2 (Oxa) as a heterogeneous recyclable catalyst: Synthesis of pyrazoles under mild reaction conditions

Article abstract of DOI:10.1039/c6nj01723a

We developed a novel and highly efficient protocol for the synthesis of important pyrazole derivatives by using some 1,3-dicarbonyl compounds and phenyl hydrazines via a one-pot protocol. As a recyclable heterogeneous catalyst, we used [Ce(l-Pro)₂]₂ (Oxa). In addition, the catalyst is recyclable, the proline is economically viable and readily available in both enantiomeric forms and the catalyst is insoluble in almost all solvents and may be easily filtered off from the reaction medium. Moreover, this new synthetic protocol features high conversion, short reaction times, a straightforward procedure and cleaner reaction profiles.

Full text of DOI:10.1039/c6nj01723a

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[Ce(L-Pro)2]2 (Oxa) as a heterogeneous recyclable
catalyst: synthesis of pyrazoles under mild
reaction conditions†
Cite this:DOI: 10.1039/c6nj01723a
Ramesh Katla,*a Rakhi Chowrasia,b Padma S. Manjari,*b Caren D. G. da Silva,a
Beatriz F. dos Santosa and Nelson L. C. Domingues*a
We developed a novel and highly efficient protocol for the synthesis of important pyrazole derivatives
by using some 1,3-dicarbonyl compounds and phenyl hydrazines via a one-pot protocol. As a recyclable
heterogeneous catalyst, we used [Ce(L-Pro)2]2 (Oxa). In addition, the catalyst is recyclable, the proline is
economically viable and readily available in both enantiomeric forms and the catalyst is insoluble in almost all
solvents and may be easily filtered off from the reaction medium. Moreover, this new synthetic protocol
features high conversion, short reaction times, a straightforward procedure and cleaner reaction profiles.
Received (in Montpellier, France)
1st June 2016,
Accepted 27th September 2016
DOI: 10.1039/c6nj01723a
www.rsc.org/njc
Introduction
Conventionally, organic chemistry includes the usage of many
hazardous, toxic or inflammable chemicals which are very
harmful to the environment, animals and humans. With regard
to this, many researchers have tried to protect the environment
through green approaches, which involves reduction to the
minimum use of such chemicals, and obtaining the maximum
conversion of reactants to the corresponding products.1 In this
perspective, we synthesized pyrazoles in the presence of
(Ce(L-Pro)2)2 (Oxa) as a green recyclable catalyst. Pyrazoles and
Fig. 1 Proposed structure of the Ce-catalyst.
their derivatives are a very significant class of heterocyclic moiety are shown in Fig. 2. However, several methodologies have
compounds which play a crucial role in the context of drug been accomplished through the synthesis of pyrazole derivatives
therapies, and drug intermediates.2 Most of the pyrazole such as by J. Wu and his co-workers,9 who have developed
derivatives are useful intermediates in synthetic organic and the synthesis of pyrazoles by using hydrazines with various
heterocyclic chemistry, as well as in medicinal chemistry.3 These 1,3-dicarbonyl compounds in pure water at rt mediated by
derivatives showed good medicinal properties such as anti- efficient 12-tungstophosphoric acid (H3PW12O) via a one-pot
inflammatory, antipyretic, antibacterial, antidiabetic, analgesic protocol. S. Chandak and co-authors10 reported the facile aqueous
and sedative–hypnotic activity.4 Their analogues also find extensive phase synthesis of pyrazoles catalyzed by amberlyst-70, by the
use not only in the pharmaceutical industry (Viagra5 and Celebrex3), condensation of hydrazines/hydrazides with 1,3-diketones.
but also in agrochemical industries (e.g. tebufenpyrad insecticide6,7). R. S. Varma and his co-workers11 demonstrated the synthesis
Furthermore, pyrazoles are omnipresent as ligands in coordi- of pyrazoles and diazepines by the condensation of hydrazines/
nation chemistry and as building blocks in heterocyclic
synthesis.8 Herein, we proposed a catalyst structure as shown
in Fig. 1, and a few marketed drugs with a pyrazole unit as a core
a Organic Catalysis and Biocatalysis Laboratory OCBL/ FACET, Federal University of
´
Grande Dourados—UFGD, Dourados/Itahum rod. km 12 s/n, 79804-970,
Dourados, MS, Brazil. E-mail: rameshkchem@gmail.com,
nelsondomingues@ufgd.edu.br
b Department of Chemistry, Osmania University, Tarnaka, Hyderabad, 500004,
India. E-mail: psmanjari76@gmail.com
Fig. 2 Some marketed drugs which are having a pyrazole skeleton.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nj01723a
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Table 2 Synthesis of pyrazole derivatives using [Ce(L-Pro)2]2 (Oxa) in
hydrazides and diamines with 1,3-diketones mediated by poly-
styrene supported sulfonic acid (PSSA) under aqueous conditions
at room temperature. S. Batra and co-workers12 described the
synthesis of pyrrolo-fused pyrazoles via a one-pot protocol using
halopyrazolecarbaldehydes and ethylisocyanoacetate in the
presence of copper and a base. N. Haddad13 et al. reported the
synthesis of pyrazoles by using aryl benzophenone hydrazones
with 1,3-bifunctional substrates in the presence of a Pd-catalyst.
Recently, X.-M. Hu14 and his co-authors reported a green
synthetic protocol for the preparation of pyrazoles using phenyl
hydrazines and various 1,3-dicarbonyl compounds under glycerol
and water used as mixed solvents at 90 1C. Despite that the
aforementioned reports suffer from one or more disadvantages
such as a lesser yield of products, environmental toxicity, and
the use of transition metal catalysts, anhydrous organic solvents,
long reaction times, non-recyclable catalysts and moisture sensi-
tive reagents. Therefore, in view of these shortcomings, there is a
need to develop a mild and atom-economic synthetic protocol for
the synthesis of pyrazole derivatives by replacing flammable toxic
or carcinogenic organic solvents.
EtOHa
Entry Substrate (1) Substrate (2)
1
Product (3)
Yieldb (%)
88
2
3
91
85
4
5
80
90
Results and discussion
6
7
84
81
We presented [Ce(L-Pro)2]2 (Oxa) as an efficient and eco-friendly
heterogeneous catalyst which is shown in the +3 oxidizing state.
Herein, the catalyst is non-toxic, easy to handle, and can be
easily filtered off from the reaction medium because it is
insoluble in organic and inorganic solvents and it is chemically
stable at high temperatures. In this research, we aimed to develop
at rt. a new green and efficient synthesis of pyrazole derivatives by
using various 1,3-diketones and several phenyl hydrazines in the
presence of [Ce(L-Pro)2]2 (Oxa) as a heterogeneous catalyst with
8
83
81
72
9
10
11
12
73
70
Scheme 1 Synthesis of pyrazole derivatives.
Table 1 Screening of different solvents on the synthesis of 3,5-dimethyl-
1-phenyl-1H-pyrazole catalysed by [Ce(L-Pro)2]2 (Oxa) (Table 2, entry 1)a
13
14
15
81
80
80
S. No.
Solvent
T (1C)
Yieldb (%)
1
2
3
4
5
6
7
EtOH
H2O
RT
Reflux
RT
Reflux
RT
RT
88c
40c
51c
55c
—
CHCl3
DCM
EtOHd
THF
39c
41c
Toluene
RT
a
Reaction conditions: acetyl acetone (1.0 mmol), and phenyl hydrazine
b
c
d
(1.0 mmol). Isolated yields. Presence of a catalyst. Absence of a
catalyst.
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Table 2 (continued)
Entry Substrate (1) Substrate (2)
Product (3)
Yieldb (%)
79
16
17
Fig. 3 SEM images of [A] the native Ce-catalyst and [B] the Ce-catalyst
after the reaction.
81
80
18
a
Reaction conditions: 1,3-dicarbonyl compounds or b-keto esters (1.0 equiv.),
phenyl hydrazine (1.0 equiv.), ethanol (10 mL), [Ce(L-Pro)2]2 (Oxa) (5 mol%),
room temperature, 2–3 h. b Isolated yields.
EtOH used as a green solvent (Scheme 1).17 Therefore, in order
to optimize the reaction conditions, firstly, we performed the
reaction between acetyl acetone (1.0 mmol) and phenyl hydrazine
(1.0 mmol) under ethanol used as a solvent in the absence of any
catalyst at room temperature. The corresponding product yield
was obtained in a very low percentage along with un-reacted
starting materials after prolonged reaction times, which is shown
in Table 1. After that, we carried out the same procedure by using
EtOH (10 mL) as a green solvent, with [Ce(L-Pro)2]2 (Oxa) (5 mol%)
used as a heterogeneous catalyst for the first time in the synthesis
of pyrazoles at room temperature, for 2–3 h. The corresponding
product was obtained in 88% yield (Table 1). All the remaining
reactions were carried out under these conditions. Moreover,
the present protocol was screened with different solvent systems
such as EtOH, CHCl3, CH2Cl2, THF, toluene and H2O, at room
temperature and under reflux conditions as shown in Table 1.
After several experiments, EtOH was proven to be the best choice,
since the other solvents furnished low yields. Furthermore, the
present reaction was successfully screened with different catalyst
loadings such as 2.5 mol%, 5 mol%, and 10 mol%. After several
reactions, we found that 5 mol% was the best catalyst loading
among them.
Fig. 4 Proposed mechanism for the synthesis of pyrazoles.
All the reactions were performed by using [Ce(L-Pro)2]2 (Oxa)
as a catalyst, which could be recovered and reused. After
completion of the reaction, the catalyst was filtered off and
cleaned with diethyl ether and dried at 80 1C for 2 h. The
recovered catalyst was reused in the same substrates, and
checked for the yields and catalytic activity as shown in
Fig. 5. It was observed that the yield of the 3,5-dimethyl-1-
phenyl-1H-pyrazole derivative reduced slightly after two to three
cycles. The SEM images of the catalyst are given in Fig. 3. All the
products were purified, and characterized by 1H, 13C-NMR, and
mass spectroscopic analysis.9,18
On the other hand, phenyl hydrazines bearing electron donating
groups such as –OMe, and electron withdrawing groups such as
–Cl, and –Br etc., at the para position of the substrates did not
influence the reaction medium and the yields of the corresponding
products (Table 2) were excellent. It is worth mentioning that the
other reactants such as 1,3-dicarbonyl compounds containing –Me,
–Et, –OEt and –CF3 groups also furnished good yields as shown
in Table 2.
Further, we proposed a suitable mechanism for the preparation
of pyrazoles: the catalyst directly influences the reaction medium
and formed a hydrogen bond between the 1,3-dicarbonyl
compound which further formed an imine intermediate using
phenyl hydrazine and subsequent cyclization followed by
aromatization, which led us to the corresponding product as
shown in Fig. 4.
Fig. 5 Recyclability of the catalyst.
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Conclusions
5.95 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H); 13C NMR (50 MHz, CDCl3)
d: 148.7, 138.8, 137.7, 132.7, 128.7, 125.3, 107, 13.0, 12.0. MS (ESI):
m/z = 207 [M + H]+.
3,5-Diethyl-1-phenyl-1H-pyrazole (Table 2, entry 5). Brown
liquid; 1H NMR (200 MHz, CDCl3) d: 7.42 (m, 5H), 6.08 (s, 1H),
2.68 (m, 4H), 1.36–1.21 (m, 6H); 13C NMR (50 MHz, CDCl3)
d: 154.7, 145.8, 140.2, 129.2, 127.3, 125.2, 103.2, 21.7, 19.6, 14.2,
13.15; MS (ESI): m/z = 201 [M + H]+.
1-(4-tert-Butylphenyl)-3,5-diethyl-1H-pyrazole (Table 2, entry 6).
Brown liquid; 1H NMR (200 MHz, CDCl3) d: 7.42 (d, 2H, J =
8.79 Hz), 7.33 (d, 2H, J = 8.05 Hz), 6.0 (s, 1H), 2.69–2.59 (m, 4H),
1.33 (s, 9H), 1.29–1.16 (m, 6H); 13C NMR (50 MHz, CDCl3) d: 151.1,
147.3, 140.2, 136.2, 124.9, 119.2, 107.3, 40.2, 31.2, 23.1, 21.2 18.1;
MS (ESI): m/z = 257 [M + H]+.
We have successfully accomplished the synthesis of pyrazole
moieties, for the first time promoted by [Ce(L-Pro)2]2 (Oxa) in EtOH
used as a green-solvent at room temperature. The catalyst can be
recovered and reused after the third cycle, with the loss of a small
significant catalytic activity. In addition, this present protocol
excludes toxic/hazardous solvents. This methodology involved
shorter reaction times, good yields, besides being environmentally
benign, inexpensive, and demanding mild reaction conditions.
Experimental
General procedure for the synthesis of pyrazole derivatives
A round-bottomed flask (25 mL) was charged with 1,3-dicarbonyl
compound (1.0 mmol) and phenyl hydrazine (1.0 mmol) was taken
in ethanol (10 mL), a catalytic amount of [Ce(L-Pro)2]2 (Oxa)
(5 mol%) was added and the mixture was stirred at room
temperature for an appropriate time. The progress of the reaction
was monitored by TLC. After the completion of the reaction was
indicated by TLC, then the catalyst ([Ce(L-Pro)2]2 (Oxa)) was filtered
off from the reaction mixture. The remaining solvent was evapo-
rated under reduced pressure. Further, the crude product was
purified by column chromatography over silica gel to afford the
corresponding product, and yields were obtained in 70–91% as
shown in Table 2.
1-Benzyl-3,5-diethyl-1H-pyrazole (Table 2, entry 7). Liquid;
1H NMR (200 MHz, CDCl3) d: 7.28–7.16 (m, 3H), 7.03 (d, 2H,
J = 7.16 Hz), 5.82 (s, 1H), 5.20 (s, 2H), 2.60 (q, 2H, J = 7.5 Hz),
2.41 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.55, 3H), 1.14 (t, 3H, J = 7.55);
13C NMR (50 MHz, CDCl3) d: 147.6, 141.2, 138.3, 129.5,
128.5, 127.3, 106.7, 53.5, 22.2, 20.1, 14.2, 12.6; MS (ESI): m/z =
215 [M + H]+.
3,4,5-Trimethyl-1-phenyl-1H-pyrazole (Table 2, entry 8).
1
Yellow liquid; H NMR (300 MHz, CDCl3) d: 7.39–7.31 (m, 5H)
2.10 (s, 6H), 1.96 (s, 3H); 13C NMR (50 MHz, CDCl3) d: 148.4,
138.6, 135.9, 132.3, 129.0, 125.5, 113.6, 11.8, 10.9, 8.1; MS (ESI):
m/z = 187 [M + H]+.
1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrazole (Table 2, entry 9)3.
Brown liquid; 1H NMR (200 MHz, CDCl3) d: 7.52 (d, 2H, J = 8.3 Hz),
Preparation of the novel [Ce(L-Pro)2]2 (Oxa) catalyst15,16
(L)-Proline (2.7 mmol) was dissolved in 15 ml of methanol, then 7.36 (d, 2H, J = 9.0 Hz), 5.91 (s, 1H), 2.28 (s, 3H), 2.26 (s, 3H);
we added aqueous solution of sodium hydroxide (2.7 mmol in 13C NMR (50 MHz, CDCl3) d: 148.4, 138.4, 137.3, 132.4, 128.5, 125.4,
1 mL) to it at room temperature and stirred the mixture for 107.8, 13.2, 12.2; MS (ESI): m/z = 251 [M + H]+.
10 minutes. Then cerium(III) chloride (1.4 mmol) was added to
5-Ethoxy-3-methyl-1-phenyl-1H-pyrazole (Table 2, entry 10).
it, and the reaction mixture was stirred for 45 minutes and then 1H NMR (200 MHz, CDCl3) d: 7.68 (d, 2H, J = 7.74 Hz), 7.35
a few drops of sodium oxalate solution (0.1 g mLÀ1) were added (t, 2H, J = 7.74 Hz), 7.17 (t, 1H, J = 7.74 Hz), 5.40 (s, 1H), 4.12
to it. We used it as a precipitating agent. The semi-solid was (q, 2H, J = 6.98 Hz), 2.42 (s, 3H), 1.44 (t, 3H, J = 6.98 Hz);
centrifuged, washed with methanol and dried overnight at 13C NMR (50 MHz, CDCl3) d: 154.6, 148.3, 138.8, 128.6, 125.5,
40 1C and a pale yellow semi-solid was obtained.
121.6, 86.1, 67.5, 14.6, 14.5; MS (ESI): m/z = 203 [M + H]+.
5-Ethoxy-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole (Table 2,
3,5-Dimethyl-1-phenyl-1H-pyrazole (Table 2, entry 1)1. Light
1
brown liquid; H NMR (200 MHz, CDCl3) d: 7.46–7.33 (m, 4H), entry 11). Brown solid; m.p. 53–55 1C; 1H NMR (300 MHz, CDCl3)
7.29–7.19 (m, 1H), 5.90 (s, 1H), 2.25 (s, 6H); 13C NMR (50 MHz, d: 7.52 (d, 2H, J = 8.78 Hz), 6.85 (d, 2H, J = 8.78 Hz), 5.37 (s, 1H), 4.08
CDCl3) d: 148.1, 139.4, 138.4, 128.3, 126.4, 124.0, 106.4, 12.9, (q, 2H, J = 6.83 Hz), 3.80 (s, 3H), 2.22 (s, 3H), 1.42 (t, 3H, J = 7.80 Hz);
11.8; MS (ESI): m/z = 173 [M + H]+.
13C NMR (50 MHz, CDCl3) d: 157.7, 154.4, 148.0, 132.2, 124.0, 113.8,
1-(4-Methoxyphenyl)-3,5-dimethyl-1H-pyrazole (Table 2, 85.5, 67.2, 55.5, 14.6, 14.4; MS (ESI): m/z = 233 [M + H]+.
1
entry 2). Brown liquid; H NMR (200 MHz, CDCl3) d: 7.27 (d,
1-(4-Chlorophenyl)-5-ethoxy-3-methyl-1H-pyrazole (Table 2,
2H, J = 9.06 Hz), 6.90 (d, 2H, J = 9.06 Hz), 5.90 (s, 1H), 3.8 (s, 3H), entry 12). M.p. 58–61 1C; 1H NMR (300 MHz, CDCl3) d: 7.58
2.26 (s, 3H), 2.23 (s, 3H); 13C NMR (50 MHz, CDCl3) d: 158.7, (d, 2H, J = 8.87 Hz), 7.47 (d, 2H, J = 8.87 Hz), 5.39 (s, 1H), 4.10
148.0, 139.1, 132.7, 125.9, 113.7, 105.9, 55.1, 13.1, 11.7; MS (q, 2H, J = 6.98 Hz), 2.22 (s, 3H), 1.45 (t, 3H, J = 6.98 Hz);
(ESI): m/z = 203 [M + H]+.
13C NMR (50 MHz, CDCl3) d: 155.1, 148.9, 137.8, 132.4, 122.8,
1-(4-tert-Butylphenyl)-3,5-dimethyl-1H-pyrazole (Table 2, 118.7, 86.6, 68.0, 14.7, 14.6; MS (ESI): m/z = 237 [M + H]+.
entry 3). Brown liquid; 1H NMR (200 MHz, CDCl3) d: 7.42
3-Methyl-1,5-diphenyl-1H-pyrazole (Table 2, entry 13). Yellow
(d, 2H, J = 8.68 Hz), 7.32 (d, 2H, J = 8.68 Hz), 5.91 (s, 1H), oil; 1H NMR (200 MHz, CDCl3) d: 7.37–7.19 (m, 10H), 6.28 (s, 1H),
2.34 (s, 3H), 2.20 (s, 3H), 1.34 (s, 9H); 13C NMR (50 MHz, CDCl3) 2.40 (s, 3H); 13C NMR (50 MHz, CDCl3) d: 148.7, 142.9, 139.7,
d: 150.1, 148.4, 139.3, 137.3, 125.7, 124.5, 106.5, 34.8, 31.3, 13.5, 130.3, 128.2, 128.1, 127.9, 127.5, 126.4, 124.5, 107.5, 13.2; MS
12.4; MS (ESI): m/z = 229 [M + H]+.
(ESI): m/z = 235 [M + H]+.
