化学学报 ›› 2019, Vol. 77 ›› Issue (9): 814-831.DOI: 10.6023/A19050170 上一篇    下一篇

所属专题: 有机自由基化学

综述

4-取代的汉斯酯(Hantzsch Esters)作为烷基化试剂参与的有机反应

叶盛青a, 吴劼abc*()   

  1. a台州学院医药化工与材料工程学院 台州 318000
    b复旦大学化学系 上海 200438
    c中国科学院上海有机化学研究所 金属有机化学国家重点实验室 上海 200032
  • 收稿日期:2019-05-12 出版日期:2019-09-15 发布日期:2019-06-12
  • 通讯作者: 吴劼 E-mail:Jie_wu@fudan.edu.cn
  • 作者简介:叶盛青, 2008年在复旦大学化学系获学士学位; 2013年在复旦大学有机化学专业获理学博士学位(导师: 吴劼教授); 2013年至2015年在美国The Scripps Research Institute从事博士后工作(导师: 余金权教授); 2015年至2019年在苏州诺华制药科技有限公司担任工艺经理; 2019年至今在台州学院医药化工与材料工程学院任副教授. 主要从事类天然产物小分子骨架的有机方法学研究.|吴劼, 1991~1995年就读于江西师范大学化学系, 1995~2000年在中国科学院上海有机化学研究所进行研究生学习(2000年获得博士学位), 2000至2004 年先后在美国哈佛大学(博士后)、洛克菲勒大学艾伦·戴蒙德艾滋病研究中心(访问科学家)及VivoQuest, Inc.(研究员)从事有机合成、药物化学及相关研究工作, 2004年9月回国加入复旦大学化学系(副教授), 2006年4月晋升为教授. 2019年8月加入台州学院医药化工与材料工程学院. 目前主要研究领域: 构建类天然小分子化合物用于抗肿瘤及免疫类疾病、炎症疾病和神经退行性疾病新药研究.
  • 基金资助:
    项目受国家自然科学基金资助(Nos.21672037);项目受国家自然科学基金资助(21532001)

4-Substituted Hantzsch Esters as Alkylation Reagents in Organic Synthesis

Ye, Shengqinga, Wu, Jieabc*()   

  1. a School of Pharmaceutical and Materials Engineering, Taizhou University, Taizhou 318000, China
    b Department of Chemistry, Fudan University, Shanghai 200438, China
    c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
  • Received:2019-05-12 Online:2019-09-15 Published:2019-06-12
  • Contact: Wu, Jie E-mail:Jie_wu@fudan.edu.cn
  • Supported by:
    Project supported by the National Natural Science Foundation of China(Nos.21672037);Project supported by the National Natural Science Foundation of China(21532001)

汉斯酯(Hantzsch Esters)在1881年被合成以来一直被用作还原剂参与加氢还原反应, 近年来科学家发现4-取代的汉斯酯可以发生碳碳键断裂而发生烷基迁移反应. 随后大量以4-取代的汉斯酯类化合物作为烷基化试剂的反应被报道出来, 科学家发现这类烷基化反应的历程主要是烷基自由基的迁移历程. 随着近年自由基化学的快速发展, 为这类新型烷基化试剂的应用发展提供了有力基础. 本文按照该烷基化试剂参与的反应类型分类, 进行简单介绍.

关键词: 4-取代汉斯酯, 1,4-二氢吡啶, 自由基, 烷基化

Hantzsch Esters were first synthesized by Arthur Rudolf Hantzsch in 1881, and widely used in pharmaceutical chemistry. The application of Hantsch Esters in organic synthesis in the early time was mainly focused on the dehydrogenation of 1,4-dihydrogen pyridines (DHPs) in the synthesis of functional pyridines. In 1955, Mauzerall and Westheimer found that Malachite Green could be reduced by Hantzsch Esters to generate the hydrogenated product. Then these DHPs were extensively used as a reductant for decades due to their electron and hydrogen donating properties. In recent years, scientist found that C—C bond cleavage at 4-position of 4-substituted Hantzsch Esters would lead alkyl transfer, and the alkylation process was a radical process. With the rapid development of free radical chemistry, various alkylation reactions using 4-substituted Hantzsch Esters as alkylation reagent have been developed, such as addition reactions of imines and alkenes; cross-coupling reactions with aryl halides; substitution reactions with functional aromatics; Tsuji-Trost reaction; radical insertion with sulfur dioxide; and asymmetric alkylation etc. The advantages in alkylation transfer by using 4-substituted Hantzsch Esters as alkyl source in the past five years were witnessed dramatically: (1) Highly toxic alkyl metal reagents could be avoided in the alkylation reactions; (2) Compared with the moisture sensitivity of alkyl metal reagents Hantzsch Esters are easily handling; (3) 1,4-Dihydrogen pyridines (DHPs) are biologically-inspired model molecular of reduced nicotinamide adenine dinucleotide (NADH), which would expand the application in biosynthesis. A brief summary in this field is presented in this review, and the advances are classified according to different reaction types. Although these creativity works were developed, there are still some challenges: (1) Could aromatic groups at 4-position of 4-substituted Hantzsch Esters serve as arylation reagents? (2) How to recover the rest pyridine part of Hantzsch Esters after alkylation; (3) New type reactions need to be developed for the asymmetric synthesis.

Key words: 4-substituted Hantzsch Ester, 1,4-dihydropyridine, free radical, alkylation