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Chapter 15. Heterocyclic chemistry

 

作者: M. J. Cook,  

 

期刊: Annual Reports Section "B" (Organic Chemistry)  (RSC Available online 1973)
卷期: Volume 70, issue 1  

页码: 471-527

 

ISSN:0069-3030

 

年代: 1973

 

DOI:10.1039/OC9737000471

 

出版商: RSC

 

数据来源: RSC

 

摘要:

15 Heterocyclic Chemistry By M. J. COOK and C. D. JOHNSON School of Chemical Sciences University of East Anglia Norwich NOR 88C The work described is classified in terms of ring size and within this scheme discussion of potentially aromatic or antiaromatic systems normally precedes that of saturated and simple unsaturated compounds. To avoid unnecessary duplication of material presented in other chapters little mention has been made of applications of physical methods and purely mechanistic studies. However the ever-increasing number of photochemical studies on heterocycles would certainly appear to warrant some description here and it is therefore hoped that readers will bear with any overlap that may thus result with Chapter 10. 1 Three-memberedRing Compounds MO calculations on oxiren 1H-azirine and thiiren reveal that these formally antiaromatic analogues of the cyclopropenyl anion should be stable,' an incentive for synthetic attempts and for postulation as reaction intermediates e.g.ref. 2 (see also Section 5). The 2H-azirine moiety figures in a number of interesting investigations its involvement in the formation of aziridines by the action of Grignard reagents on oximes has been sub-ject of further investigation and dis- c~ssion,~ and transitory 2H-azirines arising from the thermolysis of vinyl azides have been intercepted by Diels-Alder reaction (Scheme 1) leading to the formation of 2H-azepines. An interesting analogy to the formation of benzenes by the reaction of cyclopropenium cations with cyclopropene is the reaction of the 2H-azirine (1) to give the pyridine (2).5 The irradiation of 2H-azirines (3) to give the ylide (4)and the subsequent reaction of this with CH,OD established the disubstituted rather than the tri- substituted carbon as the point of highest electron density,6 a key to the regio- selectivity of photoadditions of azirines to dipolarophiles ; thus the products from the irradiation of (3; Ar = Ph R' = Me R2 = H) with methyl acrylate are the A'-pyrrolines (5a) and (5b).7 ' M.J. S. Dewar and C. A. Ramsden J.C.S. Chem. Comm. 1973,688. (a) T. L. Gilchrist G. E. Gymer and C. W. Rees J.C.S. Chem. Comm. 1973 835; (b) T. L. Gilchrist. G. E. Gymer and C. W. Rees J.C.S. Perkin I 1973 555. R. Chaabouni A. Laurent and P.Mison Tetrahedron Letters 1973 1343. D. J. Anderson and A. Hassner J. Org. Chem. 1973 38 2565. R. E. Moerck and M. A. Battiste Tetrahedron Letters 1973 4421. A. Padwa and J. Smolanoff J.C.S. Chem. Comm. 1973 342. A. Padwa M. Dharan J. Smolanoff and S. I. Wetmore J. Amer. Chem. Soc. 1973 95 1945 1954. 47 1 M. J. Cook and C. D.Johnson Me Me 0 R-CH=CH-N -[w]-(R = Ph or But) Me phse R Scheme 1 Br-Ph Ph Ph Ph (1) (2) R' N Ar R' Arc=& < A MeOD \ I hv --+ C=N-C-OMe 1 R2 R' / I + Ar R' ArCrN -C-/ D R2 \ (3) R' R2 = H Me or Ph R2 (4) phfYMe C02Me C02Me (54 (5b) The first proof of methyleneaziridine+yclopropanimine valence bond iso-merism (Scheme 2; R = H or alkyl) has now been provided by n.m.r.investi- gation.* On decomposition the products obtained R,C=CH and RCN are those arising from the chelotropic reaction of the imine (6). * H.Quast and W. Rider Angew. Chem. Internat. Edn. 1973 12 414. Heterocyclic Chemistry Re-R RbN-R R "\\ RYN-R R Scheme 2 Some interesting studies have emerged on the stereochemistry of aziridine synthesis and reactivity. Stereospecific synthesis of N-alkyl- or N-aryl-aziridines (8) can be achieved from the readily available iodo-azides of known configuration (7) by the use of alkyl or aryl dichlorob~ranes.~ Chiral ester functions may be used in the Gabriel synthesis of aziridines (9) permitting the separation of dia- stereomeric chiral aziridines and enabling the induction of asymmetry in their subsequent conversion into amino-acids,' while in related studies full report is now given of the synthesis of optically active N-acylated aziridinones and their use in peptide synthesis.' 'The mechanism and stereochemical control in thermal rearrangement of aziridinyl ketones to pyrroles has been discussed,12 and in contrast to three-membered-ring 'ene' reactions where only the cis-isomer (10) H 'N H ,\R2 /+ I."..I.. I R1 RZ reacts in this case the trans-isomer (11) reacts faster than the cis (12). This is ascribed to reaction via an alternative route i.e. through the azomethine ylides (13) which involves conrotatory ring-opening and in the cis case steric interaction between the nitrogen substituent and one or other of the 2,3-substituents.The A. B. Levy and H. C. Brown J. Amer. Chem. SOC.,1973,95,4067. lo J. W. Lown T. Itoh and N. Ono Cunad. J. Chem. 1973 51 856. " M. Miyoshi Bull. Chem. SOC.Japan 1973,46 212 1489. "A. Padwa D. Dean A. Mazzu and E. Vega J. Amer. Chem. SOC.,1973,95 7168. M. J. Cook and C. D. Johnson deamination of 2-(aminomethy1)aziridineshas also received mechanistic dis- cussion' 3-dual routes involving either carbenes or carbonium ions have been discerned 3-pyrrolines being among the products of the former pathway. t t + \ (13) Ph Ph Me or N + t The first synthesis of l-azaspiro[2,2]pentanes (14) has been described ;IbJ' a modification provides a useful route to the already known l-oxaspiro[2,2]- pentane (15).15 An attempted synthesis of the 2-azabicyclobutane (16) was however unsuccessful ; the substance proved unstable,14b but the analogous reaction with cyclobutenes affords a convenient synthesis of the 5-azabicyclo- [2,l,O]pentanes (17) a structure which unlike other aziridines is very unreactive towards dimethyl acetylenedicarboxylate.14' Ozonolysis of allenes has been used as a route to the novel heterocycles the allene oxides (18) which can be detected by n.m.r. at -78 "Cbut decompose to the oxetan structure (19) at room temperature.I6 Biological involvement of arene oxides has prompted studies on their synthesis," and on the mechanism of oxygen walks." A planar cyclohexane ring in (20) has been detected by X-ray studies," and anti-benzene dioxide (21) the final oxide of the series has now been prepared,*' stimulus being given by the discovery of an antibiotic with this structural unit.Thermally stable,(2l)nevertheless slowly decomposes on standing. l3 G. Szeimies Chem. Ber. 1973 106 3695. l4 (a)J. K. Crandall and W. W. Conover J.C.S. Chem. Comm. 1973 33; (6)D. H. Aue R. B. Lorens and G. S. Helwig Tetrahedron Letters 1973 4795; (c) D. H. Aue H. Iwahashi and D. F. Shellhamer ibid. p. 3719. l5 D. H. Aue M. J. Meshishnek and D. F. Shellhamer Tetrahedron Letters 1973 4799. l6 J. K. Crandall and W. W. Conover J.C.S. Chem. Comm. 1973 340. S. H. Goh and R. G. Harvey J. Amer. Chem. SOC.,1973,95 242; H. Yagi and D. M. Jerina ibid. p. 243. P. Y. Bruice G.J. Kasperek T. C. Bruice H. Yagi and D. M. Jerina J. Amer. Chem. SOC.,1973 95 1673; G. J. Kasperek P. Y. Bruice T. C. Bruice H. Yagi and D. M. Jerina ibid. p. 6041. l9 C. Kabuto M. Yagihara T. Asao and Y. Kitahara Angew. Chem. Internat. Edn. 1973 12 836. *O E. Vogel H.-J. Altenbach and E. Schmidbauer Angew. Chem. Internat. Edn. 1973 12 838. Heterocyclic Chemistry I R' (14) R' = Ph R2= H R' = R2= Ph m-C1C,H,C03H-CH $1,. 20°C(R' = H) p N",;'M." 14 N N-C0,Me @ N3C;,Mi &N-C0,Me But\ Room B u A Bu' But/c=c=c Bu' B,"H Bu' Bu' temp' Bu' 0 (19) (18) 00 a Photo-oxidation of indenes forms the bisepoxyperoxide (22) and on heating (22; R' = Me R2= Ph) collapses to the tetraepoxide (23).21 By contrast the 1-benzoxepin + naphthalene oxide (24)system which exists very predominantly as the former does not epoxidize with singlet oxygen but forms the peroxide (25).22 The irradiation of 9,10-epoxy-9,10-dihydrophenanthrene produces the C.S. Foote S. Mazur P. A. Burns and D. Lerdal J. Amer. Chem. SOC.,1973,95 586. 22 J. E. Baidwin and 0.W. Lever J.C.S. Chem. Comm. 1973 344. M. J. Cook and C. D.Johnson -* 0 :;.?-(_ . R2 Ph o& '-0 '0 previously unknown 2,3 :4,5-dibenzoxepin (26). The mechanism is considered to be an analogue of a photochemical Berson-Willcott rearrangement in which a [1,5] suprafacial shift of oxygen is involved (27).23 In connection with this an unsuccessful attempt to prepare benzoxiren is notable ; the adduct (28) instead of yielding the oxiren by an Alder-Rickert cleavage produced (29).24 Studies have NC NC NC NC also been reported this year of the syrn-oxabicyclo[5,1,0]octa-2,5-dienes (30)and (31) which variable-temperature n.m.r.reveals to be in equilibrium via Cope rearrangement,2 and of the Cope rearrangement in the three bicyclo[6,1,0]- nonadienes (32 ;X = CH ,0,or NCO,Et) which all produce the bicyclic system (33) irreversibly.26 23 N. E. Brightwell and G. W. Griffin J.C.S. Chem. Comm. 1973 37. 24 F.-G. Klarner and E. Vogel Angew. Chem. Internat. Edn. 1973 12 840. 25 H. Klein W. Kursawa and W. Grimme Angew. Chem. Internat. Edn. 1973 12 580. 26 W. Grimme and K. Seel Angew. Chem. Internat. Edn. 1973 12 507. Heterocyclic Chemistry 477 (32) (33) 2 Four-membered Ring Compounds In an extension of the study of the addition of diphenylketen to 2H-azirines reported last year,27 keten addition to azetine (34) to yield (35) has now been Ph Ph Ph Ph (34) (35) reported.2* 4,5-Dihydro-l,3,5-oxazaphosphole with isocyanides gives 3-imino-l- azetine (36),29 a ring system which undergoes photoinduced 1,3-dipolar cyclo- reversion to a nitrile ylide which may be trapped to give 2H-pyrroles or 1-pyrrolines e.g.