Synthesis and some properties of 2H-benzimidazole 1,3-dioxides

Article abstract of DOI:10.1016/j.tet.2015.03.096

Abstract The synthesis of novel 2H-benzimidazole 1,3-dioxides on the basis of benzofuroxans interaction with alcohols in acids is described. The formation of a stable secondary carbocation from alcohol is necessary for formation of 2H-benzimidazole 1,3-di

Full text of DOI:10.1016/j.tet.2015.03.096

Tetrahedron xxx (2015) 1e12
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Tetrahedron
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Synthesis and some properties of 2H-benzimidazole 1,3-dioxides
Elena Chugunova a , Vladimir Samsonov , Tatiana Gerasimova , Tatiana Rybalova ,c,
,
b
,
a
b
*
*
b,c
Irina Bagryanskaya
a
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov St., 420088, Kazan, Russia
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Prosp, Akad. Lavrentґeva, 630090,
b
Novosibirsk, Russia
c
Novosibirsk State University, Pirogova Str. 2, 630090, Novosibirsk, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of novel 2H-benzimidazole 1,3-dioxides on the basis of benzofuroxans interaction with
alcohols in acids is described. The formation of a stable secondary carbocation from alcohol is necessary
for formation of 2H-benzimidazole 1,3-dioxide while substituents in benzofuroxans don’t prevent the
reaction. Under heating 2H-benzimidazole 1,3-dioxides are rearranged to 3H-[2,1,4]benzoxadiazine 4-
oxides whose stability depends on substituents in the aromatic ring. Under irradiation oxadiazines are
converted back to 2H-benzimidazole 1,3-dioxides.
Received 24 November 2014
Received in revised form 13 March 2015
Accepted 26 March 2015
Available online xxx
Dedicated in memoriam of Professor Alan
Katritzky because of his great contribution
to heterocyclic chemistry
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Benzofuroxan
2
3
H-benzimidazole 1,3-dioxide
H-[2,1,4]benzoxadiazine 4-oxide
Thermal transformations
Photochromic compounds
1. Introduction
fibroblasts, of the most active trypanocidal Bfxs were comparable to
that of the reference drug, Nifurtimox. These results allowed the
Chagas disease affects an estimated 8 million people in 21
countries and is spread by human migration to a number of non-
endemic regions.1 The two registered drugs for Chagas disease
treatment were introduced in the 1960s (Nifurtimox, Bayer) and
authors to select Bfx as the lead system for further structural
modifications.
4
To search new more active compounds Cerecetto et al. studied
in this way for other N-oxide containing heterocycles using the
0
1
970s (Benznidazole, Roche). Nifurtimox and Benznidazole require
Beirut reaction for obtaining different quinoxaline N,N -dioxide
2
prolonged treatment (60 days) and have frequent side-effects.
systems and series of benzimidazole N-oxides. 2H-Benzimidazole
1,3-dioxides among other explored compounds are the most
in vitro active derivatives against T. cruzi and Leishmania spp. Fur-
thermore, these derivatives possess in vivo activity, which along-
side with excellent solubility in water makes them promising
5
candidates for drug development.
Thus an actual task is searching for new active compounds of
this class and development of new methods for synthesizing 2H-
benzimidazole 1,3-dioxides. In the current issue the synthesis of
new 2H-benzimidazole 1,3-dioxides on the basis of benzofuroxans
was examined and the transformations of 2H-benzimidazole 1,3-
dioxides on heating and on exposure to light were studied. The
main synthetic approach for new compounds creation is in-
troducing of functional groups to the second position of the imid-
azole ring and to the benzene ring of 2H-benzimidazole 1,3-
Cerecetto et al.3 evaluated a group of N-oxide containing het-
erocycles, as in vitro anti-Trypanosoma cruzi (T. cruzi) agents re-
vealing that some benzofuroxan (Bfx) derivatives are the best
parasite-growth inhibitors. Cytotoxicities, against mammalian
*
Corresponding authors. Tel.: þ7 843 2739365; fax: þ7 843 273 1872 (C.E.); tel.:
þ7 383 3308833; fax: þ7 383 3309752 (S.V.); e-mail addresses: chugunova.e.a@
gmail.com (E. Chugunova), samson@nioch.nsc.ru (V. Samsonov).
http://dx.doi.org/10.1016/j.tet.2015.03.096
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
dioxides that can provide the possibility of their further
modification.
2
. Discussion
Scheme 3. The mechanism of the formation of 2H-benzimidazole 1,3-dioxide.
The main approach to the 2H-benzimidazole 1,3-dioxides is
based on the reaction of the corresponding benzofuroxans with
secondary nitroalkanes in basic media at room temperature
This fact is confirmed in the present research by study of the
interaction of benzofuroxan 1 with 1-hexanol (Scheme 4). Isomeric
compounds 2 and 3 with ratio 1:1 are formed and separated. These
results are in agreement with the hypothesis that the reaction of
benzofuroxans with alcohols in acid occurs through the formation
of carbocation from the alcohol, which then react with
benzofuroxan.
(Scheme 1).
Scheme 1. The synthesis of 2H-benzimidazole 1,3-dioxides via the reaction of the
corresponding benzofuroxans with secondary nitroalkanes.
Limitations of such reaction are evident: (i) relatively low
availability of nitroalkane, (ii) 2H-benzimidazole derivatives are not
formed in the presence of electron-withdrawing substituents in the
Scheme 4. The interaction of benzofuroxan 1 with 1-hexanol.
6
furoxan ring, for example, in the case of 5-nitrobenzofuroxan.
The second product is produced due to isomerization of the
carbocation formed from hexanol. Thus the formation of the stable
secondary carbocation from appropriate reagent is the necessary
condition for obtaining 2H-benzimidazole 1,3-dioxide from
benzofuroxan.
If the initial alcohol yields several carbocations then several
products are expected. If the structure of alcohol allows rear-
rangement of the initially generated carbocation to the more stable
tertiary one then 2H-benzimidazole 1,3-dioxide is not formed. For
example during the interaction of benzofuroxan with cyclohexanol
formation of 2H-benzimidazole 1,3-dioxide occurs very easily, but
the reaction with menthol does not run.
In 1967 Katritsky A. and colleagues published a paper showing
the possibility of furoxan ring disclosure under the action of elec-
trophilic agents leading to the formation of benzimidazole de-
rivatives.7 Recently we have discovered in further study of
benzofuroxans a new method for the synthesis of 2H-benzimid-
azole 1,3-dioxides. Benzofuroxans were revealed to react easily
with alcohols or haloalkanes in sulfuric or perchloric acids giving
8
rise to 2H-benzimidazole 1,3-dioxides (Scheme 2). The method
allowed preparation of a large series of 2H-benzimidazole 1,3-
dioxides, including those inaccessible by other methods.
The reaction with 1,3-butanediol in acid results in 2-methyl-2-
vinyl-2H-benzimidazole 1,3-dioxide 4 instead of expected bis-2H-
benzimidazole 1,3-dioxide. 2-Methyl-2-(2-oxopropyl)-2H-benzoi-
midazole 1,3-dioxide
5 was obtained on reaction of 4-
hydroxypentan-2-one with benzofuroxan (Scheme 5).
Scheme 2. The synthesis of 2H-benzimidazole 1,3-dioxides via the reaction of the
corresponding benzofuroxans with alcohols or haloalkanes in sulfuric or perchloric
acids.
Benzofuroxans have been supposed earlier to react with alco-
hols or alkyl halides in the presence of acids via the alcohol
transformation to a carbocation, which further reacts with a nitro-
Scheme 5. Synthesis of compounds 4 and 5 from benzofuroxan 1.
8
gen atom of benzofuroxan in the 3 position (Scheme 3). The ad-
Thus the introduction of functional groups to the second posi-
tion of the molecule of 2H-benzimidazole 1,3-dioxide molecule via
the interaction of benzofuroxans with alcohols in acids is limited by
the possibility to obtaine the stable secondary carbocation from the
corresponding alcohol.
duct A obtained isomerizes with the disclosure of ring to cation B,
which loses a proton and turns into nitrosonitron C. The ring clo-
sure in nitrosonitron leads either to 2H-benzimidazole 1,3-dioxide
in the case of nucleophilic attack by the nitrogen atom of the
nitroso group or to 3H-[2,1,4]benzoxadiazine 4-oxide, in the case of
nucleophilic attack on the oxygen atom by the nitrone group. Due
to its greater stability in acidic medium 2H-benzimidazole 1,3-
dioxide is the dominant product in the reaction mixture and ben-
zoxadiazine N-oxide is formed in trace amounts. Thus, 2H-benz-
imidazole 1,3-dioxide is formed almost quantitatively upon
dissolution of 3H-[2,1,4]benzoxadiazine 4-oxide in sulfuric acid and
pouring in water.
In the next step we applied the approach stated above to syn-
thesize compounds 7a,b,f, known from literature as highly bi-
9
ological active agents against T. cruzi. and also new compounds
7
c,d,e (Scheme 6).
We also demonstrated that benzofuroxan 8 with nitro-group in
the 4th position of the benzene ring reacted readily with isopropyl
alcohol resulting in 4-nitro-2H-benzimidazole 1,3-dioxide
Scheme 7).
9
(
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E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
3
To expand the range of parent benzofuroxans used for formation
of novel 2H-benzimidazole 1,3-dioxides we have studied the re-
action of nucleophilic substitution of the chlorine atoms in 4,6-
dishlorobenzofuroxan 13a (Scheme 10). So 4-morpholinyl-6-
chlorobenzofuroxan 15b is formed in the reaction of 4,6-
dishlorbenzofuroxan 13a with morpholine as the result of chlo-
rine atom substitution in the 4th position as described in literature
10
for another similar compound, 4,6-dichloro-5-nitrobenzofuroxan.
As well as the substitution of chlorine in the 4th position of 13a
under the action of sodium methoxide gives 4-methoxy-6-
chlorobenzofuroxan 15a. The structure of compounds 13a, 15a,b
has been confirmed by X-ray analysis (Figs. 1 and 2). The reaction of
Scheme 6. Synthesis of compounds 7aef.
4,6-dichlorobenzofuroxan with ethanolamine or benzylamine
leads to reduction of benzofuroxan ring with formation of 4,6-
dichloro-1,2-benzoquinonedioxime 17.
Scheme 7. Synthesis of compound 9.
Beside this, the bulky substituents in the 5th position of the
benzene ring was revealed not to prevent the formation of
substituted 2H-benzimidazole 1,3-dioxides. So 5-((4-formyl-2-
methoxyphenoxy)methylbenzofuroxan 11a obtained by alkylation
of vanillin (a) by 5-(bromomethyl)benzofuroxan 10 reacts with
isopropyl alcohol in sulfuric acid giving 5-((4-formyl-2-
Scheme 10. Nucleophilic substitution of the chlorine atoms in 4,6-
dishlorobenzofuroxan 13a.
methoxyphenoxy)methyl)-2,2-dimethyl-2H-benzimidazole
dioxide 12a (Scheme 8). Similarly the alkylation of benzotriazole
b) by bromomethylbenzofuroxan 10 and subsequent treatment of
obtained 5-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzofuroxan
1b by isopropyl alcohol in sulfuric acid leads to 5-((1H-[1,2,3]
1,3-
(
1
benzotriazol-1-yl)methyl)-2,2-dimethyl-2H-benzimidazole
dioxide 12b.
