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.

Asymmetric Radical-Type 1,2-Alkoxy-Sulfenylation of Benzoxazole-2-Thiols to Vinylarenes Catalyzed by Chiral Vanadyl Complexes

“…Similar to Prof. Liu’s study, 2 and 3° alcohols like 2-propanol, t -butanol, and Me 3 SiOH did not work in our catalytic system, presumably due to steric reasons. Both N -hydroxyphthalimide and phenols have been utilized as stoichiometric radical trapping agents in 2-propanol in our previous studies. , The current catalytic protocol can also be applied with reduced loadings of the 1° alcohols from 123.5 equiv of MeOH as a solvent (2 mL) at 0 °C to 10 equiv of MeOH in CH 2 Cl 2 (2 mL), along with increasing loading of catalyst- 4c to 10 mol %. Under such circumstances, desired product 3a was isolated in a moderate yield of 44% and in 91% ee (Supporting Information).…”

“…Based on our previous asymmetric 1,2-aminoxy-trifluoromethylation of vinylarenes by using N -hydroxy-2-(methylthio)­quinazolin-4­(3H)-one ( N -HMTQuiz-one) as the benzylic radical trapping agent, we have selected three different N-substituted, 2-mercapto analogs (Type-I), two different 1-substituted-tetrazole-5-thiols (Type-II), and 2-mercapto-benzothia/benzoxazoles (Type-III) for preliminary screening with styrene (a limiting reagent) at ambient temperature in MeOH. All the reactions were quenched at the time with complete consumption of styrene.…”

“…At the current stage, the only asymmetric version of the radical type process by common arenethiols was recently realized by Prof. Chemler and Burde using chiral Cu­(I/II)-bisoxazoline complexes in an intramolecular manner (Scheme B). , The reactions proceeded with intramolecular asymmetric alkene oxycupration, followed by trapping of the arylsulfenyl group from a given diaryl disulfide at 120 °C. In view of our recent success in asymmetric intermolecular 1,2-alkoxyphosphinoylation of vinylarenes − (Scheme C) and the pending challenge of using REW heteroarene-thiols in asymmetric 1,2-difunctionalization of alkenes, we sought to develop the first asymmetric intermolecular variant of this type (Scheme D). In addition, the resulting products may exhibit potential anti-Alzheimer , and anti-Candida activities (Scheme E) …”