Sustainable approach to tandem catalysis: Expedient access to quinoxalines and pyrido[2,3-b]pyrazines from α-hydroxyketones via microwave-induced [(NH4)6Mo7O24·4H 2O - PEG 300] polar paste catalyst system

Article abstract of DOI:10.1016/j.crci.2012.06.007

[(NH₄)₆Mo₇O₂₄·4H ₂O-PEG 300] is introduced as a polar paste catalyst system for tandem synthesis of quinoxalines and pyrido[2,3-b]pyrazines under open-vessel focused microwave irradiation. Low conversions were obtained when catalyst or PEG was used individually. Accordingly, a convenient combination of catalyst and PEG mostly led to quantitative yield of products within 15 min microwave irradiation with good turnover frequency values (11-20 h^-1) taking a tandem process into consideration. The salient features of this environmentally benign method are fast conversions, high product selectivity and the use of a low-cost, readily available, nontoxic, catalyst and medium.

Full text of DOI:10.1016/j.crci.2012.06.007

C. R. Chimie 15 (2012) 764–767
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Full paper/M e´ moire
Sustainable approach to tandem catalysis: Expedient access to
quinoxalines and pyrido[2,3-b]pyrazines from -hydroxyketones via
microwave-induced [(NH ) Mo O ꢀ4H O – PEG 300] polar paste catalyst
a
4
6
7 24
2
system
Kioumars Aghapoor, Farshid Mohsenzadeh, Mina Mohebi Morad, Hossein Reza Darabi *
Chemistry and Chemical Engineering Research Center of Iran, Pajoohesh Boulevard, km 17, Karaj Hwy, 14968-13151 Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
[(NH ) Mo O ꢀ4H O–PEG 300] is introduced as a polar paste catalyst system for tandem
4
6
7
24
2
Received 14 April 2012
Accepted after revision 14 June 2012
Available online 15 July 2012
synthesis of quinoxalines and pyrido[2,3-b]pyrazines under open-vessel focused
microwave irradiation. Low conversions were obtained when catalyst or PEG was used
individually. Accordingly, a convenient combination of catalyst and PEG mostly led to
quantitative yield of products within 15 min microwave irradiation with good turnover
ꢁ
1
Keywords:
frequency values (11–20 h ) taking a tandem process into consideration. The salient
features of this environmentally benign method are fast conversions, high product
selectivity and the use of a low-cost, readily available, nontoxic, catalyst and medium.
ß 2012 Acad e´ mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
[
(NH
4
)
6
Mo
7
O
24ꢀ4H
2
O–PEG 300]
Tandem oxidation process
Benzo[N,N]-heterocycle
a-Hydroxy ketone
Open-vessel microwave irradiation
1
. Introduction
synthesized by a double condensation reaction of 1,2-
dicarbonyls with arene-1,2-diamines [19,20]. The use of a-
A tandem reaction utilizing a single catalyst to mediate
hydroxy ketones instead of 1,2-dicarbonyls in this reaction,
as an alternative route, has been recently developed [21–
28]. They are oxidatively cyclized with diamines in the
presence of transition metal oxides or oxygen to yield
quinoxalines. Although these methods have some synthetic
advantages individually, they are still plagued by some
limitations such as expensive catalysts and protocols,
excessive amounts of stoichiometric promoters, not readily
available materials, use of organic solvents, and difficulty of
recovery of high boiling solvents. Therefore, the develop-
ment of a practical, efficient, cost-effective and greener
alternative using a sustainable protocol is still of interest for
the preparation of these compounds.
In recent years, polyethylene glycols (PEGs) have
received increasing attention as benign reaction media
in organic synthesis due to their unique properties,
including very low volatility, biodegradability, high
stability towards acids, bases, and high temperature, and
availability in high quantities at low prices. Furthermore,
more than one transformation in a selective manner has
been recognized as one of the best methods for the
synthesis of complex skeletal organic compounds [1–6].
Tandem processes are very efficient in terms of work-up
and catalyst utilization, and provide the advantage that
intermediates do not require isolation where they are
unstable or difficult to handle (e.g., toxic, volatile or prone
to polymerize) [7,8].
