A Simple Setup for Transfer Hydrogenations in Flow Chemistry

Abstract

By using a packed-bed reactor with a palladium/charcoal catalyst and ammonium formate or triethylsilane as hydrogen/hydride source, various functional groups including nitro groups, azides and alkenes can be efficiently reduced by a transfer hydrogenation process under mild conditions in a simple flow system.

Key words

alkenes - flow chemistry - nitro compounds - packed bed reactor - transfer hydrogenation

• References and Notes

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• 20 Fixed Bed Column Preparation: Portions of Celite (1.45 g) and 5% Pd/C (200 mg) were ground together with a mortar and pestle. After inserting the end-cap (with a 10–40 μm filter) into a 150 mm Omni-Fit column (6.6 mm ID), the ground Celite/Pd/C mixture was packed by tapping on the benchtop and priming with solvent. The column was sealed with an end-cap. The column was further packed by flowing MeOH through the column at 0.5 mL/min until no air bubbles were observed. The column volume, averaging 2.17 mL, was determined from the difference between the anhydrous and wet weights divided by the density of the solvent (MeOH). General Procedure for Reductions: Nitro compound or olefin (5 mmol) and hydrogen source (25 mmol) were dissolved in MeOH (10 mL, 0.5 M). After flushing the column with MeOH, the substrate/reagent solution was pumped through the column at the specified temperature with a flow rate of 0.108 mL/min by using Vapourtec E-series equipment (with a peristaltic pump). Alternatively, a syringe pump can be used. The first column volume was discarded, the second was collected. The solvent was evaporated, the residue added to distilled water (20 mL), and extracted with diethyl ether or dichloromethane (3 × 15 mL). The combined organic phases were dried over MgSO₄, filtered, and the solvent was removed in vacuo. 2-Amino-1-(p-tolyl)ethan-1-ol (2): Yield: 138 mg (0.92 mmol, 85%); colourless solid; mp 139–140 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 7.18 (d, J = 7.9 Hz, 2 H), 7.08 (d, J = 7.8 Hz, 2 H), 4.70 (dd, J = 8.4, 2.8 Hz, 1 H), 3.57 (br s, 3 H), 2.99 (dd, J = 12.7, 3.4 Hz, 1 H), 2.84 (dd, J = 12.6, 8.8 Hz, 1 H), 2.30 (s, 3 H); in agreement with reported literature data.^21a Benzylamine (4): Yield: 113 mg (1.06 mmol, 98%); colourless liquid; ¹H NMR (CDCl₃, 400 MHz): δ = 7.18–7.31 (5 H, m), 3.81 (2 H, s); ¹³C NMR (CDCl₃, 100 MHz): δ = 143.3, 128.6, 127.1, 126.8, 46.2; in agreement with reported literature data.^21b Anthranilic acid (7): Yield: 133 mg (0.98 mmol, 90%); off-white solid; mp 147–150 °C; ¹H NMR (CDCl₃, 400 MHz): δ = 7.93 (d, J = 8.1 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 6.67 (d, J = 7.2 Hz, 2 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 173.6, 151.6, 135.6, 132.6, 117.2, 116.9, 109.9; in agreement with reported literature data.^21c 3-Ethylaniline (9): Yield: 128 mg (1.06 mmol, 98%); pale-yellow liquid; ¹H NMR (CDCl₃, 400 MHz): δ = 7.08 (t, J = 7.7 Hz, 1 H), 6.62 (d, J = 7.5 Hz, 1 H), 6.57–6.50 (m, 2 H), 3.25 (br. s, 1.5 H), 2.57 (q, J = 7.5 Hz, 2 H), 1.21 (t, J = 7.6 Hz, 3 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 146.4, 145.7, 129.2, 118.4, 115.0, 112.5, 28.9, 15.5; in agreement with reported literature data.^21d Aniline (11): Yield: 0.73 g (7.85 mmol, 78%); pale-yellow liquid; ¹H NMR (CDCl₃, 400 MHz): δ = 7.17 (d, J = 7.5 Hz, 2 H), 6.77 (t, J = 7.4 Hz, 1 H), 6.70 (t, J = 7.6 Hz, 2 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 146.5, 129.4, 118.7, 115.2. Methyl 3-phenylpropanoate (13): Yield: 172 mg (1.05 mmol, 97%); colourless oil; ¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.30 (m, 2 H), 7.18–7.21 (m, 3 H), 3.66 (s, 3 H), 2.95 (t, J = 7.8 Hz, 2 H), 2.63 (t, J = 7.8 Hz, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 140.5, 128.5, 128.3, 123.7, 51.7, 35.7, 30.9; in agreement with reported literature data.^21a 3-Phenylpropanenitrile (15): Yield: 113 mg (0.86 mmol, 80%); pale-yellow liquid; ¹H NMR (CDCl₃, 400 MHz): δ = 7.25–7.31 (m, 5 H), 2.99 (t, J = 7.4 Hz, 2 H), 2.64 (t, J = 7.4 Hz, 2 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 138.3, 129.2, 128.6, 127.8, 119.5, 32.1, 19.6 ppm; in agreement with reported literature data.^21e
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