CN104710340A - 一种制备3-磺酰基取代吡咯衍生物的方法 - Google Patents

一种制备3-磺酰基取代吡咯衍生物的方法 Download PDF

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CN104710340A
CN104710340A CN201310703200.9A CN201310703200A CN104710340A CN 104710340 A CN104710340 A CN 104710340A CN 201310703200 A CN201310703200 A CN 201310703200A CN 104710340 A CN104710340 A CN 104710340A
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万伯顺
呼延成
吴凡
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Zhongke Yulin Energy Technology Operation Co ltd
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Abstract

本发明涉及一种制备3-磺酰基取代吡咯衍生物的方法。具体方法是由简单制备得到的联烯酰胺为原料，以Pd(OAc)2为催化剂，PtBu3为配体，Selectfluor为氧化剂的条件下，发生环化反应制备3-磺酰基取代的吡咯衍生物。联烯酰胺可以由廉价易得的起始原料简单制备得到，且后续的环化反应操作简便，只是简单的通过分子内的磺酰基迁移就可构建3-磺酰基取代的吡咯，不需要进行多步反应。

Description

一种制备3-磺酰基取代吡咯衍生物的方法
技术领域
本发明涉及一种制备3-磺酰基取代的吡咯衍生物的方法。具体方法是由简单制备得到的N-磺酰基取代的联烯酰胺为原料，以Pd(OAc)2为催化剂，PtBu3为配体，Selectfluor为氧化剂的条件下，发生环化反应制备3-磺酰基取代的吡咯衍生物。 
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，消炎药托美丁，抗菌药司他霉素等（式1）。其中，3-磺酰基取代的吡咯单元常会有特殊的生理活性，例如化合物4就是一种高效的5-HT6受体的激动剂和拮抗剂。 
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.Synthesis2003,1753;(c)Furstner,A.Angew.Chem.,Int.Ed.2003,42,3582;(d)Lindquist,N.;Fenical,W.;Van Duyne,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。目前来说，构建吡咯杂环的方法主要有：过渡金属催化的C-H官能化反应（文献2：(a)Huestis,M.P.;Chan,L.;Stuart,D.R.;Fagnou,K.Angew.Chem.Int.Ed.2011,50,1338.(b)Lian,Y.;Huber,T.;Hesp,K.D.;Bergmann,R.G.;Ellmann,J.A.Angew. Chem.Int.Ed.2013,52,629.(c)Wang,L.;Ackermann,L.Org.Lett.2013,15,176.(d)Li,B.;Wang,N.C.;Liang,Y.J.;Xu,S.S.;Wang,B.Q.Org.Lett.2013,15,136.），多组分反应（文献3：(a)Balme,G.;Bouyssi,D.;Monteiro,N.Heterocycles2007,73,87.(b)Balme,G.Angew.Chem.,Int.Ed.2004,43,6238.）以及一些常见的模块反应（文献4：(a)Xin,X.Y.;Wang,D.P.;Li,X.C.;Wan,B.S.Angew.Chem.Int.Ed.2012,51,1693.(b)Sai,M.;Yorimitsu,H.;Oshima,K.Angew.Chem.Int.Ed.2011,50,3294.(c)Toh,K.K.;Wang,Y.-F.;Ng,E.P.J.;Chiba,S.J.Am.Chem.Soc.2011,133,13942.）。但所有这些方法对于构建以3-磺酰基取代的吡咯报道很少。近年来，联烯常用来作为合成杂环化合物的前体，本专利主要介绍了以联烯酰胺作为前体，在过渡金属催化的条件下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。 
发明内容
本发明涉及一种制备3-磺酰基取代的吡咯衍生物的方法。 
一种制备3-磺酰基取代的吡咯衍生物的方法，以下式所示的N-磺酰基取代的联烯酰胺1为原料，在催化剂条件下合成3-磺酰基取代的吡咯类化合物2，反应式如下： 
其中R1、R2、R3为C1-C8烷基、C1-C8烷氧基、萘基、呋喃基、苯基、或取代的苯基，苯基上的取代基为C1-C8烷基、C1-C8烷氧基、CF3、F、Cl、Br、I、NO2中的一种或二种、三种。 
具体操作步骤如下： 
于反应器中进行反应，反应器抽真空后通氩气置换，加入N-磺酰基取代的联烯酰胺1、催化剂和氧化剂，然后加入溶剂及配体，最后40℃-120℃下反应24h-48h；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，得到吡咯类化合物2。 
催化剂为Pd(OAc)2，配体为PtBu3，氧化剂为Selectfluor。 
