J. CHEM. SOC. PERKIN TRANS. I 1995 Synthesis of 7-BenzyIideneoctahydro-2H-pyridoI ,2-apyrazines, Bicyclic Analogues of the Calcium Antagonist Flunaritine M.Ashty Saleh, Frans Compernolle,' Suzanne Toppet and Georges J. Hoornaert Laboratorium voor Organische Synthese, K. U. Leuven, Celestijnenlaan 200F. 8-300I Leuven- Heverlee, Belgium The bicyclic amino ketone 4 (2-benzyloctahydro-2H-pyridol,2-apyrazin-7-one) has been con-verted in four steps into the pharmacologically interesting (Z)-and (euro;)-7-benzyIideneoctahydro-2H-pyridol.2-apyrazines 2a. b, bicyclic analogues of the calcium antagonist flunarizine 1. In the key step, olefination of the ketone group, the yield was highly improved (1 5-20+82-85) by using (a) the phosphonate anion instead of the Wittig reagent and (b) the solvent 1.3-dimethylimidazolidin-2-one instead of tetrahydrofuran.Debenzylation and final substitution of the 2- amino group with (4-FC6H,),CHCI gave the geometric isomers 2a (Z) and 2b (E) in 53 overall yield. The calcium antagonist flunarizine, a drug often used in the treatment of migraine, has the 1,Csubstituted piperazine structure 1.' In the context of our research on 2,5-substituted piperidines,2-9 we were interested in the synthesis of the bicyclic compounds 2 which integrate structural features of the piperazine 1 and the 2,5-substituted piperidine ring system. The more rigid bicyclic framework might serve to fix the 'active conformation' of the flexible monocyclic drug compound, resulting in a more selective binding to the target receptor and improved drug activity.Results and Discussion From previous work two complementary synthons, i.e. the acetal amine 3 and the N-benzyl ketone 4, were available for the synthesis of the Z-and E-isomers 2a and 2b. In a first, more straightforward approach, the amine 3 was N-alkylated to afford the 2-bis(p-fluorophenyl)methylderivative 5. However, the newly introduced N-substituent suffered rapid hydrolysis under the vigorous acidicconditions (6mol dm-3 HCI, reflux for 30 min) required for subsequent removal of the acetal protecting group. Accordingly, additional protection and deprotection of the 2-amino group had to be accommodated in our synthetic scheme, suggesting the use of the synthon 4.Our initial attempts for conversion of 4 into the 2-and E-benzylidene intermediates 6a and 6b,using the Wittig reagent Ph,P=CHPh in tetrahydrofuran (THF) were frustrated by low yields (15-20). In further experiments performed on both 4 and the monocyclic model compound 9, we varied the proportions of reagents and used different bases for generation of the Wittig reagent (ie. BuLi, NaH, KOBu') but this resulted in equally unsatisfactory yields (Table 1). Concurrent abstraction of an acidic proton by the reagent to form an enolate anion gave rise to recovery of the starting ketone and to 3 R=H 45 R = cH(ceH4F-4)~ bh H 6a R=CH2Ph 6b 'la R=COzEt 7b 8a R=H 8b 9' OnY CH2Ph bHpPh 9 1OE R' E H, R2= Ph 10b R' = Ph, R = H PCYO "Me 11 formation of more polar aldol dimers (e.g.M 488 for the aldol + derived from 4).Since the a-amino ketones 4 and 9 are inherently unstable as the free bases, we sought to suppress their self-condensation by enhancing the nucleophilic properties of the olefination reagent. When using the phosphonate anion reagent PhCH(Na)-PO(OEt), in THF, with and without addition of 15-crown-5 ether," the yields of olefins 6a, b and 10a, b were increased to 4045. Following the same line of reasoning, the solvent THF was replaced with 1,3-dirnethylimidazolidin-2-one11, a known substitute for the alkali-metal complexing agent hexamethyl- phosphoramide (HMPA).' In our application, the enhanced reactivity of the phosphonate anion led to rapid conversion of the ketones 4 and 9, at low temperature (5-20 "C), into the Table 1 Yields for olefination of ketones 4 and 9 Yields" of lOa, b Reagents Solvent Base or 6a, b (I Ph,PCH,PhCI THF BuLi 15-20 Ph,PCH,PhCl THF NaH 15-20 Ph,PCH,PhCI THF Bu'OK 15-20 Ph,PCH,PhCI 11 NaHb 40 (EtO),P(O)CH,Ph THF NaHb 4045 (EtO),P(O)CH,Ph THF + 11 NaHb 4045 (EtO),P(O)CH,Ph 11 NaHb 82-85 a The yields are based on the acetal precursor of 4 (2-benzyl-7,7-ethylenedioxyoctahydro-2H-pyrido1,2-upyrazine),' and 9-HCI.With and without the addition of 15-crown-5. Table 2 6 Values" in ppm in the I3C NMR spectra for the allylic C-atoms of Z-and E-isomers Z-isomers C-6 C-8 E-isomers C-6 C-8 2a 55.7 34.1 2b 63.2 26.8 6a 55.7 34.1 6b 63.3 26.8 7s 55.8 33.9 8a 56.2 34.3 2-isomer C-2 C-4 E-isomer C-2 C-4 10ab 54.5 35.0 lobb 62.2 27.3 "S Values were assigned by selective 'H-' 3C decoupling.Measure-ment carried out on the mixture of E,Z-lOa, b. alkenes 6a, b and 10a, b in 8245 yield. When 11 was used as a solvent in the reaction of 4 and 9 with Ph3P=CHPh, the yield was improved from 15-20 to 40 (Table 1). The geometric isomers 6a and 6b were readily separated by using column chromatography. Several methods were tried to effect deprotection of the N-benzyl group. Catalytic hydro- genation or reduction with sodium in liquid ammonia12 led to preferential saturation of the double bond (M' 320). Treatment with AIC1, in benzene gave rise to electrophilic substitution of the solvent, presumably with formation of the 7-diphenylmethyl derivative (M* 396, m/z 165).Finally, debenzylation of 6a and 6b was effected in 95 yield by reaction with ethyl chloroformate l4 in dichloromethane. The resulting carbamates 7a and 7b were converted into the corresponding amines 8a and 8b by refluxing with KOH in isopropyl alcohol15 (acidic hydrolysis of 7 was very slow and did not go to completion). The conditions required for the final N-alkylation of 8a and 8b to form the target compounds 2a and 2b proved to be quite critical. No reaction was observed with the reagent (4-FC6H,),CHCl under the usual conditions (acetone, K2C03, KI, reflux).16 However, the desired transformation was effected in high yield by subjecting the purified amines to treatment with the alkylating reagent and an excess of Bu,N+Br- in refluxing o-dichlorobenzene.No reaction