Catalyst-free synthesis of quinoxalines

Article abstract of DOI:10.14233/ajchem.2015.18680

Quinoxalines are a class of important heterocycles, so to explore a facile and practical new synthetic method is always demanded. We have developed a new catalyst-free domino synthesis of quinoxalines from phenacyl halides and 1,2-diaminoarenes. Phenacyl

Full text of DOI:10.14233/ajchem.2015.18680

Asian Journal of Chemistry; Vol. 27, No. 7 (2015), 2639-2641
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18680
Catalyst-Free Synthesis of Quinoxalines
*
DONGMING LU, QINJIE XIANG, LIHONG ZHOU and QINGLE ZENG
Institute of Green Catalysis and Synthesis, College of Materials and Chemistry and Chemical Engineering, Chengdu University of Technology,
Chengdu 610059, P.R. China
*Corresponding author: Fax: +86 28 84079074; Tel: +86 13568999842; E-mail: qinglezeng@hotmail.com
Received: 2 September 2014;
Accepted: 22 October 2014;
Published online: 30 March 2015;
AJC-17095
Quinoxalines are a class of important heterocycles, so to explore a facile and practical new synthetic method is always demanded. We have
developed a new catalyst-free domino synthesis of quinoxalines from phenacyl halides and 1,2-diaminoarenes. Phenacyl chlorides with
lower activities are first used in synthesis of quinoxalines and afford up to 97 % yield with our protocol. Our process with sodium
bicarbonate as deacid reagent is catalyst-free, simple, greener and practical.
Keywords: Quinoxalines, Domino synthesis, Phenacyl halides, 1,2-Diaminoarenes, Heterocycles.
This reaction could be accomplished through a multistep
and complex process in solid phase14, which could be catalyzed
by supported strong acid catalyst HClO4.SiO215, or by organic
base catalyst DABCO16 and pyridine17, or by supported inor-
ganic base catalyst KF-alumina18, or byAmberlite resin suppor-
ted hexafluorophosphate ion19. This reaction can also be
performed under microwave-irradiation conditions20.A simple
process without catalyst was also reported with equivalent
β-cyclodextrin as an additive21 or polyethylene glycol (PEG)
as a medium22. However the catalysts and the additives not
only increase the cost of the process and the trouble of workup,
but also potentially pollute the environment.
INTRODUCTION
Quinoxalines are a privileged class of N-containing
hetero-cycles and exhibit a wide range of biological activities,
such as anti-inflammatory, kinase inhibitory, anticancer,
antiviral, antibacterial and anthelmintic activities1. In addition
to medicinal uses, quinoxaline derivatives have found appli-
cations in other fields, for example, organic ligands2 and semi-
conductors3.
Owing to their potential biological and other applications,
a number of synthetic methods have been developed4. The most
common method for their synthesis relies on the condensation
of aryl 1,2-diamines with 1,2-dicarbonyl compounds in
refluxing ethanol or acetic acid5. The classical reaction process
generally requires severe reaction conditions, such as strong
acidic media.
Over the years, a number of synthetic approaches of
quinoxalines have been reported, such as reaction of 1,2-keto
hydroxyl compounds via Tandem oxidation procedure6,
various Brønsted acids-, Lewis acids-, or oxidants-promoted
condensations7, 1,4-addition of 1,2-diamines to diazenyl-
butenes8, Bi(0)-catalyzed oxidative coupling of epoxides and
ene-1,2-diamines9, cyclization of α-arylimino oximes inAc2O10,
Cu-catalyzed synthesis of quinoxalines from o-phenylene-
diamines and nitroolefins11, cascade synthesis from ketones
and 1,2-diamines12.
Previous study revealed that the reaction between phenacyl
bromides and 1,2-diamines yields quinoxalines as well as
hydrogen bromide. So weak basic quinoxalines will form their
HBr salts, unless certain deacid reagent, e.g. NaHCO3 is added
in the reaction to remove the HBr acid. Could NaHCO3 be
added in advance to the reaction? Perhaps it would promote
the reaction of synthesis of quinoxalines. Our primary study
convinced our idea.
