Chemoselective Demethylation of Methoxypyridine

Abstract

A chemoselective demethylation method for various methoxypyridine derivatives has been developed. Treatment of 4-methoxypyridine with L-selectride in THF for 2 h at reflux temperature afforded 4-hydroxypyridine in good yield; no reaction to anisole occurred. The utility of our method was demonstrated by the efficient synthesis of the metabolic substances of the antiulcer agent omeprazole. Chemoselective demethylation at the site of 3,5-dimethyl-4-methoxypyridine in the presence of 4-methoxybenzimidazole was achieved.

Key words

L-selectride - pyridine - anisole - chemoselective - demethylation

• References and Notes

• 1 Wuts PG. M. In Green’s Protective Groups in Organic Synthesis, 5th ed. Wiley-VCH; New York: 2014: 475
• 2a Node M, Nishide K, Fuji K, Fujita E. J. Org. Chem. 1980; 45: 4275
• 2b Nagaoka H, Schmid G, Iio H, Kishi Y. Tetrahedron Lett. 1981; 22: 899
• 2c Inaba T, Umezawa I, Yuasa M, Inoue T, Mihashi S, Itokawa H, Ogura K. J. Org. Chem. 1987; 52: 2957
• 2d Bernard AM, Ghiani MR, Piras PP, Rivoldini A. Synthesis 1989; 287
• 2e Yamaguchi S, Nedachi M, Yokoyama H, Hirai Y. Tetrahedron Lett. 1999; 40: 7363
• 3a Dodge JA, Stocksdale MG, Fahey KJ, Jones CD. J. Org. Chem. 1995; 60: 739
• 3b Hwu JR, Wong FF, Huang J.-J, Tsay S.-C. J. Org. Chem. 1997; 62: 4097
• 3c Oussa A, Thach LN, Loupy A. Tetrahedron Lett. 1997; 38: 2451
• 4 Feutrill GI, Mirrington RN. Tetrahedron Lett. 1970; 1327
• 5a Birch AJ. Q. Rev., Chem. Soc. 1950; 4: 69
• 5b Ohsawa T, Hatano K, Kayoh K, Kotabe J, Oishi T. Tetrahedron Lett. 1992; 33: 5555
• 5c Azzena U, Denurra T, Melloni G, Fenude E, Rassu G. J. Org. Chem. 1992; 57: 1444
• 6 Snyder CD, Rapoport H. J. Am. Chem. Soc. 1972; 94: 227
• 7a Coop A, Lewis JW, Rice KC. J. Org. Chem. 1996; 61: 6774
• 7b Coop A, Jametka JW, Lewis JW, Rice KC. J. Org. Chem. 1998; 63: 4392
• 7c Wu H, Thatcher LN, Bernard D, Parrish DA, Deschamps JR, Rice KC, MacKerell AD, Coop A. Org. Lett. 2005; 7: 2531
• 8 Brown HC, Krishnamurthy S. J. Am. Chem. Soc. 1972; 94: 7159
• 9a Orbe L, Carlsson E, Lindberg P. Nat. Rev. Drug Discovery 2003; 2: 132
• 9b Larsson H, Carlsson E, Junggren U, Olbe L, Sjoestrand SE, Skaanberg I, Sundell G. Gastroenterology 1983; 85: 900
• 10 Bosin TR, Raymond MG, Buckpitt AR. Tetrahedron Lett. 1973; 4699
• 11 Majetich G, Zhang Y, Wheless K. Tetrahedron Lett. 1994; 35: 8727
• 12 Demethylation of Methoxypyridines; General Procedure: To a solution of 1 (1.00 mmol) in THF (7.0 mL) was added L-selectride (1 M in THF, 3.0 mL, 3.00 mmol, 3 equiv) under an argon atmosphere. After being refluxed and monitored by TLC, the reaction mixture was quenched with MeOH and evaporated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound 2.
• 13a Ding F, Jiang Y, Gan S, Bao RL.-Y, Lin K, Shi L. Eur. J. Org. Chem. 2017; 3427
