Efficient synthesis of 2-(pyrazol-3-yl)benzimidazoles from 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones and hydrazine hydrate via a novel rearrangement

Article abstract of DOI:10.1016/j.tetlet.2009.05.116

A highly efficient method for the synthesis of 2-(pyrazol-3-yl)benzimidazoles has been developed on the basis of the novel ring contraction of 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones with hydrazine hydrate.

Full text of DOI:10.1016/j.tetlet.2009.05.116

Tetrahedron Letters 50 (2009) 5186–5189
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Tetrahedron Letters
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Efficient synthesis of 2-(pyrazol-3-yl)benzimidazoles from
3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones and hydrazine
hydrate via a novel rearrangement
*
Vakhid A. Mamedov , Anna M. Murtazina, Aidar T. Gubaidullin, Elena A. Hafizova, Il’dar Kh. Rizvanov
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of the Russian Academy of Sciences, Arbuzov str. 8, 420088 Kazan, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient method for the synthesis of 2-(pyrazol-3-yl)benzimidazoles has been developed on the
Received 22 April 2009
Revised 19 May 2009
Accepted 29 May 2009
Available online 6 June 2009
basis of the novel ring contraction of 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones with hydrazine
hydrate.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Dihydroquinoxalin-2(1H)-one,
Benzimidazole
Hydrazine hydrate
Ring contraction
Novel rearrangement
Pyrazolylbenzimidazoles
Benzimidazoles exhibit a wide range of biological properties.
This class of heterocyclic system has found commercial applications
in several therapeutic areas such as antiulcer, antihypertensive,
antiviral,1a,b antifungal,1c antitumor,1d–h and antihistamines1i as
well as anthelmintic agents in veterinary medicine.1j–n Compounds
possessing the benzimidazole moiety exhibit significant activity
against viruses such as HIV,1o,1p herpes (HSV-1),1q human cytomeg-
alovirus (HCMV),1o,1p and influenza.1r
Almost all existing methods for the synthesis of benzimidaz-
oles1n,2a–j have some synthetic shortcomings, such as rigid condi-
tions and poor yields of target products, which limit their scope.
All these methods are essentially modifications of the classical
Phillips–Ladenburg3a,b and Weidenhagen4 reactions, which involve
the condensation of ortho-phenylenediamine with carbonic acids
or their derivatives or aldehydes. The method of Fokas and co-
workers,5 which is a modification of the Weidenhagen reaction is
the most efficient for the synthesis of benzimidazoles, and involves
the Na2S2O4 reduction of o-nitroanilines in the presence of alde-
hydes in EtOH or other appropriate solvents. However, the method
is restricted to the synthesis of a limited number of benzimidazole
derivatives.
is based on a new acid-catalyzed quinoxaline–benzimidazole rear-
rangement of 30-aryl-1,2,3,4,40,50-hexahydrospiro[quinoxalin-2,50-
pyrazol]-3-ones 2a–f, which are easily obtained from the reaction
of the corresponding readily available 3-arylacylidene-3,4-dihy-
droquinoxalin-2(1H)-ones 1a–f6 with hydrazine hydrate in reflux-
ing n-BuOH (Scheme 1). Thus, both the formation of
spiroquinoxalinones 2a–f and their rearrangement into the corre-
sponding pyrazolylbenzimidazoles 3a–f proceed in high yields
(Schemes 1 and 2). As is evident from the structure of compounds
3a–f, the C(2)–C(3)@CH–C(O)–Ar fragment of quinoxalines 1a–f
and hydrazine hydrate is involved in the formation of the hetero-
cyclic systems.
The structures of compounds 2a–f and 3a–f were deduced from
their elemental analyses and 1H NMR data.7,8 The mass spectra of
these compounds displayed molecular ion peaks at appropriate
m/z values. Initial fragmentation of compounds 2a–f and 3a–f in-
volved scission of the benzimidazole and pyrazole ring systems.7,8
The 1H NMR spectrum of the spiro compounds 2a–f showed sig-
nals due to the phenyl and phenylene rings at 7.32–7.68 ppm and
6.68–6.89 ppm, respectively, three singlets at 7.04–7.97 ppm,
7.83–8.21 ppm, and 10.47–11.30 ppm, and two doublets at 3.01–
3.11 ppm and 3.90–3.96 ppm (2J ꢀ 17.5 Hz). The signals of the phe-
nylene protons are shifted to stronger fields compared with the
shifts of the protons of the phenylene ring (7.15–7.52 ppm) of qui-
noxalin-2(1H)-ones 1a–f.6 This demonstrates the involvement of
the imine carbon atom in the reaction, with the nitrogen becoming
In this Letter, an efficient and convenient approach to the syn-
thesis of 2-pyrazolylbenzimidazoles 3 is presented. The method
* Corresponding author. Tel.: +7 843 2727304; fax: +7 843 2732253.
E-mail address: mamedov@iopc.knc.ru (V.A. Mamedov).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.05.116

