Catalysis Communications 8 (2007) 211–214

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On Water: A practical and efficient synthesis of quinoxaline

derivatives catalyzed by CuSO4 Æ 5H2O
Majid M. Heravi *, Shima Taheri, Khadijeh Bakhtiari, Hossein A. Oskooie
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran

Received 24 April 2006; received in revised form 11 June 2006; accepted 12 June 2006
Available online 16 June 2006

Abstract

Cupric sulfate pentahydrate is an efficient catalyst for a one-pot synthesis of quinoxaline derivatives. The reaction can be performing
in water as well as ethanol. The procedure presented is operationally simple, practical and green.
Ó 2006 Elsevier B.V. All rights reserved.

Keywords: 1,2-Diketones; 1,2-Diamines; Quinoxaline derivatives; CuSO4 Æ 5H2O; Cupric sulfate pentahydrate

1. Introduction they also serve as useful rigid subunits in macro cyclic

receptors or molecular recognition [8] and chemically con-
The toxic and volatile nature of many organic solvents, trollable switches [9].
particularly chlorinated hydrocarbons and benzene, which A number of synthetic strategies have been developed
are widely used in organic synthetic procedures, has posed for the preparation of substituted quinoxalines [3,10]. By
a serious threat to the environment. There has been consid- far, the most common method relies on the condensation
erable research recently into replacing the use of these vol- of an aryl 1,2-diamine with a 1,2-dicarbonyl compound
atile organic solvents with clean ones as reaction media [1]. in refluxing ethanol or acetic acid for 2–12 h giving 34–
Performing organic reactions in aqueous media has 85% yields [11]. Numerous methods are available in the
attracted much attention, because water would be consid- literature for the synthesis of quinoxaline derivatives
erably safe, non-toxic, environmentally friendly and cheap including the Bi-catalyzed oxidative coupling of epoxides
compared to organic solvents [2]. Moreover, when a water- and ene-1,2-diamines [12], from a-hydroxy ketones via a
soluble catalyst is used, the insoluble products can be sep- tandem oxidation process using Pd(OAc)2 or RuCl2–
arated by simple filtration and the catalyst system can be (PPh3)3–TEMPO [13] and MnO2 [14], heteroannulation
recycled. Therefore, development of a catalyst system that of nitroketene N,S-arylaminoacetals with POCl3 [15], a
is not only stable toward water but also completely soluble solid-phase synthesis on SynphaseTM Lanterns [16], cycli-
in this solvent seems highly desirable. zation of a-arylimino oximes of a-dicarbonyl compounds
Quinoxaline and its derivatives are an important class of under reflux in acetic anhydride [17], condensation of o-
benzoheterocycles [3] displaying a broad spectrum of bio- phenylene diamines and 1,2-dicarbonyl compounds in
logical activities [4] which have made them privileged struc- MeOH/AcOH under microwave irradiation [18], and
tures in combinatorial drug discovery libraries [5]. They iodine catalyzed cyclocondensation of 1,2-dicarbonyl com-
have also found applications as dyes [6] and building pounds and substituted o-phenylene diamines in DMSO
blocks in the synthesis of organic semiconductors [7], and [19] and CH3CN [20]. Most of the existing methodologies
suffer from disadvantages such as use of volatile organic
*
Corresponding author. Tel.: +98 2188041344; fax: +98 2188047861. solvents, unsatisfactory product yields, critical product
E-mail address: mmh1331@yahoo.com (M.M. Heravi). isolation procedures, expensive and detrimental metal

