Synthesis of 1-fluoro-2-phenylvinyl piperidino ketones

摘要

J. CHEM.SOC. PERKIN TRANS. 1 1992 308 1 Synthesis of 1-Fluoro-2-Phenylvinyl Piperidino Ketones Yanchang Shen' and Yuefen Zhou Shanghai Institute of Organic Chemistry, Academia Sinica, 345 Lingling Lu, Shanghai 200032, China A new palladium-catalysed synthesis of 1-fluoro-2-phenylvinyl piperidino ketones is described. (2E)-, (2E,4E)-Unsaturated amides constitute an important class of compounds occurring widely in a number of natural products which show biological activities; e.g. the local anaesthetic activity of N-dialkylaminoalkyl cinnamamides 1 has been reported and 1,3-benzodioxol-5-ylvinylpiperidine ketone 2 has anticonvulsant activity. As unusual behaviour is XC,HH=C(R)HCONHCHN Etz 1 often ascribed to materials as the result of the introduction of fluorine atoms, and fluorinecontaining compounds are useful or show potential in medicinal chemistry,' it was of interest to prepare and evaluate pharmacologically a series of N-alkyl(2- aryl- 1 -fluorovinyl)carboxamides.However, there is no report of the synthesis of 2-aryl-1 -fluorovinylcarboxamides 3 in the literature.Results ad Discussion Recently we reported a palladium-catalysed reaction of bromo- acetic ester with aldehydes in the presence of tributylphosphines leading to the conversion ofaldehydes into a,p-unsaturated esters with high stereoselectivity in 52-85 yields4 This methodology has been successfully applied to the synthesis of fluorinated analogues, a-fluoro-a$-unsaturated N-alkylamides 3. A mix-ture of benzaldehyde, fluoroiodomethyl piperidino ketone, tributylarsine and a catalytic amount of palladium(0) (10 mol) was stirred at 110 "C for 24 h; 1-fluoro-2-phenylvinyl piperidino ketone 6d was obtained in 56 yield; there was no improvement in yield with increased reaction time or temperature.Tributyl- phosphines could also be used in this reaction, but the yield was lower (40). In order to improve the yield of the desired a-fluoro-a$-unsaturated amides, the more reactive triethylarsine was used instead of tributylarsine; thus the yield of the ketone 66 could be raised to 64 with high 2stereoselectivity (Z/E = 95/5), but a 9 yield of 2-phenylvinyl piperidino ketone 7d was also obtained with high E selectivity (E/Z = 100/0) (the total yield was 73, and two products could be easily separated by chromatography).We then attempted the reaction of a series of aldehydes 4 with fluoroiodomethyl piperidino ketone 5 and triethylarsine under palladium catalysis (Scheme l), the metal always being added in the form Pd(PPh,),. The results are collected in Table 1. Using this method, the a-fluoro-a,p-unsaturated amides could be obtained in 45-68?; yields, and the a$-unsaturated Table 1 Synthesisof a-fluoro-a$-unsaturated