7 Heterocyclic Compounds By P.W. SHELDRAKE Smith Kline Beecham Pharmaceuticals Old Powder Mills Nr Leigh Tonbridge Kent TN11 9AN UK 1 Introduction In last year's Chapter a number of examples illustrating the versatility of metallated derivatives of a variety of heterocyclic compounds were included. These convenient synthetic tools continue to be exploited and reviews have appeared that cover imida~oles,~ The metallation isoxazoles,' oxazoles,2 pyrazole~,~ and dia~ines.~ strategy can be commended for its scope and efficiency; the best examples still find their way into the body of the review. 2 Three-membered Rings Asymmetric epoxidation of styrene has been accomplished in up to 86% enantiomeric excess and 88% yield,6 using the manganese catalyst (1)with rn-chloroperbenzoic acid and N-methylmorpholine N-oxide in dichloromethane at -78 "C.With the catalyst (2) and sodium hypochlorite and a pyridine N-oxide as co-oxidants a cis-cinnamic ester was epoxidized with 96% enantiomeric ex~ess.~ A closely related catalyst has been used' in conjunction with iodosylbenzene to epoxidize trans-stilbene (65% yield 62% e.e.) and a chromene (78% yield 96% e.e.). 'But BU' ' (1) R1= Ph; R2 = OSiPrgi (2) R' = (CH& R2= Bu' ' B. Iddon Heterocycles 1994 37 1263. 'B. Iddon Heterocycles 1994,37 1321. ' M. R. Grimmett and B. Iddon Heterocycles 1994 37 2087. B. Iddon and R.I. Ngochindo Heterocycles 1994 38 2487. A. Turck N. PIC and G. Queguiner Heterocycles 1994 37 2149. ti M. Palucki P.J.Pospisil W. Zhang and E.N. Jacobson J. Am. Chern. SOC. 1994 116 7880. ' E.N. Jacobson L. Deng Y.Furukawa and L. E. Martinez Tetrahedron 1994 50 4323. N. Hosoya A. Hatayama R. hie H. Sasaki and T. Katsuki Tetrahedron 1994 50 4311. 207 P. W. Sheldrake (3) Reagents i LDA THF -78 "C;ii R'R'C=O Scheme 1 0 0&OR1 Reagents i R'Li or R'MgCI -85 "C Scheme 2 A R' (7) Reagents i R:NH [Yb(OTf),] CH,Cl Scheme 3 Manganese(rr1) tetraphenylporphyrin is the catalyst for epoxidizing cis-olefins with tetra-n-butylammonium periodate.' 2-Chloromethylpyridine (3) can be used lo to prepare oxiranes (4) a method analogous to the Darzens reaction (Scheme 1). Homochiral oxirane esters (5) are converted into ketones (6)using organolithium or Grignard reagents' with little loss of stereochemical integrity; enantiomeric excesses of 92-99Y0 were achieved (Scheme 2).The opening of oxiranes (7) by an amine in the presence of a lanthanide(I1r) trifluoromethanesulfonate occurs in high yield and with over 99% regioselectivity (Scheme 3). The ytterbium salt is especially effective." The same salt has been used in the aminolysis of N-tosylaziridines,' though in this case the regioselectivity is more variable (75-98 YO). A theoretical study of substituted oxirenes suggests that dimethyloxirene is a true minimum on the potential energy surface. l4 There is a review of the synthesis of chiral aziridines and their use in stereoselective transformations.' The readily available 2-bromoacrylamide (9) reacts with primary amines to give the anticipated aziridine D.Mohajer and S. Tangestaninejad Tetrahedron Lett. 1994 35,945. lo S. Florio and L. Trosi Tetrahedron Lett. 1994 35,3175. L. Pegorier Y. Petit A. Mambu and M. Larcheveque Synthesis 1994 1403. M. Chini P. Crotti L. Favero F. Macchia and M. Pineschi Tetrahedron Lett. 1994 35,433. M. Meguro N. Asao and Y. Yamarnoto Tetrahedron Lett. 1994 35,7395. l4 J. E. Fowler J. M. Galbraith G. Vacek and H. F. Schaefer 111 J. Am. Chem. SOC.,1994 116 9311. I5 D. Tanner Angew. Chem. Int. Ed. Engl. 1994 33,599. Heterocyclic Compounds Reagents i RNH Scheme 4 i Ria&@ 92-98% R2 (11) RY2But Reagents i LDA R' = alkyl; R2 = H Me * (12) Scheme 5 Ar R' + ArN=S=NAr 53% R2 I Reagents i [PdCl,(PhCN),] toluene 130"C Scheme 6 derivatives (10) as single diastereoisomers (Scheme 4).In only one case was a minor diastereoisomer detected. ' Aziridines (11) undergo an aza-[2,3]Wittig rearrangement on treatment with strong base to give 1,2,3,6-tetrahydropyridines(12) (Schemes 5).' The palladium-catalysed reaction of aziridines (13) with sulfur diimides (14) produces imidazolidine-2-thiones (1 5) that have mysteriously gained a carbon atom (Scheme 6). Carbon-13 labelling showed that both the methylene carbon and the thiocarbonyl carbon atom of the product derive from the methylene carbon of the starting aziridine i.e. two mols of (13) produce one of (15).'* Treatment of olefins with N-(p-tolysulfony1)iminophenyliodinanein the presence of l6 P.Garner 0. Dogan and S. Pillai Tetrahedron Lett. 1994 35 1653 " J. Ahrnan and P. Sornfai J. Am. Chem. SOC. 1994 116 9781. J.-0. Baeg and H. Alper J. Am. Chem. Soc. 1994 116 1220. P.W. Sheldrake s n3 II n Reagents i (EtO),PSSBr; ii TBAF Scheme 7 Ph Reagents i Oxone@ (C,H,,),NMeCI CHzCIz HzO Scheme 8 (211 Reagents i hv (2305 nm) Scheme 9 copper(1) or copper(I1) triflate or perchlorate gives N-to~ylaziridines'~ in 55-95 % yield. An olefin (16) can be converted into a thiirane (18)using the thioxaphosphorane sulfenyl bromide indicated via the adduct (17) which is reacted with tetra-n-butylammonium fluoride (Scheme 7).20 Oxidation of the bis-thioketal(19) with buffered Oxone@ gives the dithiirane (20)in modest yield;*' compound (20) is the first isolable dithiirane (Scheme 8).More difficult to capture is l,1-dimethyl-1H-silirene (22)prepared by irradiation of 2-sila-l,3-bis(diazo)propane(21) in an argon matrix at 10K (Scheme 9). It is the first silirene to be observed without substituents on the double bond.22 3 Four-membered Rings Heterocyclic chemists might regard paclitaxel (TaxoP) as an oxetane with complicated l9 D. A. Evans M. M. Faul and M.T. Bilodeau J. Am. Chem. SOC. 1994 116 2742. 2o G. Capozzi S.Menichetti S. Neri and A. Skowronska Synlett 1994 267. A. Ishii T. Akazawa T. Maruta J. Nakayama M. Hoshino and M. Shiro Angew. Chem. Int. Ed. Engl. 1994 33 777. 22 M. Trommer W. Sander and C. Marquard Angew. Chem. Int. Ed. Engl. 1994 33 766.Heterocyclic Compounds 21 1 TBDMSO TBDMSO ___c BuQC iii 77% Bu’02C NCH2Ph H Reagents i LiN(TMS)CH,Ph MeCHO; ii TBDMSCl; iii EtMgBr Scheme 10 appendages! In the noteworthy achievement of its total synthesis23 oxetane formation was possibly the most straightforward step. There are reviews on the synthesis of natural /?-lactam antibiotic^^^ and on the use of organosilicon and organotin compounds in the synthesis and transformation of lactam tam^.