A reusable zirconium(IV) Schiff base complex catalyzes highly efficient synthesis of quinoxalines under mild conditions

Article abstract of DOI:10.1007/s11243-012-9657-5

A zirconium(IV) complex of a bidentate Schiff base (ZrL₂Cl ₂) has been synthesized by the reaction of (z)-N-benzylidene-2- hydroxypropane-1-amine (HL) and ZrCl₄. Spectroscopic data and elemental analyses are consistent with a monomeric complex with a ligand:Zr ratio of 2:1. The catalytic activity of ZrL₂Cl₂ has been investigated for the efficient synthesis of a wide variety of quinoxaline derivatives under mild conditions. The employment of ethanol as an environmentally benign solvent in this high yield method, along with high turnover numbers and reusability of the catalyst providing ready scalability, makes it appropriate for practical applications.

Full text of DOI:10.1007/s11243-012-9657-5

Transition Met Chem (2013) 38:31–36
DOI 10.1007/s11243-012-9657-5
A reusable zirconium(IV) Schiff base complex catalyzes highly
efficient synthesis of quinoxalines under mild conditions
•
Maasoumeh Jafarpour Abdolreza Rezaeifard
•
•
Reza Haddad Somayeh Gazkar
Received: 24 July 2012 / Accepted: 1 October 2012 / Published online: 28 October 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract A zirconium(IV) complex of a bidentate Schiff
base (ZrL2Cl2) has been synthesized by the reaction of (z)-
N-benzylidene-2-hydroxypropane-1-amine (HL) and ZrCl4.
Spectroscopic data and elemental analyses are consistent
with a monomeric complex with a ligand:Zr ratio of 2:1.
The catalytic activity of ZrL2Cl2 has been investigated for
the efficient synthesis of a wide variety of quinoxaline
derivatives under mild conditions. The employment of
ethanol as an environmentally benign solvent in this high
yield method, along with high turnover numbers and reus-
ability of the catalyst providing ready scalability, makes it
appropriate for practical applications.
Zirconium(IV), with a high charge-to-size ratio (Z2/r is
22.22 e2 m-10) [9], has a strong coordinating ability with
oxygen- and nitrogen-containing ligands. This has led to
the development of zirconium Schiff base complexes
which are efficient catalysts both in homogeneous and
heterogeneous reactions. The activity of these complexes
varies markedly with the type of ligands and coordination
sites [10–16].
In continuation of our ongoing research on the devel-
opment of new eco-friendly organic synthesis, particularly
by mediation of zirconium salts [17–26], in this paper, we
introduce (ZrL2Cl2) [26] (Scheme 1) as a new and efficient
catalyst for the condensation of aryl 1,2-diamines with 1,2-
dicarbonyl compounds in ethanol under mild conditions in
good to high yields (Scheme 2).
Introduction
Quinoxalines play an important role as a basic skeleton for
the design of a number of antibiotics such as echinomycin,
actinomycin and leromycin [1]. Quinoxaline derivatives
have also found applications in dyes [2], organic semi-
conductors [3], DNA cleaving agents [4–6] and as useful
rigid subunits in macrocyclic receptors and molecular
recognition [7]. Despite remarkable efforts made in the last
decade, the development of an effective and general
method for synthesis of the quinoxaline ring is still an
important challenge [8].
Experimental
Materials and methods
All chemicals were purchased from Merck or Fluka. The
progress of the reaction was monitored by TLC using silica
gel SIL G/UV 254 plates and also by GC–FID on a Shi-
madzu GC-16A chromatograph using a 25-m CBP1-S25
(0.32 mm ID, 0.5 lm coating) capillary column. NMR
spectra were recorded on Bruker Avance DPX 250 MHz
and 400 MHz spectrometers. Mass spectra were recorded
on a Shimadzu GC–MS–QP 5050A instrument.
M. Jafarpour (&) ꢀ A. Rezaeifard (&) ꢀ R. Haddad ꢀ S. Gazkar
Catalysis Research Laboratory, Department of Chemistry,
Faculty of Science, University of Birjand, 97179-414 Birjand,
Iran
Preparation of the Schiff base
Benzaldehyde (0.1 ml, 1 mmol) was added to a solution of
1-amino-2-propanol (0.17 ml, 1.5 mmol) in distilled water
(0.2 ml). The mixture was refluxed for 1 h. The product
e-mail: mjafarpour@birjand.ac.ir
A. Rezaeifard
e-mail: rrezaeifard@birjand.ac.ir; rrezaeifard@gmail.com
123

