(Invited) Titanium-Catalyzed Intermolecular Radical Addition to Ketones Via Sp 3 C-H Bond Activation

Abstract

Tertiary alcohols are widely present in natural products, pharmaceuticals, and agrochemicals. Radical addition reaction to ketones is a simple and waste-free synthetic method for preparation of tertiary alcohols with high functional group tolerance. Therefore, direct radical addition reactions to ketones can be applied to a wider range of substrates. However, radical addition to carbonyl groups is a thermodynamically unfavored process, especially in the case of intermolecular radical addition to ketones, where the resulting alkoxy radical can easily undergo β-fragmentation to yield the starting material. For successful radical addition, therefore, the alkoxy radical must be trapped by a proper trapping reagent. In this study, we have found that a ternary hybrid catalytic system consisting of acridinium photoredox catalyst, thiophosphoric imide (TPI) catalyst, and titanium complex catalyst can promote intermolecular addition reactions of various ketones with organic molecules by activation of sp3 C-H bonds. The thiyl radicals generated by the excited photoredox-catalyzed one-electron oxidation of TPI extracted hydrogen atoms from organic molecules such as toluene, benzyl alcohol, alkenes, aldehydes, and THF. The carbon-centered radical species thus generated are added to various ketones and aldehydes. This method can be applied to the first direct reaction to aliphatic ketones using a variety of hydrocarbon feedstocks. The unfavorable bond-forming step was facilitated by the simultaneous one-electron reduction of the intermediate alkoxy radical by catalytically generated titanium(III) species. This reaction provided an efficient and simple approach to tertiary alcohols and was successfully applied in the late-stage functionalization of drugs and their derivatives. The proposed mechanism was supported by both experimental and theoretical studies. Figure 1