Facile and efficient synthesis of 3,10-DISUBSTITUTED-BIS-1,2,4-TRIAZOLO[4, 3-a][3',4'-c]- QUINOXALINES using copper dichloride as an oxidant

Article abstract of DOI:10.1080/00397911.2010.524341

Various 3,10-disubstituted-bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines (4) have been synthesized in a facile and efficient manner by copper dichloride mediated oxidative intramolecular cyclization of bis-arylidene derivatives of 2,3-dihydrazinoquinoxal

Full text of DOI:10.1080/00397911.2010.524341

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Facile and Efficient Synthesis of 3,10-
Disubstituted-bis-1,2,4-triazolo[4,3-
a][3′,4′-c]quinoxalines Using Copper
Dichloride as an Oxidant
Ranjana Aggarwal a , Garima Sumran b , Mamta Yadav a & Anju a
a Chemistry Department, Kurukshetra University, Kurukshetra,
Haryana, India
b Technology Education and Research Integrated Institutions,
Kurukshetra University, Kurukshetra, Haryana, India
Accepted author version posted online: 20 Jul 2011.Published
online: 06 Oct 2011.
To cite this article: Ranjana Aggarwal , Garima Sumran , Mamta Yadav & Anju (2012) Facile
and Efficient Synthesis of 3,10-Disubstituted-bis-1,2,4-triazolo[4,3-a][3′,4′-c]quinoxalines Using
Copper Dichloride as an Oxidant, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:3, 350-357, DOI: 10.1080/00397911.2010.524341
To link to this article: http://dx.doi.org/10.1080/00397911.2010.524341
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Synthetic Communications1, 42: 350–357, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.524341
FACILE AND EFFICIENT SYNTHESIS OF 3,10-
DISUBSTITUTED-BIS-1,2,4-TRIAZOLO[4,3-a][3’,4’-c]-
QUINOXALINES USING COPPER DICHLORIDE AS
AN OXIDANT
Ranjana Aggarwal,1 Garima Sumran,2 Mamta Yadav,1 and
Anju1
1Chemistry Department, Kurukshetra University, Kurukshetra, Haryana,
India
2Technology Education and Research Integrated Institutions, Kurukshetra
University, Kurukshetra, Haryana, India
GRAPHICAL ABSTRACT
Abstract Various 3,10-disubstituted-bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines (4) have
been synthesized in a facile and efficient manner by copper dichloride mediated oxidative
intramolecular cyclization of bis-arylidene derivatives of 2,3-dihydrazinoquinoxaline (3).
Keywords Bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines;
quinoxalines; copper dichloride; oxidative cyclization
2-3-bis-(arylidenehydrazino)
INTRODUCTION
Several 1,2,4-triazoles fused with a quinoxaline ring are known to exhibit diverse
pharmacological activities such as antitumor,[1] antimicrobial,[2,3] antidepressant,[4]
and anticonvulsant,[5] activity and can act as potent antagonists of several receptors
such as adenosine,[6] benzodiazepine,[7] highly selective glycine=N-methyl-D-aspartic
acid (NMDA), and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid
(AMPA) receptors.[8]
Recently, we have reported that 1-aryl-4-methyl-1,2,4-triazolo[4,3-
a]quinoxalines display significant antifungal activity against plant pathogens.[9] It
encouraged us to extend our work to the synthesis of bis-1,2,4-triazoloquinoxalines
Received June 16, 2010.
Address correspondence to Ranjana Aggarwal, Chemistry Department, Kurukshetra University,
Kurukshetra, Haryana, India. E-mail: ranjana67in@yahoo.com
350

COPPER DICHLORIDE AS AN OXIDANT
351
to explore their biological activities. The study is of particular interest as
1,6-diamino-bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxaline has shown moderate activity
against Gram-positive and Gram-negative microorganisms.[2]
The most frequently used methods for construction of bis-1,2,4-triazoloqui-
noxaines consist of reaction of 2,3-dichloroquinoxaline with acid hydrazides in a
1:2 molar ratio using hexamethylphosphorus triamide (HMPT) as solvent,[10]
reaction of 2,3-dichloroquinoxaline with 4 equivalents of thiosemicarbazide,[2] cycli-
zation of 1-amino-4-hydrazino-1,2,4-triazolo[4,3-a]quinoxaline by carbon disulfide
in alcoholic potassium hydroxide,[2] ring closure of 1-aryl-4-hydrazino-1,2,4-
triazolo[4,3-a]quinoxalines with certain esters or orthoesters or acid anhydrides,[3]
and 1,3-dipolar cycloaddition reaction of aryl nitrilimines to quinoxalines.[11] These
methods suffer from poor conversions, multistep synthesis, harsh reaction con-
ditions, long reaction times at higher reaction temperature, tedious workup proce-
dures, and toxic and expensive reagents.
We reported earlier that arene carbaldehyde-3-methylquinoxalin-2-yl hydra-
zones may conveniently be oxidatively cyclized to the corresponding 1-aryl-4-
methyl-1,2,4-triazolo[4,3-a]quinoxalines in excellent yields.[12] However, oxidation
of various bis-hydrazones with iodobenzene diacetate (IBD) could not be achieved
to successfully synthesize the title bis-triazoles. This prompted us to explore the use
of Cu(II) reagent as an attractive and cheap alternative. In the past two decades,
copper(II) reagents have emerged as very popular oxidizing agents, replacing the
mercury(II), thallium(II), and lead(IV) compounds, because of their similarity in
oxidation reactions, relatively less toxic nature, ready availability, easy handling,
and low cost. CuCl2 (copper dichloride) is one of the most frequently used reagents
to perform several useful synthetic transformations, recent examples of which include
oxidative heterocyclization via atmospheric oxygen using CuCl2 catalyst,[13] regiose-
lective C-allylation of enaminones,[14] (3 þ 2) cycloaddition of alkynes with azides,[15]
synthesis of heteroaryl-substituted 1,4-benzo- and 1,4-naphthoquinones,[16] and
synthesis of various 2,4-diaryl-1,2,3-triazoles via CuCl2-mediated cycloaddition of
a-hydroxyacetophenones with phenylhydrazines.[17] In the present investigation,
copper dichloride was found to be the reagent of choice for the oxidative cyclization
of bis-2,3-quinoxalinylhydrazones to bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines,
and we report herein the results.
RESULTS AND DISCUSSION
The strategy for this work is based on the presumption that hydrazone
moiety present at the a-position of nitrogen hetrocycles, on oxidation with copper
Scheme 1. General strategy for the synthesis of fused triazoloheterocycles.

352
R. AGGARWAL ET AL.
dichloride, might afford fused triazoloheterocycles by intramolecular cyclization
(Scheme 1).
Synthesis of 3,10-disubstituted-bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines (4a–e)
is depicted in Scheme 2. Condensation of 2,3-dihydrazinoquinoxaline (1) with various
aromatic=heteroaromatic aldehydes (2a–e) in refluxing ethanol afforded corresponding
2,3-bis-(arylidenehydrazino)quinoxalines (3a–e), which subsequently underwent oxi-
dative cyclization to yield corresponding bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines
4a–e in absolute dimethylformamide (DMF) under nitrogen with 4 equivalents of
copper dichloride (Scheme 2).
The structures of the products 3 and 4 were established by a careful comparison of
1
their spectral data [infrared (IR), H NMR] and elemental analyses. IR spectra of 3
showed characteristic absorption bands due to NH stretching at ꢀ3450 cmꢁ1, C¼N
1
(C¼C) stretching in the range 1600–1620cmꢁ1. As expected, the H NMR spectra of
compounds 3 exhibited a sharp singlet at d 8.7 for two aldehydic protons and a
broad singlet at d 11.1 assignable to NH as it disappeared on shaking with D2O. IR spec-
tra of 4 were found to be transparent in the region of NH stretching and NH bending,
thus confirming the oxidation of 3 into 4. An important characteristic feature in the 1H
NMR spectra of 4 was the disappearance of the signals at d 8.7 and 11.1 for aldehydic H
and for NH, respectively, which were present in the spectra of the intermediate hydra-
zone 3, thus suggesting the cyclization of bis-hydrazone 3 to bis-triazole 4 had taken
place.
The mechanism of this transformation is not certain, and a probable mechanism
is outlined in Scheme 3 on the basis of the mechanism proposed by Bluhm et al.[18]
Bis-hydrazones 3 coordinate with Cu(II) chloride in a bidentate manner (A),
which then undergoes an oxidative dehydrogenation to yield monodentate Cu(I)
complex. In this process, a C-N bond was generated between the imino-carbon atom
and nitrogen atom of the 2,3-quinoxalinyl group in 3, leading to the formation of
bis-triazole (4).
Scheme 2. Cu(II)-mediated synthesis of 3,10-disubstituted-bis-1,2,4-triazolo[4,3-a][30,40-c]quinoxalines
(4a–e).