amides 6" Yield'() Z:Ed Com- poundb R 6 7 6 7 a CClC6H4 64 16 93:7 0:100 b 4-No,C,H, 68 19 86:14 0:100 C CFC 56 9 95:5 0:100 d C6H 5 64 9 95:5 0:100 e 1,3-Benzodioxol-5-y1 47 4 93:7 0:100 f gh i i k (E)-PhCHXH2-Fury1 2-Naphthyl 4C12C6H3 C-C,jH1 I 2-BrC6H,- 50 45 50 54 50 51 4 7 16 6 14 9 62:38 86:14 71:29 93:7 85:15 89:ll 37:63 0:lOO 0:100 0:100 0:100 0:loO ICHFCONCH,,CH, (2 mmol), Et,As (2 mmol), RCHO (1 mmol) and Pd(PPh,), (0.1 mmol), T 110 "C, t = 24 h.All products are new and were characterized by 'H NMR, 19F NMR, IR, MS and elemental analysis.'Isolated. Ratios of E- and Z-isomers estimated on the basis of 19F NMR spectra. Pd(PPh3), (0.2 mmol). RCHO + ICHFC-N 4a-k 5"3 0 R-CH=+dJ + "3F 6a-k 7a-k Scheme 1 Reagents and conditions: i, Et,As, Pd(PPh,), (10 molz), 110 "C, 24 h amides were obtained in 419 yields; the total yields were 51-88. On the basis of literature data5 referring to RCH= CFCO,Et, the chemical shift of the fluorine of the 2-isomer is upfield and that of the E-isomer is downfield.This olefination method could be used with aliphatic aldehydes, both saturated and a$-unsaturated, as well as aromatic aldehydes with different ring substituents. When an a,p-unsaturated aldehyde was used, the attack was also at the carbonyl carbon giving a 4-alkyl-1-fluorobuta- 1,3-dienyl piperidino ketone. Unfortunately, when ICHFCONHz was used, the desired product 2-fluoro-3-phenylpropenamidewas obtained, but the yield was low (30). Fluoroiodomethyl piperidino ketone was prepared by a Finkelstein reaction of fluorochloromethyl piperidino ketone ' (Scheme 2). CICH$-N=) + Nal ,e,,ux,3d * ICHFC-NMeO ' 3+ NaCl Scheme 2 Therefore, this one-pot reaction provides an efficient and practical method for the convenient synthesis of the title compounds which have not been reported previously.It is noteworthy that in the absence of Pd(PPh3)4, no reaction occurred; the Pd catalyst is required in the reaction, but the mechanism is not clear and is being investigated. Experimental M.p.s and b.p.s are uncorrected. IR spectra were obtained as KBr disks (solid products) and as films (liquid products) on a Shimadazu IR-440 spectrometer. 'H NMR spectra were deter- mined at 200 iMHz using a XL-200 spectrometer, and chemical shifts are reported downfield from internal Me4Si; 19FNMR spectra were recorded at 84.26 MHz using a FX-90 spectrometer, and chemical shifts are reported upfield from external CF3C02H.J-Values are given in Hz. Mass spectra were recorded on a Finnigan-4021 mass spectrometer and HRMS spectra were recorded on a Finnigan MAT 8430 mass spectro- meter. Fluorochloromethyl piperidino ketone,' Pd(PPh,), and triethylarsine were prepared by literature methods; the aldehydes were commercially available research grade chemi- cals, and were redistilled or recrystallised prior to use. General Procedure for Preparation of 1-Fluorovinyl Piperidino Ketones.