1-(4-Chlorophenyl)-3,5-dimethyl-1H-pyrazole (Table 2, entry 4)1.
1,5-Diphenyl-3-(trifluoromethyl)-1H-pyrazole (Table 2, entry 14)2.
1
Thick brown liquid; H NMR (200 MHz, CDCl3) d: 7.45 (m, 4H), Light yellow solid; m.p. 86–90 1C; 1H NMR (200 MHz, CDCl3)
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d: 7.36–7.26 (m, 8H), 7.23–7.18 (m, 2H), 6.71 (s, 1H); 13C NMR
(50 MHz, CDCl3) d: 144.8, 139.2, 129.0, 128.9, 128.7, 128.6, 128.3,
125.4, 105.5; MS (ESI): m/z = 289 [M + H]+.
1-(4-Chlorophenyl)-3,5-diethyl-1H-pyrazole (Table 2, entry 15).
Liquid; 1H NMR (200 MHz, CDCl3) d: 7.41–7.31 (m, 4H), 6.01
(s, 1H), 2.69–2.57 (m, 4H), 1.33–1.19 (m, 6H); 13C NMR (50 MHz,
CDCl3) d: 154.5, 145.4, 140.5, 128.9, 127.8, 125.9, 103.5, 21.5, 19.9,
14. 3, 13.3; MS (ESI): m/z = 235 [M + H]+.
1-(4-Bromophenyl)-3,5-diethyl-1H-pyrazole (Table 2, entry 16).
Liquid; 1H NMR (200 MHz, CDCl3) d: 7.55 (d, 2H, J = 8.79 Hz), 7.29
(d, 2H, J = 8.05), 6.05 (s, 1H), 2.70–2.59 (m, 4H), 1.33–1.20 (m, 6H);
13C NMR (50 MHz, CDCl3) d: 151.8, 147.7, 140.1, 136.3, 124.4,
119.2, 107.0, 21.6, 20.4, 15.1, 14.2; MS (ESI): m/z = 279 [M + H].
3,5-Diethyl-1-(4-methoxyphenyl)-1H-pyrazole (Table 2, entry 17).
Brown liquid; 1H NMR (200 MHz, CDCl3) d: 7.26 (d, 2H, J =
9.06 Hz), 6.81 (d, 2H, J = 8.3 Hz), 5.92 (s, 1H), 3.84 (s, 3H), 2.69–
2.52 (m, 4H), 1.30–1.15 (m, 6H); 13C NMR (50 MHz, CDCl3) d: 158.8,
148.3, 139.4, 133.5, 126, 114, 108, 55, 22.3, 19.8, 13.7, 12.8; MS (ESI):
m/z = 231.15 [M + H]+.
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1
Liquid; H NMR (200 MHz, CDCl3) d: 7.28–7.15 (m, 3H), 7.02
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(d, 2H, J = 7.32), 5.85 (s, 1H), 5.14 (s, 2H), 2.22 (s, 3H), 2.11
(s, 3H); 13C NMR (50 MHz, CDCl3) d: 147.2, 138.9, 137.2, 128.9,
127.5, 126.5, 105.7, 52.5, 13.5, 11.3; MS (ESI): m/z = 187.16
[M + H]+.
Acknowledgements
Brazilian authors (R. K. and N. L. C. D) thank Conselho
´
´
Nacional de Desenvolvimento Cientıfico e Tecnologico for the
BJT fellowship and the financial support (Process: 314140/2014-0
˜
and 400706/2014-8 CNPq-Brazil) and Fundaçao de Apoio ao
ˆ
Desenvolvimento do Ensino, Ciencia e Tecnologia do Estado
de Mato Grosso do Sul (FUNDECT-PRONEM-Brazil). Brazilian
˜
author also thanks Coordenaçao de Aperfeiçoamento de Pessoal
´
de Nıvel Superior (CAPES-Brazil) for her fellowship. The authors
thank Dr Y. V. D. Nageswar, Chief Scientist at Indian Institute
of Chemical Technology (IICT) Hyderabad, India for their
spectroscopic analysis.
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10 H. S. Chandak, N. P. Lad and D. S. Dange, Green Chem. Lett.
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