Highly enantioselective synthesis of both tetrahydroquinoxalines and dihydroquinoxalinones via Rh–thiourea catalyzed asymmetric hydrogenation

• Published in: Chemical science (Cambridge) Vol. 14; no. 34; pp. 9024 - 9032
• Main Authors: Xu, Ana, Li, Chaoyi, Huang, Junrong, Pang, Heng, Zhao, Chengyao, Song, Lijuan, You, Hengzhi, Zhang, Xumu, Chen, Fen-Er
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 06.07.2023; The Royal Society of Chemistry
• Subjects: Asymmetry; Chemistry; Chloride ions; Continuous flow; Density functional theory; Deuterium; Dihydrides; Enantiomers; Hydrogen chloride; Hydrogenation; Molecular structure; NMR; Nuclear magnetic resonance; Room temperature; Substrates; Thioureas
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d3sc00803g

Chiral tetrahydroquinoxalines and dihydroquinoxalinones represent the core structure of many bioactive molecules. Herein, a simple and efficient Rh–thiourea-catalyzed asymmetric hydrogenation for enantiopure tetrahydroquinoxalines and dihydroquinoxalinones was developed under 1 MPa H 2 pressure at room temperature. The reaction was magnified to the gram scale furnishing the desired products with undamaged yield and enantioselectivity. Application of this methodology was also conducted successfully under continuous flow conditions. In addition, 1 H NMR experiments revealed that the introduction of a strong Brønsted acid, HCl, not only activated the substrate but also established anion binding between the substrate and the ligand. More importantly, the chloride ion facilitated heterolytic cleavage of dihydrogen to regenerate the active dihydride species and HCl, which was computed to be the rate-determining step. Further deuterium labeling experiments and density functional theory (DFT) calculations demonstrated that this reaction underwent a plausible outer-sphere mechanism in this new catalytic transformation.