-Reactions were carried out in an oven-dried Schlenk bottle equipped with a nitrogen inlet and magnetic stirrer and flushed with nitrogen. Triethylarsine (2.0 mmol) was injected into a mixture of aldehyde 4 (1.0 mmol), fluoroiodomethyl piperidino ketone 5 (2.0 mmol) and Pd(PPh,), (0.1 mmol) under nitrogen.The mixture was stirred and heated at 110 "C for several hours after which chromatography on silica gel eluting with light petroleum (b.p. 60-90 "C)-ethyl acetate (8:2) gave the pure product 6. 2-(p-Chlorophenyl)-1-Juorovinyl piperidino ketone 6a. Yield 64; Z/E = 93/7; m.p. 71-72.5 "C (2);6aZ. (CDC13) 34.92 (1 F, d, J37.6); GH(CDC13)1.63 (6 H, m), 3.58 (4 H, m), 6.45 (1 H, d, J 37.6), 7.32 (2 H, d, J 8) and 7.50 (2 H, d, J 8); 6aE: (CDC13) 29.70 (1 F, d, J 22.0); d~(cDC13)1.34 (2 H, m), 1.58 (4 H, m), 3.69 (2 H, m), 3.35 (2 H, m), 6.42 (1 H, d, J 22.0) and 7.21-7.32 (4 H, m); v,,,/cm-' 2940, 1630,1500,1450, 1280 and 825; m/z 267 (M', 100), 269 (33), 268 (23), 248 (12), 247 (24.5), 218 (M),183 (41), 156 (30.5), 155 (17), 135 (ll), 120 (69) and 84 (67) (Found C, 62.8; H, 5.5;N, 5.0.Cl4Hl5C1FNO requires C, 62.80; H, 5.61; N, 5.23).2-(p-Chlorophenyl)vinyl piperidino ketone 7a. Yield 16; E/Z = IOO/O dH(cc14) 1.55 (6 H, m), 3.5 (4 H, m), 6.78 (1 H, d, J 16) and 7.15-7.65 (5 H, m). 1-Fluoro-2-(p-nitrophenyl)vinylpiperidino ketone 68.Yield 68; Z/E = 86/14;m.p. 129-130 "C (2);6bZ dF(CDC13)30.06 (1 F,d,J37.4);d,(CDC13) 1.65(6H,m),3.60(4H,m),6.48(1 H, d, J 37.4), 7.66 (2 H, d, J 9) and 8.21 (2 H, d, J 9); 6bE (CDC13) 23.92 (1 F, d, J 21.6); d~(cDCl3)1.41 (2 H, m), 1.61 (4H,m),3.40(2H,m),3.63(2H,m),6.45(1H,d,J21.6),7.51(2 H, d, J 8.4) and 8.20 (2 H, d, J 8.4); v,,,/cm-' 2950, 1630, 1600, 1510,1450,1340,1260,1102,860 and 750; m/z 278 (M+,94), 279 (13), 259 (8), 258 (6), 194 (ll), 156 (12), 136 (7), 84 (34) and 58 (100) (Found: C, 60.3; H, 5.2; N, 9.8. C14H15FN203requires C, 60.4; H, 5.4;N, 10.07).2-(p-Nitrophenyl)vinyl piperidino ketone 7b. Yield 19; E/Z = 100/0;dH(cDCl3)1.63 (6 H, m), 3.63 (4 H, m), 7.06 (1 H, d, J 16), 7.53-7.93 (3 H, m) and 8.16-8.43 (2 H,m). 1-Fluoro-2-(p-Juorophenyl)vinylpiperidino ketone 6c. Yield 56; Z/E = 95/5;m.p. 53.5-54.5 "c (2);6cZ GF(CDC13)34.54 (1 F, s) and 36.89 (1 F, d, J 38.0); dH(CDC1,) 1.68 (6 H, m), 3.60 (4 H, m), 6.49 (1 H, d, J 38.0), 7.08 (2 H, t, J 8.8) and 7.58 (2 H, m); 6cE: dF(cDc1,) 31.09 (1 F, d, J 22.0) and 36.16 (1 F, s); SH(CDC13)1.31 (2 H, m), 1.57 (4 H, m), 3.35 (2 H, m), 3.59 (2 J. CHEM. SOC.PERKIN TRANS. 