Wang Jiang, Hoerrner Megan E, Watson Mary P, Weix Daniel J
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
Angew Chem Int Ed Engl. 2020 Aug 3;59(32):13484-13489. doi: 10.1002/anie.202002271. Epub 2020 Jun 5.
While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N-alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2-pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.
虽然酮是最多功能的官能团之一,但其合成仍然依赖于反应性高且丰度低的起始原料。相比之下,酰胺形成是药物化学中最常用的键构建方法,因为该化学方法可靠且基于大量多样的底物库。本文介绍了一种合成酮的新方法,该方法采用与酰胺键合成相同的底物:胺和羧酸。一种三联吡啶镍催化剂在还原条件下(锰金属)将N-烷基吡啶鎓盐与原位形成的羧酸氟化物或2-吡啶酯偶联。该反应具有广泛的适用范围,合成了35种带有各种官能团的不同酮,平均产率为60±16%,证明了这一点。这种方法能够偶联包括药物中间体在内的各种底物,以快速形成复杂的酮。