Zirconium triflate: An efficient catalyst for the synthesis of quinolines and quinoxalines

Article abstract of DOI:10.1007/s13738-013-0252-2

An environmentally friendly method is described for the preparation of substituted quinoline and quinoxaline derivatives using Zr(OTf)₄ as an efficient catalyst. The method is based on using 1,3-diketones, ketones and 2-aminoaryl ketones under solvent-free conditions and also on using 1,2-diketone, 1,2-diamine in EtOH/H₂O at room temperature for quinloine and quinoxaline synthesis, respectively. The advantages in using this method, include its environmental friendliness, simple operating process and good yields.

Full text of DOI:10.1007/s13738-013-0252-2

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0252-2
ORIGINAL PAPER
Zirconium triflate: An efficient catalyst for the synthesis
of quinolines and quinoxalines
•
Eskandar Kolvari Mohammad Ali Zolfigol
•
•
Nadiya Koukabi Maryam Gilandust
•
Abdol-Vahid Kordi
Received: 16 November 2012 / Accepted: 17 March 2013
Ó Iranian Chemical Society 2013
Abstract An environmentally friendly method is descri-
bed for the preparation of substituted quinoline and quin-
oxaline derivatives using Zr(OTf)4 as an efficient catalyst.
The method is based on using 1,3-diketones, ketones and
2-aminoaryl ketones under solvent-free conditions and also
on using 1,2-diketone, 1,2-diamine in EtOH/H2O at room
temperature for quinloine and quinoxaline synthesis,
respectively. The advantages in using this method, include
its environmental friendliness, simple operating process
and good yields.
reactions are mostly carried out by employing conventional
mineral acids, such as H2SO4, HNO3, and HF or Lewis
acids, such as AlCl3 and BF3. In view of environmental and
economical reasons, there is an ongoing effort to replace
the conventional catalysts with newer solid acids. This is
mainly due to the distinct advantages of solid acid cata-
lysts, such as non-toxicity, non-corrosiveness, ease of
handling, and ease to recover and reusability [1]. In this
direction, various solid acid systems were introduced
which include hetropolyacids, zeolites, and clays. The main
disadvantage associated with hetropolyacids is that they are
soluble in polar solvents and lose their activity at higher
temperatures by losing structural integrity. To prevent this
there are some attempts to immobilize them in silica or
activated carbon matrix, which, however, limits the
accessibility and efficiency of the catalysts. Although clays
and zeolites are quite reliable, activities of these materials
are much lower than those of the conventional homoge-
neous acids due to pore blocking and hydration. Consid-
ering these reasons, there is an ongoing effort to develop
stronger solid acid systems, which are water tolerant, stable
at high temperatures and suitable for both liquid and sol-
vent-free media. Metal-based catalysts offer several
advantages over zeolite and clay-based catalysts. These are
active over a wide range of temperatures and more resistant
to thermal excursions. Therefore, comprehensive investi-
gations were undertaken on promoted zirconium (IV) cat-
alysts for organic synthesis and transformation reactions
[2].
Keywords Zirconium triflate Á Quinolines Á Quinoxalines
Introduction
Acid catalysts play a predominant role in organic synthesis
and transformations. Many organic reactions, such as
alkylation, acylation, isomerization, nitration, esterifica-
tion, and rearrangements like pinacol, Beckman, etc. are
accomplished by acid catalysts. All these acid catalyzed
E. Kolvari (&) Á N. Koukabi (&)
Department of Chemistry, Semnan University, Semnan, Iran
e-mail: kolvari@semnan.ac.ir
N. Koukabi
e-mail: n.koukabi@semnan.ac.ir
M. A. Zolfigol (&) Á M. Gilandust
Faculty of Chemistry, Bu-Ali Sina University,
P.O. Box 4135, Hamedan, Iran
e-mail: zolfi@basu.ac.ir
For many years, synthesis of quinoline and quinoxaline
has been of considerable interest in organic and medicinal
chemistry since a large number of natural products and
drugs contain these heterocyclic nucleuses [3–5]. There are
many reported methods for the synthesis of quinoline rings
[6], the Friedlander procedure [7, 8] is still one of the
A.-V. Kordi
Department of Chemistry, Payame Noor University,
