A catalyst free, one pot approach for the synthesis of quinoxaline derivatives via oxidative cyclisation of 1,2-diamines and phenacyl bromides

Article abstract of DOI:10.1016/j.tetlet.2015.01.138

A simple, efficient and eco-friendly method has been developed for quinoxaline synthesis from inexpensive and readily available diamines and phenacyl bromides by catalyst- and additive-free protocol.

Full text of DOI:10.1016/j.tetlet.2015.01.138

Accepted Manuscript
A catalyst free, one pot approach for the synthesis of quinoxaline derivatives
via oxidative cyclisation of 1,2-diamines and phenacyl bromides
Kapil Kumar, Sagar Ravso Mudshinge, Sandeep Goyal, Mukesh Gangar, Vipin
A. Nair
PII:
S0040-4039(15)00176-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.138
TETL 45808
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 December 2014
19 January 2015
20 January 2015
Please cite this article as: Kumar, K., Mudshinge, S.R., Goyal, S., Gangar, M., Nair, V.A., A catalyst free, one pot
approach for the synthesis of quinoxaline derivatives via oxidative cyclisation of 1,2-diamines and phenacyl
bromides, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.138
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
A catalyst free, one pot approach for the
synthesis of quinoxaline derivatives via
oxidative cyclisation of 1,2-diamines and
phenacyl bromides
Leave this area blank for abstract info.
Kapil Kumar, Sagar Ravso Mudshinge, Sandeep Goyal, Mukesh Gangar and Vipin A. Nair*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A catalyst free, one pot approach for the synthesis of quinoxaline derivatives via
oxidative cyclisation of 1,2-diamines and phenacyl bromides
Kapil Kumar, Sagar Ravso Mudshinge, Sandeep Goyal, Mukesh Gangar and Vipin A. Nair∗
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160062, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple, efficient and eco-friendly method has been developed for quinoxaline synthesis
from inexpensive and readily available diamines and phenacyl bromides by catalyst- and
additive-free protocol.
Received in revised form
Accepted
© 2014 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Quinoxaline
Phenacyl bromide
o-Phenylenediamine
Regioselectivity
Water
Quinoxaline is a ubiquitous nitrogen containing fused heterocyclic
motif which paved the attention of organic and medicinal chemists
due to its biological properties and pharmaceutical importance.1
Quinoxaline containing compounds have found use as potential
anticancer,2 antiviral,3 antibiotic,4 and anti-inflammatory agents. A
few quinoxaline containing pharmacologically active molecules are
shown in figure 1. For instance, quinacillin is highly effective in
penicillin sensitive or penicillinase producing strains of
staphylococcus aureus. Brimonidine is used to treat open angle
glaucoma or ocular hypertension through the mechanism of reducing
the synthesis of aqueous humor. Varenicline is prescribed as a
medicine to treat nicotine addiction. This scaffold was also
recognised in bioacids,5 organic synthons,6 electroluminescent
scaffold through a cyclisation-oxidation process.19 In addition to
these, stoichiometric amounts of TMSCl promoted quinoxaline
synthesis was achieved, in water.22 Furthermore, copper catalysed
quinoxaline synthesis was also explored using o-phenylenediamines
and costly terminal alkynes in presence of toxic and excess amounts
of DMAP as a base27a. Ga(ClO4)3 catalysed cycloaddition reaction
was also developed for quinoxaline synthesis.23 Later on the utility of
surfactants as microreactors was explored for quinoxaline synthesis
in water using 1,2-diketones by a simple condensation approach.27b
Subsequently quinoxaline synthesis from 1,2-diketones was done
using manganese ferrite (MnFe2O4) nanoparticles.27c Recently Lewis
acid catalysed asymmetric version of fused pyrroloquinoxaline was
achieved27d. Cerium-oxide nanoparticles have also shown their utility
in quinoxaline synthesis.27e In majority of these methods, toxic
materials,7
dyes,8
organic
semiconductors,9
cavitands,10
dehydroannulenes11 and ligands in coordination chemistry12.
wastes are formed with a clear and imminent danger of
environmental pollution. Eco-friendly reactions have always
attracted organic chemists in which the reactions are carried out in
greener solvents. Thus the development of an efficient and
environmentally benign methodology for the synthesis of
quinoxaline derivatives remains highly desired.
