Recent advances in transition metal-catalyzed Csp(2)-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

Abstract

In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon-fluorine bond formation has become a landmark achievement in fluorine chemistry. This rapidly growing research field has been the subject of some excellent reviews. Our approach focuses exclusively on transition metal-catalyzed reactions that allow the introduction of -CFH2, -CF2H, -C n F2 n +1 and -SCF3 groups onto sp² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups.

Keywords: catalysis; cross-coupling; difluoromethylation; fluorine; monofluoromethylation; organo-fluorine; transition metal; trifluoromethylation; trifluoromethylthiolation.

Scheme 1

Pd-catalyzed monofluoromethylation of pinacol phenylboronate [44].

Scheme 2

Cu-catalyzed monofluoromethylation with 2-PySO₂CHFCOR followed by desulfonylation [49].

Scheme 3

Cu-catalyzed difluoromethylation with α-silyldifluoroacetates [57].

Figure 1

Mechanism of the Cu-catalyzed C–CHF₂ bond formation of α,β-unsaturated carboxylic acids through decarboxylative fluoroalkylation [61].

Scheme 4

Fe-catalyzed decarboxylative difluoromethylation of cinnamic acids [62].

Scheme 5

Preliminary experiments for investigation of the mechanism of the C–H trifluoromethylation of N-arylbenzamides [68].

Figure 2

Plausible catalytic cycle proposed by Z.-J. Shi et al. for the trifluoromethylation of acetanilides [69].

Figure 3

Plausible catalytic cycle proposed by M. S. Sanford et al. for the perfluoroalkylation of simple arenes using perfluoroalkyl iodides [70].

Figure 4

Postulated reaction pathway for the Ag/Cu-catalyzed trifluoromethylation of aryl iodides by Z. Q. Weng et al. [73].

Figure 5

Postulated reaction mechanism for Cu-catalyzed trifluoromethylation reaction using MTFA as trifluoromethylating agent [81].

Scheme 6

Formal Heck-type trifluoromethylation of vinyl(het)arenes by M. Sodeoka et al. [83].

Figure 6

Proposed catalytic cycle for the copper-catalyzed trifluoromethylation of (het)arenes in presence of a pivalamido group (C. Chen, C. Xi et al.) [84].

Figure 7

Proposed catalytic cycle for the copper-catalyzed trifluoromethylation of N,N-disubstituted (hetero)arylhydrazones by D. Bouyssi, O. Baudoin et al. [85].

Figure 8

Proposed catalytic cycle by Y. Zhang and J. Wang et al. for the copper-catalyzed trifluoromethylation of quinones [87].

Figure 9

Mechanistic rationale for the trifluoromethylation of arenes in presence of Langlois’s reagent and a copper catalyst (B. R. Langlois et al.) [88].

Scheme 7

Trifluoromethylation of 4-acetylpyridine with Langlois’s reagent by P. S. Baran et al. (* Stirring had a strong influence on the reaction efficiency; see the original article for details) [89].

Scheme 8

Catalytic copper-facilitated perfluorobutylation of benzene with C₄F₉I and benzoyl peroxide [90].

Figure 10

F.-L. Qing et al.’s proposed mechanism for the copper-catalyzed trifluoromethylation of (hetero)arenes with the Ruppert–Prakash reagent [91].

Figure 11

Mechanism of the Cu-catalyzed/Ru-photocatalyzed trifluoromethylation and perfluoroalkylation of arylboronic acids [96].

Figure 12

Proposed mechanism for the Cu-catalyzed trifluoromethylation of aryl- and vinyl boronic acids with NaSO₂CF₃ [97].

Figure 13

Possible mechanism for the Cu-catalyzed decarboxylative trifluoromethylation of cinnamic acids [62].

Scheme 9

Ruthenium-catalyzed perfluoroalkylation of alkenes and (hetero)arenes with perfluoroalkylsulfonyl chlorides (N. Kamigata et al.) (R_f = CF₃, C₆F₁₃) [101].

Figure 14

N. Kamigata et al.’s proposed mechanism for the Ru-catalyzed perfluoroalkylation of alkenes and (hetero)arenes with perfluoroalkylsulfonyl chlorides [100].

Figure 15

Proposed mechanism for the Ru-catalyzed photoredox trifluoromethylation of (hetero)arenes with trifluoromethanesulfonyl chloride [105].

Figure 16

Late-stage trifluoromethylation of pharmaceutically relevant molecules with trifluoromethanesulfonyl chloride by photoredox Ru-catalysis (D. W. C. MacMillan et al.) (The position of the CF₃ group in the other isomers produced is marked with # or an arrow) [105].

Figure 17

Proposed mechanism for the trifluoromethylation of alkenes with trifluoromethyl iodide under Ru-based photoredox catalysis (E. J. Cho et al.) [106].

Scheme 10

Formal perfluoroakylation of terminal alkenes by Ru-catalyzed cross-metathesis with perfluoroalkylethylenes (S. Blechert et al.) [108].

Figure 18

One-pot Ir-catalyzed borylation/Cu-catalyzed trifluoromethylation of complex small molecules by Q. Shen et al. [37].

Figure 19

Mechanistic proposal for the Ni-catalyzed perfluoroalkylation of arenes and heteroarenes with perfluoroalkyl chlorides by Q.-Y. Chen and coworkers [111].

Scheme 11

Electrochemical Ni-catalyzed perfluoroalkylation of 2-phenylpyridine (Y. H. Budnikova et al.) [71].

Scheme 12

Fe(II)-catalyzed trifluoromethylation of arenes and heteroarenes with trifluoromethyl iodide (T. Yamakawa et al.) [–115].

Figure 20

Mechanistic proposal by T. Yamakawa et al. for the Fe(II)-catalyzed trifluoromethylation of arenes and heteroarenes with trifluoromethyl iodide [114].

Scheme 13

Ytterbium-catalyzed perfluoroalkylation of dihydropyran with perfluoroalkyl iodide (Y. Ding et al.) [119].

Figure 21

Mechanistic proposal by A. Togni et al. for the rhenium-catalyzed trifluoromethylation of arenes and heteroarenes with hypervalent iodine reagents [113].

Figure 22

Mechanism of the Cu-catalyzed oxidative trifluoromethylthiolation of arylboronic acids with TMSCF₃ and elemental sulfur [135].

Scheme 14

Removal of the 8-aminoquinoline auxiliary [136].

Figure 23

Mechanism of the Cu-catalyzed trifluoromethylthiolation of C–H bonds with a trifluoromethanesulfonyl hypervalent iodonium ylide [138].