7 Heterocyclic Compounds By D.E. AMES Department of Chemistry Queen Mary and Westfield College London El 4NS UK 1 Introduction The significance of bond lengths and bond orders of many simple heteroaromatic molecules has been discussed.' X-ray crystallographic data were used to assess the presence of delocalization in conjugated n-systems. The importance of heteroaroma-ticity and its role in the tertiary structures of DNA are emphasized. Other topics reviewed include heterocyclic N-oxides and N-imides,2 alkaloid N-~xides,~ and the synthesis of oxygen-containing heterocycles by intramolecular ~xypalladation.~ 2 Three-membered Rings A one-pot procedure achieves efficient stereospecific transformation of 1,2-diols(1) via halogenoacetates (2) into epoxides (3) (Scheme l).5 OAc ;I' R1& R2 i.ii * R' &R2 + Rl/yR2 OH x OAc (2) iiiI Reagents i H+ MeC(OMe),; ii AcX or Me,SiX; iii K,CO,-MeOH Yield 86% (99% e.e.) when R' = 2-Ph(CH,),C6H and RZ = C0,Me Scheme 1 Direct epoxidation of chalcones (4) with dimethyldioxirane gives epoxides (5)which are acid- and base-sensitive (Scheme 2).6 ' V. G. S. Box Heterocycles 1992 34 1631. A. R. Katritzky and J. N. Lam Heterocycles 1992 33 101 1. A. Albini Heterocycles 1992 34 1973. T. Hosokawa and S. I. Murahashi Heterocycles 1992 33 1079. H.C. Kolb and K.B. Sharpless Tetrahedron 1992 48 10515. W. Adams J. Bialas L. Hadjiarapoglou and T. Patonay Synthesis 1992 49. 167 168 D.E. Ames 0 0 (4) (5) Reagents i Dimethyldioxirane Yield 100% (Ar = Ph) Scheme 2 Phenylsulfonyloxiranes (6) have been converted into a-bromoketones (7) by reaction with magnesium bromide.Desilylation and base-catalysed cyclization yields a-epoxyketones (8) (Scheme 3).' Br (7) Reagents i MgBr,; ii Bu,N+F- H,O; iii Et,N Scheme 3 A Darzens-type reaction of bromoketones (9) promoted by a tributylstannyl carbamate gives epoxyketones or epoxyesters (10) in a one-pot reaction (Scheme 4).* 0 Reagents i R'CHO Bu,SnNEtCO,Me Yield 85% (for R' = Me X = Br R2 = Ph) with cis:trans = 79:21 Scheme 4 Primary 2,3-epoxyamines e.g. (1l) react with butyl lithium and then trimethylaluminium to form the aluminium complex (12). Rearrangement and hydrolysis then gives (hydroxyalky1)aziridine (1 3) stereospecifically (Scheme 5).9 Treatment of optically active oxirane-2-carboxylic esters (14) with sodium azide yields azidoalcohols (15) which react with triphenylphosphine to form aziridine- 2-carboxylic esters (16) in good yields and high optical purity (Scheme 6).1° S.F.C. Dunn and R. F. W. Jackson J. Chem. Soc. Perkin Trans. I 1992 2863. I. Shibata H. Yamasaki A. Baba and H. Matsuda J. Org. Chem. 1992 57 6909. R. Najime S. Pilard and M. Vaultier Tetrahedron Lett. 1992 33 5351. lo J. Legters L. Thijs and B. Zwanenburg Rec. Trav. Chim. Pays-Bas 1992 111 1. Heterocyclic Cornpounds N-Chlorination followed by dehydrochlorination provides 2H-azirine-2-carboxylic esters (17). Me..+NH2 i ii ~ 69% H H Me O h N AlMe3 H (12) (13) Reagents i BuLi; ii AIMe,; iii NaF H,O Scheme 5 OH (14) (15) lii H N iii iv c- A" R C02R' (17) Reagents i NaN, NH,CI; ii Ph,P; iii Bu'OC1; iv DBU Yield 69% (R = Pr R' = Et) Scheme 6 Conversion of amides (18) into lithium enolates followed by treatment with diphenylphosphorochloridate generates ketiminium salts (19) which react with sodium azide to give the 3-amino-2-substituted-2H-azirine (20) (Scheme 7).12 (19) (20) Reagents i LiNPr;; ii CIPO(OPh),; iii NaN Yield 50% (R = Me or Ph) Scheme 7 Reactions of halodiazirines by S,2' and electron-transfer initiated processes have been reviewed.'' J. Legters L. Thijs and B. Zwanenburg Rec. Trau. Chim. Pays-Bas 1992 111 75. *'J. M. Villalgordo and H. Heimgartner Helu.Chim. Acta 1992 75 1866. l3 X. Creary Acc. Chem. Res. 1992 25 31. 170 D. E. Ames Dialkyl- and alkylarylimines are efficiently oxidized to oxaziridines by 'oxone' (potassium peroxymonosulfate) in the presence of sodium hydrogencarbonate whereas diarylimines give only nitrones. l4 3 Four-membered Rings Benzil in the lowest excited triplet state adds regio- and stereoselectively to 2-morpholinoacrylonitrile (21) to form oxetane (22) (Scheme 8).' Reagents i (PhCO), hv Scheme 8 Highly enantioselective hydrogenation of diketene (4-methyleneoxetan-2-one) in the presence of a ruthenium catalyst having an (S)-ligand gives (R)-4-methyloxetan- 2-one in up to 97% selectivity and 92% e. e.I6 Trans-disubstituted p-lactones such as (23) have been synthesized using a titanium chloride-mediated enantioselective aldol condensation reaction.' Chiral ester (24) was converted into silyl enol ether (25) which was condensed with an aldehyde-amide to obtain the aldol(26).Hydrogenolytic cleavage of the chiral group and double-bond reduction gave acid (27) which was cyclized to trans-oxetanone (23) (Scheme 9). iv 95% 1 R2 = CH2(CH2),Me 78% HO& (CH2),CONEt2 0 OH Reagents i LiNPr;; ii Me,SiCl; iii TiCl, trans-OCHCH=CH(CH,),CONEt,;iv H, Pd-C; v PhSO,Cl pyridine Scheme 9 A. R. Hajipour and S.G. Pyne J. Chem. Res. (S) 1992 388. D. Dopp H. R. Memarian M. A. Fischer A. M. J. van Eijk and C. A. G. 0.Varma Chem. Ber. 1992,125 983. l6 T. Ohta T. Miyake and H. Takaya J. Chem. Soc..Chem. Commun. 1992 1725. S. Cardani C. De Toma C. Gennari and C. Scolastico Tetrahedron 1992 48 5557. Heterocyclic Compounds 171 Obafluorin (28) an antibacterial agent from Pseudomonas jluorescens is a cis-disubstituted fi-lactone. Its synthesis is summarized in Scheme 10.l8 The amino acid (29; R = H) reacted with 2-nitrophenylsulfenyl chloride to give (29; R = 2-O,NC,H,S) which was cyclized to give lactone (30). Removal of the arylthiol group and an acylation process led to obafluorin in an optically pure form. i ___) 24% (30) ii. iiii iv 39% I HO OH 0 Reagents i 4-BrC,H,S02C1 pyridine; ii TsOH; iii 2,3-(OSO,)C,H3COC1; iv H,O Scheme 10 In an efficient synthesis of 3-oxetanones a,fi-epoxy diazo-methyl ketones (31) are treated with tin(1v) chloride at -78 "Cto form chlorohydrins (32) in a syn manner with retention of configuration at C,.Cyclization of the diazomethyl a-hydroxyalkyl ketone (32) with boron trifluoride then gives the 3-oxetanone (33) (Scheme 1l).l9 (31) (32) (33) Reagents i SnC1,; ii NaHCO, H20; iii BF,-Et,O Yield 37% overall (R'= Ph R2 = R3 = H) Scheme 11 Photolysis of thiolactone (34) yields thiete (35) (Scheme 12).20 Oxidation of 3,4-di(t-butyl)-2,5-dimethylthiophene1,l-dioxide (36) with m-chloro- perbenzoic acid gives the acylthiete (37) but in the presence of base epoxide (38) is produced (Scheme 1 3).21 l8 C. Lowe Y. Pu and J.C. Vederas J. Org. Chem. 1992 57 10. l9 L. Thijs P. J. M. Cillissen and B. Zwanenburg Tetrahedron 1992 48 9985. 