Efficient and selective demethylation of heteroaryl methyl ethers in the presence of aryl methyl ethers

Article abstract of DOI:10.1080/00397911.2010.493262

A new and efficient method for the demethylation of 6-membered aza-heterocyclic methyl ethers is described using lithium chloride and para-toluenesulfonic acid. This process is chemoselective for aza-heterocyclic methyl ethers in the presence of aryl methyl ethers.

Full text of DOI:10.1080/00397911.2010.493262

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Efficient and Selective Demethylation of
Heteroaryl Methyl Ethers in the Presence
of Aryl Methyl Ethers
a
a
a
a
Ajay Soni , Akhilesh Dutt , Viswajanani Sattigeri & Ian A. Cliffe
a
Department of Medicinal Chemistry, New Drug Discovery Research,
Ranbaxy Research Laboratories, Gurgaon, Haryana, India
Published online: 29 Apr 2011.
To cite this article: Ajay Soni , Akhilesh Dutt , Viswajanani Sattigeri & Ian A. Cliffe (2011) Efficient
and Selective Demethylation of Heteroaryl Methyl Ethers in the Presence of Aryl Methyl Ethers,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:12, 1852-1857, DOI: 10.1080/00397911.2010.493262
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Synthetic Communications , 41: 1852–1857, 2011
Copyright # Ranbaxy Research Laboratories
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493262
EFFICIENT AND SELECTIVE DEMETHYLATION OF
HETEROARYL METHYL ETHERS IN THE PRESENCE OF
ARYL METHYL ETHERS
Ajay Soni, Akhilesh Dutt, Viswajanani Sattigeri, and
Ian A. Cliffe
Department of Medicinal Chemistry, New Drug Discovery Research,
Ranbaxy Research Laboratories, Gurgaon, Haryana, India
GRAPHICAL ABSTRACT
Abstract A new and efficient method for the demethylation of 6-membered aza-heterocyclic
methyl ethers is described using lithium chloride and para-toluenesulfonic acid. This process
is chemoselective for aza-heterocyclic methyl ethers in the presence of aryl methyl ethers.
Keywords Demethylation; lithium chloride; 2-methoxypyrdidine; p-toluenesulfonic acid;
pyridine-2-one
INTRODUCTION
The methylation of the phenol hydroxy group is regarded as an effective
protecting-group strategy in organic synthesis because of the stability of aryl
[
1,2]
methyl ethers to many reaction conditions.
However, the deprotection of the aryl
methoxy group often involves rather harsh reaction conditions, which can cause side
reactions when the molecule contains other sensitive functionalities. Under such
circumstances, it is often necessary to standardize the demethylation reaction by trial
and error and to investigate a number of different demethylating reagents and
various reaction conditions.
We wished to convert a compound of general formula A that contained a
-methoxypyridinyl group, a methoxy phenyl group, and other acid-sensitive func-
2
tionalties to the 2-pyridone derivative B (Scheme 1). Unfortunately, several com-
monly known methods for the demethylation of aryl methyl ethers such as boron
Received February 5, 2010.
Address correspondence to Ajay Soni, Department of Medicinal Chemistry, New Drug Discovery
Research, Ranbaxy Research Laboratories, Plot 20, Sector 18, Udyog Vihar Industrial Area, Gurgaon
122015, Haryana, India. E-mail: ajay.soni@ranbaxy.com
1
852