1,3-
Fig. 1. Molecular structures of 6-chloro-4-methoxybenzofuroxan 15a (a) and parent
6,4-dichlorobenzofuroxan 13a (b) mixed in crystal with approximate ratio 30:70.
Scheme 8. Synthesis of compounds 11a,b, 12a,b.
Thus, the monosubstituted benzofuroxans can easily form 2H-
benzimidazole 1,3-dioxides.
4
,6-Disubstituted benzofuroxans was established also easily to
form 2H-benzimidazole 1,3-dioxides via reaction with isopropyl
alcohol in sulfuric or perchloric acids (Scheme 9). However, 4,6-
dinitrobenzofuroxan does not react this way.
Fig. 2. Molecular structure of 6-chloro-4-morpholinobenzofuroxan 15b.
4-Methoxy-6-chloro-2,2-dimethyl-2H-benzimidazole
1,3-
dioxide 16 is smoothly formed in the reaction of 4-methoxy-6-
chlorobenzofuroxan 15a with isopropyl alcohol in the perchloric
acid.
A new compound 18 was obtained in the reaction of 4-
morpholinyl-6-chlorobenzofuroxan 15b with isopropyl alcohol in
sulfuric acid (Scheme 11). The H NMR spectrum of this compound
contains the signals of the isopropyl group protons, morpholine
ring proton signals and signals of two protons of the benzene ring
(see Experimental part). Additionally we observed a broad signal of
one proton of NH-group related with intramolecular hydrogen
Scheme 9. Synthesis of compounds 14aec from 4,6-disubstituted benzofuroxans.
1
The use of sulfuric or perchloric acid in each case was de-
termined experimentally, because in some cases the reaction do not
occur in the presence of sulfuric acid in the right way, giving the
products of sulfonation. Therefore, the main criterion when
choosing the acid was the product yield and its purity.
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4
E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
Table 2
Energies and Gibbs free energies of reactions 1 and 5, computed with different
methods, kcal/mol
Reaction B3LYP/
B3LYP/
B3LYP/
B97D/
a
b
b
6-311þþG** 6-311þþG** d3 6-311þþG** pcm 6-311þþG** pcm
1
5
ꢀ18
ꢀ23
ꢀ22
ꢀ25
ꢀ17
ꢀ23
ꢀ21
ꢀ26
a
Dispersion-corrected energies were calculated (for B3LYP functional) within the
recently developed approach DFT-D3.
Solvent effects were taking into account with the use of the polarized contin-
uum model (PCM).
Scheme 11. The reaction of 4-morpholinyl-6-chlorobenzofuroxan 15b with isopropyl
alcohol in sulfuric acid.
b
bond at 12.14 ppm. These data with the data of 13C NMR and mass
spectrum allowed us to suppose structure of the resulting com-
pound: 5-chloro-N-isopropyl-3-morpholino-2-nitrosoaniline 18.
Apparently, the first benzofurazan has been formed from benzo-
furoxan and further reaction of benzofurazan with secondary al-
cohols in sulfuric acid lead to disclosure of benzofurazan ring and
Thus, we suppose that the presence of two nitro groups in
benzofuroxan greatly reduces the electron density on the nitrogen
atom, which inhibits the reaction and the reactions with dini-
trobenzofuroxans do not proceed.
2
H-Benzimidazole 1,3-dioxides in reactions with nucleophilic
11
and electrophilic agents at elevated temperatures lose very easy
one N-oxide oxygen atom. Perhaps because of this these com-
pounds are oxidants, for example, they easily oxidize hydroquinone
formation of o-nitrozoaniline.
Trisubstituted
benzofuroxand4,6-dichloro-5-
nitrobenzofuroxan 19 reacts with isopropyl alcohol in sulfuric
acid giving 2,2-dimethyl-4,6-dichloro-5-nitro-2H-benzimidazole
12
to benzoquinone. Mono-N-oxide 21a and benzaldehyde were
isolated with 90% yield in reaction of 2H-benzimidazole 1,3-dioxide
1,3-dioxide 20 (Scheme 12).
14a with benzylamine in chloroform under heating.
3. Thermal isomerization of 2H-benzimidazole 1,3-dioxides
and photochromism of obtained 3H-[2,1,4]benzoxadiazine 4-
oxides
Alongside their high biological activity another interesting
property of the systems under study is that they can be involved
into thermal reactions. Thermal transformations of 2H-benzimid-
azole 1,3-dioxides are poorly studied and present doubtless interest
for chemists. Only few papers describe the heating of 2H-benz-
imidazole 1,3-dioxides leading to formation of benzoxadiazine N-
Scheme 12. Synthesis of compound 20.
Attempts to obtain 2H-benzimidazole 1,3-dioxides in reactions
of 4,6-dinitrobenzofuroxan, 4,6-dinitro-5,7-dichlorobenzofuroxan
and 4,6-dinitro-7-chlorobenzofuroxan with alcohols failed.
To shed light on the reasons that cause the failure of the latter
reactions we have estimated with quantum-chemical methods
relative energies of products for the model reactions 1e5 (Table 1)
of benzofuroxanes with the number of substituents from 2 to 4.
Table 1 represents relative energies of the reactions, computed with
B3LYP/6-31G* method. Computations show that in all cases prod-
ucts are more energetically favorable independent on number of
substituents as well as their positions.
12
oxides easily transforming to the starting dioxide in the light.
Earlier it was shown that heating of 5-nitro-2H-benzimidazole
1
,3-dioxide results in 3O-[2,1,4]benzoxadiazine 4-oxide and more
prolonged heating causes sequential elimination of the N-oxide
oxygen atom to form 2H-benzimidazole mono N-oxide, the final
product of thermal reaction at moderate temperatures. The re-
action runs with the change of colour from violet (2H-benzimid-
azole 1,3-dioxides) to orange (3O-[2,1,4]benzoxadiazine 4-oxide
12
and 2H-benzimidazole mono N-oxides).
Probably the transformation of 2H-benzimidazole 1,3-dioxide
under heating to 3H-[2,1,4]benzoxadiazine 4-oxides is another
example of Cope rearrangement (nitrones under heating become
Table 1
Energies and Gibbs free energies of reactions, computed with B3LYP/6-31G* method,
kcal/mol
13
the oxime ethers). Herein we present the proposed mechanism of
H-benzimidazole 1,3-dioxide rearrangement to 3H-[2,1,4] ben-
2
Reaction
Relative energy,
kcal/mol
zoxadiazine 4-oxide (Scheme 13):
R1
R2
R3
R4
E
G
1
2
3
4
5
Cl
Br
Cl
NO
NO
H
H
NO
Cl
H
Cl
NO
Cl
NO
NO
H
H
H
Cl
Cl
ꢀ8
ꢀ9
ꢀ9
ꢀ6
ꢀ7
ꢀ8
ꢀ8
ꢀ5
2
2
2
2
ꢀ10
ꢀ7
Scheme 13. Probable scheme of 2H-benzimidazole 1,3-dioxide rearrangement to 3H-
2
2
[
2,1,4] benzoxadiazine 4-oxide.
The observed rearrangement is a thermal process. It is possible
that:
We also attempted to estimate effects from enlarging the basis
set, taking dispersion corrections and solvent effects into account
on the examples of reactions 1 from Table 1, which takes place and
reaction 5 which failed. All methods predict the same tendency as
B3LYP/6-31G*: both reactions are energetically favorable (Table 2).
1. Upon heating homolytic bond cleavage occurs with the for-
mation of the biradical B.
2. Iminoyl radical isomerizes to the more stable iminoxyl radical
forming compound C. It is a driving force of rearrangement.
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E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
5
(
The arrow shows the movement of the electron from oxygen
to nitrogen.)
3
. Dimerization of radicals leads to the product of rearrangement
D.
Such thermo- and photochromic properties of 2H-benzimid-
azole 1,3-dioxides open additional perspectives for photochromic
switches design. Molecular photochromic switches are an in-
triguing class of organic molecules, which allow the control of
molecular structures and properties. Consequently, this offers the
possibility of effecting dramatic changes to the bulk properties of
a system by irradiation. Attractive features of these systems include
their short response times, reversibility, clean and tunable energy
input, and the ability to convert an optical input into a variety of
useful output signals. This is demonstrated by the fact that these
molecules have already found commercial application in optical
memory devices (including the recordable compact discs, CD-R),
light-sensitive sun glasses and ophthalmic lenses. More recently,
there has been a growing interest in using these materials in new
applications such as molecular electronics, smart surfaces, control
Fig. 3. Molecular structure of 6,8-dichloro-3,3-dimethyl-7-nitro-3H-[2,1,4]benzox-
adiazine 4-oxide 21d.
(
l
max.¼389e495 nm) while 2H-benzimidazole di-N-oxides 22aef
are strongly colored from dark red to violet compounds
¼510e560 nm).
14
(l
max.
of supramolecular organization, and nanomachinery.
UV spectrum of 4,6-dichloro-2H-benzimidazole 1,3-dioxide 14a
Similar behaviour was observed in the present study for 4,6-
dichloro-2H-benzimidazole 1,3-dioxide 14a, heating (Scheme 14)
of which leads to formation of compound 21a with high yield
contains a band at 527 nm (Fig. 4) that corresponds to absorbed
yellow-green color and observed violet-purple color of the sample.
In the UV spectra of benzoxadiazine 21a and 2H-benzimidazole
mono-N-oxide 22a, obtained by heating of compound 14a, the
corresponding band is blue-shifted to 452 nm and 438 nm (Fig. 4)
accordingly that corresponds to absorbed violet light and observed
red color of the samples.
7
5e80%. The further heating leads to formation of 2H-benzimid-
azole mono-N-oxide 22a.
Scheme 14. Transformation of 2H-benzimidazole 1,3-dioxides under heating to 3H-
[2,1,4]benzoxadiazine 4-oxides.
To find out the influence of substituents in the aromatic ring on
the thermal stability of oxadiazines we carried out the in-
vestigations with compounds 9, 14b,c, 16a and 20.
Unsubstituted
3H-[2,1,4]benzoxadiazine
4-oxide
1
2
3
(
R ¼R ¼R ¼H) is a less stable compound than other substituted
8
benzoxadiazines, but the introduction of an electron-withdrawing
substituent into the aromatic ring increases their stability. For ex-
ample, benzoxadiazine with a cyano group in the 2-position is
stable.15 So, for formation of 3H-[2,1,4]benzoxadiazine 4-oxides 21a
from 4,6-dichloro-2H-benzimidazole 1,3-dioxide 14a boiling tem-
p
Fig. 4. Experimental UV spectra of compounds 14a (black), 21a (red) and 22a (blue).
perature of dichloroethane (87 S) is enough while boiling tem-
perature of chlorobenzene (130 S) is necessary for the similar
conversion of 5-nitro-2H-benzimidazole 1,3-dioxide. 3H-[2,1,4]
benzoxadiazine 4-oxide 21d obtained from 4,6-dichloro-5-nitro-
p
12
The trend represented in Fig. 4 for compounds 14a, 21a and 22a
is similar for all compounds 9, 14aec, 16a, 20, 21aef and 22aef and
is confirmed computationally: the wavelength of the lowest exci-
tation, assigned to the transition from the highest occupied mo-
lecular orbital (HOMO) to the lowest unoccupied molecular orbital
(LUMO), in all cases decreases in the row dioxideddiazinedmon-
oxide (Table 3). According to computations HOMO and LUMO are
partially localized on benzyl moiety of compounds 14a, 21a and
22a, thus, substituents in 4e6 position should affect the wave-
length of the first excitation. According to computations in-
2
H-benzimidazole 1,3-dioxide 20 is stable and easily formed even
at room temperature (Fig. 3).
