11 Heterocyclic Compounds By T. M. CRESP Department of Chemistry University College London 20 Gordon Street London WClH OAJ 1 Three-Membered Rings Photolysis of the azimine (1) gives the triaziridine (2) which is the first authentic triaziridine to be isolated.' On standing (2) slowly (tllz= 3.5 days) reverts to azimines. Oxygen-oxygen bond homolysis followed by @-scission is the normal photochemical fate of ozonides. The reaction has been used to prepare some very y (1) unstable aziridinediones (Scheme 1).2 They were characterized by examination of their infrared spectra recorded at 77 K and of their decomposition to carbon monoxide and isocyanates on warming. On reaction with alkynyl-lithium reagents aziridones undergo ring-opening followed by ring-closure (Scheme 2) to provide a novel synthesis of pyrrolinones (4).The a-bromo-amide precursors of the aziridones R = H Me Pri or CH2CH2Ph Reagents i hv at 77K Scheme 1 0 Br Reagents i LiCzCR3; ii H,O Scheme 2 ' C. Leuenberger L. Hoesch and A. S. Dreiding J. Chem. Soc. Chem. Commun. 1980 1197. 'H. Aoyama M. Sakamoto and Y. Omote J. Am. Chem. SOC.,1980,102,6902. 179 180 T. M. Cresp afford the same products presumably but not necessarily through the intermediacy of (3).3This represents a useful synthesis of those pyrrolinones that do not tautomer- ize to pyrroles. A number of preliminary reports have been brought together in a full paper4 describing the chemistry of thiiranimines. They are readily prepared from sulphonyl isocyanates and diphenyldiazomethane the reaction involving 1,3-dipolar cyclo- addition to yield 1,2,3-thiadiazoliniminesfollowed by decomposition to the thiiran- imines (5).Ring-opening reactions are dominated by cleavage of the unusually long C(2)-S bond (1.94A).The two other ring-forming bonds are shorter than the sum of the covalent radii a situation also encountered in aziridinimines.’ In solution thiiranimines (5) rearrange to benzothiophens (7) with methanol ring- opening gives thioxosulphonamides (6). Reviews covering this chemistry and the chemistry of other heterocyclic analogues of methylenecyclopropanes6*7make fascinating reading. S \ S0,Ar (5) (7) Oxidation of the (E)-oxime carbamate (8) in a Neber-type reaction gives the 1-azirine (9).’ The corresponding (2)-isomer (lo) under the same conditions fails to yield (9);instead the monosulphoxide (11)is isolated (Scheme 3).The observed stereospecificity would seem to militate against nitrene formation at least for this qSMe MeHNfjsMe But Bu‘ S0,Me SMe (9) (8) NHMe But Bu‘ SMe S0,Me (10) (11) Reagents i KMnO Scheme 3 E. R. Talaty A. R. Clague M. 0. Agho M. N. Deshpande P. M. Courtney D. H. Burger and E. F. Roberts J. Chem. SOC.,Chem. Commun. 1980,889. G. L’abbC J.-P. Dekerk C. Martens and S. Toppet J. Org. Chem. 1980,45,4366. * H. Quast P. Schefer K.Peters and H. G. von Schering Chem. Ber. 1980,113 1921. G. L’abbC Angew. Chem. Int. Ed. Engl. 1980,19,276. ’H. Quast Heterocycles 1980 14 1677.H. G. Corkins L. Storace and E. Osgood J. Org. Chem. 1980,45,3156. Heterocyclic Compounds Neber reaction. Products from the reaction of amino-azirines (12) and ketens proceed via the intermediacy of the much-studied zwitterion (13) (see Annu. Rep. Prog. Chem. Sect. B 1979 76 224) which usually undergoes ring-cleavage to (14).9Irradiation of 3-(2-thienyl)-2,2-dimethyl-2H-azirine (15)generates the nitrile isopropylide (16) which adds to activated carbon-carbon and carbon-oxygen double-bonds to give 1-pyrrolines and 3-oxazolines respectively. lo A brief review on azirines concentrates on their conversion into other heterocyclic systems. l1 NMe K' A- n I (13) (14) R4 (15) (16) N-Heteroaryl vinylaziridines undergo thermal isomerization to azepines; for example the aziridine (17) isomerizes to (20) in refluxing xylene.l* The correspond- ing N-isothiazolo- and N-thieno-aziridines (18) and (19)also rearrange to azepines at room temperature.Electrochemical oxidation of tertiary amines usually gives iminium salts; however N-benzylaziridine affords the known tetramer (2 1)from a chain process that is initiated by formation of a radical cation.13 As would be expected oxa,aza-bis- (22) and dioxa,aza-tris-u-homobenzenes(24) undergo [2 + 2 + 21-cycloreversions to (23) and (25) respectively. l4 Cyclic polyepoxides are the subject of a concise review" that is a pleasure to read. Ar (17) Ar= GN ; (18)Ar= (19) Ar= PhJ 6 S (21) E. Schaumann S. Grabley M. Henriet L. Ghosez R.Touillaux J.-P. Declercq G. Germain and M. Van Meerssche J. Org. Chem. 1980,45,2951. lo K.-H. Pfoertner and R. Zell Helv. Chim. Acta 1980,63,645. A. Hassner Heterocycles 1980 14 1517. H. P. Figeys and R. Jammar Tetrahedron Lett. 1980,21 2995. l3 R. Kossai J. Simonet and G. Dauphin Tetrahedron Lett. 1980,21,3575. H. Prinzbach K.-H. Muller C. Kaiser and D. Hunkler Tetrahedron Lett. 1980,21 3475. Is W.Adam and M. Balci Tetrahedron 1980,36,833. 182 T.M. Cresp 2 Four-Membered Rings General.