A Simple and Efficient Method for the Preparation of Heterocyclic N-Oxide

Article abstract of DOI:10.1081/SCC-120027260

Pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-dimethylpyridine, quinoline, isoquinoline and 2-chloropyridine are readily oxidized to their N-oxides with a solution of trichloroisocyanuric acid, acetic acid, sodium acetate and water in acetonitrile and methylene dichloride in 78%-90% yields.

Full text of DOI:10.1081/SCC-120027260

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A Simple and Efficient Method for the Preparation of
Heterocyclic N-Oxide
Ping Zhong a , Sheng-rong Guo a b & Cai-sheng Song b
a Department of Chemistry, Wenzhou Normal College, Xueyuanzhong Road, Wenzhou,
325027, P.R. China
b Department of Chemistry, Jiangxi Normal University, Nanchang, P.R. China
Published online: 18 Oct 2011.
To cite this article: Ping Zhong , Sheng-rong Guo & Cai-sheng Song (2004): A Simple and Efficient Method for the
Preparation of Heterocyclic N-Oxide, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:2, 247-253
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 2, pp. 247–253, 2004
A Simple and Efficient Method for the
Preparation of Heterocyclic N-Oxide
Ping Zhong,1, Sheng-rong Guo, and Cai-sheng Song2
1,2
*
1Department of Chemistry, Wenzhou Normal College, Wenzhou,
P.R. China
2Department of Chemistry, Jiangxi Normal University, Nanchang,
P.R. China
ABSTRACT
Pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-
dimethylpyridine, 2,6-dimethylpyridine, quinoline, isoquinoline and
2-chloropyridine are readily oxidized to their N-oxides with a solution
of trichloroisocyanuric acid, acetic acid, sodium acetate and water in
acetonitrile and methylene dichloride in 78%–90% yields.
Key Words: Heterocyclic N-oxide; Oxidation; Acetonitrile; Methylene
dichloride; Trichloroisocyanuric acid.
*
Correspondence: Ping Zhong, Department of Chemistry, Wenzhou Normal College,
Xueyuanzhong Road, Wenzhou 325027, P.R. China; E-mail: zhongp0512@sina.com.
cn.
247
DOI: 10.1081/SCC-120027260
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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248
Zhong, Guo, and Song
Pyridine-N-oxide is a useful building block in organic synthesis.[1–3]
Pyridine or other heterocyclic nitrogen compounds can be converted into
pyridine-N-oxide or other heterocyclic N-oxides using various oxidizing
[5]
agents,[4–10] which including peracetic acid,[4] HOF CH3CN, m-chloro-
.
perbenzoic acid,[6] sodium perborate in acetic acid[7] and H2O2-catalyzed by a
Mn-porphyrin.[8] Trichloroisocyanuric acid [1,3,5-trichloro-1,3,5-triazine-
2,4,6-(1H,3H,5H)-trione] has been a useful reagent in organic synthesis,[11]
it has been used to oxidized secondary alcohol to ketones,[12] sulfides to
sulfoxide[13] in good yields. We have now found that trichloroisocyanuric acid
[1,3,5-trichloro-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione] (2) is very efficient,
highly selective reagent for oxidation of pyridine or other heterocyclic
nitrogen compounds, which can be converted into pyridine-N-oxide or other
heterocyclic N-oxides.
A solution of pyridine or other heterocyclic nitrogen compounds 1, acetic
acid, sodium acetate, water and trichloroisocyanuric acid 2 in acetonitrile and
methylene dichloride underwent oxidation to produce the corresponding
pyridine-N-oxide or other heterocyclic N-oxides 3 along with cyanuric acid 4
and hydrogen chloride. Yields are good to excellent (Sch. 1 and Table 1).
Although acetonitrile generally worked well, in some instances other
solvents such as methelene dichloride were more suitable due to that some
heterocyclic nitrogen compounds have relative poor solubility in acetonitrile.
To enhance the rate of oxidation a trace of water was added to the heterocyclic
nitrogen compounds reaction mixture. In absolute anhydrous condition the
reaction hardly proceed under similar conditions. But excessive water will
reduce the rate of oxidation and give poor yields. Since hydrogen chloride is
produced in the reaction and it can then react with 2 to form chlorine,[14]
Scheme 1.

