Aqueous Benzylic C–H Trifluoromethylation for Late-Stage Functionalization

Abstract

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C−H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.

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

“…Nevertheless, this protocol was applicable only to primary C(sp 3 )-H bonds with electron-rich substitution on the aromatic ring. A variant of the method with the use of (bpy)Cu(CF 3 ) 3 , (NH 4 ) 2 S 2 O 8 , and i Pr 3 SiH was published by the Cook group 32 during the preparation of this work (Scheme 1A). However, it requires the use of UV (365 nm) light and the use of excess (2 equiv) alkylarenes as substrates, and the yields are based on the copper complex.…”

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.…”

“…Examination of different photocatalysts showed that the use of [Ir(dF(CF 3 )ppy) 2 (5,5'-dCF 3 bpy)](PF 6 )( PC-V, E 0 1/ 2 III*/II =+1.69 Vv s. SCE in MeCN) [23] enabled the best balance between reaction yield and selectivity,a lbeit with moderate conversion (entries 1-6). Further fine tuning the reaction conditions eventually led to the formation of 3a in 79 %y ield (entries [9][10][11]. Notably,c ontrol experiments indicated the vital importance of the photocatalyst and light irradiation in this protocol (entries 7a nd 8).…”

1,2‐(Bis)trifluoromethylation of Alkynes: A One‐Step Reaction to Install an Underutilized Functional Group

“…[12] Liu et al and our group disclosed benzylic C(sp 3 )ÀHt rifluoromethylation that can be employed for late-stage functionalization (Scheme 1c). [13] Here,wedescribe the simultaneous introduction of two trifluoromethyl groups across alkynes using bpyCu(CF 3 ) 3 , persulfate and blue light to access E-HFBs (Scheme 1d). Under irradiation, bpyCu(CF 3 ) 3 liberates one trifluoromethyl radical.…”