2o H.Hinrichs and P. Margaretha Chem. Ber. 1992 125 2311. 21 J. Nakayama and H. Kamiyama Tetrahedron Lett. 1992 33 7539. 172 D.E. Ames Me Me CH2Ph hv CH2Ph -31% Bu' But Scheme 12 COMe i i ii -s,r 0 Me Me 0 Me // \\ Me Me J 'b 00 (37) (36) Reagents i 3-C1C,H4C0,H; ii Na,CO Scheme 13 The thietanone (39)has been obtained by a photochemical ring contraction reaction (Scheme 14).22 Ketoester (40) gave thiapyrandione (41) by an internal Claisen condensation. The derived enol ether (42; R = OEt) was reduced to dihyd-rothiapyranone (42; R = H) the substrate for the photochemical reaction to produce (39). COMe /CM% --of I i ii iii. iv,v vi s\ 68% 50% 96% y2 C02Et (40) Reagents i NaOEt; ii HCl H,O; iii EtOH TsOH A; iv LiAlH,; v H,SO, H,O; vi hv Scheme 14 1-Alkyl-3-hydroxy-2-phenylazetidines(43)are obtained by reaction of 2-( l-bro-mobenzy1)oxirane (44)with aliphatic primary amines (Scheme 15).23 RNH2 PhL 65% (R = Pr") -ph&=-oH 0 Scheme 15 22 E.Er and P. Margaretha Helv. Chim. Acta 1992 75 2265. 23 T. Toda M. Karikomi M. Ohshima and M. Yoshida Heterocycles 1992 33 511. Heterocyclic Compounds 173 Oxa-and thiaphosphetanes azaphosphetidines and diphosphetanes have been reviewed.24 In a synthesis of 1,2-azaphosphetidines (45) the a-diazo-p-ketophosphonamidate (46) was heated with rhodium acetate to effect cyclization by carbene attack upon an isopropyl group (Scheme 16).25 i,ii 334b EtO-P EtO' II 0 Reagents i Rh,(OAc), A; ii H,O Scheme 16 fLLactams.-Ring enlargement of the alkyl-N-tosylaziridine (47)has been effected first by reaction with methanolic potassium cyanide to form acyclic nitrile (48) then by hydrolysis and cyclization to give p-lactam (49) (Scheme 17).26 I? r!y I? Y mCH2OR i y C H 2 0 R ii.iii,iv,v 828 CN NHTs 608 * 0 mCH20R Ts Me Me Ts Me (47) (48) (49) R = CH2Ph Reagents i KCN MeOH A; ii NaOH H,O A; iii HC1 H,O; iv 4-pyrrolidino-pyridine dicyclohexylcar-bodiimide; v H,O Scheme 17 When diketene is heated with an imine (R'N=CHR2) and imidazole p-lactam (50) is produced.27Anodic fluorination of 2-aryl-4-thiazolidinones (51; R' = H) is highly regioselective.28Oxidation of the product (51;R' = F),followed by thermolysis of the corresponding sulfone gives monofluoro-&lactams (52).4-Sulfinylazetidin-2-ones (53; R2 = SOPh) react with tributyltin alkoxides in the presence of trimethylsilyl trifluoromethanesulfonate to give the 4-alkoxyazetidin-2-ones (53; R2 = OR).29 A photochemical reaction of chromium carbene complexes with iminodithiocarbon-ates (54) produces 4,4-bis(methylthio)-p-lactams (55). These are oxidized by N-bromosuccinimide to azetidine-2,4-diones (56) (Scheme 18).30 Turning to fused-ring p-lactams tricyclic 3-azadethiacepham (57)has been prepared " K. Afarinkia Heterocycles 1992 34 369. 25 K. Afarinkia J.I.G. Cadogan and C. W. Rees J. Chem. Soc. Chem. Commun. 1992 285. D. Tanner and H. M. He Tetrahedron 1992 48 6079. 27 A. Sasaki K.Goda M. Enemoto and M. Sunagawa Chem. Pharm. Bull. 1992,40 1095. T. Fuchigami S. Narizuka and A. Konno J. Org. Chem. 1992 57 3755. 29 Y. Kita N. Shibata N. Yoshida and T. Tohjo Chem. Pharm. Bull. 1992 40 1044. 30 B. Alcaide G. Dominguez J. Plumet and M. A. Sierra J. Org. Chem. 1992 57 447. 174 D.E. Ames by condensation of the aminoalkyl lactam (58) with the vinyl vicinal tricarbonyl compound (59) (Scheme 19).31 Reagents i (CO),Cr=CRzR3 hv; ii N-bromosuccinimide H,O Yield 70% (R' = Ph RZ= OMe R3 = Me) Scheme 18 Reagents i pyridinium tosylate Scheme 19 2-exo-Methylenepenam (60) a promising intermediate has been prepared from the unsaturated ester (61 ). Ozonolysis conversion into enol triflate (62) and elimination of trifluoromethanesulfonic acid led to allene (63).Reduction of the S-sulfonyl group by a zinc-bismuth(II1) chloride bimetal redox system was followed by cyclization to form (60) (Scheme 20).32 A synthesis of isocephem analogues (64) is based on conversion of alkenyl lactam (65) into tosylate (66) by ozonolysis reduction and tosylation. Base-catalysed condensation with carbon disulfide followed by ethylation gave ester (64; R2 = 4-O,NC,H,CH,) and then by palladium-catalysed hydrogenolysis the acid (64; R2 = H) (Scheme 21).33 31 H. H. Wasserman S. L. Henke and E. Nakanishi J. Org. Chem. 1992 57 2641. 32 H. Tanaka Y. Kameyama T. Yamauchi and S. Torii J. Chern. SOC. Chem. Cornrnun. 1992 1793. 33 S. Shakaya and T. Durst Heterocycles 1992 34 67. Heterocyclic Compounds (63) iv 41% 1 Reagents i 0,;ii (CF,SO,),O Et,N; iii Et,N A; iv Zn BiCI Scheme 20 SEt Reagents i O, Me,S; ii Na(CN)BH,; iii TsCl pyridine; iv LiN(SiMe,), CS,; v NaH EtI Scheme 21 A route to the potent penem antibacterial agent sulopenem (67; R' = R2 = H) has been described.34 Condensation of chlorolactam (68) with thiocarbonate salt (69) and acylation gave the trithiocarbonate ester (70).Cyclization with triethyl phosphite yielded penem analogue (67; R' = SiMe2Bu' R2 = CH2CCl=CH2) and removal of the protecting groups gave the hydroxy acid (67; R' = R2 = H) (Scheme 22). 4 Five-membered Rings The boron trifluoride-catalysed condensation of aldehydes with 1,6-di(trirnethyl- silyl)hexa-2,4-diene (71) yields 2,5-dialkyl-3,4-divinyltetrahydrofurans(72) (Scheme 23).35 A polymer-supported synthesis of 2,5-disubstituted tetrahydrofurans (73) (Scheme 24)36 has been developed based on the construction of an isoxazole as in (74).34 R.A. Volkrnann P. R.Kelbaugh D. M. Nason and V. J. Jasys J. Org. Chem. 1992 57 4352. 3s C. Brouard J. Pornet and L. Miginiac Tetrahedron 1992 48 2385. 36 X.Beebe N.E. Schore and M.J. Kurth J. Am. Chem. SOC. 1992 114 10061. 176 D.E. Awes Reaction with iodine monochloride then effects ring cleavage recyclization and removal from the polymer to produce (73). i ii COC02CH2CCl=CH2 Reagents i H,O; ii FCOCO,CH,CCI=CH, PriNEt; iii P(OEt) Scheme 22 Reagents i RCHO BF,.OEt Yield 51% (R = Me) 75% (R = CH,Ph) Scheme 23 OSiMe3 Polymer-CHO -Polymer-1 CH-CH2N02 iii1 OSiMe3 I Polymer -c,H iv N-0 c- Reagents i MeNO, Et,N; ii Me,SiCl Et,N; iii PhNCO Et,N CH,=CH(CH,),CH=CH, A; iv ICl Overall yield 29% Scheme 24 Heterocyclic Compounds 177 2,5-Cis- or trans-substituted tetrahydrofurans can be obtained from either (E)-or (2)-alkenols (75) and (76) respectively by choosing the appropriate electrophile as shown in Scheme 25.37 Addition of 2-(metallomethyl)-2-alkenylethers (77; M = ZnBr or MgCl) to aldehydes or ketones generates metal alkoxides (78) which undergo palladium(0)- catalysed cyclization to form 3-methylenetetrahydrofurans (79) (Scheme 26).38 Imines react similarly to give 3-methylenepyrr0lidines.