N_溴代_2_吡咯甲酰基_氨基酸甲酯的合成_曾向潮

2005年第25卷有机化学V ol. 25, 2005第11期, 1420～1426 Chinese Journal of Organic Chemistry No. 11, 1420～1426xczeng@*E-mail:Received February 1, 2005; revised April 29, 2005; accepted June 1, 2005.国家863计划(No. 2004AA628030)和广东省科技计划(No. 2004B30101011)资助项目.No. 11 曾向潮等：N-(溴代-2-吡咯甲酰基)氨基酸甲酯的合成14213a: R＝H, 3b: R＝CH3; 2a: R＝X＝H, 2b: R＝H, X＝Br, 2c: R＝CH3, X＝H, 2d: R＝CH3, X＝Br; 1a: R＝X＝R'＝H, n＝0; 1b: R＝X＝R'＝H, n＝1; 1c: R＝X＝H, R'＝CH3, n＝0; 1d: R＝X＝H, R'＝CH2CH(CH3)2, n＝0; 1e: R＝R'＝H, X＝Br, n＝0; 1f: R＝R'＝H, X＝Br, n＝1; 1g: R＝H, X＝Br, R'＝CH3, n＝0; 1h: R＝H, X＝Br, R’＝CH2CH(CH3)2, n＝0; 1i: R＝CH3, X＝R'＝H, n＝0; 1j: R＝CH3, X＝R’＝H, n＝1; 1k: R＝CH3, X＝H, R'＝CH3, n＝0; 1l: R＝CH3, X＝H, R’＝CH2CH(CH3)2, n＝0; 1m: R＝CH3, X＝Br, R'＝H, n＝0; 1n: R＝CH3, X＝Br, R'＝H, n＝1; 1o: R＝CH3, X＝Br, R'＝CH3, n＝0; 1p: R＝CH3, X＝Br, R'＝CH2CH(CH3)2, n＝0Scheme 11 实验1.1 主要仪器和试剂熔点用XRS-1数字熔点仪(温度未经校正)测定; 红外光谱用Bruker Eqinox55红外光谱仪测定; 核磁共振(1H NMR)用Inova 500NB或300NB核磁共振仪测定, TMS为内标; Vario EL元素分析仪测定C, H, N含量; 质谱用VG ZAB-HS质谱仪或Finnigan Trace GC-MS气质联用仪测定; WZZ-2A型数字显示自动旋光仪测定旋光度; Brucker SMART 1000 CCD X射线单晶衍射仪[以单色化Mo Kα(λ＝0.071073 nm)辐射为光源]进行单晶X 射线衍射分析.试剂和溶剂均为市售分析纯或化学纯试剂, 未进一步纯化. α-氨基酸均为L-构型. TLC薄板用青岛海洋化工厂生产的GF254 (10～40 µmol/L)制备, 柱层析使用薄层层析硅胶(青岛海洋化工厂, 10～40 µmol/L), 实验中所用水为去离子水.1.2 2-三氯乙酰基吡咯(3)的合成2-三氯乙酰基吡咯(3a)按文献[9]方法合成, 产物收率84.0%.1-甲基-2-三氯乙酰基吡咯(3b)的合成参考2-三氯乙酰基吡咯的合成: 20 mmol新蒸1-甲基吡咯, 14 mL无水乙醚, 混合均匀, 搅拌下缓慢滴20 mmol三氯乙酰氯[10]的8 mL无水乙醚溶液, 20 min内滴加完毕, 室温下反应2 h. 搅拌下缓慢滴加1.6 g K2CO3的12 mL水溶液, 分出醚层, 水层用5 mL乙醚萃取; 合并有机相, 无水Na2SO4干燥, 蒸馏回收乙醚. 剩余物用正己烷重结晶, 得产物3b.浅黄色片状晶体, 收率91.3%, m.p. 65～66 ℃(正己烷); 1H NMR (300 MHz, CDCl3) δ: 7.51～7.49 (m, 1H, PyH), 6.98～6.97 (m, 1H, PyH), 6.24～6.22 (m, 1H, PyH), 3.99 (s, 3H, PyNCH3).1.3 溴代2-三氯乙酰基吡咯(2a～2d)的合成250 mL三口烧瓶中加入10 mmol 2-三氯乙酰基吡咯, 70 mL CCl4和2 mg碘, 磁力搅拌下缓慢滴加指定量的Br2的20 mL CCl4溶液, 1 h滴完, 维持温度25～30 ,℃继续搅拌0.5～1.5 h, TLC跟踪反应. 至反应完全, 滴加20% Na2CO3水溶液至pH 7～8, 过滤除去不溶物, 分出有机层, 水相用10 mL的CCl4萃取, 合并有机相, 无水Na2SO4干燥; 减压蒸出CCl4, 固体剩余物经重结晶纯化.4-溴-2-三氯乙酰基吡咯(2a): 灰色片状晶体, m.p. 136～138 ℃ (C2H5OH H∶2O＝51∶, V∶V), 与文献[14]值相符); 1H NMR (500 MHz, CDCl3) δ: 9.50 (brs, 1H, PyNH), 7.35 (dd, J＝1.5, 3.0 Hz, 1H, PyH), 7.15 (dd, J＝1.5, 3.5 Hz, 1H, PyH); IR (KBr) ν: 3307, 3136, 2982, 1651, 1358, 744, 591 cm－1; FABMS m/z (%): 290, 292 (M＋, 12, 13), 172, 174 ([C4H3NBrCO]＋, 13, 13). Anal. calcd for C6H3BrCl3NO: C 24.73, H 1.04, N 4.81; found C 24.83, H 1.23, N 4.88.4,5-二溴-2-三氯乙酰基吡咯(2b): 淡黄色片状晶体. m.p. 116～117 ℃ [C2H5OH H∶2O＝41∶, V∶V]; 1H NMR (300 MHz, CDCl3) δ: 9.79 (brs, 