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.

Methyl ether is considered to be the most useful and effective protective group for phenols in synthetic chemistry because of its tolerance of a variety of reaction conditions.[1] For the demethylation of aromatic methyl ethers, a variety of cleavage methods have been developed, including strong acids[2] or bases,[3] nucleophilic reagents,[4] alkali metals,[5] and oxidizing[6] or reducing[7] reagents. These methods are often drastic, in many cases resulting in side reactions and lower reaction yields. In the course of our synthetic study of drug metabolites consisting of heterocyclic aromatic ethers, we found that L-selectride[8] is an efficient chemoselective agent to fit the purpose. Here, a new method for nucleophilic cleavage of the methyl group in methoxypyridine using L-selectride, which is unresponsive to methoxybenzene (anisole), is reported. The simple method was applied to the chemoselective synthesis of the metabolic substances of the antiulcer agent omeprazole.[9]

Table 1 Optimization of Reaction Conditions

Entry	Reducing agent	Equiv	Solvent	Yield (%)
1	L-selectride	1	THF	32
2	L-selectride	2	THF	58
3	L-selectride	3	THF	87
4	L-selectride	3	toluene	86
5	L-selectride	3	1,4-dioxane	65
6	L-selectride	3	Et2O	23
7	L-selectride	3	CH2Cl2	0
8	N-selectride	3	THF	7
9	K-selectride	3	THF	4
10	LiBHEt3	3	THF	30
11	LiBH4	3	THF	0

L-Selectride is known to be a highly stereoselective reducing agent.[10] In 1994, Majetich et al. found that L-selectride is useful for the nucleophilic deprotection of methyl phenyl ethers.[11] In their report, the reactions proceeded rapidly when the phenyl ring had more electron-withdrawing substituents. Inspired by this, we envisioned that L-selectride could lead to the efficient demethylation of the methoxy group in electron-poor heterocyclic aromatics. For the purpose of our synthesis of drug metabolites, a new chemoselective demethylation method for heterocyclic compounds seemed advantageous. Therefore, we started a survey of the reaction conditions of L-selectride to 4-methoxy pyridine 1a (Table [1]).

The use of 1 to 2 equivalents of L-selectride under reflux conditions in THF did not complete the reaction (Table [1], entries 1 and 2). However, using 3 equivalents of L-selectride provided satisfactory yield of 4-hydroxypyridine 2a (entry 3). Screening revealed that THF was the best solvent (entries 3–7). Changing the counterion of L-selectride decreased the yields (entries 8 and 9). A similar bulky reagent, LiBHEt₃ (entry 10), and less bulky LiBH₄ (entry 11) were not suitable for this reaction. Examination of anisole 3 under the same conditions (THF, reflux, 2 h) showed that the reaction did not proceed at all, and intact 3 was recovered. It was clear that electron-poor heterocyclic pyridine was more reactive than benzene. Further examination revealed that some demethylation in 3 was observed after prolonged reflux conditions in THF (12 h). Thus, chemoselective demethylation of 4-methoxy pyridine 1a in the presence of anisole 3 should be performed by refluxing in THF within 12 h.

After determining the suitable reaction conditions, we then investigated the generality of our protocol. As shown in Scheme [1, a] broad range of methoxypyridines 1a–j was subjected to treatment with L-selectride in THF at reflux temperature. Intriguingly, the position of the -OCH₃ group had a profound influence on the reactivity for demethylation, and the reaction was completed in 2 h for 2a, while 24 h was needed for 2b. With the exception of 1d, which provided strangely complex mixtures, other methoxypyridines, irrespective of their electronic nature (electron-rich/electron-poor), furnished the corresponding demethylated compounds 2e–i in 56–84% yields.

It is noteworthy that sterically hindered and electron-rich 1i afforded 2i in 84% yield. In contrast, the reaction of 2-amino-4-methoxypyridine 1j was very slow, and thus additional agent (6 equiv) and a longer reaction time (3 days) were utilized to obtain 2j in 88% yield. Examination of 2,4-dimethoxy 1,3,5-triazine under slightly modified conditions [L-selectride (6 equiv), THF, reflux, 0.5 were selectively providedh] showed that it underwent demethylation to provide 4 in 83% yield.

