One-pot new synthetic method for 3-amino-2-quinoxalinecarbonitrile

Article abstract of DOI:10.1080/00397910903013721

A new method for the preparation of 3-amino-2-quinoxalinecarbonitrile (1) was studied. A successful condensation reaction between bromomalononitrile and o-phenylenediamine in the presence of Lewis acid catalyst (AlCl₃) was achieved to produce compound 1.

Full text of DOI:10.1080/00397910903013721

This article was downloaded by: [Illinois State University Milner Library]
On: 25 November 2012, At: 05:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
One-Pot New Synthetic Method for 3-
Amino-2-quinoxalinecarbonitrile
a
a
Mohamed Attia Waly , Sameh Ramadan El-Gogary & Osama
a
Zakaria El-Sepelgy
a
Faculty of Science (Damiatta), Chemistry Department, Mansoura
University, Egypt
Version of record first published: 04 Feb 2010.
To cite this article: Mohamed Attia Waly, Sameh Ramadan El-Gogary & Osama Zakaria El-
Sepelgy (2010): One-Pot New Synthetic Method for 3-Amino-2-quinoxalinecarbonitrile, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:5, 739-743
To link to this article: http://dx.doi.org/10.1080/00397910903013721
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

1
Synthetic Communications , 40: 739–743, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903013721
ONE-POT NEW SYNTHETIC METHOD FOR
-AMINO-2-QUINOXALINECARBONITRILE
3
Mohamed Attia Waly, Sameh Ramadan El-Gogary, and
Osama Zakaria El-Sepelgy
Faculty of Science (Damiatta), Chemistry Department,
Mansoura University, Egypt
A new method for the preparation of 3-amino-2-quinoxalinecarbonitrile (1) was studied. A
successful condensation reaction between bromomalononitrile and o-phenylenediamine in
3
the presence of Lewis acid catalyst (AlCl ) was achieved to produce compound 1.
Keywords: Aerobic oxidation; aminoquinoxalinecarbonitrile; bromomalononitrile; cyanation; Lewis acid
catalyst; quinoxaline-1,4-dioxide
INTRODUCTION
3-Amino-2-quinoxalinecarbonitrile 1 and its 1,4-dioxide 2 were characterized
as important precursors in the syntheses of biologically active fused quinoxaline ring
[
1,2]
[3–5]
systems
the compound 2 exhibited hypoxia-selective properties similar to those for
and complexes.
In the past few years, extensive studies showed that
[6–8]
tirapazamine.
Four steps for the synthesis of compound 1 starting from o-nitroaniline, with
an overall yield about 23%, have been reported as a common method for its syn-
[
9,10]
thesis.
quinoxaline-1,4-dioxide derivative 2 with sodium dithionite to form compound
.
The last step in the previous procedure includes the reduction of
[
10]
1 However, three different products were obtained with equal ratios when we
used the same methodology, which indeed will reduce the overall yield of compound
1
(12%). Two other syntheses for compound 1 have been reported by the
Received October 11, 2008.
Address correspondence to Mohamed Attia Waly, Faculty of Science (Damiatta), Chemistry
Department, Mansoura University, Egypt. E-mail: mohamedwaly7@yahoo.com
7
39

