Hypervalent iodine-mediated synthesis of 1-aryl-4-methyl-1,2,4-triazolo[4, 3-a]quinoxalines by oxidative cyclization of arene carbaldehyde-3- methylquinoxalin-2-yl hydrazones

Article abstract of DOI:10.1080/00397910600602586

Arene carbaldehyde-3-methylquinoxalin-2-yl hydrazones (2) obtained by the condensation of 2-hydrazino-3-methylquinoxaline (1) with various aromatic aldehydes, on treatment with iodobenzene diacetate (IBD) in dichloromethane, undergo oxidative cyclization

Full text of DOI:10.1080/00397910600602586

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Hypervalent Iodine‐Mediated Synthesis of
1‐Aryl‐4‐methyl‐1,2,4‐triazolo[4,3‐a]quinoxalines
by Oxidative Cyclization of Arene
Carbaldehyde‐3‐methylquinoxalin‐2‐yl
Hydrazones
a
a
Ranjana Aggarwal & Garima Sumran
a
Chemistry Department , Kurukshetra University , Kurukshetra, Haryana,
India
Published online: 18 Aug 2006.
To cite this article: Ranjana Aggarwal & Garima Sumran (2006) Hypervalent Iodine‐Mediated
Synthesis of 1‐Aryl‐4‐methyl‐1,2,4‐triazolo[4,3‐a]quinoxalines by Oxidative Cyclization of Arene
Carbaldehyde‐3‐methylquinoxalin‐2‐yl Hydrazones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 36:13, 1873-1878, DOI: 10.1080/00397910600602586
To link to this article: http://dx.doi.org/10.1080/00397910600602586
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Synthetic Communications , 36: 1873–1878, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602586
Hypervalent Iodine-Mediated Synthesis
of 1-Aryl-4-methyl-1,2,4-triazolo[4,3-a]
quinoxalines by Oxidative Cyclization of
Arene Carbaldehyde-3-methylquinoxalin-
2
-yl Hydrazones
Ranjana Aggarwal and Garima Sumran
Chemistry Department, Kurukshetra University, Kurukshetra,
Haryana, India
Abstract: Arene carbaldehyde-3-methylquinoxalin-2-yl hydrazones (2) obtained by
the condensation of 2-hydrazino-3-methylquinoxaline (1) with various aromatic
aldehydes, on treatment with iodobenzene diacetate (IBD) in dichloromethane,
undergo oxidative cyclization to exclusively afford 1-aryl-4-methyl-1,2,4-
triazolo[4,3-a]quinoxalines (5) in excellent yield.
Keywords: Iodobenzene diacetate, oxidative cyclization, triazolo[4,3-a]quinoxalines
INTRODUCTION
Fused 1,2,4-triazoles present interesting biological activities such as antimi-
[
1]
[2]
[3,4]
crobial and anxiolytic activities and can also act as adenosine
and
benzodiazepine receptor antagonists. A literature survey has revealed that
,2,4-triazolo[4,3-a]quinoxalines, in particular, are among the most potent
[
5]
1
[6]
and A - or A -selective nonxanthine adenosine antagonists known and
1
2
[7]
reduce the extent of ischemia-induced injury.
Although there are several ways to obtain 1,2,4-triazolo[4,3-a]quinoxa-
[
8–11]
lines,
with acid chlorides, pyrolysis of hydrazones,
traditional methods involve the reaction of quinoxaline hydrazine
[
8]
[8,9]
and the reaction of
Received in India December 29, 2005
Address correspondence to Ranjana Aggarwal, Chemistry Department, Kuruks-
hetra University, Kurukshetra 136119, Haryana, India. E-mail: ranjana67in@yahoo.com
1
873

