Quinoxaline synthesis in novel tandem one-pot protocol

Article abstract of DOI:10.1016/j.tetlet.2011.03.110

A variety of quinoxalines were synthesized via tandem one-pot procedure for the first time in water medium. The key strategy was the in situ preparation of α-halo-β-keto esters by the reaction of N-bromo succinimide with β-keto esters and further condensa

Full text of DOI:10.1016/j.tetlet.2011.03.110

Tetrahedron Letters 52 (2011) 2862–2865
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Quinoxaline synthesis in novel tandem one-pot protocol
⇑
B. S. P. Anil Kumar, B. Madhav, K. Harsha Vardhan Reddy, Y. V. D. Nageswar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of quinoxalines were synthesized via tandem one-pot procedure for the first time in water med-
Received 24 December 2010
Revised 17 March 2011
Accepted 24 March 2011
Available online 1 April 2011
ium. The key strategy was the in situ preparation of a-halo-b-keto esters by the reaction of N-bromo suc-
cinimide with b-keto esters and further condensation with phenylene diamines. This novel eco-friendly
approach offers an easy, efficient, and mild synthesis of highly substituted quinoxalines in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b Diketones/b-keto esters, N-Bromo
succinimide
Phenylene diamines
Quinoxalines
Neutral conditions
Water
Quinoxaline and its derivatives represent one of the most bio-
logically active classes of compounds,1 possessing a wide and di-
verse spectrum of pharmacological properties2, such as
anticancer3, antiviral,4 antibiotic (echinomycin), and anti-inflam-
matory activities.5 The quinoxaline nucleus is also associated with
applications in dyes,6 organic semiconductors,7 dehydroannu-
lenes,8 and cavitands.9
using other non-conventional synthetic protocols like solid phase
synthesis,13 microwaves,14 and zeolites.15 Recently Meshram
et al. described the preparation of quinoxaline derivatives from
1,2-diamines and a
-halo-b-ketoesters using ionic liquids.16
However, most of the reported methods suffer from drawbacks
such as the use of expensive reagents/additives, metal catalysts,
inflammable organic solvents or harsh reaction conditions, as well
as the difficult experimental/work-up procedures. In view of the
above shortcomings, development of a mild and eco-friendly
one-pot synthetic protocol for these highly significant classes of
compounds is desirable.
Consequently a number of synthetic strategies have been devel-
oped for the synthesis of various substituted quinoxalines involv-
ing the condensation of 1,2-diamines with
a
-diketones,10
oxidation of a-hydroxy ketones followed by the condensation with
1,2-diamines,11 and oxidative cyclization of phenacyl bromides
with 1,2-diamines.12 These compounds were also synthesized
Recently, there has been increasing recognition for the develop-
ment of green synthetic protocols, such as reactions in aqueous
NH2
O
O
O
O
O
N
R1
NBS, H2O
NH2
R2
R
R1
R
R1
70 0C, 20 mins
70 0C, 4 hrs
N
R
R2
Br
R = Me. Et, Ph, CF3; R1= Me, Et, Ph, OEt, OBn;
R2 = H, 4,5-Dimethyl, 4-Nitro, 4-Methyl;
Scheme 1.
⇑
Corresponding author.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.110