(37) and (38).30 [2 + 21 Cycloaddition of isocyanates and keteni- (36) a; R' = H R2 = alkyl or Ar RCECR b; R' = Ar R2 = cyclohexyl RCH=CHR J \ Ar Ar (38) R = H or alkyl (37) R = H or alkyl mines gives good yields of 4-iminoacetidin-2-ones (39),3 and the cyanomalondi- hide (40) undergoes thermolysis to the 2,4-dioxa-3-azetidine carbonitrile (41) a precursor to the azetinone (42).32 Fused azetinones may be produced by Ann.Reports (B) 1972 69 429. 28 A. Hassner M. J. Haddadin and A. B. Levy Tetrahedron Letters 1973 1015. 29 K. Burger J. Fehn and E. Miiller Chem. Ber. 1973 106 1. 30 K. Burger W. Thenn and E. Miiller Angew. Chem. Internat. Edn. 1973 12 155. 31 Naser-ud-Din J. Riegl and L. Skattebral J.C.S. Chem. Comm. 1973 271. 32 L. Capuano and R. Zander Chem. Ber. 1973 106 3670. M. J. Cook and C. D. Johnson R' N-C,H,Me-p R'+f CN CNCH(CONHPh) ,,f,, 0J0 CH*N .&*Me N N I I Ph Ph photolysis or pyrolysis of tria~inones,~~ e.g. (43)-+(44),while the production of (47)from the action of heat on N-hydroxytriazonine (45) is taken as evidence for the intermediacy of (46) a valence tautomer of benza~etinone.~~ The azetidinone (48)decomposes on irradiation in methanol to give a compound whose structure has been ascertained by use of lanthanide shift reagents to be (49).35 2-Phenyl- benzazete (50)has been prepared for the first time by the vapour-phase pyrolysis of 4-phenyl-1,2,3-triazine(51);36 it is stable only at -80 "C,readily dimerizing or 33 N.Bashir and T. L. Gilchrist J.C.S. Perkin I 1973 868. 34 P. Ahern T. Navratil and K. Vaughan Tetrahedron Letters 1973 4547. 35 H. L. Ammon P. H. Mazzocchi W. J. Kopecky H. J. Tamburin and P. H. Watts J. Amer. Chem. SOC.,1973 95 1968. 36 B. M. Adger M. Keating C. W. Rees and R.C. Storr J.C.S. Chem. Comm. 1973 19. Heterocyclic Chemistry reacting with nucleophiles but its analogue (52)is stable at room temperature. -&Substituted lH-2,3-benzoxazin-l-ones are reported to yield biphenylenes on pyrolysis,37 presumably via the extrusion of CO to give (50) and then loss of PhCN to give benzyne. Another ni trogen-containing analogue of cyclobutadiene N H (49) Ph Me2PjY7fNMe2 Me,N FN-Me2PjPNMe2 Me,N (53) has been prepared by pyrolysis of tris(dimethylamino)-1,2,3-triazine; this formally antiaromatic structure owes its stability to the canonical form (53b).38 Various aspects of the mechanism of irradiation of a-pyrone to give (54) and thence cyclobutadiene as a matrix in argon at 8 K which thus enables its spectro- scopic investigation have received much attenti~n.~~" Similar treatment of pyridine also leads to cyclobutadiene oia species(55),39bwhile phthaloyl peroxide affords benzpropiolactone (56)and thence ben~yne.~' [2 + 21 Photocycloaddition of unsaturated carbon-carbon linkages to carbonyl groups continues to attract investigation.Irradiation of cis-but-2-ene with acetone yields both stereoisomers (57) and (58) which suggests that the biradical (59) is an intermediate with a sufficiently long lifetime for bond ro- tation ;41 this contention receives support from the isolation of open-chain 37 M. P. David and J. F. W. McOmie Tetrahedron Letters 1973 1361. '* G. Seybold U. Jersak and R. Gompper Angew. Chem. Internat. Edn. 1973 12 847; H.-U.Wagner ibid. p. 848. 39 (a)0. L. Chapman C. L. McIntosh. and J. Pacansky J. Amer. Chem. SOC.,1973 95 614; C. L. McIntosh and 0. L. Chapman ibid.,p. 247; R. G. S. Pong and J. S. Shirk ibid. p. 248; 0.L. Chapman D. De La Cruz R. Roth and J. Pacansky ibid. p. 1337; A. Kranz C. Y.Lin and M. D. Newton ibid.,p. 2744; (b) 0. L. Chapman C. L. McIntosh and J. Pacansky ibid. p. 244. 40 0.L. Chapman C. L. McIntosh J. Pacansky G. V. Calder and G. Orr J.Arner. Chern. Soc. 1973 95 4062; 0.L. Chapman K. Mattes C. L. McIntosh J. Pacansky G. V. Calder and G. Orr ibid. p. 6134. 41 H. A. J. Carless Tetrahedron Letters 1973 3173; J.C.S. Chem. Comm. 1973,316. M. J. Cook and C. D. Johnson 1 compounds such as (60) from the reaction of 2,3-dimethylbut-2-ene.A study of oxetan formation from benzophenone and alkenes suggests initial irreversible formation of a complex with triplet benzophenone before this biradical for- mati~n,~~ whereas participation of ester carbonyls involves the excited singlet state.43 The 2-and E-rotamers (61) arise from the irradiation of benzaldehyde with but-2-yne at 20 "C;44 the oxeten (62) is involved as intermediate and at lower temperatures this leads on to the 2,5-dioxabicyclo[2,2,O]hexanestructure (63a). An oxeten (64) is also involved as an intermediate in the acid-catalysed reaction of 3-chloro-3-dimethylaminopropenoneto give 3-chloro-NN-dimethylacryl-amide.45 A 2,5-dioxabicyclo[2,2,0]hexane(63b) further arises from irradiation of 3-methyl-4-oxa-5-hexen-2-one (65).46 Another novel structure although not (62) (63) a; R' = RZ= Ph R3= Me (64) b; R' = Me RZ = R3 = H Me 42 R.A. Caldwell G. W. Sovocool and R. P. Gajewski J. Amer. Chem. SOC. 1973 95 2549. 43 T. S. Cantrell J.C.S. Chem. Comm. 1973 468. 44 L. E. Friedrich and J. D. Bower J Amer. Chem. SOC.,1973 95 6869. 4s M. Neuenschwander and A. Niederhauser Chimia (Switz.) 1973 27 379. 46 J. C. Dalton and S. J. Tremont Tetrahedron Letters 1973 4025. Heterocyclic Chemistry 481 isolated is tetraoxaspirocycloheptane(66),a plausible intermediate in the for- mation of aldehydes or ketones by irradiation of allenes with singlet oxygen in carbon di~ulphide.~’ The dioxetan (67) reacts quantitatively with triphenyl- phosphine to yield (68) which decomposes on warming to give an ~xiran.~~ 0-0 R 0-0 MewMe 0’ PPh ‘0 +ttRR 0-0 Me Me Me .-!&Me Me Me (66) R = H alkyl or Ph Notable analogues of the carbonyl-alkene reactions discussed above are those of thiophosgene4’ or the thiocarbonate (69)” with 2,3-dimethyibut-2-ene ; in the first case irradiation produces the thietan (70) and thence by hydrolysis the 3hio- lactone (7 l),whereas in the latter the spirothietan (72) arises.Thiacyclobutene or thiet serves as a source of previously unknown thioacrolein. Reaction with iron carbonyl gives the complex (73) and thence the red dicarbonyl- triphenylphosphineiron complex of thioacrolein (74).” The isolation of the first stable a-dithione 4,4’-bis(dimethylamino)dithiobenzilis reported.’ It exists as an equilibrating mixture of (76) and (77) and the position of this equilibrium is co Ar Ar IS>-.“v Ar s Ar (75) Ar = Me2NC6H4-(76) (77) 4’ T. Greibrokk Tetrahedron Letters 1973 1663. 4g P. D. Bartlett A. L. Baumstark and M. E. Landis J. Amer. Chem. SOC.,1973 95 6486. 49 H. Gotthardt Tetrahedron Letters 1973 1221. 50 H. Gotthardt and M. Lid Tetrahedron Letters 1973 2849. 51 K. Takahashi M. Iwanami A. Tsai P. L. Chang R. L. Harlow L. E. Harris J. E. McCaskie C. E. Pfluger and D. C. Dittmer J. Amer. Chem. Soc. 1973 95 61 13. 52 W. Kiisters and P. de Mayo J. Amer. Chem. Soc. 1973,95 2383. M. J.Cook and C.D. Johnson solvent- light- and temperature-dependent. Studies of the activation energy of the processes indicate that the dithiet (77) has a high stability owing to the n-electron delo~alization.’~ Two important studies in the area of Wittig alkene syntheses are the first direct (n.m.r.) observation of the oxaphosphetan (78)’ and in its sulphur analogue a scheme for the formation of alkenes from p-sultines (79).54 0 Ph3P-0 0-Mem MeCH=PPh,+ THF -70°C OH +v+-CHR1-CR2R3I -+ S+-&HR1 c1 +:-cR2R3 0 c1-R’ R2 R3 = alkyl or Ar 0-CR2R3 -so I I R’CH=CR2R3 + //s-CHR1 0 (79) 3 Penams and Cephams The search for details of the biosynthetic pathway from the amino-acids L-valine and L-cysteine to p-lactam antibiotics remains a key interest of obvious impor- tance.Experiments involve the synthesis of (2S,3S)-[4-’3C]valine,55(2RS,3S)-[4-’3C]valine,56 and (2RS,3S)-[4,4,4-2H3]valine57and a study of their incorpora- tion into cephalosporin C (80),55~56 with a particular emphasis on the fate of the isopropyl group.Other work in this area includes a demonstration of the oxi- dation of cysteinyldehydrovaline[81; R’= H,R2= PhCH,CO R3= -C(C0,-Me)=CMe,] and N-phthaloylcystinylvaline [81 R’R2= phthaloyl R3= -C(CO,Me)H-CHMe,] to isothiazolidinones (82),’* new peptide derivatives which may constitute intermediates in the biosynthetic pathway to penam and 53 E. Vedejs and K. A. J. Snoble J. Amer. Chem. SOC.,1973,95 5778. 54 F. Jung N. K. Sharma and T. Durst J. Amer. Chem. SOC.,1973,95 3420. ” H. Kluender C. H. Bradley C. J. Sih P. Fawcett and E. P. Abraham J. Amer. Chem. SOC.,1973 95 6149. 56 J.E. Baldwin J. Loliger W. Rastetter N. Neuss L. L. Huckstep and N. De La Higuera J. Amer. Chem. SOC.,1973 95 3796; N. Neuss C. H. Nash J. E. Baldwin ’’ P. A. Lemke and J. B. Grutzner ibid. p. 3797. D. J. Aberhart and L. J. Lin J. Amer. Chem. SOC.,1973 95 7859. ’* J. E. Baldwin S. B. Haber and J. Kitchen J.C.S. Chem. Comm. 1973 790; see also R. B. Morin E. M. Gordon and J. R. Lake. Tetrahedron Letters 1973 5213. Heterocyclic Chemistry 483 R'R'N 0z!R lR 0 'R3 cepham structures (Scheme 3) which fits in with the experiments on chiral ['3C]valine.56 Not surprisingly the search for interconversions of penams and cephams continues. Last years9 the structure (85) was shown to be an intermediate from RN H RNHg$-RN:n$ 0 'ene' -0 C0,Me C0,Me C0,Me 'Diels-Alder' 0 , C0,Me C02Me Scheme 3 which both antibiotic types could be obtained ;it has now been demonstrated6' that a facile route to (85) is available via halogenation of (84) obtained by the action of 2-mercaptobenzothiazole on penicillin sulphoxide (83).A further noteworthy route from penicillins to cephalosporins involves the conversion of benzyl 6P-(triphenylmethylamino)penicillanate into the azeti- dinone from whence the cepham (87) can be obtained using an intra- 59 Ann. Reports (B) 1972 69 445. 