Simple and practical procedure for the preparation of benzofurazan-N-oxides in the presence of cyclodextrin in neutral condition

Article abstract of DOI:10.1080/00397910902906552

A simple and practical procedure for the aqueous-phase preparation of benzofurazan-N-oxides has been developed in the presence of cyclodextrin at room temperature in neutral condition for the first time. Organic solvent can be precluded for the application of cyclodextrin, which can be recovered and reused in subsequent reactions without loss of activity. The reaction mechanism was studied based on the complexation of cyclodextrin and o-nitroaniline, which was proved by 1H NMR and IR spectroscopy.

Full text of DOI:10.1080/00397910902906552

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Simple and Practical Procedure
for the Preparation of
Benzofurazan-N-oxides in the
Presence of Cyclodextrin in
Neutral Condition
Tao Sun a , Aiyou Hao a , Jian Shen a & Liqiang Song a
a School of Chemistry and Chemical Engineering,
Shandong University, Jinan, China
Version of record first published: 29 Oct 2009.
To cite this article: Tao Sun , Aiyou Hao , Jian Shen & Liqiang Song (2009): Simple
and Practical Procedure for the Preparation of Benzofurazan-N-oxides in the Presence
of Cyclodextrin in Neutral Condition, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:23, 4309-4314
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Synthetic Communications1, 39: 4309–4314, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902906552
Simple and Practical Procedure for the
Preparation of Benzofurazan-N-oxides in the
Presence of Cyclodextrin in Neutral Condition
Tao Sun, Aiyou Hao, Jian Shen, and Liqiang Song
School of Chemistry and Chemical Engineering, Shandong University,
Jinan, China
Abstract: A simple and practical procedure for the aqueous-phase preparation of
benzofurazan-N-oxides has been developed in the presence of cyclodextrin at
room temperature in neutral condition for the first time. Organic solvent can
be precluded for the application of cyclodextrin, which can be recovered and
reused in subsequent reactions without loss of activity. The reaction mechanism
was studied based on the complexation of cyclodextrin and o-nitroaniline, which
1
was proved by H NMR and IR spectroscopy.
Keywords: Benzofurazan-N-oxides, cyclodextrin, green chemistry, neutral
condition, o-nitroaniline
Benzofurazan-N-oxides (BFOs), are considered as some of the most
important drug reagents[1] as well as intermediates, especially for the
sythesis of quinoxaline compounds.[2] BFOs are also widely used in the
areas of analytical chemistry,[3a,3b,3d] military,[3c] agriculture,[2d,2e]
biology,[2d,2e] and materials.[3e]
The formal synthetic method of BFO is oxidation of o-diphenol,
which has poor yield, because of the difficult formation of the quinone
oxime intermediate. Recently, a new method was developped to achieve
the target, which is oxidation of o-nitroaniline with sodium hypochlorite.[4]
Received December 16, 2008.
Address correspondence to Aiyou Hao, School of Chemistry and Chemical
Engineering, Shandong University, Jinan 250 100, China. E-mail: haoay@sdu.
edu.cn
4309

4310
T. Sun et al.
Chart 1. Structures of cyclodextrins.
Though different approaches have been reported, there are various
limitations such as the use of strong basic conditions, elevated tempera-
tures, long reaction times, and hazardous organic solvents.
In our efforts to develop a biomimetic approach through supramole-
cular catalysis, now we report a simple and practical method of the synth-
esis of BFO from o-nitroaniline in neutral condition in the presence of
b-cyclodextrin. Organic reactions in aqueous media have recently become
a topic of focus in organic synthesis because they overcome the harmful
effects of organic solvents and are environmentally benign.[5] These aqu-
eous reactions can be made more sophisticated if they are performed
under supramolecular catalysis. Cyclodextrins (CDs), which are cyclic
oligosaccharides (Chart 1), have generated interest as enzyme models
because of their ability to bind substrates selectively and catalyze chemi-
cal reactions by supramolecular catalysis, involving the reversible forma-
tion of host–guest complexes with the substrates by noncovalent
bonding, as seen in enzyme complexation processes.[6] Because complexa-
tion depends on the size, shape, and hydrophobicity of the guest mole-
cule, CDs have been utilized for biomimetic modeling of the synthesis
in water.[7] b-CD was chosen because it is easily accessible and the least
expensive among the CDs.
The reaction was carried out by the in situ formation of the complex
of CD and o-nitroaniline in water followed by the addition of sodium
hypochlorite. It was stirred for 20 min at room temperature to give
BFO in a good yield (Scheme 1). The reaction proceeded smoothly
without heating. CDs were recovered by filtration and reused for
five consecutive runs in this reaction without basically no change in the
Scheme 1. Synthesis of benzofuran-N-oxides from o-nitroaniline in the presence
of cyclodextrin.

