Mechanochemical Asymmetric Transfer Hydrogenation of Diketones to Access Chiral 1,3-Diols under Solvent-Free Conditions

Abstract

A mechanochemical asymmetric transfer hydrogenation (ATH) of diketones in the presence of a ruthenium complex under solvent-free conditions was developed to provide chiral 1,3-diol derivatives. This protocol benefits from rapid reaction kinetics, no use of solvents, and excellent enantioselectivity. In addition, the mechanochemical ATH reaction can easily be performed on a gram scale.

Key words

asymmetric catalysis - transfer hydrogenation - mechanochemistry - diols - ruthenium catalysis - solvent-free reaction

Publication History

Received: 11 March 2022

Accepted after revision: 21 July 2022

Accepted Manuscript online:
21 July 2022

Article published online:
19 August 2022

• References and Notes

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• 18 Solvent-Based Reaction: Experimental Procedure A 25 mL Schlenk tube was charged with ketone 1a (224.3 mg, 1 mmol), catalyst C (31.8 mg, 0.1 mmol), 1:1 HCOOH/NEt₃ (0.28 mmol), and DCE (10 mL), and the mixture was stirred at 35 °C. During the first hour of the reaction, 0.5 mL aliquots of the solution were sampled every 15 min and then 0.5 mL aliquots were sampled every hour. Each sample of the solution was evaporated and the residue was dissolved in CDCl₃ (1 mL) containing 0.05 mmol of 1,3,5-trimethoxybenzene. [NOTE: To eliminate experimental error, the deuterated solvent should be prepared on a large scale by dissolving 1,3,5-trimethoxybenzene (5 mmol) in CDCl₃ (100 mL).] Finally, the yield of 2a was determined by ¹H NMR spectral analysis of the crude sample solution.
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• 20 Diols 2a–p: General Procedure A 25 mL stainless steel milling vessel was charged the appropriate ketone 1 (0.2 mmol), catalyst C (0.01 mmol), 1:1 HCOOH/NEt₃ (0.056 mmol), and eight 5 mm diameter zirconia milling balls. Then the milling vessel was then placed on a planetary ball mill (900 rpm) and the mixture was milled for 45 min at approximately 35 °C. Upon completion of the reaction, the organic compounds were taken up in Et₂O. The solution was concentrated and the residue was purified by column chromatography (silica gel). (1S,3S)-1-(4-Methoxyphenyl)-3-phenylpropane-1,3-diol (2k) Purple oil; yield: 95% (99% ee, 99:1 dr) [α]_D ²⁵ = -50.2 (c 1.0, CHCl₃). HPLC [IC; hexane–i-PrOH (93:7), 1.1 mL/min, 25 °C, λ = 215 nm]: t ₁ = 18.2 min (major), t ₂ = 28.2 min, t ₃ = 29.4 min, t ₄ = 37.3 min (minor). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.32 (d, J = 2.4 Hz, 4 H), 7.28–7.18 (m, 3 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.26 (d, J = 4.9 Hz, 1 H), 5.18 (d, J = 4.9 Hz, 1 H), 4.75 (m, 2 H), 3.73 (s, 3 H), 1.79 (dt, J = 8.2, 3.8 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 158.5 (C), 147.2 (C), 139.1 (C), 128.5 (CH), 127.3 (CH), 127.0 (CH), 126.1 (CH), 113.9 (CH), 69.6 (CH), 69.1 (CH), 55.5 (CH₃), 50.2 (CH₂).