6o T. Kamiya T. Teraji Y.Saito M. Hashimoto 0.Nakaguchi and T. Oku,Tetrahedron Letters 1973 3001. 61 J. H. C. Nayler M. J. Pearson and R. Southgate J.C.S. Chem. Comm. 1973 57; D. H. R. Barton I. H. Coates P. G. Sammes and C.M. Cooper ibid. p. 303. M. J. Cook and C. D. Johnson 0-Ph,CN H SCH,C=CPh CH2CoN :E>CH Ph OE&COZCH Ph CO,H (86) (87) molecular Wittig reaction to construct the dihydrothiazine ring,62 while the synthesis of deacetoxy-cephalosporin S-oxides from penicillins takes advantage of the nucleophilicity of the S atom in sulphenic acids (Scheme 4).63 0-0 I II Ft SO,CI,) Ft OH pz 0 CO2R C02R CO2R / Ft = phthalimido 0-I CO2R Scheme 4 Attention has been paid to the introduction of a C-6 (7) methoxy substituent into penam and cepham nuclei. This can be done stereospecifically by addition of methanol to the cation (88)64 or the kine (89).65 The isolation of p-lactam 62 J. H. C. Nayler. M. J. Pearson and R.Southgate J.C.S. Chem. Comm. 1973 58. '' S. Kukolja and S. R. Lammert Angew. Chem. Internat. Edn. 1973 12 67. 64 L. D. Cama and B. G. Christensen Tetrahedron Letters 1973 3505. 65 J. E. Baldwin F. J. Urban R. D. G. Cooper and F. L. Jose J. Amer. Chem. SOC.,1973 95 2401. Heterocyclic Chemistry RTNlx)( 0 phcH=AE> 0 antibiotics of cepham structure bearing a 7-methoxy-group a functionality previously unknown in such compounds has also inspired a one-step stereo- selective synthesis of 7a-methoxycephalosporin C66(see also ref. 67). A related report68 deals with the direct C-6 epimerization of penicillin V methyl ester through the vicinal dianion (90). I PhCH,-C=N Li+ -o C0,Me Cephalosporin Cefoxitin (91) is unique in possessing not only a 7cx-methoxy substituent but also a 3-carbamoyloxymethyl group.Its synthesis69 exemplifies the use of (92)as a key intermediate in the preparation of p-lactam antibiotics. I C0,Me CO,H (91) (92) Finally in this brief Report which can do scant justice to the wealth of ingenious and novel reactions reported in this field this year an important synthesis of p-lactams by photolytic Wolff rearrangement (93)-(94) which can be ex-panded to cepham and penam preparation is noted.” 0 I1 PhCMe,O,CNHNHC. 0m C02CH,Ph (94) 66 G. A. Koppel and R. E. Koehler J. Amer. Chem. SOC.,1973,95,2403. ‘’ G. A. Koppel and R. E. Koehler Tetrahedron Letters 1973 1943. 68 G. A. Koppel Tetrahedron Letters 1973 4233. 69 R. W. Ratcliffe and B.G. Christensen Tetrahedron Letters 1973 4645 4649 4653. ’O G. Loweand D. D. Ridley J.C.S. Chem. Comm. 1973,328;J.C.S. Perkin I 1973,2024. M. J. Cook and C. D. Johnson 4 Five-membered Ring Compounds Several interesting pyrrole syntheses have appeared. Lithium ethylidenecyclo- hexylamine with P-halogeno-ketones yields a variety of pyrrole structures e.g. (95),71while other one-step routes include anodic dimerization of enamino- ketones or treatment of imines (96)with lithium or Grignard reagent,73 and reaction of alkoxymethyl-substituted bromoallene derivatives (97) with .............. -c=o ether. -78°C [CH,-CH-N-C,Hl,]Lif +(CH,) 1 7 CHX I X = C1 or Br; n = 4-6 CP 1 R' R' R' Li-ether. -70 "C R 1 -CH -CH Pr'MgCI , 0 bRl I I I1 I Br NR2 R2 (96) R' R2 = alkyl benzyl R2 ROCH,C=C=CHCH,CI Bu'NH ROCH,C-CCHCH,NHBu' + I MeCN 120°C I Br NHBu' I (97) Bu' primary amine~.~~ Pyrrole formation by heating the azetidinopyridine (98) in benzene is explained by invoking the formation of a lP-diazocine followed by a [1,3] sigmatropic (C +N).alkyl shift and cyclore~ersion.~~ A variety of new routes to indoles has also been presented pre-eminent of which is a method utilizing N-chloroanilines with ~ulphides,~~ affording a general and viable alternative to the Fischer indole synthesis.The scope of the reaction is shown in Scheme 5 while a modification involves using halogen- sulphide complexes e.g. (99)+( Among other syntheses involving base catalysis is that of (101),which exploits the ability of nitrosoamines to form carb- anionic species,78 and (102) by a process which has a formal analogy to the 71 G.Wittig R.Roderer and S. Fischer Tetrahedron Letters 1973 3517. 72 D. Kock and H. Schafer Angew. Chem. Internat. Edn. 1973 12 245. 73 P. Duhamel L. Duhamel and J.-Y. Valnot Tetrahedron Letters 1973 1339. 74 M. V. Mavrov A. P.Rodionov and V. F. Kucherov Tetrahedron Letters 1973 759. 75 J. W. Lown and M. H. Akhtar Tetrahedron Letters 1973 3727. 76 P. G. Gassman and G. Gruetzmacher J. Amer. Chem. SOC. 1973,95,588; P. G. Gass- man and T. J. van Bergen ibid. p. 590 591 2718. 77 P. G. Gassman T. J. van Bergen and G. Gruetzmacher J. Amer. Chem. SOC. 1973 95 6508. 7a A. Walser and G. Silverman J. Heterocyclic Chem.1973 10 883. Heterocyclic Chemistry (98) R = C,H,, C12H23 or Bu' / Me0,C C0,Me a+ R-N=C=CHPh Ph I R CH2SMe i MeSCHR4C0,R3 i. MeSCH,COR' ii. base R' R' Scheme 5 MeOoNH2 ii. Et,N Me (99) H M. J. Cook and C. D. Johnson Ph ,Me -K0Bu'-THF c ' ~ ~Ph o HTi,H,-RaNi "a7JphI I \ I NO I NO i H (101) Fischer synthesis. 79 Other starting points are the dihydroquinoline [( 103)-+ ( 104)],'0 arylhydroxylamines [( 105)+(106)],'1 and N-2-chloroallylanilines [(107)-+ (108)],82 while a convenient synthesis of 4,5,6,7-tetrafluoroindole(109) has also been gi~en.'~ hv I C0,Et (103) A note that the action of p-chlorobenzoyl chloride and pyridine on 3,3-dimethyl-3H-indole yielded stereoisomers of structure (1 was later corrected" to show that the compounds were in fact (11l),the first diastereomeric atropisomers to be isolated involving the heterocyclic ring of an indole and arising from restricted rotation about the bond indicated.3- 4- and 6-substituted indoles (1 13)-(115) are available by Fries-type photochemical rearrangement of 1-substituted indoles (112) where R' is a wide variety of groups e.g. CO,Et COMe PhCH ,etc.,'6 and vinylogous Favorskii reactions of 3-(a-halogenoacyl)- 79 L. N. Yakhontov and M. F. Marshalkin Tetrahedron Letters 1973 2807. 8o M. Ikeda S.Matsugashita H. Ishibashi and Y. Tamura J.C.S. Chem. Comm. 1973 922. K. Okamoto and K. Shudo Tetrahedron Letters 1973 4533. 82 B. McDonald A. McLean and G. R.Proctor J.C.S. Chem. Comm. 1973. 208. 83 R. Filler S. M. Woods and A. F. Freudenthal J. Org. Chem. 1973 38 81 1. 84 K. Takayama M. Isobe K. Harano and T. Taguchi Tetrahedron Letters 1973 365. 85 V.Dave J. B. Stothers and E. W. Warnhoff Tetrahedron Letters 1973 4229. M. Somei and M. Natsume Tetrahedron Letters 1973 2451. Heterocyclic Chemistry (105) R' = H Me or C1 R2 = H or Me OH 0 F F indoles (1 16) under mildly basic conditions lead to the formation of indole acetic acids (118) in good yield presumably via the intermediate (117).87 A simple one-step high-yield route to isoindoles and related compounds is illustrated by the first synthesis of a pyrrolo[3,4-b]quinoline heterocycle (1 19).88 Isoindole derivatives (122) whose structure have been confirmed by X-ray crystallography have also been derived from dimerization of nitrile ylides (121) J.Bergman and J.-E. Backvall Tetrahedron Letters 1973 2899. ** M. J. Haddadin and N. C. Chelhot Tetrahedron Letters 1973 5185. M. J. Cook and C. D. Johnson R' QT&r NaOH-EtOH ' -H,O I H J I H mz CH,NH,-EtOH-NaBH; 0 Ph (119) Heterocyclic Chemistry 49 1 formed from oxazaphospholes ( while the first stable 2-azapentalene (124) has been derived from the lactam (123).90 The synthetic utility of the ylide salt (125) has been demonstrated in the preparation of the pyrazine (126) and the pyrazole (127),” and another method for preparation of pyrazoles e.g. (129) is / (121) (120) X = H Me or OMe CF3 CF NPX e- X CF CF NMe NMe NMe, I I I 0 OEt OEt (123) (124) + Br -Ph,P-CH -C-CH=PPh3 II N-N=CHCOPh CH,PPh Br-1 CH,COPh the reaction of hydrazidic bromides (128) and anions of acetylacetone dibenzoyl- methane ethyl acetoacetate etc.in ethanol at room ternperat~re.~~ A good route 89 K. Burger K. Einhellig G. Suss and A. Gieren Angew. Chem. Internat. Edn. 1973 12 156; A. Gieren K. Burger and K. Einhellig ibid. p. 157. 90 K. Hafner and F. Schmidt Angew. Chem. Internat. Edn. 1973 12 418. 91 E. E. Schweizer C. S. Kim 6.S. Labaw and W. P. Murray J.C.S. Chem. Comm. 1973 7. 92 A. S. Shawali and H. M. Hassaneen Tetrahedron 1973 29 121. M. J. Cook and C. D. Johnson to the pyrazolopyridine (130) is provided by action of primary aromatic amines HCI or EtOH on 2-arylaminomethy1-3-nitro-pyridine~,~~ and pyrazoles (132) arise from a spontaneous [1,5] acyl migration of the intermediate in the reaction of (131) with alkyne~.~~ R'-C LNHAr/Br R' COR' N,9 R r (128) I Ar X (129) (130) X = ArNH CI or EtO Very simple routes have been described for the synthesis of aryl-substituted imidazoles (133),95 and also for N-amir~o-~~ and N-hydroxy-benzimida~oles,~~ N-hydroxybenzimidazolones,972-aminoben~imidazole,~* and polychlorobenz- imida~oles.