COPPER DICHLORIDE AS AN OXIDANT
353
Scheme 3. Proposed mechanism for the synthesis of 4.
CONCLUSION
Finally, the noteworthy features of present study are the following:
i. CuCl2 offers convenient and general access to the synthesis of bis-triazoloqui-
noxalines 4, which could not be obtained by using iodobenzene diacetate as
oxidizing agent.
ii. Compared to the other literature reports, this method is remarkably easy, affords
comparable or better yields, and thus offers a valuable alternative.
iii. The reagent is nontoxic, inexpensive, and easily available.
EXPERIMENTAL
Melting points were determined in open capillaries using a melting-point
apparatus and are uncorrected. The homogeneity of the compounds was checked
by thin-layer chromatography (TLC) using silica gel G (Acme). The IR spectra were
recorded on a Buck Scientific IR M-500 spectrophotometer in KBr discs (n max in
cmꢁ1), 1H NMR spectra were measured in CDCl3 on a Bruker instrument at
400 MHz, and chemical shifts are expressed in d scale downfield from tetramethylsi-
lane (TMS) as an internal standard.
2,3-Dihydrazinoquinoxaline (1) was synthesized following the literature
procedure.[19,20] Aldehydes 2a–e were commercially available.

354
R. AGGARWAL ET AL.
Synthesis of 2,3-Bis-(benzylidenehydrazino)quinoxaline (3a–e)
2,3-Dihydrazinoquinoxaline (1) (0.4 g, 2 mmol) was dissolved in 35 ml of etha-
nol. The solution was heated for 15 min and then 4 mmol of corresponding aldehydes
(2a–e) and 0.5 ml of hydrochloric acid were added. The reaction mixture was heated
under reflux for 20 min. After cooling to room temperature, the hydrazones 3a–e
thus formed were filtered off and dried.
The physical, analytical, and spectral data of synthesized hydrazones (3a–e) are
given.
2,3-Bis-(benzylidenehydrazino)quinoxaline (3a). Mp > 250 ꢂC; yield 67.2%;
1
IR: 3436 (NH str); H NMR (400 MHz, CDCl3) d: 7.07–7.14 (m, 2H, quinox-6-H,
7-H), 7.42–7.48 (m, 6H, 2 ꢃ Ph-30,40,50-H), 7.55–7.61 (m, 2H, quinox-5-H, 8-H),
7.91–7.99 (m, 4H, 2 ꢃ Ph-20,60-H), 8.77 (s, 2H, ¼C-H), 11.29 (s, 2H, NH). Anal.
