Photocatalytic fluoroalkylations of (hetero)arenes enabled by the acid-triggered reactivity umpolung of acetoxime esters

Abstract

The importance of trifluoromethyl (CF 3 ) group-containing compounds in pharmaceuticals, agrochemicals, and materials has spurred tremendous efforts devoted to the development of methods for incorporation of the trifluoromethyl group into molecular frameworks and discoveries of trifluoromethylating reagents. In this paper, we report a general photocatalytic method for regioselective C–H fluoroalkylation of (hetero)arenes and olefines that uses readily available fluoroalkyl carboxylic anhydrides as fluoroalkylating reagents in the presence of simple acetoxime as an activator. The success achieved in the development of such a photocatalytic C–H fluoroalkylation method is attributed to discovery of the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward single-electron reduction-induced cleavage of N–O σ bond. Such a new reactivity mode of oxime esters will stimulate efforts to expand the synthetic applications of readily available oxime esters. • The unprecedented acid-triggered reactivity umpolung of acetoxime ester • Photocatalytic method for C–H fluoroalkylation of (hetero)arenes and olefines • Inexpensive and easily available fluoroalkyl carboxylic anhydrides • Simple acetoxime as an efficient activator to fluoroalkyl carboxylic anhydrides Over the past decades, considerable efforts have been devoted toward exploring readily available trifluoroacetic acid or its anhydride as a CF 3 source for trifluoromethylation reactions. Herein, a general photocatalytic method was developed for fluoroalkylation of arenes and aromatic heterocycles with fluoroalkyl carboxylic anhydrides using simple acetoxime as the activator. The established conditions were also applicable to oxytrifluoromethylation and intramolecular carbotrifluoromethylation of alkenes, and the modification of biologically active molecules and gram-scale synthesis further highlighted its potential utility. Compared with the fact that single-electron transfer (SET) reduction of oxime trifluoroacetate esters generates preferentially iminyl radical and stable trifluoroacetate anions, our work discovered the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward delivering a CF 3 radical. An ongoing challenge in trifluoromethylation reaction is the use of less expensive and more practical trifluoromethyl sources. We describe herein a general photocatalytic method for regioselective C–H fluoroalkylation of (hetero)arenes and olefines that uses readily available fluoroalkyl carboxylic anhydrides as fluoroalkylating reagents in the presence of simple acetoxime as an activator. The success achieved in the development of such a method is attributed to the discovery of the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward single-electron reduction-induced cleavage of N–O σ bond.