CN103664730B - 基于亚甲基环丙烷环加成反应合成吡咯衍生物的方法 - Google Patents

基于亚甲基环丙烷环加成反应合成吡咯衍生物的方法 Download PDF

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CN103664730B
CN103664730B CN201210336562.4A CN201210336562A CN103664730B CN 103664730 B CN103664730 B CN 103664730B CN 201210336562 A CN201210336562 A CN 201210336562A CN 103664730 B CN103664730 B CN 103664730B
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万伯顺
潘斌
吴凡
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Dalian Institute of Chemical Physics of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond

Abstract

本发明涉及一种制备1,2,3-三取代吡咯衍生物的方法。具体方法是由N-取代亚甲基氮杂环丙烷与二炔，以Ni(COD)2为催化剂，发生[3+2]环加成反应制备1,2,3-三取代吡咯衍生物。该方法起始原料廉价易得，操作简便，条件温和，不使用配体。

Description

基于亚甲基环丙烷环加成反应合成吡咯衍生物的方法
技术领域
本发明涉及一种制备1,2,3-三取代吡咯衍生物的方法。具体方法是由N-取代亚甲基氮杂环丙烷与二炔，以Ni(COD)2为催化剂，发生[3+2]环加成反应制备1,2,3-三取代吡咯衍生物。
背景技术
吡咯及其衍生物是重要的杂环化合物之一，此类化合物广泛存在于各种具有生理活性的化合物和天然产物结构中，如卟啉，维生素B12等。除此之外，还可以用来合成很多药物，例如抗真菌药吡咯尼群，抗菌药司他霉素，消炎药托美丁，抗肿瘤药长春新碱等（式1）。
式1
因此，吡咯及其衍生物是有机合成中非常有用的构建模块（文献1：(a)O’Hagan,D.Nat.Prod.Rep.2000,17,435;(b)Ho□mann,H.;Lindel,T.Synthesis 2003,1753;(c)Furstner，A.Angew.Chem.,Int.Ed.2003,42,3582;(d)Lindquist,N.;Fenical,W.;VanDuyne,G.D.;Clardy，J.J.Org.Chem.1988,53,4570.）。
由于吡咯及其衍生物的应用广泛，因此，此类化合物的合成一直是有机合成中的重要研究方向。而环加成反应由于原子利用率高、条件温和，因此在吡咯类化合物的合成中得以应用（文献2：(a)Katritzky，A.R.;Yao,J.;Bao,W.;Qi,M.;Steel,P.J.J.Org.Chem.1999,64,346;(b)Washizuka,K.I.;Minakata,S.;Ryu,I.；Komatsu,M.Tetrahedron 1999,55,12969.）。但对于过渡金属催化的环加成构建吡咯的方法目前报道还较少。
发明内容
本发明涉及一种基于亚甲基环丙烷环加成反应合成吡咯衍生物的方法，制备1,2,3-三取代吡咯衍生物的方法。
本发明采用的技术方案为：
基于亚甲基环丙烷环加成反应合成吡咯衍生物的方法，以下式所示的N-取代取代亚甲基氮杂环丙烷和二炔为原料合成1,2,3-三取代吡咯类化合物，反应式如下：
其中R为C1-C8烷基、C3-C8环烷基、苯基、取代的苯基、萘基、苄基、取代的苄基中的一种，苯基或苄基上的取代基为C1-C8烷基、C1-C8烷氧基、F、Cl、Br、I、NO2中的一种、二种或三种；R1、R2为氢、甲基、苯基、C2-C8烷基、三甲基硅基；X为-O、-NTS、-NCOPh、-C(CO2CH3)2、或-C(CO2C2H5)2。
具体操作步骤如下：
于反应器中进行反应，反应器抽真空后通氮气或惰性气体置换，加入催化剂、N-取代亚甲基氮杂环丙烷1、二炔2和溶剂，最后20℃-40℃下反应1天-7天；反应结束后，抽掉溶剂，固体纯化后得到1,2,3-三取代吡咯衍生物3。
催化剂为Ni(COD)2，即双(1,5-环辛二烯)镍(0)。
N-取代亚甲基氮杂环丙烷1和二炔2摩尔比例为5:1-2:1。
溶剂为四氢呋喃、N,N-二甲基甲酰胺、苯、甲苯、乙醚、四氯化碳、1,4-二氧六环、乙腈中的一种或多种。
相对于二炔的摩尔量，催化剂的用量为5mol%-20%mol。
相对于二炔的摩尔量，溶剂的用量为5ml/mmol-30ml/mmol。
惰性气体为氩气；
反应结束后，用旋转蒸发仪抽掉溶剂，固体溶于二氯甲烷上样进行硅胶柱层析，得到1,2,3-三取代吡咯衍生物3。
N-取代亚甲基氮杂环丙烷是一种化学性质丰富，但是相对稳定存在的三元环状化合物，我们发现N-取代亚甲基氮杂环丙烷和二炔，利用Ni(COD)2为催化剂，在温和条件下可以选择性的和二炔中的一个炔基发生[3+2]环加成反应，以中等收率获得吡咯衍生物。该方法原料廉价易得，操作简便，条件温和，不使用配体。所获得的吡咯衍生物容易进一步衍生化。
附图说明
图1为3a的1H NMR(400MHz,CDCl3)δ7.31-7.20(m,3H),6.92(d,2H),6.32(s,1H),4.92(s,2H),3.68(s,6H),3.2(s,2H),2.71(q,2H),1.97(s,3H),1.93(s,3H),1.78(t,3H);