EFFICIENT METHOD FOR DEMETHYLATION
1853
Scheme 1. Demethylation in vivo of 2-methoxypyridine A to form the 2-pyridone analog B (R ¼ other
acid-sensitive groups).
[
tribromide, boron trichloride, silyl iodides (e.g., trimethylsilyliodide or tert-butyl-
3]
[4]
[
5]
[6]
dimethylsilyliodide), protic acids (e.g., aqueous hydriodic or hydrobromic acids),
[
7]
[8]
[9]
thiolates, pyridine hydrochloride, and aluminum trichloride resulted in either
poor conversions (10–20%) or decomposition because of the intolerance to the reac-
tion conditions of other substituents present in the molecule.
We were pleasantly surprised, therefore, that heating compound A at 110 C
10]
with 5 molar equivalents of sodium iodide in glacial acetic acid or 5 molar equiva-
lents of potassium iodide in neat phosphoric acid produced a 40–50% yield of
compound B, albeit with some decomposition products. We were equally intrigued
by the fact that the in situ generation of hydrogen iodide from iodocyclohexane
by thermal elimination
60–70%). The conclusion drawn from these experiments is that hydrogen iodide is
ꢀ
[
[
11]
[12]
led to a reasonable conversion of compound A to B
(
responsible for the dealkylation but its concentration is sufficiently low as not to
induce too severe of a decomposition of other portions of molecule A or B. There-
fore, we examined in more detail the conditions required for a high conversion of
compound A to B by using 2-methoxypyridine 1 as a model substrate.
The reaction of compound 1 with 5 molar equivalents of potassium iodide in
ꢀ
neat phosphoric acid at 110 C, or with 5 molar equivalents of lithium iodide in neat
ꢀ
glacial acetic acid at 110 C, gave 2-pyridone 2 in quantitative yield (Table 1, entries
1
and 2). Application of the same reaction conditions to the demethylation of com-
pound A led to some decomposition and suboptimal yields of compound B. In an
attempt to attenuate the reactivity of the system, the reaction of compound 1 with
lithium iodide in glacial acetic acid at lower reaction temperatures resulted only in
incomplete reactions (Table 1, entries 3 and 4). It was evident, therefore, that rela-
tively high temperatures were necessary to induce the dealkylation reaction but that
such high temperatures and a highly acidic environment were proving detrimental to
the stability of compound A or B. We chose to explore the use of high-boiling, polar,
aprotic amides as solvents for the reaction but were disappointed when the reaction
of compound 1 with 5 molar equivalents of both lithium iodide and glacial acetic
ꢀ
acid in dimethylformamide (DMF) at 120 C produced only a modest yield of pro-
duct 2 (Table 1, entry 5). Acetic acid is a relatively weak acid, and we resolved to
examine stronger acids. We were delighted that the reaction of compound 1 with
5
molar equivalents of phosphoric, sulfuric, methanesulfonic (MsOH), or para-
toluenesulfonic (pTSA) acid and 5 molar equivalents of lithium iodide furnished
compound 2 in excellent yields (Table 1, entries 6–9). Changing the solvent from
dimethylformamide to dimethylacetamide (DMA) or N-methylpyrrolidone (NMP)
produced lower yields of product (Table 1, entries 10 and 11).

1854
A. SONI ET AL.
Table 1. Demethylation of 2-methoxypyridine
ꢀ
a
Entry
Salt (5 eq.)
Acid (5 eq.)
Solvent
PO
Temp. ( C)
Yield by HPLC (%)
1
2
3
4
5
6
7
8
9
KI
LiI
—
—
H
3
4
110
110
55
99
100
13
36
54
91
93
96
94
75
90
99
89
86
95
0
AcOH
AcOH
AcOH
DMF
DMF
DMF
DMF
DMF
NMP
DMA
DMF
DMF
DMF
DMF
DMF
DMF
LiI
LiI
—
—
80
LiI
LiI
AcOH
120
120
120
120
120
120
120
120
120
120
120
120
120
H
H
3
PO
SO
4
LiI
LiI
2
4
MsOH
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
LiI
LiI
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
LiI
LiBr
NaCl
KCl
CsCl
CsF
LiCl
100
a
The reactions were quenched after 30 min, and the extent of reaction was determined by HPLC.
Evaluation of the role of metal halides other than lithium iodide showed that
most metal halides (e.g., lithium bromide, sodium chloride, potassium chloride,
cesium chloride: Table 1, entries 12–15) gave good conversions of compound 1 to
2 in the presence of pTSA in dimethylformamide. The highly ionic cesium fluoride
induced no reaction (Table 1, entry 16), whereas lithium chloride produced a quan-
titative yield of product 2 (Table 1, entry 17). By analogy with the metal iodide reac-
10,11]
[
tions,
the combination of lithium chloride and pTSA appears to generate
hydrogen chloride, which is the agent responsible for demethylation. The effect of
LiCl or pTSA alone on the demethylation reaction was evaluated by heating each
ꢀ
reagent with 2-methoxypyridine in DMF at 110 C. No reaction was observed in
either case after 8 h.
The reaction of the phenyl ethers 3–6 with lithium chloride and pTSA gave
ꢀ
only starting materials in dimethylformamide at 120 C. Demethylated products
ꢀ
could be produced, however, by employing a higher reaction temperature (180 C),
N-methylpyrrolidone as solvent, longer reaction time (8 h), and 10 molar equivalents
of both lithium chloride and pTSA (Table 2, entries 1–4). The demethylation of the
3
-methoxy- and 4-methoxypyridines 7 and 8 was more facile than that of the aryl
methyl ethers 3–6 and occurred in the short reaction time of 1 h (Table 2, entries 5
and 6). The demethylation of 6-chloro-2-methoxypyridazine 9 was likewise rapid
ꢀ
and could be achieved using dimethylformamide at 120 C (Table 2, entry 7).

