Understanding and Controlling Fluorinated Diacyl Peroxides and Fluoroalkyl Radicals in Alkene Fluoroalkylations

Abstract

The demand for practical methods for the synthesis of novel fluoroalkyl molecules is increasing owing to their diverse applications. Our group has achieved efficient difunctionalizing fluoroalkylations of alkenes using fluorinated carboxylic anhydrides as user‐friendly fluoroalkyl sources. Fluorinated diacyl peroxide, prepared in situ from carboxylic anhydrides, enables the development of novel reactions when used as a radical fluoroalkylating reagent. In this account, we aim to provide an in‐depth understanding of the structure, bonding, and reactivity of fluorinated diacyl peroxides and radicals as well as their control in fluoroalkylation reactions. In the first part of this account, the physical properties and reactivity of diacyl peroxides and fluoroalkyl radicals are described. In the subsequent part, we categorize the reactions into copper‐catalyzed and metal‐free methods utilizing the oxidizing properties of fluorinated diacyl peroxides. We also outline examples and mechanisms.

Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch

“…2a–i ) 55 and difluoromethylation of the oxazino pyridine 3 could not be achieved under the tested conditions. Indeed, the difluoromethyl radical is considered as a nucleophilic radical 22 , 56 , 57 . Therefore, the difluoromethyl reagent has to be equipped with a removable electron-withdrawing auxiliary group, which will enhance the electrophilicity of the corresponding difluorinated C-radical (•CF 2 H to [•CF 2 (EWG)]) 55 , 58 .…”

“…Homolyis of 2 occurs at 0 °C to generate the difluoromethyl radical along with CO 2 (Fig. 2a–ii ) 56 , 58 . To our knowledge, this readily available radical difluoromethylation reagent studied by Sodeoka for alkene difluoromethylation 58 has not yet been used in Minisci-type alkylations.…”