-Pyrolysis of the tosylhydrazone (26) gives oxeten.I6 It can be hydro- genated to oxetan and it smoothly rearranges in solution to form acrolein. Base- induced cyclization of the 3-methoxy-selenoxides derived from the vinyl selenide (27) gives oxetans." Carboxamides (28) which have been postulated as intermedi- ates in the photochemical ring-contraction of succinimides to azetidine-2,4-diones (see Annu.Rep. Prog. Chem. Sect. B 1979 76 225) also yield azetidinediones (29) on irradiation.'* A full account of the preparation and reactions1' of the related 4-thioxo-2-azetidinones has appeared. Oxidation of the (2)-oxime (30) with m-chloroperbenzoic acid gives the oxazete (3 1)in high yield. The correspond- ing (E)-oxime (32) fails to cyclize under the same conditions and the sulphoxide (33) is isolated.20 The fate of the carbamates derived from these oximes has also been examined (see previous Section). 0 'qYHo Li\/N=QI phseq~ R2 N\ R1%Me R2 N OH Me 0 0 Ts/ (26) (27) (28) (29) N ,OH HO\ BulssMe Bu'IqSMe Bu' %R N-0 SMe SMe SMe (30) (31) (32) R=SMe (33) R=S02Me In a careful study,21 the two oxa-azabicyclo[2.2.0]hexanones (34) and (35) have been identified as intermediates in the photochemical equilibrium between oxazinones (36) and (37).It has been suggested that the zwitterion (38) is the common intermediate. The dimer derived from the sulphine oxide (40) (the lachrymator in onions) is not (39) but the much more interesting 1,2-dithietan 1,l-dioxide (41).22 This first example of an isolable 1,2-dithietan derivative arises from a dimerization in which (40) acts both as a 1,3-dipole and as a dipolarophile. R2mO -0"N 9 R2?JJC N yo Me R' (34) R' = Ph R2 =Me (36) R' = Ph R2= Me (38) (35) R' =Me R2 = Ph (37) R' = Me R2= Ph l6 P.C. Martino and P. B. Shevlin J. Am. Chem. Soc. 1980,102,5429. M. Shimizu and I. Kuwajima J. Org. Chem. 1980 45 4063. K. Maruyama T. Ishitoku and Y. Kubo Chem. Lett. 1980,265. l9 M. D. Bachi 0.Goldberg A. Gross and J. Vaya J. Org. Chem. 1980 45 1477 1481. 2o H. G. Corkins L. Storace and E. R. Osgood Tetrahedron Lett. 1980 21,2025. *' P. de Mayo A. C. Weedon and R. W. Zabel J. Chem. Soc. Chem. Commun. 1980,881. 22 E. Block A. A. Bazzi and L. K. Revelle J. Am. Chem. Soc. 1980,102 2490. Heterocyclic Compounds 183 0-0 Et H Et Et 0-Et’ H (39) (40) (41) (42) Peroxidase-catalysed oxygenative decarboxylation of 3-indolylacetic acid gives electronically excited indole-3-carboxaldehyde,suggesting the intermediacy of the a-peroxy-lactone (42).A report23 on the ingenious but futile attempts to prepare dioxetans related to (42) makes heart-rending reading. p-Lactams.-The Merck Sharp and Dohme group has used carbene insertion as the key step in a synthesis of the carba-2-penem system (Scheme 4).24 The a0 i_ q0 I;I zoqs4NHco2R 0 CO2CH2Ph O N2 H C02CH2Ph C02CH ,Ph Reagents i [Rh,(OAc),]; ii Ts,O; iii HSCH,CH,NHCO,R PriNEt Scheme 4 1 C0,H CO,H (43) (44) efficacy of this methodology has been elegantly demonstrated by the synthesis of of (*)-thienamycin starting from diethyl acetone-l,3-dicarbo~ylate,~~ (+)-thienamycin (43) from L-aspartic acid,26 and of (-)-homothienamycin (44).” Full details of the group’s earlier synthesis of (*)-thienamycin which relies on formation of the C(2)-C(3) bond by displacement of a bromide by malonate anion (Scheme 3,have appeared.28 pSMe 2 SMe OA 0 PhCH,02C CO2CH2Ph PhCH202C CO,CH,Ph Reagents i Br,; ii NaH DMF Scheme 5 23 W.Adam and K. Takayama J. Org. Chem. 1980 45,447. 24 R. W.Ratcliffe T. N. Salzmann and B. G. Christensen Tetrahedron Lett. 1980 21 31. 25 D. G.Melillo I Shinkai T. Liu K. Ryan and M. Sletzinger Tetrahedron Lett. 1980 21 2783. 26 T. N. Salzmann R. W. Ratcliffe B. G. Christensen and F. A. Bouffard J. Am. Chem. Soc. 1980 102,6161. 27 T. N. Salzmann R. W. Ratcliffe and B. G. Christensen Tetrahedron Lett. 1980,21 1193. 28 F. A. Bouffard D..B. R. Johnston and B. G. Christensen J. Org. Chem. 1980 45 1130; S. M. Schmitt D.B. R. Johnston and B. G. Christensen ibid. pp. 1135,1142. 184 T. M. Cresp The other 'classical' route involving C(2)-C(3) bond formation by intramolecular Wittig reaction has been developed into a versatile synthesis of thienamycin analogues (45)2g as well as of analogues of the antibiotic MM13902 (46).30 Isoxazoline (48) formed from a 1,3-dipolar cycloaddition between the nitrile oxide (47) and methyl crotonate has been converted into the thienamycin precursor (49).31 Conversion of (49) into thienamycin was achieved32 by utilizing the carbene- insertion method. The promised details (see Annu. Rep. Prug. Chem. Sect. B 1979 76 227) of the synthesis of authentic 2-(alky1thio)penems (51) have been delivered twice.33 Wittig-type reaction between the phosphorane and trithiocarbonate ester of the lactam (50)was used to form the C(2)-C(3) bond.OS0,Na NHCOMe mR'= flR1 M e w S4 0 )cPPh 0 C02R2 N/ R2O2C' (45) 0 C0,Na (46) CH(OMe) 0,COPNB I MemoLe 04J-N (49) C0,PNB (50) PNB =p-nitrobenzyl The 1,l-dimethyl-1-carbapenem(53) has been prepared by an intramolecular aldol condensation taking advantage of the non-enolizable aldehyde (52).34 The cost of synthetic convenience was lack of biological activity in the product. The reaction of the unsaturated sulphoxide (54) with the Vilsmeier reagent gives via a vinylogous Pummerer rearrangement the C(2)-vinylchloro-cephem (55). The product (55) is the starting material for the synthesis of a number of novel p-lac tarn^.