Hamedan, Iran
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J IRAN CHEM SOC
Ph
N
O
O
O
O
R1
R1
R3
Zr(OTf)4(20mol%)
60 °C, Solvent-free
R2
R3
R2
NH2
1
2
3
R1= Cl, H
R2 = CH3, Ph
R3= OMe, OEt, CH3,Ph
Ph
N
O
Ph
N
O
O
R1
R1
R1
O
O
Zr(OTf)4 (20mol%)
60 °C, Solvent-free
or
or
NH2
3
1
2
R1= Cl, H
Scheme 1 Zirconium triflate catalyzed synthesis of quinolines under solvent-free conditions
Table 1 Effect of different solvents for the synthesis of quinolines
(A) and quinoxalines (B) catalyzed by Zr(OTf)4
Table 2 Effect of various amount of Zr(OTf)4 for the synthesis of
quinolines (A) and quinoxalines (B)
Entry
Solvent
Time (h:min)
Yield (%)a
Entry
Zr(OTf)4 (mol %)
Time (h:min)
Yield (%)a
Ab
Bc
Ab
Bc
Ab
Bc
Ab
Bc
1
2
3
4
5
6
7
8
9
a
THF
1:00
04:00
04:00
00:30
04:00
04:00
04:00
04:00
00:10
04:00
90
82
50
92
95
52
57
85
98
89
90
94
87
85
87
80
96
78
1
2
3
4
5
6
a
5
01:15
01:00
01:00
00:30
01:30
24:00
00:20
00:10
00:20
00:20
00:20
24:00
90
93
95
98
94
86
78
96
90
86
80
73
Ethanol
Methanol
CH3CN
H2O
04:00
04:00
01:00
00:30
04:00
04:00
01:00
00:30
10
15
20
25
d
Ether
–
CH2Cl2
H2O/Ethanol
–
Isolated yield
b
All reactions were performed on a 1.0 mmol scale under solvent-
free conditions at 60 °C
c
All reactions were performed on a 1.0 mmol scale in H2O/Ethanolat
Isolated yield
R.T.
d
b
All reactions were performed on
20 mol %of Zr(OTf)4 in 5 ml of solvent
a
a
1.0 mmol scale using
1.0 mmol scale using
Without Zr(OTf)4
c
All reactions were performed on
10 mol %of Zr(OTf)4 in 5 ml of solvent
the synthesis of these heterocyclic compounds has been
usually carried out in harmful solvents such as acetonitrile,
THF, DMF, and DMSO, leading to difficult product iso-
lation and recovery procedures, thus making these methods
unsuitable for scale up in an environmentally benign
and economical way. When considering the wide spread
applications of the resultant compounds, we felt that a
catalyst of choice should be one that is easily available, less
toxic, and operable under environmentally friendly condi-
tions so as to fulfil the ‘triple bottom line’ hilosophy of
green chemistry.
simplest and straightforward methods for the synthesis of
polyfunctional quinolines. Alternatively, this reaction was
also investigated using different protic and Lewis acids,
such as Nano-Flake ZnO [9], Bi(OTf)3 [10], FeCl3 and
Mg(ClO4)2 [11], AcOH under microwave irradiation [12],
HCl [13], PBBS and TBBDA [14]. In addition, a number of
synthetic strategies have been developed for the prepara-
tion of substituted quinoxalines, such as the bi-catalyzed
oxidative coupling reaction [15], via a tandem oxidation
process using Pd(OAc)2 or RuCl2–(Ph3P)3–TEMPO [16],
heteroannulation of nitroketene N,S-arylaminoacetals with
POCl3 [17], etc [18–21].
Thus to continue our investigation on developing new
methodologies in synthesis of heterocyclic compounds
[22–25] and to explore the applicability of zirconium
in various reactions, we became interested in zirconium-
triflate promoted synthesis of quinolines and quinoxalines
containing reactive functionalities.
However, most of the synthetic protocols reported so far
suffer from high temperatures, prolonged reaction times,
low yields and the use of hazardous catalysts. Moreover,
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J IRAN CHEM SOC
Table 3 Synthesis of quinolines derivatives catalyzed by Zr(OTf)4 using different 1,3-diketones,ketones and 2-aminoaryl ketones
MP
2-Aminoaryl
Yield
(%)b
Entry
1,3-Diketone
Product
( C)
Time(min)
ketone
Found
1
2
157-158
101-102
134-135
217-218
136-138
185-186
165-166
111-113
98-100
90
90
30
30
120
60
30
30
30
90
97
88
98
89
85
98
90
85
83
80
3
4
5
6
7
8
9
10
106-108
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J IRAN CHEM SOC
Table 3 continued
MP
( C)
2-Aminoaryl
ketone
Yield
(%)b
Entry
1,3-Diketone
Product
Time(min)
Found
11
12
13
14
140-141
130-133
158-160
146-148
30
60
88
93
95
91
90
120
All reactions were performed on 1.5 mmol of 1,3-diketone, 1.0 mmol of 2-aminoaryl ketone, 20 mol % of Zr(OTf)4, at 60 °C under solvent-free
conditions
a
1
Isolated yield of quinolines, confirmed by HNMR
Scheme 2 Zirconium triflate
catalyzed synthesis of
quinoxalines at room
temperature
R1
EAA
R2
R2
NH2
NH2
R1
O
O
N
N
R2
R2
Zr(OTf)4 (10 mol%)
EtOH/ H2O, r.t.