Quinoxalines and pyrido[2,3-b]pyrazines are the subject
of considerable interest from both academic and industrial
perspectives because they are significant intermediates for
the manufacturing of pharmaceuticals and advanced
materials [9–18]. Conventionally, these heterocycles are
*
Corresponding author.
E-mail addresses: darabi@ccerci.ac.ir, r_darabi@yahoo.com
(
H.R. Darabi).
1
631-0748/$ – see front matter ß 2012 Acad e´ mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.06.007

K. Aghapoor et al. / C. R. Chimie 15 (2012) 764–767
765
OH
NH2
NH2
N
N
(NH ) Mo O ·4H O (0.1 mmol)
4
6
7
24
2
+
PEG 300
O
1
a
0
.5 mmol
1.0 mmol
Scheme 1. Oxidative cyclization of benzoin with benzene-1,2-diamine using [(NH
4
)
6
Mo
7
O
24ꢀ4H
2
O] as catalyst in PEG 300.
their well-known low toxicity makes them greener
versions of conventional halogenated solvents [29–33].
From the perspective of microwave chemistry [34–37], the
polar nature of PEGs and their application in phase transfer
catalysis make them attractive green reaction media in
microwave-assisted organic reactions [38–44].
filtered off. The resulting solid mixture was washed with
dichloromethane (10 mL) and filtered. The combined
organic medium was subjected to GC in order to find
out the conversion and then removed with a rotary
evaporator under reduced pressure to afford the product 1.
The crude products were purified by column chromatog-
raphy using ethyl acetate/hexane (2:8 v/v) [dichloro-
methane/ethanol (9:1 v/v) for products 1f–1j] to afford
pure products for analytical measurements. The products
were identified by comparison of their NMR and mass
spectra with authentic samples.
As part of our continuous efforts to develop sustainable
processes for benzo[N,N]-heterocyclic condensation [45–
5
2], herein, we introduce an oxidative polar paste of
(NH Mo O]–PEG as an efficient catalytic system
24ꢀ4H
for the tandem synthesis of quinoxaline derivatives from
-hydroxy ketones under microwave conditions. The
[
4
)
6
7
O
2
a
advantage of the present protocol is the use of ammonium
heptamolybdate tetrahydrate as a cheap, air stable and
commercially available catalyst [53] and PEG 300 as the
benign reaction medium under microwave irradiation in
3. Results and discussion
In an initial study, microwave-promoted oxidative
cyclization of benzoin (0.5 mmol) with benzene-1,2-
diamine (1 mmol) was chosen as a model reaction to
afford the product 1a (Scheme 1). As all employed
materials are non-volatile, the reactions were carried
out under open-vessel microwave conditions (420 W).
To optimize the reaction conditions, the effects of
catalyst loading, the PEG amount and the irradiation time
were investigated (Table 1). The microwave-promoted
reaction in the absence of PEG or (NH ) Mo O ꢀ4H O or
an open vessel without the aid of air, O
atmosphere.
2
or an inert
2
. Experimental
.1. General remarks
A laboratory microwave oven from Landgraf Laborsys-
2
4
6
7
24
2
teme HLL GmbH (model MW 3100, Langenhagen,
Germany) equipped with a magnetic stirrer operating at
both of them afforded the product 1a in low yield (Table 1,
entries 1, 5, 10). In contrast, the yield of 1a in the presence
of catalyst and PEG sharply increased to show their
synergistic cooperation in this tandem process (Table 1,
entries 2–4).
2
450 MHz was used for all syntheses. Microwave heating
was carried out using 420 W (70% of maximum power).
The temperature inside the open vessel was monitored
using a Precision Temperature Logger EBI-2 T Type 311
In the study of catalyst loading, the optimum amount of
(NH ) Mo O ꢀ4H O was found to be 0.1 mmol of catalyst
1
(possessing an external probe) from ebro Electronic
4
6
7
24
2
GmbH and Co KG. The recorded temperature after 15 min
per 0.5 mmol of benzoin (Table 1, entries 2–4). The
optimum amount of PEG was 0.2 g per 0.1 mmol of
irradiation was 90 8C.