Quinoxaline can be synthesized by (a) condensation of 1,2-
diamines with 1,2-dicarbonyl compounds13 (b) oxidative cyclisation
of α-haloketones and 1,2 diamines14 (c) from α-hydroxy ketones15
(d) from epoxides16 and (e) from diols.17 Reported methodologies for
this scaffold include various catalysts/oxidants such as Bi(0),18
23
HClO4/SiO2,19 CeCl3.7H2O,20 DABCO,21 TMSCl,22 Ga(ClO4)3 and
transition metals24 like Mn, Ru, Pd and Cu. Solid phase synthesis25
and microwave assisted26 synthesis for quinoxaline derivatives are
also reported. Numerous methodologies are available for quinoxaline
synthesis which require either expensive catalysts or hazardous
additives. One such method involves manganese(IV) dioxide
catalysed quinoxaline synthesis using unsubstituted diamines and α-
hydroxy ketone precursors with moderate yields and limited
substrate scope via tandem oxidative reaction. On the other hand,
hazardous perchloric acid was used to synthesize this privileged
———
∗ Corresponding author. Tel.: +91-172-229-2045; fax: +91-172-221-4692; e-mail: vn74nr@yahoo.com; vnair@niper.ac.in
Figure 1: Biologically active scaffolds based on quinoxaline

Table 1: Effect of temperaturea
pot oxidative cyclization reaction in water. A typical experiment was
performed by choosing o-phenylenediamine 1a and phenacyl
bromide 2a as model substrates to synthesize 2-phenylquinoxaline
3a (Scheme 1). With the advantages of using a greener solvent in
mind, water was employed as the medium for the reaction. However
at ambient temperature the reaction was found to be sluggish. To
accelerate the reaction, dependence on temperature was examined at
intervals of 20oC over a range from 0 to 100oC. As the temperature
increased the yield of the product also increased affording a
maximum yield of 85% at 80oC. More noticeably the time of the
reaction was reduced to 2.5h and the results obtained are summarised
in Table 1.
Entry
Temperature (oC)
Time (h)
Yieldb (%)
1
2
0
20
40
40
40
40
40
60
80
80
100
5
5
20
50
3
1
trace
20
50
4
2
5
3
6
4
60
65
7
5
8
5
77
85
9
2.5
5
10
11
87
80
2.5
aReaction condition: o-phenylenediamine (1.2 mmol), phenacyl bromide (1.0
mmol), water (3.0 mL). bIsolated yield.
Table 2: Reactions of symmetrical diamines with phenacyl bromidesa
Entry
Diamine
Phenacyl
bromide
Product
Time Yieldb
(h) (%)
1
2.5
3.0
85
83
Scheme 1: One pot synthesis of quinoxaline through oxidative condensation
2a
2b
3a
3b
1a
To generalise the scope of the reaction, experiments were performed
with various symmetrical diamines and substituted phenacyl
bromides containing electron withdrawing as well as electron
donating groups. The results are provided in Table 2. The reaction
proceeded smoothly in all the cases illustrating that the presence of
withdrawing/donating substituents on the aromatic ring of phenacyl
bromide was well tolerated. The reaction was further examined by
employing unsymmetrical diamines which would afford the
regioisomeric products. With electron withdrawing substituents on
the phenylene diamines, two regioisomeric products with
substituents at positions 6 and 7 were obtained in a ratio of 2:1
respectively. The isomers were separable by column chromatography
using a mixture of EtOAc/Hexane. However with electron donating
groups, an inseparable mixture of the regioisomers were obtained
(Table 3). Based on these observations, we envisaged a plausible
reaction mechanism for the formation of quinoxaline derivatives
from o-phenylenediamine and phenacyl bromide (Figure 2). Initially
a nucleophilic substitution occurs on the phenacyl bromide to afford
the intermediate 3. Intermediate 3 spontaneously cyclises to form 3-
phenyl-1,2-dihydroquinoxaline 4, which undergoes aromatization
under air oxidation to afford 2-phenylquinoxaline 5 as the final
product.
2
1a
3
4
5
3.0
2.5
2.5
81
78
2c
3c
1a
1a
2d
3d
76
2e
2a
1a
1b
3e
6
2.5
77
3f
7
8
9
3.0
3.0
2.5
78
79
75
1b
1b
1b
3g
3h
2b
2c
2d
2e
3i
3j
10
2.5
73
1b
Figure 2: Plausible reaction mechanism
aReaction condition: o-phenylenediamine (1.2 mmol), phenacyl bromide (1.0
mmol), water (3.0 mL), bIsolated yield.
In conclusion, we present here
a catalyst or additive free
methodology for quinoxaline synthesis from substituted o-
phenylenediamines and α-bromoketones. The overall procedure
involves substitution, cyclisation and aromatisation reactions in a
one-pot process under environmentally benign conditions.
In continuation of our work on heterocyclic chemistry,28 we were
keen to develop a catalyst free and greener approach for the synthesis
of quinoxalines from 1,2-diamines and phenacyl bromides via a one-

3
Table 3: Reactions of unsymmetrical diamines with phenacyl bromidesa
Entry
Diamine
Phenacyl bromide
Products
Time (h)
2.5
Yieldb(%)
Ratio of isomers
78b (2:1)c
1
2a
1c
1c
2
3
3.0
3.0
78b (2:1)c
81b(2:1)c
2b
2c
1c
4
5
2.5
2.5
75b (2:1)c
1c
1c
2d
2e
75b(2:1)c
CH3
Cl
CH3
N
N
N
N
and
Cl
3o'
3o
6
7
8
2.5
2.5
3.0
78 b (2:1)c
78 b (2:1)c
75 b (2:1)c
1d
1d
1d
2a
2b
2c
9
2.5
3.0
75 b (2:1)c
1d
1d
1e
2d
2e
10
72 b (2:1)c
11
12
13
2.0
2.5
2.5
78b (10:7)c,d
77b (10:7)c,d
76 b (10:7)c,d
2a
2b
1e
1e
2c
14
15
2.0
2.0
79b (10:7) c,d
1e
1e
2d
78b (10:7) c,d
2e
aReaction condition: Substituted o-phenylenediamine (1.2 mmol), phenacyl bromide (1.0 mmol), water (3.0 mL),bOverall isolated yield,cRatio of regioisomers
d
were determined by 1H NMR from the reaction mixture, Mixture of regioisomers.

Acknowledgments
Research funding from the Department of Science and Technology
(DST), Government of India is gratefully acknowledged.
20. Narsaiah, A. V.; Kumar, J. K. Synth. Commun. 2012, 42, 883.
21. Meshram, H. M.; Kumar, S. G.; Ramesh, P.; Reddy, B. C.
Tetrahedron Lett. 2010, 51, 2580.
Supplementary Material
22. Wan, J. P.; Gan, S. F.; Wu, J. M.; Pan, Y. J. Green Chem. 2009, 11,
1633.
Supplementary material which includes experimental procedures,
compound data and scanned spectra (1H NMR, 13C NMR and
HRMS) can be found in the online version.
23. Pan, F.; Chen, T.; Cao, J.; Zou, J.; Zhang, W. Tetrahedron Lett.
2012, 53, 2508.
24. (a) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Chem. Commun.
2003, 2286; (b) Kim, S. Y.; Park, K. H.; Chung, Y. K. Chem.
Commun. 2005, 1321; (c) Robinson, R. S.; Taylor, R. J. K. Synlett
2005, 1003; (d) Marques, C. S.; Moura, N.; Burke, A. J.
Tetrahedron Lett. 2006, 47, 6049; (e) Cho, C. S.; Oh, S. G. J. Mol.