Such behaviour is in agreement with quantum chemical com-
putations predicting compound 21d to be more stable than com-
pound 20 with energy difference 2.9 kcal/mol. Similar energy
differences (2.7 kcal/mol) are predicted between 21a and corre-
sponding benzimidazole dioxide 14a. At the same time for unsub-
8
stituted benzoxadiazine, described earlier and compound 21e
computations predict almost negligible energy compared to initial
dioxides (0.7 and 0.2 kcal/mol respectively). Thus according to
computations introducing chlorine atoms makes 3H-[2,1,4]ben-
zoxadiazine 4-oxides more stable.
troducing of electron-withdrawing NO
bathochromic shift (0ee, aed) of the corresponding band with
more pronounced effect in 0ee case compared to aed, as in d NO
2
group leads to
2
group is orthogonal to the benzyl ring. Introduction of Cl atoms also
In all cases the reaction occurs with the change of colour.
Benzoxadiazine N-oxide 21aef are yellow and orange compounds
shifts considered band bathochromicaly (0ea) with less notable
effect. Replacement of Cl atom by NO group in 6th position (aeb)
2
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6
E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
Table 3
Comparison of calculated and experimental wavelength (nm) of the low-energy
transitions
aR1
aR2
aR3
H
H
H
Cl
H
Cl
Br
H
Cl
NO
H
OMe
H
2
H
NO
2
Cl
NO
2
NO
2
Cl
H
Cl
(0) (a) (b) (c)
(d) (e)
(f)
2
3
2
H-benzimidazole 1,3-dioxides
H-[2,1,4]benzoxadiazines
H-benzimidazole 1-oxides
E
C
E
C
E
C
525 527 555 561 556 547 512
564 576 616 619 588 616 542
452 495 482 446 470 459
Fig. 6. Photochemical transformation of 3H-[2,1,4]benzoxadiazine 4-oxides (yellow
color) surfaced on filter paper to 2H-benzimidazole 1,3-dioxides (blue color). Image
was obtained with help of stencil in sunlight.
453 468 483 483 470 467 464
416 438 457 455
463 433
428 445 453 454 447 457 436
C
E
Calculated value.
Prerequisite for formation of 2H-benzimidazole 1,3-dioxide from
benzofuroxan and alcohol is the formation of a stable secondary
carbocation from alcohol. Substituents in benzofuroxans do not
prevent the reaction. Under heating 2H-benzimidazole 1,3-dioxides
are rearranged to 3H-[2,1,4]benzoxadiazine 4-oxide, which under
irradiation is converted back to 2H-benzimidazole 1,3-dioxides. It is
shown that the introduction of electron-withdrawing substituents
in the aromatic ring increases the stability of obtained 3H-[2,1,4]
benzoxadiazine 4-oxides. More prolonged heating causes sequen-
tial elimination of an oxygen atom leading to the formation of 2H-
benzimidazole mono N-oxide.
Experimental value.
a
Substituents is numbering according Scheme 14.
leads to further increasing of the wavelength of the band, whereas
replacement of Cl atom in the obtained compounds (b) by Br atom
(
experimental results. Introducing an electron donating OMe group
in 4th position should lead to hypsochromic shift of the lowest
transition that is observed in experiment for oxides. Thus, it is
possible to obtain compounds with definite color controlled by
light and temperature, further tuning could be achieved by varia-
tion of substituents in benzyl ring.
c) do not lead to any notable differences in full agreement with
Under heating of 5-substituted 2H-benzimidazole 1,3-dioxides
two isomeric 3H-[2,1,4]benzoxadiazine 4-oxides are formed, fur-
5. Experimental section
ther heating leads to two isomeric mono-N-oxides of 2H-benz-
imidazole.12 However in the case of 4-nitro-2,2-dimethyl-2H-
5.1. General
benzimidazole 1,3-dioxide 9 and compounds 14aec, 16a and 20
only one isomeric 3H-[2,1,4]benzoxadiazine 4-oxide and one cor-
responding mono N-oxide of 2H-benzimidazole are formed under
heating.
The position of N-oxide oxygen atom in mono-N-oxide 22a is
established by X-ray analysis (Fig. 5). These data are in agreement
with those published earlier, which confirms that heating of 3H-
The analytic and spectral measurements were carried out in the
Chemical Service Center for collective use of the Siberian Division,
Russian Academy of Sciences.
The IR spectra were recorded in KBr (sample concentration
0.25%) on a Bruker Vector-22 spectrometer; given are the most
intense absorption bands. The UV spectra were measured on
a HewlettePackard 4853 spectrophotometer from solutions in
[
2,1,4]benzoxadiazine 4-oxides cause loss of an oxygen atom lo-
1
13
16
ethanol. The H and C NMR spectra were obtained on a Bruker AV-
4
cated in oxadiazine ring.
1
13
ꢁ
00 instrument (400.13 ( H) and 100.61 MHz ( C)) at 25 C from
0% solutions in CDCl or DMSO-d ; the chemical shifts were de-
termined relative to the residual proton and carbon signals of the
solvent (CHCl 7.24, 76.90 ppm; DMSO-d 2.50,
9.50 ppm). Signal multiplicities in the C NMR spectra were de-
termined using J-modulation (JMOD) technique. The mass spectra
electron impact, 70 eV) were recorded on a Thermo Scientific DFS
1
3
6
3
,
d
d
C
6
,
d
d
C
13
3
(
mass spectrometer with direct sample admission into the ion
ꢁ
source (ion source temperature 180 C); ion peaks with a relative
intensity higher than 10% are given. The progress of reactions and
the purity of products were monitored by TLC on Sorbfil UV-254
plates (Sorbpolimer, Krasnodar, Russia); the chromatograms were
developed under UV light and by treatment with iodine vapor.
Column chromatography was performed on silica gel (60-mesh,
Merck). The melting points were measured on a Kofler hot stage.
The elemental compositions were determined at the Microanalysis
Laboratory, Novosibirsk Institute of Organic Chemistry, Siberian
Division of the Russian Academy of Sciences.
Fig. 5. Molecular structure of 4,6-dichloro-2,2-dimethyl-2H-benzimidazole 1-oxide
2a.
2
Obtained 3H-[2,1,4]benzoxadiazine 4-oxides are easily trans-
formed into initial 2H-benzimidazole 1,3-dioxides on exposure to
sunlight (Fig. 6). Transition of 3H-[2,1,4]benzoxadiazine 4-oxides to
For the experiments concentrated chemically pure grade sul-
furic acid and 65% chemically pure grade perchloric acid were used.
All other solvents were purified and dried according to standard
procedures.
2
H-benzimidazol-1,3-dioxide under the action of sunlight occurs
both in solution and in crystalline form.
The following compounds were prepared following the litera-
ture procedures indicated: 5-formylbenzofuroxan 6c and 5-
17
4
. Conclusion
trifluoromethylbenzofuroxan 6d, 4-chloro-6-nitrobenzofuroxan
1
8
19
13b,
5-hydroxyiminomethylbenzofuroxan
6b,
4,6-
2
0
21
The interaction of benzofuroxans with alcohols in sulfuric or
perchloric acid results in novel 2H-benzimidazole 1,3-dioxides.
dichlorobenzofuroxan 13a, 4-bromo-6-nitrobenzofuroxan13c,
4-nitrobenzofuroxan 8,
2
2
23
5-carboxybenzofuroxan 6e,
5-
Please cite this article in press as: Chugunova, E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.096

E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
7
bromomethylbenzofuroxan
10,24
nitrobenzofuroxan 19,2 4-hydroxypentan-2- one.
4,6-dichloro-5-
1.63 (3O, s, SO
7.13e7.19 (2O, m, 2CH). C NMR (CDCl
24.5, 36.8, 99.6, 115.2, 130.5, 137.3. MS, m/z (I, %) 220 [M] (18), 203
(25), 164 (25), 147 (25), 132 (15), 121 (12), 106.(16). HRMS: m/z (M )
3
), 2.04e2.10 (2O, m, SO
2
), 6.80e6.86 (2O, m, 2SO),
5
26
13
3
),
d
(ppm): 13.4, 24.0, 21.7,
þ
Benzofuroxan 1, 5-methylbenzofuroxan 6a and 1,3-butanediol
are commercially available research-grade chemicals and were
used without further purification.
The X-ray diffraction experiments for compounds 15a, 15b, 21d
and 22a were carried out on a Bruker KAPPA APEX II diffractometer
þ
calcd for C12
C H N O
12 16 2 2
H
16
N
2
O
2
: 220.1206; found: 220.1203. Anal. Calcd (%) for
(220.2): C, 58.25; H, 4.85; N, 13.59. Found: C, 58.3; H,
4.88; N, 13.50.
(
graphite-monochromated Mo Ka radiation). Reflection intensities
were corrected for absorption by SADABS program. The structures
was solved by direct methods using the SHELXS-97 program and
refined by anisotropic (isotropic for all H atoms) full-matrix least-
5
.3. Synthesis of 2-methyl-2-vinyl-2O-benzimidazole 1,3-
dioxide (4)
2
squares method against F of all reflections using SHELX-97 pro-
gram.27 The positions of the hydrogen were calculated geo-
To a solution of 1.36 g (0.01 mol) of benzofuroxan 1 in 10 mL of
5% perchloric acid was added dropwise 1.8 g (0.02 mol) of 1,3-
6
metrically and refined in riding model.
ꢁ
butanediol. The reaction mixture was stirred at 30 C for 36 h
then poured into 100 mL of ice-water. The product was extracted
with chloroform (5ꢂ20 mL), the extract was washed with water
Crystallographic data for the structures of cocrystals of com-
pounds 15a and 13a, compounds 15b, 21d and 22a have been de-
posited at the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 991083-991085 and 1040866
accordingly. Copy of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
þ44 122 3336033 or e-mail: deposit@ccdc.cam.ac.uk; internet:
www.ccdc.cam.ac.uk).
