CN106045914B - 一种三取代咪唑类化合物的合成方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明属于有机合成化学技术领域，本发明涉及一种从简单易得原料异腈在碳酸银催化一步合成三取代咪唑类化合物的合成方法。在一定的反应温度和溶剂中，由芳基异腈与官能团异腈制备三取代咪唑类化合物。在氮气保护下，使用碳酸银作为催化剂，反应温度为80°C。溶剂可以选择二氯甲烷、1,4‑二氧六环、四氢呋喃、二甲基亚砜，其中以1,4‑二氧六环最好。本发明具有操作简单，原料和试剂易得，条件温和，产物易分离纯化，适用于合成各种多取代咪唑类化合物，特别适用于大规模的工业生产，可以高效、高收率地制得三取代的咪唑类化合物。
Description
技术领域
本发明属于有机合成化学技术领域，具体涉及一种一步合成三取代咪唑类化合物的方法。
技术背景
咪唑是一类重要的杂环化合物，是许多生物活性天然产物、药物分子以及功能材料的关键结构单元。作为药物分子的一类重要的药效基团，咪唑具有广泛的治疗应用，如抗癌、抗-HIV病毒、抑菌、抗炎、抗过敏、胰高血糖素受体拮抗剂等其它药用。此外，咪唑在作为金属酶以及过渡金属催化剂的配体，有机反应催化剂，超分子化学反应中的接收器，离子液体、天然产物的合成方面起着关键的作用。由于多取代咪唑在药物化学及其他领域的广泛应用，其合成方法的研究一直受到人们的重视（Med. Res. Rev.2014, 34, 340; J. Med. Chem.1998, 41, 4744; Nature1994, 372, 739.）。
合成咪唑的方法有很多，常见的如1）Bredereck咪唑合成法，以α-二酮或者α-羟基酮与甲酰胺缩合环化得到有取代的咪唑，2）碱促进对甲苯磺酰基甲基异腈和醛亚胺或者亚胺酰氯的环合反应。到目前为止，过渡金属催化异腈与异腈的[3+2]环加成反应直接合成咪唑类化合物的报道仅有3例。分别是Grigg课题组报道的银催化异腈的二聚环合法，Yamamoto课题组在氧化亚铜/三苯基膦催化芳基异腈与甲基异腈的交叉环加成反应，以及Hong课题组利用NHC-铜作催化剂将异腈范围扩展到苯基异腈。然而，这三例报道合成的产物都是1,4-二取代咪唑。
芳基异腈与异腈的[3+2]环加成反应是一条简便的合成三取代咪唑类化合物的方法，并且是首次从简单易得的原料两种不同的异腈出发，通过1, 2-迁移直接得到三取代的咪唑类化合物。这种反应符合原子经济性，能够高效、简单合成具有高度官能化的咪唑类型化合物。摆脱以往合成缺陷：需要使用强碱以及高温，常有副产物产生如酸。
发展廉价易得的商业原料合成复杂分子，一直都是有机化学的重要研究方向。异腈分子经常作为一类活泼分子参与到有机化学反应中，用于高效合成一些含氮分子或杂环化合物，其参与的反应往往具有高化学、区域、立体选择性和较高的原子经济性等优点（Chem. Rev., 2015, 115, 2698.）。同时，异腈的结构和一氧化碳类似，是重要的 C1 源和具有强的金属配位能力，能够有效地参与过渡金属催化的一些反应。到目前为止，芳基异腈与异腈合成三取代咪唑类化合物的反应还未见文献报道。
发明内容
本发明的目的是芳基异腈与磺酰氧基、酰氧基以及氨基甲酰基取代的异腈反应制备三取代的吡咯类化合物方法的[3+2]型环加成反应，例如，使用简单、易得的两种异腈在温和的条件下，直接反应，一步合成三取代咪唑类化合物，提供一种价格低廉、原子经济的合成方法，更加简便、高效地合成高度官能化的咪唑类化合物。
本发明提供一种高度官能化的咪唑类化合物的制备方法。在本发明里，我们首次发展了一种两种不同的异腈的环加成反应，制备了一系列三取代吡咯类化合物。
本发明所涉及的合成高度官能化的咪唑类化合物，其反应方程式如下：
包括将一种芳基异腈1与官能团异腈2加热到80℃在非水溶剂中反应得到三取代的吡咯类化合物3，其中，TG为磺酰氧基、酰氧基、氨基甲酰基，R为烷基、苯基、酯基、烯基、芳基。用本发明方法可以高效地得到高纯度的三取代咪唑类化合物。
本发明的三取代咪唑类化合物的制备方法包括芳基异腈与官能团异腈的成环反应。
具体过程可表示如下：
（1）在一定的反应温度和溶剂中，由芳基异腈1与官能团异腈2制备三取代咪唑类化合物3。
官能团异腈2的用量是芳基异腈用量的1.2倍，在氮气保护下，使用碳酸银作为催化剂，反应温度为80°C。溶剂可以选择二氯甲烷、1,4-二氧六环、四氢呋喃、二甲基亚砜，其中以1,4-二氧六环最好。
本发明具有操作简单，原料和试剂易得，条件温和，产物易分离纯化，适用于合成各种多取代咪唑类化合物，特别适用于大规模的工业生产，可以高效、高收率地制得三取代的咪唑类化合物。
附图说明
图1为咪唑3a的1H-NMR的核磁共振谱；
图2为咪唑3a的13C-NMR的核磁共振谱；
图3为咪唑3i的1H-NMR的核磁共振谱；