We questioned whether we could further apply our method to various 4-alkoxypyridines 5–9 (Scheme [2]). Compared with the methoxypyridines, these compounds were poorly reactive and therefore a longer reaction time (2 days) was necessary. MOM-protected 5 and allyl-protected 6 were converted into 2a in moderate yields. Disappointingly, other protected compounds (benzyl-protected 7, p-methoxybenzyl-protected 8, ethyl-protected 9) furnished 2a in only 11–20% yields. Examination of the corresponding 4-alkoxybenzenes 10–14 under the same reaction conditions confirmed that benzene derivatives were nonreactive. Although the yields were not satisfactory, it is worth noting that the reaction is rather chemoselective, and only the 4-alkoxy pyridines were transformed into 4-hydroxypyridine 2a.

We have only limited information on the possible mechanism of this nucleophilic deprotection. Considering that 3 equivalents of L-selectride were necessary to complete the reaction (Table [1], entry 3), the N atom of pyridine forming a complex with L-selectride should activate the methoxy group remotely. Added to this, the formation of a lithium cation-activated complex at the reaction site, which was proposed by Majetich,[11] facilitates nucleophilic attack by hydride to generate methane (Scheme [3]).

Omeprazole, 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole, is a potent, long-acting inhibitor of gastric acid secretion.[9] In the metabolic pathway, the sulfoxide group of omeprazole is reduced to give the corresponding sulfide 15.[13] When the methoxy groups in the pyridine and benzimidazole rings are oxidatively O-demethylated, the phenolic metabolites 16, 17, and 18 are generated.[14] Thus, the practicality of our demethylation method was demonstrated by the synthesis of the metabolic substance 16. The synthetic plan started from sulfide 15, from which the metabolites 16, 17, and 18 were selectively provided[15] using diverse reaction conditions (Table [2]). Central to this issue is the problem of chemoselective demethylation at the site of 3,5-dimethyl-4-methoxypyridine in the presence of 4-methoxybenzimidazole. Gratifyingly, treatment of 15 with 3 equivalents of L-selectride resulted in only the deprotection of the sterically bulky congested methoxypyridine, and thus the 4-hydroxy pyridine derivative 16 was obtained in 94% yield (entry 1). It is important to note that no reaction occurred at the 4-methoxybenzimidazole site. For the selective synthesis of metabolite 17, the acidic reagent BBr₃ was suitable. The treatment of 2.5 equivalents of BBr₃ with 15 in CH₂Cl₂ at 0 °C for 12 h provided 4-hydroxybenzimidazole derivative 17 in 79% yield, and 9% of dihydroxy compound 18, which were easily separated by silica-gel chromatography (CH₂Cl₂/MeOH, 9:1; entry 2). It was elucidated that partial chemoselectivity for 4-methoxybenzimidazole was achieved by using BBr₃ at a lower temperature. To obtain dihydroxy compound 18, harsher conditions (5 equivalents of BBr₃ in CH₂Cl₂ at r.t. for 5 h) were employed, which provided 18 in 82% yield (entry 3).

Table 2 Selective Synthesis of Omeprazole Metabolites 16–18

Entry	Agent	Reaction conditions	Yield (%)
			16	17	18
1	L-selectride	3.0 equiv, THF reflux, 3 h	94	0	0
2	BBr3	2.5 equiv, CH2Cl2, 0 °C, 12 h	0	79	9
3	BBr3	5.0 equiv, CH2Cl2, rt, 4 h	0	0	82

In summary, we described the demethylation of methoxypyridine derivatives using L-selectride.[16] The reaction occurs at the methoxypyridine derivatives chemoselectively, without reaction to the corresponding methoxybenzene analogues. The usefulness of our method was demonstrated by the efficient synthesis of metabolite 16 of the antiulcer agent omeprazole, in which only the 3,5-dimethyl-4-methoxypyridine moiety reacted without affecting the 4-methoxybenzimidazole moiety. We anticipate that this method will be useful in preparing biologically active heterocyclic compounds. Related studies are under way in our laboratory.

