无溶剂研磨合成6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a- 四氢异喹啉衍生物.pdf

2009 年第 29 卷 有 机 化 学 Vol.29,2009 第 6 期,962965 Chinese Journal of Organic Chemistry No.6,962965 *E-mail:lcrong or lcrong2005 Received April 13,2008;revised December 8,2008;accepted January 7,2009.江苏省高校自然科学基础研究基金(No.08KJB150017)和徐州师范大学培育基金(No.07PYL06)资助项目.研究简报 无溶剂研磨合成 6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物 荣良策*,a,b 韩红霞a 姜 虹b 庄启亚a 王苏惠a 屠树江a,b (a徐州师范大学化学化工学院 徐州 221116)(b江苏省药用植物生物技术重点实验室 徐州 221116)摘要摘要 NaOH 存在下,无溶剂室温研磨芳醛、丙二腈、N-甲基哌啶-4-酮,方便地合成了一系列 6-氨基-8-芳基-2-甲 基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物,该反应产率高,操作简单.所有产物的结构均经 IR,1H NMR,元素分析进行了表征,并采用 X-ray 晶体衍射分析进一步确定了产物 4d 的结构.关键词关键词 芳醛;丙二腈;N-甲基哌啶-4-酮;无溶剂;研磨 Synthesis of 6-Amino-8-aryl-2-methyl-5,7,7(1H)-tricarbonitrile-2,3,8,8a-tetrahydroisoquinoline Derivatives under Solvent-Free Conditions Using a Ginding Method Rong,Liangce*,a,b Han,Hongxiaa Jiang,Hongb Zhuang,Qiyaa Wang,Suhuia Tu,Shujianga,b(a College of Chemistry and Chemical Engineering,Xuzhou Normal University,Xuzhou 221116)(b Key Laboratory of Biotechnology for Medicinal Plant,Xuzhou 221116)Abstract A series of 6-amino-8-aryl-2-methyl-5,7,7(1H)-tricarbonitrile-2,3,8,8a-tetrahydroisoquinoline derivatives were synthesized from aromatic aldehydes,malononitrile and N-methylpiperidin-4-one in the presence of sodium hydroxide under a solvent-free condition.The advantages of this procedure were simple protocol and high yields.The structures of products were determined by IR,1H NMR spectra,elemental analysis,and 4d was additionally confirmed by X-ray diffraction analysis.Keywords aromatic aldehyde;malononitrile;N-methylpiperidin-4-one;solvent-free;grinding异喹啉及其衍生物在自由界中广泛存在,结构类型复杂,具有多种生物活性,例如许多化合物具有镇痛麻醉、抗炎、抗癌、降血糖、降血压等作用1,广泛应用于医药、农药等领域,因而异喹啉及其衍生物的合成越来越受到广泛的关注.国外内已有许多文献报道异喹啉及其衍生物的合成研究2,但多数都是在溶剂相中进行反应.在溶剂中虽然反应物分子可以均匀分散,稳定交换能量,但是,溶剂相反应也有些明显的缺点.比如,有机溶剂成本高、易燃、有毒、难以回收,造成环境污染等.近年来无溶剂反应发展迅速3,这是由于无溶剂反应可以有效避免有机溶剂对于环境的影响,而且还可以有效地提高反应速率和反应选择性.此外,无溶剂反应还有操作简单、时间短、降低反应成本等特点,因而无溶剂条件下的有机合成已经成为绿色化学新的发展方向之一,具有广泛的应用前景.无溶剂有机合成目前已经运用于许多类型的反应,例如,重排反应4、氧化反 No.6 荣良策等：无溶剂研磨合成 6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物 963 应5、偶联反应6、Michael 加成反应7等.