图2为3a的13C NMR(100MHz,CDCl3)δ170.0,137.7,127.6,126.1,125.3,123.6,117.8,114.2,113.9,77.8,73.4,57.7,51.4,49.3,26.5,21.8,8.7,8.3,2.5;
图3为3a的HRMS Calculated for C23H27NO4Na[M+Na]+404.1838,found404.1828。
图4为3b的1H NMR(400MHz,d6-acetone)δ7.33-7.26(m,3H),7.06(d,2H),6.70(s,1H),5.06(s,2H),4.42(s,2H),4.08(s,2H),2.86(s,3H),1.99(s,3H),0.19(s,9H);
图5为3b的13C NMR(100MHz,d6-acetone)δ140.1,129.4,127.9,127.3,125.8,121.2,118.4,104.1,90.5,64.1,56.8,50.8,9.7,9.5;
图6为3b的HRMS Calculated for C26H35NO4NaSi[M+Na]+476.2233,found476.2232。
图7为3c的单晶x-衍射图。
具体实施方式
（1）参照文献，经两步合成N-取代亚甲基氮杂环丙烷：第一步，胺和2,3-二溴乙丙烯在DMF中生成化合物1（文献5：Mori,M.;Chiba,K.;Okita,M.;Kayo,I.;Ban,Y.Tetrahedron 1985,41,375.）（式1,反应方程式1）。第二步，制备氨基钠的液氨悬浊液，缓慢滴加化合物1的乙醚溶液，反应得到N-取代亚甲基氮杂环丙烷（文献7：Jason J.S.;Michael S.;Jerome F.H.;Alexandra M.Z.J.Am.Chem.Soc.2004,126，6868.）（式1,反应方程式2）。
式1.N-取代亚甲基氮杂环丙烷的合成步骤
（2）由N-取代亚甲基氮杂环丙烷和二炔制备1,2,3-三取代吡咯衍生物
式2.1,2,3-三取代吡咯衍生物的合成步骤
反应方程式见式2,于反应器中进行反应，反应器抽真空后通氩气置换三次后，加入5-20mol%的催化剂,然后加入N-取代亚甲基氮杂环丙烷1和0.2mmol的二炔2，加入1ml溶剂,最后20℃-40℃下反应1天-7天。反应结束后旋蒸掉溶剂后，固体进行硅胶柱层析，得到卤代1,2,3-三取代吡咯衍生物3。
实施例1
于10ml Schlenk反应管中进行反应，反应器抽真空后通氩气置换三次后，加入5.5mg(10mol％)的催化剂Ni(COD)2,然后加入0.5mmol亚甲基氮杂环丙烷1a和0.2mmol的二炔2a，加入1ml甲苯,最后25℃下反应2天。反应结束后旋蒸掉溶剂后，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到41mg的1,2,3-三取代吡咯3a，分离收率为60%。
1a的表征数据如下：
1H NMR(400MHz,CDCl3)δ7.35–7.24(m,5H),4.72(s,2H),3.69(s,2H),2.13(s,2H);
13C NMR(100MHz,CDCl3)δ138.3,137.1,128.5,128.3,127.5,83.7,62.9,30.6.3a的表征数如下：
1H NMR(400MHz,CDCl3)δ7.31-7.20(m,3H),6.92(d,2H),6.32(s,1H),4.92(s,2H),3.68(s,6H),3.2(s,2H),2.71(q,2H),1.97(s,3H),1.93(s,3H),1.78(t,3H);（谱图见说明书附图1）
13C NMR(100MHz,CDCl3)δ170.0,137.7,127.6,126.1,125.3,123.6,117.8,114.2,113.9,77.8,73.4,57.7,51.4,49.3,26.5,21.8,8.7,8.3,2.5;（谱图见说明书附图2）
HRMS Calculated for C23H27NO4Na[M+Na]+404.1838,found 404.1828。（谱图见说明书附图3）
实施例2
于10ml Schlenk反应管中进行反应，反应器抽真空后通氩气置换三次后，加入5.5mg(10mol％)的催化剂Ni(COD)2,然后加入0.5mmol亚甲基氮杂环丙烷1a和0.2mmol的二炔2b，加入1ml甲苯,最后25℃下反应2天。反应结束后旋蒸掉溶剂后，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到41mg的1,2,3-三取代吡咯3b，分离收率为50%。
3b的表征数如下：
1H NMR(400MHz,d6-acetone)δ7.33-7.26(m,3H),7.06(d,2H),6.70(s,1H),5.06(s,2H),4.42(s,2H),4.08(s,2H),2.86(s,3H),1.99(s,3H),0.19(s,9H);（谱图见说明书附图4）
13C NMR(100MHz,d6-acetone)δ140.1,129.4,127.9,127.3,125.8,121.2,118.4,104.1,90.5,64.1,56.8,50.8,9.7,9.5;（谱图见说明书附图5）
HRMS Calculated for C26H35NO4NaSi[M+Na]+476.2233,found 476.2232。（谱图见说明书附图6）
实施例3
于10ml Schlenk反应管中进行反应，反应器抽真空后通氩气置换三次后，加入5.5mg(10mol%)的催化剂Ni(COD)2,然后加入0.5mmol亚甲基氮杂环丙烷1b和0.2mmol的二炔2a，加入1ml甲苯,最后25℃下反应2天。反应结束后旋蒸掉溶剂后，固体进行硅胶柱层析，以石油醚：乙酸乙酯=20:1的洗脱剂冲洗柱子，得到41mg的1,2,3-三取代吡咯3c，分离收率为55%。
3c的单晶x-衍射图如下：（谱图见说明书附图7）。

