Uncatalyzed condensation between aryl-1,2-diamines and diethyl bromomalonate: a one-pot access to substituted ethyl 3-hydroxyquinoxaline-2-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2007.06.065

A one-pot method for the synthesis of substituted ethyl 3-hydroxyquinoxaline-2-carboxylates under solvent and catalyst free conditions has been developed.

Full text of DOI:10.1016/j.tetlet.2007.06.065

Tetrahedron Letters 48 (2007) 5855–5857
Uncatalyzed condensation between aryl-1,2-diamines and diethyl
bromomalonate: a one-pot access to substituted ethyl
3
-hydroxyquinoxaline-2-carboxylates
Pranab Haldar, Bishnupada Dutta, Joyram Guin and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 9 April 2007; revised 7 June 2007; accepted 13 June 2007
Available online 20 June 2007
Abstract—A one-pot method for the synthesis of substituted ethyl 3-hydroxyquinoxaline-2-carboxylates under solvent and catalyst
free conditions has been developed.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
use of organic solvents (e.g., acetic acid, ethanol, DMSO)
expensive and toxic catalysts and reagents [e.g.,
1
7a
17b,c
Substituted quinoxalines are an important class of benzo-
heterocycles, which constitute the building blocks of
some organic semiconductors and a wide range of
Pd(OAc)2, RuCl –(PPh ) –TEMPO,
MnO2,
2
3 3
1
POCl ] and tedious work-up procedures, which limit
3
2
their use. Hence, there is still a need to develop improved
methods for the synthesis of quinoxaline derivatives pay-
ing attention avoid toxic reagents and solvents, economic
viability and operational simplicity.
pharmacologically active compounds having antican-
3
3,4
5
6
cer, antimicrobial,
antibacterial and antitumour
activities. Some quinoxaline derivatives serve as DNA
photo-cleaver, antagonists of the 5-HT3 receptor,
inhibitors of HCV NS5B RNA-dependent RNA poly-
merase and MAO-A and also act as dyes. Further-
more they act as useful rigid subunits in macrocyclic
7
8a
In view of the recent trend towards the development
of clean and environment friendly green chemical
processes, investigations of solvent- and hazardous
reagent-free reactions have become important in syn-
thetic organic chemistry.
8
b
8c
9
1
0
receptors for molecular recognition and chemically
1
1
controllable switches.
,3-Disubstituted quinoxalines are usually synthesized by
2
Although there have been numerous publications on
1
2
18
condensation of aryl-1,2-diamines with epoxides or a-
dicarbonyl compounds or their equivalents. Difunc-
tional quinoxalines can also be prepared by cyclization
of a-aryliminooximes of a-dicarbonyl compounds and
both solution phase and solid phase synthesis of qui-
1
3
noxaline derivatives, to the best of our knowledge, there
is no report of the synthesis of quinoxalines under sol-
vent-free conditions without using any commercial oxi-
dants or catalysts. In continuation of our ongoing
interest in novel classes of biologically active aza-hetero-
1
4
by POCl mediated hetero-annulation of a-nitroketene
3
1
5
N,S-anilinoacetals. Very recently, while this manuscript
was being prepared, a report appeared describing an effi-
cient protocol for the synthesis of quinoxaline derivatives
at room temperature using cupric sulfate pentahydrate as
catalyst in water. However, many of these processes suf-
fer from drawbacks, such as drastic reaction conditions,
1
9
cycles, herein we describe a simple one-pot strategy to
synthesize differently substituted quinoxalines from very
simple starting materials at room temperature under sol-
vent- and catalyst-free conditions.
1
6
In a model reaction, a 1:1 mixture of ortho-phenylenedi-
amine 1a and diethyl bromomalonate was kept under
vacuum without solvent at room temperature. After
6 h the reaction was complete and furnished with ethyl
3-hydroxy-quinoxaline-2-carboxylate 2a.
Keywords: Condensation; Oxidative aromatization; Quinoxaline;
Solvent-free conditions.
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222
82252; e-mail: jkray@chem.iitkgp.ernet.in
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.065

