摘要:

8 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By 6. V. SMITH Department of Chemistry Chelsea College Manresa Road London SW3 6LX 1 Alcohols and Ethers The direct oxidation of tertiary hydrogen in an alkane by a peroxycarboxylic acid has been reported. 3-Methylpentane with p-nitroperbenzoic acid gave a 49% conversion into product of which 84% was the alcohol Et,C(OH)Me.' Isoalkanes were shown to react with iodine tris(trifluoroacetate) to form esters R02CCF3 under conditions in which n-alkanes were inert.2 An interesting conversion of an alcohol (1)into the corresponding tosylate (2) has been shown to proceed with inversion of c~nfiguration.~ Reagents i EtO,CNNCO,Et-Ph,P ZnOTs-C,H Scheme 1 Synthesis of an (E)-alk-3-en-l-o1 (4) in high yield (83%) has been achieved by the stereospecific ring-opening of 2,3 -dihydrofuran (3)by the organocuprate from BuLi-CuI as shown in Scheme 2.4 Reagents i 0 "C 30 min; ii 0 "C (3) 3 h Scheme 2 Prop-2-en-1-01 has been used as a starting point for the preparation of cyclopro-panes via a sequence involving stannylation oxidation and a Wittig reaction to a H.-J.Schneider and W. Muller Angew. Chem. Int. Ed. Engl. 1982 21 146. ' H. Plettenberg B. Gosciniak and J. Buddrus Chem. Ber. 1982 115 2377. I. Galynker and W. C. Still Tetrahedron Len. 1982 23,4461. T. Fujisawa Y.Kurita M. Kawashima and T. Sato Chem. Lett. 1982 1641. 150 B. V. Smith stannylated alkene; efficient ring-closure was achieved by the use of TFA at room temperature (Scheme 3).' CH2=CHCH20H Bu3Sn(CH2)2CH20H 1 ii Bu~S~(CH~)~CH=CHAC Bu~S~(CH~)~CHO 1 iv C~H~CH~AC(goo/,) Reagents i Bu3SnH ii N-chlorosuccinimide Me,S Et,N; iii Ph,P=CHAc; iv TFA 25 "C Scheme 3 A route to (2)-alk-7-en-1-01s via ring-opening of a trans-alkenylborepane (5) (NaOMe-12 then elimination and oxidation of the resulting dimethoxyalkenyl- borane) ha been used as a convenient synthesis of insect pheromones containing this structural pattern.6 Further elaboration' of the 'unitized construction principle' has been published in an article on the synthesis of alkadienols and related com- pounds of biological interest.An elegant stereocontrolled synthesis which was successfully completed of the key precursor to 29-hydroxy-3,11 -dimethyl- nonacosan-2-one (cockroach pheromone) is remarkable for its seeming com- pIexity.8 A high degree of asymmetric synthesis of diastereoisomeric esters (6) was ob- served in the base-catalysed addition of (S)-(:)-1-phenylethanol to the ketene PhC(R)=C=O (R = Et); pyridine in toluene gave S,S R,S = 89 1lq9 Use of (7) and (8) [from (S)-proline] as chiral auxiliaries in the addition of Bu"Li to PhCHO A LJ% PhCH(Et)C02CH(Me)Ph (6) R (5) (7) R = Li (8) R = Me gave moderate e.e.'s; the optimum value was 36% of (R)-isomer." Racemic 3-aminopropan-1,2-diol was selectively acylated by several protected (S)-amino-' Y.Ueno M. Ohta and M. Okawara Tetrahedron Lett. 1982,23,2577. ' D. Basaviah and H. C. Brown J. Org. Chem. 1982,47 1792.' H. J. Bestmann K. H. Koschatzky and 0.Vostrowsky Liebig's Ann. Chem. 1982 1478. * U. Jensen-Korte and H.4. Schafer Liebigs Ann. Chem. 1982 1532. U. Salz and C. Ruchardt Tetrahedron Lett. 1982,23,4017. "' L. Colombo C. Gennari G. Poli and C. Scolastico Tetrahedron Lerr. 1982,38,2725. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 151 acids using 1,l -carbonyldi-imidazole-THF; a diastereoisomeric amide (S,S)precipi-tated in favourable cases." Mercuration of styrenes 4-R-C6H4CH=CMe2 in methanol afforded a diether adduct with 2eq. H~(OAC)~; a mechanism was proposed which involved Me0 participation in the initial adduct with displacement of Hg.'* Alkylation of alcohols (or phenols) with RX-KF-AI2O3-DMF afforded good yields of the appropriate ether.I3 Ring-opening of cis-and trans-(9) (Me3Al-BuLi-PhMe -20 "C)was regioselective (99:1) in favour of Me2CHCH(OH)CH20CH2Ph; an excess (9 :1) of Me3Al over MeOLi gave a 95 :5 ratio which was lowered however by THF or Et20.14 Trimethylsilyl triflate opens epoxide rings with concomitant elimination; (2)-cyclo-octene oxide gave the product of transannular reaction endo-cis-2-trimethylsilyloxybicyclo[3.3.0]octane (lo)? Interestingly epoxyketone (1 1) gave @ 6 112) by this route..OSiMe Me &oCH2p H f j (9) (1 1) OSiMe (10) (12) Conversion of 1,2-diols into alkenes has been achieved via treatment of the thionocarbonates with 1,3-dimethyl-2-phenyl-l,3,2-diazaphospholidine (13).16 3- Methoxypropene can be efficiently converted into monoethers (15) as shown in Scheme 4 with high selectivity; it was proved that if the (E)-isomer was used MeOd 2 PB(NMe2'2 Me0 1 iii Q OMe (14) (15) Reagents i Bu"Li-TMEDA-THF -78 "C; ii CIB(NMe,), -78 -* -25 "C; iii Ho* -Et,O 25 "C; iv RCHO-N(CH,CH,OH) HO Scheme 4 I' M.Angrick and D. Rewicki Liebig's Ann. Chem. 1982 1394. l2 R. K. Norris and T. A. Wright Aust. I. Chem. 1982 35 2161. l3 T. Ando J. Yamawaki T. Kawate S. Sumi and T. Hanafusa Bull. Chem. SOC.Jpn. 1982 55 2504. l4 A. Pfatz and A. Mattenberger Angew. Chem. Int. Ed. Engl. 1982 21 71. Is S. Murata M. Suzuki and R. Noyori Bull. Chem. SOC.fpn. 1982.55 247. I' E. J. Corey and P. B. Hopkins Tetrahedron Lett. 1982 23 1979. 152 B. V.Smith instead of (14) then the enantiomer of (15) was formed in high yield." A variation on this process uses Et2AlCI in stage ii of Scheme 4; the importance of temperature control during quenching was stressed.17 Monophenylation of diols via Ph3Bi(OAc)2-CH2C12 has been reported.'' 2 Aldehydes and Ketones There has been a continuing interest in the exploration of methods which can lead to asymmetric induction.A number of these reports show an elegant approach and chemical artistry. Successful resolutions of a chiral ketone through the use of the lithiated sul-phoximine (16) followed by pyrolysis of the (separated) adducts (17) has been (16) (17) 1iii 0 II -PhS-CH2 + R' I KR2 NHMe 0 Reagents i Bu"Li -78 "C; ii R'R2CO; iii A 120"C Scheme 5 reported." Unfortunately acyclic compounds usually show a low diastereoface selectivity and the method is not applicable; for 2-phenylcyclohexanone high yields of optically pure enantiomers were obtained.This method represents a new approach to an old problem and will surely be elaborated (see Scheme 5). Reduction of carbonyl groups by R4N+BH4- offers the advantage that reactions are carried out in CH2C12.*' Decarbonylation (with coupling) under reductive conditions (NbC15-NaAIH4) yields alkenes from carbonyl compounds (and epoxides).21 Several methods of asymmetric reduction of prochiral ketones have been repor- ted. Acetophenone with B-(3-pinanyl)-9-borabicyclo[3.3.l]nonane in THF gave PhCH(0H)Me with e.e. 7 By using a concentrated solution of the reagent better yields were obtained and in shorter times.Temperature affects the e.e; thus for AcC02Et at rat. 76% and at O'C 82% was realized. A new reagent (18) l7 R. W. Hoffmann and B. Kemper Tetrahedron Lett. 1982,23 5263;M.Koreeda and Y. Tanaka J. Chem. SOC.,Chem. Commun. 1982,845. l8 S. David and A. Thieffry Tetrahedron Lett. 1981,22 5063. l9 C.R. Johnson and J. R. Zeller J. Am. Chem. SOC.,1982,104,4021. *' D.J. Raber W. C. Guida and D. C. Schoenberger Tetrahedron Lett. 1981,22 5107. 21 M.Sat0 and K. Oshima Chem. Lett. 1982 157. 22 H.C.Brown and G. G. Pai J. Org. Chem. 1982,47,1606. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds derived from 9-BBN has been shown to yield (S)-enantiomers with several ketones (in contrast to the behaviour of the borane from (-)-a-pinene) with reasonable e.e.e. g. MeCOE t (76 O/O ) and MeCOHex” (79 %).23 (S)-4-Anilino-3-(methyl-amino)-butan-1-01 with LAH affords a chiral reagent (19) which reduces ketones to (S)-alkylphenylcarbinols in high chemical and optical yield.24 With HexCOMe the e.e. was low (33%) but with PhCOPr‘ was much better (77%). In a similar fashion chiral hydrides from optically active threo-or erythro-2- dimethylamino-1,2- diphenylethanol + LAH gave (R)-or (S)-alcohols from prochiral ketones cOCH,Ph Li+ p-H N-AI-H I Ph (depending on which diastereoisomer was used) in 26-72% e.eq2’ An observation of some interest in this paper was the ready separation by crystallization of diastereoisomeric cinnamate salts of PhCH(OH)CH(NH,)Ph.Hydrogenation of ketoesters Me(CH2),COCH2C02Me (n = 0,6,8,10 or 12) over (R,R)-tartaric acid supported on NaBr-Raney Ni gave the hydroxyesters with an average optical yield of 85%. Conversion of the ester into the dicyclohexylammonium salt of the acid recrystallization and decomposition (H,O’) afforded optically pure (R)-hydroxy-acid; with (S,S)-tartaric acid the optically pure enantiomer was obtained.26 a,@-Unsaturated carbonyl compounds can be reduced to saturated compounds in excellent yields by Bu3SnH in the presence of a Pdo catalyst whereas the cluster compound Rh6(C0)16-N,N,N‘,N’- tetramethylpropane- 1,3-diamine with co-H20 afforded unsaturated alcohol^.^' The same reagent was effective for reduction of saturated aldehydes. Some very comprehensive reviews of carbonyl compounds in synthesis have been published with an emphasis on stereoregulation and regioselectivity.Reetz has reviewed Lewis acid-induced a-alkylation of carbonyl compounds with emphasis on ‘SN1-active’ halides or acetates as reagents and has summarized his concept of ‘variable adjustment of carbanion selectivity’ via the use of organotitanium com- pounds.28 The diastereogenic addition of crotyl-metal compounds to aldehydes has been reviewed.28 D. A. Evans has summarized much work in the field of stereoselec- tive aldol condensations including the role of boronates as well as providing a full account of strategies for generating and using chiral enolate synthons.28 A compre- hensive listing of acyl anion equivalents has also been made.’* 23 M.Midland and A. Kazubski J. Org. Chem. 1982 41 2495. 24 T. Sato Y. Goto and T. Fujisawa Tetrahedron Lett. 1982 23,4111. 25 K.Saigo S. Ogawa S. Kikuchi A. Kasahara and H. Nohira Bull. Chem. SOC. Jpn. 1982 55 1568. 26 M. Nakahata M. Imaida H. Ozaki T. Harada and A. Tai Bull. Chem. SOC.Jpn. 1982 55 2186. 27 P. Four and F. Guibe Tetrahedron Lett. 1982 23,1825; K. Kaneda M. Yasumura T. Imanaka and S. Teranishi,J. Chem. SOC. Chem. Commun. 1982,935. 28 M. T. Reetz Angew. Chem. Int. Ed. Engl. 1982 21 96; Top Curr. Chem. 1982 109 1; R. W. Hoffmann Angew. Chem. Inf. Ed. Engl. 1982,21 555; D. A. Evans J. V. Nelson and T. R. Taber Top. Stereochem. 1982 12,1; D. A.Evans Aldrichimica Acta 1982 15,23. 154 B. V. Smith Ashby and co-workers have suggested that the aldol reactions between Bu’COMe or 2,2-dimethylpentan-3-oneand PhCOPh proceeds via an electron-transfer mechanism.They ascribed e.s.r. signals which were observed to (21) and showed that ketyl(22) appeared if k2(see Scheme 6) was small; (22) did not generate (22a) with the appropriate enolate (20).29 Me3CCOMe + Me3CF=CH2 I li PhCAr Me3CC=CH2 OLi [( 8 ) ( I:] ~~(sIow) Ph \ PhCAr .*. I OLi ‘C=CHCOBu‘ / Reagents i PhCOAr;ii (20) Scheme 6 Pre-formed Li enolates with R3B (R= Et or Bu) when added to an aldehyde afforded a product rich in threo-aldol although selectivity was not high for acyclic systems. This complements methods which are available for erythro-aldols.” An efficient one-pot conversion of an aldehyde R’CHO into an alcohol (24) was achieved with a high degree of enantio- and diastereo-selectivity by reactions with allylborane (23) when R2was isopinocampheyl.The preference (96:4) for threo-(24) was interpreted in terms of a chair-like transition state (25).” A palladium-catalysed (23) (24) (25) R’ = cycfo-CaHll or isopinocampheyl R3= alkyl or phenyl R = Pr’ or n-C5H11 allylation shown in Scheme 7 is remarkable for retention of enolate regiochemistry and ally1 geometry.’* Asymmetric induction in the addition of (26) to an aldehyde 29 E. C. Ashby J. N. Argyropoulos G. R. Meyer and A. B. Goel J. Am. Chem. SOC.,1982,104,6788. 30 Y. Yamamoto H. Yatagai and K. Maruyama Tetrahedron Lett. 1982 23,2387. ’’ M.M. Midland and S.B. Preston J. Am. Chem. Soc. 1982,104,2330. 32 E.Negishi H. Matsushita S. Chatterjee and R. A. John J. Org. Chem. 1982,47,3188. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds OBEt3K / R’COCHRZR3 R’C \CRZR3 1ii R4 R1COCR2R3CH2C/ R5 \/ ‘R6 Reagents i BEt,-KN(SiMe,),; ii XCH,C(R4)=CR5R*-Pd(PPhs)4 Scheme 7 afforded (27);33the ratio of ‘Cram’ to ‘anti-Cram’ addition products [(30) (31)] from the addition of (2)-(28) to (S)-(+)-a-methylbutyraldehyde (29) is dependent on the chirality of the boronate. The (E)-isomer of (28) afforded mainly (32). Elaboration of this reaction led to the Prelog-Djerassi lactone (33).33 QH 0 In the addition of aldehyde (34) to the dienol diether (35) (Scheme 8) there was ‘no detectable erosion of optical integrity’ in the formation of (36);ozonolysis of (36)gave (37)as a single isomer.34 This principle was used in a short stereospecific synthesis of statine (38) (isolated as the Boc-derivative).Regio- and stereo- selective coupling between silyl-ally1 carbanions and aldehydes in the presence of RzBCl or EtA1Cl2 afforded threo-products (39) whereas Bu3SnCl-BF3 favoured production of the erythro-isomers (40). Elimination (KH) of Me3SiOH afforded stereospecific routes to (2)-or (E)-dienes (41) or (42) as shown in Scheme 9.35 Acrolein and EtCOCMe20SiMe3 were condensed with LDA to generate an unsaturated aldol which after several steps gave a key intermediate in a synthesis 33 S. Masamune T. Kaiho and D. S. Garvey J. Am. Chem. SOC.,1982 104 5521; R.W. Hoffmann H.-J. Zeiss W. Ladner and S. Tabche Chem. Ber. 1982 115,2357. S. Danishefsky S. Kobayashi and J. K. Kerwin Jr. J. Org. Chem. 1982 47 1981. ’’Y. Yamamoto Y. Saito and K. Maruyama J. Chem. SOC.,Chem. Commun. 1982 1326. 156 B. V.Smith CH ,OAc 0 0L 0 (R,S)-(36) Reagents i ZnC12-C6H,; ii 0,,H,O,-NaOH Scheme 8 R02c4H NHBoc CH2Pri (38) Reagents i Bu'Li HMPA-THF -78 "C 2 h; ii R,BCI Pr'CHO; iii KH; iv Bu,SnCl-BF, C9H19CH0 Scheme 9 Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 157 of Vitamin E.36The silylated ester (45) prepared from (43) and (44) gave a preference (92 :8)for the (E)-isomer of (46) when treated with C,H11CHO-TiCls.37 Asymmetric induction in the methylation of benzil with titanium reagents [MeTi(OR)3 MezTi(OR)z Me,Ti] is in contrast to results when e.g.MeZr(OR), MeLi or MeMgX was used. These differences have been rationalized in terms of Anh’s Several papers have appeared which refer to work on organotin compounds. A simple one-pot regioselective arylation of ketones has been published.39 Essential details are shown in Scheme 10. C5Hl1CH(OH)CH2C(Me)=CH I LiYCozEt SiMe SiMe CO,Et (43) (44) (45) Reagents i Bu,SnF; ii ArBr-PdCIJPAr,) Scheme 10 Allyltins react with aldehydes in the presence of a Lewis acid at low tem- peratures to form homoallyl alcohols. Stereoselectivity was high and interesting features were noted; thus the erythro-product preference from a 2-alkenyltin was reversed with a cinnamyl derivative.Such differences were ascribed to transition- state structure being non-cyclic (alkenyl) or cyclic (cinnamyl) leading to erythro-or threo-isomers (47) and (48).40Low-temperature additions of trialkyltin enolates of ketones to PhCHO led to a predominance of the threo-aldol.*l Tin(II)enolates derived from an a-bromoketone and tin have been reported to add to aldehydes with product distribution in favour of the erythro-isomer (usually >90 :10). An a-bromoketone and ti&) triflate were reported to generate a species capable of adding to an aldehyde (see Scheme 11); the stereoselectivity in formation of the bromoketones (49) and (50) is sensitive to solvent. The most favourable ratio (81:19) for syn:anti product formation was in THF.Some stereoselectivity was R R’L R R (471 36 C. H. Heathcock and E. T. Jarvi Tetrahedron Lett. 1982,23,2825. 37 P.Albaugh-Robertson and J. A. Katzenellenbogen Tetrahedron Lett. 1982,23,723. 38 M.T. Reetz R. Steinbach J. Westermann R. Urz B. Wenderoth and R. Peter Angew. Chem. Int. Ed. Engl. 1982,21 135; T. R.Anh Top. Curr. Chem. 1980,88,40. 39 I. Kuwajima and H. Urabe J. Am. Chem. SOC.,1982,104,6831. 40 M.Koreeda and Y. Tanaka Chem. Lett. 1982,1299. 41 S.Shervi and J. K. Stille Tetrahedron Lett. 1982,23 627. 158 B. V.Smith observed in the elimination leading to epoxide; the optimum cis-trans ratio (70:30) was realized with KF-dicyclohexylcrown ether.42 Although crossed aldol reactions from ketones are not normally as efficient as with aldehydes acceptable yields have been achieved with SII(OT~)~.In certain cases very high selectivity was observed; e.g. PhCOCH2Me and PhCOMe yielded (40 min) 60% of threo-product. Alkyl ketones tended to give an erythro-threo product ratio close to 1:l.43 Br 1 1iii 1iv H R 2 R'COA; R 'CO H 2 cis trans Steps i Sn(OTf),-base; ii R'CHO; iii syn-elimination; iv anti-elimination Scheme 11 Use of a chiral diamine (S)-l-methyl-2-[(pyrrolidin-l-yl)methyl]pyrrolidine (51) as a chiral auxiliary allowed substantial stereospecificity in stannous triflate-medi- ated aldol reactions. Thus PhCOEt and PhCHO yielded at -78 "C a product of erythro-threo ratio 6 1 and of ca. 60% optical purity. Addition of aldehyde at -95 "C slightly increased this latter quantity (65%).With Bu'CHO-PhCOEt only erythro-isomer (go0/ e.e.) was Lower yields were found in the 1,2-diketone-aldehyde system mediated by 'active' tin (from SnC12-K) and a surprising result is the observation of enhanced selectivity in the presence of hexafluoroben- ~ene.~~ Selective @-methylation of a,@-unsaturated aldehydes in excellent yields has been noted by using Me,Cu,Li, in ether or ether-~entane.~' A chiral Cu' azaenolate derived from (52) by sequential treatment with BuLi-THF and cuprous iodide will alkylate a,@-unsaturated cycloalkenones to form (53) with e.e.17-75Yo .46 Me A. " T. Harada and T. Mukaiyama Chem. Lett. 1982,467. 43 T. Mukaiyama T. Haga and N. Iwasawa Chem. Lett. 1982,1601. " R.W. Stevens N. Iwasawa and T. Mukaiyama Chem. Lett. 1982 1459; cf. W. S. Wadsworth. Org. React. 1975 25 102; N. Iwasawa and T. Mukaiyama Chem. Lett. 1982 1441; T. Mukaiyama J. Kato and M. Yamaguchi ibid. 1982 1291. 45 D. L. J. Clive V. Farina and P. L. Beauiieu J. Org. Chem. 1982,47,2572. 46 K. Yamamoto M. Iijima and Y. Ogimura Tetrahedron Lett. 1982,23 3711. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 159 The mercurated ketone MeCH(Hg1)COEt with benzaldehyde formed the expec- ted aldol with a significant (9 :1)selectivity in favour of the erythro-f~rm.~’ The use of organochromium species is highlighted by a report of selectivity in alkylation of C6H&HO by MeCrC12.(THF)3 to yield C6H,,CH(OH)Me; EtCOEt was not attacked. Reduction (by LAH) of chromic chloride produced a low valent species which with alkyl halides gave an allylchromium capable of reacting with a carbonyl group with high stereo- and chemo-selectivity .Aldehydes gave high threo-selec-tivity except for Bu‘CHO which afforded a 65:35 erythro:threo mixture with l-bromobut-2-ene. The usual threo-preference was interpreted in terms of a chair- like transition state (54).48 Optically active 3-phenylalkanals have been obtained from an alkyl halide and a chiral homoenolate equivalent derived from a chiral acid as shown in Scheme 12. Methyl iodide gave best results in methylation and the optical purity of (S)-PhCH(R)CH,CHO was 85% in the most favourable case.49 Homoaldol reactions . Ph-OH 4Ph TOMe -% PhrOh4e Me’ Me-Me‘C02€-I OH OCH,CH=CHPh 1iii Ph Me H MexoMe -Ph<--’” R I UPh Me’ Reagents i CH,N,; LAH; ii PhCH=CHCH,Br; iii KNPri; iv RX; v H’ Scheme 12 have been explored using l-oxyallyl anions (55) as synthetic equivalents of homoenolates.The scope of this reaction has been extended by the novel use of dialkylcarbamates [(56); R5 = CONRJ which is advantageous for several reasons. 47 Y. Yamamoto and K. Maruyama J. Am. Chem. Soc. 1982,104,2323. O8 T.Kaufmann A. Hamsen and C. Beirich Angew. Chem. Znf. Ed. Engl. 1982 21 144; T.Hiyama, Y.Okude K. Kimura and H. Nozaki Bull. Chem. SOC.Japan 1982,55,561. O9 T.Mukaiyama H. Hayashi T. Miwa and K. Narasaka Chem. Left. 1982 1637. 160 B. V.Smith The carbamyl group is not attacked solutions of the lithium salt are easily prepared and stable at -50 "C preferential attack occurs at the y-position and (2)-en01 esters are formed preferentially in most cases.Yields were good to excellent and the method seems to offer scope for exploration. The major product of reaction between (55) and R6COR7 was (56) which on solvolysis in MeOH or with TiC1,- H20 afforded (S)-hydroxycarbonyl compounds (as lactols or ethers); acetylation of (56) prior to solvolysis led to a high yield of M~,CCH(OAC)(CH~)~COM~ (from BU'CHO).~' A useful one-pot method for synthesizing ketones is the interaction of RC02Li and N,N-diphenyl-p-methoxyphenylchloromethyleneiminiumchloride (57) fol-lowed by treatment with a Grignard reagent. Yields are good even with branched structures; thus Bu'C02Li gave Bu'CO(CH2),Ph (77%) with (57) and Ph(CH2),MgBr.'l (55) (56) (57) Homologation of carbonyl compounds via enamidines has been achieved by treatment of the intermediate (59) from (58) with hydrazine or Bu'Li-BuI then N2H4 as shown in Scheme 13.In the first case an aldehyde R'R2CHCH0 and Reagents i Bu"Li -20 "C Me,SiCl; ii Bu"Li R'R'CO Scheme 13 in the second a ketone R'R2CHCOBu' is formed.s2 This method offers considerable scope therefore. Di-t-butylketene by sequential treatment with Bu'Li and H20 gave a 1:9 mixture of BuiCHCOBu' and Bu~CHCHO.~~ Triphenylbismuth carbon- ate is a useful reagent for preparation of highly hindered polyphenylated ketones; (PhCH2),C0 afforded pentaphenylacetone (but no hexaphenylated product) which gave the corresponding carbinol on reduction (without elimination of Ph3C-).54 Alkenes can be converted into ketones by treatment of the derived halogenohydrin with (AcO)~P~[P(~- in toluene." t01),]~-K~C0~ 50 D.Hoppe R. Hanko A. Bronneke and F. Lichtenberg Angew. Chem. Int. Ed. Engl. 1981,20,1024. 51 T. Fujisawa T. Mori and T. Sato Tetrahedron Lett. 1982 23,5059. 52 A.I. Meyers and G. E. Jagdmann Jr. J. Am. Chem. SOC.,1982,104,877. 53 D. Lenoir H. R. Seikaly and T. T. Tidwell Tetrahedron Lett. 1982 23,4987. 54 D.H. R. Barton M. T. B. Papoula J. Gulheim W. B. Motherwell C. Pascard and E. T. H. Dan J. Chem. SOC., Chem. Commun. 1982,732. 55 J. Tsuji H. Nagashima and K. Sato Tetrahedron Lett. 1982 23,3085. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 161 A carbon analogue of the Hofmann degradation has been noted for the anion derived from an a-bromoketone; rearrangement to a ketenanion (R-C=C=O *R-C=C-0) is rapid even at -78 "C.Quenching the ynolate with ethanol gave the ester RCH2C02Et in a homologation process.s6 Various published routes to a,@-unsaturated carbonyl compounds include a Michael addition of a secondary nitro-compound to an unsaturated sulphoxide followed by sequential treatment with (CF3C0)20-NaHC03 and 1,8-diazabicyclo[5.4.0]undec-7-ene-Et20 (to yield (E)-a,@-unsaturated aldehydes) the regioselective reaction of a masked acyl(ally1) anion with an alkyl halide (to give after hydrolytic cleavage good yields of a,@-unsaturated ketones) and another synthesis of the latter compounds via an efficient dehydrogenation-decarbonylation of ally1 @-ketocarboxylates." A ketal-Claisen rearrangement has been employed to prepare remotely unsaturated (y,S) ketone^.^' Ketoester synthesis has been the subject of several papers.59 Routes to protected fumardialdehydes and fluorinated malondialdehydes have been developed.60 3 Carboxylic Acids Enzymatic synthesis of fluorocitric acid from fluoroacetyl CoA and citrate synthetase gave a product which on methylation contained 97-98'/0 of ester of (lR,2R) configuration.The minor component was not formed by epimerization or on g.1.c. Fluoro-oxaloacetate gave a 35:65 mixture of acids (1S,2S and 1R,2S respec- tively).61 Catalytic reduction (H2/Rh-C) of (60a) gave only (61); the stereochemistry was checked via enzyme-mediated reduction of (62) in D,O and hydrolysis.62 The product (63) was derived from (60b) via rhodium-catalysed reduction and hydro- lysis.HO. C0,H H-~-D Me+(R C0,Et AcOeYco HMCoSCoA AcO Me H Me H (60) a R = H (61) (62) (63) bR=*H Formation of a-chloroacids catalysed by ClS03H or oleum is thought not to involve a ketene but to occur via a cyclic enol of a m~noacylsulphate.~~ Darzens reactions have been 'revisited'; the di-lithiated derivative of RCH(X)C02H reacts smoothly with a carbonyl component to form a glycidic (epoxy) acid. Pyrolysis of this product gives homologated ketone but an efficient method for this step is desirable. Ion-exchange resin (H') offers a po~sibility.~~ " C.J. Kowalski and K. W. Fields J. Am. Chem. Soc. 1982 104 321. '' N. Ono H. Miyake R. Tanikaga and A. Kaji J. Org. Chem. 1982 47 5017; K.Takahashi A. Honma K. Ogura and H. Iida Chem. Lett. 1982 1263; I. Shimizu and J. Tsuji J. Am. Chem. Soc. 1982,104 5844. '* G. W. Daub M. G. Sanchez R. A. Cromer and L. L. Gibson J. Org. Chem. 1982,47,745. 59 M. P. Cooke Jr. ibid. 1982 47 4963; T. Sato T.Itoh and T. Fujisawa Chem. Lett. 1982 1559; K. Hirai H.Suzuki H. Kashigawa Y. Moro-Oka and T. Ikawa ibid. 1982,23. K. Rustemeier and E. Breitmaier Chem. Ber. 1982 115 3898; R. Dersch and C. Reichardt Liebig's Ann. Chem. 1982,1330. 61 S. Brandange 0.Dahlman A. MAhlen and L. Morch Acta Chem. Scand. Ser. B 1982 36,67. 62 J. D.Rozzell Tetrahedron Lett. 1982,23 1767. Y. Ogata and K.Adachi J. Org. Chem. 1982,47 1182. 64 C. R.Johnson and T. R. Bade J. Org. Chem. 1982,47 1205. 162 B. V.Smith A simple one-pot method for t-butyl ester production from acids has been developed. Masked a-halogenoalkyl aryl ketones and silver(1) salts form esters in high yield; this process represents a marked improvement on previous attempts to use this approach. Aldehydes can be dimerized to esters under the influence of hydridoruthenium complexes.65 High yields have been obtained in reduction of esters by NaBH4 through the addition of LiEt3BH or LiH.9BBN as catalyst. With aryl-substituted esters it was noted that chloro- or nitro-groups were unaffected. Efficient reduction of esters was also obtained by using M(Li Na or Ca)BH4 in ether-THF-diglyme.Unsatur-ated esters underwent concomitant hydroboration. Use of 2 eq. of borane-THF has been recommended for rapid reduction of acids,in high yields. LAH-SiO was selective for the keto-group of keto-esters.66 A route of some generality to a,P-unsaturated esters is shown in Scheme 14; the (E)-isomer predominated in the produ~t.~’ R’ R’ \ ,0SiMe3 \CHCOZR3 i, / R2/c=c OSiMe R2 1iii Reagents i LDA Me,SiCI; ii MeCHC1,-BuLi(4lCMe); iii Ft MeOH Scheme 14 Two extensive reviews in this area deal with reactions of dianions of acids and ester enolates and synthetic applications of dealkoxycarbonylations of malonate esters and related compounds.68 4 Lactones Evidence has been given for the intermediacy of a p-lactone in the Perkin reaction of 4-nitrobenzaldehyde and acetic anhydride-trieth~lamine.~~ Bases e.g.quinidine catalyse the addition of ketene to chloral; the lactone (64) was obtained in 98% e.e. Hydrolysis (H30’) gave C13CCH( OH)CH2C02H converted by OH- (Dowex 50) into malic acid. Depending upon the base used (R)-or (S)-malic acid was obtained.” 65 S. Ohta A. Shimbayashi M. Aono and M. Okamoto Synthesis 1982 833; C. Giordano G. Castaldi F. Casagrande and A. Belli J. Chem. SOC.,Perkin Trans. 1 1982,2575; T. Ito H. Horino Y. Koshiro and.A. Yamamoto Bull. Chem. SOC.Jpn. 1982,55,504. 66 H. C.Brown and S. Narasimhan J. Org. Chem. 1982 47 1604; H. C. Brown S. Narasimhan and Y. M. Choi Tetrahedron Lett. 1982 23 2475; Y. Kamitori M. Hojo R. Masuda T. Inoue and T.Izumi ibid. 1982 23 4585. 67 N. Slougui G. Rousseau and J.-M. Conia Synthesis 1982 58. 68 N. Petragnani and M. Yonashiro Synthesis 1982 521; A. P. Krapcho ibid. 1982 893. 69 S. Kinastowski and A. Nowacki Tetrahedron Lett. 1982,23 3723. ’’ H. Wynberg and E. G. J. Staring J. Am. Chem. SOC.,1982,104 166. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Methods for y-lactones which have been reported include a carbonyl insertion- dehydrobromination sequence catalysed by Pd" from (65) and treatment of (66) with AcO~H.~' Stereoselective lactone syntheses have enjoyed variable success. (E)-MeCH=CHCHO was transformed into threo-(67) which on hydrolysis gave a lactol oxidized by pyridiniumachlorochromate to trans-(68) in 89% yield.72 Homogeneous catalytic hydrogen transfer from prochiral diols using Ru,C14.[ (-)-DIOP] and PhCH=CHCOMe as hydrogen acceptor gave low (lO.8YO)e.e.in the formed 6-lactone; selective oxidation with distinction between pro-R and pro-S sites gave >50% e.e. An attempt to oxidize (69)with a number of Gluconobacter species gave only (S)-mevalonolactone (of unnatural configuration); in the most favourable case 79% e.e. was The approach to (71)via use of (I?)-(+)-(70) is shown in Scheme 15 and was to obtain the product (a hornet pheromone) in e.e. > 80%. -.OH (R)-(+)-(71) Reagents i Bu'MgBr-THF R'CHO; ii AI-Hg/THF dihydropyran-CH,CI,-pyridinium toluene-p-sulphonate LAH-Et,O TsC1-py Mg1,-Et,O LiCH2C02Bu'-THF-HMPT; iii PPTS-EtOH TS0H-C HI6 Scheme 15 L.D.Martin and J. K. Stille J. Org. Chem. 1982 47 3630; I. Kuwajima and H. Urabe Tetrahedron Left. 1981,22,5191. " A. J. Pratt and E. J. Thomas J. Chem. Soc. Chem. Commum. 1982 1115. Y. Ishii K. Osakada T. Ikariya M. Saburi and S. Yoshikawa Chem. Lett. 1982 1179; H. Ohta H. Tetsukawa and N. Noto J. Org. Chem. 1982,47 2400. 74 G. SolladiC and F. M.-Moghadam J. Org. Chem. 1982 47 91. '3 164 B. V. Smith Ring-opening of lactones e.g. (72) by RMgX-CuI or R,CuMgX gave principally (86:14)the (E)-isomer of RCH2CH=CH(CH2)2C02H and the method was further developed and applied in the synthesis of pheromones. A route to 4-oxoacids was reported via silyation of a lactone with Ph,MeSiCl addition of RMgX and Jones ~xidation.~’ The erythro-threo ratio in the aldol reaction of y-butyrolactone and PhCHO has been rationalized in terms of an intermediate (73)which can be formed when zinc chloride-LDA-THF is used (but not when Li’ alone is present).76 3-Alkoxyenolates of y-butyrolactones can be stereospecifically methylated at C-2; the 4,4-dimethyl compound gave a 2a :2p ratio of 93 :7.This method was adapted for natural product synthesis.77 A novel chiral induction is via reaction of (74) which with (75) gave (76);the latter compound with a nucleophile e.g. piperidine gave (77) as the major product converted into (3s)-(-)-3-methylvalerolactone. (73) (75) (76) (77) Glycal esters can be converted into unsaturated lactones by treatment with rn-chloroperoxybenzoic acid followed by BF3.78 5 Amines and Amides A simple one-pot method for converting alkyl halides or tosylates into amines via azides uses phase-transfer catalysis in the reduction step.A simple reduction route to hindered amines has been described. The ‘electro-organic Hofmann degradation’ of amides in methanol as solvent works for hindered (Bu‘CONH2) and bridgehead (1-AdCONH2) compounds; in the latter case the isocyanate was reported to be the major product together with the carbamate ester (the usual product of this process). A range of organo-lithiums (RLi; R = alkyl or phenyl) react smoothly with MeONH2-MeLi (=NH2+) followed by hydrolysis to give primary amines in excel- lent yield. CS2 deoxygenates several t-amine oxides (but not that derived from picoline).79 ” T. Fujisawa T.Sato M. Kawashima K. Naruse and K. Tamai Tetrahedron Lett. 1982 23 3583; L. M. Fuentes and G. L. Larson ibid. 1982,23 271. 76 D. A. Widdowson G. H. Wiebecke and D. J. Williams Tetrahedron Lett. 1982 23,4285. ’I’ A. R. Chamberlin and M. Dezube Tetrahedron Lett. 1982,23,3055. ’* Y. Nagao T. Ikeda M. Yagi and E. Fujita J. Am. Chem. SOC.,1982 104 2079; P. Jarglis and F. W. Lichtenthaler Tetrahedron Lett. 1982 23 3781. 79 F. Rolla J. Org. Chem. 1982 47 4327; J. T. Lai Tetrahedron Lett. 1982 23 595; T. Shono Y. Matsumura S. Yamane and S. Kashimura Chem. Lett. 1982 565; P. Beak and B. J. Kokko J. Org. Chem. 1982,47,2822; T. Yoshimura K. Asada and S. Oae Bull. Chem.SOC.Jpn. 1982,55,3000. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds A regio- and stereo-specific synthesis of allylic tertiary amines employed the sequence shown in Scheme 16.Depending upon the nature of R' and R2 (78)+(79) 0 0 (79) II Reagents i Ph,PQ ii BuLi then R'R'CO; ii NaH-DMF Scheme 16 may be described as an erythro -P (2)-conversion if R' > R2; conversely the threo-isomer furnished the (E)-allylamine in a process generating single species.8o The diene (35) was added to an imine (R'N=CHR2) at room temperature to furnish A protecting group for amines [from (81) + R'R2NH] can be easily removed photochemically with loss of S02.82 Direct conversion of secondary-alkyl primary-amines into alkenes has been achieved through reaction with pyrylium salts; an intermediate carbonium ion was impli~ated.~~ Deprotonation of unsymmetrical imines usually occurs at the more substituted a-carbon; however MeC(=NR)(CH2)4Me with BuLi-HMPA-PhCH2Cl gave after work-up only Ph(CH2)2CO(CH2)4Me.84 The mechanism of diazoalkane formation from NOCl at low temperature has been further studied and the role of acetic acid ~larified.~' Several chiral amino-compounds have been prepared and studied.2-Amino-2- phenylethanol was most efficient for resolution of several carboxylic acids. Stereoselective synthesis of diastereoisomeric amino-alcohols from aminocarbonyl compounds has been reviewed.86 Synthesis of ethyl (2S,3S,4R)- and (2R,3R,4R)- 2- amino-3,4,5-trihydroxypentanoatehas been achieved through reaction of 2,3-0- isopropylidene-D-glyceraldehydeand ethyl cyanoacetate and hydrolysis of the isomeric oxazolines f~rmed.~' 'O D.Cavalla and S. Warren Tetrahedron Lett. 1982 23,4505. J. F. Kerwin Jr. and S. Danishefsky Tetrahedron Lett. 1982,23 3739. 82 G. A. Epling and M. E. Walker Tetrahedron Lett. 1982,23 3843. 83 A. R. Katritzky and J. M. Lloyd J. Chem. SOC.,Perkin Trans 1 1982 2347. 84 A. Hosorni Y. Araki and H. Sakurai J. Am. Chem. SOC.,1982,104,2081. '' J. M. Bakke Acta Chern. Scand. Ser. B 1982 36 127. 86 K. Saigo H. Miura K. Ishizaki and H. Nohira Bull. Chem. SOC.Jpn. 1982,55 1188; M. Trarnontini Synthesis 1982 605. '' I. Hoppe and U. Schollkopf Leibig's Ann. Chem. 1982 1548. 166 B. V. Smith The bromoamide (82; R' = R3 = But R2 = H) was cyclized in good yield by KOH-C6H6-18-crown-6 to form (83).88An unprecedented solvent effect on the reduction (NaBH,) of chiral ketoamides (84) has been claimed for THF-MeOH yH2S0,C1 N-R' Bu*HC(Br)CONHBu' a C,H,Me-p (82) 0 BUjrN PhCH202CCHR'R2 R2 B u' (86) (83) (85) (99:1);(S)-(+)-mandelic acid was obtained from reduction of (84) (R = Ph) and hydrolysis in nearly twice the e.e.observed in THF alone.89 Low e.e. was observed in MeOH alone. Asymmetric alkylation of (85) proceeds smoothly and the product with PhCH'OLi formed (86) with 0.2%racemization; reduction of the product (LAH- THF) afforded the alcohol R'RZCHCH20H in high optical purity." Dimetallated succinamides (2 eq. LDA-THF) on quenching in DzOAave principally threo-dideuterio-product; cyclization with a bis-electrophile('E E') led to annelation." Amides can be acylated by diketene with phase-transfer catalysis.A transamida- tion R'CONHR' +R'CONHR3 has been effected easily. Thioamides form nitriles with Bu;S~O-M~OH.~~ 6 Other Nitrogen-containing Compounds A one-pot synthesis of nitriles (from RCOCl and H2NS02NH2) is general in scope. Terminal or cyclic alkenes undergo cis-addition of DCN with Pd(DIOP) catalyst.93 Acyl cyanides continue to attract attention and the topic has been reviewed.94 A route to an a,& unsaturated nitrile Me2C=C(R)CN involves decarbonylation of the first-formed cycl~propanone.~~ Conjugate addition of Bu'NC to a,& unsatur-88 P. Scrimin F. D'Angeli and A. C. Veronese Synthesis 1982 586. x9 K. Soai K. Komiya Y.Shigematsu H. Hasegawa and A. Ookawa J.Chem. Soc. Chem. Commun. 1982,1282. 90 D. A. Evans M. D. Ennis and D. J. Mathre J. Am. Chem. Soc. 1982,104 1737. 91 K. K.Mahalanabis M. Mumtaz and V. Snieckus Tetrahedron Lett. 1982 23 3971. 92 E.V. Dehmlow and A. R. Shamout Leibig's Ann. Chem. 1982 2062; J. Garcia and J. Vilarrasa Tetrahedron Lett. 1982,23,1127; Ren and R. S. Klein,J. Org. Chem. 1982,47,4594. M.-I. Lim W.-Y. 93 A. Hulkenberg and J. J. Troost Tetrahedron Lett. 1982 23 1505; W.R. Jackson and C. G. Lovel ibid. 1982. 23 1621. 94 K. Haase and H. M. R. Hofmann Angew. Chem. Int. Ed. Engl. 1982. 21 83; H. M. R.Hofmann K. Haase Z. M.Ismail S. Preftitsi and A. Weber Chem. Ber. 1982 115 3880; S. Hiinig and R. Schaller Angew. Chem. Int. Ed. Engl. 1982 21 36. 95 R. Herter and B. Fohlisch Chem.Ber. 1982,115 381. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 167 ated ketones occurs under catalytic influence of TiCl or Et2AlCl; in the first case 'normal' addition of HCN was observed but in the second cyclization occurs. The reagent is thus capable of behaving as 'masked' HCN.96 Salts of nitroparaffins gave aldehydes or ketones in good yield with KMnO,; surprisingly a remote double bond was not attacked in e.g.CH2=CH(CH2)8CHN02. The SRNlreaction of aci-nitronates with 4-02NC6H4CH2C1 has been extensively studied to define substituent and structural effects. Double deprotonation of methyl 3-nitropropanoate furnished an intermediate which can be alkylated or acylated exclusively at C-2. Silyl nitronates (87) add to an alkene; the 2-isoxazolidines formed were transformed into a variety of cyclic sy~tems.~' / nn 0 Xl Me IY ii II **--srOMenthyl Me-/s=o 8 (87) Pk C,H,Me-p Ph 7 Sulphur Compounds Fungal oxidation of ArSMe and ArCH2SMe gives products in which the oxygen is not derived from water.98 Bromine adds to a dialkyl sulphide to yield a dialkylbromosulphonium ion capable of adding to an alkene; the adduct forms a vinyl sulphonium salt with base.99 Dimethyl(methy1thio)sulphoniumtetrafluorobor-ate (DMTSF) with a nitrogen nucleophile adds to an alkene R'CH=CHR2 (azasulphenylation) to form Nuc(R')CHCH(R2)SR; variation can be achieved by the use of oxygen nucleophiles to form hydroxy- or acetoxy-adducts.Thus Pr;C=CH2 gave Pr;C(OH)CH,SMe with DMTSF-CaC03-H20 or PriC(SMe)CH20Ac with DMTSF-KOAc-MeCN.loO Thermolysis of alkyl thiosulphinates led to thioaldehydes trappable by anthracene; a photolytic Norrish Type I1 pathway from PhCOCH2SCH2R1 led to R'CHS which could be trapped by a reactive diene.Propynethial (HC-CCHS) has been prepared by flash pyrolysis and its microwave spectrum examined."' Double asymmetric induction has been shown to occur in (90)due to the presence of two (asymmetric) chiral sulphur atoms. (S,S)-(+)-90was prepared by (LDA) base-catalysed reaction of (S)-(-)-(88) and (S)-(+)-(89); alkylation (EtBr) of (S,S)-(90) gave a 100 :0 diastereoisomeric product ratio. The (S,R)-enantiomer of (90) gave a markedly lower ratio (80:20) in alkylation. A route to oxoalkyl sulphides of high e.e.starts from condensation (LDA-THF) of hydrazones (91) 96 Y. Ito H. Kato H. Imai and T. Saegusa J. Am. Chem. SOC.,1982 104,6449. 97 N. Kornblum A. S. Erickson W. J. Kelly and B. Heuggler J. Org. Chem. 1982 47 4534; R.K. Norris and D. Randles Aust. J. Chem.,1982,35,1621;D. Seebach R. Henning and T. Mukhopadhyay Chem. Bet. 1982,115 1705; S. H. Andersen N. B. Das R. D. Jfirgensen G. Kjeldsen J. S. Knudsen S. C. Sharma and K. B. G. Torssell Acta Chem. Scand. Ser. B 1982 36 1. 98 H. L. Holland and I. M. Carter Can.J. Chem. 1982 60 2420. 99 Y. L. Chow and B. H. Bakker Synthesis 1982,648. loo B. M. Trost and T. Shibata J. Am. Chem. SOC.,1982,104,3225,3228. J. E. Baldwin and R. C. G. Lopez J. Chem. SOC.,Chem. Commun. 1982 1029; E. Vedejs T. H. Eberlein and D.L. Varie J. Am. Chem. SOC.,1982 104 1445; R. D. Brown P. D. Godfrey R. Champion and M. Woodruff Ausr. J. Chem. 1982,35 1747. 168 B. V. Smith and (S)-menthyl p-toluenesulphinate and transformation of the product. Reduction of the prochiral sulphinamides (92) generates (93) in which e.e. is dependent on the reagent; optimum e.e. (80%)was given with R = C10H7 and LiAlH,.OMenth. Hydrolysis of (93) affords a route to chiral amines. The lithium derivative of (89) with prochiral aldehydes and ketones gives diastereoisomeric pairs of p-hydroxysul-phoximines. After separation ketone adducts with Raney Ni gave tertiary alcohols and aldehydes furnished secondary alcohols of e.e. 30-100%. A nitrile also served to condense with (89); after the same sequence 18-69% e.e.was found in the product. An efficient route to methylcarbinols formed with high e.e. (80-100%) relies on reduction of ketosulphoxides (94) and subsequent desulphurization of the N' R II /R C p-MeC6H4 SN=C / p-MeC6H4SNHCH I\ II RTH( 'RI 0 'Ph 0 'Ph (92) (93) (94) products. lo* These applications of chiral sulphur compounds will doubtless be extended in future asymmetric syntheses. A general review of chiral organosulphur compounds has appeared.lo3 Other applications include the preparation of Bu3Sn-SR (a protected thiol) the use of thioacetals for umpolung synthesis of vinylsulphides (masked carbonyls) and preparation of triketones from diacyl sulphonium ylides. lo4 Thioethers PhSCHzSnPh3 can be metallated and condensed with PhCHO to form (E)-and (2)-PhSCH=CHPh."' The structure and stereochemistry of the thietane from the anal secretion of the stoat have been confirmed as (95).lo6 The chemistry of the S=S bond has been surveyed.lo7 8 Phosphorus Compounds Asymmetric hydrogenation via a cationic Rh' complex containing (R)-1,2-bis(dipheny1phosphino)phenylethane (96) is efficient giving e.e.88% in the optimum example. A chiral sugar residue bound to phosphorus has been used in 102 R. Annunziata and M. Cinquini Synthesis 1982 767; L. Banfi L. Colombo C. Gennari R. Annun-ziata and F. Cozzi ibid. 1982 829; R. Annunziata M. Cinquini and F. Cozzi J. Chem. SOC.,Perkin Trans. 1 1982 339; C. R. Johnson and C. J. Stark Jr. J. Org. Chem. 1982 47 1193 1196; G. SolladiC C. Greck G.Demailly and A. SolladiC-Cavallo Tetrahedron Lett. 1982 23 5047. M. Mikolajczyk and J. Drabowicz Top. Stereochem. 1982,13 333. 104 Y. Ueno M. Nozomi and M. Okawara Chem. Lett. 1982 1199; M. Lissel Liebig's Ann. Chem. 1982 1589; T. Agawa M. Ishikawa M. Komatsu and Y. Ohshiro Bull. Chem. SOC.Jpn. 1982 55 1205; K. Schlank and C. Schuhknecht Chem. Ber. 1982,115,3032. 105 T. Kauffmann R. Kriegesmann and A. Hamsen Chem. Ber. 1982,115 1818. '06 D. R. Crump Ausr. J. Chem. 1982 35 1945. "'G. W. Kutney and K. Turnbull Chem. Rev. 1982,82 333. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds a similar fashion with Rh' to direct reduction of the double bond in PhCH=C(NHAc)C02H.'OS The phosphoramidate (97a) has been suggested as a substitute for phthalimide in the Gabriel reaction; the advantages are (i) ease of deprotonation at N (ii) easy alkylation (iii) mild conditions for hydrolysis and decarboxylation (HC1-C6H6-r.t.) and (iv) alternative cleavage of (97b) if desired to form (Et0)2P(=O)NHR and hence a secondary amine.'09 Such advantages have to be balanced against ease of preparation of (97a) but are useful for sensitive systems.Ph [l;P-lV Ph3%HCH(OEt)2 Ph (99) (98) a R' = NMe2 b R' = OH The diazaphospholidine (98a) with ROH in toluene gave the phospholane (98b) smoothly converted into RHal (with inversion of configuration) by Br2 or S02C12 or MeI.l1° The phosphoallenyl ylide (99) gave by addition to RCHO and hydrolysis of the acetal the aldehyde RCH=CHCHO in which the (2)-isomer was pre- dominant."' The mechanism of the acid anhydride-ethoxycarbonylmethylene triphenylphosphorane reaction has been investigated in detail and the approach geometry of Wittig reactions has been discussed.Although the (2)- isoper_predomi- nates in the alkene formed in a series of reactions of RCHO and Ph,PCHMe with Et,PCHMe the (E)-alkene is the major product which difference was discussed as a function of steric demanfls on the process.'12 Sulphenyl chlorides and triphenyl phosphines react to form RSPPh3Cl- which decomposed on heating to form RCl and Ph,PS.ll3 A useful review of the stereochemistry of enzymatic reactions of phosphates has been p~b1ished.l'~ 9 Miscellaneous Synthetic methods used in 1981 have been reviewed."' The structure and reactions of halogenosulphonium salts and the reactions of trimethylsilyl iodide have been surnmarized.'l6 J.M. Brown and B. A. Murrer J. Chem. SOC.,Perkin Trans. 2,1982,489; M. Yamashita K. Hiramatsu M. Yamada N. Suzuki and S. Inokawa Bull. Chem. SOC.Jpn. 1982,55 2917. A. Zwierzak and S. Pilichowska Synthesis 1982 922. 'lo S. Hanessian Y. Leblanc and P. LavallCe Tetrahedron Lett. 1982,23 4411. '" H. J. Bestmann K. Roth and M. Ettlinger Chem. Ber. 1982 115 161. 'I2 A. D. Abell and R. A. Massy-Westropp Ausr. J. Chem. 1982 35,2077; M. Schlosser and B. Schaub J. Am. Chem. SOC., 1982,104,5821. 'I3 I. W. Still G.W. Kutney and D. McLean J. Org. Chem. 1982 47 560. 'I4 P. A. Frey,Tetrahedron 1982,38 1541. '15 L. G. Wade Jr. and M. J. O'Donnell Annu.Rep. Org. Synth. (1981) Academic Press (N.Y.) 1982. 'Id G. E. Wilson Jr. Tetrahedron 1982 38 2597; G. A. Olah and S. C. Narang ibid. 1982 38. 2225.