~~ (75) (76) Reagents i I, CF,CO,Ag; ii PhSeCl Scheme 25 -MOR~ ii ~ "I>""'-R20 ~T-J$ R20 R4 R4 MO (77) (79) Reagents i R3R4CO; ii Pd(PPh,), A Scheme 26 A new route to 3,4-disubstituted furans involves addition of bis(tributy1stan- ny1)ethyne (80) to phenyl isoxazole (81) to form furans (82; 190/,) and (83; R = H; 23%) with elimination of benzonitrile (Scheme 27).Palladium-catalysed replacement of the substituents in (82) by reaction with aryl iodides gives 3,4-diar~lfurans.~~ When (82)is treated with butyllithium the metal derivative (83; R = Li) is generated and this reacts with electrophiles to form various products (83; R = alkyl acyl etc.) (Scheme 27).40 3' B. H. Lipshutz and J.C. Barton J. Am. Chem. Soc. 1992 114 1084. J. van der Louw J. L. van der Baan H.Stichter G.J. J. Out F. J. J. de Kanter F. Bickelhaupt and G. W. Klumpp Tetrahedron 1992 48 9877. 39 Y. Yang and H.N.C. Wong J. Chem. Soc. Chem. Commun. 1992 656. 40 Y. Yang and H. N.C. Wong J. Chem. SOC..Chem. Commun.. 1992 1723. 178 D. E. Ames Scheme 27 5-Substitution of 3-furanaldehyde can be effected by protection with lithium morpholide followed by metallation at C-5 and reaction with an electrophile (Scheme 28).41 OLi Reagents i Lithium morpholide; ii Bu'Li; iii electrophile Yield 70% (E = Me,Si from Me,SiCl); 30% (E = C,H,,CH(OH) from C,H,,CHO} Scheme 28 Michael addition of P-ketoesters to alkenyl sulfoxides (84) followed by Pummerer rearrangement of sulfoxides (85) provides an efficient route to dihydrofurans (86) (Scheme 29).Oxidation with peracid leads to syn-elimination from the corresponding sulfoxide to give substituted furans (87).42 R' x-73 i(c" R~~ jiR1 i I1 PhSO PhSO 0 PhS 0 R2 iii 1 CO,R~ R2 (87) Reagents i R2COCH,C0,R3 NaOR3; ii CI,CCO,H (CH,CO),O A; iii 3-CIC,H,C03H Scheme 29 The furanocyclohexadienone subunit (88) is present in some antifungal antibiotics. The first synthesis of this highly reactive system has been reported.43 The sequence 41 G.C.M. Lee J.M. Holmes D.A. Harcourt and M.E. Garst J. Ore. Chem. 1992 57 3126. 42 W. H. Chan A. W. M. Lee and E.T. T. Chan J. Chem. SOC.. Perkin Trans. 1 1992 945. 43 C.A. Broka and B. Ruhland J. Orq. Chem. 1992,57,4888. Heterocyclic Compounds summarized in Scheme 30 is based on the protected hydroxyaldehyde (89).Removal of the silyl group yields hydroxypyran (90) which is oxidized to the corresponding lv 0 ~ vi,vii HO MezN&$ @ 0 0 0 Reagents i Bu,N+F- H,O; ii pyridinium dichromate mol. sieves; iii H+-H,O; iv Fetizon's Reagent; v HC(NMe,),; vi Cu(OAc),; vii HCI-H,O Scheme 30 lactone. Hydrolysis of the isopropylidene ketal and oxidation of the diol with Fetizon's reagent leads to ketol(91). This is condensed with tris(dimethy1amino)methane to give enamine (92). Oxidation of the ketol group to a dione and acid-catalysed cyclization then produces the furan system.43 Oxidative thermolysis of cyclic a-azohydroperoxides (93) provides a convenient route to 3-hydroxy- 1,2-dioxolanes (hemi-perketals) (94) (Scheme 3 1).44 Scheme 31 Reaction of potassium p-toluenethiosulfonate (TsSK) with two molecules of acetylenedicarboxylic ester unexpectedly yielded tetramethyl thiophenetetracar- boxylate in good yield.45 Conjugated polythiophenes have been reviewed.46 44 A.L. Baumstark and P.C. Vasquez J. Org. Chem. 1992 57 393. 45 T.G. Kutateladze J. L. Kice and N. S. Zefirov J. Org. Chem. 1992 57 5270. 46 J. Roncali Chem. Rev. 1992 92 711. 180 D. E. Ames Lithiation of fluorobenzenes (95) and reaction with N,N-dimethylformamide provide the reactive fluoroaldehydes (96). Displacement of fluoride using methyl thioglycolate and base constitutes a general preparation of benzothiophene-2- carboxylate esters (97) (Scheme 32).47 (95) (96) Reagents i LiNPri HCONMe,; ii HSCH,CO,Me NaH Scheme 32 Use of cerium(1v) ammonium nitrate for oxidative demethylation of 4,7-dimethoxybenzo[b] thiophene -selenophene and 4,7-dimethoxyindole (98) affords the corresponding quinones (99).In contrast the benzofuran (98; X = 0) gives the bisquinone (100) (Scheme 33).48 Reagents i (NH,),Ce(NO,) Scheme 33 Rearrangement of alkynyl sulfone (101) generates allene (102) which undergoes intramolecular addition across the furan unit to form (103). Base-catalysed rearrange- ment yields 5-hydroxy-ly3-dihydrobenzo[c]thiophene2,2-dioxide (104) (Scheme 34).49 Sterically-congested ly9-di(ary1thio)dibenzothiophenescan be obtained by a ring contraction process (Scheme 35).50 In a general synthesis of bridged bicyclic disulfides a dibromoketone e.g.(105; R = Br) is converted into the di(thio-cyanate) (105; R = SCN) by reaction with potassium thiocyanate. Reduction to the hydroxy-dithiol(l06) followed by oxidation with iodine gave the bridged disulfide (107) (Scheme 36).5' Trans-1-benzyl-2,5-di(benzyloxymethyl)pyrrolidine(108) has been prepared by A. J. Bridges A. Lee E. C. Maduakor and C. E. Schwartz Tetrahedron Lett. 1992 33 7499. 48 M. Cherif P. Cotelle and J.-P. Catteau Heterocycles 1992 34 1749. 49 K. Kanematsu and I. Kinoyama J. Chem. SOC. Chem. Commun. 1992 735. T. Kimura Y. Horie S. Ogawa H. Fujihara F. Iwasaki and N. Furukawa Hererocycles 1992,33 101. P. L. Folkins and D.N. Harpp J. Org. Chem. 1992 57 2013. Heterocyclic Compounds cACH2S02CH2GCH ,502 Reagents i A1,0,; ii A; iii KOBu‘ Scheme 34 SAr 0-SAr SAr SAr Scheme 35 Reagents i KSCN; ii LiAlH,; iii I, NaOAc Yield 50% overall Scheme 36 heating benzylamine with ditosylate (109) which had been obtained from D-mannitol by a number of steps (Scheme 37).52 A radical route to (2S)-4-exo-methyleneproline (110) is based on a favoured 5-exo-dig cyclization of the radical derived from acetylenic bromide (1 1 1 ) to form the pyrrolidine derivative (112).The product (110) is then obtained by removal of the protecting groups (Scheme 38).53 When alkene (113) is oxidized with peracid and heated the epoxide undergoes 5-em-tet ring closure (Scheme 39) to form pyrrolidine derivatives (114 and 115; 52 M. Marzi P. Minetti and D. Misiti Tetrahedron 1992 48 10 127.53 R. M. Adlington and S.J. Mantell 7etrahedron 1992 48 6529. 