Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis of ethyl-5-(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4- carboxylates

Article abstract of DOI:10.1007/s11164-011-0360-5

A series of pyrazole-4-carboxylates have been synthesised using indium bromide catalyst and the cyclisation of respective 3-substituted- isoquinolinylhydrazines 1 into their corresponding ethyl-2-(ethoxymethylene)-4, 4,4- trifluoro-3-oxobutanoates 3 in et

Full text of DOI:10.1007/s11164-011-0360-5

Res Chem Intermed (2012) 38:429–441
DOI 10.1007/s11164-011-0360-5
Indium bromide catalysed, ultrasound-assisted,
regio-selective synthesis of ethyl-5-(trifluoromethyl)-1-
(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4-
carboxylates
•
•
•
K. Prabakaran F. Nawaz Khan Jong Sung Jin
P. Manivel
Received: 20 April 2011 / Accepted: 2 August 2011 / Published online: 20 August 2011
Ó Springer Science+Business Media B.V. 2011
Abstract A series of pyrazole-4-carboxylates have been synthesised using
indium bromide catalyst and the cyclisation of respective 3-substituted-iso-
quinolinylhydrazines 1 into their corresponding ethyl-2-(ethoxymethylene)-4,4,4-
trifluoro-3-oxobutanoates 3 in ethanol solvent under ultrasonic irradiation at 90 °C
for 30 min. The regio-selective cyclisation products were efficiently provided
by indium bromide catalyst and are confirmed by nuclear Overhauser effect
spectroscopy–nuclear magnetic resonance (NOESY–NMR) studies.
Keywords Ultrasonic irradiation Á Pyrazole-4-carboxylates Á
1-(3-Substituted-isoquinolin-1-yl) hydrazines Á Microwave Á Indium bromide Á
Cyclisation Á Regio-selectivity
Introduction
Pyrazoles occupied an important position as bio-active drugs in the pharmaceu-
tical industry [1], in both lead identification and lead optimisation processes [2].
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-011-0360-5) contains supplementary material, which is available to authorized users.
K. Prabakaran Á F. Nawaz Khan (&) Á P. Manivel
Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F. Nawaz Khan Á J. S. Jin (&)
Division of High Technology Materials Research, Busan Center,
Korea Basic Science Institute (KBSI), Busan 618 230, Korea
e-mail: jsjin@kbsi.re.kr
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K. Prabakaran et al.
Pyrazoles are well established in the literature as important biologically effective
heterocyclic compounds [3]. Pyrazole derivatives had demonstrated potential
pharmacological activities such as anti-inflammatory [4], anti-pyretic [5], anti-
microbial [6], anti-viral [7], anti-tumour [8], anti-convulsant [9], anti-histaminic
[10] and anti-depressant activities [11]. It has been proved that those 1H-
pyrazole-4-carboxylic acids and their esters had potential as in vitro anti-bacterial
agents against Gram-positive bacteria. Pyrazole carboxylic acid derivatives
provided important building blocks in organic and medicinal chemistry. Celecoxib
[12] (Fig. 1) is the first-to-market drug of a number of selective cyclo-oxygenase
2 (COX-2) inhibitors, which are promising anti-inflammatory and analgesic
agents.
In recent years, various synthetic methods have been introduced, including
microwave irradiation or sonication conditions, with the aim of increasing the
efficiency of the reactions, catalysts and reagents used in these reactions. Further
attempts were made to save time, solvent quantity and safe handling, and in
achieving economically and environmentally benign reaction conditions. The
synthesis of simple pyrazole and their carboxylic acid derivatives [13–17] were also
attempted with the above methodologies. However, most of these methods involved
were multi-step synthesis with longer reaction times and lesser yields. Here, an
efficient ultrasound-assisted regio-selective synthesis of a series of ethyl-5-
(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4-carboxylates
using indium bromide catalyst in the presence of ethanol at 90 °C for 30 min under
ultrasonic conditions is reported.
Fig. 1 Celecoxib
F
F
F
N
N
O
S
O
H2N
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Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis
431
EtO2C
F3C
N
N
N
NHNH2
O
InBr3/Ethanol
N
CO2Et
OEt
F3C
Ultrasonic irradiation
at 90 oC/30 min
R
R
2
1a-h
3a-h
H3CO
O
Cl
R =
S
N
OCH3
CH3
F
Cl
F
a
b
c
d
e
f
g
h
Scheme 1 Synthesis of ethyl-5-(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4-
carboxylates 3
Results and discussion
In our continued interest of research on isoquinolines and related compounds
[18–38], in this communication, an efficient, ultrasound-assisted and indium
bromide catalysed synthesis of a series of ethyl-5-(trifluoromethyl)-1-(3-substituted-
isoquinolin-1-yl)-1H-pyrazole-4-carboxylates is reported. The reaction of various
1-hydrazino-3-substituted-isoquinolines 1 with ethyl-2-(ethoxymethylene)-4,4,4-
trifluoro-3-oxobutanoate 2 in absolute ethanol solvent in the presence of indium
bromide catalyst and ultrasonic irradiation at 90 °C for 30 min afforded ethyl-5-
(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4-carboxylates 3 in
excellent yields and high purity (Scheme 1; Table 1).
By choosing cyclisation of 1-hydrazino-3-phenylisoquinoline 1a and ethyl-2-
(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate 2 as a model reaction (Scheme 2),
the optimisation of cyclisation was carried out by screening different acidic catalysts
as reported in Table 2. The results suggested that the cyclisation proceeds well with
indium bromide catalyst (Table 2, entry 6) with an excellent yield and purity.
However, other acidic catalysts such as Con. HCl, MK-10, Amberlyst 15 (H) and
HClO4–SiO2 produced moderate yields (Table 2, entries 2, 4, 5, 8 and 9), and rest of
the catalysts were found to be less effective.
The influence of the catalyst load was then investigated using 1a and 2 (Table 3).
The results indicated that an increasing amount of indium bromide enhanced the
reaction yield until 15 mol%; however, further increases did not significantly
improve the yield (see Table 3, entries 6–10). The effect of solvents in the cyclisation
reaction of 1a and 2 was also explored (Table 4). Among all of the solvents tested,
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K. Prabakaran et al.
Table 1 Cyclisation of 1-hydrazino-3-substituted-isoquinolines 1 and ethyl-2-(ethoxymethylene)-4,4,4-
trifluoro-3-oxobutanoate, 2
Reaction conditions: 1 (0.1 mmol), 2 (0.11 mmol), indium bromide (20 mol%), ethanol (8 mL) in
ultrasonic irradiation at 90 °C for 30 min
a
Isolated yield
absolute ethanol proved to be an efficient solvent under ultrasonic irradiation
at 90 °C (Table 4, entry 4), while other solvents, 1,4-dioxane, 2-methyl THF,
2-propanol and toluene, were found to be moderate solvents (Table 4, entries 5–8).
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Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis
433
Scheme 2 Synthesis of ethyl-5-(trifluoromethyl)-l-(3-phenylisoquinolin-1-yl)-lH-pyrazole-4-carboxylate
3a
Table 2 Effect of catalyst in
the reaction of 1a and 2
Entry
Catalyst
Yielda (%)
1
2
3
4
5
6
7
8
9
No catalyst
CH3COOH
PTSA
50
68
35
85
72
94
66
68
70
Montmorillonite K-10
Con. HCl
Reaction conditions: 1
InBr3
(0.1 mmol), 2 (0.11 mmol),
catalyst (20 mol%), absolute
ethanol (8 mL) in ultrasonic
irradiation at 90 °C for 30 min
HClO4–SiO2
MK-SF
Amberlyst 15 (H)
a
Isolated yield
Table 3 Optimisation of
catalyst load in the reaction of
1a and 2
Entry
Indium
bromide (mol%)
Yielda (%)
1
1
55
60
68
72
88
92
92
93
93
93
2
3
3
6
4
9
5
12
15
18
21
24
27
Reaction conditions: 1
(0.1 mmol), 2 (0.11 mmol),
indium bromide catalyst,
absolute ethanol (8 mL) in
ultrasonic irradiation at 90 °C
for 30 min
6
7
8
9
10
a
Isolated yield
In continuation, the ethyl-5-(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-
1H-pyrazole-4-carboxylates 3 were synthesised using microwave heating, as well as
by ultrasonic irradiation, and were compared as shown in Table 5. It should be
noted that conventional heating offered lesser yields of desired products after
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K. Prabakaran et al.
Yielda (%)
Table 4 Effect of solvent in the
reaction of 1a and 2
Entry
Solvent
1
2
3
4
5
6
7
8
DMF
62
60
68
93
75
73
83
80
DMSO
THF
Reaction conditions: 1
(0.1 mmol), 2 (0.11 mmol),
catalyst indium bromide
(20 mol%), ethanol (8 mL) in
ultrasonic irradiation at 90 °C
for 30 min
Absolute ethanol
1,4-Dioxane
2-Methyl THF
2-Propanol
Toluene
a
Isolated yield
Table 5 Comparison of
conventional microwave heating
and ultrasonic irradiation of 1
and 2
Entry
Hydrazine, 1
Microwave
irradiation,
3 yielda (%)
Ultrasonic
irradiation,
3 yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
50
61
63
68
52
67
60
57
93
88
89
91
82
92
87
83
Reaction conditions: 1
(0.1 mmol), 2 (0.11 mmol),
indium bromide catalyst
(20 mol%), ethanol (8 mL) at
90 °C for 30 min
1g
1h
a
Isolated yield
prolonged reaction. The result indicated that the ultrasonic-assisted reaction gave an
excellent yield in comparison to conventional and microwave heating.