Claims (7)

1.基于亚甲基环丙烷环加成反应合成吡咯衍生物的方法，
以下式所示的N-取代亚甲基氮杂环丙烷和二炔为原料合成1,2,3-三取代吡咯类化合物，反应式如下：
其中R为C1-C8烷基、C3-C8环烷基、苯基、取代的苯基、萘基、苄基、取代的苄基中的一种，苯基或苄基上的取代基为C1-C8烷基、C1-C8烷氧基、F、Cl、Br、I、NO2中的一种、二种或三种；R1、R2为氢、甲基、苯基、C2-C8烷基、三甲基硅基；X为O、NTs、NCOPh、C(CO2CH3)2、或C(CO2C2H5)2。
2.按照权利要求1所述的方法，其特征在于：
具体操作步骤如下：
于反应器中进行反应，反应器抽真空后通氮气或惰性气体置换，加入催化剂Ni(COD)2、N-取代亚甲基氮杂环丙烷1、二炔2和溶剂，最后20℃-40℃下反应1天-7天；反应结束后，抽掉溶剂，固体纯化后得到1,2,3-三取代吡咯衍生物3。
3.按照权利要求1或2所述的方法，其特征在于：N-取代亚甲基氮杂环丙烷1和二炔2摩尔比例为5:1-2:1。
4.按照权利要求1或2所述的方法，其特征在于：溶剂为四氢呋喃、N,N-二甲基甲酰胺、苯、甲苯、乙醚、四氯化碳、1,4-二氧六环、乙腈中的一种或多种。
5.按照权利要求1或2所述的方法，其特征在于：相对于二炔的摩尔量，催化剂的用量为5mol％-20mol％。
6.按照权利要求1或2所述的方法，其特征在于：相对于二炔的摩尔量，溶剂的用量为5ml/mmol-30ml/mmol。
7.按照权利要求2所述的方法，其特征在于：
惰性气体为氩气；
反应结束后，用旋转蒸发仪抽掉溶剂，固体溶于二氯甲烷上样进行硅胶柱层析，得到1,2,3-三取代吡咯衍生物3。
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