An efficient one-pot synthesis of 1,2,4-triazoloquinoxalines

Article abstract of DOI:10.1016/j.tet.2014.05.029

A transition metal-free tandem process for the synthesis of 1,2,4-triazoloquinoxalines was described. The construction of this tricyclic system went through a one-pot condensation/nucleophilic aromatic substitution approach. This methodology applied to a broad range of substrates, which included 2-halogenated or 2-nitro aryl aldehydes and ketones.

Full text of DOI:10.1016/j.tet.2014.05.029

Tetrahedron 70 (2014) 4657e4660
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An efficient one-pot synthesis of 1,2,4-triazoloquinoxalines
Xiaoyi Niu a, Bingchuan Yang a, Shuai Fang a, Yanqiu Li a, Zeyuan Zhang a, Jiong Jia a,
,b,
Chen Ma a
*
a Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong
University, 250100 Jinan, PR China
b State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A transition metal-free tandem process for the synthesis of 1,2,4-triazoloquinoxalines was described. The
construction of this tricyclic system went through a one-pot condensation/nucleophilic aromatic sub-
stitution approach. This methodology applied to a broad range of substrates, which included 2-
halogenated or 2-nitro aryl aldehydes and ketones.
Received 2 January 2014
Received in revised form 5 May 2014
Accepted 8 May 2014
Available online 17 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1,2,4-Triazoloquinoxaline
One-pot synthesis
Transition metal-free
Broad range of substrates
1. Introduction
1,2,4-Triazoloquinoxaline derivatives have attracted consider-
able attention due to their medicinal activities. For instance, com-
pound 1 exhibits positive anticonvulsant activity with the 50%
effective dose (ED50) of 78.9 mg/kg, which is evaluated by Maximal
Electroshock Test.1 Meanwhile, compound 2 is able to perform as
an effective adenosine receptor antagonist (Fig. 1).2 Structures with
the 1,2,4-triazoloquinoxaline scaffold are tested to display re-
markable activity against coxsackievirus B4, adenovirus type 7 and
mycobacterium tuberculosis.3,4 Besides, anti-HCV, anti-in-
flammatory and antimalarial properties are studied through ex-
tensively exploring the tricyclic heteroaromatic system.5e8
As a class of privileged substructures, 1,2,4-triazoloquinoxalines’
synthesis has attracted enormous attention. Charushin’s group
proposed a procedure of acylation of 3-amino-1,2,4-triazoles with
tetrafluorobenzoyl chloride in refluxing toluene, followed by
heating for 5 h.9 Quan and co-workers developed a three-
component and five-step protocol, while the products were ob-
tained in relatively low yield.1 Substituted 2-hydrazinobenzoic
acids and N-cyanoimidocarbonates were prepared by Al-Salahi as
the reactants, which reacted with each other in the presence of
triethylamine using an ice water cooling bath. The target
Fig. 1. Structures of some biologically important 1,2,4-triazoloquinoxalines.
compound was isolated after treatment with phosphorus oxy-
chloride in refluxing benzene for 2 h.10,11
The existing methods are not effective and economical since
multiple steps and harsh conditions were required in these sys-
tems. We have been engaged in the development of economical
syntheses of heterocyclic systems.12,13 Herein, we provide a novel
approach to prepare a series of 1,2,4-triazoloquinoxalines, which
are obtained in a reaction of 1H-1,2,4-triazol-5-amines with
substituted aryl aldehydes and ketones.
2. Results and discussion
To optimize the conditions, 1H-1,2,4-triazol-5-amine 3 and 2-
fluorobenzaldehyde 4a were selected as the model substrates
(Table 1). Several bases were screened, and Cs2CO3 was relatively
efficient with 84% yield of 5a (entry 2). K2CO3 and NaOH behaved
less successfully (entries 1 and 3), while t-BuOK gave the product in
relatively low yield (entry 4). Solvent was investigated and DMF
was found to be more effective than DMSO (entries 4 and 5).
