Microwave assisted rapid preparation of N-alkyl-2-pyridones under neutral conditions by Hilbert-Johnson reaction

Article abstract of DOI:10.3987/COM-10-12006

The reactions of 2-methoxypyridine with haloalkanes without solvent and catalyst under microwave irradiation (100-200 °C, 5 min) yielded the corresponding N-alkyl-2(1H)-pyridones in good to moderate yields. However, the reactions were sensitive to length of haloalkanes. In contrast, the reactions of 2-alkoxypyridines with corresponding iodoalkanes under microwave irradiation (150 °C) proceeded rapidly without catalyst and solvent, and were complete within 5 min to afford N-alkyl-2(1H)-pyridones in good to excellent yields. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12006

HETEROCYCLES, Vol. 81, No. 9, 2010
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HETEROCYCLES, Vol. 81, No. 9, 2010, pp. 2057 - 2062. © The Japan Institute of Heterocyclic Chemistry
Received, 5th July, 2010, Accepted, 29th Juy, 2010, Published online, 30th July, 2010
DOI: 10.3987/COM-10-12006
MICROWAVE
ASSISTED
RAPID
PREPARATION
OF
N-ALKYL-2-PYRIDONES UNDER NEUTRAL CONDITIONS BY
HILBERT-JOHNSON REACTION
Hirokazu Iida,* Machiko Suda, Etsuko Nakajima, Hiroko Hakamatsuka,
Yuka Nagashima, Kouta Joho, Kenta Amemiya, Tatsuya Moromizato,
Kiyoshi Matsumoto, Yasuoki Murakami, and Hiroshi Hamana*
Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba,
288-0025, Japan (e-mail: hiida@cis.ac.jp; hhamana@cis.ac.jp)
Abstract – The reactions of 2-methoxypyridine with haloalkanes without solvent
o
and catalyst under microwave irradiation (100-200 C, 5 min) yielded the
corresponding N-alkyl-2(1H)-pyridones in good to moderate yields. However, the
reactions were sensitive to length of haloalkanes. In contrast, the reactions of
2-alkoxypyridines with corresponding iodoalkanes under microwave irradiation
o
(150 C) proceeded rapidly without catalyst and solvent, and were complete
within 5 min to afford N-alkyl-2(1H)-pyridones in good to excellent yields.
INTRODUCTION
N-Alkyl- and N-aryl-2(1H)-pyridones have been screened for their biological activity.1-3 Recently, it was
reported that the N-phenyl-2(1H)-pyridone derivative, perampanel acted as a noncompetitive and
selective AMPA-receptor (subtype of ionotropic glutamate receptors) antagonist and that it demonstrated
evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease.4 From the
synthetic view point, N-alkyl-2(1H)-pyridones are also useful as building blocks.5,6
The synthesis of N-alkyl-2(1H)-pyridones is feasible by alkylation of 2-pyridones. In this case selectively
switching the reaction course is required to induce the N- or O-alkylation. In general, N-alkylation is
performed via the sodium salt and O-alkylation via the silver salt, but a mixture of N- and O-alkylation
was obtained in almost all cases.7 Since these reactions were performed under basic conditions, a milder
procedure using the Mitsunobu reaction was reported.8 This method gave O-alkylation products mainly
accompanied with lower ratio of N-alkylation products (<3.5:1). The other promising method for the
synthesis of N-alkyl-2(1H)-pyridones under milder conditions is the use of Hilbert-Johnson type reaction.

