微波辅助他化法合成1,4-二氢吡啶

微波辅助他化法合成1,4-二氢吡啶

1.4-二羟基吡啶是抗结剂、钙抗剂和神经醇抗剂。它具有神经保护、抗血小板聚集和对糖尿病的抵抗力。它也是一种抗帕金森疾病的抗脑萎缩剂和肿瘤治疗的化疗剂。1.4-二羟吡啶可以作为相应的吡啶衍生物。三组分复合的汉茨反应广泛用于合成1、4-二羟吡啶。在醋酸或乙醇中，在回收过程中，为了获得1、4-羟吡啶的产率，必须将其转化为微波反应。然而，传统的汉茨反应方法的反应时间很长，产率很低。因此，利用微波代替加热进行汉茨反应，得到了1、4-二羟基吡啶的产率。乙腈用泰米林鲁姆反应6.8小时，取平均值（73%80%）后，可获得1.4-二羟基吡啶。虽然没有溶剂，但乙酰基丙烯酸乙酯、甲醛和乙酸铵的混合温度为80，反应为0.25.4.5小时，取1、4-二羟基吡啶的产量为83%99%，但合成方法没有研究其他1、3-2-二羟基化合物（如丙烯酸）的情况，而且，分离和提取样品的问题。因此，我们需要发展一种简单有效的1、4-二羟基吡啶合成方法。在无溶剂、较低的反应温度下,我们通过醛、1,3-二羰基化合物和碳酸氢铵的缩合实现了1,4-二氢吡啶的合成(Eq.1).1原料醛和1,3-二氢吡啶的合成碳酸氢铵受热分解提供Hantzsch合成反应所需的氨,而二氧化碳从反应体系排除.因此,在无溶剂条件下,用碳酸氢铵代替氨水或者醋酸铵,实际上可以有几个优点,例如:可以得到更高的反应收率,缩短反应时间(表1)和简化后处理工艺.我们发现原料醛:1,3-二羰基化合物:碳酸氢铵的摩尔比为1∶2∶2时1,4-二氢吡啶的合成收率最高.与改进后的Hantzsch合成相比,本方法具有经济、操作简单,产物易于分离纯化的特点,并且容许使用多种取代醛和1,3-二羰基化合物.在相似的条件下,各种取代芳香醛不论是吸电子基取代(4b～4f)还是供电子基取代(4g～4i)都以极好的产率转化成所期望的1,4-二氢吡啶.而且,使用乙酰丙酮也高产率地得到了相应的1,4-二氢吡啶.然而,按照文献,我们考察了4n～4q的合成,得到的产率分别是59%,63%,68%和53%.2实验部分2.1si-ms和ir谱所用试剂均为国产AR或CP级试剂.熔点用XRC-1显微熔点测定仪测定,温度计未校正;ESI-MS和IR谱分别由FinniganLCQDECA质谱仪、PerkinElmerspectrumoneFT-IRspectrometer红外光谱仪记录;1HNMR谱由BrukerAvance600或400核磁共振仪记录,TMS作为内标.2.2esi-msm/z%苯甲醛(0.503g,5mmol)、乙酰乙酸乙酯(1.30g,10mmol)和碳酸氢铵(0.79g,10mmol)混合物加热到70℃反应1h,待反应完成后(TLC监控),反应混合物冷却至室温,往混合物中加入水(30mL),强力搅拌10min,弃去水层,残余物用乙酸乙酯溶解,无水硫酸镁干燥,过滤干燥剂,减压蒸去溶剂得到粗产物4a(纯度>95%,经HPLC分析).粗产物经热的乙醇重结晶得到纯度更高的产物(1.57g,产率95%).相似地,摩尔比为1∶2∶2的取代醛、1,3-二羰基化合物和碳酸氢铵混合物加热至70℃,以86%～97%的收率得到具有较好纯度的1,4-二氢吡啶4.进一步纯化4,可以通过乙醇或者石油醚/乙酸乙酯(8～9∶1,V∶V)重结晶.4a:黄色结晶(EtOH),m.p.157～159℃;1HNMR(CDCl3,600MHz)δ:1.28(t,J=7.2Hz,6H),2.36(s,6H),4.05(q,J=7.2Hz,4H),5.05(s,1H),5.56(brs,1H),7.13～7.18(m,3H),7.25(dd,J=8.2,2.4Hz,2H);IR(KBr)ν:3341,3060,1688,1651,1488,1372,1229,1211,1123,1091,1020,768,703,680cm-1;ESI-MSm/z(%):330([M+H]+,98),328([M-1]+,3).4b:浅黄色固体,m.p.148～150℃;1HNMR(CDCl3,400MHz)δ:1.23(t,J=7.2Hz,6H),2.34(s,6H),4.10(q,J=7.2Hz,4H),4.96(s,1H),5.52(brs,1H),6.87～6.89(m,2H),7.20～7.23(m,2H);IR(KBr)ν:3344,3067,2985,2905,1687,1652,1603,1507,1487,1371,1333,1299,1213,1170,1118,1093,1016,830,785,745cm-1;ESI-MSm/z(%):347([M]-,21),346([M-H]-,100).4c:浅黄色固体,m.p.151～152℃;1HNMR(CDCl3,400MHz)δ:1.25(t,J=7.2Hz,6H),2.35(s,6H),4.07(q,J=7.2Hz,4H),5.04(s,1H),5.55(brs,1H),6.98(d,J=8.2Hz,2H),7.24(d,J=8.2Hz,2H);IR(KBr)ν:3358,3093,2987,2960,1696,1651,1603,1507,1489,1372,1300,1245,1210,1166,1123,1090,1018,856,786,755,695cm-1;ESI-MSm/z(%):362([M-H]-,100),364([M-H+2]-,33).4d:黄色固体,m.p.168～170℃;1HNMR(CDCl3,400MHz)δ:1.19(t,J=7.0Hz,6H),2.18(s,6H),4.01(q,J=7.2Hz,4H),5.58(s,1H),5.85(brs,1H),7.44(dd,J=8.2,2.4Hz,1H),7.52～7.55(m,2H),7.73(dd,J=8.2,2.4Hz,1H);IR(KBr)ν:3330,3092,2977,2931,1695,1678,1612,1528,1489,1354,1308,1280,1212,1100,1020,859,830,785,715cm-1;ESI-MSm/z(%):398([M+Na]+,100).4e:浅黄色固体,m.p.155～157℃;1HNMR(CDCl3,600MHz)δ:1.22(t,J=7.2Hz,6H),2.35(s,6H),4.10(q,J=7.2Hz,4H),4.94(s,1H),5.60(brs,1H),7.12(dd,J=8.2,1.7Hz,1H),7.31(d,J=8.2Hz,1H),7.33(d,J=1.7Hz,1H);IR(KBr)ν:3359,3093,2990,2962,2942,1699,1651,1603,1507,1485,1371,1334,1299,1213,1166,1115,1098,1018,979,886,818,791,749cm-1;ESI-MSm/z(%):398([M+2-H+2]-,11),398([M+2]-,69),397([M+2-H]-,33),396([M-H]-,100).4f:白色固体,m.p.173～175℃;1HNMR(CDCl3,400MHz)δ:1.22(t,J=7.2Hz,6H),2.33(s,6H),4.10(q,J=7.2Hz,4H),5.08(s,1H),5.52(brs,1H),7.26(d,J=7.2Hz,2H),8.32(d,J=7.2Hz,2H);IR(KBr)ν:3332,3089,2965,2925,1692,1675,1603,1512,1476,1350,1298,1276,1112,1043,906,865,775,695cm-1;ESI-MSm/z(%):353([M+Na]+,100),331([M+H]+,62).4g:白色固体,m.p.161～162℃;1HNMR(CDCl3,600MHz)δ:1.25(t,J=7.2Hz,6H),2.33(s,6H),3.85(s,3H),4.09(q,J=7.2Hz,4H),4.92(s,1H),5.43(s,1H),5.53(brs,1H),6.74～6.77(m,2H),6.85(d,J=1.7Hz,1H);IR(KBr)ν:3401,3316,2985,2835,1668,1637,1614,1508,1483,1371,1309,1270,1208,1131,1114,1050,1017,958,856,799,765cm-1;ESI-MSm/z(%):376([M+H]+,7),375([M]-,23),374([M-H]-,100).4h:白色固体,m.p.158～159℃;1HNMR(CDCl3,400MHz)δ:1.25(t,J=7.2Hz,6H),2.32(s,6H),3.83(s,3H),4.07(q,J=7.2Hz,4H),4.91(s,1H),5.48(s,1H),5.53(brs,1H),6.68(d,J=8.2Hz,1H),6.79(dd,J=8.2,2.0Hz,1H),6.83(d,J=2.0Hz,1H);IR(KBr)ν:3351,2983,2953,2934,1681,1653,1598,1514,1489,1370,1303,1272,1218,1160,1122,1095,1020,859,800,753cm-1;ESI-MSm/z(%):375([M]-,18),374([M-H]-,100).4i:白色固体,m.p.165～167℃;1HNMR(CDCl3,400MHz)δ:1.26(t,J=7.2Hz,6H),2.35(s,6H),4.09(q,J=7.2Hz,4H),4.90(s,1H),5.40(s,1H),5.46(brs,1H),6.70(d,J=8.2Hz,2H),6.82(d,J=8.2Hz,2H);IR(KBr)ν:3347,2987,2939,2905,1660,1634,1611,1511,1488,1369,1316,1227,1171,1130,1022,856,845,761cm-1;ESI-MSm/z(%):384([M+K]+,52),368([M+Na]+,21),346([M+H]+,100),345([M]-,22),344([M-H]-,100).4j:白色固体,m.p.148～150℃;1HNMR(CDCl3,400MHz)δ:1.25(t,J=7.2Hz,6H),2.35(s,6H),3.87(s,3H),4.07(q,J=7.2Hz,4H),4.98(s,1H),5.60(brs,1H),6.80(d,J=8.2Hz,2H),6.98(d,J=8.2Hz,2H);IR(KBr)ν:3343,3096,2956,2905,2836,1690,1651,1610,1510,1489,1372,1301,1253,1210,1174,1121,1089,1031,834,786,750cm-1;ESI-MSm/z(%):359([M]-,26),358([M-H]-,100).4k:白色固体,m.p.152～153℃;1HNMR(CDCl3,400MHz)δ:1.27(t,J=7.2Hz,6H),2.34(s,6H),4.12(q,J=7.1Hz,4H),4.15(q,J=8.2Hz,4H),5.20(s,1H),5.66(brs,1H),5.96(d,J=3.6Hz,1H),6.21(m,1H),7.22(s,1H);IR(KBr)ν:3346,3094,2983,2901,1699,1650,1488,1393,1369,1301,1206,1149,1120,1096,1007,921,805,749,729cm-1;ESI-MSm/z(%):320([M+H]+,72),252([M-furyl]+,62),251([M-furyl-H]+,100).4l:白色结晶(EtOH),m.p.123～125℃;1HNMR(CDCl3,600MHz)δ:0.97(d,J=6.8Hz,3H),1.28(t,J=7.2Hz,6H),2.27(s,6H),3.49(q,J=6.8Hz,1H),4.17(q,J=7.2Hz,4H),5.47(brs,1H);IR(KBr)ν:3345,3104,2983,2963,2939,2865,1697,1654,1491,1392,1370,1299,1215,1134,1110,1058,984,777,697cm-1;ESI-MSm/z(%):290([M+Na]+,100),268([M+H]+,45).4m:白色固体,m.p.95～97℃;1HNMR(CDCl3,400MHz)δ:0.75(d,J=6.8Hz,6H),1.31(t,J=7.2Hz,6H),1.55(m,1H),2.31(s,6H),3.93(d,J=6.8Hz,1H),4.15(q,J=7.2Hz,4H),5.62(brs,1H);IR(KBr)ν:3344,3026,2959,2934,2872,1697,1651,1487,1371,1257,1216,1106,1051,772,744cm-1;ESI-MSm/z(%):297([M+H+1]+,5),296([M+H]+,100).4n:黄色结晶(EtOH),m.p.180～182℃;1HNMR(CDCl3,400MHz)δ:2.25(s,6H),2.35(s,6H),5.02(s,1H),5.58(brs,1H),7.12～7.16(m,3H),7.23(dd,J=8.8,2.4Hz,2H);IR(KBr)ν:3321,3062,2929,1670,1603,1475,1376,1361,1299,1227,1113,1021,962,936,790,727,703,659cm-1;ESI-MSm/z(%):269([M]-,6),268([M-H]-,100).4o:黄色结晶(EtOH),m.p.169～170℃;1HNMR(CDCl3,600MHz)δ:2.27(s,6H),2.33(s,6H),5.04(s,1H),5.66(brs,1H),6.76(d,J=8.8Hz,2H),7.15(d,J=8.8Hz,2H);IR(KBr)ν:3345,3013,2973,2930,2830,1667,1646,1606,1509,1459,1374,1357,1260,1222,1118,1015,932,841,793,744cm-1;ESI-M