Cooperative Brønsted Acid and Photo‐Promoted Stereoselective Synthesis of Substituted Piperidones

Abstract Saturated nitrogen heterocycles are highly prevalent in medicinal chemistry, agrochemistry, and material science. Despite extensive research to access substituted piperidines and related compounds, there remains a strong demand for new stereoselective approaches. We present a Brønsted acid‐promoted, light‐induced formal ring‐insertion strategy for the efficient synthesis of piperidone and pyrrolidone derivatives. This method enables the efficient construction of thermodynamically disfavored cis ‐disubstituted piperidone and pyrrolidone derivatives. A key aspect of this strategy is the use of an acyl imidazole as a uniquely capable chromophore activator, in cooperation with the Brønsted acid, which controls both reactivity and stereoselectivity without the need for photosensitizers. The unique properties of the in situ generated carbonyl triplet diradical enable a selective 1,5‐hydrogen atom transfer process, followed by C─N bond cleavage and a subsequent Mannich reaction, offering broad functional group tolerance. The synthetic utility of this methodology was exemplified by the preparation of key intermediates for the synthesis of neurokinin 1 antagonist drug candidates.