occurred for the unpurified amines 8a and 8b obtained upon alkaline treatment of the carbamates la and 7b. The overall yield for compounds 2 was 53 (14 for 2a and 39 for 2b) when calculated from the acetal precursor' of the synthon 4 and 63 and 60 from the intermediates 6a and 6b. Relative structure assignments of the Z-and E-isomers were based on the y-effect exerted by the phenyl group on the proximate allylic C-6 or C-8 atoms in the I3C NMR spectrum (Table 2). For the E-isomers, shielding of C-8 and deshielding of C-6 was observed, whereas the reverse situation occurred for the Z-isomers.No significant pharmacological activity was observed for compounds 2a and 2b from the in vitro and in oivo tests responding to flunarizine 1. Although a molecular model of the E-isomer 2b is superimposable with some of the more stable conformations of piperazine compound 1, apparently the rather I. CHEM. SOC. PERKIN TRANS. I 1995 rigid bicyclic structure of 2b does not fit well onto the binding site of the receptor molecule involved. Conclusions The synthesis of the bicyclic analogues 2a and 2b of flunarizine involved 13 steps starting from 1-benzylpiperidin-3-one, and was accomplished with an overall yield of 27 (7 for 2a and 20 for 2b). By a suitable choice of reagent and solvent, the crucial step in this sequence, i.e.olefination of the bicyclic 1-amino ketone 4, was optimized to give an 85 yield of intermediates 6a and 6b. The lack of bioactivity observed for the E-isomer 2b may give an important clue with respect to the 'active conformation' of the piperazine drug 1, i.e. the distance and orientation of active centres such as the N-atoms and the phenyl group. Experimental All m.p.s are uncorrected. IR spectra were recorded as thin films between NaCl plates or as solids in KBr pellets on a Perkin- Elmer 297 grating IR spectrometer. 'H NMR and NMR spectra were recorded on a Bruker WM 250 instrument operating at 250 MHz for 'H and 63 MHz for I3C measurements. The 'H and 13Cchemical shifts are reported in ppm relative to tetramethylsilane as an internal reference.J Values are recorded in Hz. Mass spectra were run on a Kratos MS50 instrument; the ion source temperature was 150-250 "C as required. Exact mass measurements were performed at a resolution of 10 000. Analytical thin layer chromatography was performed using Merck silica gel 60 PF-224. Column chromatography was carried out using 70-230 mesh silica gel 60 (E. M. Merck). 24Bis(p-fuorobenzylidene)-7,7-ethylenedioxyoctahydro-2H-pyrido 1,2-apyrazine 5.-A stirred mixture of the crude product 3 (350 mg) prepared from 7,7-ethylenedioxyocta- hydro-2H-pyridoC 1,2-apyrazin-3-one (400 mg, 1.89 mmol) and LiAlH, in o-dichlorobenzene (10 cm3), Bu,NBr (600 mg, 1.86 mmol) and chlorobis(4-fluoropheny1)methane(630 mg, 2.73 mmol) was heated at reflux for 10 min under an atmosphere of nitrogen.The cooled mixture was chromatographed on a silica column with EtOAc as the eluent to afford 5 (600 mg, 80) as a solid, m.p. 19@191 "C (from EtOAc) (Found: C, 68.6; H, 6.6; N, 6.9. C,,Hz6FzNZOz requires C, 68.98; H, 6.54; N, 7.00); ~,(CDCl,)1.