1
874
R. Aggarwal and G. Sumran
[8]
2-chloroquinoxaline with mono- or diacylhydrazine. In continuation of our
work to explore the utility of I(III) reagents
[12–14]
for the synthesis of various
types of heterocyclic compounds, we hereby report a new, facile, and highly
efficient synthesis of some new 1-aryl-4-methyl-1,2,4-triazolo[4,3-a]quinoxa-
lines (5) through iodobenzene diacetate (IBD)-mediated oxidative cyclization
of arene carbaldehyde-3-methylquinoxalin-2-yl hydrazones (2).
Synthesis of 1-aryl-4-methyl-1,2,4-triazolo[4,3-a]quinoxalines (5) is
depicted in Scheme 1. The key intermediate (2) was prepared by the
condensation of 2-hydrazino-3-methylquinoxaline (1) with various aromatic
aldehydes in ethanol. Subsequent oxidative intramolecular cyclization of a
variety of 2 with 1.1 equivalents of IBD in dichloromethane at room tempera-
ture provided the desired 1,2,4-triazolo[4,3-a]quinoxalines in 80–93% yields.
The characterizations of products 5a–g were based upon a careful comparison
1
of their IR and H NMR spectra with those of 2a–g. IR spectra of 5 was found
to be transparent in the region of NH stretch and NH bend, thus confirming the
1
oxidation of 2 into 5. An important characteristic feature in the H NMR spectra
of 5 was the disappearance of the signals at d 8.5 and 9.3 for aldehydic H and
for NH, respectively, which were present in the spectra of the intermediate
1
hydrazone 2. H NMR spectra of 5 further revealed the presence of the
methyl signal at d 3.0 instead of d 2.4 as shown in the NMR of 2. This
downfield shift can be attributed to the lone pair effect of the nitrogen of the
triazole ring on the methyl protons at position-3 of quinoxaline ring.
The strategy for this work is based on the presumption that hydrazone
moiety present at a-position in nitrogen heterocycle, on oxidation with
IBD, might afford fused triazoloheterocycles by intramolecular cyclization.
A plausible pathway for this IBD-mediated transformation is outlined in
Scheme 2. First of all, electrophilic attack of IBD on the lone pair of
terminal nitrogen of hydrazone gives intermediate 3, which then undergoes
Scheme 1.

1-Aryl-4-methyl-1,2,4-triazolo[4,3-a]quinoxalines
1875
Scheme 2.
reductive elimination of iodobenzene along with the expulsion of a molecule
of acetic acid to give nitrene intermediate 4. Finally, intramolecular cycliza-
tion of 4 gives the triazolo compound.
In summary, the present study provides an effective, convenient, and
environmentally benign protocol superior in terms of faster reaction rates,
increased yields, and operational simplicity as compared to the conventional
methods for synthesizing new 1,2,4-triazolo[4,3-a]quinoxalines and illustrates
the generality and versatility of I(III) as an oxidizing agent.
EXPERIMENTAL
Melting points were determined in open capillaries in an electrical apparatus
and are uncorrected. The IR spectra were recorded on a Buck Scientific
2
IR M-500 spectrophotometer in KBr discs (n max in cm ), and H and
1
1
1
3
C NMR spectra (CDCl ) on a Bruker instrument at 300 MHz and 75 MHz,
3
respectively; chemical shifts are expressed in d-scale downfield from TMS
as an internal standard. Elemental analysis were performed at RSIC,
Lucknow, India. 2-Hydrazino-3-methylquinoxaline was prepared by
[8]
reaction of 2-chloro-3-methylquinoxaline with hydrazine hydrate. Arene
carbaldehyde-3-methylquinoxalin-2-yl hydrazones (2a–g) were prepared
[
15]
according the general procedure.
Cyclization of Hydrazones (2a–g) to 1-Aryl-4-methyl-1,2,4-
triazolo[4,3-a]quinoxalines (5a–g), General Procedure
IBD (0.354 g, 1.1 mmol) was added in small portions to a stirred suspension
(or) solution of hydrazone (2) (1.0 mmol) in dichloromethane (20 ml) over a
period of 5 min at room temperature. The reaction mixture was allowed to
stir for about 2 h or until the completion of reaction as monitored by TLC.

