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A Bifunctional Iminophosphorane Squaramide Catalyzed Enantioselective Synthesis of Hydroquinazolines via Intramolecular Aza-Michael Addition to α,β-Unsaturated Esters

preprint
submitted on 18.01.2021, 18:14 and posted on 19.01.2021, 13:06 by Guanglong Su, Connor J. Thomson, Ken Yamazaki, Daniel Rozsar, Kirsten Christensen, Trevor Hamlin, Darren J. Dixon
An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael addition of urealinked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97:3 e.r.) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined activation strain model (ASM) and energy decomposition analysis (EDA).

History

Email Address of Submitting Author

guanglong.su@chem.ox.ac.uk

Institution

University of Oxford

Country

United Kingdom

ORCID For Submitting Author

0000-0002-7712-6205

Declaration of Conflict of Interest

no conflict of interest