^^ A three-component condensation initiated by Michael addition of lithium N-benzyl(trimethylsily1)amide to unsaturated ester (23) and followed by capture of acetaldehyde gives the fi-amino acid derivative (24) stereoselectively.26 This is ring closed to the fi-lactam (25) in good yield (Scheme 10).The carbamoylcobalt (111) salophen derivative (26) undergoes homolytic cleavage on heating in toluene.27 Cyclization (4-exo-trig) and dehydrocobaltation gives the /?-lactam (27). Irradiation2* of (28) permits isolation of the intermediate (29); the subsequent thermal elimination of cobalt to form (30) was inefficient (Scheme 11). Isoxazolines (31) are converted into /?-lactams (32) on treatment with tetra-n- butylammonium fluoride,29 but the yields are only moderate (Scheme 12). The /?-lactam (33) is converted into penam (34) by ferric nitrate/cupric nitrate. Manganese acetate/cupric acetate gives the corresponding acetate (35). The relevance of the study to the Baldwin mechanistic hypothesis on the biosynthesis of penicillin is described3’ (Scheme 13).The bicyclic thiazinone (36) gives a 1-fi-methylcarbapenem (37) by Eschenmoser sulfide contraction (Scheme 14). The phosphate ester was then displaced by a thiol in good overall yield.31 Azet-2(3H)-one (39) derived from 4-acetoxyazetidin-2-one (38) reacts with 1,3- dipoles to give for example (40) (Scheme 15). Polymer-bound derivatives of (38) and of the 1,3-dipole precursor were used to confirm the presence of free (39) by the three-phase test . Treatment of the malonate (41) with cyanide in DMSO gives the expected product (43); but use of chloride gives the rearranged product (44)(Scheme 16). The behaviour is explained by different reactions of common intermediate (42) with the two anions.33 23 K. C. Nicolaou Z. Yang J. J. Liu H.Ueno P.G. Nantermet R. K. Guy,C. F. Claibourne J. Renaud E. A. Couladouros K. Paulvannan and E. J. Sorensen Nature (London) 1994 367 630. 24 R. Southgate Contemp. Org. Synth. 1994 1 417. 25 G. A. Veinberg and E. Lukevies Heterocycles 1994 38 2309. 26 N. Asao T. Shimada N. Tsukada and Y. Yamamoto Tetrahedron Lett. 1994 35 8425. ” G. Pattenden and S. J. Reynolds J. Chem. SOC.,Perkin Trans. I 1994 379. 28 G.B. Gill G. Pattenden and S.J. Reynolds J. Chem. SOC. Perkin Trans. I 1994 369. 29 C. Ahn J. W. Kennington Jr. and P. De Shong J. Org. Chem. 1994,59 6282. ’O W. Cabri I. Candiani and A. Bedeschi J. Chem. SOC. Chem. Commun. 1994 597. ” 0.Sakurai T. Ogiku M. Takahashi H. Horikawa and T. Iwasaki Tetrahedron Lett. 1994,35 2187. ’’A.M. Costero M. Pitarch and M.L. Cano J. Chem. Res. (S) 1994 316. 33 P. J. Gilligan and P. J. Krenitsky Tetrahedron Lett. 1994 35 3441. P. W. Sheldrake OBn 40% i N Bn (salophen)CoKNBn )-FOB. 0 0 Reagents i A toluene; ii hv Scheme 11 R (31) R = Ph C02Et Reagents i TBAF THF 0 “C Scheme 12 Oxetanes (45) are rearranged by boron trifluoride etherate to give derivatives (46) of larger cyclic ethers (Scheme 17). A similar rearrangement of the corresponding oxiranes is also reported.34 The preparation of 2H,SH-benzo[ 1,2-b;4,5-b’)bisthiete (48) by flash vacuum pyrolysis of (47) is rep~rted.~’ Further reactions of the bisthiete often involve thiaquinonemethides giving for example (49) with dimethyl acetylenedicar- boxylate3’ (Scheme 18). lH-NaphthoC2,l-blthiete and 2H-naphtho[2,3-b]thiete were also prepared by this meth~dology.~~ 4 Five-membered Rings There are reviews of the chemistry of 2-oxazolines (1985Spre~ent);~~ benzotriazolylal-34 A.Itoh Y. Hirose H. Kashiwagi and Y. Masaki Heterocycles 1994 38 2165. 35 H. Meier and A. Mayer Angew. Chem. lnt. Ed. Engl. 1994,33 465. A. Mayer and H. Meier Tetrahedron Lett. 1994 35 2161. 37 T. G. Grant and A. I. Meyers Tetrahedron 1994 50 2297. 213 Heterocyclic Compounds (33) (34) X = NO2 (35) X = COCH3 Reagents i Fe(NO,),/Cu(NO,),; ii Mn(OAc),/Cu(OAc), MeCN Scheme 13 Reagents i NaH PPh, DMF; ii (PhO),POCl Scheme 14 H Ph (38) (39) (40) Reagents i PhCH(CO,Me)N=CHPh Scheme 15 kylations and benzotriazole-mediated heteroalkylations;38 and recent advances in the cycloaddition chemistry of isomiinchnones and thioisomiinchnones.39 Also reviewed are synthetic approaches to b~tenolides;~' the ketoxime-based pyrrole ~ynthesis;~' recent (1990-93) developments in indole ring synthesis;42 and anellated heterophos- ph01es.~~ 4-Iodo-3-trimethylsilylfuran,a potentially useful intermediate is available in 80% yield44 from 3,4-bis(trimethylsilyl)furan on treatment with iodine/silver trifluoro- 38 A.R. Katritzky X.Lan and W.-Q. Fan Synthesis 1994 445. 39 M. H. Osterhout W. R. Nadler and A. Padwa Synthesis 1994 123. 40 D. W. Knight Contemp. Org. Synth. 1994 1 287. *' B. A. Trofinov and A. I. Mikhaleva Heterocycles 1994 37 1193. *' G.W. Gribble Contemp. Org. Synth. 1994 1 145.43 R. K. Bansal K. K. Karaghiosoff and A. Schmidpeter Tetrahedron 1994 50 7675. ** Z.Z. Song and H.N.C. Wong Liebigs Ann. Chem. 1994 29. P. W.Sheldrake Ph-N (43) (44) Reagents i NaCN DMSO; ii NaCl DMSO Scheme 16 Me (45) n= 1,2,3 Reagents i BF,.OEt, CH,Cl Scheme 17 acetate at -78 "C.The tributyltin-substituted butenolide (50) can be converted into the corresponding chloro bromo or iodo derivatives (51) on treatment with the halogen in a chlorinated solvent.45 The iodo compound had not been previously reported (Scheme 19). 2,5-Dimethoxy-2,5-dihydrofuran (52) reacts with 2-iodophenol (53)under pallad- ium catalysis to give the 2,3-dihydrobenzofuran (54).Treatment with boron tri- fluoride gives the benzofuran (55) (Scheme 20).46 Using a 2-iodoaniline-derived carbamate (56) as substrate produces (57).Cycliz-ation to the indole (58)is effected with trifluoroacetic acid (Scheme 21).47 The exocyclic methylene compound (60) is readily prepared from cyclohexane- 1,3- dione (59) and diethylpropargylsulfonium bromide. It reacts with electron-deficient alkenes in an ene reaction giving furans (61) (Scheme 22).48 3-Lithiothiophene is stable in hexane at room temperature:' a significant solvent 45 G. J. Hollingworth J. R. Knight and J.B. Sweeney Synth. Commun. 1994 24 755. 46 K. Samizu and K. Ogasawara Heterocycles 1994 38 1745. 47 K. Samizu and K. Ogasawara SYNLETT 1994 499. 48 A. Ojida A. Abe and K. Kanematsu Heterocycles 1994 38 2588. 