Straightforward one-pot synthesis of benzofuroxans from o-halonitrobenzenes in ionic liquids

Article abstract of DOI:10.1016/j.mencom.2012.03.015

Treatment of o-halonitrobenzenes with sodium azide in a [empyrr][BF4]/Bu4NBr/H2O system gives benzofuroxans in high yields, with the recovery and reuse of the ionic liquid for at least ten times.

Full text of DOI:10.1016/j.mencom.2012.03.015

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 95–97
Straightforward one-pot synthesis of benzofuroxans
from o-halonitrobenzenes in ionic liquids
Aleksei B. Sheremetev,*a Nataliya S. Aleksandrova,a Nikolai V. Ignat’evb and Michael Schulteb
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: sab@ioc.ac.ru
b PM-ABE, Ionic Liquid Research Laboratory, Merck KGaA, 64293 Darmstadt, Germany.
E-mail: nikolai.ignatiev@merckgroup.com
DOI: 10.1016/j.mencom.2012.03.015
Treatment of o-halonitrobenzenes with sodium azide in a [empyrr][BF4]/Bu4NBr/H2O system gives benzofuroxans in high yields,
with the recovery and reuse of the ionic liquid for at least ten times.
N3
Cl
Benzofuroxans (benzo-2,1,3-oxadiazole N-oxides) exhibit diverse
biological activity and have been extensively investigated as
NO-releasing agents, calcium channel modulators, monoamine
oxidases inhibitors, herbicides1 or energetic materials.2 Among
various methods for the preparation of benzofuroxans,3 thermal
cyclization of o-nitroaryl azides is most widely used. This reac-
tion is typically carried out at 100–160°C in toluene, xylene,
decalin, DMSO, acetic or propionic acid. The principal drawback
of this method is that the starting azides are hazardous compounds
and can explode on impact and grinding. In an alternative one-
pot approach, a few benzofuroxans were synthesized from the
corresponding o-chloronitrobenzenes upon nucleophilic substi-
tution with sodium azide in chlorobenzene or dichloroethane
under phase transfer conditions.4 However, many of the reported
methods suffer from the following drawbacks: (i) long reaction
times, (ii) high temperatures, (iii) application of combustible
solvents, (iv) use of toxic and/or explosive reagents, (v) use of
uncommon starting materials. Thus, the development of efficient
methods for the preparation of benzofuroxans is required.
Ionic liquids (ILs) have been widely investigated as substi-
tutes for common solvents in a variety of chemical processes.5–7
Although many types of reactions have been investigated in ILs,
synthesis of benzofuroxan in ILs by thermolysis of o-nitroaryl
azides, which would either be prepared beforehand or generated
in situ, are absent from the literature.
NO2
NO2
NaN3,
IL
, IL
IL, – N2
NO2
NO2
1a
2a
O
N
O
N
N
N
O
NaN3,
NO2
3a
NO2
4
Scheme 1
target furoxan 3a,† and benzofurazan byproduct‡ 4. In this study,§
the best yield (95%) of furoxan 3a was achieved on treatment of
2,4-dinitrochlorobenzene 1a with 1 equiv. of NaN3 at 60°C for 4 h
in [empyrr][BF4] or [bmim][MeSO3] as the solvent.
In an attempt to improve the time of conversion and reduce
reaction temperature, the azidation was carried out in the presence
of phase transfer catalysts (Table 1). We were pleased to see that
the use of Bu4NBr (entries 5 and 9) was effective enough. When
a control reaction was run in the presence of water (entries 10–
12) and in the absence of a phase transfer catalyst, cyclization
also occurred. Small amounts of water (entry 12) was required to
shorten the reaction duration time and to provide the highest
yield of the product. Finally, we found that combination of both
additives, Bu4NBr and water (entries 13 and 14), improved the
reaction rate and the conversion significantly. In practice, after
stirring the mixture of compound 1a, sodium azide and Bu4NBr
with the IL in the presence of 5 vol% of H2O at 55°C for ~2 h,
the product 3a was separated by vacuum sublimation.
R
ecently, D’Anna et al.8 have reported the nucleophilic aromatic
substitution of some activated aryl or heteroaryl halides in ILs
([bmim][BF4], [bmim][PF6], [bmim][NTf2], [bm2im][NTf2] and
[bmpyrr][NTf2]), using 1-butyl-3-methylimidazolium azide
([bmim][N3]) as a nucleophile. More attractive azidation with
NaN3 in IL proceeded slowly giving lower yield of product after
70 h at 25°C. Note that treatment of o-bromonitrobenzene with
[bmim][N3] in [bmim][BF4] at 60°C after 24 h provides only
33% conversion whereas the yield of o-azidonitrobenzene was
19% only.
Herein, we report a convenient method for the synthesis of
a range of benzofuroxans in IL as reaction medium, o-nitroaryl
halides and NaN3 being the principal reactants.
We chose the reaction between the commercially available
2,4-dinitrochlorobenzene 1a and NaN3 to yield 2,4-dinitroazido-
benzene 2a that can be further transformed to 6-nitrobenzo-
furoxan 3a as a model one (Scheme 1).
One important feature of the use of ILs is the possibility of their
recycling and reuse. We found that the recycling of [empyrr][BF4]
is feasible for the process herein studied. Recycling reactions were
performed at 55°C for 2 h using 2,4-dinitrochlorobenzene as a
model precursor in the [empyrr][BF4]/H2O/Bu4NBr system. After
†
The identity of product 3a was confirmed by NMR spectra, CHN
analysis, mp, MS, and comparison with the literature data.9
‡
Reduction of benzofuroxans with NaN3 to benzofurazans was previously
reported.10
A variety of ILs and conditions were screened to optimize the
yield of furoxan 3a. The reactions were monitored by measuring
the yields of the returned compound 1, intermediate azide 2, the
§
See Online Supplementary Materials for more detailed optimization
data (Table S1).
© 2012 Mendeleev Communications. All rights reserved.
– 95 –