1H, PyNH), 7.18 (d, J＝1.8 Hz, 1H, PyH); IR (KBr) ν: 3279, 3138, 2958, 1655, 1366, 747, 590 cm－1; FABMS m/z (%): 369, 371, 373 (M＋, 3, 4, 2), 250, 252, 254 ([C4H2NBr2CO]＋, 2, 4, 2). Anal. calcd for C6H2Br2Cl3NO: C 19.46, H 0.54, N 3.78; found C 19.63, H 0.59, N 3.70.1-甲基-4-溴-2-三氯乙酰基吡咯(2c): 淡黄色针状晶体, m.p. 98～99 ℃ (95%乙醇); 1H NMR (300 MHz, CDCl3) δ: 7.38 (d, J＝1.8 Hz, 1H, PyH), 6.88 (d, J＝1.8 Hz, 1H, PyH), 3.88 (s, 3H, PyNCH3); IR (KBr) ν: 3145, 2958, 1672, 1343, 749, 587 cm－1; FABMS m/z (%): 305, 307 (M＋, 10, 10), 186, 188 ([CH3C4H2BrNCO]＋, 12, 12). Anal. calcd for C7H5BrCl3NO: C 27.5, H 1.65, N 4.59; found C 27.76, H 1.79, N 4.64.1-甲基-4,5-二溴-2-三氯乙酰基吡咯(2d): 淡黄色棱形晶体, m.p. 94～95 ℃ (95%乙醇); 1H NMR (500 MHz, CDCl3) δ: 7.58 (s, 1H, PyH), 4.03 (s, 3H, PyNCH3); IR (KBr) ν: 3158, 2963, 1670, 1350, 767, 594 cm－1; FABMS m/z (%): 383, 385, 387 (M＋, 5, 7, 4), 264, 266, 268 (C4H- Br2NCO]＋, 5, 10, 4). Anal. calcd for C7H4Br2Cl3NO: C1422有 机 化 学 V ol. 25, 200521.88, H 1.05, N 3.65; found C 22.11, H 1.17, N 3.77.1.4 N -(溴代-2-吡咯甲酰基)氨基酸甲酯(1a ～1p)的合成在50 mL 圆底烧瓶中加入5 mmol 氨基酸甲酯盐酸盐[8]、5 mmol 溴代2-三氯乙酰基吡咯(2)和8 mL 乙腈, 搅拌下滴加1 mL 三乙胺, 5 min 滴完, 室温继续搅拌10～13 h (TLC 跟踪反应). 减压蒸出乙腈, 剩余物中加入10 mL 水, 使三乙胺盐酸盐及过量的三乙胺溶解, 收集不溶性有机物, 得固体或粘稠状N -(溴代-2-吡咯甲酰基)氨基酸甲酯. 水相用2×5 mL 乙酸乙酯萃取, 无水Na 2SO 4干燥, 减压蒸去乙酸乙酯, 剩余物与上述甲酯合并. 粗产物经重结晶或经200～300目硅胶柱层析纯化.N -(4-溴-2-吡咯甲酰基)甘氨酸甲酯(1a ): 反应10 h, 橙黄色片状晶体, 收率77.3%, m.p. 181～182 ℃ (95% 乙醇); 1H NMR (300 MHz, DMSO-d 6) δ: 11.88 (brs, 1H, PyNH), 8.57 (t, J ＝6.0 Hz, 1H, CONH), 7.01～6.99 (m, 1H, PyH), 6.87～6.86 (m, 1H, PyH), 3.96 (d, J ＝6.0 Hz, 2H, 2-CH 2), 3.64 (s, 3H, OCH 3 ); IR (KBr) ν: 3375, 3217, 3140, 1732, 1644, 1566, 1524, 1335, 1224, 1130 cm －1;FABMS m /z (%): 261, 263 ([M ＋H]＋, 13, 13). Anal. calcd for C 8H 9BrN 2O 3: C 36.80, H 3.48, N 10.73; found C 36.71, H 3.32, N 10.59.N -(4-溴-2-吡咯甲酰基)-β-丙氨酸甲酯(1b ): 反应11 h, 浅黄色晶体, 收率83.7%, m.p. 78～79 ℃ (95% 乙醇); 1H NMR (300 MHz, CDCl 3) δ: 9.91 (brs, 1H, PyNH), 6.85～6.83 (m, 1H, PyH), 6.54 (brs, 1H, CONH), 6.52～6.50 (m, 1H, PyH), 3.66 (s, 3H, OCH 3 ), 3.61 (q, J ＝6.0 Hz, 2H, 3-CH 2), 2.57 (t, J ＝6.0 Hz, 2H, 2-CH 2); IR (KBr) ν: 3384, 3194, 3082, 1718, 1643, 1569, 1528, 1330, 1234, 1179 cm －1; FABMS m /z (%): 275, 277 ([M ＋H]＋, 47, 47),172, 174 ([BrC 4H 3NCO]＋, 16, 16). Anal. calcd for C 9H 11- BrN 2O 3: C 39.29, H 4.03, N 10.18; found C 39.52, H 3.89, N 10.38.N -(4-溴-2-吡咯甲酰基)-L -丙氨酸甲酯(1c ): 反应11 h, 浅黄色片状晶体, 收率78.6%, m.p. 169～170 ℃(95%乙醇); 27D []α＋5.72 (c 0.10, C 2H 5OH); 1H NMR(300 