EFFICIENT METHOD FOR DEMETHYLATION
1855
Table 2. Demethylation of aryl methyl ethers and other aza-containing heteroaromatic systems
LiCl (molar
equivalents)
pTSA (molar
equivalents)
Temperature Time Isolated
ꢀ
a
Entry
1
Substrate
Solvent
NMP
( C)
(h)
yield (%)
10
10
180
8
82
2
3
4
10
10
10
10
10
10
NMP
NMP
NMP
180
180
180
8
4
4
95
76
86
5
6
10
10
5
10
10
5
NMP
NMP
DMF
180
180
1
99
85
92
1
7
120
0.5
a 1
All products were purified by column chromatography and characterized by H NMR and mass spec-
troscopy.
The data in Table 2 indicate clearly that six-membered aza-heterocyclic methyl
ethers ought to be chemoselectively demethylated by lithium chloride and pTSA in
the presence of aryl methyl ethers. This suggestion was confirmed by the result of
the reaction of compound 10 with lithium chloride and pTSA in dimethylformamide
ꢀ
at 120 C wherein clean monodemethylation of the pyridinyl methyl ether group in
the presence of a phenyl methyl ether gave compound 11 (Scheme 2). The same
reaction conditions when applied to the compound A on a multigram scale (i.e.,
30–50 mmol) pleasingly resulted in the formation of 2-pyridone compound B in
97% yield.

1856
A. SONI ET AL.
Scheme 2. Selective demethylation of pyridinyl methyl ether in the presence of a phenyl methyl ether.
General Demethylation Procedure
A solution of the methyl ether (1 mmol) in the desired solvent (2 ml) was
treated with alkali halide (5 or 10 molar equivalents) and acid (5 or 10 molar equiva-
lents), heated at the desired temperature for the set period of time, cooled to room
temperature, quenched with water (10 ml), and extracted with ethyl acetate
(
2 ꢁ 10 ml). The combined extracts were washed with water (2 ꢁ 5 ml) and saturated
aqueous brine (2 ꢁ 5 ml), dried (Na SO ), and concentrated in vacuo to give the
2
4
crude product.
Preparation of 5-(4-Methoxyphenyl)pyridin-2-one (11)
A solution of compound 10 (100 mg, 0.47 mmol) in DMF (2 ml) was treated
with lithium chloride (97 mg, 2.33 mmol) and pTSA (441 mg, 2.33 mmol), heated
ꢀ
at 120 C for 30 min, cooled to room temperature, quenched with water (5 ml),
and extracted with ethyl acetate (2 ꢁ 5 ml). The combined extracts were washed with
water (2 ꢁ 5 ml) and saturated aqueous brine (2 ꢁ 5 ml), dried (Na SO ), and concen-
2
4
trated in vacuo to give the desired product (93 mg, 99%).
CONCLUSION
In summary, the reaction of six-membered aza-heterocyclic methyl ethers such
as pyridinyl methyl ethers or a pyridazinyl methyl ether in the presence of 5 molar
equivalents of both lithium chloride and pTSA is a new method for smooth and
efficient demethylation. This process is efficient and selective for aza-heterocyclic
ꢀ
methyl ethers in the presence of aryl methyl ethers at 120 C in dimethylformamide.
ACKNOWLEDGMENTS
We thank the Analytical Chemistry Department of New Drug Discovery
Research, Ranbaxy Research Laboratories, for spectral and chromatographic data.
We also thank Dr. Jitendra Sattigeri for helpful suggestions and comments.
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EFFICIENT METHOD FOR DEMETHYLATION
1857
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