Mendeleev Commun., 2012, 22, 95–97
Hal
O
Table 1 Preparation of 5-nitrobenzofuroxan 3a in ILs.a
ILb
N
N
NO2
O
NaN3, cat.
IL
Yield (%)
3a
R
R
Entry Additive
T/°C t/h
1a
4
1b–q
3b–q
1
2
Bu4NBr, 0.5 mmol [bmpyrr][OTf] 40
Bu4NBr, 0.5 mmol [bmpyrr][OTf] 50
Bu4NBr, 0.5 mmol [bmpyrr][OTf] 60
9
3
2
trace 84
trace 88
0
2
5
8
5
4
0
0
0
1
1
0
O
O
O
O
O
O
N
N
N
N
3
0
93
N
N
N
N
O
O
O
O
4
Bu4NBr, 0.5 mmol [bmpyrr][OTf] 70–80 2 trace 71
5
Bu4NBr, 0.1 mmol [bmpyrr][OTf] 60
Bu4NCl, 0.1 mmol [bmpyrr][OTf] 60
3
0
92
Cl
HO2C
6
3.5 trace 61
trace 47c
trace 91
trace 92
Cl
CF3
N
7
Bu4NI, 0.1 mmol
[bmpyrr][OTf] 60
7
4
2
3b
3c
3d
3e
8
Et3NBnCl, 0.1 mmol [bmpyrr][OTf] 60
Bu4NBr, 0.1 mmol [empyrr][BF4] 55
9
O
O
O
N
N
10
11
12
H2O, 1 ml
[empyrr][BF4] 60
[empyrr][BF4] 60
[empyrr][BF4] 60
5.5 7
85
N
N
N
O2N
O
O
H2O, 0.5 ml
H2O, 0.1 ml
5.5 trace 88
3
2
trace 94
Cl
H2O, 0.1 ml
Bu4NBr, 0.1 mmol
H2O, 0.1 ml
Bu4NBr, 0.1 mmol
13
14
[empyrr][BF4] 55
[bmim][MeSO3] 55
0
96
96
0
0
CHO
Cl
CF3
3f
3g
3h
2.5 0
O
O
O
N
N
N
a Reaction conditions: 1 mmol of compound 1a and 1 mmol of NaN3 in 2 ml
of IL indicated. b [bmpyrr] is 1-butyl-1-methylpyrrolidinium, [empyrr] is
1-ethyl-1-methylpyrrolidinium, [bmim] is 1-butyl-3-methylimidazolium.
c Complicated reaction mixture was formed; compound 3a was isolated by
silica gel chromatography.
N
N
N
O2N
O2N
O
O
N3
NH2
NO2
NO2
NO2
3i
3j
3k
each cycle, the mixture was diluted with water, the product was
filtered and the IL was extracted from water with EtOAc. Then,
the IL/EtOAc solution was evaporated, next portions of 2,4-dinitro-
chlorobenzene and NaN3 were added to the IL. Note that ten
cycles were tested and the isolated yield was high (~95%) in
each cycle.
O
N
O
N
O
S
N
O2N
H2N
O
N
O
N
N
N
NH2
O
N
NO2
The simple procedure and the mild conditions of this one-
pot synthesis provide an easy access to a wide diversity of the
benzofuroxan derivatives¶ by reacting a variety of substituted
o-nitroaryl halides and sodium azide in IL (Scheme 2, Table 2).
All substrates bearing electron-withdrawing groups provide high
yields of the corresponding furoxans, with the reaction rate being
higher when –M effect being greater. Substrates with electron-
donating groups (not shown), such as methyl, methoxy and amino,
required elevated temperatures (>150°C) and gave poor yields
of the corresponding benzofuroxans that proved to be unstable
and/or inseparable from other side products. Interestingly, sub-
strates bearing both electron-donating and electron-withdrawing
groups showed good reactivity (entries 10 and 11). o-Nitrohalo