49 X.Wu T.A. Chen L. Zhu and R.D.Rieke Tetrahedron Lett. 1994 35 3673. Heterocyclic Compounds TOH ii HS HO' (47) (49) E=C02Me Reagents i FVP; ii Me0,CC-CC0,Me Scheme 18 0 Bu&n d o -d 5940% o i X (50) (51)X = CI Br I Reagents i X, chlorinated solvent Scheme 19 I + Uo* (53) (55) (54) Reagents i Pd(OAc), PriNEt BnEt,NCI DMF 70°C; ii BF,.Et,O Scheme 20 effect. The thioanhydride (62) reacts with bis(cyclopentadieny1)dimethyltitanium to give the 2,Sdimethylenethiolane (63),which is stable to isomerization in the absence of acid.50 Tosic acid brings about quantitative conversion into the thiophene (64) (Scheme 23). M.J. Kates and J. H. Schauble J. Org. Chem. 1994 59 494. P. W. Sheldrake OMe (56) R' = H OMe; (57) (58) R2 = Et Bu' Reagents i (52) Pd(OAc), PriNEt BnNEt,Cl DMF 80°C; ii 6% TFA CH,CI Scheme 21 (59) (60) (61) Z = COCH3,C02Et,CN Reagents i HC-CCH,SEt,Br KOBu' THF; ii CH,=CHZ Scheme 22 i ii ___t 0 0-Me Me (62) R' R2 = H alkyl Ph (W Reagents i [TiMe,Cp,]; ii TsOH Scheme 23 The tributylphosphine/carbon disulfide adduct reacts with a strained olefin for example (65) and benzaldehyde to give a 2-benzylidene- 1,3-dithiolane (66) (Scheme 24)?' Treatment of the thienopyrrolotriazole (67) with tosic acid gives thieno[3,4-c] pyrrole (68) as its tosylate salts2 by 1,3-dipolar cycloreversion.The free base is obtained using sodium carbonate. Reactions of (68) uia its dipolar tautomer (69) were recorded (Scheme 25). It has been found that treatment of 1-arylpyrrole-2-carboxaldehydes with triflic acid in refluxing 1,Zdichloroethane brings about their conversion into l-arylpyrrole-3- carboxaldehydes; at equilibrium the proportion of the latter is 95% or better.53 There is a convenient synthesis of 2-arylpyrroles (71) starting from 1-propargylbenzotriazole (70) as indicated54 in Scheme 26.51 R.A. Aitken T. Massil and S.V. Rant J. Chem. SOC.,Chem. Commun. 1994 2603. 52 C.-K. Sha and C.-P. Tsou J. Chem. SOC.,Perkin Trans. I 1994 3065. s3 P. Dallemagne S. Rault F. Fabis H. Durmoulin and M. Robba Synth. Commun. 1994,24 1855. 54 A. R. Katritzky J. Li and M. F. Gordeev Synthesis 1994 93. Heterocyclic Compounds Reagents i Bu,P-CS, PhCHO Scheme 24 (67) R’ R2= H Me,Ph (68) (69) Reagents i TsOH; ii Na,CO Scheme 25 I ii.iii mAr 4540% N H Reagents i BuLi; ii ArCH=NTos; iii NaOH EtOH Scheme 26 Another application of benzotriazole meth~dology~~ converts the iminophos- phorane (72) into the synthon (73). This can be converted into 3H-benzazepine (74)or into a 2,3-diarylpyrrole (75) both in good yield (Scheme 27). Substituted 1,3 -dienes (76) undergo cycloaddi tion with N-sulfinyl-p-toluenesul-fonamide. Treatment of the adducts (77) with trimethylphosphite/triethylamine gives 1-tosylpyrroles (78) (Scheme 28).56 Reaction of 1,3-diketones (79) with the azoalkene (80)gives access to pyrroles (82) via the protected 1-(Boc-amino) derivatives (81) (Scheme 29).57 55 A. R. Katritzky J. Jiang and P. J. Steel J.Org. Chem. 1994 59 4551 56 P. J. Harrington and I. H. Sanchez Synth. Commun. 1994 24 175. 57 A. J.G. Baxter J. Fuher and S. J. Teague Synthesis 1994 207. P. W. Sheldrake <N =PPh3 Reagents i Ph,P=CH,; ii BuLi; iii o-C,H,(CHO),; iv ArCOCOAr Scheme 27 i ii 8344% 80% R' XR4 I Tos (76) R' R2 R3 R4 = H,Me Ph (77) (78) Reagents i TosN=S=O; ii P(OMe), NEt Scheme 28 Reagents i Bu'OH heat; ii HC1 MeOH; iii NaNO, HCl MeOH Scheme 29 Heterocyclic Compounds - i ii R’YNH2 C02R2 2048% (83)R’ = alkyl; R2 = Me Et Reagents i MeO,ECCO,Me; ii NaOMe MeOH Scheme 30 0 (MeO),P ,C02Me Reagents i (MeO),POCH,COMe NaH THF; ii (EtO),POCH,CN NaH THF Scheme 31 R’ R2 - iRq &O2CH2Ph -76% R’ H (88)R’ R2= alkyl (89) Reagents i CNCH,CO,CH,Ph DBU THF Scheme 32 Esters of a-aminoacids (83) are quickly converted into 3-hydroxypyrroles (84)by way of their adducts with dimethyl acetylenedicarboxylate (Scheme 30).58 1,2-Diaza- 1,3-dienes (85) are starting materials for the preparation of pyrroles with less usual sub~tituents.~’ Reaction with dimethyl (2-oxopropy1)phosphonategives the pyrrole-3-phosphonates (86)and use of a cyanomethylphosphonate results in similar 2-aminopyrrole-3-phosphonates(87) (Scheme 31).A range of 2-unsubstituted pyrroles (89) is available by the condensation of benzyl isocyanoacetate with the readily prepared nitroolefins (88) (or the corresponding 2-acetoxynitroalkanes) (Scheme 32).60 The oxidation of substituted pyrrolidines (90) into pyrroles (91) with ‘activated’ 58 P.Kolar and M. Tisler Synth. Cornmun. 1994 24 1887. 59 O.A. Atlanasi P. Filippone D. Giovagnoli and A. Mei Synthesis 1994 181. 6o T. D. Lash J. R. Bellettini J. A. Bastian and K. B. Couch Synthesis 1994 170. P.W.Sheldrake (90) R' R2 R3 R4 seetext (91) Reagents i activated MnO, THF reflux Scheme 33 But // But (92)X = 0,S (93) (94) Reagents i FVP 400°C Scheme 34 manganese dioxide has been studied.6' In general one of the substituents R, R, or R must have a carbonyl group next to the ring; the reaction fails if R,is benzoyl (Scheme 33). Flash vacuum pyrolysis of the benzofurylnitrone (92) gives a mixture of a benzofuro[2,3-c]pyrrole (93) and a benzofuro[2,3-c]pyridin-3-one (94) (Scheme 34).The mechanism involves an initial 1,7-dipolar cyclization. The corresponding benzothiophene starting material reacts similarly.62 The acid-catalysed cyclization of B,y-unsaturated amides has been studied.63 Thus (3E)-pent-3-enamide (95) gives 5-methylpyrrolidin-2-one (96) but (3E)-hex-3-enam- ide (97) gives a piperidin-2-one (98) (Scheme 35). If benzaldehyde is added to such reactions further interesting though mechanisti- cally distinct cyclizations are apparent.64 Thus the secondary pentenamide (99a) undergoes both condensation and cyclization onto the benzene ring giving (100).The primary amide (99b) gives a pyrrolidin-2-one (101),which in a different acid system is converted into a piperidin-2-one (102) (Scheme 36).Radical-induced cyclization is effective for the formation of five-membered rings. Homolytic cleavage of the N-S bond of imine (103) gives the cyclized radical (104) and a product is obtained either by hydrogen abstraction (105)or following reaction with a suitable acceptor giving for example (106) (Scheme 37).65 61 B. Bonnaud and D. C. H. Bigg Synthesis 1994 465. 62 J. Bussenius. N. Laber T. Muller and W. Eberbach Chem. Ber. 1994 127 247. 63 C. M. Marson and A. Fallah Tetrahedron Lett. 1994 35 293. 64 C.M. Marson U. Grabowska T. Walsgrove D. S. Egglestone and P. W. Baures J. Org. Chem. 1994,59 284. 65 J. Boivin E. Fouquet and S.Z. Zard Tetrahedron 1994 50 1745. Heterocyclic Compounds 221 Reagents i CF,SO,H Scheme 35 I !H i - 74% HR (99a) R = CH2Ph (100) R = CH2Ph (9%) R = H iii (101) Reagents i PhCHO PPA; ii PhCHO MeSO,H P,O,; iii PPA Scheme 36 If an amine radical is similarly generated from (107) then the ensuing cyclizations form a quite complex ‘cage’ amine (108) (Scheme 38).66 Palladium-catalysed chemistry gives access to cyclic amines (111) from simple acyclic starting materials (Scheme 39).A Heck olefination of vinyl bromide (109) by the W.R. Bowman D.N. Clark and R.J. Marmon Tetrahedron 1994 50 1295. P.W. Sheldrake (106) R =C02Et etc. Reagents i Bu,SnH; ii CH,=CHE Scheme 37 4NSPh i>F&- (107) Reagents i Bu,SnH Scheme 38 Tos (109) (110) n =1,2 Reagents i Pd(o) Na,CO Scheme 39 protected aminoalkyl olefin (110) is followed by a catalysed cy~lization.~’ Cyclizations brought about by olefin metathesis using a molybdenum-carbene complex have been used to prepare a range of bicyclic amides (113).The dienes (1 12) are readily prepared and entry is gained to pyrrolizidine indolizidine quinolizidine pyrrolidinoazocines and piperidinoazocine systems68 (Scheme 40). Treatment of N-Boc-proline methyl ester (114) with iodosylbenzene and azido- 67 R.C. Larock H. Yang S. M. Weinreb and R.J. Herr J. Org. Chem. 1994 59 4172. 68 S.F.Martin Y. Liao H.-J. Chen M. Patzel and M.N.Ranser Tetrahedron Lett. 1994 35 6005. Heterocyclic Compounds 0 i I (112) n =1,2;n =0,1,2,3;R=H,Me (113) Reagents i PhMe,CCH=Mo=N[2,6( Pr'),C,H ,][OCMe(CF,),] , C,H, 20-50 "C Scheme 40 i C02Me 70% N3 +co2Me I 1 C02Bu' C02Bu' (114) (1 15) Reagents i (PhIO), Me,SiN, CH,Cl, -40°C Scheme 41 (116) R = H Me Ph; n = 14 (1 1 7a) (117b) Reagents i Me0,CC-CCO ,Me DMSO 135 "C Scheme 42 trimethylsilane leads to functionalization at C-5,producing6' the azide (1 15) (Scheme 41)'' Enamines (116) better viewed as vinylogous carbamates react with dimethyl acetylenedicarboxylate to give the bicyclic products (1 17a) and (1 17b) (Scheme 42) with a notable scission of the double bond in the starting material.71 The authors suggest a mechanism.The first catalytic iron-mediated carbon-nitrogen bond formation involving allenyl imines (1 18) and carbon monoxide is reported,72 the products being 3-alkylidene-4- pyrrolin-2-ones (1 19) (Scheme 43).A good degree of asymmetric induction is achieved in the intramolecular Heck 69 P. Magnus and C. Hulme Tetrahedron Lett. 1994 35 8097. 'O P. Magnus C. Hulme and W. Weber J. Am. Chem. Soc. 1994 116 4501. " S. Jiang Z. Janousek and H. G. Viehe Tetrahedron Lett. 1994 35 1185. l2 M.S. Sigman and B. E. Eaton J. Org. Chem. 1994 59 7488. P. W. Sheldrake i 62-72% -R1$0 44mNR3 R2 Y R3 (118) R, F$ R3 = alkyl (119) Reagents i lOmol YOFe(CO), CO THF Scheme 43 H Reagents i Pd(o) optically active ligand Scheme 44 (122) R = Ph alkyl (1 23) (124) Reagents i Ph,C=NH; ii THF 5&55 "C Scheme 45 reaction of (120) using chiral ligands for the palladium.73 One of the less common ferrocene phosphine derivatives (R)-(S)-BPPFOH,gives the best results (Scheme 44).The addition of an imine to a (1-alkyny1carbene)chromiumcarbonylcomplex (122) gives an adduct (123) which on heating to eliminate chromium forms a substituted 2H-pyrrole (124) (Scheme 45).74 A synthesis of the antibiotic (+ )-preussin (127)is based on the protic acid promoted aza-Cope rearrangement of the oxazolidine (125) to the pyrrolidine (126) (Scheme 46).75 3H-Indole (129)has been observed spectroscopically for the first time76 (Scheme 47). It is stable in ether at -100"C. Using an alternative preparation it was found that even in aqueous solution at pH9 it had a half life of about 100 seconds. 73 Y. Sato S. Nukai M. Sodeoka and M. Shibasaki Tetrahedron 1994,50 371. 74 F.Funke M. Duetsch F. Stein M. Noltemeyer and A. de Meijere Chem. Ber. 1994 127 911. 75 W. Deng and L. E. Overman J. Am. Chem. SOC. 1994,116 11 241. 76 I.G. Gut and J. Wirz Angew. Chem. Int. Ed. Engl. 1994 33 1153. Heterocyclic Compounds Reagents i CSA CF,CH,OH; ii EtOCOCl; iii CF,CO,H; iv LiAlH Scheme 46 Reagents i hv Scheme 41 Ring closure of trichloroacetamide (1 30) is brought about by nickel/acetic acid to give N-methylindolone (13 1).77 Similarly,78 haloacetamides (132) are closed onto an alkene to give the saturated compounds (133) (Scheme 48). Isonitriles (134) are starting materials for a novel tin-mediated indole synthesis.79 Treatment with tributyltin hydride gives the hitherto unreported N-unprotected 2-stannylindoles (135) (Scheme 49).These are prone to destannylation a process readily completed with aqueous acid but they may be further transformed in situ by palladium-catalysed coupling with aryl halides. Yields are good. Diazo-compounds (136) are converted into isomunchnones (137) using rhodium acetate. Intramolecular addition to the alkene gives (138) in high yield.80 The isomiinchnone from (139) adds across the indolyl n-bond to give (140) (Scheme 50).81 Acylation of acetone oxime (141) using an N-methyl-N-methoxyamide followed by cyclization of the intermediate gives 3-methyl-5-substituted isoxazoles (142) (Scheme 51).82 Treatment of isoxazoles (143) with hexacarbonylmolybdenum effects conversion into 4-pyridones (144) (Scheme 52).83 Treatment of imidazoles (145a) with ethyl chloroformate and allyltributylstannane gives the adduct (146a) (Scheme 53).The reaction extends to oxazoles (145b) and thiazoles (145~).~~ l7 J. Boivin M. Yousfi and S.Z. Zard Tetrahedron Lett. 1994 35 9553. 'I3 J. Boivin M. Yousfi and S.Z. Zard Tetrahedron Lett. 1994 35 5629. 79 T. Fukuyama X. Chen and G. Peng J. Am. Chem. SOC. 1994 116 3127. A. Padwa D.J. Austin and A.T. Price Tetrahedron Lett. 1994 35 7159. A. Padwa D. J. Hertzog and W.R. Nadler J. Org. Chem. 1994,59 7072. 82 T. J. Nitz D. L.Volkots D.J. Aldous and R.C. Oglesby J. Org. Chem. 1994 59 5828. 83 M. Nitta and T. Higuchi Heterocycles 1994 38 853. 84 T. Itoh H. Hasegawa K. Nagata and A. Ohsawa J. Org. Chem. 1994 59 1319. P.W.Sheldrake i Q,%" Me 0 ___) Me 70% (Ph (Ph (132) R = Me,CI;X = CI,Br (133) Reagents i Ni AcOH IPA; ii Ni AcOH PhSeSePh IPA Scheme 48 The substituted imidazole (148) was prepared from the substituted pyrrolidinone (147) using the tactic of preferential anion formation adjacent to the pyridine ring (Scheme 54).85 The story of how this reaction was developed into an industrial process makes interesting reading.86 The bicyclic imidazoles (150) are obtained by the tin(1v) or titanium(1v)-mediated condensation of the simple cyclic amides (149) with aminoacetaldehyde diethyl acetal (Scheme 55).