^^ Pyrolysis of sulphoxides to give sulphenic acids provides the basis for the conversion of simple p-lactams (56) into penam sulphoxides (57).36 Unlike penicillanic sulphone the isomeric isopenam sulphone (59) is not an inhibitor of p-la~tamase.~~ The penems (60) prepared from methyl (5R)-penicillate S-oxide 29 L.Cama and B. G. Christensen Tetrahedron Lett. 1980 21 2013. 30 A. J. G. Baxter R. J. Ponsford and R. Southgate J. Chem. SOC.,Chem. Commun. 1980,429. 31 T. Kametani S.-P. Huang S. Yokohama Y. Suzuki and M. Ihara J. Am. Chem. SOC.,1980,102,2060. 32 T. Kametani S.-P. Huang T. Nagahara and M. Ihara Heterocycles 1980,14 1305. 33 M. Lang K..Prasad J. Gosteli and R. B. Woodward Helu. Chim. Acta 1980 63 1093; S. Oida A. Yoshida T. Hayashi N. Takeda T. Nishimura and E.Ohki J. Antibiot. 1980 33 107. 34 M. Shibuya and S. Kubota Tetrahedron Lett. 1980,21,4009. 35 D. 0.Spry Tetrahedron Lett. 1980 21 1289 1293. 36 A. C. Kaura C. D. Maycock and R. J. Stoodley J. Chem. SOC., Chem. Commun. 1980,34. 37 C. M. Pant and R. J. Stoodley J. Chem. SOC.,Chem. Commun. 1980,928. 185 Heterocyclic Compounds 0 MeCONH 0qcHo C02CH2Ph C02R (53) (54) 0 PhH,CCONH R' H \I 0 R2 R2 (56) (57) R1=NHCOCHZPh R2 =H (58) R' = H R2 =C02Me 0 PhH,CONH 0 0 xx02r C02H (59) PhH,CCONH H ON^. yCOzH 0H>OMe C0,Bu' C02H C02Bu' (62) (63) (64) (58),38have pronounced biological activity. Attempted ring-closure from (61) by carbene insertion under identical conditions to those used to generate the carba- penem failed to give any of the desired 2-0x0-dinorpenicillate.Ring- closure from (62) by formation of an s-C(2) bond was more rewarding providing an entry into the 2-methoxypenem system (63).39The 1-oxa-2-oxocephalosporins (64),40designed in an attempt to enhance the reactivity of the @-lactam ring towards cleavage share an absence of significant antibacterial activity with the 2-oxocephalosporins (see Annu. Rep. Prog. Chern. Sect. B 1979,76,228). Oxidation of the tricarbonyliron-lactam complex (65) is an interesting and unusual route into the @-lactam ring sy~tern.~' Hydrogenolysis of @-lactams provides a facile entry into dipeptide~.~' 38 M. Foglio G. Franceschi C. Scarafile and F. Arcamone J. Chem. SOC.,Chem. Commun. 1980 70. 39 J.Marchand-Brynaert L. Ghosez and E. Cossement Tetrahedron Lett. 1980,21,3085. 40 M. Aratani D. Hagiwara H. Takeno, K. Hernrni and M. Hashimoto J. Org. Chem. 1980,45 3682. 41 G. D. Annis E. M. Hebblethwaite andS. V. Ley J. Chem. SOC.,Chem. Commun. 1980 297. 42 I. Ojima S. Suga and R. Abe. Tetrahedron Lett. 1980,21 3907. 186 T.M. Cresp 3 Five-Membered Rings 2,5-Bis(trimethylsiloxy)furan (66) can be readily prepared from succinimide and has been to be a useful synthetic intermediate in a number of reactions. The use of nitro-olefins in the formation of the furan ring has been refined and used in the preparation of a number of furan~terpenoids.~~ The 'one-pot' synthesis (66) (67) of 2,4,5-trisubstituted furans (67)from ketones and ethyl 3,4-dibromo-2-butenoate is a useful addition to a well-tried theme.45 A short efficient synthesis of cantharidin (68) (Spanish fly) emphasizes the importance of high-pressure Diels-Alder reactions where furan is the diene (Scheme 6).46 Q+s*L&-$ A&$$ 0 0 S (68) Reagents i 15 kbar; ii Raney nickel Scheme 6 Benzo[c]furans generated from acetals (69)47or benzalphthalans (70);' continue to provide a source of polycyclic aromatics.The trisepoxyhexaradialene (7 1)49 represents the third member in that series to be prepared and it will enable comparisons to be made with the nitrogen (72) and sulphur (73) analogues. A review of benzo[c]furans covers the literature to mid 197tL50 Tetrahydrofurans have become respectable synthetic targets because of their presence in many naturally occurring ionophores.Permanganate-promoted oxida- tive cyclization of 1,5-dienes'* and photochemical cyclization of P-allyloxy-CHAr XG X R (71) X=O (70) (72) X = NCHzPh (73) x=s 43 P. Brownbridge and T.-H. Chan Tetrahedron Lett. 1980 21 3423,3427,3431. 44 M. Miyashita T. Kumazawa and A. Yoshikoshi J. Org. Chem. 1980,45 2945. 45 L. Moubarak and R. Vessiere Synthesis 1980 52. 46 W. G. Dauben C. R. Kessel and K. H. Takemura J. Am. Chem. SOC.,1980,102,6893. 4'7 B. A. Keay D. K. W. Lee and R. Rodrigo Tetrahedron Lett. 2980 21 3663; K. Naito and B. Rickborn J. Org. Chem. 1980,45,4061. 48 J. G. Smith S. S. Welankiwar B. S. Shantz E. H. Lai and N. G. Chu J. Org. Chem. 1980,45 1817. 49 M. B.Stringer and D. Wege Tetrahedron Lett. 1980,21,3831. " W. Friedrichsen Ado. Heterocycl. Chem. 1980 26 135. 