7 Heterocyclic Compounds By D. E. AMES Department of Chemistry Queen Mary and Westfield College London El 4NS 1 Introduction Reviews of aromaticity’ and prototropic tautomerism2 of heteroaromatic compounds have been published. Other reviews have covered heterocycles in bio-organic chemistry3 and the use of isothiocyanates in synthesis of heterocycle^.^ 2 Three-membered Rings Highly enantioselective epoxidation catalysts derived from trans-1,2-diaminocyclo-hexane have been introduced.’ For example an 84% yield of oxirane with 92% ee is obtained from (2)-1-phenylprop-1-ene when catalyst (1) is used with sodium hypochlorite as oxidant. Lithiation of phenylsulfonyloxiranes (2; R = H) with butyl lithium at low tem- peratures occurs a to the sulfonyl group.The unstable anions (2; R = Li) react with electrophiles to form functionalized phenylsulfonyloxiranes e.g. acetone gives (2; R = C(OH)Me,) in 67% yield.6 2-Substituted oxiranemethanols (3) have been resolved by enzymatic trans-acetyla- tion using Pseudornonas fluorescens lipase as biocatalyst with vinyl acetate as an acyl donor.’ For example (R,S)-(3) yielded alcohol (4) and acetate (5) in 35-38% yields and 96% ee (Scheme 1). * A. R. Katritzky M. Karelson and N. Malhotra Heterocycles 1991 32 127. A. R. Katritzky M. Karelson and P. A. Hams Heterocycles 1991 32,329. ‘Heterocycles in Bio-organic Chemistry’ ed. J. Bergman Royal Society Chemistry 1991. A. K. Mukerjee and R. Ashare Chem. Reu. 1991,91 1. E. N. Jacobsen W. Zhang A. R. Muci J.R. Ecker and L. Deng J. Am. Chern. Soc. 1991 113,7063. M.Ashwell W. Clegg and R. F. W. Jackson J. Chem. Soc. Perkin Trans. 1 1991 897. ’ P. Ferraboschi D. Brembilla P. Grisenti and E. Santaniello J. Org. Chem. 1991 56 5478. 149 150 D. E. Arnes OH AcO (3) (4) (5) R = n-CgHI9 Reagents i Lipase vinyl acetate Scheme 1 2,3-Dimethylbenzo[ blfuran (6) has been oxidized with dimethyldioxirane to form 2,3-epoxy-2,3-dihydro-2,3-dimethylfuran (7).*This is the proposed ultimate car- cinogen of the benzofuran dioxetane (8) which has also been reduced to oxirane (7) (Scheme 2). 07Me +iQ-Jo c-ii Q3y \ ' 'Me \ \ 0 0 Me Me -Scheme 2 N-Ethoxycarbonylaziridines (9) undergo a smooth thermal transformation into 1,3-oxazolidin-2-ones (10) on flash pyrolysis.' The tandem reaction sequence is equivalent to direct insertion of carbon dioxide into the parent 1H-aziridine (Scheme 3).n N-0,C,NH I II (9) 0 (10) Reagents i Flash pyrolysis Scheme 3 A photochemical reaction of the l-pyridinium alkenylborane (1 1; R = 1-C5H5N+) forms the air-sensitive trans-boratirane (12; R = 1-C5H5N+).'* Similarly (1 1; R = Ph) as the tetramethylammonium salt gives the analogous ion (12; R = Ph)." R Ph \-/ Ph B-C H =CHPh I R Ph (11) W. Adam L. Hadjiarapoglou T. Mosandl C. R. Saha-Moller and D. Wild Angew. Chem. Znr. Ed. Engl. 1991 30,200. M. R. Banks J. I. G. Cadogan I. Gosney P. K. G. Hodgson and D. E. Thomson J. Chem. SOC.,Perkin Trans. 1 1991 961. S.E. Denmark K. Nishide and A.-M. Faucher J. Am. Chem. SOC.,1991 113 6675. M. A. Kropp M. Baillargeon K. M. Park K. Bhamidapaty and G. B. Schuster J. Am. Chem. SOC. 1991 113 2155. Heterocyclic Compounds The halogen-substituted carbenes generated by thermolysis of diazirines (13) add onto phosphaalkynes to form adducts (14) which rearrange to 1-halogeno-1H-phosphirenes (15) (Scheme 4).12 r R2 1 (14) Reagents i A R’CGP Scheme 4 (16) Ar = 2,4,6-tri(t-butyl)phenyl 1 (18) @Ph2 -ArP’I ‘C %C12 (17) Reagents i CC14 BuLi Scheme 5 Reaction of dichlorocarbene with phosphabutatriene (16) gives the dialkyl- idenephosphirane (17) via ethenylidenephosphirane (18) (Scheme 5).13 A diphosphirenium salt (19) has been prepared by cyclization of (20).14 X-Ray evidence indicates that the ion is planar at C-1 and N-2 showing substantial participation of resonance structure (21) in the ion (Scheme 6).A (20) R = Pr’ (19) Reagents i BF3-Et,N Scheme 6 3 Four-membered Rings Photolytic reaction of benzophenone with alkenyl methyl sulfides gives 3-methyl- thiooxetanes regio- and stereo-selectively (Scheme 7).15 12 0. Wagner M. Ehle M. Birkel J. Hoffmann and M. Regitz Chem. Ber. 1991 124 1207. 13 K. Toyota H. Yoshimura T. Uesugi and M.Yoshifuji Tetrahedron Lett. 1991 32 6879. 14 F. Castan A. Baceiredo J. Fischer A. De Cian G. Commenges and G. Bertrand J. Am. Chem. Soc. 1991 113 8160. Is N. Khan T. H. Moms E. H. Smith and R. Walsh J. Chem. Soc. Perkin Trans. 1 1991 865.152 D. E. Ames i Ph2C-0 MeS H MeS H Reagents i Ph2C0 hv Scheme 7 Whereas 2,2-dialkyloxetanes (22) are cleaved by lithium 4,4’-di-t-butylbiphenylide (LDBB) to form primary organolithium-tertiary oxyanions (23) in the presence of triethylaluminium 3-lithio-3,3-disubstitutedpropoxides (24) are produced exclus- ively.I6 Trapping with carbonyl compounds generates diols e.g. (25) and (26) respectively (Scheme 8). OH (25) OH CHMe2 iii bd?6 OH Reagents i LDBB; ii Et,AI; iii Me,CHCHO Scheme 8 Treatment of 3-(chloromethyl)azetidin-2-ones (27) with sodium ethoxide-dimethylformamide effects rearrangement to the azetidine-3-carboxylic acid esters (28) in high yields.” Highly selective reduction of P-lactams (29; X = 0) to azetidines (29; X = H2)has been achieved in high yields using dichloroalane (AIHC~~).~~ R2 R2 EtO2CQ H20wp NR’ XC-NCHZPh An efficient synthesis of l-acetyl-2-azetidine (30)19 utilizes (3 1) which is obtained from epichlorhydrin and benzhydrylamine.Mesylation hydrogenolysis and acetyla- tion give amide (32). Elimination of mesylate forms azetine (30). This on pyrolysis undergoes electrocyclic ring opening to generate l-acetyl-1 -azabutadiene (33) (Scheme 9). 16 B. Mudryk and T. Cohen J. Org. Chem. 1991,56 5760. 17 D. Bartholomew and M. J. Stocks Tetrahedron Lett. 1991 32 4795. 18 I. Ojima M. Zhao T. Yamato and K. Nakahashi J. Org. Chem. 1991 56 5263. 19 M. E. Jung and Y. M. Choi J. Org. Chem. 1991 56 6729. Heterocyclic Compounds MsO ..I-LV -* "OD (32) (30) NCHPh2 79% 'NCOMe 'NCOMe N (31) I COMe (33) Reagents i MsCl Et3N; ii HCl; iii H2-Pd; iv MeCOCl Et3N; v KOBU'; vi flash vacuum pyrolysis Scheme 9 Tetraphenylporphine-sensitized photooxygenation of benzofurans (34) gives dioxetanes (35) (Scheme 10) which are strongly mutagenic.20 Similarly singlet oxygen in a dye-sensitized photooxygenation of 4,5-dimethyl-2,3-dihydrothiophene (36)gives dioxetane (37)which is stable at low temperatures but forms keto-thioester (38) on warming (Scheme 11).21 (34) (35) (Yield 53% when R' = R2 = Me) Reagents i 02,TPP hv Scheme 10 Me 10 ii I\COMe Reagents i O,-hv; ii A Scheme 11 Silicon-functionalized silacyclobutenes (39) have been prepared from tri-chloro(viny1)silane (0) by action of t-butyl lithium to generate the unstable inter- mediate (41)(Scheme 12).22Cycloaddition to alkyne forms the silacyclobutene (39; X = C1) and then by reduction with lithium aluminium hydride (39;X = H).C1,SiCH = CH -!+ [C12Si=CH-CH2But] -!!+ (40) (41) (39) Reagents i Bu'Li; ii PhC-CSiMe Scheme 12 2o W.,Adarn 0.Albrecht E. Feineis I. Reuther C. R. Saha-Moller P. Seufert-Baumbach and D. Wild Liebigs Ann. Chem. 1991 33. 21 K. Gollnick and K. Knutzen-Mies J. Org. Chem. 1991 56 4027. 22 N. Auner C. Seidenschwarz and E. Herdtweck Angew. Chem. Int. Ed. Engl. 1991 30,1151. 154 D. E. Ames p-Lactams.-Rhodium diacetate-induced intramolecular insertion reactions of diazomalonic acid methyl ester and diethylamide (42) gives P-lactones (43) and P-lactams (44) respectively (Scheme 13).23 Me02C po-Me02C c’,N2 X = OMe I X = NEt -Me02C-* i,40% NEt 0 Reagents i Rh2(OAc) Scheme 13 Conversion of /3 -halogenopropanamides into monocyclic p -1actams has been effected under phase-transfer conditions using crown ethers tris(po1yoxa-alky1)amines or quaternary phosphonium halides as catalysts.24 The vinylaziridine (45) prepared efficiently by cyclization of the allylic mesylate (46) undergoes highly stereoselective conversion into azetidinone (47) by a palladium(0)-catalysed carbonylation process (Scheme 14).25 @CH2Ph -i MsO-CHzPh N HNCO,CH,Ph 700h COzCHzPh OCH2Ph 1 0&NCO2CH2Ph Reagents i NaH; ii Pd2(dba), Ph3P CO (47) Scheme 14 Treatment of 2-pyridylthioesters (48) with triethylamine and titanium( IV) chloride affords titanium enolates which add to imines to give p-lactams with moderate stereoselectivity (Scheme 15).26 (48) Reagents i TiC14 Et3N; ii PhCH=NCH,Ph Scheme 15 23 V.G. S. Box N. Marinovic and G. P. Yiannikouros Heterocycles 1991 32 245. 24 M. J. Meegan B. G. Fleming and 0. M. Walsh 3. Chem Rex (S) 1991 156. 25 G. W. Spears K. Nakanishi and Y. Ohfune SYNLET 1991,91. 26 M. Cinquini F. Coui P. G. Cozzi and E. Consolandi Tetrahedron 1991 47 8767. Heterocyclic Compounds 155 P-Lactams with an exocyclic double bond have been prepared from a-methylene P-aminoacid hydrochlorides according to Scheme 16.27 Palladium-catalysed carbonylation of 4-amino-2-alkynyl carbonates (49) pro- ceeds via allenic intermediates to form the alkynyl-substituted azeridinone (50) (Scheme 17).28 Reagents i MsCI Bu,N+HSO; KHCO, CHCI, H20 Scheme 16 R R 66% )--E-CMe2 2 I Me02C0 NHTs (49) R = n-C,HI5 MeOPd L Reagents i Pd(OAc), CO K2C03 PqO ''Y;A J 0 Scheme 17 4-Acetoxy-2-azetidinone has been obtained from the 4-carboxylic acid by elec- trolysis in the presence of sodium acetate and acetic acid.29 3-Amino-2-azetidinones have been reviewed3' and the compounds have been prepared by reaction of imines with amino-esters as the zinc enolates3' and the aluminium enolate~.~~ Turning to fused-ring p-lactams the keto-ester (51; X = H) has been converted into the diazo-compound (51;X = N) which undergoes a rhodium-catalysed cycliz- ation to form the 1-carba-1-dethiapenam (52) with elimination of the N-benzyloxy- group (Scheme 1 8).33 30% (51) C02Me (52) Reagents i Rhz(OAc2), A Scheme 18 27 R.Buchholz and H. M. R. Hoffmann Helv. Chim Acta 1991 74 1213. T. Mandai K. Ryoden M. Kawada and J. Tsuji Tetrahedron Lett. 1991 32 7683. 29 M. Mori K. Kagechika H. Sasai and M. Shibasaki Tetrahedron 1991,47 531. 30 F. H. van der Steen and G. van Koten Tetrahedron 1991 47 7503. 31 F. H. van der Steen H. Kleijn J. T. B. H. Jastrzebski and G. van Koten J. Org. Chem. 1991 56 5147. 32 F. H. van der Steen G. P. M. van Mier A. L. Spek J. Kroon and G. van Koten J. Am. Chem. SOC. 1991 113 5742. 33 M. A. Williams C.-N.Hsiao and M. J. Miller J. Org. Chem. 1991 56 2688. 156 D. E. Ames An enantio-controlled synthesis of the antifungal P-lactam (2K5S) -2- (hydroxy- methy1)clavam (53) has been achieved.34 The acetoxy-lactam (54) was condensed with chiral alcohol (55) to form ether (56). Removal of the phthaloyl and silyl protecting groups and diazotization generated chloro-compound (57) which was protected and reduced to give (58). Conversion of tosylate into iodide followed by treatment with potassium carbonate effected ring closure to form the clavam skeleton and removal of the silyl group completed the synthesis of the target structure (53) (Scheme 19). XNyoAc + H& ,,', X y N y 0 NH OTs 0 OTs OR (54) X = phthaloyl (55) R = SiMe,Bu' (56) Reagents i Zn(OAc), A; ii NH,NH,; iii HCI H20 KNO,; iv K2C03 H,O; v CISiMe,Bu'; vi Bu3SnH azobisisobutyronitrile (AIBN) A; vii NaI; viii K2CO3 ;ix Bu4N+F- HOAc Scheme 19 -..p-; 55% 0 0 0 (59) Scheme 20 Photolysis of N-(methacryloyl) thioamide (59) generates an n7r* triplet excited state (60) which collapses to the thietane-fused p-lactam (61) (Scheme 20).35 A synthesis of 3-oxacepham 1,l-dioxide derivatives (62) is based on the prepar- ation of diazo-compound (63; R = SiMe,Bu') from sulfide (64).Removal of the silyl group yielded (63; R = H) but in only 11% yield; another rhodium-cata- lysed cyclization via a carbene then gave a 2 1 mixture of stereoisomers (62) (Scheme 21).36 34 T. Konosu and S. Oida Chem. Pharm. Bull. 1991 39 2212.3s M. Sakamoto T. Yanase T. Fujita S. Watanabe H. Aoyama and Y. Omote J. Chem. SOC. Perkin Trans. 1 1'991 403. 36 P. H. Crackett P. Sayer R. J. Stoodley and C. W. Greengrass J. Chem. Soc. Perkin Trans. 1 1991,1235. Heterocyclic Compounds C02Me i 0flSCH2C02Me S02-CN2 iii iv --4d 6% NkosiMe2But 30% O \yORI C02Bu' C02Bu' CO~BU' (64) (63) Reagents i KMnO,; ii TsN3; iii HF H,O; iv Rh,(OAc), A Scheme 21 4 Five-membered Rings Terpenoid tetrahydrofurans such as (65) have been synthesized by palladium-catalysed cyclization of 4,6-dienols (Scheme 22h3' A silicon-directed asymmetric synthesis of substituted tetrahydrofurans is based on diastereoselective addition of chiral (E)-crotylsilanes (66) to a-alkoxy-and p -alkoxyaldehydes (Scheme 23).38For example condensation of (66) with 3-benzyl-oxypropanal gave (67; R = SiMe2Ph) in 96% diastereoisomeric excess.Oxidative desilylation with peracetic acid and mercury(11) acetate then gave the hydroxyfuran derivative (67; R = OH; 55%). (65) Reagents i Pd(OAc) ,benzoquinone; ii Pd(dba), Bui3N 1,2-bis-(diphenylphosphino)ethane Scheme 22 Me Me. I H4$RH,C02Me Reagents i PhCH,O(CH,),CHO BF3.Et20 Scheme 23 An interesting preparation of the dihydroxyfuran intermediate (68) is a key step in a synthesis of penicillium metabolite (*)-~itreoviral.