ISSN:0069-3030    

DOI:10.1039/OC9827900149

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

9 Alicyclic Chemistry By J. M. MELLOR Department of Chemistry The University Southampton SO9 5NH 1 Introduction The pace of discovery of new carbocyclic skeletons in Nature is only matched by the ever increasing efficiency of their total synthesis in the laboratory. The state of the art is indicated by the remarkable number of reports of total synthesis of complex natural products in which only two Authors are named. Pride of place must go to Gibbons for his lone effort on the first efficiently stereoselective synthesis' of pleuromutilin (1). However the new level of skill in synthetic design and execution is witnessed by synthesis from readily prepared intermediates of khusimone (2)*(9 synthetic steps; 11%overall yield) modhephene (3)3(7 steps; 8% yield) silphinene (4)4 (15 steps; 10% yield) vetispirene (5)5 (5 steps; 38% yield) mycorrhizin A (6),6hibiscone C(7),7 confertin (8),8aromatin (9),9hirsutene I E.G. Gibbons J. Am. Chem. SOC.,1982,104,1767. W..Oppolzer and R. Pitteloud I. Am. Chem. Soc.. 1982,104,6478. P. A. Wender and G. B. Dreyer J. Am. Chem. SOC.,1982,104 5805. A. Leone-Bay and L. A. Paquette J. Org. Chem. 1982,47,4173. T.-H. Yan and L. A. Paquette TetrahedronLett. 1982 23,3227. E. R. Koft and A. B. Smith J. Am. Chem. SOC.,1982,104,2659. E. R. Koft and A. B. Smith J. Am. Chem. SOC.,1982,104,5568. A. G. Schultz and L. A. Motyka J. Am. Chem. SOC.,1982,104 5800. P. T. Lansbury and J. P. Vacca Tetrahedron 1982.38 2797. 172 J.M. Mellor (lo)," capnellenediol (ll)," the complement inhibitor K-76 (12)12 (a fungal meta- bolite which inhibits a step contributing to the inflammatory process in rheumatoid arthritis) a chiralI3 and a racemic14 synthesis of compactin (13) synthesis of the aglycone phyllanthocin (14)," and two syntheses of verrucarol (15).16 Many other CHO syntheses merit discussion but space prohibits such luxury.However synthesis of cyclopentanoids has been reviewed" and the discussion of many other fascinating structures may be found in a symposium on Animal Defence Mechanisms." The importance of cyclopentanoid targets is emphasized by the review of prostacyc- lins" and of the development of methodologies based on cyclopentenones20 and '(I S. V. Ley and P. J. Murray J. Chem. SOC.,Chem. Commun. 1982 1252. '' G.Pattenden and S. J. Teague Tetrahedron Lett. 1982 5471. E. J. Corey and J. Das J. Am. Chem. SOC.,1982,104 5551. l3 M. Hirama and M. Uei J. Am. Chem. SOC.,1982,104,4251. l4 N. N. Girotra and N. L. Wendler Tetrahedron Lett. 1982 5501. P. R. McGuirk and D. B. Collum J. Am. Chem. SOC.,1982,104,4496. l6 R. H. Schlessinger and R. A. Nugent J. Am. Chem. SOC.,1982 104 1116; B. M. Trost and P. G. McDougal ibid. p. 6110. l7 B. M. Trost Chem. SOC.Reu. 1982,11 141. Tetrahedron 1982 38 1855. l9 W. Bartmann and G. Beck Angew. Chern. Int. Ed. Engl. 1982,21,751. 2n M. Harre P. Raddatz R. Walenta and E. Winterfeldt Angew. Chem. Int. Ed. Engl. 1982 21,480. Alicyclic Chemistry 173 on photochemical routes to cyclopentanoids.21 Examples of the importance of intramolecular [2 + 21 photoadditions in synthesis are discussed below but the subject has been reviewed2’ and similarly the use of siloxydienes in the Diels-Alder reaction has been reviewed by Dani~hefsky~~ and further examples are given below.A further Symposium in print concerns various aspects of the chemistry of biradi~als’~ and the norbornyl cation is the subject of a review by summariz-ing his view that there is still no definitive evidence which requires the nonclassical structure for the 2-norbornyl cation. A balanced viewz6 by Grob incorporating many recent results from Basle suggests that the original nonclassical/classical argument has lost most of its meaning. A gradation of bridging behaviour is to be observed in differently substituted 2-norbornyl cations.The applications of molecular mechanics in alicyclic chemistry” have been reviewed and the extent to which orbital interactions through several bonds affect physical and chemical properties2* has been analysed. Again further recent examples are discussed below. The full impact of exciting new methods of obtaining structural information by n.m.r. techniques has yet to be experienced. An insight into the future is given by the determination of ~tructure’~ of the photoproduct (16) obtained from (17).The structure of (16) is assigned using two-dimensional correlated spectra. Again 2D 0 0 (16) (17) techniques are used to prove the structure of (18) a steroid photodimer. Here the analysis is based3’ on 13C-13C couplings at a natural abundance level which required a large sample weight (0.84g).Structures of other steroids have been estab1ished3l by related methods but again with present spectrometers gram quantities are required. The first structural determination of a natural product using these double quantum coherence methods is reportedj2 for velloziolide (19); the sample weight was 500 mg. 2‘ M. Demuth and K. Schaffner Angew. Chem. Int. Ed. Engl. 1982,21 820. 22 W. Oppolzer Acc. Chem. Res. 1982 15 135. 23 S. Danishefsky Acc. Chem. Res. 1981 14 400. 24 Tetrahedron 1982 38 735. 25 H. C. Brown Pure Appl. Chem. 1982 54 1783. 2h C. A. Grob Angew. Chem.. Int. Ed. Engl. 1982 21 87. *’ E. Osawa and H. Musso Top. Stereochem. 1982 13 117. 28 M. N. Paddon-Row Acc.Chem. Res. 1982,15 245. 29 D. Leibfritz E. Haupt M. Feigel W. E. Hull and W.-D. Weber Annalen 1982 1971. ’’ R. Freeman T. Frenkiel and M. B.Rubin J. Am. Chem. SOC.,1982,104 5545. 31 R. Jacquesy C. Narbonne W. E. Hull A. Neszmelyi and G. Lukacs J. Chem. Soc. Chem. Commun. 1982,409. 32 A. C. Pinto M. L. A. Goncalves R. B. Filho A. Neszmelyi and G. Lukacs J. Chem. SOC.,Chem. Commun. 1982,293. 174 J. M. Mellor 0dP @@ OH -0 0 2 Synthesis Monocyclic Compounds.-The stimulus of the insecticidal activity of the derivatives of the chrysanthemic acids -particularly the unnatural cis-series -has resulted in further synthetic studies. Russian chemists describe33 an improved route to 3,3- dimethylcyclopropene and subsequent formation in 70%yield of cis-chrysanthemic acid (20) by reaction with 2-methylpropenyl magnesium bromide and then carbon dioxide.A later report however a lower yield (39%). A very attractive alternative proceeding with intermediacy of a cyclopropene concerns forma- tion of a 3H-pyrazole (21) by hydrazine addition to an @-unsaturated ketone and subsequent MnO oxidation of the intermediate pyrazoline. Photolysis of (21) and stereospecific hydrogenation gives (22) in 94% yield for the two steps. Enantioselec- tive rqute~~~ towards synthesis of the chrysanthemic acids are noted. 33 0. A. Nesmeyanova T. Y.Rudashevskaya A. I. Dyachenko S. F. Savilova and 0.M. Nefedov Synthesis 1982 296. 34 H. Lehmkuhl and K. Mehler Annalen 1982 2244. 35 M. Franck-Neumann and M.Miesch Tetrahedron Lett. 1982 23 1409. 36 M. Franck-Neumann D. Martina and M. P. Heitz Tetrahedron Lett. 1982 23 3493; M.4. De VOS and A. Krief J. Am. Chem. Soc. 1982,104,4282. Alicyclic Chemistry 175 Me0,C ArS0,fS OH * Acow (22) (24) 0 1-Arylsulphonylbicyclo[1.1.O]butanes [e.g. (23)] are easily prepared from 76-epoxysulphones and provide surprising intermediates in the synthesis of some natural products [e.g. the pheromone (24),37 and mc-junionone (25)38]. Progress in the understanding of cyclobutadiene chemistry has centred on the carbene route (Scheme l) which can give either cyclobutadiene~~~ [e.g. (26)] or acetylenes by fragmentation It is suggested4' that (26) is formed from a singlet carbene but the triplet carbene leads to fragmentation.+=+ $-C02 Bu' CO Bu' Scheme 1 Reductive cyclization of ao-dihalides has been of little importance other than for formation of cyclopropanes. Now by careful definition of conditions excellent yields are obtained41 in the formation of both four- and five membered rings. The of rhodium(I1) catalysed decompo~ition~~ a-diazo-@-keto-esters leads very efficiently to the formation of cyclopentane derivatives by intramolecular C-H insertion (Scheme 2). A number of palladium(0) catalysed processes for construction Scheme 2 37 Y. Gaoni Tetrahedron Lett. 1982,23,5215. 38 Y.Gaoni Tetrahedron Lett. 1982,23,5219. 39 P.Eisenbarth and M. Regitz Chem. Ber. 1982 115 3796. 40 P. Eisenbarth and M. Regitz Angew. Chem. Int. Ed. Engl. 1982,21,913.41 W.F.Bailey and R. P. Gagnier Tetrahedron Lett. 1982,23,5123. 42 D.F.Taber and E. H. Petty J. Org. Chem. 1982.47.4808. 176 J. M. Mellor of five-membered rings are reported. Trost and Runge describe43 full details of their synthesis of cyclopentanones by isomerization of tetrahydrofurans (Scheme 3). Palladium(0) catalysis permits efficient ~earrangement~~ of cyclopropane deriva- tives to give five-membered rings (Scheme 4). The method is applicable to construc- tion of spirocycles. An intramolecular [3 + 21 cy~loaddition~~ leads to formation Scheme 3 Pd" &CO2Me C0,Me 4 C0,Me C0,Me Scheme 4 of a five-membered ring and construction of a bicyclic system from acyclic precursors (Scheme 5). The Grignard reagent (27) can be used in alternative methods of construction of carbocycles.Thus 1,4-addition to cyclohex-2-enone followed by a SiMe H i ii / SOzPh ,6 0 OAc liii SiMe (27) @ PhSO Reagents i (27);ii AcCl; iii Pd(dppe),; 65% Scheme 5 43 B. M. Trost and T. A. Runge I. Am. Chem. SOC.,1981 103,7559. 44 Y.Morizawa K. Oshima and H. Nozaki Tetrahedron Lett. 1982,23,2871. 4s B.M. Trost and D. M. T. Chan J. Am. Chem. Soc. 1982,104,3733. Alicyclic Chemistry Lewis acid promoted cyclization leads46 to (28)in -80% overall yield. The acylation of acetylenes with py-unsaturated acid chlorides4’ promoted by Lewis acids leads to cyclopent-2-enones. The method is particularly efficient for formation of spirocycles. Thus from (29) and propyne by rearrangement (30) is obtained in 65% yield.Two important new procedures for construction of five-membered rings have been developed by Stork’s group. In one case trans-hydrindanes are constructed by an intramolecular Michael addition4’ with high stereoselectivity. In a further procedure cyclization is via intramolecular addition of a vinyl radical to a double bond. Irradiati~n~~ of a vinyl halide with excess tri-n-butylstannane generally leads to efficient cyclization (see Scheme 6). A quite different reductive cyclizationS0 proceeds via an organomercury intermediate (Scheme 7). eN Scheme 6 Reagents i Hg(OAc), AcOH; ii NaBH(OMe),; iii KOH H20 MeCN; iv CrO Scheme 7 The recent interest in the ene-reaction as a method of ring synthesis has been extended by the intermolecular reaction of cup-unsaturated carbonyl corn pound^^' with alkenes (Scheme 8) and by the use of organomagnesium compounds in intramolecular ene reactions.The known ‘metallo-ene’ reaction has been adapted5* 46 B. M. Trost and B. P. Coppola J. Am. Chem. Soc. 1982,104,6879. 47 M. Karpf Tetrahedron Lett. 1982 23 4923. 48 G. Stork C. S. Shiner and J. D. Winkler J. Am. Chem. SOC.,1982,104 310. 49 G. Stork and N. H. Baine J. Am. Chem. SOC.,1982,104 2321. ” S. Danishefsky S.Chackalamannil and B.-J. Wang J. Org. Chem. 1982 47 2231. ” B. B. Snider and E. A. Deutsch J. Org. Chem. 1982,47,745. ’* W. Oppolzer E. P. Kundig P. M.Bishop and C. Perret Tetrahedron Len. 1982 23 3901; W. Oppolzer R. Pitteloud and H. F. Strauss J.Am. Chem. SOC.,1982,104 6476. 178 J. M. Mellor Reagents i methyl vinyl ketone Me,AlCl Scheme 8 by efficient generation of the allylic Grignard reagents using a procedure requiring fresh magnesium obtained by distillation. Subsequent heating of the allylic Grignard reagents leads to effective ring synthesis by intramolecular cyclization. Khusimone (2) and ~apnellene~~ (Scheme 9) have been synthesized by such procedures. 1iv H vii iv-vi HH 1 t Reagents Mg powder Et,O; ii 60T 23h; iii acrolein; iv SOCl,; v Mg powder Et,O; vi r.t. 20h; vii several steps Scheme 9 Later we note the improved methods for construction of six-membered rings in steroids. Few real innovations in the synthesis of six-membered rings are to be reported.However enantioselectivity in the Diels-Alder reaction of cyclopen- tadiene with acrylate has reached the point that asymmetric induction is described as ‘virtually quantitative’. The great problem in construction of macrocycles is avoidance of conditions requiring high dilution. Use of polymer-supported palladium catalysts55 enables isomerization to give macrocycles to be effected in concentrated solutions (0.5 M) [e.g. formation of (31)and (32) from (33)]. High dilution is required in the coupling of dicarbonyl compounds by titanium. A testimony to the importance of the method however is the stereospecific con~ersion~~ of (34) into humulene (35)in 60%yield. Three photochemical procedures lead to important bicyclic systems. Irradiation of phenol57 in CF3S03H-SbF5 gives (36) in 20% yield.Full details are reported of ’3 W. Oppolzer and K. Battig Tetrahedron Lett. 1982 23,4669. 54 W. Oppolzer C. Chapuis G. M. Dao D. Reichlin and T. Godel Tetrahedron Lett. 1982 23,4781. ” B. M. Trost and R. W. Warner J. Am. Chem. SOC.,1982,104 6112. 56 J. E. McMurray and J. R. Matz Tetrahedron Lett. 1982 23 2723. ’’ R. F. Childs G. S. Shaw and A. Varadarajan Synthesis 1982 198. Alicyclic Chemistry 502ph procedures58 permitting copper(1) promoted photocyclization of alkenylallyl alcohols [e.g.conversion of (37) into (38) (83% yield)]. Although further examples are reported5’ of observation of norcaradienes in equilibrium with cyclohep- tatrienes the first observation of the parent norcaradiene (39) has been achieved6’ by low temperature photolysis of (40).& e&o& (37) (38) (39) (40) (36) Bridged and Polycyclic Compounds.-Examples of [4.1.1] and [3.1.1] propellanes have previously been prepared and are known to be highly unstable because of the ease with which the strained central carbon-carbon bond can be cleaved to give radicals. In contrast Wiberg’s group have calculated61 that in [1.1.13propellane (41) a higher bond dissociation energy may be expected because of the greater strain energy in the products relative to those formed from for example [4.1.1] propellane. Preparation of (41) by the reaction of (42) with t-butyl-lithium permits R. G. Salomon D. J. Coughlin S. Ghosh and M. G. Zagorski J. Am. Chem. Soc. 1982 104 998; R.G. Salomon S. Ghosh M. G. Zagorski and M. Reitz J. Org. Chem. 1982 47 829. 59 K. Takeuchi T. Kitagawa T. Toyama and K. Okamoto J. Chem. Soc. Chem. Commun. 1982 313; W. Bauer J. Daub G. Maas M. Michna K. M. Rapp and J. J. Stezowski Chem. Ber. 1982,115 99. M. B. Rubin J. Am. Chem. Soc. 1981,103,7791. 61 K. B. Wiberg and F. H. Walker J. Am. Chem. Soc. 1982,104,5239. 180 J. M. Mellor the remarkable thermal stability of (41) to be confirmed (ti 114"C-5 min). In sharp contrast [2.2.llpropellane (43)has only been observed6* using matrix-isola- tion techniques. A related cyclization from the dibromide (44)permits the first synthesis63 of octavalene (49,which only at 80°C slowly isomerizes to cyclo- octatetraene Lack of product stability is not the difficulty in synthesis of dodecahedrane (46) (no evidence of melting even at 450°C),which has at last been ~ynthesized~~ in 23 steps from the cyclopentadienide anion.The detailed studies of Paquette's group in this area have resulted in the synthesis of both m~nomethyl-~~ and a dimethyl- dodecahedrane.66 The proposal by Australian chemisd7 that the biogenetic pathway to the series of endiandric acids (A B C and D) having unusual structures might proceed by a series of non-enzymatic electrocyclizations has been confirmed6* by the group of Nicolaou in an outstanding study. A retro-synthetic analysis in Scheme 10shows the possible origin of the known acids which occur in Nature as racemates from an achiral diacetylene precursor. In one of the more remarkable parts of the synthetic study hydrogenation of (47)and subsequent electrocyclization leads directly to the methyl esters of endiandric acids B and C.Developments in steroid synthesis have centred on new methods of construction of six-membered rings leading to racemic products and on improvements to estab- lished methods permitting induction of chirality. Sternberg and Vollhardt6' have used a cobalt mediated [2 + 2 + 2lcyclo-addition in a short route to the Torgov intermediate (Scheme 11).Stork and Sherman7' have based a new route to 11-ketoprogesterone on synthesis and elaboration of the acid (48).The value of the 62 F. H. Walker K. B. Wiberg and J. Michl J. Am. Chem. SOC.,1982,104,2056. 63 M. Christ1 and R. Lang J. Am. Chem. Soc. 1982,104,4494.64 R. J. Ternansky D. W. Balogh and L. A. Paquette J. Am. Chem. Soc. 1982,104,4503. 65 L. A. Paquette R. J. Ternansky and D. W. Balogh J. Am. Chem. SOC., 1982,104,4502. 66 L. A. Paquette and D. W. Balogh J. Am. Chem. Soc. 1982,104,774. '' W. M. Bandaranayake J. E. Banfield and D. St. C. Black J. Chem. Sac. Chem. Commun.,1980,902. 68 K. C. Nicolaou N. A. Petasis R. E. Zipkin and J. Uenishi J. Am. Chem. Sac. 1982 104 5555; ibid.,p. 5557; K. C. Nicolaou R. E. Zipkin and N. A. Petasis ibid.,p. 5558; ibid.,p. 556U. 69 E. D. Sternberg and K. P. C. Vollhardt J. Org. Chem. 1982,47 3447. '' G. Stork and D. H. Sherman J. Am. Chem. SOC.,1982,104,3758. Alicyclic Chemistry 181 n = 0 Endiandric acid A Endiandric acid C Endiandric acid D n = 1 Endiandric acid B R1 RZ Q c‘=-=> C0,Me Ph (47) R’ RZ Scheme 10 Johnson biomimetic polyene cyclization as a route to a variety of steroids is well recognized.Now it is established71 that a benzyloxy-substituent at a chiral centre (pro-C-7) induces considerable diastereoselection. Using racemic sub~trates,’~ the 71 W. S. Johnson D. Berner D. J. Dumas P. J. R. Nederlof and J. Welch J. Am. Chem. SOC.,1982 104,3508. 72 W. S. Johnson D. J. Dumas and D. Berner J. Am. Chem. SOC.,1982 104 3510. 182 J. M. Mellor 1ii 0 n Reagents i CpCo(CO) ,A; ii FeCI, MeCN; iii pTsOH Scheme 11 methodology is used in a synthesis of the important aldosterone blocking agent spironolactone(49). A simple and efficient method of elaboration of 17-ketosteroids to obtain a corticosteroid side-chain via ethylenediamine-catalysed condensation with nitromethane to give an intermediate nitroalkene which is then treated with formaldehyde.3 Chemistry Neutral Species Strained Alkenes and A1kynes.-Recent studies have concerned not only a continuation of the many reports of the chemistry of bridgehead alkenes and of cyclic allenes but also the limiting ring size embracing a trans-alkene linkage and an acytylenic group. Photoisornerizati~n~~ of cis-cycloheptene using photo-sensitizers has permitted the first observation of the kinetics of the conversion of trans-cycloheptene into cis-cycloheptene. Truns-cycloheptene is stable at -78 “C. 73 D. H. R. Barton W. B. Motherwell and S. Z.Zard J. Chem. SOC.,Chem. Commun. 1982 551. 74 Y. Inoue T. Ueoka T. Kuroda and T. Hakushi J. Chem. SOC.,Chem. Commun.,1981,1031. Alicyclic Chemistry 183 Cyclopentyne is highly reactive and in fresh trapping it has been shown that reaction of (50) with phenyl-lithium provides a new route to cyclopentyne. Photoelectron spectroscopy has an established importance in determination of ionization potentials. A satisfactory experimental method for determination of electron affinities has been slower in development. Now the electron affinities of cis-and trans-cyclo-octene have been measured using electron transmission measurernent~:~~ the difference (0.14eV) is less than the observed difference in ionization potentials (0.29eV). Br The earlier investigations of the chemistry of (51) and (52) (Annu.Rep. Bog. Chem.,Sect. B 1981,78,199)have been extended by matrix isolation experiment~~~ that have permitted the recording of the i.r. spectrum of (52). Trapping provide further evidence for the intermediacy of both (51) and (52). Further studies of both a Wittig route7' to strained bridgehead alkenones and the use of intramolecular Diels-Alder reactions in construction of bridgehead alkenes" are reported. Direct irradiation" of the bridgehead alkene (53) leads to cis-trans-isomerization and trapping studies suggest formation of the more reactive (54). The sterically hindered bridgehead alkene (55) isso stabilized to the anticipated [2 + 21 mode of dimerization that it survives unchanged8* at 185 "Cover 24 h.75 L. Fitjer U. Kliebisch D. Wehle and S. Modaressi Tetrahedron Lett. 1982 23 1661. " M. Allan E. Haselbach M. von Buren and H.-J. Hansen Helo. Chim. Acta 1982,65 2133. 77 P. R. West 0.L. Chapman and J.-P. LeRoux J. Am. Chem. SOC., 1982,104 1779. 78 M. Balci W. R. Winchester and W. M. Jones J. Org. Chem. 1982 47 5180; J. W. Harris and W. M. Jones J. Am. Chem. SOC., 1982,104,7329. 79 H. J. Bestmann and G. Schade Tetrahedron Lett. 1982 23 3543. *" K. J. Shea S. Wise L. D. Burke P. D. Davis J. W. Gilman and A. C. Greeley J. Am. Chem. SOC. 1982,104 5708. J. R. Wiseman and J. E. Kipp J. Am. Chem. SOC.,1982,104,4688. ** S. F. Sellers T. C. Klebach F. Hollowood and M. Jones J. Am. Chem. SOC., 1982,104 5492. 184 J. M. Mellor Other Neutral Species.-The distinction between valence isomerization and mesomeric interaction in cyclobutadienes has been probed by two very different techniques.I3CN.m.r. analysisB3 at -82°C suggests the existence of a dynamic equilibrium between the valence isomers (56a) and (56b). A kinetic analysis84 of [1,2-2H2]cyclobutadiene using trapping experiments confirms a low activation energy for the valence isomerization and excludes the possibility of a delocalized T-sys tem. Structures (57) and (58)are related as an aromatic phenol and a ketone tautomer. Both spectroscopic observationE5 and calculationsB6 indicate that (58) is the more stable showing that the aromaticity of (57) is inadequate to compensate for the greater strain relative to the non-aromatic but less strained ketone (58).Carbenium 10ns,-'~C N.m.r. spectra of the norbornyl cation have probedB7 the nature of this cation at very low temperatures. Useful spectra have been obtained at 5 K which establish that in super acid media if equilibration between structures having a localized charge is occurring then the activation energy for such a process cannot be more than 0.2 kcal mol-I. Hence a delocalized structure seems probable. Both solvolytic studies proceeding with ionizationE8 and SN2 displacement^^^ at norbornyl derivatives indicate that some earlier views overemphasize the import- ance of steric effects in controlling exolendo rate ratios. Radical Species.-Electrochemical studies establishg0 the rapid cycloreversion of the radical anion of tetraphenylcyclobutane by a [u2,+ u2,]process.It is suggested that this cycloreversion has considerable generality in the chemistry of substituted cyclo bu t anes. 83 G. Maier. H.-D. Kalinowski and K. Euler Angew. Chem. Int. Ed. Engl. 1982 21 693. 84 D.W. Whitman and B. K. Carpenter J. Am. Chem. SOC., 1982,104,6473. 85 R. McCague C. J. Moody and C. W. Rees J. Chem. SOC.,Chem. Commun. 1982,622. 86 H. S.Rzepa J. Chem. Res. 1982 324. 87 C. S.Yannoni V. Macho and P. C. Myhre J. Am. Chem. SOC.,1982 104 907;*C. S.Yannoni V. Macho and P. C. Myhre ibid. p. 7380. 88 C. A.Grob B. Gunther and R. Hanreich Helu. Chim. Acta 1982,65,2110. 89 K.Banert and W. Kirmse J. Am. Chem. SOC.,1982,104,3766. 90 M.Homer and S. Hunig Liebigs Ann. Chem. 1982 1409.Alicyclic Chemistry There are reports of attempted observations of a variety of important radicals. E.s.r. studies have failed again to give evidence of the parent cyclopropenyl radical. However both (59) and (60) have been observed. It is interesting that the structure of (60) is as represented" and that no evidence for a tertiary radical centre was obtained. Picosecond fluorescence has been used by excitation of (61) to observe the singlet biradical (62). An attempt93 to prove that sensitized photolysis of (63) might proceed via in part the tetraradical (64) is inconclusive but a failure to observe products indicating the intermediacy of radicals strongly that the mechanism of oxidation of (65) and hence by implication other alcohols by NAD(H) and alcohol dehydrogenase does not involve radical inter- mediates.Carbanions.-Redu~tion~~ of (66) gives the dianion (67) which has been character- ized spectroscopically and chemically. Both the 'H and 13Cn.m.r. spectra of (67) show a characteristic symmetry and there is strong evidence that (67) is a bis- homoconjugatively stabilized species. Electrochemical reduction of (66) suggests that the second electron transfer to the radical anion is relatively facilitated; this behaviour is well known with cyclo-octatetraene. Further calculation^^^ contradict 91 R. Sutcliffe D. A. Lindsey D. Griller J. C. Walton and K. U. Ingold J. Am. Chem. SOC.,1982 104,4674. 92 D. F. Kelley P. M. Rentzepis M. R. Mazur and J. A. Berson J. Am. Chem. SOC., 1982 104 3764.93 L. McElwee-White and D. A. Dougherty J. Am. Chem. SOC., 1982,104,4722. 94 1. MacInnes D. C. Nonhebel S. T. Orszulik and C. J. Suckling J. Chem. SOC., Chem. Commun. 1982,121. W. Huber K. Mullen R. Busch W. Grimme and J. Heinze Angew. Chem. Inr. Ed. EngI. 1982 21 301. 96 J. M. Brown R. J. Elliott and W. G. Richards J. Chem. SOC. Perkin 2 1982 485. '.5 186 J. M. Mellor the views expressed last year (see Annu. Rep. Prog. Chem. Sect. B 1981 78 202) of the lack of homoaromatic character in the anions of bridged hydrocarbons. In particular the homoaromaticity of (68) is again supported. 4 Stereochemical Aspects The interest in long range substituted effects has led to their observation by new techniques that are responsive to subtle effects which are dependent on both distance and stereochemical pathways.Thus analysis9' of I3C chemical shifts by n.m.r. of steroids shows the importance of through-space field-eff ects of electronegative substituents over six bonds. Ob~ervation~~ of fluorescence using single photon counting methods proves that intramolecular quenching by electron transfer of excited states can occur over large distances for example in (69). Electron trans- mission spectroscopy has been to measure the electron affinities and hence to observe the interactions of T orbitals in some dienes. A large through-space interaction is observed in (70)but a substantial through-bond interaction is observed in (71); the chemical consequences of such interactions have recently been dis- cussed.28A continued focus of attention in the chemistry of norbornyl derivatives has been the differential reactivity at exo- and endo-sites and the view that such differences are electronic rather than steric in origin.Both 2H and I3Cn.m.r. results show"' the importance of electronic factors [see the relative chemical shifts in (72)]. Further studies of Diels-Alder additions to dienes closely related to (72) show that subtle factors are controlling the preferred face of addition. Huisgen in examining both the abnormally fast reactivity of norbornene in cycloaddition reactions and the preference for reaction at the exo-face coined the phrase 'factor 97 H.-J. Schneider and W. Gschwendtner J. Org. Chem. 1982 47 4216. 9R P. Pasman N.W. Koper and J. W. Verhoeven Red. Trav. Chim. Pays.-Bas 1982 101 363; P. Pasman F. Rob and J. W. Verhoeven J. Am. Chem. SOC., 1982,104,5127. 99 V. Balaji K. D. Jordan P. D. Burrow M. N. Paddon-Row and H. K. Patney J. Am. Chem. SOC. 1982,104,6849. IfloL. A. Paquette and P. Charumilind J. Am. Chem. SOC.,1982 104 3749. Alicyclic Chemistry x’ as the key for the observed phenomena (Annu. Rep. Prog. Chem. Sect. B 1980 77 150). Further explanations of ‘factor x’ have appeared. Extended Huckel calculations”’ indicate that a bending of the double bond in norbornene in an endu-direction (corresponding to the result of an exo-addition) is energetically more favourable than a bending in an exo-direction (corresponding to the result of an endo-addition).This analysis explains the preference for endu-bending by hypercon- jugative effects. A different viewlo2 re-emphasizes the importance of ‘non-equivalent orbital extension’ a factor originating from hybridization changes by ‘orbital tilting’. A third view’03 rejects the importance of factors originating either from ‘non-equivalent orbital extension’ or hyperconjugative interactions. Instead a preference for allylic groups to adopt a staggered conformation with respect to partially formed bonds in the transition state of addition to alkenes.is restated. In addition to norbornene em-attack leads to a relatively staggered arrangement of partially formed bonds with respect to the allylic bonds but endo-attack leads to larger eclipsing interactions.These proposals close to the original Schleyer analysis of torsional strain receive some support from the experimental result that (73) undergoes cycloaddition reactions at comparable rates to norbornene. In the more strained norbornene hyperconjugative effects might have been expected to lead to faster rates. lo’ J. Spanget-Larsen and R. Gleiter Tetrahedron Leff. 1982 23 2435. . lo* S. Ito and A. Kakehi Bull. Chem. SOC.Jpn. 1982 55 1869. N. G. Rondan M. N. Paddon-Row P. Caramella J. Mareda P. H. Mueller and K. N. Houk J. Am. Chem.SOC.,1982,104,4974.

ISSN:0069-3030    

DOI:10.1039/OC9827900171

出版商:RSC    

年代:1982

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10 Aromatic Compounds By H. HEANEY Department of Chemistry Loughborough University of Technology Leicestershire LE113TU 1 General The plenary lectures presented at the fourth international symposium on the chemistry of novel aromatic compounds have been published.' It is now apparent that the transition from bond equalization an accepted criterion for an aromatic structure to bond alternation will be gradual.* In borderline cases the degree of distortion will be small. Substitution by methyl groups does not appear to affect the magnetic anisotropy of the benzene nucleus. Despite some criticism large anisotropies in the molar susceptibilities are stil! used as a test for ar~maticity.~ The possibility of cycloheptatriene-norcaradieneisomerization in the presence of an annelated cyclobutadiene has been investigated as a probe for the anti- aromaticity of the latter sub-unit.The n.m.r. spectroscopic results are in favour of a significant negative resonance en erg^.^ The extent and pattern of .rr-electron delocalization in aromatic (and olefinic) aldehydes have been investigated using lanthanum-induced diamagnetic shifts in 13C n.m.r. ~pectra.~ The free-radical 2,2,6,6-tetramethylpiperidin-l-oxylhas been used as a shift reagent and paramag- netic effects have been reported for a number of arenes.6 The temperature dependence of 'H spin-lattice relaxation times has been used to determine the size of the rotational barriers in methyl-substituted tripty~enes.~ Barriers involving bridgehead methyls are significantly increased by a peri-methyl group.This suggests that a gear effect is probably absent. The ground-state energy in for example l-fluoro-9-(l-naphthyl)fluoreneis higher than in the parent hydro- carbon and results in a lowering of the rotational energy barrier.' Restricted rotation at the 1,8-positions has been observed by differential scanning calorimetry in 1,8-di(1-na~hthyl)naphthalene.~ A series of papers report the results of further investigations on the conforma- tional behaviour of benzo-derivatives of medium-sized ring systems by dynamic ' Pure Appf. Chem. 1982,54,927-1155. R. C. Haddon and K. Raghavachari I. Am. Chem. Soc. 1982,104,3517. M. M. Abdel-Kader. Chem. Phys. Lett. 1982,93,297. F.-G. Klarner E. K.G. Schmidt and M. A. Abdel Rahman Angew.Chem. Int. Ed. Engl.. 1982 21 138; F.-G. Klarner E. K. G. Schmidt M. A. Abdel Rahman and H. Kollmar ibid. p. 139. R. J. Abraham H. A. Bergen D. J. Chadwick and F. Sancassan J. Chem. Soc. Chem. Commun. 1982,998. 'Z. W. Qui D. M. Grant and R. J. Pugmire J. Am. Chem. SOC.,1982,104,2747. F. Imashiro K. Takegoshi T. Terao and A. Saika J. Am. Chem. Soc. 1982 104,2247. E. Ibuki S. Ozasa Y. Fujioka and H. Mizutani Bull. Chem. SOC.Jpn. 1982,55,845. S. Murata T. Mori and M. Oki Chem. Lett. 1982 271. 190 H. Heane y n.m.r. spectroscopy. The compounds reported include meta-disubstituted benzo- derivatives.1° Conformational studies have also been reported for helicenes that contain five-membered rings,’ and for 3,4”-ethano-o- terphenyl. * lb Chiral binaphthyls have been prepared in high enantiomeric excess (87-96%) using the nucleophilic displacement of a methoxy-group activated by an ortho chiral oxazolinyl residue.” The reaction of 2-methoxy-l-naphthyl-magnesiumbromide with (1)gives (2) and hence (3).Asymmetric induction in the synthesis of chiral Ph Me0 ‘1 Me0 (1) (3) R = -CH20H biaryls has also been achieved using a chiral leaving group.An optical yield in excess of 95% was achieved in the reaction between 2-methoxy-l-naphthyl-lithium and l,l-menthoxy-2-(4,4-dimethyl-A2-oxazolino)naphthalene.13 The racemization of 1,l’-binaphthyl on various carbon surfaces could result from a planar adsorbed species. However heterogeneous catalysts such as Raney nickel and platinum are unlikely to present a sufficiently regular surface for that mechanism to operate.Evidence has been pre~ented’~ that the active sites function as electron donors in the racemization process. The crystal structure shows that 2-hydroxyhomotropylium hexachloroantimonate has bond lengths as expected for a homoaromatic cation. The 13C n.m.r. data for the crystalline material using magic-angle spinning and for the compound in solution are very similar and hence it is concluded that it is identical in both states.” Further examples in which stable 7r-carbocations are protonated to afford a di-cation have been studies principally by n.m.r. spectroscopy. The results can be explained on the basis of classical concepts. The non-planar 2,2’,2”,6,6’,6”- hexamethoxytrityl cation is one such example.16 17 0 N.m.r.data for a range of substituted nitrobenzenes allow conclusions to be drawn about the electronic environment of the oxygen atoms in the nitro-gro~ps.~~ lo W. D. Ollis. J. Stephanidou Stephanatou and J. F. Stoddart I. Chem. Soc. Perkin Trans. I 1982 1629; G. B. Guise W. D. Ollis J. A. Peacock J. Stephanidou Stephanatou and J. F. Stoddart ibid. p. 1637; A. Hoorfar W. D. Ollis J. A. Price J. Stephanidou Stephanatou and J. F. Stoddart ibid. p. 1649; S. J. Edge W. D. Ollis J. Stephanidou Stephanatou and J. F. Stoddart ibid. p. 1701; W. D. Ollis J. Stephanidou Stephanatou and J. F. Stoddart ibid. p. 1715; A. Hoorfar W. D. Ollis and J. F. Stoddart ibid. p. 1721; F. E. Elhadi W. D. Ollis and J. F. Stoddart ibid.p. 1727. (a) J. W. Diesveld J. H. Borkent and W. H. Laarhoven Tetrahedron 1982,38 1803; J. H. Borkent J. W. Diesveld and W. H. Laarhoven ibid. p. 1809; (b)M. Wittek and F. Vogtle Chem. Ber. 1982 115,1363. l2 A. I. Meyers and K. A. Lutomski J. Am. Chem. SOC.,1982,104,879. l3 J. M. Wilson and D. J. Cram J. Am. Chem. SOC.,1982,104,881. l4 L. G. Hutchins and R. E. Pincock J. Org. Chem. 1982 47 607. Is R. F. Childs A. Varadarajan C. J. L. Lock R. Faggiani C. A. Fyfe and R. E. Wasylishen J. Am. Chem. SOC.,1982,104,2452. l6 R. J. Smith T. M. Miller and R. M. Pagni J. Org. Chem. 1982 47 4181. ” K. B. Lipkowitz J. Am. Gem. Soc. 1982,104 2647. Aromatic Compounds In contrast to the commonly held view it appears that the nitro-group withdraws a constant amount of electron density from the benzene ring irrespective of whether that ring is electron rich or electron poor.The effect of an electron-releasing substituent in a para-position is better represented by (4) rather than by (5).The precise nature of the participation by a naphthyl residue in solvolyses of for example 2-a-naphthylethyl tosylate has been difficult to establish. Substituted ions for example (6)and (7),have now been generated under stable ion conditions but simple systems still elude identification." (6;R = H) (4) (7;R = Me) 2 Benzene Derivatives Ring Syntheses.-The elaboration of cycloalkanones to give benzoannelated prod- ucts is an increasingly important objective The production of the arene system at a late stage is indicated by the preparation of (8) from (9)." The interaction of allylic Grignard reagents with trialkylsilyl enol ethers derived from p -keto-aldehydes gives products that can be cyclized to benzene derivatives in high yields using p-toluenesulphonic acid.20 This method can be modified to give phenolic products as shown in Scheme 1.21 0 OH Reagents i O,-CuCl-PdCl,; ii MeOH-KOH Scheme 1 l8 G.A. Olah and B. P. Singh J. Am. Chem. SOC.,1982,104,5168. l9 R. W. Thies and S. T. Yue J. Chem. Soc. Chem. Commun. 1982 174. M. A. Tius and S. Ali J. Org. Chem. 1982,47,3163. M. A. Tius A. Thurkanf arid J. W. Truesdell Tetrahedron Lett. 1982 23 2819; 2823. 192 H. Heaney The use of dianions derived from /3-0x0-esters in the synthesis of phenols has been extended to 5-substituted 2-hydro~ybenzoates.~~ A new route to 1,8-dioxy- genated naphthalenes starts with 5,6-dimethyI-2-indan0ne.~~ The controlled ozon- olysis of (10) gives the tetraketone (ll) which cyclizes spontaneously to (12) on silica gel.Regiospecific condensation then affords 1,8-dihydroxy-3-methylnaph-thalene. OH 0 mMe a OMe Me0 (10) (11) (12) Diels-Alder reactions followed by aromatization steps have again provided valuable routes to benzene derivatives. The conjugation of cyclohexa- 1,4-dienes the major products from the Birch reduction of anisoles is best achieved using tris(tripheny1phosphine) chlor~rhodium.~~ Reactions have been reported using various 2-pyrone derivative^.^' Inverse electron-demand Diels-Alder reactions using 1,l -dimethoxyethane and 5,6-substituted 3 -metho~ycarbonyl-2-pyrones~~ have been used in the preparation of juncuso1266 and benzomorphans.26C (lE)-1,3-Dimethoxybuta-l,3-diene has been prepared and used in numerous Diels-Alder reaction^,^' but it appears to be less stable and in many cases less useful (because of the possibility of losing either of the two methoxy groups) than l-methoxy-3- [(trimethylsilyl)oxy]buta-l,3-diene.This latter diene has been used together with 1,4-dichloro-3,3,4-trifluorocyclobutane, in the large-scale synthesis of 4-hydroxy- benzocyclobutendione.28 1,4-Dimethoxybuta-l,3-dienehas also been used in Diels-Alder reactions.29 [Ethyl(diethoxy)phosphinyl]propyonateis a highly reactive and regiospecific dien~phile,~' and useful results have also been obtained using 3-thiolen-2-0ne.~~ The cyclization of two moles of o-bis[(trimethylsilyl)ethynyl]benzene (13) in the presence of catalytic amounts of (q5-cyclopentadienyl)dicarbonyl cobalt affords the biphenylene derivative (14) in 72% yield.32 The remarkable rearrangement of cyclododeca-1,5,9-triyneto hexaradialene has now been shown not to involve the intermediacy of tricyclob~tabenzene.~~ The cyclotrimerization of three acetylenic units to afford a benzene derivative has been calculated to have a high activation energy despite being an allowed concerted process by the conservation of orbital 22 D.H. R. Barton G. Dressaire B. J. Willis A. G. M. Barrett and M. Pfeffer J. Chem. SOC.,Perkin Trans.1 1982,665. 23 G. Bringmann Angew. Chem. Int. Ed. Engl. 1982 21 200. 24 P A. Harland and P. Hodge Synthesis 1982,223. *' H. Meier T. Molz U. Merkle T. Echter and M. Lorch Liebigs Ann. Chem. 1982,914. " (a) D. L. Boger and M. D. Mullican Tetrahedron Lett. 1982 23 4551; (b) ibid. p. 4555; (c) D. L. Boger M. Patel and M. D. Mullican ibid. p. 4559. 27 P. Dowd and W. Weber Tetrahedron Lett. 1982,23,2155; J. Org. Chem. 1982,47,4775. M. S. South and L. S. Liebeskind J. Org. Chem. 1982 47,3815. 29 H. Hiranuma and S. I. Miller J. Org. Chem. 1982,47 5083. 30 R. G. Hall and S. Trippett Tetrahedron Lett. 1982 23 2603. 31 P. Dowd and W. Weber J. Org. Chem. 1982,47,4777. 32 E. R. F. Gesing J. Org. Chem. 1982 47 3192. 33 K. W. Dower and K. P. C.Vollhardt J. Am. Chem. SOC.,1982,104,6878. Aromatic Cornpounds Experimental evidence including '3C-labelling studies has now been obtained involving the pyrolysis of deca-1,5,9-triyne which results in the formation of 1,2-4,5-dicyclobutabenzene. o -Diethynylbenzene is co-cyclized with alkynes and gives biphenylenes in fair to excellent yields.35 MeoY SiMe3 A gas flow reactor system has been described that allows experiments to be carried out to yield approximate rate values for flash vacuum pyrolysis including the preparation of benzocyclobutenes carrying a substituent on the four- membered ring.36b The pyrolytic elimination of methoxytrimethylsilane has been used in the preparation of several cyclobutarenes including the formation of (16) from (15).37 Reactions with E1ectrophiles.-An analysis of a number of reactions suggests that in the absence of large steric constraints the transition state most closely resembles the valence-bond resonance form of lowest energy.With large electrophiles such as bromine steric preference becomes imp~rtant.~' Recent work on the protonation of simple aromatic compounds using superacids has been re~iewed.~' The insertion of carbon monoxide between the ring and a t-alkyl group occurs in superacid media.40 The established4' analogies for solution and gas-phase acidities lead to the suggestion4* that protonated allylbenzene and iso-propylbenzene and the products of the reactions between allyl- and 2-propyl-cations in gas-phase reactions have Wheland intermediate structures.Methylation and allylation are both observed in 34 K. W. Dower and K. P. C. Vollhardt Angew. Chem. Int. Ed. Engi. 1Y82 21,685. " B. C.Berris Y.-H.Lai and K. P. C. Vollhardt J. Chem. SOC. Chem. Commun. 1982 953. 36 (a)P.Schiess S. Rutschmann and V. V. Toan Tetrahedron Lett. 1982 23 2665; (b) ibid. p. 3669. 37 T. A. Engler and H. Schechter Tetrahedron Lett. 1982 23,2715. 38 L. I. Kruse and J. K. Cha J. Chem. Soc. Chem. Commun. 1982,1333. 39 D. Fibcash Acc. Chem. Res. 1982,15,46. 40 D. Flircqiu and R. H. Schlosberg J. Org. Chem. 1982,47 151. J. E. Bartrness J. A. Scott and R. T. McIver J. Am. Chem. SOC.,1979 101 6056; D. K. Bohme A. B. Rakshit and G. I. Mackay ibid. 1982,104 1100. D. L. Miller J. 0.Lay and M. L. Gross,J.Chem. Soc. Chem. Commun. 1982,970. 194 H. Heaney the reaction of the thermal gaseous cyclopropyl(methy1)bromonium ion with ben- ~ene.~~ Acetone cyanhydrin-aluminium chloride is a useful formylating system as an alternative to the Gatterman method since it avoids handling hydrogen cyanide Acid-catalysed reactions of N-acyl- and N-sulphonyl-0-arylhydroxylamines with benzene involve the phenoxenium ion and afford 2- and 4-hydro~ybiphenyls.~’ Intramolecular reaction of the aryloxenium ion gives dibenzofuran in 47% yield when 2-biphenyloxyamine is diazotized with nitrosonium fl~oroborate.~~ The first examples of reactions of a nitrenium ion with aromatic substrates result from the interaction of ethyl azidoformate with trifluoroacetic The nitration of a range of arenes with nitric acid (70%) over a Nafion-H catalyst in the presence of mercury(I1) nitrate gives significant differences in isomer ratios as compared with reactions carried out in the absence of mercury(r1) ions.48 The nitroarenes are formed both by direct nitration and by nitrodemercuration (or nitrosodemercuration-oxidation).Very high positional and substrate selectivity is observed in the nitration of benzene and toluene using nitronium fluorborate in the presence of 21-cr0wn-7.~~ The results indicate that mixing problems are no longer present.Nitrogen kinetic isotope effects have been measured for the benzidine p -semi-dine and diphenyline rearrangement^.'^ The results have been interpreted in terms of a concerted process for the first two and a non-concerted pathway for the latter rearrangement.A hetero-Cope rearrangement has been developed to give 0-aminati~n.’~ The sodium salts of hydroxamic acids such as (17) react with imidoyl chlorides; thus with (18) the o-phenylenediamine derivative (19) was obtained in 75% yield. The principle of obtaining better para-regioselectivity by increasing the size of the electrophile is demonstrated by the reactions of (phenylse1eno)dimethylsul-phonium fluoroborate with electron-rich aromatic Selenation occurs 43 M. Colosimo and R. Bucci J. Chem. SOC.,Chem. Commun. 1982,461. 44 A. Rahm R. Guilhemat and M. Pereyre Synth. Commun. 1982,12,485. 45 Y.Endo K. Shudo and T. Okamoto J. Am. Chem. SOC.,1982,104.6393. 46 R. A. Abramovitch R.Bartnik M. Cooper N. L. Dassanayake H. H.-Y. Hwang M. N. Inbasekaran and G. Rusek J. Org. Chem. 1982,47,4817. 47 H. Takeuchi and K. Koyama J. Chem. SOC.,Chem. Commun. 1982,226. 48 G. A. Olah V. V. Krishnamurthy and S. C. Narang J. Org. Chem. 1982,47,596. 49 B. Masci J. Chem. SOC.,Chem. Commun. 1982,1262. ” H. J. Shine H. Zmuda K. H. Park H. Kwart A. G. Horgan and M. Brechbiel J. Am. Gem. Soc. 1982 104 2501; H. J. Shine H. Zmuda H. Kwart A. G. Horgan and M. Brechbiel ibid. p. 5181. 51 R. Hofelmeier and S. Blechert Angew. Chem. In?.Ed. Engl. 1982,21 370. 52 P. G. Gassman. A. Miura and T. Miura J. Org. Chem. 1982 47,951. Aromatic Compounds 195 para to the electron-releasing substituent and anilines usually give better yields than anisoles or phenols.Trimethylsilyl ~hlorosulphate’~ and bis(trimethylsily1)sul- hate^^ have been used as sulphonating agena. The latter reagent reacts with anisole to afford 4-methoxybenzenesulphonicacid in 78% yield. Phenylthioalkyla- tion of phenols using a-chloroalkylphenyl sulphides and a Lewis acid of which tin (IV) chloride was the most generally reliable shows ortho-selectivity.” The method is complementary to acylation that shows para-selectivity in that the two products can be converted into the alkyl phenols easily. Improved regioselectivity is also a feature of several papers that are concerned with halogenation reactions. The incorporation of a tertiary hydroxyl group in a detergent chain p-to the ionic head group improves the regioselectivity in the chlorination of a phenol by t-alkyl hypo~hlorites.~~ It is argued that a phenol is principally solubilized in micelles close to the head group and therefore any conversion of the p -hydroxy group into the corresponding hypochlorite promotes ortho- chlorination.Regiospecific chlorination of phenol either ortho- or para- can be achieved using 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienoneor 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dienone,re~pectively.~~ N-Phenylbenzo- and N-phenyl-aceto-hydroxamic acids react with thionyl chloride at low temperatures to give o -chloroaniline derivatives in good yield.58 The reactions are presumed to involve intramolecular electrophilic attack. Bromodestannylation has been reported using bromide ion including 82Br and oxidizing agent such as chloroamine-T and hyp~chlorite.’~ Initial charge-transfer interactions between electron-rich aromatic species and hexabromocyclopentadiene may explain the observed regioselectivity in bromination reactions involving that reagent.60 Intramolecular bromine shift to the thermodynamically stable rn -bromophenol occurs in the presence of hexafluoroantimonic acid,6’ and proto- debromination-bromodeprotonation also occurs in the naphthalene series.62 Bromodealkylation has been reported for reactions involving 2,4-dimethylphenol and 4-t-b~ty1-2-methylphenol.~~ A solid-phase exchange between no-carrier-added radioiodide and iodoarenes occurs under mildly acidic oxidizing condition~.~~ The results suggest the involve- ment of electrophilic iododeiodination.Relatively unreactive species such as chlorobenzene are iodinated by iodine in the presence of copper(I1) chloride- aluminium ~hloride.~’ A mild iodinating system has been devised for substrates 53 K. Hoffmann and G. Simchen Liebigs Ann. Chem. 1982,282. 54 M. Voronkov V. K. Roman and E. A. Maletina Synthesis 1982,277. 55 I. Fleming and J. Iqbal Synthesis 1982 937. S. 0.Onyiriuka and C. J. Suckling J. Chem. SOC.,Chem. Commun. 1982,833. ” A. Guy M. Lemaire and J.-P. GuettC Tetrahedron 1982,38 2339. 58 N. R. Ayyangar W. R. Kalkote and P. V. Nikrad Tztrahedron Lett. 1982 23 1099. 59 M. J. Adam T. J. Ruth B. D. Pate and L. D. Hall J. Chem. SOC.,Chern. Commun. 1982,625; R. S. Coleman R. H. Seevers and A. M. Friedman ibid. p. 1276.60 B. Fuchs Y. Belsky E. Tartakovsky J. Zizuashvili and S. Weinman J. Chem. SOC.,Chem. Comrnun. 1982,778. 61 J.-C. Jacquesy and M. P. Jouanntaud Tetrahedron Lett. 1982,23 1673. 62 P. Z. de Croos S. F. Hewitt and F. Scheinmann J. Chem. Res. (S) 1982,s. J. M. Brittain P. B. D. de la Mare P. A. Newman and W. S. Chin J. Chem. SOC.,Perkin Trans. 2 1982,1193. 64 T. J. Mangner J,L. Wu and D. M. Wie!and J. Org. Chem. 1982.47 1487. ” T. Sugita M. Idei Y. Ishibashi and Y. Takegami Chem. Lett. 1982 1481. 196 H. Heane y that are more nucleophilic than iodobenzene. In these cases phenyliodine diacetate and the corresponding bistrifluoroacetate react with halogens and boron and aluminium halides to generate the electrophile.66 Reactionswith Nucleophi1es.-Nucleophilic substitution reactions in decafluoroan- thracene take place mainly or entirely at the 2-position.Although this is in accord with the original interpretation of nucleophile attack on polyfluoroaromatic com- pounds it is not in accord with the more recent I, repulsion theory.67 A new all-embracing theory must now be sought. The replacement of hydride ion by phosphorus-stabilized carbanions in an o-or g-position relative to a nitro-group occurs with several nitro-arenes even those containing an otherwise activated chlorine.68 The displacement of nitro-groups by means of thiolates occurs regio- ~eiectively.~~ Kinetic attack at the 3(3’)-positions occurs prior to the formation of stable 1:1-and 1:2-Meisenheimer complexes with 2,2’,4,4’,6,6’-he~anitrobibenzyl.~~ In the reactions of alkoxides with 2,2’,4,4’,6,6‘-hexanitrostilbene a third type of interaction is observed probably involving attack at the double bond,71 as in (20).The sulphodechlorination of 2,4-dinitrochlorobenzeneaffords 2,4-dinitrobenzenesuI- phonic acid in high yield in the presence of tertiary amine salts. N.m.r. spectroscopy shows that the primary attack of the nucleophile occurs at C-5.72Meisenheimer complexes that carry more than one negative charge associate particularly strongly with sodium ions. The 1:1adduct (21) obtained by the addition of sodium methoxide to 2-methoxy-3,5-dinitrobenzoic acid is an example.73 O,N. NO2 The dediazoniation of (4-diazoniobenzyl)trimethylammoniumdibromide [non- micellar] and (4-diazoniobenzyl)dimethyl-n-hexadecylammonium dibromide [micellar] both proceed uia an aryl cation.74 However the non-micellar reaction gave only the phenol and the micellar the aryl bromide in the concentration range 0.005 s [Br-] s 0.050M.66 J. Gallos and A. Varvoglis J. Chem. Res. (S),1982 150. 67 J. Burdon A. C. Childs I. W. Parsons and J. C. Tatlow J. Chem. Soc. Chem. Commun. 1982 534. 68 M. Makosza and J. Golibski Angew. Chem. Int. Ed. Engf.,1982,21,451. 69 F. Benedetti D. R. Marshall C. J. M. Stirling and J. L. Leng J. Chem. Soc. Chem. Commun. 1982 918. 70 M. R. Crampton P. J. Routledge G. C. Corfield R. M. King and P. Golding J. Chem. Soc. Perkin Trans. 2 1982 31. 71 M. R. Crampton P. J. Routledge and P. Golding J. Chem. Soc.Perkin Trans. 2 1982 1621. ’* J. F. Bunnett M. Gisler and H. Zollinger Helu. Chim. Acra 1982,65 63. 73 A. D. A. Alaruri and M. R. Crampton J. Chem. Res. (S) 1982,60. 74 R. A. Moss F. M. Dix and L. Romsted J. Am. Chem. Soc. 1982,104 5048. Aromatic Compounds 197 Reactions involving Radicals.-The dediazoniation of substituted benzene-diazonium ions is accelerated by @-cyclodextrin. Radicals are formed irrespec- tive of the nature of substituents and even with flu~roborates.~~ The intermediacy of a common radical species is implicated in the Sandmeyer reaction on the basis of competitive bromo- and chloro-dediazoniation reactions in the presence of copper(I1) and a variety of reducing Radical involvement has also been reported for dediazoniation reactions involving nitrite,77 with certain Grignard reagent^,^' and in the presence of biacetyl and redox The activated magnesium that is formed by the reduction of magnesium chloride with potassium in the presence of potassium iodide reacts with (Z)-2-chlorostilbenes to afford phenanthrenes in good yields.80 The reactions are presumed to involve the inter- mediacy of aryl radicals.The oxidation of mandelic acid which forms a stable 1 1 complex with Fe2' in acid solution is oxidized by Fenton's reagent to benzaldehyde and hydroxymandelic acids. Cage reactions of newly formed hydroxyl radicals are important." A radical mechanism has been proposed for the intramolecular acy- loxylation of phenylacetic acid that occurs in the presence of palladium(I1) acetate potassium peroxydisulphate and methane sulphonic acid." Radical anion fragmentations that occur during the course of aromatic SRNl reactions have been reviewed.83 The radical anion pathwayg4 for the substitution reactions of trityl halides with lithium or potassium butoxide in THF has been ~hallenged.'~Addition of the radical anion scavenger m -dinitrobenzene leads to an increase in the total yield of substitution products and a simultaneous decrease in the yields of reduction and dimeric products.SRNl reactions have been initiated by an electrochemical method,86 and increasing evidence is becoming available that suggests a similar mechanism for reactions of nucleophiles with aryl halides in the presence of copper(1) halide^.'^ Synthetic Procedures.-Gas-liquid phase-transfer catalysis has been used for the preparation of aryl ethers and sulphides.'' The reactants are passed in the gas phase through a bed of potassium carbonate (or sodium hydrogen carbonate) containing catalytic amounts of 'Carbowax 6000'.A new method for the preparation of aryl t-alkyl ethers uses nickel(r1) acetylacetonate as a catalyst in a procedure that is much simpler than previous methods.89 7s K. Fukunishi H. Kazurnura H. Yamanaka M. Nornura and S. Kojo J. Chem. SOC., Chem. Commun. 1982,799. 76 G. Galli J. Chem. SOC., Perkin Trans 2 1982 1139. 77 P. R. Singh R. Kurnar and R. K. Khanna Tetrahedron Lett. 1982 23 5191. 78 P. R. Singh R. K. Khanna and B. Jayaraman Tetrahedron Lett. 1982 23 5475. 79 A.Citterio M. Serravalle and E. Vismara Tetrahedron Lett. 1982 23 1831. C. Brown B. J. Sikkel C. F. Carvalho and M. V. Sargent J. Chem. SOC., Perkin Trans. 1,1982,3007. C. Walling and K. Armarnath J. Am. Chem. SOC., 1982,104 1185. T. Fukagawa Y. Fujiwara and H. Taniguchi J. Org. Chem. 1982 47 2491. 83 R. A. Rossi Acc. Chem. Res. 1982 15 164. 84 E. C. Ashby A. B. Goel and R. N. DePriest J. Org. Chem. 1981 46,2429. P. Huszthy K. Lernpert and G. Simig J. Chem. Res. (S) 1982 126. 86 K. Boujlel J. Simonet G. Roussi and R. Beugelmans Tetrahedron Lett. 1982 23 173. 87 S. Sugai H. Ikawa T. Okazaki S. Akaboshi and S. I. Kegami Chem. Lett. 1982,597. E. Angeletti P. Tundo and P. Venturello J. Chem. SOC., Perkin Trans. 1 1982 1137. 89 F. Camps J. Coll and J.M. Moret6 Synthesis 1982 186. 198 H. Heaney The reactions of dialkyl sulphates with the dianions prepared from the xylenes result in the formation of n-dialkylben~enes.’~ The aromatization of 1,l‘-bicyclo- hexenyl and several methyl derivatives can be achieved in high yield by a metalla- tion-elimination sequence.” 33-Dimethylcyclohexanone gives 3,3’,5,5’-tetramethylbiphenyl using an excess of a 1:1mixture of n-butyl-lithium-potassium t-amylate. A 95% yield was obtained in the elimination step. A wide range of carbanionic species including aryl Grignard reagents are converted into the corre- sponding primary amines after reactions with o-(diphenylphosphinyl)hydroxyl-amir~e,’~ and vinyl azides have also been used as aminating agents in reactions with aryl-lithium reagent^.'^ The palladium-catalysed vinylation of organic halides has been re~iewed.’~ The well known arylation reactions of conjugated dienes using haloarenes in the presence of palladium catalysts have been extended to reactions with 1,4-diene~,’~ and allenyl- lithium reagent^.'^ Good yields of acylarenes are obtained when arenediazonium salts are treated with carbon monoxide and a trialkylstannane in the presence of palladium(I1) a~etate.’~ Arenecarboxylic anhydrides are formed when alkyl halides such as 1,2-dibromoethane are allowed to interact with palladium(I1) acetate in the presence of an arene and carbon monoxide.98 The palladium-catalysed cross-coupling of for example phenylzinc chloride with 7-oxabicyclo[3.2.l]oct-2-en-6-onehas been shown to proceed with almost complete inversion of configuration at the participating allylic centre to give in the example quoted (22).” HO,CP CHO Coupling reactions between arylzinc halides and iodoarenes in the presence of a nickel(0) catalyst promised to be a good alternative to mixed Ullmann reactions.The reaction between 3,4-methylenedioxyphenyl-zincchloride and N-cyclohexyl- 2-iodo-3,4,5-trimethoxybenzylideneaminegave the biaryl (23) in high yield after hydrolytic removal of the protective group.1oo 90 R. B. Bates and C. A. Ogle J. Org. Chem. 1982,47 3949. 91 D. Wilhelm T. Clark and P. von R. Schleyer Tetrahedron Lett. 1982 23,4077. 92 E. W. Colvin G. W. Kirby and A. C. Wilson Tetrahedron Lett. 1982,23,3835;G.Boche M.Bernheim and W. Schrott ibid. p. 5399. 93 A. Hassner P. Munger and B. A. Belinka Tetrahedron Lett. 1982 23 699. 94 R. F. Heck Org. React. 1982 27 345. ” D. F. Bender F. G. Stakem and R. F. Heck J. Org. Chem. 1982,47 1278. 96 T. Jeffery-Luong and G. Lhstrumelle Synthesis 1982,738. 97 K. Kikukawa K. Kuno F. Wada and T. Matsuda Chem. Lett. 1982 35. 98 Y. Fujiwara I. Kawata T. Kawauchi and H. Taniguchi J. Chem. SOC.,Chem. Commun. 1982 132. 99 H. Matsushita and E. I. Negishi J. Chem. SOC.,Chem. Commun. 1982 160. loo E. R. Larson and R. A. Raphael J. Chem. Soc. Perkin Trans. 1 1982 521. Aromatic Compounds The remarkable activation of arenes using soluble transition-metal complexes that result effectively in electrophilic metallation has been suggested as involving initial arene co-ordination.lO1 Chemical evidence has now been presented for the intermediacy of an q *-arene complex involving rhodium."* Reviews have appeared on the progress made during the past decade involving the formation of aryl-lithium species that also bear electrophilic groups1o3 and on the direct lithiation of aromatic tertiary amides.lo4 Tertiary amides for example NN-di-isopropylbenzamide gives the o -1ithiated product on treatment with sec- butyl-lithium-TMEDA or n-butyl-lithium-TMEDA at -78 OC,lo5 and reactions with aryl ketones or aldehydes afford lactones that can be elaborated to give polycyclic systems.lo6 The condensation of (0-1ithiozryl)oxazolines with aroylchlorides has been used to prepare various derivatives of o-benzoylbenzoic acid.O7 The anodic oxidation of veratrole in alkaline methanol gives 1,1,2,2-tetra- methoxycyclohexa-3,5-diene,an Umpolung reagent of veratrole. lo' Organolithium reagents react to form the 3- and 4-alkylveratroles. The oxidative removal of the methoxybenzyl group from protected alcohols by means of DDQ has been shown to tolerate a wide range of other functional group^.'^' The reaction proceeds via an oxygen-stabilized benzylic cation that can be captured as dioxolanes or as 1,3-dioxans. The oxyfunctionalization of arylacetones ortho to the side-chain can be achieved using singlet oxygen on the t-butyldimethylsilyl enol ethers."' [3,3]-Sigmatropic rearrangements of silyl ester enolates obtained from allylic dihydroaromatic esters a hydrid Claisen-Birch method followed by oxidative decarboxylation allow regio- and stereo-controlled arylation of allylic groups.The sequence is exemplified in Scheme 2."' LI iv;;** .(J pJ sKg "3i,, CO,H CO,H A ,~i Reagents i Na-NH,-THF-Bu'OH; ii Et,N-MeS0,Cl; iii &OH iv -Me,SiCI;v, 6 \ NaH,PO,; vi Pb(OAc),-Cu(OAc) 2. H,O Scheme2 G. W. Parshall 'Homogeneous Catalysis' Wiley New York 1980. lo' W. D. Jones and F. J. Feher J. Am. Chem. SOC. 1982,104,4240. '03 W. E. Parham and C. K. Bradsher Acc. Chem. Res. 1982,15,301. '04 P. Beak and V. Snieckus Acc. Chem. Res. 1982,15 306. lo' P. Beak and R. A. Brown J. Org. Chem.. 1982,47,34. '06 R. G. Harvey C. Cortez and S. A. Jacobs J. Org. Chem. 1982,47,2120. lo' K. J.Edgar and C. K. Bradsher I. Org. Chem. 1982,47,1585. '08 Y. Kikuchi Y. Hasegawa and M. Matsumato Tetrahedron Lett. 1982,23,2199. '09 Y. Oikawa T. Yoshioka and 0.Yonemitsu Tetrahedron Lett. 1982 23 885; 889. 'lo I. Saito R. Nagata H. Kotsuki and T. Natsuura Tetrahedron Lett. 1982,23 1717. S. Chandrasekaran and J. V. Turner Tetrahedron Lett. 1982 23 3799. 200 H. Heaney A hydroxy-group in spatial proximity to an o-xylene residue results in abnormal effects in Birch reductions."2 The substrates are reduced rapidly to cyclohexenes and protonation occurs at the alkylated positions possibly as a result of intramolecular protonation. 3 Photochemical Processes There is still no general agreement particularly about the relative timing of the three bond-making steps regarding the mechanism of the 1,3-photocycloaddition reactions of alkenes with arenes.'I3 Evidence in favour of exciplex formation involves the detection of long wavelength emission and by measuring identical quenching constants of both exciplex emission and product f~rmation."~ Reactions of ethyl vinyl ether and cyclopentene with 3,5-dimethylanisole also appear to give products from an exciplex.' l5 Mechanisms involved in the 1,2-photocycloaddition of alkenes to arenes have also been reconsidered."6 The triplet-sensitized intramolecular photocycloaddition of 1-ally1 indenes afford benzotricyclo[3.3.0.02~7]octanes;for example (24).'" Irradiation of 9-(2-anilino- ethy1)phenanthrene gives 9-methylene-9,10-dihydrophenanthrene,presumably via the azetane (25).'18 The pentacyclic products obtained by the photodimerization of biphenylene can be converted into derivatives for example (26) that have been given the trivial name buttaflanes.'" 'I2 E.Cotsaris and M. N. Paddon-Row J. Chem. SOC.,Chem. Commun. 1982,1206. 'I3 D. Bryce-Smith G. A. Fenton and A. Gilbert Tetrahedron Lett. 1982,23 2697. '14 J. Mattay J. Runsink H. Leismann and H. D. Scharf Tetrahedron Lett. 1982,23,4919. A. W. H. Jans J. J. van Dijk-Knepper J. Cornelisse and C. Kruk Tetrahedron Lett. 1982,23 1111. 'I6 A. Gilbert.and P.Yianni Tetrahedron Lett. 1982 23,4611. 'I7 A. Padwa S. Goldstein and M. Pulwer J. Org. Chem. 19$2,41 3893. 'I8 A. Sugimoto and S. Yoneda J. Chem. SOC.,Chem. Commun. 1982,376. 'I9 K. Kimura H. Ohno K.Morikawa Y. Tobe and Y. Odaira J. Chem. SOC.,Chem. Commun. 1982 82. Aromatic Compounds 201 The photochemical intramolecular cyclization of the anion (27) solubilized using 18-crown-6 allows the formation of the spirocyclic dienone (28) in good yield.'20 The quantitative conversion of (28) to (29) in ethanol confirms previous suggestions concerning the solvolytic formation of benzofurans from o-methoxyarylvinyl bromides.'21 4 Polycyclic Systems The existence of enantiomeric forms of (30) results from the absence of a centre of symmetry in the non-planar molecule. 12* The properties of benz~[c]octalene'~~ indicate that it exists as an equilibrating mixture of double bond isomers whereas dibenzo[c ;j]o~falene'~~ (31) shows conformational ring inversion.Some bridged quaterphenyls for example 3,3"'-ethano-o -quaterphenyl have been shown to have rather rigid helical rn -Quinomethane has been generated previously in two valence tautomeric forms. Highly exothermic reactions of the bicyclic dienone form with 2-methyl- propene results in the formation of a mixture of phenolic products that are thought to arise from either a six-membered zwitterion or singlet diradical form.126 Semibull-valene has been shown to be very easily reduced by lithium in THF at -78 "Cto afford what might initially be regarded as the homoanti-aromatic dianion (32).12' A key intermediate in the synthesis of 9,lO-Dewar-anthracene is the compound (33). It is formed by the cycloaddition reaction between 3,6-dihydrophthalic anhydride and 3,6-dihydrobenzocyclobutadiene.128 The first example of a monosubstituted benzene derivative functioning as a diene in an intramolecular Diels-Alder reaction results in the formation of (34) in 90% yield.'29 (32) (33) (34) T. Ikeda S. Kobayashi and H. Taniguchi Synthesis 1982 393. ''I T. Ikeda S. Kobayashi and H. Taniguchi Chem. Lett. 1982 391. '*' A. G. Anastassiou and M. Hasan Helv. Chim. Actu 1982,65 2526. lZ3 E. Vogel H.-W. Engels S. Matsumoto and J. Lex Tetrahedron Lett. 1982 23 1797. 124 H.-W. Engels J. Lex and E. Vogel Tetruhedron Lett. 1982,23 1801. ''' M. Wittek and F. Vogtle Chem. Ber. 1982,115 2533. 126 A. R. Matlin T. A. Inglin and J. A. Berson J. Am. Chem. Soc. 1982 104,4954. '" M. J. Goldstein T. T. Wenzel G.Whittaker and S. F. Yates J. Am. Chem. SOC.,1982,104 2669. ''' W. Pritschins and W. Grimme Tetrahedron Lett. 1982 23 1151. lZ9 G. Himbert and L. Hem Angew. Chem. Int. Ed. Engl. 1982,21,620. 202 H. Heaney Thermal rearrangement reactions of aromatic compounds have been re~iewed.'~' Pyrene has been shown to automerize less rapidly than na~hthalene,'~' and homoazulene (35) gives several products including phenylcyclopentadienes which appear to be formed aia the thermal di-wmethane rearrangement to (36).132 The flash vacuum pyrolysis of (37) at 700°C (10-4Torr) gives a mixture of dichl~roazulenes.'~~ The methoxy-Dewar-azulene (38)has been prepared and is converted into (39) smoothly at ca. 1500C.134 The reaction between dimethyl acetylene dicarboxylate and azulene is strongly accelerated by carrying out the reaction at high pressure and involves the formation of the intermediate (40).13' The conversion of a simple azulene derivative into the pentalene system has been achieved using cycloaddition reactions of 1-diethylaminopropyne with 1-azulene-carbonitrile.136 A retro-Diels-Alder reaction is involved in the final step.2-Diazo[2h]indene is unknown. A sterically stabilized derivative has now been p~epared,'~' but it decomposes thermally (20°C) or on exposure to light to give products from the carbene or quinodimethane. Some isoindene-related naphtho- and phenanthro-quinodimethaneshave been generated. 13' The compound (41) is stable. Arylquinodimethanes have been used as the diene components in Diels- Alder lignan Spiro[fluorene-9,3'-indazoles]are formed by 1,3-dipolar cycloadditions of arynes to 9-diazofl~orene~,'~~ They fragment by loss of nitrogen and form 7bH- indeno[ 1,2,3-jk]fluorenes.L. T. Scott Ace. Chem. Res. 1982 15 52. 13' L. T. Scott M. A. Kirms A. Berg and P. E. Hansen Tetrahedron Lett. 1982,23 1859. 13' L.T.Scott and I. Erden J. Am. Chem. SOC.,1982,104 1147. '33 E. V.Dehmlow and M. Slopianska Angew. Chem. Int. Ed. Engl. 1982,21,444. Y. Sugihara T. Sugimura and I. Murata J. Am. Chem. SOC.,1982,104,4295. F.-G. Klarner B.Dogan W. R. Roth and K. Hafner Angew. Chem. Znt. Ed. Engl. 1982 21,708. K. Hafner and M. Goltz Angew. Chem. Inr. Ed. Engl. 1982 21 695. 13' D. W. Jones and A. Pornfret J. Chem. SOC.,Chem. Commun. 1982,919.W.R.Dolbier J.-P. Dulcere S. F. Sellers H. Koroniak B. T. Shatkin and T. L. Clark J. Ore. Chem. 1982.41.2298. J. Mann and S. E. Piper J. Chem. SOC.,Chem. Commun. 1982,430. W.Burgert M. Grosse and D. Rewicki Chem. Ber. 1982,115,309. Aromatic Compounds 203 The protonation or alkylation of stable carbanions is important in synthesis and kinetic versus thermodynamic control can lead to different stereochemistry. The kinetic protonation of the anions formed from methyl 10-methyl-9,lO-dihydro- phenanthrene-9-carboxylate and lO-methyl-9,10-dihydro-phenanthrene-9-carbonitrile in DMSO give CQ. 80% of the trans- isomer. Base-catalysed equilibra- tion gives predominantly the trans-ether and cis- nitrile.14' It was concluded that conformational inversion of 9,lO-dihydrophenanthrenesand their anions is more rapid than either protonation or deprotonation.2,7-Dihydro-2,2,7,7-tetramethylpyrene(42)is stable in solution if light is excluded. However solutions are rapidly bleached in diffuse daylight to afford valence isomers for example (44)and the trans- isomer presumably via the diradical (43).14*Several mono- and di-benzo-annelated dihydropyrenes have been prepared in order to probe the influence of the benzo-ring on the aromaticity of the macrocycle.143 The compound (45) is of particular interest. 'H N.m.r. spectroscopy indicates that the annelating ring causes bond localization in the dihydropyrene ring but only produces a minor perturbation in the ring current. Nitration and Friedel-Craf ts reactions proceed under mild conditions.(41) 5 Annulenes The preparation and reactivity of planar dehydro[8]annulenes has been reviewed.'44 Comparison between calculated bond orders and bond lengths and between calcu- lated and experimental ionization potentials for bridged annulenes has been pre- 14' F. D. Lewis and R. J. DeVoe J. Org. Chem. 1982,47,888. 142 J. Ackermann H. Angliker E. Hasler and J. Wirz Angew. Chem. Int. Ed. Engl. 1982,21 618. 143 R. H. Mitchell R. J. Carruthers L. Mazuch and T. W. Dingle J. Am. Chem. Soc. 1982,104,2544; R. H. Mitchell J. S. H. Yan and T. W. Dingle ibid. p. 2551; R. H. Mitchell R. V. Williams and T. W. Dingle ibid. p. 2560; R. H. Mitchell R. V. Williams R. Mahadevan Y.-H. Lai and T. W. Dingle ibid.. p. 2571.144 N. 2.Huang and F. Sondheimer Ace. Chem. Res. 1982,15,96. 204 H. Heaney sented as evidence in favour of homoconjugative interactions at bridging posi- tion~.~~~ The valence tautomerism between 1,6-methano[ lolannulene and the tricyclic form has been the subject of a theoretical It was predicted that there will be a greater concentration of the tricyclic tautomer than is the case (of the bicyclic tautomer) with the pair cycloheptatriene-norcaradiene. The reaction of 1l-cyano-l,6-methano[ 101annulene with n-butyl-lithium and then phenyl cyan- ate affords the tricyclic compound (46) at low temperatures. In solution at room temperature (46) is readily isomerized to (47).14' The protonation of 1l-methylene-1 ,6-methano[ 101annulene under stable ion conditions indicates that the annulene residue has the greater ~basicity.'~~ The ion (48) is formed exclusively.Protonation of 7,9-dimethyl-3H- benz[c,d]azulene-3- one results in the location of the positive charge being predominantly in the six- and seven-membered rings. The structure is of a benzotropylium ion rather than a bridged azulenium The cycloaddition reaction between benzocyclopropene and the mesoionic 1,3- dithiolone (49) affords the expected adduct which fragments in boiling xylene to afford (5O).l5O 1,6-0xido[10]annulene is isomerized quantitatively to the 1-naphtholate ion by potassium amide in liquid amm~nia.'~' The first metal complexes of the tricyclic form of 1,6-methano[ lolannulene are formed by interaction with -cyclopent adien ylbis(et hane)cobalt.lS2 (49) (50) (51) (52) A new synthesis of the [lOIannulene (52) involves as the key step the intramolecular aldol condensation of the diketone (51).153a Reactions with a range of ele~trophiles~~~' are in accord with expectation the 5-aldehyde is the major 14' W. C. Herndon and C. PhkBnyi Tetrahedron 1982,38,2551. 146 D. Cremer and B. Dick Angew. Chem. Int. Ed. Engl. 1982.21.865. E. Vogel T. Scholl J. Lex and G. Hohlneicher Angew. Chem. Inr. Ed. Engl. 1982 21,869. K. Lammertsma J. Am. Chem. SOC.,1982 104 2070. 149 R. Neidlein W. Kramer and D. Schentzow Helu. Chem. Actu 1982,65 1804. lSo H. Kato and S. Toda I. Chem. SOC.,Chem. Commun. 1982 510. '" A. W. Zwaard and H. Kloosterziel Tetrahedron Lett. 1982,23,4151.lS2 P. Mues R. Benn C. Kruger Y.-H. Tsay E. Vogel and G. Wilke Angew. Chem. Znt. Ed. Engl. 1982,21,868. lS3 (a)Z. Lidert and C. W. Rees J. Chem. SOC.,Chem. Commun. 1982 499; (b) R. McCague C. J. Moody and C. W. Rees ibid. p. 497. 14' 14' Aromatic Compounds 205 product of formylation. The 2-hydroxy-derivative of (52) has also been prepared but unlike phenol the tautomeric equilibrium lies far on the side of the keto- form.”4 6 Cyclophanes The calixarenes are among the small number of ‘cone’ shaped ‘~avitands’~~~ that possess the potential for forming guest-host complexes in which the guest resides in a cavity completely within a single host. A conformationally fixed calix[4]arene (53)with a potentially functionalizable ally1 group has been prepared by a tetra- Claisen rearrangement.lS6 Other calix[4]arenes have also been prepared’” includ- ing a stepwise synthesis of p -phenylcali~[4]arene.’~~ The chemical behaviour of multibridged [2n]cyclophanes has been reviewed.lS9 Their most distinctive property is the ease with which they take part in addition reactions.The cis-trans photoisomerization of azobenzenophanes that can only occur by inversion has been studied.16’ This study is of importance in view of the rotation versus inversion controversy. The tetrahydro-5 -indacenophane (54) has been pre- pared as part of a programme aimed at investigating phanes with non-benzenoid aromatic and anti-aromatic decks.16’ f [2](5,7)Azuleno[2]-para-and -meta-cyclophanes have been prepared in order to investigate the effect of having a seven-membered aromatic ring facing close to a benzene ring.16* A range of a-aryl( 1,n)paracyclophanes have been prepared in order to investigate their stere~chemistry’~~ and the generation and reactions of the related radicals R.McCague C. J. Moody and C. W. Rees J. Chem. SOC.,Chem. Commun. 1982,622. Is’ J. R. Moran S. Karbach and D. J. Cram J. Am. Chem. SOC.,1982,104. 5826. lS6 C. D. Gutsche and J. A. Levine J. Am. Chem. SOC.,1982,104,2652. K. H. No and C. D. Gutsche J. Org. Chem. 1982,47,2713. C. D Gutsche and K. H. No J. Org. Chem. 1982,47. 2708. J. Kleinschroth and H. Hopf Angew. Chem. Int. Ed. Engl. 1982 21,469. 160 H. Rau and E. Luddecke J. Am. Chem. Soc. 1982,104 1616. P.Bickert V. Boekelheide and K. Hafner Angew. Chem.. Int. Ed. Engf. 1982,21 304. Y. Fukazawa M. Sobukawa and S. It& Tetrahedron Lett. 1982 23 2129. 163 H. A. Staab A. Ruland and C. Kuo-Chen Chem. Ber. 1982 115 1755. 206 H. Heaney and carbenium ions. 164 The full paper on triply-fixed triphenylmethyl radicals and carbenium ions has been p~blished.'~' The syntheses of double- and triple-decked cyclophanes have been reported using the selenium analogues166 of the established thiacyclophane route. Silicon- silicon bridged [2.2lcyclophanes have been prepared and characteri~ed'~~ and p -toluenesulphonylmethyl isonitrile has been used under phase-transfer conditions as the carbonyl group equivalent in the preparation of cyclophane-diones. 16' Protodealkylation-realkylationhas been observed with several methyl substituted [2.2]paracyclophanes.The examples include the case of an intramolecular migration from one deck to another.'69 The reaction of phenyl-lithium with the bis(bromomethyl)[2,2]metacyclophane (55) results in the formation of the spirocyclic compound (56).l7' A standard sequence of reactions has been used to convert [2.2]paracyclophane into the reactive species having an eth~n0-bridge.l~~ Trimerization occurs in low yield to give trifoliaphane. The oxidation of [2.2]-and [3.3]-paracyclophanols with benzeneseleninic anhydride result in the formation of cyclophane-o -quinone~.''~ [2]Paracyclo[2](3,7)p -tropoquinonophane (57) has also been reported. 173 Significant charge-transfer interaction is observed and accounts in part for the reduction in the quinone character.(56) Ring enlargement of [2.2]metacyclophane-l 10-dione with diazomethane pro- vides a more convenient entry to the [3.2]-and [3.3]-metacyclophanes than those previously available. 174 Four-fold intermolecular coupling of a tetrathiol with a tetrabromide has been achieved in a single step using caesium carbonate in DMF.I7'" Oxidation to the tetrasulphone and pyrolysis affords a cyclobutabenzene derivative or a cyclophane at different temperature~.'~'~ 164 H. A. Staab C. Kuo-Chen and A. Ruland Chem. Ber. 1982,115 1765. S. Karbach and F. Vogtle Chem. Ber. 1982,115 427. 166 H.Higuchi and S. Misumi Tetrahedron Lett. 1982 23 5571. 167 H.Sakurai Y. Nakadaira A. Hosomi and Y.Eriyana Chem. Lett. 1982 1971. 168 K. Kurosawa M. Suenaga T. Inazu,and T. Yoshino Tetrahedron Lett. 1982,23 5335. 169 J. Kleinschroth S. El-tamany H. Hopf and J. Bruhin Tetrahedron Lett. 1982 23 3345. 170 M. Tashiro and T. Yamata Chem..Lett.,1982 61. 171 M. Psiorz and H. Hopf Angew. Chem. Int. Ed. Engl. 1982,21,623. 17* Y. Miyahara T. Inazu,and T. Yoshino Tetrahedron Lett. 1982 23,2189. A. Kawamata Y. Fukazawa Y. Fujise and S. It& Tetrahedron Lett. 1982 23 1083. D.Krois and H. Lehner J. Chem. SOC.,Perkin Trans. I 1982,477. (a)B. Klieser and F. Vogtle Angew. C'hem. Int. Ed. Engl. 1982,21 618; (b) ibid. p. 928. 17' Aromatic Compounds The smallest member of the [m]metacyclophane series has [m = 51 the next lower homologue exists as the Dewar isomer.The analogue in the tropone series with [m= 41 has been prepared.'76 The high degree of ring strain in [5]metacyclo- phane that results in a reduction in aromaticity is evident from the ease with which Diels-Alder reactions can be carried A new approach to the [6]paracyclo- phane system involves as the key step the conversion of (58) to (59) using McMurry's reagent (TiC1,-LAH 4 :1).178 The conformational switching that occurs between (59a) and (59b) occurs with AG' = 58.16 kJ mol-' at +4 0C.179 Photolysis of (59) yields the prismane derivative (60) in 56% yield.'80 (60) (61) The acylation of the enol ethers of cyclic ketones with malonyl dichloride results in the formation of several bicyclic products including interesting [m](2,4)- phloroglucinophanes.The possibility of tautomerism in the arene residue allows conclusions to be drawn about the structure and reactivity of metacyclophanes. 18' [m](9,1O)Anthracenophanes where [m < 101 have not been characterized. The formation of some 9,lO-anthraquinone has been suggested as evidence for the formation of for example [8](9,lO)anthracenophane after the treatment of (61) with boron trifluoride.'82 17' 17' Y. Fujise T. Shiokawa Y. Mazaki. Y. Fukazawa M. Fujii and S. Ito Tetrahedron Lett. 1982,23,1601. L. A.M. Turkenburg P. M. L. Blok W. H. de Wolf and F. Bickelhaupt Angew. Chem. Int. Ed. Engl. 1982,21 298. 17* J. Liebe C. Wolff and W. Tochtermann Tetrahedron Lett. 1982 23 171. C. Wolff J. Liebe and W. Tochtermann Tetrahedron Lett.1982,23,1143. J. Liebe C. Wolff and W. Tochtermann Tetrahedron Lett. 1982 23 2439. F. Effenberger K.-H.Schonwalder and J. J. Stezowski Angew. Chem. In?.Ed. Engl. 1982,21,871. M.F. Pero C. M. Cotell K. A. Choe and S. M. Rosenfeld Synth. Commun. 1982 12,299.