51 D. M. Walba and P. D. Edwards Tetrahedron Lett. 1980 21 3531. HeterocyclicCompounds ketoness2 represent two interesting approaches that exhibit sufficient stereochemical control to warrant further attention. In the total synthesis of lasalocid A (74)s3 the tetrahydrofuran ring is obtained by reduction of a sugar-derived y-lactone while the tetrahydrofuran rings necessary for the total synthesis of monemsin (75)s4 arise from 1,4-diols. CO,H HOH,C-H HO (75) A synthesis of pyrroles from a-diketones takes advantage of the ready amination of (r-allyl)palladium(o) complexes (Scheme 7).” N-Alkylation of pyrroles with potassium t-but~xide’~ or potassium hydroxides7 in the presence of 18-crown-6 may offer some advantages over previous methods when C-alkylation is a problem.R2 R2 I Ph Reagents i AMgBr; ii Ac,O; iii PhCH2NH2 [Pd(Ph,P),I Scheme 7 The NN’-dipyrrolylmethane (77) that results from N-alkylation using the alternative method of employing dipolar aprotic solvents to solvate the counter-ion has been converted5* (Scheme 8) into the stable aromatic anion (78) which is an analogue of the fluorene anion. The second step in the alkylation to produce (77) may proceed through the interesting azoniafulvene (76). (NN-Dimethylamino)pyridine,better known as a superior catalyst for 0-acetylation and silylation also appears to offer advantages when used for the N-acetylation of pyrroles and in dole^.^^ Full details 52 H.J. Carless and D. J. Haywood J. Chem. Soc. Chem. Commun. 1980,657. 53 R. E. Ireland S. Thaisrivongs and C. S. Wilcox J. Am. Chem. SOC.,1980,102 1155. 54 D. B. Collum J. H. McDonald 111 and W. C. Still J. Am. Chem. Soc. 1980 102 2117 2118 2120. s5 B. M. Trost and E. Keinan J. Org. Chem. 1980,45,2741. 56 W. C. Guida and D. J. Mathre J. Org. Chem. 1980,45,3172. 57 E. Santaniello C. Farachi and F. Ponti Synthesis 1979 617. 58 U. Burger and F. Dreier Helu. Chim. Am 1980,63 1190. 59 K. Nickischi W. Klose and F. Bohlmann Chem. Ber. 1980 113,2036. 188 T. M. Cresp 1ii,iii (78) Reagents i CH,Cl, HMPA; ii Bu"Li;iii CuCl,; iv MeLi Scheme 8 of the photocycloaddition of dimethyl acetylenedicarboxylate to indoles have appeared,60 and they include a detailed mechanistic study.The dianion (79) from N-methylphthalimide gives mono- e.g. (go) and di-alkylated products e.g (81). The ratio of bridgehead to benzylic alkylation is very dependent on the nature of the electrophile.6' Both pyrroles6* and is~indoles~~ give 1:2 adducts with diethyl azodicarboxylate that result from Michael additions to both a-positions. d M\- e &NMe\ +~\ N M e OLi HO RO (79) (80) (81) A historical account of the frustrations and successes in the synthesis of ergot alkaloids makes interesting reading.64 More recent efforts have resulted in an improvement in the Bowman procedure for the preparation of Uhle's ketone (82)65 and an efficient route to methyl indole-4-carbo~ylate.~~ The former is a favourite intermediate in ergot alkaloid synthesis and the latter has been used in two impressive syntheses of chanoclavine I (83).67 HOTMe NHMe (84) R=CH H H (85) R=B (82) (83) 'O P.D. Davies and D. C. Neckers J. Org. Chem. 1980 45 456; P.D. Davies D. C. Neckers and J. R. Blount ibid. p. 462. G. A. Flynn J. Chem. SOC. Chem. Commun. 1980,862. C. K. Lee S. J. Kim and C. S. Hahn J. Org. Chem. 1980,45,1692. R.Kreher D.Schmitt and K. J. Herd Tetrahedron Left.,1980 21 3471. 64 D. C. Horwell Tetrahedron 1980,36 3123. "G.S.Ponticello J. J. Baldwin P. K. Lemma and D. E. McClure J. Org. Chem. 1980,45,4236. "A. P.Kozikowski H. Ishida and Y.-Y. Chen. J. Org. Chem. 1980 45 3350. 67 A. P.Kozikowski and H.Ishida J. Am. Chem. SOC. 1980 102,4265; W.Oppolzer and J. I. Grayson Helv. Chim. Acta 1980,63 1706; W.Oppolzer Heterocycles 1980 14 1615. Heterocyclic Compounds Polycyclic polyamines can provide information about the relationship between structures conformation and angle strain. Conformational analysis of a series of tricyclic orthoamides (84)68 and the effect of angle strain on hybridization in a series of tris(amino)boranes (85)69 are two examples from this area. An extension of the known photocyclization of S-aryl vinyl sulphides to thiophens has been used to prepare benzothiophens (87)from readily available methyl 2-(ary1thio)acetoacetates(86).70 a-Bisulphenylate ketones (88)cyclize equally well presumably by the same mechanism.” Tetrachlorothiophen 1,l-dioxide undergoes addition to a wide range of dienophiles and as expected the adducts lose sulphur dioxide.72 With furans the loss of sulphur dioxide is followed by rearrangement; a process best illustrated by the reaction between 3,4-dichlorothiophen 1,l- dioxide and 2,5-dimethylfuran where the initial adduct (89) which loses sulphur dioxide and rearranges to (90) can be isolated.73 Photocyclization of 3-acetoxybenzo[b]thiophen 1,2-dioxide (91) with cycloalkanes gives [2 + 21 adducts (92) ;these undergo ring-expansion to benzo[b]thiepinones (93).74 The kinetics of intramolecular acylation of long-chain o-(2-thienyl)alkanoic acids have been and the results used to advantage in a five-step synthesis of mu~cone,~~ where the cyclization of (94) gives a 59% yield of (95) without using unnecessarily high dilution.Publications in the area of donors for organic superconductors include two new syntheses of tetramethyltetraselenafulvene (96),77 a full on the synthesis 68 G. R. Weisman V. Johnson and R. E. Fiala Tetrahedron Lett. 1980,21,3635. 