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Synlett 2008(8): 1125-1128  
DOI: 10.1055/s-2008-1072717
LETTER
© Georg Thieme Verlag Stuttgart · New York

Microwave-Assisted Hydrogenation of Pyridines

Leonarda Pirasa, Eva Genesiob, Chiara Ghironb, Maurizio Taddei*a
a Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Fax: +39(0577)234333; e-Mail: taddei.m@unisi.it;
b Siena Biotech SpA, Via Fiorentina 1, 53100 Siena, Italy
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Publikationsverlauf

Received 19 January 2008
Publikationsdatum:
16. April 2008 (online)

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Abstract

Using a commercially available device for controlled introduction of hydrogen in a vial for reactions under microwave dielectric heating, we developed a protocol for the transformation of substituted pyridines into the corresponding piperidines. Complete reduction occurred in 40 minutes, or even less, on substrates that require 24-48 hours to be reduced under standard conditions. Moreover, the reduction proved to be as stereoselective as the corresponding reaction carried out at room temperature.

Key words

microwave - hydrogenation - piperidines - heterogeneous catalysis

    References and Notes

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12

Pipecolinic acid was obtained in 95% by reduction of picolinic acid with H2 (100 psi) on PtO2 in EtOH at 80 °C for 20 min as reported in ref. 7.

13

N -Methyl-2-(piperidin-2-yl)ethanamine (25) - General Procedure A suspension of PtO2 (0.045 mmol, 10.3 mg, 10%mol) in AcOH (1.5 mL) was placed in the vial of a Discover Microwave Synthesizer and purged three times with H2 (120 psi). The vial was submitted to microwave irradiation (200 W) at 50 °C for 15 min. The vial was vented, flushed with nitrogen, and then opened to introduce N-Boc-N-methyl-2-(pyridin-2-yl)ethanamine (11, 107 mg, 0.45 mmol). The vial was closed and purged again with H2 (120 psi). The reaction mixture was then heated under microwave irradiation (200 W) at 80 °C (applying pulse cooling of the vial with a steam of air to avoid overheating) for 20 min. During this period we observed absorption of H2 as the internal pressure of the vial decreased to 70 psi. After cooling to r.t. the reaction mixture was filtered through Celite®. The filter was washed with MeOH (2 mL) and the solution concentrated under reduced pressure. The crude was mixed with EtOAc (10 mL) and to this mixture solid Cs2CO3 (1.2 mmol, 390 mg) was added. The suspension was stirred at r.t. for 10 h, then filtered again through Celite® and the filter washed with additional EtOAc. The collected fractions were evaporated to give pure N-methyl-2-(piperidin-2-yl)ethanamine (25, 107 mg, 98% yield). 1H NMR (400 MHz, DMSO-d 6): δ = 3.16 (m, 2 H, CH2N), 2.89 (m, 1 H, CH-6), 2.7 (s, 3 H, CH3), 2.53-2.37 (m, 2 H, CH-6, CH-3), 2.32 (m, 1 H, CH-2), 1.70 (m, 1 H, CH-4), 1.56 (m, 1 H, CH-4), 1.50-1.17 (m, 13 H, CH2CHN, CH-3, CH-5, CH3C), 1.06-0.91 (m, 1 H, CH-5). ES-MS: m/z = 243.2 [M+1]+.
Characterisation of piperidines that are not previously described:
Compound 24: 1H NMR (400 MHz, DMSO-d 6): δ = 6.75 (br s, 1 H, NHCO), 2.30-2.85 (m, 3 H, CH2N, CH-6), 2.51-2.85 (m, 2 H, CH-6, CH-2), 1.66 (m, 1 H, CH-4), 1.54 (m, 1 H, CH-4), 1.45-1.16 (m, 14 H, CH2CHN, CH-3, CH-5, CH3C), 0.96 (m, 1 H, CH-5). ES-MS: m/z = 229.2 [M + 1]+.
Compound 28: 1H NMR (400 MHz, DMSO-d 6): δ = 3.7 (s, 6 H, CH3O), 3.36 (dd, 1 H, J 1 = 4 Hz, J 2 = 12.4 Hz, CH-2), 3.05-2.86 (m, 3 H, CH-2, CH-3, CH-6), 2.78-2.71 (m, 1 H, CH-6), 2.70-2.62 (m, 1 H, CH-4), 2.01-1.92 (m, 1 H, CH-5), 1.87-1.78 (m, 1 H, CH-5). ES-MS: m/z = 202.2 [M + 1]+.
Compound 26 (as a cis-trans mixture): 1H NMR (400 MHz, CDCl3): δ = 3.66 (s, 3 H, CH3O), 3.62 (s, 3 H, CH3O), 3.32 (m, 1 H, CH-2), 3.26 (m, 1 H, CH-2), 3.04 (m, 1 H, CH-6), 2.94 (m, 1 H, CH-6), 2.75 (dd, 1 H, J 1 = 3.6 Hz, J 2 = 13.2 Hz, CH-2), 2.65-2.55 (m, 2 H, CH-2, CH-3), 2.27 (t, 1 H, J = 8 Hz, CH-6), 2.16 (t, 1 H, J = 12 Hz, CH-6), 2.06 (m, 2 H, CH-3, CH-4), 1.68 (m, 2 H, CH-5), 1.34 (m, 1 H, CH-4), 1.12 (2 H, m, CH-4), 0.83 (m, 6 H, CH3). ES-MS: m/z = 158.2 [M + 1]+.

15

In this experiment we observed the formation of about 25% of the expected acetamide. This kind of product was never observed under microwave dielectric heating.

16

The ratio was determined by 1H NMR analysis of the crude reaction mixture. The stereochemistry was determined after purification of the corresponding tosylates prepared under standard conditions. The isomeric tosylates were separated by flash chromatography on silica gel and the relative stereochemistry of the substituents assigned by comparison of the coupling constants determined through gDQCOSY.

17

Except for compound 28 that is not reported in the literature, the other products have been previously obtained by hydrogenation of the corresponding pyridines over heterogeneous catalysts under higher pressure for longer times: