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Chapter 9. Heterocyclic compounds

 

作者: E. H. Smith,  

 

期刊: Annual Reports Section "B" (Organic Chemistry)  (RSC Available online 1984)
卷期: Volume 81, issue 1  

页码: 183-210

 

ISSN:0069-3030

 

年代: 1984

 

DOI:10.1039/OC9848100183

 

出版商: RSC

 

数据来源: RSC

 

摘要:

9 Heterocyclic Compounds By E. H. SMITH Department of Chemistry Imperial College of Science and Technology London SW7 2AY 1 General Dedicated issues of two journals contain the reports of presentations at two inter- national meetings on heterocyclic chemistry held at Tokyo'" and Kaiserslautern.'b Two new books of general interest to heterocyclic chemists deal with 1,3-dipolar cycloadditions2 and with physical methods in heterocyclic chemi~try.~ Advances in Heterocyclic Chemistry continues to advance and a review on the photocyclization of stilbenes and related molecules contains some interesting heterocyclic example^.^ Two general procedures have been described for the N-methylation of benz-imidazoles indoles and benzotriazoles which involve heating these compounds with dimethylformamide dimethyl aceta16" or with dialkyl oxalates plus potassium alkoxides in dimethylformamide.6b Improvements over methods using methyl iodide or dimethyl sulphate are claimed.A sequence of reactions entailing o-thallation of an aromatic acid or amide followed by palladium-catalysed coupling with an olefin and concomitant cyclization forms the basis of a general synthesis of a range of benzo-fused heterocycles (Scheme l).' 2 Three-membered Rings Two new versions of the synthesis of epoxides from 2-hydroxyalkyl derivatives use dichlorocarbene to generate the leaving group and ostensibly the oxyanion in one step (Scheme 2).8 Both methods are stereoselective but the stereochemical results suggest that a cyclic mechanism intimated by Krief and his co-workers (depicted by the arrows) is not correct.A reaction between imines and the anions of chlorosulphones provides a route to aziridines analogous to the glycidic ester synthesis of epoxides (Scheme 3).9 The ' (a) 9th International Congress on Heterocyclic Chemistry Koshi University Tokyo August 1983 Heterocycles 1984,21; (b)10th European Colloquium on Heterocyclic Chemistry Kaiserslautern October 1983 Bull. SOC. Chim. Belg. 1984 93. 509605. * '1,3-Dipolar Cycloaddition Chemistry' ed. A. Padwa Wiley-Interscience New York 1984. 'Physical Methods in Heterocyclic Chemistry' ed. R. R. Gupta Wiley-Interscience New York 1984. Adu. Heterocycl. Chem. 1983 34; 1984 35 36. F. B. Mallory and C. W. Mallory Org. React. 1984 30,1. (a) R.W. Middleton H. Monney and J. Parrick Synthesis 1984 740; (b)J. Bergman and P. Sand Tetrahedron Letr. 1984 25 1957. ' R. C. Larock C.-L. Liu H. H. Lau and S. Varaprath Tetrahedron Lett. 1984 25 4459. (a) L. Castedo J. L. Castro and R. Riguerra Tetrahedron Letr. 1984 25 1205; (6) J. L. Laboureur W. Dumont and A. Krief ibid. 1984 25 4569. (a) V. Reutrakul V. Prapansiri and C. Panyachotipun Tetrahedron Lett. 1984,25 1949; (b)C. Mahidol V. Reutrakul V. Prapansiri. and C. Panyachotipun Chem. Lett. 1984 969. 183 184 E. H.Smith II 71% TI(02 C. C F3)2 Reagents i Tl(02C.CF3)3 CF,CO,H; ii Li2PdC14 MeCN base or heat Scheme 1 /Ref 8b It HO-C-C-X 1 II SMe2 /\ 0 Reagents i CHC13 50% NaOH Bun4N+CI-; ii TlOEt CHC13 Scheme 2 S02Ph Ar' 3Ar2 c1 N Ar2 N Ar2 Scheme 3 Heterocyclic Compounds Thai workers also show that the resultant sulphonyl aziridines can be readily alkylated?' In a potentially general approach to unstable methyl-substituted Dewar-furans a novel formal [2 + 21 cycloaddition forms the first step followed ultimately by a photoaromatization (Scheme 4)." In an adjacent paper," the authors report a successful trapping of the related species (1) by furan.(1) Reagents i DMSO; ii Zn-Ag dimer THF reflux; iii m-CPBA; iv diglyme reflux; v hv (254nm) -90°C Ph Scheme 4 Suitably mild methods for the deoxygenation of epoxides are sparse. It is now reported that a combination of dimethyl diazomalonate and catalytic quantities of rhodium(11) acetate in boiling benzene effects just such a process stereospecifically.12 An alternative stereospecific ring-opening occurs when thiiranes are heated with the benzyne precursor benzenediazonium-2-carboxylate(Scheme 5).13 Derivatives of thiiranes also prove to be of value in the synthesis of other heterocycles.Thus the allene episulphide (2) acts like the zwitterion (3) (Scheme 6) usually in the presence of Lewis acids,14 and the thiirene 1,l-dioxides (4) are more reactive equivalents of the corresponding acetylenes in their cycloadditions (Scheme 7)." lo R. N. Warrener I. G. Pitt and R. A. Russell J. Chem. SOC.,Chem. Commun. 1984 1464. 'I R.N. Warrener I. G. Pitt and R. A. Russell J. Chem. Soc. Chem. Commun. 1984 1466.12 M. G. Martin and B.Ganem Tetrahedron Lett. 1984,25 251. l3 J. Nakayama S.Takeue and M.Hoshino Tetrahedron Lett. 1984 25 2679. 14 W. Ando T. Furukata Y. Hanyu and T. Takata Tetrahedron Lett. 1984 25 4011. M.Komatsu Y.Yoshida M. Uesaka Y. Ohshiro and T. Agawa J. Org. Chem. 1984,49,1300. 186 E. H. Smith PhS PhvPh -h S Ph Ph T-7 PhN,+CI-. 0 reflux PhS)JPh phb-*Ph S Ph Scheme 5 R,C=O 48-70% -sxo RR Scheme 6 R R PhCzk-NPh phQphR R ArQPhH + HN \I R R R = Me Ph R = Ph Scheme 7 Heterocyclic Compounds Attempts to form oxirenes and reactions which possibly proceed through such species are the subject of a review16 and the family of electron-excessive irenes is extended by the synthesis of the phosphorus example (9.'' Ph vPh P I Ph (5) 3 Four-membered Rings In the presence of boron trifluoride etherate oxetanes can be opened by lithium ester or amide enolateslgn or acetylides,'8b the former reaction resulting in a sub- sequent closure to 6-lactones after acidification (Scheme 8).'GX R- 2 n R 3 - R 2 n 1 3 +\ R' 0- R1 0-0 x R' 0 Scheme 8 The bis-alkylidene-1,3-dithietane(6) has been shown to act as a stable form of the thioketene (7) in [3 +21-(with sodium azide) and [2 +21-(with an ynamine and an imine) cycloadditions across the C=S bond." In contrast the cyanoalkyl- idene- 1,3-dithietanones (8) react with imines to give the six-membered heterocycles (9) (Scheme 9) which eliminate COS to give thio-P-lactams only in sterically hindered cases (see P-lactam section).20 R' (9) Scheme 9 16 E.G. Lewars Chem. Rev. 1983,83 519. l7 A. Marinetti F. Mathey J. Fischer and A. Mitschler J. Chem. SOC..Chem. Commun. 1984 45. 18 (a) M. Yamaguchi K. Shibato and I. Hirao Tetrahedron Lett. 1984 25 1159; (b) M. Yamaguchi Y. Kobayashi and I. Hirao Tetrahedron 1984 40,4261. 19 G. L'Bbbe P. Vangheluwe S. Toppet G. S. D. King and L. van Meervelt Bull. SOC.Chim Belg. 1984 93 405. 20 E. Schaumann K. Wriede and G. Adiwidjaja Chem. Ber. 1984 117 2205. 188 E. H.Smith P-Lactams.-A number of phosphorus substituted P-lactams have been synthesized including the thienamycin phosphonate analogues ( which were stable to renal dehydropeptidase the cis-and trans-1-phosphacephalosporins (11),22a (12),22band (13),22cand the monocyclic p-lactam (14).23aIn the synthesis of the last compound OEt HO M eO 0&NyJ C0,Me (Scheme 10) the formation of only that stereoisomer indicated was claimed whereas the analogous synthesis starting from the cyano-amide (15) is reported to give a mixture of stereoisomers epimeric at C-4 (ratio = 51 :22).23bThe few data that are available suggest that the phosphorus groups have not enhanced the antibacterial activity.Scheme 10 Phosphorus reagents have proven to be eminent mediators in two p-lactam closures.24 Both research teams report that the unsubstituted phosphoramidate (PhO)P(Cl)NHPh is ineffective in the condensations (Scheme 11).A new route to carbapenams and carbacephams has been described in which the key steps are generation and ring-closure of a tricarbonyl intermediate (Scheme 21 A. Andrus B. G. Christensen and J. V. Heck Tetrahedron Lett. 1984 25 595. 22 (a) H. Satoh and T. Tsuji Tetrahedron Lett. 1984 25 1733; (b) H. Satoh and T. Tsuji ibid. 1984 25 1737; (c) M. M. Campbell M. C. Carruthers S. J. Michel and P. M. Winter J. Chem. SOC.,Chem. Commun. 1984 200. 23 (a) M. Shiozaki and H. Masuko Heterocycles 1984,22 1727; (b) M. Shiozaki H. Maruyama and N. Ishida ibid. 1984 22 1725. 24 (a)J. M. Aizpurua I. Ganboa F. P. Cossio A. Gonzalez A. Meta and C. Palomo Tetrahedron Lett. 1984 25 3905; (6) S. R. Shridhar B. Ram V. L. Narayana A. K. Awasthi and G. J. Reddy Synthesis 1984 846.Heterocyclic Compounds 0 CI R4XCH,C0,H COY K+ I1 Y I PhOPCl ? (PhO)P( NMePh) + + _____ 0Ei32 Et,N KR2 = NhOMe,XR4 0 Scheme 11 n = 1,2 1ii Reagents i Me2NCH(OMe), 25 "C; ii lo2;iii HF. pyridine MeCN Scheme 12 12).25"The method was used for the synthesis of the antibiotic (*)-PS-5 (16).25b A sulphoxide derivative of this antibiotic is reported to undergo displacement by two stabilized carbanions generated using the base tetramethylguanidine (Scheme 13).26 Other bases such as NaH NaOMe or KOBu' resulted in rupture of the 25 (a)H. H. Wasserman and T H. Han Tetrahedron Lett. 1984 25 3743; (b) H. H. Wasserman and T. H. Han ibid. 1984 25 3747. 26 T. Yoshioka K. Yamamoto Y. Shimauchi Y. Fukugawa and T.Ishikura J. Chem. Soc. Chem. Commun. 1984 1513. 190 E. H. Smith X = H,Y = NO X = CN,Y = C0,Me Scheme 13 p-lactam ring. A potential precursor (17; X = OAc) of the related asparenomycins (18)was prepared by the addition of chlorosulphonyl isocyanate to an allenyl acetate (Scheme 14).27Functionalization of the methyl groups could be achieved by allylic bromination in the more stable sulphone (17; X = S0,Ph). 07) Scheme 14 FN 20 "C, +=-s- 7 days ShoMe An X-ray structure determination of the thio-P-lactam (19) indicated a flatter N-pyramid and a shorter N-1 to C-7 distance implying a higher strain in the four-membered ring imposed by the thiocarbonyl group,28 a feature which must be reckoned with in future attempts at the synthesis of these analogues.A new N-protecting group for the synthesis of N-unsubstituted p-lactams is the formylmethyl group prepared from an ally1 or 2,2-dichloroethyl ~rogenitor.~~ A book on small ring heterocycles contains a section on p-lactarn~.~' 21 J. D. Buynak H. Pajouhesh D. L. Lively and Y. Ramalakshmi,J. Chem. Soc. Chem. Cornmun. 1984,948. 28 E. Schaumann W.-R. Forster and G. Adiwidjaja Angew. Chem Int. Ed. EngL 1984 23,439. 29 T. Fukuyama A. A. Laird and C. A. Schmidt Tetrahedron Len 1984 25 4709. 30 .G. A. Koppel in 'Small Ring Heterocycles. Part 2. Azetidines /3-Lactams Diazetidines and Diaziridines,' ed. A. Hassner J. Wiley New York 1983. Heterocyclic Compounds 4 Five-membered Rings A few rare 2-amino-5-sulphinylfuranscan be made by the reaction of alkynyl sulphones with ynamines (Scheme 15).31 The full scope of this reaction has yet to be realised.A new route (Scheme 16) to 2-substituted-4-trimethylsilylfurans involves epoxidation of the vinylsilane (20) followed by ring-opening and re-clos~re.~~ An alternative reaction of (Y -silylepoxides leads to 2,3-disubstituted furans (Scheme 17).33 Careful choice of the substituents allows predominant production of one regioisomer. R' ArSO,C=CH + R'-=-N(Ph)Me -* h MeN 0 SAr I I1 Ph 0 Scheme 15 JJR -Me,Si Me Si i Zn,ultrasound i m-CPRA RCN ii O.2M-HCI iii H,O' (20) iv molecular sieves Scheme 16 R2 R' R2 R' Scheme 17 Acid-catalysed isomerization of bis(pheny1thio)cyclopropane aldehydes provides a useful route to 2,3-dihydrofurans the starting materials being readily available.34 The amenable dichloropyran (21) acts as a useful precursor of the dithioacetals of tetrahydrofuran-2-carbaldehyde, which is much less ac~essible.~' The potential use of furans in synthesis is yet again underlined by the publication of an account of a convenient conversion of them into the ene-diones (22) using ceric ammonium nitrate.36 " G.Himbert. S. Kosach. and G. Maas Angew. Chem. Int. Ed. Engl. 1984 23 321. 32 P. Knochel and J. F. Normant Tetrahedron Lett. 1984 25 4383. 33 F. Sato H. Kankara and Y. Tanaka Tetrahedron Lett. 1984 25 5063. 34 0.G. Kulinkovich I. G. Tishchenko and N. A. Roslik J. Org. Chem. USSR (Engl. Transl.),1984,20,480.35 A. Mottoh and C. B. Reese J. Chem SOC.,Chem. Commun. 1984 1028. 36 L. Lepage and Y. Lepage Svnthesir 1983 1018. 192 E. H.Smith The effectiveness of trimethylsilyl and trimethylstannyl groups in promoting ipso-substitution is emphasized in the reported regiospecific C-2 acylation (SQ3'" and nitration [Sn using C( N02)4]37b of benzofurans. The ?r-complexed thiophene (23) suffers attack by a limited number of nucleophiles at the position indicated.38 The products of hydride attack can be protonated and decomplexed to give 2,3-dihydrothiophene. CF3S03-(23) Nu = -CN PBun3,BH,- HFe(CO),- HW(COb- Various new reductive routes to pyrroles have been described including the treatment of 4-alkoxy-A3-pyrrolin-2-ones(24)39 or succin~nitriles~~ with di-isobutyl- aluminium hydride and the reaction of 4-nitro-ketones with tributylphosphine and diphenyl disulphide mixture (Scheme 18).,l Di-isobutylaluminium hydride also reduces 2,2-disubstituted-4-halogenonitriles to A'-pyrrolines (25).42 The tetramic acid derivatives (24) required for the first method are simply available on treatment of the common 4-bromo-3-alkoxybut-2-enoates(26) with primary amines or ammonia.43 R' R30 RI R2 Dibal 0_Dibal X=CN NC x R2=H N No H H I";"~L,ci.cH,I (24) R2 (25) Scheme 18 I (26) R2 37 (a) M.Gill Tetrahedron 1984,40 621 ; (b)J. Einhorn P. Demerseman and R. Royer Synthesis 1984 978. 38 D. A. Lesch J. W. Richardson R. A. Jacobson and R. J. Angelici J. Am. Chem. SOC.,1984 106 2901.39 K. S. Kochhar and H. W. Pinnick J. Org. Chem. 1984,49 3222. 40 J. H. Babler and K. P. Spina Tetrahedron Lett. 1984 25 1659. 41 D. H. R. Barton W. B. Motherwell and S. Z. Zard Tetrahedron Lett. 1984 25 3707. 42 L. E. Overman and R. M. Burk. Tefrahedron Lett. 1984 25 5737. 