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HETEROCYCLES, Vol. 81, No. 9, 2010
The Hilbert-Johnson reaction9 involves a coupling of 2-methoxypyridine and iodoalkane for the synthesis
of N-alkyl-2-pyridones on the basis of irreversible lactim-lactam tautomerization, and was applied to the
synthesis of pyrimidine-nucleoside.10 We have applied the Hilbert-Johnson reaction to the synthesis of
N-alkyl-2(1H)-pyridones (2) (Scheme 1). Reaction of 2-methoxy-5-nitropyridine 1 with iodoalkanes
afforded the corresponding N-alkyl-5-nitro-2-pyridone 2 in moderate to poor (63-15%) yields
accompanied by the N-methyl form 3 as a by-product under high pressure (0.8 GPa, 80-100 oC) and with
long reaction times (2 d - 4 d).11 These results suggested that N-alkyl-2(1H)-pyridones were obtained
under neutral conditions using the Hilbert-Johnson reaction, but formation of side product 3,
N-methyl-2-pyridone and the long reaction time were problematic.
O2N
O2N
+
O2N
R
I
0.8 GPa
100 oC
2-4 d
N
R
O
N
O
N
OMe
Me
1
2
3
R=Me: 63%
R=Et: 15%
R=Pr: 31%
-
not detected
30%
Scheme 1
In order to optimize reaction conditions, we investigated the effect of microwave irradiation on the
Hilbert-Johnson reaction. We have also been interested in the reaction in the absence of solvent and
catalyst. We have reported12,13 that microwave irradiation might assist such 1,2- and/or conjugate
additions using TMSCN without catalyst and additive. We applied the method of microwave irradiation
without catalyst and solvent to Hilbert-Johnson reaction for the synthesis of N-alkyl-2(1H)-pyridones
possessing long alkyl chains.
RESULTS AND DISCUSSION
At first, we investigated direct N-alkylation of 2-pyridone under high pressure conditions. Under neutral
conditions, we have not succeeded in introduction of long alkyl chains. However, the reaction of 4 with
iodoethane and iodopropane proceeded in the presence of TMSCl and HMDS in MeCN under high
o
pressure (0.6 GPa and 50 C) for 4 d to afford the corresponding N-alkyl-2-pyridones (5) in moderate
yields, 65 and 70% respectively (Table 1). Using longer iodoalkanes (R=n-Bu, n-Hex, n-Hept) under
similar conditions, the reaction yielded the corresponding N-alkyl-2-pyridones in moderate yields
(45-63%, isolated yields) (Table 1). We succeeded in the synthesis of N-alkyl-2(1H)-pyridones
possessing long alkyl chain as above. However these reactions were not complete in 4 days.

HETEROCYCLES, Vol. 81, No. 9, 2010
2059
Table 1. Reaction of iodoalkanes with 4 under high pressure
0.6 GPa
50 oC
TMSCl
HMDS
MeCN
4 days
+
R
I
N
O
N
H
O
R
5
4
R
Isolated yield of 5 (%)
Me
Et
74
65
70
63
56
45
Pr
n-Bu
n-Hex
n-Hept
In order to improve yields and shorten reaction times, we investigated the effect of microwave14
irradiation for Hilbert-Johnson reaction using 2-methoxypyridine (6) without catalyst and solvent (Table
2). Reaction of 6 with iodomethane was complete within 5 min to afford 5a (equal to 7 in this case) in
o
excellent yield (94%) under microwave irradiation (200 C) (Table 2, entry a).14 We succeeded in
shortening the reaction time dramatically for preparation of N-methyl-2(1H)-pyridone 5a under neutral
conditions. Using iodoethane and iodopropane, similar reactions gave 5b and 5c respectively in lower
yields, along with 7 (Table 2, entries b and c).11 Using bromoalkanes instead of iodoalkanes, the yields of
5 decreased remarkably (Table 2, entries d-f). And yet these reactions were not completed within 5 min.
Table 2. Reaction of 6 with haloalkanes under microwave irradiation
microwave
+
+
R
X
200 oC, 5 min
N
O
N
O
N
OMe
Me
R
5
7
6
Entry
R
X
6 : 5 : 7*
Isolated yield of 5
a
b
c
d
e
f
Me
Et
Pr
Et
Pr
I
I
I
Br
Br
Br
0 : 1 : -
0 : 3 : 2
10 : 2 : 1
0 : 1 : 2
10 : 2 : 1
10 : 2 : 1
94 %
60 %
32 %
31 %
24 %
10 %
Bu
* Determined by 1H NMR.