~1.6(4H,m,8,9-H),1.78(1H,td,JlO,3,3,,-H), 1.82(1 H, t,JIO, I,,-H),2.02(1 H,m,9aa,-H),2.17(1 H,d,JlI, 6,,-H), 2.20-2.35 (2 H, m. 4,,-H, Icq-H), 2.60-2.74 (2 H, m, 4eq- H, 3,,-H), 2.75 (1 H, dd, J 11, 2, 6,,-H), 4.0 (4 H, m, OCH2CH20), 4.25 (1 H, s, CHAr,), Ar, 7.0 (4 H, t, J8.5, 3-H) and 7.35 (4 H, m, 2-H). (E,Z)-l-Benzyl-3-benzyIidenepiperidine10a,b.-A solution of 1-benzylpiperidin-3-one.HCl (2.00 g, 8.86 mmol) in water (20 cm3) was made alkaline with K2C03 and extracted with CH2CI, (2 x 100 cm3).The combined extracts were evapor- ated to dryness to give the free base I-benzylpiperidin-3-one 9 (1.55 g) as an oil. To a stirred slurry of NaH (80 dispersion in mineral oil; 333 mg) in I ,3-dimethylimidazolidin-2-one(3 cm3), a mixture of 9 and PhCH,PO(OEt), (2.20 g, 9.6 mmol) in 1,3-dimethylimidazolidin-2-one (3 cm3) was added dropwise over 5 min. The reaction mixture was stirred for 30 min, and then was quenched with water and extracted with CH2C12 (200 cm3). The extract was washed with water (2 x 50 cm3) and evaporated. The residue was chromatographed over a silica column, using 50 EtOAc-hexane as eluent to give 10 (1.88 g, 81 from 9.HC1) as a semisolid. 'H and I3C NMR analysis showed that the product 10 consisted of two isomers: the Z-isomer 10a (45) and E-isomer 10b (55).J. CHEM. SOC. PERKIN TRANS. 1 1995 lOa:G,(CDCl,) 1.74(2H,quintet,J5.6,5-H),2.42(2H,t,36, 4-H), 2.58 (2 H, t, J 6, 6-H), 3.17 (2 H, S, 2-H), 3.50 (2 H, NCH,Ph, s), 6.3 (1 H, s, vinyl-H) and 7.25 (10 H, m, 2 Ph); Gc(CDCI3) 26.6 (C-5), 34.95 (C-4), 54.15 (C-6), 54.45 (C-2), 63.0 (NCH,Ph) and 123.7 (CHX). lob: (Found: M', 263.1672. C,,H,,Nrequires M, 263.1672); S,(CDCI,) 1.65 (2 H, quintet, J5.5,5-H), 2.28 (2 H, t, J6,4-H), 2.55(2H,t,J6,6-H),3.07(2H,~,2-H),3.61(2H,~,NCH,Ph),(C-o), 129 (C-m) and 137 (C-@so). 37 1 3.5,4,,-H),2.30(1H,td,J12,5,8,,-H),2.60(1H,d,J12,6,,-H), 2.6-2.7(2H,m,3,,-H,4,,-H),3.0(1H,t,Jll,la,-H),3.85(1H, d, J 12,6,,-H), 3.9-4.1 (2 H, m, lcq-H, 3,,-H), 4.1 5 (2 H, q, J 7, CH,CH,), 6.38 (1 H, s, vinyl-H) and 7.15-7.4 (5 H, m, Ph); Gc(CDCI3) 14.7 (CH,), 30.1 (C-9), 33.9 (C-8), 43.4 (C-3), 48.8 (C-l), 54.6 (C-4), 55.8 (C-6), 60.5 (C-9a), 61.3 (CH,O), 124.5 (CHX), 137.1 (C-7), 155.2 (M),C=CHPh, 126.3 (C-p), 128 6.30 (1 H.s, vinyl-H) and 7-7.5 (10 H, m, 2 Ph); Gc(CDCI3) 25.7 (C-51, 27.3 (C-4), 53.9 (C-61, 62.2 (C-2), 63.1 (NCH,Ph) and 124.2 (CH=C). (Z)-and (E)-2- Benzyl-7-benzylideneoctahydro-2H-pyrido-1,2-apyra;ine 6a, 6b.-To a stirred and cooled (5 "C) slurry of NaH (80 dispersion in mineral oil; 790 mg) in 1,3-dimethyl- imidazolidin-Zone (7 cm3) was added dropwise over a period of 15 min a mixture of PhCH,PO(OEt), (5.30 g, 23.2 mmol) and the crude product 4 (5.0 g) prepared from the acetal precursor of 4 (6.25 g, 21.7 mmol) and 6 mol dm-3 HCI (180 ~m~).