7 Heterocyclic Compounds By P.W. SHELDRAKE SmithKline Beecham Pharmaceuticals Old Powder Mills nr Leigh Tonbridge Kent TN11 9AN UK 1 Threemembered Rings Oxiranes are valuable intermediates standing at the interface of acyclic and heterocy- clic chemistry and provide interest to both areas. Oxiranes exempIified by (11 can be prepared stereoselectively and rearrange on treatment with stannic chloride to give keto-alcohols (Z),again stereoselectively and in excellent yield (Scheme 1).’ Reagents i SnCl Scheme 1 Lithium tetrachlorocuprate(r~) has been shown to be efficient at opening epoxides to give chloro-a1cohok2 For example the bis-oxirane (3)gives (4) in 65% yield (Scheme 2). Reagents i Li2CuCl, THF Scheme 2 When the racernic oxirane (5) is treated with acid the product is a (racemic) C.M.Marson A. J. Walker J. fickering A.D. Hobson R. Wrigglesworth and S. J. Edge J. Org. Chem. 1993,58,5994. 2.-X. Guo,A. H. Haines and R. J. K. Taylor SYNLETT. 1993 607. P. W.Sheldrake tetrahydrofuran (6). However on treatment with antibodies raised against (7) the product is predictably optically active but is the tetrahydropyran (8) (Scheme 3).3 f" -0.g Me02 (7) Reagents i H+; ii antibodies Scheme 3 The biosynthetically-patternedcascade oxirane cyclization of (9)has been used as a key step to produce (lo),in 30% yield in studies directed towards the synthesis of etheromycin (Scheme 4).4 Reagents i 0.5 M HCL THF Scheme 4 Treatment of hydroxylamine derivatives (1 1)with sodium hydride in the presence of suitable olefins (12) gives aziridines (13) in yields of up to 95% (Scheme 5).5 K.D.Jandu C.G+Shevlin and R.A. Lerner,Science 1993,259,490. 'I. Paterson R.D. TilIyer and J. B.SmaiI1 Tetrahedron Lett. 1993,34,7137. M. M.Pereira P. P. 0.Santos L. V. Reis A.M. Lobo and S. Prabhaker J. Chem. Soc. Chem. Commun. 1993 38. Heterocyclic Compounds Reduction of 6H-1,2-oxazines (14) with lithium aluminium hydride gives aziridincs (lS).' The cis-isomer predominates; for example where R' = R2= Me the yield is 64% with a 94 :6 ratio of cis :trim (Scheme 6). 0 Ar Reagents i NaH Scheme 5 Reagents i LiAIH, Et,O Scbeme 6 The chiral auxiliary (16) has been used in the asymmetric synthesis of aziridines (18) fromoIefins (17).7 Enantiorneric excesses up to 96% were observed with yields up to 76% (Scheme 7).Reagents i PhFNTs CuOTf (16) Scheme 7 Dimethyldioxirane has been used to oxidize furans (including furan itself) to maleaIdehydes.* These were reacted in situ e-g. with Wittig reagents and the products isolated in good yields (Scheme 8). MethyI(trifluoromethy1)dioxiraneoxidizes unactivated carbon-hydrogen bonds in R.Zimmer. K.Hommann and H.-U. Reissig Liebigs Ann. Chem. 1993 1155. ' D. A. Evans M.M. Fad,M.T. Bilodcau B. A. Anderson and D. M. Barnes J. Am. Chem. Soc. 1993,115 5328. a B.J. Adger C. Barrett J. Brennan P. McGuigan M. A. McKervcy and B. Tarbit J. Chem. Soc. Chem. Commun. 1993,1220. P.W. Sheldrake amine salts with remarkable ~electivity.~ The ultimate products from derivatives of pentylarnine salts (19) are 3,4,5,6-tetrahydropyridines(20) (Scheme 9).I rn I1 OXwC02El CHO CHO 04% * Reagents i dimethyldioxirane;ii Ph,P=CHCO,Et (1 equiv.) &heme 8 Reagents i methyl(trifluoramethy1)dioxirane Scheme 9 The oxaziridines (21) transfer the N-Boc group to nitrogen or carbon nucIeophiles.** (21) X= H,CN 2 Four-membered Rings There are reviews of industrial transformations of penicillins and cephaiosporins' and of 0x0 and imino-functionalized 1,2-0xazetidines. On treatment with silver triflate the silyl enol ethers (22) cyclize onto the oxonium ion intermediate and an oxetane is annulated to the existing ring giving the unusual bicycles (23) (Scheme Reagents i AgOTf CH,CI, 4A Sieves Scheme 10 Tin bis(hexamethyldisi1azide) was studied as a reagent for converting esters into G.Asensio M.E. Gonzalez-Nunez C. B.Bernardini R. MeIlo,and W. Adam,J. Am. Chem.SOC.,1993,115 7250. lo J. Vidal L. Guy S.Stenn and A. Collett J. Org. Chem. 1993,58,4791. J. Verweij and E. de Vroom Red. Tmo. Chim. Pays-Bas,1993 112,66. D.Monderhack J. Heterocycl. Chem. 1993,30 579. l3 D. Craig and V. R.N. Munasinghe J. Chem. Soc. Chem. Commun. 1993,901. Heterocyclic Compounds secondary amides14 and was found to be efficient in cycIizing #?-alkylamino esters to /3-lactams (Scheme ll)." Reagents i. Sn[N(SiMe,),] scheme 11 Ally1 diethyl phosphate was used to form an ally1 palladium species from which b-lactams(24) were constr~cted'~ by carbonylation followed by reaction with an imine (Scheme 12).The 2-aza-1,3-dienes (25) were prepared in good yield. I' Staudinger reaction with acid chlorides gave fi-lactams (26) in which the cis isomer predominated and from which the nitrogen substituent was removed using potassium permangarsate (Scheme 13). Reagents i CO; ii truns-R'CH=NR2 scheme 12 (25) Reagents i RCH,CQCl Et,N; ii KMnO Scbeme 13 A new synthesis of the important intermediate (29)was reported" starting with the furanyl /?-lactarn (28). Degradation of the furan was brought about using singlet oxygen and the resuIting proxy-cumpounds rearranged thermally (Scheme 14). A radical-mediated ring closure formed the carbapenam (31)from the dithiane (30) (Scheme 15)." Another radical-mediated cyclization2" demonstrated formation ofthe f4 W.B. Wang J. A. Restituyo and E.J. Roskamp Tetrahedron Lett. 1993,34,7217. I' W.