B. S. P. Anil Kumar et al. / Tetrahedron Letters 52 (2011) 2862–2865
2863
studies on Diels–Alder reactions by Breslow.17 Water is a preferred
solvent medium18 compared to the other organic solvents, due to
its associated advantages, such as safety, non-toxicity, easy avail-
ability, affordability, and environmental acceptability.
In continuation of our on-going research program on the explo-
ration of novel environment friendly approaches in synthetic
organic chemistry,19 we describe herein a tandem one-pot proce-
dure for the preparation of quinoxalines directly from readily avail-
able and inexpensive b-diketones/b-ketoesters and 1,2-phenylene
Table 1
Investigation of various solvents in the synthesis of quinoxalines.
Entry
Solvent
Temperature
Yield (%)
1
2
3
4
5
6
7
H2O
H2O
H2O
PEG-400
DCM
rt
70
90
80
Reflux
Reflux
Reflux
20
85
85
55
25
15
62
CH3CN
MeOH
diamines (Scheme 1). The in situ preparation of
a-halo-b-ketone/
a-halo-b-ketoester as the main reactant reduces the steps and time
involved in the reaction strategy. The advantages of the present
protocol are the shorter reaction pathway and the use of aqueous
medium for the conduct of the reaction. The present one-pot
approach also helps us to simplify reaction handling and product
medium or catalyst/solvent-free conditions. These protocols have
been replacing the conventional methodologies. Organic reactions
in aqueous medium acquired prominence since the pioneering
Table 2
Synthesis of quinoxalines In aqueous mediuma.
Entry
1
Substrate (1)
Substrate (2)
Product
Yield (%)b
85
NH2
O
O
N
N
COMe
COEt
NH2
NH2
O
O
N
2
84
Et
Et
NH2
NH2
N
Et
O
O
N
COOEt
3
4
5
6
84
83
79
80
OEt
NH2
NH2
N
N
O
O
O
COPh
Ph
Ph
NH2
NH2
N
N
Ph
O
COOEt
Ph
OEt
NH2
NH2
N
N
Ph
O
O
O
COOEt
F3C
OEt
NH2
NH2
N
N
CF3
O
O
COOBn
Bn
7
8
83
82
NH2
NH2
N
N
O
O
COOMe
O
N
N
NH2
NH2
O
O
COOEt
N
9
78
OEt
N
NH2
N
NH2
O
O
O
O
O
N
COMe
COOMe
COOEt
COOBn
COPh
10
11
12
13
14
15
16
88
82
86
84
85
80
NH2
NH2
N
O
N
O
N
NH2
NH2
O
N
OEt
NH2
NH2
N
N
O
Bn
O
NH2
NH2
N
N
O
O
Ph
Ph
Ph
NH2
NH2
N
Ph
O
O
O
N
COOEt
OEt
Et
N
Ph
NH2
NH2
O
N
COEt
88
Et
NH2
N
Et
(continued on next page)

