Microwave-Assisted Hydrogenation of Pyridines

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

• 1a Dallinger D. Kappe CO. Chem. Rev.  2007,  107:  2563 
• 1b Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 
• 2 Baghurst DR. Mingos DMP. J. Chem. Soc., Chem. Commun.  1992,  674 
• 3 Varma RS. Green Chem.  1999,  1:  43 
• 4 Loupy A. Varma RS. Chemistry Today  2005,  24:  36 
• 5 Herrero MA. Kremsner JM. Kappe CO. J. Org. Chem.  2008,  73:  36 ; and references therein
• 6 Nilsson P. Olofsson K. Larhed M. Top. Curr. Chem.  2006,  266:  103 ; and references therein
• 7 Vanier GS. Synlett  2007,  131 
• 8a Daly JW. Spande TF. Garraffo HM. J. Nat. Prod.  2005,  68:  1556 
• 8b Buffat MGP. Tetrahedron  2004,  60:  1701 
• 9 Donohoe TJ. Garg R. Stevenson CA. Tetrahedron: Asymmetry  1996,  7:  317 ; and references therein
• 10 Petricci E. Taddei M. Chemistry Today  2007,  25(3):  45 
• 11 Petricci E. Mann A. Rota A. Schoenfelder A. Taddei M. Org. Lett.  2006,  8:  3725 ; with this device it is possible to carry standard reactions in sealed tube, under nitrogen atmosphere, and under a reactive gas pressure up to 200 psi; see http://www.cem.com
• 14 For analogous examples, see: Alongi M. Minetto G. Taddei M. Tetrahedron Lett.  2005,  46:  7069 
• 18 (a) Compound 29 - conditions: r.t., 15 h, 45 psi, only cis isomer isolated: Chênevert R. Dickman M. J. Org. Chem.  1996,  61:  3332 
• 18 (b) Compound 31 - conditions: 110 °C, 60 h, 50 psi of H₂, ratio 3:1: Urban FJ. J. Heterocycl. Chem.  1995,  32:  857 
• 19 Curran TP. Smith MB. Pollastri MP. Tetrahedron Lett.  1994,  35:  4515 
• In the case of compound 32 we were expecting a good selectivity, relying on the possibility of an intramolecular hydrogen bond between the OH, the N, and the Pt catalyst. Surprised of finding a 2:1 ratio, we repeated the reduction reported to give a high dr (EtOH, PtO₂, 400 psi for 24 h at r.t.). However, we still observed the formation of 32 as a 2:1 mixture of diastereoisomers (¹³C NMR analysis), the same ratio observed by us under microwave irradiation. See:
• 19a Jones TH. Tetrahedron Lett.  1990,  31:  1535 
• 19b Cooke GA. Fodor G. Can. J. Chem.  1968,  46:  1105 

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: