Copper-Catalyzed Enantioselective Trifluoromethylthiolation of Secondary Propargyl Sulfonates

Abstract

Although trifluoromethylthiolated compounds have privileged applications in pharmaceuticals and agrochemicals, efficient strategies for the asymmetric construction of C sp 3 -SCF 3 bonds are limited. Specifically, the catalytic asymmetric nucleophilic trifluoromethylthiolation remains challenging. Here, we report a copper-catalyzed enantioselective nucleophilic trifluoromethylthiolation of secondary propargyl sulfonates with trifluoromethylthio silver. The reaction exhibits high efficiency, good enantioselectivity, high functional group tolerance, and broad substrate scope, paving a new way for the asymmetric synthesis of trifluoromethylthiolated compounds.

Copper‐Catalyzed Enantioselective Trifluoromethoxylation of Propargyl Sulfonates

“…The protonated products may originate from moisture. Though dinuclear copper complex was proposed to be the key catalytic species in many propargyl substitution reactions, [11, 5c–d] the absence of a non‐linear relationship [19] between the enantiopurity of L1 and 5 a (Scheme 3b) indicated that mono‐nuclear copper served as active species here. Therefore, a plausible mechanism was proposed: Copper reacts with the propargyl sulfonate to generate copper allenylidene complex; [11] nucleophilic attack of OCF 3 anion and subsequent protonation offered the final product (Scheme 3c).…”

Copper‐Catalyzed Enantioselective C(sp3)−SCF3 Coupling of Carbon‐Centered Benzyl Radicals with (Me4N)SCF3

“…Only until very recently have Zhang and co-workers elegantly achieved an enantioselective nucleophilic trifluoromethylthiolation of excessive secondary propargyl sulfonates with AgSCF 3 via a chiral copper-allenylidene intermediate (Scheme 1C). [12] Given the easy availability of racemic benzyl halides and nucleophilic (Me 4 N)SCF 3 reagent, [3b,f-h,13] we envisioned that the aforementioned enantioconvergent C(sp 3 )À SCF 3 cross-coupling of racemic benzyl electrophiles with nucleophilic (Me 4 N)SCF 3 reagent would be appealing to access enantioenriched trifluoromethylthiolated molecules (Scheme 1B). As such, we expected that our recently developed copper catalysts with chiral multidentate anionic ligands for enantioconvergent radical cross-coupling reac-tions could overcome the difficulties of the above-described approach.…”

“…In contrast, the catalytic asymmetric transformations utilizing easily available nucleophilic SCF 3 reagents have remained rare. Only until very recently have Zhang and co‐workers elegantly achieved an enantioselective nucleophilic trifluoromethylthiolation of excessive secondary propargyl sulfonates with AgSCF 3 via a chiral copper‐allenylidene intermediate (Scheme 1C) [12] . Given the easy availability of racemic benzyl halides and nucleophilic (Me 4 N)SCF 3 reagent, [3b,f–h,13] we envisioned that the aforementioned enantioconvergent C(sp 3 )−SCF 3 cross‐coupling of racemic benzyl electrophiles with nucleophilic (Me 4 N)SCF 3 reagent would be appealing to access enantioenriched trifluoromethylthiolated molecules (Scheme 1B).…”

Enantioselective Construction of C−SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction

“…Therefore, using conceptually divergent route to accessing enantioselective syntheses of diverse SCF 3 -containing compounds is highly demanded. [8] 1,1-Diarylalkanes bearing various functional groups on the linked carbon have long been regarded as core structural motifs that are widely found in diverse naturally occurring compounds and pharmaceuticals (Scheme 1A). [9] Considering the variation of functional group on linked carbon could significantly change the biological activity of bioactive molecules as well as the "magic effect" in drug development introduced by SCF 3 moieties, the synthesis of trifluoromethylthiolated 1,1diarylalkanes in an efficient and especially enantioselective manner would suggest significant application potential in medicinal and agrochemistry.…”

“…Utilizing recently developed electrophilic SCF 3 reagents, few examples based on electrophilic trifluoromethylthiolation have been reported for enantioselective introduction of SCF 3 group to the α ‐position of carbonyl compounds, [5] especially for construction of chiral quaternary carbon centers [6] . Meanwhile, known synthetic methods for asymmetric construction of tertiary trifluoromethylthiolated stereocenters are also very rare [5a,7,8] . As the electrophilic S N 2 strategy works only for carboxylic acid derivatives with preinstalled chiral auxiliary group, [5a] the asymmetric catalytic construction of SCF 3 ‐containing stereocenters could only been categorized into (1) intra‐ and inter‐molecular difunctionalization of alkenes with electrophilic SCF 3 reagent [7] and (2) nucleophilic trifluoromethylthiolation of secondary propargyl sulfonates with trifluoromethylthio anion [8] .…”