Defluorinative Carboimination of Trifluoromethyl Ketones

Abstract

The monofunctionalized carbodefluorination of readily accessible CF3 groups is acknowledged as an attractive approach to the preparation of partially fluorinated molecules. However, their defluorinative difunctionalization remains a challenging and unmet goal. Herein, we report an unprecedented defluorinative carboimination of trifluoromethyl ketones via a strategy of silver carbene-initiated rearrangement, in which both C–F bond and carbonyl group of the trifluoromethyl ketones were functionalized simultaneously, thus providing a straightforward synthetic method for medicinally relevant α,α-difluoroimines. The current approach involves a silver carbene-initiated intramolecular cascade process by integrating successive cleavage of C–F bond and formation of C–C and C=N bonds on a single molecule entity, which differs relevantly from the stepwise mechanism of reported carbodefluorination of CF3 groups. Mechanistic studies disclose that silver catalysis plays a critical role, particularly in the stages of C–F bond cleavage and aza-Claisen rearrangement.

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“…Next, we directed our attention to the reaction of allylamines, which involves the cleavage of C–N bonds. After slight adjustment of the reaction parameters, we were pleased to find that various allylamines proved to be effective, thus providing a straightforward synthetic method for medicinally relevant α,α-difluoroimines (Scheme D) . Note that this is the first example of simultaneous difunctionalization of the C–F bond and π-system of π-CF 3 molecules.…”

“…After slight adjustment of the reaction parameters, we were pleased to find that various allylamines proved to be effective, thus providing a straightforward synthetic method for medicinally relevant α,αdifluoroimines (Scheme 4D). 33 Note that this is the first example of simultaneous difunctionalization of the C−F bond and π-system of π-CF 3 molecules. Taken together, the above achievements constitute a powerful methodology for the carbodefluorination of C(sp 3 )−F bonds of fluoroalkyl ketones through a novel strategy of silver carbene-induced rearrangement of β,γ-unsaturated alcohols/amines.…”