MHz, CDCl 3) δ: 9.78 (brs, 1H, PyNH), 6.83 (t, J ＝1.2 Hz, 1H, PyH), 6.57 (d, J ＝1.2 Hz, 1H, PyH), 6.39 (d, J ＝7.2 Hz, 1H, CONH), 4.68～4.64 (m, 1H, 2-CH), 3.71 (s, 3H, OCH 3), 1.43 (d, J ＝6.9 Hz, 3H, 3-CH 3); IR (KBr) ν: 3368, 3209, 3128, 1730, 1633, 1564, 1518, 1325, 1220, 1128 cm －1; FABMS m /z (%): 275, 277 ([M ＋H]＋, 13, 13).Anal. calcd for C 9H 11BrN 2O 3: C 39.29, H 4.03, N 10.18; found C 39.44, H 3.92, N 10.16.N -(4-溴-2-吡咯甲酰基)-L -亮氨酸甲酯(1d ): 反应12h, 浅黄色晶体, 收率89.6%, m.p. 113～114 ℃ (95%乙醇); 24D []α＋46.30 (c 0.10, C 2H 5OH); 1H NMR (300 MHz,CDCl 3) δ: 9.94 (brs, 1H, PyNH), 6.89～6.88 (m, 1H, PyH), 6.63～6.62 (m, 1H, PyH), 6.34 (d, J ＝8.1 Hz, 1H, CONH), 4.82～4.74 (m, 1H, 2-CH), 3.75 (s, 3H, OCH 3), 1.74～1.60 (m, 3H, 3-CH 2, 4-CH), 0.98～0.95 [m, 6H, 4-CH- (CH 3)2]; IR (KBr) ν: 3370, 3269, 3119, 1734, 1633, 1561, 1523, 1347, 1210, 1155 cm －1; FABMS m /z (%): 317, 319([M ＋H]＋, 58, 58). Anal. calcd for C 12H 17BrN 2O 3: C 45.44, H 5.40, N 8.83; found C 45.57, H 5.29, N 8.73.N -(4, 5-二溴-2-吡咯甲酰基)甘氨酸甲酯(1e ): 反应7h, 浅棕色片状晶体, 收率77.3%, m.p. 212～214 ℃ (95%乙醇); 1H NMR (300 MHz, DMSO-d 6) δ: 12.75 (brs, 1H, PyNH), 8.63～8.55 (m, 1H, CONH), 6.94 (s, 1H, PyH), 3.96 (d, J ＝5.7 Hz, 2H, 2-CH 2), 3.64 (s, 3H, OCH 3); IR (KBr) ν: 3389, 3215, 3141, 1729, 1646, 1565, 1524, 1332, 1226, 1131 cm－1; FABMS m /z (%): 339, 341, 343([M ＋H]＋, 4, 7, 4). Anal. calcd for C 8H 8Br 2N 2O 3: C 28.26, H 2.37, N 8.24; found C 28.44, H 2.26, N 8.06.N -(4,5-二溴-2-吡咯甲酰基)-β-丙氨酸甲酯(1f ): 反应8 h, 橙黄色片状晶体, 收率78.3%, m.p. 137～138 ℃(95%乙醇); 1H NMR (300 MHz, DMSO-d 6) δ: 12.61 (brs, 1H, PyNH), 8.14 (brs, 1H, CONH), 6.88 (s, 1H, PyH), 3.60 (s, 3H, OCH 3), 3.43 (q, J ＝4.2 Hz, 2H, 3-CH 2), 2.55 (t, J ＝4.2 Hz, 2H, 2-CH 2); IR (KBr) ν: 3338, 3158, 3125,1713, 1643, 1570, 1528, 1331, 1237, 1183 cm －1; FABMSm /z (%): 353, 355, 357 ([M ＋H]＋, 7, 15, 7). Anal. calcdfor C 9H 10Br 2N 2O 3: C 30.54, H 2.85, N 7.91; found C 30.32, H 2.66, N 8.02.N-(4,5-二溴-2-吡咯甲酰基)-L -丙氨酸甲酯(1g ): 反应8 h, 浅黄色片状晶体, 收率81.4%, m.p. 210～212 ℃(95%乙醇); 27D []α＋11.52 (c 0.10, C 2H 5OH); 1H NMR(300 MHz, DMSO-d 6) δ: 12.71 (brs, 1H, PyNH), 8.42 (d, J ＝6.9 Hz, 1H, CONH), 7.02 (d, J ＝2.7 Hz, 1H, PyH),4.43～4.38 (m, 1H, 2-CH), 3.62 (s, 3H, OCH 3), 1.36 (d, J ＝7.2 Hz, 3H, 3-CH 3); IR (KBr) ν: 3392, 3161, 1733,1646, 1563, 1520, 1329, 1219, 1159 cm －1; FABMS m /z(%): 353, 355, 357 ([M ＋H]＋, 4, 8, 4). Anal. calcd. for C 9H 10Br 2N 2O 3: C 30.54, H 2.85, N 7.91; found C 30.27, H 2.69, N 8.07.N -(4,5-二溴-2-吡咯甲酰基)-L -亮氨酸甲酯(1h ): 反应9 h, 浅黄色片状晶体, 收率86.9%, m.p. 163～164 ℃(95%乙醇); 27D []α＋33.57 (c 0.10, C 2H 5OH); 1H NMR(300 MHz, CDCl 3) δ: 10.99 (brs, 1H, PyNH ), 6.58 (d, J ＝2.7 Hz, 1H, PyH), 6.52 (d, J ＝8.4 Hz, 1H, CONH), 4.85～No. 11曾向潮等：N -(溴代-2-吡咯甲酰基)氨基酸甲酯的合成14234.78 (m, 1H, 2-CH), 3.69 (s, 3H, OCH 3), 1.68～1.53 (m, 3H, 3-CH 2, 4-CH), 0.91～0.88 (m, 6H, 4-CH(CH 3)2); IR (KBr) ν: 3363, 3172, 1726, 1640, 1562, 1519, 1363, 1216, 1156 cm －1; FABMS m /z (%): 395, 397, 399 ([M ＋H]＋, 20,38, 20). Anal. calcd for C 12H 16Br 2N 2O 3: C 36.39, H 4.07, N 7.07; found C 36.13, H 3.96, N 7.12.N -(1-甲基-4-溴-2-吡咯甲酰基)甘氨酸甲酯(1i ): 反应10 h, 浅黄色丝状晶体, 收率85.9%, m.p. 75～76 ℃(95%乙醇); 1H NMR (300 MHz, CDCl 3) δ: 6.70 (d, J ＝1.8 Hz, 1H, PyH), 6.59 (d, J ＝1.8 Hz, 1H, PyH), 6.28 (brs, 1H, CONH), 4.13 (d, J ＝5.4 Hz, 2H, 2-CH 2), 3.88 (s, 3H, PyNCH 3), 3.78 (s, 3H, OCH 3); IR (KBr) ν: 3411, 3134, 1734, 1656, 1545, 1509, 1339, 1223, 1156 cm －1; FABMSm /z (%): 275, 277 ([M ＋H]＋, 9, 9). Anal. calcd forC 9H 11BrN 2O 3 : C 39.29, H 4.03, N 10.18; found C 39.01, H 3.92, N 9.88.N -(1-甲基-4-溴-2-吡咯甲酰基)-β-丙氨酸甲酯(1j ): 反应12 h, 浅黄色片状晶体, 收率91.1%, m.p. 65～66 ℃ (95%乙醇); 1H NMR (300 MHz, CDCl 3) δ: 6.61 (d, J ＝1.8 Hz, 1H, PyH), 6.43 (d, J ＝1.8 Hz, 1H, PyH), 6.41 (brs, 1H, CONH), 3.82 (s, 3H, PyNCH 3), 3.64 (s, 3H, OCH 3), 3.55 (q, J ＝6.0 Hz, 2H, 3-CH 2),2.54 (t, J ＝6.0 Hz, 2H, 2-CH 2); IR (KBr) ν: 3406, 3115, 1710, 1611, 1551, 1512, 1336, 1203, 1145 cm －1; FABMS m /z (%): 289, 291 ([M ＋H]＋, 100, 96). Anal. calcd for C 10H 13BrN 2O 3: C 41.54, H 4.53, N 9.69; found C 41.41, H 4.74, N 9.98.N -(1-甲基-4-溴-2-吡咯甲酰基)-L -丙氨酸甲酯(1k ): 反应12 h, 浅黄色粘稠体[硅胶柱层析分离, 石油醚-乙酸乙酯(V ∶V ＝3∶1)为洗脱剂], 收率68.2%, 27D []α ＋35.77 (c 0.10, C 2H 5OH); 1H NMR (300 MHz, CDCl 3 ) δ: 6.61 (d, J ＝1.8 Hz, 1H, PyH ), 6.53 (d, J ＝1.8 Hz, 1H,PyH), 6.34 (brs, 1H, CONH), 4.64～4.54 (m, 1H, 2-CH), 3.80 (s, 3H, PyNCH 3), 3.69 (s, 3H, OCH 3), 1.39 (d, J ＝7.2 Hz, 3H, 3-CH 3); IR (film) ν: 3358, 3123, 1740, 1645, 1546, 1511, 1344, 1212, 1165 cm －1; GC-MS (70 eV) m /z(%): 288, 290 (M ＋, 25, 25), 229, 231 ([CH 3C 4H 2NBrCO- NHCHCH 3]＋, 30, 30), 186, 188 ([CH 3C 4H 2NBrCO]＋, 100, 100), 158, 160 ([CH 3C 4H 2NBr]＋, 8, 8). Anal. calcd for C 10H 13BrN 2O 3: C 41.54, H 4.53, N 9.69; found C 41.86, H 4.72, N 9.38.N -(1-甲基-4-溴-2-吡咯甲酰基)-L -亮氨酸甲酯(1l ): 反应13 h, 浅黄色固体[硅胶柱层析分离, 石油醚∶乙酸乙酯(V ∶V ＝3∶1)为洗脱剂], 收率74.9%, m.p. 51～52℃; 27D []α＋44.83 (c 0.10, C 2H 5OH); 1H NMR (300 MHz,CDCl 3) δ: 6.61 (d, J ＝1.8 Hz, 1H, PyH), 6.53 (d, J ＝1.8Hz, 1H, PyH), 6.24 (d, J ＝8.4 Hz, 1H, CONH), 4.68～4.62 (m, 1H, 2-CH), 3.79 (s, 3H, PyNCH 3), 3.68 (s, 3H, OCH 3), 1.66～1.51 (m, 3H, 3-CH 2, 4-CH), 0.89 [d, J ＝6.3 Hz, 6H, 4-CH(CH 3)2]; IR (film) ν: 3349, 3123, 1740, 1647, 1545, 1509, 1343, 1206, 1161 cm －1; GC-MS (70 eV) m /z(%): 330, 332 (M ＋, 8, 8), 274, 276 ([CH 3C 4H 2NBrCON- HCH 2CO 2CH 3]＋, 50, 48), 186, 188 ([CH 3C 4H 2NBrC- O]＋, 100, 100), 158, 160 ([CH 3C 4H 2NBr]＋, 10, 10). Anal. calcd for C 13H 19BrN 2O 3: C 47.14, H 5.78, N 8.46; found C 46.91, H 5.85, N 8.75.N -(1-甲基-4,5-二溴-2-吡咯甲酰基)甘氨酸甲酯(1m ): 反应10 h, 浅黄色片状晶体, 收率74.6%, m.p. 115～116 ℃ (95%乙醇); 1H NMR (300 MHz, CDCl 3) δ: 6.64 (s, 1H, PyH), 6.40 (brs, 1H, CONH), 4.06 (d, J ＝5.4 Hz, 2H, 2-CH 2), 3.85 (s, 3H, PyNCH 3), 3.72 (s, 3H, OCH 3); IR (KBr) ν: 3389, 3121, 1735, 1658, 1538, 1500, 1410, 1221, 1175 cm －1; FABMS m /z (%): 353, 355, 357([M ＋H]＋, 6, 10, 5). Anal. calcd for C 9H 10Br 2N 2O 3: C 30.54, H 2.85, N 7.91; found C 30.84, H 3.05, N 8.08.N -(1-甲基-4,5-二溴-2-吡咯甲酰基)-β-丙氨酸甲酯(1n ): 反应10 h, 浅黄色固体[硅胶柱层析分离, 石油醚∶乙酸乙酯(V ∶V ＝1∶1)为洗脱剂], 收率72.0%, m.p. 64～65 ℃; 1H NMR (300 MHz, CDCl 3) δ: 6.53 (s, 1H, PyH), 6.47 (brs, 1H, CONH), 3.87 (s, 3H, PyNCH 3), 3.65 (s, 3H, OCH 3), 3.55 (q, J ＝6.0 Hz, 2H, 3-CH 2), 2.54 (t, J ＝6.0 Hz, 2H, 2-CH 2); IR (KBr) ν: 3398, 3114, 1716,1609, 1549, 1506, 1335, 1196, 1132 cm －1; GC-MS (70eV) m /z (%): 366, 368, 370 (M ＋, 21, 42, 21), 264, 266, 268 ([CH 3C 4HNBr 2CO]＋, 50, 100, 48). Anal. calcd forC 10H 12Br 2N 2O 3: C 32.64, H 3.29, N 7.61; found C 32.87, H3.45, N 7.37.N -(1-甲基-4,5-二溴-2-吡咯甲酰基)-L -丙氨酸甲酯(1o ): 反应12 h, 浅黄色片状晶体, 收率93.5%, m.p. 131～132 ℃ (95%乙醇); 24D []α＋28.04 (c 0.10, C 2H 5OH); 1H NMR (300 MHz, CDCl 3 ) δ: 6.63 (d, J ＝0.9 Hz, 1H, PyH), 6.28 (d, J ＝7.2 Hz, 1H, CONH), 4.64～4.55 (m, 1H, 2-CH), 3.86 (s, 3H, PyNCH 3), 3.71 (s, 3H, OCH 3), 1.41 (d, J ＝7.5 Hz, 3H, 3-CH 3); IR (KBr) ν: 3319, 3123, 1735, 1630, 1534, 1502, 1389, 1218, 1169 cm －1 ; FABMS m /z (%): 367, 369, 371 ([M ＋H]＋, 13, 26,12), 264, 266, 268 ([CH 3C 4HNBr 2CO]＋, 20, 40, 19). Anal. calcd for C 10H 12Br 2N 2O 3: C 32.64, H 3.29, N 7.61; found C 32.91, H 3.55, N 7.33.N -(1-甲基-4,5-二溴-2-吡咯甲酰基)-L -亮氨酸甲酯(1p ): 反应12 h, 橙黄色粘稠体[硅胶柱层析分离, 石油1424有 机 化 学 V ol. 25, 2005醚-乙酸乙酯(V ∶V ＝3∶1)为洗脱剂], 收率72.4%,27D[]α＋30.12 (c 0.10, C 2H 5OH); 1H NMR (300 MHz, CDCl 3) δ: 6.63 (s, 1H, PyH), 6.21 (d, J ＝8.4 Hz, 1H, CONH), 4.68～4.60 (m, 1H, 2-CH), 3.85 (s, 3H, PyNCH 3), 3.69 (s, 3H, OCH 3), 1.66～1.50 (m, 3H, 3-CH 2, 4-CH), 0.90 [d, J ＝5.7 Hz, 6H, 4-CH(CH 3)2]; IR (KBr) ν: 3319, 3094, 1716, 1536, 1339, 1234, 1160 cm －1; GC-MS(70 eV) m /z (%): 408, 410, 412 (M ＋, 5, 10, 5), 352, 354, 356 ([CH 3C 4HNBr 2CONHCHCO 2CH 3]＋, 15, 30, 14), 264, 266, 268 ([CH 3C 4HNBr 2CO]＋, 50, 100, 48). Anal. calcd for C 13H 18Br 2N 2O 3: C 38.07, H 4.42, N 6.83; found C 38.32, H 4.72, N 6.58. 