1 1992 H, m), 6.42 (1 H, d, J22.0), 7.00 (2 H, t, J8) and 7.28 (2 H, t, J8); v,a,/cm-l 2940, 1635, 1515, 1450, 1230, 1165,840 and 510; m/z 251 (M+,100), 252 (12), 232 (lo), 231 (25), 202 (34), 167 (99,156 (28), 138 (63) and 119 (38) (Found: C, 66.6; H, 5.8; N, 5.4. C14H15F2N0requires C, 66.93; H, 5.98; N, 5.58). 2-(p-Fluorophenyl)vinylpiperidinoketone 7c. Yield 9; E/Z = 1OO/O; hH(Cc14) 1.1-1.5 (6 H, m), 3.43 (4 H, m), 6.65 (1 H, d, J 16) and 7.06-7.56 (5 H, m). 1-Fluoro-2-phenylvinyl piperidino ketone 6d. Yield 64; Z/E = 9515; b.p. 140 "C, 0.45 mmHg; dF(Cc14) 36.1 (d, J 38, 2)and 30.0 (d, J 22, E); G,(CDCl,) 1.26 (E) and 1.66 (2)(6 H, m), 3.32 (E)and 3.57 (2)(4 H, m), 6.41 (E)and 6.48 (2)1 H, d, J 22 (E), 38 (Z) and 7.26-7.59 (5 H, m); v,,,/cm-' 3050, 2950, 1640,1450,1280,1100,760 and 670; m/z 233 (M', 100) 234 (17), 214 (9), 213 (15), 184 (12), 156 (ll), 149 (23), 121 (lo), 101 (19.8) and 84 (13.3) (Found: C, 71.9; H, 7.2; N, 6.0.C14H16FN0 requires C, 72.10; H, 6.87; N, 6.01). 2-Phenyluinyl piperidino ketone 7d. Yield 9; E/Z = 100/0; dH(Cc14) 1.6 (6 H, m), 3.5 (4 H, m), 6.7 (1 H, d, J 16) and 7.3 (6 H, m). 2-( 1,3-Benzodioxol-5-yl)-1-Juorovinyl piperidino ketone 6e. Yield 47; Z/E = 93/7; m.p. 92-93 "C (Z); 6eZ. GF(CDC1,) 38.07 (1 F, d, J 38.4); bH(CDC13)1.66 (6 H, m), 3.57 (4 H, m), 5.98(2H,s),6.44(1H,d,J38.4),6.80(1H,d,J8),7.00(1H,d,J 8) and 7.26 (1 H, s); 6eE GF(CDC13)33.04 (1 F, d, J 21.6); d~(cDCl3)1.30-1.43 (2 H, m), 1.57-1.70 (4 H, m), 3.38 (2 H, m), 3.62 (2 H, m), 5.96 (2 H, s), 6.37 (1 H, d, J21.6), 6.76-6.81 (2 H, m) and 7.26 (1 H, s); v,,,/cm-' 2920, 1670, 1620, 1500, 1490, 1450,1250,1040,930,910,820,630 and 510; m/z 277 (M+, 100), 278 (15), 257 (39), 228 (19), 194 (lo), 165 (lo), 166 (25), 135 (22), 107 (U),84 (55) and 69 (39) (Found: C, 64.7; H, 5.7; N, 4.8.C15H16FN03 requires C, 64.98; H, 5.78; N, 5.05). 2-( l,3-Benzodioxol-5-yl)vinylpiperidino ketone 7e. Yield 4; E/Z = lOO/O; dH(CCI4) 1.47 (6 H, m), 3.44 (4 H, m), 5.89 (2 H, s), 6 34 (1 H, d, J 16), 6.67-7.10 (3 H, m) and 7.40 (1 H, d, J 16). 1-Fluoro-4-phenylbuta- 1,3-dienyl piperidino ketone 6f. Yield 50; Z/E = 62/38; m.p. 79-81 "C (Z,E); 6f2,E: d~(cDC13) 38.87 (1 F, d, J 34.0); GH(CDC13)1.65 (6 H, m), 3.60 (4 H, m), 6.48 (1 H, dd, J 10, 34.0); 6.76 (1 H, d, J 16), 7.08 (1 H, dd, J 10, 16) and 7.27-7.50 (5 H, m); 6fE,E: dF(CDC13)33.9 (1 F, d, J 20.0); GH(CDC13)1.26 (2 H, m), 1.66 (4 H, m), 3.49 (2 H, m), 3.66(2H,m),6.32(lH,dd,J20.0,11.4),6.65(lH,d,J15.7),7.04 (1 H, dd, J 15.7, 1 1.4) and 7.26-7.46 (5 H, m); vmax/cm-l 2900, 1660,1635,1455,1285,760 and 695; m/z 259 (M+,loo), 260 (18), 239 (19), 210 (lo), 175 (16), 168 (9), 155 (16), 147 (24), 127 (27), 91 (7) and 84 (41) (Found C, 73.7; H, 7.0; N, 5.15.C16H18FN0 requires C, 74.13; H, 6.95; N, 5.41). 