*' (134) R = alkyl Ph C02M (1%) Reagents i Bu,SnH AlBN MeCN 100% Scheme 49 Gold's salt (151) and methyl N-methylglycinate combine under the action of methoxide to give 1-methylimidazole-5-carboxylic methyl ester (1 53) (Scheme 56).88 Reaction of bromoketone (154) with a primary amine in ether at -78 "Cgives the expected aminoketone (1 55) for immediate conversion into a 1,4-disubstituted imidazole (1 56) (Scheme 57).89 The sequential metallation and derivatization of l-methyl-2,4,5-tribromoimidazole (1 57) has been demonstrated.Operations commence at C-2 to give (1 58) and then 85 J. F. Hayes M. B. Mitchell and G. Procter Tetrahedron Lett. 1994 35 273. 86 J.F. Hayes and M.B. Mitchell Chem. Br. 1993 1037. 87 D. H. Hua F. Zhang J. Chen and P. D. Robinson J. Org. Chem. 1994 59 5084. R. Kirchlechner M. Casutt V. Heywang and M. W. Schwartz Synthesis 1994 247. 89 T. N. Sorrel1 and W. E. Allen J. Org. Chem. 1994 59 1589. Heterocyclic Compounds + 1 i -(136) n = 1,2 (137) Reagents i Rh,(OAc) Scheme 50 i ii -94% "OH (141) Reagents i BuLi PhCH,CONMe(OMe); ii H,SO, H,O Scheme 51 -0 (143) R = alkyl Ph Reagents i Mo(CO), MeCN H,O Scheme 52 P.W.Sheldrake C02Et (14s) X = NH (1 46a) X = NC02Et (145b) X = 0 (146b) X = 0 (14%) X = S (146~)X = S R, R2 = H Me Reagents i Bu,SnCH,CH=CH, ClCO,Et Et,N Scheme 53 N&N? i,85% \ ii iii -32 0 M9S / Reagents i BuLi; ii KOBu'; iii MeSC,H,CN Scheme 54 (149) n = 1,2 (150) Reagents i (EtO),CHCH,NH, mesitylene SnCI or TiCI, 140 "C Scheme 55 Reagents i MeNHCH,CO,Me NaOMe Scheme 56 Heterocyclic Compounds (154) (155) R' R2=alkyl (1w Reagents i R2NH, Et,O -78 "C; ii HCONH Scheme 57 (157) (158) (159) Reagents i Bu"Li -70°C; ii CO,; iii 2eq Bu"Li; iv electrophile (E) Scheme 58 XMe II H 0 (160) X = CI Br I (161) n = 1,3 Reagents i DBN; ii DBU Scheme 59 move to C-5,giving (159).This is capable of further transformation (Scheme 58)." DBU or DBN reacts with 4-halo-3,5-dimethyl-l-nitro-1H-pyrazoles (160) to give (161) in which unusually one of the rings of the base has been opened (Scheme 59).The postulated mechanism involves a diazaf~lvene.~' The spirocyclic derivatives (162) of 2,3-diaminopyridines can be reacted with a variety of nucleophiles (amines thiols alcohols or carbon nucleophiles) oia oxidized species (163) produced by manganese dioxide resulting in the product of 6-substitution (164) (Scheme 60)." Oxidation of glyoxal bisoxime (165) with dinitrogen tetraoxide provides the first preparation of unsubstituted furoxan (166) (Scheme 61).93 Alkylation of benzo-1,2,3-thidiazoIe results in isolation of 3-alkylated salts (167).However in basic methanol it is the 2-alkylated species in equilibrium with (167) that 90 G. Shapiro and B. Gomez-Lor J. Org. Chem. 1994 59 5524. 91 H. Lammers P. Cohen-Fernandes and C. L. Habraken Tetrahedron 1994 50 865. 92 S. Schwoch W. Kramer R. Neidlein and H. Suschitzky Helv. Chim. Acta 1994 77 2175. 93 T.I. Godovikova S. P. Golova Y.A. Strelenko M. Y. Antipin Y.T. Struchlov and L. I. Khmelnitskii Mendeleev Commun. 1994 7. 230 P. W. Sheldrake L (162) X = H Br (1W Reagents i MnO,; ii nucleophile (Nuc) Scheme 60 Reagents i N,O, CH,Cl Scheme 61 1 -’CRx-(167) R = H alkyl Ph PhCO Reagents i NEt, MeOH Scheme 62 rearranges to give a lH-4,1,2-benzothiadiazine(168) which is then alkylated by excess starting material (Scheme 62).94 The reaction of tetraazoles (169) with acetic anhydride to give 2-aryl-5-methyl-173,4- oxadiazoles (170) is reported (Scheme 63).” The 0-tosyl oximes (1 7 1) are converted after acetylation of the free amino group into pyrazolo[5,1-c]-l,2,4-triazoles (172) apparently by direct displacement of tosylate (Scheme 64).96 The symmetric diketone (173) was reacted with guanidine to produce the pentacycle (174) a model for ptilomycalin A (Scheme 65).97 In the case of the natural product itself diketone (175) was closed in two steps using 0-methylisourea (forming the left ring) then ammonia to give (176) (Scheme 66).Subsequent treatment with acid then base was needed to form the spirocyclic rings.98 Two groups have reported the total synthesis of gelsemine (177). One approach 94 S. Chandrasekhar and D.K. Josh J. Chem. Res. (S) 1994 56. ” B. S. Jursic and Z. Zdrankovski Synth. Commun. 1994 24 1575. 96 K.Kirsche E. Wolff M. Rarnrn G. Lutze and B. Schulz Liebigs Ann. Chem. 1994 1037. ’’P. J. Murphy and H. L. Williams J. Chem. Soc. Chem. Commun. 1994 819. 98 B. B. Snider and Z. Shi J. Am. Chem. SOC.,1994 116 549. Heterocyclic Compounds 23 1 Reagents i Ac,O Scheme 63 (171) R' = Me But R2= alkyl aryl Reagents i Ac,O; ii 2M NaOH MeOH Scheme 64 H& i -(173) (174) Reagents i HN=C(NH,), DMF Scheme 65 involved forming a tricyclic ketone,99" the oxindole moiety then being built on the ~arbonyl.~~' In the second approach the tetrahydropyran ring was formed last.'00 5 Six-membered Rings There is a review on iminophosphoranes as useful building blocks for the preparation of nitrogen-containing heterocycles,"' and a review on the enamine rearrangement of heterocyclic systems containing a pyridine ring102 covers much work previously only available in Russian.99 (a)Z. Sheikh R. Steel A. S. Tasker and A. P. Johnson J. Chem.Soc. Chem. Commun. 1994,763; (b)J. K. Dutton R. W. Steel A. S. Tasker V. Popsavin and A. P. Johnson J. Chem. SOC.,Chem.Commun. 1994 765. loo N. J. Newcombe F. Ya R.J. Vijn H. Hiemstra and W. N. Speckamp J. Chem. SOC.,Chem. Commun. 1994 167. lo' P. Molina and M. J. Vilaplana Synthesis 1994 1197. lo2 S. P. Gromov and A. N. Kost Heterocycles 1994 38 1127. P. W. Sheldrake Me. i ii - 37% (175) R = SiPh,Bu' (176) Reagents i HN=C(OMe)NH, PriNEt DMSO; ii NH, NH,OAc Bu'OH Scheme 66 The resolution of 1,2-diols using a C,-symmetric diphenyltetrahydrobipyran (178) is reported.lo3 The reagent when heated for a sufficient time with two equivalents of racemic diol gives a single derivative (179) leaving one enantiomer of the diol (180) (Scheme 67). The derivatized enantiomer is recovered by an exchange reaction or by lithium/liquid ammonia cleavage.A variation of the principle has been applied to the preparation of 2-substituted-2-hydroxycarboxylic acids.'04 Treatment of 2-(hydroxyalky1)dihydropyrans (181)with rhenium(vI1) oxide and 2,6-lutidine gives spiroketals (182) (Scheme 68).'05 Reaction of the ortho-quinone (183) with 1,4-diacetoxybuta-l,3-diene produces the benzodioxine (184)in the first reported exampleslo6 of such a reaction where an acyclic diene reacts as the 27c component (Scheme 69). Reaction of the dibromide (185)with catechol (as its disodium salt) is shown to give (186) with involvement of an intermediate epoxide'07 (Scheme 70). Previously it was suggested that the reaction proceeded by sequential bromide displacements to give a different product (187). The readily available (188) cyclizes on treatment with hydrogen chloride at high pressure to give (189) from which 3,5,6-trichloropyridin-2-one (190) is obtained using aqueous base (Scheme 71).'08 lo3 P.J. Edward D.A. Entwistle S.V. Ley D. R. Owen and E. J. Perry Tetrahedron Asymmetry 1994 5 553. R. Downham K.S. Kim S.V. Ley and M. Woods Tetrahedron Lett. 1994 35 769; G.J. Boons R. Downham K. S. Kim S.V. Ley and M. Woods Tetrahedron 1994 50 7157. R. S. Boyce and R. M. Kennedy Tetrahedron Lett. 1994 35 5133. lo' V. Nair and S. Kumar J. Chem. Soc. Chem. Commun. 