~~ In the realm of imidazole reactivity it has been shown that the reaction of phenylenediamine and cyclohexanones leads to an electron-transfer complex between dihydrobenzimidazole and isobenzimidazole (134) a novel oxidation-reduction system of potential synthetic utility.O0 + Phosgeneimmonium chloride Cl,C=NMe,CI -,has been shown to react with dinucleophiles in a number of useful syntheses."' Thus with arylhydrazines amidrazones and hydrazides indazoles triazoles and oxadiazoles are formed respectively and o-aminophenols or o-aminothiophenols yield benzoxazoles or benzothiazoles. The diazo-compound (135) formed from 2-amino-4,5-dicyanoimidazole readily eliminates nitrogen to form a highly zlectrophilic intermediate that inserts the 4,5-dicyanoimidazole moiety into a substrate ; e.g. with trifluoromethylbenzene it yields (136).'02 Other notable features of 93 H. E. Foster and J. Hurst J.C.S. Perkin I 1973 319. 94 M. Franck-Neumann and C. Buchecker Angew.Chem. Internat. Edn. 1973 12 240. 9s U. Lang and H. Baumgartel Chem. Ber. 1973 106 2079. D. W. S. Latham 0. Meth-Cohn and H. Suschitzky J.C.S. Chem. Comm. 1973 41. 97 D. B. Livingstone and G. Tennant J.C.S. Chem. Comm. 1973,96. S. Weiss H. Michaud H. Prietzel and H. Krommer Angew. Chem. Internat. Edn. 1973 12 841. 99 J. Martin 0.Meth-Cohn and H. Suschitzky Tetrahedron Letters 1973 4495. loo J. A. L. Herbert and H. Suschitzky Chem. and Ind. 1973 482. lol F. Hervens and H. G. Viehe Angew. Chem. Internat. Edn. 1973 12 405. lo* W. A. Sheppard and 0.W. Webster J. Amer. Chem. SOC.,1973,952695. Heterocyclic Chemistry R2 R' R2 (134) R' R2 = H or Me diazole reactivity are the synthetically useful thermal rearrangements (137)-(138)'03 and the novel transformation (139)-(l4O),lo4 the latter particularly surprising since aromaticity is lost in the process.The synthesis of triazoles has also commanded attention this year. An elusive cyclic azo-compound 1,2,4-triazoline-3,5-dione,has now been prepared in solution by oxidation of urazole and its spectral characteristics and reactivity have been examined.lo5 sym-Triazoloazines fused at the N-2-C-3 bond of the triazole ring can now be readily prepared from the corresponding aminoazines.' O6 Compound (142),the product of reaction of cyanogen bromide with (141),gives rise to a number of noteworthy compounds-to (143) a previously unknown derivative of benzimidazole and to (144) and (145),both new ring sy~terns."~ '03 J. W.A. M. Janssen H. J. Koeners C. G. Kruse and C. L. Habraken J. Org. Chem. 1973,38 1777. lo4 F. T. Boyle and R. A. Y.Jones J.C.S. Perkin I 1973 167. lo5 J. E. Herweh and R. M. Fantazier Tetrahedron Letters 1973 2101. lo6 S. Polanc B. VerEek B. Stanovnik and M. TBler Tetrahedron Letters 1973 1677. lo' R. I.-F. Ho and A. R. Day J. Org. Chem. 1973,38 3084. M. J. Cook and C.D. Johnson RR RR C N ''3. t3N N H Me Me Me Me OMe (139) NHCOR' I i. (R2C0),0 MeCOCOMe ii H+ or OH-I I Benzotriazole 1-oxides are produced by irradiation of 1-(0-nitropheny1)pyr-azoles,'08 and the synthesis of a range of H-l,2,3-triazoles by the action of azide on acetylenes demonstrates the versatility of this rarely exploited reaction.log The stability of polyaza-rings is illustrated by the preferential ring-opening of the pyridine ring in (146) on attack by nucleophiles such as borohydride morpholine and methoxide.' Two other intriguing reactions of polyaza- indolizine derivatives are the reversible Dimroth-style rearrangement (147) (148)' ' and the 1,3-photocycloaddition of alkenes to syrn-triazolo[4,3-b]pyr-idazine to give products (149) and (150) presumably via the nitrene (151).l12 P.Bouchet C. Coquelet J. Elguero and R. Jaquier Tetrahedron Letters 1973 891 Y.Tanaka S. R. Velen and S. I. Miller Tetrahedron 1973 29 3271. 'lo A. Gellkri and A. Messmer Tetrahedron Letters 1973 4295. 'I1 D. R. Sutherland G. Tennant and R. J. S. Vevers J.C.S. Perkin I 1973 943. J. S. Bradshaw B. Stanovnik and M.TiSler Tetrahedron Letters 1973 2199. Heterocyclic Chemistry 495 RcN+y .pN*? NaBH, \ N-N Ar / N-N Ar Me (147) Two groups' l3 have stressed the utility of the reaction of thiomethylisocyanides with carbonyl compounds to form substituted oxazoles and oxazolines while isoxazoles are prepared by a facile cyclization of orb-unsaturated ketoximes with the palladium complex [(Ph,P),PdCl,].' ' Two isoxazole conversions receive mechanistic interpretation :the photoisomerization of indoxazene to benzoxazole proceeds via the isocyanide (152) rather than through an azirine intermediate as previously thought,' ' and the conversion of isoxazoles to pyridones by treat- ment with diphenylcyclopropenone' ' involves the key rearrangement (153).Dioxazoles may be synthesized from hydroxamic acids and acetylenic com-pounds,' ' while selective reduction of the oxides (154) accessible as indicated leads to benzothiazoles with a wide variety of substituent groups many previously unknown.' 'I3 A. M. van Leusen and H. E. van Gennep Tetrahedron Letters 1973,627; U. Schollkopf and E. Blume ibid. p. 629; U. Schiillkopf and R. Schroder ibid. p. 633. 'I4 K. Maeda T. Hosokawa S.4. Murahashi and I. Moritani Tetrahedron Letters 1973 5075. '' J. P. Ferris F. R. Antonucci and R. W. Trimmer J. Amer. Chem. SOC.,1973 95 919. 'I6 R. Grigg R. Hayes J. L. Jackson and T. J. King J.C.S. Chem. Comm. 1973 349. F. M. F. Chen and T. P. Forrest Canad. J. Chem. 1973,51 1368. K. Wagner H. Heitter and L. Oehlmann Chem.Ber. 1973,106 640. M. J. Cook and C. D. Johnson R' R' Other syntheses worthy of mention in the realm of five-membered nitrogen- and oxygen- or sulphur-containing rings include a general method for isothiazolo- [2,3-a]pyridinium salts,' several novel isothiazolopyridines,120 5-amino-1,2,4thiadiazoles from 1-amino-3-iminoisoindolenines,' and thiadiazoles e.g. (156) and (157) from electron-depleted thiocarbonyl compounds (155) with diazoalkanes. ' Dithiolans thiadiazolines and thiirans are also available from this reaction mode. Lithio-thiazoles -thiadiazoles and -0xadiazoles (158) are reported to undergo rearrangement to ketenimines (159) which are not isolated but recognized as dimers such as (160).'23 The naturally occurring furans perillene and dendrolasin are among the 3- and 3,4-substituted furans (161) synthesized by the general route shown,'24 and a one-step synthesis of 2-substituted benzofurans by the action of palladium complexes on sodium salts of 2-allylphenols' 25 echoes the previously mentioned generation of isoxazoles.'l4 The attempted preparation of 2-amino-3-cyano-4-methylfuran (162) by the action of malononitrile on MeCOCH,OH a method l9 G.G. Abott and D. Leaver J.C.S. Chem. Comm. 1973 150. A. Taurins and V. T. Khouw Canad. J. Chem. 1973 51 1741. K. Leverenz Angew. Chem. Znternat. Edn. 1973 12 237. 12' S. Holm and A. Senning Tetrahedron Letters 1973 2389. '' A. I. Meyers and G. N. Knaus J. Amer. Chem. SOC.,1973 95 3408. 24 M. E. Garst and T. A. Spencer J. Amer.Chem. SOC., 1973,95 250. ''' T. Hosokawa K. Maeda K. Koga and 1. Moritani Tetrahedron Letters 1973 739. Heterocyclic Chemistry 497 SII (155) MeS02CNMe2 N-N CHzNz Etzo ' (S)jNMe Me,N (156) (157) (161) previously advocated,' 26q yields instead the first member of the 4,7-epoxybenzo- furan ring system (163) by a novel Diels-Alder reaction.126b 3-0xabicyclo[3,2,0]hepta-1,4-diene(165) has now been prepared from (164 ; X = 0)by partial hydrogenation,'27 and their differences in spectral properties have been ascribed to the fact that whereas the former is a perturbed furan the latter is a truly antiaromatic planar 8x-system ;in the sulphur system (164;X = S) this instability is reflected by its ready dimerization to bisthienocyclo-octatetraene (166).'** Treatment of the system (167; R' = R2 = Ph R3 = COPh) with P2S (a) K.Gewald. Chem. Ber. 1964 99 1002; (6) J. L. Isidor M. S. Brookhart and R. L. McKee J. Org. Chem. 1973,38 612. Iz7 R. G. Bergman and K. P. C. Vollhardt J.C.S. Chem. Comm. 1973,214. K. P. C. Vollhardt and R. G. Bergman J. Amer. Chem. SOC.,1973 95 7538. M. J. Cook and C.D.Johnson Ex 1 I 1 1 -( 164) (165) ( 166) in pyridine leads to thieno[3,4-f]benzo[c]thiophen (168),a non-classical 14n-electron system.129 Benzo[c]thiophen (167;R' = CO,Me R2 = R3 = H) can conveniently be prepared by alkali-induced decomposition of 1,Cdimethoxy-carbonyl-2,3-benzodithiane,'30 benzo[b]thiophens by thiophenol addition to R' F2 Ph ph Ph (167) (168) activated triple bonds,13' and thieno[3,2-b]quinoline (169)by nitrene insertion into thiophen rings.' 32 The mechanism of the oxidation of P-phenylpropanoic acids with thionyl chloride to give benzo[b]thiophens has now been inves- tigated.Arsadiazole (171)has been prepared from the hydrazine (170)and its spectral characteristics have been examined ;'34 the photoelectron spectra of phospholes and arsoles reveal that the lone pairs do not participate in cyclic conjugation and thus that they are non-aromati~.'~~ PhNH-N=CRMe "h N ,As (170) R = Me Et or Ph N I Ph (171) K. T. Potts and D. McKeough J. Amer. Chem. Soc. 1973,954 2750. I3O G. Cignarella and G. Cordella Tetrahedron Letters 1973 1871. 13' K. Undheim and R. Lie. Acta Chem. Scand. 1973 27 595.132 G. R. Cliff G. Jones and J. M. Woollard Tetrahedron Letters 1973 2401. 133 A. J. Krubsack and T. Higa Tetrahedron Letters 1973 125 4515. 