1
13
The H and C NMR spectra were recorded on a Bruker
00-MHz spectrometer using TMS as internal standard and
Table 1
5
Optimization of the reaction conditions on the model reaction.
CDCl
000 connected to a mass detector (Trio 1000) with 70 eV
was used.
3
as solvent. A Fisons instruments gas chromatograph
8
Entry
Catalyst
mmol)
PEG 300
(g)
Conditions
Time
Conversion
(%)
(
(min)
a
1
2
3
4
5
6
7
8
9
–
–
MWI
15
15
15
15
15
15
15
15
10
15
15
300
36
87
93
90
2.2. General procedure for preparation of quinoxalines and
0.05
0.10
0.15
0.10
0.10
0.10
0.10
0.10
–
0.50
0.50
0.50
–
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
90 8C
25 8C
pyrido[2,3-b]pyrazines under microwave irradiation
46
82
54
100
72
23
In a typical reaction, a mixture of arene-1,2-diamine
0.70
0.10
0.20
0.20
0.20
0.20
0.20
(
(
[
1 mmol),
0.2 g) was mixed thoroughly with 0.10 mmol of
(NH Mo O] for a few minutes in order to ensure
a-hydroxy ketones (0.5 mmol) and PEG 300
4
)
6
7
O24ꢀ4H
2
1
1
0
1
complete homogeneity. The mixture was then inserted
into the microwave chamber and the reaction was carried
out in an open vessel maintaining the power at 420 W (70%
of maximum power) for 15 min. The reaction mixture was
washed with ethyl acetate (10 mL) and the mixture was
b
0.10
0.10
100 (81)
12
10
a
Microwave irradiation / 420 W / 90 8C
b
Although quantitative conversion was observed, the selectivity of the
reaction for the target product 1a is 81%.

7
66
K. Aghapoor et al. / C. R. Chimie 15 (2012) 764–767
HO
O
R'
R'
(NH
4
)
6
Mo
7
O
24·4H
2
O
(20 mol%)
N
N
R'
R'
PEG 300 (paste)
+
MWI (420 watt) / 15 min
NH2
R
Z
1
a - o
R
Z
NH2
Z = CH, N
Scheme 2. Access to various benzo[N,N]-heterocycles from
a-hydroxy ketones via microwave-induced polar paste catalyst system.
Table 2
Evaluation of the reaction scope.
a
ꢁ1 b
)
Entry
R
R’
Z
Product
Conversion (%)
Yield (%)
TOF (h
1
2
3
4
5
6
7
8
9
H
Ph
CH
CH
CH
CH
N
1a
1b
1c
1d
1e
1f
100
100
100
83
98
90
94
72
91
93
84
92
48
35
88
81
89
80
79
20
20
20
17
20
20
20
20
12
11
20
20
20
20
20
Me
Cl
Ph
Ph
NO
H
2
2
2
Ph
Ph
100
100
100
100
60
H
4-(MeO)-Ph
4-(MeO)-Ph
4-(MeO)-Ph
4-(MeO)-Ph
4-(MeO)-Ph
Me
CH
CH
CH
CH
N
Me
Cl
1g
1h
1i
NO
H
10
11
12
13
14
15
1j
55
H
CH
CH
CH
CH
N
1k
1l
100
100
100
100
100
Me
Cl
Me
Me
1m
1n
1o
NO
H
Me
Me
a
1
13
Yields refer to those of pure isolated products characterized by H NMR, C NMR and MS spectral analyses which is consistent with literature values
[
46–51].
b
TOF: turnover frequency = moles of converted substrate (
a-hydroxy ketone)/(moles of catalyst ꢂ reaction time in h).
catalyst. Higher and lower amounts of PEG gave the lower
yield of 1a (Table 1, entries 3, 6–8).
microwave irradiation, leads to no decomposition products
through a very clean reaction within a short reaction time.
Accordingly, a convenient combination of catalyst and
PEG led to quantitative yield of 1a within 15 min
microwave irradiation (Table 1, entry 8).
In the absence of microwave irradiation, lower yield of
1
a (81%) was obtained at 90 8C for 15 min (Table 1, entry
1
1), due to the formation of some by-products such as
benzimidazole homologues of 1a. Enhanced selectivity
under microwave heating compared to the conventional
one, may be in fact due to the ‘‘non-thermal microwave
effects’’ in this reaction [54].
