Chemoselective Demethylation of Methoxypyridine

Article abstract of DOI:10.1055/s-0037-1612427

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.

Full text of DOI:10.1055/s-0037-1612427

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
K. Makino et al.
Letter
Synlett
Chemoselective Demethylation of Methoxypyridine
Kosho Makinoa
OCH3
OH
L-selectride
(3 equiv)
Yumi Hasegawab
Takahide Inouea
Koji Arakib
R
R
Li
H B
THF, reflux
N
N
Hidetsugu Tabatab
Tetsuta Oshitarib
Kiyomi Itoc
Hideaki Natsugarid
Hideyo Takahashi*a
R = H, Cl, CH3, NH2
9 examples
56–89% yield
L-selectride
OCH3
OH
N
L-selectride
(3 equiv)
S
N
THF, reflux
3 h, 94%
N
S
N
a Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641
Yamazaki, Noda, Chiba 278-8510, Japan
b Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku,
Tokyo 173-8605, Japan
HN
OCH3
HN
OCH3
Chemoselectivity
c Research Institute of Pharmaceutical Sciences, Musashino University,
1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
d Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
hide-tak@rs.tus.ac.jp
Received: 21.02.2019
Accepted after revision: 12.03.2019
Published online: 02.04.2019
L-Selectride is known to be a highly stereoselective re-
ducing agent.10 In 1994, Majetich et al. found that L-selec-
tride 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-withdraw-
ing substituents. Inspired by this, we envisioned that L-se-
lectride could lead to the efficient demethylation of the me-
thoxy group in electron-poor heterocyclic aromatics. For
the purpose of our synthesis of drug metabolites, a new
chemoselective demethylation method for heterocyclic
DOI: 10.1055/s-0037-1612427; Art ID: st-2019-v0105-l
Abstract A chemoselective demethylation method for various me-
thoxypyridine derivatives has been developed. Treatment of 4-me-
thoxypyridine with L-selectride in THF for 2 h at reflux temperature af-
forded 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. Chemo-
selective 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, demethyla-
tion
Table 1 Optimization of Reaction Conditions
OCH3
OH
reducing agent
Methyl ether is considered to be the most useful and ef-
fective 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
acids2 or bases,3 nucleophilic reagents,4 alkali metals,5 and
oxidizing6 or reducing7 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-selectride8 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
solvent, reflux, 2 h
N
N
1a
2a
Entry
Reducing agent
Equiv
Solvent
Yield (%)
1
2
L-selectride
L-selectride
L-selectride
L-selectride
L-selectride
L-selectride
L-selectride
N-selectride
K-selectride
LiBHEt3
1
2
3
3
3
3
3
3
3
3
3
THF
32
58
87
86
65
23
0
THF
3
THF
4
toluene
1,4-dioxane
Et2O
5
6
7
CH2Cl2
THF
8
7
9
THF
4
10
11
THF
30
0
LiBH4
THF
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
K. Makino et al.
Letter
Synlett
compounds seemed advantageous. Therefore, we started a
survey of the reaction conditions of L-selectride to 4-me-
thoxy pyridine 1a (Table 1).
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 ad-
ditional 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 condi-
tions [L-selectride (6 equiv), THF, reflux, 0.5 were selective-
ly 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). Com-
pared 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. Disappoint-
ingly, 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 condi-
tions 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.
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-selec-
tride 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 de-
creased 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 reac-
tion 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 de-
methylation 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 demethyla-
tion, and the reaction was completed in 2 h for 2a, while 24
h was needed for 2b. With the exception of 1d, which pro-
vided strangely complex mixtures, other methoxypyri-
dines, irrespective of their electronic nature (electron-
rich/electron-poor), furnished the corresponding demethyl-
ated compounds 2e–i in 56–84% yields.
OR
OH
L-selectride (3 equiv)
THF, reflux, 2 days
X
X
5–9: X = N
10–14: X = CH
2a: X = N
OMOM
O
OBn
N
OPMB
OEt
OCH3
OH
N
N
N
N
L-selectride (3 equiv)
THF, refluxa
X
X
5 57%
6 57%
7 19%
8 20%
9 11%
N
N
1
2
OMOM
O
OBn
OPMB
OEt
OH
N
OH
N
OH
Cl
OH
OH Cl
N
N
N
N
OH
Cl
10 trace
11 NR
12 NR
13 trace
14 NR
2d 0%
(–)b
2a 87%
(2 h)
2b 89%
(24 h)
2c 82%
(8 h)
2e 73%
(3.5 h)
2f 56%
(4 h)
Scheme 2 Dealkylation of 4-alkoxy pyridines and 4-alkoxybenzenes
OH
OH
OH
OH
We have only limited information on the possible mech-
anism 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).
N
N
N
N
N
NH2
N
OH
N
OH
2j 88%c
(3 days)
4 83%c,d
2g 84%
(24 h)
2h 67%
2i 84%
(4 h)
(9 h)
(0.5 h)
Scheme 1 Demethylation of methoxyheterocycles.12 a Reaction times
are shown in parentheses. b See main text. c L-Selectride (6 equiv) was