~ The suspension was stirred at room temp.for 25 min after which work-up in the manner described for 10a, b and column chromatography on silica gel with EtOAc as the eluent afforded two isomers: the less polar Z-isomer 6a (1.50 g, 2279, and the more polar E-isomer 6b (4.40 g, 64). Both were isolated as crystalline products, m.p. (from EtOAc) 91-92 and 121-122 "C, respectively. The total yield thus was 86 from the acetal precursor of 4. 6a: (Found: C, 82.7; H, 8.35; N, 8.7; M+, 318.2097. CZ2Hz6N2requires C, 82.98; H, 8.23; N, 8.80; M, 318.2095); vmax(KBr),cm-' 1660w (C=C exocyclic); GH(CDCI,) 1.38 (1 H, qd, J 12, 5, 9,,-H), 1.6 (1 H, m, 9,,-H), 1.9 (1 H, t, J 12, Iax-H), (E)-7-Benzylidene-2-ethoxycarbony/ocfahydro-2H-pyrido-I ,2-apyrazine 7b.-A stirred solution of 6b (2.00 g, 6.4 mmol) was treated with ethyl chloroformate (0.61 cm3, 6.4 mmol) in the manner described above to afford 7b(1.75 g, 93) as an oil after column chromatography.(Z)-7-Benzylideneoctahydro-2H-pyrido1,2-apyrazine 8a.- A stirred solution of 7a (7.59 g, 25.3 mmol) in isopropyl alcohol (6 cm3) was refluxed with KOH (20 g, 0.36 mol) for 1 h under nitrogen. The mixture was concentrated by rotary evaporation and the residue was washed with CH,CI, (4 x 300 cm3) and filtered. The filtrate was evaporated and the residue was chromatographed on a short column of silica gel eluting with Et,NH-MeOH-EtOAc (1 :5:94) to give pure 8a (4.62 g, 80) as an oil; v,,,(NaCl),krn~' 3300 (NH); G,(CDCI,) 1.39 (1 H, tdd, J 12, 10, 5, 9a-H), 1.67 (1 H, d x quint, J 12, 3, 2, 3, 2, 9,,-H),1.92(1H,s,NH),2.05(1H,tt,310,3,9aa,-H),2.2(1H, ddd,J12,9,6,4,,-H),2.32(1H,tm,J14,13,8,,-H),2.43(1H, d x quint, J 14,3,2,2,2, 8,,-H), 2.52 (1 H, dd, J 12, 10, lax-H), 2.63(1 H,d,J13,6,,-H),2.70(1 H,dt,J12,3,2,4,,-H),2.9(2 H, m.3,,-H, 3,,-H), 2.91 (1 H, dd, J11, 2.5, leq-H), 3.84 (1 H, dd, J 13, 2, 6,,-H), 6.35 (1 H, s, vinyl-H) and 7.1-7.4 (5 H, m, 2.23(1 H, tt,JI1,3,9aa,-H),2.31 (1 H,td,J11,3,4,,-H),2.1-2.5Ph); Sc(CDCI3) 30.5 (C-9), 34.3 (C-8), 45.8 (C-3), 51.9 (C-I), (3 H, m, 8,,-H,4,,-H, Ieq-H), 2.61 (1 H,d,J12,6,,-H),2.65-2.8 (3 H, m, 3,,-H, 4,,-H, leq-H), 3.47 (2 H, s, NCH,Ph), 3.85 (1 H, d, J 12, 6,,-H), 6.3 (I H, s, vinyl-H) and 7.2 (10 H, m, 2 Ph); Gc(CDCI3) 30.5 (C-9), 34.1 (C-8), 52.8 (C-3), 54.9 (C-4), 58.9 (C-I), 60.5 (C-9a), 55.7 (C-6), 62.9 (CH,Ph), 124.1 (CH=C), 137.1 (C-7),C=CHPh, 126.1 (C-p), 127.8 (C-0), 129 (C-m), 137.2 (C- ipso), CH,Ph, 126.9 (C-p), 128.1 (C-o), 128.9 (C-m) and 138 (C-ipso).6b: (Found: C,82.8:H,8.2;N,8.7; M+,318.2098. C,,H,,N, requires C, 82.98; H, 8.23; N, 8.80; M, 318.2095); v,,,(KBr):cm-' 1660w (C=C exocyclic); 6,(CDCI,) 1.25(1 H, q, 56.2 (C-6), 56.3 (C-4), 62.3 (C-9a). 124.1 (CH=C), 137.2 (C-7), 126.2 (C-p), 127.9 (C-o), 129 (C-m) and 137 (C-ipso); rniz 228 (M'), 199, 198, 186 (100) and 91. (E)-7-Ben;y/ideneocfahydru-2H-pyrido1,2-apyrazine 8b.