Selective Trifluoromethylthiolation of Unactivated C(sp³)−H Bonds Enabled by Excited Ketones

Abstract

Here we report that the selective trifluoromethylthiolation of unactivated C(sp3)−H bonds is enabled by photoexcited diaryl ketones. This method for C−H trifluoromethylthiolation features mild conditions and inexpensive organic photocatalysts and relies on 370 nm LED lights. The functional group tolerance is broad and the excellent regioselectivity for branched aliphatic positions enables trifluoromethylthiolation of a variety of substrates, including amino acid and natural product derivatives, demonstrating its potential synthetic application.

Photocatalytic Late-Stage C–H Functionalization

“…Britton and co-workers employed triplet benzophenone as hydrogen-atom abstracting species and Munavalli's reagent (PhthSCF 3 ) as trifluoromethylthiol-group transfer reagent. 585 Good tertiary C−H selectivity was observed in the presence of secondary and primary positions, but also secondary cyclic feedstock alkanes (cyclohexane and cyclododecane) were amenable substrates. Protected leucine afforded the desired γ-SCF 3 product with increased site-selectivity (>20:1 r.r.…”

“…The authors performed the synthesis of advanced intermediates of analogues of the barbituric amobarbital and buspirone, an anxiety disorder treatment. Britton and co-workers employed triplet benzophenone as hydrogen-atom abstracting species and Munavalli’s reagent (PhthSCF 3 ) as trifluoromethylthiol-group transfer reagent . Good tertiary C–H selectivity was observed in the presence of secondary and primary positions, but also secondary cyclic feedstock alkanes (cyclohexane and cyclododecane) were amenable substrates.…”

“…Scheme 147. C−H TrifluoromethylthiolationPhotocatalyzed Strategies by Glorius,582 Britton,585 Konig,584 and Co-workers…”

Electronic control over site-selectivity in hydrogen atom transfer (HAT) based C(sp3)–H functionalization promoted by electrophilic reagents

“…Along a similar line, very recently a photocatalyzed procedure for C-H bond trifluoromethylthiolation, based on the use of diaryl ketones in combination with PhthNSCF 3 as the trifluoromethylthio source has been described. 142 Reaction optimization was carried out on 3-methyl-1-butyl benzoate and identified the best conditions in the use of benzophenone as the photocatalyst (BP, 20 mol%) under irradiation at room temperature with 370 nm LEDs, in the presence of PhthNSCF 3 (0.67 equiv.) in N 2 -saturated MeCN.…”

Photocatalytic α-aminoalkyl radical addition of amines mediated by benzophenone under visible light

“…In recent years, benzophenone has been used as a photoinitiator to generate radical intermediates from aromatic carbonyls for subsequent addition, cyclization, and trifluoromethylimination reactions. 9 However, there are no reports of benzophenone directly promoting the selective alkylation of anilines and alkenes under visible light. In 2021, by combining the photocatalytic properties of aromatic carbonyls and a transition metal, Vincent and co-workers reported the DMEDA–Cu–benzophenone complex-photocatalyzed alkylation of the α-amino C–H bonds of anilines.…”