An efficient metal-free synthesis of 2-(pyrazin-2-yl)benzimidazoles from quinoxalinones and diaminomaleonitrile via a novel rearrangement

Article abstract of DOI:10.1016/j.tetlet.2011.11.013

A simple and highly efficient metal-free method for the synthesis of 2-(pyrazin-2-yl)benzimidazoles has been developed on the basis of the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2-ones with diaminomaleonitrile.

Full text of DOI:10.1016/j.tetlet.2011.11.013

Tetrahedron Letters 53 (2012) 292–296
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient metal-free synthesis of 2-(pyrazin-2-yl)benzimidazoles from
quinoxalinones and diaminomaleonitrile via a novel rearrangement
⇑
Vakhid A. Mamedov , Nataliya A. Zhukova, Tat0yana N. Beschastnova, El’vira I. Zakirova,
Saniya F. Kadyrova, Ekaterina V. Mironova, Anna G. Nikonova, Shamil K. Latypov, Igor A. Litvinov
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 25 July 2011
Revised 26 October 2011
Accepted 4 November 2011
Available online 13 November 2011
A simple and highly efficient metal-free method for the synthesis of 2-(pyrazin-2-yl)benzimidazoles has
been developed on the basis of the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2-ones
with diaminomaleonitrile.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Quinoxalinones
Diaminomaleonitrile
Ring contraction
Rearrangement
Ring formation
Benzimidazoles
2-(Pyrazin-2-yl)benzimidazoles
NMR data
X-ray diffraction analysis
Pyrazines are important flavor ingredients in food,1 and have
exhibited interesting anticancer2 and antituberculosis3 activities.
They are reported to modulate the activity of CRF1 (corticotropin-
releasing factor 1) receptors.4 Besides, they are also versatile
building blocks for the synthesis of VCAM-1 (vascular cell adhesion
molecule-1) inhibitors,5 pyrazine alkaloids (antineoplasmic activ-
ity),2d and imidazopyrazin coelenterazine (a bioluminescent
agent).6 Pyrazines are widely used as agrochemicals.7 Due to their
medicinal, agrochemical, and synthetic values, a number of meth-
ods have been developed for the synthesis of pyrazine derivatives,
especially 2-(hetero)arylpyrazines. These include the cross-
coupling of 2-chloropyrazine with: (a) ArMgX in the presence of
(PPh3)2PdCl2/ZnCl2,8 (b) ArSnBu3 in the presence of PdCl2(PPh3)2/
PPh3, (c) Ar4Sn (generated in situ from ArMgX and SnCl4) in the
presence of Pd(PPh3)4,9 (d) ArBF3K in the presence of PdCl2(dppf),
(e) ArZnCl in the presence of PdCl2(PPh3)2,10 or (f) ArB(OH)2 in the
presence of PdCl2(dppb)/Na2CO3.11 2-(Hetero)arylpyrazines can
also be prepared via the couplings of vinyl triflate with 2-pyrazinyl-
zinc bromide in the presence of Pd(PPh3)4, 2-pyrazinylthioether
with ArSnBu3 in the presence of Pd(PPh3)4/Cu(I)-3-methylsalicy-
late, or 2-pyrazinyl tributyltin with ArBr in the presence of
Pd(PPh3)4, coupling of 2-chloropyrazine with heteroarenes in the
presence of AlCl3.12 While these methodologies involve mild condi-
tions, most of them, however, often require the use of expensive
catalysts and reagents. Besides, the necessary organo-metallic re-
agents are in many cases either commercially unavailable or their
preparation often involves cumbersome procedures.
Recently, we reported a new method for synthesizing 2-(ben-
zimidazol-2-yl)quinoxalines by the reactions of aroyl(alkanoyl)
quinoxalinones and 1,2-diaminobenzenes.13a–c The key step of this
transformation involved a novel acid-catalyzed rearrangement of
intermediate spiro-quinoxaline derivatives with contraction of the
pyrazine ring of the quinoxalinone fragment. It was also shown that
the scope of this rearrangement could be extended to the use of
other functionalized quinoxalinones and N-nucleophiles for synthe-
sizing various 2-(hetero)aryl-substituted benzimidazoles.13d–f Fur-
ther exploration of this strategy has led to the development of a
novel, inexpensive, simple, and scalable method for the synthesis
of 2-(hetero)arylpyrazines. Here the results of our study on a novel
rearrangement of 3-aroyl- and alkanoylquinoxalin-2(1H)-ones and
2,3-diaminomaleonitrile as a N-nucleophile under acid catalysis
condition are presented.