This indicates that a significant difference in terms of
selectivity persist between experiments performed under
microwave heating and conventional thermal heating. In
other words, the acceleration of the reaction induced by
To expand the generality of this novel catalytic method,
various arene-1,2-diamines and
a-hydroxy ketones were
tested under the optimized conditions (Scheme 2) and the
results are presented in Table 2. Most of the reactions took
15 minutes to complete (i.e. 100% conversion) under
microwave conditions, although the yields were highly
dependent on the substrate used. To establish the scope
and limitations of catalyst for quinoxaline formation, the
Table 3
Literature results for the synthesis of 1a under various conditions.
c
Entry
Catalyst/Conditions
Time
Yield (%)
[References]
a
˚
1
2
3
4
5
6
7
MnO
Pd(OAc)
MnO octahedral MS (50 mg)/toluene/reflux
Fe–molybdophosphoric acid (50 mg)/O /CH
2
(10 equiv.)/MS 4 A/CH
2
Cl
2
/reflux
45 min
24 h
75
74
[21]
a
˚
2
(2 mol %)/MS 3 A/toluene/Et
3
N/THF/reflux
[22]
a
d
8 h
99
[24]
2
b
2
Cl
(1 equiv.)/TEMPO (10 mol%)/MWI (150 W)/sealed vial/150 8C
Ru/C (10 mol%)/Me- -cyclodextrin (300 mg)/O /H O/75 8C
(NH Mo O (20 mol%)/PEG 300 (0.2 g)/MWI (420 W)/90 8C
24ꢀ4H
2
/reflux
3 h
95
81
96
98
[25]
TiO
2
10 min
24 h
[27]
b
2
2
[28]
b
4
)
6
7
O
2
15 min
This work
a
MS: molecular sieves.
b
c
MWI: microwave irradiation.
Yields refer to those of pure isolated products.
GC yield (%).
d

K. Aghapoor et al. / C. R. Chimie 15 (2012) 764–767
767
[
[
[
[
11] Q. Weng, D. Wang, P. Guo, L. Fang, Y. Hu, Q. He, B. Yang, Eur. J.
Pharmacol. 581 (2008) 262.
12] O.O. Ajani, C.A. Obafemi, C.O. Ikpo, K.O. Ogunniran, O.C. Nwinyi, Chem.
Heterocycl. Comp. 45 (2009) 1370.
condensation between 4-nitrobenzene-1,2-diamine and
0
4
,4 -dimethoxybenzoin was considered. The presence of
0
the methoxy group in 4,4 -dimethoxybenzoin reduces the
electrophilicity of the carbonyl carbon through resonance
and the strong electron-withdrawing property of the nitro
group in 4-nitrobenzene-1,2-diamine decreases the nu-
cleophilicity of the amine group [24,45–50]. Accordingly,
the combination of these substrates provided the corre-
sponding product 1i in 48% yield (Table 2, entry 9).
The turnover frequency (TOF) for this catalytic process,
which is defined as mole of converted substrate per mole of
catalyst per hour, is listed in Table 2. In most cases,
13] S. Tanimori, T. Nishimura, M. Kirihata, Bioorg. Med. Chem. Lett. 19
(2009) 4119.
14] P. Ramalingam, S. Ganapaty, Ch. Babu Rao, Bioorg. Med. Chem. Lett. 20
(2010) 406.
[15] C. Pissot-Soldermann, M. Gerspacher, P. Furet, C. Gaul, P. Holzer, C.
McCarthy, T. Radimerski, C.H. Regnier, F. Baffert, P. Drueckes, G.A.
Tavares, E. Vangrevelinghe, F. Blasco, G. Ottaviani, F. Ossola, J. Scesa,
J. Reetz, Bioorg. Med. Chem. Lett. 20 (2010) 2609.
[16] M. Rueping, F. Tato, F.R. Schoepke, Chem. Eur. J. 16 (2010) 2688.
[
[
17] D.F. Saifina, V.A. Mamedov, Russ. Chem. Rev. 79 (2010) 351.