740
M. A. WALY, S. R. EL-GOGARY, AND O. Z. EL-SEPELGY
[
11]
condensation of o-phenylenediamine, either with diiminisuccinonitrile (31%)
with 4-chloro-5-cyano-1,2,3-dithiazolium chloride (12%). Complexity and poor
or
[
12]
yields are the major drawbacks of these two methods.
RESULTS AND DISCUSSION
As a part of our continuing efforts to synthesize 1 in good yield, several
approaches have been elaborated. Direct cyanation of 3-amino-2-chloroquinoxaline
with cuprous cyanide in dimethyl formamide through nucleaphilic aromatic substi-
tution failed. However, the reaction of 2,3-dichloroquinoxaline (3) with cuprous cyan-
ide in dimethyl formamide gave 3-(N,N-dimethylamino)-2-quinoxalinecarbonitrile
[
13]
1
(4) (Scheme 1). The physical properties of 4 as well as the H NMR spectra were
identical with the reported data.
[13]
Cyanation of 2,3-dichloroquinoxaline using
tetraethylammonium cyanide in dimethylsulfoxide (DMSO) gave quinoxaline-2,3-
[14]
dicarbonitrile.
Furthermore, direct condensation between o-phenylenediamine and bromoma-
lononitrile (5), at different reaction conditions (solvents and temperatures), gave
[
15]
massive black material. Ferris and Orgel in 1965
reported that the reaction
between bromomalononitrile and amines (morphiline, ammonia, or triethylamine)
did not give the aminomalononitrile derivatives but instead the polycyanated
products. This was attributed to the acidity of the proton for bromomalononitrile
ꢀ
5 [16]
(
dissociation constant K ¼ 10 ),
which favor, the formation of a stabilized
carbanion rather than being attacked by the nucleophile in an S 2 fashion as postu-
N
[15]
lated by Ferris and Orgel. The condensation of o-phenylenediamine with bromo-
malononitrile failed because the formation of 6, which will attack another molecule
of bromomalononitrile and displace the bromine atom to form the tetracyanoethy-
[15]
lene 8 (Scheme 2).
Bromomalononitrile also reacts with alcohols when used as
[18]
[
solvents and with carbonyl compounds.
17]
[
16]
After reports elaborated on the carbon acidity of bromomalononitrile,
no
one elsewhere could replace the bromine atom by nucleophiles or bases and could
not utilize this function in organic synthesis.
We adopted a solution to this problem by removing the bromide anion from
bromomalononitrile (5) by reaction with an equivalent amount from Lewis acid
catalyst (anhydrous AlCl ) in acetonitrile as a solvent, forming the complex 9. This
3
was followed by condensation with o-phenylenediamine in the same reaction mixture
to give compound 1 (Scheme 3). Compound 1 was detected by thin-layer chromato-
graphy (TLC) during the reaction progress and was increased by aerobic oxidation
in the presence of oxygen gas (yield ¼ 63%). The reaction mechanism may pass
through formation of 1,4-dihydroquinoxaline derivative 10, which is an inseparable
Scheme 1. Cyanation of 2,3-dichloroquinoxaline.

3
-AMINO-2-QUINOXALINECARBONITRILE
741
Scheme 2. Reaction of bromomalononitrile with bases.
and unstable intermediate and could oxidized to give compound 1 in the presence of
oxygen (Scheme 3).
Acetonitrile is a good solvent for this reaction, but dichloromethane (DCM)
ꢁ
gave poor yields (5%). Low temperature (ꢀ20 C) is essential during the addition
of o-phenylenediamine to the reaction mixture. Silver nitrate (AgNO ) as Lewis acid
3
catalyst gave the same product 1, but with fair yield (12%). It was found that with the
use of titanium tetrachloride (TiCl ) as Lewis acid catalyst, an inorganic complex
4
was formed as a result of its reaction with o-phenylenediamine, and compound 1
was not detected.
Reported melting points of compound 1 in literature have a wide value range
ꢁ
[12]
ꢁ
[11]
ꢁ
[19]
(210 C,
between 208 and 210 C. This difference in melting point encouraged us to correlate
196–200 C,
ꢁ
and 201–225 C ), but our melting point was fixed
the spectral data of compound 1 with authentic material, prepared by the reduction
[
10]
of 1,4-dioxide derivative 2 with sodium dithionite. The infrared (IR) data of com-
ꢀ
1
pound 1 showed absorption characterizing the cyano group at 2233.16 cm , and its
þ
1
mass spectrum reflected the presence of M at 170 (100%). The H NMR spectra of
compound 1 in CDCl as a solvent gave an exchangeable NH proton at d 5.38 ppm
3
2
Scheme 3. Synthesis of 3-amino-2-quinoxalinecarbonitrile.

7
42
M. A. WALY, S. R. EL-GOGARY, AND O. Z. EL-SEPELGY
12]
[
with deviation from its reported value (d 7.41 ppm).
that previously published is because the author had used a different solvent
DMSO-d ), which could form a hydrogen bond with NH protons and shift them
This change in value from
(
6
2
1
downfield. Repeating the H NMR spectrum for compound 1 in DMSO-d raised
6
the chemical shift value for NH protons to d 7.39 ppm.
2
EXPERIMENTAL
Thin-layer (TLC) and column chromatography were performed using silica gel
type 60, Merck 7731 and Merck 7734, respectively. Melting points were determined
on a Gallenkamp melting-point apparatus. The IR spectra were recorded on a Jasco
ꢀ
1
4
The H and C NMR spectra were recorded in CDCl and DMSO-d on a Bruker
100 Fourier transform (FT)-IR spectrophotometer in KBr discs (n max in cm ).
1 13
3
6
1
DRX NMR spectrometer operating at 400 MHz for H and 100 MHz for C.
13
Chemical shift (d) values are expressed in parts per million (ppm) and are referenced
to the residual solvent signals of CDCl . The mass spectrum was recorded on a
Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Elemental analysis
was recorded on a Perkin-Elmer 2400 C,H,N elemental analyzer.
3
3-Amino-2-quinoxalinecarbonitrile 1
Anhydrous aluminum chloride (1.33 g, 0.01 mol) was added to a solution of
bromomalononitrile 5 (1.45 g, 0.01 mol) in acetonitrile (20 ml), at room temperature
ꢁ
and refluxed for 2 h. The reaction mixture cooled to ꢀ20 C, and a solution of
o-phenylenediamine (1.08 g, 0.01 mol) in acetonitrile (5 ml) was added dropwise
during 20 min with stirring. After the addition was completed, the reaction mixture
was kept at this temperature for a further 2 h. Then the reaction mixture was raised
to room temperature, and oxygen gas was passed in through it for 2 h. The precipi-
tate was filtered off and washed with acetonitrile (3 ꢂ 10 ml), and the filtrate was
collected. After evaporation in vacuo, the residual mass was transferred to column
chromatography using ethyl acetate–petroleum ether (10%). The separated solid
was triturated with diethyl ether and recrystallized from cyclohexane to give a yel-
ꢁ
low powder 1 (1.07 g, 63%), mp 208–210 C. IR: 3417.24 and 3324.68 (NH ),
2
1
233.16 (CN). H NMR (CDCl ): 5.38 (2H, s, exch., NH ), 7.52–757 (1H, m,
2
ar), 7.71–7.76 (2H, m, ar), and 7.94–7.97 (1H, m, ar). C NMR (DMSO):
3
2
1
3
1
1
36.52 (C-2), 134.78 (C-3), 132.73, 129.31, 128.77, 125.65, 125.51, 125.47, and
þ
99.64 (CN). MS, m=z (%): 170 (100) [M ], 144 (17.9), 143 (21.4), 118 (25) and
0 (46.4). Anal. calcd. for C H N (170.17): C, 63.52; H, 3.55; N, 32.92. Found:
9
C, 63.22; H, 3.39; N, 33.07.
9
6
4
REFERENCES
1
. Kotovskaya, S. K.; Charushin, V. N.; Perova, N. M.; Kodess, M. I.; Chupakhin, O. N.
Intramolecular nucleophilic substitution of hydrogen in (quinoxalinyl-2)aminovinyl
derivatives as a new approach to pyrrolo- and indolo[2,3-b]quinoxalines. Synth. Commun.
2004, 34, 2531–2537.