1994 1341. lo' P. A. Procopiou P. C. Cherry M. J. Deal and R. B. Lamont J.Chem. SOC.,Perkin Trans. I 1994 1773. lo* R.G. Pews and J.A. Gall J. Org. Chem. 1994 59 6783. Heterocyclic Compounds Ph Phcf)0ie$ + &H Ph (178) (179) (180) Reagents i 2eq RCHOHCH,OH CSA toluene Scheme 67 Reagents i Re,O, 2.6-lutidine Scheme 68 (183) (184) Reagents i AcOCH=CHCH=CHOAc 120 "C Scheme 69 Reaction of 2-lithioaza heteroaromatics (191) with cyclobutenediones (192) gives the expected adducts which after acetylation and heating give pyridone-based bicycles (193) (Scheme 72).'09 Slight variation of the starting materials permits a palladium- catalysed coupling/rearrangement.1H-Benz[de]isoquinoline (195) is reported,"' formed by the action of ammonia on (194). Use of a primary amine gives (196) trapped by dipolarophiles (Scheme 73). The triptycene-substituted 2,2'-bipyridyl (197) is described as a 'molecular brake'. With the brake disengaged (as depicted) the trypticene spins freely; on addition of A.G.Birchler F. Liu and L. S. Liebeskind J. Org. Chem. 1994 59 7737. 'lo C.-K. Sha and D.-C. Wang Tetrahedron 1994 50 7495. P.W.Sheldrake Scheme 70 Reagents i HCI solvent 1W200 atm.; ii NaOH H,O CICH,CH,CI Scheme 71 0 (191) 2= S NMe CH = CH (192) R' RZ= alkyl ph OPS Reagents i combine; ii Ac,O; iii heat Scheme 72 mercury(II) coordination of the metal between the nitrogens changes the conformation of the bipyridyl unit which then acts as a barrier to rotation as evidenced by profound changes in the NMR.' The amide (198) can be substituted with a high degree of diastereoselectivity owing to the attached chiral auxiliary."' Reduction of the amide (199) allows the nitrogen substituent to be removed by catalytic hydrogenation giving access to asymmetric 3-substituted piperidines (200) (Scheme 74).The reaction of imine esters (201) with 1,3-dienes has been in~estigated."~ Since phenylmenthyl esters and either (R)-or (S)-1 -phenylethylamine are used significant 'I1 T. R. Kelly M. C. Bowyer K. V. Bhaskar D. Bebbington A. Garcia F. Lang M.H. Kim and M.P. Jette J. Am. Chem. SOC. 1994 116 3657. L. Micouin T. Varea C. Riche A. Chiaroni J.-C. Quirion and H.-P. Husson Tetrahedron Lett. 1994,35 2529. P.D. Bailey D. J. Landesbrough T.C. Hancox J. D. Heffernan and A. B. Holmes J. Chem. SOC.,Chem. Commun. 1994 2543. Heterocyclic Compounds 235 FOzEt -Em2c& Y \/ Reagents i NH,; ii RNH Scheme 73 OM / HOTPh HOTph H i ii R (198) (199) Reagents i Bu'Li; ii RX; iii LiAlH,; iv H, Pd-C !3cheIne 74 diastereoselection in the formation of (202) would be expected.A match/mismatch situation exists between the two chiral moieties but the best diastereoisomeric excess is over 95% (Scheme 75). Closure of the final ring in (204)was achieved by incorporation of the nitrogen of the nitro group in (203) under the action of tris(dimethy1amino)methane (Scheme 76).' l4 The first ring closure involved in converting (205) into (206) (the amide is made in the second step after reduction) exemplifies the vinylogous Bischler-Napieralski reaction (Scheme 77).' 'I4 D. Sole A. Pares and J. Bonjoch Tetrahedron 1994 50 9769. 'I5 A. J. Marquart B.L. Podlogar E. W. Huber D.A. Demeter N. P. Peet H. J. R. Weintraub and M. R. Angelastro J. Org. Chem. 1994 59 2092. P. W. Sheldrake (201) R' = phenylmenthyl R2 = PhCHMe Reagents i CH,=C(Me)C(Me)=CH Scheme 75 OpN-0 HN/Q 0 0 i __c Me Me (203) Reagents i HC(NMe,) Scheme 76 i ii -(205) Reagents i PPSE; ii NaBH Scheme 77 1-Benzoylindoles (207) are converted into indolo[2,3-a]isoquinolones (208) by the action of dimethyl malonate and manganese(II1) acetate (Scheme 78).' The imine (209) can be cyclized in intramolecular heteroene reactions to give either (210) using ferric chloride or (21 1) using titanium tetrachloride'l7 (Scheme 79). In both cases the enantiomeric excess is 98%. The palladium-catalysed cyclization of a range of 2-alkenylaniline and benzylamine derivatives has been investigated.'18 Conversions such as (212) into (213) and (214) l6 C.-P.Chuang and S. F. Wang Tetrahedron Lezt.. 1994 35 1283. 'I7 S. Laschat and M. Grehl Angew. Chem. Int. Ed. Engl. 1994 33 458. P. A. van der Schaaf J.-P. Sutter M. Grellier G. P. M. van Mier A. L. Spek,G. van Koten and M. Pfeffer J. Am. Chem. SOC. 1994 116 5134. Heterocyclic Compounds (207)R' = COW,CN COW R2=H,W,Ph Reagents i CH,(CO,Me), Mn(OAc) Scheme 78 i c-- Reagents i FeCl, CH,CI,; ii TiCl, CH,Cl Scheme 79 into (215) are examples (Scheme 80).The ring size obtained in the product is not readily predictable. The dithionite reduction of pyridinium salts (216) to 1,4-dihydropyridines (217) is reported (Scheme Sl).' '' More commonly such a reaction involves a pyridine with an electron-withdrawing substituent.Pyridines or pyridazines (218) react with a chloroformate and bis(tributy1- tin)acetylene to give the acetylene adducts (219) (Scheme 82).l2O The pyridine (220) is cunningly set up for a base-catalysed rearrange-ment-cyclization leading to 5-amino-1,2-dihydrothien0[2,3-h][1,6]naphthyridine (221) (Scheme 83). The nitrile-stabilized anion formed in the side chain can displace sulfur affording the carbon skeleton.' 21 Acetylenic amines (222) are cyclized in xylene at 150"Cto give (via the ketene) cyclic amides (223) usually in excellent yield (Scheme 84).'22A low point is the ten-membered ring (only lo%) but larger rings give good yields.A study was carried out of the conformation of the condensation product formed by 'I9 Y.S. Wong C. Marazano D. Gnecco and B.C. Das Tetrahedron Lett. 1994 35 707. T. Itoh H. Hasegawa K. Nagata M. Okada and A. Ohsawa Tetrahedron 1994 50 13089. K. Sasaki R.A.S. Shamsur S. Kashino and T. Hirota J. Chem. SOC.,Chem. Cornmun. 