Aryl Sulfonium Salts for Site‐Selective Late‐Stage Trifluoromethylation

Abstract

Incorporation of the CF3 group into arenes has found increasing importance in drug discovery. Herein, we report the first photoredox‐catalyzed cross‐coupling of aryl thianthrenium salts with a copper‐based trifluoromethyl reagent, which enables a site‐selective late‐stage trifluoromethylation of arenes. The reaction proceeds with broad functional group tolerance, even for complex small molecules on gram scale. The method was further extended to produce pentafluoroethylated derivatives.

Radical C−C Bond Formation using Sulfonium Salts and Light

“…An intermediate aryl radical is likely formed from the sulfonium salts 21 / 22 in these processes. Similarly, TFT and thianthrene (TT) salts 25 were used for site‐selective trifluoromethylation . Ritter and co‐workers utilised a trifluoromethyl copper species, formed in situ , as the trifluoromethylating agent under the photoredox‐catalysed conditions (Scheme ).…”

Shining Light on C−S Bonds: Recent Advances in C−C Bond Formation Reactions via C−S Bond Cleavage under Photoredox Catalysis

“…On the basis of their pioneering work, [23] Ritter and coworkers subsequently reported a photoredox‐catalyzed cross‐coupling of arylthianthrenium salts 88 with a copper‐based trifluoromethylation reagent for the para ‐selective late‐stage trifluoromethylation of C−H bonds in arenes 87 (Scheme 18). [24] This two‐step procedure entailed exquisitely selective thianthrenation under mild conditions followed by chemoselective and visible light induced trifluoromethylation of the obtained arylthianthrenium salts, which might be more general for the introduction of fluoroalkyl into complex molecules. Mechanistically, unlike former works on trifluoromethylation, [9–14] CF 3 radical might not be involved based on the radical trapping experiment and the Stem‐Volmer analysis.…”

“…On the basis of their pioneering work, [23] Ritter and coworkers subsequently reported a photoredox-catalyzed crosscoupling of arylthianthrenium salts 88 with a copper-based trifluoromethylation reagent for the para-selective late-stage trifluoromethylation of CÀ H bonds in arenes 87 (Scheme 18). [24] This two-step procedure entailed exquisitely selective thianthrenation under mild conditions followed by chemoselective and visible light induced trifluoromethylation of the obtained arylthianthrenium salts, which might be more general for the introduction of fluoroalkyl into complex molecules. Mechanistically, unlike former works on trifluoromethylation, [9][10][11][12][13][14] Following the metallic photosensitizer catalyzed site selective CÀ H bond functionalization of arenes via CÀ S bond cleavage by Ritter group, [23][24] Procter and co-workers [25] reported an organic photoredox catalyzed chemo-and regioselective formal CÀ H/CÀ H coupling reaction of two non-prefunctionalized arenes partners through the CÀ S bond cleavage of dibenzothiophenium salts, which were obtained via interrupted Pummerer activation pathway using benzothiophene S-oxide mediator (Scheme 20).…”

Photoredox Catalytic Trifluoromethylation and Perfluoroalkylation of (Hetero)Arenes Using Trifluoroacetic and Related Carboxylic Acids

“…8 Very recently, Ritter reported a site-selective latestage trifluoromethylation of arenes via the aryl sulfonium salt intermediates. 9 Moreover, there is a renaissance in aromatic C-H trifluoromethylation by the CF3 radical addition mechanism. 10 A variety of reagents have been extensively used as CF3 radical precursors, including CF3I, 11 CF3Br, 12 CF3SO2Cl, 13 (CF3SO2)2O, 14 CF3SO2CH(Me)COPh, 15 Togni reagent, 16 Umemoto reagent, 17 TMSCF3, 18 Langlois reagent NaSO2CF3, 19 and Zn(SO2CF3)2.…”