本文报道在NaOH 存在下,室温无溶剂研磨芳醛、丙二腈、N-甲基哌啶-4-酮一步法方便高产率地合成 6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物.反应如 Eq.1 所示.(1)Ar:C6H5(4a),4-CH3OC6H4(4b),4-CH3C6H4(4c),4-FC6H4(4d),4-ClC6H4(4e),4-BrC6H4(4f),2,4-Cl2C6H3(4g),2-ClC6H4(4h)1 实验部分 1.1 仪器和试剂 玛瑙研钵;熔点测定使用北京科仪电光仪器厂生产的 TX5 显微熔点仪测定(温度未经校正);红外光谱采用FT/IR-8101 型红外光谱仪测定(KBr 压片);核磁共振氢谱采用 Bruker-400 MHz 型核磁共振仪测定,DMSO-d6为溶剂,TMS 为内标;元素分析用 Perkin-Elmer 2400II型元素分析仪测定;晶体结构用Siemens P4四圆衍射仪测定.所用试剂均为分析纯或化学纯.1.2 6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物 4 的合成 将芳醛(2 mol),丙二腈(4 mmol),N-甲基哌啶-4-酮(2 mmol),NaOH(0.2 g)置于玛瑙研钵中混合均匀,室温研磨 2 min,得黄色固体,然后用水充分洗至中性,抽滤,干燥,固体粗产物用 95%EtOH 重结晶,得目标化合物 4.4a:黄色固体,产率 89%;m.p.198199;1H NMR(DMSO-d6,400 MHz):7.447.63(m,7H,NH2,ArH),5.66(d,J1.6 Hz,1H,C8-H),3.65(d,J12.4 Hz,1H,C3-H),3.003.06(m,1H,C8a-H),2.65(d,J17.2 Hz,1H,C3-H),2.40(dd,J4.8,4.8 Hz,1H,C1-H),2.12(s,3H,CH3),1.65(t,J11.2 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3422,3335,3232,3061,3033,2946,2847,2778,2211,1654,1602,1500,1457,1396,1385,1344,1290,1278,1234,1204,1149,1114,1081,1032,979,945,888,818,784,759,712 cm1.Anal.calcd for C19H17N5:C 72.36,H 5.43,N 22.21;found C 72.29,H 5.47,N 22.33.4b:黄色固体,产率 91%;m.p.146148;1H NMR(DMSO-d6,400 MHz):7.517.54(m,3H,NH2,ArH),7.34(d,J8.0 Hz,1H,ArH),7.08(d,J9.2 Hz,1H,ArH),6.98(d,J8.0 Hz,1H,ArH),5.65(d,J2.0 Hz,1H,C8-H),3.80(s,3H,OCH3),3.57(d,J12.8 Hz,1H,C3-H),2.952.98(m,1H,C8a-H),2.64(d,J17.6 Hz,1H,C3-H),2.41(dd,J4.8,4.8 Hz,1H,C1-H),2.12(s,3H,CH3),1.63(t,J10.4 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3606,3382,3318,3092,22952,2836,2787,2213,1655,1596,1493,1460,1397,1383,1350,1311,1289,1277,1261,1233,1184,1147,1119,1032,889,838,766 cm1.Anal.calcd for C20H19N5O:C 69.55,H 5.54,N 20.28;found C 69.62,H 5.46,N 20.33.4c:黄色固体,产率 90%;m.p.185187;1H NMR(DMSO-d6,400 MHz):7.237.51(m,6H,NH2,ArH),5.64(d,J2.0 Hz,1H,C8-H),3.57(d,J12.4 Hz,1H,C3-H),2.962.99(m,1H,C8a-H),2.64(d,J17.6 Hz,1H,C3-H),2.40(dd,J4.8,4.8 Hz,1H,C1-H),2.35(s,3H,CH3),2.12(s,3H,CH3),1.63(t,J10.8 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3357,3328,3267,3095,3033,2980,2963,2850,2798,2214,1713,1675,1650,1600,1516,1462,1448,1400,1382,1362,1307,1288,1272,1221,1190,1146,1120,1078,1030,980,946,889,827,763,745,619 cm1.Anal.calcd for C20H19N5:C 72.93,H 