8 Heterocyclic Compounds By D.E. AMES Department of Chemistry Queen Mary College London Mile End Road London El 4NS 1 Introduction The flow of publications on heterocyclic chemistry has continued to grow in 1989 so that this Report is by necessity highly selective emphasizing preparative work. Useful reviews dealing with heterocyclic sonochemistry' and with the hetero-Cope rearrangement2 have been published. Many reactions leading to phosphorus-containing heterocycles are covered in a review3 of phosphaalkynes and phos- phaal kenes. 2 Three-membered Rings A series of crystalline arenesulphonate derivatives of enantiomerically enriched glycidol have been ~repared.~ They react with nucleophiles with very high regioselec- tivity (Scheme 1). Vinyloxiranes have received much attention during the year and their SN2'addition reactions (Scheme 2) have been reviewed.' Addition of functionalized alkenes across ?H NCAOTS -io ?H 96% ii boTs Ph\j\/oTs Reagents Et,AlCN; ii PhMgBr Li2CuC1 Scheme 1 R4 R2 R3 R3 Scheme 2 ' Y.Goldberg R. Sturkovich and E. Lukevics Heterocycles 1989 29 597. 'S. Blechert Synthesis 1989 71. L. N. Markovski and V. D. Romanenko Tetrahedron 1989,45,6019. J. M. Klunder T. Onami and K. B. Sharpless J. Org.Chem. 1989,54 1295. J. A. Marshall Chem. Reu. 1989 89 1503. 189 190 D. E. Ames the epoxide unit by a radical process yields tetrahydrofurans (Scheme 3).6 Vinyl-oxiranes prepared from aldehydes and the lithium dienolate of ethyl 2-bromobut-2- enoate rearrange to dihydrofurans on thermolysis (Scheme 4).7 wAr a-AAr Me02aTAAr Me02C + -Reagents hv Ph2S2 AIBN CH2=CHC02Me Scheme 3 Br Reagents i furan-2-aldehyde; ii A Scheme 4 The preparation and reactions of dioxiranes' and of oxaziridines9 have been reviewed.A stereospecific synthesis of aziridines from diols via the cyclic sulphates has been reported (Scheme 5)." Aziridination of vinylsilanes (or vinylstannanes) with an N-acetoxyaminoquinazolone(1) followed by elimination of the trimethylsilyl and quinazolone groups gives azirines (2) (Scheme 6)." oso; NR3 iii R' TR22 R2 -LRZ R' R' 62-89% OH +NH2R3 LO Reagents i SOCl, A; ii RuCl, NaIO,; iii R3NH2 A; iv Bu"Li Scheme 5 Ph 86% N 91% N + Ph I Q QNHOAc (1) Reagents i CsF DM F; Q=3-Ethyl- 1-oxo-1,2-dihydroquinazolin-2-y1 Scheme 6 K.S. Feldman and T. E. Fisher Tetrahedron 1989 45 2969. ' T. Hudlicky A. Fleming and T. C. Lovelace Tetrahedron 1989 45 3021. * (a) W. Adam R. Curci and J. 0. Edwards Acc. Chem. Res. 1989 22 205; (b) R. W. Murray Chem Rev. 1989 89 1187. F. A. Davis and A. C. Sheppard Tetrahedron 1989,45 5703. B. B. Lohray Y. Gao and K. B. Sharpless Tetrahedron Lett. 1989 30,2623. R. S. Atkinson and B. J. Kelly J. Chem. Soc. Chem. Commun. 1989 836. Heterocyclic Compounds The first tricyclic diaziridines (3) have been prepared (Scheme7),12 but they undergo acid-catalysed rearrangement to form a bicyclic salt (4). 3,3-Dialkyl-2-diphenylphosphinoyloxaziridines by oxidation of are ~btained'~ N-diphenylphosphinoylimines with the anhydrous potassium fluoride-rn-chloroperbenzoic acid complex (Scheme 8).'H and I3C NMR spectroscopy shows that these undergo rapid inversion at N at room temperature. N-N (3) H (4) Reagents i NaOCI-NaOH-H20; ii CF,C02H Scheme 7 0 l\ R1 / / /C=N\ i_ /c-N \ R2 PPh2 R2 I1 FPh2 0 0 Reagents i anhydrous KF-MCPBA Scheme 8 Mesoionic bicyclic imine (5) is oxidized in the thiadiazole ring to give an unusual hetero-fused oxaziridine (6).14 Reaction of calcium-cyclooctatetraene complexes with a substituted di-chlorophosphine ( RPC12) produces the fused-ring phosphacyclopropane (7).15 Q P R l2 S. N. Denisenko E. Pasch and G. Kaupp Angew. Chern. Znt. Ed. EngL 1989 28 1381.l3 W. B. Jennings S. P. Watson and D. R. Boyd Tetrahedron Lett. 1989 30,235. l4 P. J. Dunn and C. W. Rees J. Chern SOC.,Perkin Trans.1 1989 2485. l5 D. S. Hutchings P. C. Junk W. C. Patalinghug C. L. Ralston and A. H. White J. Chem. SOC.,Chern. Cornmun.,1989 973. 192 D. E. Ames 3 Four-membered Rings The ester enolate-imine condensation route to P-lactams has been reviewed,I6 and development of this approach continues. The reaction of zinc enolates from amino- esters with silylated imines gives high yields of amino-substituted P-lactams (Scheme 9).17 Zinc and trimethylsilyl chloride have been used to condense 2-bromoesters with imines (Scheme lo)." -R IR2 R'R'N H Reagents i LDA; ii ZnC12; iii R3CH=NSiMe3; iv H20 Scheme 9 1 BrCHzCOzEt +PhCH=NPh -82% Reagents i Zn Me,SiCI Scheme 10 Glyoxal diimines react with lithium ester-enolates to form 4-(iminoalkyl)azetidin- 2-ones (8; X = NAr) and by acidic hydrolysis aldehydes (8; X = 0)(Scheme 1 l).19 P-Lactams have been prepared from P-aminothiol esters (9) without epimeriz- ation by heating with copper( I) trifluoromethanesulphonate and calcium carbonate in toluene (Scheme 12)." Benzoylation of thioformamides (10) gives S-H H I O-Li+ ArN /$/NAr + Me&< -Mesx 90% OMe 0 H Ar = 4-methoxyphenyl Scheme 11 A-! s H-NHCHzPh -85% H i NCHzPh SPh (9) Reagents i CF3SO;Cu+ CaCO, toluene A Scheme 12 l6 D.J. Hart and D.-C. Ha Chem. Rev. 1989 89 1447. l7 F. H. van der Steen H. Kleijn J.T. B. H. Jastnebski and G. van Koten Tetrahedron Lett. 1989,30,765. C. Palomo F. P. Cossio A. Arrieta J. Modriozola M. Oiarbide and J. M. Ontoria J. Org. Chem. 1989 54 5736. l9 B. Alcaide A. Gomez J. Plumet and J. Rodriguez-Lopez Tetrahedron 1989 45 2751. 20 N. Miyachi F. Kanda and M. Shibasaki J. Org. Chem. 1989 54 3511. Heterocyclic Compounds 193 benzoylthioimidates (1 1).These unstable intermediates have been converted directly into 4-benzoylthioazetidinones (12) (Scheme 13).2' 4,4-Dialkoxyazetidin-2-ones have been obtained by reaction of ketene acetals with isocyanates (Scheme 14).22 A new synthesis of p-lactams has been effected by stereoselective oxidative coupling of dianions of acyclic amide~.