69 J. E.Richman N.-C. Yang and L. L. Andersen J. Am. Chem. SOC.,1980,102 5790. 70 T.Sasaki and K. Hayakawa Tetrahedron Lett. 1980 21 1525. 71 T.Sasaki K. Hayakawa and S. Nishida Tetrahedron Lett. 1980 21 3903. 72 M. S.Raasch J. Org. Chem. 1980 45 856. 73 M. S.Raasch J. Org. Chem. 1980,45 867. 74 N.V.KirbyandS. T. Reid J. Chem. SOC.,Chem. Commun. 1980 150. C. Galli G. Illuminati and L. Mandolini J. Org. Chem. 1980,45 311. 76 G. Cantoni C. Galli and L.Mandolini J. Org. Chem. 1980,45 1906. 77 F. Wudl and D. Nalewajek J. Chem. Soc. Chem. Commun. 1980,866;L.-Y. Chiang T.0.Poehler A. N. Bloch and D. 0.Cowan ibid. p. 866. M. V.Lakshmikantham and M. P. Cava J. Org. Chem. 1980,45,2632. 190 T. M. Cresp RR (95) Se X e Fe R&/ R Ye Se ' (96) X =Se R =Me (99) 6 m (97) X=S,R=H (98) of diselenadithiafulvene (97) and a description of the synthesis of diferrocenyl- tetrathiafulvene (98).79Seleno[3,4-b]selenophen (99) originally claimed to be a product from the reaction of selenium with acetylene has been prepared for the first time by a more rational route.80 The a-diazo-ketone (101) undergoes thermal ring-contraction to form the thietanone (100). With benzene as solvent the product of irradiation of (101) is the dihydrothiophen (102),whereas in methanol the heterocyclic products are (103) and (104).'l There is obviously much mechanistic and synthetic potential left in (101).OMe 70,Me Treatment of chloro-anilines (105) with base followed by irradiation provides a conceptually if not mechanistically (an intramolecular S,,l mechanism has been proposed) straightforward route to oxindoles (106).82The 2 1 adduct from con- 79 Y. Ueno H. Sano and M. Okawara J. Chem. SOC.,Chem. Commun. 1980,28. A. Konar and S. Gronowitz Tetrahedron 1980,36,3317. J. Bolster and R. M. Kellog J. Org. Chem. 1980,45,4804. 82 J. F. Wolfe M. C. Sleevi and R. R. Goehring J. Am. Chem. SOC.,1980,102,3646. Heterocyclic Compounds densation of diphenylketen with 1-methylbenzimidazole has structure (107),83 and not (108) (as previously reported).t-Butyl(cyan0)keten adds to the C(4)-C(5) double-bond of 2-(dimethy1amino)thiazoles(109) to give the tetrahydropyranone (110y4 (110) Trimethylaluminium adds stereospecifically to the (ptosy1)pyrazolines (111)and (114) yielding (112) and (115) respectively. Oxidation provides a convenient route to trans-(113) and cis-pyrazolin-4-ones (116).85 The method of preparation of allenic esters by treatment of 3,4-dialkyl-2-pyrazolin-5-ones with thallium(II1) nitrate has been extended to include a number of cyclic allenic esters (117).86 MeR&R4 MeR4;-,.e4 Me N=N N-N N=N /Ts (111) / (117) n =6-9 Ts (114) 83 M. J. Haddadin and H.H. N. Murad J. Org. Chem. 1980 45 2518. 84 A. Dondoni A. Medici C. Venturoli L. Forlani and V. Bertolasi J. Org. Chem. 1980,45 621. 85 W. H. Pirkle and D. J. Hoover J. Org. Chem. 1980 45 3407. A. Silveira Jr. M:Angelastro R. Israel F. Totino and P. Williamsen J. Org. Chem. 1980 45 3533. 192 T. M. Cresp Acyl-amidines which are well established as isoxazole precursors and have more recently (see Annu. Rep. Prog. Chern. Sect. B 1979 76 230) been used in the preparation of 1,2,4-0xadiazoles and 1,2,4-triazoles provide a convenient route to thiadiazoles (118) isoxazoles (119) and isothiazoles (120).87 .I NMe X-N R’ A/‘n 2 Y=C + RIG >RZ Y 1. (118) X=S,Y=N (119) X=O,Y=CH (120) X=S,Y=CH Irradiation of triazolines results in extrusion of nitrogen affording a 1,3-diradical which closes to form an aziridine ring.By having the carbon radical in conjugation with an a@-unsaturated ketone radical recombination results in the formation of a five-membered ring. In the example reported,*’ the intermediate (121) undergoes a retro-Diels-Alder reaction followed by trapping of the resultant keten (122) by solvent (Scheme 9). A similarity between reactions of singlet oxygen and triazolinediones with olefins and dienes suggests that they may react by much the same mechanism. Preliminary resultss9 on the mechanism of addition of triazolinediones to olefins suggest that this is indeed the case. ‘Et li fii ’Et Reagents i hv; ii MeOH Scheme 9 Primary amines react with 4-formylbenzofuran oxides (123) to give imines which rearrange to nitro-indazoles (124).Modification to oxime or hydrazone formation can be successfully incorporated providing a route to 2-oxy- (125) and 2-amino- indazoles (126) (Scheme A full report on the formation of quinoxaline monoxides (128) and (129) from benzofuran oxide (127) enones and amines has appeared.” By-products arise from reactions of (127) with amine detracting from an otherwise attractive synthetic route. The reaction is initiated by conjugate Y.-I. Lin S. A. Lang Jr. and S. R. Petty J. Org. Chem. 1980 45 3750; Y.-I. Lin and S. A. Lang Jr. ibid. p. 4857. A. G. Schultz and C.-K. Sha J. Org. Chem. 1980,45,2040. 89 C. A. Seymour and F. D. Greene J. Am. Chem. SOC.,1980,102,6384.90 A. J. Boulton T. Kan-Woon S. N. Balasubrahmanyam I. M. Mallick and A. S. Radhakrishna J. Org. Chem. 1980,45 1653. 