It should be noted that, although microwave-assisted reaction often takes place
quickly compared to ultrasonic condition, in the present study, ultrasonic condition
offered better results of the desired products under the optimised reaction time of
30 min.
With the optimised result in hand, various ethyl-5-(trifluoromethyl)-1-(3
substituted-isoquinolin-1-yl)-1H-pyrazole-4-carboxylates 3 were regio-selectively
synthesised, as depicted in Scheme 1 and Table 1. The desired product 3a–h were
obtained in high yield and purity and were characterised by different spectral
techniques, including 1H, 13C, LC–MS and elemental analysis. The proposed
mechanism of the regio-selective reaction is depicted in Scheme 3.
Further, the nuclear Overhauser effect spectroscopy–nuclear magnetic resonance
(NOESY–NMR) technique was utilised in confirming the regio-selective isomer. In
the pyrazole cyclisation, the –CF3 group and –H position were confirmed by the
NOESY–NMR technique using compound 3d (Fig. 2). The NOESY study was
performed in a one-dimensional fashion by pre-selecting individual resonances.
Initially, the spectra read with the pre-selected H from the 1c position in pyrazole
gave a large negative signal, while there were no weaker positive signals. However,
in order to confirm this further, the next singlet proton from the 4 position in NMR
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Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis
435
Scheme 3 Mechanism of the reaction
Fig. 2 NOE spectrum of 3d
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K. Prabakaran et al.
was pre-selected, which showed a large negative signal and two weaker positive
signals corresponding to –2H (from the 3b, 3f positions) and –1H (from the 5
position). Based on the above NOESY result, it is suggested that the –CF3 group is
in the 5 position and the –H group is in the 3 position of the pyrazole ring moiety.
Experimental
All reagents purchased from Sigma-Aldrich, Lancaster and Qualigens were used
without further purification. Ethyl-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobu-
tanoates were purchased from Lancaster and used as received. Infrared (IR) spectra
were recorded using Avatar 330 apparatus equipped with a DTGS detector. The
NMR spectra were recorded on a Bruker Spectrospin Avance DPX400 Ultrashield
(400 MHz). Mass spectra were obtained using Agilent mass spectrometry.
Sonication was performed in a Sonics Vibra-Cell VC 130 ultrasonic processor
with an operating frequency of 20 kHz and a power output 0–130 Watt. Melting
points were determined in open capillaries.
The starting material hydrazine derivatives were synthesised and characterised by
1H NMR, 13C NMR, FTIR, LC–MS and elemental analysis techniques.
1a: Yellow solid, mp 182–183 °C, IR (cm-1) 3,283, 3,185, 3,054, 2,922, 1,949,
1,617, 1,595, 1,565, 1,504, 1,441, 1,422, 1,378, 1,325, 1,183, 1,140, 1,073, 1,030,
1
960, 914, 842, 818, 797, 766, 747, 683, 642, 574, 520, 411. H NMR (400 MHz,
DMSO-D6, ppm): d 8.80 (bs, 1H), 8.26–8.22 (m, 3H), 7.82–7.80 (d, J = 8.0 Hz,
1H), 7.65–7.61 (t, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.50–7.44 (m, 3H), 7.40–7.37 (t,
J = 7.6 Hz, 1H), 4.64 (bs, 2H). 13C NMR (100 MHz, DMSO-D6, ppm): d 156.9,
148.0, 140.0, 137.8, 2 9 130.4, 2 9 128.8, 128.5, 127.5, 126.8, 126.0, 123.1, 117.1,
106.3. LC–MS: m/e 236.1, C15H13N3 requires Mol. Wt.: 235.11. Elemental analysis,
calculated: C, 76.57; H, 5.57; N, 17.86%. Found: C, 76.49; H, 5.51; N, 17.78%.