~~ For example amide (13) gave p-lactam in 58% yield 90% of which was isomer (14) (Scheme 15).XN H -SCOPh Reagents i PhCOCI Et,N; ii XCH,COCI (X = phthalimido-) Et3N Scheme 13 (OMe)2 Me + PhN=C=O -H2CXMe 90% 0P N P h Scheme 14 (PhCHJZN CO~BU' . .. H 1,Il + Ph Ph (13) (14) Reagents i Bu"Li TMEDA; ii N-iodosuccinimide Scheme 15 Turning to syntheses of fused-ring p-lactams a new route24 is based on a pal- ladium-catalysed carbonylation reaction of a bromoalkenylpiperidine salt (Scheme 16). [2 + 21 Cycloaddition of ketenes (formed in situ) to 1,3-benzoxazine and quinazoline derivatives forms a p-lactam system fused to the original hetero- cyclic ring,25 as illustrated by Scheme 17. Reagents CO Pd(OAc) PPh, Bu;N Scheme 16 21 M. P. Wentland P.E. Hansen S. R. Schow and S. J. Daum Tetrahedron Lett. 1989 30,6619. 22 M. L. Graziano and G. Cimminiello Synthesis 1989 54. 23 T. Kawabata K. Sumi and T. Hiyama J. Am. Chem. SOC. 1989 111 6842. 24 M. Mori Y. Higuchi K. Kagechika and M.Shibasaki Heterocycles 1989 29 853. 25 S. D. Sharma and V. Kaur Synthesis 1989 677. 194 D. E. Ames SMe Reagents i ArOCH,COCl Et3N; ii Raney Ni Scheme 17 l,l-Dioxo-7-substituted cephems have been prepared26 from the acid (15; R = H X = S) which is first protected as the t-butyl ester. This is oxidized with sodium tungstate and hydrogen peroxide to the sulphone (15; R = But X = SO2)and then converted into the diazo compound (16). A rhodium-catalysed reaction with methanol leads to the trans-7-methoxy compound (17) whereas reaction with triethylboron gives cis-and trans-7-ethyl derivatives (Scheme 18).0. .o COzR (15) Reagents i PrONO CF,CO,H; ii MeOH Rh2(02CC7H,&, Et,N Scheme 18 Displacement of the mesylate group of (18; R = S02Me) to prepare 3-functional- ized 3-norcephalosporins often involves isomerizations. These are avoided2' by using the trifluoroacetate (18; R = 02CCF3)so that 3-halogeno 3-pyrrolidino and other derivatives can be prepared efficiently. PhCHzCONH 0 Penicillin and cephalosporin esters (19 and 20 X = S) are conveniently oxidized to the corresponding sulphoxides (X = SO) by hydrogen peroxide formic acid and polyphosphoric acid.28 26 T. J. Blacklock J. W. Butcher P. Sohar T. R. Lamenec and E. J. J. Grabowski J.Org. Chern. 1989 54 3907. 27 V. Farina S. R. Baker and S. I. Hauck J. Org.Chern. 1989 54 4962. 28 M. Tanaka T. Konoike and M. Yoshioka Synthesis 1989 197. Heterocyclic Compounds R'CONH R'CONH C02R2 C02R2 (19) (20) Four-membered rings containing phosphorus have received particular attention during the year. Dihydrophosphetes have been obtained29 from diphenyltitanacy- clobutene as shown in Scheme 19. Earlier examples were metal complexes or P=O oxide derivatives. TiCp -ii Pfl-OEf - 66% 73% Ph Ph Ph Ph Ph Ph Reagents i RPCl,; ii EtOPCI Scheme 19 Phosphenium cations react with isocyanides to produce 1 -aza-3-phosphetine cations (Scheme 20).30 Condensation of iminophosphanes with a phosphaalkyne forms diphosphirene (21) which isomerizes to azadiphosphetine (22)31 (Scheme 21) and a novel thermal cyclotetramerization of the phosphaalkyne leads to yellow crystals of tetra-t-butyltetraphosphacubane(23).32 t Me2N NMe2 \/ P-c I I CF3SO; /c-N\ Bu'N But Scheme 20 R' NR2 \/ RIP-NR~ -It /Bu'C=P // BUT=P BUT P (21) But Reagent i R'P=NR2 (23) Scheme 21 29 K.M. Doxsee G. S. Chen and C. B. Knobler J. Am. Chem. SOC.,1989 111,9129. 30 C. Roques M. R. Mazieres J.-P. Majoral and M. Sanchez J. Org. Chem. 1989 54 5535. 31 E. Niecke and D. Barion Tetrahedron Lerr. 1989 30,459. 32 T. Wettling J. Schneider 0.Wagner C. G. Kreiter and M. Regitz Angew. Chem. Int. Ed Engl. 1989 28 1013. 196 D. E. Ames 4 Five-membered Rings An ingenious synthesis of 2-substituted 4-methylene tetra hydro fur an^^^ is based on a palladium-catalysed cycloaddition of an aldehyde to 2-(trimethylsilyloxy-methy1)allyl acetate (Scheme 22).In another palladium-catalysed (Scheme 23) an alkenyl alkynyl ether is cyclized to a 3,4-dialkenyltetrahydrofuran. MeSiO i.' AcO-Ph 1 Reagents i PhCH=CHCHO Pd(OAc), Me3SnOAc (Pr'O),P (=L) Scheme 22 Ph Reagents i (Ph,As),.Pd(OAc) complex Scheme 23 New syntheses of y-lactones have been reported. Reductive cyclization of allylic y-bromoacid esters gives 2,3-disubstituted butyrolactones (Scheme 24).35 Cobalt and ruthenium carbonyls together catalyse the regiospecific insertion of carbon monoxide into the least-substituted carbon-heteroatom bond of an oxetane or thietane to form butyrolactones or thiobutyrolactones (Scheme 25).36 In a general asymmetric syn- Ph Reagents i Bu,SnH AIBN A Scheme 24 Reagents i Co,(CO), Ru,(CO),, CO A Scheme 25 33 B.M.Trost S. A. King and T. Schmidt J. Am. Chem. SOC.,1989 111 5902. 34 B. M. Trost E. D. Edstrom and M. B. Carter-Petillo J. Org. Chem. 1989 54 4489. 35 J. L. Belletire and N. 0. Mahmoodi Tetrahedron Lett. 1989 30,4363. 36 M.-D. Wang S. Calet and H. Alper J. Org. Chem. 1989 54 21. Heterocyclic Compounds thesis of chiral butenolide~,~~ diastereocontrolled alkylation at the y-position of hydroxybutenolides is achieved using the tin enolate of a chiral thiazolidine deriva- tive (Scheme 26). R' R1&T* R' HOzC OH 0 T' Reagents i CH,=C(T*)OSnOSO,CF, T* = -N*' Scheme 26 Allenylsilanes react with acylium ions in a one-step [3 + 21 annulation process to form substituted furans (Scheme 27).38 In another annulation sequence39 indene was converted into the bromoindenyl propargyl ether (24) which was cyclized with cobaloxime-sodium borohydride to form the fused tetrahydrofuran system (25) (Scheme 28).H.. /SiMezBut Et SiMe2But _ Et 11 -Et/C=C=C \Me 71% 86% -PhCHzV M e PhCHz Reagents i AICI3 PhCH,COCI; ii HF C,H,N Scheme 27 (24) Reagents i NBS HCrCCH,OH; ii cobaloxime NaBH Scheme 28 Cyclization of silylated diynes with 2,6-dimethylphenyl isocyanide4' in the pres- ence of bis(cyclooctadiene)nickel(O) leads to iminocyclopentadienes with a fused heterocyclic ring (Scheme 29).TF-Ph 0 i, o*NAr 82% SiMe3 SiMe3 Reagents i ArNC Ni(cod), A Scheme 29 37 Y. Nagao W.-M. Dai M. Ochiai and M. Shiro J. Org. Chem. 1989 54 5211. 