5.81,N 21.26;found C 72.84,H 5.90,N 21.33.4d:黄色固体,产率 91%;m.p.208210;1H NMR(DMSO-d6,400 MHz):7.68(s,1H,ArH),7.55(s,2H,NH2),7.50(s,1H,ArH),7.38(t,J8.4 Hz,1H,ArH),7.30(t,J8.4 Hz,1H,ArH),5.66(d,J2.0 Hz,1H,C8-H),3.73(d,J12.4 Hz,1H,C3-H),2.983.07(m,1H,C8a-H),2.65(d,J17.6 Hz,1H,C3a-H),2.40(dd,J4.4,4.4 Hz,1H,C1-H),2.13(s,3H,CH3),1.64(t,J10.8 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3413,3326,3033,2984,2953,2877,2810,2211,1665,1603,1513,1467,1449,1396,1383,1352,1342,1306,1288,1223,1165,1117,1081,1029,1015,981,888,863,841,809,765,750 cm1.Anal.calcd for C19H16FN5:C 68.46,H 4.84,N 21.01;found C 68.41,H 4.76,N 20.96.4e:黄色固体,产率 87%;m.p:178180;1H NMR(DMSO-d6,400 MHz):7.457.67(m,6H,NH2,ArH),5.66(d,J2.0 Hz,1H,C8-H),3.75(d,J12.8 Hz,1H,C3-H),3.013.07(m,1H,C8a-H),2.66(d,J17.6 Hz,1H,C3a-H),2.40(dd,J4.8 Hz,4.8 Hz,1H,C1-H),2.14(s,3H,CH3),1.65(t,J10.4 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3357,3320,3090,2962,2796,2212,1711,1674,1650,1598,1494,1462,1448,1400,1383,1363,1307,1286,1269,1250,1222,1205,1165,1146,1119,1093,1046,1029,1014,979,946,964 有 机 化 学 Vol.29,2009 888,835,803,789,762,748,610 cm1.Anal.calcd for C19H16ClN5:C 65.24,H 4.61,N 10.13;found C 65.41,H 4.56,N 10.23.4f:黄色固体,产率 90%;m.p.183185;1H NMR(DMSO-d6,400 MHz):7.75(d,J8.0 Hz,1H,ArH),7.68(d,J8.0 Hz,1H,ArH),7.60(s,1H,ArH),7.56(s,2H,NH2),7.40(d,J8.0 Hz,1H,ArH),5.66(d,J2.0 Hz,1H,C8-H),3.74(d,J12.4 Hz,1H,C3-H),3.013.03(m,1H,C8a-H),2.65(d,J17.6 Hz,1H,C3-H),2.40(dd,J4.4,4.4 Hz,1H,C1-H),2.13(s,3H,CH3),1.64(t,J10.8 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3355,3327,3266,3097,3031,2981,2950,2855,2214,1712,1674,1650,1600,1491,1462,1448,1400,1384,1362,1307,1285,1269,1222,1204,1119,1076,1030,1010,979,946,888,856,831,809,787,762,746,632,607 cm1.Anal.calcd for C19H16BrN5:C 57.88,H 4.09,N 17.76;found C 57.94,H 4.13,N 17.63.4g:黄色固体,产率 88%;m.p.189191;1H NMR(DMSO-d6,400 MHz):7.85(d,J8.8 Hz,2H,ArH),7.68(d,J8.8 Hz,1H,ArH),7.61(s,2H,NH2),5.70(d,J2.0 Hz,1H,C8-H),3.93(d,J12.8 Hz,1H,C3-H),3.073.08(m,1H,C8a-H),2.68(d,J17.6 Hz,1H,C3-H),2.34(dd,J4.8,4.8 Hz,1H,C1-H),2.13(s,3H,CH3),1.61(t,J10.4 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3587,3439,3351,3092,3069,2962,2889,2216,1638,1597,1561,1478,1460,1395,1385,1347,1309,1288,1203,1148,1115,1107,1082,1053,1033,981,888,863,828,799,761 