Solvent and substituent effects on the conversion of 4-methoxypyridines to N-methyl-4-pyridones

Article abstract of DOI:10.1080/00397911.2017.1290804

In the reaction of 4-methoxypyridine derivatives with alkyl iodides in the presence or absence of solvent, not only the pyridinium ions but also the related 1-methylpyridones are produced. The presence of solvent favors the formation of the 1-methylpyridone. Electron withdrawing groups on the pyridine ring also favor this conversion. A possible mechanism is presented.

Full text of DOI:10.1080/00397911.2017.1290804

Synthetic Communications
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Solvent and Substituent Effects on the Conversion
of 4-methoxypyridines to N-Methyl-4-pyridones
Xiao Yi, Jing Chen, Xiuling Xu & Yongmin Ma
To cite this article: Xiao Yi, Jing Chen, Xiuling Xu & Yongmin Ma (2017): Solvent and
Substituent Effects on the Conversion of 4-methoxypyridines to N-Methyl-4-pyridones, Synthetic
Communications, DOI: 10.1080/00397911.2017.1290804
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Date: 17 February 2017, At: 01:44

Solvent and Substituent Effects on the Conversion of 4-Methoxypyridines to N-
Methyl-4-Pyridones
Xiao Yi1, Jing Chen1, Xiuling Xu1, Yongmin Ma1
1College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, P
R China
Corresponding Author: Yongmin Ma E-mail: yongmin.ma@zcmu.edu.cn
Abstract
In the reaction of 4-methoxypyridine derivatives with alkyl iodides in the presence or
absence of solvent, not only the pyridinium ions but also the related 1-methylpyridones
are produced. The presence of solvent favours the formation of the 1-methylpyridone.
Electron withdrawing groups on the pyridine ring also favours this conversion. A
possible mechanism is presented.
Graphical Abstract
KEYWORDS: substituent effect; rearrangement; solvent effect; pyridine
INTRODUCTION
Aromatic heterocycles have many key roles in metabolism and other cellular processes.
A large number of aromatic N-heterocycles are used as structural components of
pharmaceuticals and agrochemicals, due to their biological activity. Among these
1

compounds, pyridine derivatives are found as compounds of herbicides, insecticides,
vitamins, pharmaceuticals and adhesives.[1]
The compound 4-hydroxypyridine has an interesting chemical structure due to the
presence of two tautomers, 4-hydroxypyridine and pyridine-4-one.[2] The hydroxy-
tautomer is detected in significant amounts in nonpolar solvents such as in petroleum
ether or in the gas phase[3]; in contrast, the more polar pyridone tautomer is favoured in
polar solvents such as N-methylpyrrolidinone[4]. The polar nature results from the charge-
separation in the pyridine form[5].
Hydroxypyridine has two different reactive nucleophilic centers and the alkylation of
such compound can occur on either the phenolic oxygen or the pyridine nitrogen. The
favoured route depends on the alkylating agent and the reaction conditions. N-alkylation,
as well as O-alkylation can be afforded during the alkylation in normal case.[4,6]
Generally, O-alkylation occurs in non-polar solvents and N-alkylation proceeds in polar
solvents. O-alkylation predominates for reactions with silyl chloride[7], whereas N-
alkylation occurs exclusively when 4-hydroxypyridine reacts with 1,2-dibromo-4,5-
dimethylbenzene[8]. The 4-pyridone can also be converted from its corresponding 4-
pyridyl ether with base in a polar solvent.[4]
Hydroxypyridinium is an important intermediate which is not synthesized from
hydroxypyridine via direct alkylation due to the mixture of tautomers present. Generally,
an O-protecting group is induced via the Mitsunobu reaction which yields the
2

corresponding O-alkylated product in preference to N-alkylation[9]. The O-protecting
group was then deprotected to afford the hydroxypyridinium analogues[9,10]
.
N-methylated derivatives of 4-pyridone have found application as useful functional
intermediates in the production of pharmaceuticals, veterinary drugs, pesticides and
liquid crystal materials.[11] One of the 4-pyridone derivatives, 1,2-dimethylpyridin-4-one
is currently used to treat iron overload in β-thalassemia patients.[12]
Recently, we reported that the presence of fluorine on the 3- position of 4-pyridyl ethers
strongly influenced its reaction with methyl iodide. The predicted 1-methylpyridinium
salts were not formed and instead the 1-methylpyridone was obtained.[13] Here we would
like to report the effects of solvent and substituents at the 2- or 3-position of 4-
methoxypyridine on its reaction with alkyl iodides.
In order to obtain 2- or 3-substituted 4-methoxypyridines (1) as starting materials, the
commercially available 4-hydroxypyridine analogues were first treated with POCl3 to
afford 4-chloropyridine derivatives[14], followed by methoxylation with NaOMe to obtain
4-methoxypyridine analogues.[15] The 2- or 3-substituted 4-methoxypyridines were then
treated with methyl iodide in the presence or absence of solvent, the corresponding 1-
methylpyridinium ions and/or 1-methylpyridones were afforded (Scheme 1).
RESULTS AND DISCUSSION
3

When 4-methoxypyridine was treated with methyl iodide in the absence of any solvent
for 12h, only the expected 4-methoxy-1-methylpyridin-1-ium salt was formed (Entry 1,
Table 1). However, in the presence of acetone, a different reaction was observed. TLC
showed that apart from the main spot (4-methoxy-1-methylpyridin-1-ium), another spot
above the main spot was observed. NMR and MS data demonstrated that the methyl
group of 4-methoxypyridine disappeared and the product 1-methylpyridin-4-one was
obtained (Entry 2). Similar phenomena were observed for the reaction in the presence of
other solvents such as toluene, acetonitrile, methanol and THF. The ratio of the products
2 and 3 is around 1:1 (see for example Entries 3-6). Prolonging the reaction time does not
change the product ratio. Surprisingly, when solvent DMF was used, only product 3 was
observed (Entry 7). However, when 4-methoxypyridine was treated with dimethyl
sulphate or bromoethane instead of methyl iodide in the presence or absence of any
solvent, the reaction failed and only the starting material was observed as assessed by
TLC (Entry 8). Similarly, when an electron donating group such as methyl or methoxy
was substituted at the 3-position of the pyridine ring, only pyridinium 2 was afforded in
the absence of any solvent, whereas a mixture of 2 and 3 was obtained in the presence of
acetone (Entries 9-12). When the position 3 of pyridine was substituted by an electron
withdrawing group such as NO2, the 1-methylpyridinium derivative was not formed
either in the presence or absence of acetone. Instead, the 1-methylpyridin-4-one
derivative was obtained (Entries 13-14). Similarly, when the adjacent position of 4-
methoxypyridine was substituted by another electron withdrawing atom such as Br, the
same phenomena were observed, that is, only the 1-methylpyridin-4-one derivative was
afforded (Entries 15-18). In contrast to the 3-substituted 4-methoxypyridines, the 2-
4

substituted analogues reacted with methyl iodide to afford product in a slightly different
way. All the selected 2-substituted 4-methoxypyridines reacted with methyl iodide in the
absence of solvent to afford the 1-methylpyridinium derivative, regardless of the presence
of an electron donating or an electron withdrawing group at position 2 (1g, 1h, 1i). In the
presence of acetone, although the main product was the 1-methylpyridinium derivative,
trace amount of the 1-methylpyridone was also detected (Entry 20). By changing the
electron donating group methyl to electron withdrawing group Cl or COOH at position 2,
the yield of the corresponding 1-methylpyridone was increased (Entry 22, Entry 24).
However, the presence of electron withdrawing groups on position 2 of pyridine
inactivated the lone pair of electrons on N and therefore the reaction required in harsher
conditions.
In addition, when 3,5-dibromo-4-methoxypyridine (1f) was treated with ethyl iodide
instead of methyl iodide in the presence or absence of acetone, besides the expected
product 3,5-dibromo-1-ethylpyridin-4(1H)-one (4f), a small amount of 3,5-dibromo-1-
methylpyridin-4(1H)-one (3f) was also obtained (4f:3f = 3:1) (Scheme 2). This
phenomenon indicated that EtI reacted with 1f to produce traces of MeI. MeI is more
susceptible than EtI to be attacked by the lone pair of electrons on N of the pyridine.
Similarly, a mixture of 3,5-dibromo-1-isopropylpyridin-4(1H)-one (5f) and 3,5-dibromo-
1-methylpyridin-4(1H)-one (3f) (1:1) were afforded when 1f was treated with isopropyl
iodide. The higher proportion of 3f in this reaction compared to that of the reaction with
EtI results from the steric effect of the isopropyl group.
5

A possible mechanism for this conversion may involve a rearrangement of methyl from
4-methoxy to N. Theoretically the lone pair of electrons on N atom attacks the
electrophilic methyl iodide to form 1-methylpyridinium. The resulting intermediate 1-
methylpyridinium could be attacked by the iodide ion. The presence of an electron
withdrawing group at position 3 drives this reaction, favouring 1-methylpyridone
derivatives. In contrast to the presence of 3- electron withdrawing groups, electron
withdrawing groups at C-2 of pyridine inactivates the lone pair of electrons on N and
reduces the methylation at N. The presence of solvent facilitates the rearrangement.
EXPERIMENTAL SECTION
General Procedure For Methylation Of Compounds In Solvent-Free System
To a round bottle flask containing 1 (2 mmol) was added methyl iodide (10 mmol; 5
equiv.) and the mixture was stirred at room temperature or refluxed overnight. The
reaction was monitored by TLC. After completion, the resulting precipitate was separated
by filtration and purified by recrystallization.
General Procedure For Methylation Of Compounds In The Presence Of Solvent
Methyl iodide (4 mmol; 2 equiv.) was added to a solution of 1 (2 mmol) in various
solvents (15 ml) and the mixture was refluxed overnight. The reaction was monitored by
TLC. After completion, the solvent was removed under reduced pressure and the residue
was purified by column chromatography (EtOAc: MeOH, 20:1→5:1) to obtain the
products.
6