38 R. L. Danheiser E. J. Stoner H. Koyama D. S. Yamashita and C. A. Klade J. Am. Chem. Soc. 1989 111 4407. 39 K. Last and H. M. R. Hoffmann Synthesis 1989,901. 40 K. Tamao K. Kobayashi and Y. Ito J. Org. Chem. 1989 54 3517. 198 D. E. Ames New approaches to the synthesis of isobenzofurans include a general procedure based on reductive condensation of phthalide with a 1,l-dibromide. Under acidic conditions the resulting alkylidenephthalan (26) is in equilibrium with alkylisoben- zofuran (27) and can be trapped by reaction with dienophiles (Scheme 30).41Isoben-zofuran derivative (28) has been prepared from dialdehyde (29) and glyoxal via the dione (30) and reductive acetylation (Scheme 31)?2 Reagents i PhCHBr, Zn TiCI, TMEDA; ii MeO2CC=CCO2Me Scheme 30 0 + o%Ac ii OH I/OAc Ph OAc 0 (29) (30) (28) Reagents i (CHO),.NaHSO, C,H,N KCN H20;ii Zn Ac20 CSHsN Scheme 31 a Albidin (6-methoxy-3-methylisobenzofuran-4,5-dione) red pigment from Penicillium albidum Sopp has been synthesized from the vinyl ether (31)."3 A radical cyclization process using tributyltin hydride gives an 87% yield of cyclic ethers 70% of which is the five-membered ring product (32).Hydrolysis and then oxidation lead to the quinone albidin (33) (Scheme 32). OAc OAc OAc (32) ii,iii iv I 0 Reagents i Bu,SnH AIBN; ii OH- H20; iii H30+; iv DDQ Scheme 32 41 S.K. Meegalla and R. Rodrigo Synthesis 1989 942. 42 D. Passerieux M. Casteignan L. Lepage and Y. Lepage Bull. SOC.Chim. Fr. 1989 441. 43 S. Tennant and D. Wege J. Chem. SOC.,Perkin Trans. 1 1989 2089. Heterocyclic Compounds A palladium-catalysed carbonylation process4 gives 4-or 7-acetoxybenzofuran or the corresponding benzothiophenes (Scheme 33) in high yields. A one-pot prepar- ation of benzothiophenes is based on cyclization of an aryl zirconocene (34) with a silylated alkyne. The cyclic zirconium compound (35) is produced and this reacts with sulphur dichloride to form a benzothiophene (36) (Scheme 34).45 OAc Reagents i PdCl,(PPh,), AqO CO Et,N OAc Scheme 33 -.R2 R2 R’ R2 R3 R2 (34) (35) (36) Reagents i Cp2Zr (Me)Cl; ii Me,SiC=CR3; iii S2C12; iv Bu4N+ F- H,O;v HCI-H,O Scheme 34 Novel fused-ring thiophene systems have been reported; for example photocyliz- ation of terthiophenes (37; R = 2- or 3-thienyl) gives the tetracyclic product (38),46 and reductive dimerization of 3,4-dibromothieno [2,3-b]thiophene (39) forms 3,3’:4,4’-bis(thieno[2,3-b]thiophene)(40).47 This last fused heteroarene is a planar (37) Br )-/r I I Ny, I SR; (39) S (40) 44 M. Iwasaki J. Li Y. Kobayashi H. Matsuzaka Y. Ishii and M. Hidai Tetrahedron Lett. 1989 30,95. 45 S. L. Buchwald and Q. Fang J. Org. Chem. 1989 54 2793. 46 N. Jayasuriya J. Kagan J. E. Owens E. P. Kornak and D. M. Perrine J.Org. Chern. 1989,54 4203. 47 Y. Kono H. Miyamoto Y. Aso T. Otsubo F. Ogura T. Tanaka and M. Sawada Angew. Chem. Int. Ed. Engl. 1989 28 1222. 200 D. E. Ames centrosymmetric electron-donating component for the synthesis of organic metals. Condensation of quinoxaline with the lithium derivative of dimethyl sulphone gives cyclic sulphone (41) (Scheme 35).48 182% Reagents i Li[CH2S02Me] Scheme 35 3,4-Dimethylselenophene can be prepared efficiently by passing 2,3-dimethyl- butadiene and selenium vapour over sand in a glass tube at 450 0C.49 Diselenides (42; R = NH2or Me,) are oxidized and cyclized by hydrogen peroxide in acetonitrile to form 1,2-benzisoselenazol-3(2H) -one 1-oxide (43) and benzo[ b]selenophen-3(2H)-one 1-oxide (44).50 0 0 II II +aciHZ Se I1 0 2 Se/II 0 (43) (42) (44) (+)-(2S,5S)-Hexanediol obtained from the dione by reduction with yeast has been converted into (-)-(2&5R) -2,5-dimethylpyrrolidine (84%) by reaction of the dimesylate with benzylamine followed by catalytic debenzylation." (*)-2,3-Methanoproline a weak inhibitor of ethylene biosynthesis has been synthesized from an enaminone as summarized in Scheme 36.52 I I H COzCHzPh COZCHzPh Reagents i PhCH20COCI; ii CH2N2; iii hv; iv H,-Pd/C; v HCl-H20; vi AcO- resin Scheme 36 48 J.M. Vierfond L. Legendre J. Mahuteau and M. Miocque Heterocycles 1989 29 141. 49 G. Barbey G. Dian N. Merlet F. Outurquin add C. Paulmier Synthesis 1989 181. 50 K. Kloc J. Mlochowski and L. Syper Liebigs Ann.Chem. 1989 811. 51 R. P. Short R. M. Kennedy and S. Masamune J. Org. Chem. 1989 54 1755. 52 F. L. Switzer H. Van Halbeek E. M. Holt and C. H. Stammer Tetrahedron 1989 45 6091. Heterocyclic Compounds N-Triisopropylsilylpyrrolehas been converted successively into the 3-bromo and 3-lithio derivative^.^^ Reaction with electrophiles and removal of the N-protecting group then gave 3-substituted pyrroles conveniently. Oxidative alkoxycarbonylation of dipropargylamines generates 3,4-bis(alkoxycarbonylmethylene)pyrrolidines which are easily isomerized to pyrrolediacetic acid esters (Scheme 37).54 Zir- conocene-imine complexes react with alkyne and carbon monoxide in a new syn- thesis of trisubstituted pyrroles shown in Scheme 38.55 Another route to polyalkyl- pyrroles is based on the condensation of a ketone enolate to a nitroalkene to form a nitr~ketone.~~ Reductive cyclization of the acetic nitronic anhydride then gives the pyrrole derivative (Scheme 39).A regioselective synthesis of pyrroles (Scheme 40) by coupling a$-unsaturated imines with esters is promoted by a niobium chloride cata~yst.~' R'NLE IINZZZl:] rE Reagents i C02 air R'OH Pd/C KI; ii Et,N DMSO Scheme 37 Li R'CH2NSiMe3 + Me /CP2Zr\ [ Cp21,,,] R'CH2NSiMe3 -CH RICH -NSiMe3 Cp2Zr(THF) \/ c1 ... . N R' H Reagents i THF; ii R2C_CR3; iii CO; iv NH4Cl H,O Scheme 38 R3 R3 Reagents i LiNPr,; ii R3CH=CR4(N02); iii Ac,O; iv Zn/Cu NH,CI H20 EtOH Scheme 39 53 K.-P. Stefan W. Schuhmann H.Parlar and F. Korte Chem. Ber. 1989 122 169. 54 G. P. Chiusoli M. Costa and S. Reverberi Synthesis 1989 262. 55 S. L. Buchwald M. W. Wannamaker and B. T. Watson J. Am. Chem. SOC.,1989 111 776. 56 M. Miyashita B. Z. E. Awen and A. Yoshikoshi J. Chem. SOC.,Chem. Commun. 1989 841. 57 E. J. Roskamp P. S. Dragovich J. B. Hartung and S. F. Pedersen J. Org. Chem. 1989 54 4736. 202 D. E. Ames I I R' R' Reagents i R5C0,Et; ii NbCI,( DME) complex Scheme 40 Photo-oxygenation of tetraethylpyrromethenone (45) in methanol in the presence of dioxygen and a porphyrin photosensitizer gives the corresponding methanol- propentdyopent adduct (46) (72%).58 Methanolysis of diazasilacyclopentenes (47) produces 3-aminopyrroles (48) but with only small amounts of methanol a pyrrolo[3,2-b]pyrrole (49) is formed (Scheme 41).59 NHBu' u!ir 1 N NHBu' B ut (48) NHBu' But prN1 But (49) Scheme 41 Oxidation of 2-phenylindole with sodium tungstate-hydrogen peroxide yields 1-hydroxy-2-phenylindole(56%).60 1-Methoxyindole can be isolated by oxidizing indole similarly and methylating the unstable hydroxy compound with diazomethane.1-Methoxymethylindole-2-carboxylicacid can be lithiated at the 3-position using s-butyl lithium in the presence of hexamethylphosphoramide.613-Substitution prod- ucts are then obtained by reaction with electrophiles (Scheme 42). R.Bonnett S. Ioannu and F. J. Swanson 1. Chem. SOC.,Perkin Trans. I 1989 711. 59 H. tom Dieck U. Verfiurth K. Diblitz J. Ehlers and G.Fendesak Chem. Ber. 1989 122 129. 60 M. Somei and T. Kawasaki Heterocycles 1989 29 1251. Y.Yokoyama M. Uchida and Y. Murakami Heterocycles 1989 29 1661. Heterocyclic Compounds 203 ___* I MeOCH MeOCH2 OLi CH20Me Reagents i Bu”Li HMPA; ii electrophile (e.g. HCONMe2 X = CHO); iii H20; iv CH2N2 Scheme 42 Contrary to earlier conclusions electrochemical oxidation of 5,7-dihydroxytryp- tamine (50) at low pH gives a radical intermediate. The initial step is a le- 1H+ oxidation and the predominant form of the intermediate has an unpaired electron at C4 (51).62 Nucleophilic attack by water yields 4,5,7-trihydroxytryptamine(52) which is rapidly oxidized further to 5-hydroxytryptamine-4,7-dione (53) (Scheme 43). H 4,4’-dimers OH 0 (52) (53) Scheme 43 Indoloquinones have also been obtained by a route based on an internal trapping reaction of azomethine ylides generated from oxazolium salts.63 The sequence is summarized in Scheme 44.Benzo[f]indole-4,9-dioneshave been prepared by ther- mal condensation of 2-acetonyl-3-alkoxy- 1,4-naphthoquinones with primary amines (Scheme 45).64 Radical cyclization of allylic halogenoacetamides gives cis-fused 2-pyrrolidones and piper id one^,^^ triphenylgermanium hydride being preferable to tributyltin hydride (Scheme 46). In work on possible intermediates for the synthesis of Amaryl- lidaceae alkaloids,66 cerium (111) compound (54) was condensed with the cyclopen- 62 G. Dryhurst A. Anne M. Z. Wrona and D. Lemordant J. Am.Chem. SOC.,1989 111 719. 63 E. Vedejs and S. L. Dax Tetrahedron Lett. 1989 30,2627. 64 K. Maruyama A. Osuka K. Nakagawa T. Nabeshima and K. Tabuchi Synthesis 1989 628. 65 G. Stork and R. Mah Heterocycles 1989 28 723. 66 L. E. Overman and H. Wild Tetrahedron Lett. 1989 30,647. 204 D. E. Ames OSiMe,Bu' OSiMe2But OSiMezBut it J%fC"" 'N Reagents i Me,SiCN CsF; ii Bu~N+F-,H20; iii DDQ Scheme 44 0 0 Reagents i MeNH,; ii 2M-HCl Scheme 45 R ii iii ~ NCOCH2Br N aR aR CT;.. NCOCHzBr I H I H COCFS Reagents i (CF3C0)20 base; ii Ph3GeH AIBN; iii KF H20 Scheme 46 tanone (55) to form a single product (56). On heating with copper(I1) trifluoroacetate tandem aza-Cope and Mannich cyclization reactions gave hydroindolone (57; X = SiMe,Ph) and thence the 3-hydroxy compound (57; X = OH) (Scheme47).Isoindoles have been prepared by an ingenious sequence of cycloaddition re- arrangement and elimination reactions67 summarized in Scheme 48. Thermal reaction of triphenyl(viny1imino)phosphoranes (58) with tropones and oxidation of intermediate (59) provides a short route to 1-azaazulenes (60) (Scheme 49).68 Intramolecular Diels- Alder reaction of 3-( 3-indolyl)prop-2-enoates with olefinic substituents at the 1-position leads stereoselectively to fused indole compounds (Scheme 50).69 67 A. R. Katritzky M. H. Paluchowska and J. K. Gallor J. J. Heterocycf. Chem. 1989 26 421. 68 M. Nitta Y. Iino E. Hara and T. Kobayashi J. Chern. Soc, Perkin Trans. I 1989 51. 69 Y.Shimoji F. Saito S. Sako K. Tomita and Y. Morisawa Heterocycles 1989 29 1871. Heterocyclic Compounds4"+ao4 205 C12Ce NMe I SiMe2Ph CHzCN (54) (55) Reagents i Cu(OTf), A; ii HBF,-Et,O; iii H202 KF Scheme 47 mR3-H20%0 R2 I IRl \' HO A2 Rl Scheme 48 H (59) Scheme 49 206 D. E. Ames R'R2 = 2H(47%) (CH2),(87%) or (CH,),(20%) Scheme 50 An efficient synthesis of 1-ethoxyphosphindole oxide7' has been based on the nickel-catalysed reaction of ethyl 2-iodobenzoate with diethoxymethylphosphine (Scheme 51). 0' 'OEt Reagents i (EtO),PMe NiCI,; ii KOBu'; iii NaBH,; iv PBr,; v Et,N Scheme 51 Regioselective addition reactions of organometallic reagents with benzy-lideneimine (61) have been applied to the synthesis of pyrrolizidines.Use of a protected aldehyde group in the Grignard reagent gives (62) which on hydrolysis cyclizes to form the single isomer (63) of the hydroxypyrrolizidine (Scheme 52).71 Excellent stereoselectivity is also achieved in a synthesis of pyrrolizidin-2-ones by a radical cyclization process (Scheme 53).72 .OH 89% Ph Reagents i (1)-(CH2),MgBr; ii 1M-HCl EtOH; iii LiAIH Scheme 52 a An enantioselective synthesis of ~wainsonine,~~toxic fungal indolizidine alkaloid utilizes hydroxyester (64; X = OH) derived from 2,3- O-isopropylidene-~- erythrose. Conversion via tosylate to azide (64; X = N,) led to intramolecular 1,3-dipolar cycloaddition to give triazole (65). Loss of nitrogen forms ester (66; 70 A. Sedqui T.Lakhlifi B. Lande and-J. Amaudrut Bull. SOC.Chim. Belg. 1989 98 865. 71 D. H. Hua D. Bensoussan and A. A. Bravo J. Org. Chem. 1989 54 5399. 72 P. F. Keusenkothen and M. B. Smith Tetrahedron Lett. 1989 30 3369. 73 R. B. Bennett J.-R. Choi W. D. Montgomery and J. K. Cha J. Am. Chem. SOC.,1989 111 2580. Heterocyclic Compounds Reagents i Bu3SnH AIBN Scheme 53 R = Et) and thermal cyclization of the corresponding acid (66; R = H) gives lactam (67) which by hydration and removal of the protecting group is converted into trio1 (68) (Scheme 54). Reagents i NaN,; ii K,CO,-H,O; iii A; iv BH,; v H,O,-NaOH; vi 6M-HCl Scheme 54 Interesting sulphur heterocycles prepared from toluene-p-sulphonyl hydrazone (69) include the new welectron donor system (70) (Scheme 55).74 (70) Reagents i SOCl,; ii CS, A; iii P(OMe)3 A Scheme 55 C.Rovira N. Santa and J. Veciana Tetrahedron Lett. 1989 30,7249. 208 D. E. Ames An intramolecular aza-Wittig reaction has been applied to the synthesis of sub- stituted oxazoles (Scheme 56).75 \ N3 RZ R2 Reagents i LiNPrb; ii R3COCl; iii P(OEt), A Scheme 56 Regiospecific nucleophilic substitution reactions involving the attack of the N-atom of oximes on an epoxide have been used76 to generate nitrones; these are trapped in 1,3-dipolar cycloaddition reactions to form fused-ring isoxazolidines (Scheme 57). LiCl 60% -0 -t ,OH -N Scheme 57 Reissert compounds (71; X = 0 or S) have been prepared from the corresponding five-membered ring heterocycles (72) under non-aqueous conditions using trimethyl- silyl cyanide as the source of CN (Scheme 58).77 COR 1 Reagents i RCOCI Me3SiCN Scheme 58 Protection of pyrazole (73; R = H) as the 1-hydroxymethyl derivative (73; R = CH,OH) allows conversion into the dilithio derivative (74; X = Li) which reacts with electrophiles.For example benzaldehyde yields (74; X = CHPhOLi); treat- ment with acid then removes the metal and the protecting group to give the 5-substituted pyrazole (75).’* A review of pyrazole 1-oxides and 1,2-dioxides has been published.79 75 H. Takeuchi S. Yanagida T. Ozaki S. Hagiwara and S. Eguchi J. Org. Chem. 1989 54 431. 76 R. Grigg and J. Markandu Tetrahedron Lett. 1989 30,5489. 77 B. C. Uff Y.-P.Ho D. S. Brown I. Fisher F. D. Popp and J. Kant J. Chem. Res.(S) 1989 346. ” A. R.Katritzky P. Lue and K. Akutagawa Tetrahedron 1989 45 4253. 79 A. Kotali and P. G. Tsoungas Heterocycles 1989 29 1615. Heterocyclic Compounds 209 Cfi2% Art X = CHPhOLi b N' X N' I I R LiOCH2 (75) (73) (74) Propargyl azides undergo a base-catalysed prototropic rearrangement to short- lived allenyl azides. These rapidly cyclize to triazafulvenes which can be trapped by nucleophiles to form 1,2,3-triazoles (Scheme 59).80 H pNh 5 7% Me0-G nN3 2 [HycA~]-+ -*/ H H/ $ Nu N CH20Me CH20Me CH20Me Reagents i NaOMe; ii NuH (e.g. MeOH NH3) Scheme 59 7-Azaindolizine (76) shows lower propensity to undergo electrophilic substitution than indolizine (or other azaindolizines) and fails to undergo Vilsmeier formylation nitrosation or azo-coupling reactions." Chichibabin amination of (76) also fails but 8-halogeno and 8-methyl groups are reactive.5 Urothione (77) urinary metabolite of the molybdenum co-factor is a unique sulphur-containing pterin. Its structure has been confirmed82 by an unequivocal total synthesis of the (*)-mixture (10% overall yield in fourteen steps) (Scheme 60). It is based on thiophene annulation of chloronitrile (78) containing a protected amino group. After introduction of the methylthio group in (79) the carbonyl is converted into methoxy and the protecting group removed to give (80).Construction of the pyrimidine ring using guanidine and cleavage of the ether groups leads to the target molecule (77).In an efficient synthesis of benzoisothiazol-3-0nes~~ and benzoisoselenazol-3-ones benzanilide is dilithiated with n-butyl lithium. The salt (81) is treated with sulphur or selenium to introduce the element as in (82). Cyclization with copper(r1) bromide then gives the products (83) in good yields (X = S 44%; X = Se 63%). The selenium compound ebselen is used to treat cell damage caused by hydrogen peroxide etc. 8o K. Banert Chem. Ber. 1989 122 1963. 81 R. Buchan M. Fraser and P. V. Lin J. Org. Chem. 1989 54 1074. 82 E. C. Taylor and L. A. Reiter J. Am Chem. SOC.,1989 111 285. 83 L. Engman J. Org. Chem. 1989 54 2965. 210 D. E. Ames OMe CN / OMe + HSyOBui -x\s-(OMe12 [;I:?:: H NMe2 ii iii OBu' I (78) = X/CN \n.SMe OBu' 'OBu' (79) ix-xi. HN~I;& H ~~1:;fioMe H2N H2 N A N OBu' OH (80) (77) Reagents i EtNH2; ii LiBF, H20; iii NaOAc; iv Bu'ONO CuBr,; v NaSMe; vi NaBH,; vii HC(OMe), p-TsOH; viii MeOH p-TsOH; ix guanidine; x TFA; xi 3M-H2S04 Scheme 60 Di-t-butyldiazomethane and carbon diselenide react in hot toluene to form 2,2-di-t- butyl-5-(di-t-butylmethylene)-2,5-dihydro-l,3,4-selenadiazole (Scheme 61).84 31% I I CSe2 + Bu:C=N2 -Bu:C\ N=N /C=CBu Se Scheme 61 5 Six-membered Rings Cycloaddition reactions of heteroaromatic six-membered rings have been reviewed.85 Trimethylsilyl enol ethers of aldehydes and ketones react with carbon suboxide to form substituted 4-(trimethylsilyloxy)-2H-pyran-2-oneswhich are hydrolysed to give 4-hydroxy-2H-pyran-2-ones (Scheme 62).86 84 R.H. Berg N. Harrit E. Larsen and A. Holm Acta Chem. Scand. 1989,43 885. 85 A. R. Katritzky and N. Dennis Chem. Rev. 1989,89 827. 86 L. Bonsignore S. Cabiddu G. Loy and D. Secci Heterocycles 1989 29 913. Heterocyclic Compounds 21 1 OSiMe OH ii+ R2 0 Reagents i O=C=C=C=O; ii H,O Scheme 62 Problems arising in the synthesis of 4-chromanones by condensation of 2-hydroxyacetophenones with formaldehyde can be avoided by isolation of Mannich base hydrochloride (84) and cyclization by titration with potassium hydroxide (Scheme 63).87 Chromanochromanone (85) related to rotenone has been synthesized (Scheme 64).88 0 0 c1-(84) Reagents i HCHO-Me2NH; ii KOH Scheme 63 v vi I H (85) Reagents i Bu"Li HMPA; ii ZMeOC,H,COCl; iii Raney Ni; iv 12 EtOH; v BCI,; vi KOAc EtOH Scheme 64 Formation of a chromium complex of benzodioxin allows metallation and thence alkylation and functionalization at the 5-position (Scheme 65) whereas the uncom- plexed molecule reacts at C2.89 87 B.Cox and R. D. Waigh Synthesis 1989 709. S. M. F. Lai J. J. A. Orchison and D. A. Whiting Tetrahedron 1989 45 5895. 89 T. V. Lee A. J. Leigh and C. B. Chapleo Tetrahedron Lett. 1989 30,5519. 