1566-7367/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2006.06.013
212 M.M. Heravi et al. / Catalysis Communications 8 (2007) 211–214

precursors and harsh reaction conditions, which limit their 6.30 Hz, 2H), 7.79 (dd, J = 3.43, 6.30 Hz, 2H), 7.5
use under the aspect of environmentally benign processes. (m, 4H), 7.39 (m, 6H); IR (KBr) mmax (cm 1): 3055,
Recently we reported the use of CuSO4 Æ 5H2O for the 1541, 1345, 768, 729.
synthesis of 1,1-diacetates under solvent-free condition (2) 2,3-Bis(4-methoxy-phenyl) quinoxaline: m.p. 151–
[21]. This experience motivated us to use this catalyst for 152 °C; 1H NMR (CDC13, 300 MHz) d (ppm): 8.15
the synthesis of 2,3-disubstituted quinoxalines. As part of (dd, J = 3.44, 6.32 Hz, 2H), 7.7 (dd, J = 3.39,
our ongoing interest in synthesis of heterocyclic compounds 6.36 Hz, 2H), 7.55 (d, J = 8.75 Hz, 4H), 6.89 (d,
containing nitrogen [22], we disclose herein our results for J = 8.73 Hz, 4H), 3.81 (s, 6H); IR (KBr) mmax
the synthesis of quinoxalines using catalytic amounts of (cm 1): 3003, 2931, 1604, 1510, 1345, 1057, 876.
cupric sulfate pentahydrate in ethanol and water. (3) 6-Nitro-2,3-diphenylquinoxaline: m.p. 193–194 °C; 1H
NMR (CDC13, 300 MHz) d (ppm): 9.2 (d,
2. Experimental J = 2.38 Hz, 1H), 8.53 (dd, J = 2.50, 9.10 Hz, 1H,),
8.39 (d, J = 9.17 Hz, 1H), 7.6 (m, 4H), 7.42 (m,
Melting points were measured by using the capillary 6H); IR (KBr) mmax (cm 1): 3057, 2935, 1621, 1341,
tube method with an electro thermal 9200 apparatus. 1H 1135, 699.
NMR spectra were recorded on a Bruker AQS (4) 2,3-Bis(4-methoxy-phenyl)-6-nitroquinoxaline: m.p.
AVANCE-300 MHz spectrometer using TMS as an inter- 192–194 °C; 1H NMR (CDC13, 300 MHz) d (ppm):
nal standard (CDCl3 solution). IR spectra were recorded 9.1 (d, J = 2.44 Hz, 1H), 8.49 (dd, J = 2.46,
from KBr disk on the FT-IR Bruker Tensor 27. All prod- 9.14 Hz, 1H), 8.24 (d, J = 9.15 Hz, 1H), 7.56 (m,
ucts were characterized by spectra and physical data. 4H), 6.98 (d, J = 7.9 Hz, 4H), 3.9 (s, 6H); IR (KBr)
mmax (cm 1): 2924, 1337, 1169, 1021, 835.
2.1. Preparation of quinoxalines in water (method I): (5) 6-Methyl-2,3-diphenylquinoxaline: m.p. 116–117 °C;
1
general procedure H NMR (CDC13, 300 MHz) d (ppm): 8.1 (d,
J = 8.55 Hz, 1H), 7.96 (s, 1H), 7.63 (dd, J = 1.72,
A mixture of 1,2-diketone 1 (1 mmol), 1,2-diaminoben- 8.56 Hz, 1H), 7.5 (m, 4H), 7.35 (m, 6H), 2.6 (s, 3H);
zene derivative 2 (1 mmol) and CuSO4 Æ 5H2O (10 mol%) IR (KBr) mmax (cm 1): 3063, 1660, 1592, 1210, 874,
in water (3 mL) was stirred at room temperature. The pro- 719, 640.
gress of the reaction was monitored by TLC. After comple- (6) 2,3-Bis(4-methoxy-phenyl)-6-methylquinoxaline: m.p.
tion of the reaction, the solid which separated was filtered 125–127 °C; 1H NMR (CDC13, 300 MHz) d (ppm):
and then recrystallized from ethanol to afford pure quinox- 8.05 (d, J = 8.52 Hz, 1H), 7.92 (s, 1H), 7.58 (dd,
aline 3. J = 1.55, 8.50 Hz, 1H), 7.48 (d, J = 7.64 Hz, 4H),
6.9 (d, J = 8.75 Hz, 4H), 3.9 (s, 6H), 2.6 (s, 3H); IR
2.2. Preparation of quinoxalines in ethanol (method II): (KBr) mmax (cm 1): 2925, 2580, 1657, 1597, 1264,
general procedure 1159, 833, 696.