+
1'
2'
3'
Results and discussion
columns A). In the absence of Zr(OTf)4, the reaction takes
more than 24 h to complete (Table 2). In an optimized
reaction condition, 1,3-diketone (1.5 mmol) and 2-am-
inoaryl ketones (1.0 mmol) were mixed with Zr(OTf)4
(0.2 mmol) and stirred at 60 °C under solvent-free con-
ditions for 0.5–2 h. After the completion of the reaction
(monitored by TLC), a simple work up affords the prod-
ucts in excellent yields.
We initially investigated the effect of different solvents on
the reaction rate as well as the yield of product in the
synthesis of 6-chloro-3-(methylformato)-2-methyl-4-phe-
nylquinoline from 2-amino-5-chlorobenzophenone and
methyl acetoacetate in the presence of Zr(OTf)4 as a
model reaction. Screening different solvents, shows H2O
afford the products in good yields and with higher reaction
rates but under solvent-free conditions, the reactions pro-
ceeded to afford the corresponding product in less time
and excellent yield (Scheme 1; Table 1, columns A). We
also evaluated the amount of Zr(OTf)4 required for this
transformation to improve the yield and optimize the
reaction conditions, using a 20 % mol of catalyst is most
effective in terms of both time and yield (Table 2,
To evaluate the efficiency of this methodology, a
number of 1,3-diketones, ketones and 2-aminoaryl ketones
were further subjected to condensation using catalytic
amount of Zr(OTf)4 (Table 3). Reactions proceeded very
cleanly at 60 °C and no undesirable side reactions were
observed.
Subsequently, this catalyst was explored for the syn-
thesis of quinoxalines. A blank reaction was conducted
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J IRAN CHEM SOC
Table 4 Synthesis of quinoxaline derivatives catalyzed by Zr(OTf)4 using different 1,2-diketones and 1,2-diamines
Mp ( C) Time Yield
Entry
1
1,2-Diamine
1,2-Diketone
Product
(min) (%)b
Found
10
96
124-125
(30)c (90)c
2
3
4
151-152
189-192
132-134
30
20
30
87
87
87
5
189-191
30
94
6
7
187-189
242-244
20
30
94
94
8
198-200
20
94
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J IRAN CHEM SOC
Table 4 continued
Mp ( C) Time Yield
Entry
9
1,2-Diamine
1,2-Diketone
Product
(min) (%)b
Found
240-243
30
96
10
11
12
115-117
189-191
205-207
15
20
20
97
85
95
13
14
N.R.d
N.R.d
----
----
360
360
-
-
15
16
N.R.d
N.R.d
----
----
360
360
-
-
Reaction conditions: 1,2-diketone (1.0 mmol), 1,2-diamine (1.2 mmol), Zr)OTf(4 (10 mol %) in 5 ml of H2O/EtOH at R.T.
a
Isolated yield of quinoxalines
b
Reaction conditions: 1,2-diketone (1.0 mmol), 1,2-diamine (1.2 mmol), CF3SO3H (10 mol %) in 5 ml of H2O/EtOH at R.T.
c
No reaction was observed
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J IRAN CHEM SOC
using benzil and o-phenylenediamine, for initial optimi-
zation of the reaction conditions and the identification of
the best solvent, and amount of catalyst. The mixture of
EtOH/H2O was found to be more effective when compared
with the other solvent tested (Table 1, Entry 8, column B).