13* G. Markl and C. Martin Tetrahedron Letters 1973 4503. W. Schafer A. Schweig G. Markl H. Hauptmann and F. Mathey Angew. Chem. Internat. Edn. 1973 12 145; cf. Ann. Reports (B) 1972 69 435. Heterocyclic Chemistry 499 Notable among preparation of other non-aromatic five-membered heterocycles reported this year are a general and versatile method illustrated by the conversion (172)-P (173)136andthepreparationoftriazolidines,pyrrolidines,andimidazolin-4-ones and -4-thiones by the reaction of lithium salts (174)with azo-compounds alkenes isocyanates and isothiocyanates respectively.' With carbon disulphide the spiro-compound (175)is formed.Other syntheses in this area include the I NH,(CH,),XH RNC-AgC% N' NCdX+ RNH2 (172) X = 0 NH,or S (173) n=2or3 H H H I Ph Ph (174) Ph I H photochemical formation of 3-oxazolidines from aryl ketones and aliphatic imines,' 38 2-oxazolidinones (177)with 8-hydroxy-amides (1 76)as intermediates in a Hofmann-style reaction,' 39 stable 1,4,2-dioxaphospholaniumsalts (1 78)140 prepared for the first time 3,4-dimethyIenethiolan and its I-oxide and I,1- dioxide,'41 and thiolactone systems (179) formed by cleavage of o-metallated cornplexe~,'~~ which constitute a potential entry into the benzo[c]thiophen ring system. Vinylketens are implicated in the photolysis of pyrazolenines and the detailed mechanistic pathways have been eiu~idated'~~ (Scheme 6 is an example).2-Phenyl-(180)and 2-thiono-1,3-dioxol-4-en (181)appear to be useful alternatives to acetylenes as dienophiles in Diels-Alder rea~ti0ns.l~~ Finally in this section 136 Y. Ito Y.Inubushi M. Zenbayashi S.Tomita and T. Saegusa J. Amer. Chem. Sac. 1973,95.4447. 13' T. Kauffmann A. Busch K. Habersaat and B. Scheerer Tetrahedron Letters 1973 4047 T. Kauffmann and R. Eidenschink Angew. Chem. internat. Edn. 1973. 12 568 T. Kauffmann. A. Busch. K. Habersaat and E. Koppelmann. ibid. p. 569. 138 A. A. Baum and L. A. Karnischky J. Amer. Chem. SOC.,1973 95 3072. 139 S. S. Simons J. Org. Chem. 1973 38 414. I4O N. J. De'Ath J. A. Miller and M. J. Nunn Tetrahedron Letters 1973 5191.I4I S. Sadeh and Y. Gaoni Tetrahedron Letters 1973 2365. 142 H. Alper and A. S. K. Chan J. Amer. Chem. SOC.,1973,95,4905. 143 A. C. Day A. N. McDonald B. F. Anderson T. Bartczak and 0.J. R. Hodder J.C.S. Chem. Comm. 1973 247; M. Franck-Neumann and C. Buchecker Tetrahedron Letters 1973 2875. 144 W. K. Anderson and R. H. Dewey J. Amcr. Chem. SOC., 1973,95 7161. M. J. Cook and C. D.Johnson Ar I Ph 0 (178) R = Phz or -CMe2CHzCMe2-COMe COMe COMe COMe hv Et,O GN Scheme 6 Heterocyclic Chemistry 50 1 we may note the high stereoelectronic control of the stepwise addition of triplet SO generated from thiiran oxide to dienes to form 3-thiolen S-oxides demon- strating that stereochemical integrity is not necessarily proof of a concerted mechanism.' 45 5 Six-memberedRing Compounds Research into heteroaromatic rings containing a Group V atom has produced the first 2-phosphanaphthalene (1 82),14(j a route to 4-substituted phospha- and arsa-benzenes (Scheme 7),147and has shown that there is still scope for novel R OMe R Scheme 7 syntheses of pyridinoid systems.A new route to 3,5-dialkylpyridines using compounds based on simple petrochemicals is illustrated in Scheme 8,14* and variously substituted pyridines are available by treating alkynes with nitriles MeC(CH,OH) CH,=C-CH,OH I CH,OH Scheme 8 over a catalytic amount of the cobalt complex (183) or indeed by treating nitriles with (183) dire~t1y.l~~ 2-Phenoxy- and 2-alkoxy-quinolines (185) are obtained 145 P.Chao and D. M. Lemal J. Amer. Chem. SOC.,1973 95 920; D. M. Lemal and P. Chao ibid. p. 922. 146 H. G. de Graaf 3. Dubbeldam. H. Vermeer and F. Bickelhaupt,Tetrahedron Letters 1973 2397. 14' G. Mark1 and F. Kneidl Angew. Chem. Infernat. Edn. 1973 12 931. 148 D. Dieterich H. Reiff H. Ziemann and R. Braden Annalen 1973 11 1. 149 Y. Wakatsuki and H. Yamazaki Tetrahedron Letters 1973,3383; J.C.S. Chem. Comm. 1973,280. M. J. Cook and C. D. Johnson from 2-azidocinnamates (184) via phosphorimidates in an elegant high-yield pathway,' 50 and quinoline-8carboxylic acids arise on treatment of 3,l -benzox- azin-4-ones with enamines.' 51 In an intriguing one-step reaction (but involving a number of mechanistic steps !) 2-bromopyridine reacts with lithium piperidide OR OR to yield 8-cyanoquinoline.' 52 Decomposition of 1-alkyltriazines (186) to imino- carbenes provides a novel synthesis of isoquinolines.2" Significantly both (186b) and (186c) afford 3-methylisoquinoline demonstrating that the intermediate imino-carbenes are in an equilibrium presumably involving the 1H-azine cf.ref. 2b. Me (186) a; R' = R2 = Ph b; R' = Ph R2 = Me c; R' = Me R2= Ph Substituent reactivity studies show that alkylpyridines surprisingly undergo deuteriation of the alkyl group in organic and that in KNH,-liquid ammonia 4-methylpyridine is more acidic than the 2-methyl isomer.' 54 Related to the latter observation is the report that 2,4-lutidine 2,3,4-collidine and 2,4- dimethylquinoline metallate exclusively at the 4-methyl group with alkali amides in ammonia or lithium di-isopropylamide in ether-hexane but at the 2-methyl I5O S.A. Foster L1. J. Leyshon and D. G. Saunders J.C.S. Chem. Comm. 1973 29. ls1 W. Steglich and 0.Hollitzer Angew. Chem. Internat. Edn. 1973 12 495. lS2 H. N. M. van der Lans and H. J. den Hertog Terrahedron Lerters 1973 1887. 153 W. E. Parham and P. E. Olson Tetrahedron Letters 1973 4783. Is4 J. A. Zoltewicz and L. S. Helmick J. Org. Chem. 1973 38 658. Heterocyclic Chemistry 503 group with n-b~tyl-lithiurn.'~~ Unlike the methylation of 3-amino- and 2- methylamino-pyridine which occurs at the ring nitrogen methylation of 3- amino-2-methylaminopyridineis now shown to occur exclusively at the 3-amino- group.' 56 Methylation of 2,3-diaminopyridine takes place at both basic sites'56 whereas alkylation of 4-and 5-aminoquinolines occurs at either or both depending upon the alkylating agent.' 57 A novel method of selectively alkylating 2-amino- pyridines at the 3-position has been described (Scheme 9);'58 using p-carbonyl sulphides azaindoles are obtained (cf.refs.76 and 77). H H 1 Scheme 9 2-Pyridyl acetate has been converted in one step into the quinolizinone (187),' 59 and the bispyridyl compound (188) undergoes smooth acid-catalysed rearrange- ment to (189).160 Sodium hydride has now been found to reduce quinolines and 155 E. M. Kaiser G. J. Bartling W. R. Thomas S. B. Nichols and D. R. Nash J. Urg. Chem. 1973,38 71. 156 K. Oyama and R.Stewart J.C.S. Perkin I 1973 673. 57 C. Feller and J. Renault Bull. SOC.chim. France IZ 1973 11 12; J. Berlot and J. Renault ibid. p. 2866. P. G. Gassman and C. T. Huang J. Amer. Chem. SOC. 1973,95 4453. G. R. Newkome J. M. Robinson and N. S. Bhacca J. Org. Chem. 1973 38 2234. 160 G. R. Newkome R. A. Martin and N. S. Bhacca Tetrahedron Letters 1973. 2541. M. J. Cook and C. D Johnson isoquinolines and provides a route to dihydroheteroaromatics not readily accessible previously,'6 ' while the reducing properties of N-alkyl- 1,4-dihydro- nicotinamides have been exploited to reduce the double bond of unsaturated nitriles.'62 Among papers on six-membered rings containing two or more nitrogen atoms are notes on the formation of the novel pyrrolo[l,2-d]triazine (190)163 and the dehydropyridazine system (191).lh4 The latter was trapped as the adduct (192) during oxidation of (193) in the presence of furan.Pyrolysis of both (192) and the pyridazinotriazine (194) afforded the butadiyne (195) considered to be the fragmentation product of (191).'64 (1931 Ph(CFC),Ph (195) The pyrimidine derivative (196) is unexpectedly formed during the Leuckart reaction on (197),16' and a new pathway for the thermolytic isomerization of the pyridazine nucleus to the pyrimidine nucleus is reported during the conversion of (198) into (199).'66 A facile H-D exchange in the n-deficient heterocycle (200) occurs in both basic and neutral media ;it is suggested that under the latter con- ditions exchange proceeds via the covalent hydrate (2Ol).' 67 Electrophilic bromination of the tetra-azacycl[3,3,3]azines (202a) and (202b) occurs at C-9 in the former and at C-6 in the latter.16' 16' M.Natsume S. Kumadaki Y. Kanda and K. Kiuchi Tetrahedron Letters 1973,2335. 16* K. Wallenfels W. Ertel and K. Friedrich Annalen 1973 1663. 163 J. P. Cress and D. M. Forkey J.C.S. Chem. Comm. 1973 35. T. L. Gilchrist G. E. Gymer and C. W. Rees J.C.S. Chem. Comm. 1973 819. 165 D. T. Hill and B. Loev J. Org. Chem. 1973 38 2102. 166 R. D. Chambers M. Clark J. R. Maslakiewicz and W. K. R. Musgrave Tetrahedron Letters 1973 2405. 16' W. W. Paudler J. Lee and T.-K. Chen Tetrahedron 1973 29 2495. 0.Ceder and K. Rosen Acra Chem. Scand. 1973 27 359 2421. Heterocyclic Chemistry (202) a; X = CH Y = N b;X = N Y = CH Heterocyclic N-oxides re a continuing source of intriguing chemistry.R action of quinoxaline dioxide with acetyl chloride chlorinates the benzene ring and deoxygenates the N+-0-function (Scheme the benzotriazine oxide (203) reacts with PhMgBr to form the ring-contraction products (204) and (205),'70 and 2-azidopyridine N-oxides undergo thermolytic ring contraction to the pyrroles (206).' 71 Photochemical studies of N-oxides have again been numer- ous. Further details of photolysis of pyridazine N-oxides are reported ; thus (207; R' = H R2 = Me) decomposes into (208; R' = H R2 = Me) and (209) Y. Ahmad M. S. Habib M. I. Qureshi and M. A. Farooqi J. Org. Chem. 1973 38 2 176. "O H. Igeta T. Nakai and T.Tsuchiya. J.C.S. Chem. Comm. 1973 622. R. A. Abramovitch and B. W. Cue J. Org. Chem. 1973 38 173. M.J.Cook and C.D.Johnson oQAcf OAc Scheme 10 OH (211) R = H or Me Heterocyclic Chemistry and (207; R' = R2 = Ph) into (208; R' = R2 = Ph) and (210).172 Interestingly the carbonanalogue of (207) uiz.the ylide (21 l) undergoes photolysis by pathways formally similar to those for the N-0~ides.I~~ In the benzo-fused series the phthalazine (212) photodecomposes to the isobenzofuran (213) [cf (207)-+ (208)],'72 and the cinnoline N-oxides (214) and (215) hitherto considered to be photochemically inert give among other compounds the ring-contracted products indi~ated.'