Despite the wide application range of hypervalent iodine based reagents for electrophilic trifluoromethylation, the formation of quaternary carbons bearing a CF3-group still remains a challenge. This is even more true for their stereoselective synthesis. So far the only reported all-carbon substituted centers that undergo trifluoromethylation with the so-called Togni-reagents are �-keto esters, a-nitro esters and silyl ketene acetals. The pool of quaternary carbon centers bearing a CF3-unit that have been synthesized via direct electrophilic trifluoromethylation in an enantioselective fashion is even smaller. The only direct electrophilic catalytic enantioselective trifluoromethylation of �-keto esters was reported by Gade and coworkers using Togni-reagent, copper(II) triflate, and a chiral pincer ligand. (JACS, 134, 10769)To extend the scope of the reagents we have been working on the direct trifluoromethylation of secondary nitriles to form a quaternary carbon center, which can be used as an intermediate towards highly functionalized organic molecules.The deprotonation of a secondary nitrile and subsequent addition of a direct electrophilic trifluoromethylating reagent only resulted in decomposition of the reagent.To avoid harsh conditions with strong bases present in the reaction mixture silyl ketene imines have successfully been applied as nucleophiles in the a-trifluoromethylation of nitriles. After reaction optimization we were able to synthesize a variety of a-trifluoromethyl nitriles using 5 mol% of a vanadyl catalyst with a salen-type ligand in up to 93% yield. Furthermore, the reaction can be performed under solvent-free conditions, which is highly desirable. The products can be derivatized using standard protocols for the transformation of nitriles.To the best of our knowledge, this is the first example for trifluoromethylation of silyl ketene imines, for vanadium-catalyzed activation of our reagents, and for neat reaction conditions. The development of an enantioselective version of this reaction is currently under investigation.

Electrophilic trifluoromethylation and the formation of quaternary stereogenic centers

248th National Meeting (2014)

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