V. A. Mamedov et al. / Tetrahedron Letters 50 (2009) 5186–5189
5187
H
H
Ar
H
H
N
R1
R2
R1
R2
N
Ar
N
n-BuOH, Δ
N
H
+
NH2NH2 H2O
O
-H2O
N
H
O
N
H
O
1a-f
2a-f
Entry
R1
H
Me
H
NO2
H
H
R2
Ar
Substrate
Product (yield)
2a (81%)
2b (76%)
2c (64%)
2d (73%)
2e (77%)
2f (73%)
M.p. (°C)
310-312
237-240
243-246
235-238
230-231
235-237
1
2
3
4
5
6
H
Me
Cl
H
H
H
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
p-MeC6H4
p-ClC6H4
Scheme 1.
Ar
R1
R2
N
AcOH, Δ
-H2O
2a-f
NH
N
N
H
3a-f
Entry
R1
H
Me
H
NO2
H
H
R2
H
Me
Cl
H
Ar
Ph
Ph
Ph
Ph
Substrate
Product (yield)
3a (99%)
3b (99%)
3c (98%)
3d (96%)
3e (99%)
3f (85%)
M.p. (°C)
316-317
264-265
305-307
295-296
309-310
343-345
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
H
p-MeC6H4
p-ClC6H4
Scheme 2.
an electron-donating amine nitrogen. IR spectroscopy also con-
firmed the structure of spiro-compounds 2a–f. The 1H NMR spec-
tral characteristics of pyrazolylbenzimidazoles 3a–f are
multiplets for protons H(4) and H(7) and broad singlets due to pro-
tons H(5) and H(6) at 7.21–7.23 ppm and 7.50–7.60 ppm,
respectively.9a,b
The molecular structures of spiro-compound 2e and pyrazolyl-
benzimidazole 3a were unambiguously confirmed by single-crys-
tal X-ray analyses (Fig. 1)10 and (Fig. 2).11
On the basis of the known chemistry of hydrazines,12a,b ketones,
13a,b and quinoxalinones14a,b it is reasonable to assume that the first
stage of the reaction mechanism involves the addition of hydrazine
to the carbonyl group of the 3-arylacylidene fragment of quinoxalin-
2(1H)-one 1 with the formation of intermediate A which can under-
go tautomerization with intermediate B. The next step involves
nucleophilic attack of the amino group on C-3 of the quinoxalin-
Figure 1. ORTEP drawing of 2e. Displacement ellipsoids are drawn at the 30%
Figure 2. ORTEP drawing of 3a. Displacement ellipsoids are drawn at the 30%
probability level. H atoms are represented by circles of arbitrary size.
probability level. H atoms are represented by circles of arbitrary size.

5188
V. A. Mamedov et al. / Tetrahedron Letters 50 (2009) 5186–5189
H
N
H
N
Ar
Ar
N
Ar
NH2NH2 H2O, Δ
2
O
N
N
n-BuOH
N
H
O
N
H
O
N
H
O
NH2
NH2
R
R
R
H+
B
A
1
H
H
Ar
H
H
+
Ar
H
N
NH2
N
N
H
O
N
3
N
H
-H+
N
H
-H2O
N
H
OH
N
H
N
H
O
Ar
R
R
R
HN
N
E
D
C
Scheme 3.
2(1H)-one to form the spiroquinoxaline derivative 2. Rearrange-
ment of the spiroquinoxaline is then assumed to occur according
to Scheme 3, which proceeds by cascade reactions involving: (a)
acid-catalyzed ring-opening of spiro-compound C with the forma-
tion of pyrazolo derivative D, (b) intramolecular nucleophilic attack
by the amino moiety on the carbonyl group leading to the formation
of hydroxy derivative E, and (c) elimination of water to give the final
product 3. It was shown that the reaction does not proceed in neutral
or aprotic solvents.
B0. Cyclization then occurs through nucleophilic attack of the ami-
no moiety on the carbonyl group of the 3-arylacylidene fragment
of B0 (Scheme 4).
It is worth noting that the reaction of phenylhydrazine with 3-
arylacylidene-3,4-dihydroquinoxalin-2(1H)-one 1a proceeds simi-
larly to the reaction with hydrazine hydrate. This involves the
formation of spiro-compound 4, which rearranges into pyrazolyl-
benzimidazole 5, and not the other possible regioisomer 5a, in boil-
ing acetic acid (Scheme 5).
It should be pointed out that the formation of spiroquinoxaline
To summarize, we have reported an efficient and versatile one-
step method for the preparation of a series of benzimidazoles as
well as other imidazole-containing ring systems. This was accom-
plished via a novel quinoxalinone–benzimidazole rearrangement
of 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones on exposure
derivative
2 can also be explained via Michael addition of
hydrazine to the partially positive C(3) atom of the quinoxalin-
2(1H)-one 1 in the first stage of the reaction with the formation
of intermediate A0 which can tautomerize with intermediate
Ar
Ar
H
H
H
N
H
N
OH
O
NH2NH2 H2O, Δ
1
2
NHNH2
O
NHNH2
O
n-BuOH
-H2O
N
H
N
H
R
R
B'
A'
Scheme 4.
H
H
Ph
Ph
H
H
N
N
Ph
N
PhNHNH2, Δ
N
AcOH, Δ
N
N
O
N
-H2O
N
H
Ph
O
N
H
O
N
H
Ph
5
1a
4
86%, 164-167 oC
49%, 204-205 oC
Ph
N
N
Ph
N
N
H
5a
Scheme 5.