To optimize the process, we initially carried out the reaction of
3-benzoylquinoxalin-2(1H)-one (1a) with 2,3-diaminomaleonitrile
(2) in boiling acetic acid with various ratios of reagents and over
different reaction times. Regardless of the molar ratio of the
⇑
Corresponding author. Fax: +7 (843 2) 73 2253.
E-mail addresses: mamedov@iopc.ru, mamedov@iopc.knc.ru (V.A. Mamedov).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.013

V. A. Mamedov et al. / Tetrahedron Letters 53 (2012) 292–296
293
Ph
O
H
Ph
N
Het
N
NC
NC
NH2
NH2
N
N
N
AcOH, reflux
O
Het
CN
+
-H2O
N
H
H
O
N
H
N
H
N
N
H
1a
CN
2
3a
Scheme 2. A schematic presentation of the rearrangement.
Scheme 1. Acid-catalyzed rearrangement.
their way to the benzimidazole derivative with the spiro-forming
component in position 2’ (Scheme 2).14
reagents (1:1, 1:1.1, 1:2; 1a:2) and reaction time (3, 9 or 17 h) the
reaction proceeded in the same way with the formation of a ꢀ45%
yield of the rearrangement product 3a (Scheme 1), whereas 50% of
3-benzoylquinoxalin-2(1H)-one (1a) was recovered. Diaminoma-
leonitrile 2 apparently undergoes polymerization. Adding a second
equivalent of diaminomaleonitrile 2 to the reaction mixture
obtained after boiling the equimolar ratio of reagents in acetic acid
for 5 h did not lead to an increased yield of the desired product.
Neither did heating for an additional 5 h.
In order to improve the yield of the rearrangement product we
turned to our previously proposed hypothesis that ‘any of the spiro
derivatives of 1,2,3,4-tetrahydroquinoxalin-3-one with at least one
mobile hydrogen atom in their spiro-forming component are on
In accordance with this hypothesis there appeared the problem
of the synthesis of the spiro[pyrazine-2,20-quinoxaline]-30(40H)-
one derivative. For this purpose we installed the necessary pyrazine
ring system at position 2 of quinoxalin-2(1H)-one 1a via the
modified Kerner and Hinsberg15 reaction (the synthesis of quinoxa-
lines by the condensation of
a-dicarbonyl compounds with 1,
2-diaminobenzene). This was achieved by the reaction of 1a with
diaminomaleonitrile 2 in a boiling solution of MeOH in the presence
of a catalytic amount of H2SO4. In this reaction we considered 3-
benzoylquinoxalin-2(1H)-one 1a as a heteroanalogue of an a-dicar-
bonyl compound. The reaction proceeded smoothly for 2 h to give
the desired spiro compound, 5,6-dicyano-3R-1H,10H-spiro[pyra-
zine-2,20-quinoxalin]-30(40H)-one (4a) in a 96% yield (Table 1,
Table 1
Synthesis of 5,6-dicyano-3R-1H,10H-spiro[pyrazine-2,20-quinoxalin]-30(40H)-ones
R1
R1
N
CN
CN
R2
R3
NH2
O
H
R2
N
R2
R3
N
R1
H2SO4 (cat)
O
N
H
2
+
N
H
N
MeOH, reflux, 2 h R3
N
H
O
(1.1 eq)
N
H
O
N
CN
4a-i
4'a-i
1a-i
(1 eq)
CN
in the crystalline state
in DMSO-d6
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
Ph
Ph
CH2Ph
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
96, 74a, 91b
92, 85a, 88b
93, 82a
93, 77a
H
95, 77a
COPh
CO2H
H
95, 61a
89, 64a
95, 60a
H
75, 61a
a
p-TsOH was used instead of H2SO4.