A mixture of 1,2-diketone 1 (1 mmol), 1,2-diaminoben-

zene derivative 2 (1 mmol) and CuSO4 Æ 5H2O (10 mol%) 3. Results and discussion
in EtOH (3 mL) was stirred at room temperature. Upon
completion of the reaction, the reaction mixture was In a model condensation reaction, benzil 1a and 1,2-
heated, the product dissolves in ethanol and the catalyst diaminobenzene 2a in EtOH were stirred at room temper-
separated easily from the reaction mixture by simple filtra- ature using a catalytic amount of CuSO4 Æ 5H2O (Scheme 1).
tion. The pure product 3 was crystallized from ethanol. After 8 min the reaction was completed. It is noteworthy to
mention that CuSO4 Æ 5H2O is insoluble in ethanol. Then
2.3. Recycling of the catalyst the reaction mixture was heated, the product dissolves in
ethanol and the catalyst separated easily from the reaction
At the end of the reaction in ethanol, the catalyst was fil- mixture. Without any further recrystallization, the pure
tered, washed with diethyl ether, dried at 80 °C for 1 h, and product 3a was obtained (97% yield).
re-used in another reaction. The recycled catalyst was used The applicability of the present methodology is further
for five reactions without observation of appreciable loss in extended by performing the reaction in an aqueous media,
its catalytic activities. In the case of water as solvent, after to our surprise, the reaction was performed well in water
evaporation of water, the catalyst was obtained and could and the reaction rates as well as the yields of products
be reused in another reaction. are satisfactory. CuSO4 Æ 5H2O is highly soluble in water
and can be easily remove from the reaction mixture by sim-
2.4. Physical and spectra data of the products ple filtration (Table 1). Using water as solvent, affected the
rate of reaction and the reaction time, in comparison with
(1) 2,3-Diphenylquinoxaline: m.p. 126–127°C; 1H NMR ethanol, require only little longer time to complete. How-
(CDC13, 300 MHz) d (ppm): 8.2 (dd, J = 3.43, ever, this process is green, environmental friendly, clean,
 M.M. Heravi et al. / Catalysis Communications 8 (2007) 211–214 213

R1 R1
O H 2N R2 CuSO45H2O(10 mol%), RT N R2
+
O Method I: H2O
H 2N N
R1 Method II: EtOH
R1
1 2 3a-f

Scheme 1

Table 1
Synthesis of quinoxaline derivatives catalyzed by CuSO4 Æ 5H2O
Entry R1 R2 Product Method I Method II
a
Time (min) Yield (%) Time (min) Yielda (%)
3a H H 15 96 8 97

3b MeO H MeO 12 95 10 97

MeO

3c H NO2 30 94 15 95
N NO2

3d MeO NO2 MeO 10 95 8 96

N N

MeO

3e H CH3 14 96 12 94
N CH3

3f MeO CH3 MeO 12 98 10 92

N C

MeO
a
Yields refer to isolated pure products.

can perform easily at room temperature and no undesirable 1,2-dicarbonyl compounds using catalytic amount of
side reactions were observed. CuSO4 Æ 5H2O in both ethanol and water (Table 1).
The scope and the generality of the present method was However, it could be seen that the variations in the
then further demonstrated by condensation of various yields were very little and both substituted aromatic
substituted o-phenylene diamines with 1,2-disubstituted diamines such as 4-nitro and 4-methyl gave the condensed
214 M.M. Heravi et al. / Catalysis Communications 8 (2007) 211–214

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