(
2ꢂ100 mL), dried over magnesium sulfate, and evaporated in
vacuo to give the crude product, which was purified by column
chromatography (25% hexaneeethyl acetate), pure fractions were
collected, solvents were evaporated in vacuo and the residue was
triturated with hexane to give red powder. Yield 0.82 g (43%). Mp:
ꢁ
1
53e55 C. UV,
l
max (lg ε) 247 (4.34), 515 (3.80) nm; O NMR (CDCl
3
),
All quantum-chemical computations were carried out using the
Gaussian 0928 suite of programs. Calculations were performed with
d
(ppm): 1.75 (3O, s, SO
3
), 5.54 (1O, d, SO, J¼10.5 Hz), 5.66 (1O, d,
2
9
SO, J¼16.8 Hz), 5.93 (1O, dd, SO, J¼10.5 Hz), 6.84 (2O, s, 2SO), 7.16
Becke’s three parameter hybrid exchange functional and the
13
3
0
(2O, s, 2SO). C NMR (CDCl
3
),
d
(ppm): 22.8, 97.9, 115.5, 130.8,
gradient-corrected nonlocal correlation functional of Lee et al.
þ
31
131.2, 121.4, 136.9. MS, m/z (I, %) 190 [M] (100), 174 (22), 157 (19),
149 (54), 131 (41), 120 (51). HRMS: m/z (M ) calcd for C10
(
B3LYP) and B97D functional. Standard 6e31G* and 6e311þG*
þ
32e37
10
H N
2
O
2
:
basis sets were used.
Dispersion-corrected energies were
190.0737; found: 190.0736. Anal. Calcd (%) for S10
10 2 2
H N O (190.2):
calculated (for B3LYP functional) within the recently developed
38
S 63.15; O 5.30; N 14.73. Found: C, 63.19; O 5.24; N 14.71.
approach DFT-D3 together with the Becke-Johnson (BJ) damping
39
function. For this purpose the program dftd3 v2.1 Rev1 was
used.40 The obtained values were added to the electronic energies.
For simulation of solvent effects the polarized continuum model
5
.4. Synthesis of 2-methyl-2-(2-oxopropyl)-2H-benzimidazole
1,3-dioxide (5)
(
PCM) was used.41,42 All stationary points were characterized as
minima by analysis of the Hessian matrices. UV/Vis spectra were
Compound
5 was prepared from 4-hydroxypentan-2-one
4
3
calculated with the use of wB97xD functional for structures op-
according to the same procedure as that described for compound
. Yield of red powder is 0.28 g (25%). Mp: 76e79 C. IR (KBr),
4
4,45
timized with PBE
functional in combination with def2-TZVP
ꢁ
4
1
(
n
:
basis set.46
ꢀ1
1
712 (C]O) cm . UV,
DMSO-d ), (ppm): 1.53 (3O, s, SO
s, SO ), 6.97 (2O, m, 2SO), 7.16 (2O, m, 2SO). C NMR (DMSO-d
l
max (lg ε) 248 (4.12), 513 (3.26) nm; O NMR
), 2.03 (3O, s, SO ), 3.43 (2O,
),
6
d
3
3
5
1
.2. Synthesis of mixture 2-ethyl-2-propyl-2H-benzimidazole
,3-dioxide (2) and 2-methyl-2-butyl-2H-benzimidazole 1,3-
dioxide (3)
13
2
6
d
(ppm): 25.5, 30.0, 46.7, 95.0,115.1,130.9,137.5, 202.6. MS, m/z (I, %)
þ
2
20 [M] (36), 204 (15), 161 (17),143 (31), 130 (17), 119 (38). HRMS:
þ
m/z (M ) calcd for C11
12
H N
2
O
3
: 220.0842; found: 220.0845. Anal.
(220.2): S 59.99; O 5.49; N 12.72. Found:
S 59.90; O 5.38; N 12.49.
To a solution of 1.36 g (0.01 mol) of benzofuroxan 1 in 10 mL of
concentrated sulfuric acid was added dropwise 1.2 g (0.012 mol) of
-hexanol. The reaction mixture was stirred at room temperature
12 2 3
Calcd (%) for S11H N O
1
for 1.5 h then poured into 100 mL of ice-water. The products were
extracted with chloroform (3ꢂ20 mL), the extract was washed with
water (2ꢂ100 mL), dried over magnesium sulfate, and evaporated
in vacuo to give the crude products, which were separated by col-
umn chromatography (25% hexaneeethyl acetate) to give the 2
pure fractions. The first fractiond2-ethyl-2-propyl-2H-benzimid-
5.5. Synthesis of compounds 7aee
5.5.1. 5-Formyl-2,2-dimethyl-2O-benzimidazole l,3-dioxide (7c). To
a solution of 1.0 g (0.01 mol) of 5-formylbenzofuroxan 6c in 10 mL
of concentrated sulfuric acid was added dropwise 1.0 g (0.016 mol)
of isopropyl alcohol. The reaction mixture was stirred at room
temperature for 1.5 h then poured into 100 mL of ice-water. The
product was extracted with chloroform (3ꢂ20 mL), the extract
was washed with water (2ꢂ100 mL), dried over magnesium sul-
fate, and evaporated in vacuo to give the crude product, which was
purified by column chromatography (25% hexaneeethyl acetate),
pure fractions were collected, solvents were evaporated in vacuo
and the residue was triturated with hexane to give 0.76 g (68%) of
ꢁ
azole 1,3-dioxide (2), red powder. Yield (38%). Mp: 101e103 C. UV,
1
l
max (lg ε) 249 (4.00), 518 (3.40) nm; O NMR (CDCl
3
),
d
(ppm): 0.62
(
3O, t, SO
3
, J¼7.2 Hz), 0.80 (3O, t, CH3, J¼7.2 Hz), 0.91e1.03 (2O, m,
SO
6
2
), 1.99e2.06 (2O, m, SO ), 2.09 (2O, q, SO
2
2
, J¼7.0 Hz, J¼7.4 Hz),
13
3
.80e6.86 (2O, m, 2SO), 7.13e7.19 (2O, m, 2CH). C NMR (CDCl ),
d
(ppm): 5.9, 13.0, 14.9, 30.8, 38.9, 103.3, 114.9, 130.8, 138.6. MS, m/z
þ
(
(
(
I, %) 220 [M] (51), 178 (57), 161 (13), 147 (19), 130 (12). HRMS: m/z
M ) calcd for C12
%) for C12
þ
H
16
N
2
O
2
: 220.1206; found: 220.1212. Anal. Calcd
(220.2): C, 58.25; H, 4.85; N, 13.59. Found: C,
8.4; H, 4.88; N, 13.64.
ꢁ
ꢀ1
16
H N
2
O
2
red powder. Mp: 128e130 C. IR (KBr),
n
: 1691 (C]O) cm . UV,
1
5
lmax (lg ε) 255 (4.34), 298 (3.70), 513 (3.65) nm; O NMR (CDCl
3
),
The second fraction gives 2-methyl-2-butyl-2H-benzimidazole
d
3
(ppm): 1.64 (6O, s, 2SO ), 7.25 (2O, s, 2SO), 7.64 (1O, s, SO),
ꢁ
13
1
,3-dioxide (3), red powder. Yield (42%). Mp: 95e97 C. UV,
l
max (lg
9.75 (1O, s, CH). C NMR (CDCl
189.1, 98.9, 122.6, 136.5, 136.6. HRMS: m/z (M ) calcd for
C
3
),
d
(ppm): 24.2, 116.9, 126.4, 138.0,
1
þ
ε) 248 (4.06), 515 (3.40) nm; O NMR (CDCl
3
),
d
(ppm): 0.78 (3O, t,
),
SO ), 1.18e1.27 (2O, m, SO
3
J¼5.8 Hz), 0.90e0.99 (2O, m, CH
2
2
10
H
10
N
2
O
3
: 206.0686; found: 206.0684. Anal. Calcd (%) for
Please cite this article in press as: Chugunova, E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.096

8
E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
1
S
10
H
10
N
2
O
3
(206.2): S 58.59; O 4.89; N 13.58. Found: S 58.90; O
356 (3.18) nm; O NMR (DMSO-d
6
),
d
(ppm): 3.88 (3O, s, PSO
3
),
C
1
3
5
.38; N 13.29.
5.30 (2O, s, OSO
NMR (DMSO-d ),
2
), 7.22e7.83 (6O, m, 6SO), 9.88 (1O,s, CH).
In a similar manner starting from benzofuroxans 6a,b,d,e and
6
d
(ppm): 55.8, 68.8, 110.0, 112.9, 125.8, 130.3,
benzofuroxan 1 were prepared:
149.5,152.5,191.5. Six signals of benzofuroxan carbon atoms are not
observed due to their strong broadening owing to tautomerism.
Signals of benzofuroxan carbon ring appear during recording the
5.5.2. 2,2,5-Trimethyl-2O-benzimidazole 1,3-dioxide (7a). Yield
ꢁ
9
ꢁ
ꢁ
13
ꢁ
2
5%. Dark red powder. Mp: 116e118 C. (lit. 116.4e117.7 C).
spectrum at 80 C on account averaging. C NMR (DMSO-d ), 80 C,
6
d
(ppm): 55.8, 69.1, 111.2, 111.8, 113.7, 115.2, 124.6, 130.5, 131.0, 140.6,
þ
5
.5.3. 5-Hydroxyiminomethyl-2,2-dimethyl-2O-benzimidazole
152.4,190.6. MS m/z (I, %) 300 [M] (12), 284 (7), 151 (34),149 (100),
133 (17), 95 (39). HRMS: m/z (M ) calcd for C15
ꢁ
þ
l,3-dioxide (7b). Dark red powder. Yield 64%. Mp: 177e178 C.
H
12
N
2
O
5
: 300.0741;
9
ꢁ
(
lit. 177.5e177.6 C).
found: 300.0742. Anal. Calcd (%) for S15
.03; N 9.33. Found: S 60.00; O 4.38; N 9.29.
H N O (300.2): S 60.00; O
12 2 5
4
5
.5.4. 2,2-Dimethyl-5-(trifluoromethyl)-2H-benzimidazole 1,3-
ꢁ
dioxide (7d). Dark blue powder. Yield 67%. Mp: 123e125 C. IR
5.7.2. 5-((1H-[1,2,3]Benzotriazol-1-yl)methyl)benzofuroxan
(11b). 5-((1H-[1,2,3]Benzotriazol-1-yl)methyl)benzofuroxan (11b)
was synthesized as described above for compound 11a from 11.13 g
(0.04 mol) of 5-(bromomethyl)benzofuroxan 10, 5.76 g (0.04 mol)
ꢀ
1
(
KBr),
n
: 1593 (C]N) cm . UV,
lmax (lg ε) 251 (3.80), 525 (3.30) nm;
1
O NMR (CDCl ), (ppm): 1.66 (6O, s, 2SO
3
d
3
), 6.93 (1O, d, SO,
13
J¼8.8 Hz), 7.29 (1O, d, SO, J¼8.8 Hz), 7.50 (1O, s, SO). C NMR
(
CDCl
3
),
d
(ppm): 24.2, 98.6, 114.5 (SO, q, J¼6.0 Hz), 117.3, 126.1
of 1,2,3-benzotriazole and 9.6 g (0.09 mol) of potassium carbonate.