催化剂的用量为原料用量的5mol%-20mol%；配体的用量为原料用量的10mol%-40mol%；氧化剂的用量为原料用量的2当量。 
溶剂为乙腈、二氯甲烷、二氯乙烷、N,N-二甲基甲酰胺、甲苯、乙醚、四氯化碳、1,4-二氧六环的一种或二种以上。 
溶剂的用量为原料用量的10ml/mmol-30ml/mmol。 
反应温度范围在40℃-120℃。反应时间为24h-48h。 
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3-磺酰基取代的吡咯衍生物2。 
本发明有以下优点： 
1、反应物N-磺酰基联烯酰胺1由廉价易得的原料醛、磺酰胺和炔醇经简单反应步骤得到。 
2、生成的3-磺酰基取代吡咯衍生物2的反应操作简单，只通过简单的一步反应就可构建吡咯杂环，不需要进行多步反应。 
附图说明
图1为1a的1H NMR图； 
图2为1a的13C NMR图； 
图3为1a的HRMS(ESI)图； 
图4为2a的1H NMR图； 
图5为2a的13C NMR图； 
图6为2a的HRMS(ESI)图； 
图7为2a的晶体衍射图。 
具体实施方式
（1）参照文献，经五步合成N-磺酰基联烯酰胺：第一步，芳香醛和磺酰胺在原硅酸乙酯中反应生成亚胺（文献5：Love,B.E.;Raje,P.S.;Williams II,T.C.Synlett1994,493.）（式2,反应方程式1）；当醛为脂肪醛时，将醛、磺酰胺和对甲苯亚磺酸钠溶在甲酸和水中反应，得到脂肪族亚胺（文献6：Chemla,F.;Hebbe,V.;Normant,J.F.Synthesis2000,75.）（式2，反应方程式2）。第二步，以二氯甲烷为溶剂，对甲苯磺酸作为催化剂的条件下将炔丙醇进行羟基的保护（式2,反应方程式3）。第三步，在低温下将羟基保护后的炔丙醇先进行锂化，然后将亚胺的四氢呋喃溶液滴加到反应体系中得到产物炔丙胺4（文献7：Katritzky,A.R.;Li,J.Q.;Gordeev,M.F.Synthesis1994,93.）（式2,反应方程式4）。第四步，以甲醇为溶剂，对甲苯磺酸作为催化剂，将上一步得到的固体进行羟基的脱保护得到产物5（式2,反应方程式5）。第五步，在LiHMDS作为质子碱的条件下，对产物5的两个活泼氢上两分子酰氯，然后再加入2-3当量的有机碱Et3N反应2h，最终得到目标产物N-磺酰基取代的联烯酰胺1（文献7：Yu,X.Z.;Xin,X.Y.;Wan,B.S.;Li,X.W.J.Org.Chem.2013,78,4895.）（式2,反应方程式6）。 
式2.N-磺酰基取代的联烯酰胺的合成步骤 
（2）由N-磺酰基联烯酰胺制备3-磺酰基取代吡咯衍生物 
式3.一种3-磺酰基取代吡咯衍生物的合成步骤 
反应方程式见式3，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0.2mmol的N-磺酰基联烯酰胺1，10%mmol Pd(OAc)2和0.4mmol Selectfluor，然后加入4ml溶剂和20%mmol PtBu3，40℃-120℃下反应24h-48h。反应结束后旋蒸掉溶剂后，固体进行硅胶柱层析，得到3-磺酰基吡咯衍生物2。 
实施例1 
于10ml Schlenk反应管中进行反应，反应管抽真空后通氩气置换三次后，加入0.2mmol（91.9mg）的联烯酰胺1a，10%mmol（4.9mg）Pd(OAc)2和0.4mmol（141.7mg）Selectfluor（购买于Aldrich），然后加入4ml CH3CN和20%mmol（10.2μL）PtBu3，120℃下搅拌反应24小时。反应结束后，用旋转蒸发仪抽掉溶剂后，固体溶于二氯甲烷上样进行硅胶柱层析，用石油醚：乙酸乙酯=10:1的洗脱剂冲洗柱子，得到36.9mg的吡咯衍生物2a，分离收率为50%。 
1a的表征数据如下： 
1H NMR(400MHz,CDCl3)δ7.92(d,J=8.2Hz,2H),7.45–7.21(m,7H),6.11(t,J=6.4Hz,1H),4.95–4.68(m,2H),4.20(q,J=7.1Hz,2H),4.12(q,J=7.1Hz,2H),2.44(s,3H),1.29(t,J=7.1Hz,3H),1.10(t,J=7.1Hz,3H).（谱图见说明书附图1） 
13C NMR(101MHz,CDCl3)δ206.2,154.9,151.7,145.0,136.0,133.3,129.4,129.2,128.7,128.3,125.5,111.9,96.9,64.5,63.74,63.70,21.8,14.3,14.1.（谱图见说明书附图2） 
HRMS(ESI)m/z calcd for C23H25NO7NaS[M+Na]+482.1249,found482.1250.（见说明书附图3） 
2a的表征数如下： 
1H NMR(400MHz,CDCl3)δ7.43–7.37(m,1H),7.35(d,J=3.6Hz,1H),7.34–7.27(m,4H),7.18–7.02(m,4H),6.79(d,J=3.6Hz,1H),4.13(q,J=7.1Hz,2H),2.34(s,3H),1.02(t,J=7.1Hz,3H).（谱图见说明书附图4） 
13C NMR(101MHz,CDCl3)δ149.6,143.4,139.3,136.0,130.6,130.0,129.1,128.8,128.7,127.4,120.8,111.0,64.1,21.5,13.5.（谱图见说明书附图5） 
HRMS(ESI)m/z calcd for C20H20NO4S[M+H]+370.1113,found370.1108.（见说明书附图6） 
2a的晶体衍射图（见说明书附图7）。 