~~ The anthranil(216) is also formed on photolysis of (217; R = Me); the analogue (217; R = Ph) however is converted into (218) and (219).175 Me Me Me Me H H "* K.B. Tomer N. Harrit. 1. Rosenthal 0. Buchardt P. L. Kumler and D. Creed J. Amer. Chem. Soc. 1973 95 7402; T. Tsuchiya H. Arai and H. Igeta Tetrahedron 1973,29 2741. 73 H. Arai H. Igeta and T. Tsuchiya J.C.S. Chem. Comm. 1973 521. W. M. Horspool J. R. Kershaw and A. W. Murray J.C.S. Chem. Comm. 1973,345. W. M. Horspool J. R. Kershaw A. W. Murray and G. M. Stevenson J. Amer. Chem. SOC.,1973 95 2390. M. J. Cook and C.D. Johnson 1,3-Cycloadditions involving ylides derived from pyridinoid rings have again been reported'76 (cf. last year's Report'") and of interest this year is the first report of 1,3-cycloaddition to an azoxy-compound ;thus (220) with DMAD forms (222) presumably via the adduct (221).' 78 The compound previously assigned the structure (223) has now been shown to be (224).'79 The betaine itself rapidly rearranges into (224) but can be trapped with methyl acrylate to form the adducts (225).' 79 .NO,rJo-No (223) Anumber of papers on pyridinium pyrylium thiapyrylium and related cations have appeared; synthetic studies include a novel route to pyrylium cation'" and the isolation of the stable thianthrene dication (226) obtained by oxidation of the corresponding thianthrene.' '' Addition of -CCl to pyridinium cations yields both 2- and 4-addition products,' ** while the action of amines on thiapy- rylium causes ring cleavage.' 83 2,4,6-Triarylpyrylium salts (227) undergo attack by nitrite in alcohols to yield the dihydropyran (228) the nitro-group being the oxidation product of the nitroso-group initially formed.In boiling acetic acid (228) is converted into (229).la4 176 E.g. Y. Hayasi H. Nakamura and H. Nozaki Bull. Chem. SOC. Japan 1973,46 667; N. S. Basketter and A. 0.Plunkett J.C.S. Chem. Comm. 1973 188. 177 Ann. Reports (B),1972,69 453. S. R. Challand C. W. Rees and R. C. Storr J.C.S. Chem. Comm. 1973 837. 179 N. Dennis B. Ibrahim A. R. Katritzky and Y. Takeuchi J.C.S. Chem. Comm. 1973 292. J. Andrieux J.-P. Battioni M. Giraud and D. Molho Bull. SOC. chim. France 11 1973 2093. R. S. Glass W. J. Britt W. N. Miller and G. S. Wilson J. Amer. Chem. SOC. 1973 95 2375. V. Mann G. Schneider and F.Krohnke Tetrahedron Letters 1973 683. lB3 Z. Yoshida H. Sugimoto T. Sugimoto and S. Yoneda. J. Org. Chem. 1973,38 3990. lS4 C. L. Pedersen 0. Buchardt S. Larsen and K. J. Watson Tetrahedron Lefters 1973 2195. Heterocyclic Chemistry + The photochemistry of pyrylium salts has been the subject of a series of studies. Photodecomposition of trialkylpyrylium cations e.g. (230) appears to proceed by way of an oxoniabenzvalene (231)18' and such intermediates have been in- voked in the photoisomerization (232)-+ (233).'86 (233) itself undergoes photorearrangement to (234) possibly via the intermediate indicated.' 86 Closely related to these studies are the photoisomerizations of 4-pyrones into 2- pyrones' 86b*' "where rearrangement is reported to be facilitated by increasing solvent polarity and the conversion of hindered 4-pyridones into 2-pyridones.' 88 (For discussion of the photochemistry of 2-pyrones see ref.39 and Section 2.) Further evidence has been presented which demonstrates that the 2-pyri- done *2-hydroxypyridine equilibrium favours the latter tautomer in the gas J. A. Barltrop K. Dawes A. C. Day S. J. Nuttall and A. J. H. Summers J.C.S. Chem. Comm. 1973 410. J. W. Pavlik and E. L. Clennan J. Amer. Chem. SOC.,1973,95 1697; J. W. Pavlik and J. Kwong ibid. p. 7914. N. Ishibe M. Sunami and M. Odani J. Amer. Chem. SOC.,1973 95 463. la' N. Ishibe and J. Masui J. Amer. Chem. SOC.,1973,95 3396. 5 10 M. J. Cook and C. D. Johnson phase,'89 and new routes to both 2- and 4-pyridones have been described.Thus the isocyanate (235) from sorbic acid undergoes electrocyclic ring closure to (236) which rearranges to the pyridone,' 90 and 2-and 4-halogeno-pyridinium and -quinolinium salts readily react with DMSO to form the corresponding pyridones and q~inolones.'~~ 4-Pyridones are also available through the sequence (237)-(238),'92 or by treating (239; X = 0)with the amido-acid phfih ~ RNH acid or base NaO ONa RNH RNH I (237) R (238) MeN(CPhOJCHPhC0,H ' (240) Ph A Ph ph)AJph Ph Ph (239) I Me The sulphur analogue (239; X = S) provides access to the corresponding py- ridthione.lg3 The reactivity of 2-pyridthione has been exploited in syntheses of thiazolopyridinium salts as exemplified by the sequence (241) -+(242).194 MeCH=CBrCO,H+ -+ os I H Ho2c2 Me Br-+Np;e (241) Br CO,H (242) lE9P.Beak and F. S. Fry J. Amer. Chem. SOC. 1973,95 1700. 190 J. H. MacMillan and S. S. Washburne J. Org. Chem. 1973 38 2982. 19' R. E. Lyle and M. J. Kane J. Org. Chem. 1973 38 3740. 192 I. El-S. El-Kholy M. M. Mishrikey and R. F. Atmeh 1. Heterocyclic Chem. 1973 10 665. 193 K. T. Potts and J. Baum J.C.S. Chem. Comm. 1973 833. 194 K. Undheim and R. Lie Acta Chem. Scand. 1973 27 1749; R. Lie and K. Undheim ibid. p. 1756; J.C.S. Perkin I 1973 2049. Heterocyclic Chemistry 511 The reaction of diketen with (243) and (244) provides simple routes to the pyrone derivatives (245) and (246) respectively. 19' A convenient synthesis of alkylated 4-hydroxy-2-pyrones has also been reported196 while in the sulphur series the dithioacetate (247) reacts with (248) to form (249) in neutral medium ; however in the presence of pyridine the 2-thiopyranthione (250) is ~btained.'~' s-s-s Ph+SMe S PhC=CH-C-SMeII I OH + A \ COPh (249) (247) (248) pJPh Ph (250) Pathways to cyclic thiazine S-oxides and benzothiadiazine S-oxides have been described,' 98 and in one paper optically pure derivatives were prepared e.g.(251).19" N.m.r. data indicate negligible aromatic character in these systems. Addition of sulphenes to thiomide vinylogues provides access to 1,2-dithiin-l,1- dioxide (252),19' and reaction of (253) with BF afforded a route to (254) which apparently exists as the potentially aromatic tautomer (254b).200 Further 195 R.Gompper and J. Stetter Tetrahedron Letters 1973 233. 196 E. Suzuki. H. Sekizaki and S. Inoue J.C.S. Chem. Comm. 1973 568. 19' F. Clesse J. P. Pradere and H. Quiniou Bull. Soc. chim. France II 1973 586. 198 (a)T. R. Williams and D. J. Cram J. Org. Chem. 1973 38 20; (6) Y. Tamura T. Miyamoto H. Taniguchi K. Sumoto and M. Ikeda Tetrahedron Letters 1973 1729; A. C. Barnes P. D. Kennewell and J. B. Taylor J.C.S. Chem. Comm. 1973 776. '99 M. Bard J. C. Meslin and H. Quiniou J.C.S. Chem. Comm. 1973 672. H. Zinnes and J. Shavel J. Heterocyclic Chem. 1973 10 95. M. J. Cook and C. D. Johnson evidence has been presented for aromatic stabilization of anions of type (255) systems electronically analogous to (252) and the heterocyclic ring of (254b).Thus the conjugate acid of (255)is a stronger acid than open-chain analogues,201 and structures of type (256)show partial dipolar character.202 \ \/ -N H Ar (252) Me Me I 1 (256) Chlorosulphonyl isocyanate adds to ketones to give both (257) and (258),203 and the salt of methoxycarbonylsulphamoyl chloride (259) reacts with nitriles to form (260).204 The latter undergoes thermal decomposition to the nitrile "' G. Gaviraghi and G. Pagani J.C.S. Perkin II 1973 50. 202 G.Pagani J.C.S. Perkin II 1973 1184; G. D. Andreetti G.Bocelli and P. Sgarabotto ibid. p. 1189. '03 J. K. Rasmussen and A. Hassner J. Org. Chem. 1973 38 21 14. '04 E. M. Burgess and W. M. Williams J. Org. Chem. 1973 38 1249; J.K. Rasmussen and A. Hassner Tetrahedron Letters 1973 2783. 513 Heterocyclic Chemistry and MeO,CN=SO, which adds to alkenes to provide access to the oxathia-zine (261). Conformational analysis of six-membered rings has advanced on ‘various fronts. Theoretical approaches have been described for calculating the ‘strain 02 02 o/s NH N/s\ N R1+0 Me LoL OMe R2 (257) R4 R3so:N RYoyoMe ‘ energy minimized’ geometry of heterocycle^'^^ and the preferred pathway for conformational inversion :’06 the former has been applied to heterocycles with one to three heteroatoms and the latter to the IC CI inversion of a-D-glucose. Results of a photoelectron spectroscopic study of 172-dimethylhexahydro-pyridazine have been interpreted in terms of a predominance of conformer (262),207and in the 0.r.d.x.d.field measurable Cotton effectsarising from hetero-atoms in b-hetero-cyclohexanones have been observed.208Further c.d. studies on y-lactones and lactams have also been rep~rted.”~ The effect of heteroatoms on ring-inversion barriers continues to attract study. Barriers for inversion of selenan selenan monoxide and dioxide and telluran have been determined using variable-temperature n.m.r. and correlate well with 205 I. D. Blackburne R. P. Duke R. A. Y. Jones A. R. Katritzky and K. A. F. Record J.C.S. Perkin II 1973 332. 206 A. A. Lugovskoy V. G. Dashevsky and A. I. Kitaigorodsky Tetrahedron 1973 29 287. 207 S. F. Nelson and J. M. Buschek J. Amer. Chem.SOC.,1973 95 201 1 ; S. F. Nelson J. M. Buschek and P. J. Hintz ibid. p. 2013. 208 M. M. Cook and C. Djerassi J. Amer. Chem. SOC.,1973 95 3678. 