Preparation of Benzofurazan-N-oxides
4311
1
yield and purity. The product was characterized by H NMR, IR, and
elemental analysis and was compared with the known compounds[4] by
thin-layer chromatography (TLC).
In the absence of CDs, the reaction does take place but the yield was
poor (less than 20%) and overoxidation by-product was observed. We
tried a-CD (56%), b-CD (85%), c-CD (93%), hydroxypropyl b-CD
(47%), and sulfonebutyl b-CD (61%) to find a suitable catalyst, but only
b-CD and c-CD, produced a favorable yield, possibly because of the sui-
table size of cavity of b-CD and c-CD as well as the stenosis cavity of
a-CD and the hindering of b-CD derivatives. Inclusion complexation
takes place in situ during the reaction, and the complexes have been
1
isolated and characterized by H NMR and IR studies.
The inclusion complex of cyclodextrin and o-nitroaniline in the CD-
catalyzed reactions in water has been presumed based on the following evi-
dence: the fact that the yield was so poor in the absence of CDs and that
o-nitroaniline is almost insoluble in water at room temperature. We deduced
that CDs play the part of phase-transfer catalyst to bring o-nitroaniline into
an aqueous phase. Besides, perhaps by forming an H-bond to stabilize the
intermediate, the overoxdition could decrease dramatically. The cavity of
CD is also a proper shield for the active phenyl to exclude the side reaction.
1
Evidence for this mechanistic approach was deduced from H NMR
1
and IR spectroscopy. A comparison of the H NMR spectra (D2O) of
b-CD and b-CD-o-troaniline complex was undertaken. There was a clear
upfield shift of H1 (0.137 ppm), H2 (0.156 ppm), H3 (0.164 ppm), H4
(0.164 ppm), H5 (0.149 ppm), and H6 (0.092 ppm) protons of b-CD in
the b-CD-o-nitroaniline complex as compared to b-CD, indicating the
formation of an inclusion complex of o-nitroaniline with b-CD.[8]
A comparison of the Fourier transform (FT)-IR spectra of
o-nitroaniline, b-CD, the solid inclusion complex, and the physical mix-
ture of o-nitroaniline and b-CD was also undertaken. In the physical mix-
ture, stretching vibration of hydroxyl group appeared in the region of
3355 cmꢀ1, whereas in the solid inclusion complex, the peak shifted to
3407 cmꢀ1 and became much wider, which might be related to the inclu-
sion complexation between b-CD and o-nitroaniline.[9]
Based on the spectra studies, we deduce the mechanism as shown in
Chart 2.
In conclusion, our methodology provides a method for the conver-
sion of o-nitroaniline to benzofurazan-N-oxides under neutral and mild
conditions, and the reaction can be carried out easily at room tempera-
ture by recycling cyclodextrin. We also suggest the mechanism of reaction
through the study of 1H NMR and FT-IR spectra: cyclodextrins not only
play the part of phase-transfer catalyst but also protect the intermediate
of the reaction from overoxidation by H-bonding and with the cavity.