Among different amounts of catalyst used, 10 mol % gave
the optimum yield (Table 2, Entry 2, column B). In sum-
mary, the optimal conditions for the zirconium-triflate
catalyzed quinoxaline synthesis involved a combination of
Zr(OTf)4 (10 mol %), 1,2-diketone (1.0 mmol) and 1,2-
diamine (1.2 mmol) and EtOH/H2O as solvent at room
temperature. Encouraged by these results, a number of 1,2-
diketones and 1,2-diamines were further subjected to
Table 5 Reuse of Zr(OTf)4 for the synthesis of 6-chloro-3-)methyl-
formato(-2-methyl-4-phenylquinoline (A) and 2,3-diphenylquinoxa-
line (B)
Run
1
2
3
Aa
Bb
96
Aa
Bb
94
Aa
Bb
93
Yield (%)c
98
97
94
a
Reaction conditions: 2-amino-5-chlorobenzophenone (1.0 mmol),
methyl acetoacetate (1.5 mmol), and Zr(OTf)4 (0.20 mmol), under
solvent-free conditionsat 60 °C
b
Reaction conditions: o-phenylenediamine (1.2 mmol), benzyl
(1.0 mmol), and Zr(OTf)4 (0.10 mmol) in EtOH/H2O at room
temperature
c
Isolated yield of the quinolone and quinoxaline
Scheme 3 Suggested
mechanism pathway for
synthesis of quinolines
catalyzed by zirconium triflate
R3
O
R3
O
Zr(OTf)4
R1
O
- Zr(OTf)4
O
H2N
R2
-H+
+ H+
R2
O
H
R2
N
HO
O
R1
Zr(OTf)4
O
R3
1
(TfO)4Zr
O
H
Ph
R3
R1
-H2O
-H2O
O
+ Zr(OTf)4
N
Ph
N
O
R2
R1
R3
2
R2
R2
Scheme 4 Suggested
O
mechanism pathway for
zirconium triflate catalyzed
synthesis of quinoxalines
4(OTf)Zr
H2N
R1
R2
O
R2
R2
O
O
H2N
R2
R2
H2N
R1
O
O
4(OTf)Zr
H2N
Zr(OTf)4
R2
R2
N
N
H
N
R1
HO
R2
R1
- H+
-2 H2O
+ H+
R2
HO
N
H
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J IRAN CHEM SOC
General experimental procedure for the preparation
condensation using catalytic amount of Zr(OTf)4
(Scheme 2; Table 4). Reactions proceed very cleanly at
room temperature and no undesirable side reactions were
observed.
of quinoxalines
A mixture of 1,2-diketone (1.0 mmol), 1,2-diamine 2
(1.2 mmol) and Zr(OTf)4 (0.1 mmol) in EtOH/H2O
(3:2 ml) was stirred at room temperature. The progress of
the reaction was monitored by TLC. After completion of
the reaction, the solvent was evaporated in vacuum.
To separation of catalyst ‘‘Zr(OTf)4’’, ethyl acetate (15 ml)
was added to the reaction mixture. Organic materials were
dissolved in ethyl acetate and insoluble Zr(OTf)4 was
separated by simple filtration and saved for the next reac-
tion. The solvent evaporated under reduced pressure to
afford the crude product, which was recrystallized by
suitable solvent like ethanol to obtain pure quinoxaline.
All of the obtained quinolines and quinoxalines are
known compounds and identified by 1H-NMR and melting
point when compared with the literature values.
The possibility of recycling the catalyst was examined.
For this reason, the reaction of 2-amino-5-chloroben-
zophenone and methyl acetoacetate at 60 °C under solvent-
free conditions and the reaction of o-phenylenediamine and
benzil in EtOH/H2O at room temperature in the presence of
Zr(OTf)4 was studied. When the reaction was completed,
solvent was evaporated in vacuum, ethyl acetate was added
and organic materials were extracted and Zr(OTf)4 was
saved for the next reaction. The recycled catalyst could
be directly reused. We have found that Zr(OTf)4 is a
reusable catalyst and even after three runs for the synthesis
of quinoline and quinoxaline, the catalytic activity of
Zr(OTf)4 was almost the same as that of the freshly used
catalyst (Table 5).
The mechanisms for these reactions are shown in
Schemes 3, 4. The nucleophilic attack of 2-aminoaryl
ketone to ketone take place to give intermediate 1 in the
presence of Lewis acid Zr(OTf)4 (Scheme 3). The dehy-
dration of 1 gives another intermediate 2 which is further
activated by Lewis acid Zr(OTf)4 and serves as an elec-
trophile. An intramolecular attack of a-carbon of enamine
on the activated carbonyl group of 2-aminoaryl ketone then
occurs to give the cyclization product, followed by dehy-
dration, forming the desired quinoline product. On the
other hand, the condensation reaction of 1,2-diamine with
1,2-dicarbonyl compounds follows the regular mechanism
of acid-catalyzed condensation reactions [2], we assumed
that the step involve the complexation of Zr(OTf)4 with the
diketone by acting as an acid, followed by nucleophilic
attack of 1,2-diamine on the resulting intermediate.
Following dehydration, the products obtained, as shown in
Scheme 4.
Conclusion
In this article, we have successfully developed a new, and
easy catalytic protocol for the preparation of various
quinolines and quinoxalines, using catalytic amounts of
Zr(OTf)4 under solvent-free conditions and at room tem-
perature, respectively. The use of non-toxic Zr(OTf)4 as
catalyst for the synthesis of quinolines in moderate to
excellent yields is also significant under the aspect of
environmentally benign process.
Acknowledgments The authors acknowledge to Bu-Ali Sina Uni-
versity Research Council and Center of Excellence in Development of
Chemical Methods (CEDCM) and national foundation of elites
(BMN) for support of this work.
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