HCl was used instead of H2SO4.
b
Table 2
Acid-catalyzed rearrangement of 5,6-dicyano-3R-1H,10H-spiro[pyrazine-2,20-quinoxalin]-30(40H)-ones
R1
R2
R3
N
N
AcOH, reflux
4a-i
4'a-i
CN
N
H
N
CN
3a-i
Entry
R1
R2
R3
Product
Time
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
COPh
CO2H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
10 min
10 min
10 min
10 min
10 min
3 h
3 h
10 min
10 min
90
90
91
89
92
89
85
92
93
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
Ph
Ph
CH2Ph
Me
H

294
V. A. Mamedov et al. / Tetrahedron Letters 53 (2012) 292–296
Table 3
The synthesis of 4-alkyl 5,6-dicyano-1H,10H-spiro[pyrazine-2,20-quinoxalin]-30-ones, and 1-alkyl-2-(pyrazin-2-yl)benzimidazoles
Ph
Ph
N
CN
CN
Ph
H
N
AcOH,
N
N
p-TsOH (20 mol%)
N
N
reflux, 7 h
O
2
N
H
+
CN
(1.1 eq)
MeOH, reflux, 6 h
N
R
O
N
N
R
4j-l
O
CN
R
1j-l
3j-l
(1eq)
Product
R
Yielda (%)
Product
R
Yielda (%)
3j
3k
3l
n-C4H9
n-C8H17
n-C9H19
95
94
97
4j
4k
4l
n-C4H9
n-C8H17
n-C9H19
58
60
60
a
Yield of purified product after filtration through a short silica gel plug with CH2Cl2 as eluent.
entry 1). The optimum molar ratio of reagents 1a:2 was 1.0:1.1. Un-
der these conditions other 3-aroyl- (4a-g) and 3-alkanoyl- (4h,i)
derivatives of quinoxaline-2(1H)-ones behaved similarly resulting
in high (75–96%) yields of the corresponding spiro-derivatives on
reaction with diaminomaleonitrile 2 (Table 1). These examples of
the reactions of 1a,d with 2 showed that increasing the reaction time
to 10 h resulted in a mixture of the products of rearrangement
of 3a,d and spiro-derivatives of quinoxalinones 4a,d in a ratio of
ꢀ1:3 (yield 89%), and up to 20 h in a ratio of ꢀ1:1 (yield 97%). When
carrying out the reactions of quinoxalines 1a–i with diaminomaleo-
nitrile 2 for 6 h in the presence of p-TsOH (20 mol %) as catalyst the
formation of spiro-compounds 4a–i occurred in yields of 60–85%
(Table 1). The reactions of quinoxalin-2(1H)-ones 1a,b with 2 show
that in the presence of catalytic amounts of HCl, spiro-compounds
4a,b are formed in 2 h and the yields of the products were 91% and
88%, respectively (Table 1, entries 1 and 2).
Spiro-compounds 4a–e,h,i without substituents on the benzene
ring of the quinoxaline system were transformed quantitatively
into the desired 2-(pyrazin-2-yl)benzimidazole 3a–e,h,i in boiling
AcOH in 10 min (Table 2, entries 1–5, 8 and 9). The substituted
spiro-derivatives of quinoxalin-2(1H)-ones 4f,g underwent the
rearrangement only after 3 h in boiling AcOH (Table 2, entries 6
and 7).
The formation of spiro-compounds also proceeded with N-alkyl-
ated derivatives of quinoxalin-2(1H)-ones 1j–l to give N-alkylated
spiro[pyrazine-2,20-quinoxalin]-30(40H)-ones 4j–l (Table 3). p-TsOH
was more suitable as the catalyst for these cases. It should be
pointed out that the rearrangement of N-alkylated spiro-com-
pounds 4j–l occurred more slowly than with nonalkylated spiro-
compounds 4a–i. Thus, heating spiro-compounds 4j–l for 5 min
resulted in formation of the product of rearrangement in a ꢀ25%
yield, 30 min: ꢀ50%, 3 h: ꢀ75%, 7 h: ꢀ100%.16,17
The structures of compounds 3a–i, 4a–i and 40a–i were deduced
from their elemental analyses and 1H and 13C NMR data.16,17 The
mass spectra of these compounds displayed molecular ion peaks
at appropriate m/z values. The initial fragmentation of 3a–l involved
scission of the benzimidazole and pyrazine ring systems.16,17
The molecular structures of compounds 3d and 40d were con-
firmed unambiguously by single-crystal X-ray analysis (Fig. 1a
and b).18–20
It is worthy of note that the products of the reaction of 3-
aroyl(alkanoyl)quinoxalin-2(1H)-ones 1a–i and N-alkyl-3-benzoyl-
quinoxalin-2(1H)-ones 1j–l with diaminomaleonitrile 2 in DMSO-
d6 exist solely in spiro cyclic-forms 4a–l, whereas in the crystalline
state they exist only as open chain forms 40a–l (e.g., see Fig. 1b).