4312
T. Sun et al.
Chart 2. Deduced mechanism from o-nitroaniline to benzofuran-N-oxides in the
presence of cyclodextrin.
EXPERIMENTAL
General
Sodium hypochlorite and o-nitroaniline were purchased from Country
Medicine Reagent Co., China. Cyclodextrins were purchased from
Guangdong Yunan Chemical Reagent Co. and recrystallized three times
from distilled water before application. Hydroxypropyl b-CD was pur-
chased from Shandong ZiBo Xinda Chemical Reagent Co. Sulfonebutyl
b-CD was a gift from Dr. Shen Jian.
1H NMR and 13C NMR spectra were performed at 400-MHz on a
Bruker Avance 400-MHz NMR. IR spectra were performed on an Ava-
tar 370 FT-IR spectrometer. Elemental analysis were performed on a
Vario El III, Elmentar Co. Thin-layer chromatographic (TLC) analysis
was performed on glass plates precoated with silica gel F254 obtained
from Qingdao Haiyang Chem, China.
Synthesis of Benzofurazan-N-oxides
b-CD (1.05 mmol) was dissolved in water at 60ꢁC (15 mL), and a clear
solution was formed. o-Nitroaniline (1 mmol) dissolved in methanol
(0.5 mL) was added dropwise and stirred for half an hour until the inclu-
sion was formed. Then, aqueous sodium hypochlorite (4 mmol) was
added, and the mixture was stirred at room temperature until the reaction
was complete (as monitored by TLC). The mixture was extracted with
ethyl acetate (20 ml ꢂ 3), and the extract was filtered. The organic layer
was dried over anhydrous Na2SO4, the solvent was removed under

Preparation of Benzofurazan-N-oxides
4313
reduced pressure, and the resulting product was further purified by
column chromatography using ethylacetate–petroleum ether(v:v ¼ 5:1)
as eluent.
Benzofurazan-N-oxides: yellow powder, mp ¼ 67–68ꢁC. 1H NMR
(400 MHz, DMSO-d6): d 7.69 (2H, s, Ar-H), 7.46 (2H, s, Ar-H); IR nmax
(KBr) (cmꢀ1): 3443, 2925, 2363, 1616, 1589, 1539, 1485, 1424, 1125, 1016,
893, 835, 750, 671, 572. Anal. calcd. for C6H4N2O2: C, 52.94; H, 2.94; N,
20.59. Found: C, 52.56; H, 2.99; N, 20.52.
Preparation of Inclusion of o-Nitroaniline and b-CD
b-CD (1.05 mmol) was dissolved in water at 60ꢁC (15 mL), and a clear
solution was formed. o-Nitroaniline (1 mmol) dissolved in methanol
(0.5 mL) was added dropwise and stirred for half an hour until precipita-
tion appeared. The precipitate was collected by filtration under reduced
pressure, washed with water, and dried.
Inclusion of o-nitroaniline and b-CD: yellow powder.1H NMR
(300 MHz, D2O): d 8.05 (1H, d, Ar-H), 7.44 (1H, t, Ar-H), 6.98 (1H, d,
Ar-H), 6.74 (1H, t, Ar-H), 5.07 (1H, s, CD-H1), 3.96 (1H, t, CD-H5),
3.84 (1H, s, CD-H6), 3.69 (1H, s, CD-H2), 3.67 (1H, s, CD-H3), 3.61
(1H, s, CD-H4); IRmax(KBr) (cmꢀ1): 3408, 2927, 1627, 1572, 1510,
1436, 1257, 1155, 1079, 1029, 943, 867, 750, 703, 580, 529.
Preparation of Physical Mixture of o-Nitroaniline and b-CD
To do FT-IR, a physical mixture of o-nitroaniline and b-CD was needed.
o-Nitroaniline (1 mmol) and b-CD (1.05 mmol) need to be ground with
KBr separately, well mixed, and then extruded to avoid the inclusion
of guest and host molecule during the grinding procedure.[7,10]
Physical mixture of o-nitroaniline and b-CD: grey powder,
IRmax(KBr) (cmꢀ1): 3355, 2927, 1628, 1570, 1508, 1429, 1348, 1255,
1156, 1081, 1031, 942, 851, 745, 701, 579, 527.
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