Deoxygenation of Pyridine N-Oxides by Palladium-Catalysed Transfer ­Oxidation of Trialkylamines

Abstract

A convenient and chemoselective method for deoxygenation of pyridine N-oxide derivatives by transfer oxidation of triethylamine-catalysed by [Pd(OAc)₂]/dppf is described.

Key words

deoxygenation - homogeneous catalysis - palladium - pyridine N-oxides - ligand effects

References and Notes

• 1a Toganoh M. Fujino K. Ikeda S. Furuta H. Tetrahedron Lett.  2008,  49:  1488 
• 1b Singh SK. Reddy MS. Mangle M. Ganesh KR. Tetrahedron  2006,  63:  126 
• 1c Yoo BW. Choi JW. Yoon CM. Tetrahedron Lett.  2005,  47:  125 
• 1d Sanz R. Escribano J. Fernandez Y. Aguado R. Pedrosa MR. Arnaiz FJ. Synlett  2005,  1389 
• 1e Kumar S. Saini A. Sandhu JS. Tetrahedron Lett.  2005,  46:  8737 
• 1f Ilias M. Barman DC. Prajapati D. Sandhu JS. Tetrahedron Lett.  2002,  43:  1877 
• 1g Boruah M. Konwar D. Synlett  2001,  795 
• 1h Nicolau KC. Koumbis AE. Snyder SA. Simonsen KB. Angew. Chem. Int. Ed.  2000,  39:  2529 
• 1i Keith JM.
  J. Org. Chem.  2006,  71:  9540 
• 1j Bjorsvik H.-R. Gambarotti C. Jensen VR. Gonzalez RR. J. Org. Chem.  2005,  70:  3218 
• 1k Chandrasekhar S. Reddy CR. Rao RJ. Rao JM. Synlett  2002,  349 
• 1l Hwu JR. Tseng WN. Patel HV. Wong FF. Horng D.-N. Liaw BR. Lin LC. J. Org. Chem.  1999,  64:  2211 
• 1m Rosenau T. Potthast A. Ebner G. Kosma P. Synlett  1999,  623 
• 2a Mandal PK. McMurray JS. J. Org. Chem.  2007,  72:  6599 
• 2b Fessard TC. Motoyoshi H. Carreira EM. Angew. Chem. Int. Ed.  2007,  46:  2078 
• 2c Leclerc J.-P. Fagnou K. Angew. Chem. Int. Ed.  2006,  45:  7781 
• 2d Mori A. Mizusaki T. Miyakawa Y. Ohashi E. Haga T. Maegawa T. Monguchi Y. Sajiki H. Tetrahedron  2006,  62:  11925 
• 2e Rahaim RJ. Maleczka RE. Synthesis  2006,  3316 
• 2f Campeau L.-C. Rousseaux S. Fagnou K. J. Am. Chem. Soc.  2005,  127:  18020 
• 2g Rahaim RJ. Maleczka RE. Org. Lett.  2005,  7:  5087 
• 2h Zacharie B. Moreau N. Dockendorff C. J. Org. Chem.  2001,  66:  5264 
• 2i Xu S. Xi X. Shi J. Cao S. J. Mol. Catal. A: Chem.  2000,  160:  287 
• 2j Islam SM. Palit BK. Mukherjee DK. Saha CR. J. Mol. Catal. A: Chem.  1997,  124:  5 
• 2k Petrini M. Ballini R. Rosini G. Synthesis  1987,  713 
• 3a Clarke ML. Fuentes JA. Angew. Chem. Int. Ed.  2007,  46:  930 
• 3b Fuentes JA. Clarke ML. Slawin AMZ. New J. Chem.  2008,  32:  689 