212 D. E. Ames Li PhCH2 Reagents i Bu"Li; ii PhCH,Br; iii I Scheme 65 OH OH I I Ph2v 2Phyo\l PhCH-0-0-CHPh + 0 40y0 0,0,CPh2 Reagents i WO,; ii CIS03H Scheme 66 172,4-Trioxanes can be obtained by treating peroxides and epoxides with tung- sten(v1) oxide and then with acid (Scheme 66).90 Conformational analysis of six-membered sulphur-containing saturated heterocycles has been reviewed." Optically active thiadecalins and thiahydrindans have been prepared by a proline-catalysed intramolecular Michael reaction (Scheme 67).92 Chiral 2,6-dithiabicyclo[3.1 .l]heptane (86) the dithia-analogue of 0 H Reagent i L-proline Scheme 67 the parent ring of the thromboxane A2nucleus has been ~ynthesized.~~ (-)-Menthy1 mercaptoester (87) adds to thiapyrone (88) to form thioether (89) and reduction then gives alcohol (90) as the major isomer (2 1 ratio).Chromatographic separation of the isomers and cyclization via the mesylate affords the (+)-enantiomer of bicyclic product (86) (Scheme 68).Selenoxanthen-9-ones are obtained by coupling benzyne intermediates with selenium-lithiated selenosalicylamides (Scheme 2-Dialkylaminopyridines can be prepared from aminonitriles and acetylene by a cobalt-catalysed process (Scheme 70) ?5 5-Alkyl-2-(p-toluenesulphony1)pyridines T.Fujisaka M. Miura M. Nojima and S. Knsabayashi 1 Chem. Soc. Perkin Trans. 1 1989 1031. 91 E. Juaristi Acc. Chem. Res. 1989 22 357. 92 A. P.Kozikowski and B. B. Mugrage J. Org. Chem. 1989 54 2274. 93 K. Steliou and G. Milot J. Org. Chem. 1989 54 5821. " M. Watanabe M. Date M.Tsukazaki and S. Furukawa Chem. Pharm. Bull. 1989 37 36. 95 A. P. Ivanov D. Z. Levin E. S. Mortikov and V. K. Promonenkov J.Org. Chem. USSR 1989,25,629 (Engl. Transl. p. 566). 213 Heterocyclic Compounds b0LSH+b S + Q-iii iv A (90) Reagents i PriNEt2; ii LS-Selectride; iii MsC1 Et,N; iv (Me3Si),NLi Scheme 68 Reagents i lithium N-isopropylcyclohexylamide;ii PhBr Scheme 69 R' I __+ NC-C-NR3R4 i QE1,R3R4 I R2 I R2 Reagents i HC-CH CoCp, A Scheme 70 +[ ]-"Q RQ SO,Ar R4+ ArSo2CN EtO S02Ar OEt Scheme 71 are formed by [4 + 21 cycloaddition of tosyl cyanide to 2-alkyl-l-ethoxybuta-1,3-dienes followed by aromatization of a dihydropyridine (Scheme 71).96 Efficient deoxygenation of heteroaromatic N-oxides can be achieved at room temperature using ammonium formate as hydrogen transfer agent and a palladium catalyst in methanol.97 96 U.Ruffer and E. Breitmaier Synthesis 1989 623. 97 R Balicki Synthesis 1989 645. 214 D. E. Ames Diastereoselective aza-Diels-Alder reaction using tetra-0-pivaloylgalac-topyranosylamine (91) as a chiral template allows the synthesis of enantiomerically pure 2-substituted piperidines e.g. tobacco alkaloid (S)-anabasin (Scheme 72).98 F& RO X-N+?c! XCs RO NH2 / RO H \ (91) = XNH,(R = Bu'CO) N ii-iv 192% Reagents i MeOCH=CHC(OSiMe,)=CH, ZnCl,; ii Selectride; iii (HSCH2)2 BF,-EtzO; iv Raney Ni; v HCI MeOH Scheme 72 Pyrimidines carrying an w-alkynyl side chain at the 2-position undergo intramolecular inverse electron demand Diels- Alder reactions across the C2 and C5 positions. Loss of hydrogen cyanide by a retro-Diels-Alder reaction then leads to annulated pyridines (Scheme 73).99 Scheme 73 The first total synthesis of the alkaloid (*)-meloscine has been accomplished by a highly stereocontrolled sequence."' This shows the value of tandem cationic aza-Cope rearrangement and Mannich cyclization reactions [(92) 4(93)] and is summarized in Scheme 74.A convenient route to chiral indolizidines is based on 1,4-addition-ring closure reactions of chiral a-sulphinyl ketimine anions with unsaturated esters (Scheme 79.''' 98 W.Pfrengle and H. Kunz J. Org. Chem. 1989,54 4261. 99 A. E. Frissen A. T. M. Marcelis G. Geurtsen D. A. de Bie and H. C. van der Plas Tetrahedron 1989 45 5151. 100 L. E. Overman G. M. Robertson and A. J. Robichaud J.Org. Chem. 1989 54 1236. 101 D. H. Hua S. N. Bharathi F. Takusagawa A. Tsujimoto J. A. K. Panangadan M.-H. Hung A. A. Bravo and A. M. Erpelding J. Org. Chem. 1989 54 5659. Heterocyclic Compounds 76% “’?OR R = CH,Ph Y = NHCOBU‘ i ii I78% ON,CO \ H (93) (92) Reagents; i Ph,P=CH2; ii KOH EtOH H20 Scheme 74 V c- 85% Reagents i Bu”Li; ii CH,=CHCO,Et; iii NaCN-BH, HOAc CF,C02H; iv Raney Ni; v LiAIH4 Scheme 75 Iminophosphorane (94) reacts with isocyanates to give 2-alkylamino-3-nitro-9- phenyl-9H-pyrido[ 2,3-b]indoles (95).’02 Annulation of the pyridine ring onto indole occurs by a tandem aza-Wittig-electrocyclization strategy (Scheme 76). Rhodium(11) acetate catalyses the decomposition of vinyl diazomethanes in the presence of N-alkoxycarbonylpyrrolesto provide a direct route to the skeleton of the tropane alkaloids (Scheme 77).’03 (3 S,4S) -3 -Carboxy-4-hydroxy-2,3,4,5-tetrahydropyridazine (96) is an unusual amino acid constituent of the anti-tumour agent Luzopeptin A.An enantiospecific synthesis (Scheme 78) of (96) has been reported. lo4 102 P. Molina and P. M. Fresneda Synthesis 1989 878. 103 H. M. L. Davies W. B. Young and H. D. Smith Tetrahedron Lett. 1989 30,4653. 104 P. Hughes and J. Clardy J. Org. Chem. 1989 54 3260. 216 D. E. Ames I Ph Ph 1 (94) 80% Q&-JQNO' NHEt I Ph Reagents i EtNCO A (95) Scheme 76 NC02Me ll C02Me COzEt COZEt Scheme 77 .. ... II 111 I K'O Me02C I NHNHp (96) Reagents i Bu'OOH Ti(OPr'), L(+)-diethyl tartrate; ii RuO,; iii CH2N2; iv K2C03 MeOH H,O; v NH2NH2.H20; vi CF3C02H H20 Scheme 78 Phthalazine forms a Reissert compound (97) on treatment with trimethylsilyl cyanide benzoyl chloride and aluminium ~hloride."~ The anion from (97) con-denses with aldehydes to give a 1-substituted phthalazine (98) (Scheme 79).Lithiation of phenoxazine (99) with butyllithium occurs regiospecifically adjacent to the oxygen atom i.e. at the 4-and/or 6-positions. This has been applied to the syntheses of 4-mOnO- and 4,6-disubstituted phenoxazines; the N-protecting group can be removed by catalytic reduction.'06 B. C. Uff,Y.-P. Ho F. Hussain and M.S. Haji J. Chem. Res.