3
-AMINO-2-QUINOXALINECARBONITRILE
743
2
3
. Monge, A.; Palop, J. A.; Urbasos, I.; Fernandez-Alvarez, E. New quinoxaline and pyri-
mido[4,5-b]quinoxaline derivatives: Potential antihypertensive and blood platlet anti-
aggregating agents. J. Heterocycl. Chem. 1989, 26, 1623–1626.
. Urquiola, C.; Vieites, M.; Aguirre, G., Marın, A.; Solano, B.; Arrambide, G.; Noblia, P.;
Lavaggi, M. L.; Torre, M. H.; Gonzalez, M.; Monge, A.; Gambino, D.; Cerecetto, H.
1
4
Improving anti-trypanosomal activity of 3-aminoquinoxaline-2-carbonitrile N ,N -
dioxide derivatives by complexation with vanadium. Bioorg. Med. Chem. 2006, 14,
5503–5509.
4
5
. Torre, M. H.; Gambino, D.; Araujo, J.; Cerecetto, H.; Gonz a´ lez, M.; Lavaggi, M. L.;
Azqueta, A.; L o´ pez de Cerain, A.; Monge Vega, A.; Abram, U.; Costa-Filho, A. J. Novel
Cu(II) quinoxaline N ,N -dioxide complexes as selective hypoxic cytotoxins. Eur. J. Med.
Chem. 2005, 40, 473–480.
1
4
. Noblia, P.; Vieites, M.; Torre, M. H.; Costa-Filho, A. J.; Cerecetto, H.; Gonzalez, M.;
Lavaggi, M. L.; Adachi, Y.; Sakurai, H.; Gambino, D. Novel vanadyl complexes with
1
4
quinoxaline N ,N -dioxide derivatives as potent in vitro insulin-mimetic compounds. J.
Inorg. Biochem. 2006, 100, 281–287.
6
. Amin, K. M.; Ismail, M. M. F.; Noaman, E.; Soliman, D. H.; Ammard, Y. A. New quin-
oxaline 1,4-di-N-oxides, part 1: Hypoxia-selective cytotoxins and anticancer agents
derived from quinoxaline 1,4-di-N-oxides. Bioorg. Med. Chem. 2006, 14, 6917–6923.
. Monge, A.; Palop, J. A.; Lopez de Cerain, A.; Senador, V.; Martinez, F. J.; Sainz, Y.;
Narro, S.; Garcia, E.; Carlos de Miguel.; Gonzalez, M.; Hamilton, E.; Barker, A. J.;
Clarke, E. D.; Greenhow, D. T. Hypoxia-selective agents derived from quinoxaline
7
1,4-Di-N-oxides. J. Med. Chem. 1995, 38, 1786–1792.
8. Chowdhury, G.; Kotandeniya, D.; Daniels, J. S.; Barnes, C. L.; Gates, K. S.
Enzyme-activated, hypoxia-selective DNA damage by 3-amino-2-quinoxalinecarbonitrile
1,4-di-N-oxide. Chem. Res. Toxicol. 2004, 17, 1399–1405.
9. Smith, P. A. S.; Boyer, J. H. Benzofurazan oxide II: Decomposition of o-nitrophenyl
hydrazide. Orga. Synth. Coll. Vol. 1963, 4, 74.
1
0. Monge, A.; Palop, J. A.; Del Castillo, J. C.; Calder o´ , J. M.; Roca, J.; Romero, G.; Del
Rio, J.; Lasheras, B. Novel antagonists of 5-HT3 receptors: Synthesis and biological
evaluation of piperazinylquinoxaline derivatives. J. Med. Chem. 1993, 36, 2745–2750.
1. Begland, R. W.; Hartter, D. R. Hydrogen cyanide chemistry, IV: Diiminosuccinonitrile
reactions with nucleophiles, acyl halides, and carbonyl compounds. J. Org. Chem. 1972,
1
37, 4136–4145.
1
1
1
1
1
1
1
1
2. Panayiotis, A. K.; Charles, W. R. Chemistry of 4-chloro-5-cyano-1,2,3-dithiazoliumchlor-
ide. J. Chem. Soc., Perkin Trans. 1 1999, 111–118.
3. Titov, V. V.; Kozhokina, L. F. Reactions of 2,2 ,3,3 -tetrachloro-6,6-diquinoxalyl with
nucleophilic reagents. Chem. Heterocycl. Comp. 1977, 13, 337–339.
4. Hermann, K.; Simchen, G. Synthese cyan-substituierter heterocyclen mit
tetraethyl-ammoniumcyanid. Liebigs Ann. Chem. 1981, 333–341.
5. Ferris, J. P.; Orgel, L. E. The reactions of bromomalorronitrile with bases. J. Org. Chem.
0
0
1965, 30, 2365–2367.
6. Pearson, R. G.; Dillon, R. L. Rates of ionization of pseudo acids IV: Relation between
rates and equilibria. J. Am. Chem. Soc. 1953, 75, 2439–2443.
7. Hart, H.; Kim, Y. C. A new synthesis of tetracyanocyclopropanes. J. Org. Chem. 1966, 31,
2784–2789.
8. Hart, H.; Freeman, F. The synthesis and NMR spectra of some tetracyanocyclopropanes.
J. Org. Chem. 1963, 28, 1220–1222.
9. Brown, D. J. The Chemistry of Heterocyclic Compounds: Quinoxalines Supplement II; John
Wiley & Sons: Hoboken, New Jersey, 2004; pp. 367.