~' Acid-catalysed intramolecular reaction of epoxide and hydroxyl groups of compound (69) produces (68) (Scheme 24). 37 P. G. Andersson and J.-E. Backvall J. Org.Chem. 1991 56 5349. 38 J. S. Panek and M. Yang J. Am. Chem. SOC., 1991 113 9868. 39 M. C. Bowden P. Patel and G. Pattenden J. Chem. SOC.,Perkin Trans. 1 1991 1947. 158 D. E. Ames OH OH H Reagents i 4-MeC6H,S03H H20 Scheme 24 Dihydrofuran (70) is formed in 91% ee by a silver-catalysed rearrangement and cyclization of the acetylenic alcohol (71)(Scheme 25).40 The rearrangement of allylic acetals (72)promoted by tin(1v) chloride provides a stereocontrolled route to tetrahydrofurans (73)(Scheme 26).41 OCOCMe3 Phf-' qze H &Ph"HdTk OCOCMe3 Me (71) (70) Reagents i AgBF, A Scheme 25 (72) (73) Yields 76%(R = Et) 64% (R = Ph) Reagents i SnCI,; ii H,O Scheme 26 Addition of the enolate anion of ethyl 2-bromo-4-trialkylsilyloxycrotonate (74) to aldehydes yields the silyl enol-ether terminated oxiranes (75) which undergo a low temperature rearrangement in the presence of trimethylsilyl iodide to form functionalized dihydrofurans (76) (Scheme 27) .42 OR' ... iii R'OCH,CH=CBrCO,Et 3 + (74) H COzEt R' = SiMe,Bu' (75) Reagents i LiNPr;; ii RCHO; iii Me3SiI Scheme 27 40 Y. Shigemasa M. Yasui S.4. Ohrai M. Sasaki H. Sashiwa and H. Saimoto J. Org. Chem. 1991 56 910. 41 M. H. Hopkins L. E. Ovennan and G. M. Rishton J. Am. Chem. SOC.,1991 113 5354. 42 T. Hudlicky and G. Barbieri J. Org. Chem 1991 56 4598. Heterocyclic Compounds Alkynyloxiranes (77) rearrange in the presence of potassium t-butoxide to produce furans (78) probably via the cumulene alkoxide ion (79).The process is of particular interest in that it uses basic conditions whereas most furan syntheses employ acids (Scheme 28).43 R2 R'CH2CZC r==.=*-I.. R' -0 (77) (79) Reagents i KOBU' Scheme 28 Oxidative ring opening of furan with dimethyl dioxirane gives maleic dialdehyde efficiently.44 Substituted maleic anhydrides e.g. (80),and sodium dimethyl phosphite react in refluxing benzene to form furan-2( 5H)-one 5-phosphonates (81). These condense with carbonyl compounds to provide a neat synthesis of 5-alkylidenefuran-2-ones (82; 2-and E-isomers) (Scheme 29).45 Me0)qPh oc ,co0 1+ 41% 11+ 45% Me0 Ar (80) (82) Ar = 2-MeOC6H Reagents i (MeO),POH NaH A; ii ArCOCOzMe Scheme 29 Nafion-H a perfluorinated sulfonic acid resin catalyses ring closure of 2,2'- dihydroxybiphenyls to dibenzofurans under relatively mild condition^.^^ Similarly 2,2'-diaminobiphenyls cyclize on heating with the resin to give carba~oles.~~ Treatment of aromatic acyloxycarbonyl- or acylamidocarbonyl-compounds with titanium on graphite affords benzofurans and indoles respectively (Scheme 30)?* XCOR' R' X = OorNH Reagents i Ti/graphite A Scheme 30 43 J.A. Marshall and W. J. Du Bay J. Org. Chem. 1991 56 1685. 44 B. M. Adger C. Barrett J. Brennan M. A. McKervey and R. W. Murray J. Chem. SOC.,Chem. Commun. 1991 1553. 45 G. Pattenden M. W. Turvill and A. P. Chorlton J. Chem. SOC.,Perkin Trans. 1 1991 2357. 46 T. Yamato C. Hideshima G. K. S. Prakash and G.A. Olah J. Org. Chem. 1991 56 3192. 47 T. Yamato C. Hideshima K. Suehiro M. Tashiro G. K. S. Prakash and G. A. Olah J. Org. Chem. 1991 56 6248. 48 A. Furstner D. N. Jumbam and H. Weidmann Tetrahedron Lett.. 1991 32 6695. 160 D. E. Ames An interesting study has been made of 2,3-dibenzylidene-2,3-dihydrothiophene (83).49 This was generated from (84) by elimination of methanol. Dimerization forms (85) the structure of which was established by X-ray study. On trapping the monomer by reaction with norbornene adduct (86) is produced (Scheme 31). Ph 1H Ph c-7 IH Ph (86) Reagents i LiNPr',; ii norbornene Scheme 31 Heating 3,5-dibroma-2-methylthiophene1,l-dioxide (87) in t-butanol leads to the formation of dimer (88) .50 Hydrogen bromide elimination gives benzo[ blthiophene 1,l-dioxides (89) (Scheme 32).A new route to 1,3-disubstituted benzo[ clthiophenes (90) has been developed (Scheme 33).51 Thioanhydride (91) reacts with phosphorus pentachloride to give Me H BI (88) Reagents i Bu'OH A Scheme 32 1 -@: 83% \ c1 (92) Reagents i PC15 POCI,; ii NaI DMF Scheme 33 49 J. Skramstad and 0. Eriksen Acta Chem. Scand. 1991 45 919. 50 S. Gronowitz G. Nikitidis and A. Hallberg Acta Chem. Scand. 1991 45 632. 51 Y. Okuda M. V. Lakshrnikantham and M. P. Cava J. Org. Chem. 1991 56 6024. Heterocyclic Compounds 161 tetrachloro-derivative (92). Treatment with sodium iodide effects dechlorination to form 1,3-dichlorobenzo[ clthiophene (90; X = Cl).Reaction with butyl lithium produces mono-lithium compound (90; X = Li) which with electrophiles gives functionalized derivatives. For example use of dimethylformamide yields (90; X = CHO; 87%) and methoxycarbonyl chloride affords ester (90; X = C02Me; 75%). Alkylation of l-substituted-lH-pyrro1-3(2H)-ones, e.g. (93) with a soft alkylating agent such as methyl iodide favours C-alkylation but hard alkylating agents give 0-alkylation. Thus (93) can be converted into 3-methoxy-1-phenylpyrrole (94) using methyl tosylate (Scheme 34) .52 LJ0&qoMe Ph Ph (93) (94) Reagents i NaH MeOTs Scheme 34 The enol-ester (99 obtained from cyclohexane-1,3-dione and pyrrole-2-carbonyl chloride rearranges in the presence of triethylamine to form enamino-acid (96).Esterification and aromatization of the carbocyclic ring then leads to the phenolic pyrrole-ester (97) (Scheme 35).53 Reagents i Et3N A; ii CH,N,; iii Hg(OAc)* Scheme 35 3-Nitropyrroles (98) are formed in high yields from nitromethane and l-isocyano- 1-tosylalkenes (99) in the presence of potassium t-butoxide (Scheme 36).54 1,3-Dipolar addition of munchnone (100) (a 1,3-oxazolium Solate) to p-chloro-p- (trifluoromethy1)vinyl phenyl ketone gives the trifluoromethylpyrrole ketone (101) (Scheme 37).55 (98) Yields 94% (R= Ph) 91% (R= But) Reagents i MeNO? KOBU' Scheme 36 52 G. A. Hunter H. McNab L. C. Monahan and A. J. Blake J. Chem. Soc. Perkin Trans. 1 1991 3245. s3 J. E. Oliver W. R. Lusby and R. M. Waters J. Heterocycl. Chem.1991 28 1565. 54 D. van Leusen E. Flentge and A. M. van Leusen Tetrahedron 1991 47 4639. 55 T. Okano T. Uekawa N. Morishima and S. Eguchi J. Org. Chem. 1991 56 5259. 