used. d 2,4-Dimethoxy-1,3,5-triazine was used as the substrate.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
K. Makino et al.
Letter
Synlett
Table 2 Selective Synthesis of Omeprazole Metabolites 16–18
+
Li
H
R
B
R
R
OCH3
OCH3
+
O
+
R
R
Li
H
Li
H
BR3
+
CH4
Li
reduction
OCH3
B
R
S
O
B
R
O
OH
N
S
R
O
R
N
N
aqueous
work up
N
N
HN
HN
omeprazole
sulfide
+
N
N
OCH3
N
+
R
15
+
Li
H
B
R
R
Li
H
R
R
Li
H
oxidative
O-demethylation
B
R
OR1
N
B
R
R
R
L-selectride (for 16)
or BBr3 (for 17, 18)
R = sec-butyl
S
15
N
Scheme 3 Proposed reaction mechanism for demethylation of me-
thoxypyridine
HN
16: R1 = H, R2 = CH3
17: R1 = CH3, R2 = H
18: R1 = H, R2 = H
OR2
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 meta-
bolic pathway, the sulfoxide group of omeprazole is re-
duced to give the corresponding sulfide 15.13 When the me-
thoxy 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 de-
methylation 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 provided15 using diverse reaction condi-
tions (Table 2). Central to this issue is the problem of che-
moselective demethylation at the site of 3,5-dimethyl-4-
methoxypyridine in the presence of 4-methoxybenzimid-
azole. 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 (CH2-
Cl2/MeOH, 9:1; entry 2). It was elucidated that partial che-
moselectivity 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).
Entry Agent
Reaction conditions
Yield (%)
16
17
18
1
2
3
L-selectride
3.0 equiv, THF
reflux, 3 h
94
0
0
0
BBr3
BBr3
2.5 equiv, CH2Cl2,
0 °C, 12 h
79
0
9
5.0 equiv, CH2Cl2,
rt, 4 h
0
82
thoxybenzimidazole moiety. We anticipate that this meth-
od will be useful in preparing biologically active heterocy-
clic compounds. Related studies are under way in our
laboratory.
Funding Information
This work was supported in part by the Hoansha Foundation.()
References and Notes
(1) Wuts, P. G. M. In Green’s Protective Groups in Organic Synthesis,
5th ed; Wiley-VCH: New York, 2014, 475.
(2) (a) Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem. 1980, 45,
4275. (b) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron
Lett. 1981, 22, 899. (c) Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue,
T.; Mihashi, S.; Itokawa, H.; Ogura, K. J. Org. Chem. 1987, 52,
2957. (d) Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A.
Synthesis 1989, 287. (e) Yamaguchi, S.; Nedachi, M.; Yokoyama,
H.; Hirai, Y. Tetrahedron Lett. 1999, 40, 7363.
(3) (a) Dodge, J. A.; Stocksdale, M. G.; Fahey, K. J.; Jones, C. D. J. Org.
Chem. 1995, 60, 739. (b) Hwu, J. R.; Wong, F. F.; Huang, J.-J.;
Tsay, S.-C. J. Org. Chem. 1997, 62, 4097. (c) Oussa, A.; Thach, L.
N.; Loupy, A. Tetrahedron Lett. 1997, 38, 2451.
(4) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327.
(5) (a) Birch, A. J. Q. Rev., Chem. Soc. 1950, 4, 69. (b) Ohsawa, T.;
Hatano, K.; Kayoh, K.; Kotabe, J.; Oishi, T. Tetrahedron Lett. 1992,
33, 5555. (c) Azzena, U.; Denurra, T.; Melloni, G.; Fenude, E.;
Rassu, G. J. Org. Chem. 1992, 57, 1444.
In summary, we described the demethylation of me-
thoxypyridine derivatives using L-selectride.16 The reaction
occurs at the methoxypyridine derivatives chemoselective-
ly, 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-me-
thoxypyridine moiety reacted without affecting the 4-me-
(6) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
K. Makino et al.
Letter
Synlett
(7) (a) Coop, A.; Lewis, J. W.; Rice, K. C. J. Org. Chem. 1996, 61, 6774.
(b) Coop, A.; Jametka, J. W.; Lewis, J. W.; Rice, K. C. J. Org. Chem.
1998, 63, 4392. (c) Wu, H.; Thatcher, L. N.; Bernard, D.; Parrish,
D. A.; Deschamps, J. R.; Rice, K. C.; MacKerell, A. D.; Coop, A. Org.
Lett. 2005, 7, 2531.
(8) Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159.
(9) (a) Orbe, L.; Carlsson, E.; Lindberg, P. Nat. Rev. Drug Discovery
2003, 2, 132. (b) Larsson, H.; Carlsson, E.; Junggren, U.; Olbe, L.;
Sjoestrand, S. E.; Skaanberg, I.; Sundell, G. Gastroenterology
1983, 85, 900.
CD3OD):  = 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
C
16H18N3O2S: 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):  = 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):  =
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):  = 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):  = 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
(10) Bosin, T. R.; Raymond, M. G.; Buckpitt, A. R. 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-selec-
tride (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 chromatog-
raphy to give the desired compound 2.
(13) (a) Ding, F.; Jiang, Y.; Gan, S.; Bao, R. L.-Y.; Lin, K.; Shi, L. Eur.
J. Org. Chem. 2017, 3427. (b) Joseph, K. M.; Larraza-Scnces, I. Tet-
rahedron Lett. 2011, 52, 13.
(14) Hoffmann, K. J. 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):  = 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,
C
15H16N3O2S: 302.0958; found 302.0959
(16) For general experimental methods, see the Supporting Informa-
tion.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D