Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 2-17-85, Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan.
J Org Chem. 2013 Jun 21;78(12):5843-50. doi: 10.1021/jo400408t. Epub 2013 Jun 4.
The double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound, and its synthetic application to a series of δ-hydroxy-β-ketoesters has been developed. The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ generated zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and esters.
双 Reformatsky 反应，即两个分子的锌烷酸酯与羰基化合物的串联加成反应，及其在一系列 δ-羟基-β-酮酯合成中的应用已经得到了发展。加速双 Reformatsky 反应的关键被认为是原位生成的锌烷氧化物与底物或双齿胺的吡啶基之间的配合物诱导的近邻效应。该反应体系的一个显著特点是由于有机锌试剂的中等亲核性和温和的反应条件，对官能团具有很高的容忍度。此外，双 Reformatsky 产物的锌配合物的光谱和晶体学分析支持了酮、醛、腈、羧酸酐和酯的反应位点选择性的提出机制。