162 D. E. Ames 0' Ph -co -HCI -ODMe ObMe 56% N N N CF3cxPh oc Ph ClO Ph Ph COPh 1 Scheme 37 Cyclopentadiene complexes of cobalt carbonyl catalyse reaction of alkynes with trimethylsilyl cyanide to form 5-amino-1 H-pyrrole-2-carbonitrile derivatives (102).56 Reaction of 1-phenyl-1 H-pyrrol-3(2H)-one (103; X = H) with benzene diazonium chloride under acidic conditions gives 2-coupled products in hydrazono-form (103; X = NNHPh).57 Autoxidation of 3-methoxy-1-methyl-2-phenylpyrrole in acetone solution produces the 5-hydroxypyrrol-2-one (104).58 Similar products have been obtained by oxidative decarboxylation of pyrrole-2-carboxylic acids by a photo- chemical process involving singlet oxygen (Scheme 38).59 N Me Me Reagents i 02,hv Scheme 38 Pyrrole reacts with methylsulfenyl chloride to form 2,3,4,5-tetra(methylthio)pyr-role which can be oxidized to the corresponding sulfoxides and sulfones.60 Phenylselenomethylpyrroles (105) react rapidly under mild conditions with a-free pyrroles (106) in the presence of copper(1) triflate to form dipyrrylmethanes (107) (Scheme 39).61 The process has also been used to prepare tripyrranes from a dipyrrylmethane having one free a-position.Electrochemical oxidation of 3-acetyl-2,5-diphenylpyrrole(108) under anhydrous conditions gives (109) but when water is present the coupling product (110) is obtained.Reduction then leads to the 3,3'-dipyrrole (1 11) (Scheme 40).6* 56 N. Chatani and T. Hanafusa J. Org. Chern. 1991 56 2166. 57 A. J. Blake H. McNab and L. C. Monahan J. Chern. Soc. Perkin Trans. 1 1991 701. 58 A. J. Blake G. A. Hunter and H. McNab J. Chem. Res. (S) 1991 316. 59 D. L. Boger and C. M. Baldino J. Org. Chem. 1991 56 6942. 60 H. M. Gilow C. S. Brown J. N. Copeland and K. E. Kelly J. Heterocycl. Chem 1991 28 1025. 61 C. J. Hawker A. Philippides and A. R. Battersby J. Chern. Soc Perkin Trans. 1 1991 1833. 62 S. Petruso S. Caronna S. Gambino G. Filardo and G. Silvestri J. Heterocycl. Chern. 1991 28 793. Heterocyclic Compounds (106) R = CH,Ph R' = CH2C02Me R2 = (CH,)2C02Me Reagents i CU(I) triflate CaCO Scheme 39 MeCO ~1 Ph i ii 70% I MeCO epph - iii iv Me:-) ::Me Ph I I Ph HO Ph I I Ph Ph N N N H H H (1 10) (111) Reagents i Bu4N+C10h 0.6V; ii H20; iii Zn HOAc; NH3 HzO Scheme 40 The preparations and reactions of ninhydrin and its analogues have been re~iewed.6~ Another useful review covers work on marine natural products containing the indole ring system.64 N-Tosylindole can be prepared efficiently by an acid-catalysed cyclization of the substituted-alkyl N-tosyl anilides (Scheme 41).65 A new general synthesis of indoles is based on a palladium-catalysed heteroannula- tion of internal alkynes (Scheme 42)66by reaction with o-iodoarylamines.SPr' QpoR-aT NHTs Ts Reagents i H,SO, Bu'OH Yields 63% (R = Ac) 67% (R = Me) Scheme 41 63 M.M. JoulliC T. R. Thompson and N. H. Nemerof Tetrahedron 1991 47 8791. 64 M. Alvarez M. Salas and J. A. Joule Heterocycles 1991 32 1391. 65 Y. Murai G.Masuda S. Inone and K. Sato Heterocycles 1991 32 1377. 66 R. C. Larock and E. K.Yum J. Am. Chem. SOC. 1991 113 6689. 164 D. E. Ames 0:""' i_ R' Reagents i R2CrCR3 Pd(OAc), PPh3 Bu4NCC1- Na2C03 Yield e.g. 98% when R' = H R' = SiMe3 R3 = Me Scheme 42 Lithiation of 1 -methoxyindole occurs regioselectively at the 2-po~ition.~~ Reaction with electrophiles then leads to 1 -methoxy-2-substituted indoles. For example dimethylformamide gives 2-formyl-1-methoxyindolewhich can be hydrogenolysed catalytically to produce 2-formylindole.A synthesis of 3,4-disubstituted indoles is based on the reaction of an N-allyl-2- halogenoaniline (1 12) with a zirconocene complex to form the benzyne complex (113) and thence (114). Iodine displaces the metal giving di-iodide (115). Elimination of hydrogen iodide gives the unstable exomethylene compound (116) which reacts with diethyl ethynedicarboxylate to produce the 1,3,4-trisubstituted indole (117) (Scheme 43).68 H I by bgcH2 ii CHpI iii iv a-jOzEtI + __* _.+ 70% \ 53% \ C02Et \N N CH2Ph CH2Ph CHzPh (115) (116) (117) Reagents i Bu'Li Cp,Zr(Me)CI; ii I,; iii DBU A; iv EtO,CC=CCO,Et Scheme 43 New syntheses of lycorine alkaloids involve an interesting new route to 7-substituted hexahydroindole~.~~ A stereo-controlled palladium-catalysed intra- molecular 1,4-chloroamidation of diene (1 18) generates allylic chloride (119).An anti-stereoselective copper( 11)-catalysed reaction with Grignard reagent is then used to elaborate the 7-substituted hydroindole (120) (Scheme 44). The amide (121) derived from 2-iodo-N-methylaniline and ethyl fumarate can be cyclized using butyl lithium at low temperature in the presence of excess of trimethylsilyl chloride to form the 3-substituted oxindole (122) (Scheme 45)." 67 T. Kawasaki A. Kodama T. Nishida K. Shimizu and M. Somei Heterocycles 1991 32 221. 68 J. H. Tidwell D. R. Senn and S. L. Buchwald J. Am. Chem. Soc. 1991 113 4685. 69 J.-E. Backvall P. G. Anderson G. B. Stone and A. Gogoll J. Org. Chem.1991 56 2988. 70 S. Horne N. Taylor S. Collins and R. Rodrigo J. Chem. SOC.,Perkin Trans. 1 1991 3047. Heterocyclic Compounds COzR &O2R (118) R = CH2Ph (119) (120) Ar = 3,4-CH202C,H Reagents i Pd(OAc)z LiCl benzoquinone HOAc; ii ArMgBr Li2CuCl4 Scheme44 CO2Et I Reagents i BuLi Me,SiCl Scheme45 N-Phenylphthalimide has been obtained by a palladium-catalysed carbonylation and coupling of o-di-iodobenzene with aniline.71 Oxidation of benzothiazine dioxides (123) in the presence of base provides substituted isoindole (124) (Scheme 46).72 NMe -H,O I-\ so2 69% so2 -so, 02"' -E NO -NO2 OH (123) Reagents i KZCO, Bu,N+Br- air Scheme46 The final steps of an enantiocontrolled synthesis of (-)-physovenine (125; R = MeNHCO) are summarized in Scheme 47.73 The cyclopentene unit of (126) is used to generate trio1 (127) and by periodate oxidation the Q -hydroxyethylaldehyde (128).Acidic hydrolysis of the amide group then leads to ring closure to form (125; R = Me). Demethylation with boron tribromide to give phenol (125; R = H) followed by reaction with sodium hydride and methyl isocyanate yielded the urethane (125; R = MeNHCO). Pyrazolediazonium salts e.g. (129; X = NfC1-) undergo an efficient sulfur dioxide-catalysed chlorodediazoniation process to form chloropyrazoles (129; X = Cl). Catalysis with copper or its salts was less effective.74 When the acid azide (130) is heated with water Curtius degradation to isocyanate is accompanied by hydrolysis of the trifluoroacetyl group and cyclization to form 4-arylimidazolin-2-one ( 13 l).75 71 R.J. Perry and S. R. Turner X Org. Chem. 1991 56 6573. 