1994 1767 D. I. MaGee and M. Ramaseshan Synlett 1994 743. P.W. Sheldrake G*i ii 7 k2 cr Reagents i [PdCI,(MeCN),] NaOAc MeOH; ii Ph,P Scheme 80 (216) R' = alkyl R2,R3= H Me Reagents i Na,S,O, K,CO, H,O toluene Scheme 81 (218) X= CH N R' R2 = H C02Me Reagents i Bu,SnCGCSnBu, CIC0,Et Scheme 82 5-chloro-2-methylpentanaland l-amino-3-hydroxybutane.'23 The finding that there is a single preferred conformation suggested a synthesis of xestospongin A (224) based on the retrosynthesis via (225) and (226) indicated in Scheme 85.Intramolecular palladium-catalysed coupling of (227) produced a coupled product (228) but it was found that the stereochemistry of the N-0 bond relative to the lZ3 T.R. Hoye J.T. North and L. J. Ho J. Am. Chem. SOC.,1994 116 2617. Heterocyclic Compounds Reagents i KOBu' dioxane Scheme 83 (222) n = 1-6,8,10 Reagents i 150 "C,xylene Scheme 84 CN ?*" Scheme 85 dioxolane ring had been inverted (Scheme 86). The phenomenon was confined to the 2 enol ether (227) and a rationalization was presented.' 24 Reaction of 3-methyl-5-nitropyrimidin-4(3H)-one (229) with cyclohexanone gives the pyrimidine (230) (Scheme 87).'25 Other ketones may also be used; a similar reaction of nitropyridinones is already known.4-(Hydroxyimino)hexahydropyrimidines (231) are shown to interconvert with 4-aminotetrahydropyrimidin-3-oxides(232) according to the nature of the solvent 12' K. F. McClure S. J. Danishefsky and G.K. Schulte J. Org. Chem. 1994 59 355. 12' N.Nishiwaki T. Matsunaga Y. Tohda and M. Ariga Heterocycles 1994 38 249. P. W.Sheldrake ,OMe Reagents i 10% Pd on C NEt, MeCN Scheme 86 [T; -i I Reagents i cyclohexanone NH Scheme 87 Reagents i MeOH; ii aprotic solvent Scheme 88 (233) Reagents i NaH DMF Scheme 89 Heterocyclic Compounds 24 1 (235) R' R2 R3 = H alkyl Reagents i combine; ii oxidize Scheme 90 CI No2 (238) R = Me Et (239) (240) X = S n = I 2 X=O,n =1 Reagents i A Scheme 91 (Scheme 88).Directed syntheses of each tautomer were used to approach the equilibrium from each direction.'26 Treatment of the dichloropyridazine (233) with sodium hydride was not expected to give the pyrazolylquinoxalinone (234). The structure of the product was established by X-ray crystallography (Scheme 89).' 27 Reaction of chloroiminium salts (235) with the S-methylisothiocarbonhydrazide salt (236) followed by oxidation gives unsymmetrically substituted 1,2,4,Stetraazines (237) (Scheme 90). The yields are certainly not good but this is a quick preparation of the target using readily available materials.lz8 Reactions of the ylid (238) have been reported for the first time.'" With suitably activated aromatic or heteroaromatic compounds it gives products exemplified by (239) obtained from 4-chloro- 1-nitrobenzene.Therrnolysis of a-alkylthio-N-aziridinylimines (240)gives good yields of 1,4-dithiins 1,4-oxathiins or lP-dithiepines (241) (Scheme 91).I3O D. Korbonits E. Tobias-Heja K. Simon and P. Kalonits Liebigs Ann. Chem. 1994 19. G. Heinisch B. Matuszczak and K. Mereiter Heterocycles 1994 38 2081. ''' S.C. Fields M.H. Parker and W. R. Erickson J. Org. Chem. 1994 59 8284. 129 M. Makosza and M. Sypniewski Tetrahedron 1994 50 4913. 130 S. Kim and C. M. Cho Heterocycles 1994 38 1971. P. W. Sheldrake Reagents i Li NH,(liq); ii I, KI H,O Et,O Scheme 92 (244) (245) Reagents i 200"C Smin Scheme 93 (246) (247) Reagents i [Rh,(OAc),] Scheme 94 Dienes (242) are readily available from diacetylenes and thiols.Where R2 is benzyl lithium/liquid ammonia deprotection followed by mild oxidation forms 1,2-dithiins (243) (Scheme 92).13' On brief heating at 200 "Cthe 1,2-dithiin (244) does not undergo the expected sulfur extrusion but instead forms the 1,2,3-trithienepine (245) (Scheme 93).132 6 Seven-membered Rings Recent developments in the synthesis of medium ring ethers have been reviewed.'33 The diazo-compound (246) on treatment with rhodium acetate gives ether (247) (Scheme 94). In this instance the phosphonate and ketone groups provide convenient 131 M.Koreeda and W. Yang SYNLETT 1994 201.w. schroth*E. Hintzsche*R. SPltzner H.hgartinger and V. Siemund Tetrahedron Lett. 1994,35 1973. M.C. Elliott Contemp. Org. Synth. 1994 457. Heterocyclic Compounds Reagents i CH,=CCICN K,CO, DMF Scheme 95 I R4 (251) R' R2 R3,R4 = H But,Br CI (252) Reagents i for X = NR H,NR K,CO, THF; for X = S Li,S A1,0, THF; for X = P(O)Ph Na,PPh toluene reflux H,O Scheme % means for further elaboration of the product.' 34 The combination of oxygen and benzaldehyde brings about the conversion of cyclohexanone into caprolactone in the absence of metal catalysts.' 35 The reaction occurs at 40 "C but if benzoyl chloride is included in the mix yields are increased and a temperature of 20 "C suffices. 2,2'-Dihydroxybiphenyl (248) reacts with 2-chloroacrylonitrile under basic condi- tions to give the dibenzo[dfl[1,3]dioxepine (250) (Scheme 95).It is believed that the initial Michael adduct loses HCl giving (249); otherwise an eight-membered ring might have formed.' 36 The dibromides (251) are available from catechol. On treatment with a range of nucleophiles they are converted into nitrogen sulfur or phosphorus-containing heterocycles (252) (Scheme 96).137 The diol precursors of (251) can be converted into the corresponding cyclic ethers. Catalytic reduction of the sugar-derived azide (253) gives the stable bicyclic hemiaminal (254) (Scheme 97). Further hydride reduction produces the hexahydro- 1H-azepine (255).' 38 lJ4 C.J. Moody E.-R. H. B. Sie and J. J. Kulagowski J. Chem.Soc. Perkin Trans. I 1994 501. lJ5 K. Kaneda S. Ueno T. Imanaka E. Shimotsuma Y. Nishiyama and Y. Ishii J. Org. Chem. 1994,59 2915. R. E. Johnson and E. R. Bacon Tetrahedron Lett, 1994 35 9327. J.G. Walsh P. J. Furlong and D. G. Gilheany J. Chem. Soc. Chem. Commun. 1994 67. 13' R.A. Farr A. K. Holland E. W. Huber N. P. Peet and P. M. Weintraub Tetrahedron 1994 50 1033. P. W. Sheldrake HO Reagents i H, Pd; ii NaBH,CN HOAc Scheme 97 OAc (2%) Reagents i [(Ph,P),Pd] NaPF, MeCN Scheme 98 L PhthNQ P"thNvN-$ )" 589b i ii 0 1" co#3 C0,Me (258)n = 1,2 (2%) Reagents i CF,SO,H (CF,SO,),O CH,Cl,; ii NaI Scheme 99 Palladium-catalysed cyclization of the acetate (256) gives the benzazepinium salt (257) (Scheme 98).'39 Compare the parallel study' l8 mentioned above (Scheme 80).Both 7,5- and 7,6-fused bicyclic lactams (259) can be formed by intramolecular N-acyliminum ion cyclization of enamides (258) (Scheme 99). 