V. A. Mamedov et al. / Tetrahedron Letters 50 (2009) 5186–5189
5189
after recrystallization from CH3CN gave additionally 0.04 g (30%) of 2a: 1H NMR
(400.13 MHz, DMSO-d6) d: 3.03 (1H, d, CHAHB, JAB = 17.4 Hz); 3.93 (1H, d,
CHAHB, JAB = 17.4 Hz); 6.70 (1H, dd, H6, J = 7.5; 7.5 Hz); 6.74 (1H, d, H8,
J = 7.2 Hz); 6.84 (1H, dd, H7, J = 7.5; 7.5 Hz); 6.85 (1H, d, H5, J = 7.5 Hz); 7.32
(1H, br s, NH); 7.35 (1H, d, Hp, J = 7.5 Hz); 7.42 (2H, dd, 2Hm, J = 7.9; 7.2 Hz);
7.67 (2H, d, 2Ho, J = 7.2 Hz); 7.98 (1H, br s, NH); 10.64 (1H, br s, NH). IR (KBr)
cmꢂ1: 3445, 3318, 3261, 3080, 2960, 1664, 1617, 1604, 1504, 1446, 1413, 1377,
1356, 1312, 1218, 1062, 1002, 915, 871, 755, 735, 687. MS (EI), m/z (%): 278
(32) M+, 250 (27), 249 (11), 221 (17), 202 (32), 172 (18), 171 (15), 161 (12), 160
(52), 133 (17), 131 (100), 119 (13), 118 (19), 117 (10), 114(16). Anal. Calcd for
C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C, 68.83; H, 4.92; N, 20.19.
8. Typical procedure for the preparation of 3. A solution of spiroquinoxalinone
(0.2 g, 0.7 mmol) 2a in acetic acid (10 mL) was heated at reflux for 8 h. The
reaction mixture was evaporated in vacuo to give 0.19 g (99%) of 3a which was
analytically pure. 1H NMR (400.13 MHz, DMSO-d6) d: 7.22 (2H, m, H7, H4); 7.33
(1H, s, H4’); 7.40 (1H, dd, Hp, J = 7.2; 7.5 Hz); 7.51 (2H, dd, 2Hm, J = 7.8; 7.2 Hz);
7.60 (2H, br.s, H5, H6); 7.87 (2H, d, 2H°, J = 7.5 Hz). IR (KBr) cmꢂ1: 3427, 3212,
3167, 3110, 3026, 2605, 2526, 1693, 1566, 1499, 1456, 1438, 1419, 1363, 1280,
1267, 1196, 1025, 968, 889, 806, 762, 749. MS (EI), m/z (%): 260 (100) M+, 232
(11), 231 (33). Anal. Calcd for C16H12N4: C, 73.83; H, 4.65; N, 21.52. Found: C,
73.41; H, 4.58; N, 21.50.
to hydrazine hydrate. The reaction is readily applicable to large-
scale synthesis. Application of this methodology to the synthesis
of other heterocyclic ring systems is currently under investigation
and the results will be published in due course.
Acknowledgment
This work was financially supported by the Russian Foundation
for Basic Research (Grant No. 07-03-00613-a) and the State con-
tract No. 02.512.11.2237 Federal target program ‘‘Research and de-
sign on priority directions of development of science and
technology complex in Russia 2007–2012 years”.
References and notes
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10. The X-ray diffraction data for crystals of 2e were collected on a Smart Apex II CCD
diffractometer at 296 K. Crystallographic data for 2e. C17H16N4O, colorless prism,
formula weight 292.34, orthorhombic,
P
212121, a = 5.609(3), b = 9.854(5),
c = 27.272(15) Å, V = 1507.4(1) Å3, Z = 4,
q
calc = 1.288 g cmꢂ3
,
l
(kMo ) =
Ka
0.84 cmꢂ1
.
F(0 0 0) = 616, reflections collected = 16658, unique = 3574,
R(int) = 0.1120, full-matrix least-squares on F2, parameters = 213, restraints =
0. Final indices R1 = 0.0352, wR2 = 0.0544 for 1358 reflections with I > 2 (I);
r
R1 = 0.0676, wR2 = 0.1481 for all data, goodness-of-fit on F2 = 0.884, largest
difference in peak and hole (0.099 and ꢂ0.128 e Åꢂ3). Crystallographic data