cm1.Anal.calcd for C19H15Cl2N5:C 59.39,H 3.93,N 18.23;found C 59.44,H 9.90,N 18.31.4h:黄色固体,产率 89%;m.p.174176;1H NMR(DMSO-d6,400 MHz):7.81(d,J8.0 Hz,1H,ArH),7.517.65(m,5H,NH2,ArH),5.70(d,J2.0 Hz,1H,C8-H),3.94(d,J12.4 Hz,1H,C3-H),3.063.08(m,1H,C8a-H),2.69(d,J17.6 Hz,1H,C3-H),2.32(dd,J4.4,4.4 Hz,1H,C1-H),2.12(s,3H,CH3),1.62(t,J10.4 Hz,1H,C4-H),1.06(t,J7.2 Hz,1H,C1-H);IR(KBr)v:3588,3426,3028,2953,2860,2788,2210,1644,1598,1476,1440,1395,1344,1310,1287,1272,1231,1204,1147,1118,1083,1055,1031,983,888,775,750,704,632 cm1.Anal.calcd for C19H16ClN5:C 65.24,H 4.61,N 20.02;found C 65.30,H 4.67,N 19.89.1.3 X 射线衍射实验与晶体结构分析 晶体学数据和衍射强度数据的收集在 Siemens P4 四圆衍射仪进行晶体结构分析.将 0.35 mm0.30 mm0.22 mm 的黄色长方形单晶置于装有单色器的四圆衍射仪上,用 Mo K(0.071073 nm)辐射和 扫描方式收集衍射数据,在 1.8725.01范围内共收集 3163 个独立衍射点,可观测衍射点1605个I2(I).晶体结构由直接法(SHELXS97 程序)解出,经多轮 Fourier 合成获得全部非氢原子,全部氢原子由理论后直接加氢而得到.全部非氢原子的坐标及各向异性热参数,采用 w22o1/()F(0.0548P)20.0000P,P22oc(2)/3,FF 经全矩阵最小二乘法修正及收敛.最终的偏离因子为 R0.0522,wR0.1173.最终差值电子密度的最高峰为215 enm3,最低峰为191 enm3.(/)max0.000,S1.005.图图 1 4d 的分子结构示意图 Figure 1 Molecular structure of compound 4d 2 结果和讨论 今天,人类和环境的和谐可持续发展已经成为我们生活的主题,越来越多的化学工作者致力于发展对环境友好的新方法去合成与人们生活息息相关的有机化合物.传统的有机液相反应中,有机溶剂具有易挥发,难于回收,后处理污染环境等缺点,所以无溶剂条件下的反应研究已经变得十分必要.无溶剂合成方法不仅简单易行,而且高效、经济.本研究将三种反应底物混在一起,加入0.2 g NaOH,采用室温研磨的方法,短时间高产率地合成了 6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物.产物的结构通过 IR,1H NMR,元素分析确定,并且产物 4d 的 X 射线衍射分析进一步确证了产物的结构.在红外光谱中,3300 cm1附近出现氨基(NH2)的特征伸缩振动吸收峰;在2220 cm1附近出现氰基(CN)强的伸缩振动吸收峰.在氢谱中,氨基两个质子的吸收峰在 7.50 附近出现,甲基的吸收峰受异喹啉环上 N 原子的影响移向低场,出现在的 2.10 附近,取代芳基上的芳氢吸收峰出现在 7.407.85 范围内.异喹啉环的上质子吸收峰出现在 1.003.90 范围内.本论 No.6 荣良策等：无溶剂研磨合成 6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物 965 文为合成该类化合物提供了一条简单、方便且环境友好的方法.References 1 Banik,B.K.;Vegesna,S.;Manhas,M.S.;Bose,A.K.Het-erocycles 1998,47,639.2 Frisch,K.;Landa,A.;Saaby,S.;Jorgensen,K.A.Angew.Chem.,Int.Ed.2005,44,6058.3(a)Tanaka,K.;Toda,F.Chem.Rev.2000,100,1025.(b)Li,L.;Ren,Z.J.;Cao,W.G.;Huang,P.G.;Zhu,H.Chin.J.Org.Chem.2007,27,120(in Chinese).(李磊,任仲皎,曹卫国,黄培刚,朱华,有机化学,2007,27,120.)(c)Zeng,H.Y.;Yin,S.F.;Li,Y.Chin.J.Org.Chem.2007,27,528(in 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