Synergic effects of ionic liquid and microwave irradiation in promoting trifluoromethylpyrazole synthesis

Article abstract of DOI:10.1007/s10562-011-0571-9

The synthesis of 5-trifluoromethyl-1-phenyl-1H-pyrazoles from the reactions of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF₃C(O)CH=C(R ¹)OR, where R = Me, Et; R¹= H, Me, Bu, i-Bu, Ph, 4-MeC₆H₄, 4-FC

Full text of DOI:10.1007/s10562-011-0571-9

Catal Lett (2011) 141:1130–1135
DOI 10.1007/s10562-011-0571-9
Synergic Effects of Ionic Liquid and Microwave Irradiation
in Promoting Trifluoromethylpyrazole Synthesis
•
Lilian Buriol Clarissa P. Frizzo Lizie D. T. Prola
•
•
ˆ
Dayse N. Moreira Mara R. B. Marzari Elisandra Scapin
•
•
•
•
Nilo Zanatta Helio G. Bonacorso Marcos A. P. Martins
•
Received: 14 December 2010 / Accepted: 24 February 2011 / Published online: 10 March 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The synthesis of 5-trifluoromethyl-1-phenyl-
1H-pyrazoles from the reactions of 4-alkoxy-1,1,1-trifluoro-
3-alken-2-ones [CF3C(O)CH=C(R1)OR, where R = Me,
Et; R1 = H, Me, Bu, i-Bu, Ph, 4-MeC6H4, 4-FC6H4,
4-ClC6H4, 4-BrC6H4, 4-IC6H4, fur-2-yl] with phenyl
hydrazine in the presence of ionic liquid [BMIM][BF4] is
reported. Synergic effects of ionic liquid and microwave
irradiation in promoting pyrazole synthesis have been shown
for the first time.
economic energy sources to promote organic reactions has
been one of the most prominent tactics in this effort. The
development and use of ionic liquids have emerged as a
fascinating technology because, in addition to their negli-
gible vapor pressure and recyclability, they present unique
physicochemical properties such as tunable polarity, high
thermal stability and miscibility with a number of organic
solvents [1, 2]. With regard to alternative energy sources,
the use of microwave ovens for synthesis has been
accepted as a way of reducing reaction times, often by
orders of magnitude, and of increasing product yields when
compared to conventional methods [3, 4]. A key advantage
of modern scientific microwave equipment is the ability to
control very specific reaction conditions, monitoring tem-
perature, pressure, and reaction times. Several methods
have been developed for performing reactions using
microwaves, including under solvent-free conditions, with
the adsorbtion of reactants onto inorganic supports such as
silica (or clays) and in ionic liquids [5].
Keywords Microwave Irradiation Á Ionic Liquid Á
Pyrazole Á Catalysis Á Halogenated compounds
1 Introduction
In recent decades, there has been an extensive search for
new synthetic methodologies which minimize environ-
mental impacts. The use of nonvolatile solvents and more
Enabling technologies and methodologies have been
established and combined to afford various environmen-
tally benign processes for laboratory scale synthesis and for
the production of fine chemicals. In this context, a recent
trend in this area is microwave-assisted synthesis using ILs
as solvent, co-solvent, catalyst, and/or template [6]. Due to
their ionic nature, ILs allow highly effective interactions
with microwave (MW) energy for the rapid generation of
products with generally high yields [7].
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-011-0571-9) contains supplementary
material, which is available to authorized users.
L. Buriol Á C. P. Frizzo (&) Á L. D. T. Prola Á
D. N. Moreira Á M. R. B. Marzari Á N. Zanatta Á
H. G. Bonacorso Á M. A. P. Martins
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE),
Our research group has developed a general procedure
for preparing b-alkoxyvinyl trihalomethyl ketones and we
have exhaustively studied the versatility of the b-alkoxy-
vinyl trihalomethyl ketones in heterocyclic synthesis [8].
Recently, we have published a number of works related to
the minimization of environmental impacts through the use
of ionic liquids [9–11] or solvent-free reactions [12, 13]
´
Departamento de Quımica, Universidade Federal de Santa
Maria, 97105-900 Santa Maria, RS, Brazil
e-mail: clarissa.frizzo@yahoo.com.br
E. Scapin
´
´
Laboratorio de Quımica, Coordenac¸a˜o de Engenharia Ambiental,
Universidade Federal do Tocantins, Av. NS 15 ALC NO 14,
Bloco II, 109 Norte, Palmas, TO, Brazil
123

Synergic Effects of Ionic Liquid and Microwave Irradiation
1131
and by using ultrasound [14, 15] or MW [12, 13] to pro-
mote the reactions. Our current review about heterocyclic
synthesis in ionic liquid [16] has demonstrated that there is
a lack of reports dealing with pyrazole synthesis in this
media. Substituted pyrazoles are important synthetic tar-
gets in the pharmaceutical industry because the pyrazole
motif makes up the core structure of numerous biologically
active compounds, including blockbuster drugs such as
Celecoxib [17] and Sildenafil [18]. Although several
methods have been developed, regioselective synthesis of
the pyrazole ring remains a significant challenge for
organic chemists [19–22]. In this context, our aim in this
work is to demonstrate the synergic effects of ionic liquid
and microwave irradiation in promoting the synthesis of
trifluoromethyl pyrazoles.
Microwave irradiation A 10 mL microwave vessel
equipped with a standard cap (vessel commercially fur-
nished by Discover CEM) was filled with 1 mmol of enone
1a–k, 1.2 mmol of phenylhydrazine 2 and 1 mmol of ionic
liquid ([BMIM]BF4]). After the vessel was sealed, the
sample was irradiated for the times and temperatures as
indicated in Scheme 1, which was plotted in Synergies
Version 3.5.9 software applying the power of 200 W as the
maximum level of irradiation and a maximum level of
internal vessel pressure of 250 psi. The irradiation power
was in the range of 6–30 W for reactions at 100 °C, with
simultaneous cooling, and at 14–46 W for reactions at
150–200 °C, without simultaneous cooling. The reaction
mixture was subsequently cooled to 50 °C by compressed
air. The products were isolated with chloroform (5 mL)
and washed with water (3 9 5 mL). The chloroform was
evaporated under vacuum (reduced pressure) and the
products were obtained in a pure form without further
purification. For the data of compound 3a–e, 1H NMR
spectra were found to be identical with the one described in
Ref. [12, 25, 26].
2 Experimental
2.1 General
The experiments were performed in a Discover CEM MW
using the mode of operation: with and without simulta-
2.2.1 5-Trifluoromethyl-1,3-diphenyl-1H-pyrazole (3e)
1
neous cooling. H and 13C NMR spectra were recorded on
a Bruker DPX 400 (1H at 400.13 MHz and 13C at
100.62 MHz) and Bruker DPX-200 (1H at 200.13 MHz
and 13C at 50.32 MHz) in CDCl3/TMS solutions at 298 K.
Mass spectra were registered in a HP 5973 MSD connected
to a HP 6890 GC and interfaced by a Pentium PC. The GC
was equipped with a split-splitless injector, cross-linked to
a HP-5 capillary column (30 m, 0.32 mm i.d.), and helium
was used as the carrier gas. The melting points were
The crystallographic data for the structure reported in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Center (CCDC 803591). Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (Fax:
01223-336033.
2.2.2 5-Trifluoromethyl-3-(4-methylphenyl)-1-phenyl-1H-
pyrazole (3f)
´
measured using a Microquımica MQAPF 301. The ionic
liquid 1-butyl-3-methyl imidazolium tetrafluoroborate
[BMIM][BF4] was prepared according to procedures from
the literature [23]. The enones 1a–k were obtained from
the acylation reaction of enol ether or acetal with trifluo-
roacetic anhydride in accordance with the methodology
developed in our laboratory [24]. Phenylhydrazine was
obtained commercially.
C17H13F3N2 M.p.:127–130 °C; Yield: 89%, 1H NMR
(200 MHz, CDCl3): d = 2.38 (s, 3H, Me), 7.07 (s, 1H,
H4), 7.22 (d, 2H, Ar), 7.46–7.56 (m, 5H, Ph), 7.74 (d, 2H,
Ar); 13C NMR (400 MHz, CDCl3): d = 21.3 (CH3), 105.9
(q, 3J 2, C4), 119.7 (q, 1J 268, CF3), 125.6 (q, J 1.4,
Cortho),125.6, 128.8, 129.0, 129.2, 129.5, 138.5, 139.1
(C–Ar), 133.7 (q, 2J 39, C5), 151.6 (C3); MS (70 eV):
m/z = 302 (100), 281 (42), 77 (20).
2.2 Preparation and Characterization
of Pyrazoles (3a–k)
2.2.3 5-Trifluoromethyl-3-(4-fluorophenyl)-1-phenyl-1H-
pyrazole (3g)
Conventional method Enones 1a–k (1 mmol), phen-
ylhydrazine 2 (1.2 mmol) and ionic liquid ([BMIM][BF4])
(1 mmol) were placed into a round-bottom flask equipped
with a stir bar. After the mixture was stirred for the times
and temperatures indicated in Scheme 1, the products were
isolated with chloroform (5 mL) and washed with water
(3 9 5 mL). The chloroform was evaporated under vac-
uum (reduced pressure) and the products were obtained in a
pure form without further purification.
C16H10F4N2 M.p.: 58–60 °C; Yield: 89%; 1H NMR
(200 MHz, CDCl3) d = 7.07 (s, 1H, H4), 7.39 (d, 2H, Ar),
7.50–7.55 (m, 5H, Ar), 7.83 (d, 2H, Ar); 13C NMR
(400 MHz, CDCl3): d = 105.8 (q, 3J 3, C4), 115.8 (d,
2J 22, CAr), 119.67 (q, 1J 269, CF3), 125.6 (q, J 1.4,
C
ortho), 125.6 (C–Ar), 129.1, 129.3, (C–Ar), 127.6 (d, 3J 8,
4
C–Ar), 127.9 (d, J 3, C–Ar), 133.98 (q, J 39, C5), 150.7
2
123

1132
L. Buriol et al.
R1
Scheme 1 Synthesis of
compounds 3a-k
H2N
NH
O
R1
N
i or ii
F3C
+
N
F3C
OR
1a-k
2
3a-k
i: [BMIM][BF4], 25-150°, 1-3 h
ii: [BMIM][BF4], MW (100-200 °C), 6 min
Conventional
MW
Yielda (%)
80
Enone
R
R1
H
Prod.(s)
3ab
3b
Yielda (%)
1a
1b
1c
1d
1e
1f
Et
80
93
91
92
85
89
89
90
96
-
Me
Me
Me
Me
Me
-Bu
Bu
Ph
92
i
3c
90
3d
91
3e
82
Me 4-Me-C6H4
Me 4-F-C6H4
Me 4-Cl-C6H4
Me 4-Br-C6H4
Me 4-I-C6H4
3f
83
1g
1h
1i
3g
82
3hc
3i d
3j
82
94
1j
96
1k
Me
Fur-2-yl
3k
72
56
aYield of isolated products. b A mixture of regioisomers was isolated in conventional heating and
c
under MW in a molar ratio of 1:1. A mixture of regioisomers was isolated in conventional
heating and under MW in a molar ratio of 10:1. d A mixture of regioisomers was isolated in
conventional heating and under MW in a molar ratio of 5:1. e Reaction performed in 10 min.
1
(C3), 163.05 (d, J 248, C–Ar); MS (70 eV): m/z = 306
(100), 285 (42), 273 (9), 77 (12).
2.2.5 5-(4-Chlorophenyl)-3-trifluoromethyl-1-phenyl-1H-
pyrazole (3h)
16H10ClF3N2 Oil; 1H NMR (200 MHz, CDCl3) d = 6.74 (s,
1H, H4); 7.16 (d, 2H, H–Ar), 7.29 (d, 2H, H–Ar), 7.47–7.55
(m, 5H, Ar); 13C NMR (400 MHz, CDCl3): d = 105.6 (q,
3J 2, C4), 121.6 (q, 1J 268, CF3), 127.5, 128.6, 128.8, 129.2,
129.6, 133.1, 138.9 (C–Ar), 143.4 (C5); MS (70 eV): m/
z = 322 (100), 301 (36), 267 (13), 77 (10).
2.2.4 3-(4-Chlorophenyl)-5-trifluoromethyl-1-phenyl-1H-
pyrazole (3h)
C16H10ClF3N2 Oil; Yield: 90%; 1H NMR (200 MHz,
CDCl3) d = 7.08 (s, 1H, H4); 7.38 (d, 2H, H–Ar),
7.47–7.55 (m, 5H, Ar), 7.79 (d, 2H, H–Ar); 13C NMR
(400 MHz, CDCl3): d = 105.9 (q, 3J 2, C4), 119.6 (q,
1J 268, CF3), 125.6 (q, J = 1.4, Cortho), 125.6 (C–Ar),
127.0, 128.9, 129.1, 129.4, 130.2, 134.47, 139.0 (C–Ar),
2.2.6 3-(4-Bromophenyl)-5-trifluoromethyl-1-phenyl-1H-
pyrazole (3i)
2
1
134.0 (q, J 38 C5), 150.5 (C3); MS (70 eV): m/z = 322
(100), 301 (61), 267 (20), 77 (19).
C16H10BrF3N2 Oil; H NMR (200 MHz, CDCl3) d = 7.08
(s, 1H, H4), 7.13–7.52 (m, 7H, Ar), 7.72 (d, 2H, Ar); 13C
123

Synergic Effects of Ionic Liquid and Microwave Irradiation
1133
NMR (400 MHz, CDCl3): d = 105.9 (q, 3J 3, C4),119.6 (q,
1J 267, CF3), 125.4 (q, J 1.4, Cortho), 125.5 (C–Ar),127.3,
129.1, 129.4, 130.2, 131.7, 131.92, (C–Ar), 134.1 (q, 2J 39,
C5),150.4 (C3). MS (70 eV): m/z = 366 (100), 347 (21),
267 (17), 133 (12), 77 (30).Due the low concentration of
1,3-isomer, the signals of C5 were not observed.
compound 3c, in 75% yield, was described in the literature
[25] in two steps: (i) ethanol reflux for 3 h, (ii) addition of a
mixture of dichloromethane and sulfuric acid 96% and
heating at 40 °C for 2 h. This comparison demonstrates
that the reaction of enones 1a–k with phenylhydrazine 2 in
[BMIM][BF4] is a more versatile and efficient method to
obtain a series of 1-phenyl-5-trifluoromethyl-1H-pyrazoles
from alkyl and aryl/hetroaryl enones when compared with
molecular solvents. The reaction in [BMIM][BF4] resulted
in products in only one step, in a reduced reaction time and
in excellent yields.
2.2.7 5-(4-Bromophenyl)-3-trifluoromethyl-1-phenyl-1H-
pyrazole (3i)
1
C16H10BrF3N2 Oil; H NMR (200 MHz, CDCl3) d = 6.75
(s, 1H, H4), 7.07 (d, 2H, Ar), 7.45 (d, 2H, Ar), 7.51–7.57
(m, 5H, Ar); 13C NMR (400 MHz, CDCl3): d = 105.6 (q,
3J 2, C4),121.1 (q, 1J 269, CF3), 122.6, 125.4, 128.0, 128.7,
129.2, 129.8, 130.6, 138.9 (C–Ar), 143.3 (q, 2J 39,
C3),143.4 (C5); MS (70 eV): m/z = 366 (100), 347 (31),
267 (23), 133 (47), 77 (44).
Subsequently, to investigate the synergic effects of ionic
liquid and microwave irradiation in promoting trifluoro-
methyl pyrazole synthesis, we carried out all the reactions
under MW irradiation, using [BMIM][BF4]. We applied
the times and temperatures established in our previous
studies of pyrazoles synthesis using microwave irradiation
[12]. From the results (Scheme 1), we found that the
microwave irradiation condition were superior, because
they furnished the pyrazoles 3a–k in better yields
(56–96%) and a shorter time (6 min) than did the con-
ventional method. The regioselectivity of the products was
the same for both methods, for all substituted enones
studied. However, the conventional method was more
sensitive to the enone structure, since enones containing
4-alkyl substituents were more reactive and presented
shorter reaction times and lower temperatures, while
4-aryl-substituted enones required a longer reaction time
and higher temperature. In addition, to formation of pyra-
zole 3k under MW conditions was necessary 10 min, and
the yield was not satisfactory (56%). Synthesis of com-
pounds 3a–d in toluene using a domestic microwave oven,
or in K-10 under solvent-free conditions is described in
literature [12]. Compound 3a was isolated as a mixture of
dehydrated pyrazole and 1,5-regioisomer (ratio of 2:1) and
compounds 3b–d were obtained in 85–91% yields. Results
for the reactions combining the use of microwave irradia-
tion and ionic liquid were similar to those for the reactions
performed in microwave under solvent-free conditions for
products 3a, 3b, 3d [12], however regioselectivity was
higher in the presence of ionic liquids.
2.2.8 3-(4-Iodophenyl)-5-trifluoromethyl-1-phenyl-1H-
pyrazole (3h)
C16H10IF3N2 M.p.: 76–79 °C;1H NMR (200 MHz, CDCl3)
d = 7.09 (s, 1H, H4), 7.51–7.62 (m, 7H, Ar), 7.76 (d, 2H,
Ar); 13C NMR (400 MHz, CDCl3): d = 105.9 (q, 3J 3, C4),
1
119.6 (q, J 269, CF3), 94.3, 125.6, 127.5, 129.1, 129.4,
131.3, 137.9, 139.5 (CAr), 134.1 (q, 2J 38, C5), 150. 6 (C3);
MS (70 eV): m/z = 414 (100), 393 (9), 218 (16), 55 (53).
2.2.9 5-Trifluoromethyl-3-(fur-2-yl)-1-phenyl-1H-pyrazole
(3k)
C14H9F3N2O Oil;1H NMR (200 MHz, CDCl3) d = 6.47
(dd, 1H, H13), 6.79 (d, 1H, H12), 7.04 (s, 1H, H4),
7.48–7.53 (m, 6H, Ar); 13C NMR (400 MHz, CDCl3):
3
1
d = 105.7 (q, J 3, C4), 119.5 (q, J 269, CF3), 107.1,
111.4, 144.1, 146.9 (Fur-2-yl), 125.7, 129.0, 129.3, 138.7,
2
(CAr), 133.5 (q, J 39, C5), 142.5 (C3); MS (70 eV): m/
z = 278 (100), 249 (22), 139 (22), 77 (50).
3 Results and Discussion
Recently, Martinez-Palou published
a review [7]
We started the studies with the reaction of b-alkoxyvinyl
trihalomethyl ketones 1a–k with phenylhydrazine 2 in the
presence of ionic liquid under conventional heating. Based
on previous observations of good results for cyclocon-
densation reactions [9–11], the ionic liquid selected for
these reactions was [BMIM][BF4]. The reaction times were
of 1 h for alkyl enones and 3 h for nonsubstituted and aryl/
heteroaryl enones and temperatures were of 25 °C for alkyl
enones and 150 °C for nonsubstituted and aryl/heteroaryl
enones (Scheme 1). Pyrazoles 3a–k were obtained in
moderate to excellent yields (60–96%). Synthesis of
showing synergic effects of ionic liquids and MW for
important reactions. Some of these are cyclocondensation
reactions leading to 2-aminothiophenes, tiotetrahydropyr-
imidinones, 4-H-pyrans, triazines and imidazoles, and the
ionic liquids were used as specific functions, such as acid
catalyst, liquid support or co-solvent. There is not report of
any heterocyclic synthesis in a simple ionic liquid, such as
[BMIM][BF4], in MW. We believed that the synergic effects
of ionic liquid and MW in promoting this reaction is due
ionic nature of ILs. This fact allows highly effective inter-
actions with MW energy generating products in short time
123

1134
L. Buriol et al.
Acknowledgments The authors are grateful to Conselho Nacional
´
de Desenvolvimento Cientıfico e Tecnologico (CNPq Procs. No.
578426/2008-0; 471519/2009-0), Fundac¸a˜o de Amparo a Pesquisa do
´
`
Estado do Rio Grande do Sul (FAPERGS/CNPq-PRONEX Edital No.
008/2009, Proc. No. 10/0037-8) and Coordenac¸a˜o de Aperfeic¸oa-
´
mento de Pessoal de Nıvel Superior (CAPES/PROEX) for financial
support. The fellowships from CNPq (M.A.P.M., L.B., D.N.M.,
M.R.B.M., L.D.T.P., N.Z., H.G.B.) and CAPES (C.P.F.) are also
acknowledged.
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1
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times and better yields when compared with the classical
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123

Synergic Effects of Ionic Liquid and Microwave Irradiation
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123