1.3 晶体结构的测定为进一步确证所合成产物的结构, 培养了化合物1m 的单晶并进行单晶X 射线衍射分析. 把1m 配成甲醇稀溶液, 室温下静置数天, 使部分溶剂挥发, 培养得到浅黄色透明柱状单晶. 通过切片选取大小为0.50mm ×0.30 mm ×0.17 mm 的单晶, 在温度273(2) K 下, 用X 射线单晶衍射仪以ω/2θ扫描方式在2.10°＜θ＜27.04° 范围内收集反射数据, 共收集到7341个衍射点, 其中独立衍射点(R int ＝0.0227)2621个, 2257个可观测点[I ＞2σ(I )]. 数据的处理使用SAINT ＋程序包, 采用SHELXTL 程序包由直接法解出晶体结构. 最终结构偏离因子R ＝0.0275, wR ＝0.0682, 在最终的差值Fourier 图上最高峰和低谷峰分别为274和－584 e/nm 3.2 结果与讨论2.1 单溴代和二溴代2-三氯乙酰基吡咯的合成溴代2-三氯乙酰基吡咯是合成本文的目标化合物的中间体. 卤代2-三氯乙酰基吡咯常用的合成方法是Bailey 等[11]的方法和Bélanger 等[12]的方法. Bailey 等以冰醋酸为溶剂, 2-三氯乙酰基吡咯与氯在室温下反应, 合成4,5-二氯-2-三氯乙酰基吡咯. Bélanger 等在0 ℃条件下, 以氯仿为溶剂, 2-三氯乙酰基吡咯与溴反应, 合成4-溴-2-三氯乙酰基吡咯, 但其反应条件相对苛刻, 且产率仅为75%. 而4,5-二溴-2-三氯乙酰基吡咯、溴代1-甲基-2-三氯乙酰基吡咯的合成未见有详细的报道.本研究采用的合成方法是以四氯化碳为溶剂, 2-三氯乙酰基吡咯(3)与溴在室温下进行溴代反应, 通过调整反应物的摩尔比, 方便地合成单溴代或二溴代产物2a ～2d . 合成反应条件和结果见表1. 制备单溴代产物时, 应严格控制化合物3与Br 2的摩尔比为1∶1; 为避免溴的局部过量, 以在搅拌下把溴的四氯化碳溶液滴加到前者的四氯化碳溶液中进行反应为宜.表1 溴代2-三氯乙酰基吡咯衍生物2a ～2d 的合成反应条件和结果aTable 1 The synthetic reaction conditions and the results of bromo-2-trichloroacetylpyrroles 2a ～2dProduct Substrate Substrate ∶Br 2b t /h Yield/% 2a 3a 1∶1 0.5 92.6 2b 3a 1∶2 1.5 96.3 2c 3b 1∶1 0.5 95.0 2d 3b1∶21 98.6aReact at room temperature; b molar ratio.化合物3的分子结构中, 5-位碳是吡咯环的α-位, 也处在三氯乙酰基的β-位, 从理论上来说亲电取代反应有利于在此处进行. 但实验结果表明, 化合物3进行单溴代反应时, 产物是4-位取代产物, 未分离到5-位取代产物. 这与当吡咯的2-位有吸电子基团时, 室温下的亲电取代反应有利于生成热力学较稳定的4-位取代产 物[12,13]的结果相一致. 化合物3的溴代反应结果还表明, 当3与Br 2的摩尔比为1∶1时, 反应产物是单溴代的4-溴-2-三氯乙酰基吡咯(2a , 2c ); 而当两者摩尔比为1∶2时, 反应产物是4,5-二溴代产物2b , 2d . 这是一个很有意义的实验结果, 其反应机理有待进一步研究. 2.2 N -(溴代-2-吡咯甲酰基)氨基酸甲酯的合成Boatman 等[14]报道, 以2-吡咯甲酸为原料, 经酰氯化, 再与β-丙氨酸甲酯缩合生成N -(2-吡咯甲酰基)-β-丙氨酸甲酯. 该法存在2-吡咯甲酸价格昂贵、2-吡咯甲酰氯转化率低和不易存放等缺点. 2-三氯乙酰基吡咯是高活性酰基化试剂, 能在温和条件下与多种亲核试剂反应生成α-吡咯酰基衍生物[15]. 本合成方法以吡咯或N -甲基吡咯为起始原料, 经三氯乙酰化生成2-三氯乙酰基吡咯, 后者在室温下与溴作用, 得到4-位单溴代产物或4,5-二溴代产物; 室温下, 以三乙胺为缚酸剂, 溴代三氯乙酰基吡咯与氨基酸甲酯盐酸盐经酰基化反应生成系列N -(溴代-2-吡咯甲酰基)氨基酸甲酯, 总产率为59.2%～84.2 % (以吡咯或N -甲基吡咯为原料计).在酰基化反应中, 介质的pH 值、三乙胺的用量对反应有很大影响, 以pH 8～9的弱碱性条件下进行为宜, 碱性过高时反应产率降低, 这可能是由于强碱作用使产物氮位去质子, 导致副反应发生. 三乙胺的用量过少会使氨基酸甲酯盐酸盐的氨基释放不彻底, 不利其酰基化反应.2.3 晶体结构分析晶体结构分析结果显示, 化合物1m 分子式为C 9H 10Br 2N 2O 3, 相对分子量354.01, 晶体属于正交晶系, P 212121 空间群, a ＝0.64237(18) nm, b ＝1.3445(4) nm, c ＝1.4054(4) nm, α＝β＝γ＝90°, V ＝1.2138(6) nm 3, Z ＝No. 11曾向潮等：N -(溴代-2-吡咯甲酰基)氨基酸甲酯的合成14254, D c ＝1.937 Mg/m 3, µ(Mo K α)＝6.672 mm －1, F (000)＝688. 