Chemoselective Catalytic α-Functionalization of Carboxylic Acid Equivalent and Carboxylic Acid through Radical Process

Abstract

Enolization of carboxylic acid derivatives is the central science of fundamental carbonyl chemistry. The catalytic methods to activate carboxylic acid remained unexplored due to the intrinsic low acidity of α-protons, although enormous examples of catalytic activation (enolization) method for aldehydes, ketones, and ester derivatives have been reported. The innate Brønsted acidic carboxylic acid functionality also disrupts the deprotonation of α-protons. Therefore, more than two equivalents of a strong base such as lithium diisopropylamide are required for efficient enolization, which makes chemoselective enolization of carboxylic acid over more acidic carbonyls a formidable task. Furthermore, recent enolization methods were only applied to redox-neutral coupling using 2e^- electrophiles and catalytic α-functionalization of carboxylic acids through a 1e^- radical process, which could complement the chemoselectivity, and functional group tolerance restricted in the classical 2e^- ion reaction, has never been achieved. Herein, we developed chemoselective catalytic activation of carboxylic acid equivalent, acylpyra-zole, and carboxylic acid for a 1e^- radical process without external addition of stoichiometric amounts of Brønsted base. The present chemoselective catalysis could be applied to late-stage α-amination and oxidation, allowing for concise access to highly versatile unnatural α-amino acid and hydroxy acid derivatives. Moreover, chemoselective α-functionalization of less reactive carboxylic acids was achieved over innately more reactive carbonyl functionalities.