(S) 1989 24. Y. Antonio P. Barrera 0.Contreras F. Franco E. Galeazzi J. Garcia R. Greenhouse A. Guzman E. Velarde and J. hl. Muchowski J. Org. Chem. 1989 54 2159. Heterocyclic Compounds H' CN A~CHOH (97) (98) Reagents; i NaH; ii ArCHO; iii KOH H,O EtOH Scheme 79 I MeCHPh (99) 2-Substituted pyrido[3,2-e]- 1,3 -thiazin-4(4H)-ones ( 100) have been prepared from the sodium derivative of 2-chloronicotinamide (101) and thioester~.'~' Diazoalkanes react as ylides with tetrasulphur tetranitride to give red crystalline trithiadiazines ( 102).'08 0 flcoNHz NaH; RCS(0Et); H,O 63% N C1 - + 38% SXS S4N4 H Ph The tellurium heterocycle (103) has been prepared from ylide (104) and elemental tellurium. Tellurobenzaldehyde is formed and is trapped with dimethylbutadiene to obtain ( 103).'09 Te Ph3PCHPh L_ [Te=CHPh] n '(104) Ph (103) 107 A.Couture P. Grandclaudon and E. Huguerre Tetrahedron 1989 45 4153. 108 R. M. Bannister and C. W. Rees J. Chem. SOC.,Perkin Trans. 1 1989 2503. 109 G. Erker and R. Hock Angew. Chem. Znt. Ed. Engf. 1989 28 179. 218 D. E. Ames Diels- Alder reactions of cr-pyrones with phosphaalkynes yields phosphinines (Scheme 80). The process has been applied to the preparation of 2-hydroxyphos-phabenzene ( 105).110 This is a genuine heterocyclic phenol which undergoes 0-methylation not P-methylation. Me3Si0 Me3Si0 But HO But Reagents i Bu'CEP; ii H+,MeOH Scheme 80 6 Seven-membered Rings Oxepanes have been prepared by new routes. First by a rhodium( 11)-carbenoid- mediated cyclization (Scheme 81)"' and second by an acid-catalysed ring opening of hydroxyepoxides (Scheme 82).lt2In the case of (106) oxepane (107) constitutes 82% of the mixed products.Benzoxepine-3,5(2H,4H)-diones(108) have been pre- pared (Scheme 83) by a Claisen conden~ation."~ Me Scheme 81 HO H (106) (107) Reagents i camphorsulphonic acid Scheme 82 0 L "VC Et NaOEt R2 OAMe Me R3 R3 (108) Scheme 83 'lo G. Mark1 and A. Kallmunzer Tetrahedron Lett. 1989 30,5245. 111 M. J. Davies J. C. Heslin and C. J. Moody J. Chem. SOC.,Perkin Trans. 1 1989 2473. 112 K. C. Nicolau C. V. C. Prasad P. K. Somers and C.-K. Hwang J. Am. Chem. SOC.,1989 111 5335. 113 G. Gabriel R. Pickles and J.H. P. Tyman 1. Chem. Res. (S) 1989 348. Heterocyclic Compounds Flash vacuum pyrolysis of the Meldrum's acid derivative (109) at 500 "C gives good yields of lH-azepin-3(2H)-one (1 10). X-Ray studies show that the dienaminone conjugated system is approximately planar although the ring as a whole is markedly n~n-planar.''~ A synthesis of fused-ring azepine-2,Sdione (1 11) is based on a photochemical [2a + 2~1 ring expansion of a substituted N-pentenylphthalimide (1 l2).Il5 N NMe2 Me 0 Two separate Michael additions of methyl propynoate occur at the methyl group and nitrogen atom of 2-methylbenzothiazole to form a mixture of azepine derivatives (113; R = H and CH=CHCO2Me).ll6 The annual herb Isotropis forrestii poisons sheep in Australia.The nephrotoxic compound (+)-iforresthe has been isolated and shown117 by X-ray studies to be the fused-ring 1,4-diazepinedione (114). 54 MeOzC Co2Me 114 A. J. Blake H. McNab and L. C. Monahan J. Chem. SOC.,Perkin Trans. 1 1989 425. 115 M. A. Weidner-Wells A. Decamp and P. H. Mazzochi J. Org. Chem. 1989 54 5746. 116 R. M. Letcher K.-K. Cheung and D. W. M. Sin 1. Chern. Res. (S) 1989 115. 117 S. M. Colegate P. R. Dorling C. R. Huxtable T. J. Shaw B. W. Skelton P. Vogel and A. H. White Aust. J. Chem. 1989 42 1249. 220 D. E. Ames 5-( Chloromethy1)tetrazole reacts with hexamine in aqueous ethanol to give the methanoditetrazolo[ 1,3,6,8]tetrazecine (1 15) in which two seven-membered rings have an NCH2N unit in common."8 Photochemical oxidation of the pyrazine (1 16) produces endoperoxide (117) which is converted into the 1,3,6-oxadiazepine (1 18) by triphenylphosphine (Scheme 84).l19 Reagents i 02,hv Methylene Blue; ii PPh Scheme 84 Cyclization of the substituted nicotinoyl chloride (119) (Scheme 85) forms a pyrido[3,2-f]-1,4-oxazepinone(120; X = 0;Y = C1) which reacts with dimethyl- amine to give the base (120; X = 0 Y = NMe2).12' Analogues (120; X = S and CHJ were also prepared.An intramolecular Pictet-Spengler reaction of the N-hydroxytryptamine deriva- tive (121) gave the oxathiazepine system (122).121 D. Moderhack K.-H. Goos and L. Preu Liebigs Ann. Chem. 1989 689. 119 I. M. Dawson A. J. Pappin C. J. Peck and P. G. Sammes J. Chem. Soc. Perkin Trans.1 1989 453. 120 A. D. Cale T. W. Gero K. R. Walker Y.S.Lo W. J. Welstead L. W. Jaques A. F. Johnson C. A. Leonard J. C. Nolan and D. N. Johnson J. Med. Chem. 1989,32 2178. P. H. H. Hermkens J. H. van Maarseveen C. G. Kruse and H. W. Scheeren Tetrahedron Lett. 1989 30,5009. Heterocyclic Compounds 7 Larger Rings With research in the field expanding rapidly the publication of an updated volume ‘Crown Ethers and Analogs’ is welcome.’22 Macrocyclic lactones have been obtained’23 by cyclization of (a-carboxyalky1)sul- phonium salts (123) (Scheme 86). The formation of mono- and dilactones is solvent- dependent e.g. (123; n = 10) gives mainly dilactone (124) in acetonitrile but predominantly monolactone (125) in acetone. Scheme 86 Hydrolysis of racemic medium-ring lactones with horse or pig liver esterase gives the lactone with excellent enantiomeric excess and provides a general procedure for obtaining optically pure medium-ring lac tone^.'^^ The 18-membered ring lichen macrolide (+)-aspicilin (126) has been built up in fifteen steps (13% overall yield)’25 from D-mannose which provides the stereogenic centres at C4 C5 and C6.The stereogenic centre at C17 is derived from (S)-ethyl lactate. The final steps of the synthesis are summarized in Scheme 87 which shows the cyclization step and the removal of protecting groups. m-: )Me . ... 