图1和图2分别是化合物1m 的分子结构和分子1-D 链状结构示意图, 如图2所示, 1m 分子通过N(2)H 与O(2)分子间氢键连成一维链状结构.图1 化合物1m 的分子结构 Figure 1 Structure of compound 1m2.4 抑菌活性实验采用双倍稀释法测定其中部分合成产物对金黄色葡萄球菌(Staphylococcus aureus )、粪链球菌(Streptoco- ccus faecalis )等5个常见的细菌的抑制活性, 初步结果 表明, 所测化合物对这几种细菌均有一定的抑制作用,图2 化合物1m 的分子1-D 链状结构(沿b 轴观察)Figure 2 The 1-D arrangement of compound 1m viewed along axis b其中N -(1-甲基-4-溴-2-吡咯甲酰基)-β-丙氨酸甲酯(1j )对藤黄微球菌(Micrococcus luteus )的抑制作用最大, MIC 值为0.078 mg/mL. 抑菌实验结果见表2.表2 N -(溴代-2-吡咯甲酰基)氨基酸甲酯的抑菌活性(MIC a )Table 2 Antibiotic activities (MIC) of N -(bromopyrrole-2-carbonyl)amino acid methyl estersSample Salmonella choleraesu Micrococcus luteus Streptococcus faecalis Staphylococcus aureus Escherichia coli1b 0.156 0.313 0.156 0.156 0.156 1d 0.156 0.313 0.156 0.156 0.313 1f 0.313 0.156 0.313 0.156 0.313 1h 0.156 0.156 0.156 0.313 0.313 1i 0.313 0.156 0.156 0.313 0.313 1j 0.313 0.078 0.156 0.156 0.625 1m 0.313 0.313 0.156 0.313 0.156 1n0.313 0.156 0.156 0.313 0.156aMinimum inhibitory concentration (mg/mL).References1 Seref, D.; Cagri, K. A.; Nuri, K. Eur . J . Med . Chem . 1999,34, 275.2 Roberto, D. S.; Roberta, C.; Marino, A.; Massa, S. Bioorg .Med . Chem . Lett . 1998, 8, 2931.3 Konig, C. M.; Wright, A. D.; Linden, A. Planta Med . 1998,64, 443.4 Morales, J.; Rodrigues, A. D. J . Nat . Prod . 1991, 54, 629.5 Xu, S.-H.; Cen, Y .-Z.; Zeng, L.-M.; Su, J.-Y . Chin . J . Org .Chem . 2000, 20, 248 (in Chinese).(徐石海, 岑颖洲, 曾陇梅, 苏镜娱, 有机化学, 2000, 20, 248.)6 Tang, X.-L.; Xu, S.-H. Chin . Pharm . Bull . 1998, 14, 148 (inChinese).(唐效礼, 徐石海, 中国药理学通报, 1998, 14, 148.)7 Annoura, H.; Tatsuoka, T. Tetrahedron Lett . 1995, 36, 413. 8 Zeng, X.-C.; Xu, S.-H.; Li, Y .-Q.; Shi, W.-B.; Deng, Q.-Y .Chin . J . Org . Chem . 2004, 24, 802 (in Chinese).(曾向潮, 徐石海, 李毅群, 施文兵, 邓芹英, 有机化学, 2004, 24, 802 )9 Bailey, D. M.; Johnson, R. E.; Albertson, N. F. In OrganicSyntheses , V ol. 51, Eds.: Breslow, R.; Benson, R. E.; Brossi, A.; Ireland, R. E., John Wiley & Sons, New York, 1971, p. 100.10 Krepski, L. R.; Hassner, A. J . Org . Chem . 1978, 43, 2879. 11 Bailey, D. M.; Robert, E. J. J . Med . Chem . 1973, 16, 1300.1426有机化学V ol. 25, 200512 Bélanger, P. Tetrahedron Lett. 1979, 27, 2505.13 Anderson, H. J.; Lee, S. F. Can. J. Chem. 1965, 43, 409.14 Boatman, R. J.; Whitlock, H. W. J. Org. Chem. 1976, 41,3050. 