CN107353266A - 一种烯酸溴内酯化的制备方法 - Google Patents
一种烯酸溴内酯化的制备方法 Download PDFInfo
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Abstract
本发明涉及结构式如下所示的烯酸溴内酯化的制备方法:
Description
本发明涉及一种烯酸溴内酯化的制备方法。
溴内酯化反应指的是烯酸类化合物在含溴素试剂的作用下,发生分子内关环得到溴内酯类化合物。在这个反应过程中,涉及反应的烯键一步即产生两个新的碳杂(O-C-C-Br)单键。对于同时产生两个手性中心的烯酸底物,溴内酯化反应表现出立体专一性。该反应自发现以来就在有机合成化学中占据着重要的地位,广泛应用于天然产物的全合成研究中,是一种非常有效的合成方法。
鉴于溴内酯化反应的重要性,其合成方法近年来受到越来越多的关注。烯酸与溴单质的反应是目前应用最为广泛,也是最常见的溴内酯化的方法。但由于溴单质是一种有毒、有腐蚀性、挥发性的液体,不易操作,此方法的应用受到了限制。于是越来越多的研究在传统方法上进行改进,寻找可替代液溴的溴代试剂。目前主要的合成方法有以下两种:(1)烯酸在N-溴代丁二酰亚胺(NBS)及其类似物作用下的溴内酯化;(2)烯酸在氧化剂和金属溴化物作用下的溴内酯化。这些改进方法为溴内酯化反应提供了丰富的安全的可选择途径,但存在不同的缺陷:试剂价格昂贵,产率不高,区域选择性不好。
本发明的目的是提供一种新的烯酸溴内酯化的制备方法。其特征是以烯酸(3-烯酸,4-烯酸,5-烯酸)为原料,以二氯甲烷为溶剂,在二苯亚砜/草酰溴组合试剂的作用下,得到相应的溴内酯化产物。本发明的制备方法具有试剂价廉易得、操作简便、产率高、选择性好的优点。反应式如下:
本发明涉及结构式如下所示的烯酸溴内酯化的制备方法:
其主要过程是:在-78℃先将二苯亚砜(1.5eq)的二氯甲烷溶液滴加至草酰溴(1.5eq)的二氯甲烷溶液中,再滴加原料烯酸,然后回至0℃反应,得到相应的溴内酯化产物,3-烯酸及4-烯酸得到γ-内酯产物,5-烯酸则得到δ-内酯产物,产率在50~95%。
本发明方法中制备的烯酸溴内酯化产物的结构都通过核磁共振进行了确认。分析结果附在实施例后。
具体实施方式
(1)(4R*,5S*)-4-溴-5-苯基-二氢呋喃-2(3H)-酮的制备
氮气保护,在装有温度计的100mL三口烧瓶中,加入草酰溴(7.5mmol,1.1mL,1.5eq)和无水二氯甲烷(10mL)。液氮-乙醇浴-78℃下,用恒压滴液漏斗缓慢滴加二苯亚砜(7.5mmol,1.52g,1.5eq)的无水二氯甲烷(10mL)溶液。滴加完毕后,-78℃下继续搅拌10min,再滴加(E)-4-苯基-3-丁烯酸(5mmol,810mg,1.0eq)的无水二氯甲烷(10mL)溶液。滴加完毕后,-78℃下继续搅拌10min,然后回至0℃反应2h。冰浴0℃下,加入30mL碳酸氢钠水溶液(5%),分液,取有机相,用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥。过滤,旋蒸除去溶剂得粗品,经柱层析分离提纯(石油醚/乙酸乙酯=15∶1),得到(4R*,5S*)-4-溴-5-苯基-二氢呋喃-2(3H)-酮985mg,产率为82%。1H NMR(300MHz,CDCl3)δ7.46-7.36(m,5H),5.66(d,J=5.1Hz,1H),4.37(ddd,J=7.2,6.3,5.1Hz,1H),3.24(dd,J=18.3,7.5Hz,1H),2.97(dd,J=18.3,6.6Hz,1H)。13C NMR(75MHz,CDCl3)δ173.08,135.98,129.48,129.18,125.52,87.99,45.70,38.94。
(2)5-(溴甲基)-3,3-二甲基-二氢呋喃-2(3H)-酮的制备