140 Apparently similar is the titanium tetrachloride induced cyclization of (260). However the product is not a 7,5-fused bicycle,14' although the intermediacy of such a species is indicated. Bond migration results in the 6,5-fused product (261 ) (Scheme 100). The benzothiadiazepine (262) was treated with methylamine in the expectation of producing a fused diketopiperazine. The product is however the bisamide (264) M. Grellier M. Pfeffer and G. van Koten Tetrahedron Lett. 1994 35 2877. J. A. Robl Tetrahedron Lett. 1994 35 393. 14' K. D. Moeller C. E. Hanau and A.d'Avignon Tetrahedron Lett. 1994 35 825. Heterocyclic Compounds Reagents i TiCl Scheme 100 (262) (263) Reagents i NaHCO,; ii MeNH Scheme 101 (265) R = H Ph (266)R = H Ph formed from the b-lactam (263) which could be prepared in excellent yield by the action of bicarbonate (Scheme 101).l4* The thienoborepins (265) and (266) have been prepared. As might be expected (265) is the more labile. MO calculations redox properties and spectroscopic data are R. Silvestri E. Pagnozzi G. Stefancich and M. Artico Synth. Commun.,1994 24 2685. P.W. Sheldrake TBDP!SOGCO,H he i I “-& OMPM 7Me’* Me OTBDPS (270) (2711 Reagents i 2,2’-dipyridyldisulfide Ph,P CH,Cl,; ii AgBF, toluene 110”C Scheme 102 re~0rted.I~~ of which varacin (267) is the best known 1,2,3,4,5-Benzopentathiepins have been shown to be asymmetric molecules.There is a high energy barrier to inversion of the low energy chair conformation of the polysulfide ring. With a chiral derivatizing agent diastereoisomers are formed.144 The indolopentathiepin (268) has been prepared albeit in 7% yield by the action of phosphorus pentasulfide on isatin. 45 4-Phenyl-4,5-dihydr0-3H-dinaphtho[2,1-c;l’,2’-e]phosphepine (269) has been resolved as a palladium complex.146 It is an effective ligand for asymmetric rhodium-catalysed hydroformylation of styrene. 7 Larger Rings The cyclization of the saturated 7-hydroxyacid (270) in 73% yield represents an unprecedented yield for the formation of an eight-membered lactone (Scheme lO2).I4’ High yields of lactones have also been achieved by the combined action of titanium dichloride ditriflate (1 to 5 mol%) p-trifluorobenzoic anhydride (1.1 equivalents) and chlorotrimethylsilane (three equivalents) on hydroxyacids.Slow addition was used giving yields from 56% for a 12-membered lactone to nearly 90% for 15-membered or larger lactones. 148 2-(o-Haloalkyl)dithianes or thioxoanes (272) undergo ring expansion via the sulfonium or ononium salt intermediates (273) (Scheme 103). Eight- nine- or ten-membered ring products (274) are e~ernplified.’~’ 143 Y. Sugihara R. Miyatake T. Yagi T. Murata M. Jinguji T. Nakazawa and A. Imamura Tetrahedron 1994 50 6495. 144 B. S. Davidson P. W. Ford and M. Wahlman Tetrahedron Lett.1994 35 7185. 145 J. Bergmann and C. Stalhandske Tetrahedron Lett. 1994 35 5279. 146 S. Gladiali A. Dore D. Fabbri 0.DeLucchi and M. Manassero Tetrahedron Asymmetry 1994,5,511. 14’ K. R. Buszek N. Sato and Y. Jeong J. Am. Chem. SOC. 1994 116 5511. 14’ I. Shiina and T. Mukaiyama Chem. Lett. 1994 677. J. J. De Voss and Z. Sui Tetrahedron Lett. 1994 35 49. Heterocyclic Compounds R2 (272) Z = 0 S; X= CI Br rn =2,3n =O,l (273) (274) Reagents i PriNEt DMF reflux Scheme 103 Ar i - (27%) n = 1; R = H Me (275b)n =OR=H Reagents i acid Scheme 104 Reagents i Me,AlCl toluene reflux; ii LiAlH Scheme 105 Acid-catalysed cyclization of (275a) gives l-azabicyclo[3,3,l]nona-3,6-dienes(276) (Scheme 104).150Similar reaction of (275b) gives a pyrrolizine derivative after a rearrangement.' '' The stereochemistry of the 3-aza-Cope rearrangement of N-alkyl-N-allylenamines (277) has been investigated.15* The initial product (278) was reduced to (279) (Scheme 105).l-Methyl-2-vinylpyrrolidine or the corresponding piperidine (280) undergoes a E. Csuzdi I. Ling G. Abraham I. Pallagi and S. Solyom Liebigs Ann. Chern. 1994 347. 151 E. Csuzdi I. Pallagi G. Jerkovich and S. Solyom SYNLETT 1994 429. 152 G. R. Cook and J. R. Stille Tetrahedron 1994 50,4105. P.W.Sheldrake Reagents i Me0,CC-CCO,Me H' Scheme 106 Reagents i hv H,O MeCN Scheme 107 (285) X = CH2 (CH2)2 S (286) Reagents i (HCHO), HCECC0,Me Scheme 108 Michael addition with a suitable acetylenic ester followed by an aza-Claisen rearrangement to give unsaturated cyclic amines (28 1) (Scheme 106).'53 Irradiation of the chloroenaminoketones (282) gives a mixture of products in which the rearranged keto-amide (283) predominates over diketone (284) (Scheme 107).' s4 When amino acids (285) are reacted with paraformaldehyde and methyl propiolate the first-formed product of azomethine ylid [3 + 2) cycloaddition (286) reacts further after Michael addition finally giving (287) (Scheme 108).' 55 Macrocyclic imides (289) released in situ from (288) are more electrophilic than succinimide and amide-esters (290) are produced in high yield by transacylation (Scheme 109).' 56 153 E.Vedejs and M. Gingras J. Am. Chem. SOC. 1994 116 579. 15* J.B. Bremner B.M. Eschler B. W. Skelton and A. H. White Aust. J. Chem. 1994 47 1935. 155 H. Ardill R. Grigg J. F. Malone V. Sridharan and W. A. Thomas Tetrahedron 1994 50 5067. T. Koch and M. Hesse Helu. Chim. Acta 1994 77 819. Heterocyclic Compounds (288)n = 1,5 (289) Reagents i [Pd(Ph,P),] HCO,H NEt, dioxane 100"C (290) Scheme 109 (291) R= H Ar (292) Reagents i K,CO, DMF Scheme 110 The cyclic dipeptide (292) is formed from (291) in high yield by fluoride displacement.157 This is the first such S,Ar based macrocyclization (Scheme 110). The preparation of dithiacyclooctynes (293) (294) and (295) is reported,' 58 together with enthalpies of formation and ring-strain calculations. Treatment of dithiols (296) with a thiirane (297) produces benzotrithiepins or benzotrithiocins (298) usually in good yields (Scheme 11 1).15' lS7 R.Beugelmans J. Zhu N. Husson M. Bois-Choussy and G. P. Singh J. Chem. SOC.,Chem. Commun. 1994,439. H. Meier Y. Dai H. Schuhmacher and H. Kolshorn Chem. Ber. 1994 127 2035. 159 R. Sato M. Okanuma S. Chida and S. Ogawa Tetrahedron Lett. 1994 35 891. P. W. Sheldrake (--I (]I 5 S C31 S i SH n (296) n = 0,l (297) (298) R = H Ph (CH,) Reagents i Et,N DMSO Scheme 111 (299) (300) Reagents i KOH 0, EtOH Scheme 112 And finally potassium hydroxide/oxygen treatment of bis(se1enocyanate) (299) gives (300); its 3,4,13,14-tetraselenatricyclo[14.4.0.0601 ']icosa-l(16),6,8,10,17,19- hexaene structure was securely proven by X-ray crystallography (Scheme 112).160 160 S.Ogawa S. Ohara Y. Kawai and R. Sato Heterocycles 1994 38 491.