Claims (8)

1.一种制备3-磺酰基取代的吡咯衍生物的方法：
以下式所示的N-磺酰基取代的联烯酰胺1为原料，在催化剂条件下合成3-磺酰基取代的吡咯类化合物2，反应式如下：
其中R1、R2、R3为C1-C8烷基、C1-C8烷氧基、萘基、呋喃基、苯基、或取代的苯基，苯基上的取代基为C1-C8烷基、C1-C8烷氧基、CF3、F、Cl、Br、I、NO2中的一种或二种、三种。
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，反应器抽真空后通氩气置换，加入N-磺酰基取代的联烯酰胺1、催化剂和氧化剂，然后加入溶剂及配体，最后40℃-120℃下反应24h-48h；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，得到吡咯类化合物2。
3.按照权利要求1或2所述的方法，其特征在于：催化剂为Pd(OAc)2，配体为PtBu3，氧化剂为Selectfluor。
4.按照权利要求1或2所述的方法，其特征在于：催化剂的用量为原料用量的5mol%-20mol%；配体的用量为原料用量的10mol%-40mol%；氧化剂的用量为原料用量的2当量。
5.按照权利要求1或2所述的方法，其特征在于：溶剂为乙腈、二氯甲烷、二氯乙烷、N,N-二甲基甲酰胺、甲苯、乙醚、四氯化碳、1,4-二氧六环的一种或二种以上。
6.按照权利要求1或2所述的方法，其特征在于：溶剂的用量为原料用量的10ml/mmol-30ml/mmol。
7.按照权利要求1或2所述的方法，其特征在于：反应温度范围在40℃-120℃；反应时间为24h-48h。
8.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3-磺酰基取代的吡咯衍生物2。
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