-8. Wang and E.J. Roskarnp J. Am. Chem. Soc. 1993 115,9417. I6 S. Toni. H. Okumoto M. Sadakane A.K.M. A. Hai and H. Tanaka Tetrahedron Lett. f993,M 6553. G. I. Georg P. He J. Kant and Z.J. Wu J. Org. Chem. 1993,58 5771. '' J. E. Lynch W. L. Laswell R. P. Volante R. A. Reamer D. M.Tschaen,and I. Shinkai Heterocycles 1993 35 1029. l9 J. Anaya D. €I. R. Barton S. D. Gero M. Grande N. Martin and C. Tachdijian Angew. Chem. Int. Ed. Engf, 1993,32 867. '* H. Ishibashi C,Karneoka A. Yoshikawa R. Ueda K.Kodama,T. Sato and M. Ikeda SYNLETT. 1993 649. 184 P. W.Sheldrake B-lactam ring itself in the conversion of (32) into (33) (Scheme 16).TBDMSO g3Q TBDMSO TBDMSO 9 0 Reagents i lo2; ii KOAc Scberne 14 Reagents i 3u,SnH AfBN Scheme 15 i ____) SPh 50% FMB Reagents i BuJnH AIBN Scheme 16 Titanium tetrachloride was used to cyclize (34) to the carbapenem (35) (Scheme 17),2*which was taken on to thienarnycin. Irradiation of a powdered inclusion complex of N-(aroyImethy1)lactams (36)in the chiral auxiliary (37) produces the azetidino-lactams (38) in yields up to 59% and up to 98% enantiomeric excess (Scheme 18).” G. B. Feigelson Tetrahedron Lett. I993,34,4747. ’’F. Toda K.Tanaka 0.Kakindii and T. Kawakami J. Org. Chem. 1993,58 3783. 185 Heterocyclic Compounds OH CO~PNB (34) (35) Reagents i TiCI, CH,CI Scheme 17 Ar H Ho-9 0 Ph2C-OH (36) (37) Reagents i (37); ii hv Scheme 18 Rhodium(1r) acetate mediated closure of the diazo-esters (39) has been studied (Scheme 19).23When n = 0 there is no ring closure because the sulfur interferes with the carbene intermediate; for the sulfoxide or sulfune the reaction is fairly efficient.The chemistry of the 3-methylidene-#Hactams (41) has been in~estigated:~~ the double bond can be epoxidized or cyclopropanated and is a good MichaeI acceptor arid dienophile. On reaction with a hydrazine (Scheme 20) the primary product is the spiro compound (42) from which it is possible to obtain the pyrazole (43). (39)n = 0.1,2 (4) Reagents i Rh,(OAc) Scheme 19 Deprotection ofb-lactam (44)with ceric ammonium nitrate proceeds as e~pected.~ However on similarIy treating its diastereoisomer (45) there is an unprecedented oxidative ring transformation giving (46) in high yield (Scheme 21).'' P. Bissolino M. Alpegiani D. Botghi E. Perrone and G. Francexhi Heterocycles 1993,36 1529. '' S. Gurthler M. Johner S. Ruf and H.-H. Otto Helv. Chim. Acba 1993 76 2959. 25 F. Bertha J. Fetter M. Kajtar-Peredy G.M. Kesura K. Lernpot L. Parkanji,and J. Tarnas Tetrahedron. 1993,49 7803. P. W.Sheldrake The b-lactams (47a) and (47b)on treatment with stannous chloride give rise to a pyrazine dione (48a) or 1,4-oxazine dione (48b) (Scheme 22).26 Reagents i RNHNH Scheme 20 The #?-lactam (49) is readily opened with dimethyloxosulfunium methylide and the product cyclizes on treatment with rhodiurn(I1) acetate to give the 3-ketopyrrolidine (50) (Scheme 23).27 The silacyclobutane (51 reacts with lithium carbenoids thus undergoing ring expansion to give 2-iodo-1,l-dimethyl- 1-silacyclopentane (52) (Scheme 24)'' ""a OMe t 64% I909C x..y2 0 Reagents i (NH,)Ce(NO,) scheme 21 26 B.AIcaide Y. Martin-Cantelejo 3. Rodnquez-Lopez and M. A. Sierra J. Org. Chem. 1993,58,4767. " J. E. Baldwin R. M. AdIington C. R.A. Godfrey D.W,Gollins and J.G. Vaughan 1.Ckm.Soc. Chem. Commun. 1993 1434. K. Matsumoto Y. Aoki K. Oshima K. Utirnoto and N. A. Rahman Termhedron 1993,49 8487. Heterocyclic Compounds (474 X=NAr (47b) x=o (4&) X=NAr(a)x=o Reagents i SnCl -2H,O Scheme 22 tw Reagents i Me,SOCH, DMSO; ii Rh fOAcf Scheme 23 Bis(diisopropy1amino)phosphanylazide (53) reacts with dimethyl acetylenedicar- boxylate to give the six-membered ring (54),29 from which on heating nitrogen is lost producing the I,2-i5-azaphosphate (55) (Scheme 25).The product is air-stable and melts (mp 109-1 10"C)without decomposition! Reagents i LiCHI Scheme 24 3 Five-membered Rings A review of the use of isocyanides in heterocyclic synthesis" predominantly covers five-membered rings. More specifically there are reviews of new chemistry of oxa~oles,~ and recent progress in preparation and synthetic uses of 3H-pyra~oles,~~ the preparation and reactions of indolin-2(3H)-ones ox in dole^).^^ J. Tejeda R. Reau F. Dahan and G.Bertrand 1.Am. Chem. Soc. 1993 115 7880. 30 S.Marcaccini and T.Torroba Org. Prep. Proced. Int. 1993 25 143. 31 A. Hassner and B. Fischer Heterocycles 1993,35 1441. 32 T.Nagai and M. Hamaguchi Org. Prep. Proced. lnt. 1993 25,403. '' G.M. Karp Org. Prep. Proced. int. 1993,25,483. P. W. Sheldrake +-(P~:N)~P-N=N=N Reagents i MeO,CCECCO,Me; ii A Scheme 25 There is a review of the lateral metallation of i~oxazoles.~~ Metallation of heterocycles continues to grow as a powerful synthetic tool complementary to 'classical' synthetic routes. A definitive pape? on the metallation of benzo-fused nitrogen heterocycles covers reaction both adjacent to nitrogen with formamidine derivatives (56) and in the aromatic ring with t-butoxycarbonyl derivatives (58) (Scheme 26).The t-butoxycarbonyl derivatives of pyrrolidine piperidine and hexamethyleneimine can also be lithiated efficiently (Scheme 27).36 Dilithiation of #l-bromo-/?