Revisiting the Hinsberg reaction: Facile and expeditious synthesis of 3-substituted quinoxalin-2(1H)-ones under catalyst-free conditions in water

Article abstract of DOI:10.1002/hlca.200900358

Substituted benzene-1,2-diamine reacted with various α-keto esters at 50° under mild conditions for 15 min using H₂O as reaction medium, providing a variety of 3-substituted quinoxalinone derivatives in excellent yields. The reaction was instantaneous, and products were isolated by simple filtration.

Full text of DOI:10.1002/hlca.200900358

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Helvetica Chimica Acta – Vol. 93 (2010)
Revisiting the Hinsberg Reaction: Facile and Expeditious Synthesis of
3
-Substituted Quinoxalin-2(1H)-ones under Catalyst-Free Conditions in
Water
by Sabbavarapu Narayana Murthy, Bandaru Madhav, and Yadavalli Venkata Durga Nageswar*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road,
Hyderabad 500-607, India (phone: þ 914027160512; e-mail: dryvdnageswar@gmail.com)
Substituted benzene-1,2-diamine reacted with various a-keto esters at 508 under mild conditions for
1
5 min using H O as reaction medium, providing a variety of 3-substituted quinoxalinone derivatives in
2
excellent yields. The reaction was instantaneous, and products were isolated by simple filtration.
Introduction. – Heterocycles have been very important structural motifs in
medicinal chemistry. The Hinsberg reaction [1] is a practical method to obtain 3-
substituted quinoxalin-2(1H)-one derivatives. Quinoxalinones, a class of N-containing
structural compounds, attracted the attention of many scientists [2]. These quinox-
alinone derivatives are versatile scaffolds for drug-related molecules [3] (Fig.), and
they possess a wide variety of biological activities such as anti-inflammatory,
antimicrobial [4], antidiabetic [5], and antiviral against retroviruses including HIV
[
6]. Moreover, these quinoxalinones can be identified as platforms for diversity-
oriented synthesis in solid phase [7], and they are established as inhibitors of aldose
reductase [8], and agonists of g-aminobutanoic acid (GABA)/benzodiazepine receptor
complex [9].
Figure. Biologically active quinoxalinone derivatives
Fernandez and co-workers reported the kinetic study on Hinsberg reaction by
reacting unsymmetrical benzene-1,2-diamines with pyruvate (2-oxopropanoate) de-
rivatives and explained the positional isomerism [10]. To improve the regioselectivity
in the positional isomerism, Lumma et al. synthesized the related compounds in acidic
medium [11]. Recently, Ballini et al. developed a one-pot synthesis of polyfunction-
alized dihydroquinoxalinone derivatives via anti-Michael reaction [12]. Suschitzky
et al. described the reactions of benzene-1,2-diamine with different acetylenedi-
ꢀ
2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 93 (2010)
1217
carboxylates [13], and Mahaney et al. reported the synthesis of quinoxalinone core
moiety by nucleophilic aromatic substitution of o-halo nitrobenzene with chiral 2-
aminobutanoic acid, followed by reduction and cyclization [14]. Moglioni and co-
workers prepared several chemotherapeutic quinoxalinone derivatives by using S.
cerevisiae as a biocatalyst and also by means of microwave-assisted organic synthesis
[
15]. In general, most of these methods involve use of toxic/volatile organic solvents
with longer reaction times, poor yields, and tedious product-isolation procedures.
With ꢂgreen chemistryꢃ becoming an important branch of chemistry, there is surge in
environment-friendly and clean synthetic processes [16], which address the problem
faced by conventional organic synthetics. H O is a cheap, nontoxic and environment-
2
friendly solvent, which precludes environmental hazards associated with organic
solvents. In continuation of our efforts towards developing ꢂgreenꢃ synthetic protocols
[
17], we report the synthesis of 3-substituted quinoxalinones in H O under mild and
2
catalyst-free conditions.
Results and Discussion. – In our initial study towards the development of
cyclocondensation reaction, benzene-1,2-diamine (1) and ethyl pyruvate (¼ethyl 2-
oxopropanoate; 2) were warmed in H O at 508 for 15 min to furnish 3-methylquinox-
2
alin-2(1H)-one (3) in 89% yield (Scheme 1). The same reaction, when run at room
temperature, was very slow, and in some cases, at room temperature the solubility of
substituted benzene-1,2-diamine in H O was not sufficient. So, to circumvent this
2
situation, we have carried out the reaction at optimal temperature (508). The progress
of the reaction could be simply monitored by naked eye, as solid separated out of the
medium. Initially, benzene-1,2-diamine (1) was dissolved in H O at 508. At this
2
temperature, ethyl pyruvate (2) was added, and the mixture was stirred until
precipitation of the product 3 from H O. The same protocol was extended by reacting
2
different substituted benzene-1,2-diamines with various a-keto esters, and the
1
13
corresponding products were characterized by H- and C-NMR spectroscopy, and
mass spectrometry, and the results were compiled in the Table.
Scheme 1. Synthesis of 3-Substituted Quinoxalinones in H O
2
The plausible mechanism involves the intermolecular condensation of benzene-1,2-
diamine with the a-keto group of the ester to produce an intermediate ethyl 2-[(2-
aminophenyl)imino]propanoate, which undergoes intramolecular cyclization to afford
the corresponding 3-substituted quinoxalinone derivatives (Scheme 2).
Conclusions. – We have developed a facile ꢂgreenꢃ protocol for the synthesis of a
wide variety of 3-substituted quinoxalinone derivatives. This methodology is advanta-
geous over the existing methods in terms of rapid product isolation, operational
simplicity, which precludes organic solvents.