- A stirred solution of 7b (3.40 g, 11.3 mmol) in isopropyl alcohol (5 cm3) was refluxed with KOH (17 g, 0.30 mol) under nitrogen for 1 h.Work-up as described for 8a and column chro-matography on silica afforded 8b (2.08 g, 81) as an oil; mass and IR spectra were similar to those of 8a. J11.4,9a-H),1.56(1H,m,9,,-H),1.88(1H,t,Jll,l,,-H),1.98(Z)-7-Benzylidene-2-b is( p-juorop henyi )methyl octahydru-(1 H, td, J 1 1.5,4, 8,,-H), 2.2 (1 H, tt, J 11,4,9aa,-H), 2.33 (1 H, td,J 11.3.4,,-H),2.4(1 H,td,Jl l.3,3ax-H), 2.73(1 H,dt,J11,3, 2, I eq-H),2.88 (I H, d, J 12,6,,-H), 2.73-3.0 (3 H, m, 3,,-H, 4eq- H,8,,-H),3.31 (1 H,d,J12,6,,-H),3.45-3.52(2H,dd,J12,12, NCH2Ph),6.4 (1 H, s, vinyl-H) and 7.1-7.4 (10 H, ni, 2 Ph); Gc(CDCI3) 26.8 (C-8), 30.2 (C-9), 52.9 (C-3), 54.8 (C-4), 58.9 (C-I), 60.9 (C-9a), 63.3 (C-6), 63 (CH,Ph), 124.5 (CH=C) and 137.1 (C-7),C=CHPh, 126.2(C-p), 128(C-0), 129.1 (C-nf), 137.3 (C-@so), CH,Ph, 126.9 (C-p), 128.1 (C-o), 128.9 (C-m) and I38 (C-ipso).(Z)-7-Ben~ylidene-2-ethoxycarbonyloctahydro-2H-pyrido-1,2-apyrazine 7a.-To a stirred solution of 6a (2.00 g, 6.3 mmol) in CH,Cl, (50 cm3) was added dropwise at 0 "C ethyl chloroformate (0.61 cm3, 6.4 mmol). The reaction mixture was kept under nitrogen at 0 "C for 2 h and then at room temp. for 1 h. The solution was made alkaline with aq. K,C03 and extracted with CH,CI, (2 x 200 cm3). The combined extracts were evaporated and the residual product was chromato-graphed on silica with EtOAc-CHCI, (3 :7) to afford 7a (1.78 g, 95)as an oil (Found: M', 300.1838.C,,H,,N,O, requires M, 300.1836); v,,,(NaCl)/cm 1700 (C0,Et); G,(CDCI,) 1.25 (3 H, t, J 7, CH,CH,), 1.38 (1 H, qd, J 13, 12, 11, 5, 9a-H), 1.74 (1 H, ni, 9,,-H), 2.07 (I H, tt, J I1,3,9a,,-H), 2.18 (1 H, td, J 12, 2H-pyridoC 1,2-apyruzine 2a.-A stirred mixture of 8a (4.46 g, 19.6mmol) in o-dichlorobenzene (70 cm3), Bu,NBr (1 1.4g, 35.4 mmol) and chlorobis(4-fluoropheny1)methane(7.00 g, 29.3 mmol) was heated at reflux under nitrogen for 40 min. The solvent was removed by rotary evaporation and the residue was dissolved in CH,Cl, (300 cm3). The solution was treated with aqueous K2C03 and the aqueous phase was further extracted with CH,CI, (200 cm3).The combined extracts were evaporated and the residue was chromatographed over silica gel (gradient elution 5 to 10 EtOAc-CHCl,) to afford 2a (6.9.82) as pale brown crystals. Recrystallization from methanol or hexane gave an analytical sample, m.p. 124 "C (Mettler) (Found: C, 77.9; H, 6.6: F, 8.76; N, 6.4; M+,430.2221. Cz8Hz8FzNz requires C. 78.11; H, 6.55; F, 8.83; N, 6.51; M, 430.2219); GH(CDC13) 1.32 (1 H, tdd, J 14, 10.5, 5,9a-H), 1.52 (1 H, m, geq-H), 1.77 (1 H, dd, J 1 1, 10, Iax-H), 2.08 (1 H, td, J 1 I, 2.5, 3,,-H), 2.22(1 H,tt,J10,2.5,9aa,-H),2.34(1H,td,J11,3,4,,-H),2.2-2.45 (2 H, m, 8-H), 2.62 (I H, dd, J 1 1,2.5, leq-H),2.63 (1 H, d, J 12,6,,-H), 2.6-2.67 (2 H, m, 3,,-H, 4,,-H), 3.85 (1 H, d, J 12, 6,,-H),4.2(1 H,s,CHAr,),6.31 (1 H,s,vinyl-H)and7.7(13H,m, Ar); Gc(CDCI3) 30.6 (C-9), 34.1 (C-8), 51.4 (C-3), 55.7 (C-6), 57.6 (C-l), 60.8 (C-9a), 74.3 (CHAr,), 124.2 (CH=C), 137.3 (C- 7), Ph, 126.2 (C-p), 127.9 (C-o), 129 (C-m), 137.1 (C-ipso), CH- Ar,, 115.3 (C-m),129.2 (C-o), 138.1 (C-ipso) and 161.7 (C-F).(E)-7-Benzylidene-2-bis(p-fluorophenyl)methyloctahydro-2H-pyrido1,2-apyrazzne2b.