72 K. Wojciechowski Liebigs Ann. Chem. 1991 831. 73 S. Takano M. Moriya and K. Ogasawara J. Org. Chem. 1991 56 5982. 74 S. Yamamoto K. Morimoto and T. Sato J. Heterocycl. Chem. 1991 28 1545. 75 S. Rault 0. N. Tembo P. Dallemagne and M. Robba Heterocycles 1991 32 1301. 166 D. E. Ames Reagents i 0,; ii NaBH,; iii HCl-H,O; iv NaIO,; v HCl-H,O Scheme47 I,J;2Me ArCHCH,CON HNKNH NLN I Me NHCOCF 0 It has been that N-alkylation of benzotriazole and 1,2,Ctriazole with alkyl halides proceeds efficiently in the presence of sodium hydroxide in dimethylfor- mamide.76 Treatment of 0-tributylstannyl aldoximes (132) with t-butyl hypochlorite gener- ates nitrile oxides which react with alkenes and alkynes to form isoxazolines (133) and isoxazoles (134) by [3 + 21 dipolar cycloaddition (Scheme 48).77 H i\ phFJ/ C=NOSnBu3 -(j:% phyph Ph 82% NxO Ph NxO (133) (132) (134) Reagents i Bu'OCl PhCH=CH2; ii Bu'OCl PhC=CH Scheme 48 1,2,3-Benzoxathiazole 2,2-dioxides have been prepared for the first time by the processes shown in Scheme 49.78 The N-tosyl group could be removed by fluoride-ion catalysed hydrolysis.Reaction of alkylaminodithiocarbamate salts with gem-dicyanoepoxides (135) involves 5-exo-tet ring opening then nucleophilic attack on a nitrile group. The process provides a synthesis of 2-imino-4-amino-5-cyano-1,3-dithioles (136) (Scheme 76 A.R. Katritzky W. Kuzmierkiewicz and J. V. Greenhill Rec. trau. Chim. Pays-Bus 1991 110 369. 77 0. Moriya H. Takenaka Y. Urata and T. Endo J. Chem. Soc. Chem. Commun. 1991 1671. 78 K. K. Andersen D. D. Bray S. Chumpradit M. E. Clarke G. J. Habgood C. D. Hubbard and K. M. Young J. Org. Chem. 1991 56 6508. 79 M. Guillemet M. Baudy-Floc'h and A. Robert J. Chem Soc. Chem. Commun. 1991 907. Heterocyclic Compounds ii \ NHTs Ts Ts Reagents i 3-chloroperbenzoic acid; ii S02C12 Et,N Scheme 49 R CN RCH+C=N CN n Ho ' y WCN-0-S G Reagents i R'NHCS;K+ A Scheme 50 i_ oc$ QC02H +ii \ SeMe \ /Se \ /Se NO2 NO2 NO2 (139) (137) (138) Reagents i Br2 C5H5N; ii SOClz DMF Scheme 51 2,1-Benzoxaselenol-3-one (137) and 2,1-benzothiaselenol-3-one(138) have been prepared from the methylselenobenzoic acid (139) according to Scheme 51.80 3,5-Disubstituted 1,2,4-~elenadiazoles (140) are obtained by reaction of primary selenoamides with N-bromosuccinimide at low temperatures.81 Pyridoazaphospholes (141) have been prepared82 from 2-alkylpyridines by quater- nization with phenacyl halides followed by condensation of the salt (142) with phosphorus trichloride in the presence of triethylamine.5 Six-membered Rings Treatment of the silver salt of a 4-or 5-terminal alkynoic acid (143) with bromine effects a highly stereoselective cis-addition of carboxylate and bromine across the acetylenic bond to form the 2-bromo-enol lactone (144). Conversely the action of N-bromosuccinimide on the potassium salt gives E-isomer (145) (Scheme 52).83 80 C.Lambert and L. Christiaens Tetrahedron 1991 47 9053. 81 K.Shimada Y. Matsuda S. Hikage Y. Takeishi and Y. Takikawa Bull. Chem. SOC.Japan 1991,64,1037. 82 R. K. Bansal K. Karaghiosoff N. Gupta A. Schmidpeter and C. Spindler Chem. Ber. 1991 124,475. 83 W.Dai and J. A. Katzenellenbogen J. Org. Chem 1991,56 6893. 168 D. E. Ames Br (144) (143) (145) Reagents i NaOH H,O; ii AgNO,; iii Br, H,O; iv K,CO, H,O Nibromosuccinimide Scheme 52 Yields 50%(Ar = Ph R = H),24% (Ar = Ph R = Me) Reagents i piperidine Scheme 53 The enolate ion of 3-oxobutanolactone (146) adds to 1,l-dicyanoalkenes to give enol-lactone (147) and thence the pyran-lactone system (148) (Scheme 53).84 Epoxidation of flavones has been achieved using dimethyl dioxirane in acetone solution at subambient temperature^.^^ On warming to room temperature the epoxide (149) rearranges to 3-hydroxyflavone (150) but with methanol it gives 3-hydroxy-2-methoxyflavanone(1 5 1) (Scheme 54).Mercury( 11)-catalysed cyclization of prop-2-ynyloxyacetic acid (152) yields 6- methylene-l,4-dioxan-2-one(153) (Scheme 55).86 Lineatin (154) is a pheromone of the ambrosia beetle a pest in coniferous forests. It has been synthesized neatly from the substituted cyclobutane acetal (155) by 0 0 (1 50) (149) Reagents i A to r.t.; ii MeOH Scheme 54 /0\1 -69% ("7 Reagents i HgO Scheme 55 84 N. Martin J. L. Segura C. Seoane J.L. Soto M. Morales and M. Suarez Liebigs Ann. Chem. 1991 827. 85 W. Adam D. Golsch and L. Hadjiarapoglou J. Org. Chern. 1991 56 7292. 86 M. Yamamoto T. Dewa H. Munakata S. Kohmoto and K. Yamada J. Chem Res. (S),1991 165. Heterocyclic Compounds action of methylmagnesium iodide to form diol (156) followed by acid-cata- lysed conversion of the dimethyl acetal unit into the bicyclic acetal system of (154) (Scheme 56).87 CH(OMe)2 CH(OMe), I I . .. 1 II -d’ I, ,. AcO’ ‘COMe H0‘ CMe2 OH (155) Reagents i MeMgBr; ii H+ H20 Scheme 56 3,3,6,6-Tetramethyl-1,2,4-trioxan-5-one (1 57)has been prepared by condensation of acetone with trimethylsilyl a-[(trimethylsilyl)peroxy]alkanoates (158) in the presence of trimethylsilyl trifluoromethanesulfonate as catalyst (Scheme 57).88 Reagents i Me2C0 Me,SiOTf; ii pyridine Scheme 57 Hemiperacetals (159) obtained from aldehydes and 2,3-dimethylbut-l -en-3-yl hydroperoxide undergo an intramolecular oxymercuriation on treatment with mer- cury(I1) acetate to form after ion exchange the mercury compounds (160) (Scheme 58).89 These can be reduced to the 1,2,4-trioxanes (161).(159) (160) Reagents i Hg(OAc)* HClO, H20; ii KBr H20; iii NaBH, NaOH H20 Scheme 58 Intramolecular cycloaddition of a carbonyl ylide to an acetylenic group provides a short route to the furobenzopyran system (162) (Scheme 59).90 87 P. Baeckstrom L. Li I. Polec R. Unelius and W. R. Wimalasiri J. Org. Chem. 1991 56 3358. 88 C. W. Jefford J. Currie G.D. Richardson and J.-C. Rosier Helu. Chim. Acta 1991 74 1239. 89 A. J. Bloodworth and A. Shah J. Chem. SOC.,Chem. Commun. 1991 941. C. Bernaus J. Font and P. de March Tetrahedron 1991 47 7713. 