An efficient and facile synthesis of quinoxaline derivatives catalyzed by KHSO4 at room temperature

Article abstract of DOI:10.1007/s00706-007-0694-2

A facile synthesis of quinoxaline derivatives catalyzed by KHSO₄ in very high yields at room temperature is reported.

Full text of DOI:10.1007/s00706-007-0694-2

Monatshefte fu¨r Chemie 138, 875–877 (2007)
DOI 10.1007/s00706-007-0694-2
Printed in The Netherlands
An Efficient and Facile Synthesis of Quinoxaline Derivatives Catalyzed
by KHSO4 at Room Temperature
Ã
Ã
Hossein A. Oskooie , Majid M. Heravi , Khadijeh Bakhtiari, and Shima Taheri
Department of Chemistry, School of Sciences, Azzahra University Vanak, Tehran, Iran
Received March 31, 2007; accepted April 15, 2007; published online July 5, 2007
# Springer-Verlag 2007
Summary. A facile synthesis of quinoxaline derivatives cat-
alyzed by KHSO4 in very high yields at room temperature is
reported.
for the preparation of substituted quinoxalines [13].
To the best of our knowledge the following methods
have been applied: Bi-catalysed oxidative coupling
of epoxides and ene-1,2-diamines [14], from ꢀ-
hydroxy ketones via a tandem oxidation process using
Pd(OAc)2 or RuCl2-(PPh3)3-TEMPO [15] and MnO2
[16], heteroannulation of nitroketene N,S-arylimino-
acetals with POCl3 [17], solid-phase synthesis on
SynPhaseTM Lanterns [18], cyclization of ꢀ-aryl-
imino oximes of ꢀ-dicarbonyl compounds under
reflux in acetic anhydride [19], condensation of 1,2-
dicarbonyl compounds and o-phenylenediamines in
MeOH=AcOH under microwave irradiation [20],
iodine catalyzed cyclocondensation of 1,2-dicarbo-
nyl compounds and substituted o-phenylenediamines
in DMSO [21] and CH3CN [22]. However, these meth-
ods have many disadvantages, such as low yields, long
reaction times, the use of toxic solvents, and harsh
reaction conditions. Thus, the development of a new
catalyst for the synthesis of quinoxaline derivatives
would be highly desirable.
Keywords. 1,2-Diketones; o-Phenylenediamines; KHSO4;
Quinoxaline derivatives.
Introduction
The synthesis of quinoxaline derivatives has been of
considerable interest to chemists because of their
wide range of biological and pharmaceutical proper-
ties. Quinoxaline is an important component of phar-
macologically active compounds. Although rarely
occurring in Nature, the synthetic quinoxaline ring
is a part of various antibiotics such as Echinomycin,
Levomycin, and Actinoleutin [1] that are known to
inhibit growth of Gram-positive bacteria and are
active against various transplantable tumors [2]. In
addition, quinoxaline derivatives have been reported
to possess significant biological activities, such as
antihelmintic, anticancer [3], antimicrobial, antifun-
gal, and antidepressant [4, 5], and have applications
in dyes [6]. They are efficient electroluminescent
materials [7], organic semiconductors [8], building
blocks for the synthesis of anion receptors [9], cavi-
tands [10], dehydroannulenes [11], and DNA cleav-
ing agents [12].
KHSO4 is one of the components of a triple salt
with the formula 2KHSO5 Á KHSO4 Á K2SO4, the so-
called Oxone, which is used as highly efficient, mild,
and sole oxidizing agent in many organic reagents
[23]. Synthesis of 2-arylsubstituted benzimidazoles
by oxidative condensation of aldehydes with o-phe-
nylenediamine in the presence of KHSO4 has also
been reported [24].
Thus, the synthesis of quinoxalines currently is of
great interest. Various methods have been developed
Recently, we have reported the use of KHSO4 as
an efficient catalyst for the synthesis of 1,1-diace-
Ã
Corresponding author. E-mail: mmh1331@yahoo.com