ISSN:0069-3030    

DOI:10.1039/OC9827900189

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

11 Heterocyclic Compounds By E. H. SMITH Department of Chemistry Imperial College of Science and Technology London SW7 2AY 1 Introduction Two further Specialist Periodical Reports cover the literature of heterocyclic chemistry from July 1979 to June 1981.’ More comprehensive reviews of narrower fields are contained in two volumes of the Advances in Heterocyclic Chemistry series2 and the latest issues of Weissberger and Taylor concentrate on the chemistry of pyrazines3” and q~inolines.~’ A compilation of antibiotics includes one volume devoted to heterocyclic com- pounds4 and a new book on the synthesis reactions and applications of heterocyclic compounds5 is a welcome addition to the undergraduate and research library. 2 Three-membered Rings Predictions that bulky electron-withdrawing substituents would stabilize an (Y -lactone have been vindicated by the formation of the fluorinated example (1)by sodium hypochlorite/acetonitrile epoxidation of ketene (2).6Lactone (1)is stable for several days at room temperature but on heating it decarbonylates to the ketone (3).(1) (2) x = co (4) x = 0 (3) x = 0 (5) x = s Presumably similar electronic and steric effects pertain to the first example of a cyclobutadiene epoxide (Dewar furan) (4) prepared by a necessarily convoluted ‘Heterocyclic Chemistry’ a Specialist Periodical Report ed. H. Suschitzky and 0. Meth-Cohn The Royal Society of Chemistry London 1981 Vol. 2; 1982 Vol. 3. * Adv. Heterocycl. Chem. 1981 29; 1982 30. (a)‘Pyrazines’,G. B. Barlin Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’ Wiley-Interscience New York 1982 Vol.41; (6) ‘Quinolines’ ed. G. Jones ibid. 1982 Vol. 32 Part 2. ‘Handbook of Antibiotic Compounds’ ed. J. Berdy CRC Press Inc. Boca Raton 1981 Vol. 5. G. R. Newkome and W. W. Paudler ‘Contemporary Heterocyclic Chemistry’ Wiley-Interscience New York 1982. P. L. Coe A. Sellars J. C. Tatlow G. Whittaker and H. C. Fielding J. Chem. SOC. Chem. Commun. 1982.362. 210 E. H.Smith route from the corresponding episulphide (5) involving protection of the double bond (Diels-Alder reaction with pyrrole) desulphurization protection of the pro- tecting group (!) epoxidation and two-fold deprotection.' The exalted dienophilic character of both heterocycles (4) and (5) (the furan is some three times more reactive than the thiophene) is ascribed to their partially antiaromatic (cyclo- butanoid) nature.Unlike the thiophene (9,furan (4) does not rearomatize on heating but rearranges to the very stable cyclopropenyl ketone (6). The thiiranoradialene sulphoxide (7) (Annu. Rep. Prog. Chem. Sect. B. 1981 78,235) undergoes cycloaddition with 1,2,4-triazoline-3,5-diones to yield the novel fused thiirene sulphoxides (8).8In view of these rapid quantitative additions it is interesting that a number of other dienophiles do not react with the radialene (7). (7) R = MeorPh (8) (9) (10) (11) 1,3-Dipolar addition of hindered thioketene S-oxides [9:R1 and R2 = But Pr' or -C(Me)2CH2CH2CH2C(Me)2 -1 to 3-dime t hylamino- 2H -azirines provides a high-yielding and simple route to thiiranimines (lo),possibly by way of the bicyclic intermediates (1l).9 The 3-arizinylcyclopropene (12) undergoes thermolysis or photolysis to the pyridine (13) in quantitative yield." A mechanism involving a nitrile ylide and an azabenzvalene is consistent with the results of experiments using an alternative starting material (14) with a different substitution pattern; the heteroatom thus allows a pathway not open to the all-carbon analogue of (12).The potential of 2-cyanoaziridines as precursors of azomethine ylides makes them important intermediates. A new route which has its analogy in the synthesis of 2-cyanoepoxides makes some of these aziridines readily available from a-chloro-ketimines (Scheme 1).The corresponding aldimines do not give cyclized products. An interesting rearrangement of bis-benzylic amine oxides (19,induced by n-butyl- lithium provides the cis-diary1 aziridines (16) albeit in low yields (20-42'/0).'~ D. Wirth and D. M. Lemal J. Am. Chem. Soc. 1982,104 847. W. Ando Y. Hanyu T. Takata and K. Ueno J. Am. Chem. Soc. 1982,104,4981. E. Schaumann H. Nimmesgern and G. Adiwidjaja Angew. Chem. Int. Ed. Engl. 1982,21,694. A. Padwa M. Akiba L. A. Cohen H. L. Gingrich and N. Kamigata J. Am. Chem. Soc. 1982 104 286. N. De Kimpe L. Mdns R. Verhe L. De Buyck N. Schamp J. Chem. Soc. Chem. Commun.,1982 19. H. Takayama and T. Nomoto J. Chem. Soc. Chem. Commun. 1982,408. Heterocyclic Compounds 211 Me Ph A+ \NS Ph Me&h Ph or hv Ph Ph Ph Ph Ph (12) Ph Ph k? N Ph Ph The method finds application in the synthesis of the novel ring system found in (17);the mechanism of the rearrangement remains obscure however.Scheme 1 A simple procedure for the preparation of aziridinones is represented by the conversion of hydroxamic acid (18) into (19) using trifluoromethanesulphonic anhydride and triethylamine at low temperat~re.'~ Unfortunately no other examples of the synthesis of isolable aziridinones by this attractive method were offered. Phase transfer catalysis has considerably improved the classical synthesis " C. M.Bladon and G. W. Kirby J. Chem. SOC.,Chem. Commun. 1982 1402. 212 E. H. Smith of aziridinones from a-haloamides14 and also the epoxidation of sulphonimines to the versatile 2-sulphonyloxaziridines (Annu.Rep.Prog. Chem. Sect. B. 198 1,78 235).l5 The preparation of small rings containing heavier Group IV elements continues to attract attention. Three notable achievements in this area this year are the preparations of the oxasilacyclopropane (20),16 the cyclotrisilane (2 l)," and the cyclotrigermane (22),18 all of which are isolated as crystalline solids. Ar= -Q Ar Ar (21) M = Si (22) M = Ge (20) 3 Four-membered Rings General.-Ketene and chloral undergo a [2 + 21 cycloaddition in the presence of 1-2 mol% quinidine at low temperature to give the p-lactone (23) of S-configuration in high chemical (89%) and optical (98%) yields.lg A promising new approach to functionalized 1,2-dioxetanes involves phase transfer catalysed intramolecular ring opening of /3 -peroxyepoxides." Yields are good and no five-membered ring peroxides are observed (Scheme 2).R4 0-0 "12; cc13 R' R2 (23) Scheme 2 In two full papers Hogeveen discloses some fascinating chemistry of cyclo- butadiene-aluminium halide complexes (24) (prepared by dimerization of alkynes with the Lewis acids) in their reactions with heterocumulenes. Thus reaction with isocyanates*'* and carbodi-irnides2lb provide a non-photochemical route to Dewar- l4 P. Scrimin F. D'Angeli and A. C. Veronese Synthesis 1982 586. l5 F. A. Davis and 0.D. Stringer J. Org. Chem. 1982 47 1774. l6 W. Ando Y. Hamada A. Sekiguchi and K. Ueno Tetrahedron Lett.1982 23 5323. 17 S. Masamune Y. Hanzawa S. Murakami T. Bally and J. F. Blount J. Am. Chem. SOC.,1982,104 1150. S. Masamune Y. Hanzawa and D. J. Williams I. Am. Chem. SOC.,1982 104,6136. l9 H. Wynberg and E. G. J. Staring J. Am. Chem. SOC.,1982 104 166. 2o D. Leclercq J.-P. Bats P. Picard and J. Moulines Synthesis 1982,778. 21 (a) H. Hogeveen and D. M. Kok,J. Org. Chem. 1982,47,997; (b) H. Hogeveen R. F. Kingma and D. M. Kok ibid. 1982 47 1909. HeterocycZic Compounds pyridones and -pyridinimines respectively whereas with isothiocyanates products may result from addition across either C=S or C=N bonds depending on the complex used (Scheme 3).21!' It appears that the Dewar-thiapyrans (25) may be the thermodynamic products of these latter reactions since it is found that the Dewar- pyridthiones (26) rearrange to (25) on treatment with acid.The thermal reactions of adducts (25) and (26) differ from those of the Dewar-pyridones in that no pyridine species are produced in the former ring opening of the heterocyclic portion or formation of thiapyran-2-imines being competitive processes. 1_ R3 R4 Reagents i R'NCO MX = AICl or AI,Br,; ii R'NCNR' MX = AICI,; iii R'NCS MX = AI,Br, < -30°C; iv R'NCS MX = AICI, OOC; v CF,CO,H CH,CI, r.t. Scheme 3 The spectroscopic properties of the magenta liquid obtained by treatment of thionoketone (27) with Lawesson's reagent are closer to those expected for the dithiet (28) than for the dithione (29).22 Flash vacuum thermolysis of the oxadithiolane-2-oxide (30) or of the thiirane sulphoxide (31)is proposed to result in the transient formation of the oxathietane (32) on the basis of the observation of ketene and acetaldehyde amongst the Another new heterocycle of sc (27) X = 0 (29) x = s *' B.Kopke and J. Voss,J. Chem. Res. (S) 1982,314. 23 L. Carlsen and H. Egsgaard J. Chem. SOC.,Perkin Trans. 2 1982 279. 214 E. H. Smith proposed fleeting existence is the tetra-azetidine (33) implicated in the photo- chemical metathesis of the azoxy-azo compound. In contrast under analogous treatment the corresponding bis-azo parent suffers cheleotropic loss of one molecule of N N=N 0-N=N+ hv A Me Me Me (33) 8-Lactams.-Two new potentially general approaches to p -1actams have been formulated.Ganem has shown that halogeno-lactamization instead of the normal halogeno-lactonization in an olefinic amide is possible if the amide nitrogen bears a sulphonyl group.25 Dehalogenation of the relatively unstable intermediate halogeno-lactams gives the monobactam analogues (Scheme 4). Alternatively photochemical reaction (Colorado sunlight) of the chromium carbene complex (34) (easily prepared from chromium hexacarbonyl) with imines gives the 3-methoxy-P -lactams (35)of undefined stereochemistry; the method has been applied to the direct synthesis of penam (36) (81%) from 2-thia~oline.~~ Scheme 4 There has been further interest in the displacement of leaving groups at C-4 of azetidinone by carbon nucleophiles as a preliminary step in carbapenam synthesis; thus allyl~ilanes~~ and cyanide" may serve as the nucleophilic species.Two novel methods which achieve the same end involve stereospecific carbene insertion into the C-S bond of 4-thia-azetidinones (Scheme 5)29and ring closure from a gener- 24 H. Prinzbach G. Fischer G. Rihs G. Sedelmeier E. Heilbronner and Yang Z.-z. Tetrahedron Lett. 1982,23.1251. *' A. J. Biloski R. D. Wood and B. Ganem J. Am. Chem. Soc. 1982,104,3233. 26 M. A. McGuire and L. S. Hegedus J. Am. Chem. SOC., 1982,104,5538. 27 G. A. Kraus and K. Neuenschwander J. Chem. SOC. Chem. Commun. 1982 134; M. Aratani K. Sawada and M. Hashimoto Tetrahedron Lett. 1982,23 3921. 28 K. Hirai Y. Iwano. and K. Fujimoto Tetruhedron Lett. 1982 23,4025.29 (a)K. Prasad. P. Kneussel G. Schulz and P. Stutz Tetrahedron Lett. 1982,23,1247; (b)T. Kametani N. Kanaya T. Mochizuki. and T. Honda Heterocycles 1982 19 1023. Heterocyclic Compounds ated C-4 radical (Scheme 6).30If diazomalonate is replaced by diazoacetoacetate in the first method a potential precursor (37) of oxapenams results.29bNew car-bapenams of note are the highly unstable ketones (38) produced by low temperature Scheme 5 Bu,"SnH AIBN 0 C0,Me C02Me Scheme 6 photolysis of the diazocephalosporin (39) in a reaction assumed to proceed through the undetected sulphines (40).31Stabilization of this ring system may be achieved by conversion of the enones (38)into the saturated ketones or to the allylic acetates.0-/O-R&R3 C0,R2 0 I C0,R2 CO R2 A high yielding desulphurization of the 2-thiacephems (41),prepared either by displacement of a vinylmesylate to give (41;R = Me)32"or (better)by intramolecular trapping in a sulphoxide-sulphenate rearrangement to give (41;R = SAC),^*' results in the formation of the penems (42) (Scheme 7). Desulphurization (at a later stage) also features in the conversion of the oxalimide (43) into penem (44) effected by triethyl ph~sphite;~~ although the method is formally similar to that of the standard Woodward-Wittig route the evidence implicates the carbene (45) in the crucial C-2-C-3 bond-forming step rather than a phosphorane. 30 T. Kametani and T. Honda Heterocycles 1982 19 1861. 31 R.L. Rosati L. V. Kapili P.Morrissey J. Bordner and E. Subramanian J. Am. Chem. SOC.,1982 104,4262 32 (a)A. Henderson G. Johnson K.W. Moore and B. C. Ross J. Chem. SOC.,Chem. Commun. 1982 809; (b)N. J. Daniels G. Johnson B. C. Ross and M. A. Yeomans J. Chem. SOC.,Chem. Commun. 1982 1119. 33 A. Afonso F. Hon J. Weinstein A. K. Ganguly and A. T. McPhail J. Am. Chem. SOC., 1982 104 6138. 216 E. H. Smith -s+s 1 C0,PNB C0,PNB (41) 1iii 0 C0,PNB (42) Reagents i KSAc; ii BF,. EtzO or TsOH; iii PhlP Scheme 7 A different approach to the penem ring derives from a Pummerer rearrangement of the penam sulphoxide (46),although the yield is only moderate (37’/0).~~ 0-$ (CF,CO),O J-J--CO2Me 0fi>co2Me 3 2.6-lutidine ’ 0 C0,PNB C0,PNB The synthesis of carbapenams has been reviewed35 in an issue of the journal Heterocycles which is dedicated to Professor K.Tsuda. A new publication devoted to the chemistry and biology of p-lactams has appeared.36 3* C. U. Kim P. F. Misco and D. M. McGregor J. Org. Chem. 1982,47 170. 35 T.Kametani K. Fukumoto. and M. Ihara Heterocycles 1982 17,463. 36 ’Chemistry and Biology of /3-Lactam Antibiotics’ ed. R. B. Morin and M. Gorman Academic Press New York 1982. Heterocyclic Compounds 217 4 Five-membered Rings Treatment of conjugated keto-ketene dithioacetals (easily prepared see pyridines later) with dimethylsulphonium methylide gives 2,2-bis(methylthio)-2,5-dihy-drofurans in excellent yields; these intermediates serve as useful precursors to furans.The synthesis of perillene (47) illustrates the sequence (Scheme Q3' \ SMe -Me 0 SMe 0 SMe 0 SMe SMe (47) Scheme 8 Reagents i Bu"Li Me,C=CHCH,Br; ii Me,kH,; iii H30'; iv Raney-Ni 3-Metallated-1-methoxyallenes also prove to be ready progenitors of 2,3-38" or 2,5-38bdisubstituted furans. The production of silylated furans by this method represents a useful alternative to metallation-silylation of the parent compounds (Scheme9). In the latter vein precise conditions for favoured p -metallation in the 2-(2'-oxazoliny1)-furan (48) and -pyrrole (49) have been defined by Chadwick's group.39 OH M = AIEt2:R' = SiMe3 Me; R2 = H M = Li R' = H; R2= SiMe3 Scheme 9 Catalysis of cycloadditions to furans using Zn12[4 + 2],40n Cu"'[4 + 2],40b LiCi04/Et3N[4 + 3],40c and Et3N/2,2,2-trifluoroethanol[4 + 3I4Od increaies the potential of these reactions.A new gambit in benzofuran (and indole) synthesis involves homolytic addition- elimination of an aryl radical to an allylic sulphide. Careful control of the 37 R. Okazaki Y. Negishi and N. Inamoto J. Chem. SOC.,Chem. Commun. 1982 1055. 38 (a)M. Ishiguro N. Ikeda and H. Yamamoto Chem. Lett. 1982 1029; (b)P. Pappalardo E. Ehlinger and P. Magnus Tetrahedron Lett. 1982,23,309. 39 D. J. Chadwick M. V. McKnight and R. Ngochindo J. Chem. SOC.,Perkin Trans. 1 1982 1343. 40 (a)F. Brion Tetrahedron Lett. 1982,23 5299; (6) E. Vieira and P. Vogel Helv. Chim. Acta 1982 65 1700; (c) R. Herter and B. Fohlisch Synthesis 1982 976; (d) B. Fohlisch E.Gehrlach and R. Herter Angew. Chem. Int. Ed. Engl. 1982 21,137. 218 E. H. Smith concentration of tin hydride used to generate the radical is required in order to avoid over-redu~tion.~~~ The same strategy provides a convenient route to tetrahy- drofurans although in this case the use of polymer-bound tin hydride is shown to improve yields (Scheme A reaction well known to lead to tetrahydrofurans (49) X = NMe Scheme 10 is that between dipolarophiles and carbonyl ylides the latter usually being generated by ring-opening of epoxides. Now two groups have described the formation of carbonyl ylides from aryl aldehydes and carbenes in the presence of electrophilic (to avoid trapping the carbene) dipolarophiles resulting in a one-pot synthesis of the fully saturated furans (Scheme 1l).42 Et02CI CO,E Et0,C L Et0,C C0,Et Ph HgCBrCI J-* Scheme 11 An interesting new type of reaction formally a cycloaddition results in the formation of butyrolactones by addition of dichloroketene generated ideally from trichloroacetyl chloride and zinc to vinyl ~ulphoxides.~~ A sequence of events illustrated for sulphoxide (50) proceeding through a [3,3] sigmatropic shift and intramolecular trapping of a Pummerer-like intermediate (51) is proposed.The potential of this reaction for the production of a wide variety of furan types is obvious. From a paper in which more fuel is added to the controversy about the mechanism of dihydrofuran formation by copper-catalysed reaction of cy -diazocarbonyl com- pounds with alkenes two conclusions emerge that a mechanism involving non- (51) 41 (a) Y.Ueno K. Chino and M. Okawp-d Tr:m.''edron Lett. 1982,23 2575;(b)Y.Ueno K. Chino. M. Watanabe 0.Moriya arid M. Okawara J. Am. Chem. SOC.,1982 104 5564. (a) R. Huisgen and P. de March J. Am. Chem. SOC.,1982 104 4953; (6)H.S. Gill and J. A. 42 Landgrebe Tetrahedron Lett. 1982,23 5099. 43 J. P.Marino and M. Neisser J. Am. Chem. SOC.,1981,103,7687. Heterocyclic Compounds 219 synchronous but stereospecific addition of a metal carbene to the olefin should be considered as an alternative to earlier proposals (1,3-dipolar addition of a metal a-oxo-carbene complex or formation of a a-ketocyclopropane followed by 1,3- sigmatropic shift of oxygen) and that use of (hexafluoroacetoacetonato)-copper(I1) as catalyst often improves yields (Scheme 12).44 Bu"0 Bu"0 aC0,Et 0 Scheme 12 Photoextrusion of water from 3,6-dihydro- 1,2-0xazines (52) augments existing routes to pyrroles from these heterocycle^;^' sulphilimines (53) act as new sources of pyrroles possibly by way of an electrocyclization-Stevens rearrangement sequence.46 In an alternative cyclization process azabutadiene anions give uniformly good yields (80-90%) of pyrrole-2-carboxylates (Scheme 13).47 R' .CO,Me k An improvement in the classical Piloty-Robinson synthesis of pyrroles from enolizable azines (54) results from prior benzoylation of both nitrogens of the 8 R4&R2 -Ethyl C0,Et /N7J4 R4AR2 AN glycinate N R' PY N R' R4 NH2 HN\ R' R3 C0,Et H (54) Scheme 13 \-1 44 M.E. Alonso A. Morales and A. W. Chitty J. Org. Chem. 1982 47 3747. 45 R. S. Givens D. J. Choo S. N. Merchant R. P. Stitt and B. Matuszewski Tetrahedron Lett. 1982 23,1327. 46 Y. Gaoni Tetrahedron Letf.,1982 23 2051. 47 J. Barluenga V. Rubio and V. Gotor J.Org. Chem. 1982,47 1696; see also S. Mataka K. Takahashi Y.Tsuda and M. Tashiro Synthesis 1982 157. 48 J. E. Baldwin and J. C. Bottaro J. Chem. Sac. Chem. Commun. 1982,624. 220 E. H. Smith Intramolecular aminopalladation previously used to good effect in indole syn- thesis has had to undergo a minor modification of reactant (NH +NHTs) in order to allow formation of the hydrolysis-sensitive 2-pyrrolines (Scheme 14).49 Rare oxidative-addition of an a-iodoamide to a palladium(0) complex appears to be involved in ring closure of (55) to pyrrolidine (56);50the generality of this intriguing method has yet to be established.-NHTs 1 -10 mol’k PdC1,(MeCN)2 Na,CO,. LiCI benzoquinone’ Ts Scheme 14 I Caesium fluoride aids in a trimethylsilyl triflate-catalysed pyrrolidine synthesis believed to proceed through 173-dipolar addition of a silylated iminium ylide (57).51 In contrast to previous cases involving such ylides this method makes available N-unsubstituted pyrrolidines (Scheme 15). The same group of researchers describe de-trimerization-alkylation of 1-pyrroline trimer (58) with trimethylsilylrnethyl triflate followed by desilylation to produce another 1,3-dipole which adds to a,@-unsaturated esters to give pyrrolizidines e.g.(59).52 H N Ph /+v Reagents i Me,SiOTf(20 mol %) CsF(20 mol %) HMPA; ii cis-MeO,CCH=CHCO,Me Scheme 15 (58) (59) 49 L. S. Hegedus and J. M. McKearin J. Am. Chem. SOC.,1982,104,2444. M. Mori I. Oda and Y. Ban Tetrahedron Lett. 1982 23 5315. ” K. Achiwa and M. Sekiya Tetrahedron Lett. 1982,23,2589. ’’ Y. Terao N. Imai K. Achiwa and M. Sekiya Chem. Pharm. Bull. 1982 30 3167. Heterocyclic Compounds Iminium salts particularly acyliminium examples have been utilized extensively in recent syntheses of pyrrolidine natural product precursors. Inter- and intra- molecular addition of allylsilanes to the photoactivated iminium group53 extends the rich chemistry of these salts.The radical equivalent of the above mentioned acyliminium ion cyclizations gives a smaller exo-endo selectivity than anticipated on the basis of simple hexenyl radical closures although with high stere~selectivity.~~" Although cyclization regiochemistry may be controlled in the analogous alkynyl closures by suitable choice of substituent simple reduction pathways to non-cyclized products become competitive in these cases (Scheme 16).546 R3 0 Bu;SnH 1 AIBN R2 R3 R2 R0 + 1aRZ R" 1 .30 ?' (endo) R' = R2 = R3 = H 20 12 R' + R2 = bond,R3 = TMS 0 22 R' + R2 = bond R3 = But 0 35 R' + R2 = bond,R3 = Me 27 61 Scheme 16 Heating l-(pyrrolidin-l-yl)-buta-1,3-dienesresults in a [1,6]-hydrogen shift and subsequent closure to a pyrrolizidine; an illustration of the potential use of the reaction is provided by the synthesis of the mitomycin-C analogue (60).55A more direct approach to this antibiotic class requires the Nenitzescu-like condensation of quinone-acetal (61) with ethyl (pyrrolidin-2-y1idene)acetate (62)followed by 53 Intermolecular K.Ohga and P. S. Mariano J. Am. Chem. Soc. 1982 104 617; intramolecular T. Tiner-Harding J. W. Ullrich F.-T. Chiu S. Chen and P. S. Mariano J. Org. Chem. 1982 47 3360. 54 (a) D. J. Hart and Y. M. Tsai J. Am. Chem. SOC.,1982,104 1430; (b)J. K. Choi D. J. Hart and Y. M.Tsai Tetrahedron Lett. 1982 23,4765. " G. W. Visser W. Verboom P. H. Benders and D. N. Reinhoudt J. Chem. SOC.,Chem. Commun. 1982,669. 222 E.H. Smith (60) acid catalysed rearrangement,56 which procedure overcomes the problems of regiochemistry observed in this reaction using the free quinone (Scheme 17). I Me -I OMeOMe Me0 Me Me0 (61) (62) Reagents i NaH THF ii HCI Scheme 17 The prize of easy synthetic access to ergot alkaloids has made 4-substituted indoles particularly favourite targets this year. Approaches include lithiation of a 2-trimethylsilyl indole chromium(0) tricarbonyl complex protected on nitrogen by the bulky tri-isopropylsilyl group (to prevent removal of C-7-H);57"Birch reduction of indole in the presence of chlorotrimethylsilane which curiously only gives the N,4-bis-silylated indole (after reoxidation) (no N,4,7-tri~-derivative),'~~ and a one-pot classicalsynthesis of 4-hydroxymethyl indole from 2-methyl-3-nitrobenzoic acid.57c Two isolable 2H-isoindoles are the benzo-fused compound (63)58aand the 5-pivaloyl derivative (64);58bin the latter case the acyl group is essential since the corresponding 5-t-butyl-2H-isoindole is unstable.A simple synthesis of 3-amino-or 3-hydroxythiophene-2-carboxylatesderives from reaction of alkyl 2-thiolacetates with alkoxymethylene-cyanoacetates or 56 R. M. Coates and P. A. MacManus J. Org. Chem. 1982,47,4823. 57 (a)G. Nechvatal and D. A. Widdowson J. Chem. SOC.,Chem. Commun. 1982 467; (6) A. G. M. Barrett D. Dauzonne and D. J. Williams J. Chem. SOC.,Chem. Commun. 1982 636; (c) M. Somei and T. Shoda Heterocycles 1982,17,417. 58 (a)R. Kreher and G. Use Heterocycles 1982 19 637; (6)R.Kreher N. Kohl and G. Use Angew. Chem. Int. Ed. Engl. 1982,21 621. Heterocyclic Compounds 223 -malonodinitriles (Scheme 18).59An improvement in the classical Paal-Knorr syn-thesis of thiophenes from 1,4-diketones can be made by substituting Lawesson's reagent for P,S,; yields are in the range 80-98°/~.60 2-Acylation of thiophenes by acid anhydrides is conveniently catalysed by the polyfluorinated sulphonic acid resin Nafion-H.61 IC. OH R~O~C. 5' 'CO,R~ RI" R'gN -* CO,R~ NvH2 R20 CN R' Reagents HSCH2C0,R3 R30H KOAc Scheme 18 Zinc-acetic acid reduction of the tribromothiophene (65) results in a novel side-chain shift from C-3 to C-2;62 a benzylic oxygen is a pre-requisite. A mechanism is proposed which includes the zwitterion (66) or its cyclopropane equivalent as an intermediate.Br R Br R Br 3-Thiolen-2-one (67) acts as a moderately good Diels-Alder dienophile whose endo-selectivity has yet to be determined however.63 The use of cyclopropanes in heterocyclic synthesis has been reviewed briefly.64 A common route to isoxazolidines involves addition of nitrones to olefins. However the use of electron-rich olefins in this reaction suffers from the disadvan- tage that the nitrones often degrade at the temperatures required to induce addition; 59 K. Saito S. Karnbe A. Sakurai and H. Midorikawa Synthesis 1982 1057. 6" D. R. Shridnar M. Jogibhukta P. S. Rao and V. K. Handu Synthesis 1982 1061. '' H. Konishi K. Suetsugu T. Okano and J. Kiji BUN. Chem.SOC.Jpn. 1982,55 957. 62 A. S. Alvarez-Insua S. Conde and C. Corral J. Heterocycl. Chem. 1982 19,713. h3 P. Dowd and W. Weber J. Org. Chem. 1982,41,4777. h4 M. L. Deem Synthesis 1982 701. 224 E. H. Smith in these cases subjecting the reactions to high pressure (up to 4kbar) may be expedient although stereoselectivities may change under these condition^.^^ The application of cyanogen chloride-N- oxide as a nitrone has been severely limited by its apparent unreactivity. A new method of generation from dichloroformal- doxime using silver nitrate instead of aqueous base produces good yields of olefin adducts;66 fortunately removal of a second chlorine atom by silver in the nitrone or in the adduct is slow. 4-Isoxazolines are renowned for their multifarious rearrangements.A new example is provided by the thermal reaction of the benzodiazepino-fused derivative (68),whose X-ray structure suggests good alignment of the 'migrating' bond (X-X) and the weak N-0 link.67 Me C0,Et The use of oxazolines as protecting groups requires acid or base hydrolysis for deprotection. Weinreb has shown that this ring may be cleaved very simply with laundry bleach provided that ethyl acetate is used as the organic co-solvent (Scheme 19).68In a convenient mild procedure which represents an extension of 0 n-NaOCI. 0 "yo BU,N+HSO; phKov/NC1 PhAOnCN EtOAc,H,O Ph u SiO, Scheme 19 recent work on benzimidazoles photolysis of vinyltetrazoles (69) readily generated from 2-tributylstannyltetrazoles and oxiranes followed by dehydration gives mod- erate to good yields of imidazoles (Scheme 20).69 R' R' 1.11 H ... RkJNh4NFY R'PN N+ ,NSnBu3 N R3 R2 (69) Reagents i ; ii Me$(OPh)31-;.iii,hv 2AR3 R Scheme 20 65 C. M. Dicken and P. De Shong J. Org. Chem. 1982,47,2047. 66 P. A. Wade M. K. Pillay and S. M. Singh Tetrahedron Lett. 1982 23 4563. 67 J. P. Freeman D. J. Duchamp C. G. Chidester G. Slomp J. Szmuszkovicz and M. Raban J. Am. Chem. SOC.,1982,104 1380. 68 J. I. Levin and S. M. Weinreb Tetrahedron Lett. 1982 23 2347. 69 M. Casey C. J. Moody and C. W. Rees J. Chem. SOC.,Chem. Commun. 1982,714. Heterocyclic Compounds Base catalysed condensation of methyl isocyanoacetate and nitriles forms the basis of another new imidazole synthesis.The method has been used to prepare the 4,5-functionalized imidazoles (70) and (71) which are useful as precursors of a number of purine n~cleosides.~~ Tosylmethylisocyanide and isothiocyanates react CH(0Etl2 !$CHO (Et0)2CHCN KH N’ aq.AcOH, + C$C02Me 95% C02Me C=&CH2C02Me H H to give either a predominance of imidazoles or of thiazoles depending on the number of equivalents of base ring opening of the dilithio-thiazole (72) followed by rotation and ring closure to the imidazole is assumed to occur (Scheme 21). An improved synthesis of 2-nitroimidazoles (73) requires N-protec- tion (CPh3) of the parent imidazole 2-lithiatioq and nitration with n-propyl nit~ate.’~ Reagents i Bu”Li(1 equiv.) RNCS; ii Bu”Li(1 equiv.) Scheme 21 A novel [4 + 13 cycloaddition of benzyl isocyanide to tetrazines gives the tetra- azabicyclo-derivatives (74) which lose nitrogen and tautomerize to the benzy- lidenamino-pyrazoles (75).73 Hydrolysis gives the corresponding aminopyrazoles.R NnPh N\\3, NyNH RTR NO2 RN NbPh (73) (74) (75) 70 T. Murakami M. Otsuka and M. Ohno TetrahedronLett. 1982,23,4729. 71 S. P. J. M. van Nispen J. H. Bregman D. G. van Engen A. M. van Leusen H. Saikachi T. Kitagawa and H. Sasaki Recl. Trav. Chim. Pays-Bas 1982,101 28. 72 D. P. Davis K. L. Kirk and L. A. Cohen J. Heterocycl. Chem. 1982 19,253. 73 P. Imming R. Mohr E. Miiller W. Overheu and G. Seitz Angew. Chem. Int. Ed. Engl. 1982 21 284. 226 E. H. Smith 3,5-Dihydroxypyrazoles (76) form the starting point for a synthesis of the unusual 4n~-pyrazolo[ 1,2a]pyrazolium betaines (77) by reaction with 1,3-diketones or 1,3-dialdehyde~.~~ The whole ring in these 'para-ionic' diazapentalenes is non- aromatic and there is no conjugation between rings as evidenced by the long C-1-N-8 and C-3-N-4 bonds (1.49 A) determined by X-ray.Polyanion formation in aryl hydrazides (78) leads to good yields of indazol-3(2H)- ones (79) with loss of hydride anion.75 An attempt to extend this interesting reaction to heteroaryl hydrazides led to reduction of the hydrazide to the aldehyde. 0 Alkynyl isothiocyanates bear all the atoms of thiazoles in catenary form and initiation by a nucleophile in the presence of a Lewis acid is all that is needed to induce cyclization (Scheme 22).76 2-Alkylaminothiazoles may be obtained alterna- tively by condensation of an a-thiolatoketone with a cyanamide (Scheme 22).77 I R'XH znci, I 20°C SCN Scheme 22 74 G.Zvilichovsky and M. David J. Org. Chem. 1982,47 295. 75 D. H. R. Barton G. Lukacs and D. Wagle J. Chem. Soc. Chem. Commun. 1982,450. 76 R. L. P. De Jong J. Meijer R. S. Sukhai and L. Brandsma Red. Trau. Chim. Pays-Bas 1982 101 310. 77 M. D. Brown D. W. Gillon G. D. Meakins and G. H. Whitham J. Chem. SOC.,Chem. Commun. 1982,444. Heterocyclic Compounds 227 In another welcome incursion of transition metals into heterocyclic chemistry the carbene complexes (80) are easily made and cleaved to the thiones (81);78 the latter may serve as precursors to electrically conducting fulvalenes.CO,Me Y C0,Me \' I I \SACO,Me tl C0,Me PPh '%,Me The propensity for 1,3,4-0xadiazoles to produce s-triazoles on reaction with amines or hydrazines has now been observed in the production of fused s-triazolo systems e.g. (82) and (83) by intramolecular attack in the oxadiazole (84).79 A common assumption is that thioaroylhydrazines form hydrazones with aldehydes and ketones in a similar fashion to the aroylhydrazines. This assumption is now shown to be false; the sulphur analogues cyclize to A*-1,3,4-thiadiazoles (85) in a new general route to these heterocycles.80 The open-chain isomer (86) could not be detected. Boron trifluoride etherate catalyses the transmutation of ozonides (or a,a'-dihydroxyperoxides) and olefins into 1,2-dioxacyclopentanes (87) and ketones.81 Increasing interest in the organic compounds of tellurium is reflected in the synthesis of two new heterocyclics containing this element the tellurafulvalene (89)82and 78 M.Ngounda H. Le Bozec and P. Dixneuf J. Org. Chem. 1982,47,4000. 79 T. Sasaki E. Ito and I. Shimizu J. Org. Chem. 1982 47 2757. D. M. Evans and D. R. Taylor J. Chem. Soc. Gem. Commun. 1982,188. 81 M. Minra M. Yoshida M. Nojima and S. Kusabayashi J. Chem. SOC.,Chem. Commun. 1982 397. 82 F. Wudl and E. Aharon-Shalom J. Am. Chem. SOC.,1982,104 1154. 228 E. H. Smith the telluradiazole (90).83Both types of compound behave in the main as would be expected by extrapolation from their lower element analogues.Attempted acylation of lithio-trimethylsilyldiazomethane (91)resulted in a for- tuitous synthesis of silylated tetrazoles (92) by further reaction of (91) with the acylated intermediate.84 Me,Si Me,Si )=N + RC0,Me + FN2 Li RCO RCOCH, R2 (93) L’abb6 and Vermeulen have reported the synthesis of the first penta-azapen- talenes (93) from the reaction of thiadiazolimines with aryl diazonium tetrafluoro- borate~.*~ The unusual sulphenyl carboxylate (94) is isolated after thermal extrusion of acetaldehyde from sulphoxide (95) and represents only the third example of its type which is not stabilized by electron withdrawing groups adjacent to sulphur.86 &* \ 0 0 5 Six-membered Rings A continuing major influence in the synthesis of rings containing one heteroatom is the Diels-Alder reaction examples of which will be seen throughout this section.83 V. Bertini F. Lucchesini and A. DeMunno Synthesis 1982,681. 84 T. Aoyama and T. Shioiri Chem. Pharm. Bull. 1982 30,3450. 85 G. L’abbC and G. Vermeulen Bull. SOC.Chim. Belg. 1982,91 97. 86 B. Krische W. Walter and G. Adiwidjaja Chem. Ber. 1982. 115 3842. Heterocyclic Compounds Thioaldehydes are generally unstable and have seen little use in organic synthesis. Vedejs etal. now describe the generation of such species bearing electron withdraw- ing groups which are excellent dienophiless7 and complement the a-0xodithioesters previously used in thiapyran synthesis (Annu. Rep. Progr. Chem. Sect. B. 1980 77 197) (Scheme 23).R3 Z = CN C02RS,COMe or COPh Scheme 23 Sixteen publications testify to the popularity of the Diels-Alder reaction in pyran synthesis. Seven of these come from Danishefsky's group and deal with the Lewis acid catalysed addition of electron-rich dienes to carbonyl compounds (Scheme 24a);ssa** some88c-K of the remainder remind us of the alternative substitu- tion pattern possible by adding electron-poor a,p-unsaturated carbonyl compounds (aldehydes or acyl cyanides) to olefins (usually electron-rich) (Scheme 24b). A modification of this approach uses ketenes as the dien~philes;~~ the diene must bear two alkoxy-groups and the product after thermolysis or hydrolysis of the intermediate (96),is a pyran-4-one. X X = electron donor; Z = electron acceptor Scheme 24 E.Vedejs T. H. Eberlein and D. L. Varie J. Am. Chem. SOC.,1982,104 1445. 'I3 (a) S. Danishefsky E. R. Larson and D. Askin J. Am. Chem. Soc. 1982 104 6457; (b) E. R. Larson and S. Danishefsky ibid. 1982 104 6458; (c) H. K. Hall H. A. A. Rasoul M. Gillard M. Abdelkader P. Nogues and R. C. Sentman Tetrahedron Lett.. 1982 23,603; (d) L.-F. Tietze K.-H. Gliisenkamp K.Harms G. Remberg and G. M. Sheldrick ibid. 1982 23,1147; (e) R. R. Schmidt and M. Maier ibid. 1982 23 1789; (f) D.Dvorak and Z. Arnold ibid. 1982 23,4401; (g) Z.M. Ismail and H. M. R. Hoffmann Angew. Chem. Suppl. 1982 1819. 89 W. T. Brady and M. 0.Agho Synthesis 1982 500. 230 E. H. Smith o -Hydroxy- and o-mercapto-cinnamic acids (97) suitable for ring closure to coumarin~~~~ respectively are obtained in good yields by and thioco~rnarins~~~ ortho-ester Claisen rearrangements.Although subsequent closure to thiocoumarins is only moderate yielding (49-57%) the whole process is an improvement on earlier methods. In a Peterson analogue of an intramolecular Wittig-like process trimethylsilylketene reacts with the sodium salts of u-hydroxyacetophenones to give excellent yields of coumarins (Scheme 25).91 C02Et -I--C(OEt) -+ X = OorS (97) 1. NaH R2 2. Me,SiCH=C=O R~ 0 R2 Scheme 25 The cycloaddition of oxidopyrylium betaines to olefins reported earlier (Annu. Rep. Progr. Chem. Sect. B. 1980 77 196) proceeds in better yields in the intramolecular version e.g. using (98).92 The 4-methoxy-2-pyrone system (99) has been chain extended at C-5 (a rare achievement) by Claisen rearrangement of a 6-hydroxymethyl derivative93 and at C-6 by addition of enolates to a 6-methoxy deri~ative.~~ Both products may be of importance in the synthesis of some naturally occurring 2-pyrones.Consideration of the electronic requirements for the use of aza-1,3-dienes in pyridine synthesis has led to the development of the l-95a species and 2-a~a~’~ [(loo) and (101)respectively] both of which are readily available (Scheme 26). (a) J. A. Panetta and H. Rapoport J. Org. Chem. 1982,47 946; (6) J. A. Panetta and H. Rapoport ibid. 1982 47 2626. ” R. T. Taylor and R. A. Cassell Synthesis 1982,672. 92 P. G. Sammes and L. J. Street J. Chem. SOC.,Chem.Commun. 1982,1056. 93 R. Bacardit M. Moreno-Manas and R. Pleixats J. Heterocycl. Chem. 1982,19 157. 94 J. A. Ray and T. M. Harris Tetrahedron Lett. 1982 23 1971. 95 (a) B. Serckx-Poncin A.-M. Hesbain-Frisque and L. Ghosez Tetrahedron Lett. 1982,23 3261; (b) F. Sainte B. Serckx-Poncin A.-M. Hesbain-Frisque and L. Ghosez J. Am. Chem. SOC. 1982 104 1428. He teroc yc lie Compounds 231 doir t / N 'N I N' NMe2 0 NMe 0 (100) iv v Bu'Me2SioY H "YH N/ Qco2Me OSiMe2Bu' OAc (101) Scheme 26 Problems associated with the cycloaddition of preformed enamines to 1,2,4-triazines to give pyridines are surmounted by allowing the parent ketone and triazine to react in the presence of a catalytic amount of pyrrolidine and 4A molecular The utility of the method is illustrated in a synthesis of a penta-substituted pyridine (102) a potential precursor of the antibiotic ~treptonigrin.~~~ Enamines 1 OMe (102) 96 (a)D.L. Boger J. S. Panek and M. M. Meier J. Org. Chem.. 1982 47 895; (6) D. L. Boger and J. S. Panek I. Org. Chem. 1982 47 3763; see also J. C. Martin preceding paper. 232 E. H.Smith also provide the major part of the pyridine ring in a high yielding thermal condensation with N-methylene-t-b~tylimine;~' the resultant 3,5-disubstituted pyridine is thought to arise by addition of a second molecule of enamine to the l-aza-1,3-diene (103) initially produced. A common route to pyridines involves reaction of ammonia with an 2-ene-1,5- dione. It is therefore welcome to read a full paper detailing a simple procedure for the preparation of (104) from the readily available a-0xoketene dithioacetals (from methyl ketones CS2 NaH and MeI) (Scheme 27).98 The analogous a-oxoketene S,N-acetals may serve as starting materials for pyridones the other half of the molecule being provided by cyanoa~etamides;'~ the method is reputed to be the best for the preparation of 4-amino-2-pyridones (Scheme 27).(104) Reagents i R2COCH3 Bu'OK; ii R4NHCOCH2CN NaOPr' Scheme 27 Regiospecific ips0 -acylation of pyridines quinolines and isoquinolines is observed in the exothermic reaction of the 2-pyridyl- 2-quinolyl- and 1-isoquinolyl-trimethylstannaneswith acyl chlorides. looa The 3-stannylated deriva- tives of each heterocycle are unreactive under these conditions without the addition of catalytic quantities of palladium(I1) salts.Iodination-destannylationin the same two series shows less selectivity.'0ob 97 M. Komatsu H. Ohgishi S. Takamatsu Y. Ohshiro and T. Agawa Angew. Chem. Int. Ed. Engl. 1982,21 213. 98 K.T. Potts M. J. Cipullo P. Ralli and G. Theodiridis J. Org. Chem. 1982 47 3027. 99 V. Aggarwal G. Singh H. Ila and H. Junjappa Synthesis 1982 214. loo (a) Y. Yarnarnoto and A. Yanagi Chem. Pharm. Bull. 1982 30 2003; (b) Y. Yamamoto and A. Yanagi ibid. 1982 30 1731. Heterocyclic Compounds Yet another use for pyridinium salts in organic synthetic methodology has been developed. This year's variation involves intramolecular attack of a photochemically generated acyl nitrene on an N-benzyl C-H bond to yield benzaldehydes after hydrolysis (Scheme 28).lo' Unfortunately a mixture of aldehydes results from the N-phenethyl derivative because insertion into the benzylic C-H is competitive with insertion into the C-H of the pyridinium N-methylene. Ph Ph Ar R = CH2CH2Ph hv LPh Ph Ph minor major Scheme 28 Latest attempts to detect or isolate 2,3- and 3,4-pyridynes at low temperature (12 K) in a N2-matrix were unsuccessful only ring fragmentation products being observed;lo2 the authors were cautiously optimistic however that the arynes had been formed. Beckman rearrangement of cycloalkanone oximes has long been a favourite way of preparing saturated nitrogen heterocycles. Now Yamamoto has shown that alkylalumini~rns'~~" or Grignard reagents'03b may serve the dual purpose of inducing oxime tosylates to rearrange to intermediate nitrilium ions and trapping the latter to give an imine; reduction of the imine which may be carried out in the same vessel completes the sequence.The method has been used in a synthesis of solenopsin A (105) (Scheme 29),lo3' in which the choice of reducing agent proved crucial in securing the necessary trans-product. R = CH3(CHZ)gCH*-Scheme 29 '01 A. R. Katritzky and T. Siddiqui J. Chem. SOC.,Perkin Trans. 1 1982 2953. '02 I. R. Dunkin and J. G. MacDonald Tetrahedron Lett. 1982,23,4839. (a) K. Hattori Y. Matsumura T. Miyazaki. K.Maruoka and H. Yamamoto J. Am. Chem. Soc. 1981,103 7368; (6) K. Hattori K.Maruoka and H.Yamamoto Tetrahedron Lett. 1982 23 3395; (c)Y. Matsumura K. Maruoka and H. Yamamoto ibid. 1982 23 1929. 234 E. H. Smith A new isoquinoline synthesis results from insertion of acrylonitrile or styrene into cyclopalladated imines (106)'04 followed by cyclization induced by heating or mercuric acetate respectively. (106) X = CNorPh Annulation of N-benzyl isoquinolinium salts proceeds through initial attack of a vinylogous Reformatsky reagent and subsequent debenzylation-cyclization (Scheme 30).'05 The same group report a second heterocycle annulation method"' ii-iv 1 OMe Reagents i BrCH,C(OMe)=CHCO,Me Zn MeCN; ii dry HCI; iii H, Pd-C; iv Et,N Scheme 30 through generation of the iminium salt equivalent (107) by anodic oxidation of N,N-dimethylaniline in methanol followed by treatment of aminal (107) with an electron-rich olefin in the presence of titanium tetrachloride.Respectable yields of 4-substituted tetrahydroquinolines are obtained. X Me I Me (107'1 lo' I. R. Girling and D. A. Widdowson Tetrahedron Lett. 1982,23 1957; ibid.,1982 23,4281. lo' T.Shono M. Sasaki. K. Nagami and H. Hamaguchi Tetrahedron Lett. 1982 23 97. lo6 T.Shono Y. Matsumura,K. Inoue H. Ohmizu and S. Kashimura,J. Am.Chem. SOC.,1982,104,5753. Heterocyclic Compounds 235 Lithiation (C-1)of tetrahydroisoquinolines is possible in the formamidine (108) (R = H) chelation being a probable stabilizing factor;lo7subsequent alkylation by benzyl halides allows a potentially convenient synthesis of some medicinally important alkaloids.Unfortunately only one reaction (methylation) of lithiated formamidine (108) (R = OMe) is reported. R = H; 1. Bu'Li N1 3. alkylation R m 2. H,NNH,,AcOH Me0-Q/ OMe The full paper on the preparation and stability of stibabenzene and bismabenzene has made a welcome appearance.lo8 A rational route to the rare 1,2,3,5-tetrazinones (109) is reported."' Thermal decomposition of these compounds results in elimination of nitrogen but the products are not the desired diazetinones but aryl isocyanates and N,N-dimethyl-cyanamide. 0 Glyoxal is an important component of many heterocyclic syntheses but it is difficult to obtain in anhydrous form. A report"' of an improved procedure for making 2,3-dihydroxy-1,4-dioxane(110),a stable equivalent of anydrous glyoxal which generally gives better yields of heterocycles is therefore of interest.Of similar practical significance is the improved preparation of isatoic anhydride (111) from phthalimide,' ' The cyclazine (112) has been the subject of many earlier theoretical calculations and is now available by a more rational route than hitherto;'12 the central nitrogen deviates only slightly (0.015A) from the plane of the periphery. The pyridinium sulphides (113) are remarkably stable to thermal or photochemical conditions and respresent members of a new heterocyclic system.' l3 lo' A. I. Meyers S. Hellring and W. T. Hoeve TetrahedronLett. 1981 22 5115. lo' A. J. Ashe T. R. Diephouse and M.Y. El-Sheikh J. Am. Chem. SOC.,1982,104,5693. 109 A. E. Baydar G. V. Boyd P. F. Lindley and A. Walton J. Chem. SOC.,Chem. Commun. 1982,225. M. C. Venuti Synthesis 1982 61. Y. R. Rao M. Bapuji and S. N. Mahaputra Org. Prep. Proced. Int. 1982 14 199. R. S. Hosmane M. A. Rossman and N. J. Leonard J. Am. Chern.SOC.,1982,104,5497. 'I3 R. A. Abramovitch M. N. Inbasekaran A. L. Miller and J. M. Hanna J. Heterocycl. Chem. 1982 19,509. 236 E. H. Smith Z = CN or NOz (113) An interesting ring contraction occurs on aqueous base treatment of the diacetoxy-pyrimidines (114);'14quinone-methide species (115) are believed to be intermediates on the pathway to the hydantoins (Scheme 31). 0 0 Scheme 31 The full paper on the phase-transfer catalysed synthesis of arene diazocyanides and their use in the preparation of reduced pyridazines has a~peared."~ 6 Seven-membered and Larger Rings 2,7-Di-t-butylthiepin (116) is the simplest member of this ring system to resist facile valence tautomerism to a thianorcaradiene and subsequent aromatization by sulphur extrusion.116 The reason for this is assumed to lie in the greater steric crowding between vicinal t-butyl groups in the norcaradiene isomer providing an energy barrier which can only be overcome at T > 130"C.Two new members of a 1,3-dioxocine series have been the trans-isomer (117) is readily converted into the cis-compound (118) on treatment with iodine. In a subsequent the same author reports evidence for the inter- mediacy of two trans-tetrahydro-oxepins prepared in an analogous way to the 'I4 B.A. Otter I. M. Sasson and R. P. Gagnier J. Org. Chem. 1982 47 508. 'I5 M. F. Ahern A. Leopold J. R. Beadle and G. W. Gokel J. Am. Chem. SOC.,1982,104 548. '16 K.Yamamoto S. Yamazaki Y. Kohashi I. Murata Y. Kai N. Kanehisa K.Miki and N. Kasai Tetrahedron Lett. 1982 23 3195. 'I7 (a)H. Jendralla Chem. Ber. 1982 115 201; (6) H. Jendralla ibid. 1982 115 220. 237 Heterocyclic Compounds -I, 30 "C (-J 0 'h.OMe 0 H OMe 1,3-dioxocine (by generation of a bicyclic cyclopropane carbene and methanol trapping of the cyclic allene resulting from electrocyclization of the carbene). An opportunity to study the chemistry of monocyclic 1,2-diazocines has arisen through the recent preparation of some members (119)of this uncommon class.118 Initial experiments indicate useful transformations into pyridines or benzenes.R -N2 Ph Ph N-N R R = HorCI The 1,5-benzoxazepinium betaine structures (120) have been proposed for the products of reaction of N-benzylidene-2-hydroxyanilines with carbon ~uboxide;"~ further details of this novel heterocycle would be welcome. Protonation of the bicyclic olefinic amine (12 1)occurs preferentially on carbon with rapid participation by the inward pyramidalized nitrogen,lZ0 yet a further example of the intriguing chemistry to be gleaned from a study of these medium ring bicyclic amines. The first molecular Mobius strip has been synthesized by crossed condensation of the two ends of the diol ditosylate (122).'*' S.Yogi K. Hokama and 0.Tsuge Chem. Lett. 1982 1579. L. Bonsignore G. Loy M. Secci and S. Cabiddu Synthesis 1982 945. I 20 R. W. Alder R. J. Arrowsmith C. S. J. Boothby E. Heilbronner and Yang Z-z. J. Chem. SOC. Chem. Commun. 1982,940. D. M. Walba R. M. Richards and R. C. Haltiwanger J. Am. Chem. SOC.,1982,104,3219. 238 E. H. Smith nn 0 0 OTs wu Two books on crown-ether chemistry have been published122 as well as a review on pyridino-phanes -crowns and -cryptands. 123 lZ2 F. De Jong and D. N. Reinhoudt ‘Stability and Reactivity of Crown Ether Complexes’ Academic Press New York 1981; G. W. Gokel and S. H. Korzeniowski ‘Macrocyclic Polyether Synthesis’ (Concepts in Organic Synthesis Vol. 13) Springer-Verlag New York 1982.123 V. K. Majestic and G. R. Newkome Topics Curr. Chern. 1982,106 79.