ꢁ
(
SO, q, J¼3.3 Hz), 122.2 (SF
3
, q, J¼271.4 Hz), 132.6 (SO, q,
White powder. Yield 10.8 g (97%). Mp: 145e146 C. IR (KBr),
n
: 1603
),
7.15e7.77 (6O, m, 6SO), 7.92 (1O, d, CH, J¼8.5 Hz), 8.03 (1O, d, CH,
19
ꢀ1 1
(C]N) cm .
J¼33.0 Hz), 135.3, 136.0. F NMR (CDCl
3
),
d
(ppm): 95.76 (3F, s, CF
3
).
6 2
O NMR (DMSO-d ), d (ppm): 5.53 (2O, s, CH
þ
MS m/z (I, %) 246 [M] (100), 231 (28), 188 (27), 158 (30) 145 (23),
þ
13
1
2
38 (18). HRMS: m/z (M ) calcd for C10
H F
9 3
N
2
O
2
: 246.0611; found:
(246.0): S 48.78; O 3.66;
F 23.17; N 11.39. Found: S 49.00; O 3.68; F 23.22; N 11.40.
J¼8.5 Hz). C NMR (DMSO-d
6
), d (ppm): 50.6, 110.9, 119.6, 124.7,
128.2, 133.1, 145.6. The signals of furoxan ring carbon atoms are not
observed in the C NMR spectrum due to the strong broadening of
these signals. MS m/z (I, %) 267 [M] (100), 251 (25), 222 (7), 192
9 3 2 2
46.0605. Anal. Calcd (%) for S10H F N O
13
þ
þ
5
.5.5. 5-Carboxy-2,2-dimethyl-2H-benzimidazole 1,3-dioxide
(23), 179 (38), 178 (45), 149.(16), 133 (23). HRMS: m/z (M ) calcd for
ꢁ
(7e). Dark blue powder. Yield 72%. Mp: 168
C
with de-
C
13
H
9
N
5
O
2
:
267.0751; found: 267.0744. Anal. Calcd (%) for
ꢀ
1
composition. IR (KBr),
n
: 1712 (C]O) cm . UV,
l
max (lg ε) 256
S
13
H
9
N
5
O
2
(267.2): S 58.43; O 3.37; N 26.22. Found: S 58.90; O
1
(
4.00), 521 (3.80) nm; O NMR (CDCl
3
),
d
(ppm): 1.56 (6O, s, 2SO ),
3
3.38; N 26.39.
7
.19 (1O, d, SO, J¼9.8 Hz), 7.39 (1O, d, SO, J¼9.8 Hz), 7.65 (1O, s,
13
SO), 4.54 (1O, br s, PO). C NMR (CDCl
3
),
d
(ppm): 23.8, 97.4, 115.2,
5.7.3. 5-((4-Formyl-2-methoxyphenoxy)methyl)-2,2-dimethyl-2H-
benzimidazole 1,3-dioxide (12a). 5-((4-Formyl-2-methoxyphenoxy)
methyl)-2,2-dimethyl-2H-benzimidazole 1,3-dioxide (12a) was syn-
þ
116.7, 130.9, 136.2, 136.4, 136.8, 166.6. MS m/z (I, %) 222 [M] (15),
2
06 (47), 190 (41), 161 (49), 149 (20), 130 (21), 117 (47). HRMS: m/z
þ
(
M ) calcd for C10
H
10
N
2
O
4
: 222.0635; found: 220.0636. Anal. Calcd
thesized as described above for compound 7c from compound 11a
ꢁ
(
%) for S10
H
10
N
2
O
4
(222.2): S 54.05; O 4.54; N 12.61. Found: S
as dark red powder. Yield 48%. Mp: 162e164 C. IR (KBr),
n
: 1680
ꢀ
1
5
4.18; O 4.48; N 12.59.
(C]O) cm . UV,
(
l
max (lg ε) 270 (3.40), 254 (3.39), 231 (3.30), 309
3.20) nm; O NMR (DMSO-d ), (ppm): 1.53 (6O, s, 2SO ), 3.83
), 5.07 (2O, s, SO
), 6.98 (1O, d, SO, J¼9.0 Hz),
1
6
d
3
5.5.6. 2,2-Dimethyl-2H-benzimidazole 1,3-dioxide (7f). Dark red
(3O, s, PSO
3
2
ꢁ
9
ꢁ
powder. Yield 75%. Mp: 122e123 C. (lit. 122.6e123.4 C).
7.29e7.38 (3O, m, 3SO), 7.41 (1O, s, SO), 7.52 (1O, d, SO, J¼9.0 Hz),
13
9
.82 (1O, s, CH). C NMR (DMSO-d
6
), d (ppm): 23.7, 55.7, 110.0,
5
.6. Synthesis of 2,2-dimethyl-4-nitro-2H-benzimidazole 1,3-
112.8, 112.9, 115.9, 125.7, 130.9, 96.8, 130.2, 135.5, 136.6, 140.1, 149.4,
þ
29
15
35
dioxide (9)
152.5. MS m/z (I, %) 342 [M] (5.8), 326, 191, 175 (100), 159,
3
5
43
þ
1
51, 144.(59), 133. HRMS: m/z (M ) calcd for C18
342.1210; found: 242.1212. Anal. Calcd (%) for S18
S 63.15; O 5.30; N 8.18. Found: S 63.40; O 5.38; N 8.10.
18 2 5
H N O :
H N O (342.2):
18 2 5
Compound 9 was prepared from 4-nitrobenzofuroxan 8 as de-
scribed above for compound 7c. Dark blue powder. Yield 72%. Mp:
ꢁ
ꢀ1
1
l
03e106 C. IR (KBr),
max (lg ε) 254 (3.90), 547 (3.80) nm; O NMR (CDCl
6O, s, 2SO
.40 (1O, d, SO, J¼9.4 Hz). C NMR (CDCl
n
: 1595 (C]N), 1357, 1537 (NO
2
) cm . UV,
(ppm): 1.68
1
3
),
d
5.7.4. 5-((1H-[1,2,3]Benzotriazol-1-yl)methyl)-2,2-dimethyl-2H-
benzimidazole 1,3-dioxide (12b). 5-((1H-[1,2,3]Benzotriazol-1-yl)
methyl)-2,2-dimethyl-2H-benzimidazole 1,3-dioxide (12b) was syn-
thesized as described above for compound 7c from compound 11b.
(
7
3
), 6.84e6.95 (1O, m, SO), 7.29 (1O, d, SO, J¼7.4 Hz),
13
3
),
d
(ppm): 24.4, 99.0,
þ
120.2, 126.8, 127.9, 127.1, 137.2, 140.1. MS m/z (I, %) 223 [M] (100),
þ
ꢁ
2
07 (23), 165 (18), 130 (19), 105 (37). HRMS: m/z (M ) calcd for
Red powder. Yield 36%. Mp: 126e129 C with decomposition. IR
ꢀ
1
C
S
H
9 9
N
3
O
4
:
223.0588; found: 223.0587. Anal. Calcd (%) for
(KBr),
n
: 1598 (C]N) cm . UV,
O NMR (CDCl ), (ppm): 1.64 (6O, s, 2SO
(1O, d, SO, J¼9.0 Hz), 7.09 (1O, s, SO), 7.15 (1O, d, SO, J¼9.0 Hz),
l
max (lg ε) 255 (4.25), 515 (3.60) nm;
1
9
9
H N
3
O
4
(223.0): S 48.43; O 4.04; N 18.84. Found: S 48.60; O
3
d
3
), 5.62 (2O, s, CH ), 6.75
2
4
5
5
.08; N 18.80.
13
7
.49e7.37 (3O, m, 3SO), 8.07 (1O, d, CH, J¼9.0 Hz). C NMR
.7. Synthesis of compounds 11a,b, 12a,b
.7.1. 5-((4-Formyl-2-methoxyphenoxy)methyl)benzofuroxan
(CDCl
1
3
),
d
(ppm): 23.7, 50.3, 97.4, 110.7, 113.5, 116.5, 119.5, 124.8,
þ
28.3, 131.5, 132.9, 135.7, 135.9, 139.7, 145.3. MS m/z (I, %) 309 [M]
(11), 293 (100), 277 (27), 264 (40), 248 (30), 234 (55), 159 (32), 149
þ
(11a). To a solution of 2.29 g (0.01 mol) of 5-(bromomethyl)ben-
(70), 144 (54), 119 (72). HRMS: m/z (M ) calcd for C16
H
15
N
5
O
2
:
zofuroxan 10 in 100 mL of acetonitrile was added 1.7 g (0.012 mol)
of vanillin and 1.5 g (0.01 mol) of potassium carbonate. The reaction
mixture was stirred at room temperature for 3 h. Solvent was
evaporated under reduced pressure, resulting solid was washed
with water, filtered and dried in vacuo (1 h, 0.01 Torr) to give
15 5 2
309.1220; found: 309.1214. Anal. Calcd (%) for S16H N O (309.3):
S 62.12; O 4.89; N 22.64. Found: S 62.00; O 5.08; N 22.62.
5.8. Synthesis of compounds 14aes
ꢁ
compound 11a as a white powder. Yield 2 g (88%). Mp: 166e168 C.
Compounds 14aes were prepared as described above for com-
pound 7c.
ꢀ
1
IR (KBr),
n
: 1690 (C]O) cm . UV,
lmax (lg ε) 274 (3.40), 310 (3.20),
Please cite this article in press as: Chugunova, E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.096

E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
9
5
.8.1. 4,6-Dichloro-2,2-dimethyl-2H-benzimidazole 1,3-dioxide
5.10. Synthesis of 6-chloro-4-morpholinobenzofuroxan (15b)
ꢁ
(
14a). Dark blue powder. Yield 85%. Mp: 147e148 C with de-
composition. UV, max (lg ε) 262 (4.34), 336 (3.00) 527 (3.80) nm;
(ppm): 1.67 (6O, s, 2SO ), 6.76 (1O, d, SO,
l
8 mL of morpholine were added to the solution of 3.0 g
(0.015 mol) of benzofuroxan 13a. The reaction mixture was stirred
at room temperature for 24 h. The resulting crystal mass was
washed with water, residue filtered, and dried in vacuo (1 h, 0.01
Torr) to give orange powder of compound 15b with yield 2.82 g
1
O NMR (CDCl
3
),
d
3
13
J¼1.5 Hz), 7.15 (1O, d, SO, J¼1.5 Hz). C NMR (CDCl
3
),
d
(ppm): 24.4,
þ 42
9
8.7, 113.0, 131.6, 124.0, 131.9, 135.9, 136.6. MS m/z (I, %) 246 [M] ,
þ
35
188 (53), 158 (100). HRMS: m/z (M ) calcd for C
9
H
8
Cl
Sl
2
N
2
O
2
:
ꢁ
ꢀ1
2
46.9957; found: 246.9956. Anal. Calcd (%) for S
9
H
8
2
N
2
O
2
(67%). Mp: 179e180 C. IR (KBr),
n
: 1608 (C]N) cm . UV,
lmax (lg ε)
1
(
247.0): S 43.73; O 3.24; Cl 28.75; N 11.34. Found: S 43.60; O 3.38;
236 (3.93), 417 (3.60) nm; O NMR (DMSO-d
6
), (ppm): 3.53e3.59
d
Cl 28.39; N 11.36.