-A mixture of 8b (2.10 g, 9.2 mmol) in o-dichlorobenzene (50 cm3), Bu,NBr (4.00 g, 12.4 mmol) and chlorobis(4-fluoropheny1)methane (2.50 g, 10.5 mmol) was heated at reflux for 40 min under nitrogen. Work-up in the manner described above and column chromatography of the resulting product on silica gel using 10 EtOAc-CHCl, afforded 2b (3.2 g, 80) as pale brown crystals, m.p.122.8 OC (from MeOH) (Found: C, 77.9; H, 6.6; F, 9.00; N, 6.4; M', 430.2210. C,8H,,F,N, requires C, 78.11; H, 6.55; F, 8.83; N, 6.51; M, 430.2219); SH(CDCI,) 1.20 (1 H, tdd, J 14, 10.5, 5, 9a-H), 1.46 (1 H, m, 9,,-H), 1.76 (1 H, t, J 10, lax-H),1.98 (1 H, td, J 14, 5, 8,,-H), 2.18 (1 H, td, J 11, 3, 3,,-H), 2.22 (1 H, m, 9a,,-H), 2.40 (1 H, td, J 11, 3,4,,-H), 2.71 (1 H, dd, J 10,2, lcq-H), 2.7-2.8 (2 H, m, 3,,-H, 4,,-H), 2.90 (2 H, br d, 6,,-H, 8,,-H), J. CHEM. SOC. PERKIN TRANS. I 1995 References 1 The Merck Index, 11th edn., S. Budavari, ed., Merck amp; Co. Inc., U.S.A.,1989, p. 4070. 2 F. Compernolle, M. A. Saleh, S. Toppet and G. Hoornaert, J. Org. Chem.,1991,56,5192. 3 F. Compernolle, M. A. Saleh, S. Van den Branden, S. Toppet and G. Hoornaert, J.Org. Chem. 1991,56, 2386. 4 F. Compernolle, M. A. Saleh, S. Toppet, W. De Buysser and G. Hoornaert, J. Heterocycl. Chem., 1991.28, 1965. 5 S. Van den Branden, F. Compernolle and G. Hoornaert, J. Chem. Sac., Perkin Trans. 1, 1991, 1035. 6 S. Van den Branden, F. Compernolle and G. Hoornaert, Tetrahedron, 1992,48,9753. 7 M. A. Saleh, F. Compernolle, S. Van den Branden, W. De Buysser and G. Hoornaert, J. Org. Chem., 1993,58, 690. 8 N. Baens, F. Compernolle, S. Toppet and G. Hoornaert, Tetrahedron, 1993,49, 3193. s, vinyl-H), 7.00 (4 H, t, J 8, Ar) and 7-7.1 (9 H, m, Ar); 6,(250 MHz, CDC13) 30.1 (C-9), 26.8 (C-8), 5 1.4 (C-3), 54.9 (C-4), 63.2 (C-6), 57.4 (C-I), 61.1 (C-9a), 74.3 (CHAr,), 124.6 (CHS), 137.3 (euro;-7), Ph, 126.3 (C-p), 128 (C-o), 129 (C-m), 137.1 (C- ipso), CHAr,, 115.3 (C-m), 129.2 (C-o), 139.1 (C-@so)and 161.8 (C-F). Acknowledgements The authors are indebted to the F.K.F.O. and the Ministerie voor Wetenschapsbeleid, I.U.A.P. for financial support. The authors are also grateful to R. De Boer for mass spectral analysis and to the firm Janssen Pharmaceutica for element analysis. 9 M. A. Saleh, F. Compernolle,3.32(1H,dd,J12,2,6,,-H),4.20(1H,s,NCHAr,),6.41(1H, I I. S. Toppet and G. Hoornaert, Tetruhedron, 1994,50, 18 10 R. Balker and R. J. Sims, Synthesis, 1981, 117. 11 H. Normant, Russ. Chem. Reo., 1970,39,457. 12 D. A. J. Ives, Can. J. Chem., 1969,47, 3697. 13 Y.Murakami, T. Watanabe, A. Kobayashi and Y. Yokoyama, Synrhesis, 1984, 738. 14 H. Kapnang and G.Charles, Tetrahedron Lett., I983,24, 3233. 15 M. M. Cid, J. A. Seijas, M. C. Villaverde and L. Castedo, Tetrahedron, 1988,44,6197. 16 J. B. Hendrickson and R. Bergeron, Tetrahedron Lett., 1970, 345. 17 R. J. Abraham and P. Loftus, Proron and Carbon-13 NMR Spectroscopy, Heyden, 1978, p. 29. Paper 410639 1K Received 19th October 1994 Accepted 27th October 1994
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