4-Phenylbuta-1,3-dienylpiperidinoketone 7f. Yield 4; E/Z = 63/37; GH(CDC13)1.70 (6 H, m), 3.66 (4 H, m), 6.54 (2)and 6.76(E)1 H,d,J14.8(E), 10.8(2),6.93-6.96(1 H,m)and7.2-7.6 (7 H, m).1-Fluoro-2-(2-fuyl)MyinrlpipridiBo ketone 6g. Yield 45; Z/E = 86/14; m.p. 41.5-44.5 "C; GF(CDC13) 33.96 (d, J 20.4, E) and 34.32 (d, J 37.2,Z); G,(CDCl,) 1.28 (E) and 1.67 (2)(6 H, m), 3.42-3.49 (E)and 3.60 (2)(4 H, m), 6.33 (E)and 6.64 (2) l H, d, J20.4 (E),37.2 (2),6.40-6.74 (2 H, m) and 7.30-7.50 (1 H, m); v,,,/cm-' 2950,1640,1450,1280,1020 and 670; m/z 223 (M', 100), 224 (25), 203 (21), 139 (60.9,112 (52) and 84 (43) (Found: M +,223.0994. C12H14FN02 requires M,223.1009). 2-(2-Furyl)vinylpiperidinoketone 7g. Yield 7; E/Z = l00/0; d~(cDCl3)1.62 (6 H, m), 3.62 (4 H, m), 6.42-6.53 (2 H, m), 6.82 (1 H, d, J 16) and 7.36-7.48 (2 H, m). 2-Cyclohexyl-1-Juorovinyl piperidino ketone 6h. Yield 50; Z/E = 71/29; m.p. 30-32 "c (2);6hZ SF(CDCl3)41.82 (1 F, d, J 36.8); dH(CDC13)1.26-1.76 (16 H, m), 2.46-2.64 (1 H, m), 3.52 (4 H, m) and 5.47 (1 H, dd, J 8.4, 36.8); 6hE SF(CDCI3) 37.41 (1 F, d, J 22.6); d~(cDC13)1.W1.70 (16 H, m), 2.10-2.30 (1 H, m), 3.40 (2 H, m), 3.54 (2 H, m) and 5.26 (1 H, dd, J J.CHEM. SOC. PERKIN TRANS. 1 1992 22.6, 10.8); vmax/cm-'2900,1640,1450,1280,1030and 660;m/z 239(M', 61.5),240 (20), 156 (84), 136(46),112(14),84(loo),73 (17)and 55 (51) (Found: C, 70.4;H, 9.7;N, 5.5. CI4H2,FNO requires C, 70.29;H, 9.21;N,5.86). 2-Cyclohe.~yluinyl piperidino ketone 7h. Yield 16; E/Z = 100/0;6,(CC14) 1.28-1.93 (17 H, m), 3.53(4H, m), 6.16(1 H, d, J 16)and 6.78(1 H, dd, J 7, 16). 1-Fluoro-2-(2-naphthyl)vinylpiperidino ketone 6i. Yield 50; Z/E = 93/7;m.p.8688"C(2);6: dF(CDC13)35.50(1 F, d, J 38.4);G,(CDCI,) 1.70(6H, m), 3.64(4H, m), 6.68(1 H, d, J 38.4), 7.48-7.54 (2 H, m), 7.72-7.76(1 H, m), 7.83-7.87(3H, m) and 8.05 (1 H, s); 6iE dF(CDC13) 30.51 (1 F, d, J 22.0); G,(CDCl,) 1.25 (2 H, m), 1.52-1.55(4H, m), 3.33-3.38 (2 H, m), 3.62-3.68 (2 H, m), 6.55(1 H, d, J22.0), 7.39-7.51 (3H, m) and 7.77-7.81(4H, m); v,,,/cm-' 3050,2920, 1670, 1635, 1610, 1505,1470,1455,1440,1275, 1100,915, 830, 740 and 480;m/z 283(M+, loo), 284 (27), 264 (17), 263 (69), 199 (65), 171 (54), 151 (25), 128(11) and 84(59)(Found: C, 76.1;H, 6.1;N, 4.8. C1gH 1gFNO requires c, 76.33;H, 6.36;N, 4.95). 2-(2-Naphthy1)vinyl piperidino ketone 7i. Yield 6; E/Z = lOO/O; G,(CDCl,) 1.64(6H, m), 3.62(4H, m), 6.98(1 H, d, J 15.8)and 7.40-7.88 (8 H, m).2-( 2,4- Dichloropheny1)-1-Jluorovinyl piperidino ketone 6j. Yield 54; Z/E = 85/15;G,(CDCl,) 28.05(d, J 20.0,E), 33.81 (d, J 37.2,2);GH(CDC13)1.26(E) and 1.66(2)(6H, m), 3.32 (E)and 3.60(2)(4H, m), 6.63(E)and 6.80(2)l H,d, J20.0 (E),37.2(Z),7.19-7.31(1 H, m),7.38-7.43(1 H, m) and 7.78(1 H, d, J 8.4);v,,,/cm-' 2900, 1640, 1470, 1440,1275,1100 and 670m/z 301 (M', 39),303 (24), 282 (6), 284 (3), 268(51), 266(loo),219 (18), 217 (26), 156 (33,154(42)and 84(15)(Found: M +,301.0435.CI4Hl4FNO requires M, 301.0437). 2-(2,4-DichlorophenyI)uinyl piperidino ketone 7j. Yield 14; E/Z = lOO/O;6,(CDCl,) 1.62 (6 H, m), 3.60(4H, m), 6.83(1 H, d, J 15.8), 7.14-7.54 (3H, m) and 7.85(1 H, d, J 15.8). 2-(2-Bromopheny1)-1-Jluorouinyl piperidino ketone 6k. Yield 51; Z/E = 89/11;m.p.52-55"C; a~(cDC13) 23.92(d, J 20.0, E) and 30.06(d, J 37.0,2);d,(CDCl,) 1.46(E)and 1.68(2)(6 H,m),3.26(E)and3.6O(Z)(4H,m),6.65(E)and6.80(2)1H, d, J20.0(E),37.0(Z),7.14-7.22(1 H, m), 7.31-7.38(1 H, m), 7.62(1 H, d, J 8) and 7.83(1 H, d, J 8);vmax/cm-'2920, 1630, 1450,1100, 1020,730and 680;m/z 311 (M', 36),313(34),294 (2), 292 (3), 232(loo), 148(59, 149(23), 120 (49)and 84 (19) (Found: C, 53.85;H, 4.7;N,4.2.C14Hl,BrFN0 requires C, 53.85;H, 4.81;N,4.49). 2-(2-Bromophenyl)uinyl piperidino ketone 7k. Yield 9; E/Z = d~(cDC13)1.64 (6 H, m), 3.60(4 H, m), 6.80(1 H, d, J 15.5), 7.12-7.60 (4 H, m) and 7.88(1 H, d, J 15.5). Fluoroiodomethyl Piperidino Ketone 5.-A solution of NaI (22.7g, 15 mol) in absolute acetone (60cm3) was added to a stirred solution of fluorochloromethyl piperidino ketone (9.1g, 0.05 mol) in acetone (10cm3).After the addition, the mixture was heated under reflux for ca. 3 days until the reaction was complete ("F NMR). After cooling and removal of the solvent, distilled water (50 cm3) was added to the deep red residue, and the oily material was extracted with ethyl acetate (3 x 150cm3) and the extract dried and concentrated. The residue was isolated by column chromatography on silica gel with light petroleum (b.p. 60-90"C)-ethyl acetate (8:2)as eluent to give the pure ketone 5, (8.9g, 65), m.p. 60-62"C; G,(CDCI,) 78.8(1 F, d, J 52);G,(CDCI,) 1.61 (6 H, m), 3.46(4H, m) and 7.19(1 H, d, J 52);v,,,/cm-' 2900,2800,1650,1450,1250,1050,1000and 506; m/z 271( M+, 5), 272 (M' + 1, 25), 144(M' -I, 100), 112 (99), 84 (38), 69 (90),55 (29)and 42 (59). Acknowledgements Thanks are due to the National Natural Science Foundation of China and Academia Sinica for financial support. References 1 E. Saifah, V. Jongbunprasert and C. T. Kelley, J. Nut. Prod., 1988,51, 80; R. Bloch and D. Hassan-Gonzales, Tetrahedron, 1986,42,4975. 2 W. A. Lott, USP 2 103 26511937; 2 139 68711938; 2 251 28711941; 2 251 94611941; 2 310 97311943. 3 R. Filler, CHEMTECH, 1974,752; F. A. Smith, CHEMTECH, 1973, 422. 4 Yanchang Shen and Yuefen Zhou, Tetrahedron Lett., 1991,32,513. 5 T. Kitazuml and N. Ishikawa, Chem. Lett., 1981,1259. 6 (a)H. Finkelstein, Ber. Dtsh. Chem. Ges., 1910,43,1528; (b)W. Treibs, J. Herrmann and G. Zimmermann, Chem. Ber., 1960,93,2198. 7 M. Cecilia Luz and W. P. Dailey, Org. Prep. Proceed. Int., 1987,19,468. 8 D. R. Cousion, Inorg. Synth., 1972,13, 121. 9 W. J. C. Dyke and W. J. Jones, J. Chem. SOC.,1930,2426. Paper 2/03568E Received 6th July 1992 Accepted 26thAugust 1992