2864
B. S. P. Anil Kumar et al. / Tetrahedron Letters 52 (2011) 2862–2865
Table 2 (continued)
Entry
Substrate (1)
NH2
Substrate (2)
Product
Yield (%)b
80
O
O
N
N
COOEt
17
18
19
20
F3C
O
OEt
NH2
NH2
CF3
O
N
COMe
70
72
70
72
NH2
NH2
N
O
O
O
O
N
COOBn
Bn
O
N
NH2
NH2
O
O
N
COOEt
OEt
O2N
O2N
N
N
O2N
O2N
NH2
NH2
COOBn
Bn
21
O
N
NH2
a
Reaction conditions: b ketones/b keto esters (1 equiv), NBS (1.2 equiv), phenylene diamine (1 equiv), H2O (15 ml).
Yields of the isolated product.
b
purification, improve synthetic efficiency, and reduce solvent con-
1,2-diamine had also reacted in the present reaction conditions
resulting in lower yield of the product (entries 20 and 21).
In conclusion, a novel, tandem, mild, and environ friendly, one
pot synthetic protocol was developed for obtaining quinoxalines
directly from the corresponding 1,2-phenylene diamines and 1,3-
dicarbonyl compounds for the first time in aqueous medium, in
the absence of any catalyst which will contribute for the growth
of green chemistry.
sumption as well as disposal, thereby minimizing the harmful im-
pact of various chemicals on environment.20 More over this novel
methodology offers an improvement over the recent report of
quinoxaline synthesis in ionic liquids by Meshram et al.16 and
our earlier report on quinoxaline synthesis by supramolecular
catalysis using b-cyclodextrin.21 Meshram et al. used
a-halo-b-
ketoesters as reactants, which in turn are to be prepared by addi-
tional reactions, whereas the present facile novel work minimized
the number of steps to synthesise the desired quinoxalines, offer-
Acknowledgment
ing
a faster, simpler, and atom-economic one-pot direct
methodology.
We thank CSIR, New Delhi, India for fellowships to B.S.P.A.K.,
B.M. and K.H.V.R.
Initially a reaction was attempted between benzene 1,2-dia-
mine and 3-bromopentane-2,4-dione (prepared in situ) as a model
reaction in aqueous medium. 3-Bromopentane-2,4-dione was pre-
pared by adding N-bromosuccinamide (1.2 equiv) to acetyl acetone
in water at 70 °C and stirring for 20 min. 1,2-Phenylene diamine
was added to the reaction mixture and heated for 4 h to obtain
the desired quinoxaline in 85% yield. In these reactions succini-
mide was obtained as the by-product. This has been recycled to
NBS as described in the general procedure.22 The reaction is envis-
aged to proceed in the proposed mechanistic pathway (Scheme 1)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.110.
References and notes
1. Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002, 45, 5604.
2. (a) Ali, M. M.; Ismail, M. M. F.; EI-Gabby, M. S. A.; Zahran, M. A.; Ammar, T. A.
Molecules 2000, 5, 864; (b) Sarges, R.; Howard, H. R.; Browne, R. C.; Label, L. A.;
Seymour, P. A. J. Med. Chem. 1990, 33, 2240; (c) Arthur, G.; Elor, K. B.; Robert, G.
S.; Guo, Z. Z.; Richard, J. P.; Stanley, D.; John, R. K.; Sean, T. J. Med. Chem. 2005,
48, 744; (d) Lainne, E. S.; William, J. S.; Robert, C. R. J. Med. Chem. 2002, 45,
5604; (e) Andres, J.; Belen, Z.; Ibnacio, A.; Antonio, M. J. Med. Chem. 2005, 48,
2019.
3. Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.; Defeo
Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J. R.; Huber, H. E.; Duggan, M. E.
Bioorg. Med. Chem. Lett. 2005, 15, 761.
4. Loriga, M.; Piras, S.; Sanna, P.; Paglietti, G. Farmaco 1997, 52, 157.
5. (a) Sakata, G.; Makino, K.; Kurasawa, Y. Heterocycles 1988, 27, 2481; (b) He, W.;
Meyers, M. R.; Hanney, B.; Sapada, A.; Blider, G.; Galzeinski, H.; Amin, D.;
Needle, S.; Page, K.; Jayyosi, Z.; Perrone, H. Bioorg. Med. Chem. Lett. 2003, 13,
3097; (c) Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med. Chem. Lett.
2004, 14, 541.
involving the in situ formation of a-halo-b-ketone/a-halo-b-keto-
ester, followed by further cyclizations to yield the expected prod-
uct. In order to evaluate the effect of solvent on the reaction,
various solvents, such as PEG-400, methanol, acetonitrile, dichloro-
methane and water were examined. Among different solvents,
water proved to be the best medium for this reaction (Table 1).
On the basis of the preliminary results, various 1,2-phenylene
diamines and 1,3-diketones were subjected to the present reaction
conditions to investigate the scope and limitation of the reaction,
the results of which were represented in Table 2. In view of the
interesting results obtained with 1,3-diketones, the scope of the
reaction was extended further to b keto esters (Scheme 1) and
the results were incorporated in Table 2. The reactions proceeded
well to obtain encouraging yields in the case of both 1,3-diketones
as well as b-keto esters.
As replacing N-bromo succinimide with N-iodo succinimide did
not improve the yields further, reaction studies were conducted
only with N-bromo succinimide (Scheme 1). Unsymmetrical 1,2-
diamine (4 methyl 1,2-phenylene diamine) yielded isomeric prod-
ucts with 75:25 ratio (entries 18 and 19). CF3 substituent on 1,3-
diketone as well as b-keto ester had less effect on the reaction
progress and yields the products (entry 6 and 17). 4-Nitro benzene
6. Brock, E. D.; Lewis, D. M.; Yousaf, T. I.; Harper, H. H. (The Procter & Gamble
Company, USA) WO 9951688, 1999.
7. (a) Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.; Wood, E. L. J. Mater.
Chem. 2001, 11, 2238; (b) Brien, D. O’.; Weaver, M. S.; Lidzey, D. G.; Bradley, D.
D. C. Appl. Phys. Lett. 1996, 69, 881.
8. Sascha, O.; Rudiger, F. Synlett 2004, 1509.
9. (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.
10. (a) VOGEL’S Textbook of Practical Organic Chemistry 5th ed., 1989, p 1190.; (b)
Brown, D. J. In Chemistry of Heterocyclic Compounds; Taylor, E. C., Wipf, P., Eds.;
John Wiley and Sons: New Jersey, 2004. Quinoxalines Supplements II; (c)
Bhosale, R. S.; Sarda, S. R.; Andhapure, S. S.; Jadhav, W. N.; Bhusare, S. R.; Pawar,