18] B.R. Yeo, A.J. Hallett, B.M. Kariuki, S.J.A. Pope, Polyhedron 29 (2010)
1
088.
[19] U. Urleb, in: E. Schaumann (Ed.), Methods of Organic Chemistry
Houben-Weyl), Vol. E9b/Part 2 (Hetarenes IV), Thieme, Stuttgart,
ꢁ1
moderate to good values of TOF in the range of 11 to 20 h
were achieved.
(
New York, 1998, p. 193.
There are recent reports of carrying out this reaction in
the presence of other catalysts under various conditions.
The data presented in Table 3 show the promising features
of this protocol in terms of reaction rate, product yield,
cost-effectiveness, catalyst availability and eco-friendli-
ness when compared with other protocols.
[
20] M. Sako, in: Y. Yamamoto (Ed.), (Volume Ed.): Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations, Vol. 16, Thieme,
Stuttgart, New York, 2003, p. 1269.
[
[
21] S.A. Raw, C.D. Wilfred, R.J.K. Taylor, Org. Biomol. Chem. 2 (2004) 788.
22] R.S. Robinson, R.J.K. Taylor, Synlett. 6 (2005) 1003.
[23] C.S. Cho, S.G. Oh, J. Mol. Catal. A: Chem. 276 (2007) 205.
[24] S. Sithambaram, Y. Ding, W. Li, X. Shen, F. Gaenzler, S.L. Suib, Green
Chem. 10 (2008) 1029.
[25] K.T. Venkateswara Rao, P.S. Sai Prasad, N. Lingaiah, J. Mol. Catal. A:
Chem. 312 (2009) 65.
4
. Conclusions
[26] C.S. Cho, W.X. Ren, J. Organomet. Chem. 694 (2009) 3215.
[27] V. Jeena, R.S. Robinson, Beilstein J. Org. Chem. 5 (2009) 24.
[28] V.K. Akkilagunta, V.P. Reddy, R.R. Kakulapati, Synlett. 17 (2010) 2571.
[29] C.K.Z. Andrade, L.M. Alves, Curr. Org. Chem. 9 (2005) 195.
In conclusion, we have developed a novel and benign
tandem oxidation protocol for the microwave-induced
direct synthesis of quinoxaline and pyrido[2,3-b]pyrazine
[30] T.J. Dickerson, N.N. Reed, K.D. Janda, Chem. Rev. 102 (2002) 3325.
[
[
[
[
31] J. Chen, S.K. Spear, J.G. Huddleston, R.D. Rogers, Green. Chem. 7 (2005)
derivatives from
a-hydroxy ketones and arene-1,2-dia-
64.
mines. Due to the wide range of functional groups
tolerated via this approach, various benzo[N,N]-hetero-
cycles were attained in moderate to excellent yields. The
32] D.J. Heldebrant, H.N. Witt, S.M. Walsh, T. Ellis, J. Rauscher, P.G. Jessop,
Green Chem. 8 (2006) 807.
33] N.R. Candeias, L.C. Branco, P.M.P. Gois, C.A.M. Afonso, A.F. Trindade,
Chem. Rev. 109 (2009) 2703.
use of (NH
4
)
6
Mo
7
O
24ꢀ4H
2
O as an inexpensive air stable
34] V. Molteni, D.A. Ellis, Curr. Org. Synth. 2 (2005) 333.
catalyst and PEG 300 as a green paste can provide an
alternative route to expensive protocols and reduce the
harmful effects of conventional organic solvents on the
environment.
[35] D. Bogdal, A. Loupy, Org. Process Res. Dev. 12 (2008) 710.
[
[
[
36] C.O. Kappe, D. Dallinger, Mol. Divers. 13 (2009) 71.
37] C.R. Strauss, Aust. J. Chem. 62 (2009) 3.
38] V. Polshettiwar, R.S. Varma, Acc. Chem. Res. 41 (2008) 629.
[39] V.V. Namboodiri, R.S. Varma, Green Chem. 3 (2001) 146.
[
40] F.M. Kerton, S. Holloway, A. Power, R.G. Soper, K. Sheridan, J.M. Lynam,
A.C. Whitwood, C.E. Willans, Can. J. Chem. 86 (2008) 435.