• 13b Joseph KM, Larraza-Scnces I. Tetrahedron Lett. 2011; 52: 13
• 14 Hoffmann KJ. Drug Metab. Dispos. 1986; 14: 341
• 15 Synthetic procedure and characterization of compounds: 2-{[(6-Methoxy-1H-benzimidazol-2-yl)thio]methyl}-3,5-dimethyl-4-pyridinol (16): To a solution of 15 (103.1 mg, 0.299 mmol) in THF (2.1 mL) was added L-selectride (1 M in THF, 0.90 mL, 0.897 mmol) under an argon atmosphere. After being refluxed for 3 h, the reaction mixture was quenched with MeOH and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, 1:19) to give 16 (88.1 mg, 0.280 mmol, 94%) as colorless crystals; mp 140–143 °C. ¹H NMR (600 MHz, CD₃OD): δ = 7.56 (s, 1 H), 7.37 (br, J = 9.0 Hz, 1 H), 6.97 (br, 1 H), 6.83 (dd, J = 3.0, 9.0 Hz, 1 H), 4.38 (s, 2 H), 3.79 (s, 3 H), 1.99 (s, 3 H), 1.97 (s, 3 H); ¹³C NMR (150 MHz, CD₃OD): δ = 180.6, 158.4, 158.4, 148.5, 144.8, 144.8, 136.1, 124.9, 124.9, 124.3, 124.3, 113.7, 56.4, 33.9, 14.4, 11.2; IR (ATR): 3057, 1487 cm^–1; HRMS (ESI-TOF): m/z [M+H]⁺ calcd for C₁₆H₁₈N₃O₂S: 316.1114; found: 316.1113. 2-{[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio}-1H-benzimidazol-6-ol (17): To a solution of 15 (104 mg, 0.300 mmol) in CH₂Cl₂ (2.5 mL) at –78 °C was added BBr₃ (1 M in CH₂Cl₂, 0.75 mL, 0.750 mmol) under an argon atmosphere. After being stirred at 0 °C for 12 h, the reaction mixture was quenched with MeOH and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, 1:9) to give 17 (73.6 mg, 0.234 mmol, 78%) and 18 (9.0 mg, 0.028 mmol, 9%) as colorless crystals; mp 117–118 °C; ¹H NMR (600 MHz, CD₃OD): δ = 8.10 (s, 1 H), 7.29 (d, J = 9.0 Hz, 1 H), 6.85 (br, 1 H), 6.74 (dd, J = 1.8, 9.0 Hz, 1 H), 4.50 (s, 2 H), 3.74 (s, 3 H), 2.24 (s, 3 H), 2.34 (s, 3 H); ¹³C NMR (150 MHz, CD₃OD): δ = 166.3, 166.3, 155.6, 155.6, 155.0, 149.7, 149.7, 127.6, 127.6, 127.2, 127.2, 113.1, 60.6, 38.0, 13.4, 11.3; IR (ATR): 3208, 1434 cm^–1; HRMS (ESI-TOF): m/z [M+H]⁺ calcd for C₁₆H₁₈N₃O₂S: 316.1114; found: 316.1115. 2-{[(4-Hydroxy-3,5-dimethyl-2-pyridinyl)methyl]thio}-1H-benzimidazol-6-ol (18): To a solution of 15 (104 mg, 0.300 mmol) in CH₂Cl₂ (1.5 mL) at 23 °C was added BBr₃ (1 M in CH₂Cl₂, 1.50 mL, 1.50 mmol) under an argon atmosphere. After being stirred at 23 °C for 4 h, the reaction mixture was quenched with MeOH and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, 1:9) to give 18 (73.8 mg, 0.245 mmol, 82%) as colorless crystals; mp 214–216 °C; ¹H NMR (600 MHz, CD₃OD): δ = 7.66 (s, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 6.86 (dd, J = 2.4 Hz, 1 H), 6.76 (dd, J = 2.4, 9.0 Hz, 1 H), 4.42 (s, 2 H), 2.02 (s, 3 H), 1.98 (s, 3 H); ¹³C NMR (150 MHz, CD₃OD): δ = 179.4, 155.3, 147.4, 145.0, 140.2, 136.3, 135.3, 124.6, 124.1, 116.6, 113.6, 99.6, 33.8, 14.0, 10.9; IR (ATR): 3345, 1483 cm^–1; HRMS (ESI-TOF): m/z [M+H]⁺ calcd for C₁₅H₁₆N₃O₂S: 302.0958; found 302.0959
• 16 For general experimental methods, see the Supporting Information.