170 D. E. Ames 16% Reagents i A Scheme 59 -(11 $ ,;yy(oH)Me ’. (163) + Et (46%) (163) (164) (50%) (165) Reagents i TsOH A; ii TsCI pyridine 2-dimethylaminopyridine Scheme 60 The 2,3-dihydro-174-dithiin (163) is obtained when 2-( l-hydroxyalkyl)-1,3-dithiolan (164) is heated with 4-toluenesulfonic acid (Scheme 60).91 In the example given treatment of (164) with 4-toluenesulfonyl chloride and base gives the 2- alkylidene-174-dithiane (165) as well as (163). Benzo-l,2,4-trithiins (166) have been prepared by reaction of benzopentathiepin (167) with a phosphorus ylide (Scheme 61).92 Ar PPh3 as-;--34% s-s-s-s -Ar = 4-MeOC6H4 Reagents i ArCH,$Ph,Cl- NaH Scheme 61 The anion from (168) has been condensed with aldehyde (169) to give (170) as a mixture of (2)-and (E)-isomers in a 1:2 ratio.The mixture was treated with titanium (IV) chloride to effect ring closure forming (171; R = Me). Demethyla- tion with boron tribromide at low temperature gave the phenol (171; R = H) which was cyclized under basic conditions to produce the Sthiorotenoid core (172) (Scheme 62).93 Optically active pipecolic acid derivatives (173) have been prepared enantio- and diastereo-selectively by an aza-Diels-Alder reaction of dienes with an imine obtained from ethyl glyoxylate and chiral 1-phenylethylamine (Scheme 63)?4 91 C.A. M. Afonso M. T. Barros L. S. Godinho and C. D. Maycock Synthesis 1991 575. 92 R. Sat0 and K. Chino Tetrahedron Lett. 1991 32 6345. 93 L. Crornbie J. L. Josephs J. Larkin and J. B. Weston J. Chem. SOC.,Chem Commun. 1991 973. 94 P. D. Bailey R. D. Wilson and G. R. Brown J. Chem. SOC.,Perkin Trans. 1 1991 1337. Heterocyclic Compounds OMe I OMe E t 0)21;^0 .'. 1 II QCHO + -0 50% I CH,CH(OE t)2 (170) 111 IV I52% "' ' Reagents i LiNPr',; ii A; iii TiCI,; iv MeOH; v NaOEt A Scheme 62 The strongly electrophilic fluorine of acetyl hypofluorite reacts with pyridine to form an N-fluoropyridinium salt in which the ring is activated for nucleophilic attack. Elimination of hydrogen fluoride then gives overall nucleophilic substitution in the 2-po~ition.'~For example pyridine with acetyl hypofluorite in methanol yields 2-methoxy-pyridine (70%).An efficient [5 + 11 heterocyclization route to 4(1H)-pyridones (174) has been developed?6 2-Aza-l,3-dienes (175) react with 1,l'-carbonyl-diimidazoleto form the pyridones (Scheme 64) and they also react with thiophosgene to produce the corresponding 4-chloropyridine. Substituted 4-hydroxy-2-pyridones have been prepared from ethyl a-methyl-acetoacetate and benzylamine (Scheme 65).97 Conversion into the P-aminoacrylate (176) followed by N-acylation gave (177) which was cyclized to pyridone (178) by heating with sodium ethoxide. Palladium-catalysed hydrogenolysis then removed the N-benzyl group quantitatively.95 D. Hebel and S. Rozen J. Org. Chem. 1991 56,6298. 96 J. Barluenga F. J. Gonziilez and R. P. Carlon J. Org. Chem. 1991 56 6751. 97 K. H. Chung K. Y. Cho Y. Asami N. Takahashi and S. Yoshida Heterocycles 1991 32 99. 172 D. E. Ames r 1 L N Reagents i 1,l '-carbonyldiimidazole BF3.Et20 Scheme64 OH Me NH I I N I CH2Ph CH2Ph CH2Ph (176) (177) (178) Reagents i R20CH2COCI; ii NaOEt EtOH A Scheme65 1,l-Di(methylthio)-2,2-dicyanoethenereacts with cyanothioacetamide with elimi- nation of methanethiol to form intermediate (179) which rearranges uia (180) into the 2-( 1H)-pyridinethione (181) (Scheme 66).98 The structures biological activities and syntheses of marine natural products containing quinoline and/or isoquinoline nuclei have been reviewed.99 A photochemical reaction generates the cyclopenta[ blquinoline (182) from ben- zoisonitrile and 1-iodohex-4-yne (183) (Scheme 67)'" by a novel [4 + llradical annulation.98 D. Briel S. Dumke G. Wagner and B. Olk J. Chem. Res (S) 1991 178. 99 M. Alvarez M. Salas and J. A. Joule Heterocycles 1991 32 759. loo D. P. Curran and H. Liu J. Am. Chem. Soc. 1991 113 2127. Heterocyclic Compounds (183) Reagents i PhNC (Me,Sn), A hv Scheme 67 The dihydronaphthalene derivative (184) forms a chromium carbonyl complex (185). After hydrolysis of the N-acyl group this undergoes a photochemical reac- tion to close a piperidine ring which generates the benzomorphan skeleton (186) (Scheme 68)."' - Me0 \ NMe Me0 NMe I \ I MeOQ,Me Reagents i Cr(CO),; ii K2C03H20 ultrasound; iii 02,hv Scheme 68 A modified Bischler-Naperalski process for the preparation of 3-aryl-3,4-dihy- droisoquinolines is based on treatment of amide (187) with oxalyl chloride to form (188).Elimination of chloride ion by reaction with iron(Ir1) chloride gives ion (189) which cyclizes to give (190) the oxalyl derivative of a 1-hydroxytetrahydroisoquino-line. Acid hydrolysis then yields the dihydroisoquinoline (191) (Scheme 69).'02 The interesting functionalized hydroisoquinolinone (192) has been obtained by a thermal or Lewis-acid mediated Diels- Alder cyclo-addition to the unsaturated piperidone-ester (193) (Scheme 70).'03 4,5-Dimethyl- and 4,5,6-trimethylpyridines are brominated at the 5-methyl-group by N-bromosuccinimide but at the 4- or 6-methyl group by bromine in acetic acid to give bromomethyl derivatives in good yields (Scheme 71).'04 A 2-methylthio- substituent is not oxidized under these conditions.101 M. Sainsbury M. F. Mahon C. S. Williams A. Naylor and D. I. C. Scopes Tetrahedron 1991,47,4195. 102 R. D. Larsen R. A. Reamer E. G. Corley P. Davis E. J. J. Grabowski P. J. Reider and I. Shinkai J. Org. Chem. 1991 56 6034. 103 D. 0. Imbroisi and N. S. Simpkins J. Chem. Soc. Perkin Trans. 1 1991 1815. 104 L. Strekowski R. L. Wydra L. Janda and D. B. Harden J. Org. Chem. 1991 56 5610. 174 D. E. Ames I-NH PPh I COR q:co R 0-co/ R (191) Yields 72% (R = H) 88%(R = Me) Reagents i (COCI);; ii FeCI,; iii H,SO, MeOH Scheme 69 i ii MeJSiOp -+ MeOzC QNC02Me 100% '*NCO2Me MeOzC OMe 0 (193) Reagents i; A; ii camphorsulfonic acid Scheme 70 CH2Br Me f)Me 2nMe 2 R R R Yields; 77% (R = H); 68% (R = SMe) Yields; 75% (R = H); 81% (R = SMe) Reagents i N-bromosuccinimide; ii Br, HOAc Scheme 71 In a regioselective synthesis of alkylpyra~ines"~ an (Y -0ximinoketone (194) is condensed with allylamine to form imine (195) which is isomerized by heating with potassium t-butoxide to form the conjugated system (196; R = H).The O-methoxy- carbonyl derivative (196; R = C02Me) undergoes thermal cyclization to form the pyrazine (197) in good yield (Scheme 72).'05 3H-4,1,2-Benzothiadiazines(198; X = S) and the corresponding S,S-dioxides have been obtained by diazotization and cyclization of aminoamides (199; X = S or SO2) (Scheme 73).'06 A useful synthesis of 1,4-thiazines has been based on the addition of reactive alkenes to 2-(dialkylhydrazono)thioacetophenones(200).'07 Elimination of dialkyl- amine from adduct (201) produced 1,4-thiazine (202) (Scheme 74).105 G. Buchi and J. Galindo J. Org. Chem. 1991 56 2605. 