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. 2020 Sep 7;59(37):15918-15922.
doi: 10.1002/anie.202005531. Epub 2020 Jul 15.

Trifluoromethyl Sulfoxides: Reagents for Metal-Free C-H Trifluoromethylthiolation

Dong Wang  1 , C Grace Carlton  1 , Masanori Tayu  1   2 , Joseph J W McDouall  1 , Gregory J P Perry  1 , David J Procter  1
Affiliations

Trifluoromethyl Sulfoxides: Reagents for Metal-Free C-H Trifluoromethylthiolation

Dong Wang et al. Angew Chem Int Ed Engl. .

Abstract

Trifluoromethyl sulfoxides are a new class of trifluoromethylthiolating reagent. The sulfoxides engage in metal-free C-H trifluoromethylthiolation with a range of (hetero)arenes. The method is also applicable to the functionalization of important compound classes, such as ligand derivatives and polyaromatics, and in the late-stage trifluoromethylthiolation of medicines and agrochemicals. The isolation and characterization of a sulfonium salt intermediate supports an interrupted Pummerer reaction mechanism.

Keywords: Pummerer reaction; arenes; reaction mechanisms; sulfoxides; trifluoromethylthiolation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
A) Current methods for transition metal‐free C−H trifluoromethylthiolation. B) This work: C−H trifluoromethylthiolation by an interrupted Pummerer reaction.
Scheme 2
Scheme 2
Scope[a] of the metal‐free C−H trifluoromethylthiolation of heteroarenes. [a] Procedure A, conditions: i) 2 (0.3 mmol, 1.5 equiv), 1 a (0.2 mmol, 1.0 equiv), Tf2O (0.24 mmol, 1.2 equiv), MeCN (1.0 mL, 0.2 m) at 0 °C for 1 h. ii) Et2NH (0.5 mmol, 2.5 equiv). [b] Reaction run on a gram scale. [c] Numbers within parenthesis indicate ratio of C2 versus C3 trifluoromethylthiolation.
Scheme 3
Scheme 3
Scope[a] of the metal‐free C−H trifluoromethylthiolation of arenes. [a] Procedure B, conditions: i) 4 (0.2 mmol, 1.0 equiv), 1 b (0.24 mmol, 1.2 equiv), Tf2O (0.3 mmol, 1.5 equiv), MeNO2 (1.0 mL, 0.2 m) at −25 °C for 10 min, then at RT for 3 h. ii) Et2NH (0.7 mmol, 3.5 equiv) at RT for 15 h. [b] Numbers within parenthesis indicate ratio of C4 versus C2 trifluoromethylthiolation. The major regioisomer is shown. [c] Procedure A (see Scheme 2). [d] See the Supporting Information for modified reaction stoichiometry. [e] Numbers within parenthesis indicate ratio of C4 versus C2 trifluoromethylthiolation. The major regioisomer is shown. [f] Numbers within parenthesis indicate ratio of C1 versus C2 trifluoromethylthiolation. The major regioisomer is shown.
Scheme 4
Scheme 4
A) Proposed mechanism for the trifluoromethylthiolation of (hetero)arenes using sulfoxides. B) Computational investigation of the chemoselective dealkylation. [a] The process was modelled using the cation of 7 m. See the Supporting Information for further details.
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