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