NbCl5 as an efficient catalyst for rapid synthesis of quinoxaline derivatives

Article abstract of DOI:10.1002/jhet.388

(Chemical Equation Presented) A series of quinoxaline derivatives have been synthesized in excellent yields by the condensation of 1,2-diketones and 1,2-phenylenediamines in the presence of a catalytic amount of NbCl₅ at room temperature in sho

Full text of DOI:10.1002/jhet.388

May 2010
NbCl5 as an Efficient Catalyst for Rapid Synthesis of Quinoxaline
Derivatives
703
Jun-Tao Hou, Yong-Hui Liu, and Zhan-Hui Zhang*
The College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050016,
People’s Republic of China
*E-mail: Zhanhui@126.com
Received November 8, 2009
DOI 10.1002/jhet.388
Published online 11 May 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of quinoxaline derivatives have been synthesized in excellent yields by the condensation of
1,2-diketones and 1,2-phenylenediamines in the presence of a catalytic amount of NbCl5 at room tem-
perature in short times.
J. Heterocyclic Chem., 47, 703 (2010).
INTRODUCTION
coupling of a-diazoketones with aryl 1,2-diamines [23],
reductive cyclization of 1,2-dicarbonyl compounds with
2-nitroanilines [7], heteroannulation of nitroketene N,S-
aryliminoacetals with POCl3 [24], intramolecular cycli-
zations of dialdimines [25], the reaction of aryl-1,2-dia-
mines and diethyl bromomalonate [26], the reaction of
o-phenylenediamines and ketones [27], reaction of o-
phenylenediamines and vicinal-diols [28], and palla-
dium-catalyzed reductive N-heteroannulation of enam-
ines [29] have been also developed to prepare function-
alized quinoxalines. However, the long reaction time
[15], costly catalysts, such as bismuth(III) triflate [8]
and gallium(III) triflate [10], requirement of special
effect for catalyst preparation [4,16] and a special
instrumentation, such as microwave [30], harsh reaction
conditions, such as heating at 70ꢀC [21] can not be
avoided. Because of the importance of quinoxaline
derivatives in organic synthesis, the development of a
convenient, efficient and practically useful process for
synthesis quinoxaline derivatives is in demand.
The quinoxaline derivatives are important heterocyclic
compounds, which exhibit a diverse range of biological
properties, such as antitumor [1], cytotoxic [2], antiviral,
antibacterial, anti-inflammatory, and kinase inhibitor
properties [3]. They have also been used as dyes, efficient
electron luminescent material, organic semiconductors,
DNA cleaving agents [4], photoinitiators in UV-cured
coatings [5], and donor materials [6]. In addition, the qui-
noxaline ring is a part of a number of antibiotics, such as
echinomycin, levomycin, and actinomycin that are
known to inhibit the growth of gram-positive bacteria
and are active against various transplantable tumors [7].
Therefore, the synthesis of this type of compounds
has attracted considerable attention. Synthetic routes that
are common to the preparation of these heterocycles
typically involve the reaction of 1,2-diamine and 1,2-
dicarbonyl compounds in refluxing ethanol or acetic
acid. Various catalysts, such as bismuth(III) triflate [8],
metal hydrogen sulfates [9], gallium(III) triflate [10],
molecular iodine [11], cerium (IV) ammonium nitrate
[12], stannous chloride [7], zirconium tetrakis(dodecyl
sulfate) [13], amidosulfonic acid [14], montmorillonite
K-10 [15], binary metal oxides supported on Si-MCM-
41 mesoporous molecular sieves [4], polyaniline-sulfate
salt [16], Wells-Dawson heteropoly acid [17], and ionic
liquid 1-n-butylimidazolium tetrafluoroborate [18] have
been used to promote this transformation. Alternative
approaches, such as oxidative cyclization of a-hydroxy-
ketones with o-phenylenediamines [19], reaction of o-
phenylenediamine with a-bromoketonethe [20,21], reac-
tion of a-keto oximes and 1,2-diamines [3], oxidative
coupling of epoxides and ene-1,2-diamines [22], the
In recent years, niobium pentachloride has been con-
sidered as mild Lewis acid catalyst for a variety of or-
ganic transformations [31], such as one-pot Mannich-
type reaction [32], alkoxide rearrangements [33], the
intramolecular Friedel–Crafts acylation reaction [34],
conversion of aldehydes and ketones to allylic halides
[35], cyanosilylation of aldehydes [36], synthesis of a-
aminonitriles [37], 1,1-diacetates [38], bis(indol)alkanes
[39], and 1,5-benzodiazepine derivatives [40]. However,
to the best of our knowledge, there is no report on the
synthesis of quinoxaline derivatives using niobium pen-
tachloride as a reagent. As part of our continuing inter-
est in the development of new synthetic methodologies
[41–46], we report herein an efficient and convenient
C
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J.-T. Hou, Y.-H. Liu, and Z.-H. Zhang
Vol 47
Scheme 1
nediamines and a wide of 1,2-diketones underwent the
condensation reaction smoothly to afford the corre-
sponding quinoxaline derivatives in excellent yields.
The electronic property of the substituents on the aro-
matic ring of 1,2-phenylenediamines had an obvious
effect on reaction time under the above optimal reaction