-trimethylsilylstyrene37 (60)gives an intermediate (61)into which can be inserted as the heteroatom sulfur selenium tellurium phosphorus arsenic antimony bismuth silicon germanium or tin (Scheme 28). Both enantiomers of imidazoline (63) are available via resofution. Lith-iation-alkylation gives (64)from which amino acids are obtained in high yield and high optical purity (Scheme 29).38 l-Substituted-l,2,4-triazoles, where the substituent is an alkyl or diethoxymethyl group have been lithiated at the 5-position and reacted with a range of ele~trophiles.~~ 1-Substituted-4-iodoimidazoles treated with ethyl magnesium bromide followed by an electrophile react at the 4-p~sition.~' Nu products from isomerization of the 4-metallated imidazole to the 2-metalIated species were detected.The intermediates (66) and (57) have both been funned41by direct deprotonation of the corresponding acids. 34 N. R. Natale and Y. R. Mirzaei Org. Prep. Proced. Int. 1993,25 517. 35 A.I. Meyers and G. Milot J. Org. Chem. 1993,58,6538. 36 P. Beak and W. K. Lee J. Org. Chem. 1993 58 1109. 37 J. Kurita M. Ishii S. Yasuika and T. Tsuchiya J. Chem. SOC. Chem. Cornmun. 1993 1309. 38 S. Blank and D. Seebach Angew. Chem. Int. Ed. Engl. 1993 32,1765. '' S. Ohta I. Kaawasaki A. Fukuno M. Yamashita,T.Tada and T.Kawabata,Chem. Pharm. Bull. 1993,41 1226.40 R.M.Turner S.V. Ley and S. D. Lindell SYNLETT. 1993,748. 4J C.D. Buttery R.G. Jones and D.W. Knight J. Chem. Soc. Perkin Trans. I 1993 1425. Heterocyclic Compounds (56) n = 1,2.3 (57) I ii E C0,Bu' (58) n = 1,2.3 Reagents i Bu'Li; ii electrophile E Scheme 26 QI Boc Reagents i RLi TMEDA; ii electrophile E Scheme 27 r 1 Reagents i Bu"Li Et,O; ii for M = S (PhSo,),S; for M = Se Se;for M = AsPh PhAsC1,; for M = SiMe, Me,SiCI Scheme 2.8 Reagents i LDA THF -78 T;ii RX; iii CF,CO,W CH,CI,; iv W,Of Scheme 29 P. W.Sheldrake The mesylate and tosylate (68) undergo intramolecular cyclization involving the oxygen of the ether linkage to give the tetrahydrofuran (69)?2The reaction occurs in warm DMF or in acetone or acetonitrile provided the last two solvents contain lithium bromide (Scheme 30).Reagents i Me,C=O LiBr or MeCN LiBr Scheme 30 On treatment with AIBN/tributyltin hydride the bromide (7Ua) forms a radical which ring closes to give the tetrahydrofuran (71a).43 A tetrahydropyran (71b) is available by the same methodology (Scheme 31). 4-Substituted furan-2-ylacetic acid esters are available by the route shown in Scheme (7oa)n = 1 f7ob) n=2 (71a) n =1 (71b) n =2 Reagents i Bu,SnH AIBN Scheme 31 Di- ti- or tetrasubstituted furans are available45 by base-catalysed cyclization of hydroxyenynes (72); some variations and simplification^^^ of the idea are shown in Scheme 33. 42 W. Verbroom,Y. Momherin E. Kelderman J.F. J. Engbersen,G.I. van Humrnel S. Harkema and D.N. Reinhoudt Red. Trav. Chirn. Pays-Bas 1993,112 549. 43 E. Lee J. S. Tae C. Lee and C.M. Park Tetrahedron Lett. 1993 34,4831. 44 R.W.Carling and P.D. Leeson SYNLETT. 1993,40. " 1-A Marshall and W.J. DuBay 3.Org. Chem. 1993 58 3435. 46 J. A. Marshall and W.J. DuBay 1.Org. Chem. 1993 58 3602. Heterocyclic Compounds Reagents i (Et02CCH,),C=O; ii KOH; iii CH,COCl; iv EtOH; v Cu,O quinoiine Scheme 32 HO (74) (75) R (76) Reagents i KOBu' Bu'OH 18-crown-6;ii NaOMe scheme 33 Benzotriazole is a versatile reagent. Just one of its new uses involves setting up the intermediate (78) which by cyclization and elimination of benzotriazole gives benzofurans (79) (Scheme 34).47 The sugar-derived triflate (80)is converted into (81) in high yield by but in base the more unusual bicycle (82) is produced with almost equal efficiency (Scheme 35).The unsaturated ketal (83) gives diol (84) in high yield and enantiomeric excess by Sharpless asymmetric dihydro~ylation.~~ Treatment with acid completes an efficient synthesis of (+)-em-brevicomin (Scheme 36). 47 A. R. KatritzLy X. Lan and Z. Zhang J. Heterocycl. Chem. 1993 381. J. R.Wheatley C.J. F. Bichard S. J. Mantell J.C. Son,D.J. Hughes G. W. J. Fleet and D. Brown,J. Chem. SOC.,Chem. Comn. 1993 1065. 49 J. A. Sodequist and A.M.Rane Tetrahedron Lett. 1993 34,5031. P. W. Sheldrake Reagents i TsOH AcOH Scheme 34 OH n i.H A hr OH Reagents i 9BBN; ii EtCH=CHBr Pd(PPh3), NaOH; iii OsO,,DHQD-PHAL; iv TsOH Scheme 36 The tertiary alcohoi (85) when treated with potassium hydride provides the only example of an anionic oxy-Cope reaction on a simple furan by rearranging to (86) in good yield (Scheme 37)'' Iodolactonization of unsaturated carboxylic acids using iodine and potassium so D.Martin J. A. Wurster M. J. Boylan R.M.Borziileri G.T.Engel and E.J. Walsh TetrahedronLett. 1993,34,8395. Heterocyclic Compounds iodide is well known. Generating the iodine using potassium iodide and sodium persulfate is claimed” to be more convenient faster and higher yielding. 86% Reagents i KH 18-crown-6 THF Scheme 37 The oxidative cyclization of aldehyde (87) is the key step in a synthesiss2 of aranorosin (88) which is also the subject of an independent st~dy.’~ In a related cy~lization’~ oxime (89) gives isoxazoline (90) (Scheme 38).The P-keto-esters (91a) and (91b) react with the propargyl carbonate (92) under palladium(0) catalysis to give furans (93) (Scheme 39).” The 1 -aminobenzotriazole (94) is a precursor of the dihydrobenzofuran (95) when treated with lead tetraa~etate.’