Asymmetric Defluoroallylation of 4‐Trifluoromethylpyridines Enabled by Umpolung C−F Bond Activation**

Abstract

Carbon–fluorine bond activation of the trifluoromethyl group represents an important approach to fluorine‐containing molecules. While selective defluorinative functionalization reactions of CF3‐containing substrates have been achieved by invoking difluorocarbocation, difluorocarboradical, or difluoroorganometallic species as the key intermediates, the transformations via fluorocarbanion mechanism only achieved limited success. Furthermore, the enantioselective defluorinative transformation of the CF3 group remained a formidable challenge. Here we report a defluorinative functionalization reaction of 4‐trifluoromethylpyridines involving difluoro(pyrid‐4‐yl)methyl anion as the key intermediate, which was developed based upon our previous studies on the N‐boryl pyridyl anion chemistry. In particular, asymmetric defluoroallylation of 4‐trifluoromethylpyridines and ‐pyrimidines could be achieved by using Ir‐catalysis to forge a difluoroalkyl‐substituted chiral center.

Synthetic Advantages of Defluorinative C−F Bond Functionalization

“…Jiao and co-workers developed an alternative protocol for defluoroallylation of CF 3 -substituted N-heteroarenes (Scheme 29c). [159] Here, an N-heteroarene and base-activated B 2 pin 2 react to reduce a CÀ F bond, thus generating a difluorobenzylic anion that undergoes enantioselective allylation using a chiral Ir catalyst.…”

Defluorinative 1,3‐Dienylation of Fluoroalkyl N‐Triftosylhydrazones with Homoallenols

“…[20,21,25,26] Most of these CÀ F bond functionalization reactions focused on hydrodefluorination [27][28][29][30][31][32][33][34][35][36] and defluoroalkylation, [29,35,[37][38][39][40][41][42][43][44] and the defluoroallylation is comparatively far less developed (Figure 1B). [27,[45][46][47][48] However, existing methods are limited to allylate arene-CF 3 compounds, which require the use of preprepared metal allyl reagents and strongly reducing conditions and thus lack functional group compatibility. Hence, it is highly desirable to develop a unified method for accessing diverse gem-difluoroallylic substructures from readily accessible trifluoromethyl substrates.…”

Transition-metal-catalyzed asymmetric defluorinative reactions

“…Very recently, Jiao's group reported an iridium-catalyzed asymmetric defluoroallylation of 4-trifluoromethylpyridines with allyl carbonates 23-1 (Scheme 23A). 53 In this variant, the reaction design depended on the umpolung of the CF 3 group through N -boryl pyridyl anion chemistry, proceeding via difluoro(pyrid-4-yl)methyl anion 23-6 as the key intermediate. Mechanistically, the initial reaction of CF 3 -substituted pyridine and diboron occurs via the facile B–B bond heterolytic fission in the presence of alkoxide to furnish a N -boryl pyridyl species 23-4 .…”