A Simple and Efficient Catalyst System for the Asymmetric Transfer Hydrogenation of Ketones

Abstract

Aryl alkyl ketones are efficiently and selectively reduced (up to 97% ee) under transfer-hydrogenation conditions in 2-propanol using rhodium catalysts based on readily available amino acid derived hydroxamic acid ligands.

asymmetric catalysis - hydrogen transfer - reductions - rhodium - ketones

References and Notes

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8

General Procedure for the Preparation of Hydroxamic Acid Ligands 1a-d
To a solution of 2,4,6-trichloro-1,3,5-triazine (0.1 mmol) in anhyd CH₂Cl₂ (8 mL) cooled to 0 °C, the following components were added in the order they are written: Boc-protected amino acid (3 mmol), NMM (6 mmol), DMAP (0.3 mmol), and NH₂OH·HCl (3 mmol). The reaction mixture was stirred at r.t. for 14 h and thereafter filtered through a plug of silica, using EtOAc as eluent. The residue obtained after evaporation of the filtrate was chromatog-raphed on silica (EtOAc-pentane, 10:1), followed by recrystallization from acetone-pentane to give the hydroxamic acids.
Compound 1a: yield 41%. ¹H NMR (400 MHz, acetone-d ₆, 25 °C): δ = 10.09 (s, 1 H), 8.22 (br s, 1 H), 6.06 (s, 1 H), 4.08 (q, J = 7.11 Hz, 1 H), 1.40 (s, 9 H), 1.29 (d, J = 7.11 Hz, 3 H). ¹³C NMR (100 MHz, acetone-d ₆, 25 °C): δ = 170.0, 155.1, 78.3, 47.7, 27.5, 17.8.
Compound 1b: yield 25%. ¹H NMR (400 MHz, acetone-d ₆, 25 °C ): δ = 10.18 (br s, 1 H), 8.22 (br s, 1 H), 5.91 (d, J = 8.16 Hz, 1 H), 3.75-3.85 (m, 1 H), 1.40 (s, 9 H), 0.89-0.94 (m, 6 H). ¹³C NMR (100 MHz, acetone-d ₆, 25 °C ): δ = 168.4, 155.4, 78.2, 57.5, 30.8, 27.5, 18.5, 17.6.
Compound 1c: yield 25%. ¹H NMR (400 MHz, acetone-d ₆, 25 °C): δ = 10.20 (br s, 1 H), 8.37 (br s, 1 H), 7.16-7.31 (m, 5 H), 6.12 (d, J = 7.32 Hz, 1 H), 4.23-4.36 (m, 1 H), 3.10 (dd, J = 13.71, 6.03 Hz, 1 H), 2.91 (dd, J = 13.71, 8.59 Hz, 1 H), 1.33 (s, 9 H). ¹³C NMR (100 MHz, acetone-d ₆, 25 °C): δ = 168.4, 155.1, 137.5, 129.2, 128.1, 126.3, 78.4, 53.6, 38.1, 27.5.
Compound 1d: yield 10%. ¹H NMR (400 MHz, acetone-d ₆, 25 °C): δ = 10.39 (br s, 1 H), 8.25 (br s, 1 H), 7.42-7.47 (m, 2 H), 7.26-7.37 (m, 3 H), 6.46 (d, J = 6.10 Hz, 1 H), 5.20 (d, J = 6.10 Hz, 1 H), 1.39 (s, 9 H). ¹³C NMR (100 MHz, acetone-d ₆, 25 °C): δ = 167.3, 154.7, 138.9, 128.3, 127.6, 127.0, 78.6, 55.7, 27.5.

9 For the original report on the importance of external base in transition-metal-catalyzed transfer-hydrogenation reactions, see: Chowdhury RL. Bäckvall J.-E. J. Chem. Soc., Chem. Commun.  1991,  1063 

10

General Procedure for the Transfer Hydrogenation of Ketones Using Ligands 1a-d
[{RhCl₂Cp*}₂] (0.0025 mmol), ligand (0.0055 mmol), and LiCl (0.05 mmol) were dried under vacuum in a dry Schlenk tube for 15 min. Ketone (1 mmol), i-PrOH (4.5 mL), and a 0.01 M solution of i-PrONa in i-PrOH (0.5 mL, 5 mol%) were added under nitrogen. The reaction mixture was stirred at ambient temperature. Aliquots were taken after the reaction times indicated in Tables [1] and [2] and were then passed through a pad of silica with EtOAc as the eluent. The resulting solutions were analyzed by GLC (CP Chirasil DEXCB).

11

Turnover frequencies determined after 30 min reaction time.