Mechanistic Investigation of an Organocatalytic Bromocyclization of <i>O</i>‐Allyl Carbamates

Abstract Intramolecular enantioselective halocyclization of olefins represents a valuable organic synthesis strategy. This work reports the enantioselective bromoaminocyclization of O ‐cinnamyl tosylcarbamate catalyzed by a Cinchona ‐derived organocatalyst as a model reaction to understand non‐covalent catalyzed bromoaminocyclizations. The corresponding bromo‐oxazinanone was obtained with excellent regio‐ and diastereoselectivity in 69% yield and 80:20 er, promoted by a thiocarbamate‐cinchonine catalyst. This reaction served as a compelling prototype for a comprehensive mechanistic investigation, combining experimental and theoretical approaches. Analysis of the reaction mixture by electrospray ionization mass spectrometry (ESI(+)‐MS) and detailed evaluation of key intermediates via infrared multiphoton dissociation (IRMPD) spectroscopy were performed. The thermodynamic origins of enantioselectivity were explored by analyzing the potential energy surface of the reaction using density functional theory (DFT) calculations. This analysis included relevant transition states and intermediates, as well as the role of non‐covalent interactions within the active catalytic species as revealed by natural bond orbital (NBO) analysis. Consistent with the experimental observations, DFT calculations indicated that the electrophilic bromo species is activated by the sulfur atom of the (thio)carbonyl group of the catalysts, and bromonium ion formation constitutes the enantiodetermining step, with a calculated overall reaction barrier of 27.0 kcal mol −1 .