B. S. P. Anil Kumar et al. / Tetrahedron Letters 52 (2011) 2862–2865
2865
R. P. Tetrahedron Lett. 2005, 46, 7183; (d) More, S. V.; Sastry, M. N. V.; Wang, C.;
Yao, C. F. Tetrahedron Lett. 2005, 46, 6345.
11. (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) Robinson, R.
S.; Taylor, R. J. K. Synlett 2005, 1003; (d) Cho, C. S.; Renb, W. X.; Shim, S. C.
Tetrahedron Lett. 2007, 48, 4665.
12. Das, B.; Venkateswarlu, K.; Suneel, K.; Majhi, A. Tetrahedron Lett. 2007, 48,
5371.
13. (a) Zemin, W.; Nicholas, J. E. Tetrahedron Lett. 2001, 42, 8115; (b) Orazio, A. A.;
Lucia, D. C.; Paolino, F.; Fabio, M.; Stefania, S. Synlett 2003, 1183; (c) Sanjay, K.
S.; Priya, G.; Srinavas, D.; Bijoy, K. Synlett 2003, 2147.
R.; Nageswar, Y. V. D. Helv. Chim. Acta 2009, 92, 2118; (c) Murthy, S. N.;
Madhav, B.; Prakash Reddy, V.; Rama Rao, K.; Nageswar, Y. V. D. Tetrahedron
Lett. 2009, 50, 5009; (d) Madhav, B.; Murthy, S. N.; Rao, K. R.; Nageswar, Y. V. D.
Helv. Chim. Acta 2010, 93, 257; (e) Murthy, S. N.; Madhav, B.; Nageswar, Y. V. D.
Helv. Chim. Acta 2010, 93, 1216; (f) Murthy, S. N.; Madhav, B.; Prakash Reddy,
V.; Nageswar, Y. V. D. Tetrahedron Lett. 2010, 51, 3649; (g) Shankar, J.; Karnakar,
K.; Srinivas, B.; Nageswar, Y. V. D. Tetrahedron Lett. 2010, 51, 3938.
20. Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
21. Madhav, B.; Murthy, S. N.; Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D.
Tetrahedron Lett. 2009, 50, 6025.
22. General procedure for the synthesis of substituted quinoxalines: To
a round
14. (a) Shyamaprasad, G.; Avijit, K. A. Tetrahedron Lett. 2002, 43, 8371; (b) Zhijian,
Z.; David, D. W.; Scoot, E. W.; William, H. L.; Craig, W. L. Tetrahedron Lett. 2004,
45, 4873.
bottom flask of water (15 mL) acetyl acetone (1 mmol) was added followed by
NBS (1.2 mmol) and stirred for 20 min at 70 °C. To this reaction mixture, 1,2-
phenylene diamine (1.0 mmol) was added and stirred until completion of the
reaction as indicated by TLC. The reaction mixture was extracted with ethyl
acetate (3 Â 10 mL) .The organic layers were washed with water, saturated
brine solution and dried over anhydrous Na2SO4. The combined organic layers
were evaporated under reduced pressure and the resulting crude product was
purified by column chromatography. To the filtrate, which contained
succinimide and HBr was added NaBrO3 and concd H2SO4 as already
reported23 and the mixture stirred for 30 min, extraction with ethyl acetate
giving NBS in an isolated yield of 70–80%.
Data of representative example: 1-(3-methylquinoxalin-2-yl)ethanone (Table 2,
entry1): Solid. Mp 78–80 °C. 1H NMR (300 MHz, CDCl3): d 2.82 (3H, s), 2.96 (3H,
s), 7.70–7.83 (2H, m), 8.00–8.13 (2H, m). 13C NMR (75 MHz, CDCl3): d 14.96,
28.50, 29.58, 95.93, 126.84, 128.94, 132.15, 133.78, 143.94. ESI-MS: m/z 187
(M+H)+. HRMS calcd for 187.1123, found 187.1232.
15. (a) Sylvain, A.; Elisabet, D. Tetrahedron Lett. 2002, 43, 3971; (b) Jose, B.;
Fernando, A.; Ramon, L.; Maria-Paz, C. Synthesis 1985, 313; (c) Steven, A. R.;
Cecilia, D. W.; Richard, J. K. T. Chem. Commun. 2003, 2286; (d) Shyamaprosad,
G.; Avijit, K. A. Tetrahedron Lett. 2005, 46, 221; (e) Yoram, C.; Amatzya, Y. M.;
Mordecai, R. J. Am. Chem. Soc. 1986, 108, 7044; (f) Xekoukoulotakis, N. P.;
Hadjiantoniou, M.; Maroulis, A. J. Tetrahedron Lett. 2000, 41, 10299; (g) Venu
Gopal, D.; Subrahmanmyam, M. Catal. Commun. 2001, 2, 219.
16. Meshram, H. M.; Ramesh, P.; Santosh Kumar, G.; Chennakesava Reddy, B.
Tetrahedron Lett. 2010, 51, 4313.
17. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b) Breslow, R. Acc. Chem. Res.
2004, 37, 471.
18. (a) Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York,
1997; (b)Organic Synthesis in Water; Grieco, P. A., Ed.; Thomson Science:
Glasgow, Scotland, 1998; (c) Li, C.-J. Chem. Rev. 2005, 105, 3095.
19. (a) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D.
Tetrahedron 2009, 65, 5251; (b) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K.
23. Fujisaki, S.; Hamura, S.; Eguchi, H.; Nishida, A. Bull. Chem. Soc. Jpn. 1993, 66,
2426.