182 D. E. Ames OTs 58% -'[F02CH2Ph -Y-eHzPh 76% N "H SOzPh SOzPh H (1 11) (112) (110) Reagents i Bu,SnH AIBN (azoisobutyronitrile); ii Na/Hg K,HPO, MeOH Scheme 38 NHTs Reagents i 3-chloroperbenzoic acid; ii A Scheme 39 R' = Ts R2 = CH,Ph; R3= CH,OH). Oxidation and removal of the benzyl and tosyl groups using ruthenium(II1) chloride and sodium periodate gives cis-and trans-pyrrolidine-2,5-dicarboxylic acids (114and 115; R' = R2 = H R3= C02H).54 N-Allylarylamines (1 16) react with carbon monoxide and sodium borohydride in the presence of catalytic amounts of the zwitterionic rhodium complex (117) to form pyrrolidines (118) (Scheme 40).55 R I ArNHCH2C=CH2 + Reagents i CO NaBH, A Yield 83% (Ar = Ph R = n-C,H,,) Scheme 40 54 J.E. Baldwin C. Hulme and C. J. Schofield J. Chem. Res. (S) 1992 173. 55 J.-Q. Zhou and H. Alper J. Org. Chem. 1992 57 3328. Heterocyclic Compounds In another rhodium-catalysed reaction alkyl- or arylpropargylamines (119) carbon monoxide and hydrogen produce pyrroles (120) (Scheme 41).56 Condensation of /!I-trifluoroacetylvinyl ethers (1 2 1) with 2,2-dimethoxyethylamine followed by acid-catalysed cyclodehydration yields 3-trifluoroacetylpyrroles (122j (Scheme 42).57 Reagents i H, CO Rh(OAc), PPh, A Yield 78% (R' = Ph R2 = Me) Scheme 41 COCF EtOCR=CHCOCF3 2(MeOhCHCH,NHCR=CHCOCF (121) H Reagents i (MeO),CHCH,NH,; ii CF,CO,H Yields 87% (R = H) 100% (R = Me) Scheme 42 1-(t-Butoxycarbony1)indolinesare regioselectively lithiated at the 7-position by s-butyl lithium with tetramethylethylenediamine at low temperature.The lithiated species react with electrophiles to give 7-substituted in do line^.^^ Treatment of indole with butyl lithium and carbon dioxide gives the indole- 1-carboxylic acid salt. Addition of t-butyllithium then gives the 2-lithio derivative which reacts with hexachloroethane to produce after hydrolysis 2-chloroindole (90%j. The bromo- and iodo- analogues can be obtained similarly. They are stable at -20°C but not at room temperat~re.~' The cyclohepta[c,d lindole (123) has been prepared from 4-iodo- 1 -methylindole- 3-carboxaldehyde (1 24) by a palladium-catalysed condensation with but-3-enonit- rile.60A useful alumina-mediated C-alkylation of indoles and pyrroles is exemplified by the synthesis of dithyreanitrile (125).This indole alkaloid which is an insect-feeding inhibitor was prepared by condensation of 7-methoxyindole with chlorodi(methy1- thio)acetonitrile in the presence of alumina.61 56 E. M. Campi G. D. Fallon W. R. Jackson and Y. Nilsson Aust. J. Chem. 1992 45 1167. 57 E. Okada R. Masuda M. Hojo and R. Yoshida Heterocycles 1992 34 1435. M. Iwao and T. Kuraishi Heterocycles 1992 34 1031. 59 J. Bergman and L. Venemalm J. Org. Chem. 1992 57 2495. 6o I. Moldval C. Szantay and C. Szantay Heterocycles 1992 34 219. 61 H. Ishibashi N. Mita N. Matsuba T. Kubo M. Nakanishi and M. Ikeda,J.Chem. Soc.,Perkin Trans. I 1992 2821. 184 D.E. Awes CN 4-Iodo-1-(triisopropylsilyl)indole(126) undergoes a palladium-catalysed condensa- tion with methyl (trimethylstanny1thio)acetate to form ester (127). An aldol condensa- tion then gives the thioacrylate intermediate (128). Ring-closure by a novel fluoride ion catalysed process yields methyl ester (129) (Scheme 43).62 A mixture of cis-and trans-isomers is produced. The free acid (cis-isomer) is the ( )-form of chuangxin- mycin an antibiotic produced by the soil microorganism Actinuplanes jinanensis. Reagents i Me,SnSCH,CO,Me Pd(PPh,), A; ii LiNPr';; iii MeCHO; iv Bu,N+F- H,O A Scheme 43 Ellipticine (130; R = H) reacts with hexamethylene tetraamine in hot trifluoroacetic acid to give aldehyde (130; R = CHO).Baeyer-Villiger oxidation and hydrolysis using aqueous hydrogen peroxide and sulfuric acid then provides 9-hydroxyellipticine (130; R = 0~1.63 Condensation of arylamines with l,l-bis(methylthio)-2-nitroetheneyields al- kenylamines (13l).Cyclization by treatment with cold trifluoromethanesulfonic acid produces 2-methylthio-3H-indol-3-one oximes (132).64 Thionyl chloride pyridine and phthalaldehyde react to form the azinium salt (133) which condenses with primary amines to give 2-aryl- l-arylimino-2,3-dihydro-1H- isoindoles (134) (Scheme 44).65 A palladium-catalysed tandem cyclization of 4,6- and 5,7- diene amides e.g. (135) provides a new route to pyrrolizidine and indolizidine structures. Thus (135) is converted into pyrrolidinone (136) which on hydrogenation gives ketone (137; 62 M.J. Dickens T. J. Mowlem D. A. Widdowson A. M. Z. Slawin. and D. J. Williams J. Chem. Soc. Perkin Trans. 1 1992 323. 63 J.M. Plug G.-J. Koomen and U.K. Pandit Synthesis 1992 1221. 64 T. Kearney J. A. Joule and A. Jackson Heterocycles 1992 33 757. 65 J.-J. Van den Eynde A. Mayence A. Maquestiau and E. Anders Bull. SOC. Chim. Belg. 1992,101 509. Heterocyclic Compounds X = 0)stereospecifically. Reduction with lithium aluminium hydride then yields (f)-heliotridane (137; X = H2) (Scheme 45).66 c1 I+ RNH2 93% (R = ph) CH-NCtjHS @y-j I Cl (133) (134) Scheme 44 Reagents i Pd(OAc), CuCI, 0, A; ii PtO, H Scheme 45 In another palladium-catalysed reaction alkynyl N-acylenamine ( 138) undergoes cycloisomerization to produce the indolizinone derivative (139) (Scheme 46).67 Pr Reagents i Pd(OAc), bis(benzy1idene)ethylenediamine Scheme 46 66 P.G.Anderson and J.-E. Backvall J. Am. Chem. SOC.,1992 114 8696. 67 B. M. Trost and C. Pedregal J. Am. Chem. SOC. 1992 114 7292. 186 D. E. Ames A short highly stereocontrolled asymmetric synthesis68 of allopumiliotoxin A an indolizine alkaloid from Dendrobatid frogs is summarized in Scheme 47. N-Hydroxymethylation of keto-amine salt (140) by reaction with methanal followed by heating with p-toluenesulfonic acid yields indolizinone (141). Condensation of the lithium enolate with (R)-2-methylhexanal leads to the hydroxyalkyl derivative (142). Dehydration and selective reduction of the carbonyl group then affords only the isomer (143) ( + )-allopumiliotoxin A.68 %COMe 1'''OH I!l I'"0H" fi I'"0H" Me Me Me v vi I O'"OH H G Me (143) Reagents i HCHO H,O; ii TsOH A; iii Ph,CLi; iv (R)-BuCH(CH,)CHO; v (F,CCO),O DBU; vi [Me,N][BH(OAc),] HOAc Scheme 47 An interesting synthesis of indoli~ine-5~8-dione (144) is based on condensation of 1-lithiopyrrole with a cyclobutenedione (145) to form (146; R = H).Pyrolysis of the protected derivative (146; R = SiMe,) generated ketene (147) which cyclized to indolizine (148). Oxidation then yielded the quinone (144) (Scheme 48).69 Addition of monoalkylhydrazines to acetylenic esters e.g. (149) having either elec tron-wi t hdrawing or bulky P-subs ti tuents affords 3-hydroxypyrazoles with isomers (1 50) being the major regioisomeric product^.