As our ongoing research on synthesis of heterocycles23,
we developed a new catalyst free synthetic method for quino-
xalines with sodium bicarbonate as a deacid reagent (Scheme-
I).
EXPERIMENTAL
In addition, reaction of phenacyl bromides and 1,2-di-
aminoarenes is a good approach for synthesis of quinoxa-
lines. Phenacyl bromides can be synthesized even in a green
process13.
The chemicals and reagents were purchased fromAldrich,
Acros, Alfa Aesar, Aladdin, or Kelong Chemicals Company
and used without further purification.

2640 Lu et al.
Asian J. Chem.
lower temperature was a partial reason of the lower yields.
While DMA and DMF produced the desired product with
comparative yields (entries 14-15). But considering DMSO is
the greener solvent than DMA and DMF24, we adopted
DMSO as our solvent for this reaction. Besides, DMSO could
be recovered by distillation after the reaction.
X
R2
NH2
N
N
R1
+
NH2
R2
O
R1
1
2
3
Scheme-I:Catalyst-free synthesis of quinoxalines from 1,2-diaminoarenes
and α-halo ketones
TABLE-1
General procedure: To a dry test tube with a stir bar was
added 1,2-diaminoarene (1 mmol), phenacyl bromide (1 mmol),
NaHCO3 and DMSO (5 mL). The test tube was transferred to
a preheated oil bath pot for reaction.After a set period of time,
the reaction was cooled to room temperature and quenched
with water. The resulting mixture was extracted with ethyl
acetate (15 mL) for three times. The combined organic layer
was washed with water (5 mL) for twice and then dried over
anhydrous sodium sulfate. The filtrate was condensed under
reduced pressure on a rotator. The residual was purified on a
silica gel column chromatography with a mixture of petroleum
ether and ethyl acetate (volume ratio 5/1) as eluent to give the
desired quinoxaline.
Detection method: The purities of all the synthesized
compounds were checked by thin-layer chromatography
(TLC) using suitable organic solvents. The IR spectra were
recorded on a Bruker Tensor-27 FT-IR spectro-photometer in
KBr discs. 1H NMR spectra were recorded on a BrukerAdvance
300 MHz NMR or 400 MHz spectrometer in CDCl3 or DMSO-d6
containing tetramethylsilane (TMS) as an internal standard.
Melting points were determined on an X-4 melting-point
apparatus with microscope and are uncorrected.
OPTIMIZATION OF CONDITIONS OF REACTION
OF o-PHENYLENEDIAMINE 1a AND
2-BROMOACETOBENZENE 2aa
Entry
1
2
3
4
5
6
7
8
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
95 % EtOH
AcOEt
t (h)
24
24
24
24
24
24
12
16
20
24
24
24
24
24
24
NaHCO3 (equiv.)
Yield (%)b
0
52
0
1.0c
1.0
1.2
0.8
1.2d
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
85
99
71
68
76
84
92
74
49
36
60
94
96
9
10
11e
12e
13f
14
15
1,4-Dioxane
DMA
DMF
aReaction conditions: o-Phenylenediamine (1 mmol), 2-bromo-
acetophenone (1 mmol), NaHCO3, DMSO (5 mL), 24 h, 120 °C, under
air, unless other mentioned. bIsolated yield; cHBr (1 mmol) was used as
catalyst, but an extremely complex mixture was obtained; dK2CO3 (1.2
mmol) was added; e40 °C; f90 °C
With the optimized conditions at hand, the reactions of
α-halomethyl aryl ketones and o-phenylenediamine were next
investigated (Table-2). Both electron-donating groups and
electron-withdrawing groups on the aromatic ring of α-bromo-
methyl aryl ketones could achieve excellent yields of quinoxa-
lines (entries 2-5 vs. 1). For phenacyl bromides with nitro
groups, the substituted positions on the phenyl groups hugely
influenced the results, namely, meta-nitrophenacyl bromide
yielded the highest yield of them and the ortho-nitrophenacyl
bromide afforded the poorest yield (entry 7).