5856
P. Haldar et al. / Tetrahedron Letters 48 (2007) 5855–5857
R1
R1
NH2
CO Et
2
1) Stir, - 10 °C
N
CO Et
2
R2
R3
N
N
CO Et
R2
+
Br
NH2
CO Et
2
2
2) 10% Pd on carbon,
p-cymene, reflux
CO Et
2
N
OH
+
Br
NH2
R3
CO Et
OH
NH2
2
R4
R4
3
2a
Scheme 2.
1
2
Scheme 1.
6–8 h. The vacuum was released (to facilitate the aerial
oxidative aromatization) and the solid mass (completion
of the reaction was monitored by TLC) was purified by
column chromatography over silica gel with hexane–
ethyl acetate (2:1) as eluent.
Subsequently, the reaction was extended to other substi-
tuted aryl-1,2-diamines 1 with a view to investigate the
generality of the reaction for the synthesis of 2,3-disub-
stituted quinoxalines 2 (Scheme 1) and the results are
depicted in Table 1. The key feature of this synthesis is
in situ oxidative aromatization without using any com-
mercial oxidants and catalyst.
2
2
.1. Spectral data of representative compounds
1
.1.1. Ethyl 3-hydroxyquinoxaline-2-carboxylate 2a.
H
NMR (CDCl , 200 MHz): d 1.44–1.51 (t, 3H, J =
3
For unsymmetrically substituted diaminobenzenes 1e–f
formation of quinoxaline isomers were observed but in
the cases of 1c and 1d, 7-substituted isomers 2c and 2d
were formed exclusively. We speculate that the regio-
selectivity depends on the different reactivity of the
two amino groups being influenced by the highly elec-
tron-withdrawing nitro and benzoyl groups.
7
2
.2 Hz), 4.49–4.61 (q, 2H, J = 7.2 Hz), 7.41–7.47 (m,
H), 7.59–7.64 (m, 1H), 7.94–7.98 (m, 1H). C NMR
13
(
50 MHz, CDCl ): d 14.07, 62.43, 116.36, 124.84,
3
1
29.97, 131.84, 132.01, 132.64, 148.27, 154.46, 163.34.
Anal. Calcd. for C H N O : C, 60.55; H, 4.62; N,
1
1
10
2
3
1
7
2.84. Found: C, 60.71, H, 4.57, N, 12.81. MS (EI,
0 eV): m/z (%) = 218 (M , 75.5), 146 (100).
+
Mixing cis 1,2-cyclohexanediamine 3 with diethyl
bromomalonate at ꢀ10 °C for 15 min, followed by treat-
ment of the reaction mixture with 10% Pd on carbon in
refluxing p-cymene, gave quinoxaline 2a in 43% yield
2.1.2. Ethyl 6,7-dichloro-3-hydroxyquinoxaline-2-carbox-
1
ylate 2b. H NMR (CDCl , 200 MHz): d 1.43–1.50 (t,
3
3H, J = 7.2 Hz), 4.49–4.59 (q, 2H, J = 7.2 Hz), 7.60 (s,
1
3
(
Scheme 2).
1H), 8.05 (s, 1H). C NMR (50 MHz, CDCl ): d
3
1
4.12, 62.94, 117.81, 129.33, 130.97, 131.07, 131.56,
All the compounds were characterized from spectro-
scopic data and the ratio of the isomers were calculated
from H NMR spectra.
137.48, 148.61, 154.14, 163.45. Anal. Calcd. for
C H Cl N O : C, 46.02; H, 2.81; N, 9.76. Found: C,
46.12, H, 2.77, N, 9.80.
1
1
8
2
2
3
1
In conclusion, we have developed a novel and sim-
ple one-pot (nucleophilic substitution, amide formation
followed by in situ oxidative aromatization) procedure
under solvent- and catalyst-free conditions for the syn-
thesis of 2,3-disubstituted quinoxalines, amongst which
compound 2a is the key synthetic intermediate for the
2
.1.3. Ethyl 7-benzoyl-3-hydroxyquinoxaline-2-carboxyl-
1
ate 2c. H NMR (CDCl , 300 MHz): d 1.44–1.49 (t,
3
3
7
2
H, J = 7.09 Hz), 4.51–4.58 (q, 2H, J = 7.11 Hz),
.49–7.57 (m, 3H), 7.61–7.63 (m, 1H), 7.79–7.82 (m,
13
H), 8.20–8.23 (m, 1H), 8.37 (s, 1H). C NMR
(50 MHz, CDCl ): d 14.07, 62.74, 116.81, 128.45,
8
a,20
3
synthesis of a 5-HT receptor antagonist.
The oper-
3
1
1
29.78, 130.72, 132.69, 132.96, 133.56, 133.96, 134.93,
36.87, 149.36, 154.27, 162.84, 194.53. Anal. Calcd. for
ational simplicity, economic viability, commercial oxi-
dant, toxic catalyst- and solvent-free conditions of this
one-pot process make our methodology a useful contri-
bution to existing processes for the synthesis of 2,3-
disubstituted quinoxalines.
C H N O : C, 67.08; H, 4.38; N, 8.69. Found: C,
6
1
8
14
2
4
7.17, H, 4.36, N, 8.65.
Acknowledgements
2
1
2
. Typical experimental procedure
Financial support from DST (New Delhi) is gratefully
acknowledged. P.H. and B.P.D. thank CSIR (New
Delhi) for their fellowships.
A mixture of aryl-1,2-diamine (10 mmol) and diethyl
bromomalonate (10 mmol) was stirred under vacuum for
Table 1.
Substrate
Product
Yield (%)
1
2
3
4
1
2
3
4
1
1
1
1
1
1
a (R = R = R = R = H)
2a (R = R = R = R = H)
78
67
64
51
47, 23
44, 22
1
4
2
3
1
4
2
3
b (R = R = H, R = R = Cl)
2b (R = R = H, R = R = Cl)
1
3
4
2
1
3
4
2
c (R = R = R = H, R = PhCO)
2c (R = R = R = H, R = PhCO)
1
3
4
2
1
3
4
2
d (R = R = R = H, R = NO
2
)
2d (R = R = R = H, R = NO
2
)
1
3
4
2
1
3
4
2
0
1
2
4
3
e (R = R = R = H, R = Me)
2e (R = R = R = H, R = Me) and 2e (R = R = R = H, R = Me)
1
2
3
4
1
2
3
4
0
1
2
3
4
f (R = Me, R = R = R = H)
2f (R = Me, R = R = R = H) and 2f (R = R = R = H, R = Me)

P. Haldar et al. / Tetrahedron Letters 48 (2007) 5855–5857
5857
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1. This reaction could also be performed in the open air, but
the yield of product was found to be nearly half that
performed under vacuum. We found that the formation of
1
9
arylaminomalonate by the condensation of various
arylamines and diethyl bromomalonates occurred only
when the reaction was performed in vacuum. In the case of
diamines, we speculate that under vacuum, the formation
of diethyl 2-(2-aminophenylamino)malonate was aided,
which was responsible for the higher yield of product than
in the open air. Obviously the oxidative aromatization
occurs with aerial oxygen on release of vacuum.
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