calcd. for C22H18N6: C, 72.11; H, 4.95; N, 22.94. Found: C, 72.41; H, 4.44; N, 23.12.
2,3-Bis-(4’-methoxybenzylidenehydrazino)quinoxaline (3b). Mp 176–
1
178 ꢂC; yield 70%; IR: 3445 (NH str); H NMR (400 MHz, CDCl3) d: 3.46 (s, 6H,
OCH3), 6.97–7.0 (d, 4H, Jo ¼ 8.8 Hz, 2 ꢃ Ph-30,50-H), 7.02–7.14 (m, 2H, quinox-6-H,
7-H), 7.45–7.47 (d, 1H, Jo ¼ 8.4 Hz, quinox-5-H), 7.48–7.50 (d, 1H, Jo ¼ 8.4 Hz,
quinox-8-H), 7.80–7.85 (d, 4H, Jo ¼ 8.8 Hz, 2 ꢃ Ph-20,60-H), 8.62 (s, 2H, ¼C-H),
11.1 (s, 2H, NH). Anal. calcd. for C24H22N6O2: C, 67.59; H, 5.20; N, 19.71. Found:
C, 67.21; H, 5.59; N, 19.42.
2,3-Bis-(4’-chlorobenzylidenehydrazino)quinoxaline (3c). Mp > 250 ꢂC;
1
yield 75%; IR: 3445 (NH str); H NMR (400 MHz, CDCl3) d: 7.0–7.12 (m, 2H,
quinox-6-H, 7-H), 7.40–7.55 (m, 8H, 2 ꢃ Ph-20,30,50,60-H), 7.78–7.90 (m, 2H,
quinox-5-H, 8-H), 8.81 (s, 2H, ¼CH), 11.2 (s, 2H, NH). Anal. calcd. for
C22H16Cl2N6: C, 60.70; H, 3.70; N, 19.31. Found: C, 60.99; H, 3.42; N, 19.36.
2,3-Bis-(2’-thiophenemethylidenehydrazino)quinoxaline (3d). Mp > 250 ꢂC;
1
yield 85%; IR: 3381 (NH str); H NMR (400 MHz, CDCl3) d: 6.96–6.98 (m, 2H,
2 ꢃ thiophene-30-H), 7.13–7.28 (m, 6H, quinox-6-H, 7-H, 2 ꢃ thiophene-40,50-H),
7.53–7.61 (m, 2H, quinox-5H, 8-H), 8.79 (s, 2H, ¼ CH), 11.1 (s, 2H, NH). Anal.
calcd. for C18H14N6S2: C, 57.12; H, 3.73; N, 22.20; S, 17.11. Found: C, 57.03; H,
3.57; N, 22.48.
2,3-Bis-(3’-indolemethylidenehydrazino)quinoxaline (3e). Mp > 250 ꢂC;
1
yield 80%; IR: 3460 (NH str); H NMR (400 MHz, CDCl3) d: 7.23–7.31 (m, 2H,
quinox-6-H, 7-H), 7.33–7.38 (m, 4H, 2 ꢃ Indole-50-H,70-H), 7.53–7.55 (m, 2H, 2 ꢃ
Indole-40-H), 7.73–7.75 (m, 2H, 2 ꢃ Indole-60-H), 7.77–7.83 (m, 2H, quinox-5-H,
8-H), 8.04 (s, 2H, 2 ꢃ Indole 20-H), 8.45 (s, 2H, ¼C-H), 9.08 (s, 2H, 2 ꢃ Indole-N-
H), 11.9 (s, 2H, NH). Anal. calcd. for C26H20N8: C, 70.26; H, 4.54; N, 25.21. Found:
C, 70.12; H, 4.42; N, 25.33.
Synthesis of 3,10-Diaryl/Heteroaryl-bis-1,2,4-triazolo[4,3-a][3’,4’-c]-
quinoxalines (4a–e)
2,3-Bis-(benzylidenehydrazino)quinoxaline (3) (0.5 g, 0.001 mol) was dissolved
in absolute DMF (20 ml), and a warm solution of CuCl2 (0.79 g, 0.0046 mol) in 10 ml