derivatives of fused benzene cores were also tested and provided
excellent yields of the products (entries 12–15). On using of
1,3,5-trichloro- or trifluoro-2,4,6-trinitrobenzene, three furoxan
rings were formed (entry 16).
3l
3m
3n
O
N
O
N
O
N
O
O
N
N
O
O
O
N
N
O
N
O
N
N
N
N
O
N
O
N
O
3o
3p
3q
Scheme 2
Table 2 Synthesesa of benzofuroxans from the variety of o-nitroaryl halides.
Entry
Product
T/°C
t/h
Yield (%)
Mp/°C
1b
2b
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
110
110
80
60
60
55
55
55
60
55
55
55
80
55
55
55
8
8
4
4
4
2
1
1
2
2
0.5
2
2
1
1
1
81
86
85
96
91
87
93
93–96
87
87
96
93
82
96
87
~92
78 (lit.,12 78)
50 (lit.,13 48)
130 (lit.,13 130)
124 (lit.,14 110)
69 (lit.,13 69)
131 (lit.,15 131)
128 (lit.,16 127)
173e (lit.,17 172)
89 (lit.,18 90)
272 (lit.,19 270)
295e (lit.,19 292)
129 (lit.,20 125)
146 (lit.,21 175)
77 (lit.,22 53)
97e (lit.,22 94)
199e (lit.,18 195)
3b
4b
In conclusion, we have developed a general one-pot proce-
dure for the synthesis of benzofuroxans from o-nitroaryl halide
and have demonstrated the viability of ionic liquids as a solvent
for the process to make it environmentally friendly. The ready
availability of starting materials, combined with the high yields
5b
6b
7b
8c
9d
10b
11d
12b
13b
14b
15b
16
¶
The possible tautomeric equilibria (N1- to N3-oxide) of benzofuroxan
have been the focus of much interest for over some decades.11 NMR
evidences that, at room temperature, many benzofuroxan derivatives in
solution exhibit rapid tautomeric equilibrium.
O
R
R
N
N
N
a Reaction conditions: 1 mmol of o-nitroaryl halide and 1 mmol of NaN3
with 0.1 mmol Bu4NBr in 2 ml of [empyrr][BF4] with 5 vol% H2O. In most
cases, isolation of benzofuroxans by vacuum sublimation was satisfactory.
b o-Nitroaryl chloride was used as the substrate. c Picryl fluoride, chloride
and bromide also reacted efficiently under these conditions. d Fluoro substrate
was the precursor. e Recrystallized from HNO3.
O
O
O
N
The equilibrium concentrations are dependent on the nature and position
of the substituents at the ring, solvent and temperature.
– 96 –

Mendeleev Commun., 2012, 22, 95–97
6 (a) I. Newington, J. M. Perez-Arlandis and T. Welton, Org. Lett., 2007,
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practical. Our conditions were designed to minimize the risk of
manipulation with dangerous aryl azides often found in more
traditional benzofuroxan preparations.
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.03.015.
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Received: 5th September 2011; Com. 11/3796
– 97 –