9‘ A. F. Kluge M. L. Maddox and G. S. Lewis J. Org. Chem. 1980,45 1909. Heterocyclic Compounds -WR I R2 N R2 \ 'N (124) R' = alkyl or Ph (123) (125) R'=OR Reagents i H2N-R' (126) R'=NR2 Scheme 10 addition of an amine to the enone the enolate acting as a nucleophile and the protonated amine subsequently being eliminated to form the quinoxaline ring. It would be interesting to know if nucleophiles other than amines could be used in the reaction. 0 t 0 t + 0 0 (127) (129) A full of the Lewis-acid-promoted reaction of a-diazocarbonyl com- pounds (130) with nitriles to give oxazoles (131) will be welcomed by those seeking optimal conditions for this general synthesis of oxazoles.Tosylmethyl isocyanide the universal precursor forms a dianion (132) which condenses with ethyl benzoate to form the oxazole (1 33).93 Orthoesters condense with a-amino-ketone hydro- chlorides to provide a reasonable general route to 2,5-disubstituted oxazoles ( 134).94 Thiazolium oxazolium and selenazolium salts bearing N-(w-chloroalkyl) side- chains undergo ring-expansion on treatment with base (Scheme 1l).95 Alkylation of chiral oxazolines followed by hydrolysis yields butyrolactones and valerolac- tones. The alkylation sequence can be chosen to provide either enanti~mer.~~ Chiral (134) 92 H. P. Doyle W. E. Buhro J. G. Davidson R. C. Elliott J. W. Hoekstra and M.Oppenhuizen J. Org. Chem. 1980,45 3657. 93 S. P. J. M. van Nispen C. Mensink and A. M. van Leusen Tetrahedron Lett. 1980 21 3723. 94 J. L. La Mattina J. Org. Chem. 1980,45 2261. '' H.-J. Federsel and J. Bergman Tetrahedron Lett. 1980 21 2429. 96 A I. Meyers Y. Yamamoto E. D. Mihelich and R.A. Bell J. Org. Chem. 1980,45 2792. 194 T.M. Cresp CHO CHO Reagents i OH Scheme 11 keto-oxazolines react with organometallics to give after hydrolysis a-substituted a-hydroxy-acids in 30-87 '/o enantiomeric excess.97 A review on 1,3-thia~olines~~ places emphasis on the 1,3-thiazolinone + hydroxy- 1,3-thiazole tautomerism. Isoxazole N-oxides (135) have been isolated by benzo fusion to disfavour the ring-opened isomer ( 136).99 -0 (135) (136) (137) X=N Y=CH (138) X=CH Y=N 4 Six-Membered Rings A review"' covers the recent work on cycloaddition reactions of pyridines with special emphasis on intramolecular cyclizations.Irradiation of pyridine N-oxide in aqueous alkali forms the nitrile"' and not the isocyanide as previously reported (see Annu. Rep. Prog. Chem. Sect. B 1977,74 273). Fusion of 3-hydroxy-2-pyridone with phosphorus pentasulphide gives in addition to 3-hydroxypyridine-2-thione,the novel isomeric betaines (137) and (138).lo2 4-Methoxy-2-pyridone forms [2 + 2]cycloadducts with alkenes when irradiated in acetone solution. The regiochemistry of addition depends on the alkene that is used electron-deficient alkenes giving (139) by addition to the 5,6 double-bond.In solvents other than acetone only photo-2-pyridone (140) is formed (Scheme 12).lo3 The 2-pyrazinone (141) undergoes photochemical [4 + 41 cyclo- dirnerization to the anti-dimer (142) in the solid state; this reaction is reversed by R tfi -"ea orR~o N H o N H o N H o N H (140) (139) Reagents i hv RCH=CH Scheme 12 '')A. I. Meyers and J. Slade J. Org. Chem. 1980 45 2785. 98 G. C. Barrett Tetrahedron 1980,36 2023. 99 A. J. Boulton and P. G. Tsoungas J. Chem. SOC., Chem. Commun. 1980,421. loo W. Sliwa Heterocycles 1980,14 1793. 101 0.Buchardt J. J. Christensen D. E. Nielsen R. R. Koganty L. Finsin C. Lohse and J. Becker Actu Chem. Scand. Ser. B 1980 34 31. '02 J. S. Davies K.Smith and J. Turner Tetrahedron Lett. 1980 21 2191.H. Fujii K.Shiba and C. Kaneko J. Chem. SOC.,Chem. Commun. 1980 537. Heterocyclic Compounds Me Me hv,solid state __L c-- Ph hv,MeOH or heat N Ph heating (142) in methanol solution or by its irradiation. The N-ethyl analogue of (141) is photochemically stable in the solid state.lo4 N-Methyl-l,2-dihydropyridinebehaves as an enamine towards electron-deficient alkenes the usually observed [4 + 21 adducts being the thermodynamic product^."^ a-Pyridinones that bear an electron-attracting 4-substituent behave as dienophiles at elevated temperatures. Thus the 4-cyano-2-pyridone (143) reacts with 2,3- dimethylbuta-1,3-diene at 170 "C to give the isoquinoline (144).lo6 Pyrimidine- dienols react with electron-deficient dienophiles providing a novel route to quinazo- lines (Scheme 13).lo7 Pyridinoquinolin-2-ones (145) can be readily prepared in a 'one-pot' procedure by treatment of an acetanilide under Vilsmeier conditions (POCl in DMF) followed by addition of a secondary amine.lo8 0 Reagents i PrlNLi; ii MeO,CC=CCO,Me Scheme 13 Formation of pyridinium salts (147) from primary amines and pyrylium salts (146) followed by nucleophilic displacement with a wide range of nucleophiles has been the subject of a fruitful study by the Katritzky group in recent years.A detailed summary109 of this work is most welcome The acetate (148) serves as a convenient precursor for the pyrylium zwitterion (149). The reactions of (149) parallel those of the better known 3-oxidopyridinium zwitterion (1SO).Its thermal T. Nishio N. Nakajima and Y. Omote Tetrahedron Lett. 1980 21 2529. lo' B. W. Weinstein L. C. Lin and F. W. Fowler J. Org. Chem. 1980,45 1657. H. Tomisawa R. Fujita H. Kato and H. Hongo Heterocycles 1980 14 11 1. lo' S. Senda T. Asao I. Sugiyama and K. Hiroto Tetrahedron Lett. 1980 21 531. 