A versatile one-step method for the synthesis of benzimidazoles from quinoxalinones and arylenediamines via a novel rearrangement

Article abstract of DOI:10.1016/j.tetlet.2008.05.060

A highly efficient and versatile method for the synthesis of benzimidazoles has been developed on the basis of the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2-ones with 1,2-arylenediamines.

Full text of DOI:10.1016/j.tetlet.2008.05.060

Tetrahedron Letters 49 (2008) 4644–4647
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Tetrahedron Letters
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A versatile one-step method for the synthesis of benzimidazoles from
quinoxalinones and arylenediamines via a novel rearrangement
*
Vakhid A. Mamedov , Dina F. Saifina, Il’dar Kh. Rizvanov, Aidar T. Gubaidullin
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:
Received 17 March 2008
Revised 4 May 2008
Accepted 13 May 2008
Available online 16 May 2008
A highly efficient and versatile method for the synthesis of benzimidazoles has been developed
on the basis of the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2-ones with 1,2-
arylenediamines.
Ó 2008 Published by Elsevier Ltd.
Keywords:
Quinoxaline
Benzimidazole
1,2-Arylenediamines
Ring contraction
Rearrangement
Benzimidazole-containing compounds exhibit a wide range of
biological properties. This class of heterocyclic systems has found
commercial applications in several therapeutic areas as antiulcer,
antihypertensive, antiviral,1a,b antifungal,1c antitumor,1d–h and anti-
histamine agents1i as well as anthelmintic agents in veterinary
medicine.1j–n Medical chemists consider these heterocycles to be
promising compounds.
O
O
Ph
NH2
NH2
N
N
N
Ph
AcOH
+
N
H
1a
N
H
N
-2H2O
2a
3a (91%)
Scheme 1.
Almost all the existing methods for the synthesis of benzimi-
dazoles1n,2a–j have some synthetic shortcomings, such as rigid con-
ditions and poor yields. Indeed, the development of new synthetic
methods would be of considerable importance to chemists. The
one-step method of Fokas and co-workers3 is the most efficient
method for the synthesis of benzimidazole derivatives, which
involves the Na2S2O4 reduction of o-nitroanilines in the presence
of aldehydes in EtOH or other appropriate solvents. However, the
method is restricted by its ability to synthesize a limited number
of benzimidazole derivatives.
In this Letter, a direct, efficient, and convenient approach to the
synthesis of 2-benzimidazolylquinoxalines is presented. The meth-
od is based on a new quinoxaline–benzimidazole rearrangement of
3-aroyl- 1a,f4 and 3-alkanoylquinoxalin-2-ones 1b–e5 under the
action of 1,2-diaminobenzenes 2a–d in acetic acid. Thus, the reac-
tion of quinoxalin-2-one 1a with 1,2-diaminobenzene 2a in boiling
acetic acid led to the corresponding 2-benzimidazolylquinoxaline
3a6 in 91% yield (Scheme 1).
Table 1 shows that a variety of quinoxalinones 1b–f and
1,2-arylenediamines 2a–d are compatible with these reaction
conditions, producing diverse 2-benzimidazolyl-substituted quino-
xalines in good yields. The reactions of 3-phenylacetylquino-
xaline-2(1H)one 1b with 3,4-diaminotoluene 2c, or 4-nitro-
1,2-phenylenediamine 2d, produced a mixture of two isomers in
almost equal amounts, as was evident from the 1H NMR spectra
of the crude products. Therefore, the quinoxalinone–benzimid-
azole rearrangement considered in this study is of rather general
character.
On the basis of conventional chemistry of 1,2-phenylenediam-
ines7 and quinoxalinones8a,b it is reasonable to assume that the for-
mation of 2-benzimidazolylquinoxaline 3 involves addition of the
amino group of 2 at the C(3) atom of protonated quinoxalinone 1
as the first step. The next step involves nucleophilic attack of the
second amino group of 2 at the benzoyl carbonyl group to form
the spiro-quinoxaline derivative A. Then, ring contraction occurs
with cleavage of the C(3)–N(4) bond in the intermediate tricyclic
system B leading to formation of the final product 3 (Scheme 2).
It should be noted that the formation of benzimidazolylquinoxa-
lines can also be explained through initial attack of the amino
* Corresponding author. Fax: +7 843 2 73 2253.
E-mail address: mamedov@iopc.kcn.ru (V. A. Mamedov).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.060

