Enantioselective Copper-Catalyzed Intermolecular Cyanobenzoyldifluoromethylation of Alkenes: Access to Chiral β-Difluoroacyl Nitriles

Abstract

A novel asymmetric copper-catalyzed intermolecular cyanobenzoyldifluoromethylation of alkenes with iododifluoromethyl ketones and TMSCN has been reported, which provides a particularly valuable route to access chiral β-difluoroacyl nitriles with excellent enantioselectivities. The method permits the efficient cyanation of varied β-difluoroacyl-benzylic radicals in mild conditions with high functional group tolerance. The reaction proceeds through a radical pathway. In order to get insight into the stereochemical outcome, computational mechanistic studies were conducted.

Copper-catalyzed radical-mediated intermolecular cyanomonofluoroalkylation of alkenes and alkynes

“…Increasing or decreasing the amount of copper salt did not improve the yield of 3aa either (Table 1, entries 11 and 12). Additional control experiments confirmed that the copper catalyst, L1 and LPO are essential for this reaction (Table 1, entries [13][14][15].…”

“…14 Very recently, our group disclosed a copper-catalyzed threecomponent reaction of iododifluoroacylated ketones, alkenes and trimethylsilonitrile (TMSCN) to afford β-difluoroacyl nitriles with excellent enantioselectivities. 15 Mechanistic exploration shows that in this reaction process, the copper catalyst first reacts with cyanide to form Cu II (CN) 2 species, which could then trap the radical intermediate generated from the addition of a fluoroalkyl radical to the CvC bond. However, the cyano-monofluoroalkylation of alkenes with valuable monofluoroalkyl reagents remains unexplored, but is highly desirable.…”

Iron‐Catalyzed Intermolecular Azidabenzoyl Difluoromethylation of Alkenes to Access β‐Difluoroacyl Azides

“…Inspired by our previous work, [11d] the reaction of 2‐iodo‐2,2‐difluoroacetophenones 1 a , styrene 2 a and TMSN 3 was chosen as a model reaction to optimize the reaction conditions. The reaction was conducted in anhydrous DME at room temperature with tert ‐butyl peroxybenzoate (TBPB) as the radical initiator, and catalyzed by Fe(OTf) 2 under nitrogen (Table 1, entry 1).…”

Fluoroalkyl Iodides in Fluoroalkylative Difunctionalization of C−C Multiple Bonds

“…[205] Shortly after, the enantioselective variant of the transformation was disclosed utilizing low loading of a CuÀ bisoxazoline complex and benzoylperoxide. [206] In most cases very good yields and enantioselectivities were reported.…”

“…Recently, Wu utilized a similar catalyst system for cyanofluoroalkylation of alkynes with iododfluoromethyl ketones [205] . Shortly after, the enantioselective variant of the transformation was disclosed utilizing low loading of a Cu−bisoxazoline complex and benzoylperoxide [206] . In most cases very good yields and enantioselectivities were reported.…”