1
876
R. Aggarwal and G. Sumran
Excess dichloromethane was distilled off in vacuo, and the residual mass
was triturated with petroleum ether to give the solid product, which was
recrystallized from aqueous ethanol.
Data
[
8]
(
5a) M.p. 200–201 8C (lit. mp 200 8C); yield 80%.
(
5b) Mp 208–210 8C; yield 93%; IR: 1659, 1611, 1514, 1467, 1416, 1369;
1
0
H NMR: 2.45 (s, 3H, 4 -CH ), 2.99 (s, 3H, CH ), 7.23–7.28 (dt, 1H,
0
3
3
J ¼ 8.1 Hz, J ¼ 1.2 Hz, quinox-6H), 7.33–7.36 (d, 2H, J ¼ 8.1 Hz, Ph-3 ,
13
0
5
2 H), 7.44–7.50 (m, 2H, quinox-7H, 5H), 7.51–7.54 (d, 2H, J ¼ 8.1 Hz,
0 0
Ph-2 , 6 -H), 7.95–7.98 (d, 1H, J ¼ 8.1 Hz, quinox-8H); C NMR: 21.21,
2
1
7
1.64, 115.87, 125.18, 125.87, 127.52, 128.07, 129.85, 129.87, 130.04,
36.55, 141.32, 144.94, 150.20, 152.88. Anal. calcd. for C H N (274): C,
1
7 14 4
4.45; H, 5.10; N, 20.43; found: C, 74.41; H, 4.98; N, 20.21.
(
1
5c) Mp 185–187 8C; yield 90%; IR: 1751, 1665, 1611, 1536, 1514, 1467,
1
418, 1370, 1297, 1253 (C-O of OCH ); H NMR: 2.98 (s, 3H, CH ), 3.87
3 3
0
0
0
(
(
s, 3H, 4 -OCH ), 7.04–7.07 (d, 2H, J ¼ 8.7 Hz, Ph-3 , 5 -H), 7.23–7.29
3
dt, 1H, J ¼ 8.4 Hz, J ¼ 1.2 Hz, quinox-6H), 7.45–7.47 (m, 1H, quinox-
0
7
6
1
1
7
H), 7.50–7.52 (m, 1H, quinox-5H), 7.54–7.57 (d, 2H, J ¼ 8.7 Hz, Ph-2 ,
0
13
-H), 7.95–7.98 (d, 1H, J ¼ 8.1 Hz, quinox-8H); C NMR: 21.69, 56.02,
15.16, 116.31, 120.60, 126.43, 128.03, 128.62, 130.57, 131.97, 137.08,
45.44, 150.56, 153.41, 162.15. Anal. calcd. for C H N O (290): C,
0.34; H, 4.82; N, 19.31; found: C, 70.12; H, 5.06; N, 18.99.
1
7 14 4
1
(
5d) Mp 218–2208C; yield 91%; IR: 1604, 1517, 1453, 1416, 1369; H NMR:
2
7
7
.98 (s, 3H, CH ), 7.27–7.33 (dt, 1H, J ¼ 8.4 Hz, J ¼ 1.2 Hz, quinox-6H), 7.44–
3
0
0
.48 (m, 2H, quinox-7H, 5H), 7.53–7.55 (d, 2H, J ¼ 8.4 Hz, Ph-3 , 5 -H), 7.59–
0
0
.62 (d, 2H, J ¼ 8.4 Hz, Ph-2 , 6 -H), 7.7–8.1 (d, 1H, J ¼ 8.4 Hz, quinox-8H);
C NMR: 21.20, 115.64, 125.60, 126.64, 127.80, 128.27, 129.58, 130.29,
31.35, 136.59, 137.44, 145.06, 148.99, 152.86. Anal. calcd. for C H ClN
1
3
1
16
11
4
(294.5): C, 65.19; H, 3.73; N, 19.01; found: C, 65.24; H, 3.78; N, 18.81.
(
5e) Mp 245–246 8C; yield 87%; IR: 1607, 1527 (NO ), 1420, 1348 (NO );
2
2
1
H NMR: 3.0 (s, 3H, CH ), 7.29–7.35 (dt, 1H, J ¼ 8.4 Hz, J ¼ 1.2 Hz,
3
quinox-6H), 7.39–7.42 (m, 1H, quinox-7H), 7.52–7.57 (m, 1H, quinox-5H),
0
0
7
.89–7.92 (d, 2H, J ¼ 8.7 Hz, Ph-2 , 6 -H), 8.01–8.04 (d, 1H, J ¼ 8.1 Hz,
0 0
13
quinox-8H), 8.41–8.44 (d, 2H, J ¼ 8.7 Hz, Ph-3 , 5 -H); C NMR: 20.14,
1
1
6
14.42, 123.21, 124.16, 127.07, 127.37, 129.51, 130.11, 133.36, 135.59,
44.20, 146.86, 148.25, 151.77. Anal. calcd. for C H N O (305): C,
1
6 11 5 2
2.95; H, 3.60; N, 22.95; found: C, 63.12; H, 3.81; N, 22.57.
(
OCH ); H NMR: 3.09 (s, 3H, CH ), 3.65 (s, 3H, 2 -OCH ), 7.09–7.12
5f ) Mp 158–160 8C; yield 82%; IR: 1664, 1606, 1518, 1469, 1255 (C-O of
1
0
3
3
3
0
(
d, 1H, J ¼ 8.7 Hz, Ph-3 -H), 7.19–7.25 (dt, 1H, J ¼ 8.4 Hz, J ¼ 0.9 Hz,