0.Meth-Cohn and B. Tarnowski Tetrahedron Lett. 1980,21 3721. lo9 A. R. Katritzky Tetrahedron 1980 36 679. 196 T.M. Cresp R2 R2 (148) (150) X=NR (151) (154) X=NMe dimer (15 1)is bristling with functionality and its potential as a synthetic intermedi- ate has already been demonstrated."' The heterocarbanions (152) (153) and (154) appear to be thermally stable and parattopic."' The thioether group directs lithiation to the 5-position of the pyridine (155) giving access to a range of imidazo[l,5-a]pyridines (156) that are difficult to obtain by other methods.With benzonitrile as the electrophile the cyclazine-(158) a novel lO?r-electron system is obtained (Scheme 14). A 3,5-didehydroimidazo[ 1,5-a]- pyridine (157) has been suggested to be an intermediate.ll2 Reagents i Bu"Li; ii electrophile; iii Raney nickel; iv Bu"Li PhCN Scheme 14 A review113 covers the major synthetic routes to the 4H-pyran ring system. Cycloreversion of the ylides (159) gives a-0x0-dithioesters (160). Trapping of these intermediates with dienes is a convenient method for the preparation of functional- ized thiopyrans (141).'14 'lo J. B. Hendrickson and J. S. Farina J. Org Chem. 1980.45 3359 3361.'I' A. G. Anastassiou H. S. Kasmai and M. R. Saadein Tetrahedron Lett. 1980,21,3743. *I2 P. Blatcher and D. Middlemiss Tetrahedron Lett. 1980 21 2195; P. Blatcher D. Middlemiss P. Murray-Rust and J. Murray-Rust ibid. p. 4193. '13 C. Seoane J. L. Soto and M. Quinterio Heterocycles 1980 14 337. 'I4 E. Vedejs M. J. Amost J. M. Dolphin and J. Eustache J. Org. Chem. 1980 45 2601. Heterocyclic Compounds R' R' 0-0 (162) (163) Two groups"' have described a one-step synthesis of 2-substituted 4H-pyran-4- ones (173) by C-acylation of P-methoxy-ap-enone enolates (162) with acid chlorides anhydrides or acyl-imidazoles. The known conversion of secondary furfuryl alcohols into maltol has been considerably improved and this represents a very convenient entry into 3-hydroxy-4H-pyran-4-0nes."~ Dehydrobromination of the germacyclohexadiene (164) proceeds uia the ger- mabenzene (165) which dimerizes or which can be trapped with dienes."' Convinc-ing spectroscopic evidence has been presented to show that the retro-ene reaction of (166) and the ester cleavage of (167) both give silabenzene which can be trapped in an argon matrix."' Isatoic anhydride (168) is a heterocycle with a long history.Its rich chemistry has been beautifully put together in an impressive review.'" Other reviews include those on 1,3-0xazines,'~~ heterocyclic betaines,12' and thiocoumarins.'** 00hfi/HiGe Ge /\ Bu'Br Bu' Si / \H O-c\ No Me QfJ 0 (164) (165) (166) (167) (168) 5 Seven-Membered and Larger Rings Cycloaddition reactions of oxepin normally proceed through benzene oxide.However with the cyclopentadienone (169) the exo-[6 +41 tr-cyclo-adduct (170) can be isolated as well as the endo-[2 +41 tr-cyclo-adduct (171).'23 A molecular orbital study of the oxepin-benzene oxide valence isomerization has been repor- The course of the reaction of the dihydroazepine (172) with dimethyl acety- 11s M. Koreeda and H. Akagi Tetrahedron Lett. 1980,21,1197;T.A. Morgan and B. Ganem ibid. p. 2773. 'I6 P.D. Weeks T. M. Brennan D. P. Brannegan D. E. Kohla M. L. Elliott H. A. Watson B. Wlodecki and R. Breitenbach J. Org. Chem. 1980,45 1109. '17 G. Mark1 and D. Rudnick Tetrahedrori Lett. 1980 21 1405. G. Maier G. Mihon and H. P. Reisenauer Angew. Chem. Znt. Ed. EngL 1980,19,52.G. M. Coppola Synthesis 1980,505. T.Kato N. Katagiri and Y. Yamamoto Heterocycles 1980 14 1333. C.A. Ramsden Adu. Heterocycl. Chem. 1980 26 1. 0.Meth-Cohn and B. Tarnowski Adu. Heterocycl. Chem. 1980,26,115. lZ3 T.Ban Y. Wakita and K. Kanematsu J. Am. Chem. SOC.,1980,102,5415. lZ4 D.M. Hayes S. D. Nelson W. A. Garland and P. A. Kollman J. Am. Chem. Soc. 1980,102 1255. 198 T. M. Cresp o+q:+$p+ Ph m+ 0 Ph 0' (169) (170) 0 R = C02Me (171) lenedicarboxylate depends markedly on the solvent. In non-polar solvents [4 + 21 cycloaddition leads to the adduct (175). In polar solvents the dipolar intermediate (173) can ring-close and the resultant [2 + 21 adduct ring-open to (176) or in a protic solvent it can be protonated leading to (174).'*' Thermal interconversion of 2-pyridylnitrene (177) $ (179) may go through the carbene (180) as previously suggested but the stable intermediate in the interconversion is the cyclic carbodi- imide (178).126 Cyclic carbodi-imides are also intermediate in other nitrene re- arrangement~.'~' R MeOH ___) + + Ill polar solvent R RR (174) 1MeCN R (175) (176) o\..= N N "%N] n*9e (177) (180) (179) The dihydro-[ 14lannulene (18l) the penultimate precursor of the aromatic imino-methano[ 14lannulene (184) is a remarkably stable (i.e.decomp. above 75 "C) 1H-azepine. On chromatography on A1203 it isomerizes to the anti-isomer (183) presumably uia the Bredt rule respecting 3H-azepine (182).'