43 K. S. Kochhar. H. J. Carson K. A. Clouser J. W. Elling. L. A. Gramens J. L. Parry H. L. Sherman K. Braat and H. W. Pinnick Tetrahedron Left. 1984 25 1871. Heterocyclic Compounds 193 1,3-Oxazines have served yet again as precursors to pyrroles this time as a result of attack by cyanide ion on the 2,4-dione derivative (Scheme 19).44Dilithiation and alkylation of pyrrole-2-acetic acids followed by decarboxylation provides 2-alkylpyr- roles effectively and simply (Scheme 20):' major minor Scheme 19 R' I i2 R' Scheme 20 A highly versatile one-pot synthesis of pyrroles derives from 1,Caddition of metallo-enamines to CY -aminoacrylonitriles alkylation of the intermediate CY -metal-lated nitrile and thermolysis in acetonitrile (Scheme 21)."6 Its major disadvantage stems from the lack of total control of regiochemistry in the formation of the metallo-enamines from the precursor imines (27) although this fault does not seriously detract from its usefulness.R' NR' R4 N' -b RaycN R'$ MeNPh R3 MeNPh R3 I NR' R4 R2w5cN 4 R' NRI ~5 MeCN R3 NPh Me Scheme 21 Two groups report that the deacylation and deformylation of pyrrole ketones and aldehydes occurs on attempted ketalization with ethylene glycol and toluene-p-sul- phonic acid in boiling benzene.Yields are best when one other electron-withdrawing group is present on the ring.47 It is already known that the use of large protecting groups on nitrogen enhances the amount of electrophilic attack at C-3 of pyrroles. 44 M. Yogo K. Hirota and Y. Maki J. Chem. SOC.,Chem. Commun. 1984 332. 45 J. M. Muchowski and D. R. Solas Synth. Commun. 1984 453. 46 H. Albrecht and A. von Daacke Synthesis 1984 610. 47 K. M. Smith M. Miura and H. D. Tabba 1. Org. Chem. 1983,48,4119; M. W. Moon and R. A. Wade ibid. 1984 49 2663. 194 E. H.Smith Now it has been demonstrated that trimethylsilylation using trimethylsilyl triflate and triethylamine occurs exclusively at C-3 and it is proposed that the size of the reagent complex accounts for this?* 3-Pyrrol-2-ones (28) can be made by the Wittig condensation of diethyl (diazomethy1)phosphonatewith pyruvamides followed by spontaneous decomposi- tion of the intermediate diazoalkene and indiscriminate C-H insertion of the resultant ~arbene.~' The use of 2,5-dimethylpyrroles as protected forms of primary amines has been advocated ;" the recovery of the amine using hydroxylamine hydrochloride is usually good.Two proponents of the use of hydroxamic acid derivatives for the synthesis of indoles in a mild relative of the Fischer synthesis have published their results (Scheme 22).'l The methods provide both 2-substituted and the less-common unsub- stituted indoles.I I co px NH R' f;]? R' I 1 ii ii -.-Reagents i 7x 0°C; ii A; iii ToAc Li2PdCl4,0 + 70°C Scheme 22 48 U. Frick and G. Simchen Synthesis 1984,929. 49 J. C. Gilbert and B. K. Blackburn Tetrahedron Lett. 1984 25 4067. so S. P. Bruekelman S. E. Leach G. D. Meakins and M. D. Tirel J. Chem. Soc. Perkin Trans. 1 1984,2801. 51 S. Blechert Tetrahedron Lett. 1984 25 1547 P. Martin Helv. Chim. Acta 1984 67 1647. Heterocyclic Compounds An intramolecular Diels-Alder reaction of an acetylenic 1,2-diazine is an interest- ing route to indolines the authors stressing the ability by this method to produce 4-substituted derivatives which are of potential use in natural product synthesis (Scheme 23).52 Acetylenes also feature in a rational synthesis of 2H-isoindoles (29) which proceeds through a combination of a retro-ene reaction and a [1,5-H]sigmatropic shift.53 A OMe X = C1,H R = H,Me CH,OTBDMS Scheme 23 R2 R3 R1M\ p R4 /\ Pr’,N NPr; (30) Phosphenium ions (R2P+) undergo cycloaddition with 1,3-dienes to give phos- pholes (30) much more rapidly than the dihalogenophosphines (RPC12).54 The reaction of oxazoles with amines to give imidazoles is a well established procedure which however has previously been found to fail with 5-acetyl-2,4- dimethyloxazole.The desirability of 1H-5-acetyl-2-aminoimidazoles from the phar- maceutical viewpoint has led to a reinvestigation of this reaction.55 It was found that the use of primary amines led to a preponderance of imidazole over pyrimidine whereas secondary amines gave comparable amounts of each.Apparently the dis- crepancy between these results and the earlier work arises from the use of the 2-amino-oxazoles (31) in the later work. 5-Acylimidazoles (32) are also available by the nitrosation of oxoketene-N,S-acetals followed by thermal elimination of water from the intermediate oximes (33).56 A similar procedure using the N-phenyl derivative (34) results in the formation of a thiazole. 52 D. L. Boger and R. S. Coleman J. Org. Chem. 1984,49 2240. 53 R. P. Kreher and N. Kohl Angew. Chem. Znt. Ed. Engl. 1984 23 517. 54 A. H.Cowley R.A. Kemp J. G. Lasch N. C. Norman and C. A. Stewart J. Am. Chem. SOC.,1983 105,7444. 5s J. L. LaMattina and C. J. Mularski Tetrahedron Lett.1984 25 2957. 56 A. Rahman. H. Ila. and H. Junjappa J. Chem. Soc. Chern. Cornrnun. 1984 430. 