1-Aryl-4-methyl-1,2,4-triazolo[4,3-a]quinoxalines
1877
0
Ph-5 -H), 7.30–7.36 (dt, 1H, J ¼ 8.4 Hz, J ¼ 1.5 Hz, quinox-6H), 7.40–7.43
(
dd, 1H, J ¼ 8.4 Hz, J ¼ 1.5 Hz, quinox-7H), 7.52–7.58 (m, 1H, quinox-5H),
0
0
7
quinox-8H); C NMR: 21.22, 55.45, 111.17, 115.53, 117.57, 121.29,
.64–7.70 (m, 2H, Ph-4 , 6 -H), 8.03–8.06 (dd, 1H, J ¼ 8.1 Hz, J ¼ 1.5 Hz,
1
3
1
1
1
26.25, 127.30, 128.05, 129.61, 132.14, 132.89, 136.31, 145.01, 147.55,
52.86, 158.11. Anal. calcd. for C H N O (290): C, 70.34; H, 4.82; N,
1
7 14 4
9.31; found: C, 70.72; H, 5.06; N, 18.99.
(
1
7
5g) Mp 253–256 8C; yield 84%; IR: 3038, 1732, 1667, 1593, 1482, 1432,
1
0
371, 1285, 1229; H NMR: 3.07 (s, 3H, CH ), 3.98 (s, 3H, 3 -OCH ),
3 3
0
0
0
.14–7.23 (m, 3H, Ph-2 , 5 , 6 -H), 7.35–7.40 (dt, 1H, J ¼ 8.4 Hz,
J ¼ 1.2 Hz, quinox-6H), 7.55–7.60 (dt, 1H, J ¼ 7.8 Hz, J ¼ 1.2 Hz, quinox-
7
1
H), 7.63–7.67 (m, 1H, quinox-5H), 8.04–8.07 (d, 1H, J ¼ 8.4 Hz, quinox-8H);
C NMR: 19.82, 54.85, 111.07, 113.89, 114.55, 118.11, 122.19, 124.50,
26.25, 126.78, 127.21, 128.88, 135.21, 145.75, 146.81, 148.75, 151.50.
3
1
Anal. calcd. for C H N O (306): C, 66.66; H, 4.57; N, 18.30; found: C,
1
7 14 4 2
6
6.78; H, 4.62; N, 17.99.
ACKNOWLEDGMENTS
We are grateful to the University Grants Commission, New Delhi, India,
for financial support. Authors also thank Professor S. P. Singh for helpful
suggestions on this manuscript.
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