(4O, m, 2SO
2
), 3.76e3.80 (4O, m, 2SO
2
), 6.48 (1O, d, SO, J¼1.1 Hz),
13
7
.04 (1O, SO, d, J¼1.1 Hz). C NMR (DMSO-d
6
),
d
(ppm): 49.2, 65.9,
þ
5
.8.2. 4-Chloro-2,2-dimethyl-6-nitro-2H-benzimidazole 1,3-dioxide
100.1, 111.2, 116.0, 136.2, 140.9, 148.4. MS m/z (I, %) 255 [M] (39),
ꢁ
þ
(14b). Dark blue powder. Yield 68%. Mp: 119e121 C with de-
239 (17), 208 (28), 197 (100), 181 (18), 151 (28). HRMS: m/z (M )
calcd for C10 : 255.0400; found: 255.0397. Anal. Calcd
(%) for S10H10ClN O (255.5): S 46.97; O 3.92; Cl 13.90; N 16.44.
Found: S 47.02; O 3.76; Cl 13.80; N 16.47.
Crystallographic data for comp 15b: C
ꢀ
1
35
composition. IR (KBr),
n
: 1334, 1527 (NO
2
) cm . UV,
),
), 7.51 (1O, d, SO, J¼1.2 Hz), 8.05 (1O, d, SO, J¼1.2 Hz).
C NMR (CDCl ), (ppm): 24.6, 100.4, 111.7, 123.2, 125.9, 132.9,
36.3, 147.9. MS m/z (I, %) 259 [M] , 257 [M] (43), 243 (21), 241
62), 226 (22), 199 (32), 164 (49), 150 (15), 141 (16), 130 (26). HRMS:
l
max (lg ε) 264
(ppm): 1.70
H
10 ClN
3
O
3
1
(
4.11), 337 (3.70), 555 (3.42) nm; O NMR (CDCl
6O, s, 2SO
3
d
3 3
(
3
1
3
3
d
9
H
7
N
3
O
4
Cl
2
, M¼292.08,
þ
þ
ꢀ
1
(
monoclinic, C2/c, a 21.788(2), b 5.0093(4), c 21.317(2) A,
b
92.140(4),
ꢀ
3
ꢀ3
ꢀ1
V 2324.9(3) A , Z 8, Dcalcd¼1.669 g cm
,
m
(Mo-K
a
)¼0.569 mm
,
þ
35
ꢁ
m/z (M ) calcd for C
Calcd (%) for S ClN
Found: S 42.10, O 3.15, Cl 14.00, N 16.20.
9
H
8
ClN
3
O
4
: 257.0198; found: 257.0203. Anal.
(257.5): S 41.95; O 3.11; Cl 13.79; N 16.31.
F(000)¼1184, (
q
1.87e26.47 , completeness 99.6%), T 296(2) L,
3
9
H
8
3
O
4
yellow alongated plate, (0.60ꢂ0.20ꢂ0.04) mm , transmission
0.6763e0.7454, 28,815 measured reflections in index range
ꢀ
26ꢃhꢃ26, ꢀ6ꢃkꢃ6, ꢀ26ꢃlꢃ26, 2391 independent (Rint¼0.0374),
165 parameters, (I),
¼0.0339 (for 2391 observed I>2
wR
¼0.0883 (all data), GOOF 1.064, largest diff. peak and hole 0.375
and ꢀ0.395 e.A
5
.8.3. 4-Bromo-2,2-dimethyl-6-nitro-2H-benzimidazole 1,3-dioxide
R
1
s
ꢁ
(14c). Dark blue powder. Yield 64%. Mp: 119e121 C with de-
2
ꢀ
1
ꢀ3
composition. IR (KBr),
n
: 1332, 1525 (NO
2
) cm . UV,
),
), 7.75 (1O, d, SO, J¼1.2 Hz), 8.11 (1O, d, SO, J¼1.2 Hz).
C NMR (CDCl ), (ppm): 24.7, 100.3, 112.2, 126.9, 111.3, 133.4,
36.3, 148.3. HRMS: m/z (M ) calcd for C
found: 300.9690. Anal. Calcd (%) for S BrN
O 2.65; Br 26.49; N 13.91. Found S 36.01; O 2.65; Br 26.20; N 14.10.
l
max (lg ε) 263
.
1
(
4.11), 342 (3.80), 561 (3.40) nm; O NMR (CDCl
6O, s, 2SO
3
d (ppm): 1.71
(
3
5.11. Synthesis of 6-chloro-4-methoxy-2,2-dimethyl-2H-
benzimidazole 1,3-dioxide (16)
1
3
3
d
þ
79
1
9
H
8
3 4
BrN O : 300.9693;
9
H
8
3
O
4
(302.1): S 35.75;
Compound 16 was prepared as described above for compound
7c from compound 15a in 10 mL of 65% perchloric acid. Dark blue
powder. Yield 55%. Mp: 122e123 C. IR (KBr),
ꢁ
ꢀ1
.
n
: 1579 (C]N) cm
), (ppm):
1
5
.9. Synthesis of 6-chloro-4-methoxybenzofuroxan (15a)
UV,
l
max (lg ε) 255 (4.07), 512 (3.71) nm; O NMR (CDCl
3
d
1
.68 (6O, s, 2SO
3
), 3.89 (3O, s, PSO
3
), 6.01 (1O, s, SO), 6.52 (1O, s,
13
To a solution of 1.0 g (0.004 mol) of benzofuroxan 13a in 10 mL
SO). C NMR (CDCl ), (ppm): 24.2, 56.6, 98.2, 106.3, 107.9, 129.1,
136.4, 137.7, 150.4. MS m/z (I, %) 244 [M] (35), 242 [M] (100), 226
(23), 184 (45), 168 (10), 154 (26), 127 (47). HRMS: m/z (M ) calcd for
C
3
d
þ
þ
of methanol 1.0 g (0.018 mol) of sodium methylate was added. The
reaction mixture was boiled with reflux condenser for 4 h then
cooled. The resulting residue was filtered, washed with water, and
dried in vacuo (1 h, 0.01 Torr) to give 0.79 g (79%) of yellow powder
þ
3
5
10
H
11 ClN : 242.0453; found: 242.0455. Anal. Calcd (%) for
2
O
3
S
10
H
11ClN O (242.5): S 49.49; O 4.54; Cl 14.64; N 11.55. Found: S
2 3
ꢁ
ꢀ1
of compound 15a. Mp: 90e81 C. IR (KBr),
n
: 1624 (C]N) cm . UV,
), (ppm): 3.88 (3O, s,
49.40; O 4.38; Cl 14.52; N 11.39.
1
l
max (lg ε) 373 (3.63) nm; O NMR (DMSO-d
6
d
OSO
3
), 6.73 (1O, s, SO), 7.08 (1O, s, SO). Doubled set of signals was
5.12. Synthesis of 3,5-dichlorocyclohexa-3,5-diene-1,2-dione
dioxime (17)
13
observed in the spectrum C NMR due to isomerism of benzofur-
oxan. The spectrum of the dominant isomer in the mixture is de-
scribed. 13C NMR (DMSO-d
d
(ppm): 57.4, 102.9, 110.3, 115.1, 136.0,
5 mL of benzyl amine were added to 0.5 g (0.0025 mol) of
compound 13a. The reaction mixture was stirred at room temper-
ature for 24 h then 20 mL of water were added and a few drops of
5% hydrochloric acid until pH¼3. The resulting crystal mass was
filtered, washed with water and dried in vacuo (1 h, 0.01 Torr) to
6
),
þ
147.2, 149.4. MS m/z (I, %) 200 [M] (42), 181 (48), 169 (25), 131 (48),
þ
35
119 (34), 110 (48). HRMS: m/z (M ) calcd for C ClN
7
H
5
2 3
O :
199.9983; found: 199.9979. Anal. Calcd (%) for S ClN O (200.5):
7
H
5
2 3
S 41.90; O 2.50; Cl 17.71; N 13.97. Found: S 41.92; O 2.48; Cl 17.60;
N 13.92.
Crystallographic data for cocrystals of compounds 15a with 13a:
mixed
ꢁ
give yellow powder. Yield 0.44 g (86%). Mp: 154e156 C with de-
ꢀ1
composition. IR (KBr),
n
: 1604 (C]N) cm . UV,
(3.30). nm; O NMR (DMSO-d ), (ppm): 6.92 1O, s, SO), 7.21 (1O,
s, SO), 13.08 (1O, br s, PO), 14.25 (1O, br s, PO). C NMR (DMSO-
), (ppm): 114.4, 126.4, 133.4, 134.3, 140.8, 146.8. Anal. Calcd (%)
for S Cl (206.1): S 34.94; O 1.95; Cl 33.97; N 13.59. Found:
lmax (lg ε) 389
1
crystal
of
Cl, M¼200.59) and 6,4-dichlorobenzofuroxan 13a
Cl /c, 15.413(1),
M¼204.00), monoclinic, P2
6-chloro-4-methoxybenzofuroxan
15a
6
d
13
(
(
C
C
7
H
H
5
N
N
2
O
O
3
6
2
2
2
2
,
1
a
d
6
d
ꢀ
ꢁ
ꢀ
3
b 13.945(1), c 7.2214(6) A,
b
91.320(4) ,V 1551.7(2) A , Z 8, Dcalcd
6
H
4
2 2 2
N O
ꢀ3
ꢀ1
ꢁ
1.746 g cm
,
m(Mo-K
a
) 0.708 mm , F(000) 816, (
q
1.32e26.08 ,
S 34.82; O 1.79; Cl 33.80; N 13.57.
completeness 99.8%), T 296(2) K, yellow plate, (0.40ꢂ0.40ꢂ0.04)
3
mm , transmission 0.7326e0.8620, 22,803 measured reflections in
5.13. Synthesis of 3-chloro-N-isopropyl-5-morpholino-6- ni-
index range ꢀ19ꢃhꢃ19, ꢀ17ꢃkꢃ16, ꢀ8ꢃlꢃ8, 3068 independent
trosoaniline (18)
1
(Rint 0.0536), 255 parameters, R 0.0513 (for 2139 observed I>2s(I)),
wR
2
¼0.1133 (all data), GOOF 1.096, largest diff. peak and hole 0.199
Compound 18 was prepared as described above for compound
ꢀ3
and ꢀ0.255 e.A . The atom positions of methoxy group and one of
the chlorine atoms are disordered due to cocrystallization of
compounds 15a and 13a in the same position with ratio 70:30 in
both independent molecules.
7c from compound 15b. Dark blue oil. Yield 42%, oil. UV,
l
max (lg ε)
(ppm): 1.27 (6O, d, 2
), 3.67e3.83 (4O, m, 2
1
379 (3.33), 506 (3.32) nm; O NMR (CDCl
SO3, J¼6.0 Hz), 3.39e3.45 (4O, m, 2SO
SO ), 6.08 (1O, s, SO), 6.27 (1O, s, SO), 12.14 (1O, br s, NH).