Surprisingly, phenacyl chlorides could also achieve exce-
llent yields up to 97 % (entries 8-9). In addi-tion, 3,4-difluoro
substituted phenacyl chloride gave good yield (entry 10). How-
ever, perhaps due to the instability of catechol in the conditions,
3,4-dihydroxyphenacyl chloride afforded much low yield
(entry 11).
RESULTS AND DISCUSSION
It is noticed that some of the reported synthetic methods
of quinoxalines with α-haloketones as substrates used acids
as catalysts15, while some used bases as catalysts16-18, and some
did not use any acid or base as catalyst. So first of all, we tried
to synthesize 2-phenylquinoxaline from o-phenylenediamine
and phenacyl bromide without addition of any base or acid
and got the 2-phenylquinoxaline in 52 % yield at 120 °C in
DMSO (Table-1, entry 1).Addition of an equivalent hydrogen
bromide as catalyst resulted in an extremely complex mixture
and no desired product could be isolated (entry 2).
It was reported that DABCO and pyridine could promote
this reaction16,17. Perhaps pyridine acted as deacid reagent in
the reported reaction. In view of this, sodium bicarbonate was
used as a low-cost deacid reagent in this reaction system.
Fortunately, the yield increased dramatically (entry 3). Increase
of the amount of NaHCO3 to 1.2 equivalents obviously raised
the reaction yield to 99 % (entry 4). Lowering the amount of
NaHCO3 resulted in a decrease of the yield (entry 5).A stronger
weak base K2CO3 even decreased the yield of the reaction
(entries 6 vs. 5) and the reason perhaps is that the stronger
basicity of K2CO3 promotes the hydrolysis of phenacyl
bromide with the water produced during the condensation
(Scheme-II). Shortening the reaction time resulted in decrease
of the yields (entries 7-9 vs. 4) and lowering the temperature
also disfavored the yield (entry 10). In the screened solvents,
95 % ethanol, ethyl acetate and 1,4-dioxane gave much lower
yields of 2-phenylquinoxaline (entries 11-13) and perhaps the
The amount of the reactants was scaled up to 10 mmol
and the crude product was recrystallized once with hexane to
afford 82 % yield (entry 12).
Next, we continued to study the reaction between substi-
tuted 1,2-diaminoarenes and phenacyl bromide (Table-3). Elec-
tron donating groups on the 1,2-diaminoarenes are beneficial
to the reactions (entries 1-2) and the result is attributed to
enhancement of the basicity and nucleophilic ability of amino
groups of 1,2-diaminoarenes by electron-donating groups.
Accordingly, electron-withdrawing groups cause decrease of
the yields of quinazolines (entries 3-6). It seems that the stronger
the electron-withdrawing ability of the substitutes, the lower
the yield of the desired quinoxalines (entries 3-6).

Vol. 27, No. 7 (2015)
Catalyst-Free Synthesis of Quinoxalines 2641
TABLE-2
REFERENCES
CATALYST-FREE SYNTHESIS OF QUINAZOLINES
FROM α-HALOMETHYL ARYL KETONES AND
ortho-PHENYLENEDIAMINEa
1. A. Jaso, B. Zarranz, I. Aldana and A. Monge, J. Med. Chem., 48, 2019
(2005); R. Sarges, H.R. Howard, R.G. Browne, L.A. Lebel, P.A. Seymour
and B.K. Koe, J. Med. Chem., 33, 2240 (1990); L.E. Seitz, W.J. Suling
and R.C. Reynolds, J. Med. Chem., 45, 5604 (2002).; W. He, M.R. Myers,
B. Hanney, A.P. Spada, G. Bilder, H. Galzcinski, D. Amin, S. Needle,
K. Page, Z. Jayyosi and M.H. Perrone, Bioorg. Med. Chem. Lett., 13,
3097 (2003); Y. Kurasawa, G. Sakata and K. Makino, Heterocycles,
27, 2481 (1988).
