Chemoselective Demethylation of Methoxypyridine

Kosho Makino; Yumi Hasegawa; Takahide Inoue; Koji Araki; Hidetsugu Tabata; Tetsuta Oshitari; Kiyomi Ito; Hideaki Natsugari; Hideyo Takahashi

doi:10.1055/s-0037-1612427

Synlett, Table of Contents

Synlett 2019; 30(08): 951-954
DOI: 10.1055/s-0037-1612427

letter

Chemoselective Demethylation of Methoxypyridine

Kosho Makino

^aFaculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

,

Yumi Hasegawa

^bFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

,

Takahide Inoue

^aFaculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

,

Koji Araki

^bFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

,

Hidetsugu Tabata

^bFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

,

Tetsuta Oshitari

^bFaculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

,

Kiyomi Ito

^cResearch Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan

,

Hideaki Natsugari

^dFaculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Email: hide-tak@rs.tus.ac.jp

,

Hideyo Takahashi*

^aFaculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

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Abstract

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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

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References

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.