196 E. H.Smith 0 0 ?H H (33) I MeCN A 5-Acylamino-oxazoles57" and trisubstituted imidazoles5'' are capable of acting as masked dipeptides the unmasking being achieved by very different procedures (Scheme 24). The requirement for 2,4(5)-dialkyl imidazoles led the same research group to investigate the reduction of the easily obtainable N-hydroxyimidazoles (35). It was found that titanium trichloride in aqueous methanol was admirably suited for this purpose.58 iii H, Pd/C Scheme 24 N N /= Me< +R Tic'3' Me< *R R MeCN aq. MeOH N .. N I H OH (35) A simple synthesis of 5-aminopyrazoles (36) results from attack of hydrazine hydrate on the p-chloroacrylonitrile (37).59The 2-trimethylsilyloxazole (38) acts as an equivalent of the corresponding carbanion in reactions with some electrophiles 57 (a) B.H. Lipshutz R. W. Hungate and K. E. McCarthy J. Am. Chem SOC.,1983 105,7703; (b) B. H. Lipshutz and M. C. Morey ibid. 1984 106 457. 58 B. H. Lipshutz and M. C. Morey Tetrahedron Lett. 1984 25 1319. 59 H. Hartmann and J. Liesbcher Synthesis 1984 276. Heterocyclic Compounds Ar i DMF POCI, Ary ii. NH,OH . HCI* H OSiMe thus behaving exactly analogously to the thiazole derivative.60 However in contrast to oxazoles thiazoles are well known for their reluctance to behave as 1,3-dienes in Diels-Alder reactions. Even in the first recorded example of such a process intramolecularity is insufficient inducement and the substitution pattern appears to be critical (Scheme 25).61 The reduction of 4-cyanoisoxazoles (39) leads unexpectedly and expeditiously to the 5-aminoisoxazoles (40).62 EtO4% Lok3-R=CO,Mei X,Y = OH H or 0 s -R = Mc;X,Y = 0 Scheme 25 A.Dondoni T. Dall'Occo G. Fantin M. Fogagnolo A. Medici and P. Pedrini J. Chem SOC. Chem. Commun. 1984 258. 6' P. Jacobi K. Weiss and M. Egbertson Heterocycles 1984 22 281. '* A. Alberola A. M. Gonzalez M. A. Laguna and F. J. Pulido J. Org. Chem. 1984 49 3423. 198 E. H. Smith Japanese chemists have shown that heating a primary nitroalkane with a catalytic quantity of toluene-p-sulphonic acid in boiling mesitylene generates a nitrile oxide which can be trapped.63 This method provides a simple albeit hot and acid alternative to the use of isocyanates for the dehydration of nitro-compounds.Oximes which have already shown their versatility as precursors to imidazoles can also serve for the preparation of isothiazoles (41).64 Thiazoles are a minor side-product both heterocycles apparently deriving from sulphur extrusion by two possible modes from an intermediate dithiazine cation (42). A novel route to benzoisothiazoles (43) involves insertion of an amine into the aliphatic C-S bond of a benzothiete (44). The thermal reaction probably results in production and trapping of a o-thioquinone methide.65 A new approach to benzisoxazoles (45) results in ultimate formation of the 2-3 bond and allows the synthesis of 3-phenyl derivatives bearing bulky substituents at the ortho-position of the phenyl group (which proved impossible to make by classical methods).66 (45) 63 T.Shimizu Y. Hayashi and K. Teramura Bull. Chem. SOC.Jpn. 1984 57 2531. 64 M. Ishida H. Nakanishi and S. Kato Chem. Lett. 1984 1691. 65 K. Kankarajan and H. Meier Angew. Chem. Znt. Ed. Engl. 1984 23 244. 66 G. M. Shutske J. Org. Chem. 1984 49. 180. Heterocyclic Compounds The formation of Reissert compounds from five-membered heterocycles is nor- mally excluded by the more facile ring-opening reactions caused by the aqueous conditions of the classical route. However the use of trimethylsilyl cyanide as a non-aqueous source of cyanide allows ready formation of the first Reissert com- pounds (46; X = 0 S) from benzoxazoles and benzothia~oles.~~ 0 In the area of meso-ionic compounds two reports are interesting.1,3-Oxazolium-4- olates (47) much rarer than their Solate counterparts are available by deoxygena- tion of the phenylglyoxylic imides (48).68 The very few stable derivatives of this ring type were those which precipitated rapidly from solution and these were sufficiently long-lived to allow reaction with N-phenylmaleimide. The second report of more general interest described the production of the carba-analogue (49) of ~ydnone.~~ Compound (49) represents one of a range of possible carba-analogues of meso-ionic and betaine compounds whose reactions particularly cycloadditions could prove fascinating.0 (48) Ph Ph +-Bu'CZSP + XGY-Z -Finally in this section 1,3-dipolar cycloaddition to the C=P bond provides some triaza- oxaza- and diaza-phospholes (50).70 67 B. C. Uff S. L. A. A. Chen Y.-P. 30,F. D. Popp and J. Kant J. Chem. Soc. Chem. Commun. 1984,1245. 68 M. J. Haddadin and H. T. Tannes Heterocycles 1984 22 773. 