactone (99).82A more efficient synthesis of TX-B2 from the PG-F2a derivative (125) has been described by Schneider and Morge (Scheme 28).83 OAc (CH2)3C02Me (CH2)3C02Me A,,, OAc irr-~\.rn M-(CH2),C02Me ,*'LJcA .,-\ ( C5H1 I OAc L 5H OH C (125) OAc 1 I OAc (125) Reagents i Pb(OAc), C,H,; ii (MeO),CH C,H,N.HCI MeOH; iii HO- H,O; iv phosphoric acid H20 THF Scheme 28 Optically active TX-B2has been obtained from chiral sugars.For example Kelly has converted laevoglucosan (126) into the epoxytosylate (127). Opening of the epoxide ring with displacement of the tosyl group followed by stereoselective reduction of the new epoxide gave the alcohol (128) which was transformed into the TX-B2precursor (124) in three steps (Scheme 29).84 0 OH (126) (127) (128) Reagents i TsCI C,H,N then NaOMe; ii CH2:CHCHZMgCl,CuI THF; iii LiBHEt, THF; iv TsC1 C&N; v RuO, NaIO, H,O Me2CO;vi MeOH H' Scheme 29 The four hydroxy-groups of the simple sugar derivative (129) are fully differenti-ated. Oxidation of the free hydroxy-group followed by a Wittig reaction gave the esters (130),Reduction of the alkene unit hydrolysis of the ester and debenzoylation gave the lactone (1311,which was converted into TX-B2in standard fashion (Scheme N.A. Nelson and R. W. Jackson Tetrahedron Lert. 1976 3275. 82 R. C. Kelly I. Schletter and S. J. Stein Terrahedron Lerr. 1976 3279. 83 W. P. Schneider and R. A. Morge Tefrahedron Lerr. 1976 3283. 84 A. G. Kelly and J. S. Roberts J. Chem. Soc. Chdm. Commun. 1980 228 R. F.Newton and S. M. Roberts OCOPh PhCOO KoR& .dgz2Me -MeO' 0 MeO' 0 MeO" (129) (130) (131) R = SiMe2Bu' Reagents i l-ethyl-3-(3'-dirnethylaminopropyl)carbodi-irnide.HCl, C,H,N.CF,CO,H DMSO; ii (MeO),POCH,CO,Me KOBu'; iii Pd(OH), H,; iv K,CO, MeOH Scheme 30 30)." Another noteworthy route from a simple glucose derivative to TX-B2 has been documented.86 A total synthesis of TX-B2 has been reported by Corey et al.The readily available enone (132) was converted into (133). Reaction of (133) with the aldehyde (134) under carefully controlled conditions led to the diol (135) which cyclized under acid conditions to give the desired product (136) with the a-and w-side-chains trans-oriented. Further transformations gave the acetal (137) and hence TX-B2 (Scheme 31)." BUSfMe-BUSF-SBu SBu BUS SB"oH ' CSHII OH (132) (133) (135) Reagents i LiNPr', THF HMPA then CH,:CHCH,Br; ii LiNPr', THF then (134);iii MeCO,H H,O THF Scheme 31 IsS. Hanessian and P. Lavalle Can. I. Chem. 1981,59 870;see also H.Ohrui and S. Ernoto Agric. Bid. Chem. 1977,41,1773. *' E. J. Corey M. Shibasaki and J. Knolle Tetrahedron Lett. 1977 1625; 0.Hernandez ibid 1978,219. E.J. Corey M. Shibasaki J. Knolle and T. Sugahara Tetrahedron Lett. 1977 785. Biological Chemistry -Part (i) Prostaglandins Synthesis of Some Analogues of Thromboxane-A2.