conditions. It was observed that electron-withdrawing
groups (Table 1, entries i–o) associated with 1,2-phenyl-
enediamines decreased the reactivity of the substrate
and long reaction times were required. It is worth noting
that the reaction of 4-nitrobenzene-1,2-diamine with
benzil failed to give the desired product. On the other
hand, the effect of electronic factors associated with aro-
matic 1,2-diketons is opposite. For example, 4,40-dibro-
molbenzil could react with 4-nitrobenzene-1,2-diamine
to afford the corresponding product (3o) in 92% yield.
Besides this, when 2,20-furil and acenaphthylenequinone
were subjected for condensation reaction, the corre-
sponding products were obtained with excellent yields.
All of the quinoxaline derivatives have been character-
procedure for the synthesis of quinoxaline derivatives by
the condensation of 1,2-diketones and 1,2-phenylenedi-
amines in the presence of a catalytic amount of niobium
pentachloride at room temperature (Scheme 1).
RESULTS AND DISCUSSION
At the onset of the research, we investigated the
model reaction between 1,2-phenylenediamines and ben-
zil in EtOH in the presence of a catalytic amount of
NbCl5 (3 mol%) at room temperature. To our delight,
the product 3a was formed and the complete conversion
with 95% isolated yield was observed after 2 min. Fur-
ther studies showed that EtOH was the best solvent
among the solvents (MeOH, MeCN, THF, DMF,
DMSO, CH2Cl2, and CHCl3). Next, the amount of the
catalyst was examined and we found that 3 mol%
NbCl5 was sufficient to drive the reaction completely in
95% yield. The less amount gave low yield even after a
prolonged reaction time, and the more amount could not
cause the obvious increase for the yield of product and
could not shorten the reaction time. It is noteworthy to
mention that the reaction gave only a 60% yield in the
absence of NbCl5 after 4 h.
1
ized by H NMR, 13C NMR, and IR spectra, and the
known compounds were confirmed by comparison of
their spectral data and melting points with those
reported in the literature.
In conclusion, we have developed a simple, rapid,
and efficient methodology for the synthesis of quinoxa-
line derivatives by the condensation 1,2-diketones and
1,2-phenylenediamines at room temperature using NbCl5
as a novel catalyst. Simplicity of operation, high yields,
short reaction time, and good substrate generality are
the key advantages of this method.
To evaluate the generality of this method, we next
investigated the scope and limitation of this reaction
under optimized conditions (EtOH, 3 mol% of NbCl5,
RT) and the results are illustrated in Table 1. As shown
in Table 1, a variety of structurally diverse 1,2-phenyle-
EXPERIMENTAL
Melting points were determined using an X-4 apparatus and
are uncorrected. IR spectra were obtained using a Bruker-
Table 1
Synthesis of quinoxaline derivatives catalyzed by NbCl5.
Entry
1,2-Diketones
R
Time (min)
Yield (%)a
Mp (ꢀC)
Lit. Mp (ꢀC)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Benzil
H
H
2
3
95
93
94
93
94
95
94
93
92
93
95
93
94
95
92
120–121
141–142
190–192
243–244
130–131
113–114
183–184
234–236
116–117
167–168
227–228
152–153
203–204
255–256
187–189
124–125 [14]
142–143 [7]
190–191 [7]
242–245 [8]
129–130 [12]
112–113 [7]
184–185 [18]
4,40-Dimethylbenzil
4,40-Dibromolbenzil
Acenaphthylenequinone
2,20-Furil
H
H
1.5
2
H
2
Benzil
4-Me
4-Me
4-Me
4-Cl
2
2
4,40-Dibromolbenzil
Acenaphthylenequinone
Benzil
2
4
118–119 [7]
166–167 [7]
4,40-Dibromolbenzil
Acenaphthylenequinone
Benzil
4,40-Dibromolbenzil
Acenaphthylenequinone
4,40-Dibromolbenzil
4-Cl
4-Cl
3
4
4-PhC¼O
4-PhC¼O
4-PhC¼O
4-NO2
20
5
4
20
140–142 [10]
188–190 [18]
a Isolated yields after column chromatography.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
NbCl5 as an Efficient Catalyst for Rapid Synthesis of Quinoxaline Derivatives
705
TENSOR 27 spectrometer instrument. NMR spectra were
taken with a Bruker DRX-500 spectrometer using TMS as in-
ternal standard. Elemental analyses were carried out on a
Vario EL III CHNOS elemental analyzer.
155.0, 155.6, 195.8; Anal. Calcd. for C25H14N2O C, 83.78; H,
3.94; N, 7.82. Found: C, 83.95; H, 4.13; N, 7.68.
Acknowledgments. The authors thank the National Natural
Science Foundation of China (20872025), the Nature Science
Foundation of Hebei Province (B2008000149), and the Research
Fundation for the Graduate Program of Hebei Normal University
for financial support.
General procedure for the synthesis of quinoxaline deriv-
atives (3). A mixture of 1,2-phenylenediamine (1 mmol), 1,2-
diketone (1.0 mmol), and NbCl5 (0.03 mmol) in EtOH (3 mL)
was stirred at room temperature. The progress of reaction was
monitored by TLC. After completion, water was added and the
product was extracted with ethyl acetate. The organic layer
was separated, dried over anhydrous sodium sulphate and the
solvent evaporated under reduced pressure to afford the crude
product. The crude product was subjected to column chroma-
tography over silica gel using hexane/ethyl acetate as eluent to
obtain pure product.
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