Fig. 4: Realization of the cycloaddition to experimentally generate the α,α-difluorinated N-heterocycles predicted by the AFIR search.

a, Fluorinated N-heterocycles and associated drugs. b, Experimental conditions for realizing the predicted reaction mode. c, Experimental and computational investigation that identified the N-difluoroalkylative dearomatization. The reactions were performed with 0.30 or 0.50 mmol of 1 or 2, 3 (2 equiv.), Me3SiCF2Br (1.1 equiv.), Ph3SiF2∙NBu4 (1.1 equiv.) and THF at 0 °C for 2 h. The energy barriers for the ylide formation and dimerization of two molecules of difluorocarbene were investigated by optimizing the transition-state geometries at the ωB97X-D/Def2-SVP/CPCM(THF) level of theory. aThe yield of the product from pyridine 2a was measured using 19F NMR spectroscopic analysis with benzotrifluoride as the internal standard. bIsolated yields are shown. The ratios of endo- to exo-isomers were measured using 1H NMR spectroscopic analysis; Boc, tert-butoxycarbonyl; THF, tetrahydrofuran; NOE, nuclear Overhauser effect.