图4为咪唑3i的13C-NMR的核磁共振谱。
具体实施方式
下面的实施例将有助于说明本发明，但是不局限其范围。
实施例1
咪唑衍生物3a的制备
向带有磁力搅拌装置的10 mL耐压管中加入对溴苯基异腈1a（109.2 mg,0.6mmol, 1.2 equiv）、对甲苯磺酰基异腈（103.1 mg，0.5 mmol, 1.0 equiv）和碳酸银（27.6 mg，10 mol%），搅拌均匀并充入三次氮气保护，通过注射器加入1,4-二氧六环（2mL）。在80 ℃ 油浴锅中反应1小时，TLC检测底物消失，反应结束。待反应液冷却至室温，用硅胶过滤后在35摄氏度减压蒸馏得到混合物，经过硅胶柱层析（洗脱液为石油醚、乙酸乙酯）得到白色固体161.0 mg, 经过NMR、MS证实为咪唑衍生物3a，其收率为82%。
谱图解析数据3a：
1H-NMR (500 MHz, CDCl3) δ = 7.48 (d, J = 8.5 Hz, 2H), 7.43 (s, 1H),7.30 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H),2.67 (s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ =147.09, 144.42,140.34, 138.75, 133.84, 131.94, 129.51, 129.45, 127.12, 126.53, 123.93,21.56, 14.96。
实施例2
用1i代替实例1中的1e，其他条件同实例1，实验结果见表1。
谱图解析数据3i：
1H NMR (500 MHz, CDCl3) δ = 8.00 (d, J = 8.5 Hz, 2H), 7.49 (s, 1H),7.29 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 13.0, 8.5 Hz, 2H), 4.42 (q, J = 7.0Hz, 1H), 2.68 (s, 3H), 2.37 (s, 3H), 1.42 (t, J=7.0, 3H); 13C NMR (125 MHz,CDCl3) δ = 165.24, 147.16, 144.40, 140.19, 138.59, 138.43, 131.57, 129.94,129.48, 127.75, 126.97, 126.43, 61.46, 21.50, 14.91, 14.21。
实施例3
用1j代替实例1中的1e，其他条件同实例1，实验结果见表1。
谱图解析数据3j：
1H NMR (500 MHz, DMSO) δ = 8.29 (d, J = 8.0 Hz, 2H), 8.07 (s, 1H),7.48 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 21.1, 7.5 Hz, 4H), 2.54 (s, 3H), 2.36(s, 3H);13C NMR (125 MHz, DMSO) δ 147.77, 146.53, 144.59, 141.96, 140, 03,138.30, 130. 01, 129.28, 126.63, 125.49, 123.99, 21.09, 14.66。
实施例4
用1q代替实例1中的1e，其他条件同实例1，实验结果见表1。
谱图解析数据3j：
1H NMR (500 MHz, CDCl3) δ = 7.71 (d, J = 8.5 Hz, 2H), 7.64 (d, J =7.0 Hz,, 1H), 7.53 (td, J = 7.5, 3.5 Hz, 1H), 7.46-7.41 (m, 4H0, 7.24 (dd, J= 6.5. 0.5 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.71(d, J = 16.0 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H), 2.71 (s, 3H), 2.12 (s, 3H);13C NMR (125 MHz, CDCl3) δ = 189.54, 146.80, 144.47, 140.65, 138.35, 137.34,133.95, 133.30, 132.96, 130.57, 130.47, 130.26, 129.41, 128.60, 128.37,127.65, 127.25, 126.86, 124.57, 21.35, 14.97。
实施例5
用苄基异腈代替实例1中的甲基异腈，其他条件同实例1，实验结果见表1。
谱图解析数据3t：