On the basis of the known chemistry of quinoxalinones,21 and
diaminomaleonitrile22 and the above data, it is reasonable toassume
that the formation of 2-(pyrazin-2-yl)benzimidazoles 3 involves
addition of the amino group of diaminomaleonitrile 2 at the C(3)
atom of quinoxalin-2(1H)-one 1 as the first step. The next step
Figure 1. ORTEP plots of compounds 3d (a) and 40d (b) and partial numbering
schemes. Displacement ellipsoids are drawn at the 30% probability level. H-atoms
are represented by spheres of arbitrary radii. The two acetic acid molecules in (a)
are not shown.

V. A. Mamedov et al. / Tetrahedron Letters 53 (2012) 292–296
295
H2O
R1
H
N
H2N
O
CN
CN
H2N
OH
CN
CN
R1
R1
CN
CN
H
N
H
H
N
N
H+
N
N
H
N
H
1 + 2
H2
N
H
O
N
H
O
N
H
O
- H2O,
- H+
NH2
R1
NH R1
R1
N
CN
CN
O
H
N
N
N
N
H
N
HO
3
N
H
H
N
N
- H2O
CN
CN
N
H
4
O
CN
CN
A
4'
Scheme 3. A plausible mechanism for the formation of 2-(pyrazin-2-yl)benzimidazoles 3.
5. Weingarten, M. D.; Liming, N. I.; Sikorski, J. A. WO 2004/056727 A2;
2004:546462; Chem. Abstr. 2004, 141, 106359.
6. Kakoi, H. Chem. Pharm. Bull. 2002, 50, 301.
involves nucleophilic attack of the second amino group of 2 on the
benzoyl carbonyl group to form the spiro-quinoxaline derivative 4.
Rearrangement of the spiroquinoxalinone 4 is then assumed to oc-
cur according to Scheme 3, which proceeds via a cascade involving:
(a) acid catalysis ring-opening with cleavage of the C(3)-N(4) bond
in the spiro-compound 4 with the formation of intermediate quin-
oxaline derivative 40, (b) intramolecular nucleophilic attack by the
amino group on the carbonyl group with the formation of interme-
diate hydroxy-derivative A, and (c) the elimination of water leading
to the final product 3 (Scheme 3).
7. (a) Fales, H. M.; Blum, M. S.; Southwick, E. W.; William, D. L.; Roller, P. P.; Don,
A. W. Tetrahedron 1988, 44, 5045; (b) Tecle, B.; Sun, C. M.; Borphy, J. J.; Toia, R. F.
J. Chem. Ecol. 1987, 13, 1811; (c) Wheeler, J. W.; Avery, J.; Olubajo, O.; Shamim,
M. T.; Storm, C. B. Tetrahedron 1982, 38, 1939; (d) Brown, W. V.; Moore, B. P.
Insect Biochem. 1979, 9, 451; (e) Oldham, N. J.; Morgan, E. D. J. Chem. Soc., Perkin
Trans. 1 1993, 1, 2713.
8. (a) Adamczky, M.; Akireddy, S. R.; Johnson, D. D.; Mattingly, P. G.; Pan, Y.;
Rajarathnam, E. R. Tetrahedron 2003, 59, 8129–8142; (b) For a Ni-catalyzed
reaction, see: Godek, D. M.; Rosen, T. J. WO 91/18878, 1991; Chem. Abstr. 1992,
116, 106106.