4

Synthesis of Pyridine N -Oxide 2 (Scheme 1)
Aryl bromide 1 (67 mg, 0.29 mmol), Pd(OAc)₂ (1.9 mg, 3 mol%), and a stirring bead were placed in a 5 mL microwave process vial that was placed under a nitrogen atmosphere before the addition of dry DMF (4 mL), Et₃N (0.12 mL, 0.87 mmol), and isobutyl acrylate (0.13 mL, 0.87 mmol). The reaction mixture was heated by microwave irradiation at 140 ˚C for 60 min. After being cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The crude mixture was purified by chromatography on a SiO₂ column using EtOAc-MeOH (8:1) as eluent to give the corresponding coupling product 2 (74 mg, 0.27 mmol, 92%) as a yellow solid; mp 149-151 ˚C. IR (KBr): 3065, 2959, 2876, 1718, 1692, 1639, 1605, 1569, 1525, 1399 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 0.91 (d, J = 6.7 Hz, 6 H, CH₃), 1.94 (m, 1 H, CH), 2.26 (s, 3 H, CH₃), 3.94 (d, J = 6.7 Hz, 2 H, CH₂), 6.38 (d, J = 16.0 Hz, 1 H, =CH), 7.41 (d, J = 16.0 Hz, 1 H, =CH), 7.43 (d, J = 8.8 Hz, 1 H, ArCH), 8.33 (s, 1 H, ArCH), 8.39 (d, J = 8.8 Hz, 1 H, ArCH), 9.98 (br s, 1 H, NH). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.5, 25.4, 28.2, 71.5, 114.7, 121.6, 126.8, 127.0, 136.6, 138.5, 144.9, 166.3, 169.3. MS (TOF-ES): m/z (%) = 301.1 (100) [M + Na]⁺. HRMS (TOF-ES): m/z [M + Na]⁺ calcd for C₁₄H₁₈N₂O₄Na: 301.1164; found: 301.1173.
Synthesis of Compound 3 (Scheme 1) To aryl bromide 1 (134 mg, 0.58 mmol) and [Pd(dippf)Cl₂] (10.4 mg, 3 mol%) in a 5 mL microwave process vial were added dry DMF (4 mL), Et₃N (0.24 mL, 1.74 mmol), and isobutyl acrylate (0.35 mL, 1.74 mmol). The reaction mixture was heated by microwave irradiation at 140 ˚C for 60 min. After being cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The crude mixture was purified by chromatography on a SiO₂ column using EtOAc-hexane (3:1) as eluent to give the corresponding coupling product 3 (130 mg, 0.47 mmol, 81%) as a white solid; mp 112-114 ˚C. IR (KBr): 3245, 3095, 2959, 2876, 1720, 1687, 1641, 1604, 1586, 1542, 1369 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 0.91 (d, J = 6.7 Hz, 6 H, CH₃), 1.94 (m, 1 H, CH), 2.17 (s, 3 H, CH₃), 3.93 (d, J = 6.7 Hz, 2 H, CH₂), 6.38 (d, J = 16.0 Hz, 1 H, =CH), 7.56 (d, J = 16.0 Hz, 1 H, =CH), 7.82 (dd, J = 8.7, 2.3 Hz, 1 H, ArCH), 8.19 (d, J = 8.7 Hz, 1 H, ArCH), 8.31 (d, J = 2.3 Hz, 1 H, ArCH), 8.58 (br s, 1 H, NH). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.2, 24.8, 27.8, 70.8, 113.9, 118.7, 126.5, 136.6, 140.3, 148.2, 152.5, 166.7, 168.9. MS (TOF-ES): m/z (%) = 263.1 (14) [M + H]⁺, 285.0(100) [M + Na]⁺. HRMS (TOF-ES): m/z [M + Na]⁺ calcd for C₁₄H₁₈N₂O₃Na: 285.1215; found: 285.1206.

5

General Procedure for the Deoxygenation of Pyridine N -Oxides
Pyridine N-oxide (0.29 mmol), Pd(OAc)₂ (1.9 mg, 3 mol%), dppf (4.8 mg, 3 mol%), and a stirring bead were placed in a 5 mL microwave process vial that was then put under a nitrogen atmosphere. Dry MeCN (2.5 mL) and Et₃N (0.12 mL, 0.87 mmol) were then added by syringe. The reaction mixture was heated by microwave irradiation at the temperature and time indicated in Tables  [¹] and  [²] . After NMR analysis, the solvent was concentrated under reduced pressure. The crude mixture was purified by chromatog-raphy on SiO₂ using EtOAc as eluent to afford the corresponding deoxygenated products. The spectral data for the isolated material was in accord with the literature data, and authentic samples.