* Corresponding author. Tel.: þ86 531 8836 4464; fax: þ86 531 8856 4464;
e-mail address: chenma@sdu.edu.cn (C. Ma).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.029

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X. Niu et al. / Tetrahedron 70 (2014) 4657e4660
Table 2 (continued)
Table 1
Optimization of reaction conditionsa
Entry
Substrate 4
Product 5
Yield (%)b
5
51
Entry
Base
Solvent
T (ꢀC)
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
NaOH
DMF
DMF
DMF
100
100
100
100
100
100
Reflux
Reflux
50
135
100
100
100
2
2
2
2
2
2
2
2
2
2
1
3
2
75
84
62
34
67
52
Trace
n.d
54
6
7
42c
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMSO
NMP
CH3CN
Toluene
DMF
DMF
DMF
DMF
DMF
9
62
10
11
12
13
80
58
77
74b
The bold values are represents the optimized reaction conidition after the screening.
a
Reaction conditions: 1H-1,2,4-triazol-5-amine
3 (1.0 equiv), 2-fluorobenzal
ꢀ
dehyde 4a (1.2 equiv), base (3.0 equiv), molecular sieves 4 A (0.4 g).
8
9
37
b
Reaction conditions: 1H-1,2,4-triazol-5-amine 3 (1.0 equiv), 2-fluorobenzal
dehyde 4a (1.2 equiv), base (3.0 equiv).
c
Isolated yield.
Moderate yield was achieved in NMP (entry 6), and trace amount of
product was detectedꢀin CH3CN (entry 7). Moreover, the yield de-
Trace
ꢀ
creased to 54% at 50 C (entry 10). Without 4 A molecular sieves,
only 74% of the product was obtained (entry 13). Finally we found
the reactionꢀwas most efficient when conducted with Cs2CO3 in
ꢀ
DMF at 100 C in the presence of 4 A molecular sieves.
With the optimized condition in hand, the scope of this meth-
odology was examined. As shown in Table 2, not only 2-
fluorobenzaldehyde but also 2-chloro, 2-bromo and even 2-
nitro14 substituent worked well (entries 1e4). To accomplish the
10
11
80
77
Table 2
Synthesis of 1,2,4-triazoloquinoxaline 5a
12
13
72
Entry
1
Substrate 4
Product 5
Yield (%)b
84
53c
2
3
4
65c
72c
78
14
58
60
15
a
Reaction conditions: 1H-1,2,4-triazol-5-amine
3 (1.0 equiv), compound 4
(1.2 equiv), Cs2CO3 (3.0 equiv), molecular sieves 4 A (0.4 g), 100 ꢀC, 2 h.
ꢀ
b
Isolated yield.
c
Reaction conditions: NaOH (3.0 equiv), molecular sieves 4 A (0.4 g), 100 ꢀC, 2 h.
ꢀ

X. Niu et al. / Tetrahedron 70 (2014) 4657e4660
4659
aryl CeN coupling, metal catalyst and ligand are generally in-
dispensable when bromine acts as the leaving group.15 However, it
could be realized in this metal-free system with moderate yield
(entries 3 and 13). Compared with aldehyde, ketone is known to be
less active in the synthesis of Schiff base.16,17 Interestingly, varied
aryl ketone performed as well as substituted 2-halobenzaldehyde
in our work (entries 12e15). Substituted 2-fluorobenzaldehydes
with electron-donating groups reacted better than those with
withdrawing group (entries 5e11).
added under the optimized conditions. Compound 1 was isolated
by column chromatography.
3. Conclusion
A variety of 1,2,4-triazoloquinoxaline derivatives were synthe-
sized by condensation and nucleophilic aromatic substitution in
a one-pot transition metal-free tandem process. Not only aldehydes
but also ketones worked well to afford the tricyclic products. Fur-
ther studies on the application of this procedure to the synthesis of
pharmaceutical compounds are in progress.
The possible mechanism was proposed in Scheme 1. Conden-
sation of compound 3 and 4 provided the intermediate 6. Sub-
sequently, the Schiff base
6 underwent an intramolecular
nucleophilic aromatic substitution (SNAr), affording 1,2,4-
triazoloquinoxalines 5. To probe the above proposed mechanism,
we reacted 1H-1,2,4-triazol-5-amine 3 with 2-fluorobenzaldehyde
4a employing Cs2CO3 as base in DMF at room temperature
(Scheme 2). The Schiff base 6a was detected under the milder
conditions after 0.5 h by high resolution mass spectrum (HRMS),
which suggested that the first step was the formation of Schiff
base 6.
4. Experimental section
4.1. General
Reagents were commercially available and were used without
further purification. All reactions were monitored by thin-layer
chromatography (TLC). 1H NMR spectra were recorded on
a Bruker Avance 400 or 300 spectrometer at 400 or 300 MHz, using
CDCl3 or DMSO-d6 as solvent and tetramethylsilane (TMS) as in-
ternal standard. 13C NMR spectra were run in the same instrument
at 100 or 75 MHz. Melting points were determined on an XD-4
digital micro melting point apparatus. HRMS spectra were de-
termined on a Q-TOF6510 spectrograph (Agilent).
4.2. General procedure for the synthesis of compounds 5a
A
mixture of 1H-1,2,4-triazol-5-amine 3 (1.0 mmol), 2-
fluorobenzaldehyde 4a (1.2 mmol) and Cs2CO3 (3.0 mmol) in DMF
(10 mL) was heated to 100 ꢀC, and TLC monitored the reaction. Then
the mixture was cooled to room temperature and diluted with
brine (60 mL) and extracted with dichloromethane twice
(2ꢁ30 mL). The combined organic layers were dried with MgSO4
and the solvent was removed in vacuo to afford a residue. The
residue was purified by column chromatography (silica gel, hexane/
EtOAc¼1:5) to afford 5a.
Scheme 1. Proposed mechanism for formation of 5.
4.2.1. [1,2,4]Triazolo[1,5-a]quinazoline (5a). White solid. Mp
172.1e173.5 ꢀC. 1H NMR (300 M, DMSO-d6):
d 9.53 (1H, s), 8.69 (1H,
s), 8.42e8.38 (2H, m), 8.19e8.13 (1H, m), 7.81 (1H, t, J¼7.5 Hz); 13
C
NMR (75 M, DMSO-d6):
d 158.99, 154.36, 153.17, 136.12, 135.64,
130.16, 127.18, 119.36, 115.02; HRMS calcd for C9H6N4 (MþH)þ
Scheme 2. Reaction of 1H-1,2,4-triazol-5-amine 3 and 2-fluorobenzaldehyde 4a.
171.0626; found: 171.0682.
4.2.2. 7-Bromo-[1,2,4]triazolo[1,5-a]quinazoline (5b). Pale yellow
solid. Mp 236.9e237.7 ꢀC. 1H NMR (300 M, DMSO-d6):
d 9.47 (1H, s),
To demonstrate the application of this method, compound 1
shown in Fig. 1 was synthesized in one pot (Scheme 3). Phenyl-
methanol 7 and 2,6-difluorobenzaldehyde 4p were stirred with
Cs2CO3 in DMF at 80 ꢀC for 2 h. Then 1H-1,2,4-triazol-5-amine 3 was
8.71 (1H, s), 8.67 (1H, d, J¼1.8 Hz), 8.35e8.36 (2H, m); 13C NMR
(75 M, DMSO-d6):
d 157.48, 154.09, 152.63, 138.11, 134.23, 131.77,
120.32, 118.66,116.97; HRMS calcd for C9H5BrN4 (MþH)þ 248.9677;
found: 248.9788.
4.2.3. 7-Fluoro-[1,2,4]triazolo[1,5-a]quinazoline (5c). Pale yellow
solid. Mp 199.9e201.5 ꢀC. 1H NMR (300 M, DMSO-d6):
d
9.48 (1H, s),
8.69 (1H, s), 8.46 (1H, dd, J¼9.0, 4.5 Hz), 8.26 (1H, dd, J¼8.7, 3 Hz),
8.09e8.02 (1H, m); 13C NMR (75 M, DMSO-d6):
159.24 (1C, d,
d
J¼243.8 Hz), 157.63 (1C, d, J¼3.0 Hz), 153.87, 152.47, 132.26, 124.30
(1C, d, J¼25.5 Hz), 119.94 (1C, d, J¼9.0 Hz), 117.46 (1C, d, J¼9 Hz),
114.17 (1C, d, J¼23.3 Hz); HRMS calcd for C10H5FN4 (MþH)þ
189.0532; found: 189.0573.
4.2.4. 7-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]quinazoline
(5d). White solid. Mp 193.4e193.9 ꢀC. 1H NMR (300 M, DMSO-d6):
d
9.63 (1H, s), 8.91 (1H, s), 8.77 (1H, s), 8.56 (1H, d, J¼9.0 Hz), 8.43
(1H, dd, J¼9.0, 1.2 Hz); 13C NMR (100 M, DMSO-d6):
d 159.12, 155.01,
Scheme 3. Synthesis of compound 1 in one pot.
153.75, 137.57, 131.78 (1C, d, J¼4.0 Hz), 128.25 (1C, q, J¼4.0 Hz),

4660
X. Niu et al. / Tetrahedron 70 (2014) 4657e4660
127.16 (1C, q, J¼33 Hz), 124.10 (1C, d, J¼271 Hz), 119.02, 116.73;
HRMS calcd for C10H5F3N4 (MþH)þ 239.0500; found: 239.0518.