COPPER DICHLORIDE AS AN OXIDANT
355
absolute DMF was added. The mixture was stirred at 50 ꢂC for 20 min and then
heated at 100 ꢂC for 1 h under nitrogen. The reaction mixture was cooled to approxi-
mately 30 ꢂC and concentrated to 5 ml under vacuum. Then, a solution of 25 ml
concentrated ammonia and 8.0 g NaCl was added to remove the copper ions as a
water-soluble complex, and the mixture was stirred at 40 ꢂC for 20 min in the
presence of air. After cooling to room temperature, the precipitated solid was
filtered off and treated again with dilute ammonia solution. The solid obtained
was washed with water and recrystallized with chloroform to afford pure bis-
triazoloquinoxalines.
The physical, analytical and spectral data of synthesized bis-triazolo quinoxa-
lines (4a–e) are given.
3,10-Diphenyl-bisꢂ-1,2,4-triazolo[4,3-a][3’,4’-c]quinoxaline
(4a). Mp >
250 ꢂC (lit.[10] mp > 300 C); yield 65.3%; IR: 1601 (C C and C¼N); 1H NMR
(400 MHz, CDCl3) d: 6.89–6.92 (dt, 1H, Jo ¼ 7.6 Hz, Jm ¼ 1.6 Hz, quinox-6-H),
7.23–7.26 (m, 1H, quinox-7-H), 7.42–7.62 (m, 10H, 2 ꢃ Ph-20,30,40,50,60-H), 7.69–
7.76 (m, 2H, quinox-5-H, 8-H). Anal. calcd. for C22H14N6: C, 72.92; H, 3.89; N,
23.19. Found: C, 72.64; H, 3.44; N, 23.03.
=
3,10-Di-(4ꢂ’-methoxyphenyl)-bis-1,2,4-triazolo[4,3-a][3’,4’-c]quinoxaline
=
=
(4b). Mp > 250 C; yield 87.3%; IR: 1616 (C C and C N), 1251 (C-O of OCH3);
1H NMR (400 MHz, CDCl3) d: 3.65 (s, 6H, OCH3), 6.94–7.03 (m, 4H, 2 ꢃ Ph-30,
50-H), 7.06–7.14 (m, 2H, quinox-6-H, 7-H), 7.32–7.36 (m, 4H, 2 ꢃ Ph-20,60-H),
7.60–7.68 (m, 2H, quinox-5-H, 8-H). Anal. calcd. for C24H18N6O2: C, 68.24; H,
4.29; N, 19.89. Found: C, 68.11; H, 3.99; N, 20.12.
3,10-Di-(4’-chlorophenyl)-bis-1,2,4-triazolo[4,3-a][3’,4’-c]quinoxaline (4c).
1
ꢂ
=
=
Mp > 250 C; yield 84%; IR: 1607 (C C and C N); H NMR (400 MHz, CDCl3)
d: 7.19–7.28 (m, 2H, quinox-6-H, 7-H), 7.53–7.72 (m, 8H, 2 ꢃ Ph-20,30,50,60-H),
7.76–7.86 (m, 2H, quinox-5-H, 8-H). Anal. Calcd. for C22H12Cl2N6: C, 61.27; H,
2.80; N, 19.49. Found: C, 61.30; H, 2.72; N, 19.77.
3,10-Di-(Thiophen-2’-yl)-bis-1,2,4-triazolo[4,3-a][3’,4’-c]quinoxaline (4d).
1
ꢂ
=
=
Mp > 250 C; yield 87%; IR: 1636 (C C and C N); H NMR (400 MHz, CDCl3) d:
6.86–7.53 (m, 4H, quinox-6-H, 7-H, 2 ꢃ thiophene-30-H), 7.37–7.43 (m, 4H,
2 ꢃ thiophene-40-H, 50-H), 7.59–7.63 (m, 2H, quinox-5-H, 8-H). Anal. calcd. for
C18H10N6S2: C, 57.74; H, 2.69; N, 22.44; S, 17.13. Found: C, 57.43; H, 2.52; N,
22.09.
3,10-Di-(Indol-3’-yl)-bis-1,2,4-triazolo[4,3-a][3’,4’-c]quinoxaline (4e). Mp >
250 C; yield 81%; IR: 1604 (C C and C N); 1H NMR (400 MHz, CDCl3) d:
6.93–7.04 (m, 2H, quinox-6-H, 7-H), 7.18–7.24 (m, 4H, 2 ꢃ Indole-50,70-H),
7.48–7.50 (m, 2H, 2 ꢃ Indole-40-H), 7.55–7.62 (m, 2H, 2 ꢃ Indole-60-H), 7.67 (s,
2H, 2 ꢃ Indole-20-H), 7.80–7.86 (m, 2H, quinox-5-H, 8-H), 9.0 (s, 2H, 2 ꢃ Indole-N-H).
Anal. calcd. for C26H16N8: C, 70.90; H, 3.66; N, 25.44. Found: C, 70.81; H, 3.42;
N, 24.94.
ꢂ
=
=

356
R. AGGARWAL ET AL.
ACKNOWLEDGMENT
Thanks are due to Sophisticated Analytical Instrument Facility, Central Drug
Research Institute, Lucknow, India, for providing elemental analyses.
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