1b: Yellow solid, mp 220–221.5 °C, IR (cm-1) 3,251, 2,973, 2,261, 2,183, 2,130,
2,043, 2,020, 1,991, 1,957, 1,655, 1,616, 1,568, 1,510, 1,442, 1,417, 1,381, 1,325,
1,197, 1,143, 1,099, 1,067, 1,034, 958, 870, 841, 806, 750, 669, 618, 514. 1H NMR
(400 MHz, DMSO-D6, ppm): d 8.75–8.91 (bs, 1H), 8.27–8.24 (d, J = 8.6 Hz, 2H),
8.20–8.18 (d, J = 8.3 Hz, 1H), 7.79–7.77 (d, J = 7.7 Hz, 1H), 7.64–7.60 (t,
J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.52–7.51 (d, J = 9.3 Hz, 2H), 7.49–7.43 (t,
J = 8.8 Hz, 1H), 7.41–6.80 (bs, 2H). 13C NMR (100 MHz, DMSO-D6, ppm): d
151.4, 149.0, 138.5, 136.4, 135.1, 133.3, 131.4, 129.6, 128.9, 128.4, 128.1, 127.3,
126.5, 126.0, 116.1. LC–MS: m/e 270.0, C15H12ClN3 requires Mol. Wt.: 269.73.
Elemental analysis, calculated: C, 66.79; H, 4.48; Cl, 13.14; N, 15.58%. Found: C,
66.72; H, 4.46; N, 15.54%.
1c: Yellow solid, mp 107–108 °C, IR (cm-1) 3,251, 2,973, 2,261, 2,183, 2,130,
2,043, 2,020, 1,991, 1,957, 1,655, 1,616, 1,568, 1,510, 1,442, 1,417, 1,381, 1,325,
1,197, 1,143, 1,099, 1,067, 1,034, 958, 870, 841, 806, 750, 669, 618, 514. 1H NMR
(400 MHz, DMSO-D6, ppm): d 8.85 (bs, 1H), 8.24–8.22 (d, J = 8.4 Hz, 1H),
7.80–7.75 (m, 2H), 7.67–7.63 (t, J = 7.2 Hz, 1H), 7.57–7.38 (m, 4H), 7.22 (s, 1H),
7.20–6.60 (bs, 2H). 13C NMR (100 MHz, DMSO-D6, ppm): d 156.8, 148.1, 140.2,
137.8, 137.0, 132.2, 131.8, 130.5, 129.6, 127.5, 127.0, 126.5, 123.0, 116.7, 111.0.
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Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis
437
LC–MS: m/e 269.8, C15H12ClN3 requires Mol. Wt.: 269.73. Elemental analysis,
calculated: C, 66.79; H, 4.48; Cl, 13.14; N, 15.58%. Found: C, 66.72; H, 4.39; N,
15.51%.
1d: Yellow solid, mp 201–202 °C, IR (cm-1) 3,085, 2,913, 2,177, 2,129, 2,061,
2,026, 2,001, 1,964, 1,895, 1,692, 1,653, 1,600, 1,566, 1,505, 1,408, 1,366, 1,323,
1,277, 1,215, 1,156, 1,131, 1,093, 1,044, 1,013, 964, 883, 823, 779, 754, 682, 663,
1
614, 587, 531, 505. H NMR (400 MHz, DMSO-D6, ppm): d 8.70–8.90 (bs, 1H),
8.30–8.27 (m, 2H), 8.21–8.19 (d, J = 8.0 Hz, 1H), 7.80–7.78 (d, J = 8.0 Hz, 1H),
7.65–7.61 (t, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.47–7.43 (t, J = 8.0Hz, 1H),
7.31–7.27 (t, J = 8.8 Hz, 2H), no clear NH2 peak appeared. 13C NMR (100 MHz,
DMSO-D6, ppm): d 164.0, 161.5, 156.9, 147.0, 137.8, 136.5, 130.52, 128.8, 128.7,
127.4, 126.1, 123.1, 116.9, 115.7, 106.1. LC–MS: m/e 254.1, C15H12FN3 requires
Mol. Wt.: 253.1 Elemental analysis, calculated: C, 71.13; H, 4.78; F, 7.50; N,
16.59%. Found: C, 71.07; H, 4.69; N, 16.52%.
1e: Yellow solid, mp 162–163 °C, IR (cm-1) 3,280, 2,912, 1,778, 1,616, 1,592,
1,561, 1,499, 1,447, 1,422, 1,391, 1,322, 1,237, 1,211, 1,175, 1,156, 1,087, 959,
852, 820, 787, 743, 583, 550, 503. 1H NMR (400 MHz, DMSO-D6, ppm):
8.13–8.11 (d, J = 8.0 Hz, 1H), 7.62–7.53 (m, 2H), 7.42–7.36 (m, 3H), 7.13–7.08 (t,
J = 9.2 Hz, 2H), 6.72 (s, 1H), 3.98 (s, 2H). 13C NMR(100 MHz, DMSO-D6, ppm):
d 162.4, 160.0, 156.6, 152.1, 137.5, 136.8, 131.2, 131.2, 130.3, 126.5, 125.5, 123.0,
116.3, 115.4, 108.1, 43.2. LC–MS: m/e 267.7, C16H14FN3 requires Mol. Wt.:
267.12. Elemental analysis, calculated: C, 71.89; H, 5.28; F, 7.11; N, 15.72%.
Found: C, 71.88; H, 5.27; N, 15.76%.