ISSN:0069-3030    

DOI:10.1039/OC9827900209

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

12 Organometallic Chemistry Part (i) The Transition Elements By M. BOCHMANN and R. A. HEAD ICI New Science Group The Heath Runcorn Cheshire WA7 4QE M. D. JOHNSON Department of Chemistry University College London 20Gordon Street London WClH OAJ 1 Introduction The publication of the new Journal ‘Organometallics’ and of the nine volume ‘Comprehensive Organometallic Chemistry” were major events of 1982. Other books recently published include ‘Organotransition Metal Chemistry Applications to Organic Synthesis’,2 ‘Catalytic Aspects of Metal Phosphine Com~lexes’,~ the first volume of a new series on Inorganic and Organometallic Reaction mechanism^,^ which includes a chapter on the reactions of organochromium(II1) compounds and ‘Me tal-catalysed Oxidations’.’ The text of Hoffman’s Nobel lecture on Building Bridges between Inorganic and Organic Chemistry6 and a broad-ranging survey of Electron Transfer Catalysis7 provide perceptive views of a spectrum of organometallic chemistry whereas two reviews on the Fischer Tropsch Synthesis,8 and reviews on the Co-ordination Chemistry of Acetonitrile,’ the Co-ordination Chemistry of Metal Alkynyl Com- plexes,” Organometallic Intramolecular Co-ordination Compounds having a Cyclo- pentadienyl Donor Ligand l1 Organometallic Intramolecular T-Olefin Co-ordina- tion Compounds l2 and Palladium and Nickel Catalysed Cross Coupling Reac- tion~,~~ provide more specific coverage of earlier work.In addition two reviews by ‘Comprehensive Orgariometallic Chemistry’ ed. E.Abel F. G. A. Stone and G. Wilkinson Pergamon Press 9 vols 1982. ‘Organotransition Metal Chemistry Applications to Organic Synthesis’ S. G. Davies Pergamon Press 1982. ‘Catalytic Aspects of Metal Phosphine Complexes’ ed. E. C. Alyea and D. W. Meck Am. Chem. Soc. Adv. Chem. Ser. 1982,196. J. H. Espenson in ‘Advances in Inorganic and Bioinorganic Reaction Mechanisms’ ed. A. G. Sykes Academic Press 1982,1,2. ‘Metal-Catalysed Oxidation of Organic Compounds’ ed. R. A. Sheldon and J. K. Kochi Academic Press 1981. R. Hoffmann Angew. Chem. Int. Ed. Engl. 1982 21,711. M. Chanon and M. L. Tobe Angew. Chem. Znt. Ed. Engl. 1982,21 1. W. A. Herrman Angew. Chem. Int. Ed. Engl. 1982 21 117; C. K. Rofer-De Poorter Chem. Rev. 1981,81,447. S. J. Bryan P. G.Huggett K. Wade J. A. Daniels and J. R. Jennings Coord. Chem. Rev. 1982,44 149. lo R.Nast Coord. Chem. Rev. 1982,47,89. “ I. Omae Coord. Chem. Rev. 1982 42,31. l2 I. Omae Angew. Chem. Int. Ed. Engl. 1982,21 899. l3 E. Negishi Acc. Chem. Res. 1982 15 240. 240 M. Bochrnann R. A. Head andM. D. Johnson Halpern14 illustrate extended aspects of the topic discussed in the next section of this report and a survey of the use of transition metals in organic ~ynthesis,'~ covers the year 1980. 2 Free-radical Processes An increasing number of organometallic reactions hitherto believed to be heterolyt- ic or concerted are now being shown to proceed at least under some conditions by free-radical pathways. In a key study pertinent to the question of carbon-metal bond homolysis the enthalpies of dissociation of some carbon-cobalt bonds have been determined from equilibrium and kinetic data.l6 For l-phenyl-ethylbis(dimethylglyoximato)pyridinecobalt(III)complexes the enthalpy of dissoci- ation [corresponding to that for equation (3)] deduced from the temperature dependence of the measured equilibrium constant for reaction (l),and from PhCH(CH3)Co(dmgH),L + PhCH=CH2 + $H2 + c~(dmgH)~L (1) PhCH=CH2 + iH2 + PhCHCH3 (2) PhCH(CH3)Co(dmgH)2L + PhCHCH3 + Co(dmgH)*L (3) estimates of the enthalpy change of reaction (2),varies from 76 to 88 W mol-' for L = 4-cyanopyridine and L = 4-aminopyridine respectively.It remains to be seen what influence the solvent may have on these values. The kinetics of decomposition of (1 L = aq) in aqueous acid under non-equilibrium conditions which gives a mixture of styrene and dimers of the 1-phenylethyl radical suggest that both products are formed as a result of the homolysis shown in equation (3); in the latter case followed by free-radical dimerization in the former by abstraction of a hydrogen atom from the 2-carbon of the organic radical by the paramagnetic metal complex [equation (4);R' = Ph R2 = H M = C~(dmgH)~aq].'~ The thermo- chemistry of equation (4)is such that its endothermic reverse path may be a R'R2CCH3 + M + R'R2C=CH2 + MH (4) key step in the reaction of metal hydrides with olefins.Thus a strong CIDNP effect observed in the proton n.m.r. spectrum of the 1,l-diphenylethane formed on reduction of 1,l-diphenylethene with HCO(CO)~ has been ascribed to non-equili- brium spin states generated as a result of sequential hydrogen-atom transfers from the metal hydride to the olefin and to the 1,l-diphenylethyl radical.18 Similarly a kinetic analysis of the reaction of HMn(C0)4P(OMe)3 with PhCH,Mn(CO),P(OMe) coupled with earlier data has been interpreted in terms of homolysis of the carbon-metal bond followed by a hydrogen-atom transfer from the metal hydride to a benzyl radical." l4 J.Halpern Acc. Chem. Res. 1982,15 238; 332. L. S. Hegedus J. Organomet. Chem. 1982 237,231. 16 F. T. T. Ng G. L. Rempel and J. Halpern J. Am. Chem. Soc. 1982,104,621; M. J. Nappa R. Santi S. P. Diefenbach and J. Halpern ibid. 619. H. B. Gjerde and J. H. Espenson Organometallics 1982,1 435.T. E. Nalesnik and M. Orchin Organometallics 1982,1 222; c.f. J. Organomet. Chem. 1981 222 25. l9 T.-T. Tsou M. Loots and J. Halpern J. Am. Chem. SOC., 1982,104 623. Organometallic Chemistry -Part (i) The Transition Elements 241 The first kinetic study of the attack of an organic radical on saturated carbon in solution has been made. The radical Me2COH formed by the unimolecular homolysis of the complex (2) undergoes a bimolecular attack at the a-benzylic carbon of benzylbis(dimethylglyoximato)aquocobalt(rII)in aqueous acid to give the compound Me2C(OH)Cr(H20)52' $ Me2COH + CI-(H~O)~~' (5) (2) Me2COH + PhCH2Co(dmgH)2L $ Me2C(OH)CH2Ph+ Co(dmgH)zL (6) (3) (4) (3)and the bis(dimethylglyoximato)aquocobalt(II)complex (4),with rate coefficients of 7 x lo6and 1.9 x lo7dm3 mol-' s-l respectively.20 Bimolecular rate coefficients for the abstraction of a halogen atom from some polyhalogenomethanes by Re(CO), Mn(CO)5 and c~(dmgH)~L have also been determined [equation (7)].21*22 The formation of trichloromethyl radicals by equation (7) [M = C~(dmgH)~py] in the presence of hex-5-enylbis(dimethylglyoximato)pyridinecobalt(111)leads ci3cx+ M + CI~C + MX (7) as part of a sequence of chain-propagating steps to the radical (5) [M = C~(dmgH)~py] which undergoes an intramolecular homolytic displacement at the saturated a-carbon with the formation of trichloroethylcyclopentane; the first example of a homolytic attack of a remote organic radical on the a-carbon of an alkyl chain.23 -M CI3C Scheme 1 Cobaloxime(I1) complexes have also been used as catalysts in the reaction of halogenoethyl ethers of the type (6) with borohydride ion in methan01.~~ Electron transfer from a regenerable cobaloxime(1) species to the organic halide allows the formation of the radical (7) which after cyclization abstracts a hydrogen atom from the reagent to give a 3-methyleneoxolane.Oxidation with Cr03 then provides a route to a-methylene-y- butyrolactones. Free-radical reactions frequently occur as a consequence of one- and two-electron oxidations. Thus though the iron(I1) complex R2FeL2 (R = Me Et Pr" Bun,etc.) undergoes thermal decomposition by a p-elimination path leading to alkane and 'O R. C. McHatton J. H. Espenson and A.Bakac J. Am. Chem. Soc. 1982,104,3531. W. K. Meckstroth. R. T. Walters W. L. Waltz A. Wojcicki and L. M. Dorfman 1.Am. Chem. Soc. 1982,104 1802. '' J. H. Espenson and M. S. McDowell Organometallics 1982 1 1514. 23 P. Bougeard A. Bury C. J. Cooksey M. D. Johnson J. M. Hungerford and G. M. Lampman J. Am. Chem. Soc. 1982,104,5230. 24 M. Okabe M. Abe and M. Tada J. Org. Chem. 1982,47 1775. M. Bochmann R. A. Head andM. D. Johnson Scheme 2 alkene the corresponding iron(II1) complex reversibly formed by electrochemical oxidation undergoes homolysis of the carbon-iron bond (Scheme 3). The corre- sponding iron(1v) complex formed also by chemical oxidation with Fe(phen),,' undergoes a very rapid yet efficient apparently electrocyclic coupling of the two alkyl ligands.For example the tetramethyleneiron(1v) complex [R = (CH,)J decomposes rapidly to give a high yield of cyclobutane whereas the corresponding tetramethylene diradical would have given mostly ethene .25 Alkyl radicals formed in such processes are also capable of attacking other ligands such as the phenanthro- line ligand in Fe(~hen),~+ site-specifically.26 [R2FeL2] A R(-H) + [RFe(H)L,] + RH + [FeL,] 1-e-[R2FeL2]+ -R + [RFeL2]+ 1-e-[R2FeL2I2+ -R2 + [FeL2I2+ Scheme 3 Another process that proceeds by a one-electron oxidation is apparent hydride transfer from an a-carbon of an alkylmetal c~mplex.~' For example the formation of the hydridoethene complex (1 1) in the reaction of the dimethyltungsten complex (8) with the trityl cation takes place uia a one-electron transfer to give the tungsten(v) complex (9) which has been characterized at -78 "C,and thence via the carbene complex (10).That the oxidative path favours a-hydrogen abstraction is evident from several related reactions including the fact that the corresponding complex with R = Et does not undergo hydrogen abstraction from the ethyl Iigand but from the methyl ligand with the formation of the hydridopropene complex (12). Electron-transfer processes probably account for the formation of free radicals in the reactions between 2-benzophenonezirconocene with alkyl halides.28 Thus 25 W. Lau J. C. Hoffman and J. K. Kochi Organomefaflics,1982,1 155. 26. K. L. Rollick and J. K. Kochi J. Org. Chem. 1982 47,435.27 J. C. Hayes and N. J. Cooper J. Am. Chem. SOC. 1982,104,5570. 28 G. Erker and F. Rosenfeldt J. Organornet. Chern. 1982 224 29; Tetrahedron 1982 38 1285. Organometallic Chemistry -part (i) The Transition Elements Scheme 4 in the reaction with 2-bromo-2-methylhept-6-ene(13) the cyclic product (14) is formed in 75% yield indicative of the formation of the 2-methylhept-6-en-2-yl radical as an intermediate (Scheme 5). Me Me Cp2Zrqph + LMe + Br Ph M2' + (13) Br (14) 75% Scheme 5 3 Oxidation The oxidation of 1-alkenyl ethers and amines to their corresponding a-ketoesters and amides (15) is achieved in good isolated yields using iodosylbenzene and a ruthenium compound such as RuC~~(PP~~)~ as ~atalyst.~' Reaction (8) proceeds very,smoothly at 25 "C where no further oxidation of the product is found.Using the same catalyst and molecular oxygen (1atm. 25 "C) 3,5-di-t-butylcatechol is converted to a mixture of the muconic acid anhydride (16)and the 2H-pyran-2-one 0 C" x C,HSIO (15)(X= OR',NR'z) (8) R-c-C-x RuCI,(Ph,P) 'R / \c/II 0 29 P. Muller and J. Godoy Tetrahedron Lett. 1982 23 366. M. Bochmann R. A. Head and M. D. Johnson (17) as shown in Scheme 6.30Experiments using 1802 have confirmed that in both (16) and (17) it is only the exocyclic oxygen that is derived from molecular oxygen. 26% 0 -'Ru' 02 OH Scheme 6 A key step in the total synthesis of 14a-methyl-19-nortesterone (20) is the stereoselective epoxidation of (18) to (19).By conventional techniques only poor yields of the required stereoisomer are obtained but this problem has now been overcome by the use of the Sharpless reagent Mo(CO)~-BU'O~H.~~ At 80 "C (19) is produced in ca. 80% selectivity with near-quantitative conversion of (18) (Scheme 7). H H & & Me Mo(CO), Bu'O~H \ Me0 \ Me0 Me Me Reagents i BF,-Et,O 0-5 "C; ii Na-Pr'OH 100 "C; iii Li-NH, -60 "C;iv 1N-HCl 60 "C Scheme 7 3" M. Matsumoto and K. Kuroda J. Am. Chem. SOC.,1982,104 1433. 31 M. B. Groen and F. J. Zeelen Tetrahedron Lett. 1982 23,3611. Organometallic Chemistry -Part (i) The Transition Elements 245 Regioselective control over the oxidation of internal alkenes is highly desirable but difficult to achieve.It has now been found that palladium-catalysed oxidation of ally1 and homoallyl ethers or acetates gives predominantly p-alkoxy [reaction (9)] and -acetoxy ketones [reaction (lo)] re~pectively.~~ Palladium is introduced as PdCl with either CuCl or p-benzoquinone and high yields of these synthetically valuable products are obtained under very mild conditions (50 "C,1atm. 02). 4 Carbonylation Palladium-catalysed ring closure in the presence of CO has found an interesting application in the conversion of (21) into the anthramycin precursor The reaction (Scheme 8) proceeds under mild conditions (5 atm. CO 110 "C) with 27% isolated yield. R2> R2 Me&A P~(OAC)~-P~~P+ CO-Bun3N -, ._* CI Br N H OR' OR' 0 Anthramycin Scheme 8 A range of aromatic acid anhydrides can be prepared using a one-step synthesis directly from the aromatic compound with CO [reaction (ll)].34 Not only do the benzenoid aromatics C6H5X (X =H Me OMe C1) and naphthalene undergo the 32 J.Tsuji H. Nagashima and K. Hori Tetrahedron Lett. 1982 23 2679; H. Nagashima K. Sakai and J. Tsuji Chem. Lett. 1982 859. 33 M. Ishikura M. Mori M. Terashima and Y. Ban J. Chem. SOC.,Chem. Commun. 1982 741. 34 Y. Fujiwara I. Kawata T. Kawauchi and H. Taniguchi J. Chem. SOC.,Chem. Commun. 1982 132. 246 M. Bochmann R. A. Head and M. D. Johnson reaction but also furan and thiophene where carbonylation occurs at the @-position regioselectively to give @-furan (58%) and p-thiophene (35%) carboxylic acid anhydrides respectively.Dibromoethane is an important ingredient in the reaction although its exact function is uncertain. 00 ArH + co Pd(OAc),-BrCH,CH,Br ii II C0(15atm.) loooc b Ar-C-0-C-Ar (3246%) (11) Regular copolymers of ethylene or norbornadiene and CO are obtained under remarkably mild conditions (e.g. 350 p.s.i. CO 350 p.s.i. C2H4 25 "C) with [Pd(MeCN),][BF412.nPPh3(n = 1-3) as catalyst [equation The ethylene- CO polymer is highly crystalline (m.p. 260 "C) whereas the NBD-CO material has a molecular weight of 3380 (by osmometry). Reactions introducing one CO into an organic molecule are well known while in contrast double carbonylation is extremely rare. It is now found that tetraethyloxamide is obtained in 82% yield by carbonylation (1atm.) of (Et2NH)2NiBr2 at 20 0C.36 Carbonylation of trans-PdR(X) (PMe2Ph) (R = Me 00 0 II II II b R-C-C-NR'2 + R-C-NR'2 truns-PdR(X)(PMe2Ph)2+ R'2NH + CO l~~oo~tm.R'2NH =Et2NH,piperidine or morpholine (23) (13) X = I; R = Ph X = Br) also affords a-ketoamides (23) as the major product under similar conditions [reaction (13)].37 The latter reaction has been extended to the conversion of organic halides directly into a-ketoamides in >90% selec-ti~ity.~~ A range of metal complexes have been examined as catalysts but only with palladium is the double carbonylation observed [reaction (14)]. 00 II II RX + 2CO + 2R12NH CO(10 atm.) R-C-C-NR'z + R12NH2X (14) loo"c RX = PhBr PhI 3-bromopyridine or 2-bromothiophene 5 Miscellaneous Palladium Chemistry Aryl and vinyl phosphonates are obtained in good to excellent yield from the reaction of aryl or vinyl halides with 0,O-dialkylphosphonates in the presence of Pd(Ph,P) as catalyst [reaction (15)].39 1-Bromonaphthalene and 3-bromopyridine 35 A.Sen and T. Lai J. Am. Chem. SOC.,1982,104 3520; T. Kobayashi and M. Tanaka J. Organomet. Chem. 1982,231 C12. 36 H. Hoberg and H. J. Riegel J. Organomet. Chem. 1982,236 C53. 37 F. Ozawa and A. Yamamoto Chem. Lett. 1982,865. 38 F. Ozawa H. Soyama T. Yamamoto and A. Yamamoto Tetrahedron Lett. 1982,23,3383. 39 T. Hirao T. Masunaga T. Yamada Y. Ohshiro and T. Agawa Bull. Chem. SOC.Jpn. 1982 55 909. Organometallic Chemistry -Part (i) The Transition Elements also give the corresponding phosphonates in high yield.The reaction with vinyl bromides proceeds with retention of stereochemistry thus (E)-P-bromostyrene gives (E)-styrylphosphonate [reaction (16)]. 0 0 I1 II ArX + HP(0R)Z Pd(Ph,P),-Et,N 90 "C P ArP(OR) + Et3NHX (15) 0 (93%) Arylation of simple activated alkenes by benzoyl chloride occurs in the presence of a catalytic amount of Pd(OAc) and N-benzyldimethylamine as base [reaction ( 17)].40High stereochemical control is achieved with virtually exclusive formation PhCOCl + CH2=CHX Pd(OAc) PhCH=CHX + CO + HCI (17) base 130"c b (X = CO,Et CONMe, CN or Ph) of the (E)-isomer. Disubstituted alkenes react more slowly and a small amount of isomerization also takes place during the reaction. Functionalized vinylcyclopropanes exhibit both interesting antibiotic and insecti- cidal activities as well as having high potential as intermediates in organic synthesis.Vinyl cyclopropane carboxylates are readily prepared in a high yield synthesis by simple Pd(diphos),-catalysed cyclization of 6-acetoxy-4-heptenoates (24) as shown in equation (18).41Other Pd phosphine complexes are ineffective for the reaction which gives the (E)-isomer preferentially [(E):(2)= 7 13. Me i. NaH-DME ii Pd(diphos), 40°C ' MeC0 + (18) (24) PdCl,(MeCN) catalyses the 1,3-alkyl migration of 1-alkenyl ethyl acetals (25) to give a-alkylated (E)-a,@-unsaturated carbonyl compounds (26) in excellent yield [reaction (19)].42 After short reaction times (0.5-1 h) quantitative formation of the a-alkyl-P- ethoxy carbonyl compound is achieved which eliminates ethanol on further reaction to give (26).40 A. Spencer J. Organomet. Chem. 1982,240,209; H. U. Blaser and A. Spencer I. Organomet. Chem. 1982 233,267. J.-P. Genet M. Balabane and F. Charbonnier Tetrahedron Lett. 1982,23 5027. 42 M. Takahashi N. Ishii H. Suzuki Y. Moro-oka and T. Ikawa Chem. Lett. 1981 1361. M. Bochmann R. A. Head and M. D. Johnson 0 EtOzOKr3 0.5-1 h+ EtO k'\RJ] -R1+R2 (19) R' (26) R' *= Me Et Pr" (25) R2 = H Me Et Pr" R3 = Me Et 6 Reduction The chemoselective reduction of C=C double bonds in a,& unsaturated carbonyl compounds can be achieved under very mild conditions using Bun3SnH with Pd(Ph,P) as catalyst and water as proton Most functional groups are tolerated; however the reaction is very sensitive to electronic influences [reaction (20)].Nearly quantitative yields are obtained if R = H C1 or NO2 but no reaction occurs if R = NMe2. The value of the method has been further demonstrated by the reduction of citral p-ionone and withanolide D. In all cases only reaction of the double bond conjugated to an aldehyde or keto function was observed. The evidence suggests that radicals do not play a part in these reactions. Zinc chloride or acetic acid are strong promoters presumably by activating the carbonyl function towards nucleophilic attack.44 Bis(q5-cyclopentadieny1)titaniumdichloride (3 molo/o) catalyses the reduction by Grignard reagents of alkyl and aryl carboxylic acids to the corresponding aldehydes.The reaction proceeds at room temperature in fair to good yields whereas no aldehydes were obtained from a,@-unsaturated carboxylic acids. Scheme 9 outlines the suggested mechanism.45 Cp2TiC12 + 2Pr'-CH2MgBr 1 R-C-H II0 OMgBrI IH + Hzo RCOMgBr Cp2Ti-CH2Pr' H2C=CMe2 RCOOMgBr PriCH2MgBr H Scheme 9 43 E. Keinan and P. A. Gleize Tetrahedron Lett. 1982 23.411. 44 P. Four and F.Guibk Tetrahedron Lett. 1982,23 1825. F. Sato T. Jinbo and M. Sato Synthesis 1981 871. Organornetallic Chemistry -Part (i) The Transition Elements Low-valent titanium reagents prepared from TiC1 and magnesium powder in CH2C12-Et20 (4 l) provide a generally applicable method for the high yield synthesis of disubstituted hydrazines from nitrosamines [reaction (2 l)].The success R2N.NO -+ R2NNH2 (21) of the reaction depends critically on the oxidation state of the Ti best results being obtained if the reagent is formally Ti".46 Reductions with TiC14-LiA1H4 lead to N-N bond cleavage to give amines.For the reductive formation of C-C bonds however different combinations of metal halides and reducing agents are required. In the deoxygenative dimerization of benzaldehyde to stilbene for example NbC1,-NaA1H4 (2 :1)is far superior to NbC1,-LiAlH4 and NbCl,-Mg is unrea~tive.~~ The coupling reaction is applicable to aromatic aldehydes and ketones (to give stilbene derivatives) and to benzyl and ally1 alcohols (Scheme 10). The latter may give rise to various dimerization isomers.47 NbCI,-NaA1H4 eoH 80"C,2h ' Scheme 10 A mixture of TiC13 and LiAlH (2 1)reacts with 2-ene-1,4-diols and 2-yne-1,4- diols to yield 1,3-dienes.The ene-diols may carry aromatic and linear or cyclic aliphatic substituents. Methyl ethers may be used in diols (Scheme 1l).48 RZC-CH=CH-CR2 RzC=CH-CH=CR;? I I OH OH 1 Me Me P~~C-CGC-CP~~ 1Ph2C=C=C=CPhz I I OH OH Scheme 11 46 I. D. Entwistle R. A. W. Johnstone and A. H. Wilby Tehahedron 1982,38,419. 47 M. Sat0 and K. Oshima Chem. Lett. 1981 157. 48 H. M. Walborsky and H. H. Wust J. Am. Chem. SOC.,1982,104,5807. 250 M. Bochmann R. A. Head and M. D. Johnson 7 Grignard Analogues There has been increasing interest in recent years in the use of transition-metal alkyl complexes for alkylation reactions since they exhibit greater selectivity than their lithium magnesium or zinc analogues.For example addition of tetramethyl-titanium monoalkyltitanium alkoxides or their Zr analogues to 2-phenylpropanol gives an erythro :threo ratio of 93 :7; Li or Mg alkyls only 2 :1.Alkylation of benzil with MeTi(OBu') or TiMe gives (27) and (28) with an erythro :threo ratio of 2 :98. Zirconium lithium and magnesium alkyls however show the reverse asymmetric induction (erythro:threo -80:20). Titanium alkyls react with (29) to give (31) exclusively presumably via the chelate (30) (Scheme 12). The reactivity of the Ti reagents decreases in the order ally1 > methyl > n-butyl. Sterically highly hin- dered compounds that no longer react with LiMe can still be alkylated with ZrMe4.49 thrm erythro 7:93 ph Me OH Ph Me OH 'C-c! + 'C-C./ ' I"Me HO/ I "Ph Ph Ph Ho Ph Me (27) (28) TiMe, MeTi(OPr')3 98 :2 MeZr(OPr")319:81 1 .. Ph (29) Scheme 12 Titanated hydrazones of aldehydes and ketones react with aliphatic and aromatic aldehydes with high erythro-selectivity and in high yields." Alkenyltitanium 49 M. T. Reetz R. Steinbach J. Westermann R. Urz B. Wenderoth and R. Peter Angew. Chem. 1982 94 133. M. T. Reetz R. Steinbach and K. Kesseler Angew. Chem. 1982 94 872. Organometallic Chemistry -Part (i)The Transition Elements 25 1 triphenoxide induces a high degree (up to 97%) of diastereoselectivity in the alkylation of aldehydes and unsymmetrical ketones. Only products with terminal double bonds were isolated not the thermodynamically more stable isomers with disubstituted C=C bonds.The diastereoselectivityand the preferred configuration depends on the steric requirements of the substituents of the carbonyl compound (Scheme 13).51 R' OH R~-C-R~ + Me-Ti(OPh) - R'>(/\\ II Me 0 diastereoselectivity R' = But > H = Me > Et > Pr' R2 = Ph Scheme 13 Similar reactions with 2-methylpropanal and benzaldehyde demonstrate that during alkyl addition lk (like)topicity is preferred.52Aliphatic aldehydesgive >go% of diastereoisomerB (Scheme 14). With substituted benzaldehydes,electron-donor groups increase the diastereoselectivity up to 98% ; electron acceptors have the opposite effect.The reactions are most selective at low temperature (-50 to -100 "C). RCH + MeCH=CH-CH2-Ti(OPh)3 II 0 &/ \ 0 0 Me*HCH2Ti RYH H Me 1ul-addition 1[&-addition R L Me Me A B Scheme 14 The related alkylation with the crotyl carbamate derivative (32) gives nearly exclusively the (threo-)S-hydroxenol carbamate (33). The regioselectivity of the carbonyl addition is maintained even with 1-alkylated titanium reagents such as (34) (Scheme 15). All reactions proceed at -78 "C,1h in excellent yieldsnS3 " D. Seebach and L. Widler Helv. Chim. Acta 1982,65 1972. J2 L. Widler and D. Seebach Helv. Chim. Ada 1982 65 1085. '' R. Hanko and D. Hoppe Angew Chem. 1982,94,378. M. Bochmann R. A. Head and M. D.Johnson OH (32) M = Ti(NEt,) 2.-(33) Y = O2CNPrI2 threo OH Scheme 15 Whereas lithiated alkynyl esters (35) react with ketones to give a-addition products titanium reagents undergo exclusive y-addition.'* Only one diastereoisomer of the allene (36) is formed as well 2s very little (37) (Scheme 16; (36) :(37) = ca.95 :5). However this reaction appears to be very sensitive to Scheme 16 substituent effects. A similar titanium alkyl (35 R3 = Me& Ph Et; X = Me OTHP) is highly selective for the acetylenic a-addition products [(38a) :(38b)l ratio up to 95 :5].55A recent review describes these stereospecific reactions and proposes an unequivocal nomenclature for product configuration and diastereoselective additions.56 s4 D. Hoppe and C. Riemenschneider Angew.Chem. 1982,94,64. " M. Ishiguro N. Ikeda and H. Yamamoto J. Org. Chem. 1982,47 2225. 56 D. Seebach and V. Prelog Angew. Chem. 1982,94,696. Organometallic Chemistry -Part (i) The Transition Elements 253 Group v and VI alkyl complexes such as RM& R2MX3 (M = Nb Ta; X = C1 OEt)” and RCrC12(THF)58 react selectively with aldehydes and not with ketones. Good results were obtained even if R carried &hydrogen atoms (Pr” Bu”). The chloride-free phenylating agent PhCr(a~ac)~ has also been made.59 With C-H acidic ketones such as acetone it gives benzene 2-phenylpropan-2-01 and mesityl oxide as aldol condensation product. By analogy with Grignard reagents a nickel norbornene complex reacts with CO to give exclusively the exo-carboxylic acid on hydrolysis.60 The reaction provides a convenient high-yield route for the direct conversion of olefins into acids without an alkyl halide intermediate.cis-exo-Adducts are also the product of reacting norbornene with long-chain (q3-allyl)palladium complexes.61 Substitution of Pd in the intermediate (39) by l-lithio-3-(2-tetrahydropyranyloxy)-l-octyne affords (40) a prostaglandin endoperoxide analogue. Saponification of the ester group gives a compound which shows inhibition of blood platelet aggregation approximately half that of PGEI even without being stereochemically pure or optically active (Scheme 17). &J+y PdHfacac -*E PdHfacac E (39) 90% OTHP 1 I Li-C=C-CHC,H 1 A OH (40)E = C02Me Scheme 17 8 Catalytic C-C coupling Reactions Palladium complexes have often been used to catalyse Grignard cross-coupling reactions.Asymmetric induction by 0.5 mol% PdC12[(R)- (S)-PPFA] (41) in the reaction of (E)-vinyl bromides with a-(trimethylsily1)benzyl magnesium bromide gives allylsilanes in exceptionally high optical yields (85-95% e.e.).The R-isomers are formed preferentially in all cases.62 The (R)-(E)-allylsilanes react with elec- trophiles stereospecifically to give (S)-(E)-products via attack anti to the SiMe3 leaving group. (2)-Allylsilanes give (R)-isomers (Scheme 18). ’’ T. Kauffmann E. Antfang B. Ennen and N. Klas Tetrahedron Lett. 1982,23 2301. ” T. Kauffmann A. Hamsen and C. Beirich Angew. Chem. 1982 94 145. 59 T. Ito T. Ono K. Maruyama and A.Yamamoto Bull. Chem. SOC.Jpn. 1982 55 2212. 6o H. Hoberg and D. Schaefer J. Organomet.Chem. 1982,236 C28. 61 R. C. Larock J. P. Burkhart and K. Oertle Tetrahedron Lett. 1982,23 1071. 62 T. Hayashi M. Konishi H. Ito and M. Kumada J. Am. Chem. SOC.,1982 104,4692. M. Bochrnann,R. A. Head and M. D. Johnson Ph SiMe EbPh + BrMg-C-SiMe r3; ,Ph-Ph -, PheBr I H I HH H (R) 95% e.e. 6) E = But,MeCO CH2OH Scheme 18 The synthesis of macrocycles usually requires working in high dilution in order to avoid intermolecular condensations. A new approach to forming medium and large rings utilizes Pd-catalysed allylic substitution reactions and permits substrate concentrations of 0.1 to 0.5 M.By attaching the catalyst to an insoluble support a dilution effect arises from the substrate having to diffuse to relatively few active sites Neutral cyclization precursors such as vinyl epoxides (42) give high yields of cyclic products.Use of a soluble Pd catalyst leads only to oligomers. Temperature control is critical clean cyclizations occur at 65 "C,lower temperatures give other products (Scheme 19).63 71% S (42) S = -SO;?Ph n =\ Scheme 19 '' B. M. Trost and R. W. Warner J. Am. Chem. SOC.,1982,104,6112. Organometallic Chemistry -Part (i) The Transition Elements Catalysis of nucleophilic substitutions of allylic substrates is usually dominated by palladium. However recent findings suggest that molybdenum complexes may play a similarly useful role and allow considerable flexibility in stereocontrol by ligand variation.64 For example whereas stoichiometric nucleophilic attack by (43) on complex (44)gives only one product (43,attack on complex (46)gives a 1 1 mixture of (45)and (47)(Scheme 20).In catalytic reactions with 5-20mol% R4% oc I Mo(bipy) + (43)-* oc’ I CI (46) (47) E = C02Me Scheme 20 Mo(CO)~or M~(CO)~(bipy) chelating ligands (2,2’-bipyridyl or dimethoxyethane) favour products of the type (47).Chelating ligands such as bipy or 0,N-bis(trimethylsi1yl)acetamide(TSA) which is used as a base to generate the nucleophile in lieu of sodium hydride also control the stereochemistry of the alkylation of (48)with diethyl malonate (Scheme 21). (48) E = C02Me base E catalyst E NaH Mo(C0)4(bipy) 85 :15 NaH MO(C0)6 50 50 TSA MO(C0)6 >95 :(5 Scheme 21 Transition-metal-promoted reactions continue to prove useful in natural product synthesis.The cycloaddition of chromium carbene complexes with disubstituted 64 B. M. Trost and M. Lautens J. Am. Chem. SOC. 1982,104,5543. M. Bochmann R. A. Head and M. D. Johnson alkynes and the Pd-catalysed carbalkoxylation are interesting features in the syn- thesis of nanomycin A and deoxyfrenolicin (49).65The latter is outlined in Scheme 22. NR,' -+ L = co Scheme 22 The cobalt-mediated [2 + 2 + 2lcycloaddition reaction has been employed in a novel synthesis of the steroid framework by simultaneously constructing the B C and D-rings from a suitable A-ring precursor.66 The cycloaddition proceeds in good yield to give (50).Oxidative removal of Co with FeC13-MeCN gives a novel diene which can be converted into (*)-estrone (Scheme 23). n Scheme 23 M. F. Semmelhack J. J. Bozell T. Sato W. Wulff E. Spiess and A. Zask J. Am. Chem. SOC.,1982 104,5850. E. D. Sternberg and K.P. C. Vollhardt J. Org. Chem. 1982,47 3447.

