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