9. Namamura, H.; Takeuchi, D.; Murai, A. Synlett 1995, 1227.
To summarize, we have described an efficient and versatile me-
tal-free method for the preparation of a series of 2-(pyrazin-2-
yl)benzimidazoles. This was accomplished by the novel rearrange-
ment of 3R-5,6-dicyano-1H,10H-spiro[pyrazine-2,20-quinoxalin]-
30(40H)-ones easily obtained from 3-aroyl- and 3-alkanoylquinoxa-
lin-2(1H)-ones on exposure to diaminomaleonitrile. The key
advantages are the simplicity of the operation, high yields, easy
availability of 3-aroyl-, and alkanoylquinoxalin-2(1H)-ones, as well
as the simple work-up and purification of the products. The reac-
tion is readily applicable to large scale synthesis. Application of
this methodology to the synthesis of other heterocyclic ring sys-
tems is currently under investigation and the results will be pub-
lished in due course.
10. Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158.
11. Jones, K.; Keenan, M.; Hibbert, F. Synlett 1996, 509.
12. (a) Pal, M.; Batchu, V. R.; Dager, I.; Swamy, N. K.; Padakanti, S. J. Org. Chem.
2005, 70, 2376; (b) Kodimuthali, A.; Nishad, T. C.; Prasunamba, P. L.; Pal, M.
Tetrahedron Lett. 2009, 50, 354; (c) Pal, M.; Batchu, V. R.; Parasuraman, K.;
Yeleswarapu, K. R. J. Org. Chem. 2003, 68, 6806; (d) Pal, M.; Batchu, V. R.;
Khanna, S.; Yeleswarapu, K. R. Tetrahedron 2002, 58, 9933; (e) Kodimuthali, A.;
Chandra, B. Ch.; Prasunamba, P. L.; Pal, M. Tetrahedron Lett. 2009, 50, 1618.
13. (a) Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Chernova, A. V.; Litvinov, I.
A.; Levin, Ya. A.; Schagidullin, R. R. Russ. Chem. Bull., Int. Ed. (Engl. Transl.) 2004,
53, 164; (b) Mamedov, V. A.; Saifina, D. F.; Rizvanov, I. Kh.; Gubaidullin, A. T.
Tetrahedron Lett. 2008, 49, 4644; (c) Mamedov, V. A.; Zhukova, N. A.;
Beschastnova, T. N.; Gubaidullin, A. T.; Balandina, A. A.; Latypov, S. K.
Tetrahedron 2010, 66, 9745; (d) Mamedov, V. A.; Saifina, D. F.; Gubaidullin, A.
T.; Saifina, A. F.; Rizvanov, I. Kh. Tetrahedron Lett. 2008, 49, 6231; (e) Mamedov,
V. A.; Murtazina, A. M.; Gubaidullin, A. T.; Hafizova, E. A.; Rizvanov, I. Kh.
Tetrahedron Lett. 2009, 50, 5186; (f) Mamedov, V. A.; Saifina, D. F.; Gubaidullin,
A. T.; Ganieva, V. R.; Kadyrova, S. F.; Rakov, D. V.; Rizvanov, I. Kh.; Sinyashin, O.
G. Tetrahedron Lett. 2010, 51, 6503.
Acknowledgment
14. Mamedov, V. A.; Murtazina, A. M.; Gubaidullin, A. T.; Khafizova, E. A.; Rizvanov,
I. Kh.; Litvinov, I. A. Russ. Chem. Bull., Int. Ed. (Engl. Transl.) 2010, 59, 1645.
15. (a) Hinsberg, H. Liebigs Ann. Chem. 1887, 237, 368; (b) Murthy, S. N.; Madhav,
B.; Nageswar, Y. V. D. Helv. Chim. Acta 2010, 93, 1217.
This work was supported by the Russian Foundation for Basic
Research (Grant No. 10-03-00413-a).
16. Illustrative experimental procedure for the preparation of compounds 3. Method A.
2,3-Diaminomaleonitrile (2) (95 mg, 0.88 mmol) was added to a suspension of
benzoylquinoxalin-2(1H)-one 1a (0.2 g, 0.8 mmol) in AcOH (10 mL). The
reaction mixture was heated at reflux with stirring for 3 h. The solvent was
removed under reduced pressure and the residue treated with H2O. The
resulting precipitate was filtered, washed with H2O (20 mL) and dried in air to
give a mixture of compounds 3a and unreacted benzoylquinoxalin-2(1H)-one
1a (0.23 g, 90%) in the ratio 1.5:1 (calculated from the 1H NMR spectrum). The
mixture was recrystallized from AcOH/i-PrOH and the precipitate filtered to
give analytically pure compound 3a (0.11 g, 43%), mp 286–289 °C. [Found: C,
65.72; H, 3.70; N, 22.11. C19H10N6ꢁAcOH requires C, 65.97; H, 3.66; N, 21.99]; IR
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.013.