V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 4644–4647
4645
Table 1
The prepared 2-benzimidazolylquinoxalines
Entry
Substrate
Product (yield)
Ph
N
O
O
N
Ph
N
N
NH2
NH2
1
N
H
N
H
2a
1b
3b (81%)
Ph
N
O
O
N
NH2
N
N
Ph
2
N
H
N
H
N
NH2
2a
1c
3c (87%)
Ph
O
O
N
N
Ph
Ph
Ph
Me
Me
NH2
NH2
3
N
H
N
Me
N
H
Me
2b
1b
3d (90%)
Ph
Ph
N
O
O
N
N
N
N
N
NH2
NH2
+
4
N
H
N
H
N
Me
N
H
Me
Me
2c
1b
3e (34%)
3f (44%)
Ph
N
Ph
N
O
O
N
N
N
N
NH2
NH2
+
5
N
H
N
H
N
NO2
N
H
NO2
NO2
2d
1b
3g (36%)
3h (49%)
O
O
N
N
NH2
N
6
7
N
H
N
N
H
NH2
2a
1d
3i (82%)
Ph
N
O
Me
Me
N
Ph
NH2
NH2
Me
Me
N
N
N
H
O
N
H
2a
1e
3j (80%)
O
Ph
N
N
N
N
NH2
NH2
Ph
8
N
N
O
Et
Et
3k (86%)
1f
2a

4646
V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 4644–4647
Ph
Ph
..
Ph
NH2
NH2
H
N
H
N
H
N
+
+
H+
O
OH
2
O
+
1
N
N
H2
O
H
N
H
O
N
H
N
H
O
+
H
N
H2O
Ph
H
Ph
H
N
Ph
N
N
N
N
N
H
N
+
N
H
3
-H2O
-H2O
N
H
O
+
-
H
+
H
H
N
H
B
N
H
OH
OH
A
Scheme 2.
Figure 1. ORTEP drawing of compound 3h.
group at the carbon atom of the ketone group. The rearrangement
is then assumed to occur according to Scheme 2. This is confirmed
indirectly by the formation of spiro-compounds with a structure
similar to that of A, in the reactions of quinoxalinones with other
binucleophilic compounds.9 It has been shown that the investi-
gated reaction does not proceed in neutral or aprotic solvents.
The structures of compounds 3 were deduced from the elemen-
tal analyses and 1H and 13C NMR data. The 1H NMR spectral char-
acteristics of 2-benzimidazolylquinoxalines are broad singlets due
to protons H(5) and H(6) and multiplets for the protons H(4) and
H(7) at d 7.30–7.40 and d 7.67–7.90 ppm, respectively.10,11 The
mass spectra of these compounds displayed molecular ion peaks
at appropriate m/z values. Initial fragmentation involved scission
of the benzimidazole ring system.
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 time.
Acknowledgement
We thank the Russian Foundation for Basic Research (Grant No.
07-03-00613-a) for financial support.
References and notes
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Chemistry II. Five-membered Rings with Two Heteroatoms and Fused Carbocyclic
Derivatives; Elsevier, 1996; Vol. 3. Chapter 2.
The molecular structure of compound 3h was confirmed by
single-crystal X-ray analysis (Fig. 1).12
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
accomplished by the quinoxalinone–benzimidazole rearrangement
of 3-aroyl- and 3-alkanoyl-quinoxalin-2-ones in the presence of
arylenediamines in acetic acid. This method makes it possible to
synthesize N–H benzimidazoles as well as N- and C-substituted
benzimidazoles. The reaction is readily applicable to large-scale