References
1. (a) Saifina, D. F.; Mamedov, V. A. Russ. Chem. Rev. 2010, 79, 351;
(b) Gobec, S.; Urleb, U. In Science of Synthesis; 2004; Vol. 16, p
845–911 (c) Patidar, A. K.; Jeyakanda, M.; Mobiya, A. K.; Selvam,
G. Int. J. PharmTech. Res. 2011, 3, 386; (d) Seitz, L. E.; Suling, W.
J.; Reynolds, R. C. J. Med. Chem. 2002, 45, 5604; (e) Weissberger,
A., Taylor, E. C., Eds.; The Chemistry of Heterocyclic Compounds,
Wiley-Interscience: New York, 1979.
Catal. A: Chem. 2007, 276, 205; (f) Akkilagunta, V. K.; Reddy, V.
P.; Kakulapati, R. R. Synlett 2010, 2571.
25. Liu, J.; Liu, J.; Wang, J.; Jiao, D.; Liu, H. Synth. Commun. 2010,
40, 2047.
26. Zhou, J.; Gong, G.; Zhi, S.; Duan, X. Synth. Commun. 2009, 39,
3743.
2. (a) Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. J. Med. Chem.
2005, 48, 2019; (b) Lindsley, C. W.; Zhao, Z.; Leister, W. H.;
Robinson, R. G.; Barnett, S. F.; Defeozones, D.; Jones, R. E.;
Hartman, G. D.; Huff, J. R.; Huber, H. E.; Duggan, M. E. Bioorg.
Med. Chem. Lett. 2005, 15, 761.
27. (a) Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen, Y.; Chen, B.
Org. Lett. 2011, 13, 4514; (b) Kumar, D.; Seth, K.; Kommi, D. N.;
Bhagat, S. Chakraborti, A. K. RSC Adv. 2013, 3, 15157; (c)
Brahmachari, G.; Laskar S.; Barik, P. RSC Adv. 2013, 3, 14245; (d)
Li, Y.; Su, Y-H.; Dong, D-J.; Wu, Z.; Tian, S-K. RSC Adv. 2013, 3,
18275; (e) Edayadulla, N.; Lee, Y. R. RSC Adv. 2014, 4, 11459.
28. (a) Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966; (b)
Khatik, G. L.; Pal, A.; Mobin, S. M.; Nair, V. A. Tetrahedron Lett.
2010, 51, 3654; (c) Khatik, G. L.; Kaur, J.; Kumar, V.; Tikoo, K.;
Venugopalan , P.; Nair, V. A. Eur. J. Med. Chem. 2011, 46, 3291;
(d) Kumar, V.; Raghavaiah, P.; Mobin, S. M.; Nair, V. A. Org.
Biomol. Chem. 2010, 8, 4960; (e) Kumar, V.; Pal, A.; Khatik, G. L.;
Nair, V. A. Tetrahedron: Asymmetry 2012, 23, 434; (f) Kumar, V.;
Kumar, K.; Pal, A.; Khatik G. L.; Nair, V. A. Tetrahedron 2013,
69, 1747; (g) Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012,
14, 2442; (h) Chouhan, M.; Sharma, R.; Nair, V. A. Org. Lett.
2012, 14, 5672; (i) Chouhan, M.; Senwar, K. R.; Sharma, R.;
Grover, V.; Nair, V. A. Green Chem. 2011, 13, 2553; (j) Goyal, S.;
Patel, J. K.; Gangar, M.; Kumar, K.; Nair, V. A. RSC Adv. 2015, 5,
3187.
3. Loriga, M.; Piras, S.; Sanna, P.; Paglietti, G. Farmaco 1997, 52,
157.
4. Brown, D. J., Taylor, E. C., Wipf, P., The Chemistry of
Heterocyclic Compounds-Quinoxalines: Supplements II; John
Wiley and Sons: New Jersey, 2004.
5. (a) Sarges, R.; Howard, H. R.; Browne, R. G.; Lebel, L. A.;
Seymour, P. A. J. Med. Chem. 1990, 33, 2240; (b) Gazit, A.; App,
H.; McMahon, G.; Chen, J.; Levitzki, A.; Bohmer, F. D. J. Med.
Chem. 1996, 39, 2170.
6. Jonathan, L. S.; Hiromitsu, M.; Toshihisa, M.; Vincent, M. L.;
Hiroyuki, F. Chem. Commun. 2002, 862.
7. Thomas, K. R. J.; Velusamy, M.; Lin, J. T.; Chuen, C.-H.; Tao, Y.-
T. Chem. Mater. 2005, 17, 1860.
8. (a) Katoh, A.; Yoshida, T.; Ohkanda, J. Heterocycles 2000, 52,
911; (b) Brock, E. D.; Lewis, D. M.; Yousaf, T. I.; Harper, H. H.
U.S. Patent WO9951688, 1999.
9. (a) Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.; Wood,
E. L. J. Mater. Chem. 2001, 11, 2238.
10. (a) Jonathan, L. S.; Hiromitsu, M.; Toshihisa, M.; Vincent, M. L.;
Hiroyuki, F. J. Am. Chem. Soc. 2002, 124, 13474; (b) Peter, P. C.;
Gang, Z.; Grace, A. M.; Carlos, H.; Linda, M. G. T. Org. Lett.
2004, 6, 333.
11. Sascha, O.; Rudiger, F. Synlett. 2004, 1509.
12. (a) Saravanakumar, S.; Kindermann, M. K.; Heinicke, J.;
Kockerling, M. Chem. Commun. 2006, 640; (b) Kulkarni, M. S.;
Kumbhar, A. S.; Mohan, H.; Rao, B. S. M. Dalton Trans. 2009,
6185.
13. (a) Darabi, H. R.; Mohandessi, S.; Aghapoor, K.; Mohsenzadeh, F.
Catal. Commun. 2007, 8, 389; (b) Heravi, M. M.; Taheri, S.;
Bakhtiari, K.; Oskooie, H. A. Catal. Commun. 2007, 8, 211; (c)
Huang, T. K.; Wang, R.; Shi, L.; Lu, X. X. Catal. Commun. 2008,
9, 1143; (d) More, S. V.; Sastry, M. N. V.; Yao, C.-F. Green Chem.
2006, 8, 91; (e) Bhosale, R. S.; Sarda, S. R.; Andhapure, S. S.;
Jadhav, W. N.; Bhusare, S. R.; Pawar, R. P. Tetrahedron Lett.
2005, 46, 7183; (f) Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.;
Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett. 2004,
45, 4873.
14. (a) Singh, S. K.; Gupta, P.; Duggineni, S.; Kundu, B. Synlett 2003,
2147; (b) Wan, J. P.; Gan, S. F.; Wu, J. M.; Pan, Y. Green Chem.
2009, 11, 1633; (c) Ghosh, P.; Mandal, A. Tetrahedron Lett. 2012,
53, 6483;(d) Madhav, B.; Murthy, S. N.; Reddy, V. P.; Rao, K. R.;
Nageswar, Y. V. D. Tetrahedron Lett. 2009, 50, 6025.
15. (a) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Org. Biomol. Chem.
2004, 2, 788; (b) Kim, S. Y.; Park, K. H.; Chung, Y. K. Chem.
Commun. 2005, 1321; (c) Sithambaram, S.; Ding, Y.; Li, W.; Shen,
X.; Gaenzler, F.; Suib, S. L. Green Chem. 2008, 10, 1029; (d) Cho,
C. S.; Oh, S. G. J. Mol. Catal. A: Chem. 2007, 276, 205.
16. Antoniotti, S.; Dunach, E. Tetrahedron Lett. 2002, 43, 3971.
17. Cho, C. S.; Oh, S. G. Tetrahedron Lett. 2006, 47, 5633.
18. Yadav, J. S.; Reddy, B. V. S.; Premalatha, K.; Shankar, K. S.
Synthesis 2008, 23, 3787.
19. Das, B.; Venkateswarlu, K.; Suneel, K.; Majhi, A. Tetrahedron
Lett. 2007, 48, 5371.