41] G. Chen, J. Weng, Z. Zheng, X. Zhu, Y. Cai, J. Cai, Y. Wan, Eur. J. Org. Chem.
20 (2008) 3524.
42] G.D. Yadav, B.G. Motirale, Org. Process Res. Dev. 13 (2009) 341.
43] G.A. Burley, D.L. Davies, G.A. Griffith, M. Lee, K. Singh, J. Org. Chem. 75
Besides, open-vessel microwave irradiation without the
2
aid of air, O or an inert atmosphere leads to reaction safe
[
conditions and rate enhancement. This catalytic procedure
offers general reactivity and is illustrated by the cost-
effective, energy-efficient and rapid preparation of con-
densed benzo[N,N]-heterocyclic compounds making the
procedure a powerful tool from an environmental vantage
point.
[
[
(2010) 980.
[44] Z. Du, W. Zhou, L. Bai, F. Wang, J.-X. Wang, Synlett 3 (2011) 369.
[45] K. Aghapoor, F. Mohsenzadeh, Sh. Talebian, M.J. Tehrani, Y. Balavar, G.
Khanalizadeh, H.R. Darabi, Monatsh. Chem. 142 (2011) 619.
[
46] H.R. Darabi, K. Aghapoor, F. Mohsenzadeh, M.R. Jalali, Sh. Talebian, L.
Ebadi-Nia, E. Khatamifar, A. Aghaee, Bull. Korean Chem. Soc. 32 (2011)
References
213.
[47] K. Aghapoor, H.R. Darabi, F. Mohsenzadeh, Y. Balavar, H. Daneshyar,
Transit. Metal Chem. 35 (2010) 49.
[
[
[
[
[
1] A. Ajamian, J.L. Gleason, Angew. Chem. Int. Ed. 43 (2004) 3754.
2] C.E. Ballard, J.P. Morken, Synthesis 9 (2004) 1321.
3] K. Sato, S.S. Yudha, N. Asao, Y. Yamamoto, Synthesis 9 (2004) 1409.
4] Z.Y. Wang, G. Zou, J. Tang, Chem. Commun. 10 (2004) 1192.
5] S. Thielges, E. Meddah, P. Bisseret, J. Eustache, Tetrahedron Lett. 45
[48] H.R. Darabi, K. Aghapoor, F. Mohsenzadeh, F. Taala, N. Asadollahnejad,
A. Badiei, Catal. Lett. 133 (2009) 84.
[49] H.R. Darabi, F. Tahoori, K. Aghapoor, F. Taala, F. Mohsenzadeh, J. Braz.
Chem. Soc. 19 (2008) 1646.
(
2004) 907.
[50] H.R. Darabi, Sh. Mohandessi, K. Aghapoor, F. Mohsenzadeh, Catal.
Commun. 8 (2007) 389.
[51] F. Mohsenzadeh, K. Aghapoor, H.R. Darabi, J. Braz. Chem. Soc. 18 (2007) 297.
[52] K. Aghapoor, H.R. Darabi, F. Mohsenzadeh, Z. Naturforsch. B 60 (2005)
901.
[
[
[
[
6] S.K. Mal, D. Ray, J.K. Ray, Tetrahedron Lett. 45 (2004) 277.
7] R.A. Sheldon, Pure Appl. Chem. 72 (2000) 1233.
8] R.J.K. Taylor, M. Reid, J. Foot, S.A. Raw, Acc. Chem. Res. 38 (2005) 851.
9] A. Carta, S. Piras, G. Loriga, G. Paglietti, Mini-Rev. Med. Chem. 6 (2006)
1
179.
[53] K. Jeyakumar, R.D. Chakravarthy, D.K. Chand, Catal. Commun. 10 (2009)
1948.
[54] A. De La Hoz, A. Diaz-Ortiz, A. Moreno, Chem. Soc. Rev. 34 (2005) 164.
[
10] R. Villar, E. Vicente, B. Solano, S. P e´ rez-Silanes, I. Aldana, J.A. Maddry, A.J.
Lenaerts, S.G. Franzblau, S.-H. Cho, A. Monge, R.C. Goldman, J. Anti-
microb. Chemother. 62 (2008) 547.