Enantio- and Diastereoselective Hydrogenation of a Fluorinated Diketone

Abstract

Asymmetric hydrogenation of dibenzoyl-difluoro­methane has been studied for the first time. In contrast to ­BINAL-H, baker’s yeast and CBS reduction procedures, ruthenium-catalysed hydrogenation using axially chiral diphosphine ligands provides excellent yield, diastereoselectivity and good enantioselectivity (up to 72% ee). Enantiomer enrichment by recrystallisation allows for the pure fluorinated diol to be isolated as a single enantiomer in moderate yield.

Key words

homogeneous catalysis - hydrogenation - asymmetric synthesis - diols - organofluorine compounds

References and Notes

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9

General Procedures for Catalyst PreparationMethod 1: To a dried microwave tube was added benzeneruthenium chloride dimer (1.7 mg, 0.0034 mmol) and diphosphine (0.0068 mmol) and the air was evacuated and replaced with argon. To the mixture was added anhyd DMF (1 mL) and the mixture stirred under argon at 100 °C for 10 min. The DMF was removed in vacuo at 50 °C to give the catalyst.
Method 2:¹⁴ To a dried microwave tube was added [RuCOD(η³-2-methyl-allyl)₂] (4.6 mg, 0.014 mmol) and diphosphine (0.014 mmol) and the air displaced with argon. To this was added anhyd acetone (1 mL) followed by HBr solution [122 µL, 0.035 mmol of a solution prepared by adding acetyl bromide (22 µL) to MeOH (1 mL) in a dry Schlenk tube]. The mixture was stirred for 30 min at r.t. before removing the solvent in vacuo to give the catalyst.
Method 3: To a dried microwave tube was added benzeneruthenium chloride dimer (1.7 mg, 0.0034 mmol) and diphosphine (0.0068 mmol) and the air displaced with argon. Anhyd THF (3 mL) was added and the mixture heated in a microwave at 120 °C for 10 min. The solvent was removed in vacuo to give the catalyst.
Method 4: The [Ru(Diphos)(DPEN)Cl₂] complex was prepared by Noyori’s method.¹⁰

13

General Procedure for Catalytic Hydrogenation: An autoclave containing a reaction vial charged with catalyst and stirring bead was charged with diketone 1 (0.34 mmol). Anhydrous degassed solvent was added to the vial under an N₂ atmosphere. The autoclave was sealed, flushed with hydrogen, and brought to the initial pressure (50 bar) and stirred at 50 °C for 16 h. The mixture was concentrated in vacuo and an NMR taken of the resulting solid. The product was recrystallised from CH₂Cl₂ to give white needles. The anti/syn ratio was determined by ¹⁹F NMR and the ee value by HPLC.
Compound (+)-2a: [α]_D ²⁰ +37.8 (c 1.14, MeOH); mp 180 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.49-7.36 (10 H, m, ArH), 5.08 (2 H, td J = 13, 4 Hz, CHOH), 3.10 (2 H, d J = 4 Hz, CHOH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 138.8 (ArC), 128.6, 128.1, 128.0 (ArCH), 121.5 (t, J = 250.5 Hz, CF₂), 70.4 (t, J = 28.0 Hz, CHOH) ppm. ¹F NMR (282 MHz, CDCl₃): δ = -119.24 (2 F, s, anti). Note that the syn-diol is distinguishable by ¹⁹F NMR spectroscopy: -120.05 (1 F, d J = 255 Hz, syn), -127.23 (1 F, d J = 255 Hz, syn) ppm. MS (ES⁺): m/z = 287 [M + Na]⁺. MS (ES^-): m/z = 263 [M - H]^-. HPLC: Chiralpak AD, 93:3 hexane-i-PrOH, 1 mL/min, 210 nm; t _R = 19.84 [(+)-enantiomer], 34.24 [(-)-enantiomer], 37.52 (syn) min.