~ When N-bromosuccinimide is used as the oxidant the bromo-derivative (96) is formed (Scheme 40). Oxonium ylids are formed from cyclic ethers bearing pendant diazoketones (97) when treated with rhodium(I1). Either [1,2] or [2,3] shifts give oxygen-bridged ring systems (98) (Scheme 41).57 A variety of systems (99) are substituted when treated with 2-haloesters triethyl- borane and air.58 The products (100) are postulated to form via a radical pathway (Scheme 42).The bis(thiophene) (101) exhibits a pronounced solvatochromism;59 yellow in hexane the hue traverses the spectrum to blue in formamide-water. On treatment with fluoride the thiophenes (102a) and (102b) give 2,3-dimethyl- ene-2,3-dihydrothiophene(103)?’ Non-thermal preparations of this reactive inter- mediate are rare (Scheme 43). ” A.C. Royer R.C. Mebane and A.M. Swafford SYNLETT. 1993 899. ’* A. McKillop L. McLaren R. J. Watson R. J. K. Taylor and N. Lewis Tetrahedron Lett. 1993,34 5519. ’3 P. Wipf Y. Kim and P.C.Fritch J. Org. Chem. 1993 58 7195. 54 M. Kacun D. Koyuncu and A. McKillop J. Chem. SOC.,Perkin Trans. I 1993 1771. 55 N.Greeves and J. S. Torode Synthesis 1993 1109. s6 M.A. Birkett D. W. Knight and M. B. Mitchell Tetrahedron Lett. 1993 34 6939. 57 F.G. West T. H. Eberlein and R. W. Tester J. Chem. SOC.,Perkin Trans. 1 1993 2857. ’* E. Baciocchi and E. Muraglia Tetrahedron Lett. 1993 34 5015. 59 F. Effenberger and F. Wurthner Angew. Chem. Int. Ed. Engl. 1993 32 719. 6o K. J. van den Berg and A. M. van Leusen Recl. Trav. Chim. Pays-Bas 1993 112 7. P. W. Sheldrake i CHO NHCOR H Reagents i PhI(OCOCF,), ii H,O,. LiOH Scheme 38 (9la) X = OMe (93) (91b)X = SPh Reagents i HC-CCH,OCO,Me (92). Pd(dbaf -CHCI, dppe Scheme 39 Benzothiophenes (105) having a mercaptopropyl substituent are formed6’ when the dithianes (104) are treated with AIBN/tributyltin hydride (Scheme 44).Cyclic sulfates prepared from 12-diols are known to be usefuI for further transformation of such diols. It has been found that the corresponding cyclic sulfites (often precursors of the sulfates) can be as efficient.62 D.C. Harrowven Tetrahedron Lett. 1993 34,5653. 62 P.H.J. Carlsen and K. Aase. Acta Chim. Scad.. 1993 47 737. Heterocyclic Compounds Reagents i. Pb(OAc),; ii NBS Scheme 40 (97) n= 1,2 (98) Reagents i Rh,(OAc) Scheme 41 (99)X = 0,S. NMe,NH {loo) R = H,Me Reagents i RCHBrCO,Et BEt, air DMSO Scheme 42 (10%) X = "Me3; Y = SiMe3 (10%) X = SiMea; Y = +NEt2Me Reagents i Bu,NF scheme 43 P. W. Sheldrake Reagents i Bu,SnH AIBN Scheme 44 A review of progress in the Fischer indole reaction has appeared.63 A regioselective Fischer indole synthesis is also reported.64The 2form of hydrazone (106) on treatment with diethylaluminium tetramethylpiperidide gives 1,3-dimethyI-2-(2-methylbutyl)-indole (107) in 93% yield whereas the E isomer gave the 2-ethyl-l-methy1-3( 1-methyl)- propyl product (108) in lower yield (42%) but of 93% purity (Scheme 45).OTI-2,+-OTt Me NHN-Ph Me Me (107) (106) (108) Reagents i diethylaluminium tetramethylpiperidide Scheme 45 Keto-amides (109) readily prepared from N-vinyfpyrrolidinone yield cyclic imines (110) on successive acid and base treatment.65 If they are first alkylated the disubstituted products (111) are obtained. (Scheme 46). Reagents i,H,O'; ii NaOH; iii NaH RZX Scheme 46 The iminophosphorane (1 12) can be reacted with isocyanates either to isolate a pyridine (113) or on heating to obtain an aza-indole (114) (Scheme 47).66 The secondary amide (1 15)cyclizes under the action of phosphorus pentachloride to give 3-phenylimidazo[1,5-a]pyridine (116)(Scheme 48).The reaction also works when the amide moiety is attached at the 2-position of a thia~ole.~~ Some mechanistic studies D.L. Hughes Org. Prep. Proced. int. 1993 25 607. 64 E. Maruoka M. Oishi and H. Yamamoto J. Org. Chem. 1993,58,7638. " M.L. Haslego C.A. Maryanoff L. Scott and K. L. Sorgi Heterocycies 1993 35 643. 66 P. Molina E. Aller and M. A. Lorenzo Synthesis 1993 1239. '' T. Benincori E. Brenna and F. Sannicolo J. Chem. SOC. Perkin Trans. I 1993 675. Heterocyclic Compounds 197 were undertaken supporting a nitrile ylid intermediate in a transformation related to the Wallach imidazole synthesis.Reagents i PCl Scheme 48 The novel analgesic epibatidine (117) discovered in the skin of an Ecuadorian frog has been synthesized. Approaches include a Diels-Alder strategy from l-methoxycar- bonyipyrrole,68 and a Heck reaction pyridinating a 7-azabicycio[2.2. Ilhe~tene.~~ H &gC1 H (117) Regeneration of a nitrone from bicycles such as (118)is known. However control of which nitrone is formed can now be obtained7' from variation of the solvent in which the oxidation is carried out (Scheme 49). Isoxazoles (121) can be prepared from acetylenes and nitric acid using a gold catalyst (Scheme50).Trapping experiments using alkenes confirmed that there is an acy1 nitrile oxide inte~mediate.~' 68 D.F. Huang and T.Y. Shen Tetrahedron LPtt. 1993 34,4477. 69 S.C. Clayton and A. C. Regan Tetrahedron Lett. 1993 34,7493. 