• References and Notes

• 1 Wuts PG. M. In Green’s Protective Groups in Organic Synthesis, 5th ed. Wiley-VCH; New York: 2014: 475
  Search in Google Scholar
• 2a Node M, Nishide K, Fuji K, Fujita E. J. Org. Chem. 1980; 45: 4275
  CrossrefSearch in Google Scholar
• 2b Nagaoka H, Schmid G, Iio H, Kishi Y. Tetrahedron Lett. 1981; 22: 899
  CrossrefSearch in Google Scholar
• 2c Inaba T, Umezawa I, Yuasa M, Inoue T, Mihashi S, Itokawa H, Ogura K. J. Org. Chem. 1987; 52: 2957
  CrossrefSearch in Google Scholar
• 2d Bernard AM, Ghiani MR, Piras PP, Rivoldini A. Synthesis 1989; 287
  Thieme Connect
• 2e Yamaguchi S, Nedachi M, Yokoyama H, Hirai Y. Tetrahedron Lett. 1999; 40: 7363
  CrossrefSearch in Google Scholar
• 3a Dodge JA, Stocksdale MG, Fahey KJ, Jones CD. J. Org. Chem. 1995; 60: 739
  CrossrefSearch in Google Scholar
• 3b Hwu JR, Wong FF, Huang J.-J, Tsay S.-C. J. Org. Chem. 1997; 62: 4097
  CrossrefSearch in Google Scholar
• 3c Oussa A, Thach LN, Loupy A. Tetrahedron Lett. 1997; 38: 2451
  CrossrefSearch in Google Scholar
• 4 Feutrill GI, Mirrington RN. Tetrahedron Lett. 1970; 1327
• 5a Birch AJ. Q. Rev., Chem. Soc. 1950; 4: 69
  CrossrefSearch in Google Scholar
• 5b Ohsawa T, Hatano K, Kayoh K, Kotabe J, Oishi T. Tetrahedron Lett. 1992; 33: 5555
  CrossrefSearch in Google Scholar
• 5c Azzena U, Denurra T, Melloni G, Fenude E, Rassu G. J. Org. Chem. 1992; 57: 1444
  CrossrefSearch in Google Scholar
• 6 Snyder CD, Rapoport H. J. Am. Chem. Soc. 1972; 94: 227
  CrossrefSearch in Google Scholar
• 7a Coop A, Lewis JW, Rice KC. J. Org. Chem. 1996; 61: 6774
  CrossrefPubMedSearch in Google Scholar
• 7b Coop A, Jametka JW, Lewis JW, Rice KC. J. Org. Chem. 1998; 63: 4392
  CrossrefSearch in Google Scholar
• 7c Wu H, Thatcher LN, Bernard D, Parrish DA, Deschamps JR, Rice KC, MacKerell AD, Coop A. Org. Lett. 2005; 7: 2531
  CrossrefPubMedSearch in Google Scholar
• 8 Brown HC, Krishnamurthy S. J. Am. Chem. Soc. 1972; 94: 7159
  CrossrefSearch in Google Scholar
• 9a Orbe L, Carlsson E, Lindberg P. Nat. Rev. Drug Discovery 2003; 2: 132
  CrossrefPubMedSearch in Google Scholar
• 9b Larsson H, Carlsson E, Junggren U, Olbe L, Sjoestrand SE, Skaanberg I, Sundell G. Gastroenterology 1983; 85: 900
  CrossrefPubMedSearch in Google Scholar
• 10 Bosin TR, Raymond MG, Buckpitt AR. Tetrahedron Lett. 1973; 4699
• 11 Majetich G, Zhang Y, Wheless K. Tetrahedron Lett. 1994; 35: 8727
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 14 Hoffmann KJ. Drug Metab. Dispos. 1986; 14: 341
  PubMedSearch in Google Scholar
• 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.