1H NMR (500 MHz, CDCl3) δ = 7.49-7.46 (m, 5H), 7.34 (t, J = 7.5 Hz,2H), 7.27- 7.24 (m, 2H), 7.08 (dd, J = 8.5 Hz, 4H), 6.93 (d, J = 8.5 Hz, 2H),4.47 (s, 2H), 2.36 (s, 3H);13C NMR (125 MHz, CDCl3) δ = 149.43, 144.46,140.83, 139.10, 138.40, 133.67, 131.93, 129.63, 129.43, 129.29, 128.49,127.32, 126.41, 124.05, 34.34, 21.58。
实施例6
用酰氧基取代的异腈代替实例1中的对甲苯磺酰氯基取代的异腈，其他条件同实例1，实验结果见表1。
谱图解析数据4a：
1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.5Hz, 2H), 7.70 (s,1H), 7.64 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 4H),4.41 (q, J = 7.0 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.5 Hz,3H),1.04 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 166.51, 159.83, 147.91,140.61, 137.92, 135.94, 132.34, 130.17, 129.35, 129.07, 127.72, 123.05,120.67, 61.10, 61.04, 14.37, 13.69。
实施例7
用氨基甲酰基取代的异腈代替实例1中的对甲苯磺酰基取代的异腈，其他条件同实例1，实验结果见表1。
谱图解析数据4e：
1H NMR (500 MHz, CDCl3) δ 7.58-7.55 (m, 3H), 7.31 (d, J = 7.0 Hz,2H), 7.27 (d, J = 3.0 Hz, 1H), 7.24-7.21 (m, 3H), 7.16 (t, J = 7.0 Hz, 1H),4.02 (s, 2H), 3.38 (t, J = 7.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 1.70 (t, J= 7.0 Hz, 1H), 1.52 (t, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 161.13,142.09, 139.44, 135.89, 135.29, 132.92, 128.84, 128.34, 126.18, 124.61,124.37, 121.84, 47.40, 45.48, 34.21, 25.38, 24.10。
Claims (1)
1.一种三取代咪唑类化合物的合成方法，其特征是其反应方程式如下：
具体步骤：向带有磁力搅拌装置的10 mL耐压管中加入对溴苯基异腈1a109.2 mg,0.6mmol, 1.2 equiv、对甲苯磺酰基异腈103.1 mg，0.5 mmol, 1.0 equiv和碳酸银27.6mg，0.1mmol，搅拌均匀并充入三次氮气保护，通过注射器加入1,4-二氧六环2 mL，在80 ℃油浴锅中反应1小时，TLC检测底物消失，反应结束，待反应液冷却至室温，用硅胶过滤后在35摄氏度减压蒸馏得到混合物，经过洗脱液为石油醚、乙酸乙酯的硅胶柱层析得到白色固体161.0 mg, 经过NMR、得到MS为咪唑衍生物3a，其收率为82%。
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| Silver-catalyzed cyclization of 2-pyridyl alkynyl carbinols with isocyanides: divergent synthesis of indolizines and pyrroles;Xianyu Meng et al.,;《Chem. Commun.》;20141231;第50卷;11837-11839 |
| Silver-Catalyzed Isocyanide-Alkyne Cycloaddition: A General and Practical Method to Oligosubstituted Pyrroles;Jianquan Liu et al.,;《Angew. Chem. Int. Ed.》;20130506;第52卷;第6954页Table 1 |
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