Trifluoromethylation of Alkyl Radicals in Aqueous Solution

Abstract

The copper-mediated trifluoromethylation of alkyl radicals is described. The combination of EtSiH and KSO initiates the radical reactions of alkyl bromides or iodides with BPyCu(CF) (BPy = 2,2'-bipyridine) in aqueous acetone at room temperature to afford the corresponding trifluoromethylation products in good yield. The protocol is applicable to various primary and secondary alkyl halides and exhibits wide functional group compatibility. A mechanism involving trifluoromethyl group transfer from Cu(II)-CF intermediates to alkyl radicals is proposed.

Copper-Catalyzed Late-Stage Benzylic C(sp3)–H Trifluoromethylation

“…[34][35][36][37] The N-centered radical A abstracts a benzylic hydrogen atom to generate the corresponding benzyl radical. The benzyl radical is then intercepted by Cu(II)-CF 3 either by direct CF 3 group transfer 28,29 or by the formation of benzylcopper(III) intermediate followed by reductive elimination, [30][31][32] resulting in the formation of the corresponding trifluoromethylation product and regeneration of the Cu(I) catalyst. However, this catalytic cycle is challenging given that the oxidation of CF 3 anions to CF 3 radicals by Cu(II) is well documented.…”

“…[18][19][20][21][22] The underdevelopment of C(sp 3 )-H trifluoromethylation should be largely attributed to the lack of methods for trifluoromethylation of alkyl radicals. [28][29][30] We recently introduced the trifluoromethylation of alkyl halides by reaction with (bpy)Cu(CF 3 ) 3 (bpy = 2,2 0 -bipyridine), K 2 S 2 O 8 , and Et 3 SiH in aqueous solution and proposed the mechanism of CF 3 transfer to alkyl radicals from Cu(II)-CF 3 intermediates. 28 The method was then extended to AgNO 3 -and K 2 S 2 O 8 -mediated decarboxylative trifluoromethylation of aliphatic carboxylic acids with (bpy)Cu(CF 3 ) 3 and ZnMe 2 .…”

“…[28][29][30] We recently introduced the trifluoromethylation of alkyl halides by reaction with (bpy)Cu(CF 3 ) 3 (bpy = 2,2 0 -bipyridine), K 2 S 2 O 8 , and Et 3 SiH in aqueous solution and proposed the mechanism of CF 3 transfer to alkyl radicals from Cu(II)-CF 3 intermediates. 28 The method was then extended to AgNO 3 -and K 2 S 2 O 8 -mediated decarboxylative trifluoromethylation of aliphatic carboxylic acids with (bpy)Cu(CF 3 ) 3 and ZnMe 2 . 29 Our strategy was immediately applied to benzylic C(sp 3 )-H trifluoromethylation by the Liu group 31 (Scheme 1A).…”

Copper‐Mediated Trifluoromethylation of Benzylic Csp3−H Bonds

“…We postulated that direct Csp 3 −H trifluoromethylation reactions could be feasible if a suitable CF 3 source is identified that can transfer CF 3 groups to alkyl radicals. Recently, elegant work of Li has shown that a Cu III −CF 3 complex can efficiently transfer a CF 3 group to an alkyl radical . Inspired by these results, we report herein a general method for the direct trifluoromethylation of benzylic Csp 3 −H bonds (Scheme ).…”

Photoredox‐Coupled F‐Nucleophilic Addition: Allylation of gem‐Difluoroalkenes

“…[3] Aside from ah andful of CF 3 -radical-based functionalizations of structurally elaborated styrene derivatives, [4] these molecules could be created either by direct trifluoromethylation of aliphatic skeletons [5] or through crosscoupling using a-CF 3 -derived precursors (Scheme 1a). [6,[12][13][14][15][16] With Lisp ioneering work on trifluoromethylation of alkyl radicals using Grushinsreagent, [7] thegroups of MacMillan, [8] Cook, [9] and Liu, [10] developed decarboxylative and benzylic C À Ht rifluoromethylation protocols,a lthough the employment of expensive CF 3 reagents,aswell as restricted substrate scope,are still concerns.…”