• References and Notes

• 1 Wuts PG. M. In Green’s Protective Groups in Organic Synthesis, 5th ed. Wiley-VCH; New York: 2014: 475
  Search in Google Scholar
• 2a Node M, Nishide K, Fuji K, Fujita E. J. Org. Chem. 1980; 45: 4275
  CrossrefSearch in Google Scholar
• 2b Nagaoka H, Schmid G, Iio H, Kishi Y. Tetrahedron Lett. 1981; 22: 899
  CrossrefSearch in Google Scholar
• 2c Inaba T, Umezawa I, Yuasa M, Inoue T, Mihashi S, Itokawa H, Ogura K. J. Org. Chem. 1987; 52: 2957
  CrossrefSearch in Google Scholar
• 2d Bernard AM, Ghiani MR, Piras PP, Rivoldini A. Synthesis 1989; 287
  Thieme Connect
• 2e Yamaguchi S, Nedachi M, Yokoyama H, Hirai Y. Tetrahedron Lett. 1999; 40: 7363
  CrossrefSearch in Google Scholar
• 3a Dodge JA, Stocksdale MG, Fahey KJ, Jones CD. J. Org. Chem. 1995; 60: 739
  CrossrefSearch in Google Scholar
• 3b Hwu JR, Wong FF, Huang J.-J, Tsay S.-C. J. Org. Chem. 1997; 62: 4097
  CrossrefSearch in Google Scholar
• 3c Oussa A, Thach LN, Loupy A. Tetrahedron Lett. 1997; 38: 2451
  CrossrefSearch in Google Scholar
• 4 Feutrill GI, Mirrington RN. Tetrahedron Lett. 1970; 1327
• 5a Birch AJ. Q. Rev., Chem. Soc. 1950; 4: 69
  CrossrefSearch in Google Scholar
• 5b Ohsawa T, Hatano K, Kayoh K, Kotabe J, Oishi T. Tetrahedron Lett. 1992; 33: 5555
  CrossrefSearch in Google Scholar
• 5c Azzena U, Denurra T, Melloni G, Fenude E, Rassu G. J. Org. Chem. 1992; 57: 1444
  CrossrefSearch in Google Scholar
• 6 Snyder CD, Rapoport H. J. Am. Chem. Soc. 1972; 94: 227
  CrossrefSearch in Google Scholar
• 7a Coop A, Lewis JW, Rice KC. J. Org. Chem. 1996; 61: 6774
  CrossrefPubMedSearch in Google Scholar
• 7b Coop A, Jametka JW, Lewis JW, Rice KC. J. Org. Chem. 1998; 63: 4392
  CrossrefSearch in Google Scholar
• 7c Wu H, Thatcher LN, Bernard D, Parrish DA, Deschamps JR, Rice KC, MacKerell AD, Coop A. Org. Lett. 2005; 7: 2531
  CrossrefPubMedSearch in Google Scholar
• 8 Brown HC, Krishnamurthy S. J. Am. Chem. Soc. 1972; 94: 7159
  CrossrefSearch in Google Scholar
• 9a Orbe L, Carlsson E, Lindberg P. Nat. Rev. Drug Discovery 2003; 2: 132
  CrossrefPubMedSearch in Google Scholar
• 9b Larsson H, Carlsson E, Junggren U, Olbe L, Sjoestrand SE, Skaanberg I, Sundell G. Gastroenterology 1983; 85: 900
  CrossrefPubMedSearch in Google Scholar
• 10 Bosin TR, Raymond MG, Buckpitt AR. Tetrahedron Lett. 1973; 4699
• 11 Majetich G, Zhang Y, Wheless K. Tetrahedron Lett. 1994; 35: 8727
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 14 Hoffmann KJ. Drug Metab. Dispos. 1986; 14: 341
  PubMedSearch in Google Scholar
• 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.