A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α, β-unsaturated esters. Issue 17 (6th April 2021)

• Record Type: Journal Article
• Authors: Su, Guanglong; Thomson, Connor J.; Yamazaki, Ken; Rozsar, Daniel; Christensen, Kirsten E.; Hamlin, Trevor A.; Dixon, Darren J.
• Is Part Of: Chemical science. Volume 12:Issue 17(2021)
• Page Start: 6064
• Page End: 6072
• Publication Date: 2021-04-06
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc00856k
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : The activation of both aromatic and aliphatic ureas as N-centered nucleophiles in intramolecular Michael addition reactions to α, β-unsaturated esters was achieved under bifunctional iminophosphorane squaramide superbase catalysis. Abstract : An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked 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 er) 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 with the activation strain model (ASM) and energy decomposition analysis (EDA).