Remote Fluoro-fluoroalkylation Of Internal Alkynes Via Vinyl Radical-induced C-H Fluorination

The introduction of fluorine atom into target molecules can dramatically affect the properties including lipophilicity,metabolic stability,and bioavailability,Therefore,the incoporation of fluorine or fluoroalkyl groups into target molecules is one of the most important areas in organic chemistry.In this respect,the late-stage fluorination of ubiquitous C-H bonds is a powerful strategy for the synthesis of fluorinated analogs of lead compounds.Specifically,the radical C?sp³?-H fluorination provides a very attractive access to C?sp³?-F bonds.Despite the success of heteroatom-induced remote C-H fluorination,the radical C-H fluorination,proceeding via carbon-centered radicals has not been achieved so far.Herein,induced by vinyl radicals,formed from the radical addition to C-C triple bonds,a remote C-H fluorination has been developed,thus leading to the realization of fluoro-fluoroalkylation of internal alkynes for the first time.The reaction is featured with excellent regio,stereo-,and site-selectivity,and concurrent formation of C?sp³?-F,C?sp²?-R_f and thermodynamically less stable?Z?-olefins,thus offering an efficient and general method for the synthesis of fluorinated compounds.It represents a significant advance on the remote difunctionalization of alkynes.The whole work consists of two parts:First,an unprecedented silver-mediated remote fluoro-fluoroalkylation,including fluoro-monofluoroalkylation,fluoro-difluoroalkylation,and fluoro-trifluoromethylation,of internal alkynes is developed.With TMSR_f as the fluoroalkylation reagent,Selectfluor as the fluorine source,AgNO₃ as the promoter,PhI?OCOCF₃?₂ as the oxidant,various arylalkylalkynes can be converted to?-fluoro fluoroalkylated?Z?-alkenes in moderate to high yields with prefect control of regio-stereo-,and site-selectivity.The reaction is highlighted by broad substrate scope,and a variety of C-H bonds such as benzylic,primary,secondary,and tertiary ones can be smoothly fluorinated.Preliminary mechanistic studies suggest a mechanism consisting of alkyne fluoroalkylation,hydrogen atom transfer?HAT?,and fluorination of carbon radical.This work constitutes the first examples of vinyl radical-induced remote C-H fluorination.Secondly,a copper-catalyzed remote fluoro-trifluoromethylation of heteroalkynes is described.With the cheap CsF as the fluorination reagent,Umemoto's reagent as the trifluoromethyl source,and Cu?OTf?₂ as catalyst,a remote fluoro-trifluoromethylation of heteroalkynes has been developed.The reaction is featured with mild reaction conditions,high functional group tolerance and excellent regio-,stereo-,and site-selectivity.Preliminary mechanistic studies indicate a mechanism involving heteroatom-directed?-regioselective fluorination,HAT,and Cu-assisted fluorine atom transfer.The resultant products can be transformed to highly functionalized?Z?-alkenes via the transition-metal-catalyzed cross coupling of carbon-hetereoatom bonds.In addition to control the site-selectivity of remote C-H functionalization,HAT can also control the stereoselectivity of hydrofluoroalkylation of C-C triple bonds,hence providing a new strategy for the development of trans-stereoselective of hydrofunctionalization of alkynes.