106 A.Balbi M. Mazzei and E. Sottofattori J. HeterocycL Chem. 1991,28,1633. 107 A.Reliquet R. Besbes F. Reliquet and J. C. Meslin Synthesis 1991 543. Heterocyclic Compounds NOH NOH / R1 (194) (195) (196) (197) Reagents i CH2=CHCH2NH2 A; ii KOBu‘; iii A Scheme 72 (199) (198) Yields 57%(X = S,R = Et) 19%(X = SO2 R = Et) Reagents i NaNO, HOAc Scheme 73 N COR N Reagents i CH,=CHCOR hydroquinone; ii A Scheme 74 Enamines such as (203) can be prepared from heterocycles having a methyl group at the a-position to the ring nitrogen atom by reaction with N,N-dimethylfor- mamide dimethyl acetal.These enamines react with 2-phenyl-5-(4H) -0xazo1one to form intermediates (204) which cyclize to give azinopyridone (205) (Scheme 75).’08 Reagents i 2-phenyl-5(4H) -oxazolone Ac20 Scheme 75 lo* A. Copar B. Stanovnik and M. TiSler Bull. SOC.Chim. Belg. 1991 100 533. 176 D. E. Ames Cystodytins are antineoplastic alkaloids isolated from an Okinawan tunicate. The first total synthesis reported”’ involves eleven steps (8% overall yield) and is summarized in Scheme 76.In the final steps photolysis of the azide (206) generated a triplet nitrene which formed the pyridine (c)ring by hydrogen abstraction and radical pair recombination. Dehydrogenation then gave cystodytin A (207). CMe2 CMe2 II CH . .. co co 1 I1 -I I 31% 0 Ar = 2-Reagents i hv A; ii DDQ Scheme 76 The dione mono-N,N-dimethylhydrazone(208) obtained by trifluoroacetylation of aldehyde hydrazone (209) reacts with sodium periodate in an unusual oxidative cyclization reaction to form the 1,3,4-oxadiazine (210) (Scheme 77).’1° Reagents i (CF,C0)20; ii NaIO Scheme 77 X-Ray studies have shown”’ that peracid oxidation of 4,5,6-triaryl-1,2,3-triazines gives the 2-oxide (211). 1,2,3,4-Benzotetrazine- 1,3-dioxide (212) is a stable structure prepared by action of dinitrogen pentoxide on the amino-azoxy-compound (2 13).‘ l2 Reaction of ethyl diazoacetate with l-(methylthio)-3,4-dimethylphosphole1-sulfide (214) in refluxing xylene leads to diene-carbene [2 + 13 cycloadduct (215).109 M. A. Ciufolini and N. E. Byrne J. Am. Chem. Soc. 1991 113 8016. 110 Y. Kamitori M. Hojo R. Masuda T. Fujitani and K. Sukegawa Heterocycles 1991 32 1693. 111 A. Ohsawa T. Itoh K. Yamaguchi and C. Kawabata Chem. Pharm. Bull. 1991 39 2117. 112 A. M. Churakov S. L. Ioffe and V. A. Tartakowski Mendeleeu Commun. 1991 101. Heterocyclic Compounds This reacts with triphenyl phosphite to give the phosphinine (216). NMR evidence shows that rearrangement occurred so that the ethoxycarbonyl group is in the 2-position (Scheme 78).Il3 Me Me Me~~CO,Br ii ,Me0 75% PH 75% CO,Et 8'sMe P (214) (215) Reagents i N2CHCO2Et A; ii P(OPh), A Scheme 78 The first 1,3,5-diazaphosphinines (217) have been obtained from 3,Sdiazapyry- lium tetrafluoroborates (21 8) by phosphorus exchange using tris(trimethylsily1)phos-phane.'14 These products react with alkynes in a cascade process in which 1,4-addition gives the heterobarrelene (219).Loss of aryl cyanide and a further addition- elimination sequence leads to the phosphinine (220) (Scheme 79).'14 Reagents i P(SiMe,)3 A; ii R'C=CR2 Scheme 79 6 Seven-membered Rings Photolysis of p-[o-(aryloxy)phenyl]vinyl bromide (221) in the presence of a base gives dibenz[ 6 floxepin (222) quantitatively (Scheme (221) Reagents i hv pyridine I I3 S.Hoiand L. Ricard and F. Mathey J. Org. Chem. 1991 56 4031. 114 G. Mark1 and C. Dorges Angew. Chem. Znt. Ed. Engl 1991 30,106. 115 T. Kitamura S. Kobayashi H. Taniguchi and K. Hori J. Am. Chem. Soc. 1991 113 6240. 178 D. E. Ames The ylide generated from pyridinium salt (223) undergoes 8 .rr-electrocyclization to form the heterocyclic allene (224). In the presence of hydrogen peroxide and water this is transformed into a pyrido[ 1,2-a]azepinone (225) (Scheme 81).'16 Br-3irJMe 5;yo,m \N/ \N Me - - Me (224) 0 (223) (225) Reagents i Et,NH A; ii H,O, H,O Scheme 81 5-Azaazulenes (226) can be obtained from 2-formyl-6-dimethylaminofulvene(227) and (viny1imino)phosphoranes (228) by an aza- Wittig reaction and electrocyclization (Scheme 82)."' CHR 1 -II 24% + Ph,P=N-CPh aCHNMe2 CHO (227) (228) (226) Reagents i A Scheme 82 Bicyclic diazepines are the subject of an important monograph."' A benzodiazepine (229) which inhibits replication of viruses has been synthesized (Scheme 83) .l19 Base-catalysed dimethylallylation of diamine (230) and cyclization gave the heterocycle (231) then reduction of nitro-group to amine and reaction with carbon disulfide yielded imidazolethione (229).\ -W 03 Me (230) (231) (229) Reagents i K,CO, A Me,C=CHCH,Br; ii H, Pd/C; iii CS2 Scheme 83 W. Maier and W. Eberbach Helv. Chim. Acta 1991 74 1095. M.Nitta Y. Ino and S.Mori Tetrahedron Lett. 1991 32 6727. 118 'The Chemistry of Heterocyclic Compounds' Vol. 50 Bicyclic Diazepines ed. R. I. Fryer Wiley- Interscience New York 1991. 119 K. A. Parker and C. A. Coburn J. Org. Chem. 1991 56 4600. Heterocyclic Compounds 2-ha- 1,3-diene (232) and trimethylsilylisothiocyanate react to form the pyrimidine-4( 3H)-thione (233) which can be converted via aziridine (234) into .3,6-dimethyl-2,5-diphenyl-l H-1,4-diazepine-7(6H) -thione (235) (Scheme 84).I2' Action of sulfur dichloride on the di(alkeny1)-P-lactam (236) gives a mixture of the fused-ring thiazepines (237) and (238) (Scheme 85).12' d MeMph phNLcrMe Me I Me (232) (233) (235) Reagents i Me,SiN=C=S A; ii NaH Scheme84 Ph / PhCHCl + V 0' -c1 (237) Reagents i SClz A Scheme 85 Tetrazepinones (239) have been prepared by the sequence shown in Scheme 86."* Reduction of the quinoline (240) to the tetrahydro-derivative and reaction with methyl isocyanate gave (241).Acid-catalysed hydrolysis of the N-t-butoxycarbonyl group and diazotization then yielded the fused-ring tetrazepin-Cone (239). Varacin (242) an antifungal metabolite of the ascidian Lissoclinum uareau is the first natural ben~0pentathiepin.I~~ ... 1,II I iii-v -02- 100% I NH 23% I I AQ Bu'O~C But02C HFm 'N-NMe Me (240) (2411 (239) Reagents i H2 Pd/C; ii MeNCO; iii CF,C02H H20; iv NaHC03 H20; v NaN02 HCI Hz0 Scheme 86 120 J. Barluenga R. P. Carlh F. J. Gonzhlez and F.L. Ortiz J. Chem. Soc. Chem. Commun. 1991 1704. 121 M. Komatsu M. Mohri S. Kume and Y. Ohshiro Heterocycles 1991 32 659. 122 B. J. Jean-Claude and G. Just J. Chem. Soc. Perkin Trans. 