Selective C–F Functionalization of Unactivated Trifluoromethylarenes

Abstract

Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to the range of structural and physicochemical properties that fluorine imparts. Currently, the most abundant methods for the synthesis of the aryl-CF 2 functionality have relied on the deoxyfluorination of ketones and aldehydes using expensive and poorly atom economical reagents. Here, we report a general method for the synthesis of aryl-CF 2 R and aryl-CF 2 H compounds through activation of the corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event that provides access to arene radical anions that lie outside of the catalyst reduction potential. Fragmentation of these reactive intermediates delivers difluorobenzylic radicals that can be intercepted by abundant alkene feedstocks or a hydrogen atom to provide a diverse array of difluoalkylaromatics.

C-F bond activation under transition-metal-free conditions

“…Recently, Jui's group [56] developed an elegant photoinduced selective HDF of unactivated trifluoro methylarenes (Scheme 15). The reaction conditions involved using cesium formate (3 equiv.)…”

Regioselective Markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes

“…Qing et al used a bromodifluoromethylphosphonium salt to realize a visible-light-induced hydrodifluoromethylation of terminal alkenes 34 . Jui described the hydrodifluoroalkylation of alkenes using difluorobenzylic radicals produced in situ via the C–F cleavage of ArCF 3 36 , 37 . Most recently, Gouverneur et al accomplished an economic protocol using inexpensive difluoroacetic acid as the difluoromethyl reagent, under the action of 3 equiv.…”

“…Such a mechanism provides the regioselectivity complementary to known anti-Markovnikov radical reactions and, beneficially, substantially expands the scope of alkenes. Current hydrodifluoroalkylation reactions are largely based on monosubstituted aliphatic alkenes, with very limited examples of aryl alkenes 31 , 33 , 34 , disubstituted alkenes 30 – 34 , 36 – 38 , and trisubstituted alkenes 32 , 36 , 37 being incorporated. Furthermore, to our knowledge, tetrasubstituted alkenes have never been used.…”

Stepwise C(sp3)—F Bond Functionalizations of Trifluoroacetic Acid Derivatives

“…现有三氟甲基基团的 C-F 键转化主要 通过 C-F 键的异裂形成关键的二氟取代碳正离子中间 体进行. 近来 König [4] , Jui [5] , Bandar [6] 和 Gouverneur [7] 等 课题组相继发现通过单电子还原三氟甲基取代芳烃, 可 以完成单个 C-F 键的切断和芳基二氟甲基自由基的生 成. 然而, 选择性地活化三氟甲基化合物中的 C(sp 3 )-F 键目前还存在着诸多问题: [8] .…”