(Fluoro)alkylation of alkenes promoted by photolysis of alkylzirconocenes

Abstract

Difluoroalkylated compounds have important applications in pharmaceutical, agrochemical, and materials science. However, efficient methods to construct the alkylCF₂-alkyl bond are very limited, and the site-selective introduction of a difluoromethylene (CF₂) group into an aliphatic chain at the desired position remains challenging. Here, we report an unprecedented example of alkylzirconocene promoted difluoroalkylation of alkyl- and silyl-alkenes with a variety of unactivated difluoroalkyl iodides and bromides under the irradiation of visible light without a catalyst. The resulting difluoroalkylated compounds can serve as versatile synthons in organic synthesis. The reaction can also be applied to activated difluoroalkyl, trifluoromethyl, perfluoroalkyl, monofluoroalkyl, and nonfluorinated alkyl halides, providing a general method to controllably access fluorinated compounds. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway induced by a Zr(iii) species is involved in the reaction, in which the Zr(iii) species is generated by the photolysis of alkylzirconocene with blue light.

Fig. 1. Strategies for the difluoroalkylation and selected examples of pharmaceutical bearing CF₂ moieties. (A) Representative drugs containing a CF₂ moiety. (B) Previous works for the construction of the alkyl-CF₂R bond. (C) This work: visible-light-induced fluoroalkylation of alkylzirconocenes.

Scheme 1. Control experiments for the reaction. (a) Reaction of 2a with 1a. (b) Reaction of 2a with 1a and 5a. (c) Reaction of 2a with 1a and 5a in the presence of 5b. (d) Reaction of 2a with 5b. (e) Reaction of 5a with 1a under irradiation of blue LED.

Scheme 2. (A) lkylzirconocene promoted fluoroalkylation of alkenes with (fluoro)alkyl halides under the irradiation of blue light. (B) Alkylzirconocene 2c promoted fluoroalkylation of alkenes with difluoroalkyl halides under irradiation of blue light. ^a Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), 5 (2.5 equiv.), 6 (1.2 equiv.), and NMP (3 mL). ^b5 (3.5 equiv.) and 6 (1.8 equiv.) were used. ^c2c (∼1.5 equiv.), 5 (1.5 equiv.), and 6 (2.0 equiv.), and NMP (3 mL) were used. ^d Gram scale synthesis.

Scheme 3. (A) Transformations of difluoroalkylated compounds 3e, 3i and 3m. (B) Gram-scale synthesis of 3p and its transformations.

Fig. 2. Mechanistic studies and proposed reaction mechanism. (A) Radical clock experiments. (B) Proposed reaction mechanism.