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Helvetica Chimica Acta – Vol. 93 (2010)
Table. Synthesis of 3-Substituted Quinoxalinones in H O under Mild Conditions )
a
2
Entry
1
Diamine
Pyruvate
Product
Yield [%]b)
89
2
3
4
5
6
7
80c)
85
75
81
83
82
8
9
85
84
1
1
0
1
72
68
a) Reaction conditions: benzene-1,2-diamine (1.0 mmol), pyruvate derivative (1.0 mmol), and H O
2
b
(
3 ml). ) Yields of isolated product after recrystallization. c) Yield of isolated product after column
chromatography.

Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2. Mechanistic Pathway
1219
We thank CSIR, New Delhi, India, for fellowships to S. N. M. and B. M.
Experimental Part
General. All reactions were carried out without any special precautions in an atmosphere of air.
Chemicals were purchased from Fluka and S. D. Fine Chemicals. TLC: Precoated silica-gel plates (60
1
F
254, 0.2-mm layer; E. Merck). M.p.: Fischer– Johns apparatus; uncorrected. H-NMR Spectra: Varian
2
00 or Bruker 300 spectrometer; in CDCl ; d in ppm rel. to TMS as internal standard, J in Hz. MS: VG
3
Autospec; in m/z.
General Procedure for the Synthesis of 3-Substituted Quinoxalinone Derivatives in H O. Benzene-
2
1
,2-diamine (1.0 mmol) was dissolved in H O at 508, and under stirring a-keto ester (1.0 mmol) was
2
added. After 15 min, the solid product precipitated from H O. This solid was filtered and recrystallized
2
from EtOH to obtain the corresponding quinoxalinone derivative.
Recrystallization Procedure. After the reaction, the crude product was filtered and taken in hot
EtOH (5 ml). The resulting supersaturated soln. was allowed to attain r.t. and was further cooled in
refrigerator to obtain the pure product which was filtered, dried, and analyzed by spectroscopic
1
13
techniques ( H- and C-NMR, and ESI-MS).
-Methylquinoxalin-2(1H)-one (Table, Entry 1). Light yellow solid. M.p. 249 – 2508. H-NMR
1
3
13
(
(
(
300 MHz, CDCl þ (D )DMSO): 6.72 – 6.64 (m, 1 H); 6.34 – 6.11 (m, 3 H); 1.50 (s, 3 H). C-NMR
3
6
75 MHz, CDCl þ (D )DMSO): 158.2; 154.6; 133.5; 131.0; 128.2; 126.9; 122.1; 114.5; 19.6. ESI-MS: 161
3
6
þ
[M þ H] ).
(
4aS,8aS)-4a,5,6,7,8,8a-Hexahydro-3-methylquinoxalin-2(1H)-one (Table, Entry 2). Yellow oil.
1
H-NMR (300 MHz, CDCl ): 6.69 – 6.63 (m, 1 H); 3.18 – 3.00 (m, 2 H); 2.22 (s, 3 H); 1.95 – 1.77 (m,
3
13
4
H); 1.44 – 1.25 (m, 4 H). C-NMR (75 MHz, CDCl ): 163.0; 158.9; 62.5; 54.4; 31.7; 31.0; 25.1; 23.6; 20.8.
3
þ
ESI-MS: 167 ([M þ H] ).
1
6
,7-Dichloro-3-methylquinoxalin-2(1H)-one (Table, Entry 3). H-NMR (300 MHz, CDCl ): 7.64 (s,
3
13
1
1
H); 7.20 (s, 1 H); 1.53 (s, 3 H). C-NMR (75 MHz, (D )DMSO): 164.4; 154.4; 139.5; 131.1; 129.7; 127.9;
6
þ
22.1; 19.9. ESI-MS: 246 ([M þ H] ).
1
3
-Phenylquinoxalin-2(1H)-one (Table, Entry 5). Yellow solid. M.p. 237 – 2398. H-NMR (300 MHz,
13
CDCl ): 7.60 (d, J ¼ 7.6, 1 H); 7.45 – 7.42 (m, 2 H); 7.00 – 6.96 (m, 2 H); 6.73 – 6.39 (m, 4 H). C-NMR
3
(
75 MHz, CDCl , TMS): 154.7; 154.0; 135.2; 132.0; 131.4; 129.3; 128.6; 128.3; 127.2; 123.5; 122.7; 114.7.
3
þ
ESI-MS: 223 ([M þ H] ).
1
6
,7-Dimethyl-3-phenylquinoxalin-2(1H)-one (Table, Entry 6). H-NMR (300 MHz, CDCl ): 7.64 –
3
7.60 (m, 2 H); 7.56 (s, 1 H); 7.45 – 7.37 (m, 3 H); 7.08 (s, 1 H); 3.81 (br. s, 1 H); 2.33 (s, 3 H); 2.29 (s,