876
H. A. Oskooie et al.
Scheme 1
Table 1. Synthesis of 2,3-disubstituted quinoxalines 3 cata-
lyzed by KHSO4
tates under solvent-free conditions [25]. Because we
are interested in the synthesis of heterocyclic com-
pounds [26], very recently, we have reported the
synthesis of quinoxaline derivatives catalyzed by
CuSO4 Á 5H2O [27a], IBX [27b], Zn[L-proline] [28],
and heteropolyacid [29]. Herein, we wish to report
an efficient and facile methodology for the synthesis
of quinoxalines of high purity using KHSO4 as cat-
alyst at room temperature.
Product
R
R1 Time=min Yield=%a,b
mp=ꢀC
3a
3b
3c
3d
3e
3f
H
OCH3
H
H
H
NO2
15
12
30
10
14
12
99
97
92
93
99
98
128–129
151–152.5
193–194
192–194
117–118
125–127
OCH3 NO2
CH3
OCH3 CH3
H
a
Yields refer to isolated pure products
All products were well characterized using melting point,
b
Results and Discussion
1H NMR, and IR spectra [21, 22, 27–29]
When a mixture of benzil (1a, 1 mmol) and o-pheny-
lenediamine (2a, 1 mmol) and a catalytic amount of
KHSO4 (10 mol%) in EtOH was stirred at room tem-
perature, the mixture solidified after 15min. At this
stage, TLC analysis showed that the reactands were
completely consumed and the corresponding quinoxa-
line 3a was formed (Scheme 1). Upon heating the
reaction mixture, the product dissolved in ethanol
and the catalyst could be separated by simple filtration.
The pure product 3a (Scheme 1) was obtained (99%
yield) without any further recrystallization.
The scope and the generality of the present method
was then further demonstrated by condensation of
various substituted o-phenylenediamines with 1,2-
dicarbonyl compounds. The results are presented in
Table 1. In general, with electron donating substitu-
ents in the amine part, high yields of products were
obtained, whereas the effect is contrary with electron
withdrawing substituents. On the other hand, elec-
tron donating substituents associated with aromatic
1,2-diketone decreased the product yields and the
effect is contrary with electron withdrawing groups.
However, the variations in the yields were very small
and both substituted o-phenylenediamines, 4-nitro
and 4-methyl, gave the condensed products in excel-
lent yields with differently substituted 1,2-diketones.
Though the role of KHSO4 is not clear, we think
that it can act as a mild Brønsted acid. In the absence
of KHSO4 the reaction was slow and also requires
refluxing conditions providing unsatisfactory yields.
We also evaluated the amount of KHSO4 required
for this transformation. As less as 5 mol% of the
KHSO4 can catalyze the reaction to the same extent,
but needs a little longer reaction times (>1 h).
In conclusion, we developed a simple, clean, con-
venient, and efficient method for the synthesis of
quinoxalines from various 1,2-diketones and o-phe-
nylenediamines using KHSO4 as catalyst under mild
reaction conditions at room temperature and without
any side products. Some of the major advantages of
this procedure are the ambient conditions, very good
yields, very short reaction times, and use of an inex-
pensive, green, readily available, and easily to han-
dle catalyst, simple work-up procedure, and absence
of volatile and hazardous solvents.
Experimental
All chemicals were purchased from commercial suppliers and
were used as received. Melting points were measured by using
the capillary tube method with an electrothermal 9200 appa-

An Efficient and Facile Synthesis of Quinoxaline Derivatives
877
ratus. 1H NMR spectra were recorded on a Bruker AQS
AVANCE-300 MHz spectrometer using TMS as an internal
standard (CDCl3 solution). IR spectra were recorded from
KBr disk on the FT-IR Bruker Tensor 27. All products were
well characterized by comparison with authentic samples by
TLC, spectral, and physical data [21, 22, 27–29].
[11] Sascha O, Rudiger F (2004) Synlett 1509
[12] Louis S, Marc MG, Jory JW, Joseph PB (2003) J Org
Chem 68: 4179
[13] a) Petukhov PA, Tkachev AV (1997) Tetrahedron 53:
9761; b) Kaupp G, Naimi-Jamal MR (2002) Eur J Org
Chem 1368; c) Chen P, Barrish JC, Iwanowicz E, Lin J,
Bednarz MS, Chen B-C (2001) Tetrahedron Lett 42:
4293; d) Soderberg BCG, Wallace JM, Tamariz J
(2002) Org Lett 4: 1339; e) Suginome M, Collet S,
Ito Y (2002) Org Lett 4: 351; f) Mukhopadhyay R,
Kundu NG (2000) Tetrahedron Lett 41: 9927; g) Bunce
RA, Herron DM, Ackerman ML (2000) J Org Chem 65:
2847; h) Banik BK, Banik I, Hackfeld L, Becker FF
(2002) Heterocycles 56: 467; i) Goswami S, Adak AK
(2003) Chem Lett 32: 678
[14] Antoniotti S, Donach E (2002) Tetrahedron Lett 43:
3971
[15] Robinson RS, Taylor RJK (2005) Synlett 1003
[16] a) Raw SA, Wilfred CD, Taylor RJK (2004) Org Biomol
Chem 2: 788; b) Raw SA, Wilfred CD, Taylor RJK
(2003) Chem Commun 2286
Preparation of Quinoxalines Catalyzed by KHSO4: General
Procedure
A mixture of 1 mmol 1,2-diketone 1, 1 mmol 1,2-diaminoar-
ene 2, and 10 mg KHSO4 (10 mol%) in 3 cm3 EtOH was
stirred at room temperature. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reac-
tion mixture was heated, the product dissolved in ethanol, and
the catalyst was separated from the reaction mixture by simple
filtration. After cooling the solvent to room temperature the
pure product 3 was obtained. The structures of the synthesized
products were confirmed by FT-IR and 1H NMR spectra.
Acknowledgements
[17] Venkatesh C, Singh B, Mahata PK, IIa H, Junjappa H
(2005) Org Lett 7: 2169
[18] Wu Z, Ede NJ (2001) Tetrahedron Lett 42: 8115
[19] Xekoukoulotakis NP, Hadjiantonious MCP, Maroulis AJ
(2000) Tetrahedron Lett 41: 10299
[20] Zhao Z, Wisnoski DD, Wolkenberg SE, Leister WH,
Wang Y, Lindsley CW (2004) Tetrahedron Lett 45:
4873
[21] Bhosale RS, Sarda SR, Ardhapure SS, Jadhav WN,
Bhusare SR, Pawar RP (2005) Tetrahedron Lett 46:
7183
H.A.O. is grateful to Azzahra University research council for
the partial financial support.
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