'O S.A. Ah and M.I.M. Waxer Tetrahedron,1993 49 4339. " F. Gasparrini M.Giovannoli D. Misiti G. Natile G. Palmien and L. Maresca J. Am. Chem. Soc. 1993 115 4401. P. W. Sheldrake i ii -0 HO Reagents i mCPBA CN,CI,; ii mCPBA AcOH Scheme 49 Oximes such as (122) or acyclic examples on treatment with dimethyl carbonate and potassium carbonate give oxazdin-2-ones (123) as indicated (Scheme 51 ).72 0 Reagents i Bu,NAuCI Scheme 50 Scheme 51 Diazo compounds (124)in the presence of a nitrile and rhodium(I1) acetate produce oxazoles (125) (Scheme 52).Homochiral oxazolines are usefu1 chid auxiliaries. The phosphine (126) has been studied in the paIladium-catalysed reaction of alIylic acetates and maionic esters; high yields and enantiomeric excesses up to 99% are The thiazolidine (127)is 72 C.A. Marques M. Sehra P. Tunde and F. Montanari 3. org. Chem. 1993,58 5765. 73 R. D. Conneli M. Tebbe A.R. Ganghoff P. Helquist and B. Akermark Tetrahedron 1993,49 5445. " P. von Matt and A. Pfaltz Aogm. Chem. Int. Ed. Engl. 1993,32 566. '' G.J. Dawson C.G.Frost J. M. J. Williams and S. J. Coote Tetrahedron Lett. 1993,34 3149. Heterocyclic Compounds remarkable as the product of a seven-component c~ndensation.~~ The necessary ingredients are sodium hydrogen sulfide 2-brom0-2-methylpropana1 ammonia 2-methylpropanal carbon dioxide methanol and t-butylisonitrile.The yield is 43%. Reagents i RhJOAc), R2CN Scheme 52 Oximes (128) react with an imidoyl chloride to produce isolable amides (129) (Scheme 53). On heating these amides are transformed to imidazoles ( (129) Reagents i PhC(=NR')Cl; ii H' toluene A scbeme 53 TributyItin-radical-inducedcyclization of the amide (1 31 gives 5-butyl-3-methyl- 3H-imidazo[4,5-c]quinoIin-4[51fl-one (132) via a spirocydic radical intermediate and [1,2 Jacyl shift (Scheme54). Cyclization by a palIadium-cataIysed coupling gives the 1-methyl isomer (t33).78 Treatment of the aryI triazolyl propanol (134)with triphenylphosphine/carbon tetrachloride gives the salt (135) containing the novel SH-6-arylpyrazolo[ 1,2-a] [i,2,4]triazol-4-ium ion (Scheme 55).79 76 A.Domling and I. Ugi Angew. Chem. Znt. Ed. Engl. 1993.32 563. 77 Zhang X. Shui and D.S. Eggleston J. Org. Chem. 1993,58 7092. I. Lantos W.-Y. '* F.Suzuki and T.Kuroda J. Heterocycl. Chem. 1993 30,811. 79 Y.Arredondo R. Pleixats and M.Moreno-Manas Synth. Corn. 1!493,23 1245. P. W. Sheldrake Reagents i Bu,SnH AIBN; ii Pd(UAc) Scheme 54 Scheme 55 4 Six-membered Rings Among the reviews there is an account of the reactivity of 6-unsubstituted 2H-pyran- 2-0nes;~O the synthesis of six- and seven-membered phosphorus heterocycles by ring enlargement is covered,” as is the synthesis of 9-substituted guanines.62 The intramolecular double Michael reaction has been surveyed83 and includes heterocyclic examples; the principle is exempIified in Scheme 56.Scheme 56 There is coverage of the metallation and metal-assisted bond furmation in n-electron-deficient heterocycless4 and there are details of the lithiation of several halogen-substituted pyridines using lithium dii~opropylamide.~~ Lithiation of the pyrimidines (136a) and (136b) has been founds6 to occur at the 5-position using lithium diisopropyIamide but significant furmation of products from 6-lithiation is found with lithium tetramethylpiperidide. With two equivalents of V. Kvita and W. Fischer Chirnia 1993,47,3. ” G. Keglevich Synthesis 1993,931. F.P.Clausen and J. Juhl-Christensen Org. Prep. Proced. lnt. 1993,25,373. 83 M.Ihara and K.Fukurnoto Angew. Chem. lnf. Ed. Engl. 1993,32,1010. 84 K.Undheirn and T. Benneche Acta Chem. Scund. 1933 47 102. G.W. Gribble and M.G. Saulnier Heterocycles 1993,35 151. 86 N. Ple A. Turck P. Martin S. Barbey and G. Queguiner Tetrahedron Lett. 1993,34 1605. Heterocyclic Compounds s-butyllithium a proton can be abstracted from the methyl group of S-hydroxy-2-methylpyridine (137).87If the hydroxy substituent is first protected the approach fails. c1 (136a)X=CI (137) (136b)X = SMe The tactic of introducing temporarily a cornplexing/directing moiety has been applied to the lithiation of pyridine-2-aldehyde.** Electrophiles are introduced in the 3-pusition via the (presumed) complex (139) (Scheme 57). The metallation of iodopyridines is a little more complex.89 Lithiation (lithium diisopropyIamide was used) is ortho-directed by the iodine but a fast migration occurs to give a stabilized iodolithiopyridine from which the product is derived.Thus for example 2-chloro-3- iodopyridine (141) produces 2-chloro-4-iodo-3-substituted products (142) (Scheme 58). Me Reagents i BuLi Me,NCH,CH,N (Me)Li; ii electrophile,E Scheme 57 Reagents:i LDA THF -75 OC; ii electrophile,E Scheme 58 1,2,4-Triazines (143) have been rnetallated at the 6-position using lithium tetra- methylpiperidide," the first examples of metallated triazines. The homochiral stannane (144) on treatment with n-butyllithium at -78 "C gives with retention of configuration the corresponding organolithi~rn,~' which is configurationally stable up to -40°C.87 A. K.Saksena R.G. Lovey V. M. Girijavallabhan H. Guzik and A. K. Ganguly Tetrahedron Let?. 1993 34,3267. 88 T.R.Kelly W. Xu and J. Sundaresan Tetrahedron Lett. 1993,34 6173. 89 P. Rocca C. Cochennac F. Marsais L. Thomas-dit-Dumond M. Mallet A. Godard and G. Qukguiner J. Org. Chem. 1993 58 7832. 90 N. Ple A. Turck G. Queguiner 3. Glassl and H. Neunhoeffer Liebigs Ann. Chem. 1993 583. 