3.26.1. Rhodium-Catalyzed Asymmetric Hydrogenation of α-Aryl Enamides

Optimization

Reactions were set up using a glovebox. Rh(COD)₂OTf (0.005 mmol), ligand (0.006 mmol), N-(1-phenylvinyl)acetamide 18a (0.108 g, 0.5 mmol), and the solvent (2 mL) were added to a dry 10-mL Schlenk flask containing a magnetic stir bar under an inert atmosphere. The reaction mixture was cooled under liquid nitrogen, the atmosphere was evacuated (high vacuum), and the reaction chamber was refilled with hydrogen (balloon, reactions requiring higher pressures of hydrogen were quickly transferred to an autoclave). The reaction was stirred for the designated time, filtered through a plug of Celite^®, and washed with the solvent of choice. The solvent was removed in vacuo to yield the crude product. The ee was determined by HPLC and conversion of starting material to product by ¹H NMR spectroscopy.

Substrate Scope

The reactions were performed with 0.5 mmol of the substrate using the procedure outlined above for the optimization process, with the following exceptions. Racemic reactions were performed with (±)-BINAP (1.2 mol %) using Rh(COD)₂OTf (1.0 mol %), 40 bar H₂ in THF for 18 h for substrate 18a and Pd/C (1.0 mol %, 10 wt. % loading), 20 bar H₂ in methanol for 0.5–2 h for 18b–f. Reactions with L1 (1.1 mol %) were performed using Rh(COD)₂OTf (1.0 mol %), 40 bar H₂, in CH₂Cl₂ for 24 h at room temperature. Reactions with L4 (1.1 mol %) were performed using Rh(COD)₂OTf (1.0 mol %), 20 bar H₂, in MeOH for 1 h at room temperature. Reactions with L7 (0.22 mol %) were performed using Rh(COD)₂OTf (0.2 mol %), 10 bar H₂, in THF for 1 h at room temperature except for substrate 18f, which was subjected to Rh(COD)₂OTf (1.0 mol %), L7 (1.1 mol %), 60 bar H₂, in THF for 2 h at room temperature. For the methods and chiral columns used to determine the enantiomeric excess, and chromatograms for racemic and enantioenriched products, see Supplementary Materials (Table S1) and pages 15–20, respectively.