1f: Yellow solid, mp 161–162.5 °C, IR (cm-1) 3,184, 3,043, 2,148, 1,966, 1,614,
1,583, 1,564, 1,509, 1,422, 1,375, 1,323, 1,172, 1,090, 966, 943, 814, 786, 745, 646.
1H NMR (400 MHz, DMSO-D6, ppm): d 8.75 (bs, 1H), 8.20–8.18 (d, J = 8.4 Hz,
1H), 8.06 (s, 1H), 8.04–8.02 (d, J= 8.0 Hz, 1H), 7.80–7.78 (d, J = 8.0 Hz, 1H),
7.64–7.60 (t, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.46–7.42 (t, J = 8.4 Hz, 1H),
7.37–7.33 (t, J = 7.6 Hz, 1H), 7.20–7.18 (d, J = 7.2 Hz, 1H), 6.96–5.95 (bs, 2H),
2.41 (s, 3H). 13C NMR (100 MHz, DMSO-D6, ppm): d 156.8, 148.1, 2 9 139.9,
137.8, 130.4, 129.2, 128.7, 127.4, 127.3, 126.0, 124.0, 123.1, 117.0, 106.3, 21.7.
LC–MS: m/e: 249.8, C16H15N3 requires Mol. Wt.: 249.13. Elemental analysis,
calculated: C, 77.08; H, 6.06; N, 16.85%. Found: C, 77.03; H, 6.12; N, 16.76%.
1g: Yellow solid, mp 180–181.5 °C, IR (cm-1) 3,291, 3,191, 3,046, 2,530, 2,420,
2,443, 2,290, 2,225, 2,143, 1,897, 1,842, 1,613, 1,585, 1,566, 1,556, 1,527, 1,453,
1,391, 1,323, 1,229, 1,182, 1,140, 1,080, 1,020, 956, 897, 855, 811, 749, 704, 657,
1
635, 572. H NMR (400 MHz, DMSO-D6, ppm): d 8.84 (bs, 1H), 8.17–8.15 (d,
J = 8.0 Hz, 1H), 7.77–7.73 (m, 2H), 7.63–7.59 (t, J = 7.6Hz, 1H), 7.56–7.54 (d,
J = 6.0 Hz, 1H), 7.44–7.40 (m, 2H), 7.16–7.14 (t, J = 4.8 Hz, 1H). 13CNMR (100
MHz, DMSO-D6, ppm): d 156.6, 146.3, 144.0, 137.6, 130.7, 128.5, 127.1, 127.0,
125.8, 124.0, 123.2, 116.9, 104.4. LC–MS: m/e 242.1, C13H11N3S requires Mol.
Wt.: 241.07. Elemental analysis, calculated: C, 64.70; H, 4.59; N, 17.41; S, 13.29%.
Found: C, 64.64; H, 4.51; N, 17.37; S, 13.22%.
1h: Yellow solid, mp 153–154.5 °C, IR (cm-1) 3,292, 3,037, 2,330, 2,290, 2,251,
1,896, 1,833, 1,616, 1,561, 1,520, 1,461, 1,407, 1,321, 1,237, 1,200, 1,143, 1,104,
964, 893, 828, 793, 749, 653.6, 596, 564. 1H NMR (400 MHz, DMSO-D6, ppm): d
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K. Prabakaran et al.
8.98–8.70 (bs, 1H), 8.21-8.19 (d, J = 8.0Hz, 1H), 7.79–7.77 (d, J = 8.0 Hz, 1H),
7.66–7.62 (t, J = 7.2 Hz, 1H), 7.49–7.45 (t, J = 8.0 Hz,1H), 7.10 (s, 1H), 2.65 (s,
3H), 2.47 (s, 3H). The NH2 peak does not appear. 13C NMR (100 MHz, DMSO-D6,
ppm): d 167.0, 159.0, 156.9, 141.9, 137.4, 130.5, 127.1, 126.2, 123.0, 116.4, 116.3,
109.1, 13.1, 12.3. LC–MS: m/e 255.1, C14H14N4O3 requires Mol. Wt.: 286.11.