** The stability of (181) has encouraged a successful attempt to characterize the much more labile (i.e.stable for a few hours at -78 "C in solution) 1H-azepine (185).'29 If present lZ5 W. Eberbach and J. C. Carre Tetrahedron Lett. 1980,21,1145. 126 C.Wentrup and H.-W. Winter J. Am. Chem. SOC.,1980,102,6159. 12' C.Wentrup C. Thetaz E. Tagliaferi H. J. Linder B. Kitschke H.-W. Winter and H. P. Reisenauer Angew. Chem. Int. Ed. Engl. 1980,19,566. lZ8 E. Vegel U. Brocker and H. Junglas Angew. Chem. Int. Ed. Engl. 1980 19 1015. lZ9 E.Vogel H.-J. Altenbach J.-M. Drossard H. Schmickler and H. Stegelmeier Angew. Chem. Int. Ed. Engl. 1980,19 1016. Heterocyclic Compounds (181) L H @'' '/N R' (187) (188) the benzeneimine tautomer (186) is there in less than 1% concentration in agree- ment with thoeretical calculations.Condensation of 1,2,4-triazines with benzo- cyclopropene affords substituted 3,8-methanoaza[ 10]annulenes (187).130 Aza- [14lannulene (188) is diatropic has temperature-dependent 'H n.m.r. spectra and like aza[l8]annulene (see Annu. Rep. Prog. Chem. Sect. B 1979 76 246) the nitrogen atom occupies an inner ~0sition.l~~ N.m.r. studies of conformational and configurational effects in medium-sized heterocycles include investigations on the carbodi-imide (189),13* 1-thiacyclo-octan-5-one (190),'33 the 2-0x0-azocine (191),134 and trans-thiacyclo-oct-4-ene (192). 35 0 CN> N 0 Crowns and cryptands continue to be a major growth industry. The effects of modification and of functionalization on crown ethers have been reviewed.lJ6 The pyridino-crown (193) selectively forms inclusion compounds with aliphatic alcohols.13' Primary ammonium cations are complexed by the triaza-trioxa-macrocycle (194) with a ca.ten-fold stability factor over complexation of K+.138 130 M. L. Maddox J. C. Martin and J. M. Muchowski Tetrahedron Lett. 1980 21 7. 13' H.Rottele and G. Schroder Angew. Chem. Int. Ed. Engl. 1980,19,207. 13' R. Damrauer D. Soucy P. Winkler and S. Eby J. Urg. Chem. 1980 45 1315. 133 F.A. L. Anet and M. Ghiaci J. Org. Chem. 1980,45 1224. 134 F.A. L. Anet Tetrahedron Lett. 1980 21 2133. V. CerC A. Guenzi S. Pollicino E. Sandri and A. Fava J. Org. Chem. 1980,45261. 136 J. S. Bradshaw and P. E. Stott Tetrahedron 1980,36 461. 13' E.Weber and F.Vogtle Angew. Chem. Znt. Ed. Engl. 1980 19 1030. 13' J. M. Lehn and P. Vierling Tetrahedron Lett. 1980 21 1323. 200 T.M. Cresp Me / 4 / (194) 6 Monographs and Reviews Where appropriate secondary literature references have been included in the previous sections. A very useful contribution is a list of monographs and reviews on heterocyclic compounds published between 1965 and 1978.’39“ Other topics in the Advances in Heterocyclic Chemistry series that have not previously been mentioned are heterocyclic betaine~,’~~’ ring synthesis of heteroaromatic nitro- compo~nds,~~~~ and heteroaromatic radicals with heteroatoms of Group V in the ring.139d A characteristically detailed and stimulating review by Huisgen is concerned with the heterocyclic counterparts of the cyclopentenyl anion pentadienyl anion electrocyclic rea~ti0n.l~’ A review on cyclic azoalkenes concentrates on the strained ring systems that they form by elimination of nitr~gen.’~’ Equilibrium conformations of four- and five-membered heterocyclic (and carbocyclic) rings as measured by vibrational spectroscopy and electron diffraction have been reviewed.’42 A more general survey of conformational analysis of heterocyclic compounds has also appeared.’43 In the Weissberger-Taylor series the 1,2,3-triazole ring system has been reviewed.144 Under the heading of fused-ring heterocycles with three or more nitrogen atoms a new volume14’ of Rodd’s Chemistry of Carbon Compounds’ contains reviews on purines and related ring system~;’~’“ nucleosides nucleotides and nucleic acids;14” pteridines alloxazines flavins and related and the biosynthesis of plant alkaloids and nitrogenous microbial metabolites.145d 139 (a)A. R. Katritzky and P. M. Jones Ado. Heterocycl. Chem. 1979 25 303; (b)J. W. Bunting ibid. p. 2; (c) S. Rajappa and M. D. Nair ibid. p. 113; (d)P. Hanson ibid. p. 206. 140 R. Huisgen Angew. Chem. Int. Ed. Engl. 1980.19.947. 14’ W. Adam and 0.de Lucchi Angew. Chem. Int. Ed. Engl. 1980,19,762. 14* A. C. Legon Chem. Rev. 1980,80,231. 143 F. G. Riddell ‘The Conformational Analysis of Heterocyclic Compounds.’ Academic Press London 1980. 144 ‘Triazole 1,2,3,’ ed. J. A. Montgomery (Weissberger and Taylor’s ‘The Chemistry of Heterocyclic Compounds’) Wiley-Interscience New York,1980 Vol.39. 14’ ‘Rodd’s Chemistry of Carbon Compounds,’ 2nd edn. ed. S. Coffey Elsevier Amsterdam and New York,1980 Vol. IV Part L; (a) G. Shaw; (6)D. S. Jones; (c) K. Olta R.Wrigglesworth and H. C. S.Wood; (d)R.B. Herbert. Heterocyclic Compounds 20 1 A special edition of the journal ‘Heterocycles’ is dedicated to Professor Umezawa on the occasion of his 65th birthday.146 His enormous contribution in the area of antibiotics has uncovered many new heterocyclic ring systems. 14‘ Heterocycles 1979 Vol. 13.