(excluding structure factors) for the structure 2e reported in this Letter have
been deposited at the Cambridge Crystallographic Data Centre with
supplementary Publication Number CCDC 724170. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44 0 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
11. The X-ray diffraction data for crystals of 3a were collected on a Bruker AXS
Smart Apex II CCD diffractometer at 296 K. Crystallographic data for 3a.
C16H12N4, 2(C2H4O2), pink prism, formula weight 380.40, monoclinic,
P
21/n, a = 7.1835(4), b = 14.8945(9), c = 18.2328(12) Å, b = 92.504(1)°, V =
1948.9(2) Å3, Z = 4, calc = 1.296 g cmꢂ3 ) = 0.92 cmꢂ1
q
,
l
(kMo F(0 0 0) =
K
a
.
800, reflections collected = 21441, unique = 4624, R(int) = 0.0227, full-matrix
least-squares on F2, parameters = 271, restraints = 0. Final indices R1 = 0.0517,
wR2 = 0.1969 for 3339 reflections with I > 2r(I); R1 = 0.0684, wR2 = 0.2471 for
all data, goodness-of-fit on F2 = 0.851, largest difference in peak and hole
(0.198 and ꢂ0.141 e Åꢂ3). Crystallographic data (excluding structure factors)
for the structure 3a reported in this Letter have been deposited at the
Cambridge Crystallographic Data Centre with supplementary Publication
Number CCDC 724169. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 0 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
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Heterocycl. Chem. 1983, 20, 359. Quinoxalinones 1b–e were prepared by the
method used for 1a. Mp 298–299 °C (1b); 302–303 °C (1c); 304–306 °C (1d);
252–253 °C (1e).
7. Typical procedure for the preparation of 2. A suspension of 3-phenylacylidene-
3,4-dihydroquinoxalin-2(1H)-one 1a (0.13 g, 0.5 mmol) and hydrazine
monohydrate (0.23 g, 5 mmol) (90%) in n-BuOH (10 mL) was heated at reflux
for 16 h. After cooling to room temperature and standing overnight, the
crystals of 2a that precipitated were collected by suction filtration, washed
with EtOH (2 ꢁ 5 mL), dried in air, and recrystallized from CH3CN, to give 0.07 g
(51%) of 2a. The filtrate was evaporated to one-half of the initial volume and
left overnight at room temperature. The crystals of 2a that precipitated were
collected by suction filtration, washed with EtOH (2 ꢁ 5 mL), dried in air, and
12. (a) Behforouz, M.; Bolan, J. L.; Flynt, M. S. J. Org. Chem. 1985, 50, 1186; (b)
Buckingham, J. Quart. Rev. Chem. Soc. 1969, 23, 37.
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Mechanisms, and Structure, 5th Ed.; Wiley-Interscience: New York, 2001; p
2083; (b) Gutsche, C. D. In The Chemistry of Carbonyl Compounds; Prentice Hall:
Englewood Cliffs, NJ, 1967; p 141.
14. (a) Cheeseman, G. W. H.; Cookson, R. F.. In Condensed Pyrazines; Weissberger,
A., Taylor, E. C., Eds.; Wiley-Interscience: New York, 1979; Vol. 35, (b)
Mamedov, V. A.; Kalinin, A. A.; Yanilkin, V. V.; Gubaidullin, A. T.; Latypov, Sh.
K.; Balandina, A. A.; Isaikina, O. G.; Toropchina, A. V.; Nastapova, N. V.;
Iglamova, N. A.; Litvinov, I. A. Russ. Chem. Bull., Int. Ed. 2005, 54, 2616.