2. S. Saravanakumar, M.K. Kindermann, J. Heinicke and M. Kockerling,
Chem. Commun., 640 (2006); M.S. Kulkarni, A.S. Kumbhar, H. Mohan
and B.S.M. Rao, Dalton Trans., 6185 (2009).
3. S. Dailey, J.W. Feast, R.J. Peace, I.C. Sage, S. Till and E.L. Wood, J.
Mater. Chem., 11, 2238 (2001).
4. (a)Y.V.D. Nageswar, K.H.V. Reddy, K. Ramesh and S.N. Murthy, Org.
Prep. Proced. Int., 45, 1 (2013); (b) G.H.C. Woo, J.K. Snyder and Z.K.
Wan, in eds.: G.W. Gribble and T.L. Gilchrist, Progress in Heterocyclic
Chemistry, Pergamon: Oxford, vol. 14, p. 279 (2002).
5. D.J. Brown, The Chemistry of Heterocyclic Compounds Quinoxalines:
Supplement II, John Wiley & Sons: New Jersey (2004).
6. (a) R.S. Robinson and R.J.K. Taylor, Synlett, 1003 (2005); (b) S.A.
Raw, C.D. Wilfred and R.J.K. Taylor, Chem. Commun., 2286 (2003);
(c) S.Y. Kim, K.H. Park andY.K. Chung, Chem. Commun., 1321 (2005);
(d) R.S. Bhosale, S.R. Sarda, S.S.Ardhapure, W.N. Jadhav, S.R. Bhusare
and P.R. Pawar, Tetrahedron Lett., 46, 7183 (2005).
X
NH2
N
+
NH2
R
O
N
R
1a
2
3
Entry
1
2
3
4
5
6
7
8
R
H
X
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Br
Product
3a
3b
3c
3d
3e
3f
3g
3h
3i
Yield (%)b
99
92
96
83
97
73
59
97
93
76
41
82
4-CH3O
4-Ph
4-Br
3-NO2
4-NO2
2-NO2
4-Cl
2,4-Cl2
3,4-F2
3,4-(OH)2
H
9
10
11
12
3j
3k
3a
aReaction conditions: o-Phenylenediamine (1 mmol), α-halomethyl
aryl ketones (1 mmol), NaHCO3 (1.2 mmol), DMSO (5 mL), under
air, 120 °C, 24 h. bIsolated yield
7. J.-J. Cai, J.-P. Zou, X.-Q. Pan and W. Zhang, Tetrahedron Lett., 49,
7386 (2008); S.V. More, M.N.V. Sastry and C.-F. Yao, Green Chem.,
8, 91 (2006); M.M. Heravi, S. Taheri, K. Bakhtiari and H.A. Oskooie,
Catal. Commun., 8, 211 (2007); B.C. Raju, N.D. Theja and J.A. Kumar,
Synth. Commun., 39, 175 (2009); A. Shaabani, A.H. Rezayan, M.
Behnam and M. Heidary, Chimie, 12, 1249 (2009); M.M. Heravi, M.H.
Tehrani, K. Bakhtiari and H.A. Oskooie, Catal. Commun., 8, 1341
(2007); (g) B.C. Raju, K. Ramachandra, Indian J. Chem., 51B, 756 (2012).
8. D.Aparicio, O.A.Attanasi, P. Filippone, R. Ignacio, S. Lillini, F. Mantellini,
F. Palacios and J.M. de los Santos, J. Org. Chem., 71, 5897 (2006).
9. S. Antoniotti and E. Dunach, Tetrahedron Lett., 43, 3971 (2002).
10. N.P. Xekoukoulotakis, C.P. Hadjiantoniou-Maroulis and A.J. Maroulis,
Tetrahedron Lett., 41, 10299 (2000).
TABLE-3
CATALYST-FREE SYNTHESIS OF QUINAZOLINES FROM
PHENACYL BROMIDE AND 1,2-DIAMINOARENESa
O
NH2
N
N
Br
+
R
NH2
R
1
2a
3
Entry
1
R
Product
3l
3m
3n
Yield (%)b
4,5-(CH3)2
4-CH3O
4-Br
80
82
76
72
73
51
2c
3c
11. Y. Chen, K. Li, M. Zhao, Y. Li and B. Chen, Tetrahedron Lett., 54,
1627 (2013).