Elemental analysis, calculated: C, 58.73; H, 4.93; N, 19.57; O, 16.77%. Found: C,
58.64; H, 4.91; N, 19.61%.
General procedure for the synthesis of ethyl-5-(trifluoromethyl)-1-(3-
substituted-isoquinolin-1-yl)-1H-pyrazole-4-carboxylates, (3a–h)
A mixture of 1-hydrazino isoquinoline 1 (0.1 mmol), ethyl-2-(ethoxymethylene)-
4,4,4-trifluoro-3-oxobutanoate 2 (0.11 mmol), indium bromide catalyst (10 mol%)
and ethanol (8.0 mL) and the resulting mixture was subjected to ultrasonic
irradiation by immersing the probe directly into the reaction mixture for 30 min.
The operating frequency was 15 kHz and the output power was 100 Watt through
manual adjustment. The reaction was monitored by TLC. After completion of the
reaction, the resulting solution was concentrated in vacuo. The crude products were
subjected to silica-gel (230–400 mesh) flash column chromatography using hexane–
ethyl acetate (90:10) as an eluent to afford the pure products 3, which were
characterised by 1H NMR, 13C NMR, FTIR, LC–MS and elemental analysis
techniques.
3a: Yellow solid, mp 90–91 °C, IR (cm-1) 2,913, 2,185, 2,113, 2,036, 2,019,
1,991, 1,950, 1,906, 1,716, 1,627, 1,561, 1,465, 1,419, 1,391, 1,330, 1,297, 1,235,
1
1,195, 1,152, 1,033, 953, 881, 846, 769, 745, 680, 589, 565. H NMR (400 MHz,
CDCl3, ppm): d 8.28–8.27 (2H, d, J = 6.4), 8.14–8.12 (2H, d, J = 8.4), 8.01–7.99
(1H, d, J = 8.4), 7.79–7.73 (2H, m), 7.63–7.59 (1H, t, J = 7.6), 7.52–7.48 (2H, t,
J = 7.2), 7.45–7.41 (1H, t, J = 7.2), 4.46–4.4 (2H, q), 1.44–1.41 (3H, t, J = 6.8).
13C NMR (100 MHz, CDCl3, ppm): d 161.0, 149.5, 149.0, 142.8, 139.3, 137.7,
131.4, 129.1, 128.8, 128.6, 127.3, 126.9, 124.4, 122.9, 118.5, 117.8, 116.8, 61.3,
14.1. LC–MS: m/e 412.2, C22H16F3N3O2 requires Mol. Wt.: 411.12. Elemental
analysis, calculated: C, 64.23; H, 3.92; F, 13.85; N, 10.21; O, 7.78%. Found: C,
64.19; H, 3.86; N, 10.12%.
3b: Yellow solid, mp 108–110 °C, IR (cm-1) 3,050, 2,913, 2,850, 2,495, 2,216,
2,162, 2,135, 2,042, 2,018, 1,979, 1,947, 1,717, 1,641, 1,629, 1,600, 1,546, 1,468,
1,339, 1,305, 1,267, 1,202, 1,164, 1,109, 1,034, 905, 868, 826, 782, 743, 683, 617,
523. 1H NMR (400 MHz, CDCl3, ppm): d 8.28 (1H, s), 8.23 (1H, s), 8.09–8.06 (2H,
d, J = 8.4), 8.01–7.99 (1H, d, J = 8.4), 7.80–7.74 (2H, m), 7.65–7.60 (1H, t,
J = 8.0), 7.48–7.45 (2H, d, J = 9.2), 4.46–4.41 (2H, q), 1.44–1.41 (3H, t, J = 7.2).
13C NMR (100 MHz, CDCl3, ppm): d 160.9, 149.1, 148.2, 142.8, 139.3, 136.1,
135.3, 2 9 131.6, 2 9 129.0, 128.8, 128.1, 2 9 127.3, 2 9 124.5, 123.0, 118.4,
116.9, 61.4, 14.1. LC–MS: m/e 446.2, C22H15ClF3N3O2 requires Mol. Wt.: 445.08.
Elemental analysis, calculated: C, 59.27; H, 3.39; Cl, 7.95; F, 12.78; N, 9.43; O,
7.18%. Found: C, 59.23; H, 3.32; N, 9.36%.
