jo0c01375_si_002.pdf (21.74 MB)
Phosphoric Acid Catalyzed Formation of Hydrogen-Bonded o‑Quinone Methides. Enantioselective Cycloaddition with β‑Dicarbonyl Compounds toward Benzannulated Oxygen Heterocycles
journal contribution
posted on 2020-08-26, 18:36 authored by Fabian Göricke, Stefan Haseloff, Michael Laue, Maximilian Schneider, Thomas Brumme, Christoph SchneiderA full
account of the Brønsted acid catalyzed, enantioselective
synthesis of 4H-chromenes and 1H-xanthen-1-ones from o-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 o-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 o-quinone methide in an off-cycle equilibrium was observed,
providing a reservoir from which the o-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 o-quinone methide formation as the rate-limiting step. In combination
with Hammett plots, these studies document the relationship between o-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 tBu group
and the o-quinone methide as an important stereochemical
control element.