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Helvetica Chimica Acta – Vol. 93 (2010)
3
H). 13C-NMR (75 MHz, CDCl ): 155.1; 144.1; 139.3; 132.5; 128.7; 128.0; 115.1; 19.3; 18.6. ESI-MS: 267
3
þ
(
(
[M þ H] ).
1
3
-(Trifluoromethyl)quinoxalin-2(1H)-one (Table, Entry 7). Yellow solid. M.p. 232 – 2358. H-NMR
300 MHz, CDCl ): 7.82 (d, J ¼ 8.3, 1 H); 7.52 – 7.57 (m, 1 H); 7.31 – 7.37 (m, 2 H); 3.74 (br. s, 1 H).
3
1
3
þ
C-NMR (75 MHz, CDCl ): 151.4; 132.9; 132.4; 129.4; 129.7; 123.4; 121.2; 115.4. ESI-MS: 215 ([M þ H] ).
3
6
,7-Dimethyl-3-(trifluoromethyl)quinoxalin-2(1H)-one (Table, Entry 8). Yellow solid. M.p. 268 –
708. H-NMR (300 MHz, CDCl ): 7.57 (s, 1 H); 7.11 (s, 1 H); 3.81 (br. s, 1 H); 2.33 (s, 3 H); 2.29 (s,
H). C-NMR (75 MHz, CDCl ): 151.3; 143.0; 132.5; 128.7; 128.0; 115.1; 19.5; 18.4. ESI-MS: 243 ([M þ
1
2
3
3
13
3
þ
H] ).
3
-(2-Hydroxy-1,1-dimethylethyl)quinoxalin-2(1H)-one (Table, Entry 9). Pale yellow solid. M.p.
1
1
3
1
76 – 1788. H-NMR (300 MHz, CDCl ): 7.70 – 7.68 (m, 1 H); 7.46 – 7.42 (m, 1 H); 7.26 – 7.21 (m, 2 H);
.82 (br. s, 1 H); 3.64 (s, 2 H); 1.31 (s, 6 H). 13C-NMR (75 MHz, (D )DMSO): 164.7; 154.1; 139.9; 131.1;
3
6
þ
29.4; 128.4; 122.7; 114.7; 67.9; 44.5; 23.0. ESI-MS: 219 ([M þ H] ).
1
6
,7-Dichloro-3-(2-hydroxy-1,1-dimethylethyl)quinoxalin-2(1H)-one (Table, Entry 10). H-NMR
13
(
(
(
300 MHz, CDCl ): 7.67 (s, 1 H); 7.29 (s, 1 H); 3.82 (br. s, 1 H); 3.64 (s, 2 H); 1.31 (s, 6 H). C-NMR
75 MHz, (D )DMSO): 164.9; 153.9; 139.5; 131.0; 129.6; 128.2; 122.9; 114.5; 67.9; 44.5; 23.2. ESI-MS: 304
3
6
þ
[M þ H] ).
1
,6-Dihydro-5-methyl-6-oxopyrazine-2,3-dicarbonitrile (Table, Entry 11). 1H-NMR (400 MHz,
13
CDCl ): 3.74 (br. s, 1 H); 2.57 (s, 3 H). C-NMR (75 MHz, CDCl ): 157.6; 155.3; 123.4; 121.0; 115.4;
09.7; 19.4. ESI-MS: 177 ([M þ H] ).
3
3
þ
1
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[
Received October 8, 2009