References and notes
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2005, 61, 2803; (b) Li, W.; Fuchs, P. L. Org. Lett. 2003, 5, 2849; (c) LaCour, T. G.;
Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett. 2000, 2, 33; (d) Buron, F.; Plé, N.;
Turck, A.; Quéguiner, G. J. Org. Chem. 2005, 70, 2616.
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Microbiol. 2002, 40, 501; (c) Zhang, Y.; Permar, S.; Sun, Z. J. J. Clin. Microbiol.
2002, 40, 42; (d) Milczarska, B.; Foks, H.; Zwolska, Z. Phosphorus, Sulfur Silicon
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4. (a) Yoon, T.; Ge, P.; Delombaert, S.; Horvath, R. WO 2004/018437 A1;
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Zhang, L. Y.; Yamaguchi, Y.; Kaiser, B.; Zhang, X.; Zhang, S.; Zhao, H.; John, S.;
Moorcroft, N.; Shutske, G. WO 2005/023806 A2; 2005:238985; Chem. Abstr.
2005, 142, 316863.
(KBr) m ;
max = 1514, 1443, 1422, 1345, 1222, 765, 701 cmꢂ1 1H NMR (600 MHz,
DMSO-d6): d = 7.26 (br s, 2H), 7.45 (dd, J = 7.4, 7.3 Hz, 2H), 7.51–7.56 (m, 2H),
7.54 (ddd, J = 7.2, 6.4, 1.1 Hz, 1H), 7.65 (dd, J = 7.8, 6.4 Hz, 2H), 12.96(s 1H). MS
(EI), m/z [I(%)]: 323 (5), 322 (30) [M]+, 321 (100), 320 (7), 218 (7). (The peaks of
ions with relative intensity less then 5% are not specified).
2-{3-(4-Bromophenyl)-5,6-dicyano[pyrazin-2-yl]}-benzimidazole
brown powder; mp 300–303 °C. [Found: C, 56.81; H, 2.24; N, 21.07.
19H9BrN6 requires C, 56.88; H, 2.26; N, 20.95]; IR (Nujol) max = 3342, 1709,
1706, 1588, 1518, 1425, 1304, 1245, 1147, 1108, 1073, 1016, 935, 838, 802,
761 cmꢂ1 1H NMR (600 MHz, DMSO-d6): d = 7.25–7.29 (m, 2H), 7.55–7.59 (m,
(3d):
light
C
m
;
2H), 7.64 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 13.42 (br s 1H); MS (EI), m/z
[I(%)]: 403 (5), 402 (29), 401 (100), 400 (30) [M]+, 399 (95), 376 (8), 374 (8), 321
(10), 320 (19), 319 (18), 298 (1), 296 (11), 60 (11), 108 (15), 102 (9), 64 (5), 63
(7).
17. Illustrative experimental procedure for the preparation of compounds 4. Method A.
p-TsOH (28 mg, 0.16 mmol) was added to a suspension of benzoylquinoxalin-

296
V. A. Mamedov et al. / Tetrahedron Letters 53 (2012) 292–296
2(1H)-one (1a) (0.2 g, 0.8 mmol) and 2,3-diaminomaleonitrile (2) (95 mg,
full matrix least squares on F2, parameters = 315, restraints = 0. Final indices
0.88 mmol) in MeOH (10 mL). The reaction mixture was heated at reflux with
stirring for ca. 45 min until the formation of a homogeneous solution occured.
After 10–15 min the precipitation of orange crystals occurred gradually and the
reaction mixture was boiled for another 5 h. The mixture was cooled to room
temperature and the precipitate filtered and dried in air to give 0.11 g (40%), of
an analytically pure 4a, mp 243–246 °C (dec). [Found: C, 66.97; H, 3.52; N,
R1 = 0.0519, wR2 = 0.1352 for 2964 reflections with I >2r(I); R1 = 0.0868,
wR2 = 0.1551 for all data, goodness-of-fit on F2 = 1.021, largest difference in
peak and hole (0.971 and –0.886 eÅꢂ3).