1 1991 2525. 123 B. S. Davidson T. F. Molinski L. R. Barrows and C. M. Ireland J. Am. Chem. Soc. 1991 113 4709. 180 D. E. Ames Benzotellurepin (243) has been prepared by reaction of 1,2-di( ethyny1)benzene with sodium telluride and hydrazine in the presence of a phase transfer ~ata1yst.l~~ It is rather unstable and decomposes to naphthalene and tellurium in a few days at room temperature. The 1-benzophosphepine (244) has been obtained as shown in (Scheme 87).’25 Photochemical addition of methyl acrylate to benzophosphole oxide (245) formed a cyclobutane ring as in (246).Hydrolysis and oxidative decarboxylation gave the cyclobutene system (247). Flash vacuum pyrolysis effected ring cleavage to produce (248) which was reduced with trichlorosilane to 1-phenyl-1 -benzophosphepine. 07 6:yo a ~ ii,iii ~ 55% 0’ ‘Ph 0’ ‘Ph (245) (246) O-&+f?JJ+f7JJ P P P 0” ‘Ph 0” ‘Ph I Ph (247) (248) (244) Reagents i hv CH,=CHCO,Me; ii NaOH H,O; iii Pb(OAc), Cu(OAc), pyridine A; iv flash vacuum pyrolysis; v SiHCI3 A; vi NaOH H,O Scheme 87 7 Larger Rings Useful reviews have covered seven eight and nine-membered nitrogen heterocycles’26 and recent literature on the anthelmintic macrolides the avermectins and milbemy~ins.’~~ After successive reactions of diallylamine with n-butyl lithium and t-butyl lithium addition of ethyl lithium generates the lithium complex (249).On treatment with dichlorodimethylsilane followed by hydrolysis this yields the azasilocine (250) (Scheme 88).12* I24 H. Sashida H. Kurahashi and T. Tsuchiya J. Chem. SOC.,Chem. Commun. 1991 802. 125 J. Kurita S. Shiratori S. Vasnike and T. Tsuchiya J. Chem. SOC.,Chem. Commun. 1991 1227. 126 P. A. Evans and A. B. Holmes Tetrahedron 1991 47 9131. 127 H. G. Davies and R. H. Green Chem. SOC.Rev. 1991 20 211 271. 128 J. Barluenga F. Foubelo R. GonzalCz J. Fafianhs and M. Yus J. Chem. SOC.,Chem. Commun. 1991 1001. 181 Heterocyclic Compounds Et n . .. I I1 - 69% Reagents i Cl2SiMe2;ii H20 Scheme 88 Imides (251) react with 3-dialkylamino-2 H-azirines (252) to form adducts (253) which rearrange producing the eight-membered ring systems (254) (Scheme 89).129 An acid-catalysed rearrangement of tetrahydropyrimido[ 1,2-u]indole carbin- 01s (255) leads to the bridged-ring derivative of a 1,5-benzodiazocine (256) (Scheme H OC-N R3 R1f$H + R2 so2 (251) (252) (253) (254) Scheme 89 Reagents i 4-MeC6H,SO3H A Scheme 90 Action of hypervalent iodine compounds on the tetrahydroisoquinolinl amide (257) generates an N-methoxy- N-acyl nitrenium ion which effects a ring expansion to form the nine membered ring of (258) (Scheme 91).13' COBu' Me0 => ::ZWNCO13uf 62% \ N CH2CONHOMe 1 OMe (257) (258) Reagents i PhI(OCOCF,) ,A Scheme 91 129 A.Rahm A.Linden B. R. Vincent and H. Heimgartner Helu. Chim. Acta 1991 74 1002. 130 I. A. Cliffe K. Heatherington and A. C. White J. Chem. Soc. Perkin Trans. 1 1991 1975. 13' Y. Kikugawa and M. Kawase J. Chem. SOC.,Chem. Commun. 1991 1354. 182 D. E. Ames The 3-aza[9]metacyclophane (259) has been obtained from the tetracyclic tetrahy- droisoquinoline (260) by ring cleavage steps. First cyanogen bromide gave the unsaturated tricycle (261) then ozonolysis yielded the twelve-membered ring struc- ture (259) (Scheme 92).’32 (260) (261) (259) Reagents i BrCN K2C0,; ii 0,; iii Me,S Scheme 92 A synthesis of P-resorcyc1i.c macrolides including (S)-zearalenone (262) is based on a palladium-catalysed intramolecular coupling of aryl iodide with vinyl stannane (Scheme 93).’33 R = MeOCH Reagents i Pd(PPh,) on polystyrene support A; ii HCl HZO Scheme 93 An intramolecular Ullmann reaction has been used to prepare diary1 ethers with 14- and 15-membered meta- and para-units in a cyclophane system.First cyclization of (263) yielded the ether-lactone (264; R = Me) which was demethylated by the action of boron triiodide to give (264; R = H) the cytotoxic antibiotic combretastatin D-2 (Scheme 94).134 OMe 1 I ___,3 7% Y-30 0 (263) (264) Reagents i CuMe pyridine A Scheme 94 J. B. Bremner and W. Jaturonrusmee Aust. J. Chem. 1991 44,135. 133 A. Kalivretenos J. K. Stille and L. S. Hegedus J. Org. Chem. 1991 56 2883. 134 D. L. Boger S. M. Sakya and D. Yohannes J. Org. Chem. 1991 56 4204.Heterocyclic Compounds Second a similar process was used to construct a 14-membered amide-ether cyclophane ~tructure.'~~ Third the method was applied to the preparation of the amide-ether heterocyclic moiety of bouvardin a bicyclic hexapeptide antibiotic as part of a synthesis of deoxyb~uvardin.'~~ Heating aromatic aldehydes with pyrrole in propanoic acid and nitrobenzene gives porphyrins dire~tly,'~~ e.g. 4-methoxybenzaldehyde gives 5,10,15,20-tetra(4- methoxypheny1)porphyrin (265; X =H; Ar =4-MeOC,&) in 45% yield. Electrophilic bromination occurs regiospecifically at the antipodal pyrrolenic rings of free-base porphyrins bearing substituents which fix the aromatic delocalization pathway.'38 Thus (265; X =H; Ar =3,5-But2C6H4) gives the corresponding tetra- bromide (X =Br) which reacts with benzene-1,2-dithiol to form (266).The Wittig reaction fails with xanthoporphyrinogens (267; X =0)but methyl- lithium does react to give tetra-mesomethyleneporphyrinogen(267; X =CH2; 13% when R =H 63% when R =Me).'39 Y x=c/\c=x (267) 135 D. L. Boger and D. Yohannes J. Org. Chem. 1991 56 1763. 136 D. L. Boger and D. Yohannes J. Am. Chem. Soc. 1991 113 1427. 137 A. M. d'A. R. Gonsalves J. M. T. B. Varejio and M. M. Pereira J. Heterocycl. Chem. 1991 28 635. 138 M. J. Crossley P. L. Burn S. S. Chew F. B. Cuttance and I. A. Newsom J. Chem. Soc. Chem. Commun. 1991 1564. 139 C. Otto and E. Breitmaier Liebigs Ann. Chem. 1991 1347. 184 D. E. Ames Finally a hexapyrrolic expanded porphyrin (268) has been synthesized (Scheme 95).140 Condensation of the acetoxymethylpyrrole ester (269) with dipyrrolyl (270) gave the linear tetrapyrrole diester (271; R = CH,Ph).Hydrogenolysis to the diacid (271; R = H) and condensation with diformyl-dipyrrole (272) under acidic condi- tions produced the cyclic hexapyrrole salt (268). Salts of this 26-~-electron annulene system were stable but isolation of the free base was not achieved. Et Me Me Et EcN,'j4e Fjt N H H I ___) (270) NH HN 66% + COzR COZR COzCHzPh (271) AcO (269) Et Me Me Et (271; R = H) + H H Et . .. 1 II 40% Me Et Me Me Et (272) Reagents i 4-MeC,H,S03H A; ii O2 Scheme 95 J. L. Sessler T. Morishima and V.Lynch Angew. Chem. Int. Ed. Engl. 1991 30 977.