69 S. Araki J. Mizuya and Y. Batsuyan Chem. Lett. 1984 1045 70 Y. Y. C. Y. L. KO R. Came A. Muench and G. Becker J. Chem. Soc. Chern. Commun. 1984 1634; see also Y. Y. C. Y. L. KOand R. Came J. Chem. Soc. Chem. Commun. 1984 1640. 200 E. H. Smith 5 Six-membered Rings The Diels-Alder approach to pyrans was highlighted in these reports in 1982 (Annu. Rep. Progr.Chem. Sect. B 1982,79,228-229). A new variant of this method using a phosphacumuleneylide as the dienophile leads to a-pyrones (Scheme 26) through R' R' + It X ___,THF reflux R' 0 X- THF PhC0,H. reflux R' X (51) the intermediacy of the somewhat unstable ylides (51).7' hbPh3 0 X = NPh Scheme 26 The lure of tetrahydropyran-containingnatural products has led to the develop- ment of a new general route to 5,6-dihydropyrans which can be hydrogenated to the saturated derivatives (Scheme 27).72 The reaction did not work with two starting materials containing double bonds in which the alkyl substituents were in a trans-relationship. However the known good stereoselectivity of the Ireland-Claisen rearrangement was maintained in this new application.CdR3 dR1fJ OSiMe, i,ii iii-v Pr' Pr' C0,Me -Pr'RiiR3 Reagents i LDA -78°C; ii Me3SiCI Et3N; iii PhMe 105-110°C; iv H,O+; v CH2N Scheme 27 As the ability to form and utiiise a-lithiopyrans would also be of interest in the same synthetic context the report on the generation of these species by reductive desulphurization is timely.73 Experiments using the bicyclic congeners (52) estab-lished that the derivatives are configurationally stable at the temperature of gener- ation (-78 "C) and that the metal is directed axially but the equatorial orientation is preferred at -30°C. Although the authors correctly state that production of the lithio-species by deprotonation was not a serious alternative to their method a contemporaneous report on the deprotonation of saturated ethers including tetrahy- dropyrans using lithium-free butylpotassium suggests that this may not be the case in the future.74 71 H.J.Bestmann and G. Schmid Tetrahedron Lett. 1984 25 1441. 72 S. D. Burke D. M. Armistead and F. J. Schoenen J. 0%.Chem. 1984,49 4320. 73 T. Cohen and M.-T. Liu J Am. Chem. SOC.,1984 106 1130. 74 R.Lehmann and M. Schlosser. Tetrahedron Lett. 1984 25 745. Heterocyclic Compounds 201 Me OH A novel procedure for the synthesis of the tricarbonyliron complexes of some 6-ethoxy-a-pyrones (53) results from the addition of an alkyne to the iron carbene complex (54) and subsequent incorporation of two molecules of carbon monoxide (Scheme 28).75 On continued heating rearrangement of the complexes (53) to the isomers (55) occurs.(54) (53) (55) Scheme 28 A well established route to hydro-furans or -pyrans involves intramolecular alkoxymetallation of alkenes and alkynes. Two groups of workers have shown that the scope of this method can be increased by the utilisation of the intermediate metallated species to introduce further functionality in the resultant chrom~nes~~~ and tetrahydr~pyrans~~' (Scheme 29). A related process involves ortho-thallation of an aromatic acid and Heck olefination with concomitant oxypalladation (Scheme 30).77The latter process is applicable to simple olefins vinyl bromides 1,2- 1,3- and l,4-dienes as well as vinyl cyclopropanes (with opening of the three-membered ring). The Claisen rearrangement previously used to good effect in the synthesis of precursors to coumarins (Annu.Rep. Prog. Chem. Sect. B 1982 79 230) has provided the basis of two one-pot procedures to benzopyrans. Thus Lewis acid catalysed rearrangement of the (a-aryloxymethyl)acrylates (56) gives the methylene coumarins (57),7*awhereas thermolysis of the y-chloroallyl phenyl ethers (58) gives the chromenes (59).78b 7s M. F. Semmelhack R. Temura W. Schnatter and J. Springer J. Am. Chem. SOC.,1984 106 5363. 76 (a) R. C. Larock and W. L. Hamson J. Am. Chem. SOC.,1984 106 4218; (b) M. F. Semmelhack and C. Bodurow ibid. 1984 106 1496. 77 R. C. Larock S. Varaprath H. H. Lau and C. A. Fellows J. Am. Chem. Soc. 1984 106 5274. 78 (a) K. Sunitha K. K. Balasabramanian and K.Rajagopalan Tetrahedron Lett. 1984 25 3125; (b) N. A. Andreev V. I. Levashova and L. I. Bunina-Krivorakova J. Org. Chem. USSR (Engl. Trans/.) 1984 20. 331. 