19. The X-ray diffraction data for crystals of 40d were collected on a Bruker AXS
Smart APEX II CCD diffractometer at 296 K. Crystallographic data for 40d.
C
19H11Br1N6O1, yellow needles, formula weight 419.25, monoclinic, P 21/n,
a = 12.527(2) Å, b = 8.490(2) Å, c = 18.007(4) Å, b = 105.125(2)°, V = 1848.8
(6) Å3, Z = 4, calc = 1.506 g cmꢂ3 (kMoK ) = 22.45 cmꢂ1
F(000) = 840,
24.78. C19H12N6O requires C, 67.05; H, 3.55; N, 24.69]; IR (Nujol)
mmax = 3443,
3366, 1650, 1628, 1557, 1459, 1378, 1302, 1254, 1217, 1151, 1077, 755 cmꢂ1
;
q
,
l
,
a
1H NMR (600 MHz, DMSO-d6) d = 6.77 (d, J = 7.8 Hz, 1H), 6.81 (ddd, J = 7.8, 7.6,
1.1 Hz, 1H), 6.95 (dd, J = 7.8, 6.4 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 7.30–7.43 (m,
3H), 7.70–7.73 (m, 2H), 7.98 (s, 1H), 10.44 (s, 1H), 11.25 (s, 1H); 13C{1H} NMR
(151 MHz, DMSO-d6) d = 66.79, 105.07, 112.81, 114.90, 116.29, 116.79, 117.76,
120.19, 124.75 (br), 128.78, 129.15, 131.24, 136.70, 149.21, 161.38. MS (EI), m/
z [I(%)]: 340 (11) [M]+, 323 (9), 322 (27), 321 (100), 320 (8), 218 (8), 135 (19),
134 (5), 108 (5), 107 (22), 103 (7), 80 (14), 77 (5). (The peaks of ions with
relative intensities less then 5% are not specified). The filtrate was evaporated
in vacuo, the remaining solid was treated with H2O (20 mL) and the resulting
precipitate filtered, dried in air and recrystallized from i-PrOH to give
additionally 92 mg (34%) of compound 4a.
reflections collected = 13578, unique = 3638, R(int) = 0.0873, full matrix least
squares on F2, parameters = 256, restraints = 0. Final indices R1 = 0.0551,
wR2 = 0.1074 for 1645 reflections with I >2r(I); R1 = 0.1523, wR2 = 0.1378 for
all data, goodness-of-fit on F2 = 1.003, largest difference in peak and hole
(0.320 and –0.490 eÅꢂ3).
20. Crystallographic data (excluding structure factors) for the structures reported
in this Letter have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 832661 and 832660
(compounds 3d and 40d, respectively). Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: +44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk).
18. The X-ray diffraction data for crystals of 3d were collected on a Bruker AXS Smart
APEX II CCD diffractometer at 296 K. Crystallographic data for 3d.
21. Cheeseman, G. W. H.; Cookson, R. F. In Condensed Pyrazines; Weissberger, A.,
Taylor, E. C., Eds.; Wiley-Interscience: New York, 1979.
C
19H9Br1N6ꢁ2C2H4O2, yellow needles, formula weight 521.34, triclinic, P-1,
a = 8.639(2) Å, b = 11.695(2) Å, c = 12.595(3) Å, = 84.919(2)°, b = 88.871(2)°,
= 69.395(2)°, V = 1186.3(4) Å3, Z = 2, calc = 1.460 g cmꢂ3
(kMoK ) = 17.74
cmꢂ1, F(000) = 528, reflections collected = 9075, unique = 4607, R(int) = 0.0225,
22. (a) Kubota, Y.; Shibata, T.; Babamoto-Horiguchi, E.; Uehara, J.; Funabiki, K.;
Matsumoto, S.; Ebihara, M.; Matsui, M. Tetrahedron 2009, 65, 2506; (b) Gao, B.;
Zhou, Q.; Geng, Y.; Cheng, Y.; Ma, D.; Xie, Z.; Wang, L.; Wang, F. Mater. Chem.
Phys. 2006, 99, 247; (c) Faust, R.; Weber, Ch. Tetrahedron 1997, 53, 14655.
a
c
q
, l
a