^' In contrast the cycloconden- sation of b-ketoesters with alkylhydrazines gives isomers (1 51) (Scheme 49)." Jmidazolophanes (152) bridged by short chains (n= 5 or 6) are readily accessible by the [3 + 21 cycloaddition of imines with azaallenyl radical cations (153) generated from bicyclic azirines (154) under electron transfer conditions (Scheme 50).71 A regiospecific palladium-catalysed cycloaddition reaction of aziridines (1 55) with carbodiimides (ArN=C=NAr) yields 2-aryliminoimidazolines (156).72 68 S.W. Goldstein L. E. Overrnan and M. H. Rabinowitz J. Ory. Chem. 1992 57 1179 69 B.R. Yerxa and H. W. Moore Tetrahedron Lett. 1992 33 7811. 70 B. C. Hamper M.L. Kurtzweil and J. P. Beck J. Org. Chem. 1992 57 5680. 71 F. Miiller and J. Mattay Angew. Chem.. Int. Ed. Engl. 1992 31 209. " J.-0. Baeg and H. Alper J. Org. Chem. 1992 57 157. Heterocyclic Compounds t 0 OH 0 OSiMq (144) (148) Reagents i 1-lithiopyrrole; ii Me,SiCl; iii A; iv air or FeCI Scheme 48 (1501 (151) Product ratio 150:151 = 94:6 Scheme 49 Condensation of an arylmethylamine with formaldehyde and glyoxal (molar ratio 4 :2 :1) in the presence of formic acid gives 2,4,6,8-tetraazabicyclo[3.3.O]octanes (157) in high yields (e.g. 84% when Ar = Ph).73 An interesting paper74 describes a versatile regiospecific synthesis of di- and (154) n=5or6 Reagents i hv 1,4-dicyanonaphthalene; ii PrCH=NPr Scheme SO 73 A.T. Nielsen R.A. Nissan A. P. Chafin R. D. Gilardi and C. F. George J. Org. Chem. 1992,57 6756. 188 D.E. Ames R2b (?i?Y R2XKAr N N N R’ R’ CH2Ar CH2Ar trimethyl-2-aminoimidazoquinoxalineswhich are potent mutagens formed when protein foods are cooked at high temperatures. Key steps in the process are photocyclization to obtain the fused ring system and introduction of the required 2-amino group. In the photocyclization the pyrazinylalkenyl(bromoimidazo1e)(1 58) is converted into the tricyclic structure (159; R2 = SMe). The latter transformation is achieved by permanganate oxidation to the sulfone (159; R2 = SO,Me) reaction with benzylamine to give (159; R2 = NHCH,Ph) and debenzylation by catalytic hydro- genolysis using ammonium formate and a palladium catalyst to produce the target molecule (159; R2 = NH,) (Scheme 51).74 (158) (159) Scheme 51 Guanine 7-oxide (160; R = H) and some 9-substituted derivatives which show anti-leukemic activity have been prepared (Scheme 52).75Condensation of the chloro compound (161) with phenacylamines gave (162) and base-catalysed cyclization with elimination of benzoic acid yielded the N-oxide (160).Reagents i PhCOCH,NHR.HCl; ii NaOH Scheme 52 ’’ D. E. Bierer J. F. O’Connell J. R. Parquette C. M. Thompson and H. Rapoport J. Org. Chem.,1992,57 1390. 75 K. Ogawa M. Nishi J.4. Inagaki F. Nohara T. Saito,T. Itaya and T. Fujii Chem. Pharm. Bull. 1992,40 343. Heterocyclic Compounds Unsaturated oximes e.g. (163) react with phenylselenyl bromide to give the cyclic nitrone (164) which on heating undergoes a diastereospecific cycloaddition to form the tricyclic system (165) (Scheme 53).76 0-iii I CH(Et)SePh @?; Reagents i PhSeBr; ii K,CO,; iii A Scheme 53 2,4,6-Cycloheptatriene-1-thione ( 166) and p-toluenesulfonyl isocyanate react by an [8 + 21 type cycloaddition to produce the fused-ring thiazolone (167) (Scheme 54).77 Scheme 54 2-Vinyl-1,3-thiazetidine(168) rearranges to thiazolidine (169) in good yield on hydrogenation in the presence of a platinum catalyst (Scheme 55).78 COzEt I 76 R.Grigg M. Hadjisoteriou P. Kennewell and J. Markandu J. Chem. Soc. Chem. Commun. 1992. 1537. ” K. Ito K. Saito S. Takeuchi and K. Takahashi Heterocycles 1992 34 1415.18 N. K. Capps G. M. Davies D. Loakes. and D. W. Young Tetrahedron 1992 48 10 149. 190 D. E. Arnes 5 Six-membered Rings In a synthesis of 2-dialkylaminochromones the boron complex (1 70) obtained from 2-hydroxyacetophenone and boron trifluoride was condensed with a Vilsmeier reagent to form salt (171). Hydrolysis of the borate group and cyclization yielded the chromone (1 72) (Scheme 56).79 0 r Me I ii -78% (170) (171) (172) Reagents i Cl,C=hMe,; ii H,O A Scheme 56 Treatment of 3-ethylphthalides (1 73) or 2-(prop-1 -enyl)benzoic acids (1 74) with aluminium chloride gives 8-hydroxy-3-methyl-3,4-dihydroisocoumarins(175) (Scheme 57).80 E3 (173) Scheme 57 The palladium catalysed C-H activation of methoxy groups in aryl iodides provides an efficient route to 6H-dibenzo[b,d]pyrans (Scheme 58).81 Iodo-2,3-dimethoxyben- zene (176; R = OMe) self-condenses to form the dibenzopyran (177) but when the blocking 3-methoxy group is absent as in (176; R = H) another condensation step occurs to give (178).Oxidation of enamines (179) with anhydrous dimethyldioxirane generates the epoxides (180) which dimerize to form 1,4-dioxanes (181) in excellent yields (Scheme 59).82 A synthesis of trioxanesB3 is based on photochemical oxidation of tetraallyltin (182) to tetra(ally1dioxy)tin (183) which reacts with ethanal to form (184). Cyclization of the alkoxide units using mercury(x1) acetate yields the acetoxymercuriotrioxane (1 85; R = HgOAc). Reduction with alkaline sodium borohydride solution then gives 79 J.Morris D.G. Wishka and Y. Fang J. Org. Chem. 1992 57 6502. R. S. Mali P.G. Jagtap S. R. Patil and P. N. Pawar J. Chem. Soc. Chern. Commun. 1992 883. G. Dyker Angew. Chrm. Int. Ed. Engl. 1992 31 1023. 82 W. Adam E.-M. Peters K. Peters H.G. von Schnering and V. Voerckel Chem. Ber. 1992 125 1263. 83 J. Cai and A.G. Davies J. Chem. Soc.. Perkin Truns. I 1992 3383. Heterocyclic Compounds 3,5-dimethyl-l,2,4-trioxane (185; R = H)as a mixture of cis-and trans-isomers (Scheme 60).83 MeO c--v Me0 R=H 90% Me0 (176) (177) Reagents i Pd(OAc), Bu,fSBrf HCONMe, A Scheme 58 (179) (180) Reagents i Dry dimethyldioxirane Yield 91% (R’ = Bu’ R = Me) Scheme 59 Sn(CH2CH=CH2) ASn(02CCH2CH=CH,) (182) (1 83) ] ii iii -Sn(O-C(Me)H-0-O-CH2CH=CH2) RH2c (1 84) (185) Reagents i 0,,hv tetraphenylporphine; ii MeCHO; iii Hg(OAc) Scheme 60 The literature on the antimalarial drug artemisinin (Qinghaosu) (186) which is the only known natural 1,2,4-trioxane has been reviewed.84 6-Thiashikimic acid has been prepared as its racemic ethyl ester acetate (187) A.R.Butler and Y.-L. Wu Chem. SOC.Rev. 1992 21 85. 192 D.E. Ames 0 (186) (Scheme 61).85 Ethyl thioxoacetate (188) generated by pyrolysis of its anthracene adduct added to 1,4-diacetoxybuta-l,3-diene to give a mixture of thiopyrans (189) and (190). Hydroxylation using osmium tetraoxide furnished diol(19l) and elimination of acetic acid by heating with pyridine yielded the acetoxy-ester (187).C02Et -HO”’ OAc OH OH Reagents i 1,4-diacetoxybuta-l,3-diene; ii OsO, H,O; iii pyridine A Scheme 61 Oxoenaminoketones obtained from 1,3-diketones and N,N-dimethylformamide dimethyl acetal yield 2-thiopyrans by a regioselective one-pot thionation-[4 + 21 cycloaddition sequence (Scheme 62).86 Condensation of ethyl formate with thiochroman-4-one gives 3-hydroxy-methylenethiochroman-4-one (192). Treatment with N-chlorosuccinimide (1 molar equivalent) produces 3-chlorothiochroman-4-one (193) whereas when two equival- ents are used chlorinated thiochromones (194; X = H and X = C1) are obtained (Scheme 63).s7 85 D. Adam A. A. Freer N. W. Isaacs G.W. Kirby A. Littlejohn and M. S. Rahman .I.Chem. SOC.,Perkin Trans.1 1992 1261. 86 C.D. Gabbutt J. D. Hepworth and B. M. Heron J. Chem. SOC.,Perkin Trans. I 1992 2603. ’’ P.R.Giles and C. M. Marson Aust. J. Chem. 1992 45,439. Heterocyclic Compounds Reagents i Me,NCH(OMe),; ii Lawesson's reagent; iii CH,=CHCHO Scheme 62 (193) (192) (194) Reagents i N-chlorosuccinimide Scheme 63 An asymmetric synthesis of piperidine alkaloids is based on the diastereoselective reaction of 1,3-0xazolidine (195) with Grignard reagents. The oxazolidine derived from carbinolamine (196) undergoes a ring cleavage reaction with pent-4-enylmag- nesium bromide to form (197). Palladium-catalysed oxidation of the alkene produces methyl ketone (198) with 87% of the product having the configuration shown at C*. Hydrogenolysis to remove the benzyl-type N-substituents followed by cyclization completed the synthesis of (2R,6S)-(-)-dihydropinidine (199) (Scheme 64).88 (199) (198) Reagents i PrCHO MgSO,; ii CH,=CH(CH,),MgBr; iii PdCl,(MeCN), CuCI, 0,;iv H, Pd/C; v HCI "20 Scheme 64 K.Higashiyama K. Nakahata and H. Takahashi Heterocycles 1992 33 17. 194 D. E. Ames Tetrahydropyridines are produced by an intramolecular [2 + 2) cycloaddition of Group IV metal-imido complexes of alkyn-amines e.g. (200) is converted into (201) (Scheme 65).89 Reagents i CpTiCI, PrzNEt; ii H,O Scheme 65 Thermal cyclization of alkyne-hydroxylamines provides a route to cyclic nitrones. Thus (202) yields the tetrahydropyridine N-oxide (203) (Scheme 66).90 Scheme 66 The 3-lithio derivative is obtained exclusively by reaction of 4-methoxy- 1 -methyl- 2-pyridone with butyllithium at -78 "C.The 3-carboxylic acid (80%) and other 3-substituted products can then be obtained by reaction with electr~philes.~ Ruthenium-catalysed transformation of b-ketonitriles gives ene-lactams.'* The examples (Scheme 67) show the preparation of two hexahydroquinolinones.c02et wco R CQEt *ace +a"""" R =85% H H Reagents i RuH,(PPh,), H,O A Scheme 67 4-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols (204) are obtained by an internal Barbier reaction when halogenoketones (205) are treated with butyllithium (Scheme 68).93 Cobalt and ruthenium carbonyls catalyse a novel rearrangement of heterocyclic side-chain ketones to lactams. For example decahydroisoquinoline derivative (206) is converted into lactams (207; 90%) and (208; 9%) (Scheme 69).94 89 P.L. McGrane M. Jensen and T. Livinghouse J. Am. Chem. SOC.,1992 114 5459. 90 M. E. Fox A. B. Holmes I. T. Forbes and M. Thompson Tetrahedron Lett, 1992 33 7421. 91 J. Buck J. P. Madeley and G. Pattenden J. Chem. SOC.,Perkin Trans. 1 1992 67. 92 S.-I. Murahashi S. Sasao E. Saito and T. Naota J. Org. Chem. 1992 57 2521. 93 M. Kihara M. Kashimoto and Y. Kobayashi Tetrahedron 1992 48 67. 94 M.D. Wang and H. Alper J. Am. Chem. SOC. 1992 114 7018. Heterocyclic Compounds 195 BuLi \ (205) Yield 69% (R = CO,Et Ar = Ph) Scheme 68 Reagents i CO Co,(CO), Ru,(CO),, A Scheme 69 2-Formylation of N-(2,2-diethoxyethyl)benzylamine(209; R = H) is effected by reaction with butyllithium and N,N-dimethylformamide.The product (209; R = CHO) undergoes acid-catalysed hydrolysis and cyclization to form 2-methyl- 1,2-dihydroisoquinoIine-3-aldehyde(2 10). Borohydride reduction then gives 2-methyl-3-hydroxymethyl-l,2,3,4-tetrahydroisoquinoline (21 1) (Scheme 70).95 (209) (210) Reagents i HCI H,O; ii NaBH, MeOH Scheme 70 Asymmetric syntheses of three quinolizidine alkaloids have been accomplished with a high degree of stereoc~ntrol.~~ For example the (-)-8-phenylmenthyl ester of 4-methoxy-3-(triisopropylsilyl)pyridinium- 1 -carboxylate chloride (212) was treated with 4-chlorobutylmagnesium bromide to obtain the conjugate addition product (213). Methanolysis of the N-carboxylate group and cyclization yielded (214) and addition of a methyl group to the enone system gave (+)-myrtine (215) (Scheme 71).96 A synthesis of 3,4-dihydro-l,6-naphthyridin-2( 1H)-ones (216) is based on nuc-leophilic displacement of the methoxy group of 5-cyan0-3~4-dihydro-6-rnethoxy-2(1H)-pyridone (217).Thus (217) reacts with malononitrile to form (218) which is cyclized by hydrogen chloride to produce the chloro compound (216; X = Cl). 95 G. Sirnig J. Chem. SOC..Perkin Trans. 1 1992 1613. 96 D.L. Cornins and D.H. LaMunyon J. Org. Chem. 1992 57 5807. 196 D. E. Ames -i ii ___) Cl(H2C)d' I c1-C02R* (212) (213) (214) (215) R* = (-)-8-phenylmenthyl Reagents i Cl(CH,),MgBr; ii H,O+; iii KOMe; iv oxalic acid; v MeMgCl Scheme 71 Reduction with zinc and acetic acid then yields the dihydronaphthyridinone (216; X = H) (Scheme 72).97 (217) (218) (216) Reagents i CH,(CN),; ii dry HCI Scheme 72 Recent advances in pyridazine chemistry have been reviewed." 3-Chloro-pyridazines react with hydrazine in hot butanol to form 3-hydrazinopyridazines which can be reduced to 3-aminopyridazines by nickel-aluminium alloy and aqueous alkali .99 Condensation of acids with propane- 1,3-diamine by heating with alumina yields the 2-alkyltetrahydropyrimidines (219).By dehydrogenating over a palladium catalyst the 2-alkylpyrimidines can be obtained. loo Simple diazines and benzodiazines react with benzyloxycarbonyl chloride and sodium cyanoborohydride to give tetra- or hexahydro-N-benzyloxycarbonyl deriva-tives."' For example pyrimidine yields the tetrahydro compound (220) (37%).SMe MeS/c=c/CN Meo2ctJ \C02Me 5 H Me C02C H2Ph 97 P.J. Victory J. Teixido and J. I. Borrell Heterocycles 1992 34 1905. 98 G. Heinisch Bull. SOC. Chim. Belg. 1992 101 579. 99 J.-M. Sitamze M. Schmitt and C.G. Wermuth J. Org. Chem. 1992 57 3257. 100 J. W. Hull and K. Otterson J. Org. Chem. 1992 57 2925. 101 J. R. Russell C. D. Garner and J. A. Joule J. Chem. SOC.,Perkin Trans. 2 1992 409. Heterocyclic Compounds Reaction of the ketene dithioacetal (221) with sodium hydride and thioacetamide gives methyl 2-methyl-6-methylthio-4-thioxopyrimidine-S-carboxylate (222).lo2 173-Diaza-1,3-dienes (223) undergo a [4 + 21 cycloaddition with acetylenic ketones (224) to form pyrimidines (225).The trichloromethyl group can either be reduced to methyl or displaced by methoxide ion to give the 2-methoxy analogue (Scheme 73).'03 5,8-Quinoxalinediones can be obtained by oxidative demethylation of 5,8-dimethoxyquinoxalines using cerium(1v) nitrate.lo4 Aza-Wittig reaction of bis(iminophosphorane) (226) with phenyl isocyanate gives the pyrido[2.3.4-d7e]quinazoline (227) (Scheme 74). lo' Yield 98% (R' = H RZ= CO,Me R3 = OMe) Scheme 73 Me Me I I 1 N= PPh3 .YNPh (226) NHPh Scheme 74 The chemistry of 172,4-triazinium salts has been reviewed. lo6 A synthesis of 1,2,4-triazine-5-carboxylate esters (228) from diazo-ketoesters (229; X = N,) has been developed. Reaction with triphenylphosphine gave (229; X = NN=PPh,) which was hydrolysed to hydrazone (229; X = NHNH,).Condensation with amide ketal (230) yielded (231) which was cyclized by reaction with ammonium acetate to produce the triazine (228) (Scheme 75).'07 Substituted 3,4-dihydro-2H-l,3-oxazines(232; X = Ac; Y = Me) have been pre- pared by condensation of acetylacetone with aryl aldehydes and ammonium acetate. Similar reaction of o-sulfonylacetophenone gives (232; X = PhSO,; Y = Ph).lo8 Io2 A. Lorente M. L. Garcia M. Fernandez and J. L. Soto Heterocycles 1992 34 1573. Io3 A. Guzman M. Romero F. X. Talamas and J. M. Muchowski Tetrahedron Lett. 1992 33 3449 lo4 Y. Kitahara S. Nakahara T. Tanaka and A. Kubo Heterocycles 1992 34 1623. lo' P. Molina M. Alajarin and A. Vidal J.Org. Chem. 1992 57 6703. Io6 0.Chupakhin S. Alexeev B. Rudakov and V. Charushin Heterocycles 1992 33 931. lo' T. Ohsumi and H. Neunhoeffer Tetrahedron 1992 48 5227. K. Pandiarajan and J. C. N. Benny J. Chem. Soc. Perkin Trans. I 1992 2055. 198 D. E. Ames R2 I MQN-C(OMe)2 (230) -+ X II R'-C -COCOzEt (229) Reagents i NH~OAC-, HOAc A Scheme 75 3-Methyl-5,6-dihydro-S,S-dimethyl-l,4-oxazin-2-one (233; X = H) is converted by action of t-butyl hypochlorite into the 3-chloromethyl compound (233; X = Cl). This undergoes self-condensation in the presence of ethyl diisopropylamine to form the green bis(oxazino)pyrazine (234).'09 It has been shown by X-ray studies that condensation of the benzopyran derivative (235) with 2-trifluoroacetylpyrrole involves the formation of a morpholine ring in the product (236) (Scheme 76).' lo (235) (236) Reagents i KOBu' tetramethylethylenediamine,2-trifluoroacetylpyrrole A Scheme 76 A stereocontrolled synthesis of tetrahydro-1,4-thiazinesis based on the ring- cleavage reaction of epoxide (237) with sodium methoxide and methyl thioglycolate to form the thioether (238).Conversion into chloro-amide (239) followed by cyclization lo9 D. J.R. Brook R.C. Haltiwanger and T.H. Koch J. Am. Chem. SOC. 1992 114 6017. 'lo D. R. Buckle S.C. Connor D. S. Eggleston A. Faller I. L. Pinto S.A. Readshaw and D.G. Smith J. Chem. SOC.,Perkin Trans. 1 1992 769. Heterocyclic Compounds gave thiazanone (240; X = 0)which was reduced to thiazane (240; X = H,H) by sodium borohydride and acetic acid (Scheme 77)." Reagents i NaOMe HSCH,CO,Me; ii NH,; iii SOCI Scheme 77 The benzo-1,2-selenazin-3-one(241) has been obtained by action of bromine and a base on the methylselenoamide (242).l1 Ring expansion of 1,3-dithiolium cations (243) by reaction with iodine and aqueous ammonia yields 1,4,2-dithiazines (244).' l3 (241) (242) (243) (244) Carbonyl oxides (245) derived by ozonolysis of vinyl ethers (246) readily undergo [3 + 3lcycloaddition reactions with nitrones (247) to form dihydro-l,2,4,5-trioxazines (248) (Scheme 78).Il4 C=CH-OR3R ,C-0-0-+ R' \+ R6 R4 ,N=C,\+ I R2 R2 -0 R5 (246) R6 (248) Scheme 78 l1 J. L. G.Ruano M. C. Martinez J. H. Rodriguez E. M. Olefirowicz and E.L. Eliel J. Org. Chem. 1992,57 4215. 'I2 P. V. Jacquemin L. E. Christiaens M. J. Renson M. J. Evers and N. Dereu Tetrahedron Lett. 1992,33 3863. 'I3 M. R. Bryce G. R. Davison J. A. K. Howard and A. S. Batsanov J. Chem. SOC.,Chem. Commun. 1992 478. M. Mori,T. Sugiyama M. Nojima S. Kusabayashi and K. J. McCullough,J. Org. Chem. 1992,57,2285. 200 D. E. Ames 6 Sevenmembered Rings A general molybdenum-catalysed process for the cyclization of dialkenyl ethers to unsaturated oxygen heterocycles having five six or seven-membered rings with elimination of a small aliphatic alkene is indicated in Scheme 79 (X = O)." N-Alkyl N-heterocycles can be obtained by a similar process (Scheme 79; X = NR).l16 PhCMe;! RO OR 'FY where R = CMe(CF3)2 Scheme 79 Anodic oxidation of tributylstannylmethyl ethers containing an alk-4-enyl group in the presence of tetrabutylammonium fluoborate leads to intramolecular C-C bond formation with introduction of a fluorine atom.For example ether (249) gives a mixture of fluorohexahydrooxepine (250) and the tetrahydrooxepine (251) (Scheme 80).' 4-Fluoropyrans can be prepared similarly. snBu3 I (250; 61%) (251; 28%) Reagents i Bu,&BF, electrolysis Scheme 80 The first total synthesis of hemibrevetoxin B (252) a 'red tide' marine neurotoxin from Gyrnnodinium breve has been reported.' l8 This outstanding achievement in heterocyclic synthesis is however too long and elaborate to discuss here. The ester (253; X = CO,Me) obtained by addition of methyl acrylate to a chloroalkenyl toluene-p-sulphonamide reacts with methylmagnesium iodide to give 'I5 G.C.Fu and R. H. Grubbs J. Am. Chem. SOC.,1992 114 5426. G.C. Fu and R.H. Grubbs J. Am. Chem. Soc. 1992 114 7324. J.-i. Yoshida Y. Ischichi and S. hoe J. Am. Chem. SOC. 1992 114 7594. K.C. Nicolaou K.R. Reddy G. Skokotas F. Sato and X.