Characterization Data For Selected Compounds
1,3-Dimethyl-4-Pyridone (3b)
White needles, m.p. 110 oC-112 oC. 1H NMR (500 MHz, DMSO-d6) δ 7.68 – 7.66 (m,
1H), 7.64 (dd, J = 7.4, 2.2 Hz, 1H), 6.13 (dt, J = 7.1, 1.7 Hz, 1H), 3.64 (s, 3H), 1.85 (s,
3H). 13C NMR (126 MHz, DMSO-d6) δ 176.63, 141.51, 139.85, 126.04, 114.98, 43.34,
14.02. HRMS (ESI): m/z calcd for (C7H10NO)+: 124.0684; found: 124.0689.
2-Chloro-4-Methoxy-1-Methylpyridinium Iodide (2h)
Pale yellow needles, m.p. 115 oC -117 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.95 (dd, J =
7.2, 2.9 Hz, 1H), 8.02 (d, J = 2.9 Hz, 1H), 7.65 (dd, J = 7.2, 1H), 4.15 (s, 3H), 4.11 (s,
3H). 13C NMR (151 MHz, DMSO-d6) δ 171.65, 148.92, 148.07, 114.66, 112.95, 59.19,
35
45.89, 40.42. HRMS (ESI): m/z calcd for (C7H9 ClNO)+: 158.0367; found: 158.0370.
4-Methoxy-1,2-Dimethylpyridinium Iodide (2g)
White needles, m.p. 168 oC -169 oC (lit.[16] 168 oC). 1H NMR (600 MHz, DMSO-d6) δ
8.76 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 3.0 Hz, 1H), 7.48 (dd, J = 7.2, 3.0 Hz, 1H), 4.06 (s,
6H), 2.69 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 170.46, 157.31, 147.78, 113.90,
111.82, 58.28, 44.02, 20.36. HRMS (ESI): m/z calcd for (C8H12NO)+: 138.0913; found:
138.0917.
CONCLUSIONS
In conclusion, we have discovered a different route for the preparation of 1-substituted
pyridine-4-ones from 4-methoxypyridines at mild conditions. The presence of solvents
7

favoured the formation of the 1-methylpyridones, whereas the absence of solvents
favoured the formation of the pyridinium salts. The presence of an electron withdrawing
group on pyridine ring can lead to the conversion easily, and significantly for such group
at 3-position of the pyridine ring.
ACKNOWLEDGMENTS
The financial support from Zhejiang Provincial Natural Science Foundation of China
(LY17H300005) and Zhejiang Chinese Medical University (2015ZG15) is gratefully
acknowledged.
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9

Table 1. Methylation of 4-methoxypyridines with methyl iodide in presence or absence of
solvent
Entry Substrate R1
R2
H
R3 Solvent
Product (yield)
2
3
1
H
H
-
92%
69%
57%
-
1a
2
acetone
toluene
22%
33%
47%
36%
39%
87%
-
3
4
acetonitrile 41%
5
methanol
49%
6
THF
44%
7
DMF
-
a8
9
-
-
H
CH3
H
H
H
-
87%
-
1b
1c
1d
1e
10
11
12
13
14
15
16
acetone
36%
53%
-
CH3
H
OCH3
NO2
-
85%b
acetone
-
34%
57%
85%
95%
71%
73%
-
-
-
-
acetone
CH3
OCH3 Br -
acetone
10

17
18
19
20
21
22
23
24
H
Br
H
Br -
acetone
-
84%
91%
-
1f
-
CH3
Cl
H
H
H
-
86%
80%
71%
42%
74%
47%
1g
1h
1i
acetone
trace
-
H
-
acetone
-
37%
-
COOH H
acetone
32%d
aDimethyl sulphate or bromoethane was used instead of methyl iodide.
b4-Hydroxy-1-methylpyridinium was produced instead of 4-methoxy-1-
methylpyridinium. The reason for the removal of methyl at 4-OH is not clear.
cLonger reaction time for this methylation is required.
dCarboxyl group on C-2 was esterified by MeI. This phenomenon does not occur in the
corresponding pyrdinium product.
11

Scheme 1 Synthesis of pyridinium or/and pyridinone. (a) MeI, r.t. or reflux, 12h. (b) MeI
in organic solvent, reflux 12h.
12

Scheme 2 The generation of a mixture of N-alkyl pyridinones. (a) EtI only or EtI in
acetone, reflux, 24h; (b) i-PrI only or i-PrI in acetone, reflux, 48h.
13