3
), d
2
13
2
C
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10
E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
NMR (CDCl
3
),
d
(ppm): 22.2, 43.6, 53.2, 68.8, 103.7, 104.0, 137.4,
18ClN : S 54.26; O
J¼2.1 Hz), 8.19 (1O, d, SO, J¼2.1 Hz). 13C NMR (CDCl
3
), d (ppm):
146.4, 148.4, 157.3. Anal. Calcd (%) for S13
H
3
O
2
20.3, 97.4, 116.3, 120.7, 125.7, 128.7, 145.9, 147.9. MS m/z (I, %) 303
þ
þ
6
.26; Cl 12.35; N 14.61. Found: S 54.22; O 6.46; Cl 12.45; N 14.57.
[M] (20), 301 [M] (20), 245 (33), 243 (35), 185 (11), 157 (11), 155
þ
79
(
13). HRMS: m/z (M ) calcd for C BrN
9
H
8
3 4
O : 300.9693; found:
5
.14. Synthesis of 4,6-dichloro-2,2-dimethyl-5-nitro-2H-
300.9690. Anal. Calcd (%) for S BrN O (302.0): S 35.77; O 2.65;
9
H
8
3 4
benzimidazole 1,3-dioxide (20)
Br 26.49; N 13.91. Found: S 35.69; O 2.38; Br 26.65; N 14.09.
Compound 20 was prepared as described above for compound
5.17.3. 6,8-Dichloro-3,3-dimethyl-7-nitro-3H-[2,1,4]benzoxadiazine
4-oxide (21d). 6,8-Dichloro-3,3-dimethyl-7-nitro-3H-[2,1,4]benzox-
adiazine 4-oxide (21d) was prepared as described above for com-
pound 21a from compound 20. Dark red powder. Yield 68%. Mp:
ꢁ
7
2
c. Dark blue powder. Yield 62%. Mp: 116e118 C. UV,
l
max (lg ε)
), 7.45 (1O,
(291.1): S 37.10; O 2.41; Cl
4.05; N 14.43. Found: S 37.45; O 2.02; Cl 23.97; N 14.66.
1
68, 556 nm; O NMR (CDCl
3
),
d
(ppm): 1.74 (6O, s, 2SO
3
s, SO). Anal. Calcd (%) for C
9
H
7
Cl N O
2 3 4
ꢁ
ꢀ1
2
83e86 C. (KBr), n: 1336, 1512 (CeNO ), 1604 (C]N) cm . UV, l
2 max
1
(
lg ε) 236, 398, 446 nm; O NMR (CDCl
3
),
d
(ppm): 1.72 (6O, s,
Cl : S 37.01; O
5
.15. Thermolysis of 4,6-dichloro-2,2-dimethyl-2H-benzimid-
2SO
3
), 7.45 (1O, s, SO). Anal. Calcd (%) for C
H
9 7
2 3 4
N O
azole 1,3-dioxide (14a)
2.42; Cl 24.28; N 14.39. Found: S 37.01; O 2.38; Cl 24.15; N 14.55.
Crystallographic data for comp 21d: C10
H
10
N
3
O
c
3
Cl, M 255.66,
ꢀ
A solution of 0.5 g 4,6-dichloro-2,2-dimethyl-2H-benzimidazole
monoclinic, P2 /n, 9.0703(8), 7.5061(8),
1
a
b
16.580(2) A,
ꢁ
ꢀ
3
ꢀ3
1
,3-dioxide (14a) in dichloroethane (20 mL) was boiled with reflux
condenser for 4 h. The solvent was evaporated in vacuo, the residue
was subjected to chromatography on SiO (hexaneeethyl acetate
3:1)) to obtain 6,8-dichloro-3,3-dimethyl-3H-[2,1,4]benzoxadiazine
b
103.646(4) , V 1097.0(2) A , Z 4, Dcalcd 1.548 g cm
0.348 mm , F(000) 528, (q 2.36e28.59 , completeness 98.9%), T
, m(Mo-Ka)
ꢀ
1
ꢁ
3
2
296(2) L, yellow plate, (0.60ꢂ0.60ꢂ0.04) mm , transmission
0.8278e0.9281, 16,671 measured reflections in index range
ꢀ12ꢃhꢃ12, ꢀ10ꢃkꢃ10, ꢀ21ꢃlꢃ22, 2772 independent (Rint
(
4
-oxide (21a) as an orange powder with yield 0.4 g (80%). Mp:
ꢁ
ꢀ1
129e131 C. IR (KBr),
n
: 1598 (C]N) cm . UV,
l
max (lg ε) 241 (4.02),
), 6.80
),
(ppm): 20.5, 96.2, 115.7, 130.5, 129.0, 130.3, 133.5, 146.8. MS m/z (I,
0.0375), 154 parameters, R
wR
and ꢀ0.510 e.A
1
¼0.0466 (for 1994 observed I>2
s(I)),
1
4
52 (3.40) nm; O NMR (CDCl ), (ppm): 1.63 (6O, s, 2SO
3
d
3
2
¼0.1469 (all data), GOOF 1.087, largest diff. peak and hole 0.313
13
ꢀ3
.
(
d
1O, d, SO, J¼1.5 Hz), 7.19 (1O, d, SO, J¼1.5 Hz). C NMR (CDCl
3
þ
%
) 246 [M] (13), 204 (100), 188 (60), 158 (18), 144 (67), 111 (88).
5.17.4. 3,3-Dimethyl-8-nitro-3H-[2,1,4]benzoxadiazine 4-oxide
(21e). 3,3-Dimethyl-8-nitro-3H-[2,1,4]benzoxadiazine 4-oxide (21e)
was prepared as described above for compound 21a from com-
þ
35
HRMS: m/z (M ) calcd for C
45.9961. Anal. Calcd (%) for S
Cl 28.465; N 11.38. Found: S 43.69; O 3.38; Cl 28.80; N 11.29.
9
H
8
Cl
2
N
2
O
2
: 245.9957; found:
2
9
H
8
Cl
2
N
2
O
2
(246.1): S 43.89; O 3.25;
ꢁ
pound 9. Dark red powder. Yield 63%. Mp: 55e57 C. IR (KBr),
n
:
ꢀ1
1
344, 1529 (CeNO
2
) cm . UV,
(3.00) nm; O NMR (CDCl ),
m, SO), 7.38 (1O, m, SO), 7.53 (1O, m, SO). C NMR (CDCl
(ppm): 19.9, 96.0, 123.9, 124.4, 128.3, 129.4, 143.2, 143.8. MS m/z (I,
l
max (lg ε) 230 (4.09), 404 (3.30), 472
(ppm): 1.59 (6O, s, 2SO ), 6.78 (1O,
),
1
5
.16. Exposure of 6,8-dichloro-3,3-dimethyl-3H-[2,1,4]ben-
3
d
3
13
zoxadiazine 4-oxide (21a) to the light
3
d
þ
The solution of compound 21a (0.5 g) in chloroform (10 mL) was
exposed to the scattered sunlight (March, 55 latitude). The starting
orange solution rapidly turned dark and the starting compound 21a
disappeared withinw2 h (TLC data). The solvent was evaporated,
the residue was triturated with small amount of pentane and fil-
tered to obtain a dark blue compound 14a with yield 0.49 g (98%),
%) 223 [M] (45), 208 (22), 181 (31), 165 (29), 149 (54), 105 (58).
þ
HRMS: m/z (M ) calcd for C
9
H
9
N
3
O
4
: 223.0588; found: 223.0584.
Anal. Calcd (%) for S
Found: S 48.52; O 4.00; N 18.88.
9
H
9
N
3
O
4
(223.1): S 48.41; O 4.04; N 18.83.
5.17.5. 8-Chloro-6-methoxy-3,3-dimethyl-3H-[2,1,4]benzoxadiazine
4-oxide (21f). 8-Chloro-6-methoxy-3,3-dimethyl-3H-[2,1,4]benzox-
adiazine 4-oxide (21f) was prepared as described above for com-
pound 21a from compound 16. Yellow powder. Yield 52%. Mp:
ꢁ
mp 147e148 C. The IR spectrum of the compound was identical to
that of compound 14a synthesized earlier.
ꢁ
ꢀ1
5
.17. Thermolysis of compounds 14b, 14c, 20, 9 and 16
142e144 C. IR (KBr),
4
n
: 1606 (C]N) cm . UV,
lmax (lg ε) 240 (3.82),
1
59 (3.40) nm; O NMR (CDCl
3
), (ppm): 1.63 (6O, s, 2SO
d
3
), 3.85
5
4
.17.1. 8-Chloro-3,3-dimethyl-6-nitro-3H-[2,1,4]-benzoxadiazine
(3O, s, PSO
3
), 5.86 (1O, d, SO, J¼1.5 Hz), 6.90 (1O, d, SO, J¼1.5 Hz).
13
-oxide
(21b). 8-Chloro-3,3-dimethyl-6-nitro-3H-[2,1,4]-benzox-
C NMR (CDCl ), d (ppm): 20.6, 50.4, 96.6, 105.8, 108.6, 128.8, 135.3,
144.6,153.2. MS m/z (I, %) 244 [M] (18), 242 [M] (53),186 (25),184
3
þ
þ
adiazine 4-oxide (21b) was prepared as described above for com-
pound 21a from compound 14b. Dark red powder. Yield 63%. Mp:
þ
(82), 154 (34), 127 (24), 113 (22), 111 (39). HRMS: m/z (M ) calcd for
ꢁ
35
157e159 C with decomposition. IR (KBr),
n
: 1334, 1517 (CeNO
max (lg ε) 262 (4.12), 332 (3.70), 495 (3.12)
(ppm): 1.68 (6O, s, 2SO ), 7.58 (1O, d, SO,
2
),
C
10
H
11 ClN
2
O
3
: 242.0453; found: 242.0455. Anal. Calcd (%) for
(242.5): C 49.49; O 4.54; Cl 14.64; N 11.55. Found: S
ꢀ
1
1608 (C]N) cm . UV,
l
S
10
H11ClN
2
O
3
1
nm; O NMR (CDCl
3
),
d
3
49.24; O 4.58; Cl 14.50; N 11.49.
13
J¼1.2 Hz), 8.13 (1O, d, SO, J¼1.2 Hz). C NMR (CDCl
3
),
d
(ppm): 20.3,
þ
97.4,115.5,121.9,128.3,131.6,145.6,147.4. MS m/z (I, %) 259 [M] (8),
5.18. Synthesis of 2H-benzimidazole mono-N-oxides 22aef
þ
þ
2
57 [M] (21), 201 (100), 199 (26), 141 (10). HRMS: m/z (M ) calcd
3
5
for C
9
H
8
ClN
3
O
4
: 257.0198; found: 257.0195. Anal. Calcd (%) for
a) A solution of 0.5 g 4,6-dichloro-2,2-dimethyl-2H-benzimid-
azole 1,3-dioxide (14a) in chlorobenzene (10 mL) was boiled with
reflux condenser for 1 h until disappearance of the starting com-
pound (control by TLC). The solvent was evaporated in vacuo, the
S H ClN O (257.5): S 41.95; O 3.11; Cl 13.79; N 16.31. Found: S
4
9 8 3 4
2.10; O 3.15; Cl 14.00; N 16.20.
