Microwave activation in the synthesis of nitrogen heterocycles, N-oxides of pyridine series

Article abstract of DOI:10.1134/S1070363208080197

Oxidation of heterocycles of the pyridine series under conditions of microwave irradiation was studied. It is established that oxidation of pyridine and 4-methylpyridine with hydrogen peroxide results in the corresponding N-oxides, and oxidation of 3-(pip

Full text of DOI:10.1134/S1070363208080197

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 8, pp. 1577–1578. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © D.P. Khrustalev, G.T. Khamzina, S. D. Fazylov, Z. М. Muldakhmetov, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78,
No. 8, pp. 1342–1343.
Microwave Activation in the Synthesis
of Nitrogen Heterocycles, N-Oxides of Pyridine Series
D. P. Khrustalev, G. T. Khamzina, S. D. Fazylov, and Z. М. Muldakhmetov
Institute of Organic Synthesis and Coal Chemistry of Republic of Kazakhstan,
Alikhanova str. 1, Karaganda, 100000 Kazakhstan
e-mail: khrustalev@mail.kz
Received February 21, 2008
Abstract—Oxidation of heterocycles of the pyridine series under conditions of microwave irradiation was
studied. It is established that oxidation of pyridine and 4-methylpyridine with hydrogen peroxide results in the
corresponding N-oxides, and oxidation of 3-(piperidin-2-yl)pyridine gives δ-oximino-δ-(pyridyl-3-N-oxide)-
valeric acid.
DOI: 10.1134/S1070363208080197
N-oxides of nitrogen heterocycles, of the pyridine
series in particular, constantly grow in importance. It is
known that electrophilic substituents are more readily
introduced into the N-oxides of pyridine series than
into the initial N-heterocycles. The oxidation of the
corresponding pyridines with hydrogen peroxides in a
glacial acetic acid solution is the most important way
to such compounds. The reaction is commonly carried
out at 70–80°С for a few hours. Then the reaction
mixture is evaporated and the product is extracted with
chloroform [1]. The disadvantages of this method are
the long reaction duration and the necessity of using a
solvent.
synthesized in 20 min at the microwave irradiation of
70 W power. Their structure and identity were proved
by independent syntheses, IR and NMR spectroscopy,
and thin layer chromatography.
Oxidation of anabasine V was studied under similar
conditions:
N
H
N
V
We studied pyridine I and 4-methylpyridine II
oxidation with hydrogen peroxide in the glacial acetic
acid under microwave irradiation (MW irradiation)
according to the scheme:
30% H2O2
C
CH2 CH2 CH2 COOH
CH3COOH
N OH
MW
N
R
R
O
30% H2O2
CH3COOH
VI
MW
N
N
According to the classical procedure, the oxidation
of anabasine with 30% hydrogen peroxide in acetic
acid was completed in 24 h at heating on a water bath
[3]. We established that under MW irradiation this
reaction could be successfully carried out in 30 min at
the radiation power of 70 W. It should be noted that
reaction did not result in anabasine Ру–N-oxide or
complete oxidation to nicotinic acid as it might be
O
III, IV
I, II
R = H (I, II), Me (II, IV).
It was established that pyridine and 4-methyl-
pyridine N-oxides (III and IV, respectively) were
1577

1578
KHRUSTALEV et al.
Physicochemical constants of compounds III, IV and VI prepared under classical and MW irradiation conditions
mp, °С
Yield, %
Calculated, %
Found, %
Comp.
no.
Formula
classical
classical
MW irradiation
MW irradiation
С
Н
С
Н
conditions [2, 3]
conditions [1, 3]
67
67–68
184
92
90
85.2
87.5
65.2
C5H5NO
63.15
66.04
53.57
5.30
6.47
5.39
63.19
66.09
53.61
5.25
6.52
5.36
III
IV
VI
184–186
224–227
C6H7NO
227
68–72
C10H12N2O4
expected, but led to the opening of the piperidine ring
to form δ-oximino-δ-(pyridyl-3-N-oxide)valeric acid
VI.
wave irradiation of 70 W power during 20 min, 4 times
by 5 min. To this solution 15 ml of water was added
and then water was removed in a vacuum of the water-
jet pump. On cooling to room temperature the product
precipitated and was recrystallized from benzene.
Compound VІ is a powder-like substance, poorly
soluble in water, alcohol and organic solvents (except
DMF), and readily soluble in aqueous ammonia, alkali
and acids at heating. Structure of compound VI was
proved by independent synthesis, IR and NMR
spectroscopy, and by its physicochemical constants
corresponding to published data [2]. In the IR spec-
trum of synthesized compounds III, IV and VI we ob-
served absorption band in the region of 1250–1290 cm–1
typical of N→O bond. In the IR spectrum of
compound VI there is a carboxylic group absorption
band at 1710 cm–1.
δ-Oximino-δ-(pyridyl-3-N-oxide)valeric acid (III).
In a a heat-resistant Erlemeyer flask 5 g of anabasine
was dissolved in 30 ml of the glacial acetic acid and
15 ml of 30% hydrogen peroxide was added. The
reaction mixture was exposed to microwave irradiation
of 70 W power during 30 min, 6 times by 5 min. To
this solution 15 ml of water was added and then water
was removed in a vacuum of the water-jet pump. On
cooling to room temperature the product precipitated
and was recrystallized from ethanol. 1Н NMR
spectrum, DMSO, δ, ppm: 1.65 m (2Н, СН2), 2.3 m
(4Н, СОО–СН2–С Н2), 7.45 t (1Н, Н pyridine), 8.23 d
(1Н, Н pyridine), 8.43 s (1Н, Н pyridine), 11,75 s (1Н,
С=N–ОН), 12.10 s (1Н, СООН).
Physicochemical constants of compounds III, IV
and VI consistent with the literature data [2, 3] are
listed in the table.
Hence application of microwave activation is a
convenient laboratory way to obtain N-oxides of
nitrogen-containing heterocycles of pyridine series and
may be recommended as a highly effective method for
preparative synthesis.
REFERENCES
1. Weigand–Hilgetag, Organisch Chemische Experimenti-
erkunst. Leipzig: Barth-Verlag. Translated under the
title Metody synteza v organicheskoi khimii, Moscow:
Khimiya, 1969, p. 534.
EXPERIMENTAL
2. Gol’dfarb, Ya.L., Akashev, F.D., and Zvorykina, V.K.,
Pyridine and 4-methylpyridine N-oxides (I, II).
In a heat-resistant Erlemeyer flask, 5 g of pyridine (4-
methylpyridine) was dissolved in 30 ml of the glacial
acetic acid and 15 ml of 30% hydrogen peroxide was
added. The reaction mixture was exposed to micro-
Izv. Acad. Nauk SSSR, Ser. Khim., 1962, p. 2209.
3. Svojstva organicheskikh soyedinenii (Properties of Or-
ganic Compounds, Handbook), Potekhin, A.A., Ed.,
Leningrad: Khimiya, 1984, p. 292.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 8 2008