氮气保护,在装有温度计的100mL三口烧瓶中,加入草酰溴(7.5mmol,1.1mL,1.5eq)和无水二氯甲烷(10mL)。液氮-乙醇浴-78℃下,用恒压滴液漏斗缓慢滴加二苯亚砜(7.5mmol,1.52g,1.5eq)的无水二氯甲烷(10mL)溶液。滴加完毕后,-78℃下继续搅拌10min,再滴加2,2-二甲基-4-戊烯酸(5mmol,640mg,1.0eq)的无水二氯甲烷(10mL)溶液。滴加完毕后,-78℃下继续搅拌10min,然后回至0℃反应2h。冰浴0℃下,加入30mL碳酸氢钠水溶液(5%),分液,取有机相,用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥。过滤,旋蒸除去溶剂得粗品,经柱层析分离提纯(石油醚/乙酸乙酯=10∶1),得到5-(溴甲基)-3,3-二甲基-二氢呋喃-2(3H)-酮980mg,产率为95%。1H NMR(300MHz,CDCl3)δ4.66-4.57(m,1H),3.54(dd,J=10.8,5.1Hz,1H),3.47(dd,J=10.8,6.0Hz,1H),2.25(dd,J=12.9,6.3Hz,1H),1.91(dd,J=12.9,9.3Hz,1H),1.28(s,3H),1.26(s,3H)。13C NMR(75MHz,CDCl3)δ180.97,74.74,41.87,40.61,33.74,24.96,24.91。
(3)6-(溴甲基)-四氢吡喃-2-酮的制备
氮气保护,在装有温度计的100mL三口烧瓶中,加入草酰溴(7.5mmol,1.1mL,1.5eq)和无水二氯甲烷(10mL)。液氮-乙醇浴-78℃下,用恒压滴液漏斗缓慢滴加二苯亚砜(7.5mmol,1.52g,1.5eq)的无水二氯甲烷(10mL)溶液。滴加完毕后,-78℃下继续搅拌10min,再滴加5-己烯酸(5mmol,570mg,1.0eq)的无水二氯甲烷(10mL)溶液。滴加完毕后,-78℃下继续搅拌10min,加入碳酸钾(25mmol,3.45g,5.0eq)和18-冠醚-6(0.25mmol,66mg,0.05eq),然后回室温反应5h。抽滤,滤液中加入30mL蒸馏水,分液,取有机相,用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥。过滤,旋蒸除去溶剂得粗品,经柱层析分离提纯(石油醚/乙酸乙酯=10∶1),得到6-(溴甲基)-四氢吡喃-2-酮500mg,产率为52%。1H NMR(600MHz,CDCl3)δ4.52-4.47(m,1H),3.52(dd,J=10.8,4.2Hz,1H),3.47(dd,J=10.8,6.0Hz,1H),2.60(dddd,J=18.0,6.6,4.8,1.2Hz,1H),2.46(ddd,J=17.4,9.6,7.2Hz,1H),2.14-2.08(m,1H),1.97(ddq,J=13.8,7.2,4.8Hz,1H),1.91-1.83(m,1H),1.70(dtd,J=13.8,11.4,5.4Hz,1H)。13C NMR(150MHz,CDCl3)δ170.45,78.70,33.89,29.50,26.42,18.27。
Claims (1)
1.一种烯酸溴内酯化的制备方法,其特征是以烯酸(3-烯酸,4-烯酸,5-烯酸)为原料,以二氯甲烷为溶剂,在二苯亚砜/草酰溴组合试剂的作用下,得到相应的溴内酯化产物,反应式如下:
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RUI DING等: "A Novel Method for the Chlorolactonization of Alkenoic Acids Using Diphenyl Sulfoxide/Oxalyl Chloride", 《SYNTHESIS》 * |
SHELLI R. MELLEGAARD等: "Selenium-Catalyzed Halolactonization: Nucleophilic Activation of Electrophilic Halogenating Reagents", 《J. ORG. CHEM.》 * |
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CN108467331A (zh) * | 2018-04-25 | 2018-08-31 | 北京工商大学 | 一种由烯烃制备邻二溴化合物的方法 |
CN108467331B (zh) * | 2018-04-25 | 2020-02-14 | 北京工商大学 | 一种由烯烃制备邻二溴化合物的方法 |
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