3c: Yellow semisolid, mp 34–35 °C, IR (cm-1) 2,989, 2,908, 2,318, 2,232,
2,182, 2,130, 2,086, 2,051, 2,001, 1,958, 1,715, 1,622, 1,588, 1,557, 1,464, 1,394,
123

Indium bromide catalysed, ultrasound-assisted, regio-selective synthesis
439
1,325, 1,261, 1,235, 1,144, 1,033, 944, 883, 827, 773, 747, 692, 566, 511. 1H NMR
(400 MHz, CDCl3, ppm): d 8.27 (2H, s), 8.03–8.01 (1H, d, J = 8.4), 7.83–7.79 (1H,
m), 7.73–7.70 (1H, dd, J = 9.6, 2.0), 7.69–7.66 (2H, m), 7.53–7.50 (1H, dd,
J = 9.6, 1.6), 7.41–7.33 (2H, m), 4.44–4.38 (2H, q), 1.42–1.39 (3H, t, J = 7.2). 13
C
NMR (100 MHz, CDCl3, ppm): d 160.9, 149.0, 148.3, 142.9, 138.4, 137.5, 132.4,
132.0, 131.5, 130.3, 2 9 129.7, 129.2, 127.4, 2 9 127.1, 124.1, 124.1, 123.1, 116.7,
61.3, 14.0. LCMS: m/e 446.2, C22H15ClF3N3O2 requires Mol. Wt.: 445.08.
Elemental analysis, calculated: C, 59.27; H, 3.39; Cl, 7.95; F, 12.78; N, 9.43; O,
7.18%. Found: C, 59.23; H, 3.32; N, 9.38%.
3d: Yellow solid, mp 86–87.5 °C, IR (cm-1) 2,959, 2,279, 2,224, 2,182, 2,157,
2,132, 2,056, 2,038, 2,017, 1,971, 1,723, 1,637, 1,600, 1,564, 1,476, 1,453, 1,427,
1,337, 1,306, 1,271, 1,223, 1,156, 1,111, 1,073, 1,043, 1,026, 1,001, 923, 881, 839,
1
793, 714, 711, 680, 648, 613, 577, 525. H NMR (400 MHz, CDCl3, ppm): d 8.3
(1H, s), 8.2 (1H, s), 8.15–8.10 (2H, m), 8.00–7.98 (1H, d, J = 8.0), 7.79–7.73 (2H,
m), 7.63–7.59 (1H, t, J = 8.0), 7.20–7.15 (2H, t, J = 10.0), 4.46–4.40 (2H, q),
1.44–1.41 (3H, t, J = 6.8). 13C NMR (100 MHz, CDCl3, ppm): d 162.4, 160.9,
149.0, 148.5, 142.8, 139.4, 133.9, 131.5, 128.7, 128.7, 127.3, 124.4, 122.8, 118.2,
116.9, 115.9, 115.7, 61.4, 29.7, 14.1. LC–MS: m/e 430.2, C22H15F4N3O2 requires
Mol. Wt.: 429.11. Elemental analysis, calculated: C, 61.54; H, 3.52; F, 17.70; N,
9.79; O, 7.45%. Found: C, 61.48; H, 3.47; N, 9.70%.
3e: Yellow oily liquid, mp 34–35 °C, IR (cm-1) 2,989, 2,908, 2,318, 2,232,
2,182, 2,130, 2,086, 2,051, 2,001, 1,958, 1,715, 1,622, 1,588, 1,557, 1,464, 1,394,
1,325, 1,261, 1,235, 1,144, 1,033, 944, 883, 827, 773, 747, 692, 566, 511. 1H NMR
(400 MHz, CDCl3, ppm): d 8.25 (1H, s), 7.84–7.82 (1H, d, J = 8.0), 7.74–7.70 (1H,
m), 7.59–7.54 (3H, m), 7.28–7.25 (2H, m), 7.02–6.98 (2H,t, J = 8.8), 4.44–4.38
(2H, q), 4.27 (2H, s), 1.42–1.39 (3H, t, J = 7.2). 13C NMR (100 MHz, CDCl3,
ppm): d 160.9, 152.9, 148.9, 142.8, 2 9 139.0, 134.6, 131.3, 130.7, 130.6,
2 9 128.4, 126.6, 2 9 124.1, 122.6, 121.3, 116.6, 115.5, 115.2, 61.3, 42.8, 14.1.
LC–MS: m/e 444.0, C23H17F4N3O2 requires Mol. Wt.: 443.13. Elemental analysis,
calculated: C, 62.30; H, 3.86; F, 17.14; N, 9.48; O, 7.22%. Found: C, 62.27; H, 3.79;
N, 9.41%.