202 E. H.Smith trans 87 10 0 cis 0 0 97 Reagents i Hg(OAc), AcOH; ii aq .NaCI; iii CuCI, cat. PdCI, CO MeOH Scheme 29 -+x 4 R2 + X R2 R' Reagents i Tl(OCOCFs)3 CF3C02H; ii hRI PdC12 MeCN 25 "C; iii 2 Na,C03 2 Et,N A Scheme 30 0 (56) (57) CI R' '0-a 190"C undecane R' Heterocyclic Compounds 203 3-Nitrobenzopyrans have come to the fore during the year. The conversion of 2-hydroxy-a-nitroacetophenones (60) into their magnesium enolates and condensa- tion with aroyl chlorides provides a simple route to 3-nitro-2-aryl chromones (61).'9" The use of magnesium enolates is essential for the success of the reaction.Conditions are also critical in the synthesis of 3-nitrochromenes where the use of the indicated amine hydrochloride and ester solvent is important (Scheme 3 l).79bThe application of 3-nitro-2-aryl chromenes to the synthesis of flavonols has been highlighted in three papers from the same group,8o the method involving basic peroxide having been used to prepare the previously unknown 6-methoxy-flavonols (Scheme 32). R2wNo2 R' 0 R3R2@;H+ OHi"' i-C,H,,OAc A+ R3 BU"~NH,+CI- R4 R4 Scheme 31 NaOH H,O, MeOH R' OR CrCI, aq. HCI THF OH 0 Scheme 32 Most synthetic work during the year on pyridines has been directed towards dihydro- and tetrahydro-derivatives.Thus reduction of 4-pyridones gives rise to 5,6-dihydro-4-pyridones (62),81whereas the parent molecule (63) is obtainable by two methods and proves to be very unstable polymerizing above -80 "Cin solution.82 Lewis acid mediated transfer of carbon groups from silanes or silyl enol ethers to (a) M. Cushman and A. Abbaspour J. Org. Chem. 1984 49 1280; (b) D. Dauzonne and R. Royes Synthesis 1984 348. T. S. Rao A. K. Singh and G. K. Trivedi Heterocycles 1984 22 1377; T. S. Rao S. Deshpande H. H. Mathur and G. K. Trivedi ibid. 1984,22 1943; T. S. Rao H. H. Mathur and G. K. Trivedi Tetrahedron Lett. 1984 25 5561. P. Guerry and R. Meier Synthesis 1984 485. M.-C. Lame J.-L. Ripoli J.-C. Guillemin and J.-M. Denis Tetrahedron Lett.1984 25 3847. 204 E. H.Smith K R N N R I I C0,Et C0,Et (44) (65) R = 6, CN,O% 5,6-dihydro-4-pyridinols (64) gives A3-piperidines (65) with ally1 migration.83 Finally a totally new approach to tetrahydropyridines which is an adaptation of a process recently introduced in carbocyclic chemistry derives from a ring contraction of a macrocyclic azalactone by means of the Ireland-Claisen rearrangement (Scheme 33y4 + --70°C &3- A N Ph ‘0 Ph Scheme 33 A useful means of introducing an alkyl group at C-3 of pyridines involves initial Birch reduction to the bis-silylated 1,4-dihydropyridines (66) followed by fluoride- induced electrophilic attack by aldehydes (mainly) and ketones.” An alternative homolytic alkylation of pyridinium and quinolinium trifluoroacetates with an excess of primary or secondary iodides provides the 2-alkyl derivatives selectively (Scheme 34).86 83 A.P. Kozikowski and P. Park J. Org. Chem. 1984 49 1676. 84 R. I. Funk and J. D. Munger J. Org. Chem. 1984,49 4319. 85 0. Tsuge S. Kanemasa T. Naritomi and J. Tanaka Chem. Lett. 1984 1255. C. Castaldi F. Minisci V. Tortelli and E. Vismara Tetruhedron Lett. 1984 25 3897. 86 Heterocyclic Compounds SiMe 'N' TH F 'N-' I SiMe Scheme 34 The chemistry of pyridinium methylides has been prominent this year. Two new ways of generating the ylides have been described and reaction with dimethyl acetylenedicarboxylate proceeds normally to give an indolizidine (Scheme 35)87a-c In contrast in reactions with olefins the parent ylide acts as a methylene transfer reagent.87 'vd Re1 87a K,CO,/AI20 R2 = H n: / I R2 = SiMe Me02C.C-C . C02Me + R' = H R3+3 ,EWG N+ A / R1 C0,Me CsFRe187b7c or Bu,N+F-I! R2 R1 \ EWG R2 = SiMe,,R' = H EWG = Electron-withdrawing group Scheme 35 Just as pyrroles may act as masked primary amines (see earlier section) so can the dinitro-4-pyridones (67). Protection and deprotection occur under exceptionally mild conditions with no racemization in the amino-acids used as substrates.88 Two ncw approaches to quinolines involve the reaction of arylimidoyl radicals with alkyne~~~ and the cyclodehydration of o-hydroxyalkyl anilides (Scheme 36):' The use of the MeS group in place of the Me0 group as the aryl activating moiety in standard acid-catalysed isoquinoline syntheses has been advocated on the grounds that it is readily removed by hydrogenolysis to give the unsubstituted derivatives which are otherwise difficult to make by these procedures." 87 (a)J.Alvarez-Builla M. G. Quintinilla C. Abril and M. T. Gandesequi J. Chem. Res. (S) 1984 202; (6) 0. Tsuge S. Kanemasa S. Kuraoka and S. Takanaka Chem Lett. 1984 279; (c) Y. Miki H. Hachiken S. Takemura and M. Ikeda Heterocycles 1984 22 701; (d) 0. Tsuge S. Kanemasa S. Takenaka and S. Kuraoka Chem. Lea 1984 465. 88 E. Matsumura H. Kobayashi T. Nishikawa A. Ariga Y.Tokida and T. Kawashima Bull. Chem. SOC. Jpn. 1984 57 1961. 89 R.Leardini G.F. Pedulli A. Tundo and G. Zanardi J. Chem. SOC.,Chem Commun.,1984 1320. 90 P. D. Curran and S.-C. Kuo J. Org. Chem. 1984,49 2063. 91 M. R. Euerly and R. D. Waigh J. Chem. SOC.,Chem. Commun. 1984 127. 