Synthesis of trifluoromethyl aryl derivatives via difluorocarbene precursors and nitro-substituted aryl chlorides

Decarboxylative trifluoromethylation of aryl halides using well-defined copper–trifluoroacetate and –chlorodifluoroacetate precursors

“…The use of the methyl acetates 5 and 6 as trifluoromethyl sources is well-documented [23][24][25][26][27][28][29][30], however all of the known decarboxylation procedures generate extraneous methyl halide which complicates the development of any catalytic cross-coupling procedure with these reagents. We propose that commercial chlorodifluoroacetic acid (7) should be a better trifluoromethyl source than 5 or 6 for both cost reasons and for the fact that the by-products of a catalytic reaction involving 7 could be readily handled.…”

“…Price per mole of various trifluoromethyl sources. The total cost of using 5-7 would also be affected by the need for a fluoride source to either generate a trifluoromethyl group [24,25,28] or facilitate decarboxylation [30,38]. is well-known that heating copper salts with sodium trifluoroacetate leads to a decarboxylation reaction and the formation of a trifluoromethyl source that can be trapped with various organic substrates [31][32][33][34][35][36][37], including aryl halides [34][35][36].…”

Metal-Catalyzed Decarboxylative Fluoroalkylation Reactions

“…5–7 To develop such transformations, we have reinvestigated Chen's Cu-catalyzed decarboxylative trifluoromethylation reactions between sp 3 -electrophiles and halodifluoroacetates to provide access to target compounds in economical and green fashion. 7,8 Halodifluoroacetates are appealing precursors to trifluoromethanes, because they are inexpensive and readily synthesized from industrial fluorinated building blocks, such as tetrafluoroethylene and vinylidene fluoride. 9 In the presence of Cu and KF, halodifluoroacetates decarboxylate to generate [Cu–CF 3 ], which reacts with electrophiles to create C–CF 3 bonds.…”

“…Previously, Chen demonstrated that alcohols can be converted to halodifluoroacetate esters, and upon treatment with stoichiometric Cu and KF, these electrophilic species undergo decarboxylative trifluoromethylation. 7 However, reactions only tolerated the narrow subset of –Br, –Cl, and –NO 2 functional groups, and required use of stoichiometric Cu. Considering these features, we sought to develop mild and functional group tolerant catalytic processes for trifluoromethylation of simple alcohol-derived substrates.…”

“…To develop these Cu-catalyzed methods, we studied Chen's proposed mechanism for Cu-mediated trifluoromethylation (Scheme 1C), 7e and noticed three striking features: 1) CuI was used as a reactant, and emerged as a product. Therefore, catalytic use of Cu might be possible.…”