1-111 -51% H‘ Me 0 (126) Reagents i Et3N 2,4,6-trichlorobenzoyl chloride; ii pyrrolidinopyridine; iii CF3C02H MeOH Scheme 87 New methodology for the synthesis of macrolactones has been applied to the preparation of the dihydroxybislactone colletodiol ( 127).’26 The route is summarized in Scheme 88.A silver ion-induced cyclization of hydroxydithioketals (128) gives oxacene (129; X = SEt); oxidative removal of the thioether group with peracid followed by I22 E. Weber J. Toner I. Goldberg F. Vogtle D. A Laidler J. F. Stoddart R. A. Bartsch and C. L. Liotta ‘Crown Ethers and Analogs’ John Wiley New York 1989. 123 H. Matsuyama T. Nakamura and N. Kamigata J. Org. Chem. 1989 54 5218. 124 E. Fouque and G. Rousseau Synthesis 1989 661. 125 G. Quinkert E. Fernholz P. Eckes D. Neumann and G. Durner Helu. Chim. Acta 1989 72 1753. 126 G. E. Keck E. P. Baden and M.R. Wiley J. Org.Chem. 1989 54 896. 222 D. E. Ames OCH2SMe Ox O u * . M e 1+ HO “ ‘0 S d . . Me (127) Reagents i AgNO H20 2,6-lutidine ii dicyclohexylcarbodiimide;iii H+ resin H20 MeOH Scheme 88 .. I-1v + & Me (128). (129) Reagents i N-chlorosuccinimide; ii AgNO,; iii MCPBA; iv Et,SiH BF,*Et,O Scheme 89 triethylsilane then provided the product (129; X = H) in 88% overall yield (Scheme 89).’27 Two interesting routes to oxathiocine derivatives have been reported. First an intramolecular ene reaction of an unsaturated thioketone (130) gives ( 131).12’ Second in a rhodium( 11)-catalysed process tetrachlorothiophene and diazoketone (132) form the stabilized thiophenium S,C-ylide (133) which on warming rearranges to the 1,4-0xathiocine (134) (Scheme Ph Ph 127 K.C. Nicolau C. V. C. Prasad C.-K. Hwang M. E. Duggan and C. A. Veale J. Am. Chem. SOC.,1989 111 5321. 128 S. Motoki T. Watanabe and T. Saito Tetrahedron Lett. 1989 30,189. 129 0. Meth-Cohn E. Vuorinen and T. A. Modro J. Org. Chem. 1989 54,4822. 223 Heterocyclic Compounds c1 c1 67% Me 0 c1 (132) (133) (134) Reagents i Rh2(OAc), tetrachlorothiophene; ii A Scheme 90 Cycloaddition of nitrone (135) to methylenecyclobutane formed isoxazolidine (136) which on flash vacuum photolysis at 500 "C,rearranges to seven and nine- membered ring products (137; 42%) and (138; 12%) respectively (Scheme 91).130 A photochemical 1,2-addition of nitrile group to phenol provides a new route to azocinones (Scheme 92).13' N 70% a H Ph 0 Ph/ '0-Ph (135) (136) (137) Reagents i methylenecyclobutane Scheme 91 I-- Scheme 92 Oxidation of N-acylenamides of dihydrobenzazepines e.g.(139) with lead tetraacetate effects ring expansion and leads conveniently to N-acyltetrahydroben- zazocines (140).'32 76% -Me0 Pb(OAc) " T N COMe Meoq, Me0 CHI 0 I3O F. M. Cordero A. Goti F. De Sarlo A. Guama and A. Brandi Tetrahedron 1989 45 5917. 131 N. Al-Jalal J. Chem. Res. (S) 1989 110. 132 R. A. Lessor P. W. Rafalko and G. R. Lenz J. Chem. SOC.,Perkin Trans. 1 1989 1931. 224 D. E. Ames The use of methyl azidoformate in a nitrene insertion reaction with the methylene- bridged cyclopentadecaene (141) forms ester (142; R = C0,Me).Removal of the methoxycarbonyl group gives 4,9-methano-1 H-aza[ 1llannulene (142; R = H) a 12~-homologueof pyrr01e.l~~ X-Ray evidence shows that the double bonds are localized. 3,7-Diphenyl-1,5-dithia-2,4,6,8-tetrazocine ( 143) has been prepared by two routes. In the fir~t,”~ action of lithium bis( trimethylsily1)amide on benzonitrile gives amidine salt (144) which reacts with sulphur dichloride to form the heterocycle (143). In the second the product is obtained by reaction of benzamidine with bis(phtha1imido)sulphide and bis( ptoluenesulphony1)sulphurdiimide (Scheme 93). Heterocycle (143) is planar but one dimethylamino substituent group is enough to destroy the planarity of the ring.’35 (144) (143) Reagents i S2C12;ii benzarnidine; iii Ts=N=S=NTs Scheme 93 Nine-membered diazonine ring products are formed by oxidation of tetrahydro-P-carboline derivatives (145) with sodium ~eri0date.I~~ The indole ring is cleaved at the 2,3-bond but mono- or dicarbonyl compounds may be produced according to the substituents in the starting material (Scheme 94).C02Me C02Me NalO -R = H;42% -I .I %NH NalO R =Me; 62% HRR Scheme 94 133 W. Lange W. Haas H. Schickler and E. Vogel Heterocycles 1989,28 633. 134 U.Scholz H. W. Roesky J. Schimkowiak and M. Noltemeyer Chem. Ber. 1989,122 1067. 135 M.Amin and C. W. Rees J. Chem. SOC.,Chem. Comrnun. 1989 1137. 136 F.Gatta and D. Misiti J. Heterocycl. Chem. 1989,26 537. Heterocyclic Compounds 225 A one-step ring enlargement reaction with isocyanates has been used to convert P-ketoester or P-ketonitrile systems into macrocyclic imides (Scheme 95) the C-N atoms of the cyanate group being inserted into the ring.I3’ Ar - ArNCO ‘0” Scheme 95 Tetraaza[ 14lannulenes (146) have been prepared by reaction of enamine salt (147) with o-phenylenediamine.13’ Condensation of 1-ethyl-3,4-diformyl-2,5-dimethylpyrrole (148; R = Et) with 1,2-diaminoethane gives the dipyr-rolotetraazacyclohexadecine (149; R = Et; 69%). When pyrrole (148; R = H) is used the product (80%) exists predominantly as (150) a 2-azafulvene 2c10; (147) R “‘fiMe (“ ”) N OHC N Mel$:R MegMe R (148) (149) 137 V. I. Ognyanov and M. Hesse Helv. Chim.Acta 1989 72 1522.138 F. Adams R. Gompper and E. Kujath Angew. Chem. Int. Ed. Engl. 1989 28 1060. 139 S. A. N. Taheri R. 4. Jones S. S. Badesha and M. M. Hania Tetrahedron 1989 45 7717. 226 D. E. Ames The effect of 0-substituents on the synthesis of tetraphenylporphyrins has been in~estigated.'~' Improved yields of 2-alkyl- 2-alkoxy- and 2.6-dialkoxyphenyl com- pounds were obtained using boron trifluoride-ethanol co-catalysis but halogeno- substituted compounds failed to react. Photochemical cyclization of an 18r-electron open-chain precursor has been achieved141 as the key step in syntheses of two 20-methyl isobacteriochlorins and two-20-cyano-compounds (Scheme 96). H AMe = CH2C02Me PMe= CH2CH2C02Me Reagents i MeOH HC(OMe)3 CF3C02H hv H Scheme 96 140 J.S. Lindsey and R. W. Wagner J. Org. Chem 1989 54 828. 141 D. M. Amott P. J. Harrison G. B. Henderson Z.-C. Sheng F. J. Leeper and A. R. Battersby J. Chem. SOC. Perkin Trans. 1 1989 265.