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Preparation of Heterocyclic N-Oxide
249
Table 1. Synthesis of compounds 3a–i.
Product
R1
R2
R3
R4
Yield (%)a
3a
3ab
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
H
81
61
84
82
89
78
80
90
79
80
CH3
H
H
H
H
CH3
H
H
H
H
CH3
CH3
H
H
CH3
CH3
H
H
H
CH3
H
3g
3h
3i
–CH55CH–CH55CH–
H
Cl
H
–CH55CH–CH55CH–
H
H
H
H
aIsolated yield.
bWithout sodium acetate–acetic acid buffer media.
sodium acetate–acetic acid buffer media is used. Without sodium acetate and
acetic acid in the reaction mixture the products 3 were produced in only 50–
60% yields along with a few byproducts.
Heterocyclic N-oxides 3 have recently emerged as valuable reagents for
organic synthesis. For example, 2-chloropyridine-N-oxide 3i was transformed
into 2-mercaptopyridine-N-oxide 5 in 94% yield by treatment with sodium
sulfide and sodium hydrosulfide in aqueous solution (Sch. 2). 2-Mercapto-
pyridine-N-oxide 5 and its alkali metal salts were used for the preservation
animal skins and leather.[17]
In conclusion, the oxidation reaction of nitrogen containing heterocycles
with compound 2 provides a direct route to the N-oxides. The method has
some attractive advantages such as cheap, safe and stable source of starting
materials, high yields, mild reaction conditions, simple procedure and shorter
reaction time.
Scheme 2.

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Zhong, Guo, and Song
EXPERIMENTAL
1H NMR spectra were recorded on AVANVE-300 spectrometer with
TMS as internal standard. IR spectra were determined on VECTOR-55
instrument. Silica gel 60 GF254 was used for analytical and preparative TLC.
All products were characterized by comparison with authentic samples using
IR, 1H NMR and m.p.
General Procedure for the Synthesis of 3a–i
In a 25 mL two-neck flask were placed 2 mmol of the heterocyclic
nitrogen compounds 1, 2 mmol of acetic acid, 3 mmol of sodium acetate, 2 mL
of acetonitrile, 2 mL of methylene chloride, 0.1 mL of water. The mixture in
flask was allowed to stir for 5 min before the addition of the solution of 2 was
started. The solution of 2 (1.5 mmol) in 1.5 mL of acetonitrile was added
dropwise through a syringe. After a few minutes, the reaction temperature
began to rise. The addition took a total of 15 min and that was followed by an
additional 2 h of stirring at 408C. Excess 2 was destroyed by the slow addition
of saturated NaHSO3 solution. During this process, wet iodide-starch test
paper was used to periodically test for the presence of oxidizing power. The
precipitate of cyanuric acid 4 was removed by filtration and washed with
diethyl ether. Most of the solvent was removed from the filtrate with a rotary
evaporator and the residue was diluted with 20 mL of diethyl ether. The ether
solution was washed with saturated NaCl solution (2 Â 3 mL) and dried over
MgSO4. After filtration and concentration, the crude product was purified by
preparative TLC on silica gel and eluted with hexane and ethyl acetate (3/1).
3a. A white solid. m.p. 63–658C (lit.:[15] 61–658C). 1H NMR: d ¼ 8.18
(d, J ¼ 7.2 Hz, 2H), 7.62 (d, J ¼ 7.34 Hz, 1H), 7.42 (dd, J ¼ 7.2 Hz, 7.34 Hz,
2H); IR (nmax, KBr) 3050, 1625, 1480, 1455, 1045, 1020 cm21
.
3b. A white solid. m.p. 48–508C (lit.:[18] 48–508C). 1H NMR: d ¼ 8.44
(d, J ¼ 5.67 Hz, 1H), 8.30 (m, 1H), 7.71 (m, 2H), 2.64 (s, 3H); IR (nmax, KBr)
3041, 1618, 1398, 1046 cm21
.
1
3c.[19] Oil. H NMR: d ¼ 8.11 (s, 1H), 8.04 (d, J ¼ 7.34 Hz, 1H), 7.26
(dd, J ¼ 7.3 Hz, J ¼ 7.34 Hz, 1H), 7.18 (d, J ¼ 7.34 Hz, 1H), 2.23 (s, 3H); IR
(nmax, film) 3050, 1615, 1455, 1055, 1010 cm21
.
3d. A white solid, mp: 183–1858C (lit.:[18] 182–1858C). 1H NMR:
d ¼ 8.47 (d, J ¼ 6.09 Hz, 2H), 7.76 (d, J ¼ 6.09 Hz, 2H), 2.54 (s, 3H); IR
(nmax, KBr) 3045, 1643, 1612, 1510, 1449, 1383, 1030 cm21
.
3e.[20] A white solid, m.p. 290–2928C (dec). 1H NMR: d ¼ 8.15 (s, 1H),
7.29 (m, 2H), 2.45 (s, 3H), 2.33 (s, 3H); IR (nmax, KBr) 3054, 1634, 1406,
.
1054, 806 cm21

