Rh-Catalyzed Asymmetric Hydrogenation of 4-Quinolone-2-carboxylic Acids: Direct Access to Versatile Chiral 2,3-Dihydroquinolones

Abstract

This work reports the first example of rhodium-catalyzed asymmetric hydrogenation of 4-quinolone-2-carboxylic acids, providing direct access to chiral 2,3-dihydro-4-quinolones—a privileged scaffold in medicinal chemistry. Through systematic optimization of ligands, metal precursors, and solvents, the optimal catalytic system was identified as Rh(COD)₂OTf combined with the chiral bisphosphine ligand (R,R)-Ph-BPE. The reaction proceeds smoothly under 40 atm of H₂ in t-BuOH at 80 °C, affording a broad range of enantioenriched 2,3-dihydro-4-quinolones in moderate to excellent yields (40%–99%) and with high enantioselectivities (up to 99% ee). A broad range of substituents, including N-alkyl, N-benzyl, and electron-donating or electron-withdrawing groups on the quinolone core, are well tolerated, though the position and electronic nature of the substituents can affect enantioselectivity. Deuterium labeling experiments using D₂/t-BuOH and D₂/t-BuOD confirmed that molecular hydrogen (H₂/D₂) is the exclusive hydrogen source, with no direct participation of the protic solvent in the reduction step. Control experiments using C2-methyl or C2-ester substituted quinolones resulted in no conversion, demonstrating that the free carboxylic acid group is essential for substrate coordination to the rhodium center. Based on these findings and previous mechanistic studies, a plausible catalytic cycle is proposed involving oxidative addition of H₂, carboxylate-directed substrate coordination, migratory insertion into the C=C bond, and reductive elimination. Gram-scale reactions successfully delivered the desired products in high yields (92%–95%) and enantioselectivity (88% ee). Furthermore, product derivatization successfully furnished a new class of non-natural chiral amino esters, underscoring the synthetic utility of this method for constructing pharmaceutically relevant scaffolds.