5
.17.2. 8-Bromo-3,3-dimethyl-6-nitro-3H-[2,1,4]benzoxadiazine 4-
2
residue was subjected to chromatography on SiO (hexaneeethyl
oxide
(21c). 8-Bromo-3,3-dimethyl-6-nitro-3H-[2,1,4]benzox-
acetate (3:1)) to obtain 72% of 4,6-dichloro-2,2-dimethyl-2H-benz-
imidazole 1-oxide (22a) as a orange powder.
adiazine 4-oxide (21c) was prepared as described above for com-
pound 21a from compound 14c. Dark red powder. Yield 41%. Mp:
b) A solution of 0.5 g 6,8-dichloro-3,3-dimethyl-3H-[2,1,4]ben-
zoxadiazine 4-oxide (21a) in chlorobenzene (10 mL) was boiled
with reflux condenser for 1 h until disappearance of the starting
compound (control by TLC). The solvent was evaporated in vacuo,
ꢁ
1
64e165 C with decomposition. IR (KBr),
n
: 1330, 1512 (CeNO
max (lg ε) 265 (4.02), 337 (3.72), 482 (3.18)
(ppm): 1.68 (6O, s, 2SO ), 7.82 (1O, d, SO,
2
),
ꢀ1
1
604 (C]N) cm . UV, l
1
nm; O NMR (CDCl
3
),
d
3
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E. Chugunova et al. / Tetrahedron xxx (2015) 1e12
11
the residue was subjected to chromatography on SiO
aneeethyl acetate (3:1)) to obtain 84% of 4,6-dichloro-2,2-dimethyl-
2
(hex-
(275.0): C 39.28; H 2.55; Cl 25.46; N 15.28. Found: C 39.34; H 2.47;
Cl 25.33; N 15.05.
2H-benzimidazole 1-oxide (22a) as a orange powder.
c) 0.5 g of benzylamine were added to 1.0 g of compound 14a in
5.18.4. 2,2-Dimethyl-4-nitro-2H-benzimidazole 1-oxide (22e). 2,2-
Dimethyl-4-nitro-2H-benzimidazole 1-oxide (22e) was prepared as
described above for compound 22a from compound 9. Dark red
chloroform (20 mL). The mixture was boiled with reflux condenser
for 2 h until disappearance of the starting compound (control by
TLC). The solvent was evaporated in vacuo, the residue was sub-
ꢁ
powder. Yield 61%. Mp: 148 C. IR (KBr),
n
: 1344, 1529 (CeNO
2
)
ꢀ1
1
jected to chromatography on SiO
2
(hexaneeethyl acetate (3:1)).
cm . UV,
(CDCl ),
l
max (lg ε) 314 (3.11), 382 (3.40), 463 (3.00) nm; O NMR
(ppm): 1.58 (6O, s, 2SO ), 6.89 (1O, dd SO, J
The first fraction gives benzaldehyde with yield 89%. IR spectrum is
identical for spectrum of benzaldehyde. The second fraction gives
compound 22a with yield 89%.
3
d
3
1
¼7.2 Hz,
1
3
J
2
¼7.2 Hz), 7.52 (1O, d, SO, J¼9.0 Hz), 8.15 (1O, d, SO, J¼7.0 Hz).
C
NMR (CDCl
1
3
),
d
(ppm): 23.7, 105.2, 123.9, 124.9, 135.5, 136.6, 142,2,
þ
53.8. MS m/z (I, %) 207 [M] (100), 190 (15), 149 (35), 130 (88), 118
ꢁ
ꢀ1
þ
Mp: 138e140 C. IR (KBr),
n
: 1593 (C]N) cm . UV,
l
max (lg ε)
(18). HRMS: m/z (M ) calcd for C
207.0635. Anal. Calcd (%) for S
20.28. Found: S 52.22; O 4.40; N 20.17.
H
9 9
N
3
O
3
: 207.0638; found:
1
2
2
1
2
(
31 (4.12), 438 (3.40) nm; O NMR (CDCl
3
),
),
d
(ppm): 1.53 (6O, s,
(ppm): 23.5, 104.3,
13.8, 135.4, 131.2, 133.9, 134.7, 157.9. MS m/z (I, %) 232 [M] (60),
30 [M] (100), 217 (18), 215 (34), 187 (24), 185 (23), 166 (28), 165
9 9 3 3
H N O (207.1): C 52.17; H 4.38; N
13
SO
3
), 7.13 (2O, s, 2SO). C NMR (CDCl
3
d
þ
þ
5.18.5. 4-Chloro-6-methoxy-2,2-dimethyl-2H-benzimidazole 1-oxide
(22f). 4-Chloro-6-methoxy-2,2-dimethyl-2H-benzimidazole 1-oxide
(22f) was prepared as described above for compound 22a from
þ
35
83), 164 (80). HRMS: m/z (M ) calcd for C
found: 230.0003. Anal. Calcd (%) for S Cl
O 3.48; Cl 30.43; N 12.17. Found: S 46.68; O 3.38; Cl 31.04; N
2.23.
Crystallographic data for comp 22a: C
9
H
8
Cl
2 2
N O: 230.0008;
9
H
8
2 2
N O (230.1): S 46.94;
ꢁ
compound 16. Yellow powder. Yield 55%. Mp: 103e105 C. IR (KBr),
ꢀ
1
1
1
n
: 1606 (C]N) cm . UV,
NMR (CDCl ), (ppm): 1.49 (6O, s, 2SO
(1O, s, SO), 6.79 (1O, s, SO). C NMR (CDCl
l
max (lg ε) 233(4.06), 433 (3.32) nm; O
H
9 8
Cl
2
N
2
O, M 231.07,
3
d
3
), 3.90 (3O, s, PSO ), 6.12
(ppm): 23.5, 56.2,
103.4, 107.3, 110.5, 134.8, 136.3, 153.3, 156.7. MS m/z (I, %) 228 [M]
3
ꢀ
13
monoclinic, P2
1
/m,
a
8.5840(3),
b
6.9731(3), c 8.5885(4) A,
104.761(3) , V 497.12(4) A , Z 2, Dcalcd 1.544 g cm
3
),
d
ꢁ
ꢀ
3
ꢀ3
þ
b
0
2
0
,
m
(Mo-K
a)
ꢀ
1
ꢁ
þ
.618 mm , F(000) 236, (
q
2.45e26.98 , completeness 99.9%), T
(32), 226 [M] (100), 225 (16), 211 (24), 209 (19), 161 (41), 146 (54),
3
þ
35
93(2) L, orange prism, (0.57ꢂ0.49ꢂ0.39) mm , transmission
132 (15), 118 (41). HRMS: m/z (M ) calcd for C10
H11 ClN
2 2
O :
.6658e0.7455, 4530 measured reflections in index range
226.0504; found: 226.0499. Anal. Calcd (%) for S10
H11ClN O
2 2
ꢀ
10ꢃhꢃ10, ꢀ8ꢃkꢃ8, ꢀ10ꢃlꢃ10, 1169 independent (Rint 0.0194),
(226.5): C 52.98; H 4.86; Cl 15.64; N 12.37. Found: S 53.28; O 4.98;
Cl 15.62; N 12.39.
8
3 parameters, R (I)), wR ¼0.0830
1
¼0.0319 (for 1063 observed I>2
s
2
(
all data), GOOF 1.051, largest diff. peak and hole 0.304 and ꢀ0.283
ꢀ
3
e.A
.
Acknowledgements
5
.18.1. 4-Chloro-2,2-dimethyl-6-nitro-2H-benzimidazole 1-oxide
This work was supported by Russian Scientific Foundation
(grant 14-50-00014).
(22b). 4-Chloro-2,2-dimethyl-6-nitro-2H-benzimidazole
1-oxide
(22b) was prepared as described above for compound 22a from
ꢁ
compound 14b. Dark red powder. Yield 71%. Mp: 149e151 C. IR
Supplementary data
ꢀ
1
(
KBr),
n
: 1317, 1514 (CeNO
2
) cm . UV,
),
l
max (lg ε) 262 (4.01), 327
(ppm): 1.61 (6O, s, 2SO ),
1
(
3.40), 457 (3.42) nm; O NMR (CDCl
3
d
3
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.03.096.
13
7
.97 (1O, d, SO, J¼1.2 Hz), 8.14 (1O, d, SO, J¼1.2 Hz). C NMR
(
CDCl
3
),
d
(ppm): 23.8, 107.3, 113.8, 126.9, 132.3, 133.8, 145.7, 158.3.
þ
MS m/z (I, %) 241 [M] (100), 226 (32), 224 (20), 195 (9), 166 (31),
References and notes
þ
165 (20), 164 (86), 150 (26), 130 (23). HRMS: m/z (M ) calcd for
3
5
C
S
4
9
H
8
ClN
ClN
3
O
3
: 241.0249; found: 241.0250. Anal. Calcd (%) for
(241.5): S 44.72; O 3.32; Cl 14.70; N 17.40. Found: S
1
. World Health Organ. Tech Rep Ser 2012.
2. Cavalli, A.; Bolognesi, M. L. J. Med. Chem. 2009, 52, 7339.
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H
8
3
O
3
3
4
4.79; O 3.15; Cl 14.70; N 17.36.
5
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6324.
(22c). 4-Bromo-2,2-dimethyl-6-nitro-2H-benzimidazole
1-oxide
5
. Boiani, M.; Boiani, L.; Merlino, A.; Hern aꢁ ndez, P.; Chidichimo, A.; Cazzulo, J. J.;
(
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ꢁ
compound 14c. Dark red powder. Yield 44%. Mp: 151e153 C. IR
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1
(
KBr),
3.65), 482 (3.43) nm; O NMR (CDCl
SO
), 8.12 (1O, d, SO, J¼1.9 Hz), 8.14 (1O, d, SO, J¼1.9 Hz).
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58.9. MS m/z (I, %) 287 [M] (100), 285 [M] (91), 272 (18), 270
n
: 1317, 1508 (CeNO
2
) cm . UV,
l
max (lg ε) 265 (4.00), 337
1
(
2
3
), (ppm): 1.56 (6O, s,
d
8
9
13
3
C
3
d
þ
þ
1
þ
79
(
2
(
19), 210 (11), 130 (13). HRMS: m/z (M ) calcd for C
84.9744; found: 284.9745. Anal. Calcd (%) for S
286.0): S 37.77, O 2.80, Br 27.98, N 14.69. Found: S 37.62, O 2.80,
Br 28.20, N 14.72.
9
H
8
BrN
3
O
3
:
9
H
8
BrN
3 3
O
1
1
1
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(22d). 4,6-Dichloro-2,2-dimethyl-5-nitro-2H-benzimidazole 1-oxide
2
(
22d) was prepared as described above for compound 22a from
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compound 20. Orange powder. Yield 51%. Mp: 95e97 C. (KBr),
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1
n
:
1
1
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d
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.69 (6O, s, 2SO ), 7.10 (1O, s, SO). Anal. Calcd (%) for C
3
9
H
7
Cl N O
2 3 3
Please cite this article in press as: Chugunova, E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.096

12
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Please cite this article in press as: Chugunova, E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.096