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Preparation of Heterocyclic N-Oxide
251
1
3f.[18] A white solid, m.p. 52–558C. H NMR: d ¼ 8.17 (t, J ¼ 7,90,
1H), 7.52 (d, J ¼ 7.90 Hz, 2H), 2.62 (s, 6H); IR (nmax, KBr) 3027, 1719, 1462,
1397, 1052, 779 cm21
.
1
3g. A white solid, mp: 58–608C (lit.:[9] 59–618C). H NMR: d ¼ 8.76
(d, J ¼ 4.89 Hz, 1H), 8.57 (d, J ¼ 8.4 Hz, 1H), 7.84 (m, 3H), 7.62 (m, 2H); IR
(nmax, KBr) 3046, 1637, 1596, 1502, 1056, 812 cm21
.
3h. A white solid, m.p. 135–1368C (lit.:[16] 1378C). 1H NMR:
d ¼ 8.41(s, 1H), 8.24 (d, J ¼ 8.3 Hz, 1H), 7.42 (m, 3H), 7.53 (m, 2H); IR
(nmax, KBr): 3030, 1630, 1500, 1045 cm21
.
3i. A white solid, m.p. 140–1428C (lit.:[20] 140–1428C). 1H NMR:
d ¼ 8.04 (d, J ¼ 8.0 Hz, 1H), 7.56 (m, 2H), 7.40 (m, 1H); IR (nmax, KBr):
3085, 3020, 1590, 1495, 1440, 1205, 1100 cm21
.
The Synthesis of 2-Chloropyridine 5
In a 25 mL two-neck flask wase placed a solution of 3j (2 mmol) and
1.5 mL of water. The mixture in flask was allowed to heated to 958C before the
addition an aqueous solution containing 1.5 mL of water, 1.5 mmol of sodium
sulfide and 2.2 mmol of sodium hydrosulfide was started. After the addition
was completed, the reaction mixture was heated at 958C for an additional
30 min. The reaction mixture was poured into water (5 mL), neutralized with
1 M HCl and extracted with methylene chloride (3 Â 5 mL). The combined
organic layer was washed with brine (2 Â 3 mL) and dried over MgSO4. After
filtration and concentration, the crude product was purified by preparative
TLC on silica gel and eluted with hexane and ethyl acetate (4/1) to give 5 in
94% yield.
1
5. A white solid, mp: 71–728C (lit.:[20] 70–728C). H NMR: d ¼ 8.50
(s, 1H), 8.02 (d, J ¼ 8.0 Hz, 1H), 7.40 (m, 1H), 7.12 (m, 1H), 6.90
(d, J ¼ 8.0 Hz, 1H); IR (nmax, KBr): 3100, 1600, 1570, 1130, 810,
750 cm21
.
ACKNOWLEDGMENT
Project 20272043 was supported by The National Nature Science
Foundation of China. This work was also supported by The National Nature
Science Foundation of Zhejiang Province (201015).

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Zhong, Guo, and Song
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Received in Japan May 12, 2003

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