Trifluoromethyl Sulfoxides: Reagents for Metal‐Free C−H Trifluoromethylthiolation

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.

Alkylation Reactions with Alkylsulfonium Salts

“…6 The dealkylative functionalization of alkylsulfonium salts has also been explored to conveniently afford elegant sulfides. 7 Inspired by the biological relevance of triorganosulfonium salts as alkylating reagents, 5 the alkylation using alkylsulfonium salts has flourished over the past years and has become one of the major focuses for synthetic chemists.…”

Electrophilic (Ethoxycarbonyl)difluoromethylthiolation Using Difluoroalkyl Sulfonium Salts

“…In order to exploit an alternative method to incorporate "-SCF2CO2R" into organic molecules, we turned our attention to a sulfonium salt mediated electrophilic substitution process. [6][7][8] As shown in Scheme 1b, the electrophilic activation of alkyl/aryl sulfoxides by acid anhydride generates a highly electrophilic sulfonium species which can be trapped by nucleophilic electron-rich arenes and heteroarenes to form aryl/heteroaryl sulfonium salts. The subsequent dealkylation of the sulfonium salts affords aryl/heteroaryl sulfide products.…”

“…7 Most recently, while our study was underway, Procter reported the first application of the alkylthiolating protocol for the fluorine chemistry in which the trifluoromethyl sulfoxide was used as a trifluoromethylthiolating source for installing the "-SCF3" moiety into arenes. 8,9 Inspired by the previous works, we describe here the transfer of "-SCF2CO2R" into a diverse of nucleophiles with the well-established sulfonium salt mediated "alkylthiolating" protocol (Scheme 1c).…”

Trifluoromethyl Sulfoxides: Reagents for Metal‐Free C−H Trifluoromethylthiolation

“…We developed a new route for the synthesis of 1 a, which was obtained as a freeflowing, bench-stable, crystalline solid and has been characterized by X-ray crystallographic analysis (Scheme 1 B). [15] With a novel sulfoxide in hand, we attempted the trifluoromethylthiolation of indole (2 a; Scheme 2). The sulfoxide was activated using triflic anhydride [9] to give the desired trifluoromethylthiolated indole 3 a in 70 % yield.…”

“…Firstly, the sulfonium salt 7 m was isolated from the reaction between p-xylene (4 m) and 1 b. [15,19] We then modelled the dealkylation step using DFT calculations. These results showed that the transition state for attack of the amine (Et 2 NH) at the -CH 2 CO 2 Et group lies 40.8 kJ mol À1 lower in energy than the transition state for attack at the -CF 3 group.…”