8.67 (1H, s), 8.07 (1H, d, J¼1.2 Hz), 7.92 (1H, d, J¼1.2 Hz), 7.61 (2H, d,
J¼1.2 Hz); 13C NMR (100 M, DMSO-d6):
d 156.97, 154.58, 153.32,
137.67, 136.64, 136.48, 129.10, 128.67, 128.19, 110.55, 109.02, 106.98,
4.2.5. 7-Nitro-[1,2,4]triazolo[1,5-a]quinazoline (5e). Pale yellow
solid. HRMS calcd for C9H5N5O2 (MþH)þ 216.0516; found:
216.0500.
70.94; HRMS calcd for
277.1062.
C
16H12ON4 (MþH)þ 277.1045; found:
Acknowledgements
4.2.6. 8-Methoxy-[1,2,4]triazolo[1,5-a]quinazoline (5f). White solid.
Mp 193.6e194.3 ꢀC. 1H NMR (300 M, DMSO-d6):
d 9.35 (1H, s), 8.65
We are grateful to the National Science Foundation of China (No.
21172131) and State Key Laboratory of Bioactive Substance and
Function of Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences and Peking Union Medical College
(No. GTZK201405) for financial support of this research.
(1H, s), 8.27 (1H, d, J¼9.0 Hz), 7.72 (1H, d, J¼2.4 Hz), 7.36 (1H, dd,
J¼9.0, 2.7 Hz); 13C NMR (75 M, DMSO-d6):
d 164.83, 157.09, 153.87,
153.00, 137.30, 131.52, 116.94, 113.41, 95.98, 56.44; HRMS calcd for
C
10H8N4O (MþH)þ 201.0771; found: 201.0751.
4.2.7. 7-Methoxy-[1,2,4]triazolo[1,5-a]quinazoline (5g). White solid.
Mp 186.7e187.9 ꢀC. 1H NMR (300 M, DMSO-d6):
9.43 (1H, s), 8.63
d
Supplementary data
(1H, s), 8.32 (1H, d, J¼9.0 Hz), 7.87 (1H, d, J¼2.7 Hz), 7.75 (1H, dd,
J¼9.0, 2.7 Hz); 13C NMR (75 M, DMSO-d6):
d 157.46, 157.24, 153.49,
152.01, 130.10, 125.60, 120.06, 116.20, 109.41, 55.92; HRMS calcd for
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.05.029.
C
10H8N4O (MþH)þ 201.0771; found: 201.0765.
4.2.8. 5-Methyl-[1,2,4]triazolo[1,5-a]quinazoline (5h). White solid.
Mp 167.5e168.6 ꢀC. 1H NMR (300 M, DMSO-d6):
8.58 (1H, s),
8.42e8.37 (2H, m), 8.14e8.09 (1H, m), 7.80e7.75 (1H, m), 2.99 (3H,
s); 13C NMR (75 M, DMSO-d6):
165.94, 153.62, 151.86, 135.15,
References and notes
d
1. Zhang, C. B.; Yang, C. W.; Deng, X. Q.; Quan, Z. S. Med. Chem. Res. 2011, 21, 3294.
2. Al-Salahi, R.; Geffken, D.; Koellner, M. Chem. Pharm. Bull. 2011, 59, 730.
3. Al-Salahi, R.; Al-Omar, M. A.; Alswaidan, I.; Marzouk, M.; El-Senousy, W. M.;
Amr, A. E.-G. E. Res. Chem. Intermed. 2013, 1e11.
4. Ekins, S.; Freundlich, J. S.; Hobrath, J. V.; Lucile White, E.; Reynolds, R. C. Pharm.
Res. 2014, 31, 414.
d
134.67,128.12,126.43,118.21,114.83, 22.73; HRMS calcd for C10H8N4
(MþH)þ 185.0822; found: 185.0828.
5. Al-Salahi, R. A.; Gamal-Eldeen, A. M.; Alanazi, A. M.; Al-Omar, M. A.; Marzouk,
M. A.; Fouda, M. M. Molecules 2013, 18, 1434.
6. Farghaly, T. A.; Abdel Hafez, N. A.; Ragab, E. A.; Awad, H. M.; Abdalla, M. M. Eur.
J. Med. Chem. 2010, 45, 492.
7. Ashour, H. M.; Shaaban, O. G.; Rizk, O. H.; El-Ashmawy, I. M. Eur. J. Med. Chem.
2013, 62, 341.
8. Marwaha, A.; White, J.; El_Mazouni, F.; Creason, S. A.; Kokkonda, S.; Buckner, F.
S.; Charman, S. A.; Phillips, M. A.; Rathod, P. K. J. Med. Chem. 2012, 55, 7425.
9. Lipunova, G. N.; Nosova, E. V.; Laeva, A. A.; Kodess, M. I.; Charushin, V. N. Russ. J.
Org. Chem. 2005, 41, 1071.
4.2.9. 5-Ethyl-[1,2,4]triazolo[1,5-a]quinazoline (5i). White solid. Mp
190.8e192.0 ꢀC. 1H NMR (300 M, DMSO-d6):
d 8.60 (1H, s),
8.46e8.38 (2H, m), 8.13e8.08 (1H, m), 7.80e7.74 (1H, m), 3.40 (2H,
q, J¼7.5 Hz), 1.41 (3H, t, J¼7.5 Hz); 13C NMR (75 M, DMSO-d6):
d
169.38, 153.66, 151.96, 135.00, 134.76, 127.44, 126.47, 117.60,
114.99, 27.71, 11.55; HRMS calcd for C11H10N4 (MþH)þ 199.0978;
found: 199.1018.
10. Al-Salahi, R. A. Molecules 2010, 15, 7016.
11. Al-Salahi, R. A.; Geffken, D. Synth. Commun. 2011, 41, 3512.
12. (a) Zhao, Y.; Wu, Y.; Jia, J.; Zhang, D.; Ma, C. J. Org. Chem. 2012, 77, 8501; (b)
Yang, B.; Niu, X.; Huang, Z.; Zhao, C.; Liu, Y.; Ma, C. Tetrahedron 2013, 69, 8250;
(c) Yang, B.; Huang, Z.; Guan, H.; Niu, X.; Li, Y.; Fang, S.; Ma, C. Tetrahedron Lett.
2013, 54, 5994.
13. (a) Huang, A.; Chen, Y.; Zhou, Y.; Guo, W.; Wu, X.; Ma, C. Org. Lett. 2013, 15,
5480; (b) Huang, A.; Feng, L.; Qiao, Z.; Yu, W.; Zheng, Q.; Ma, C. Tetrahedron
2013, 69, 642.
4.2.10. 5-Phenyl-[1,2,4]triazolo[1,5-a]quinazoline (5j). White solid.
Mp 182.2e183.8 ꢀC. 1H NMR (300 M, DMSO-d6):
d 8.70 (1H, s), 8.49
(1H, d, J¼8.4 Hz), 8.18e8.13 (1H, m), 8.09 (1H, d, J¼8.4 Hz),
7.82e7.79 (2H, m), 7.77e7.72 (1H, m), 7.69e7.64 (3H, m); 13C NMR
(75 M, DMSO-d6):
d 165.94, 154.70, 152.37, 137.12, 136.23, 135.78,
130.65, 130.22, 129.90, 129.05, 127.11, 117.87, 115.63; HRMS calcd for
C
15H10N4 (MþH)þ 247.0978; found: 247.1025.
14. (a) Zhang, X.; Jia, J.; Ma, C. Org. Biomol. Chem. 2012, 10, 7944; (b) Li, Y.; Zhan, C.;
Yang, B.; Cao, X.; Ma, C. Synthesis 2012, 45, 111.
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Yu, M.; Tu, H.; Zou, J.; Zhang, Y. Chem. Commun. 2013, 701; (c) Zhou, F.; Guo, J.;
Liu, J.; Ding, K.; Yu, S.; Cai, Q. J. Am. Chem. Soc. 2012, 134, 14326.
4.2.11. N-(2-Fluorobenzylidene)-1H-1,2,4-triazol-5-amine
(6a). HRMS calcd for C9H7N5F (MþH)þ 191.0728; found: 191.0748.
ꢁ
ꢁ
16. Barluenga, J.; Jimenez-Aquino, A. N.; Aznar, F.; Valdes, C. J. Am. Chem. Soc. 2009,
131, 4031.
4.2.12. 6-(Benzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(1). White
ꢂ ꢁ
17. Mrsic, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am. Chem. Soc. 2009, 131,
solid. Mp 175.8e176.3 ꢀC. 1H NMR (400 M, DMSO-d6):
d
9.59 (1H, s),
83.