N-Heteroaryl Carbamates from Carbon Dioxide via Chemoselective Superbase Catalysis: Substrate Scope and Mechanistic Investigation

We report a mildsuperbase-catalyzed and nitrogen-selective carboxylationof N-heteroaryls, with subsequent alkylation enablingthe synthesis of drug-like O-alkyl carbamates ingood yields (av. 86%). Our findings suggest a partial revision ofthe current mechanistic understanding as superbases upon mixing withindoles and azoles generally form uncharged hydrogen-bonded complexesand not ionic salts as previously proposed. However, when these complexesare exposed to CO2, carbamate salts are formed. These canbe categorized into two subgroups, stable and fluxional carbamatesalts, where the latter undergo fast and reversible CO2 exchange, thus being poor substrates for alkylation. Experimentsand DFT calculations indicate that the fluxional behavior is primarilycaused by substrate-specific electronic destabilization effects. Thedegree of destabilization depends on the number of nitrogen atomswithin and the functional group substitution on the heterocyclic ringstructures. Fluxionality can be compensated for by the use of lowertemperatures and/or higher CO2 pressures as both measuresstabilize the carbamate salts sufficiently, enabling subsequent alkylation.