3f: Yellow solid, mp 93–94.5 °C, IR (cm-1) 3,068, 2,983, 2,925, 1,961, 1,728,
1,628, 1,566, 1,470, 1,443, 1,413, 1,324, 1,299, 1,268, 1,237, 1,085, 1,038, 959,
1
898, 854, 754, 689, 523. H NMR (400 MHz, CDCl3, ppm): d 8.28–8.25 (2H, d,
J = 12.0), 8.00–7.90 (3H, m), 7.78–7.71 (2H, m,), 7.62–7.58 (1H, m), 7.40–7.36
(1H, t, J = 7.6), 7.25–7.23 (1H, d, J = 8.4), 4.46–4.40 (2H, q), 2.45 (3H, s),
1.44–1.41 (3H, t, J = 7.2). 13C NMR (100 MHz, CDCl3, ppm): d 161.0, 149.6,
148.9, 142.8, 139.3, 138.5, 137.6, 131.3, 129.9, 128.7, 128.5, 127.6, 127.3, 124.4,
124.0, 122.9, 120.5, 118.5, 116.8, 61.4, 29.7, 21.5, 14.1. LC–MS: m/e 426.2,
C23H18F3N3O2 requires Mol. Wt.: 425.41. Elemental analysis, calculated: C, 64.94;
H, 4.26; F, 13.40; N, 9.88; O, 7.52%. Found: C, 64.90; H, 4.19; N, 9.82%.
3g: Yellow solid, mp 128–129 °C, IR (cm-1) 2,989, 2,908, 2,318, 2,232, 2,182,
2,130, 2,086, 2,051, 2,001, 1,958, 1,715, 1,622, 1,588, 1,557, 1,464, 1,394, 1,325,
1
1,261, 1,235, 1,144, 1,033, 944, 883, 827, 773, 747, 692, 566, 511. H NMR (400
MHz, CDCl3, ppm): d 8.27(1H, s), 8.09 (1H, s), 7.95–7.93 (1H, d, J = 8.0),
7.76–7.71 (3H, m), 7.58–7.55 (1H, t, J = 7.2), 7.41–7.40 (1H, d, J = 5.2),
123

440
K. Prabakaran et al.
7.15–7.13 (1H, t, J = 4.8), 4.46–4.40 (2H, q), 1.44–1.40 (3H, t, J = 7.2). 13C NMR
(100 MHz, CDCl3, ppm): d 160.9, 148.8, 145.0, 143.1, 142.8, 139.3, 134.7, 134.3,
131.6, 128.2, 127.6, 127.0, 125.3, 124.6, 122.7, 120.4, 117.7, 116.6, 61.4, 14.1. LC–
MS: m/e 418.2, C20H14F3N3O2S requires Mol. Wt.: 417.41. Elemental analysis,
calculated: C, 57.55; H, 3.38; F, 13.65; N, 10.07; O, 7.67; S, 7.68%. Found: C,
57.49; H, 3.32; N, 10.01; S, 7.65%.
3h: Yellow solid, mp 106–108 °C, IR (cm-1) 3,726, 3,623, 3,345, 2,984, 2,904,
2,190, 2,153, 1,964, 1,713, 1,625, 1,563, 1,468, 1,397, 1,326, 1,270, 1,240, 1,150,
1
1,041, 958, 903, 842, 753, 716, 688, 605, 539, 453, 403. H NMR (400 MHz,
CDCl3, ppm): d 8.29 (1H, s), 8.19 (1H, s), 7.99–7.97 (1H, d, J = 8.4 Hz), 7.85 (1H,
s), 7.83–7.79 (1H, t, J = 8.0), 7.66–7.59 (1H, m), 4.45–4.40 (2H, q), 2.61 (3H, s),
2.47 (3H, s), 1.43–1.40 (3H, t, J = 7.2). 13C NMR (100 MHz, CDCl3 ppm):
d 168.0, 160.8, 158.7, 149.4, 143.0, 142.7, 138.9, 134.9, 131.8, 129.0, 126.9, 124.3,
122.9, 121.5, 116.7, 114.8, 113.4, 61.4, 14.0, 12.4, 11.5. LC–MS: m/e 463.2,
C21H17F3N4O5 requires Mol. Wt.: 462.12. Elemental analysis, calculated: C, 54.55;
H, 3.71; F, 12.33; N, 12.12; O, 17.30%. Found: C, 54.50; H, 3.65; N, 12.05%.
Conclusion
In conclusion, an efficient method for the regio-selective synthesis of series of ethyl-
5-(trifluoromethyl)-1-(3-substituted-isoquinolin-1-yl)-1H-pyrazole-4-carboxylates
using indium bromide catalyst in the presence of absolute ethanol solvent is reported
under the ultrasonic irradiation method.
Acknowledgements The authors wish to express their gratitude to the Management, VIT University,
India, for the support and facilities.
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