4c
4-Cl
4-CF3
4-NO2
3o
3p
3q
5c
12. M. Lian, Q. Li,Y. Zhu, G.Yin andA. Wu, Tetrahedron, 68, 9598 (2012).
13. (a) B.C. Ranu, K. Chattopadhyay and R. Jana, Tetrahedron, 63, 155
(2007); (b) S. Adimurthy, S. Ghosh, P.U. Patoliya, G. Ramachandraiah,
M. Agrawal, M.R. Gandhi, S.C. Upadhyay, P.K. Ghosh and B.C. Ranu,
Green Chem., 10, 232 (2008).
14. S.K. Singh, P. Gupta, S. Duggineni and B. Kundu, Synlett, 2147 (2003).
15. B. Das, K. Venkateswarlu, K. Suneel and A. Majhi, Tetrahedron Lett.,
48, 5371 (2007).
16. H.M. Meshram, G. Santosh Kumar, P. Ramesh and B. Chennakesava
Reddy, Tetrahedron Lett., 51, 2580 (2010).
17. S.B. Wadavrao, R.S. Ghogare and A.V. Narsaiah, Org. Commun., 6, 23
(2013).
6c
aReaction conditions: o-Phenylenediamine (1 mmol), α-halomethyl
aryl ketones (1 mmol), NaHCO3 (1.2 mmol), DMSO (5 mL), under air,
120 °C, 24 h. bIsolated yield
If non-symmetric 1,2-diaminoarenes are used as substrates,
there exist two isomers in the resulting product quinazolines
(entries 2-6), which are not isolatable on flash silica gel column
chromatography due to the similarity of two isomers.
18. S. Paul and B. Basu, Tetrahedron Lett., 52, 6597 (2011).
19. P. Ghosh and A. Mandal, Tetrahedron Lett., 53, 6483 (2012).
20. J.-F. Zhou, G.-X. Gong, L.-T. An, Y. Liu, F.-X. Zhu, Y.-L. Zhu and S.-J.
Ji, Synlett, 3163 (2008).
21. B. Madhav, S. Narayana Murthy, V. Prakash Reddy, K. Rama Rao and
Y.V.D. Nageswar, Tetrahedron Lett., 50, 6025 (2009).
Conclusion
We have developed a new efficient, greener synthetic
method of 2-arylquinoxalines from readily available 1,2-
diaminoarenes and substituted phenacyl halides. The hard
substrate substituted phenacyl chlorides are firstly used as
efficient substrates for synthesis of quinoxalines. Our protocol
with sodium bicarbonate as deacid reagent is facile, greener
and practical.
22. L. Nagarapu, R. Mallepalli, G.Arava and L.Yeramanchi, Eur. J. Chem.,
1, 228 (2010).
23. (a) C. Dai, X.F. Sun, X.Z. Tu, L. Wu, D. Zhan and Q. Zeng, Chem.
Commun., 48, 5367 (2012); (b) D. Zhan, T. Li, H. Wei, W. Weng, K.
Ghandi and Q. Zeng, RSC Adv., 3, 9325 (2013); (c) D. Zhan, T. Li, X.
Zhang, C. Dai, H. Wei, Y. Zhang and Q. Zeng, Synth. Commun., 43,
2493 (2013).
ACKNOWLEDGEMENTS
24. K. Alfonsi, J. Colberg, P.J. Dunn, T. Fevig, S. Jennings, T.A. Johnson,
H.P. Kleine, C. Knight, M.A. Nagy, D.A. Perry and M. Stefaniak, Green
Chem., 10, 31 (2008).
The authors thank the National Natural Science Foundation
of China (No. 21372034) and the Incubation Program for Excellent
Innovation Team of Chengdu University of Technology (No.
0084) for the financial support.