15 Hort, E. V.; Anderson, L. R. Encyclopedia of ChemicalTechnology, 3rd ed., V ol. 19, Eds.: Mark, H. F.; Othmer, D.F.; Overberger, C.G.; Seaborg, G. T., John Wiley & Sons,New York, 1982, p. 505.(Y0502019 QIN, X. Q.)IVChinese Journal of Organic Chemistry V ol. 25, 2005Synthesis of Menthyl Esters of N-Benzo- xycarbonylaminoacid Using DCC/DMAPLI, Qian-Rong *; GU, Cheng-Zhi; YIN, Hao; ZHANG, YiChin. J. Org. Chem. 2005, 25(11), 1416Five N -Cbz-aminoacid menthyl esters (3a ～3e ) were synthesized from the reactions between N -Cbz-aminoacids (2a ～2e ) and (－)-menthol in the presence of DCC/DMAP in acetonitrile under mild conditions. Full spectral data of the products are reported.Synthesis of N -(Methoxycarbonylalkyl)- bromopyrrole-2-carboamidesZENG, Xiang-Chao *; XU, Shi-Hai; LI, Yi-Qun; LIU, Po-Run; LI, Yu-XiaChin. J. Org. Chem. 2005, 25(11), 1420A series of N -(methoxycarbonylalkyl)bromopyrrole-2-carboamides were synthesized by acylation of amino acid methyl esters with bromo-2-trichloroacetylpyrroles at room temperature. The crystal structure of methyl (4,5-dibromo-1-methylpyrrole-2-carbonylamino)acetate was characterized by single crystal X-ray diffraction analysis.Preliminary antibiotic tests showed that some target compounds have good antibiotic activity. Synthesis of Complexes of Bidentate Ligands with Cd(II) and Hg(II)LIU, Xiao-Lan; LIU, Yong-Hong *; YUAN, Dong-Mei; JING, Xiao-Bi; SHI, Yao- Cheng Chin. J. Org. Chem. 2005, 25(11), 1427Six complexes, Cd(MFC)2•H 2O, Cd(MFC)OAc, Cd(BFC)2, Hg(MFC)2, Hg(MFC)OAc and Hg(BFC)2, have been synthesized via reaction of two Schiff base ligands of methyl 1-ferrocenylcinnamylidene hydrazinodithiocarboxylate (HMFC) and benzyl 1- ferro-cenylcinnamylidene hydrazinodithiocarboxylate (HBFC) with M(OAc)2•n H 2O [M ＝Cd(II) or Hg(II), n ＝2, 0]. Their structures were characterized by elemental analysis, molar conductance, IR and 1H NMR spectrum measurements.Simple Total Synthesis of Photodynamic Compound 5-Aminolevulinic AcidLIU, Hai-Ling; JIANG, Huan-Feng *; WANG, Yu-Gang; LIU, PengChin. J. Org. Chem. 2005, 25(11), 14315-Aminolevulinic acid (5-ALA) was prepared from γ-butyrolactone via alcoholysis,oxidation, Henry reaction, oxidation and hydrogenation. Especially Henry reaction was carried out through a solvent-free procedure in the presence of alumina supported potas-sium fluoride, and then oxidation of the nitroalkanol was finished using wet alumina supported chromium(VI) oxide. The structures of all the compounds were confirmed by 1H NMR, IR and MS spectra.。