Phosphoric Acid Catalyzed Formation of Hydrogen-Bonded <i>o</i>‑Quinone Methides. Enantioselective Cycloaddition with β‑Dicarbonyl Compounds toward Benzannulated Oxygen Heterocycles

A full account of the Brønsted acid catalyzed, enantioselective synthesis of 4<i>H</i>-chromenes and 1<i>H</i>-xanthen-1-ones from <i>o</i>-hydroxybenzyl alcohols and β-dicarbonyl compounds is provided. The central step of our strategy is the BINOL–phosphoric acid catalyzed, enantioselective cycloaddition of β-diketones, β-keto nitriles, and β-keto esters to in situ generated, hydrogen-bonded <i>o</i>-quinone methides. Upon acid-promoted dehydration, the desired products were obtained with generally excellent yields and enantioselectivity. Detailed mechanistic studies including online-NMR and ESI-MS measurements were conducted to identify relevant synthetic intermediates. A reversible formation of a dimer from the starting alcohol and the reactive <i>o</i>-quinone methide in an off-cycle equilibrium was observed, providing a reservoir from which the <i>o</i>-quinone methide can be regenerated and introduced into the catalytic cycle again. Reaction progress kinetic analysis was utilized to determine kinetic profiles and rate constants of the reaction uncovering <i>o</i>-quinone methide formation as the rate-limiting step. In combination with Hammett plots, these studies document the relationship between <i>o</i>-quinone methide stabilization by electronic effects provided by the substituents and the reaction rate of the described process. In addition, DFT calculations reveal a concerted yet highly asynchronous [4 + 2]-cycloaddition pathway and an attractive CH−π interaction between the catalyst’s <i>t</i>Bu group and the <i>o</i>-quinone methide as an important stereochemical control element.