-The dithia-analogue (139) of TX-A2 has been prepared by a series of transformations outlined in Scheme 32.88 I5 steps c- s \ (CHz)zCO,Me (138) 6 steps OMS 2)3C02Me -iii-v ~z)3c02Na / Call / CJll s \ OBz OH (CH2),COzMe (139) Reagents i H2S NaOAc EtOH; ii HSCH,CH,CO,Me EtNPr', DMF; iii KOBu' HMPA; iv NaOMe MeOH; v NaOH THF H,O Scheme 32 0.+CHO -fQ"CN C0,Me OTHP 0 (140) (141) 18 steps a<H2)3c02Me SAC 11 steps HO OH (142) Scheme 33 S.Ohuchida N. Hamanaka and M. Hayashi J. Am. Chem. SOC.,1981,103,4597 R. F. Newton and S. M. Roberts The key stage involves the triple conjugate addition to the enynone (138). The same research group have prepared 9,ll-thia-ll,12-methylene-TX-A2 (142) from the readily available ester (140) via formation of the lactone (141) and thereafter a series of standard transformations (Scheme 33).*' The isomeric analogue (143)" and the 11,12-methylenethrornboxaneA2(146)" were prepared from cis-1,3-disubstituted cyclobutanes. In the former synthesis an intramolecular Michael reaction is employed to form the second six-membered ring (Scheme 34) whereas in the latter synthesis an iodoetherification reaction C0,Me OH (143) Reagents i NaSCH,(OEt), DMSO; ii HAIBu',; iii CH,(CO,Me), AcOH pyrrolidine; iv H'; v AcOH pyrrolidine Scheme 34 CH,OSiMe,Bu' bC0,Et i-iii -0 0 OH OH (146) Reagents i MeOH H'; ii MeC(OEt), EtC0,H then 1N-HCI; iii NaBH, EtOH; iv Hg(OCOCF,), benzene then 1,; v NaN,; vi FS0,Me then pH4 buffer Scheme 35 89 S.Ohuchida N. Hamanaka and M. Hayashi Tetrahedron Len. 1981 22 1349. 90 S. Kosuge N. Hamanaka and M. Hayashi Tetrahedron Lett. 1981,22 1345. 91 E. J. Corey J. W. Ponder and P.Ulrich Tetrahedron Len. 1980 21 137. Biological Chemistry -Part (i) Prostaglandins (under carefully controlled conditions) was involved in the key step (144) + (145) (Scheme 35). 11,12-MethylenethromboxaneA2 (147) has been prepared from PG-A2 using the strategy illustrated in Scheme 36." -HO 2)3 e r z 2 M e ~HCHZNH cH20H C31 OR OR 0 16 steps OH OH OR (147) R = SiMe2Bu' Reagents i Me,SiCN HOC,H,,"eo KCN 18-crown-6; ii LiAIH,; iii HONO; iv (CF,SO,),O; v LiOH THF,H,O Scheme 36 The bicyclo[3.l.l]heptanone (148) is available by two routes starting from readily accessible materials.It has been converted into 9,ll 11,12-dimethylenethrorn-boxane A2 (149) by the route shown in Scheme 37.93 The thrombanoid (149) is a potent TX-A2 antagonist in platelet aggregation assays. Reagents i MeOCHPPh then PhSeCI; ii m-CIC,H,CO,H; iii (26) then K2C0, MeOH Scheme 37 92 K. M. Maxey and G. L. Bundy Terrahedron Lerr.1980 21 445 93 K. C. Nicolaou R. L. Magolda and D. A. Claremon J. Am. Chem. Soc. 1980,102 1404. R. F.Newton and S.M. Roberts The bicyclo[2.2. llderivative (150)94 and the corresponding oxa-compound (151)9s have been synthesized. The norbornane (150) is a weak inhibitor of throm-boxane synthetase. E2)3c02Me c 2 ) 3 c 0 2 H / C,H,I / CSHll OH OH (150) (151) 94 P. Barraclough Tetrahedron Len. 1980 21 1897. 95 T. Kametani T. Suzuki A. Tamino and K. Umo Hererocycles 1981 16 905.

ISSN:0069-3030    

DOI:10.1039/OC9817800347

出版商:RSC    

年代:1981

数据来源: RSC