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HETEROCYCLES, Vol. 81, No. 9, 2010
As the reaction of 2-methoxypyridine with iodomethane gave an excellent yield while the reaction using
other haloalkanes yielded 7 as by-products, we changed starting materials to 2-alkoxypyridine and
corresponding iodoalkanes. Starting 2-alkoxypyridines were prepared from the reactions of
2-bromopyridine and alcohols according to the method reported previously.15 Reaction of the synthesized
2-propoxypyridine 8b with 2 molar equivalents of iodopropane without catalyst and solvent under
o
microwave irradiation (150 C) proceeded smoothly, and was completed within 5 min to afford
N-propyl-2-pyridone 5b exclusively in 99% yield (Table 3, entry b). Generally, reaction of the
2-alkoxypyridine 8 with corresponding iodoalkanes (R=Me, n-Bu, n-Pent, n-Hex, n-Hept) under similar
conditions yielded corresponding N-alkyl-2-pyridones 5, exclusively in good to excellent yields (75-99%)
(Table 3, entries a-f).16 However, the reaction of 8a with an excess of iodomethane under high pressure
o
(0.6 GPa, 100 C) yielded 5a in 93% yield, but long reaction time (4 d) was required to complete the
reaction. Now, we succeeded in the high yield and short reaction time preparation of
N-alkyl-2(1H)-pyridones 5 including long alkyl chain under neutral conditions by microwave irradiation.
Table 3. Reaction of 8 with corresponding iodoalkanes under microwave irradiation
R
I
NaH
microwave
ROH
N
O
150 oC, 5 min
N
Br
N
OR
R
5
8
Entry
R
Isolated yield of 5
a
b
c
d
e
f
Me
Pr
94 %
99 %
99 %
75 %
94 %
98 %
n-Bu
n-Pent
n-Hex
n-Hept
In order to understand the reaction mechanism, 2-methoxypyridine (6) was treated under microwave
conditions in the absence of iodoalkanes, but no reaction occurred at all. This result indicated that the
reaction requires iodoalkanes. Next, 6 was allowed to react with iodoethane for 1 day at rt, and then was
microwave irradiated affording mainly pyridinium salt. On the basis of above result, the proposed
mechanism of this reaction is an initial quaternization of pyridine nitrogen (9), followed by lactim-lactam
tautomerization assisted by the attack of iodide ion (10) successively, under microwave irradiation
(Scheme 2).17 N-Methyl-2-pyridone 7 was presumably formed in the reaction of liberated MeI with 6
(Table 2).

HETEROCYCLES, Vol. 81, No. 9, 2010
2061
R
I
Me
Me
I
+
N
R
OMe
N
R
O
N
R
O
+
+
N
OMe
I-
I-
5
6
9
10
Scheme 2. Proposed mechanism of Hilbert-Johnson reaction
In conclusion, we have demonstrated that reaction of 2-alkoxypyridine with corresponding iodoalkanes is
suitable for the synthesis of N-alkyl-2-pyridones under neutral conditions by Hilbert-Johnson reaction.
Microwave irradiation method made it possible to perform the reaction without solvent and catalyst and
to reduce reaction time markedly. Reactions of halogenosugars and alkoxypyrimidines in microwave
irradiation under neutral conditions for the synthesis of nucleoside will be reported in due course.
ACKNOWLEDGEMENTS
We would like to appreciate Dr. J. William Lown, Professor Emeritus, University of Alberta, Canada, for
kind suggestions and encouragement. This work was supported in part by a Grant-in-Aid for Scientific
Research (C, No. 21590120) from the Ministry of Education, Culture, Sports, Science, and Technology,
Japan (to HH).
REFERENCES AND NOTES
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HETEROCYCLES, Vol. 81, No. 9, 2010
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(218 mg, 2 mmol) were thoroughly mixed in a CEM vial. This was capped and irradiated in a CEM
o
Discover microwave to keep reaction temperature at 150 C for 5 min. After cooling to rt, the
mixture was evaporated in vacuo and the resulting oil was subjected to a short column
chromatography on SiO2 using EtOAc and MeOH (10:1) as an eluent to afford 10a (205 mg, 94%).
N-methyl-2(1H)-pyridone (10a): colorless oil, 1H NMR (CDCl3) : 3.28 (3H, s), 5.92 (1H, dt, J=14.4,
13
1.2 Hz), 6.27 (1H, d, J=9.2 Hz), 7.06-7.10 (1H, m), 7.10-7.15 (1H, m); C NMR (CDCl3) : 37.4
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agreement with those reported in the literature.16-18 Yields were isolated ones after SiO2 column
chromatography and not optimized.
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