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Transition Met Chem (2013) 38:31–36
Scheme 1 Synthesis of
ZrL2Cl2
CHO
N
H2O
reflux/1 hr
H2N
+
OH
OH
N
Cl
O
ZrCl4
N
Zr
O
Cl
2
dry CH2Cl2
OH
N
Scheme 2 Synthesis of
R2
N
R2
Cl
O
Zr
O
Cl
quinoxaline derivatives in the
presence of ZrL2Cl2 (1 mol %)
in ethanol at room temperature
N
R1
N
N
O
R1
NH2
NH2
1 mol%
+
Ethanol/ rt
O
R2
R2
which was precipitated after cooling the reaction mixture,
was filtered off and washed with cold water. The Schiff
base was purified by recrystallization from n-hexane.
reaction mixture was stirred at room temperature for an
appropriate time, as monitored by TLC (Table 1). When
the reaction was complete, the precipitate was filtered off
and washed with ethanol. The remaining product in the
filtrate was isolated from excess 1,2-diamine by plate
chromatography, eluted with n-hexane/EtOAc (10/2).
HL1; M.P: 73–75 °C; IR (KBr,): (C=N) 1,638 cm-1
;
1H NMR (250 MHz, CDCl3) dppm = 1.33 (d, 3H, J =
6.25 Hz), 2.69 (s, 1H, OH), 3.43–3.51(m, 1H), 3.66–3.72 (m,
1H), 4.04–4.11 (m, 1H), 7.40–7.74 (m, 5H, Ar), 8.3 (s, 1H,
CH=N);13CNMR(CDCl3, 63 MHz)d(ppm) = 20.6, 67.47,
68.59, 128.18, 128.62, 130.88, 135.85, 162.77; Anal. Calcd
for (C10H13NO): C, 73.6; H, 8; N, 8.6. Found: C, 73.6; H, 8.1;
N, 8.6; MS (m/e) = 163 [M]?.
1
Structural assignment of each product was based on its H
NMR, 13C NMR and MS spectra.
Results and discussion
Preparation of the complex
Characterization of the complex
Zirconium(IV) chloride (0.233 g, 1 mmol) was added to a
solution of HL (0.326 g, 2 mmol) in dry CH2Cl2 (10 ml).
The reaction mixture was stirred under N2 for 2 h at room
temperature. The precipitated product was filtered off,
washed with cold dry CH2Cl2 and then dry n-hexane. The
complex was dried under reduced pressure as a deep yel-
low powder and obtained in 80 % yield. M.P: 143 °C; IR
The Schiff base ligand HL (Scheme 1) was prepared by the
condensation of 1-amino-2-propanol with benzaldehyde in
water. Reaction of HL with ZrCl4 in CH2Cl2 gave the
expected complex, ZrL2Cl2, as a yellow powder.
Analytical and spectroscopic data for the complex are
given in the experimental section. The spectroscopic data
and elemental analyses are consistent with a monomeric
complex with a ligand:Zr ratio of 2:1. When the synthesis
was repeated using three equivalents of HL, the same
product was obtained as with two equivalents. The char-
acteristic imine band of the Schiff base (1,638 cm-1) is
shifted to higher wave number after coordination of the
azomethine nitrogen to the Zr center, appearing at
1,665 cm-1 for the complex. A sharp singlet at 8.3 ppm in
(KBr,): (C=N) 1,665 cm-1 1H NMR (400 MHz, d6-
;
DMSO) dppm = 1.17 (d, 6H, J = 6.4 Hz), 3.58–3.88 (m,
4H, CH2), 4.26 (m, 2H), 7.49–7.62 (m, 10H, Ar), 9.05(s,
2H, CH=N). 13C NMR(100.64 MHz, d6-DMSO): 21.31,
63.46, 64.16, 128.21, 129.03, 130.06, 137.07, 171.72;
Anal. Calcd for (C20H24N2O2ZrCl2): C, 49.4; H, 5; N, 5.8.
Found: C, 49.4; H, 5; N, 5.7. MS (m/e) = 484 [M?].
1
General procedure for synthesis of quinoxalines
the H NMR spectrum of the free Schiff base, assigned to
the azomethine proton is shifted downfield after complex-
ation, appearing at 9.05 ppm due to coordination of the
azomethine nitrogen. The absence of a broad singlet at
*2.75 ppm in the spectrum of the zirconium complex
The appropriate 1,2-diamine (1.2 mmol) was added to a
solution of the 1,2-dicarbonyl compound (1 mmol) and the
complex (0.0048 g, 0.01 mmol) in ethanol (1 ml). The
123

