Li Zhen, Yu Jin-Quan
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
J Am Chem Soc. 2023 Dec 6;145(48):25948-25953. doi: 10.1021/jacs.3c09340. Epub 2023 Nov 20.
Selective oxidation of the γ-C-H bonds from abundant amine feedstocks via palladium catalysis is a valuable transformation in synthesis and medicinal chemistry. Despite advances on this topic in the past decade, there remain two significant limitations: C-H activation of aliphatic amines requires an exogenous directing group except for sterically hindered α-tertiary amines, and a practical catalytic system for C(sp)-H hydroxylation using a green oxidant, such as oxygen or aqueous hydrogen peroxide, has not been developed to date. Herein, we report a ligand-enabled selective γ-C(sp)-H hydroxylation using sustainable aqueous hydrogen peroxide (7.5-10%, w/w). Enabled by a CarboxPyridone ligand, a series of primary amines (1°), piperidines, and morpholines (2°) were hydroxylated at the γ-position with excellent monoselectivity. This method provides an avenue for the synthesis of a wide range of amines, including γ-amino alcohols, β-amino acids, and azetidines. The retention of chirality in the reaction allows rapid access to chiral amines starting from the abundant chiral amine pool.
通过钯催化从丰富的胺类原料中选择性氧化γ-C-H键是合成化学和药物化学中一种有价值的转化反应。尽管在过去十年中关于这一主题取得了进展，但仍存在两个重大限制：除了空间位阻较大的α-叔胺外，脂肪族胺的C-H活化需要一个外源导向基团，并且迄今为止尚未开发出一种使用绿色氧化剂（如氧气或过氧化氢水溶液）进行C(sp)-H羟基化的实用催化体系。在此，我们报道了一种使用可持续的过氧化氢水溶液（7.5-10%，w/w）的配体导向选择性γ-C(sp)-H羟基化反应。在羧基吡啶酮配体的作用下，一系列伯胺（1°）、哌啶和吗啉（2°）在γ位发生羟基化反应，具有优异的单选择性。该方法为合成多种胺类化合物提供了一条途径，包括γ-氨基醇、β-氨基酸和氮杂环丁烷。反应中手性的保留使得能够从丰富的手性胺库快速获得手性胺。
