Asymmetric Synthesis of Trifluoroethyl-Based, Chiral 3-Benzyloxy-1- and -2-Phenyl-quinazolinones of Biomedicinal Interest by Radical Type Cross-Coupling to Olefins

Abstract

Several 2-substituted (H, Ph, and S-Me) and 1-substituted (H, Ph, and Bn), 3-hydroxy-1,3-quinazolin(di)ones were utilized for the first time as radical trapping agents in asymmetric 1,2-oxytrifluoromethylation of styrenes catalyzed by chiral vanadyl methoxide complexes bearing 3,5-disubstituted-N-salicylidene-t-leucinate templates. The effects of catalysts and solvents on the asymmetric induction were systematically examined. The best and complementary scenarios involved the use of vanadyl complexes V(O)-1 and V(O)-2, which bear 3-(2,5-dimethyl)phenyl-5-bromophenyl and 3-t-butyl-5-bromophenyl groups in an i-propanol solvent at ambient temperature. The corresponding (R)-cross-coupling products by V(O)-1 were obtained in 45–71% (for 2-substituted series) and 59–93% yields (for 1-substituted series) for p-/m-methylstyrenes and m-halo/CF3/CO2Me-styrenes in 38–63% ees (the best in 2-H case) and 60–84% ees (the best in 1-benzyl cases), respectively. The corresponding (S)-cross-coupling products by V(O)-2 were obtained in 28–55% (for 2-substituted series) and 45–72% yields (for 1-substituted series) for the same substrate class in 50–91% ees (85–91% ees in 2-phenyl cases) and 64–75% ees (up to 74–75% ees for each 1-H, Ph, and Bn cases), respectively. Theoretical calculations were carried out to explain the origin and extent of enantiocontrols. They both may serve as potential inhibitors of acetohydroxyacid synthase and epidermal growth factor receptor (EGFR) kinases.