-Y. Xiao J. Am. Chem. SOC. 1992,114,7935. Heterocyclic Compounds 201 carbinol (253; X = CMe,OH). Cyclization under acidic conditions yields 53-dimethyl- l-tosylazepan-3-one (254) (Scheme 8 1).' (253) (254) Reagents i 90% H,SO Scheme 81 In a synthesis of 1,3-benzoxazepines (255) (Scheme 82)l2' azido-ester (256; X = 0 Y = N3) was treated with triphenylphosphine to generate iminophosphorane (256; X = 0 Y = NzPPh,) which cyclized by an internal Wittig reaction to form the heterocycle (255).1,3-Benzodiazepines (257) were obtained similarly from the azido-amide (256; X = NH Y = N3). ,CO,Et 11 -X=NH R (255) (257) Reagents i Ph,P; ii A Scheme 82 Pyrrolo[2,1-c][ 1,4]benzodiazepines e.g. (258) have been prepared by the process shown in Scheme 83.121 Acid chloride (259) was condensed with pyrrolidine- 2-aldehyde diethyl dithioacetal and reduction of the nitro-group then gave amino-amide (260). Mercury(l1)-catalysed cyclization led to the tricyclic product (258). 119 F.A. Fraser G. R. Proctor and J. Redpath J. Chem. SOC..Perkin Trans. 1 1992 445. 12" J. Kurita T. Iwata S. Yasuike and T. Tsuchiya J. Chem. SOC. Chem. Commun.1992 81 lZ1 D.S. Bose G. B. Jones and D. E. Thurston Tetrahedron 1992 48 751. 202 D.E. Ames Me0 cocl Me0 0 (259) iii 83% 1 0 Reagents i pyrrolidine-2-aldehyde diethyl thioacetal; ii SnCl, A; iii HgCl, CaCO, H,O Scheme 83 1l-Phenyl-5H,11H-pyrrolo[2,l-c][1,4]benzothiazepine (261) has been prepared from sulfide (262). Oxidation to the sulfoxide followed by treatment with acetic anhydride led to an intramolecular electrophilic cyclization onto the pyrrole producing (261) (Scheme 84).’22 Ph Reagents i 3-C1C,H,CO3H; ii Ac,O A Scheme 84 7 Larger Rings Thermal cycloaddition of dimethyl acetylenedicarboxylate to the tetrahydropyridine (263) leads to (264) which undergoes a ring cleavage to form the tetrahydroazocine derivative (265) (Scheme 85).lZ3 3,4-Dihydro-2H- 1,2-benzothiazin-3-0ne 1,l-dioxide (266) reacts with the azirine (267) at ambient temperatures to give adduct (268) which rearranges spontaneously to 1,2,5-benzothiadiazonin-6-0ne1 ,l-dioxide (269).This structure was indicated by X-ray studies (Scheme 86). 24 ”’ A. Garafolo G. Campiani V. Nacci and 1. Fiorini Heterocycles 1992 34 51. lZ3 P. Sanna A. Carta and G. Paglietti J. Chem. Res. (S) 1992 16. lZ4 A. S. Orahovats A. Linden and H. Heimgartner Helv. Chim. Acta 1992 75 2515. Heterocyclic Compounds CH2CH2NEt2 (264) (265) Reagents i MeO,CCECCO,Me Yield 79% (R = C0,Me) Scheme 85 00 Flash vacuum pyrolysis of the o-vinyl esters (270) generates thione (271) by elimination of cyclopentadiene.Cyclization leads to (272; mixed isomers) which can be reduced using ‘diimide’ to 3-thianonanolide (273) (Scheme 87).12’ The process is applicable to the preparation of thialactones with 7- to 1 l-membered rings. 1,4-Dihydr0-2,3-benzodithiin(274) reacts with 2,3-dimethylbuta- 1,3-diene in the presence of boron trifluoride etherate to effect 1,4-addition with concomitant S-S bond cleavage thus forming heterocycle (275) which has a 10-membered ring (Scheme 88).’26 C02(CHz)sCH=CH2 H-!-C02(CH2)&H=CH2 [ 1 163% Reagents i Flash vacuum pyrolysis; ii KO,CN=NCO,K HOAc H,O Scheme 87 125 S.S.-M. Choi G. W. Kirby and M.P. Mahajan J. Chem. SOC.,Perkin Trans. I 1992 191. R. Sato J. Kumagai K. Yonesaka and S.4. Satoh Tetrahedron Lett. 1992 33 947.204 D.E. Ames Reagents i BF,.Et,O CH,=CMeCMe=CH Scheme 88 Oxidation of bithiazolium salt (276) with potassium superoxide-18-crown-6 gives 1,2,5,8-dithiadiazecin-6,7-dione (277) (Scheme 89).12’ L N-C-C-N Me II I100 Me (276) (277) Reagents i KO, 18-crown-6 MeCN Scheme 89 Intramolecular palladium(0)-catalysed cross-coupling of structures terminating in an acyl chloride and a /3-stannyl alkenoate e.g. (278) provides a new and efficient route to 10-to 20-membered y-oxo-a,B-unsaturated macrolides. Monomers (279) and dimers (280) are produced (Scheme 90).’* Both (2)-and (E)-/3-stannylalkenoatesgive identical macrocycles indicating thermodynamic equilibration during the reaction. Ii RT&o 0 + (279) Reagents i CO trans-benzylchlorobis(triphenylphosphine)palladiurn(o),A Scheme 90 ’” T.Itoh K. Nagata M. Okada K. Yarnaguchi and A. Ohsawa TetrahedronLett. 1992 33,6983. lZ8 J. E. Baldwin R. M. Adlington and S. H. Ramcharitar Tetrahedron,1992. 48. 2957. Heterocyclic Compounds 205 In the crown ether field reviews have dealt with macrocyclic polyethers (cages) and related compounds'29 and crown ethers with sidearms (lariat ethers).' 30 A convenient one-pot synthesis of tropocoronands (28 1) is based on a heterocycle exchange reaction occurring when benzo[b]cyclohepta[e][ 1,4]oxazine (282) is heated with x,m-diaminoalkanes (Scheme 91).' 31 (282) (281) Reagents i H2N(CH,),NH, A Scheme 91 The use of metalloporphyrins as catalysts for oxidation reactions including DNA cleavage has been reviewed.' 32 Octaethylporphyrin can be fluorinated at its rneso-positions by heating with N-fluoropentachloropyridinium trifluoromethanesulfonate.'33 The tetrafluoro de- rivative (20%) is obtained together with small amounts of monosubstitution products.Tolyporphin (283) is a novel multidrug resistance reversing agent isolated from an alga. It potentiates the cytotoxicity of adriamycin or vinblastine at low doses. The structure (283) was established mainly by NMR studies.'34 Me 0 Me Ho+p$ OAc \> AcO I OH 0 Me (283) Finally oxidative thermolysis of (1,19-dimethyloctadehydrocorrinato)nickel(11) chloride (284)occurs surprisingly easily (Scheme 92).'35The corrin frame is expanded one angular methyl group becomes a methine bridge and the furanoid ring is formed.lZ9 H. An J.S. Bradshaw and R.M. Izatt Chem. Rev. 1992 92 543. 130 G. W. Gokel Chem. SOC.Rev.,1992 21 39. 13' T. Nozoe K. Shindo H. Wakabayashi and S. Ishikawa Heterocycles 1992 34 881. B. Meunier Chem. Rev. 1992 92 1411. 133 Y. Naruta F. Tani and K. Maruyama Tetrahedron Lett. 1992 33 1069. 134 M. R. Prinsep F.R. Caplan R. E. Moore G. M. L. Patterson and C. D. Smith J. Am. Chem. SOC.,1992 114 385. 135 C. K. Chang W. Wu S.S. Chern and S. M. Peng Angew. Chem. Int. Ed. Engl. 1992 31 70. 206 D. E. Ames The structure of the green pigment (285)formed was indicated by X-ray studies; the 18 n-electron system has only three pyrrolic components. The corresponding free base was also obtained from the nickel compound (285).Scheme 92