The direct gem‐difluoroalkenylation of X−H bonds represents the most straightforward approach to access heteroatomic gem‐difluoroalkenes that, as the isostere of the carbonyl group, have great potency in drug discovery. However, the construction of tetrasubstituted heteroatomic gem‐difluoroalkenes by this strategy is still an unsolved problem. Here, we report the first direct X−H bond gem‐difluoroalkenylation of amines and alcohols with trifluoromethyl ketone N‐triftosylhydrazones under silver (for (hetero)aryl hydrazones) or rhodium (for alkyl hydrazones), thereby providing a most powerful method for the synthesis of tetrasubstituted heteroatomic gem‐difluoroalkenes. This method features a broad substrate scope, high product yield, excellent functional group tolerance, and operational simplicity (open air conditions). Moreover, the site‐specific replacement of the carbonyl group with a gem‐difluorovinyl ether bioisostere in drug Trimebutine and the post‐modification of bioactive molecules demonstrates potential use in medicinal research. Finally, the reaction mechanism was investigated by combining experiments and DFT calculations, and disclosed that the key step of HF elimination occurred via five‐membered ring transition state, and the difference in the electrophilicity of Ag‐ and Rh‐carbenes as well as the multiple intermolecular interactions rendered the effectiveness of Rh catalyst selectively for alkyl hydrazones.

The C–F bond cleavage and C–C bond formation (i.e., carbodefluorination) of readily accessible (per)fluoroalkyl groups constitutes an atom-economical and efficient route to partially fluorinated compounds. However, the selective mono-carbodefluorination of trifluoromethyl (CF3) groups remains a challenge, due to the notorious inertness of C–F bond and the risk of over-defluorination arising from C–F bond strength decrease as the defluorination proceeds. Herein, we report a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones with β,γ-unsaturated alcohols to provide skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated ketones. The reaction starts with the formation of silver carbenes from fluoroalkyl N-triftosylhydrazones, followed by nucleophilic attack of a β,γ-unsaturated alcohol to form key silver-coordinated oxonium ylide intermediates, which triggers selective C–F bond cleavage by HF elimination and C–C bond formation through Claisen rearrangement of in situ generated difluorovinyl ether. The origin of chemoselectivity and the reaction mechanism are determined by experimental and DFT calculations. Collectively, this strategy by an intramolecular cascade process offers significant advances over existing stepwise strategies in terms of selectivity, efficiency, functional group tolerance, etc.

The conversion of inexpensive aqueous ammonia (NH3·H2O) into value-added primary amines by N−H insertion persists as a longstanding challenge in chemistry because of the tendency of Lewis basic ammonia (NH3) to bind and inhibit metal catalysts. Herein, we report a chemoselective carbene N−H insertion of NH3·H2O using a TpBr3Ag-catalyzed two-phase system. Coordination by a homoscorpionate TpBr3 ligand renders silver compatible with NH3 and H2O and enables the generation of electrophilic silver carbene. Water promotes subsequent [1,2]-proton shift to generate N−H insertion products with high chemoselectivity. The result of the reaction is the coupling of an inorganic nitrogen source with either diazo compounds or N-triftosylhydrazones to produce useful primary amines. Further investigations elucidate the reaction mechanism and the origin of chemoselectivity.

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The conversion of inexpensive aqueous ammonia (NH3·H2O) into value-added primary amines by N − H insertion persists as a longstanding challenge in chemistry because of the tendency of Lewis basic ammonia (NH3) to bind and inhibit metal catalysts. Herein, we report a chemoselective carbene N − H insertion of NH3·H2O using a TpBr3Ag-catalyzed two-phase system. Weak coordination by a homoscorpionate ligand enables silver compatible with NH3 and H2O and ensures the generation of electrophilic silver carbene. Water promotes subsequent [1, 2]-proton shift to generate N − H insertion mono-substituted products with high chemoselectivity. The end result of the reaction is the coupling of an inorganic nitrogen source with either diazo compounds or N-triftosylhydrazones to produce useful primary amines. Further investigations elucidate the reaction mechanism and the origin of chemoselectivity.