91 R.E. Gawley and Q. Zhang J. Am. Chem. Soc. 1993 115 7515. P.W.Sheldrake N,N-Dimethylcinnamide has been reacted photochemically with (145) the first example of a photochemicaf addition to a flavone (Scheme 59).92 Reagents i PhCH=CHCONMe, hv Scheme 59 Pyran-2-ones (149) are produced in moderate to good yields by the reaction of trimethylsilylketene (147) and 1,3-dienes (148) the first examples of [4 + 23 addition of such components.(Scheme 6U).93 c=c=od + rns (147) (148) R' =Me.Meo TMSO; R2= Me.TMS (149) Scbeme 60 Isochroman (150) is converted into an acetal (151) by the action of dichloro-dicyanoquinone in water or methanol (Scheme 61). There are other more complex examples.94 Reagents i DDQI ROH Scheme 61 92 H.C. Hailes R.A. Raphael and J. Staunton Tetrohedron Lett. I993,34 5313. 93 T. Ito T. Aoyama and T.Shirori TetrahedronLett. 1993 34 6583. 94 Y.C.Xu E. Lebeau J.W. Gillard and G. Attardo Tetrahedron Lett. 1993 34 3841. Heterocyclic Compounds Treatment of diazo-ketones (152) with copper complexes (the hexa-fluoroacetylacetonate being the most efficient) gives rise to usefully substituted and functionaIized cyclic ethers (153)? The mechanism involves oxygen insertion of a rnetaI carbenoid fdlowed by rearrangement.Seven- and eight-rnernbered rings are available by the same methodoiogy (Scheme 62). no83% 5 I l-2 Reagents i Cu(hfacac), CH,CI, reflux Scheme 62 Reaction of pyrylium tetrafluoroborate (154) with methylenetriphenylphosphorane followed by deprotonation (n-butyllithium/TMEDA) gives a phosphorane (I 55) which will give six-carbon homologation of aromatic but not enolizable aliphatic aldehydes (Scheme 63).96 Reagents i Ph,P=CH,; ii BuLi TMEDA; iii ArCHO &beme 63 The acrylic ester of salicylaldehyde (157) in the presence of DABCO gives a crystalline coumarin salt (158) (Scheme64).Its isolation confirmsthe hitherto putative intermediate in the Baylis-Hillman reaction.97 Reagents i DABCO CH,Ci Scheme 64 Diazo-ketones (159) on treatment with rhodium@) acetate give cyclic arnino- ” J.S.Clark S.A. Krowiak and L. J. Street Terruhedron Lett. 1993 34,4385. 96 K. Henning and R.J. K. Taylor J. Chem. Soc. Chem. Commun, 1993 1409. 97 S.E Drewes 0.L. Njamela N. D. Emslie N. Ramsar and 3. S.Field Synth. Conunun. 1993.23 2807. P.W. Sheldrake ketones (161) by nitrogen insertion of the carbenoid folIowed by rearrangement of the intermediate (160) (Scheme 65);98compare with the analogous Scheme 62. Reagents i Rh,(OAc) Scheme 55 Oximes of 5-oxoalkanenitriles [(162) R' = Me Et)] have been cyclized with acetyl chloride/acetic anhydride mixtures to give 2-aminopyridine derivatives (163)(Scheme 66).Oximes of 5-oxopentanenitriles[(162) R' = H] gave only glutaronitrile~.~~ In phosphorus oxychloride at 80 "CN-methylformanilide(164) reacts with tertiary amides (165) to give 3-substituted-4-chloroquinulinium salts (166) from which 4-quinolones (167) are obtained by hydrolysis.'*' Yields are generally good (Scheme 67). The formanilide reacts as its Vilsmeier salt and the alkanoamide as an a-chloroenamine. R,&cN i R2JJ"R' NHAc R2 R3 (162) R2. R3= H.aikyl (1s3) Reagents i,AcCl Ac,O Scheme 66 Reagents i RCH,CONMe f165) POCL,; i NaOH Scheme 57 5-Phenylpyrroline-2,3-diones(158) (available from an imine and oxalyf chloride) react with benzyne (from benzenediazoniurn-2-carboxylate) to give 3-phenyl-98 F.G. West and B.N. Naidu J. Am. Chem. Soc. 1993 115 1I77. 99 R.J. Vijn H. J. Arts P.J. Maas and A. M.Castelijns J. Org. Chem. 1993 58 887. loo 0.Meth-Cohn and D. L. Taylor TetrahedronLett. 1993,34,3629. Heterocyclic Compounds isoquinolones (149) (Scheme 68). Mechanistic hypotheses are discussed. Io1 R' I Ph N. R2 A2 0 (168) R' = H,Me,Et; RZ= alkyl phenyl (169) Reagents i benzyne Scheme 68 Both R and S forms of enaminoester (170) are available thus allowing the preparation of (R)-or (S)-2-alkylpiperidines(171) by the protocol' O2 of Scheme 69. (170) (171) Reagents i EtC(O)CH=CH,; ii BH, 50% aq. H,SO,; iii NaBH,CN; iv H, catalyst Scheme 59 Lithiated 2-chloro-Ncycioalkylidene-3-pyridinimines derived from (1 72) react with suitable 0-ethyl thiocarboxylates (173) to give pyrid0[2,3-b][1,5]thiazepines (174) (Scheme 70).A thermally induced ring contraction then gives the 6-arylcycloalka[b] C1,Slnaphthyridines (175) in moderate to good yield.lo3 Ar (175) Reagents i LDA -78°C; ii ArCSOEt (173); iii A Scheme 70 'Of A. Cobes,E. Guitian and L. Castedo J. Org. Chem. 1993,58,3113. lo' R.C. F. Jones I. Turner,and K.J. Howard,Tetruhedron Lett. 1993,34,6329. '03 A. Couture E. Deniau P. Grandclaudron and C. Simion Synthesis 1993 1227. P. W. Sheldrake The nitrobenzene (176) forms a delocalized coloured anion on treatment with sodium hydroxide. As the appropriately localized anion cyclizes onto the nitro group quinoline N-oxides (177) are formed (Scheme 71).lo4 CN CN Reagents i NaOH MeOH scberne 71 6,8-Dioxabicyclo[3.2.lloctanes (1 78) are readily prepared from methyl vinyl ketone and are efficiently transformed into 2,6-disubstituted pyridines (179) by the action of hydroxylamine and aluminium chloride (Scheme 72).'05 Reagents i NH,OH. HCI,AlCI, AcOH Scheme 72 The iminophosphoranes (180) react with or,P-unsaturated aldehydes and the resulting azatriene system gives the pyridines (181) by cyclization and dehydrogena- tion. By contrast if the iminophosphorane is based on furan or thiophene (182) the product is a mixture ofthe (181) analogue together with a fury1 or thienylpyridine (183) (Scheme 73).'06 In the course of a quinocarcin synthesis the phosphonium salt (184) was treated with potassium t-butoxide to produce dihydroisoquinoline (1851 a synthesis claimed to he the first of a dihydroisoquinoline by Wittig methodology (Scheme 74).'