209 0.cervinka L. Hub F. Snatzke and G. Snatzke CON.Czech. Chem. Comm. 1973 38. 897. M. J. Cook and C.D. Johnson torsional properties of the carbon-heteroatom bond.21 1.3.2-Dioxathian has a lower barrier than 1,2,3-trithian but a higher barrier than 1,3-dioxan. These comparisons and others support the general contention tnat substitution of 0 for S lowers ring-inversion barriers and that lone pairs on adjacent atoms hinder the inversion process.21 Similarly the barrier to inversion of (263) is substantially higher than that of cyclohexene.212 Microcalorimetric measurements of the equilibrium (264a) S(264b) have provided the basis of an estimate of the enthalpy difference (37.3 kJmol-') between the chair and 1,4-twist conformations of 1,3-dio~an,~'~ and n.m.r.has \A-Me Me (264a and b) revealed an unusual slow (on the n.m.r. time-scale) chair-boat equilibrium viz. (265a) (265b).214 In the latter study signal integration of the spectrum at 0 "C showed that (265a) is marginally favoured in CCl whereas (265b) predominates (265) a; n = 9 (265) b; n = 9 (266) a;n = 8 (266) b;n = 8 in (CD3),C0 and CDC1,. The homologue (266) was isolated as conformer (266b) from the reaction of furan with 2,1l-dibromocycloundecanone,and did not ring-invert into (266a) below 140 0C.214 Studies on cis fused bicyclics have shown that the 'heteroatom inside' conformer (i) is favoured for (267; R = H) whereas the 'heteroatom outside' form (0)is *lo J.B. Lambert C. E. Mixan and D. H. Johnson J. Amer. Chem. Soc. 1973,95 4634. 211 G. Wood R. M. Srivastava and B. Adlam Cunud. J. Chem. 1973,51 1200. *I2 M. L. Kaplan and G. N. Taylor Tetrahedron Letters 1973 295. R. M. Clay G. M. Kellie and F. G. Riddell J. Amer. Chem. SOC.,1973 95 4632. *I4 J. G. Vinter and H. M. R. Hoffmann J. Amer. Chem. Soc. 1973,95 3051. Heterocyclic Chemistry preferentially adopted for (267; R = CD,CH,).Z’S In the series (268 269; n = 4) conformer (i) predominates but for (268 269; n = 5) the equilibrium is X ‘3 0 (4 (268) X = 0,Y= NH (269) X = NH Y = 0 reversed.’I6 Similar results were reported independently for bicyclic 1,3-dioxan~.~’ ’ The conformational equilibrium in (270) shows a temperature dependence favouring the equatorial methyl conformer at low temperature and the axial methyl one at room temperature.’18 In the series (271) the sub-stituent on the nitrogen preferentially adopts the equatorial site (at -82 0C),219 and a dipole moment study showed that the equatorial S=O conformer of (272) predominates at 25 0C,220a reversal of the normal preference of the S=X bond (see last year’s Report221).(271) R = H or Me Details of a methylation of rigid thian oxides and a thorough investigation of the chlorination of both mobile and fixed thian oxides have been reported. Thus monomethylation (BuLi-MeI) of both (273)and (274)introduced the methyl ‘I5 H.Boothand D. V. Griffiths J.C.S. Chem. Comm. 1973 666. 216 G. Bernhth Gy. Gondos K. Kovhcs and P. Sohhr Tetrahedron 1973 29,981. ’I7 A. K. Bhatti and M. Anteunis Tetrahedron Letters 1973 71. S. I. Featherman and L. D. Quin J. Amer. Chem. Soc. 1973 95 1699. 2L9 R. A. Y.Jones A. R. Katritzky A. R. Martin and S. Saba J.C.S. Chem. Comm. 1973 908. 220 M. J. Cook and A. P. Tonge Tetrahedron Letters 1973 849. 221 Ann. Reports (B) 1972 69 440. M. J. Cook and C. D.Johnson group trans to the S=O bond,222 whereas chlorination (CI in pyridine) con- verted (273) and (274) into the same product (275).223 H/D Exchange of the a-methylene protons in (276) and (277) has been compared;224 the reactivity ratio 0 & (273) Me Me OMe I I 0 (276) for the two pairs of diastereotopic hydrogens in (276) is ca.1 1 but in the five- membered ring it is ca. 12 l.224 Stereochemical studies on certain 1,3,2-dioxaphosphorinans have shown an unusual retention of configuration in the displacement of chlorine by methylmagnesium iodide22 and confirmed that oxidation of the two isomers of (278) occurs with retention of configuration.226 In the synthetic field the intermediacy of 4,5-dihydropyridazine (280) has been postulated in the conversion of (279) into (281),227 and the first synthesis of a 5,6-dihydropyridazine (282) is described.228 The latter undergoes a thermal [1,5] sigmatropic shift to give (283) whereas on photolysis the ring opens to give diazatrienes.228 The rate of the [2,3] sigmatropic rearrangements (284) -+(285) is slow compared with acyclic ylides and suggests bonding in the transition state consistent with a concerted mechanism.By contrast smooth rearrangement of (286) into (287) is interpreted in terms of a non-concerted Further studies on tetra-azabicyclononanes (288) show that dinitrogen tetroxide smoothly cleaves the molecule to give (289).230 Syntheses of 9-azabarbaralane (290)23 and the intriguing bridgehead alkenes (291) and (292) have been described.232 Spectral and chemical properties of 222 R. Lett S. Bory B. Moreau and A. Marquet Bull. SOC.chim. France II 1973 2851. 223 J. Klein and H. Stollar J. Amer. Chem. SOC.,1973 95 7437. 224 0. Hofer and E. L. Eliel J. Amer. Chem. Soc.,1973 95 8045 see also A. Garbesi G. Barbarella and A.Fava J.C.S. Chem. Comm. 1973 155; G. Barbarella A. Garbesi A. Boicello and A. Fava J. Amer. Chem. SOC.,1973 95 8051. 225 T. D. Inch and G. J. Lewis Tetrahedron Letters 1973 2187. 226 J. A. Mosbo and J. G. Verkade J. Amer. Chem. SOC.,1973,95,4659. 227 B. K. Randlish J. N. Brown J. W. Timberlake and L. M. Trefonas J. Org. Chem. 1973 38 1102. 228 P. de Mayo and M. C. Usselman Canad. J. Chem. 1973,51 1724 1729. 229 S. Mageswaran W. D. Ollis and I. 0. Sutherland J.C.S. Chem. Comm. 1973 656; W. D. Ollis I. 0.Sutherland and Y. Thebtaranonth ibid. p. 657. 230 H. Yoshida G. Sen and B. S. Thyagarajan J. Heterocyclic Chem. 1973 10 279 725. 231 A. G. Anastassiou A. E. Winston arid E. Reichmanis J.C.S. Chem. Comm. 1973 779. 232 C. B. Quinn and J.R. Wiseman (a) J. Amer. Chem. SOC.,1973 95 1342; (6) ibid. p. 6120. Heterocyclic Chenz istry 517 -(3coph X 'Rl I-R'CCOPh (285) (284) X = NMe or S R' RZ = H Et Bu' or Ph A n Ph NO NO (289) K = COMe (291)232"show the expected absence of conjugation while in (292) the structure inhibits overlap between the double bond and the sulphur 3p-orbitals but allows interaction with 3d-0rbitals.~~'~ Sulphur participation has been invoked to explain the solvolytic elimination reactions (293) -+(294),233 and an intra- 233 P. H. McCabeand C. M. Livingston Tetrahedron Letters 1973. 3029. M.J. Cook and C. D.Johnson molecular aldol condensation to account for the equally unexpected acetylation product (296) of (295).234 CN (291) X = 0 (292) X = S C1BC1 (293) (294) s 5 OWS More conventional routes than the above to heteroadamantanes as well as to heterotwistanes continue to command attention.Reports include details of the syntheses of 2,6-dia~a-adarnantanes,~~~ oxabenzo-2-0xa-6-aza-adarnantane,~~~ horn~adamantenes~~~ and [eg (297)] 2-oxa-7-azatwistane and isot~istane,~~~ the first heterotwistene and twistadiene (298).239 Methanolysis of (299) is shown to give solely (300),240and through-bond interaction is proposed to account for modified carbonyl character in l-aza-adamantan-4-0ne~~' and some diaza- derivatives.242 234 P. H. McCabe and W. Routledge Tetrahedron Letters 1973 3919. 235 R.-M. Dupeyre and A. Rassat Tetrahedron Letters 1973 2699; R.E. Portmann and C. Ganter Helu. Chim. Acta 1973 56. 1986. 236 R.E. Portmann and C. Ganter Helv. Chim. Acta 1973 56 1962. 237 B. Fohlisch U. Dukek. I. Graessle B. Novotny E. Schupp G. Schwaiger and E. Widmann Annalen. 1973 1839. 238 R. E. Portmann and C. Ganter Heh. Chim. Acta 1973 56 1991. 239 P. Ackermann and C. Ganter Helv. Chim. Acta. 1973 56 3054. 240 H. Teufel E. F. Jenny and K. Heusler Tetrahedron Letters 1973 3413; H.-C. Mez and G. Rihs ibid. p. 3417. 24 1 A. W. J. D. Dekkers J. W. Verhoeven and W. N. Speckamp Tetrahedron 1973 29 1691. 242 T. Sasaki S. Eguchi T. Kiriyama and Y. Sakito J. Org. Chem. 1973 38 1648. Heterocyclic Chemistry C1 (299) 6 Medium-sized Ring Compounds A number of novel potentially aromatic or antiaromatic compounds have been investigated this year.The oxonin derivative (302) prepared from (301) shows instability and reactivity indicative of antiaromatic destabilization ;243 such destabilization in benzo[b]thiepin may well account for the stability of its valence tautomer (303) now synthesized.244 The synthesis of the cyc1[4,3,2]azine (304) (302) is described and n.m.r. reveals that the system sustains a paramagnetic ring current.245 Among potentially aromatic medium-sized rings are the aza-azulenone (305),which protonates to form a diatropic cation,246 the hydrazine- bridge [14lannulene(306),which evidently supports a diamagnetic ring current,247 and the first examples ofthe monobenzo-fused analogues ofthe previously reported heteronin~.~~~ None of the derivatives in the last series sustains a ring current.Fluxional behaviour of the tricarbonyliron complex of 1-( lH)-2-diazepine (307) has been detected by variable-temperature n.m.r.,249 and reactions of the 243 M. P. Cava and K. T. Buck J. Amer. Chem. SOC.,1973 95 5805. 244 1. Murata T. Tatsuoka and Y. Sugihara Tetrahedron Letters 1973 4261. 245 W. Flitsch and B. Muter Angew. Chem. Internal. Edn. 1973 12 501. 246 W. Flitsch B. Muter and U. Wolf Chem. Ber. 1973 106 1993. 247 W. Flitsch and H. Peeters Chem. Ber. 1973 106 1731. A. G. Anastassiou E. Reichmanis and R. L. Elliott Tetrahedron Letters 1973 3805. 