ISSN:0069-3030    

DOI:10.1039/OC9827900239

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

12 Organometallic Chemistry Part (ii) Main-Group Elements By John D. KENNEDY Department of Inorganic and Structural Chemistry Universiw of Leeds Leeds LSZ 9JT 1 Introduction The year 1982 marked the publication of the nine-volume major reference work ‘Comprehensive Organometallic Chemistry’ of which three volumes deal prin- cipally with the main-group metals.’ Individual chapters cover the organometallic chemistry of beryllium aluminium thallium silicon germanium tin lead and mercury and the other metals are grouped appropriately in five other chapters. There is an interesting introductory chapter on structural and bonding relationships among the main-group organometallic compounds;2 perhaps surprisingly this type of overview seems to be rarely attempted and so this one is particularly useful.Specifically interesting for the organic (rather than the organometallic) chemist is that one volume is principally concerned with the main-group metals in organic synthesis with individual chapters on the alkaline and alkaline earths organoboron compounds aluminium compounds thallium compounds and organosilicon species. Subject to the occasional mild idiosyncracies of some of the authors (without which the world of chemistry would be less interesting) and the limitations of space (even in work of this size) it is fair to say that in general the work fulfills its aspirations of comprehensiveness and thereby obviously constitutes a most impor- tant source of information on state-of-the-art late 1970’s/early 1980’s organo- metallic chemistry.A second important literature event has been the launching of the journal Orgunometullics by our sibling institution the American Chemical Society. As its title implies this journal is concerned principally with most aspects of the chemistry of the metal-to-carbon bond. It too is a valuable addition to our libraries and will obviously be well consulted by the organometallic chemist although as with all increasingly specialized journals it will however subtly inevitably lead to a diminu- tion of the specialists’ awareness of chemical developments in other areas. It is of interest that in the first year of this new journal only some 20% of the papers have been concerned principally with main-group organometallic chemistry the other 80% being concerned principally with transition-metal chemistry.These figures may be a reasonable reflection of the relative numbers and accessibilities of transition-metal elements compared to the main-group metallic elements ’ ‘Comprehensive Organometallic Chemistry’ ed. G. Wilkinson F. G. A. Stone and E. W. Abel Pergamon 1982. * M. E. O’Neill and K. Wade Chapter 1 in ref. 1 vol. 1 pp. 142. 258 J. D. Kennedy although it is often difficult to avoid the impression that the general variety of novel chemistry reported for transition-element organometallic compounds seems to be much greater than for main-group species. This may be a partial consequence of the relative middle-age of much main-group organometallic chemistry so that a significant amount of the important new work (with notable exceptions) is that of refinement and consolidation rather than a brash exploitation of a rapidly expanding area.It may also be because much of the main-group organometallic chemistry of yesteryear has proved to be so generally useful that it has now become the domain of the synthetic organic chemist rather than the more speculative organometallic chemist. In this last regard a lot of the organic chemistry of lithium magnesium boron aluminium silicon mercury and to some extent tin comes very readily to mind. In this context also a recent review ‘New Possible Applications of Heavy Main-Group Elements in Organic Synthesis’ which highlights the current and potential usage of compounds of germanium arsenic antimony tellurium lead bismuth tin etc.in this area should also be noted.3 Significant new types of chemical behaviour are however still being discovered and prospects of continuing development are excellent. Recently also it has been encouraging to see a diminution of main-group permutational chemistry in which for example various combinations of main-group atoms joined by essentially straightforward u-frameworks are synthesized in what often appears to be a stamp- collecting type of approach or in which similarly trivial substituent variants are synthesized often in order to measure correspondingly insignificant variations in spectroscopic or other physical properties. Although in its place there can be great value in this type of routine synthesis and documentation one has often been left with the impression that the development of the discipline would be served better by chemistry conceived and conducted in a more outward-looking manner especially so since unexplored areas ripe for development can readily be pinpointed.At present therefore it seems that one can still look forward to continuing interesting developments in both novel and more established areas of main-group organometallic chemistry. Many of the modern instrumental techniques for example multi-element n.m.r. spectroscopy for the investigation of solution proper- ties are particularly suited for much main-group work and this together with the general explosion in the use of single-crystal X-ray diffraction analysis is giving valuable insight into many older problems and also makes the investigation of (and the generation of) interesting new areas much easier.2 Group1 The organic compounds of sodium potassium rubidium and caesium are prin- cipally ionic in character and often prepared only in solution and therefore it is difficult to discuss these in terms of the metal-carbon bond. Interesting exceptions to this generalization occasionally arise one such being the acetylcyclopentadienyl compound [(C,H,COCH,)NaTHF] (THF = tetrahydrofuran) which has a penfa-hapto-C co-ordination to the metal atom in a three-legged ‘piano-stool’ configur- ation as in (1).However the metal-carbon interaction is rather weak the distances T. Kaufmann Angew. Chem. Int. Edn. Engl. 1982 21,410. Organometallic Chemistry -Part (ii)Main-Group Elements being 277( 1)-294( 1)pm similar to the previous example of [(CSHS)Na.TMEDA] (TMEDA = tetramethylethylenediamine)and obviously in contrast to the stronger Na-0 bonds of ca.230 pm. The compound is prepared from methyl acetate and NaC5Hs in THF and additional interesting features include intermolecular co- ordination from the acetyl group which imparts a unique polymeric bridged structure to the solide4 o/\Na . "0 0 Lithium by contrast which has been called a 'sticky' metal continues to reveal much interesting covalent chemistry. The bulk of the usage of organolithium compounds is in synthetic organic chemistry via deprotonation reactions metal- halogen exchange processes etc. Often however surprisingly little is known about the nature of the reacting species or of the mechanisms involved since the organolithium compounds are usually prepared in situ as part of a complex synthetic scheme and procedures are often determined as 'recipes' by essentially trial and error approaches.Thus it is of interest to see mechanistic studies such as the report on the kinetics of halogen-metal exchange between n-butyl-lithium and aromatic bromides in hexane solution.' Bu"Li +ArBr +Bu"Br +ArLi (1) This is one of the more widely applicable synthetic routes for the preparation of aromatic lithium reagents and was found to be first order in both reactants (Bu"Li considered as the hexamer) with AG' 52 kJ mol-' for bromobenzene. A Hammett relationship for the substituted bromobenzenes suggested negative charge character in the transition state (p =2).Several transition-state structures were considered; available evidence was taken to suggest that the exchange may be concerted with either a four-centred structure (2) or SN2-type attack of the n-butyl anionic centre at the bromine of the aryl bromide. Ar--BI 1 I I I I I I i Li __-R (2) The precise nature of organolithium reagents in solution for example the degree of aggregation and how this may be modified by donor solvents or other ligands on the metal atom is critical in most reactions. Again little information is generally available on this although reports on multi-element n.m.r. studies including 'Li R. D. Rogers J. L. Atwood M.D. Rausch D. W. Macomber and W. P. Hart J. Organomet. Chem. 'H. 1982,238,79.R.Rogersand J. Houk J. Am. Chem. SOC.,1982,104,522. 260 J.D. Kennedy work on species such as the substituted lithiomethane LiCH(PPh2)2 augur well for the application of this technique to organolithium compounds in the more general case. In this instance for example it was concluded that the compound is monomeric in Et,O at low temperatures and that it probably exists as the phosphine-bridged species (3)rather than a C-bonded species such as (4).6 H Ph2P I A-C -\ 'CH-Li Ph,P PPh / \/ PhzP Li (3) (4) Information on solution structures is often inferred from X-ray structural studies on crystalline species that may be isolated from solution and there is still consider- able activity in this interesting area.Thus the use of PMEDTA (pentamethyl- diethylenetriamine) rather than TMEDA with Bu"Li offers some advantage in lithiation experiments and this has been ascribed to the co-ordinative saturation of the lithium centre which tends to be confirmed by an X-ray study of the monomer [Li{CH(SiMe,),}(PMEDTA)].This is prepared from CH2(SiMe3)2 and has what may be described as a distorted tetrahedral co-ordination about the metal and carbon atoms with the Li-C(a) distance 213(5) pm (5). The Si-C(a)-Si bond-angle is much larger than tetrahedral at 124(2)" which together with the short Si-C(a) distance of 179(3)pm may reflect some back-bonding from C(a) to the silicon d-~rbitals.~ In another study neighbouring-group participation in lithiation reactions is demonstrated by the isolation and crystallographic study of the ortho-lithiated dimethylbenzylamine species [Li4{C6H4(2-cH2NMe2))41.This has a central tetrahe- dral {Li4} cluster with each triangular face capped by an ips0 aryl carbon atom and with each lithium cluster vertex co-ordinhted by the corresponding nitrogen atom.8 One such unit is represented in (6). It is also of interest that this is the first example of a face-bridged aryl group. In the same study the dimeric bis(ortho- substituted)-compound [Li2{C6H3(CH2NMe2)2}2] was also isolated with a postu- lated structure as in (7). Other interesting dilithium compounds which have been structurally character- ized include the TMEDA complexes [(C6H4)2Li2(TMEDA)2] (2,2'-dilithium biphenyl) and [orfho-C6H4(CHSiMe3),Li,(TMEDA),], both prepared by treatment 'I.J. Colquhoun H. C. E. McFarlane and W. McFarlane J. Chem. SOC.,Chem. Commun. 1982 220. M. F. Lappert L. M. Engelhardt C. L. Raston and A. H. White J. Chem. SOC.,Chem. Commun. 1982 1323. J. T. B. H. Jastrzebski G. van Koten M. Konijn and C. H. Stam J. Am. Chem. SOC.,1982,104,5490. 261 Orgunometallic Chemistry -Part (ii) Muin-Group Elements of the non-lithiated C-H precursors and Bu"Li in the presence of TMEDA. The structure of the orth~-c~H~(CHSiMe~)~Li~ compound shows that the organic moiety is conjugated and planar with two lithium centres connected symmetrically in a bis(tetruhupto) manner as indicated in (8). The isolation of crystalline alkylating agents such as this in pure form is claimed to be an important feature leading to the possibility of using exact stoicheiometries of highly pure organolithium starting materials in synthetic processes.It is also claimed to be 'the first structurally characterized dilithioalkane'.' The biphenylene compound (9) on the other hand which also has a planar organic residue is symmetrically bonded to the two lithium atoms in a bis(dihupto) rather than a bis(tetruhupto) manner (9). This is claimed to be consistent with predictions based on MO calculations thus underscoring the power of such calculations as an initial means of exploring the rule-breaking structures of lithium compounds.10 Another interesting and isolable dilithium compound obtained as a white powder in 70-80% yield is 1,3-dilithio-2,3-dimethylpropane, prepared from the corre- sponding dibromide according to reaction 2 which also has elements of novelty." The dilithiated product appears to be particularly stable for example a solution in Et,O at room temperature had tIl2 cu.70 days a finding quite exceptional for a primary alkyl-lithium. Ab initio calculations indicate that some of the stability may derive from a doubly bridged structure analogous to (9)above although kinetic factors are important since the corresponding unmethylated compound Li2C3H4 prepared by the same route readily decomposes to give allyl-lithium and lithium hydride." M. F. Lappert C. L. Ralston B. W. Skelton and A. H. White J. Chem. Soc. Chem. Commun.1982 14. J. Schubert W. Neugebauer and P. von R. Schleyer J. Chem. Soc. Chem. Commun. 1982,1184. J. W. F. L. Seetz G. Schat 0.S. Akkerman and F. Bickelhaupt I. Am. Chem. SOC.,1982,104,6848. 262 J. D. Kennedy Me Me HgBr THF Mxe-A M;x;Ie Br Br Et,O BrMg MgBr BrHg HgBr (’-,+ 9+ LiH (3 Li Li Li Higher polylithiated species also continue to attract attention both from an experimental and a theoretical point of view. Thus (Li,CH) ‘trilithiomethane’ he missing member of the H4-,CLin lithiomethane set has been identified as a product of the vapour-phase reaction of Li with CHCl,; mass spectroscopy showed units up to tetramen.’* In another study by the same group flash vaporization of ‘dilithiomethane’ (Li2CH2) has been shown to lead to a remarkable variety of species C H,Li including what may be the dilithiomethane hexamer (Li2CH2),; these were again detected mass spectr~metrically.~~ Many of these unsolvated polylithio-compounds at present are observed at best as transients (see also last year’s report) but this does not inhibit the theoretical chemist -on the contrary it has been claimed that calculations constitute one of the most valid ways of investigat-ing these species.Certainly the small size of the lithium attracts quantum mechanical calculations which may well have useful predictive and interpretive value in this area. A recent example is the structure of dilithiated propene (Li2C3H4) for which an initio 3-21G//3-2 1G calculations indicate that symmetrical double-bridging structures such as (10) are energetically most fav0~red.l~ H 3 Group11 Organoberyllium chemistry continues in general to be a neglected area.Although (a) there is a continuing theoretical interest in known compound^,^^ (b) the inter- mediate position of beryllium between lithium and boron in the periodic table l2 F. J. Landro J. A. Gurak J. W. Chinn R. M. Newman and R. J. Lagow J. Am. Chem. SOC., 1982 104,7345. l3 J. A. Gurak J. W. Chinn and R. J. Lagow J. Am. Chem. SOC.,1982 104 2637 and refs. therein. P. von R. Schleyer and A. J. Kos,J. Chem. SOC.,Chem. Commun. 1982,449. I’ E. D. Jemmis and P. von R. Schleyer J. Am. Chem. Soc. 1982,104,4781. Organometallic Chemistry -Part (ii)Main-Group Elements readily predicts a rich variety of novel structural and reaction behaviour and (c) recent reports of 9Be n.m.r.data which include a number of organoberyllium species,16 emphasize that n.m.r. provides a useful means of examining organoberyl- lium chemistry in solution the amount of novel work is in fact surprisingly small. An exception to this which also exemplifies the potential variety of behaviour is the structural examination of the dimeric species [(Mec~c)~BeNMe~]~ by X-ray diffraction analysis. The crystal in fact contains two independent dimers the 'electron deficient' species (1 1) and its 'electron precise' isomer (12). That both exist in the same crystal indicates that the energies of both are ~irni1ar.l~ Me /c+C' The compound is prepared by the reaction of dipropynyl beryllium with trimethyl- amine.In both isomers the geometry about the Be atom grossly approximates to tetrahedral and the Be2C2 ring is planar. In molecule (11) the angles C-Be-C and Be-C-Be are 103.4(6) and 76.6(6)"respectively and the distances Be-Be 231.9(6)pm and Be-C (within the plane) 171.9 and 190.4 pm. In molecule (12) the corresponding dimensions are 96" 83.8" 254.9(6) pm 173.5 pm and 204.1 pm respectively with Be-C' 253.8 pm.17 Neglecting for the purposes of this report the world of organomagnesium chemistry which seems to have passed almost entirely into the domain of the synthetic organic chemist significant developments in the organic chemistry of the rest of the Group I1 metals are again surprisingly limited and as with beryllium seem not in general to be fulfilling the potential for new chemistry that is available.Organozinc and cadmium seem to be particularly neglected. The interaction of organomercury compounds with biochemically significant substrates continues to attract attention and in this context it should be noted that 'Comprehensive Organometallic Chemistry' referred to in the Introduction,' con- tains a chapter on 'environmental aspects of organometallic chemistry' in which mercury compounds figure a lot.17n The year saw an increasing incidence of the use of n.m.r. in this area for example in the investigation of adducts of ethylmercury-phosphate with amino-acids and ribonuclease l8 in the study of the complexation of methylmercury residues by glutathione ergothioneine and haemoglobin l9 and l6 D.F. Gaines K. M. Coleson and D. F. Hillenbrand J. Mugn. Reson. 1981 44 84. l7 N. A. Bell I. W. Nowell and H. M. M. Shearer J. Chem. SOC.,Chem. Commun. 1982,147. P. J. Craig Chapter 18 in ref. 1 vol. 2 pp. 979-1020. '' D. A. Vidusek M. F. Roberts and G. Bodenhausen J. Am. Chem. SOC.,1982,104,5452. l9 R. S. Reid and P. L. Rabenstein J. Am. Chem. SOC.,1982 104 6733. 264 J. D. Kennedy in the examination of the rates of cytidine aminomercuration by methylmercury species. O The classical decarboxylation reaction of mercury carboxylates to give organomercury species which normally requires heating or radical initiation has been found to go readily and spontaneously at room temperature with polymethoxy- benzoates.Thus reaction of Hg(OAc) with 2,6-dimethoxy- 2,3,4- and 2,4,6- trimethoxybenzoic acid ArCOSOH gives yields of [ArHgOCOAr] of 15-90% in 15-90 minutes (equation 4). With the 2,3,4-trimethoxy-compounda reaction time of 120 min gives [Hg{C6H,(OMe),},] (equation 5).,l Hg(OAc) + 2ArC02H + ArHg02CAr + 2MeC02H + C02 (4) H~(OAC)~ + 2ArC02H + HgAr2 + 2MeCO2H + 2C02 (51 The substituent effects suggest that C02 elimination occurs by classical elec- trophilic aromatic substitution a mechanism rarely encountered in decarboxylation syntheses of organometallics. Thermal decarboxylations usually proceed by elec- trophilic attack of the metal on the carbon atom which develops considerable carbanionic character in the transition state. In these reactions here it is of particular interest that the strong electron-donating substituents lead to specific ips0 attack with no competition from mercuration.21 Other interesting aspects of organomercury chemistry noted during the year include a study of the yellow + blue photodichroic behaviour of arylmercury dithizonates.Photodichroic behaviour is generally observable in all heavy-metal dithizonates but the return reaction is usually too rapid to enable the photogenerated isomer to be examined. It has been found that the effect of an aromatic group on mercury is to slow the return reaction so that the more unstable blue isomer (14) may be examined more readily for example by n.m.r. spectroscopy; the work also records further crystallographic confirmation of the ligand conformation in the more stable yellow form (13).22 Other crystallographic studies recently reported include those of the interesting trimercurated carbon species [(ClHg),CCH=O-DMF] and [(BrHg)3CCH=O*DMSO].These compounds are readily prepared; for example the chloromercury species is obtained via the reaction of an ethanolic solution of HgCl with sodium acetate., RHP; :Ni N” 7-1 I N’ yellow R‘ blue I R’ (13) 2o B. McConnell J. Am. Chem. Soc. 1982,104 1723. 21 G. B. Deacon M. F. O’Donoghue G. N. Stretton and J. M. Miller J. Organomet. Chem. 1982,233 C1. 22 A. T. Hutton and H. M. N. H. Irving J. Chem. Soc. Dalton Trans. 1982,2299. 23 D. Grdenic B. Korpar-Colig M. Sikirica and M. Bruvo I. Organornet. Chem. 1982 238 327. Organometallic Chemistry -Part (ii) Main-Group Elements 265 An increasing amount of Group I1 organometallic chemistry is directed at the formation of metal-metal bonds to transition metals for example in the linking of halogenated organyl mercury units to metals such as and platin~m.~’ In this area the formation of a variety of cyclopentadienylzinc-transition-metal is compounds such as [(C5H,Zn),Co(C,H5)(PPh3)] of some novelty.These however are all generally unstable with respect to decomposition to give dicyclo- pentadienylzinc (equation 6).26 ~[(C,HSZ~)~CO(C,HS)(PP~~)~ -+(C5Hd2Zn + [Zn{Co(C,H,)(PPh3)}21 (6) 4 Group111 Organoaluminium chemistry in 1982 has been characterized by some interest- ing structural work. The dimeric pentamethylcyclopentadienyl species [(CSMe5)A1RC1] (where R = methyl and isopropyl) exhibit a trihapto co-ordination of the (CsMe5) moiety to the metal atom (15).For the methyl compound (R = Me) the aluminium-carbon distances are 210 pm (to the central C atom) and 225 and 228pm (to the outer C atoms). For the isopropyl species (R = CHMe2) the corresponding distances of 210 234 and 245pm have been taken to suggest a tendency towards a dihapto mode of co-ordination arising from increased intramolecular steric interaction.” Two other aluminium compounds [Al(C5H5)Me2] and [A1(CH2C6H5)3] have bridged polymeric structures in the solid state. The tribenzyl species has a chain- structure in which the ortho-carbon on one of the three benzyl groups on each metal atom co-ordinates weakly in a unique monohapto manner to the metal atom in the next molecule in the chain.This interaction distance is ca. 245 pm ‘only’ some 25 pm greater than the aluminium-carbon distance observed for Al-C- A1 bridge bonds but clearly much 24 S. V. Hoskins and W. R; Roper J. Organomet. Chem. 1982,234 C9. 25 0.Rossell. J. Sales and M. Seco J. Organomet. Chem. 1982,236,415. 26 P. H. M. Budzelaar J. Boersma G. J. M. Van der Kerk A. L. Spek and A. J. M. Duisenberg Inorg. Chern. 1982,21,3777. 27 P. R. Schonberg R. T. Paine C. F. Campana and E. N. Duesler Organometallics 1982 1,799. 266 J. D. Kennedy weaker than a direct aluminium-carbon bond e.g. Al-C(benzy1) of ca. 199 pm in this species. The geometry about each metal atom deviates substantially from the planar the C-A1-C angles in the monomer (AIC,) unit averaging at 114.5" and with the metal atom 47.5pm from the C plane.In the intermonomer link the aluminium atom lies just outside the aromatic ring almost directly above the co-ordinated carbon atom and not over the 7r-system.28 The intermolecular co-ordination has similarities to that in [A1(CSHS)Me2] which has precedent in the corresponding structures for gallium and iridium analogues. This compound also has a chain structure represented schematically in (17) with non-planar geometry about the metal atom. The two cyclopentadienyl carbon- aluminium distances are 220.3(2) and 224.8(2)pm and again the metal-to-ring interactions both types are almost perpendi~ular.'~ Other organoaluminium work of interest includes an examination of the adducts between crown ethers and triethylaluminium to form complexes such as [(A1Me3)z(dibenzo-18-crown-6)] and [(AIMe3)4(15-crown-5)].In these the tetra- co-ordinate metal atoms are bound by oxygen atoms in exo-ring positions (18)(in contrast to the thallium species mentioned below). These compounds can be used with considerable advantage in the formation of anionic species such as [Me6AI2CI]- according to equation (7). Corresponding gallium syntheses are also possible and a variety of other anions may be inc~rporated.~~ KCI AlR3 + crown + [(A1R3),crown] -[Kcrown]+[R3 AlCIAlR3]- (7) (18) Advances in the organic chemistry of gallium indium and thallium have been relatively sparse although as with aluminium structural work has been significant.A. F. M. Rahman K. F. Siddiqui and J. P. Oliver Organometallics 1982,1 881. 29 B. Teclt P. W. R. Corfield and J. P. Oliver Inorg. Chem. 1982 21,458. 30 J. L. Atwood D. C. Hrncir R. Shakir M. S. Dalton R. D. Priester and R. D. Rogers Organometallics 1982,1 1021. Organometallic Chemistry -Part (ii)Main-Group Elements Of some novelty is the use of organogallium species as transition-metal ligands for example in the dimeric vinylgallium complex [(THF)(C,H,)GaFe(CO)&; this has a planar (Ga2Fe2) unit and the co-ordination about gallium approximates closely to tetrahedral (19).31Other structural work includes that of the bis(trimethy1- gal1ium)acetate anion (20) which also has a tetrahedral co-ordination about the metal atom.32 THF, ,,F.%(W /vinyl y 3 vinyl/ Ga\F/ GayTHF Me,Ga ,C,0 ,GaMe,0 (CO) (19) (20) In organoindium chemistry although there has been some interest in relatively straightforward structural aspects (e.g.ref.33) the subject is not well represented. In organothallium chemistry an amusing species that has been reported is the cationic complex between the dimethylthallium(IrI) ion and the crown-ether dibenzo-18-crown-6 (21). In this moiety the dimethylthallium(II1) cation is threaded through the crown ether with the linear (TIC2) unit held perpendicularly to the plane containing the six ether oxygen atoms and the thallium atom.34 5 GroupIV The organometallic chemistry of the Group IV elements continues as the most populous of the fields covered in this Report and it also continues to generate a large amount of novel and interesting chemistry.This makes selection difficult and it may be noted that some aspects of novel 1982 chemistry not covered here will be covered in subsequent reports. 31 J. C. Vanderhooft R. D. Ernst F. W. Cagle R. J. Neustadt and T. H. Cymbaluk Inorg. Chem. 1982 21 1876. 32 M. J. Zaworotko R. D. Rogers and J. L. Atwood Organornetallics 1982 1 1179. 33 J. T. B. H. Jastrzebski G. van Koten D. G. Tuck H. A. Meinema and J. G. Noltes Organornetallics 1982,1 1492. 34 K. Henrick R. W. Matthews B. L. Podejrna and P. A. Tasker J. Chem. Soc. Chem. Commun. 1982 118. 268 J. D. Kennedy Organosilicon chemistry again constitutes the bulk of the new work reported in the year.Reviews include one on aspects of silicon-transition metal chemi~try,~’ and one on nucleophilic displacement at silicon.36 In addition a survey of the silatranes has a~peared,~’ and it may well be that a perusal of this will illuminate some of the philosophy behind the extensive amount of work that has been carried out in this area over the past years. For the synthetic organic chemist there is a monograph on ‘Silicon in Organic Synthesis’ in which emphasis is placed on the concept of silicon as ‘ferryman’ mediating the transformation of one wholly organic molecule into an~ther.~’ Group IV-metal-subrogated analogues of unsaturated hydrocarbons continues to be a fascinating area of study although one of the problems is that these compounds have been often detectable at best only as transient intermediates or identifiable only by trapping experiments etc.Thus evidence for a transient disilabenzene (Me2Si2C4Me,) comes from the species (23) which is obtained by the treatment of the disilahexadiene (22) with dilithioanthracene. Photolysis or ther- molysis of (23) in the presence of F3CC,CCF3 then yields anthracene plus disilabenzene trapped as the disilabarellene (24) in a yield of 88O/0.~~ CI Me 2& Me ‘Si‘ Me ,Si I Li,An hv or A ___+ CF,CiCCF, Me‘Si’Me /\ C1 Me It is of interest to note here incidently that the unsubstituted silabarellene (25) like barellene itself undergoes photochemical rearrangement to the 1-silasemibull-valene (26).In contrast to semibullvalene itself however which undergoes a degenerate 3,3-shift at -150 “C with an activation energy of only 20 kJ mol-’ the 1-sila-species appears to be static even at +150 0C.40 Returning to the sila-alkenes however it is obviously much more satisfactory to have stable species to examine and in this regard 1982 has been an exciting year. The stable silaethylene [(Me3Si),Si=C(OSiMe3)(Cl0H15)3(where CloH15 = 35 B. J. Aylett Adv. Inorg. Chem. Radiochem. 1982 25 1. 36 R. J. P. Corrin and C. Guerin Adv. Organomet. Chem. 1982 20,265. 37 M. G. Voronkov V. M. Dyakov and S. V. Kirpichenko J. Organomet. Chem. 1982,233,l. 38 E. W. Colvin ‘Silicon in Organic Synthesis’ Butterworths 1981. 39 J. D. Rich and R. West J. Am. Chem. SOC. 1982,104,6884.40 M. Vuper and T. J. Barton J. Chem. SOC. Chem. Commun. 1982 1211. Organometallic Chemistry -Part (ii) Main-Group Elements 269 1-adamantyl) mentioned in last year's Report has now been structurally character- ized (27). The geometry at the central silicon and carbon atoms approximates to formally sp2-hybridized trigonal planar the angles at silicon being 114.5 118.9 and 126.5" with those at carbon being 112.2,117.5 and 130.1". The Si=C distance is 176.4pm and there is a slight twist angle of 14.6" between the two trigonal planes (which may arise from steric intera~tion).~~ Me$ o/ si \.s1=c / /\ Me3Si adamantyl The first silacyclopropene to be structurally characterized has also been reported. -This is the compound [(2,4,6-Me3C6H2),siC(Ph)=C(SiMe3)] (29) which was prepared by the photolysis of the trimethylsilylsilylacetylene species (28).Additional interesting features include the near co-planarity of the phenyl and cyclopropenyl rings the distances within the cyclopropene ring being C=C 134.9(3) pm with Si-C 180.0(2) and 183.9(2) pm.42 hw (9) The second stable disilene R2Si=SiR2 has also been reported. Treatment of Ar,SiCI (where Ar =2,6-xylyl) with lithium naphthalene gives the novel trisilacyc- lopropane (cyclotrisilane) (Ar2Si)3 in a yield of 10%. This is unexpectedly stable to heat light and moisture up to its melting point of 272-273 "C but upon U.V. photolysis in solution gives the disilane Ar,Si=SiAr which may be isolated as a yellow crystalline reactive compound m.p.216-217.5 "C (equation 10 M =Si).43 In an interesting reaction the known tetramesityl analogue [(Me3C6H,)4Si2] has been made by the irradiation of lithium wire and [(Me&H2)2SiC12] with ultrasonic waves in THF; complete conversion occurs in 20 minutes.44 41 A. G. Brook S. C. Nyburg F. Abdesaken B. Gutekunst G. Gutekunst R. K. M. R. Kallury Y. C. Poon Y.-M. Chang and W. Wong-Ng J. Am. Chem. SOC.,1982,104,5667. 42 K. Hirotsu T. Higuchi M. Ishikawa H. Sugisawa and M. Kumada I. Chem. SOC.,Chem. Commun. 1982,726. 43 S. Masamune Y. Hanzawa S. Murakami T. Bally and J. F. Blount J. Am. Chem.SOC.,1982,104,1150. 44 P. Boudjouk 8.-H. Han and K. R. Anderson I. Am. Chem. SOC.,1982,104,4992. 270 J.D. Kennedy The reactions of equation (10)have also been carried out for ge~manium.~' The cyclotrigermane was obtained as a crystalline solid m.p.234 "C in 17% yield and photolysis in solution gave the digermene. This species is apparently stable but 1'; Ar ArMC, L~+N~~',DME hw,C,D,, \ /Ar (10) M-M /M=M\ Ar2 Ar2 Ar Ar decomposes photolytically under the conditions of its preparation and therefore has so far proved to be difficult to isolate in its pure form. It will be interesting to see structural work on these disilenes and digermenes. In this work the cyclotrisilane and cyclotrigermane were both examined by crystallography; the Si-Si and Ge-Ge distances were 240 pm and 254 pm respectively both extraordinarily 1ong.43*45 An additional small-ring persila-alicyclic compound is the dodecasilane [(Me3Si)*SiI4 obtained in 35% yield from the pyrolysis of neat (Me3Si),SiOMe (equation 1 250 T/2h 4(Me3Si)3SiOMe-[(Me3Si)2Si]4+ 4Me3SiOMe (11) This has a pleasingly symmetrical SiI2 skeletal structure [represented in (30)].The central Si4 ring is planar in contrast to the highly puckered Si ring in compounds such as [(Me3C)MeSiI4. (30) Other new work on larger permethylated cyclic polysilanes includes some interest- ing AlC1,-catalysed rearrangements. For example treatment of isomers (3 1)and (32) of SiloMe16 with AlCl,-MeMgBr in refluxing benzene gave conversion into further isomeric polysilanes believed to have Silo skeletal configurations as in (33) and (34); a number of other similar interconversions were rep~rted.~' Another area of organosilicon chemistry which enjoys success is that concerned with the effects of large degrees of steric hindrance afforded by very bulky methyl- silylmethyl groups.Some aspects of this type of chemistry have been reviewed.48 Some of this work is now becoming routine but of interest in this area are the syntheses of the first stable silyl cyanate [(Me3Si)3CSiMe2(OCN)],49 the first stable diphosphine (Me3Si)3C-P=P-C(SiMe3)3 (which also has a record low-field 45 S. Masamune Y. Hanzawa and D. J. Williams J. Am. Chem. SOC.,1982,104,6136. 46 Y.-S.Chen and P. P. Gaspar Organometallics 1982 1 1410. 47 M. Ishikawa M.Watanabe J. Iyoda H. Ikeda and M. Kumada Organometallics 1982,1 317. 48 C. Eaborn J. Organomet. Chem. 1982,239,93.49 C. Eaborn P. D. Lickness G. Marquina-Chidsey and E. Y. Thorli J. Chem. Soc. Chem. Commun. 1982,1326. Organometallic Chemistry -Part (ii) Main-Group Elements 271 lP (31)or 31 Pn.m.r. chemical shift of ca. +600 p.p.m.),” and the compound [(Me3C)Me2Si]2C=C(SiMe3)2;this last is the ‘most twisted olefin known’ with a dihedral angle between the two trigonal carbon planes of 49.6O.’l Organotin and organolead chemistry in 1982 has also been characterized by some interesting single-crystal X-ray diffraction work. The solid-state structure of trimethyltin chloride Me3SnC1 has been determined at last; the work was carried out at low temperatures because of the low melting point and volatility of this species. The geometry about the tin atom (35) is distorted from tetrahedral towards trigonal bipyramidal because of weak intermolecular C1+ Sn interaction the inter- and intramolecular tin-chlorine distances being 326 and 243 pm respectively with the angles C1-Sn-C(mean) and CI...Sn-C(mean) being 100.1 and 80.0” re~pectively.~~ Me Me Me ri 1 I ,*.Me MeLvLG (35) An interesting structural survey has been made of the complexes of DMSO (dimethylsulphoxide) with the distannylmethanes CI3SnCH2SnCI3 Me,CISnCHzSnMeC1, and MeCI2SnCH2SnMeCl2. The first of these forms a com- plex [(DMS0)2C13SnCHzSnC13(DMS0)2] in which each metal has a straightfoi ward (distorted) octahedral co-ordination. The second forms a complex with one DMSO molecule bridging the two tin centres and has trigonal bipyramidal geometry at each tin atom (36).The third complexes with two bridging DMSO molecules as in (37),again with pseudo-octahedral stereochemistry about each metal atomOs3 Molecular compounds containing Pb-P bonds are far from common and so there is some novelty in the preparation and structural characterization of tris(trimethylplumbyl)heptaphosphanortricyclene [(Me3Pb)3P7].The reaction between the known species [(Me3Si)3P7] and Me3PbC1 is facile and quantitative in monoglyme at -50 “C and is presumed to go via an SN2-type process.54 (Me3Si)3P7+ 3Me3PbC1 + (Me3Pb)3P7+ 3Me3SiC1 (13) A. H. Cowley J. E. Kilduff T. H. Newman and M. Pakulski J. Am. Chem. SOC.,1982,104,5820. H. Sakurai H. Tobita Y. Nakadaira and C. Kabuto J. Am. Chem. SOC.,1982 104,4288.52 J. L. Lefferts K. C. Molloy M. B. Hossain D. van der Helm and J. J. Zuckerman J. Organomef. Chem. 1982,240,349. 53 J. R. Hyde T. J. Karol J. P. Hutchinson H. G.Kuivila and J. Zubleta Organomerdics 1982 1,404. 54 D. Weber C. Mujka and H. G. von Schnering Angew. Chem. Inf. Edn. Engl. 1982,21 863. 272 J D. Kennedy Me ,Me s The tin analogue is similarly prepared although the germanium compound is prepared directly from Na,P and Me3GeC1 in a heterogeneous reaction. In contrast to the very sensitive silicon analogue the lead compound a colourless crystalline solid is air-stable for days. X-Ray diffraction analysis reveals the structure represen- ted in (38). The molecules are chiral with only one enantiomer being present in each crystal (P2,); bond lengths Pb-P average at 261.1 pm.’ PbMeJ 6 GroupV A significant amount of organoarsenic chemistry is concerned with the synthesis of ligands which are of interest principally to the transition-metal chemist.One interesting one is the ‘tripod’ ligand HC(AsPh,), prepared from the corresponding diarseniomethane H2C(AsPh3)2 via treatment with Bu”Li followed by diphenylchloroarsine. ‘Tripod’ has use in the stabilization of triangular faces of metal clusters for example in the formation of [Rh,(CO),(tripod)] in which each rhodium atom in one triangular face of the Rh tetrahedron is co-ordinated by one of the arsenic atoms.55 Increasing attention is being paid to the potential of organoarsenic compounds in organic synthesis. In this respect it is noted that there is a recent review on arsonium ylides which has sections on their preparation their structure and physical proper- ties and their chemical reactions and synthetic applications.An emphasis is placed on studies at the University of Shanghai extending back over many years but which have not until recently become available; it may therefore offer new perspective^.'^ 55 A. A. Bahsoun J. A. Osborn C. Voelker J. J. Bonnet and G. Lavigne Organometallics 1982,1 1114. 56 Y. Z. Huang and Y. C. Schen Adv. Organomet. Chem. 1982,20,115. 273 Organometallic Chemistry -Part (ii) Main-Group Elements There has been some interest in the ‘spiroarsorane~’;~~~~~ examples of these are readily prepared from RAsO(OH)~ and the appropriate aromatic 1,2-diol (equation 14).Structural studies show that there is a tetragonal pyramidal co-ordination about the arsenic atom with the organic group at the pyramidal apex. This is in contrast to the essentially trigonal bipyramidal co-ordination which is often found in five-co- ordinate arsenic(v) compounds. General conclusions arising out of this type of work are that the basic structural principles developed for phosphorane stereochemistry apply also to pentaco-ordinate arsenic compounds and apparently also to antimony.58 An interesting macrocyclic arsa-aza+xa ‘cryptand’ [{N(CH2CH2)3}8{A~404}6] has been reported. This is made via the cleavage reaction of N(CH2CH2AsPh2)3 with HI to give [HN(CH2CH2As12),]I which upon treatment with concentrated ammonia gives the cryptand product (equations 15 and 16).59 N[(CH2)2AsPh2J3 + 7HI CH2C’2 + [HN{(CH2)2AsI2hlI+ C6H6 [HN{(CH2)2A~12}3]I [{N(CH2CH2)3}8{A~404}6] + 24H20 + 56NH3’Ts + 56NH4I (15) (16) The molecule consists of six eight-membered (AS404) rings roughly located on the faces of a trigonally distorted cube.These are connected together by triethyl- eneamine groups linked to arsenic (39) with the nitrogen atoms occupying the corners of the cube. The (AS404) rings are puckered with the arsenic atoms pointing into the cage and the oxygen atoms pointing outwards. There is however as yet no report on the cryptating ability of this amazing species. (39) 57 R. H. Fish and R. S. Tannous Organometallics 1982 1 1238. 58 R. 0.Day J.M. Holmes A. C. Sau J. R. Devillers R. R. Holmes and J. A. Deiters J. Am. Chem. SOC.,1982,104 2127. 59 J. Ellerman A. Veit E. Linder and S. Hoehne J. Chem. SOC.,Chem. Commun. 1982 382. 274 J. D. Kennedy There is not a large amount of activity in organoantimony or organobismuth chemistry but what activity there is remains reasonably lively. Although as with many main-group metals an increasing amount of organoantimony chemistry is directed towards the synthesis of ligands for transition metals this disease at present is not nearly so serious as it is with arsenic. There is a recent review6' of organo- bismuth chemistry which covers the literature 'through 1980'. Much of the chemistry has been concerned with Sb-Sb and Bi-Bi bonded species. Of these the simple dinuclear bismuth compounds Me4Bi2 and Et4Bi2 have been investigated/reinvestigated.61*62 The ethyl compound is made via the treat- ment of triethylbismuth with sodium (equation 17) followed by addition of ammonium bromide to destroy ethylsodium (equation 18); treatment with dichloroethane then results in the formation of tetraethyldibismuth Et4Bi2 (equation 19).The compound is an unstable red oil at room temperature; on cooling it becomes dark red then almost black at -3O"C becoming yellow again at -196 0C.61 BiEt + Na 3Et2BiNa + EtNa (17) EtNa + NH4Br -+ EtH + NH3 + NaBr (18) 2Et2BiNa + (CH2C1)2 4EtzBiBiEt + C2H4 + 2NaCI (19) The methyl analogue Me4Bi2 prepared similarly from Me3Bi is also thermo- chromic.62 It is a red-yellow liquid at room temperature but solidifies at -12.5 "C to give iridescent violet-blue crystals.Like the ethyl compound it is also thermally very unstable and decomposes readily to Me3Bi and elemental bismuth (tica. 6 h in C6H6 at +25"C). This contrasts to Me4Sb2 which does not decompose until heated to 160-200 "C. Me4Bi2 fumes in air but is stable towards water; it reacts instantly with iodine at 25 "C giving principally Me2BiI MeBi12 Bi13 and elemental bismuth.62 It may be noted en passant that the synthesis of the tetrasilyldibismuth (Me,Si),BiBi(SiMe,) has also been reported in 1982.63 Thermochromic effects on melting are often noted for these diatomic-like organometallic compounds at the lower right-hand corner of the periodic table. The electronic origin of this has been investigated in an extended Huckel study on 2,2',5,5'-tetramethylbistibolyl (40) and has been explained in terms of a one- dimensional electronic band structure for the material in the solid This last as reported last year is characterized by weak intermolecular Sb-.-Sb links of 362.5 pm in addition to the intramolecular Sb-Sb bond at 283.5 pm (41).Other reports of Group V metal-metal bonds in organometallic compounds include the synthesis of the all-cis organocyclotristibane H3CC(CH2)3Sb3 (42)which 6" L. D. Freedman and G. 0.Doak Chem. Rev. 1982,82,15. 61 H. J. Breunig and D. Muller Angew. Chem. Inr. Edn. Engl. 1982,21,439. " A. J. Ashe and E. G. Ludwig Organometallics 1982 1. 1408. 63 G. Becker and M. Rhsler 2. Naturforsch.Teil B 1982,37,91. 64 T. Hughbanks R. Hoffman M.-H. Whangbo K. R. Stewart 0.Eisenstein and E. Canadell J. Am. Chem. SOC.,1982,104,3876. Organometallic Chemistry -Part (ii) Main-Group Elements I (40) (41) is prepared according to the scheme summarized in equations (20)-(22). The compound has some use as a transition-metal ligand.65 MeC(CH2Br) + 3NaSbR2 NH3 b MeC(CH2SbR2)3+ 3NaBr (20) MeC(CH2SbC12)3+ 6RHCHIC12MeC(CH2SbR2)3+ 6HC1 MeC(CH2SbC12)3+ 6Na -(42) + 6NaCl (21) (22) (42) Some interesting work on the antimony and bismuth analogues of pyridine and substituted pyridines has been reported. These are prepared from stannahexadienes via reaction with SbCl or BiCl followed by treatment with the currently popular base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (equation 23).These ‘stibaben- zene’ and ‘bismabenzene’ species readily undergo Diels-Alder addition reactions for example with acetylenedicarboxylic acid derivatives. The pure compounds themselves in fact exist in rapid dynamic equilibrium with their auto-Diels-Alder dimers which have metal-metal bonds as in (43).66 Other work reported includes a study of the thermolytic decomposition of Ph4SbSAr species in organic ~olvents.~’ The solvent-derived products from decompositions in CC1 and cyclohexane confirm the free-radical nature of the reactions the principal product being Ph3Sb. Thermal decompositions of Ph,( p- Tol)SbSC,H,-p-OMe and Ph( p-Tol),SbSC6H4X (X = p-Me0 or H) provide mixed 65 J. Ellerman and A. Veit Angew. Chem.Int. Edn. Engl. 1982 21 375. 66 A. J. Ashe T. R. Diephouse and M. Y. El-Sheikh J. Am. Chem. SOC.,1982,104,5693. ‘’ B. S. Bedi D. W. Grant L. Tewnion and J. L. Wardell J. Organomet. Chem. 1982 239 251. 276 J.D. Kennedy triarylstibines Ph,-,Sb (p-Tol) (n = 0 1 or 2) disulphides (XC6H4),S2 mono- sulphides PhSC6H4X and p-TolSC6H4X arenes PhH and PhMe and the biaryls Ph, Ph-p-Tol and (p-Tol),. 7 Groups VI VII and VIIi It is interesting to witness the renaissance in organotellurium chemistry -'tellurium has been rediscovered by organic chemists as an anomalous element compared to the other chalc~gens'~~*~~ -and there is much current activity in a variety of areas including for examples the advocacy of the tellurapentadecanoic acid (44) as a mycocardial imaging agent,70 and the synthesis of a series of telluropyrylium dyes such as (45).71 Ph Ph (44) (45) Much of the work reported involves the use of organotellurium species in organic syntheses and a listing of many recent references on the use of tellurium in this area is provided in a paper by Clive ef uL7* Again there has been a significant number of structural studies particularly of mononuclear organotellurium com- pounds in which secondary bonding behaviour is often the focus of interest.For example the species [{Ph2Te(N03)20}Ph2Te(N03)(OH)], [PhTeO(N03)], and [Ph2Te(N03)2]all exhibit distorted pseudo-trigonal bipyramidal geometry about tellurium with the lone pair in one of the equatorial positions but all in addition exhibit weak secondary Te...O bonds in the range 286.2-351.4 pm.73 By contrast tetraphenyltellurium Ph4Te the first tetraorganogroup(v1) compound to be struc- turally investigated has no secondary intermolecular bonding giving a genuine four-fold co-ordination.The geometry is also pseudo-trigonal bipyramidal with the lone pair occupying one of the three equatorial positions the three angles being C(eq)-Te-C(eq) 108.6" C(ax)-Te-C(ax) 168.7" and C(eq)-Te-C(ax) 86.7'. The bond distances are as follows Te-C(eq) 213(0) pm and Te-C(ux) 227(1)-231(1) pm the last being the longest Te-C bond length yet Diorganotellurones R2Te02 were previously ill-defined but it has now been found that the telluroxide (MeOC6H4),Te0 may be oxidized readily by NaI04 to give the tellurone (46) in 82% yield as a high-melting solid.It has use as a relatively mild oxidant capable of effecting a variety of organic transformations e.g. PhSH + PhSSPh (97%) hydroquinone -+ p-benzoquinone (39%) ben-zoin + benzil (89%) piperonyl alcohol -+ piperonal (72%) veratryl alcohol + veratraldehyde (~!Y!/o), ef~.~' K.J. Irgolic J. Organome!. Chem. 1980,203 367. 69 M. R. Detty and B. J. Murray J. Org. Chem. 1982 47 1146. 70 M. M. Goodman and F. F. Knapp J Org. Chem. 1982,47,3004. 71 M. R. Detty and B. J. Murray J. Org. Chem. 1982 47 5235. 72 D. L. J. Clive P. C. Anderson N. Moss and A. Singh J. Organomet. Chem. 1982,47 1641. 73 N. W. Alcock and W. D. Harrison J. Chem. SOC.,Dalton Trans. 1982 1421. 74 C. S. Smith J.-S. Lee D. D. Titus and R. F.Ziolo Organometallics 1982,1 350. 75 L. Engman and M P. Cava J. Chem. SOC.,Chem. Commun. 1982,164. Organometallic Chemistry -Part (ii) Main-Group Elements R I I R (47) Diary1 ditellurides Ar,Te2 are oxidized by SeO to give benzenetellurenylben- zenetellurinyl selenides ArTe-Se-Te(=O)Ar in yields of up to ca. 45%; an ortho-carbonyl substituent on the aromatic ring results in the formation of bis(ben-zenetellurenyl) selenides believed to be stabilized by interactions as shown in (47). The Te-Se-Te system appears to be quite stable much more so for example than the S-Se-S Other work noted during 1982 includes the synthesis and X-ray examination of bis(ditel1uro)tetracene (48) a black air-stable solid,77 and of hexamethylenetetra- tellurafulvalene (49) which is of significance in the ‘organic metals’ area.78 Both compounds have short intermolecular Te.-.Te contacts of 370.1 and 358.3 pm respectively (the van der Waal radius sum is 412 pm).Te -Te Te-Te (48) (49) Finally in this year’s report it is of interest to note the preparation of the organoiodine(v) complex (50),as a stable salt m.p. 288-291 0C.79Although gen- erally regarded in its uncomplexed state as an element more electronegative than carbon the iodine centre in compounds such as this can certainly be regarded as having substantial metal character. In this context it is difficult to resist speculating 76 N. L. M. Dereu R. A. Zingaro E. A. Meyers and M. Renson Organometallics 1982,1 111. 77 D. J. Sandman J.C. Stark and B. M. Foxman Organometallics 1982 1 739. 78 P. J. Carroll M. V. Lakshmikantham M. P. Cava F. Wudl E. Aharon-Shalom and S. D. Cox J. Chem. Soc. Chem. Commun. 1982 1316. 79 D. B. Dess and J. C. Martin J. Am. Chem. SOC. 1982 104 902. 278 J. D. Kennedy forward from the recent syntheses of compounds containing Xe-N bonds80*81 (rather than just Xe-0 and Xe-F linkages); these indicate that the isolation of Xe-C bonded species is perhaps becoming an increasingly tenable proposition. J. F. Sawyer G. J. Schrobilgen and S. J. Sutherland J. Chem. SOL Chem. Commun. 1982 210; Inorg. Chem. 1982,21,4064; and refs. cited therein. J. Foropoulos and D. D. DesMarteau J. Am. Chem. SOC. 1982,104,4260.