Transition Met Chem (2013) 38:31–36
33
Table 1 Synthesis of quinoxaline derivatives catalyzed by ZrL2Cl2
Entry
1
Diamine
1,2-diketone
Producta
Time (min.)
Isolated yield (%)
NH2
NH2
N
N
O
O
\1
95
H3C
NH2
2
O
O
H3C
N
N
NH2
\1
94
3b
O2N
NH2
NH2
O
O
O2N
N
N
90
96
97
H2N
4
O
O
N
N
180
H2
N
NH2
OCH3
OCH3
5
O
O
N
N
NH2
35
97
OCH3
OCH3
OCH3
6c
H3C
NH2
OCH3
O
O
H3
C
N
NH2
50
94
N
OCH3
OCH3
OCH3
OCH3
O2
N
NH2
NH2
7
O
O
O2N
N
N
180
\10
OCH3
OCH3
N
CH3
CH3
NH2
O
O
CH3
8
9
2
95
94
NH2
N
CH3
H3
C
N
CH3
H3
C
NH2
NH2
O
CH3
\1
N
N
CH3
CH3
O
O
CH3
CH3
O2
N
10
11
O2
N
NH2
NH2
7
95
95
N
CH3
O
O
CH3
CH3
N
N
H2N
H2N
10
O
CH3
123

34
Transition Met Chem (2013) 38:31–36
Table 1 continued
Entry
12
Diamine
1,2-diketone
Producta
Time (min.)
Isolated yield (%)
NH2
NH2
N
N
O
O
O
5
97
O
O
O
O
O
O
13
14
15
H3
C
NH2
H3
C
N
N
O
O
O
O
O
O
NH2
3
30
80
97
64
95
O
O2
N
NH2
NH2
O2
N
N
N
O
O
O
O
H2N
H2N
N
N
O
O
O
O
The reactions were run at room temperature in 1 ml ethanol and the molar ratio of 1,2-dicarbonyl/1,2 diamine/catalyst was 100:120:1
a
All products were identified by their spectroscopic data [22, 24]
b
The molar ratio of 1,2-dicarbonyl/1,2-diamine/catalyst was 100:120:5
c
Reaction was carried out in 2 ml ethanol
compared to the free Schiff base indicates the deprotona-
tion and coordination of the hydroxyl group [14–16, 26].
was investigated. From these experiments, ethanol, which
is a standard green solvent, was found to be the best choice
in terms of both yield and selectivity; however, the desired
product was formed in only 58 % yield after 3 h [24].
Next, the reaction conditions were investigated using a
reaction of o-phenylenediamine and 4,40-dimethoxybenzil
(1.2:1), with respect to temperature, time and the molar
ratio of ZrL2Cl2 to the reactants in ethanol (1 ml). We
found that 1 mol % of ZrL2Cl2 was sufficient to obtain the
desired quinoxaline in 97 % yield within 35 min at room
Catalytic activity
Our preliminary studies were addressed to the condensation
of o-phenylenediamine with 4,40-dimethoxybenzil as a
model reaction under neat conditions, which gave 40-50 %
yield by NMR after 7 h. Next, the influence of solvent on
the reaction at room temperature in the absence of catalyst
Scheme 3 Plausible
ZrL2Cl2
mechanism for the synthesis of
quinoxalines in the presence of
ZrL2Cl2 complex (1 mol %)
R2
R2
R1
O
O
NH2
NH2
R1
N
N
- 2 H2O
+
R2
R2
ZrL2Cl2
R1= H, CH3
R1= H, CH3
R2= H, OCH3
R2= H, OCH3
123