*' 2-Chloro-3-oxiranylmethoxypyridine(186) is readily available.Various alcohol amine or hydride nucleophiles open the oxirane ring and subsequent base treatment gives the 3-substituted 2,3-dihydro- 194-dioxino[2,3-b]pyridine system (187) (Scheme 75). I O8 The conformationally restricted Claisen rearrangement of lactone (188) to pipecolic ester (189) forms the key step of a (+)-monomorine synthesis (Scheme 76).'09 The pyrirnidine-2,4-diones f 190a) and (190b) react with certain a,fl-unsaturated Io4 Z. Wrobel A. Kwast and M. Makosga Synthesis 1993 31.lo' J.-G. Jun H.S,Shin and S. H. Kim J. Chem. Soc. Perkin Trans.I 1993 1815. I*' I?. Molina A. Pastor and M. J. Vilaplanu Tetrahedron. 1993 49 7769. lo' P. Garner W.B. Ho and H. Shin J. Am. Chem. Soc. 1993 115 10742 A. Benareb P.Poirot and G. Guillaumet Heterocycles 1993 36 1589. Io9 S. R.Angle and J. G. Breitenbacher Tetrahedron Left. 1993 34,3985. Heterocyclic Compounds acyl-cyanides in a [4 + 21 manner.* lo Acid-catalysed elimination provides a new entry to 5-substituted uraciIs (192) (Scheme 77). R (182) x=o,s Reagents i RCH=CHCHO Scheme 73 (fW Reagents i KOBu' DMF Scheme 74 Reagents i nucleophile;ii NaH. DME Scheme 75 The pyrido[2,3-d-Jpyridazino[2,3-a]indole (194) is a new heterocyclic system.' ' It is prepared by an intramolecular Heck coupling in excellent yidd despite the constraintsof the system precluding an intermediate that can undergo a ciselimination of the palIadium species.A base-catalysed trans eliminationis postulated (Scheme 78). 'lo JX. Zhuo and H. WyIer Helv. Chim. Acta 1993,76 1916. P. Melnyk. J. Gasche. and C. Thal Tetruhedron Lett. 1993,34,5449. P. W.Sheldrake The fused 1,2,5-oxadiazinone (195) reacts with enamines in [4 + 21 fashion followed by elimination of carbon dioxide and amine thus providing a route to unsymmetrical pyrazines (196) (Scheme 79).' 1 Reagents i TIPSOTI; ii 25 "C Scheme 76 0 Reagents :i R'CH=CHCOCN Scheme 77 The 2,4,6-tribromophosphinines(197a) and (197b) undergo palladium-catalysed coupling with 2-trimethylstannylpyrrole,-furan -thiophene or -pyridine all of which substitute at the 2-and 6-positions(Scheme 80),L13 The Z-bmmo substituent can be selectively reduced from (197b) using tributyltin hydride/tctrakis(triphenylphos-phine)palf adium.Flash vacuum pyrolysis of dialkylvinylphosphine gives a 40% yield of phos-phinine,' l4 The synthesis of strychnine has been a popular endeavour;' "A 16.117in particular the application of aza-Cope-Mannich methodology is elegant.' I8*l 'I2 A. Ganesrrn and C.H. Heathcock J. Org. Chem,. 1993,sS,6155 'I3 P.LeFloch D.Cannichaef. L Ricard and F.Mathey J. Am. Chem. Soc. 1993,115 10665. li4 P. kFloch and F. Mathey J. Chem Soc. Chem. Cumrnun. 1993 1295. 'I5 P.Magnus M.Giles R Bonnert G. Johnson L.McQuire M. Deluca A Merritt C.S. Kim,and N. Vicker J. Am. Chem. Soc. 1993 115,81I6. M. E. Kuehne and F.Xu J. Org. Chem. 1993 58 7490. 'I' P. Magnus and M. Giles Tetruhedron Lett. 1993,34,6355. S.R.Angle J.M.Fevig S.D. Knight R.W. Marquis,Jr and L. E+Overman,J.Am. Chem. Soc, 1993,115 3966. S. D. Knight L+E.Oveman and G. Pairaudeau J. Am. Chem. Soc. 1993,115,9293. Heterocyclic Compounds Reagents i Pd(OAc), PPh, K,CO Scheme 78 fjtl Ph Reagents i R’R2NCH=;CHMe Scheme 79 Br 8r (I97a) R = H (198) X 51 0,S NMe (197b)R= Me Reagents:i Pd(dba), Ph,P Scheme 80 P. W.Sheldrake 5 Seven-membered Rings A review of the syntheses of medium-sized rings by ring-expansion reactions includes heterocyclic examples.2o The diene (199) is converted into a dilithium compound with t-butyllithiurn and serves as precursor to a variety of unusual heterocycles,'21 including the first arsepines and bismepines (200) (Scheme 811 the latter of which fM= Bi) has a half-life of only seven minutes. Ph (199) (200)M = P.AS,Sb. Bi Reagents i Bu'Li -80°C; ii PhMCl,; iii TBAF Scheme 81 The bis-cyclopropanated furan (201) isomerizes to 2,3-dihydrooxepine (202) on heating at 130"C. The corresponding anti isomer requires a temperature of 368 "C. Dienophiles react with (201)to give 9-oxabicyclo[4.2.l]nonanes (203) (Scheme82).'22 0 Reagents i 130°C; ii EHC=CHE Scheme 82 The naturally occurring antifungal benzopentathiapin varacin (205) has been synthesized.'23 Intermediate (204) is derived from a benzyne and carbon disulfide and subsequent reaction with disulfur dichloride completes construction of the penta- thiapin ring (Scheme 83).The utility of the displacement reaction of aromatic fluorides is demonstrated by the closure of the oxepine ring to form 6,7-dihydro~l]benzoxepino~4,5-c]quinolin-8(9H)-one (207) from the alcohol (206) (Scheme 84).'24 An intramolecular Heck reaction closes (208)to the dialkylmethylidene-substituted 2,3,4,5-tetrahydro-1H-3-benzazepine (209) (Scheme 85).12 ''O C.J. Roxburgh Tetrahedron Lett. 1993 49 10749. S. Yasuike H. Ohta S. Shiratori,J. Kurita and T. Tsuchiya J. Chem. Soc. Chern. Commun. 1993,1817. 12' T. Golz S.Hamrnes and F.-G. Klarner Chem. Bet. 1993 126,485. lZ3 V. Behar and S.Danishefsky J. Am. Chem. Soc. 1993 115 7017. 