ISSN:0069-3030    

DOI:10.1039/OC9827900257

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

13 Synthetic Methods By W. CARRUTHERS Department of Chemistry The University Exeter EX4 4QD 1 Introduction This year's Report again has to be selective. A limited number of areas have been reviewed in as thorough a manner as space allows selected on the grounds of their importance and of current synthetic interest as revealed by the numbers of publica- tions dealing with them. 2 Alkenes A review' shows how alkenes can be synthesized stereospecifically by carbometal- lation of alkynes. Organocopper compounds seem to be the most useful organometallic reagents in these transformations but organo derivatives of other metals also have their uses. Extending the well-known Zweifel synthesis of cis-1,2-disubstituted alkenes from terminal alkynes it is now found that dialkylvinylboranes themselves prepared conveniently by reaction of dialkylhaloboranes with an internal alkyne in the presence of lithium aluminium hydride react with iodine in the presence of sodium methoxide to form stereoselectively a tri-substituted alkene in which the two alkyl substituents on the original alkyne are trans to each other.(2)-3-rnethylpent-2-ene for example was obtained exclusively from but-2-yne in 71 per cent yield' (Scheme 1). . Et2B A MeHH Et'BBr 1 )=(H Me Me Et Me Reagents i MeCECMe $LiAlH, 0 "C,THF; ii NaOMe I, MeOH -78 "C Scheme 1 The range of Zweifel's synthesis of trans-dialkylalkenes from terminal alkenes and dialkylboranes has also been extended by development of an improved route to dialkylboranes by hydridation of dialkylhaloboranes.Dialkylboranes generated in situ by this procedure hydroborate 1-bromo-1-alkynes to give the corresponding B-(cis-1-bromo-1-alkeny1)dialkylboranes. Reaction of the latter with sodium methoxide leads to B-(trans- 1-alkyl- 1-alkenyl)alkylborinate esters which on pro-tonolysis give trans-alkenes and on treatment with iodine form trisubstituted alkenes ' J. F. Normant and A. Alexakis Synthesis 1981 841. H. C. Brown D. Basavaiah and S. U. Kulkami J. Org. Chem. 1982 47 171. 280 W. Carruthers in high yield3 (Scheme 2). (2)-7-Alken-l-als can be obtained by iodination of the trans-1-alkenylborepanes formed via monohydroboration of 1-alkenes with borepane in the presence of base.4 A variety of pure trans-disubstituted alkenes was synthesized from terminal alkenes and haloalkynes by way of the thexylborane derived from the alkene.' R,B H R R,BH +BrC-CR )=(Br R' + MeOBr R Reagents i NaOMe MeOH; ii MeCO,H reflux; iii I, NaOMe -78 "C Scheme 2 A modification of Corey's original method for the conversion of 1,2-diols into alkenes via thionocarbonates allows reaction to proceed at room temperature or a little above and can be effected with complex or sensitive molecules containing a variety of functional groups.6 A method for bringing about in effect nucleophilic addition to an alkene' ('alkene umpolung') uses as auxiliary reagent dimethyl(methy1thio)sulphonium fluoroborate (DMTSF)as in Scheme 3.Nu J" SR /* / Scheme 3 Reaction of the alkene with nitrogen nucleophiles in the presence of DMTSF takes place with a high degree of regiocontrol to give products which can be used to prepare amines by reductive cleavage of sulphur oxazolines and aziridines and also to effect cis-hydroxyamination of the alkenes by taking advantage of the leaving-group properties of sulphur.The stereochemistry of the additions is trans for both cis- and trans-disubstituted alkenes; the regiochemistry depends on the H. C. Brown and D. Basavaiah J. Org. Chem. 1982,47,754. D. Basavaiah and H. C. Brown J. Org. Chem. 1982,47 1792. H. C. Brown H. D. Lee and S. U. Kulkarni Synthesis 1982 195. E. J. Corey and P. B. Hopkins Tetrahedron Lerr. 1982,23 1979. B. M. Trost and T. Shibata J. Am. Chem. SOC.,1982,104 3225. Synthetic Methods 281 degree of substitution of the alkene and the nucleophilicity of the attacking reagent.For example 2-propylpent- 1-ene gives mainly the anti-Markovnikov product with ammonia but the Markovnikov product with trimethylsilyl azide (Scheme 4). SMc I. iv J v\-SMe SMe aSMe1--lakMe o**o)-Me "N *NHCOMe 'NHCOMe 1 Reagents i Me,S+-SMe BF; CH,Cl, 0 "C; ii Me,SiN,; iii propylene dithiol Et,N MeOH 60 "C; iv NH3 Scheme 4 Hydroxy-groups can also be introduced to give a-hydroxy-sulphides and conditions chosen so that either the Markovnikov or the anti-Markovnikov product predomi- nates. In another application nitriles are obtained using sodium cyanide as nucleophile' (Scheme 5). Reagents i Me,S+-SMe BF; MeCN; ii KCN 25 "C; iii m-ClC,H4C03H CH,Cl,; iv DMF 130°C Scheme 5 A new route to aryl- vinyl- and 1-alkenyl-allenes by reaction of propargylic or allenic halides with appropriate organozinc halides in the presence of Pd(PPh& B.M. Trost T. Shibata and S. J. Martin J. Am. Chem. SOC.,1982 104 3228. 282 W. Carruthers has been reported.' Optically active allenic halides have been prepared by reaction of optically active propargylic methanesulphonates with lithium halocuprates LiCuX2.lo Thus starting from (S)-(+)-ethynylphenyl carbinol (1)dextro-rotatory allenes (2)were obtained in 90-95% chemical yield (Scheme 6). H ph 'C-CGCH I HO OS0,Me H- (1) Reagents i BuLi; ii MeS0,CI; iii LiCuX or LiCu,X, THF -78"C Scheme 6 Allenic alcohols are produced by reaction of aldehydes and ketones with the organometallic compound formed by reaction of trimethylsilylpropargyl bromide with aluminium amalgam.Reaction takes place readily in anhydrous tetrahy- drofuran to give allenic alcohols by attack at the carbon atom adjacent to the trimethylsilyl group." This contrasts with the reactions of the corresponding (trimethylsily1)zinc bromides which lead to the propargylic alcohols. A number of new or improved routes to dienes and en-ynes have been reported. Thus E-l-substituted-1,3-dienesare obtained with high stereoselectivity by ther- mal extrusion of sulphur dioxide from 2-substituted-2,5-dihydrothiophen-l,l-dioxides themselves generated by retro Diels-Alder reaction from (3) (Scheme 7). The sequence was used in a synthesis of (E)-9,11-dodecadien-l-y1acetate a Reagent i 650"C Scheme 7 sex pheromone of the red bollworm moth.12 In another approach to the synthesis of conjugated dienes reaction of aldehydes with the 1,3-bis(trimethylsilyl)propenyl anion in the presence of magnesium bromide or trimethyl borate gives stereoselec- tively the alcohols (4) which can be transformed into either (1E,3E)-or (1E,3Z)-trimethyl~ilylbuta-l,3-dienes'~ (Scheme 8).In a related approach the q3-trimethyl- silylallyltitanium compound (q5-C5H5)2Ti(q3-l-trimethylsilylallyl) (5) (Scheme 9) formed in situ from reaction of (q5-C5H5)2TiCl with trimethylsilylallyl-lithium K. Ruitenberg H. Kleijn C. J. Elsevier J. Meijer and P. Vermeer Tetrahedron Lett. 1981 22 1451.lo C. J. Elsevier J. Meijer G. Tadema P. M. Stehouwer H. J. T. Bos P. Vermeer and W. Runge J. Org. Chem. 1982,47 2194. R.G.Daniels and L. A. Paquette TetrahedronLett. 1981 22 1579. R.Bloch and J. Abecassis Tetrahedron Lett. 1982,23,3277. l3 Tak-Hang Chan and J.-Sheng Li J. Chem. SOC.,Chem. Commun. 1982,969. Synthetic Methods SiMe SiMe, R- Reagents i RCHO MgBr,; ii H2SOo THF; iii KH THF Scheme 8 reacts with aldehydes to give (~)-(R,S)-3-trimethylsilyl-4-hydroxy-l-alkenes (6)in excellent yield. These can in turn be converted into either (E)-or (2)-terminal dienes.l4 liii iv v R vii vi --R -R-88% for R = Ph SiMe 86% for R = Ph (6) Reagents i BuLi HMPA; ii (~S-C,H,),TiCl; iii RCHO; iv aqueous HCl; v air; vi. H2S04 THF; vii KH THF Scheme 9 Conjugated dienes have also been obtained in high yield and excellenf stereochemical purity by palladium-catalysed coupling of 1-halo- 1-alkenes with magnesium vinyl-copper derivatives obtained by carbocupration of terminal al- kynes." An alternative approach makes use of the dienylcuprates that are formed Meh + *V+C5H, Et CU MgX Et -C5Hll 78% 99.5%(E,2) Reagent i catalytic Pd(PPh,), THF -15 "C Scheme 10 l4 F.Sato Y. Suzuki and M. Sato TetrahedronLett.,1982,23,4589. *' N. Jabri A. AIexakis and J. F. Normant Tetrahedron Lett. 1982,23 1589. 284 W. Carruthers by addition of some alkenylcuprates to acetylene and which may undergo further functionalization (Scheme 11).16 Some organocopper and cuprate derivatives bear- ing distally a free or protected hydroxy-group undergo addition to alkynes to give aw-bifunctional olefins.l7 In an improvement of earlier procedures both alkenyl groups of a lithium dialkenylcuprate can be engaged in palladium-catalysed reaction with alkenyl iodides to give substituted conjugated dienes by addition of one molar equivalent of magnesium chloride to the lithium cuprate. lS Reagents i CuBr.Me,S ether -30 "C; ii CH-CH 0 "C; iii CO Scheme 11 Coupling of a Grignard reagent with a vinyl halide in the presence of transition- metal salts is an important route to alkenes and can be stereospecific under appropriate conditions but vinyl halides are sometimes difficult to prepare stereoselectively. On the other hand vinyl sulphones are easily obtained in both the (E)and (2)forms and a new cross-coupling reaction of vinyl sulphones with Grignard reagents catalysed by nickel and iron complexes leads stereospecifically to trisubstituted alkenes of defined stereochemistry" (Scheme 12).Reagent i MeMgCI THF Ni(acac) Scheme 12 A convenient route to isoprene derivatives for use in Diels-Alder reactions proceeds from 2-methyl-1,3-ene-ynes by reduction with di-isobutylaluminium hydride and reaction of the derived alanates with alkylating agents or aldehydes." 1,3-Dienes have also been obtained from allyl 2-pyridyl sulphides or allyl phenyl sulphones by treatment with n-butyl-lithium in tetrahydrofuran followed by tri-n- butylstannyl-methyl iodide.20 '' A. Alexakis and J. F. Normant Tetrahedron Lett.1982 23,5151. '' M. Gardetti A. Alexakis and J. F. Normant Tetrahedron Lett. 1982 23,5155. '* J.-L. Fabre M. Julia and J.-N. Verpeaux Tetrahedron Lett. 1982 23,2469. l9 A. P.Kozikowski and Y. Kitigawa Tetrahedron Lett. 1982 23,2087. 2o M. Ochiai S. Tada K. Sumi and E. Fujita Tetrahedron Lett. 1982 23,2205. 285 Synthetic Methods The stereoselective synthesis of 1,4-alkadienes by a number of routes has been reported21 and a one-pot synthesis of 1-alken-5-ynes from propargyl halides and two equivalents of an allylmagnesium halide has been described.22 Another route to 1,5-ene-ynes and 1,5-dienes makes use of the coupling reaction between 1,3- dilithiopropargyl phenyl sulphide and allylic halides.23 A simple stereocontrolled synthesis of (E,Z)-1,5-dienes proceeds from the readily available sulphone (7) by functionalization followed by thermal extrusion of sulphur dioxide; yields of diene ranging from 30-87% were The stereochemical course of the reaction depends on the usual chair-like transition state in the Cope rearrangement of the meso-1,2-divinyl compound (8).This work has been extended to provide a route to seven-membered ring compounds (Scheme 14).25 \ 'X = C02H CH20H CH20Me (8) CH20Ac,or C02Me Reagent i 550 "C for X = C0,Me Scheme 13 Reagent i 580 "C Scheme 14 Acylcobalt complexes prepared from NaCo(CO) and organic halides react with butadiene isoprene and allene to form (acyl-vally1)cobalt complexes which undergo alkylation at the unsubstituted r-ally1 terminus on reaction with stabilized carbanions.The procedure provides an overall 1,4-acylation-a1kylation of 1,3-dienes in which three carbon-carbon bonds are formed in a one-pot four-step reaction sequence.26 The Wittig reaction continues to be widely used in the synthesis of olefinic compounds of diverse types. It has been found that addition of a catalytic quantity of a crown ether greatly facilitates the reaction of a phosphonate anion with 21 H. J. Bestmann K.-H. Koschatzky A. Plenchette J. Suss and 0. Vostrowsky Annalen 1982 536. 22 H. Priebe and H. Hopf Angew. Chem. Int. Ed. Engl. 1982,21 286. 23 E. Negishi C. L. Rand and K. P. Jadhav J. Org. Chem. 1981,46 5041. 24 J. I. G. Cadogan C. M. Buchan I. Gosney B. J. Hamill and L. M.McLaughlin J. Chem. SOC.,Chem. Commun. 1982,325. 25 R. A. Aitken J. I. G. Cadogan I. Gosney B. J. Hamill and L. M. McLaughlin J. Chem. SOC.,Chem. Commun. 1982 1164. 26 L. S. Hegedus and Y. Inoue J. Am. Chem. SOC., 1982,104,4917. 286 W. Curruthers aldehydes. Nearly quantitative yields of alkenes were obtained in short reaction times and at lower temperatures than conventionally The lithiated reagent Ph,P=CHLi readily obtained by reaction of methyl-enetriphenylphosphorane with t-butyl-lithium or from methyltriphenylphos-phonium bromide with two equivalents of s-butyl-lithium is a highly reactive ylid equivalent.28 It reacts with carbonyl compounds which resist attack by conventional Wittig reagents. Fenchone for example which fails to react with methyl-enetriphenylphosphorane at temperatures up to 50 "C reacts readily with the new reagent in the presence of hexamethylphosphoric triamide to form an adduct which decomposes to the exo methylene derivative (9) (84%) in the presence of an excess of t-butyl alcohol.The reagent also reacts readily with epoxides. With cyclopentene oxide the y-oxido-ylid (10) is formed and reacts with benzaldehyde at -78 "C to give the truns,truns-homoallylic alcohol (1 1)in 65%yield with formation of two carbon-carbon bonds and three stereo-centres in one operation (Scheme 15). In contrast cyclopentene oxide and methylenetriphenylphosphorane did not react even at 50 "Cin tetrahydrofuran. With benzaldehyde the trans-allylic alcohol (12) is produced in 60% yield by way of the P-oxido-ylid (13)which reacts with a second molecule of benzaldehyde.Reagents i Ph,P=CHLi ether 20 "C;ii PhCHO ether -78 "c Scheme 15 According to Kishi' and his co-worker~*~ the Horner-Emmons route to arp-unsaturated esters affords mixtures of cis and trans isomers the compositions of which are sensitive to the structure of the phosphonate reagents. In general a " R. Baker and R. J. Sims Synthesis 1981 117; Tetrahedron Lett. 1981 22 161; J. Chern. SOC., Perkin Trans. I 1981,3087. *' E. J. Corey and J. Kang J. Am. Chem. SOC., 1982,104,4724. 29 H. Nagaoka and Y. Kishi Tetrahedron 1981,37,3873. Synthetic Methods 287 phosphonate with large phosphonate ester groups gives predominantly the trans-a@- unsaturated ester whereas a phosphonate with small phosphonate ester groups yields mainly the cis-a@-unsaturated ester.They obtained a much higher ratio of trans-@-unsaturated ester with (Pri0)2POCH2C02Et than with Ph3P=CHC02Et. A stereoselective synthesis of (2)-a@-unsaturated aldehydes by the Wittig reac- tion uses the new reagent (16),which is obtained from (2-ethoxyviny1)triphenylphos-phonium bromide (14) directly by reaction with sodium ethoxide or by proton abstraction with sodamide followed by addition of ethanol. Reaction with aldehydes takes place with high stereoselectivity to give (2)-a&-unsaturated acetals (17) which are cleaved to the (Z)-a&unsaturated aldehydes with p-toluenesulphonic acid in aqueous acetone or with wet silica gel3' (Scheme 16). Wittig reaction of an allyl formate has been used to prepare an allyl vinyl ether employed subsequently in a Claisen rearrangement.31 Ph3P=CH2 Ph3P=CHCH0 A Ph36-CH=CHOEt Br-lvii rn R CHO Reagents i HCO,Et benzene; ii EtBr reflux; iii NaNH, ether; iv EtOH; v NaOEt; vi RCHO THF; vii p-MeC,H,SO,H aqueous acetone 0 "C Scheme 16 Oxidative elimination of 2 -pyridylseleno carbonyl compounds affords enones in cases where satisfactory results were not obtained with phenylseleno The a-pyridylseleno compounds themselves are readily obtained by the reaction of 2-pyridylselenyl bromide prepared in situ from 2,2'-dipyridyl diselenide and bromine with aldehydes and ketones in the presence of hydrogen chloride.Heptanal gave a 90% yield of the ap-unsaturated compound by this procedure whereas only low yields were obtained using the phenylseleno derivative.A convenient route to 1-acetylcycloalkenes proceeds by acylation of the cyclo- alkene with acetic anhydride and zinc chloride followed by isomerization of the mixture obtained with alumina,33 and in a new route to cyclopentenones Michael addition of allylsilanes to nitro-alkenes in the presence of aluminium chloride gives unsaturated nitronic acids which are converted into y6-enones by aqueous 30 H. J. Bestmann K. Roth and M. Ettlinger Chem. Ber. 1982 115 161. M. Suda Chem. Lett. 1981 967; Tetrahedron Lett. 1982,23,427. 32 A. Toshimitsu H. Owada S. Uemura and M. Okano Tetrahedron Lett. 1982,23,2105. 33 T. Hudlicky and T. Smak Tetrahedron Lett. 1981,22 3351.288 W. Carruthers Ti"'. Transformation of the enone into the corresponding 1,4-diketone by pal- ladium-catalysed oxygenation followed by intramolecular aldol condensation then provides the cycl~pentenone~~ (Scheme 17). -Me,% Reagents i AICI, CH2CI, -20°C; ii TiCI, aqueous glyme pH = 1; iii DMF PdCl, CuCl, 0,; iv NaOH Scheme 17 (Pheny1sepno)acetaldehyde is the synthetic equivalent of the vinyl carbonium ion CHz=CH and can be used to convert ketones into a-vinyl ketones as in the example in Scheme 18.35 The zinc enolate of the ketone is condensed with (phenyl- se1eno)acetaldehyde and the product converted into a a-vinyl ketone by the action of methanesulphonyl chloride and triethylamine. Reagents i MeLi; ii ZnCI, ether; iii PhSeCH,CHO; iv MsCI Et,N CH,CI Scheme 18 A variant of the Claisen ester-enolate rearrangement leads to A5'6-unsaturated The reaction employs trimethylsilylmethylallyl esters of type (18).With lithium di-isopropylamide compound (19) was obtained from (18) in 61% yield as a mixture containing 90% of the trans-erythro compound. Further reaction with boron trifluoride gave the unsaturated acid (20) in quantitative yield. The cor- responding rearrangement of vinyl ethers was also explored. Thus thermolysis at 110 "C of the vinyl ether (21) gave the synthetically useful functionalized allylsilane (22) in 92% overall yield. The derived alcohol (23) on oxidation with pyridinium chlorochromate gave enone (24) which was readily converted into 4-methyl-4- vinylcyclohexanone.34 M. Ochiai M.Arimoto and E. Fujita Tetrahedron Lefr. 1981,22,1115. 3s D. L. J. Clive C. G. Russell and S. C. Suri J. Org. Chem. 1982 47 1632. 36 S. A. Wilson and M. F. Price J. Am. Chem. SOC.,1982,104 1124. Synthetic Methods 289 i MeySiMe ii MeTSiMe -+ -MeTsiMe3 0 OH MeVo Me OH (18) (19) 1 iii Reagents i (EtCO),O Et,N; ii LiNPr -78 "C + 25 "C; iii BF, MeCO,Et CH2C12 Scheme 19 Reagents i 110 "C; ii @MgBr ; iii C5H5&HCr0,Ci;iv BF,.Et,O Scheme 20 Ester-enolate Claisen rearrangement of allylic esters of N-acyl a-amino-acids gave 76-unsaturated amino-acids in good yield and with high diastereo~electivity,~' but the scope of the analogous reaction with allylic esters of a-hydroxy-acids is limited by low yields and modest stereo~electivity.~~ 37 P.A. Bartlett and J. F. Barstow J. Org. Chem. 1982 47 3933. '* P. A. Bartlett D. J. Tanzella and J. F. Barstow J. Org. Chem. 1982 47 3941. 290 W.Carruthers P-Vinyl-0-propiolactone reacts regio-and stereo-selectively with Grignard reagents in the presence of a Cu’ catalyst or with diorganocuprates to give (E)-3-alkenoic acids in good yield (Scheme 21).39 Palladium-catalysed decarboxylation-carbonylation of allylic carbonates gives py-unsaturated esters under mild condition^.^' forR = Et 9 1 R = pc’ ” 23 H2 Reagent i RMgX-CuI.Me,S-THF Scheme 21 3 Alkylation A new class of reactive heterocuprates with greatly improved thermal stability based on phosphido and amido ligands has been introd~ced.~~ It has been also that highly reactive yet thermally stable reagents of general formula R2Cu(CN)Li2 are obtained by using copper cyanide instead of the more usual copper halides in the preparation of the cuprates.These copper complexes react readily with a@-unsaturated ketones in Michael fashion and undergo substitution reactions with epoxides and halides even secondary bromides and iodides reacting readily. The stereochemical course of these halogen displacements is substrate dependent. With secondary bromides both organocuprates (R,CuLi) and the mixed cuprates [R2Cu(CN)Li2] react to give products formed by inversion of configuration but with secondary iodides racemic products are formed. The difficulties in achieving controlled a-alkylation of ketones are well known and regioselective reaction can only be achieved when the enolate anion generated regiospecifically reacts with the alkylating agent before equilibration takes place uia proton transfer.These difficulties are avoided if the reaction of the silyl enol ethers with alkyl halides occurs in the presence of benzyltrimethylammonium fluoride. The corresponding monoalkylated ketone is obtained with high regioselec- tivity and in most cases polyalkylated products are not formed. Even relatively unreactive alkylating agents such as butyl iodide give reasonable yields of specifically alkylated products under these condition^.^^ a-Alkylation of carbonyl compounds by the reaction of the silyl enol ethers with alkyl halides in the presence of Lewis acid catalysts has been reviewed.44 This procedure is particularly valuable 39 T.Sato M. Takeuchi T. Itoh M. Kawashima and T. Fujisawa Tetrahedron Lett. 1981,22 1817. 40 J. Tsuji K. Sato and H. Okumoto Tetrahedron Lett. 1982,23 5189. 41 S. H. Bertz G. Dabbagh and G. M. Villacorta J. Am. Chem. SOC., 1982 104 5824. 42 B. H. Lipshutz J. Kozlowski and R. S. Wilhelm J. Am. Chem. SOC.,1982,104,2305; B. H. Lipshutz R. S. Wilhelm and D. M. Floyd ibid. 1981 103 7672. 43 I. Kuwajima E. Nakamura and M. Shimizu J. Am. Chem. SOC.,1982,104 1025. 44 M. T. Reetz Angew. Chem. Int. Ed. Engl. 1982 21,96. Synthetic Methods 291 since it is effective with alkyl halides and acetates which tend to react by an SN1 mechanism and are thus unsuitable for ordinary base-catalysed alkylation reactions.Aldehydes ketones and esters for example are readily converted into a-t-butyl derivatives (Scheme 22). Reagent i Bu'C1 TiC14 or MeCO,Bu' ZnI Scheme 22 Regiospecific allylation of ketones can be achieved in high yield by reaction of the corresponding potassium enoxyborates readily obtained from potassium eno- lates and a trialkylborane with an allylic alkylating agent in the presence of a catalytic amount of a palladium phosphine complex45 (Scheme 23). 0 81% 6 OBEt3K OL Reagents i KN(SiMe,),-BEt,; - ii AcO / catalytic Pd(PPh,),-THF -25 "C; iii KH-BEt Scheme 23 High regioslective deprotonation and alkylation of unsymmetrical imines at the more substituted a-carbon atom can be achieved under the appropriate c~nditions.~~ In contrast to alkylation of a-metalated derivatives of unsymmetrical imines pre- pared by previously described procedures deprotonation of the N-cyclohexylimine of 2-methylcyclohexanone with n- s- or t-butyl-lithium and subsequent alkylation with alkyl halides gave in every case tried a mixture of the corresponding a-alkylated-2-methylcyclohexanonesin which the product resulting from alkylation at the more substituted a-carbon atom largely predominated.With imines of acyclic ketones the regioselection was not so high but in the presence of hexamethylphos- " E. Negishi H. Matsushita S. Chatterjee and R. A. John J. Org. Chem. 1982,47 3188. 46 A. Hosomi Y. Araki and H. Sakurai J. Am. Chem. Soc. 1982,104,2081.292 W. Carruthers phoric triamide remarkably only one product resulting from reaction at the less substituted carbon atom was formed (Scheme 24). A good route to 2-alkyl- and 2-hydroxymethylcyclopentenones and cyclo- hexenones through the derived a-ketovinyl anion has been described47 (Scheme 25). Reagents i BuLi-pentane-THF -78 "C; ii PhCH,CI-HMPTA -78 "C; iii H,O' Scheme 24 Reagents i BuLi THF -78 "C; ii C,H ,I THF HMPA; iii H,O' Scheme 25 M Ph Me HOCH2 111 0 ii,&Me ... &Me &HHO,CvMe A yMe p( -+ PhCH,O CH,Ph &,Ph 93% CH,Ph CH,Ph 86% Reagents i LiNPri or NaN(SiMe,), THF -78 "C; ii e.g. E-Hal; iii PhCH,OLi PhCH,OH; iv H,-Pd; v LiAIH4 THF 0 "C Scheme 26 47 A. B. Smith 111 S. J. Branca N. N.Pilla and M. A. Guaciaro J. Org. Chem. 1982,47 1855. Synthetic Methods a'-Alkylation of cyclohexenones has been effected by the reaction of the silyl enol ethers of the corresponding epoxides with cuprate reagents.48 6-t-Butyl- cyclohex-2,3-enone for example was obtained in quantitative yield by reaction of lithium t-butylcyanocuprate with the trimethylsilyl ether of cyclohexenone epoxide followed by mild acidic hydrolysis of the resulting 1,4-addition product. A practical approach to the enantioselective synthesis of a-substituted carboxylic acids by asymmetric alkylation of chiral imide enolates has been reported.49 The enolates derived from the N-acyloxazolidones (25) and (26) with bases such as LiNPr; and NaN(SiMe& undergo complementary diastereoselective alkylation when treated with reactive alkyl halides.The alkylated oxazolidones are converted into benzyl esters by reaction with lithium benzyloxide without racemization and thence by hydrogenolysis into the free acids; with lithium aluminium hydride alcohols are produced. A novel route to chiral a-substituted succinic acids proceeds from an allylic acetate by asymmetric alkylation with malonate anions catalysed by a chiral palladium-phosphine complex. Further manipulation of the initial alkylation pro- duct as shown in Scheme 27 leads to the succinic acid." R fl'" Me02C>,,qph AcO Ph Me0,C H Ph Reagents i NaCH(CO,Me) ph3pP2 ;ii CrO,; iii -OH; iv A Scheme 27 A systematic study has been made'' of the stereochemistry of the deconjugative alkylation of a series of cup-unsaturated esters.Deconjugative protonation alkyla- tion and aldol condensation of the lithium dienolates of (2)-2-alkenoates gave products derived from the corresponding (E)-3-enoates whereas the lithium dieno- lates from (E)-2-enoates gave mainly (2)-3-enoates (Scheme 28). Reagents i LiNPr'; HMPA THF -78 "C;ii MeI; iii H,O+ Scheme 28 48 J. P. Marino and J. C. Jatn J. Am. Chem. SOC.,1982 104 3165. 49 D. A. Evans M. D. Ennis and D. J. Mathre J. Am. Chem. Soc. 1982 104 1737. " B. Bosnich and P. B. Mackenzie Pure Appl. Chem. 1982 54 189. '' A. S. Kende and B. H. Toder J. Org. Chem. 1982,47,163. 294 W.Carruthers 3-Chloro-2-(trimethylsiloxy)prop- 1-ene serves as a novel electrophilic acetonyl equivalent in reactions with a-metalated imines hydrazones and activated methyl- ene Thus reaction with the a-lithio derivative of the dimethylhy- drazone of octan-2-one and careful hydrolysis of the initial product gave undecan- 2,5 -dione in 92% yield.Similarly 2-bromoallyltrimethylsilane in the form of its Grignard reagent is the synthetic equivalent of the 1-hydroxymethylvinyl anion.53 The Grignard reagent reacts readily with epoxides to form hydroxy allylsilanes which are readily converted into hydroxy allylic alcohols on oxidation with peroxy acids as shown in Scheme 29. The diols serve as useful precursors to a-methylene-y- lactones through allylic oxidation with manganese dioxide. 1ii iii EtGo tZ-EtnoH Reagents i Cu,I,-THF -30 "C;ii m-ClC,H,CO,H; iii H2S0,-H20; iv Mn02-CH2C12 Scheme 29 A novel mild method for replacing bromine or chlorine by an ally1 group employs reaction with allyltri-n-butylstannane in toluene at 80 "C in the presence of az~bis(isobutyronitrile).~~ A variety of other functional groups including aldehydes and epoxides are unaffected under the conditions employed.4 Cyclization Ever since it was discovered that in the biomimetic cyclization of the substrates (29a) and (29b) the chiral centre at pro-C-11 induced ring-closure so as to give preferentially the 1la -substituted products (30a) and (30b) respectively it has been conjectured that a chiral centre even further removed from the initiating site of reaction for example at pro-C-7 might also mediate diastereoselective cycliz- ation.It has now been that in the substrates (31a) and (31b) the chiral centre at pro-C-7 does indeed have a profound influence on the stereochemical course of the ring closure inducing strong diastereoselection in the development of the first new bond between C-9 and C-10 which in turn determines the diastereoselectivity of the rest of the process (Scheme 30). These results were exploited in a biomimetic synthesis of the aldosterone blocking-agent ~pironolactone.~~ " A. Hosomi A. Shirahata Y. Araki and H. Sakurai J. Org. Chem. 1981,46,4631. 53 H. Nishiyama H. Yokoyama S. Narimatsu and K. Itoh Tetrahedron Lett. 1982,23 1267. 54 G. E. Keck and J. B. Yates J. Am. Chem. Soc. 1982,104,5829. " W. S. Johnson D. Berner D. J.Dumas P. J. R. Nederlof and J. Welch J. Am. Chem. Soc. 1982 104,3508. '' W. S. Johnson D. J. Dumas and D. Berner J. Am. Chem. Soc. 1982 104 3510. Synthetic Methods (30) a; R’ = R2 = Me (29) a; R’ = R2 = Me b; R’ = Me,R2 = OH b; R’ = Me,R2 = OH 0 0 + HH “OCH,Ph 6 1.5*/o 9Yo (31) a; R = Me b;R=H Reagent i CF,CO,H Scheme 30 Cyclization of (2R,3R)-2-homogeranyl-3,4-dihydroxybutanoic acid 1,4-dilac- tone (32),initiated by bromonium ion was used as the key step in a biometic synthesis of the marine anti-neoplastic agent aplysistatin (33).57A similar method was used to synthesize (*)-panacene a naturally occurring br~mo-allene.~~ Br Reagent i 2,4,4,6-tetrabromocyclohexa-2,5-dione-MeNO Scheme 31 ’’ H. M. Shieh and G.D. Prestwich Tetrahedron Lett. 1982,23,4643. ’’ K.S.Feldman Tetrahedron Left. 1982,23 3031. 296 W. Carruthers The use of organoselenium-mediated cyclizations to construct both hetero- and carbo-cyclic ring systems is now well-recognized. In a recent examples9 the alkenyl 0-keto-ester (34) treated with N-phenylselenophthalimide in the presence of a trace of stannic chloride gave a mixture of compounds (35) and (36) which were subsequently converted into the naturally occurring tetrahydropyran (37). In the presence of one equivalent of stannic chloride the cyclization took a different course to give (38) and this was exploited in a synthesis of (*)-hirsutene (39) from (40).60 (34) (36) 1ii n PhSea0 I C0,Me (37) (38) (40) Reagents i N-phenylselenophthalimide,trace SnCI, CH,CI,; ii N-phenylselenophthalimide,1 mol.SnCI, CH,CI Scheme 32 A review61 shows how the cyzlization of a-acyliminium ions can be used in the synthesis of alkaloids of various types. A variety of polycyclic piperidine derivatives has been synthesized by the cyclization with formic acid of hydroxy-lactams derived from N-alkenyl-3,4-disubstitutedsuccinimides.62 In studies of rearrangements of N-acyl-2-azahexa- 1,Sdiene it was found that carbinolamine (41) on treatment with formic acid gave the pyrrolizidine (43) as a single stereoisomer in 80% yield possibly by an initial aza-Cope rearrangement of the iminium ion to (42) followed by cyclization to (43). This sequence has been used in a synthesis of the pyrrolizidine bases traechelanthamidine and ~upenidine.~~ &QL{+J}+Hcoo+~ 0 0 0 (41) (42) (43) Reagent i HC0,H Scheme 33 59 S.v. Ley B. Lygo H. Molines and J. A. Morton J. Chem. Soe. Chem. Commun. 1982 1251. 6o S. V. Ley and P. J. Murray J. Chem. SOC.,Chem. Commun. 1982 1252. " W. N. Speckamp Reel. Trav. Chim. Pays-Bas 1981,100 345. 62 B. P. Wynberg W. N. Speckamp and A. R. C. Oostveen Tetrahedron Lett. 1982 38,209. D. J. Hart and T.-K. Yang Tetrahedron Lett. 1982,23,2761. '3 Synthetic Methods Mercury(I1)-induced cyclization of acetylenic alcohols provides a new route to enol ethers and substituted enol Thus the cis-acetylenic alcohol (44) was converted into the enol ether (45) in 89% yield by mercuric chloride and triethyl- amine.In the presence of N-bromosuccinimide the related bromo enol ether (46) was obtained. H (45) (44) (46) Reagents i HgC1,-N-bromosuccinimide-p-dimethylaminopyridine~H2Cl2; ii HgC1,-NEt,-CH2Cl Scheme 34 Factors which affect the efficiency of high-dilution procedures in the synthesis of macrolides have been critically discu~sed.~' The use of dianions in macrolide synthesis by intramolecular alkylation of protected cyanohydrins is said to decrease the possibility of intermolecular reactions and to eliminate the need for high-dilution procedures.66 A potentially useful route to medium and large ring compounds by intramolecular attack of a nucleophilic centre on a vinyl epoxide promoted by palladium complexes supported on polymers has been An advantage of the method is that it eliminates the need for high-dilution techniques.There have been several publications on the use of free radicals in cyclizations. Vinyl radicals generated by reaction of tri-n-butyltin hydride with vinyl halides react readily with suitably placed double bonds to form five- or six-membered rings. An attractive aspect of this procedure is that the new ring is formed with a double bond in a predetermined position ready for further elaboration. In at least one example the new carbon-carbon bond was formed in good yield even when a quaternary carbon centre was produced.68 Aryl radicals generated from halides with tri-n-butyltin hydride react. similarly with suitably placed double bonds in a synthesis of 2,3-dihydroindoles and 2,3-dihydrobenzof~rans,~~ and a radical version ..OH Reagent i Bu,SnH-benzene hv Scheme 35 64 M. Riediker and J. Schwartz J. Am. Chem. SOC.,1982 104,5842. 65 C. Galli and L. Mandolini J. Chem. SOC.,Chem. Commun. 1982,251. T. Takahashi T. Nagashima H. Ikeda and J. Tsuji Tetrahedron Lert. 1982 23,4361. " B. M. Trost and R. W. Warner J. Am. Chem. Soc. 1982,104,6112. 68 G. Stork and N. H. Baine J. Am. Chem. SOC.,1982,104,2321. 69 Y.Ueno K. Chino and M. Okawara Tetrahedron Lett. 1982 23 2575. 298 W. Carruthers of the acyliminium ion cyclization has been reported (Scheme 36).'O With N-acyl-2- azahex-5-ynyl radicals the regiochemical course of the reaction to give five- or six-membered rings depended on the nature of the alkynyl ~ubstituent.~~ Reagent i Bu",SnH-(NCCMe,),N,-benzene reflux Scheme 36 Photocycloaddition of alkenes to the carbon-carbon double bond of enones is a well-known method for making four-membered rings.72 The synthetic scope of the reaction is extended by subsequent modification of the four-membered ring.A review of [2 + 21 cycloreversions of cyclobutane derivatives underlines the synthetic potentialities of this procedure.73 Intramolecular [2 + 21 photoaddition followed by cyclobutane fragmentation can proceed with high regio- and stereo-selective formation and cleavage of carbon-carbon bonds. The application of this dual sequence in the synthesis of terpenoids is illustrated in a review.74 Several examples of the photoaddition of alkynes to enones have been re~orded.~' Copper-catalysed photocyclization of a-alkenylallyl alcohols to fused cyclobutane derivatives has now been extended to p-and y-alkenylallyl @-(Pent-4-eny1)allyl alcohol (47),for example gave the bicyclo-compound (48) in quantitative yield.The synthetic value of the reaction is increased by solvolytic ring expansion of the tosylates of the cyclobutylcarbinols to give five-membered rings as in the synthesis of (SO) from (49).77 Reagent i CF,SO,Cu-ether hv Scheme 37 70 D. J. Hart and Y.-M. Tsai J. Am. Chem. SOC.,1982,104,1430. 71 D. J. Hart and Y.-M. Tsai Tetrahedron Lett. 1982 23 4765. 72 Review S. W. Baldwin Organic Photochemistry 1981,5 123. 73 E. Schaumann and R. Ketcham Angew. Chem. Int. Ed. Engl. 1982,21,225.74 W. Oppolzer Acc. Chem. Res. 1982,15 135. 75 For example J. D. White T. Matsui and J. A. Thomas J. Org. Chem. 1981 46 3376; J. D. White M. A. Avery and J. P. Carter J. Am. Chem. SOC.,1982,104 5486; E. R. Koft and A. B. Smith 111 ibid.,1982 104 5568. 76 R. G.Salomon D. J. Coughlin S. Ghosh and M. G. Zagorski J. Am. Chem. SOC.,1982,47,998. 77 R. G. Salomon S.Ghosh M. G. Zagorski and M. Reitz J. Org. Chem. 1982 47,829. Synthetic Methods 299 Reagents i CuTf ether hv; ii p-MeC,H,SO,CI C,H,N; iii MeC0,H; iv H,,Pd Scheme 38 Thermal cyclization of alkynyl alkyl ketones with at least one hydrogen atom in a p '-position leads specifically to ~yclopent-2-enones.~~ This thermal process results in the formation of a new carbon-carbon bond at a non-activated @'-carbon atom of (51) and also causes a [1,2] shift of the acetylenic substituent and is explained by the formation of an intermediate alkylidene carbene (52) which inserts into the P'C-H bond.By using appropriately substituted starting materials the synthesis of cyclic polycyclic spiro and propellane carbon skeletons has been a~hieved.~' Reagents i SOCI,; ii Me,SiCEC-R; iii A Scheme 39 a-Alkynones with more than one p'-position generally afford mixtures of isomeric cyclopent-2-enones on pyrolysis and the structural and configurational factors which govern the courses of these alternative cyclizations have been elucidated.80 McMurry's titanium-induced coupling of carbonyl compounds can be effected intramolecularly to form rings compounds.This is vividly illustrated by the conver- sion of the keto-aldehyde (53)into humulene with its eleven-membered ring and three double bonds in 60% yield.81 '' M. Karpf and A. S. Dreiding Helv. Chim. Acta 1979,62 852. 79 M. Karpf and A. S. Dreiding Helv. Chim. Acta 1981,64 1123. 80 M. Karpf J. Huguet and A. S. Dreiding Helv. Chim. Acta 1982,65,13. J. E.McMurry and J. R. Matz TetrahedronLett. 1982 23 2723. 300 W. Carruthers Reagent i 6 equiv. TiC1,-Zn-Cu-DME reflux Scheme 40 Pd"-mediated cyclization of appropriate alkenyl-substituted trimethylsilyl enol ethers provides a novel and versatile route to a variety of bridged and spirocyclic ketones.82 Thus the butenylcyclohexenyl enol ether (54) on treatment with Pd(OAc) in dry methyl cyanide gave a mixture of the spiro-ketones (55) and (56) in 94% yield and the cyclopentenyl enol ether (57) gave the bridged ketone (58) in 55% yield.This cyclization was a key step in a neat synthesis of the tetracyclic sesquiterpene quadrone. C0,Et C0,Et (57) (58) Reagent i,Pd(OAc),-MeCN Scheme 41 A modification of the Nazarov cyclization which overcomes the difficulty in the conventional reaction caused by the lack of control over the position of the double bond in the cyclopentenone produced makes use of 0-silyl divinyl ketones. Cycliz- ation with anhydrous ferric chloride of the appropriately silylated precursor leads to a cyclopentenone with the double bond in a predetermined position through the ability of silicon to control the regiochemical outcome of carbonium ion processes.83 Thus with the ketone (59) only the cyclopentenone (60)was obtained.Additional examples of the formation of cyclic ketones by acid-catalysed cycliz- ation of diazo-ketones carrying an appropriately situated double bond (see Annual A. S. Kende B. Roth and P. J. Sanfilippo J. Am. Chem. SOC.,1982 104 1784. A. S. Kende B. Roth P.J. Sanfilippo and T. J. Blacklock J. Am. Chem. SOC.,1982,104 5808. 83 S. E. Denmark and T. K. Jones J. Am.Chem. SOC.,1982,104,2642. Synthetic Methods (y$ SiMe H (59) (60) (84% 100°/oCiS). Reagent i FeC1,-CH,CI, -30 “C Scheme 42 Reports 1981 p. 330) have been recorded,84 and in continuation of their earlier work (Annual Reports 1981 p. 333) Garst and Bonfiglio have synthesized 6-coniceine pyrrolizidine and other alkaloids by application of H.C. Brown’s ‘stitching and rivetting with boron’ technique to appropriate dialkenylamine~.~’ A number of intramolecular [3 + 21 cycloadditions of the general type shown in Scheme 43 have been reported.86 Thus reaction of (61) with Pd(PPh3)4 in refluxing tetrahydrofuran gave the cis-fused bicyclic compound (62) in 5 1% yield along with the triene (63). The cyclization is believed to proceed in a stepwise manner. EWG = electron withdrawing group + +D H-C02Et (62) Reagent i Pd(PPhJ,-THF reflux Scheme 43 Continuing his work on cobalt-mediated [2 + 2 + 21 cycloadditions Vollhardt describes” the conversion of an a,&@-diynene to a steroid nucleus in which rings B C and D are constructed in one step from a monocyclic precursor.Further D. W. Johnson L. N. Mander and T. J. Masters Ausr. J. Chem. 1981,34 1243; L. L. Davis B. L. Mylari M. F. Solomon R. R. du Silva S. Shulman and R. J. Warnet J. Org. Chem. 1982,47 3242. 85 M. E. Garst J. N. Bonfiglio and J. Marks J. Org. Chem. 1982 47 1494. 86 B. M. Trost and D. M. T. Chan J. Am. Chem. Soc. 1982,104,3733. 87 E. D. Sternberg and K. P. C. Vollhardt J. Org. Chem. 1982,47 3447. 302 W. Carruthers manipulations of the initial cyclization products gave (f)-oestrone. A remarkable series of 8tr and 6tr electrocyclizations led to a biomimetic synthesis of the endiandric acids from open chain precursors" (Scheme 44). i ii C0,Me __* QH H' H C0,Me i=-=> Ph H Endiandric acid A methyl ester (30%) Reagents i H,-Lindlar catalyst; ii 100 "C Scheme 44 Cyclopropanation of allylic alcohols with MeCH12 does not require the use of Et2Zn or EtZnI as previously supposed.An ordinary zinc-copper couple or a zinc dust-cuprous chloride reagent gives similar yields of methyl substituted cyclopropyl carbinols although with less reactive olefinic hydrocarbons Et2Zn and EtZnI are still the reagents of ~hoice.'~Cyclopropanes are smoothly produced from non- activated terminal alkenes by reaction with diazomethane in the presence of lead te tra-acetate .90 5 The Diels-Alder Reaction Numerous papers on the Diels-Alder reaction and on its application to the synthesis of natural products have been published during the year.Control of the regiochemistry in Diels-Alder additions is important in synthesis. It has now been found that it is possible to alter substantially the regioselectivity of acid-catalysed addition of a non-polarized diene to a hydroxyquinone by suitable choice of Lewis acid;g* hitherto such control has been observed only in reactions of hydroxyquinones with strongly polarized dienes. 2-Trimethylsilylmethylbuta-1,3-diene undergoes highly regioselective addition to dienophiles such as acrolein and methyl vinyl ketone catalysed by aluminium chloride in which the para-isomers are obtained almost exclusively; the adducts are converted readily into a variety of mono- and se~qui-terpenes.~~ Regiocontrol can also be exercised by substituents on the dienophile.Nitro-olefins are well-known to be excellent dienophiles; they require milder conditions for reaction than many other dienophiles and the nitro-group controls the regiochemistry of addition very effectively. It is now found that the nitro-group in ** K. C. Nicolaou N. A. Petasis J. Uenishi and R. E. Zipkin J. Am. Chem. Soc. 1982 104 5555 5557,5558,5560. 89 E. C. Freidrich and G. Biresaw J. Org. Chem. 1982 47 1615,2426. 90 M. Suda Synthesis 1981 714. 91 R. C. Gupta D. A. Jackson and R. J. Stoodley J. Chem. SOC.,Chem. Commun. 1982,929. 92 A. Hosomi H. Iguchi J. Sasaki and H. Sakurai Tetrahedron Lett. 1982 551. Synthetic Methods the adducts can be efficiently replaced by hydrogen by reaction with tributyltin hydride providing a new method for regioselective construction of cyclohexene derivatives (Scheme 45).93 Me3si0Y OMe + (71%) (82%) Reagents i reflux benzene; ii Bu,SnH-(NC.CMe,),N,-benzene-reflux Scheme 45 Nitro predominates over carbonyl in controlling the direction of Diels-Alder additions and this can be exploited in synthesis.Thus 3-nitrocyclohex-2-enone and pent-1,3-diene gave the product (64) after removal of the nitro-group the reverse of that obtained in the reaction of the diene with cyclohexenone itself (Scheme 46). The normal directive influence of a carbonyl group in the dienophile is overruled by a diphenylphosphinyl group on the other carbon of the dienophile double bond.94 (83'/o ) (64) (86%) Reagents i toluene 90 "C; ii Bu,SnH-(NC.CMe,),N,-benzene-reflux Scheme 46 Full details have now been published on the stereochemical aspects of the intramolecular Diels-Alder reactions of deca-2,7,9-trienoic acid esters referred to in last year's Report (p.340). The thermal reactions in general gave mixtures of cis and trans cyclo-adducts in which the trans-fused products predominated; the product selectivity was independent of the stereochemistry of the dienophile com- ponent. Catalysed reactions (EtAlCI EtAlCI and menthyloxy aluminium dichloride were particularly effective catalysts) in some cases gave mixtures of stereoisomers in others pure trans-fused In a related series of reactions the trienes (65;X = C02R,Y = CN or H) gave exclusively the trans-fused hydrin- denes (66).96Interestingly the closely related (2)-diene (67) gave only the cis-9' N.Ono,H.Miyaki and A. Koji J. Chem. SOC.,Chem. Commun. 1982 33. 94 S. D. Darling and S. J. Brandes J. Org. Chem. 1982 47 1413. " W. R. Roush H. R. Gillis and A. I. KO,J. Am. Chem. Soc. 1982,104,2269. 96 R. K. Boeckman and So0 Sung KO,J. Am. Chem. SOC., 1982,104 1033. 304 W. Carruthers 60 40 H H 65 35 Reagent i 150°C Scheme 47 hydrindene (68) in 80% yield," and the sequence provides a potentially general method for the synthesis of cis-hydrindenes. (65) (66;X = C02R Y = CN or H) ii iii Reagents i 150 "C-benzene-sealed tube; ii 230 "C-benzene-sealed tube; iii KOBu'-ether Scheme 48 Intramolecular Diels-Alder reactions of 2-alkenylbuta- 1,3-dienes have been used to prepare strained bridgehead alkene~,~~ and a similar reaction with alkenoic acid esters of 2-hydroxybuta- 1,3-diene led to synthetically useful bridgehead enol lactones (Scheme 49)." 97 R.K. Boeckman and T. R. Alessi J. Am. Chem. SOC.,1982,104,3216. 98 K. J. Shea S. Wise L. D. Burke P. D. Davis J. W. Gilman and A. C. Greeley J. Am. Chem. SOC. 1982,104,5708. 99 K. J. Shea and E. Wada J. Am. Chem. SOC.,1982,104,5715. Synthetic Methods C-O,Et 1iii ii iv C0,Et Reagents i 185 OC-benzene; ii NaOEt-EtOH 0 "C; iii. H, Pd-C; iv C,H,kHCr03Cl-CH2CI Scheme 49 The very high stereocontrol that can be attained in intramolecular Diels-Alder reactions of (2)-dienes in contrast to that in reactions of the more widely used (E)-dienes has been underlined in recent work with chiral (2)-dienes e.g.(69) to give cis-fused products e.g. (70) with very high stereo- and regio-selectivity.'" The conversion (69) + (70)was the key step in an approach to the synthesis of cytochalasin C. PhH,C CH,Ph (70) Reagent i toluene-reflux Scheme 50 A remarkable effect of orbital overlap requirements in the connecting chain on the ease of intramolecular Diels-Alder reactions has been reported. lo' The esters (71) at temperatures up to 220 "C in a high-boiling solvent gave only small yields of cyclized products whereas the closely related ethers (72) cyclized readily at 170 "C. It is suggested that the geometry of the transition state required for ready cyclization of (71) prevents complete overlap of the lone pair of electrons of the ester oxygen atom with the r-system of the carbonyl group and that the reaction is thereby kinetically disfavoured.S. G. Pyne M. J. Hensel and P. L. Fuchs J. Am. Chem. Soc. 1982 104 5719; S. G. Pyne D. C. Spellmeyer S. Chen and P. L. Fuchs ibid. 1982,104 5728. R. K. Boeckman and D. M. Demko J. Org. Chem. 1982,47 1789. 306 W.Carruthers H' 0 0 0 (72; R = C02Me) (71) R = C02Me R' = H R = H,R' = C02Me Reagent i 170 "C Scheme 51 Properly chosen optically active esters of acrylic acid undergo Diels-Alder addition to cyclopentadiene promoted by TiCl,(OR) to give efficiently and predictably optically active adducts with up to virtually complete asymmetric induction."* Danishefsky has given an interesting review of his work with siloxydienes in the synthesis of natural The initial products of reaction may be cyclo- hexenones 4-acylcyclohexenones 4,4-disubstituted cyclohexadienones or benzene derivatives depending on the precise mode of operation and the nature of the diene and dienophile.In a new line of work it has been shown that the Danishefsky diene (l-methoxy-3-trirnethylsilyloxybuta-l73-diene) reacts readily with a wide variety of aldehydes under mild conditions in the presence of zinc chloride or boron trifluoride etherate to give dihydro-y-pyrones (74).Io4 These may arise through 1 1-cycloadducts (73) although no such intermediates have been detected experi- mentally. Imines reacted in an analogous way to give 5,6-dihydr0-4-pyridones,'0~ and cup-unsaturated aldehydes and cup-unsaturated imines reacted exclusively at the carbonyl or imino group.lo6 The dihydro-y-pyrones (74) obtained in these reactions have considerable syn- thetic potential.They have been used in the synthesis of 4-desoxyhexoses which are otherwise difficultly accessible and of C-1-branched glyco~ides.'~~ The y- pyrones are readily converted into dihydro-a-pyrones and this was exploited in a short synthesis of the Prelog-Djerassi lactone from (S)-2-phenylpr0panal.~~~ In addition reactions with chiral aldehydes addition to the aldehyde group is stereoselective following Cram's rule. This was used in a stereoselective synthesis of the novel p-hydroxy-y-amino-acid statine in the form of its N-benzyloxycarbonyl derivative (75) from N-benzyloxycarbonyl-leucine (Scheme 53).Io9 lo* W.Oppolzer C. Chapuis G. M. Dao D. Reichlin and T. Godel Tetrahedron Lerr. 1982 23 4781. lo3 S. Danishefsky Acc. Chem. Res. 1981,14,400. ln4S. Danishefsky J. F. Kerwin and S. Kobayashi J. Am. Chem. SOC.,1982 104 358; S. Danishefsky N. Kato D. Askin and J. F. Kerwin J. Am. Chem. SOC., 1982,104 360. J. F. Kerwin and S. Danishefsky Tetrahedron Lett. 1982 23 3739. S. Danishefsky and J. F. Kerwin J. Org. Chem. 1982,47 3183. lo'S. Danishefsky and J. F. Kerwin J. Org. Chem. 1982 47 3803. lo' S. Danishefsky N. Kato D. Askin and J. F. Kerwin J. Am. Chem. Soc. 1982,104 360. S. Danishefsky S. Kobayashi and J. F. Kerwin J. Org. Chem. 1982 47 1981. Synthetic Methods 307 R RLN LHuR' H>o A H@oMe-Hb \ R' YOMe V"."L'J OSiMe nCiMP-0 YOMe 0 -OSiMe, (73) (74) CH,OCH,Ph CH ,OCH ,Ph OCH,Ph AcO H OAc OH H 1..vi ,OCH,Ph OH Reagents i ZnCI,-benzene or BF,.Et,O-ether; ii ZnC1,-THF; iii DIBAL-benzene; iv molybdinium oxide-H,O,; v acetylation; vi OsO4 Scheme 52 (Me HqNHBOC -0QNHBOC CH CH, Me,SiO I I CHMe CHMe lii iii H02CT NHBOC Reagents i ZnC1,-benzene; ii 0,; iii H,Oz Scheme 53 New preparations of oxygenated 1,3-butadienes have been recorded. 2-Silyloxy- 1,3-dienes can be prepared from the corresponding enones and undergo ready 308 W.Carruthers Diels-Alder reactions with typical dienophiles,"' 1,3-dimethoxybuta- 1,3-diene can be obtained readily from l,l-dimethoxybut-2-yne with sodium methoxide in dimethyl sulphoxide"' and (1E,3E)-4- acetoxy-l-trimethylsilylbuta-1,3-dienehas been made and used in a synthesis of (k)-shikimic acid."* There is continuing interest in the Diels-Alder route to nitrogen heterocycles.The preparation and Diels-Alder reactions of hetero-substituted 1,3-dienes has been reviewed113 and a report' l4 deals with synthetic aspects of Diels-Alder cycloadditions with heterodienophiles. The readily available 2-azabuta- 1,3-diene derivative (76) can be used to prepare isoquinoline and piperidine derivatives (Scheme 54),"' and the a@-unsaturated hydrazone (77) is equivalent to 1-aza-3-methylbuta-1,3-diene. It reacts regioselectively with a wide range of dienophiles to give adducts which are smoothly converted into the corresponding piperidine derivatives by reductive cleavage with zinc and acetic acid.'l6 Bu'MezSioY iii iv OAc OSiMe,Bu' NMe NMez AcOH 80 "C Scheme 54 The intramolecular cycloaddition of some N-acylimines is highly stereoselective producing 3,4-dehydropiperidine derivatives with a trans relationship of hydrogens a to the nitrogen."' The novel reagent 2,3-bis(trimethylsilyl)methylbuta-1,3-diene(78) is a synthetic equivalent of bis-allyl.By reaction with dienophiles under appropriate conditions 'lo M. E. Jung C. A. McCombs Y. Takeda and Y.-G. Pan J. Am. Chem. SOC.,1981,103,6677. ''I P. Dowd and W. Weber Tetrahedron Lett. 1982 23 2155. 'I2 M. Koreeda and M. A. Ciufolini J. Am. Chem. Soc. 1982,104 2308. 'I3 M.Petrzilka and J. I. Grayson Synthesis 1981 753. S. M. Weinreb and R. R. Staib Tetrahedron 1982 38 3087. 'I5 F. Sainte B. Serckx-Poncin A.-M. Hesbain-Frisque and L. Ghosez J. Am. Chem. Soc. 1982 104 1428. B. Serckx-Poncin A.-M. Hesbain-Frisque and L. Ghosez Tetrahedron Lett. 1982 23 3261. B. Nader T. R. Bailey R. W. Franck and S. M. Weinreb J. Am. Chem. Soc. 1981 103 7573. Synthetic Methods 309 it can be used to make compounds containing two fused six-membered rings (Scheme 55).'18 II 66% 0 Reagents i reflux toluene; ii NBS-5 equivs.. 'cp -THF; iii 7 -78 "C -b 25 "C Scheme 55 There has been increasing interest in the reactions of 2-oxyallyl cations. One of their characteristics reactions is a [3 + 41 cycloaddition to conjugated dienes to give seven-membered rings.This reaction has been classified as either a concerted [2 + 4171. pericyclic reaction or a stepwise reaction initiated by electrophilic addition followed by cyclization of an intermediate. It is now found1*' that 1,l-dialkyl-2- (trimethylsily1oxy)allyl chlorides react with 1,3-dienes in the presence of silver perchlorate to give seven-membered ring ketones in excellent yield. The reaction appears to proceed by two alternative mechanisms one concerted and the other stepwise depending on the solvent. In nitromethane all the cations react smoothly with furan and cyclopentadiene to give respectively 8-oxabicyclo[3,2,l]oct-6-en-3-ones and bicyclo[3,2,l]oct-6-en-3-onesin good yield (Scheme 56). In tetrahy- drofuran however yields depend on the structure of the ally1 cation and reaction with furan is not stereospecific.These and other factors suggest that in this solvent Me Me OSiMe . ?L I 0 Reagent i AgCI0,-MeNO Scheme 56 '" B. M. Trost and M. Shimizu J. Am. Chem. SOC.,1982,104,4299. 'I9 N. Shimizu M. Tanaka and Y. Tsuno J. Am. Chem. SOC.,1982,104,1330. 310 W. Carruthers the reactions proceed by a stepwise mechanism. A closely related sequence involving ally1 cations derived from 1,l -dimethyl-2-(trimethylsilylmethyl)allylalcohds'20 has been applied intramolecularly in a synthesis of zizaene sesquiterpenes (Scheme 57).12' \ SiMe Reagent i ZnCI,-Al,O Scheme 57 6 Oxidation Useful reviews on the uses of singlet oxygen'22 and pyridium chlorochr~mate'~~ have been published.4-(Dimethylamino)pyridinium chlorochromate has been recommended for the selective oxidation of benzylic and allylic alcohols in the presence of aliphatic primary and secondary alcohol groups.'24 A RuC~~(PP~~)~-benzene system is to be highly effective for selective oxidation of primary alcohols in the presence of secondary ones. Undecane-1,lO-diol for example gave 10-hydroxyundecanal in 89% yield. A wide variety of secondary alcohols has been oxidized to the corresponding ketones in good yield with sodium bromate catalysed by cerium(1v) salts (Scheme 58). Under the same conditions primary alcohols were unaffected allowing the preferential oxidation of secondary hydroxy-groups in the presence of primary ones and the conversion of some 1,2-diols into a-hydroxy- ketones.'26 Reagent i NaBrO,-Ce'" ammonium nitrate MeCN reflux Scheme 58 A ruthenium reagent dihydrotetrakis(tripheny1phosphine)rutheniumhas been used to bring about the homogeneous catalytic oxidation of alcohols and diols to the corresponding esters or 1act0nes.l~' Thus pentane- 1,4-diol gave y-butyrolac- tone in 96% yield and hexan-1-01 was converted into hexyl hexanoate in 98% yield.IZo R. Henning and H. M. R. Hoffmann Tetrahedron Lett. 1982,23 2305. H. M. R. Hoffmann R. Henning and 0.R. Lalko Angew. Chem. Int. Ed. Engl. 1982 21,442. ''' H. H. Wasserman and J. L. Ives Tetrahedron 1981 37 1825. G. Piancatelli A. Scettri and M. D'Auria Synthesis 1982 245. lZ4 F. S. Guziec and F. A. Luzzio J. Org. Chem.1982,47 1787. *''H. Tomioka K. Yakai K. Oshima and H. Nozaki Tetrahedron Lett. 1981 22 1605. lZ6 H. Tomioka K. Oshirna and H. Nozaki Tetrahedron Len. 1982,23 539. Iz7 S.-I. Murahashi K. Ito T. Naota and Y. Maeda Tetrahedron Lett. 1981. 22 5327. Synthetic Methods 311 A useful enantioselective enzymic oxidation of ao-diols can be effected with Gluconobacter ; prochiral diols such as 2-substituted propane- 1,3 -diols (79) and 3-substituted pentane-1,4-diols (80) are oxidized with distinction of pro-R and pro-S sites (Scheme 59).12' The steric bulkiness of the substituent on the prochiral centre and its distance from the hydroxy-groups greatly affects the rate and enan- tioselectivity of the reaction. for R = Me 47% yield 83% e.e. for R = Me 57% yield 57% e.e.Reagent i Gfuconobacter roseus pH 5 Scheme 59 Calcium hypochlorite in aqueous acetonitrile-acetic acid at room temperature efficiently oxidizes aldehydes to the corresponding carboxylic acids. 129 Under the same conditions a-diols a-diones a-hydroxy-ketones and a-hydroxy-acids are oxidatively cleaved to aldehydes ketones or carboxylic acids depending on the starting material. 130 Secondary alcohols gave ketones and primary alcohols form esters in which both the acid and alcohol portions are derived from the alcoh01.l~~ The reagent has the advantage over sodium hypoch1oritel3* previously used for some of these oxidations in that it is relatively stable and easily stored. A greatly improved procedure for Ru0,-catalysed oxidations of organic com- pounds has been rep0~ted.l~~ Addition of methyl cyanide to the traditional carbon tetrachloride-water solvent system leads to greatly improved yields; some applica- tions to olefins alcohols aromatic compounds and ethers are described,.Thus dec-1-ene is converted into nonanoic acid in 89% yield and methyl decyl ether gives methyl decanoate in 83% yield. The mildness of the reaction conditions is illustrated by the conversion of the diol(81) into the acid (82)without epimerization (Scheme 60). H. Ohta H. Tetsukawa and N. Noto J. Org. Chem. 1982 47 2400. 129 S.0.Nwaukwa and P. M. Keehn Tetrahedron Lett. 1982,23,3131. I3O S.0.Nwaukwa and P. M. Keehn Tetrahedron Lett. 1982 23 3135. I3l S.0.Nwaukwa and P. M. Keehn Tetrahedron Lett.1982,23,35. cf. R.V. Stevens K. T. Chapman C. A. Stubbs W. W. Tam and K. F. Albizati Tetrahedron Lett. 1982,23,4647. 133 P. H. J. Carlsen T. Katsuki V. S. Martin and K. Sharpless J. Org. Chem. 1981 46 3936; W.C. Still and H.Ohmizu J. Org. Chem. 1981,46 5243. 13' 312 W. Carruthers OH Reagent i NaI0,-RuCI, H,O-MeCN-CCI, 25 "C Scheme 60 Another method for the biomimetic oxidative deamination of primary amines to aldehydes by transposition of an imine functionality has been rep0~ted.l~~ Conversion of the amine into the imine with 2-pyridinecarboxaldehyde followed by transposition of the double bond by deprotonation with lithium di-isopropylamide and simultaneous kinetic protonation and hydrolysis of the product with aqueous oxalic acid gave the corresponding aldehyde.Yields were variable; in the best reported case n-undecylamine was converted into undecanal in 94% yield. Whereas permanganate in solution oxidizes unsaturated alcohols at the double bond permanganate adsorbed on a solid support attacks the alcohol group and allows the formation of unsaturated ketones in high yield.'35 Oct-1-en-3-01 for example gave oct-1-en-3-one in 92% yield with permanganate on bentonite in refluxing methylene chloride. No example of the oxidation of an unsaturated primary alcohol to the corresponding unsaturated aldehyde is reported. Sodium chlorite is a useful reagent for the oxidation of cup-unsaturated aldehydes to the acids and is said to be effective in systems where steric hindrance and the presence of other sensitive functional groups preclude the use of other A review of Baeyer-Villiger oxidation of bridged bicyclic ketones with organic peroxy-acids and with alkaline hydrogen peroxide has been published.137 A novel procedure for carrying out Baeyer-Villiger oxidations uses the readily accessible bis(trimethylsilyl)peroxide,Me3SiOOSiMe3 as the oxidizing agent. 13* This reagent is viewed as a masked form of hydrogen peroxide but unlike the latter it is thermally stable and soluble in ordinary organic solvents and is thus easily handled. When combined with trimethylsilyl trifluoromethanesulphonate as catalyst it is a valuable reagent for Baeyer-Villiger oxidation of ketones. It has the notable feature that reaction occurs specifically at the carbonyl group and carbon-carbon double bonds are unaffected.Thus cyclopent-3-enone gave only pent-3-en-5-olide and 2-allyl- cyclohexanone gave only 6-allylhexan-6-olide (Scheme 61). Reagent i (Me,SiO),-cat. Me,SiOTf CH,CI, -78 "C+10"C Scheme 61 J. H. Babler and B. J. Invergo J. Org. Chem. 1981 46 1937. 13' N. A.Noureldin and D. G. Lee Tetrahedron Lett. 1981,22 4889. 136 B.S.Bal W. E. Childers and H. W. Pinnick Tetrahedron 1981 37 2091. G. R. Krow Tetrahedron 1981 37 2697. M.Suzuki H. Takada and R. Noyori J. Org. Chem. 1982,47,902. Synthetic Methods 313 Direct a-hydroxylation of ketones can be effected with iodosobenzene or phenyl iodosoacetate in methanol-sodium hydroxide. 139 2,6-Diacetylpyridine for example was converted into the corresponding bis-acyloin without oxidation at nitrogen or further oxidation of the hydroxymethylcarbonyl groups.Phenyl iodosoacetate is also a useful reagent for conversion of carboxylic esters into the corresponding a-hydroxy-derivati~es.~~~ A different and more flexible method for converting ketones into a-hydroxy-derivatives proceeds by oxidation of the corresponding silyl enol ethers with osmium tetroxide-N-methylmorpholineN-o~ide.'~~ Since either the kinetic or thermodynamic enol ether may be used oxidation can be effected specifically at either a-position of the carbonyl compound. For example nonan-2-one was converted into the 1-or 3 -hydroxy-derivative specifically as shown in Scheme 62. The same conversions can be effected by reaction of silyl enol ethers with chromyl ch10ride.l~~ iii iv doH i ii OSiMe3 1.5 4Oh OSiMe3 0 iii. iv -,Me Or'" Reagents i LiNPr',; ii Me,SiCl; iii cat 0~0,-uLo H,O-MeCOMe -5 "C; iv H,0-H,S04; v Me,SiI-hexamethyldisilazane Scheme 62 Full experimental details have been published for the oxidation of organic substrates by pentavalent organobismuth reagents. 143 The remarkable selectivity of these reagents particularly for the oxidation of allylic hydroxy-groups under mild conditions is exemplified; glycol cleavage is also very efficient. Thus geraniol gave geranial in 95% yield at 40°C with triphenylbismuth carbonate and cis- cyclohexan- 1,2-diol was converted into hexan- 1,6-dial quantitatively by the same reagent. The uses of benzeneseleninic anhydride as an oxidizing agent for phenols and benzylic hydrocarbons and for dehydrogenation of ketones has been emphasized.Thus steroidal 3-ketones are smoothly dehydrogenated to dienones by ben- zeneseleninic anhydride generated in situ by oxygen atom transfer from iodylben- zene or better rn 4odylbenzoic acid to catalytic amounts of diphenyldi~elenide,'~~ and some benzylic hydrocarbons are readily converted into aryl ketones or aldehydes at 100-130 0C.145 Although ortho-quinones can be prepared from 1,2- R. M. Moriarty H. Hu and S. C. Gupta Tetrahedron Lett. 1981 22 1283. I4O R. M. Moriarty and H. Hu Tetrahedron Lett. 1981,22 2747. 14' J. P.McCormick W. Tomasik and M. W. Johnson Tetrahedron Lett. 1981 22 607. 14* T.V.Lee and J.Tcozek Tetrahedron Lett. 1982,23,2917. 143 D.H.R. Barton J. P. Kitchin D. L. Lester W. B. Motherwell and M. T. B. Papoula Tetrahedron 1981 37 Supplement 9,p. 73. 144 D. H. R. Barton J. W. Morzycki and W. B. Motherwell J. Chem. SOC.,Chem. Commun. 1981 1044. 14' D.H.R. Barton R. A. H. Hui and S. V. Ley J. Chem. SOC.,Perkin Trans. I 1982,2179. 314 W. Carruthers dihydroxybenzenes by a variety of methods their formation from monohydroxyben- zenes is uncommon particularly when the para-position is unsubstituted. Ben- zeneseleninic anhydride has been used as a mild oxidizing agent to convert phenols into ortho-quinones including some where the para-position was unsubstituted but the method is limited to the production of quinones that are not susceptible to further oxidation.146 A great deal of recent work has been concerned with stereoselective epoxidation of acyclic allylic alcohols. Following on from their earlier work Sharpless and his co-workers have now achieved controlled and predictable asymmetric epoxidation of a range of acyclic allylic alcohols with t-butyl hydroperoxide in the presence of titanium tetra-isopropoxide and esters of (+)-or (-)-tartaric The method leads to uniformly high asymmetric induction over a range of substitution patterns in the allylic alcohol substrate and using a given tartrate enantiomer the system delivers the epoxide oxygen to the same enantiotopic face of the double bond regardless of the substitution pattern (Scheme 63).148This reaction has been used \OH H-82%; > 90% 2(S),3(R) Reagents i Me,COOH-Ti(OPr'), @)-(+)-diethy1 tartrate CH2C12 -20 "C; ii Me,COOH-Ti(OPr'), @)-(-)-diethy1 tartrate CH2C12 -20 "C Scheme 63 to bring about kinetic resolution of racemic secondary allylic alcohols by enan- tioselective ep~xidation.'~' +)-di-isopropyl tartrate-titanium In the presence of (I-)-( alkoxide catalysts and slightly more than 0.5 mols.of t-butyl hydroxperoxide the (S)-allylic alcohol in a racemic mixture is epoxidized more rapidly sometimes much more rapidly than the (R)-enantiomer to give mainly the erythro-epoxide (Scheme 64). The recovered (R)-allylic alcohols are of very high enantiomeric purity. Thus epoxidation of the alcohol (83) gave the epoxy-alcohol derived from the (9-enantiomer with an erythro-threo ratio of 97 :3.The recovered (R)-alcohol was more than 96%optically pure. Other examples of the application of this procedure 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. T. Katsuki and K. B. Sharpless J. Am. Chem. Soc. 1980,102 5974. see also B. E. Rossiter T. Katsuki and K. B. Sharpless J. Am. Chem. Soc. 1981 103,464. 149 V. S. Martin S. S. Woodward T. Katsuki Y. Yamada M. Ikeda and K. B. Sharpless J. Am. Chem. SOC.,1981,103,6237. 14' 14' Synthetic Methods 315 (83) erythro threo Reagent i (L)-(+)-di-isopropyl tartrate-Ti(OPr'), 0.6 equiv. Bu'OOH CH,CI, -20 "C Scheme 64 in the asymmetric epoxidation of allylic alcohols are found in work on the synthesis of Rifamycin S (Scheme 65).'" The titanium alkoxide-tartrate-t-butyl hydroper-oxide system is even more erythro-selective than that using VO(acac)2-t-butyl hydroperoxide.In the absence of tartrate titanium tetra-isopropoxide alone is generally threo-selective. An example of the oxidation of a homoallylic alcohol has been recorded."' Me Me0 Me Ph,,Oh / OH Ph-O&oH + P h - O h,'.(j OH 95 1 5 Me Me PhVoYoH OH Reagent i (t)-(+)-di-isopropyl tartrate-Ti(OPr') ,t-BuOOH CH,CI Scheme 65 Using the titanium alkoxide-tartrate method it is possible to predict the direction of asymmetric induction in epoxidations of allylic alcohols. Surprisingly the same has not been true for the widely used vanadium t-butyl hydroperoxide procedure when applied to acyclic systems but a transition state model incorporating tetrahe- drally co-ordinated vanadium has now been proposed which accounts satisfactorily for the isomer distribution in the vanadium-catalysed epoxidation of a range of acyclic allylic and homoallylic A highly stereoselective synthesis of trans-epoxides from aldehydes and ketones by reaction with an unstabilized arsonium ylid has been described.153 The sequence is mechanistically analogous to the well-known sulphur ylid route but has the advantage that it proceeds with a high degree of stereochemical control. Most aldehydes react cleanly with arsonium ylids to give trans-epoxides with a selectivity 15" H. Nagaoka and Y. Kishi Tetrahedron Lett. 1981 37 3873. M. Isobe M.Kitamura S. Mio and T. Goto Tetrahedron Lett. 1982,23 221. 15* E. D. Mihelich K. Daniels and D. J. Eickhoff J. Am.Chem. Soc. 1981 103 7690. 153 W. C. Still and V. J. Novack J. Am.Chem. Soc. 1981,103 1283. 316 W. Carruthers of >50 :1 (Scheme 66). (R)-Alkylepoxides of well-defined enantiomeric purity can be prepared from (S)-arnino-acid~.~~~ 98%E H Scheme 66 Potassium hydrogen persulphate KHSO, is an excellent reagent for the oxida- tion of sulphides to sulphones under mild conditions and has the advantage over commonly used per-acids that carbon-carbon double bonds are unaffected under the conditions emp10yed.l~~ On the other hand various primary and secondary alcohols carrying phenylthio- or phenylseleno-groups can be converted into the corresponding carbonyl compounds without attack on the sulphur or seleno groups by rcaction with dimesityl di~e1enide.l~~ Phosphines can be oxidized to their oxides sulphides to disulphides and thiocarbonyl compounds transformed into their oxo- analogues with dianisyltelluroxide.15' 7 Reduction A review of homogeneous asymmetric hydrogenation using complexes of rhodium ruthenium and palladium with chiral phosphine ligands has been published Enantioselective catalytic hydrogenation of a-acetylaminoacrylic acids to the cor- responding saturated N-acetylamino-acids in good optical yield (84-96%) has been achieved using chiral rhodium complexes containing optically active ditertiary phosphine ligands prepared from (S)-phenylalanine and (S)-~aline.'~~ Catalytic asymmetric synthesis of secondary alcohols (up to 78% enantiomeric excess) was accomplished by asymmetric hydrogenation of enol diphenylphosphinates derived from open-chain prochiral ketones in the presence of a chiral ferrocenyl-phosphine- rhodium complex,'6o and highly selective hydrogenation of a number of chiral allylic and homoallylic alcohols was achieved using chelated rhodium biphosphine complexes; best results showing a preponderance of >30 1 in favour of the threo-product were obtained with 1,4-bis(diphenylphosphino)butane as chelating agent.16' Optically active y-and 6-lactones were obtained by hydrogenation of five- and six-membered cyclic anhydrides with a chiral ruthenium complex; optical yields were not high (16-20°/~).162 B.Koppenhoefer R. Weber and V. Schurig Synthesis 1982,316. B. M. Trost and D. P. Curran Tetrahedron Lett. 1981,22 1287. M.Shimizu H. Urabe. and I. Kuwajima Tetrahedron Lett. 1981 22 2183. Is' S. V. Ley C. A. Meerholz and D. H. R. Barton Tetrahedron 1981,37,Supplement No. 9,p. 213. 15* V. Capler G. Comisso and V. Sunjic Synthesis 1981,85. 159 W. Bergstein A. Kleeman and J. Martens Synthesis 1981,76; see also J. W. Scott et al. J. Org. Chem. 1981,46,5086. 160 T.Hayashi K. Kanehira and M. Kumada Tetrahedron Lett. 1981 22,4417. J. M. Brown and R. G. Naik J. Chem. SOC.,Chem. Commun. 1982,348. K. Osakada M. Obana T. Ikariya M. Saburi and S. Yoshikawa Tetrahedron Lett. 1981 22 4297. 16' Synthetic Methods Catalytic transfer reduction using a specially modified and easily prepared pal- ladium catalyst provides an alternative to the well-known Lindlar method for the stereoselective reduction of disubstituted alkynes to (Z)-alkene~.l~~ Clear solutions of lithium aluminium hydride in tetrahydrofuran reduce organic halides of different structural types rapidly and quantitatively to the corresponding hydrocarbons commonly at 25 "C.The reductions are far faster than those pre- viously realised with slurries of lithium aluminium hydride in ethereal solvents. 164 Vinyl halides and primary secondary and tertiary alkyl halides are also reduced to the corresponding hydrocarbons with a reagent composed of sodium hydride alkoxides and metal and gem-dibromides can be converted into monobromo-compounds with diethyl phosphite and triethylamine.166 2,2-Dibromophenylcyclopropane for example gave a mixture of cis-and trans-2-bromophenylcyclopropane in 93 '/o yield and &3-dibromostyrene was converted into p-bromostyrene (trans cis = 94 :6) in 96% yield. One of the most direct routes to aldehydes is catalytic hydrogenation of acid chlorides. In Rosenmund's classical procedure a stream of hydrogen is bubbled through a boiling solution of the acid chloride in xylene or toluene in presence of a catalyst but the procedure has several drawbacks often leading to over-reduction and decarboxylation. It has now been found that conducting the reaction with palladium-carbon catalyst in acetone or ethyl acetate in the presence of EtNPr; as hydrogen chloride acceptor leads to smooth conversion of aromatic and aliphatic acid chlorides into the corresponding aldehydes without over-reduction.167 A number of publications have been concerned with the selective reduction of carbonyl groups. Thus lithium tris[(3-ethyl-3-pentyl)oxy]aluminium hydride a highly hindered lithium trialkoxyaluminium hydride synthesized from lithium aluminium hydride and 3-ethylpentan-3-01 shows high selectivity for the reduction of aldehydes in the presence of ketones. Thus a mixture of hexanal and cyclo- hexanone showed 99.6% attack on the aldehyde at -78 0C.168 Bis(tripheny1phos- phine)copper(I) tetrahydroborate in the presence of acid catalysts also shows some preference for the reduction of aldehydes in the presence of ketones; ap-unsatur- ated ketones are reduced to the unsaturated alcohol.169 Trivalent lanthanide ions permit the selective reduction of conjugated aldehydes in the presence of non- conjugated ones with sodium borohydride and also the selective reduction of the less reactive of two carbonyl groups; chromium(II1) chloride is also effective in some cases in promoting selective borohydride reduction of ketones in the presence of aldehyde groups.17o Lithium n-butylborohydride is a selective reagent for the reduction of enones cyclic ketones and selected carbonyl compounds. In toluene- hexane solution it is very selective for the 1,2-reduction of acyclic enones and '" R. A. W. Johnstone and A. H. Wilby Tetrahedron,1981 37 3667. S. Krishnamurthy and H. C. Brown J. Org.Chem. 1982,47,276. R. Vanderessi J.-J. Brunet and P. Caubtre J. Org. Chem. 1981 46 1270. 16' T. Hirao T. Masunaga Y. Oshiro and T. Agawa J. Org. Chem. 1981,46 3745. J. A.Peters and H. van Beekum Reel. Trau. Chim. Pays-Bas 1981 100 21. S. Krishnamurthy J. Org. Chem. 1981,46,4628. G. W. J. Fleet and P. I. C. Harding Tetrahedron Lett. 1981 22 675 A. L. Gemal and J.-L. Luche J. Am. Chem. Soc. 1981,103,5454. 170 A. L. Gemal and J.-L. Luche Tetrahedron Lett. 1981 22 407. 318 W.Carruthers conjugated cyclohexenones and in tetrahydrofuran-hexane it reduces 3-methyl- 4-methyl- and 4-t-butyl-cyclohexanonesto the corresponding equatorial alcohol with high ~e1ectivity.l~~ Asymmetric reduction of aromatic ketones with reagents prepared from sodium borohydride and carboxylic acids in the presence of 1,2,5,6-di-O-isopropylidene-a-D-glucofuranose at 0 "Cgives (R)-alcohols with enantiomeric excess up to 83% .172 Similarly reduction of prochiral aromatic ketones with chiral alkoxy-amine-borane complexes afforded the corresponding aromatic secondary alcohols in enantiomeric excess up to 60O/0.'~~ The so-called NB-Enantride a new asymmetric reduc- ing agent prepared by hydroboration of nopol benzyl ether with 9-borabicyclo[3,3,l]nonane followed by treatment with t-butyl-lithium is useful for asymmetric reduction of aliphatic ketones.Butan-2-one for example was converted into (S)-butan-2-01 with 76% enantiomeric excess.174 (Nopol is 6,6-dimethylbicyclo[3,l,l]hept-2-ene-2-ethanol).Recently B -(3-pinanyl)-9-bora-bicyclo[3,3,l]nonane has been shown to be a very useful chiral reducing agent for the reduction of acetylenic ketones.It is now that even better results are obtained by using the neat reagent rather than solutions in tetrahydrofuran as before. Under these conditions @-unsaturated ketones and aliphatic ketones were also smoothly reduced although with the latter the optical yields of the alcohols were variable. Enzymic reduction of ketones still provides the best route to optically active alcohols when it is applicable. The range of applications has now been extended by the discovery that 2,2-disubstituted cyclopentan- 1,3-diones are smoothly converted into optically active ketols by bakers' yeast (Scheme 67); in all cases studied the ketols produced were better than 98% enantiomerically 0 OH+O -OH 10 1 Reagent i bakers' yeast pH 7,40 "C Scheme 67 Lithium 9-boratabicyclo[3,3,l]nonane,LiH.9-BBN and lithium triethylborohy- dride LiEt,BH strongly catalyse the reduction of esters by LiBHs in ether at 25 "C.The corresponding Lewis acid B-methoxy-9-borabicyclo[3,3, llnonane also permits the rapid and quantitative reduction of esters by LiBH4 and this combina- tion of reagents provides a practical method for the reduction of esters in the presence of other reducible groups such as the chloro- and nitro-groups.177 S. Kim Y. C. Moon,and K. H. Ahn J. Org. Chem. 1982,47,3311. 17' A. Hirao S. Itsumo M. Owa S. Nagami H. Mochizuki H. H. A. Zoorov S. Niakahama and N. Yamazaki J. Chem. SOC.,Perkin Trans.1 1981,900. *73 A. Hirao S. Itsumo S. Nakahama and N. Yamazaki J. Chem. Soc. Chem. Commun. 1981 315; see also M. F. Grundon D. G. McCleary and J. W. Wilson J. Chem. SOC.,Perkin Trans. 1,1981,231. 174 M. M. Midland and A. Kazubski J. Org. Chem. 1982,47,2495. H. C. Brown and G. G. Pai J. Org. Chem. 1982 47 1606. '76 D. W. Brooks P. G. Grothaus and W. L. Irwin J. Org. Chem. 1982,47,2820. 177 H. C. Brown and S. Narasimhan J. Ore. Chem. 1982 47 1604. Synthetic Methods 319 Reduction of epoxides derived from allylic alcohols has occasioned some interest because of its potential usefulness in the synthesis of macrolides and ionophores. On reduction with Red-Al [NaAlH2(0CH2CH20CH3)2] ally1 alcohol epoxides yield 1,3-diols with high regioselectivity but with trialkylaluminium compounds such as DIBAL 1,2-diols are ~btained."~ The primary factor controlling the remarkable regioselectivity with Red-A1 seems to be the hydroxy-group; the corre- sponding benzyl methyl ether in the example in Scheme 68 was recovered unchanged.Coupled with the Sharpless asymmetric epoxidation the Red- A1 reduc- tion provides a stereo- and regio-controlled route to 1,3-p0lyhydroxylated systems. OH OH + B~O~O BzowoH- Bzo-U OH Red-A1 19 1 DIBAL. benzene 1 13 Scheme 68 Nucleophilic reagents and hydride reducing agents generally attack unsymmetrical epoxides mainly at the less hindered carbon atom of the epoxide. With sodium cyanoborohydride and boron trifluoride etherate however attack takes place mainly at the more hindered position to give the less substituted alcohol; 1-methylcyclohexene oxide for example gave a product consisting of 97% cis- 2- met hylcyclo hexanol.''' Reduction of anhydrides under appropriate conditions provides a route to lac- tones. A number of ortho-substituted phthalic anhydrides were selectively reduced by L-Selectride at the less hindered carbonyl group to give 1actones.l" Similarly the partial reduction of gem-disubstituted cyclic anhydrides at the carbonyl further removed from the gem-substituents can be effected with K-Selectride; in contrast sodium borohydride and lithium aluminium hydride preferentially reduce the car- bony1 group adjacent to the substituted centre (Scheme 69).I8l 0 0 NaBH4 19 1 K-Selectride 1 6 Scheme 69 178 J.M. Finan and Y. Kishi Tetrahedron Lett. 1982,23 2719;T. Suzuki H. Saimoto H. Tomioka K. Oshima and H. Nozaki Tetrahedron Lett. 1982,23 3597. 179 R. 0.Hutchins I. M. Taffer and W. Buryoyne J. Org. Chem. 1981,46 5214. M. A.Makhlauf and B. Rickborn J. Org. Chem. 1981,46,4810. P.Morand J. Salvator and M. M. Kayser J. Chem. SOC.,Chem. Commun. 1982,458. 320 W. Carruthers Greatly enhanced rates of reduction of organic functional groups such as esters nitriles and amides by borane-dimethyl sulphide are attained by adding the reagent to the substrate in refluxing tetrahydrofuran and allowing the liberated dimethyl sulphide to distill off during the reaction.'** Sodium borohydride-rhodium chloride in hydroxylic solvents is useful for the reduction of aromatic compounds to the corresponding saturated cyclic compounds under mild condition^.'^^ It is thought that the reaction proceeds by the initial formation of a complex between the benzenoid compounds and the rhodium chloride.Carboxylic acids esters and amides are unaffected but ketones are partly reduced and olefinic double bonds are completely saturated. Reagents i NaBH,-RhCI, EtOH 40 "C Scheme 70 The reductive replacement of the nitro-group by hydrogen in secondary and tertiary aliphatic nitro-compounds can be effected in good yield with trialkyltin hydrides in refluxing benzene in the presence of azobis-isobutyronitrile. Other functional groups such as keto ester cyano chloro and organosulphur groups are unaffected.lS4 The reduction proceeds by a free-radical chain process.'85 None of the methods hitherto used for the reductive transformation of nitro into hydrogen can be applied to primary nitro-compounds but it has now been found that primary a-nitro-ketones are converted into the ethylthioacetals of the corresponding nitro- free compounds by reaction with aluminium chloride and ethanethio1.Ig6 H.C. Brown Y. M. Choi and S. Narasimhan J. Org. Chem. 1982,47 3153. M. Nishiki H. Miyataka Y. Niino N. Mitsuo and T. Satoh Tetrahedron Len. 1982 23 193. N. Ono H. Miyake R. Tamura and A. Koji Tetrahedron Lett. 1981 22 1705. D. D. Tanner E. V. Blackburn and G. E. Dim J. Am. Chem. Soc. 1981,103,1557. M. Node T. Kawabata M. Ueda M. M. Fujimoto K. Fuji and E. Fujita Tetrahedron Lett.1982 23,4047.