Transition Met Chem (2013) 38:31–36
35
temperature. It should be mentioned here that the
employment of an equimolar ratio of 1,2-dicarbonyl and
1,2-diamine in this system, decreased the yield.
Table 2 Catalytic activity of ZrL2Cl2 in comparison with other cat-
alysts used for o-phenylenediamine and benzil
Entry
Catalyst
Catalyst
(mol %)
Time
(min)
Yield
(%)
Ref.
These optimized reaction conditions were then applied
for various 1,2-diamines and 1,2-dicarbonyl compounds.
The yields of products were highly dependent on the
electronic demands of the reactants. For instance, the
condensations of diamines bearing a strongly electron-
withdrawing groups (Table 1, entries 3,7,10 and 14) or
dicarbonyl compounds with a strongly electron-donating
substituents proceeded slowly (Table 1, entries 5–7).
Based on these observations, a mechanism may be
suggested for this reaction (Scheme 3). The Zr(IV) Schiff
base complex acts as a Lewis acid, leading to its interaction
with the carbonyl oxygen atom of the 1,2-diketone, thereby
increasing the polarization of carbonyl moiety and pro-
moting the condensation reaction.
a
1
2
3
4
5
6
7
8
9
a
ZrL2Cl2/ethanol
ZrOCl2 8H2O
1
\1
2
95
97
–
10
[24]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
ZrCl4/methanol
Zr(DS)4/H2O
5
5
100
94
2.5
10 wt%
10
30
90
15
10
150
20
Zr–CAP–SG/ethanol
CuSO4 5H2O/H2O
Zn[(L)proline], HOAc
Mont K-10, H2O
[Hbim]BF4
92
96
10
95
10
100
96
2 mL
This work
(1 mmol) and o-phenylenediamine (1 mmol), and the
resulting mixture was stirred at room temperature. The
desired quinoxaline was produced after 5 min in 95 %
yield. The recovered catalyst (according to above-men-
tioned procedure) could be directly reused five times
without any treatment and no appreciable loss in its cata-
lytic activity. The comparison of electronic spectra of fresh
and reused catalyst demonstrated a durability of 88 %
during the five runs, according to intensity of the charac-
teristic absorption bands [k = 240 nm, Abs. = 1.6
(A: UV–Vis spectra of fresh complex) and 1.4 (B: UV–Vis
spectra of complex after 5 times reuses)], providing more
evidence for stability of the title catalyst under the reaction
conditions (Fig. 1).
The high yields of condensation products obtained by
this catalytic system within short reaction times indicate
the high efficiency of this Zr(IV) Schiff base complex as a
catalyst. This is further supported by high turnover num-
bers obtained for the catalyst in the condensation of
o-phenylenediamine and 4,40-dimethoxybenzil (6,000/24 h)
under mild conditions using a 12,000:10,000:1 molar ratio
of o-phenylenediamine/4,40- dimethoxybenzil/catalyst.
The possibility of reuse of the catalyst was examined.
For these experiments, the condensation of o-phenylene-
diamine (1.2) and 2,20-difuril (1 mmol) in ethanol (1 ml) at
room temperature in the presence of ZrL2Cl2 (1 mol %)
was chosen. When the reaction was complete, the precip-
itated solid was filtered off and washed with ethanol. The
filtrate was evaporated under vacuum to afford the complex
and excess diamine that was saved for the next reaction. To
this mixture was added ethanol (1 ml), 2,20-difuril
This high yielding condensation method offered ready
scalability. In the condensation of o-phenylenediamine and
benzil as substrates in a semi-scale-up procedure (20-fold),
the related product was secured in 95 % yield.
In Table 2, we have also shown the merit of this oper-
ationally simple catalytic protocol for condensation of
o-phenylenediamine and benzil in comparison with some
other known catalysts in terms of conversion rate, catalyst
loading and media.
Conclusion
In this study, we have introduced an eco-friendly synthesis
for a wide variety of quinoxaline derivatives in the pres-
ence of a reusable Zr(IV) Schiff base complex catalyst
under mild conditions. The employment of ethanol as an
environmentally benign solvent in this high yielding
method, along with high turnover numbers and reusability
of the catalyst providing ready scalability, makes it
appropriate for practical applications.
Fig. 1 UV–Vis spectra of fresh ZrL2Cl2 complex (a) and after 5
times reuses (b) in the condensation of o-phenylenediamine and 2,20-
difuril in ethanol
Acknowledgments Support for this work by Research Council of
University of Birjand is highly appreciated.
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Transition Met Chem (2013) 38:31–36
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