249 A. J. Carty R. F. Hobson H. A. Patel and V. Snieckus J. Amer. Chem. Soc. 1973 95 6835. 520 M. J. Cook and C.D. Johnson (MeOC),N @ AN/-(COMe)* NC -(306) R ““’3Fen N’ I H (307) R = H or Me free N-substituted diazepines include [2 + 21 cycloaddition with ketens and acid-catalysed dirneri~ation.~” The 1,3-oxazepin (309a) obtained by photolysing (3081 undergoes acid-catalysed hydrolysis to the pyrrole (3 10) and the hydroxy- pyridine (31 1).251in an independent acid hydrolysis of (309b) afforded the pyrrole corresponding to (3 10) but thermal or base-catalysed hydrolysis gave predominantly (312). Basic hydrolysis of the benzodiazepine (313) in- triguingly affords a benzimidazole (314) a further benzodiazepine (315) or a benzotriazepine (316) depending upon the condition^.^'^ d N R +Rc’kPh -+ c>+ ooHPh 0 (308) \o R (309) a; R = H b;R = Ph I COPh (310) (311) Ph COPh Ph aPh I H (312) 250 J.P. Luttringer and J. Streith Tetrahedron Lptters 1973 4163; B. Willig and J. Streith ibid. p. 4167. 251 T. Mukai and H. Sukawa Tetrahedroti Letters 1973 1835. C. L. Pedersen and 0.Buchardt Acta Chem. Scand. 1973 27 271. Y. Okamoto and T. Ueda J.C.S. Chem. Comm.. 1973 367. Heterocyclic Chemistry 521 In the realm of saturated and simple unsaturated medium rings a number of preparations elegant in their simplicity have been described. The reactive oxacycloheptyne (317a)254 and silaheptyne (317b)255 have been obtained from (317) a; X = 0,R = Me b; X = SiMe, R = H the corresponding acyloins as outlined and the bisalkyne (318) is precursor to the dihydrophosphepin and dihydroarsepin (319a) and (319b).2s6 The reaction of hydroxylamine with phorone originally believed to give the piperidone (320) is now shown to provide a convenient access to the oxazepinone ring system (321).257 Thermal rearrangement of both syn-and anti-2-azatricyc10[4,1,0,0,~~~]-heptanes (322) and (323) affords the dihydroazepine (324).Higher temperatures &/-7N PhXHz) cxF% & 0GMe (318) (319) a; X = P I b;X =AS OH (321) (320) 254 A. Krebs and G. Burgdorfer Tetrahedron Letters 1973 2063 255 S. F. Karaev and A. Krebs Tetrahedron Letters 1973 2853. 256 G. Mark1 and G. Dannhardt Tetrahedron Letters 1973 1455. 257 K. C. Rice and U. Weiss Tetrahedron Letters 1973 1615. 522 M. J. Cook and C. D. Johnson C0,Me I (324) are required for the conversion of (323) into (324) than for that of (322) into (324) the difference in reactivity being rationalized in terms of the ease of formation of the ylide transition state (325).2s8 Details of a general synthesis of 3H-azepines have been describedzs9 and a new synthetic entry into benzodiazepines has been realized through base-catalysed cyclization of di-imines e.g.(326)-+(327).z60 Bu' (327) An interesting route to an eight-membered ring involves an 'anti-Markovnikoff addition of H2Sto the bisalkene (328) to give (329) an addition induced photo- lyti~ally.~~~ Further routes to eight- as well as nine- and ten-membered rings (329) are exemplified by the additions of alkynes to enamines (Scheme 11),z62 the addition of alkenes and dienes to the 1,2-dithian derivative (330) (Scheme 12),263 and the thermolysis of (331) the adduct from reaction of arylnitrile oxides with hexamethyl-Dewarbenzene to give the nine-membered ring (332).264 Oxidation of (333) with rn-chloroperbenzoic acid gives (334) and is but one of several N-oxide rearrangements reported during the year.Here the reaction is suggested to proceed as indicated.265 A study of the Polonovsky rearrangement S. R. Tanny and F. W. Fowler J. Amer. Chem. SOC.,1973,95 7320. 239 F. R. Atherton and R. W. Lambert J.C.S. Perkin I 1973 1079. 260 J. A. Deyrup and J. C. Gill Tetrahedron Letters 1973 4845. 261 K. E. Koenig and W. P. Weber Tetrahedron Letters 1973 3151. 262 D. N. Reinhoudt and C. G. Kouwenhoven Tetrahedron Letters 1973 3751.263 N. E. Hester and G. K. Helmkamp J. Org. Chem. 1973 38 461. 264 G. Briintrup and M. Christl Tetrahedron Letters 1973 3369. 265 D. L. Trepanier S. Wang and C. E. Moppett J.C.S. Chem. Comm. 1973 642. Heterocyclic Chemistry 523 R3 X=SorN ~ OR3 NR'R2 R3 Scheme 11 TNBs-TNBs-TNBs-(330) Scheme 12 Me Me Me (331) Me Me (332) of prochiral substrates (335a) with chiral reagent has led to the conclusion that the rearrangement is a non-concerted one,266 while in the same area the sub-strate (335b) under Polonovsky conditions unexpectedly forms (336).267 266 V. SunjiC F. KajfeB D. Kolbah H. Hofman and M. Stromar Tetrahedron Letters 1973 3209. 26' A. Walser G. Silverman and R.I. Fryer J.Org. Chem. 1973 38 3502. 5 24 M. J. Cook and C. D. Johnson (335) a; R' R2 = H or Me b; R' = Me R2 = CH,CH=CH (336) 7 Large-ringCompounds The synthesis and properties of heteroannulenes remains an active area of research. Irradiation of (338) one of several products of addition of N-(ethoxycarbony1)- nitrene to (337) afforded an aza[l3]annulene to which the configuration (339) N (337) (338) I C0,Et (339) has been assigned.268 The compound is sensitive to air and chemical shifts of the ring protons are typical of a polyolefin ;variable-temperature n.m.r. spectra suggest that it exists in more than one conformation.268 Details of the prepara- tions of various potential 16~-systems have been reported this year and include those of the oxa[l5]annulene (340),269 the [16]annulene dioxide (341),270 and the (340) (342) a; R R = 0,X = NH 0,or S b;R =H,X =NH,O,orS series of [17]annulenones (342).27' Compounds (340) and (341) sustain a para- magnetic ring current and the separation of the inner and outer proton resonances in the latter is greater than in [16]annulene itself.Comparison of the proton 268 G. Schroder G. Frank and J. F. M. Oth Angew. Chem. Internat. Edn. 1973 12 328. 269 H. Ogawa and M. Kubo Tetrahedron 1973 29 809. 270 H. Ogawa M. Kubo and I. Tabushi Tetrahedron Letters 1973 361. 271 T. M. Cresp and M. V. Sargent J.C.S. Perkin I 1973 2961. Heterocyclic Chemistry shifts in the series (342) with those of the homoannulenes (343) show that (342; X = 0)and (342; X = NH) but not (342; X = S) are paratropic; the bulky S atom in (342; X = S) presumably forces the compound into a nonplanar con- formation.271 Syntheses are also described for the didehydroaza-[19]- and -[21]- annulenes (343) and (344).272 Proton shifts relative to those in open-chain C0,Et C0,Et I (343) (344) analogues reveal that the former is paratropic and the latter diatropi~,~'~ although the manifestation of diatropy of (344) is less marked than in the corresponding smaller [17lannulene reported last year.273 N.m.r.is not helpful in establishing the presence of a ring current in the [26]annulene (345) formed in a remarkable NH HN (345) quantitative yield by condensing 2,2'-diaminobiphenyl with diphenyl-2,2'-dicarboxyaldehyde.74 Chemiluminescence of the paracyclophane (346) on oxidation with 0,-KOBu' in DMSO has been investigated ;275 the emission of light is some 25 times 272 P. J. Beeby and F. Sondheimer Angew. Chem. Internat. Edn. 1973 12,410 41 1. 273 Ann. Reports (B),1972 69 457. 274 I. Agranat Tetrahedron 1973,29 1399. *" K.-D. Gundermann and K.-D. Roker Angew. Chem. Internat. Edn. 1973,12,425. M. J. Cook and C. D. Johnson t-s-l 0 SMe Me 0 that emitted from a mixture of (347) and (348). Syntheses of cyclophanes include those of (349)276and new multibridged systems,277 while further template syn- theses of macrocycles (cyclization promoted by metal ions) have also been (349) announced. The latter are exemplified by the formation of the furan-acetone condensation product (350),”* and 22- 33- 44- and 55-membered macrocycles (353) from the bisalcohol (351) and the dibromide (352).279 In the absence of (351) (352) (353) n = 1-4 metal ions the yield of macrocycle drops at the expense of linear products.An improved synthesis of cryptates has also been described which involves a flow 276 T. Umemoto T. Otsubo Y. Sakata and S. Misumi Tetrahedron Letters 1973 593. 277 F. Vogtle G. Hohner and E. Weber J.C.S. Chern. Cornm. 1973 366. 278 M. Chastrette and F. Chastrette J.C.S. Chem. Comm. 1973 534. 279 G. R. Newkome and J. M. Robinson J.C.S. Chem. Comm. 1973 831. Heterocyclic Chemistry technique.280 Related to cryptates are the novel tri- and tetra-cycles (354a) and (354b) and these form metal cation and molecular complexes.281 Examples of the appropriate-sized binaphtho-crown ethers (355) reported this year,28 LO\lOd (354)a; Y =CH, 0,or NH b; Y-Y =NCO(CH,),,CON or N(CH,),,N solubilize arenediazonium tetrafluoroborate and benzoyl hexafluorophosphate salts2824 in non-polar medium and also complex metal salts and a-amino- acids.282bA feature of certain members of the series is the incorporation of counter-ions (e.g.R =CH20CH2C0,-)within the system and in an important innovation,282c optically pure valine was shown to resolve racemic host crown ether in liquid-liquid chromatography.Conversely optically pure crown provides a tool for the resolution of amino-acids. J. L. Dye M. T. Lok F. J. Tehan J. M. Ceraso and K. J. Voorhees J.Org. Chem. 1973,38 1773. J.-M. Lehn J. Simon and J. Wagner Angew. Chem. Internat. Edn. 1973,12 578 579. '"(a)G. W. Gokel and D. J. Cram J.C.S. Chem. Comm. 1973 481 ;(6)R. C. Helgeson J. M. Timko and D. J. Cram J. Amer. Chem. SOC., 1973,95 3023; (c) R. C. Helgeson, K. Koga J. M. Timko and D. J. Cram ibid. p. 3021; (6)E. P. Kyba M. G. Siegel L. R. Sousa G. D. Y. Sogah and D. J. Cram ibid. p. 2691.

 



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