206 E. H. Smith aq. pyridine 02NfYNo2 + R'\C02H 7 02NhNo2 N NH2 N A. R CO,H NO 02NfiNo2+ y12 N R C02H I n-c,,H1 3 R aNJ*$2 60 "C C,H DPDC = di-isopropyl peroxydicarbonate H Scheme 36 Vinyl isocyanates generated by Curtius rearrangement have proven to be versatile starting materials for the synthesis of polyhydro-phenanthridinonesor -(iso)quino- lines (Scheme 37).92 Chloro-iminium salts continue to play an important role in the synthesis of heterocycles as shown this year by the development of the 2-azapropenylium salts (68) as precursors to a number of ring types (Scheme 38)930 and the use of phosgene-iminium salts (69) in the syntheses of q~inazolines~~ and benzo(naphth0)- 1,3-0xazines~~~ the former process allowing specific production of the less accessible 2-alkylamino-4-chloro derivatives.92 J. H. Rigby and N. Balasubramanian J. Org. Chem. 1984 49 4569. 93 (a) G. V. Boyd P. F. Lindley and G. A. Nicolaou J. Chem. SOC.,Chem. Commun. 1984 1105; (b) B. Kokel G. Menidi and M. Hubert-Habart Tetrahedron Lett. 1984 25 1557 (c) B. Kokel G. Menidi and M. Hubert-Habart ibid. 1984 25 3837. Heterocyclic Compounds 207 H PhCH, reflux 61% Scheme 37 (68) KSCN R5 R5= H,02N Me R3 + R4 = H,Ar Scheme 38 CI XH R ' d I 4 X=NH + = N NR2R3 CI R2 )+ CI ~3~1- (69) 208 E.H.Smith Pyridazinones of two different substitution patterns are obtainable by the treatment of A2-oxazolin-5-ones with aldazine~~~ or by ring-opening of 2-trimethylsilyloxy-cyclopropanecarboxylates with hydrazine hydrate (Scheme 39).95 R R R4 C0,Me H H2NNH,. H,O Me,SiO R' R2 R' R2 R3 Scheme 39 A general route to the rare 6H-1,3-oxazin-6-ones (70) uses a retro-Diels-Alder cycloaddition a now common tactic?6 Two new groups of heterocyclic compound are the 1,4,2,5-dithiadiazines (71)97 and the blue crystalline betaine (72).98 0- 6 Seven-membered Rings It has been shown that the chloroazirines (73) react with o-aminobenzylamines to give 5 H-1 ,Cbenzodiazepines (74) ." Although yields are only moderate the reaction works in those cases where the alternative use of an a-diketone fails indicating the potential use of (73) as bifunctional reagents.94 D. Konwar D. Prajapati J. S. Sandhu T. Kametani and T. Honda Heterocycles 1984 22 2483. 95 J. Reichert and H.-U. Reissig Synthesis 1984 786. % G. Stajer A. E. Szabq F. Fulop and G. Bernath Synthesis 1984 345. 97 B. G. Lenz and B. Zwanenburg J. Chem. SOC,Chem Commun. 1984 1386. 98 F. A. Neugebauer H. Fischer and C. Krieger Tetrahedron Lett. 1984 25 629. 99 K. R. Randles and R. C. Storr. J. Chem. SOC..Chem. Commun.. 1984 1485. Heterocyclic Compounds Two routes to oxocenones from six-membered rings have been published.The first case uses simple 8-lactones the two extra carbons being provided by the addition of an acetylide anion to the carbonyl group,1oou whereas the second proceeds through the base-catalysed ring expansion of a-pyrone-chloroalkene photoadducts (Scheme 40).loob 0 ii HMPA Et,N ___ -HCI R2RjJ 1.1. 0 X = H Me SMe R' = C1,H R2 = R3 = C1,CN Scheme 40 The X-ray structure of the stable oxazocine (75) establishes that unlike its precursor (76) .it is planar with much less marked bond length alternation in the eight-membered ring strongly suggesting that 1 0.n-delocalization is present."' F OaTS i,K/NH it (MeO),C,H,CH,CI ' 0~N7c6H2(0Me)3 (76) (75) 7 Fused and Bridged Systems The fluorine atoms in the derivative (77) of the 2,6-dioxabicyclo[3.1.llheptane type which is believed to be present in thromboxane-A* confer considerable stability towards acid hydrolysis the rate of reaction being approximately 100-times slower than that for acetaldehyde diethyl acetal."' OBn pH 1.27 .qJB* Fql 0 OBn HO OBn (77) 100 (a) S. L. Schreiber and S. E. Kelly Tetrahedron Lett. 1984,25 1757; (6)T.Shimo K. Somekawa J. Kuwakino H. Uemura S. Kunamoto 0. Tsuge and S. Kanemasa Chem Lett. 1984 1503. I01 B.Zipperer D.Hunkler H. Fritz G. Rihs and H. Prinzbach Angew. Chem. Inf.Ed. Engf. 1984,U,309. 102 J. Fried E. A. Hallinan and M. J. Szwedo J. Am. Chem. Soc. 1984,106. 3871. 210 E. H. Smith Two new heterocyclic systems of some theoretical and practical interest are the highly coloured betaines (78)'03 and the fascinating and exceptionally stable free- radical (79).'04 0 R = Ph,CN X = 0 S NTs C(CN)-Finally the synthesis of the hexa-azaoctadecahydrocoronene (80) pursued for its oxidation to a potential ferromagnetic organic salt involved multiple closures of the hexa-amide (81) which because of the high yield (80%) and absence of side products must have occurred in the same direction for each closure.'05 CI 0 N N 0 CI lo3 K.T. Potts and W. R. Kuehnling J. Org. Chem 1984 49 3672. A. Albini. G. F. Bettinetti G. Minoli and T. F. Soldi Chem. Lett. 1984 1197. I05 R. Breslow P. Maslak and J. S. Thomaides J. Am. Chem. SOC.,1984 106 6453.

 



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