Diversified Fluoroalkylation of Alkenes Using Quaternary Fluoroalkyl Alcohols as the Fluoroalkylating Reagents

Abstract

Given the widespread presence of fluoroalkyl functionalities in bioactive molecules, the development of fluoroalkylation reactions with bench‐stable and easy‐to‐use fluoroalkylating reagents is highly desirable. In addition, realization of mono‐, di‐, tri‐, or polyfluoroalkyation usually requires distinct types of fluoroalkylating reagents under different or even harsh reaction conditions, and a universal method to accomplish different hydrofluoroalkylation of alkenes is lacking. Herein, the use of quaternary fluoroalkyl alcohols is reported as the universal fluoroalkylating reagents to readily facilitate mono‐, di‐, tri‐, or polyfluoroalkylation of a wide range of alkene substrates in high yields. Moreover, a cascade reaction of hydrofluoroalkylation followed by intramolecular fluoroalkylation facilitates the construction of a variety of high‐value complex heterocycles bearing diverse fluoroalkyl functionalities from alkenes. Mechanistic studies suggest that a proton‐coupled electron transfer (PCET) process may be involved through a radical‐generating pathway. The utility of this method is showcased by the late‐stage fluoroalkylation of various high‐value complex molecules derived from either natural products or drug‐like compounds. Of note is that a continuous‐flow system is amenable to this homogeneous photoredox conditions, thereby opening up a possibility of using this protocol to realize large‐scale manufacturing of fluoroalkyl products with industrial interests.