124 M. Anzini A. Cappelli and S. Vomero,Heterocycles 1993 36,1065. L. F. Tietze and R. Schimpf Synthesis 1993 875. Heterocyclic Compounds 211 Reagents i S,CI, THF MeOH HCI Scheme 83 ' N OH 'NOH Reagents i NaH DMF 155"C 5 min Scheme 84 Reagents i Pd(OAc), Ph,P KOAc Scheme 85 Radical-mediated ring expansion of (210) gives the benzazepine (211) (Scheme 8S).'z6 The technique was also applied to the preparation of dibenzazepines. Base treatment of (212)was expected to induce ring closure to (213) but this turned out to be the minor (20%) pr~duct;'~' a higher yield (39%) was obtained of (214) resulting from a novel Smiles rearrangement a mechanism confirmed by the isolation of intermediate (215) in 34% yield (Scheme 87).The functionalized azepinone (2 16) on treatment with methyl propiolate gives the aryl pyrrole (217) in high yield.'z8 The mechanism involves cycloaddition an lZ6 Z. B. Zheng and P. Dowd. Tetrahedron Lett. 1993 34 7709. lZ7 J.R. Poudfoot U.R. PateI and S.J. CampbelI J. Org. Chem. 1993 58,699' 12' E. Cartmell J.E. Mayo H. McNab and I.H. Sadler J. Chem. SOC. Chem. Commun. 1993 1417. P. W. Sheldrake aromatization that liberates an a-aminoketone and condensation with a second molecule of methyl propiolate (Scheme 88). dBr CO&t ci (210) Reagents i Bu,SnH AIBN Scheme 86 i QP?Q N CI -Et/ €t (213) Ci (215) Reagents i LiHMDS THF Scheme 87 Reagents i HCECC0,Me Scheme 88 Heterocyclic Compounds The nitrilimine precursor (218) is readily prepared.CycIization gives a 3,3a-dihydro-4H,6H-pyrazolo[1,5-a][4,1 Jbenzoxazepine (219) (Scheme 89). This could be oxidized to the corresponding pyrazole with DDQ. CO Et -KyH I 0 Reagents i NEt, toluene reflux Scheme 89 The reaction of 2-aminothiophenol(220) with various 241-haloaIky1)oxiranes(221) provides a convenient synthesis of lY5-benzothiazepins(222) (Scheme 90)' 30 Reagents i NEt,; ii KOH Scheme 90 On exposure to Mitsunobu conditions dithioketals (223) give ring-expanded products (224) via 1,3-sul€urmigration (Scheme 91 (223) m=n=1,2 (224) Reagents i DEAD Ph,P THF Scheme 91 Dihydrothiepin-1,l-dioxide(225) can be lithiated and reacted with electrophiles.The products (226) are convenient precursors to trienes (227) (Scheme 92). 129 L.Garanti G. Zccchi and L. Bruche J. Heterocycl. Chem. 1993 559. 130 M.Karikorni S. Yamori and T. Toda Heterocycles 1993 35 519. 13* S.Takano H.Iida. and K.Ogasawata Heterocycles 1993 36,2203. J.H. Rigby and A.C. Kruger SYNLETT. 1993 829. P.W. Sheldrake Reagents i Bu"Li HMPA -105 "C;ii electrophile E; iii 175 "C Scheme 92 6 Larger Rings There is a review of improved methods for the synthesis of aza-crown macrocycles and crypt and^.'^^ Two accuunts'34-13J of the biosynthesis of vitamin B, have appeared. B-Methoxyborinanes(228)react with a-chloroallyllithiurn to give after treatment of the initial adduct with boron trifluoride the B-rnethoxyboracydenes (229) (Scheme 93).I 36 OMe (228) n=0-7 Reagents i CH,=CHCH,Cl LiNR, -78°C; ii BF,.Et,O; iii -78"+r.t Scheme 93 Pyrido[l,2-a]azepinone (230)is deprotonated in the pyridine ring by LDA and the lithiated species will react with a variety of electrophiles.When an aldehyde is used the intermediate alkoxide attacks the lactam giving [7)(2,6)pyridinophane (231) (Scheme 94).13' (230) Reagents i LDA; ii RCHO Scheme 94 J33 K. E. Krakowiak J.S. Bradshaw and R.M. Izatt SYNLETT. 1993,611. 13* A. I. Scott Angew. Chem. int. Ed. Engl. 1993,32,1223. 13' A.R. Battersby Acc. Chem. Res. 1993 26 15. 136 H. C.Brown and S. Jayaraman Tetrahedron Lett. 1993 34,3997. 13' W. Maier M. Keller and W. Eberbach Heterocycles 1993,35 817.Heterocyclic Compounds The N-oxide (232) is converted in methanol under reflux into 3,6-epoxyhexahyd- roazocino[5,4-b]indole (233) (Scheme 95). A radical pathway is suggested.’38 Reagents i 90% MeOH Irradiation of the j?-ketovinylogous amide (234) leads to formation of the acetylpyrrole (237). Formation of the stabiIized diradical (2351 which can form keto-irnine (2361 is a likely mechanism (Scheme 96).13’ I I / Reagents i hv scheme % The thionocarbonate (238)was treated with base to form the cyclic thionocarbonate (239) which by [3,3] sigmatropic ring expansion gave thiolcarbonate (240) (Scheme 97).14* This material was converted into yellow-scale pheromone. The subtlety of the experiments needed to elucidate the biosynthesis of haem and vitamin B (see Chapter 11)tends to obscure the underlying synthetic work.The key step in the preparation of the spiro compound (244) was the combination of ’” T.Kurihara Y. Sakamoto M. Takai K. Ohuchi,S. Harasawa and R. Yoneda Chem. Pkorm. Bull. 1993 41 1221. 139 J.D. Winkltr and M.G.Siegel Tetrahedron Lett. 1993 34 7597. S. Harusawa S. Takemura H. Osaki R. Yoneda and T. Kurihara Tetrahedron 1993,49 7657. P. W. Sheldrake iododihydrodipyrrin (241) with the pyrrole (242) to give the lactam (243) (Scheme 98);14'methodology developed specificalIy for this target. The ultimate target was the octaacid corresponding to (244) required for use in enzyme inhibition studies. Reagents i LiHMDS scheme 97 Reagents i SnC14 CH,Cl,; ii AgOAc TsOH THF H,O Scheme 98 14' W.M.Stark C.J. Hawker G.J. Hart A. Phitippides P.M.Petersen J. D. Lewis F. J. Leeper and A. R. Battersby J. Chem. SOC.,Perkin Trans. I 1993 2875.