ISSN:0069-3030    

DOI:10.1039/OC9827900279

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

14 Enzyme Chemistry By C. A. ROSS Department of Biochemistry University College Cork Lee Makings Prospect Row Cork Ireland 1 Introduction New texts devoted exclusively or almost so to enzymes and enzyme chemistry have continued to appear during the past year particularly from the publishing house of Springer-Verlag. Their first’ is devoted to the techniques of enzyme preparation while the second,* sub-titled ‘A Chemical Approach to Enzyme Action’ deals with enzyme mechanisms and has been described by one reviewer as ‘an exciting book’. The third3 is an account of the 32nd Colloquium held in Mosbach and is devoted to the structural and functional aspects of enzyme catalysis. The fourth4 is the subject of a separate section covalent catalysis of this Report.From the pen of the distinguished enzymologist G. G. Hammes has come a book,’ based upon his lecture course and review articles which follows a now familiar format. Following a discussion of protein structure enzyme kinetics is dealt with before a review of selected enzymes and the book concludes with chapters on regulatory enzymes multi-enzyme complexes and membrane-bound enzymes. Two other books with identical titles6 follow very much this same pattern. In the case of the book by Price and Stevens,60 the authors’ stated aim is to place enzyme studies in the context of the cell whereas Royer6’ wishes to stress the application of enzymes. In the event we are faced with yet more texts which differ only in detail from those which have appeared over the past few years.An unusual aspect of enzymology namely the effect of pressure has recently received attention. Thirty years after a review of the phenomenon by Laidler,’ a comprehensive theoretical treatment has now been published’ which is concerned with high-pressure effects such as might be encountered in deep sea exploration. It is conventional when discussing in general terms the control of enzyme-catalysed reactions to mention the concentration of enzyme available. Certainly in eukaryotes little work has been done on this important parameter which results from the ‘ R. K. Scopes ‘Protein Purification’ Springer-Verlag Berlin 1982. H. Dugas and C. Penney ‘Bioorganic Chemistry’ Springer-Verlag Berlin 1981. ‘Structural and Functional Aspects of Enzyme Catalysis’ ed.H. Eggerer and R. Huber Springer-Verlag Berlin 1982. L. B. Spector ‘Covalent Catalysis by Enzymes’ Springer-Verlag Berlin 1982. ’ G. G. Hammes ‘Enzyme Catalysis and Regulation’ Academic Press New York 1982. ‘(a)N. C. Price and L. Stevens ‘Fundamentals of Enzymology’ O.U.P. Oxford 1982; (b)G. P. Royer ‘Fundamentals of Enzymology’ John Wiley and Sons New York 1982. ’K. J. Laidler Arch. Biochern. 1951,30 226. E. Morild in ‘Advances in Protein Chemistry Vol. 34’,ed. C. B. Anfinsen J. T. Edsall and F. M. Richards Academic Press New York 1981. 322 C. A. Ross opposing rates of enzyme synthesis and of degradation. Now a fairly extensive study has been reported' on the turnover profile of one enzyme lactate dehy- drogenase in a variety of animal tissues and under several physiological perturba- tions.As the chosen enzyme exists in five isoenzymic forms whose proportions are tissue specific the investigation has produced a considerable amount of data. Appearing too late for inclusion in last year's Report came a monograph" from Cold Spring Harbor which promises to be for the time being at least the definitive work on the nucleases. Also in last year's Report was included reference to alcohol dehydrogenase. News has now been received'' of the death at the age of 79 of Hugo Theorell whose name will always be associated with that enzyme. 2 Covalent Catalysis Enzyme catalysis has long been assumed to occur via either a single-displacement or a double-displacement mechanism. Spector4 has now put forward a theory that all enzymes obey a double-displacement mechanism by forming a covalent inter- mediate with the substrate or with some fragment of the substrate.This is in contrast with the conclusion reached by Bell and Koshland'* some ten years ago when they stated that covalent intermediates were not essential for enzyme action. Spector opens his case with a consideration of the nature of enzymic catalysis compared with homogeneous and heterogeneous catalysis. The latter has tradi- tionally not been considered to be highly appropriate to biological systems but Spector points out that physisorbed and chemisorbed states of heterogenous cataly- sis have their counterparts in the Michaelis complex and the covalent enzyme- substrate intermediate of enzymic catalysis.Furthermore the migration of groups on a solid surface in order to react with other groups has its counterpart in those enzymes which require the migration ('surface walk') of covalently fixed fragments of substrate. Thus a parallel may be drawn between the hydrogenation of ethylene on a metal surface and the transfer of electrons from well separated donor to acceptor sites on the surface of a redox enzyme. Larger fragments are also capable of migration and Spector cites the example of so-called oxidative decarboxyl- ation (Scheme 1) where multienzyme complexes exhibit a 'triple-displacement' mechanism. The existence of a covalent enzyme-substrate intermediate was first demonstrated by Doudoroff et af.13in 1947 in the enzymic phosphorolysis of sucrose.Isotope- a-glucosyl-fructose + Pi $ a-glucosyl-1-P + fructose (1) exchange studies proved that a glycosylated enzyme was formed in the course of the reaction (Scheme 2). That the reaction proceeded by a double-displacement mechanism might have been anticipated since there is a net retention of configur- ation about C-1 of the glucose moiety following two Walden inversions. This might be thought to preclude covalent catalysis where an inversion of configuration occurs C. J. Masters Int. J. Biochem. 1982,14 685. lo 'Nucleases' ed. S. M. Linn Cold Spring Harbor Laboratory New York 1982. l1 B. Chance and B. L. Vallee Trends Biochem. Sci. 1983,8,45. l2 R. M. Bell and D. E. Koshland Science 1971 192 1253. l3 M. Doudoroff H.A. Barker and W. Z. Hassid J. Biol. Chem.. 1947 168,725. Emyme Chemistry + H+ \ (Reproduced by permission from ‘Biochemistry’ by D. E. Metzler J. Wiley & Sons New York,1977) Scheme 1 a-glucosyl-enzyme E a-glucosyi-I-P fructose fructose /3-gluWsyl-E Scheme 2 (such as would result from a single displacement reaction). Spector however cites the example of the adenine phosphoribosyltransferasereaction (Scheme 3) in which there is an inversion of configuration about C-1 of the 5’-phosphoribosyl group 324 C. A. Ross and yet a phosphoribosyl-enzyme intermediate has been isolated. It therefore follows that a 'triple-displacement' reaction has occurred to account for both the inversion and the covalent enzyme-substrate complex formation.Biochemical reasoning has long been influenced by the tenets of organic reaction mechanisms occurring in solution. Spector argues that the concept of the enzyme merely providing a special surface on which the single-displacement reaction may proceed at an enhanced rate is not tenable for over 400 enzymes for which covalent catalysis has been proved. There is an entropic advantage to be had if the enzyme is concerned with only one substrate at a time and also an enthalpic advantage when it comes to forming a covalent bond between two atoms if one of the atoms is part of the enzyme itself. Whereas enzymes have for convenience been classified by reaction types into six main groups by the Enzyme Commission of the I.U.B. on reflection one may argue that all enzymes belong to group 2 -the transferases.The bulk of Spector's book is devoted to an impressive documentation group by group of some 465 enzymes for which covalent catalysis is said to have been proved. On the grounds that a quarter of all listed enzymes have thus been shown to act by covalent catalysis and that in no case has single-displacement reaction been unambiguously proved Spector claims that all enzymes will be found to act in this manner. 3 Kinetic Analysis The enzyme kineticist has been well plied with texts on his subject in recent years. The latest title comes from Professor Lam in a very poorly printed form14 which belies the value of the contents. The book is intended as a practical guide to the devising of kinetic experiments and interpreting the resulting data in investigations of enzyme mechanisms.It has already been pointed out that many enzyme mechan- isms do not conform to the Michaelis mode1I5 and so this book deals largely with non-linear mechanisms a topic which is made relatively easy by the use of com-puters. Following a conventional opening chapter on the generation of steady-state rate equations a discussion of detailed balance and constraint equations follows. The law of micro-reversibility which states that the product of rate constants in one direction around a loop must equal the product of those in the opposite direction has to be taken into account in all but the simplest linear models. Chapters 3 and 4 are devoted to the estimation of rate and kinetic constants and a systematic approach to formulating kinetic mechanisms.The book concludes with an account of time course studies based on differential equations derived from mass-balance principles as in fast reaction methods and those based on integrated steady-state equations from progress curve methods. Another plot has been presentedI6 for the determination of initial rates from progress curves in which AP/t the chord from l4 C. F. Lam 'Techniques for the Analysis and Modelling of Enzyme Kinetic Mechanisms' Research Studies Press John Wiley and Sons Ltd. Chichester 1981. W. G. Bandsley P. Leff J. Kavanagh and R. D. Waight Biochem. J. 1980,189,739. '' E. A. Boeker Biochem. J. 1982 203 117. Enzyme Chemistry Po to to P t on a product-versus-time plot is plotted against product formed.The integrated rate equation for uncatalysed first-order reactions is In[1 -AP/(P -Po)] = -kl(l + l/Ke)r (2) = -(dP/dt,)r/(P -Po) (3) when rewritten to show the dependence on the initial rate dP/dt (the subscripts 0 and e indicate initial and equilibrium concentrations). If the left-hand side of equation (2) is approximated by AP/[-(Pe -Po) + AP/2] which has been shown to hold for up to 50% completion of reaction equation (3) can be rewritten AP/t = (dP/dto)[l -AP/2(P -Po)] (4) This is the equation of a straight line with an intercept dP/dto equal to the initial velocity. Similarly the integrated Michaelis-Menten equation may be closely approximated” by AP/t = Km(1 + Km/So) -APVmKm/2(Km + (5) Plots of AP/t against product formed result in curves approximating very closely to straight lines with an intercept at Po of dP/dt, the initial rate.Discrepancies between true initial rates and dP/dto are shown to be less than 1%for the most common form of integrated rate equation. The usual form of the integrated Michaelis-Menten equation expressed in terms of substrate concentrations is Vmax.r= (So -S) + Km.In(3 The time taken for an enzyme-catalysed reaction to achieve half-completion is obtained by substituting the relation S = S0/2 when t = t1/2into equation (6) Vmax*tl/2 = KmIn 2 + S0/2 (7) t1/2 = (Km/ Vmax) In 2 + S/2 Vmax (8) While the substrate concentration at the commencement of a reaction is the initial substrate concentration local substrate concentration refers to the substrate con- centration at any time t.Thus a plot of tlIZ against local So yields a straight line of slope $Vmaxand intercept (&,/ Vmax)In 2. The half-time plot is constructed by taking local So values at various stages of the reaction and calculating each corre- sponding value.’’ The authors have also investigated the performance of the direct linear form of the half-time plot. Equation 6 may be writtenlg in the form into which may be substituted the half-time relationship Vmax = S0/2t1/2 + (In 2Km)/t1/2 (10) Thus if local S0/2 values are plotted on the abscissa and S0/2f1/2 (which represents the slope of the chord joining a point at So to a point at S0/2 on the progress curve) ” (a)H. Goldenberg Arch.Biochem. Biophys.,1954,52 288; (b)M. R. J. Morgan Enzymologia 1972 42 219. ’* C.W. Wharton and R. J. Szawelski Biochem. J. 1982,203,351. ” R. Eisenthal and A. Cornish-Bowden Biochem. J. 1974 139,715. 326 C.A. Ross on the ordinate the intercept in the first quadrant of the plot is given by V,, In 2K (Figure 1).Data from progress curves of several enzyme-catalysed reactions have been analysed by both these plots and excellent results obtained provided certain conditions were adhered to. local IS,] -BJ/2 In 2 K Figure 1 (a) Half-time plot; (b) Direct linear half-time plot A method for determining kinetic parameters at high enzyme concentrations has been described.’’ Using the relationship [ES] = i{Et + St + K -J(Et + St + K,)’ -4E& } (11) which arises if it is not assumed that free substrate concentration is equal to total substrate concentration and by writing v/V,, for [ES]/Et it can be shown that ’(’ C.J. Halfman and F. Marcus Biochem. J.. 1982,203,339. Enzyme Chemistry Equation (12) describes the relationship between velocity and total substrate enzyme ratio as a function of enzyme concentration relative to K,. When data is plotted in these terms (Figure 2) free and bound substrate concentrations may be determined from and V Figure 2 Initial velocity curves predicted when Eo > K and enzyme concentration (b) > (c). The broken curve results when E >> K and represents the stoicheiometric relationship between u and St/E [equation (12)] The many corresponding values of o [S] and [ES]/Et which are obtained from velocity measurements at several ligand enzyme ratios and at two or more enzyme concentrations may then be analysed by conventional means.Halfman and Marcus state that the method is applicable to non-linear kinetics and they also apply it to the inhibition of fructose 1,6-bisphosphatase by the tightly-binding AMP. It has long been maintained that it is not possible to evaluate the rate constants k+l and k- by steady-state kinetic measurements for the simple Michaelis-Menten mechanism for one-substrate enzyme reactions E + S & ES % E + products k-1 328 C.A. Ross Now Wong and his collaborators2’ propose a means whereby these constants may be measured by determining the effect of temperature on Vmaxand K utilizing the constraint on the rate constants of the Arrhenius equation The procedure does require the measurement of isotopic rate effects in order to distinguish between k+l and k-l.Furthermore it is essential that a linear Arrhenius plot of log V,, versus 1/T obtains and that K varies markedly with tem-perature. Given that practical limitations may prevent the universal application of the method the authors nevertheless claim the principle disproves the contention that steady-state kinetic measurements are incapable of determining rate constants in this the simplest of enzyme mechanisms. Following his treatment of progress curves to obtain initial rate measurements as recorded in these Reports last year Waley2* has now produced a quick method for the determination of inhibition constants by the comparison of progress curves recorded in the presence and absence of an inhibitor.From the integrated form of the Michaelis-Menten equation for the case of a competitive inhibitor it can be shown that where (t -t,) is the time difference taken in the inhibited and uninhibited reactions for the initial substrate concentration So to fall to a chosen concentration S. When (t -t,) is plotted uersus In (So/S) a straight line results of slope K,/V,, * [I]/Ki from which Kimay be determined (Figure 3). The procedures for product inhibition and mixed inhibition are also dealt with. t-t (b) [PI Time Figure 3 (a) Progress curves in the absence and presence of inhibitor (I); (b) Time differences from (a) plotted against In (So/S) 21 S.Lin K. Chou and J. T. Wong Biochem. J. 1982 207 179. 22 S. G. Waley Biochem. J. 1982,205 631. Enzyme Chemistry 329 4 Regulatory Molecules Biochemists continue to identify new and surprising compounds which often have far-reaching properties in regulating enzyme action where it might have been supposed there was nothing new to discover. Possibly the best known example is that of adenosine 3',5'-monophosphate (cyclic AMP CAMP) which was first repor- ted by Sutherland in 1958 and which is now recognized to have a widespread role in mediating cellular response to external hormonal stimuli. Sites on the plasma membrane receptive to hormone molecules bring about the activation of the enzyme adenyl cyclase which causes the cyclization of ATP to cAMP which then acts as a cellular hormone or so-called 'second messenger'.The resulting effect is often the phosphorylation of a catalytic protein. The chemistry of cAMP and analogous cyclic nucleotides has been extensively reviewed;23 recently an interesting study has been published by van 001 and These authors have performed quantum chemical calculations on the formation of intermediates with trigonal-bipyramidal (TBP) configurations in the hydrolysis of cAMP with phosphodiesterases and in the activation of protein kinase by CAMP. In the case of hydrolysis of the analogue adenosine 3',5'-[thio]monophosphate (cAMP[S]) it is shown that the involvement of diequatorial ring-positioned intermediates would always result in the apical location of sulphur (la-d).The energy difference between the resulting diastereomers is calculated to be over 500 kJ mol-' and they could not therefore be hydrolysed at similar rates. The energy difference between the intermediates with an equatorial-apical cyclic phosphate ring (le) (If) is only 53 kJ mol-' and TBP configurations diequatorial ring position equatorial-apical ring position OMe (la) X = S,Y = 0 (lb) X = 0,Y = S HOKAd from endo-attack XH -0,OMe U-b0\ I '\ P-0 EWAd HS'b OH 0 (lc) x = 0,Y = s (Id) X = S,Y = 0 &Ad from exo-attack HO (If) Sp isomer of cAMP S gives rise to (la) (Id) (le) Rp isomer gives rise to (lb) (lc) (If) 23 'Cyclic 3',5'-Nucleotides Mechanisms of Action' ed.H. Cramer and J. Schultz John Wiley and Sons London 1977. 24 P. J. J. M. Van 001and H. M.Buck Eur. J. Biochem. 1982 121,329. 330 C.A. Ross these would therefore be hydrolysed at similar rates. The activation of protein kinases is assumed to proceed via diequatorial-ring-positioned TBP intermediates. The enzyme-nucleotide covalent intermediate is said to bring about the conforma- tional changes and dissociation of the catalytic and regulatory subunits which are necessary for activation of the enzyme. In glycolysis the metabolic pathway leading to the formation of pyruvate from glucose the most important step from the point of view of the control of the process is the conversion of fructose 6-phosphate to fructose-1,6-bisphosphate (Fru-1,6-P,) by phosphofructokinase (PFK or PFK 1).The bisphosphate was first discovered by Harden and Young in 1909 and the ester named after them until its chemical structure was identified by Levene and Raymond some twenty years later.Now over half a century later another fructose bisphosphate Fru-2,6-P2 (2) has been di~covered,~~~~~ which while not being an intermediate of glycolysis is a powerful regulator of PFK. This enzyme which was discussed in these Reports in 0 II O--P-O-CH20-I H Y o H 0 II 0-P-0-F 6- CHZOH OH H (2) 1980 continues to be the subject of active inve~tigation.~~" The discovery of a new allosteric effector will require a major revision of the roles played by the many controlling factors to which this enzyme responds.The identification of Fru-2,6-P2 has been and was aided by its lability to mild acid conditions. This property has been exploited in a specific method for the measurement of the ester28 in which after the removal of endogenous hexose-6-phosphate the extract is subjected to mild acid hydrolysis (pH2 for ten minutes at room temperature) when more than 95 O/O hydrolysis to fructose-6-phosphate will have occurred as compared with less than 1% with Fru-1,6-P,. The resulting Fru-6-P is then assayed in a coupled enzymic assay with bacterial NADH-dependent l~ciferase.,~ With the discovery of Fru-2,6-P2 has come identification of the enzymes respon- sible for its formation (6-phosphofructo-2-kinase PFK2) and its hydrolysis (fruc- tose-2,6-bisphosphatase FBPase 2).Just as PFK 1 is stimulated by AMP and inorganic phosphate and inhibited by phosphoenol-pyruvate and citrate so too is PFK 2. The K for Fru-6-P is 50 pM which is within the physiological range found in liver and so substrate concentration contributes to the control of biosynthesis of Fru-2,6-P2. On the other hand unlike the effects upon FBPase 1 FBPase 2 is " E. Van Schaftingen L. Hue and H.-G. Hers Biochem. J. 1980 192,897. 26 H.-G. Hers and E. Van Schaftingen Biochem. J. 1982,206 1. 27 (a) A. Sols J. G. Castano J. J. Aragon C. Domenech P. A. Lazo and A. Nieto in 'Metabolic Interconversion of Enzymes' ed. H. Holzer Springer-Verlag Berlin 1980; (b) H.-G. Hers E. Van Schaftingen and L. Hue ibid. '' L. Hue P. F. Blackmore H.Shikama A. Robinson-Steiner and J. H. Exton I. Bid. Chem. 1982 251,4308. 29 S. Golden and J. Katz Biochem. J. 1980 188 799. Enzyme Chemistry not dependent upon Mg2+ nor inhibited by AMP but is strongly inhibited by the product of the reaction Fru-6-P. The effect of glucagon a hormone which is known to stimulate glycogenolysis 'by the activation of adenyl cyclase and hence the activation of protein kinases by CAMP also causes the phosphorylation of PFK2 and of FBPase 2 with the consequent disappearance in Fru-2,6-P2 (Scheme 4). The Glucpp I I I t cyclic AMP I I I + ~ --Protein kinase ---. // \ 0 \ 0 \ / \ / \ / / \ (PEP = phosphoenolpyruvate; P-glycerol = glycerol phosphate) Scheme 4 interesting aspect of the control of Fru-2,6-P2 concentrations is that the activation- deactivation of PFK2 by dephosphorylation-phosphorylation operates in the opposite manner to that for phosphorylase and in similar manner to that for glycogen synthase.Thus CAMP prevents the formation and favours the destruction of Fru-2,6-P2. Evidence has been produced3' for a distinct mechanism of control mediated by Ca2' and calmodulin (see Scheme 1 in these Reports for 1980).The role of Fru-2,6-P2 would appear to be one of maintaining glucose levels rather than mimicking the action of phosphorylase. In this way glycolysis and glycogenoly- sis may be co-ordinated and not merely be similar routes with alternative starting points leading to the production of pyruvate (Scheme 5).Twenty five years have elapsed since Isaacs and Lindenmann first reported the isolation of a protein fraction from virus-infected animal cells which conferred resistance to viral attack in unaffected cells. The nature of the resistance appeared to be an interference with the normal development of the virus within the host cell and so they named the protein fraction interferon. Today the study of interferons '(' C.S.Richards and K. Uyeda J. Biol. Chem. 1982,257,8854. 332 C.A. Ross (bold arrows represent metabolic reactions broken arrows indicate regulatory effects) Scheme 5 has become one of the most active areas in biochemistry mainly due to the wide ranging implications for the control of viral infections and disease. In 1981 a new journal the Journal of Interferon Research commenced.There is a continuing series entitled Interferon3la which has already run to three volumes and two recent volumes in Methods in Enzymology31b have been devoted to this subject. During the past year 500 publications on interferon research have appeared together with a number of review Interferons (IFNs) are a family of proteins found in vertebrates and are divided into three antigenically distinct classes a (at least eight types) p (at least two types) and an unknown number of yIFNS. The first two classes may be induced in a variety of cells by certain viruses bacteria or double-stranded RNA (ds RNA) whereas y-IFNs are induced in lymphoid cells by mitogens and antigens to which the cells have been sensitized.It has been estimated that the genes specifying a-and @-IFNs are as old as vertebrates themselves. Originally interferons were produced in cell lines leucocytes for (Y -1FNs and fibroblasts for p-IFNs. Recently 31 (a)'Interferon' ed. I. Gresser Academic Press London and New York 1979 1980 1981 Vols. 1-3; (b) 'Methods in Enzymology Interferons Part A' ed. S. Pestka Academic Press London and New York 1981 Vol. 78; 'Part B' ibid. 1982 Vol. 79. 32 P. Lengyel Ann. Reu. Biochern. 1982,51,251. Enzyme Chemistry however using recombinant DNA technology human IFNgenes have been isolated and inserted into E. coli and shown to specify biologically active human IFNs. The protein sequences of interferons are being elucidated. Owing to the initial scarcity of material micro-sequencing proceeded slowly but now amino-acid sequences are being predicted from nucleotide sequences of cloned IFW cDNAs.~~ Interferon affects viral infection of cells by two distinct mechanisms both affecting the protein- synthesizing machinery.In one the enzyme catalysing the unusual reaction (n + 1)ATP + (2’-5’)-pppA(pA) + n pyrophosphate (18) (where n can be between 1 and 15) is stimulated in the presence of ds RNA (of at least 30 base pairs and maximally of 65 base pairs or more). The enzyme has been isolated and purified from various sources. The only well-established function of (2‘-5p)(A) is the activation of a latent endoribonuclease RNase L which cleaves only single-stranded regions of ribonucleic acid such as mRNA.Whereas in in uitro experiments RNase L is not specific in the cell it does appear to act preferentially on viral RNA. The oligonucleotide is resistant to many nucleases by virtue of its unusual (2’-5’)-phosphodiester linkage but it is degraded by a specific (2’- 5’) -phosphodiesterase. The other mechanism of interference by interferon in protein synthesis is by the phosphorylation (and hence inactivation) of an initiation factor eIF-2. The action of interferon is to bring about the activation of a protein kinase in the presence of double stranded RNA (Scheme 6). Because of the central role played by cal- mod~lin~~ in regulating cellular processes already referred to in this Section it is Interferon 1 Induction (2’-5’)synthetase Protein kinase ATP (2‘-5’)A elF-2 elF-2 phosphorylated unphosphorylated 10 Endonuclease (inactive) (active) 1 1 RNA degradation No initiation of protein synthesis I/ INo protein synthesis I Scheme 6 33 T.Taniguchi N. Mantei M. Schwarzstein S. Nagata M. Muramatsu and C. Weissmann Nature (London),1980,285 547. 34 C. B. Klee and T. C. Vanaman in ‘Advances in Protein Chemistry’ ed. C. B. Anfinsen. J. T. Edsall and F. M. Richards Academic Press New York 1982 Vol. 35. 334 C.A.Ross not surprising to find that its involvement in interferon induction has been investi- gated.35 Numerous questions still remain to be answered such as why there is such a diversity among the interferons and how it is that widely differing substances are capable of inducing interferon synthesis.It is also not known if interferon penetrates into the receptor cell or if not what is the nature of the ‘secondary messenger’ which relays the signal from the membrane receptor site. Secondary to this problem is the nature of the activation of two very dissimilar enzymes the (2’-5’)(A), synthetase and the protein kinase. 5 Conformational Changes It has now come to be widely recognized that many enzymes are composed of subunits and that practically all regulatory enzymes are multimeric and the question therefore must arise as to the functional significance of quaternary structure. Of the two original models proposed to account for co-operativity between sub-units that by Monod Wyman and Change~x~~ had as its central feature that the subunits were identical and that symmetry was conserved.As a result the model was unable to account for the phenomenon of negative co-operativity where clearly the subunits were behaving in a non-identical fashion. More recently Viratelle and Seydo~x~~ have modified the two-state model by introducing into one of the states two classes of binding sites with differing affinities for the same ligand. Negative co-operativity can now be accommodated but only at the expense of the basic criterion of the original model. On the other hand the Koshland Nemethy and Filmer3* model based on induced fit theory can readily account for negative co-operativity and can also be adapted to the situation where the subunits are initially non-identical i.e.pre-existing asymmetry. Since apparent co-operative effects may occur for other reasons than those described by the above models it has proved in practice extremely difficult to allocate many individual enzymes to one or the other model. There have been attempts to associate subunit interaction with the catalytic process. Thus the flip-flop model originally proposed by Lazdunski to account for extreme cases of negative co-operativity exhibiting Michaelian kinetics,39 envisages that binding sites act in pairs so that when one is occupied with substrate the other has a greatly diminished affinity. When a chemical event occurs at the first site the second site is reactivated to bind substrate with the consequent catalysis and release of product at the first site.Thus the two sites alternate as the catalytic site in a flip-flop cycle. The ‘alternate site’ model of Boyer4’ is basically the same but is more general not being confined to extreme negative co-operativity and can be adapted to the simultaneous binding of substrate at both sites. 35 D. Gurari-Rotman FEBS Lett. 1982,148 17. 36 J. Monod J. Wyman and J.-P. Changeux J. Mol. Biol. 1965 12 88. 37 0.M. Viratelle and F. J. Seydoux J. Mol. Biol. 1975,92 193. 38 D. E. Koshland G. Nkmethy and D. Filmer Biochemistry 1966 5 365. 39 M. Lazdunski Curr. Top. Cell. Regul. 1972,6,267. ‘’ P. D. Boyer M.Gresser C. Vinkler D. Hackney and G. Choate in ‘Structure and Function of Energy-Transducing Membranes’ ed. K. van Dam and B. F. van Gelder Elsevier Amsterdam 1977.Enzyme Chemistry 335 The whole area of subunit co-operation and enzymic catalysis has recently been reviewed.41 One enzyme in particular glyceraldehyde-3-phosphatedehydrogenase (GPDH) which catalyses reversibly the oxidative phosphorylation of D-glyceral- dehyde 3-phosphate to 1,3-bisphosphoglycerate (Scheme 7) is the subject of much GAP*&+ 1,3-BPG NAD' NADH GAP = glyceraldehyde 3-phosphate 1,3-BPG = 1,3-bisphosphoglycerate Scheme 7 investigation and debate concerning the role of subunit interaction in the catalytic mechanism. GPDH is a tetramer being composed of four chemically identical subunits each with a uniquely reactive sulphydryl group and each binding a molecule of coenzyme. However the GPDH's from different sources exhibit quite different properties and the yeast enzyme for example binds the coenzyme in a positively cooperative manner and conforms to the concerted model of Monod et al.42In contrast the binding of coenzyme by the enzymes isolated from various vertebrate muscles and from Bacillus stearothermophilus exhibits negative co-operativity although there is some disagreement among the reported dissociation constants.The differences between subunits in the affinity for NAD' and for NADH have been ascribed to two independent pairs of binding sites pre-existing in the tet~amer.~~ Similarly half-of-the-sites reactivity of the sulphydryl groups towards acylation has been interpreted in terms of a 'dimer of dimers' structure." Recently Cardon and B~yer~~ have re-examined the evidence for equivalent catalytic sites and found that tightly bound NAD' is preferentially reduced in the presence of glyceraldehyde 3-phosphate.They have proposed a scheme (Scheme 8) in which the enzyme has two interconvertible sites in an attempt to reconcile evidence for the equivalent participation of four catalytic In Scheme 8 the change in the binding of NAD' at one site from loose to tight not only promotes oxidation- reduction but may also promote phosphorolysis accompanying NAD' binding and NADH release at an alternate site. The authors readily admit that firm evidence for the 'alternate site' model is still required but they express the hope that subunit interactions contribute to catalysis and that many oligomeric enzymes will proceed by similar mechanisms.41 C. Y. Huang S. G. Rhee and P. B. Chock Annu. Rev. Biochem. 1982,51,935. 42 K. Kirschner E. Gallego I. Schuster and D. Goodall J. Mol. Biol. 1971 58 29. 43 (a)N. Kekernen N. Kellershohn and F. J. Seydoux Eur. J. Biochem. 1975,57,69;(6)N. Kellershohn and F. J. Seydoux Biochemistry 1979 18 2465. 44 0.P. Malhotra and S. A. Bernhard J. Biol. Chem. 1968,243 1243; Biochemistry 1981,20,5229. " J. W. Cardon and P. D. Boyer J. Biol. Chem. 1982 257,7615. 46 (a)D. R. Trentharn Biochem. J. 1971,122.59 71; (6) B. D. Peczon and H. 0.Spivey Biochemistry 1972 11,2209. 336 C. A. Ross RcHol 0 RC S /NA~H. E-&+ \NADH rapid redox rate limiting // release L* NAD+ f = high affinity site Scheme 8 A contribution towards techniques in detecting conformational changes in en- zymes has been presented by Christen and Gehri~~g.~’ They define two types of conformational change; that in which the change is induced by ligand binding and that in which change occurs as enzyme-substrate becomes enzyme-product.The latter has been termed syncatalytic change. The techniques discussed are the ‘differential chemical modification’ detection of the change in reactivity of side-chains to various labelling reagents as the protein passes through transitional configurations. By ‘differential chemical modification’ is meant the treatment of the protein in different states such as unliganded or complexed with substrates substrate analogues and inhibitors of various sorts.Such an approach to GPDH for example has been The case of aspartate aminotransferase is cited49” as an illustration of the value of the technique. Bromopyruvate a substrate analogue was found to inactivate the enzyme in the presence of the second substrate an amino-acid. However the presence of a second keto acid substrate did not protect the enzyme from inactivation by the haloacid which was subsequently found to be binding to a cysteine tesidue not in the active site. Hence it is concluded that bromopyruvate forms a covalent enzyme-ligand complex with consequent confor- mational change such that a sulphydryl side-chain is activated to react with 47 P. Christen and H. Gehring Methods Biochem. Anal. 1982 28 151. 48 L. D. Byers and D.E. Koshland Biochemistry 1975,14 3661. 49 (a) W. Birchmeier and P. Christen J. Biol. Chem. 1974 249 6311; Methods. Enzymol. 1977 46 41; (b)P. Christen M. Cogoli-Greuter M. J. Healy and D. G. E. Lubini Eur. J. Biochem. 1976 63 223; (c)D. G. E. Lubini and P. Christen,Proc. Natl. Acad. Sci. U.S.A. 1979,76 2527. Enzyme Chemistry bromopyruvate. The phenomenon of paracatalytic enzyme modification is also described in which a substrate becomes activated on complexing with enzyme and may then react with an extrinsic reagent. Such a situation has for example been described for the trapping by suitable oxidants of the intermediate in the fructose- 1,6-bisphosphate aldolase reaction (Scheme 9).49b*c The inactivation of the enzyme results from the crosslinking of two vital lysine residues by a substrate derivative.CH2W I c=o I H2N-E Fru-1,6-P2 DHAP ferrocyanide +2H' GAP +H20 CH2O I C=NH-E I -CHOH ferricyanide GAP = glyceraldehyde-3-phosphate1DHAP = dihydroxyacetone phosphate Scheme 9

ISSN:0069-3030    

DOI:10.1039/OC9827900321

出版商:RSC    

年代:1982

数据来源: RSC

摘要:

Author Index Aalstad B. 108 Abdel-Kader M. M. 189 229 Abdel-Magid A. 126 Abdel Rahman M. A. 189 Abdesaken F. 269 Abe M. 241 Abecassis J. 282 Abell A. D. 169 Abraham R. J. 3 189 Abramovitch R. A. 194 235 Acheson R. M. 47 Achiwa K. 220 Ackermann J. 203 Adachi K. 161 Adam M. J. 195 Addadi L. 42 Adiwidjaja G. 210 228 Afonso A. 215 Agawa T. 168 232 246 317 Aggarwal V. 232 Agho M. O. 229 Agosta W. C. 137 Aguilar D. A. 46 Aharon-Shalom E. 227 277 Ahern M. F. 236 Ahlberg P. 51 Ahn K. H. 318 Aida M. 32 Aitken R. A. 285 Akaboshi S. 197 Akada M. 114 Akhtar M. J. 12 Akiba M. 97 210 Akkerman 0. S. 261 Ahtekin N. 85 86 Alaruri A. D. A. 196 Albaugh-Robertson P.157 Albizati K. F. 311 Alcock N. W. 276 Alder R. W. 12 237 Alessi T. R. 38 304 Alexakis A. 136 142 279 283 284 Alfieri A. D. 71 Ali S. 191 Allan A. R. 91 Allan M. 183 Allinger N. L. 28 Al-Lohedan H. 63 Almasy A. 11 Almlof J. 18 25 28 29 Alonso M. E. 101 219 Alonso R. A. 81 Alvarez-Insua A. S. 223 Amatore C. 107 Ambroz H. B. 98 Ammete J. H. 18 Anastassiou A. G. 201 Andersen S. H. 167 Anderson J. E. 16 Anderson K. R. 269 Anderson P. C. 276 Anderson T. J. 145 Ando T. 151 Ando W. 95 105 210 212 Andre J. M. 28 Angeletti E. 197 Angliker H. 203 Angrick M. 151 Anh T. R. 157 Annunziata R. 168 Anselme J.-P. 104 Antfang E. 253 Antonioletti R.131 Antropiusova H. 143 Aono M. 162 Aoyama T. 228 Apeloig Y. 26 Aragan J. J. 330 Araki Y. 165 291 294 Aratani M. 214 Aratani T. 100 Arct J. 91 Argyropoulos J. N. 81 154 Arimoto M. 288 Armarnath K. 197 Arnold D. R. 109 Arnold Z. 229 Arrhenius G. M. L. 62 66 Arrowsmith R. J. 237 Asada K. 164 Asami K. 77 Ashby E. C. 80 81 154 197 Ashe A. J. 235 274 275 Askani R. 47 Askin D. 36 229 306 Astapov B. A. 7 Asveld E. W. H. 127 338 Atkinson R. S. 104 Atwood J. L. 259 266 267 Auster S. B. 31 Avery M. A. 298 Aylett B. J. 268 Ayyangar N. R. 195 Azuma S. 52 Baban J. A. 78 Babler J. H. 312 Bacardit R. 230 Bach R. D. 145 Bachovchin W. W. 10 Back T.G. 104 Backsay G. B. 18 Bade T. R. 161 Baeckstrom P. 127 Battig K. 43 178 Bahsoun A. A. 272 Bailey T. R. 308 Bailey W. F. 175 Baine N. H. 77 177 297 Bair R. A. 27 Baird M. S. 91 92 Baizer M. M. 110 Bakac A. 75 241 Baker R. 286 Bakke J. M. 165 Bakker B. H. 167 Bal B. S. 312 Balaban A. T. 26 Balabane M. 247 Balaji B. 186 Balci M. 93 183 Baldry P. J. 103 Baldwin J. E. 47 167 219 Baldwin S. W. 133 298 Bally T. 212 269 Balogh D. W. 131 180 Balschi J. A. 12 Ban Y. 220 245 Bandaranayake W. M. 180 Bandsley W. G. 324 Banerjee A. 20 Banert K. 184 Banfi L. 168 Banfield J. E. 180 Bapuji M. 235 Barba. F. 111 114 121 Author Index Barba I. 114 Barber M.71 Barber R. A. 125 Barclay L. R. C. 78 Barcus R. L. 92 Barker H. A. 322 Barker P.J. 71 Barlin G. B. 209 Barluenga J. 219 Barrett A. G. M. 192 222 Barry J. E. 112 Barstow J. F. 289 Bartetzko R. 23 Barthelat J. C. 22 Bartlett P. A. 289 Bartlett P. D. 38 Bartlett R. J. 20 Bartmann W. 172 Bartmess J. E. 193 Bartnik R. 194 Barton D. H. R. 79 160 180 192 226 313 314 Barton T. J. 105 268 Barua N. C. 137 Basangoudar L. D. 39 Basavaiah D. 136 137 150 279 280 Bates R. B. 83 198 Bats J.-P. 212 Batt L. 79 Bauer P. 81 Bauer R. K. 125 Bauer W. 179 Bauert K. 52 Bauld N. L. 24 36 Bay E. 130 Baydar A. E. 235 Beadle J. R. 236 Beak P. 140 164 199 Beaulieu P.L. 158 Beck A. 49 Beck G. 172' Becker G. 274 Becker K. B. 102 Becker J. Y. 112 113 Bedi B. S. 275 Bednardki M. D. 113 Behrens G. 80 Beirich C. 159 253 Bekhazi M. 102 Belinka B. A. 198 Bell N. A. 263 Bell R. M. 322 Bell S. 23 28 Bellamy A. J. 109 111 Belli A. 162 Bellville D. J. 24 36 Belot G. 121 Belsky Y. 66 195 Benati L. 103 Bendazolli G. L. 20 Bender D. F. 198 Benders P. H. 221 Benedetti F. 196 Benn R. 204 Bentley J. 31 Bentrude W. B. 69 Benzel M. A. 19 28 Berg A. 202 Bergen H. A. 3 189 Bergstein W. 316 Berlin K. D. 7 Bernardinelli G. 86 Berner D. 54 181 294 Bernhard S. A. 335 Bernheim M. 198 Berris B. C. 193 Berson J.A. 73 99 185 201 Berthelot J. 120 Bertz S. H. 290 Berube D. 111 Bertini V. 228 Bestmann H. J. 150 169 183,285,287 Beugelmans R. 197 Beveridge R. 54 Bhadbhade M. M. 98 Bhattacharya A. 46 Bickelhaupt F. 52 86 207 261 Bickert P. 205 Bien S. 87 Biloski A. J. 214 Bingel W. A. 17 Binkley J. S. 17 19 Birchmeier W. 336 Biresaw G. 302 Bisacchi G. S. 83 Bishop P. M. 177 Bizzigotti G. O. 65 Black D. St. C. 180 Blackburn E. V. 320 Blacklock T. J. 300 Blackmore P. F. 330 Bladon C. M. 211 Blaser H. U. 247 Blechert S. 194 Bloch R. 282 Blok P. M. L. 207 Bloodworth A. J. 139 Blount J. F. 38 212 269 Boche G. 198 Bock C. W. 25 Bodenhausen G. 263 Boeckman R.K. 38 303 304 305 Boekelheide V. 205 Boeker E. A. 324 Boersma J. 265 Boger D. L. 192 231 Boggs J. E. 29 Bohlmann F. 99 Bohrne D. K. 193 Bonaccorsi R. 28 Bonfiglio J. N. 301 Bonicamp J. M. 61 Bonneau R. 126 Bonnet J. J. 272 Bonnor F. T. 12 Bonsignore L. 237 Boothby C. S. J. 237 Borden W. T. 19 25 29 Bordner J. 215 Bordwell F. G. 59 Borenstein R. 125 Borkent J. H. 190 Born G. 19 Bos H. J. T. 282 Bosnich B. 293 Botschwina P. 31 Bottaro J. C. 219 Boudjouk P. 269 Bougeard P. 76 241 Boujlel K. 197 Boule P. 128 Bouma W. J. 18 24 26 101 Bowman J. M. 25 Boyd G. V. 235 Boyd R. J. 30 Boyer P. D. 334 335 Bozell J. J. 256 Brabender W. 132 Bracht J.115 Bradsher C. K. 199 Brady W. T. 229 Brandas E. J. 19 Branca S. J. 292 Brandange S. 161 Brandes S. J. 303 Brandsma L. 226 Brauer B.-E. 95 Brechbiel M. 45 47 75 194 Bregman J. H. 225 Breitmaier E. 161 Brettle R. 140 Breukelman S. P. 79 Breulet J. 19 23 Breunig H. J. 274 Brewster A. G. 314 Briere R. 27 Bringmann G. 192 Brinker U. H. 89 92 Brion F. 217 Brittain J. M. 195 Bronneka A. 160 Broline B. M. 47 Bronfenbrenner J. K. 89 Brook A. G. 269 Brookhart T. 44 Brooks D. W. 318 Brown C. 197 Brown F. 20 Brown H. C. 136 137 140 150 152 162 173 279 280 317 318 320 Brown J. K. 79 Brown J. M. 169 185 316 Brown M. D. 226 Brown R. A. 199 Brown R.D. 167 Brownawell D. W. 65 340 Author Index Bruck W. 96 101 Bruhin J. 206 Bruice T. C. 60 Brumby S. 71 Brunet J.-J. 317 Bruno J. W. 126 Brunsvold W. R. 43 Bruvo M. 264 Bryan S. J. 239 Bryce M. R. 12 Bryce-Smith D. 40 200 Bucci R. 194 Buchan C. M. 144 285 Buchanan J. G. 3 Buchwald S. L. 59 Buck H. M. 329 Buckingham M. J. 10 Buddrus J. 149 Budzelaar P. H. M. 265 Buenker R. J. 23 Buhro W. E. 100 Bunnett J. F. 196 Bunton C. A. 63 Burdon J. 196 Burgert W. 84 202 Burgoyne W. 319 Burgstahler A. W. 48 Burk R. M. 9 Burke L. D. 183 304 Burkhard P. 76 Burkhart J. P. 253 Burns G. T. 105 Burns S. A, 105 Burrow P. D. 186 Bury A.76 241 Busch R. 56 185 Butcher J. A. 96 Buxton S. R. 92 Byers L. D. 336 Byker H. J. 110 Cabiddu S. 237 Cabral D. J. 57 Cadiot P. 145 Cadogan J. I. G. 144 285 Cagle F. W. 267 Calcaterra L. T. 131 Camp R. C. 19 Campana C. F. 265 Campbell D. 125 Camps F. 197 Canadell E. 274 Cane D. E. 56 Capler V. 316 Capon B. 62 Capozzi G. 145 Caramella P. 187 Cardon J. W. 335 Carlsen L. 25 213 Carlsen P. H. J. 311 Caroon J. M. 84 Carpenter B. K. 184 Carr R. V. C. 38 Carroll P. J. 277 Carruthers R. J. 203 Carsky P. 20 21 Carter I. M. 167 Carter J. P. 298 Caruso T. 96 Carvalho C. F. 197 Casagrande F. 162 Case M. G. 54 Casey M. 224 Cassell R. A. 230 Castaldi G.162 Castano J. G. 330 Castedo L. 83 Castelhano A. L. 69 Caubire P. 317 Cava M. P. 276 277 Cavalla D. 165 Ceccherelli P. 99 Cha J. K. 193 Chackalamannil S. 177 Chadwick D. J. 3 189 217 Chaillet M. 23 Chamberlin A. R. 164 Champion R. 167 Chan D. M. T. 176 301 Chan T. H. 142 Chance B. 322 Chandler G. S. 18 Chandrasekaran S. 199 Chandrasekhar J. 23 26 106 Chang K.-T. 88 Chang M. J. 101 Chang S.-J. 88 94 Chang Y.-M. 269 Changeux J.-P. 334 Chanon M. 239 Chan Ryan Park 74 Chapman K. T. 311 Chapman 0.L. 93 183 Chapuis C. 37 178 306 Chapuisat X. 22 Charbonnier F. 247 Charpentier-Morize M. 54 Charumilind P. 38 186 Chatgilialoglu C. 74 75 78 Chatterjee S.154 291 Chelsky R. 24 Chen E. Y. 100 Chen S. 38 221 305 Chen S.-Y. 11 Chen Y.-S. 270 Cherney L. I. 89 Chiang Y. 62 65 Chidester C. G. 224 Childers W. E. 312 Childs A. C. 196 Childs R. F. 55 128 178 190 Chiles R. A. 21 25 Chin W. S. 195 Ching-Shih Chen 72 Chinn J. W. 26 262 Chino K. 77 218 297 Chitty A. W. 101 219 Chiu F.-T. 221 Chiu Y.-N. 92 Choate G. 334 Chock P. B. 335 Choe K. A. 207 Choi J. K. 221 Choi Y. M. 162 320 Chong D. P. 30 Choo D. J. 219 Chou C. S. 97 Chou K. 328 Chow Y.L. 167 Christ J. 47 Christen P. 336 Christensen L. 118 Christ] M. 91 180 Christoffel K. 25 Christofides J. C. 10 Chun Y. 13 Church D. F. 69 74 Cimiraglia R.23 Cinquini M. 168 Cipullo M. J. 232 Citterio A. 197 Ciufolini M. A. 308 Clark R. D. 84 Clark T. 26 84 198 Clark T. L. 202 Clarke F. W. 54 Claxton T. A. 27 Clayton J. P. 3 Clercq P. 19 Clive D. L. J. 158 276 288 Closs G. L. 70 Clouthier D. J. 30 Coates R. M. 222 Coe P. L. 209 Cogoli-Greuter M. 336 Cogswell G. 36 Cohen L. 97 Cohen L. A. 210 225 Coldrick P. J. 79 Coleman R. S. 195 Coleson K. M. 263 Coll J. 197 Collins J. R. 25 Collum D. B. 172 Colombo L. 150 168 Colosimo M. 194 Colquhoun I. J. 260 Colvin E. W. 198 268 Combs L. L. 19 Comisso G. 316 Compagnon P.-L. 121 Conde S. 223 Conia J.-M. 162 Conrad J. T. 132 Constable E.C. 41 Cook M. D. 78 Cooke M. P. Jr. 161 Cooksey C. J. 76 241 Cooper M. 194 Cooper N. J. 242 Author Index Coppola B. P. 177 Corey E. J. 137 141 151 172,280,286 Corfield G. C. 196 Corfield P. W. R. 266 Cornelisse J. 128 200 Cornish-Bowden A. 325 Corral C. 223 Correia N. S. 19 Corriu R. J. P. 268 Cortez C. 199 Cossar J. 62 Cotell C. M. 207 Cotsaris E. 200 Coughlin D. J. 127 179 298 Couture A. 130 Cowley A. H. 271 Cox D. P. 54 Cox S. D. 277 Coxon B. 4 Cozzi F. 168 Craig P. J. 263 Cram D. J. 190 205 Cramer J. A. 76 Crampton M. R. 196 Crawford R. J. 73 Cremer D. 33 204 Crighton J. S. 23 Crimmins M. T. 133 Cromer R. A. 161 Croteau R.56 Crump D. R. 168 Csizmadia I. G. 18 27 Cullen J. M. 19 20 Curini M. 99 Curran D. P. 316 Current S. P. 36 Cymbaluk T. H. 267 Dabbagh G. 290 Dahlman O. 161 Dahn H. 54 Dalal N. S. 5 Dalton M. S. 266 Dan E. T. H. 160 D’Angeli F. 166 212 Danheiser R. L. 42 Daniels J. A. 239 Daniels K. 315 Daniels N. J. 215 Daniels R. G. 282 Danishefsky S. 36 155 165 173 177 229,306 Dao G. M. 37 178 306 Dapperheld S. 113 Darling S. D. 303 Das J. 141 172 Das N. B. 167 da Silva R. R. 99 Dassanayake N. L. 194 Daub G. W. 161 Daub J. 179 Dauben W. G. 44 125 Daudel R. 18 D’Auria M. 131 310 Dauzonne D. 222 David M. 226 David S. 152 Davidson E. R. 19 20 25 29 Davies A.G. 70 71 78 Davies D. B. 10 Davies S. G. 239 Davis D. P. 225 Davis F. A. 212 Davis L. L. 99 301 Davis P. D. 183 304 Davison I. M. T. 80 Day R. O. 273 Deacon G. B. 264 Dearing A. 32 De Buyck L. 210 Decorzant R. 144 de Crooz P. Z. 195 Deem M. L. 223 De Frees D. J. 17 19 25 Degrand C. 121 Dehmlow E. V. 86 166 202 Deiters J. A. 273 De Jong F. 238 De Jong R. L. P. 226 De Kimpe N. 210 de la Mare P. B. D. 195 Delaunay J. 123 del Bene J. E. 27 31 Delniger D. 32 de Luca C. 120 Demailly G. 168 deMarch P. 39 101 218 De Mare G. R. 28 De Mayo P. 125 De Mello P. C. 18 Demko D. M. 38,305 Demonceau A. 100 De Munno A. 228 Demuth M. 131 173 den Hertog H.J. 48 Denmark S. E. 48 300 De Priest R. N. 80 197 Dereu N. L. M. 277 Dersch R. 161 Dervan P. B. 104 De Shong P. 224 De Silva N. 127 Deslongchamps P. 62 Des Marteau D. D. 278 Dess D. B. 277 Detty M. R.,276 Deutsch E. A. 44 177 Devillers J. R. 273 De Voe R. J. 203 De Vos M.-J. 174 de Wolf W. H. 52 86 207 Dezube M. 164 Diaz G. E. 320 Dick B. 204 Dicken C. M. 224 341 Diefenbach S. P. 240 Diephouse T. R. 235 275 Diesveld J. W. 190 Dingle T. W. 203 Disch R. L. 29 Di Tullio D. 72 Dix F. M. 64 196 Dixneuf P. 227 Dixon D. A. 30 Doa M. J. 42 Doak G. O. 274 Dobson C. M. 10 Dogan B. 202 Doherty J. B. 46 Dohmaru T. 77 Dolbier W. R. 202 Domenech C.330 Doncaster A. M. 71 Dondoroff M. 322 Dorfman L. M. 241 Dorow R. L. 100 Dougherty D. A. 73 185 Dowd P. 192 223 308 Dower K. W. 192 193 Dower W. V. 40 Doyle M. P. 100 Drabowicz J. 168 Dreher E.-L. 115 Dreiding A. S. 99 299 Dressaire G. 192 Dreyer G. B. 41 129 171 Duben A. J. 31 Dubiez R. 130 Dubois J.-E. 72 Duchamp D. J. 224 Duesler E. N. 265 Diitsch H. R. 69 Dugas H. 321 Duisenberg A. J. M. 265 Dulcere J.-P. 202 Dumas D. J. 181 294 Duncia J. V. 44 Dunkin I. R. 233 Dunlap R. B. 8 Dupuis M. 24 Dupuy C. 94 Durr H. 96 98 101 du Silva R. R. 301 Duus F. 10 Dvorak D. 229 Dyachenko A. I. 174 Dyakov V. M. 268 Dykstra C. E. 19 21 28 Dzarnoski J.72 Eaborn C. 270 Eberlein T. H. 167 229 Eberson L. 108 112 Echter T. 192 Edgar A. R. 3 Edgar K. J. 199 Edge S. J. 190 Effenberger F. 207 Egsgaard H. 213 Eguchi S. 102 Ehlinger E. 217 Eickhoff D. J. 315 Eisenbarth P. 90 175 Eisenstein O. 23 274 Eisenthal K. B. 94 Eisenthal R. 325 Ekiel I. 14 Elander N. 21 El-Durini N. M. K. 77 Elguero J. 11 Elhadi F. E. 190 Eliel E. I. 16 Ellam P. 30 Ellenbogen J. C. 29 Ellerman J. 273 275 Ellinger Y. 27 Elliott R. J. 75 185 El-Mobayed M. 115 El Seoud M. I. 64 El Seoud 0.A. 64 Elsevier C. J. 144 282 El-Sheikh M. Y.,235 275 El-tamany S. 10 54 206 El’yanov B. S. 35 Endo Y. 194 Engberts J.B. F. N. 63 Engdahl C. 51 Engelhardt G. 7 Engelhardt L. M. 260 Engels H.-W. 201 Engler T. A. 94 193 Engman L. 276 Ennen B. 253 Ennis M. D. 166 293 Entwistle I. D. 249 Epling G. A. 165 Erden I. 43 202 Erickson A. S. 167 Eriyana Y. 206 Erker G. 242 Ermler W. C. 23 Ernst L. 10 Ernst R. D. 267 Escher S. D. 144 Espenson J. H. 72 75 239 240 241 Ettlinger M. 169 287 Euler K. 184 Evanochko W. T. 70 Evans C. M. 62 65 Evans D. A. 153 166 293 Evans D. A. C. 43 Evans D. M. 227 Everett J. R. 10 Ewbank J. D. 28 Exton J. H. 330 Fabre J.-L. 284 Facelli J. C. 18 Fadnavis N. W. 63 Faegri K. Jr. 18 28 Faggiani R. 55 190 Fano G. 20 FiircaSiu D. 193 Farid S.35 125 Farina V. 158 Farnell L. 28 Farnum D. G. 98 Feher F. J. 199 Feigel M. 173 Feldman K. S. 295 Feller D. 25 29 Felton M. 56 Fenton G. A. 40 200 Ferreira T. W. 138 Fiandanese V. 138 Field S. J. 80 Fielding H. C. 209 Fields K. W. 161 Filho R. B. 173 Filmer D. 334 Finan J. M. 319 Finkelstein M. 11 2 Fischer G. 41 214 Fischer H. 69 76 Fish R. H. 273 Fisher R. D. 56 Fisher R. P. 137 Fitjer L. 183 Fleet G. W. J. 317 Fleming I. 137 195 Fletcher R. 23 Florjanczyk Z. 78 Floyd D. M. 290 Fluder E. M. 29 Fohlisch, B. 166 207 Forbes E. J. 79 Ford T. M. 54 Foropoulos J. 278 Forrester A. R. 84 103 Forsyth D. A. 9 Four P. 153 248 Foxman B.M. 277 Franck R. W. 37 308 Franck-Neumann M. 174 Francl M. M. 17 Frank J. P. 76 Fraser R. R. 6 Freedman L. D. 274 Freeman J. P. 224 Freeman P. K. 97 98 Freeman R. 173 Freidrich E. C. 302 Frenkiel T. 173 Frenking G. 24 Freudenberger J. H. 76 Frey P. A. 169 Friedman A. M. 195 Friege H. 85 Fripiat J. G. 28 Frisch M. S. 19 23 24 27 106 Fruchier A. 11 Fuchs B. 66 195 Fuchs P. L. 38 305 Fuentes L. M. 164 Author Index Fuji K. 320 Fujii M. 207 Fujimoto K. 214 Fujimoto M. M. 320 Fujimoto Y. 72 Fujioka Y. 189 Fujisawa T. 149 153 160 161 164 290 Fujise Y. 206 207 Fujita E. 142 164 284 288 320 Fujiwara Y. 197 198 245 Fukagawa T. 197 Fukaya M.72 Fukazawa Y. 205 206 207 Fukui K. 22 35 Fukumoto K. 216 Fukunaga T. 28 Fukunishi K. 197 Fukushima M. 89 Fukuzumi S. 80 Fyfe C. A. 55 190 Gabutti C. A. 102 Gagnier R. P. 175 236 Gaines D. F. 263 Gallego E. 335 Galli C. 197 297 Gallos J. 196 Galloy J. 38 Gallup G. A. 25 Galynker I. 65 149 Gandhi S. R. 28 Ganem B. 214 Ganguly A. K. 215 Gano J. E. 87 Gaoni Y. 175 219 Garcia J. 166 Gardetti M. 284 Gardner S. A. 36 Garrett M. D. 21 Garst M. E. 301 Garvey D. S. 155 Gaspar P. P. 270 Gaspar R. 22 Gaspar R. Jr. 22 Gassman P. G. 194 Gati E. 42 Gee S. K. 42 132 Geer R. D. 110 Gehrig K. 4 Gehring H. 336 Gehrlach E. 217 Geiser F. 132 Gemal A.L. 317 Genet J.-P. 247 Gennari C. 150 168 George P. 25 Gerlt J. A. 60 Gerothanassis I. P. 6 Gesing E. R. F. 192 Ghandi M. 98 Ghosez L. 230 308 Ghosh S. 127 179 298 Author Index Gibbons E. G. 171 Gibson L. L. 161 Giese B. 77 85 Gilbert A. 40 200 Gilbert J. C. 98 145 Gill G. B. 43 Gill H. S. 87 218 Gillard M. 229 Gillis H. R. 303 Gillon A. 87 Gillon D. W. 226 Gilman J. W. 183 Gingrich H. L. 210 Giordano C. 162 Girling I. R. 234 Girotra N. N. 172 Gisler M. 196 Givens R. S. 48 219 Gjerde H. B. 72 240 Glean R. 62 Gleiter R. 23 187 Gleize P. A. 248 Click M. D. 145 Glidewell C. 27 Glusenkamp K.-H. 229 Go C. L. 102 Goddard J. D.29 30 Goddard J. P. 71 Goddard W. A. tert. 27 30 Godel T. 37 178 306 Godfrey P. D. 167 Godoy J. 243 Goel A. B. 81 154 197 Gorlach Y. 47 Gokel G. W. 236 238 Golden D. M. 72 Golden S. 330 Goldenberg H. 325 Goldhill J. 137 Golding B. T. 98 Golding P. 196 Goldstein M. J. 201 Goldstein S. 200 Golinski J. 196 Goltz M. 202 Golyanskii B. V. 36 Gombler W. 10 Comes L. M. 123 Goncalves M. L. A. 173 Goodall D. 335 Goode N. C. 12 Goodman M. M. 276 Cora J. 120 Gordon M. S. 17 23 30 Gosciniak B. 149 Goskinski O. 21 Gosney I. 144 285 Goto T. 315 Goto Y. 153 Gotor V. 219 Gottschalk K. E. 32 Goure W. F. 105 Graf P. 18 Grant D. M.. 3 4 189 Grant D. W.275 Grasse P. E. 95 Grayson J. I. 308 Grdenic D. 264 Greck C. 168 Greeley A. C. 183 304 Greene F. D. 45 Grein F. 31 Gresser M. 334 Grieve D. McL. A. 62 Griffin R. G. 10 Griffiths G. 58 Grigg R. 39 40 Griller D. 69 70 71 76 78 94 95 96 185 Grimme W. 185 201 Grimshaw J. 107 120 Grinberg H. 32 Grob C. A. 173 184 Groen M. B. 244 Gropen O. 22 Gross M. L. 193 Grosse M. 84 103 202 Grothaus P. G. 318 Grover E. R. 113 Grundon M. F. 318 Gschwendtner W. 186 Guaciaro M. A. 292 Guanti G. 61 Gunther H. 11 Guerin C. 268 Guest M. F. 17 GuettC J.-P. 195 GuibC F. 153 248 Guida W. C. 152 Guilhernat R. 194 Guirado A. 111 114 121 Guise G. B. 190 Guitian E.83 Gulheim J. 160 Gunaratne H. Q. N. 39 Gund P. 29 Gunthard Hs. H. 23 Gunther B. 184 Guo W. 54 96 101 Gupta R. C. 302 Gupta S. C. 313 Gupta S. P. 11 Gupta Y. N. 42 Gurak J. A. 262 Gurari-Rotman D. 334 Gurusamy N. 7 Gutekunst B. 269 Gutekunst G. 269 Guthrie J. P. 62 Gutsche C. D. 205 Guy A. 195 Guyon C. 128 Guziec F. S. 310 Ha T.-K. 23 27 28 30 31 Haake P. 61 Haase K. 166 Hackney D. 334 Haddon R. C. 189 Hadel L. 94 Hafner K. 202 205 Haga T. 158 Hagedorn A. 54 Hahn G. 143 Hakushi T. 129 182 Haky J. E. 57 Halfman C. J. 326 Hall H. K. 229 Hall L. D. 195 Hall R. G. 192 Hall R. K. 48 Halla F. M. 107 Halpern J. 240 Haltiwanger R.C. 237 Hamada Y. 105 212 Hamaguchi H. 234 Hamill B. J. 144 285 Hamilton R. 120 Hammerich O. 108 Hammes G. G. 321 Hammons J. H. 99 Hamsen A. 159 168,253 Han B.-H. 269 Han G. Y. 145 Han P. F. 145 Hanafusa T. 151 Handu V. K. 223 Hanessian S. 169 Hanko R. 160 251 Hanna J. M. 235 Hanreich R. 184 Hansen H.-J. 183 Hansen P. E. 10 202 Hanus V. 143 Hanyu Y. 210 Hanzawa Y. 129,212 269 2 70 Hara S. 143 Harada T. 153 158 Hardee L. E. 29 Harding L. B. 25 Harding P. I. C. 317 Hargrove K. D. 16 Hariharan P. C. 19 Harkema S. 48 Harland P. A. 192 Harmata M. A. 48 Harms K. 229 Harre M. 172 Harris J. M. 54 Harris J. W. 93 183 Harris T. M. 230 Harrison J.F. 87 Harrison P. A. 46 Harrison W. D. 276 Hart D. J. 221 296 298 Hart H. 84 Hart W. P. 259 Hartwig W. 79 Harvey R. G. 199 Hasan M. 201 Hasegawa H. 166 344 Hasegawa Y. 199 Haselbach E. 183 Hashimoto J. 141 Hashimoto M. 214 Hasler E. 203 Hassid W. Z. 322 Hassner A. 198 Hattori K. 233 Haupt E. 173 Hawkes G. E. 10 Hawkins D. G. 103 Hayama T. 138 146 Hayashi H. 159 Hayashi S. 84 Hayashi T. 253 316 Hayes J. C. 242 Hazard R. 120 Healy M. J. 336 Heathcock C. H. 157 Hebeisen P. 98 Heck R. F. 198 Hedrinsky A. S. 138 Hegedus L. S. 128 214 220 240 285 Hehenberger M. 18 Hehre W. J. 17 19 33 Heiberg A. 25 Heidrich D. 32 Heilbronner E.41 214 237 Heimann M. R. 145 Heinze J. 185 Heitz M. P. 174 Hellring S. 235 Hellwig G. 91 Henderson A. 215 Henke K. 46 Hem L. 39 201 Henning R. 167 310 Henrick K. 267 Henriquez R. 71 Hensel M. J. 38 305 Herndon W. C. 204 Herrman W. A. 239 Hers H.-G. 330 Hershberger J. 81 Herter R. 166 217 Herzfeld J. 10 Hesbain-Frisque A.-M. 230 308 Heuggler B. 167 Hewitt S. F. 195 Hickey D. M. B. 103 Higuchi H. 129 135 206 Higuchi T. 269 Hillenbrand D. F. 263 Himbert G. 39 201 Hinsberg W. D. 104 Hinze J. 19 Hirai K. 161 214 Hitakawa K. 84 Hirama M. 172 Hitamatsu K. 169 Hiranuma H. 192 Hirao A. 318 Hirao K. 20 31 Hirao T. 246 317 Hirota N.32 Hirotsu K. 269 Hirsl-Starcevic S. 92 Hisamitsu K. 125 Hiskey R. G. 37 Hiyama T. 159 Ho P.-T. 139 Hoberg H. 246 253 Hochmann J. 76 Hodge P. 192 Hofelmeier R. 194 Hoehne S. 273 Hoeve W. T. 235 Hoffman R. 274 Hoffman H. M. R. 166,229 310 Hoffman K. 195 Hoffman R. 35 239 Hoffmann R. W. 152 153 155 Hofmann H.-J. 32 Hogeveen H. 67 212 Hohlneicher G. 204 Hojo M. 162 Hokama K. 237 Holland H. L. 167 Hollowood F. 183 Holmes J. M. 273 Holmes R. R. 273 Holzwarth J. F. 65 Hon F. 215 Honda T. 128 214 215 Hong P. 147 Honma A. 161 Hooper D. 87 Hoorfar A. 190 Hopf H. 10 54 205 206 285 Hopkins A. 61 Hopkins P. B. 137 151 280 Hoppe D. 160 251 252 Hoppe I.165 Hoppe M. 90 Horgan A. G. 194 Hori K. 140 245 Horino H. 162 Horner M. 112 184 Horton D. 14 Hoskins S. V. 265 Hosmane R. S. 235 Hosomi A. 165 206 291 294 302 Hossain M. B. 271 Houk J. 259 Houk K. N. 27 28 42 43 87 187 Houser J. J. 127 Hout R. F. Jr. 19 33 Howbert J. J. 41 Hoz S. 82 Hrncir D. C. 266 Hu H. 313 Author Index Huang N. Z. 203 Huang Y. Z. 272 Hubac I. 20 21 Huber H. 27 Huber W. 185 Hubert A. J. 100 Hudlicky T. 287 Hue L. 330 Huecas M. E. 137 Hunig S. 112 166 Hutter P. 115 Huffman J. C. 242 Hugentobier M. 4 Huggett P. G. 239 Hughbanks T. 274 Hughes S. 58 Huguet J. 99 299 Hui H. K.-W. 95 Hui R. A.H. 313 Huisgen R. 39 101 218 Hulkenberg A. 166 Hull W. E. 173 Hungerford J. M. 76 241 Hunig S. 184 Hunkler D. 49 Hurst J. R. 45 Huszthy P.,197 Hutchins L. G. 190 Hutchins R. O. 319 Hutchinson J. P. 271 Hutton A. T. 264 Huy P. T. 86 Huzinaga S. 18 30 Hwang H. H.-Y. 194 Hyang C. Y. 335 Hyde J. R. 271 Iberle K. 20 Ibuki E. 189 Ichinose M. 71 Idei M. 195 Iglesias G. Y. M. 38 Iguchi H. 302 Ihara M. 216 Ihira N. 31 Iida H. 161 Iijima M. 158 Ikar K. 31 Ikariya T. 163 316 Ikawa H. 197 Ikawa T. 161 247 Ikeda H. 270 297 Ikeda M. 314 Ikeda N. 141 146 217 252 Ikeda T. 164 201 Ikeda Y. 8 Ila H. 232 Imai H. 167 Imai N. 220 Imaida M. 153 Imanaka T.153 Imashiro F. 189 Imming P. 225 Inamoto N. 217 Author Index Inazu T. 206 Inbasekaran M. N. 194 235 Inesi A. 120 Inglin T. A. 201 Ingold K. U. 69 70 74 75 78 185 Inokawa S. 169 Inokucki T. 114 Inoue K. 116 234 Inoue M. 60 Inoue T. 162 Inoue Y. 129 182 285 Invergo B. J. 312 Iqbal J. 195 Irgolic K. J. 276 Irving H. M. N. H. 264 Irwin W. L. 318 Ishibashi Y. 195 Ishibe K. 129 Ishiguro M. 146 217 252 Ishii N. 247 Ishii Y. 163 Ishikawa M. 168 269 270 Ishikura M. 245 Ishizaki K. 165 Ismail I. M. 10 Ismail Z. M. 166 229 Isobe M. 315 Ito E. 227 Ito F. 52 Ito H. 253 Ito K. 310 lt8 S. 187 205 206 207 Ito T. 162 253 Ito Y.167 Itoh K. 294 Itoh T. 161 290 Itsumo S. 318 Ives J. L. 310 Iwamura H. 8 95 Iwano Y. 214 Iwasaki M. 72 Iwasawa N. 158 Iyer R. S. 76 Iyoda J. 270 Izawa M. 52 Izawa Y. 93 132 Izumi T. 162 Jabri N. 142 283 Jachimowicz F. 139 Jackels C. F. 24 Jackson D. A. 302 Jackson R. A. 77 Jackson W. G. 5 Jackson W. R. 166 Jacobs S. A. 199 Jacobsen E. J 48 Jacquesy J.-C. 195 Jacquesy R. 173 Jadhav K. P. 285 Jain J. C. 293 Jagdmann G. E. Jr. 160 Jancke H. 7 Janda K. D. 83 Janout V. 145 Jam A. W. H. 200 Jaouannet S. 120 Jaquet R. 21 Jarglis P. 164 Jarvi E. T. 157 Jasien P. G. 21 Jastrzebski J. T. B. H. 260 267 Jayaraman B. 197 Jeffrey-Luong T.198 Jefford C. W. 86 Jeffrey-Luong T. 144 Jemmis E. D. 26 262 Jencks W. P. 51 Jendralla H. 91 236 Jenner G. 40 45 Jennings J. R. 239 Jennings W. B. 14 Jensen-Korte U. 150 Jeung G. H. 22 Jinbo T. 248 Jonsson L. 108 112 J~rgensen,F. S. 16 J~rgensen P. 19 Jorgensen R. D. 167 Jogibhukta M. 223 John R. A. 154 291 John T. V. 37 Johnson C. R. 152 161 168 Johnson D. E. 125 Johnson D. W. 301 Johnson G. 215 Johnson L. F. 15 Johnson M. D. 76 241 Johnson M. W. 313 Johnson R. W. 113 Johnson W. S. 181 294 Johnstone R. A. W. 249 317 Jones D. W. 202 Jones G. Jr. 125 Jones M. 89 183 Jones T. K. 300 Jones W. D. 199 Jones W. M. 93 183 Jonsell G. 51 Jonvik T.29 Jordan K. D. 24 27 186 Jouanntaud M.-P. 195 Jubault M. 120 Judkins B. D. 104 Julia M. 143 284 Jung,G. 115 Jung M. E. 308 Jungen M. 21 Junjappa H. 232 Jurlina J. L. 9 Kabuto C. 271 Kahn R. A. 26 29 Kai Y. 236 Kaicho T. 155 Kaji A. 161 Kakehi A. 187 Kalhorn T. F. 125 Kalinowski H.-D. 184 Kalkote W. R. 195 Kallury R. K. M. R. 269 Kambe. S. 223 Kametani T. 128 214 215 216 Kamigata N. 210 Kamitori Y. 162 Kanaya N. 214 Kaneda K. 153 Kanehira K. 316 Kanehisa N. 236 Kaneti J. 28 Kang J. 286 Kano K. 104 Kapili L. V. 215 Kapon M. 87 Karbach S. 205 206 Karol T. J. 271 Karpf M. 99 177 299 Kasahara A. 153 Kasai N. 236 Kasch H. 107 Kashigawa H.161 Kashimura S. 116 164 234 Kato H. 167 204 Kato J. 158 Kato K. 99 Kato N. 36 306 Kato S. 23 Katritzky A. R. 165 233 Katsuki T. 311 314 Katz J. 330 Katzenellenbogen J. A. 157 Kauffmann T. 159 168 253 258 Kaufman J. J. 19 Kaufmann E. 84 Kaufmann K. J. 95 Kaur H. 79 Kausch M. 98 Kavanagh J. 324 Kawabata N. 141 Kawabata T. 320 Kawai F. 29 Kawamata A. 206 Kawashima M. 149 164 290 Kawata I. 198 245 Kawata T. 151 Kawauchi T. 198 245 Kayser M. M. 319 Kazubski A. 153 318 Kazui Y. 132 Kazumura H. 197 Keck G. E. 294 Keehn P. M. 311 Kegami S. I. 197 Keinan E. 248 Kekemen N. 335 Kellershohn N. 335 Kelley D. F. 185 Kellogg R.M. 127 Kelly C. A. 104 Kelly W. J. 167 Kemball M. L. 70 Kemp T. J. 98 Kemper B. 152 Kempf D. J. 140 Kende A. S. 98 293 300 Kennedy A. J. 70 Kennedy D. A. 39 Kent R. D. 19 Kerwin J. F. Jr. 36 155 165 306 Kerr J. B. 109 Kerr R. G. 104 Kesseler K. 250 Ketcham R. 35 298 Khalifa M. H. 11 5 Khan N. 104 Khanna R. K. 197 Kiji J. 223 Kikuchi M. 76 Kikuchi O. 46 Kikuchi S. 153 Kikuchi Y. 199 Kikukawa K. 198 Kilduff. J. E. 271 Kim C. U. 216 Kim K. S. 27 Kim S. 318 Kimura K. 159 200 Kinastowski S. 162 King H. F. 19 King J. F. 51 King K. D. 71 King R. M. 196 King T. J. 3 Kingma R. F. 212 Kipp J. E. 183 Kira M. 71 Kirby A. J. 62 65 Kirby G.W. 198 211 Kirk K. L. 225 Kirms M. A. 202 Kirmse W. 52 91 184 Kirollos K. S. 43 Kirpichenko S. V. 268 Kirxhner K. 335 Kishi Y. 286 315 319 Kitagawa T. 179 225 Kitamura M. 315 Kitaura K. 22 Kitigawa Y. 284 Kitchin J. P. 313 Kjeldsen G. 167 Klarner F.-G. 189 202 Klages C. P. 131 Klas N. 253 Klaus A. J. 4 Klebach T. C. 183 Klee C. B. 333 Kleeman A. 316 Kleier D. A. 31 Kleijn H. 282 Klein M. L. 31 Klein R. S. 166 Kleinschroth J. 54 205 206 Kliebisch U. 183 Klieser B. 206 Klimkowski V. J. 28 Kloosterziel H. 204 Klopman G. 46 Klunenberg H. 118 Klumpp G. W. 90 Klym A. 62 Knapp F. F. 276 Kneussel P. 214 Knothe L. 49 Knowles J.R. 59 Knudsen J. S. 167 KO A. I. 303 Kobayashi M. 145 Kobayashi S. 36 155 201 306 Kobayashi T. 246 Kobs K. 131 Kochanski E. 32 Kochi J. K. 80 242 Koehler K. A, 32 Kopke B. 213 Koft E. R. 171 298 Kohashi Y. 236 Kohl N. 222 Koji A. 303 320 Kojo S. 197 Kok D. M. 212 Kokko B. J. 164 Kollman P. 32 Kollmar H. 189 Kolt R. J. 139 Koltzenburg G. 80 Komatsu M. 168 232 Komiya K. 166 Konaka R. 79 Koniju M. 52 260 Konishi H. 223 Konishi M. 253 Koper N. W. 186 Koppenhoefer B. 316 Koreeda M. 152 157 308 Kornblum N. 167 Koroniak H. 202 Korpar-colig B. 264 Korsell K. 18 Korzeniowski S. H. 238 Kos A. J. 26 29 262 Koschatzky K.-H. 150. 285 Koshiro Y.162 Koshland D. E. 322 334 336 Kotsuki H. 199 Kowalski C. J. 161 Koyabu Y. 93 Koyama K. 102 194 Koziara A. 139 Kozikowski A. P. 284 Kozlowski J. 290 Kramer W. 204 Krapcho A. P. 162 Author Index Kraska A. R. 88 89 Kraus G. A. 214 Krebs C. 32 Kreher R. 222 Kresge A. J. 62 65 Kresze G. 45 Krief A. 174 Kriegesmann R. 168 Krische B. 228 Krishnamurthy S. 317 Krishnamurthy V. V. 194 Krishnan R. 19 24 Krogh-Jespersen K. 29 101 Krois D. 206 Krow G. R. 312 Kruger C. 90 204 Kruk C. 200 Kruse L. I. 193 Kudo T. 30 Kuivila H. G. 271 Kula J. 120 Kulkarni S. U. 136 137 279 280 Kumada M. 253 269 270 316 Kumar R. 197 Kundig E. P. 177 Kuno K.198 Kuo-Chen C. 205 206 Kurita Y. 149 Kuroda K. 244 Kuroda T. 182 Kurosawa K. 206 Kurtz A. 21 Kusabayashi S. 227 Kusunoki I. 23 Kutney G. W. 168 169 Kutzelnigg W. 24 Kuwajima I. 157 163 290 316 Kuwajima S. 21 Kwang Yul Choo 74 Kwart H. 45 47 75 194 Kwart L. D. 75 Laarhoven W. H. 190 L’abbk G. 228 Lablache-Combier A. 130 Lachhein S. 77 Ladner W. 155 Lagow R. J. 26 262 Lahov M. 42 Lai J. T. 164 Lai T. 246 Lai Y.-H. 193 203 Laidler K. J. 321 Lakshmikantham M. V. 277 Lalko 0.R. 310 Lam C. F. 324 Lambert J. B. 14 Lammertsma K. 204 Lampman G. M. 76 241 Landgrebe J. A. 87 218 Landro F. J.. 26 262 Author Index Lang R. 180 Langhoff S.R. 30 Langier J. 27 Lansbury P. T. 44 171 Lapham D. J. 139 Lappert M. F. 260 261 Larock R. C. 253 Larson E. R. 36 198 229 Larson G. L. 164 Lasne M.-C. 36 Lau A. N. K. 121 Lau W. 242 Lautens M. 255 Lauterwein J. 6 Lavallke P. 169 Lavigne G. 272 Lavrukhin B. D. 7 Lawrence G. A. 5 Lay J. O. 193 Lay P. A. 5 Lazdunski M. 334 Lazo P. A. 330 Leblanc Y.,169 Lebouc A. 109 123 Le Bozec H. 227 Lechner M. 91 Leclercq D. 212 Lee D. G. 312 Lee H. D. 136 280 Lee J.-S. 276 Lee T. V. 313 Lee W.-B. 85 Leff P. 324 Lefferts J. L. 271 Le Guillanton G. 122 123 Lehmkuhl H. 174 Lehner H. 206 Lehr G. F. 96 Leibfritz D. 173 Leiserowitz L. 42 Leismann H.41 200 Lemaire J. 128 Lemaire M. 195 Lemal D. M. 210 Lempert K. 197 Leng J. L. 196 Lengyel P. 332 le Noble W. J. 74 Lenoir D. 160 Leonard N. J. 235 Leone-Bay A. 171 Leopold A. 236 Le Roux J.-P. 93 183 Leska J. 46 Lessard J. 11 1 Lester D. L. 313 Lester W. A. Jr. 24 Levi B. A. 33 Levin J. I. 224 Levine J. A. 205 Lewis F. D. 126 203 Lewis K. E. 72 Lewis W. 137 Lex J. 201 204 Ley S. V. 172 296 313 314 316 Li J. S. 142 Liang G. 13 Lichtenberg F. 160 Lichtenthaler F. W. 164 Lickiss P. D. 270 Lidert Z. 204 Liebe J. 207 Liebeskind L. S. 192 Liebman J. F. 87 Liebman P. 32 Lievin J. 19 23 Lightsey J. W. 74 Lim M.-I. 166 Lin E.-C. 117 Lin S.328 Linder E. 273 Lindley P. F. 235 Lindner D. L. 46 Lindsay D. A. 70 185 Linstrumelle G. 144 198 Liotta D. 139 Lipkowitz K. B. 6 29 190 Lipshutz B. H. 290 Lissel M. 168 Little R. D. 110 Littmann M. 47 Liu M. T. H. 95 96 Lloyd J. M. 165 Lock C. J. L. 55 190 Loew C. 32 Lowdin P.-O. 17 Lomas J. S. 72 Loots M. 240 Lopez M. 114 Lopez R. C. G. 167 Lorch M. 192 Louw R. 78 Lovel C. G. 166 Loy G. 237 Lozes R. L. 21 Lubini D. G. E. 336 Lucas P. 9 Lucchesini F. 228 Luche J.-L. 317 Ludwig E. G. 274 Luddecke E. 126 205 Luthi H. 18 Luettke W. 17 Lukacs G. 4 173 226 Luke B. 26 Lusztyk E. 71 78 Lusztyk J. 71 78 Luthra N. P. 8 Lutomski K.A. 190 Luzzio F. A. 310 Lygo B. 296 Maas G. 179 McBay H. C. 145 McCague R. 184 204 205 McCleary D. G. 318 McClelland R. A. 16 McCombs C. A. 308 McConnell B. 264 McCormick J. P. 313 McCurdy C. W. 94 MacDonald J. G. 233 McDougal P. G. 172 McDowell M. S. 241 McElwee-White L. 73 185 McFarlane H. C. E. 260 McFarlane W. 260 McGall G. 16 McGarrity J. F. 52 McGarrity M. J. 51 McGregor C. J. 109 McGregor D. M. 216 McGuire M. A. 128 214 McGuirk P. R. 172 McHatton R. C. 75 241 Mach K. 143 Macho V. 13 53 184 MacInnes I. 185 McIntyre D. D. 72 McIver R. T. 193 Mackay D. 72 Mackay G. I. 193 McKearin J. M. 220 Mackenzie P. B. 293 Mackirdy I. S. 109 11 1 McKnight M.V. 217 Mclaughlin L. M. 144 285 McLean A. D. 18 23 32 McLean D. 169 McLennan D. J. 53 MacLeod J. K. 26 MacManus P. A. 222 McMillen D. F. 72 McMurray J. E. 178 299 Macomber D. W. 259 McPhail A. T. 215 MacPherson L. J. 113 Maeda M. 91 Maeda Y. 310 Magnus P. 217 Mahadevan R. 203 Mahalanabis K. K. 166 Mahaputra S. N. 235 MQhlen A. 161 Maier G. 90 99 184 Maier J. P. 31 Maier M. 229 Majerski Z. 92 Majestic V. K. 238 Makhlauf M. A. 319 Makosza M. 196 Malatesta V. 74 Malba V. 125 Maletina E. A. 195 Malhotra 0. P. 335 Malone J. F. 39 Malpass J. R. 104 Malrieu J.-P. 30 Manchandra A. K. 112 Mander L. N. 301 Mandolini L. 297 348 Mangner T.J. 195 Mani S. R. 42 Mann J. 202 Manoharan M. 16 Mantei N. 333 Manzanera C. 121 Maranon J. 32 Marchese G. 138 Marcus F. 326 Marcuzzi F. 145 Mareda J. 187 Margaretha P. 35 132 Mariano P. S. 130 132 221 Marino J. P. 218 293 Marks J. 301 Marks T. J. 126 Marquina-Chidsey G. 270 Marshall D. R. 196 Martens J. 316 Martin J. C. 231 277 Martin L. D. 163 Martin P. L. 53 Martin R. L. 31 Martin S. J. 281 Martin V. S. 311 314 Martina D. 174 Maruoka K. 233 Maruyama F. 52 Maruyama K. 154 155 159 253 Marynick D. S. 30 Masamune S. 90 155 212 269 270 Masamune T. 99 Masci B. 194 Masnovi J. 129 Mason G. 122 Massy-Westropp R. A. 169 Masters C.J. 322 Masters T. J. 301 Masuda R. 162 Masuda T. 143 Masunaga T. 246 317 Mataka S. 219 Mateescu G. D. 13 Mathre D. J. 166 293 Mathur N. C. 97 Math A. R. 201 Mathin S. A. 11 Matsuda T. 198 Matsui T. 298 Matsumoto M. 199 244 Matsumoto S. 201 Matsumoto T. 52 Matsumura Y. 116 118 164 233,234 Matsushita H. 154 198 291 Matsushita T. 32 Matsuura T. 133 Mattay J. 40 200 Mattenberger A. 151 Mattes S. L. 35 125 Matthews R. W. 267 Matuszewski B. 48 219 Matz J. R. 178 299 May D. D. 79 Mayes R. T. 97 Mazaki Y. 207 Mazuch L. 203 Mazur M. R. 73 185 Meakins G. D. 79 226 Meckstroth W. K. 241 Meerholz C. A. 316 Mehdi S. 60 Mehler E. L. 18 Mehler K. 174 Meichsner G.47 Meier H. 192 Meier M. M. 231 Meijer J. 144 226 282 Meinema H. A. 267 Mellor J. M. 41 Memming R. 131 Menger F. M. 51 Merbach A. E. 74 Merchant S. N. 219 Merkle U. 192 Merry S. 27 Meth-Cohn O. 103 Metz J.-Y. 19 Meyer G. R. 154 Meyer R. 23 Meyer W. 21 Meyers A. I. 160 190 235 Meyers E. A. 277 Mezey P. G. 18 22 Mhala M. M. 63 Michl J. 180 Michna M. 179 Midland M. M. 153 154 318 Midorikawa H. 223 Miertus S. 31 Miesch M. 174 Migron Y. 36 Mihelich E. D. 315 Miki K. 236 Mikolajczyk M. 168 Miles W. 75 Miller A. L. 235 Miller D. L. 193 Miller E. K. 121 Miller J. M. 264 Miller L. L. 118 121 Miller R. E. 71 Miller S. I.192 Miller T. 44 Miller T. M. 190 Minami Y. 84 Minch M. J. 3 Minkin V. 36 Minot C. 23 Mio S. 315 Misco P. F. 216 Mise T. 147 Misumi S. 129 135 206 Mitchell D. J. 23 52 Mitchell R. H. 203 Author Index Mitra M. 92 Mitsuo N. 320 Miura A. 194 Miura H. 165 Miura M. 227 Miura T. 145 194 Miwa T. 159 Miyahara Y. 206 Miyake H. 161 320 Miyaki H. 303 Miyashi T. 125 Miyataka H. 320 Miyazaki T. 233 Mizutani H. 189 Mochida K. 77 Mochizuki H. 318 Mochizuki T. 128 214 Modaressi S. 183 Moens L. 210 Mbrch L. 161 Moffat J. B. 28 Moffatt J. R. 54 63 Moghadam F. M. 163 Mohr R. 225 Molines H. 296 Molle G. 81 Molloy K. C. 271 Molz T. 192 Mondo J.A. 73 Mondragon A. 29 Monkhorst H. J. 18 Monod J. 334 Montevecchi P. C. 103 Montgomery C. R. 94 Moody C. J. 103 184 204 205 224 Moomaw W. R. 31 Moon Y. C. 318 Moon Ho Chang 73 Moore D. W. 15 Moore K. W. 215 Moore W. M. 112 Morales A. 101 219 Moran J. R. 205 Morand P. 319 Moreno-Manas M. 230 Moret6 J. M. 197 Morgan M. R. J. 325 Morgan T. K. 54 Mori M. 220 245 Mori T. 160 189 Moriarty R. M. 313 Moriishi H. 46 Morikawa K. 200 Morild E. 321 Morin F. G. 3 Moriya O. 77 218 Morizawa Y. 176 Moro-Oka Y. 161 247 Morrissey P. 215 Morton J. A. 296 Mortreux A. 145 Morukuma K. 17 22 23 Morzycki J. W. 313 Author Index Moseley C. G. 88 Mosher M.W. 74 135 Moskowitz J. W. 22 Moss N. 276 Moss R. A. 54 64 65 96 101 196 Motherwell W. B. 79 160 182 313 Motyka L. A. 171 Moulines J. 212 Mrozack S. R. 59 Muller D. 274 Muller E. 225 Mueller P. H. 87 187 Muller W. 149 Munsterer H. 45 Mues P. 204 Mujka C. 271 Mukai T. 125 Mukaiyama T. 158 159 Mukherjee D. 20 Mukhopadhyay T. 167 Mulder P. 78 Mullen K. 185 Muller P. 243 Mullican M. D. 192 Mulliken R. S. 23 Mumtaz M. 166 Munger P. 198 Munowitz M. 10 Murahashi S.-I. 97 310 Murai A. 99 Murakami A. 29 Murakami S. 212 269 Murakami T. 225 Muramatsu M. 333 Murata I. 202 236 Murata S. 151 189 Murray B. J. 276 Murray P. J. 172 296 Murray R.K. 54 Murrell J. N. 18 Murrer B. A. 169 Musser A. K. 132 Musso H. 17 173 Myhre P. C. 13 53 184 Mylari B. L. 99 301 Nader B. 308 Naf F. 144 Nagami K. 234 Nagami S. 318 Nagao Y. 164 Nagaoka H. 286 315 Nagaoka S. 32 Nagase S. 24 30 Nagase T. 100 Nagashima H. 140 160 245 Nagashima T. 297 Nagata C. 32 Nagata R. 199 Nagata S. 333 Nagata Y. 77 Nagese S. 97 Nahm S. 96 Naik R. G. 316 Nakadaira Y. 105 206 271 Nakahama S. 318 Nakahata M. 153 Nakajima T. 13 Nakamura E. 290 Nakamura K. 52 Nakamura N. 90 Nakane S. 114 Nakanishi K. 31 Nakanishi W. 8 Nakatsuji H. 20 Nakazaki M. 91 Nalesnik T. E. 76 240 Naota T. 97 310 Nappa M. J. 240 Narang S.C. 169 194 Narasaka K. 159 Narasimhan S. 140 162 318 3 20 Narbonne C. 173 Narimatsu S. 294 Naruse K. 164 Naso F. 138 Nast R. 239 Natsuura T. 199 Nauts A. 22 Nechvatal G. 222 Nedelec J.-Y. 71 Nederlof P.J. R. 181 294 Nee M. 13 Nefedov 0.M. 174 Negishi E. I. 154 198 239 285 291 Negishi Y. 217 Neidlein R. 204 Neisser M. 218 Nelson J. V. 153 NCmethy G. 334 Nesmeyanova 0. A. 174 Neszmelyi A. 4 173 Neuenschwander K. 214 Neugebauer W. 261 Neumann C. 85 Neumann T. E. 56 Neustadt R. J. 267 Newkome G. R. 209 238 Newman P. A. 195 Newman R. M. 262 Newman T. H. 271 Ng F. T. T. 240 Ngochindo R. 217 Ngounda M. 227 Nguyen M. T. 27. 28 30 Nguyen T.T. 71 Ni J.-D. 129 Nickon A. 89 Nicolaides C. A. 23 Nicolaou K. C. 49 180 302 Nieto A. 330 Niino Y. 320 Nikrad P. V. 195 Nimmesgern H. 210 Nishida K. 129 Nishiki M. 320 Nishimoto K. 32 Nishiyama H. 294 No K. H. 205 Nobes R. H. 18 24 26 101 Node M. 320 Noels A. F. 100 Nogues P. 229 Nohira H. 153 165 Nojima M. 227 Nokami J. 117 Noltes J. G. 267 Nomoto T. 210 Nomura M. 197 Nomura Y. 138 139 146 Nonhebel D. C. 71 185 Nordlander J. E. 57 Norin T. 127 Normant J. F. 136 142 279 283 284 Noro T. 29 Norris J. R. 70 Norris R. K. 151 167 Noto N. 163 311 Noureldin N. A. 312 Novack V. J. 315 Novak F. 94 Nowacki A. 162 Nowell I. W. 263 Noyori R.151 312 Nozaki H. 159 176 310 319 Nozomi M. 168 Nudelman N. S. 32 Nugent R. A. 172 Nugent S. T. 110 Nwaukwa S. O. 311 Nyburg S. C. 269 Oae S. 164 Obana M. 316 Obara S. 22 Ochiai M. 142 284 288 Oda I. 220 Odaira Y. 200 Odom J. D. 8 O’Donnell M. J. 169 O’Donoghue M. F. 264 Ohm Y. 21 Oertle K. 253 Ogata Y. 101 161 Ogawa S. 153 Ogilvy M. M. 103 Ogimura Y. 158 Ogle C. A. 198 Ogura F. 135 Ogura K. 161 Ohga K. 132 221 Ohgishi H. 232 Ohrnizu H. 116 234 311 Ohno H. 200 Ohno K. 17 29 Ohno M.. 225 350 Ohno T. 101 Ohshiro Y. 168 232 246 Ohta H. 163 311 Ohta K. 20 Ohta M. 150 Ohta S. 162 Oikawa Y. 199 Okabe M.241 Okada K. 125 Okamoto K. 179 Okamoto M. 162 Okamoto T. 194 Okano M. 139 287 Okano T. 102 223 Okawara M. 77 150 168 218,297 Okazaki R. 217 Okazaki S. 31 Okazaki T. 197 Okecha S. 127 Oki M. 189 Okude Y. 159 Okumoto H. 290 Okumura K. 97 Olah G. A. 13 26 169 191 194 O’Leary B. F. 113 Olejniczak B. 139 Olejniczak K. 37 Oliver J. P. 266 Oliver R. S. 3 Ollis W. D. 190 Ollmann G. W. 122 Olsen J. 19 Omae I. 239 On H. P. 137 Ona H. 90 O’Neal H. E. 72 O’Neill M. E. 257 Ono N. 161 303 320 Ono T. 253 Onyiriuka S. O. 195 Ookawa A. 166 Oostveen A. R. C. 296 Oostveen E. A. 144 Oppolzer W. 37 43 133 171 173 177 178 298 306 Orchin M.76 240 Orszulik S. T. 185 Ortega Blake I. 29 Ortiz J. V. 21 Ortolani F. 20 Osakada K. 163 316 Osamura Y.,19 24 29 Osawa E. 17 173 Osborn J. A. 272 Oshima K. 152 176 249 310 319 Oshiro Y. 317 Osman R. 22 Osowska K. 139 Otsubo T. 129 135 Otsuka M. 225 Otter B. A. 236 Outcalt R. 132 Ovadia D. 87 Overheu W. 225 Overman L. E. 48 Owa M. 318 Owada H. 287 Owens K. 81 Ownor P. 57 Ozaki H. 153 Ozaki Y. 93 Ozasa S. 189 Ozawa F. 246 Pacansky J. 27 Pack G. R. 32 Paddon-Row M. N. 17 27 28 35 43 173 186 187 200 Padwa A. 96 97 200 210 Pagni R. M. 190 Pai G. G. 152 318 Paine R. T. 265 Pakulski M. 271 Palacios S. M. 81 Paldus J. 20 Palik E.C. 92 Palla P. 28 Palmieri P. 20 Pan Y.-G. 308 Panfii J. 35 Panek J. S. 231 Panetta J. A. 230 Pang F. 29 Papadopoulos M. 40 45 Papoula M. T. B. 160 313 Pappalardo P. 217 Paquette L. A. 38 129 131 171 180 186 282 Pardo C. 54 Parham W. E. 199 Park K. H. 194 PBrkBnyi C. 204 Parker V. D. 108 Parshall G. W. 199 Parsons I. W. 196 Pascard C. 160 Pasman P. 186 Pate B. D. 195 Patel M. 192 Pathirana R. N. 41 Patney H. K. 186 Pattenden G. 172 Paudler W. W. 209 Paynter 0. I. 135 Peacock J. A. 190 Pearson N. R. 143 Peczon B. D. 335 Pedersen L. G. 32 Peinel C. 32 Pelissier M. 22 Pellacani L. 103 Pellegrin V. 11 Pellicciari R. 99 Author Index Penney C.321 Percival P. W.,76 Pereyre M. 194 Perez J. D. 97 104 Perez L. A. 101 Perkins J. 145 Perkins M. J. 79 Pero M. F. 207 Perret C. 177 Perrin C. L. 62 66 Perry D. A. 137 Petasis N. A. 49 180 302 Peter R. 157 250 Peters E.-M. 47 Peters J. A. 317 Peters K. 47 Peters K. S. 55 Peterson M. R. 27 28 Petiniot N. 100 Petit F. 145 Petit M. 145 Petragnani N. 162 Petrillo G. 61 Petrusova L. 143 Petrzilka M. 308 Pettersson L. 18 22 Petty E. H. 100 175 Petzer R. M. 31 Peyerimhoff S. D. 23 Pfatz A, 151 Pfeffer M. 192 Pflaumbaum W. 91 Philips P. 20 Phillips G. B. 44 Phillips R. B. 125 Piancatelli G. 131 310 Picard P. 212 Pietro W. J. 17 Pietrusiewicz K.M. 16 Pilichowska S. 169 Pilla N. N. 292 Pillay M. K. 224 Pincock J. A. 97 Pincock R. E. 190 Pinhas A. R. 99 Pinnick H. W. 312 Pinson J. 107 Pinto A. C. 173 Piper S. E. 202 Piras P. P. 58 Pitt I. G. 46 Pitteloud R. 43 171 177 Platz M. S. 31 87 92 94 Pleixats R. 230 Plenchette A, 285 Pletcher D. 107 Plettenberg H. 149 Podejma B. L. 267 Poirier R. A. 18 Poli G. 150 Politzer P. 32 Polley J. S. 54 Pomfret A. 202 Ponsold K. 107 Author Index Poon Y. C. 269 Popkie H. E. 19 Pople J. A. 17 19 24 25 26,27 Potter A. 75 Potts K. T. 232 Potzinger P. 80 Pouchan C. 23 Pradham J. 59 Prakash G. K. S. 13 Prasad K. 214 Prashad M.86 Pratt A. J. 163 Pratt D. R. 99 Preftitsi S. 166 Prelog V. 252 Preston S. B. 154 Prestwich G. D. 295 Price J. A. 190 Price M. F. 288 Price N. C. 321 Priebe H. 285 Priester R. D. 266 Prime S. 19 Prinzbach H. 41 49 214 Pritschins W. 201 Prodolliet J. W. 52 Pross A. 52 53 59 Pryor W. A. 69 74 Psiorz M. 206 Pugmire R. J. 189 Pulay P. 18 29 Pulcini P. 103 Pulwer M. 200 Purvis G. D. tert. 20 Pyne S. G. 38 305 Quast H. 47 102 Qui Z. W. 189 Quillen S. L. 130 Raban M. 224 Rabenstein P. L. 263 Raber D. J. 29 152 Rabideau P. W. 29 Raddatz P. 172 Radenas E. 63 Radom L. 18 24 26 28 Rafalska M. 125 Ragauskas A. J. 6 Raghavachari K. 23 25 27 30 106 189 Raghu S.98 Rahimi P. M. 74 Rahm A. 194 Rahman A. F. M. 266 Raimondi M. 21 Rakshit A. B. 193 Raksis J. W. 139 Ralli P. 232 Ramamurthy V. 98 Ramos M. 76 Rampazzo L. 120 Rand C. L. 285 Randall D. 14 Randles D. 167 Rao P. S. 223 Rao Y. R. 235 Raphael R. A. 198 Rapoport H. 230 Rapp K. M. 179 Rappe A. K. 30 Rasoul H. A. A. 229 Raston C. L. 260 261 Ratner M. 22 Rau H. 126 205 Rausch M. D. 259 Rautenstrauch V. 67 Ravi Shanker B. K. 94 Rawson D. I. 3 Ray J. A, 230 Read C. M. 314 Reddoch A. H. 5 Redman L. T. 20 Reed D. W. 75 Rees C. 19 Rees C. W. 103 184 204 205 224 Reetz M. T. 35 153 157 250 290 Regen S. L. 86 145 Regitz M. 90 175 Reichardt C.161 Reichlin D. 37 178 306 Reid R. S. 263 Reimann B. 80 Reimer J. R. 31 Rein R. 27 Reinecke M. G. 83 Reinhoudt D. N. 48 221 238 Reinsch E.-A. 21 Reisenauer H. P. 90 99 Reitz M. 179 298 Reitz T. 98 Remberg G. 229 Rempel G. L. 240 Ren W.-Y. 166 Renson M. 277 Rentzepis P. M. 185 Rewicki D. 84 151 202 Rey P. 27 Reynolds R. C. 4 Rhee S. G. 335 Rich J. D. 268 Richards C. S. 331 Richards R. M. 237 Richards W. G. 75 185 Rickborn B. 319 Ricker W. 126 Riediker M. 297 Riegel H. J. 246 Rieker A. 115 Riemenschneider C. 252 Riemenschneider J. L. 13 Rihs G. 41 214 Ring M. A. 72 351 Ripmeester J. A. 5 Ripoll J.-L. 36 Riviere P.30 Rob F. 186 Robaugh D. A. 71 Robb M. A. 19 Roberts B. P. 78 Roberts D. D. 56 Roberts J. D. 4 13 Roberts M. F. 263 Robinson G. N. 79 Robinson-Steiner A. 330 Rodriguez A. 96 Roduner E. 76 Rodwell W. R. 18 R~eggen,I. 21 Rossler M. 274 Rofer-De Poorter C. K. 239 Rogers H. R. 259 Rogers N. H. 3 Rogers R. D. 259 266 267 Rohde C. 84 Rolla F. 164 Rollick K. L. 242 Roman V. K. 195 Romeo G. 145 Romsted L. 64 196 Rondan N. G. 27 87 187 Ronlan A. 108 Ronzini L. 138 Rood I. D. C. 90 Roper W. R. 265 Rosati R. L. 215 Rose H. 13 Rosenfeld M. N. 314 Rosenfeld S. M. 207 Rosenfeldt F. 242 Rosmus P. 31 Ross B. C. 215 Ross S. D. 112 Rossell O. 265 Rossi R.A. 69 81 197 Rossier J.-C. 86 Rossiter B. E. 314 Rossman M. A. 235 Rotard W. 99 Roth B. 300 Roth K. 169 287 Roth W. R. 202 Roush W. R. 303 Rousseau G. 162 Roussi G. 197 Routledge P. J. 196 Rowland F. S. 76 Royer G. P. 321 Rozzell J. D. 161 Rubin M. B. 130 173 179 Rubio V. 219 Ruchardt C. 150 Rudashevskaya T. Y. 174 Ruelle P. 32 Ruitenberg K. 282 Ruland A. 205 206 Rule M. 73 99 Runge T. A. 176 Runge W. 282 Runsink J. 41 200 Rusek G. 194 Russell C. G. 288 Russell G. A. 81 Russell J. C. 125 Russell R. A. 43 46 Rustemeier K. 161 Ruth T. J. 195 Rutschmann S. 193 Rys P. 4 Rzepa H. S. 184 Saa J. M. 83 Sabio M. L. 29 Saburi M.163 316 Sadd J. S. 84 Sadler P. J. 10 Saegusa T. 167 Saigo K. 153 165 Saikachi H. 225 Saiko A. 189 Saimoto H. 319 Saindane M. 139 Sainte F. 230 308 Saito A. 56 Saito I. 133 199 Saito K. 223 Saito Y. 155 Saitoh N. 114 117 Sakaba H. 105 Sakai K. 245 Sakai S. 23 24 Sakai Y. 18 30 Sakata S. 79 Sakata Y. 129 135 Saket B. M. 14 Sakurai A. 223 Sakurai H. 71 105 165 206 271 291 294 302 Salama H. 126 Sales J. 265 Salinaro R.F. 99 Salomon R. G. 127 179 298 Salvator J. 319 Salz U. 150 Sammes P. G. 11 39 230 Sancassan F. 3 189 Sanchez M. G. 161 Sandman D. J. 277 Sandorfy C. 32 Sanfilippo P. J. 98 300 Sangfelt E. 21 Sano M. 31 Santi R.240 Santiago A. N. 81 Santucci S. 131 Said H. 42 Sargent M. V. 197 Sargeson A. M. 5 Sasaki H. 225 Sasaki J. 302 Sasaki M. 234 Sasaki T. 102 227 Sasaoka M. 11 7 Sasson I. M. 236 Sato F. 248 283 Sato K. 160 290 Sato M. 152 248 249 283 Sato O. 91 Sato T. 149 153 160 161 164 256 290 Sato W. 141 Satoh T. 320 Satoh Y. 143 Sau A. C. 273 Sauer J. 32 Saunders V. R. 17 Savtant J. M. 107 Savilova S. F. 174 Sawada K. 214 Sawaki Y. 101 Sawyer J. F. 278 Sayrac T. 99 Scaiano J. C. 69 74 75 76 78 94 95 96 Scarsdale J. N. 25 28 29 Scettri A. 310 Schade G. 183 Schaefer D. 253 Schaefer H. F. tert. 19 24 27 29 Schafer H.-J. 107 118 150 Schafer L.25 28 29 Schaffer C. 118 Schaffner K. 131 173 Schaller R. 166 Schamp N. 210 Scharf H.-D. 41 200 Scharfenberg P. 23 Schat G. 261 Schatz G. C. 25 Schaub B. 169 Schaumann E. 13 35 210 298 Schechter H. 193 Scheider H.-J. 56 Scheiner S. 32 Scheinmann F. 195 Schen Y. C. 272 Schenker G. 92 Schentzow D. 204 Schiess P. 193 Schimpf R. 11 Schlank K. 168 Schlegel H. B. 19 22 23 25 29 52 Schlesinger M. 19 Schlessinger R. H. 172 Schleyer P. von R. 24 26 29 84 198 261 262 Schlosberg R. H. 193 Schlosser M. 169 Schmehl R. H. 125 Schmidt E. K. G. 189 Schmidt R. R. 229 Schmidt S. P. 99 Author Index Schmitt P. 10 Schmitz L. R. 57 Schneider H.-J. 149 186 Schoeller W.W. 85 86 Schollkopf U. 165 Schoenberger D. C. 152 Schonwalder K.-H. 207 Scholl T. 204 Schonberg P. R. 265 Schrobilgen G. J. 278 Schroder M. 41 Schrott W. 198 Schubert J. 261 Schubert W. 27 Schubert W. M. 65 Schuda P. F. 145 Schueman J. M. 29 Schuhknecht C. 168 Schulman E. M. 74 Schulte-Frohlinde D. 80 Schultz A. G. 171 Schultz P. G. 104 Schultz T. H. 43 Schulz G. 214 Schumacher M. 11 Schurig V. 316 Schuster D. I. 131 Schuster G. B. 45 95 Schuster I. 335 Schuster P. 17 Schwartz J. 297 Schwarz H. 24 Schwarz W. 125 Schwarzstein M. 333 Scolastico C. 150 Scopes R. K. 321 Scott J. A. 193 Scott J. W. 316 Scott L. T. 43 202 Scott R. 40 Scrimin P.166 212 Scrocco E. 31 Se Ahn Song 74 Secci M. 237 Seco M. 265 Sedelmeier G. 41 214 Seebach D. 167 251 252 Seeger R. 23 26 Seeger U. 23 26 Seetz J. W. F. L. 261 Seevers R. H. 195 Seiferling B. 102 Seikaly H. R. 160 Seitz G. 225 Sekiguchi A. 95 105 212 Sekiya M. 220 Sellars A. 209 Sellers H. L. 28 Sellers S. F. 183 202 Semmelhack M. F. 256 Sen A. 246 Senthilnathan V. P. 87 94 Sentman R. C. 229 Serckx-Poncin B. 230 308 Author Index Serravalle M. 197 Setiloane B. P. 75 Seydoux F. J. 334 335 Seymour C. A, 45 Shahidi P. 3 Shaik S. S. 52 53 59 Shakhova S. K. 35 Shakir R. 266 Shamout A. R. 166 Sharma L. R. 112 Sharma R. P. 137 Sharma S.C. 167 Sharpless K. B. 311 314 Shaskus J. 56 Shatkin B. T. 202 Shavitt I. 19 20 Shaw G. S. 128 178 Shea K. J. 183 304 Shearer H. M. M. 263 Shechter H. 88 89 94 95 Sheldrick G. M. 229 Sheng Li J. 282 Shepard R. 19 Sheppard N. 6 Sherman D. H. 180 Shervi S. 157 Shibata T. 167 280 281 Shibib S. M. 140 Shieh H.M. 295 Shigematsu Y. 166 Shih C. 47 102 Shikama H. 330 Shimbayashi A. 162 Shimizu I. 161 227 Shimizu M. 290 309 316 Shimozono K. 133 Shine H. J. 194 Shiner C. S. 177 Shiner V. J. 56 Shioiri T. 228 Shiokawa T. 207 Shirahama H.,52 Shirahata A. 294 Shoda T. 222 Shoham G. 46 Shono T. 116 118 164 234 Shridnar D. R. 223 Shudo K. 194 Shukla V.S. 98 Shulman S. 99 301 Siddiqui K. F. 266 Siddiqui S. 95 Siddiqui T. 233 Siegel H. 84 Siegman J. E. 127 Sih C. J. 72 Sikirica M. 264 Sikkel B. J. 197 Silver D. M. 20 Simchen G. 195 Simig G. 197 Simkin B. Ya. 36 Simmonds D. J. 135 Simmons D. P. 43 Simon J. D. 55 Simonet J. 109 120 122 123 197 Simonetta M. 21 26 Simons J. 19 20 Sims R. J. 286 Singh A. 86 276 Singh B. P. 191 Singh G. 112 232 Singh P. R. 197 Singh S. 98 Singh S. M. 224 Sirakawa T. 114 Siroi T. 11 7 Sitzmann E. V. 94 Skancke P. N. 29 Skattebl L. 91 Skell P. S. 75 79 Skelton B. W. 261 Slomp G. 224 Slopianska M. 202 Slougui N. 162 Smigielski K. 120 Smit C.J. 110 Smith A. B. tert. 171 292 298 Smith C. S. 276 Smith D. E. 36 Smith G. P. 72 Smith K. M. 3 Smith P. J. 59 Smith R. J. 190 Snider B. B. 44 177 Snieckus V. 166 199 Snow J. T. 137 Snyder L. C. 22 So S. P. 27 Soai K. 166 Sobukawa M. 205 Solladit G. 163 168 Solladit-Cavallo A. 168 Solomon M. F. 99 301 Sols A. 330 Solum M. S. 3 Somanathan R. 3 Somei M. 222 Sondheimer F. 203 So0 Sung KO 303 Sorensen T. S. 57 South M. S. 192 Soyama H. 246 Spagnolo P. 103 Spanget-Larsen J. 187 Speckamp W. N. 296 Spector L. B. 321 Spek A. L. 265 Spellmeyer D. C. 38 305 Spencer A. 247 Spiess E. 256 Spitznagel G. W. 26 Spivey H. O. 335 Squillacote M. E.13 Srinivasan P. R. 11 Srnak T. 287 Staab H. A. 205 206 Staemmler V. 20 21 Staib R. R. 308 Stakem F. G. 198 Stam C. H. 52 260 Stanton R. E. 18 Stapersma J. 90 Staring E. G. J. 162 212 Stark C. J. Jr. 168 Stark J. C. 277 Stavinoha J. L. 130 Steckhan E. 113 Stehouwer P. M. 282 Stein S. E. 71 Steinbach R. 157 250 Steinmetz M. G. 97 Stephanidou Stephanatou J. 190 Stephenson L. M. 36 Sternberg E. D. 40 180 256 301 Stevens L. 321 Stevens R. V. 83 311 Stevens R. W. 158 Stevenson P. 40 Stewart K. R. 274 Stezowski J. J. 179 207 Stibbard J. H. A. 41 Still 1. W. 169 Still W. C. 65 149 311 315 Stille J. K. 157 163 Stirling C. J. M. 58 196 Stitt R. P. 219 Stoddart J.F. 190 Stoodley R. J. 302 Stork G. 77 177 180 297 Stothers J. B. 6 9 Strauss H. F. 43 177 Street L. J. 39 230 Stretton G. N. 264 Stringer 0.D. 212 Strub W. 76 Stubbs C. A. 311 Stutz P. 214 Suau R. 83 Subramanian E. 215 Subramanyam R. 38 Suckling C. J. 185 195 Suda M. 90 287 302 Suenaga M. 206 Suss J. 285 Suetsugu K. 223 Sugai S. 197 Sugawara T. 95 Sugihara Y. 118 202 Sugimoto A. 200 Sugimura T. 202 Sugisawa H. 269 Sugita T. 195 Sukenik C. N. 64 Sukhai R. S. 226 Sumi K. 142 284 Sumi S. 151 Sumitani M. 126 Sunjic V. 316 Suri S. C. 288 Sutcliffe R. 70 185 Sutherland S. J. 278 Sutter J. K. 64 Suzuki A. 143 Suzuki H. 161 247 Suzuki K.46 Suzuki M. 151 312 Suzuki N. 132 169 Suzuki S. 93 Suzuki T. 319 Suzuki Y. 283 Svaan M. 108 Svrcek M. 20 Swanson R. 130 Sway M. I. 76 Swenson K. E. 97 98 Swenton J. S. 47 102 Szabo J. F. 30 Szalewicz K. 18 Szawelski R. J. 325 Szeleczky Z. 72 Szczesniak M. M. 32 Szmuszkovicz J. 224 Tabba H. D. 3 Tabche S. 155 Taber D. F. 100 175 Taber T. R. 153 Tada M. 241 Tada S. 142 284 Tadema G. 282 Taffer I. M. 319 Taguchi T. 65 Tai A. 153 Takada H. 312 Takada T. 24 Takahashi K. 161 219 Takahashi M. 247 Takahashi T. 297 Takai K. 310 Takamatsu S. 232 Takano K. 116 Takata T. 210 Takatsu. K. 129 Takayama H. 210 Takeda A. 143 Takeda Y.308 Takegami Y. 195 Takegoshi K. 189 Takehira Y. 84 Takeshita K. 31 Takeuchi H. 102 194 Takeuchi K. 179 Takeuchi M. 290 Takeuchi Y. 138 139 146 Tak-Hang Chan 282 Tallec A. 109 120 Tam W. W. 311 Tamai K. 164 Tamblyn W. H. 100 Tamminga J. T. 128 Tamura R. 320 Tanaka H. 114 117 Tanaka K. 25 31 Tanaka M. 246 309 Tanaka Y. 152 157 Tandardini G. F. 21 Tang R. H. 69 Taniguchi H. 197 198 201 245 Taniguchi T. 333 Tanikaga R. 161 Tanner D. D. 74 75 320 Tannous R. S. 273 Tanzella D. J. 289 Tardella P. A, 103 Tartakovsky E. 66 195 Tashiro M. 206 219 Tasker P. A. 267 Tatewaki H. 18 30 Tatlow J. C. 196 209 Taylor D. R. 227 Taylor K. G. 84 Taylor R.T. 230 Tcozek J. 313 Teague S. J. 172 TeclC B. 266 Tedder J. M. 69 75 Teng P. P. 126 Teranishi S. 153 Terao T. 189 Terao Y. 220 Terashima M. 245 Ternansky R. J. 131 180 Tetsukawa H. 163 311 Tewnion L. 275 Teyssie P. 100 Tharp G. A. 132 Thea S. 61 Theodiridis G. 232 Theodorakopoulos G. 23 Thianpatangul S. 39 ThiCbault A. 107 Thieffry A. 152 Thies R. W. 191 Thomas E. J. 163 Thomas J. A. 298 Thomas P. J. 58 Thomsen T. 16 Thornson C. 27 30 Thornson R. H. 103 Thorli E. Y. 270 Thurkanf A. 191 Tidor B. 26 Tidwell T. T. 28 160 Tietze L.-F. 229 Tiner-Harding T. 221 Tirel M. D. 79 Titus D. D. 276 Tius M. A. 191 Tlumak R. L. 75 Toan V.V. 193 Tobe M. L. 239 Tobe Y. 200 Tobita H. 271 Tochtermann W. 207 Author Index Toda S. 204 Toder B. H. 98 293 Tolbert L. M. 95 Tomasi J. 28 31 Tomasik W. 313 Tomioka H. 93 310 319 Tomiyoshi N. 52 Tomoda S. 138 146 Tomora S. 139 Topiol S. 22 Torii S. 114 116 117 Toriyama K. 72 Torssell K. B. G. 167 Toshimitsu A. 139 287 Tbth G. 11 Touhara H. 31 Toullec J. 51 Toyama T. 179 Trachtman M. 25 Tramontini M. 165 Trentham D. R. 335 Trinquier C. 30 Trippett S. 192 Trocha-Grimshaw J. 120 Troll T. 122 Troost J. J. 166 Trost B. M. 167 172 176 177 178 254 255 280 281 297 301 309 316 Truesdell J. W. 191 Tsai Y.-M. 221 298 Tsay Y.-H. 204 Tschaen D.M. 46 TSOU T.-T. 240 Tsubata K. 118 Tsuboi S. 143 Tsuda Y. 219 Tsuge O. 237 Tsuji J. 140 160 161 245 290 297 Tsuno Y. 309 Tsutsui T. 91 Tuck D. G. 267 Tundo P. 197 Turecek F. 143 Turkenburg L. A. M. 52 86 207 Turnbull K. 168 Turner J. V. 199 Turro N. J. 96 129 Uchibori Y. 24 Ueda M. 320 Uei M. 172 Uemura S. 139 287 Uenishi J. 49 180 302 Ueno K. 210 212 Ueno Y.,77 150 168 218 297 Ueoka T. 182 Ullrich J. W. 221 Uneyama K. 116 Upton R. M. 11 Author Index 355 Urabe H. 157 163 316 Urz R. 157 250 Use G. 222 UskokoviC M. R. 44 Uyeda K. 331 Vacca J. P. 171 Valenta K. 31 Vallee B. L. 322 Van Alsenoy C. 25 28 29 Vanaman T.C. 333 van Beekum H. 317 Van De Mark M. R. 117 Van der Avoird A, 20 Vanderessi R. 317 van der Helm D. 271 Vanderhooft J. C. 267 Van der Kerk G. J. M. 265 Van der Saal W. 47 van Dijk-Knepper J. J. 200 van Engen D. G. 225 Van Hummel G. J. 48 van Koten G. 260 267 van Leusen A. M. 225 van Mil J. 42 van Nispen S. P. J. M. 225 Van 001,P. J. J. M. 329 Vanquickenborne L. G. 27 30 Van Schaftingen E. 330 van Tilborg W. J. M. 110 Varadarajan A. 55 128 178 190 Varie D. L. 167 229 Varma C. A. G. O. 128 Varvoglis A. 196 Vedejs E. 167 229 Veit A. 273 275 Velasco M. D. 121 Venkatesan K. 98 Venturello P. 197 Venuti M. C. 235 Verboom W. 48 221 Vercanteren D. P. 28 Verhe R.210 Verhoeven J. W. 186 Verrna R. S. 112 Vermeer P. 144 282 Vermeulen G. 228 Veronese A. C. 166 212 Verpeaux J.-N. 143 284 Vidusek D. A. 263 Vieira E. 217 Vieira R. C. 64 Vilarrasa J. 166 Villacorta G. M. 290 Villemin D. 145 Vinckler C. 334 Vinkovic V. 92 'iratelle 0. M. 334 'ismara E. 197 ;er F. 20 ;er G. W. 48 221 +le,F. 190 201 206 Voelker C. 272 Vogel E. 201 204 Vogel P. 217 Vogt J. 27 Volkmann D. 32 Vollhardt K. P. C. 40 180 192 193 256,301 von Buren M. 183 von Schnering H. G. 47 271 Voronkov M. 195 Voronkov M. G. 268 Voss J. 213 Vostrowsky O. 150 285 Vuper M. 268 Wada E. 304 Wada F. 198 Waddell W. H. 102 Waddington D. J.76 Wade K. 239,257 Wade L. G. Jr. 169 Wade P. A. 224 Wadsworth W. S. 158 Wadt W. R. 31 Warnheim T. 32 Wagle D. 226 Wagner A. F. 25 Wahlgren U. 18 22 Waight R. D. 324 Walaszek Z. 14 Walba D. M. 237 Walborsky H. M. 249 Walenta R. 172 Waley S. G. 328 Walker F. H. 179 180 Walker M. E. 165 Walling C. 197 Walsh P. A. 62 Walsh R. 71 106 Walsh T. S. 132 Walter W. 13 228 Walters R. T. 241 Walton A. 235 Walton J. C. 69 70 71 75 185 Waltz W. L. 241 Wang B.-J. 177 Wang T.-Y. 129 Wang Y. 94 Ward D. C. 47 Wardell J. L. 275 Ware W. R. 125 Warkentin J. 102 Warner R. W. 178 254 297 Warnet R. J. 99 301 Warren S. 165 Warrener R. N. 43 46 Wasilewski J.24 Wasserman H. H. 310 Wasserman Z. R. 22 Wasylishen R. E. 55 190 Waszczylo Z. 53 Watanabe M. 71 77 218 270 Watson W. H. 38 Watts R. O. 31 Wayner D. D. M. 109 Weber A. 166 Weber D. 271 Weber R. 316 Weber W. 192 223 308 Weber W.-D. 173 Webster B. C. 76 Weerasooriya U. 98 145 Wehle D. 183 Weiner B. 21 Weinman S. 66 195 Weinreb S. M. 46 224 308 Weinstein H. 22 Weinstein J. 215 Weiss C. 32 Weissmann C. 333 Weitz E. 126 Welch J. 181 294 Wender P. A. 41 129 171 Wenderoth B. 157 250 Wendler N. L. 172 Wendoloski J. J. 24 Wenkert E. 99 138 Wenzel T. T. 201 Werner H.-J. 21 West P. R. 93 183 West R. 268 Westaway K. C. 53 Westerrnann J. 157 250 Wettach R.H. 87 Whangbo M.-H. 274 Wharry S. M. 14 Wharton C. W. 325 White A. H. 260 261 White J. D. 298 White R. F. M. 3 Whitesell J. K. 46 Whiteside R. A, 19 Whitham G. H. 226 Whiting M. C. 135 Whitman D. W. 184 Whittaker G. 201 209 Whitten D. G. 125 Whittenberg S. L. 32 Wiberg K. B. 179 180 Widdowson D. A. 164 222 234 Widdler L. 251 Wiebecke G. H. 164 Wieland D. M. 195 Wightman R. H. 3 Wijekoon D. 127 Wilby A. H. 249 317 Wild U. P. 31 Wilhelm D. 198 Wilhelm R. S. 290 Wilke G. 204 Willen B. H. 87 Willer R. L. 15 Williams A, 61 Williams D. J. 164 212 222 270 Williams D. L. H. 51 Williams D. Y. 51 Williams J. R. 126 Williams R.V. 38 203 Willis B. J. 192 Wilson A. C. 198 Wilson G. E. Jr. 169 Wilson J. M. 190 Wilson J. W. 318 Wilson K. D. 140 Wilson R. M. 132 Wilson S. 20 Wilson S. A. 288 Wilson S. R. 138 Winchester W. R. 93 183 Winkler J. D. 177 Winter W. 115 Winterfeldt E. 172 Wirth D. 210 Wirz J. 203 Wise S. 183 304 Wiseman J. R. 183 Wistrand L.-G. 108 Withers J. D. 3 Wittek M. 190 201 Wlostowska J. 101 Wojcicki A. 241 Wolfe S. 23 52 Wolff C. 207 Wolff S. 137 Wong J. T. 328 Wong P. C. 76 95 Wong-Ng W. 269 Wood R. D. 214 Woodruff M. 167 Woodthorpe K. L. 104 Woodward C. E. 24 101 Woodward R. A. 145 Woodward R. B. 46 Woodward S. S. 314 Wormer P. E. S. 20 Workulich P.M. 44 Wright B. B. 94 Wright T. A. 151 Wu J. L. 195 Wu K. C. 125 Wubbels G. G. 125 Wudl F. 227 277 Wurthwein E.-U. 26 Wust H. H. 249 Wulff W. 256 Wulff W. D. 105 Wunderlin D. A. 104 Wunderly S. W. 132 Wyman J. 334 Wynberg B. P. 296 Wynberg H. 162 212 Yagi M. 164 Yamabe S. 31 Yamada M. 169 Yamada T. 246 Yamada Y. 314 Yamaguchi H. 135 Yamaguchi M. 158 Yamaguchi Y. 19 Yamamoto A. 162 246 253 Yamamoto H. 141 146 217 233 252 Yamamoto K. 91 158 236 Yamamoto T. 246 Yamamoto Y. 154 155 159 232 Yamanaka H. 197 Yamane S. 164 Yamashita M. 169 Yamata T. 206 Yamawaki J. 151 Yamazaki H. 147 Yamazaki N. 318 Yamazaki S. 236 Yan J. S.H. 203 Yan T.-H. 171 Yanagi A. 232 Yanagiya M. 52 Yang J.-C. 97 Yang N. C. 129 Yang T.-K. 296 Yang Z.-Z. 41 214 237 Yannoni C. S. 13 53 184 Yasumura M. 153 Yatagai H. 154 Yates J. B. 294 Yates S. F. 201 Yavari I. 4 13 Yeager D. L. 19 Yeomans M. A. 215 Yerino L. 132 Yianni P. 200 Yogi S. 237 Yokoyama H. 294 Yonashiro M. 162 Yoneda S. 200 Author Index Yonemitsu O. 199 Yoneyoshi Y. 100 Yong Eun Lee 74 Yoon U. C. 130 Yoshida J. 141 Yoshida M. 227 Yoshida T. 138 Yoshihara K. 126 Yoshikawa S. 163 316 Yoshimura T. 164 Yoshino T. 206 Yoshioka T. 199 Yoshioka Y. 24 Young D. W. 80 Yranzo G. I. 97 104 Yue S. T. 191 Zagorski M. G. 127 179 298 Zakova M.46 Zapata A. 111 Zard S. Z. 182 Zask A. 256 Zaworotko M. J. 267 Zeelen F. J. 244 Zeiss H.-J. 155 Zeller J. R. 152 Zerner M. C. 18 19 20 Zhdanov A. A. 7 Zhen-yi W. 19 Zhu Z. H. 18 Zielinski T. J. 27 Zilm K. W. 4 Zima G. 139 Zingaro R. A. 277 Zinger B. 112 113 Ziolo R. F. 276 Zipkin R. E. 49 180 302 Zizuashvili J. 66 195 Zmuda H. 194 Zollinger H. 196 Zoorov H. H. A. 318 Zuber J. A. 86 Zubleta J. 271 Zuckerman J. J. 271 Zurawski B. 32 Zvilichovsky G. 226 Zwaard A. W. 204 Zwart L. 67 Zweifel G. 137 143 Zwierzak A. 139 169

ISSN:0069-3030    

DOI:10.1039/OC9827900338

出版商:RSC    

年代:1982

数据来源: RSC