V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 4644–4647
4647
2. (a) Wright, J. B. Chem. Rev. 1951, 48, 397; (b) Preston, P. N. Chem. Rev. 1974, 74,
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3. Yang, D.; Fokas, D.; Li, J.; Yu, L.; Boldino, C. M. Synthesis 2005, 47.
4. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Ya. A.
Chem. Heterocycl. Compd. 2002, 38, 1504.
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8. (a) Cheeseman, G. W. H.; Cookson, R. F. In Condensed Pyrazines; Weissberger, A.,
Taylor, E. C., Eds.; Wiley-Interscience: New York, 1979; (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.
9. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A. Russ. Chem. Bull.,
Int. Ed. 2007, 56, 2386.
10. Navarrete-Vazqueez, G.; Cedillo, R.; Hernandez-Campos, A.; Yepez, L.;
Hernandez-Luis, F.; Valdez, J.; Morales, R.; Cortes, R.; Hernandez, M.; Castillo,
R. Bioorg. Med. Chem. 2001, 187.
11. Valdez, J.; Cedillo, R.; Hernandez-Campos, A.; Yepez, L.; Hernandez-Luis, F.;
Navarrete-Vazqueez, G.; Tapia, A.; Cortes, R.; Hernandez, M.; Castillo, R. Bioorg.
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6. Experimental procedure. A solution of 0.30 g (1.14 mmol) of 3-phenylacetyl-
quinoxaline-2(1H)one 1b and 0.12 g (1.14 mmol) of 1,2-phenylenediamine 2a
in 8 ml of acetic acid was heated under reflux for 2 h. After cooling to room
temperature, the crystals of 3b that precipitated were collected by suction
filtration. Mp 224–225 °C. 1H NMR (600 MHz, DMSO-d6), d 5.34 (2H, s, CH2);
7.15 (1H, dd, Hp, J = 7.14, 7.24 Hz); 7.23 (2H, dd, 2Hm, J = 7.57, 7.58 Hz); 7.33–
12. The X-ray diffraction data for the crystal structure of 3h were collected
on a Bruker AXS Kappa Apex diffractometer at 293 K. Crystallographic data for
3h. C22H15N5O2ꢀC2H6OS, colorless prismatic crystal, formula weight 459.52,
monoclinic, C2/c, a = 36.400(10), b = 6.2540(10), c = 26.552(4) Å, b = 131.60(3)°,
V = 4520(2) Å3, Z = 8,
0.180 mmꢁ1
Rint = 0.0560, full-matrix least-squares on F2, parameters = 308. Final indices
R1 = 0.0543, wR2 = 0.1238 for 1455 reflections with I > 2 (I); R1 = 0.2634,
q
calc = 1.351 g cmꢁ3
,
l
(k Mo
K
a
0.71073 Å) =
.
F(000) = 1920, reflections collected = 4627, unique = 4514,
0
0
0
0
7.36 (2H, m, H5 , H6 ); 7.35 (2H, d, 2Ho, J = 6.3 Hz); 7.78 (2H, br s, H4 , H7 ); 7.91–
7.96 (2H, m, H6, H7), 8.11–8.15 (1H, m, H5 or H8), 8.20–8.24 (1H, m, H8 or H5);
13C NMR (150.93 MHz, DMSO-d6), d 41.84; 113.05; 120.86; 123.08; 124.97;
126.87; 129.03; 129.40; 129.46; 130.02; 131.31; 131.93; 135.35; 140.06;
140.59; 141.83; 143.49; 144.75; 150.24; 155.92. MS (EI), m/z (I(%)): M+Å
336(98); 335(100); 321(9); 259(6); 219(7); 218(19); 217(12); 216(7); 190(8);
168(40); 167(26); 154(7); 91(11); 90(7); 89(7); 77(6); 76(7). Anal. Calcd for
r
wR2 = 0.1869 for all data, goodness-of-fit on F2 = 0.902, largest difference in
peak and hole (0.222 and ꢁ0.188 e Åꢁ3). Crystallographic data
(excluding structure factors) for structure 3h in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 683079. Copies of these 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).
Deposited data may be accessed by the journal and checked as part of the
refereeing process.
C22H16N4: C, 78.55; H, 4.79; N, 16.66. Found: C, 78.39; H, 4.60; N, 16.72.
7. Lindsey, R. J. In Comprehensive Organic Chemistry. The Synthesis and Reactions of
Organic Compounds; Barton, D., Ollis, W. D., Sutherland, I. O., Eds.; Pergamon
Press, 1979; Vol. 2, Chapter 6.3.