Synthesis and antibacterial activity of some 5-hydroxy-5-trifluoromethyl-4, 5-dihydropyrazol-1-thiocarboxamides, 3-trifluoromethylpyrazol-1-thiocarboxamides and 4-aryl-2-(5(3)-trifluoromethyl-1-pyrazolyl)thiazoles

Article abstract of DOI:10.1016/j.jfluchem.2011.07.029

5-Hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides 3 and 3-trifluoromethylpyrazol-1-thiocarboxamides 4, regioselectively obtained by the condensation of trifluoromethyl-β-diketones with thiosemicarbazide under neutral and acidic conditions,

Full text of DOI:10.1016/j.jfluchem.2011.07.029

Journal of Fluorine Chemistry 132 (2011) 965–972
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and antibacterial activity of some 5-hydroxy-5-trifluoromethyl-4,5-
dihydropyrazol-1-thiocarboxamides, 3-trifluoromethylpyrazol-1-
thiocarboxamides and 4-aryl-2-(5(3)-trifluoromethyl-1-pyrazolyl)thiazoles
a
a
b
b
b
Ranjana Aggarwal a, , Rajiv Kumar , Sunil Kumar , Gaurav Garg , Ritu Mahajan , Jitender Sharma
*
a Department of Chemistry, Kurukshetra University, Kurukshetra – 136 119 Haryana, India
b Department of Biotechnology, Kurukshetra University, Kurukshetra – 136 119 Haryana, India
A R T I C L E I N F O
A B S T R A C T
Article history:
5-Hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides 3 and 3-trifluoromethylpyrazol-
1-thiocarboxamides 4, regioselectively obtained by the condensation of trifluoromethyl- -diketones
Received 2 May 2011
b
Received in revised form 22 July 2011
Accepted 27 July 2011
with thiosemicarbazide under neutral and acidic conditions, on further reaction with phenacyl bromides
5 afforded 4-aryl-(5-trifluoromethyl-pyrazol-1-yl)thiazoles 6 and 4-aryl-(3-trifluoromethyl-pyrazol-1-
yl)thiazoles 7, respectively. Five 4,5-dihydropyrazoles (3a–e) and two pyrazolylthiazoles (6a and 6c)
were tested against one Gram-positive and one Gram-negative bacteria to assess their in vitro
antibacterial activity. Compounds 3a, 3b and 3e showed moderate antibacterial activity against Gram-
positive bacterium, Bacillus pumilus.
Available online 4 August 2011
Keywords:
5-Hydroxy-5-trifluoromethyl-4,5-
dihydropyrazol-1-thiocarboxamides
3-Trifluoromethylpyrazol-1-
thiocarboxamides
ß 2011 Elsevier B.V. All rights reserved.
3/5-Trifluoromethylpyrazolylthiazoles
Trifluoromethyl-b-diketones
Thiosemicarbazide
Antibacterial activity
1. Introduction
reaction suffers with the draw-back of regioselectivity and affords
non-separable mixture of regioisomeric pyrazolylthiazoles. There
Heterocyclic compounds bearing trifluoromethyl group play an
important role in medicinal and agricultural fields [1–5]. Celecoxib
and SC-588 are the selective cyclooxygenase-2 (COX-2) inhibitors
with fewer gastrointestinal side effects to traditional NSAIDs and
are being used for the treatment of rheumatoid arthritis and
osteoarthritis [6,7]. These compounds also act as nuclear factor of
activated T-cells (NFAT) transcription factor regulator [8] and are
widely used as agrochemicals [9,10]. Pyrazolylthiazoles have been
used in cardiovascular diseases as selective inhibitors of fibrino-
gen-mediated platelet aggregation [11]. Many of these compounds
display antinociceptive activity [12], toxicity towards Candida
elegans [13] and phototoxicity against mosquito larvae [14]. In
view of these observations, it was aimed to synthesize a series of
pyrazolylthiazoles derivatives bearing trifluoromethyl group on 3
and/or 5 positions of pyrazole ring as potential antibacterical
agents. A perusal of literature revealed that the most common
route to the synthesis of pyrazolylthiazoles comprised of the
are contradictory reports also in the literature concerning the
structure of the products obtained in these reactions. For instance,
the reaction between 4-aryl-2-hydrazinothiazoles with
b-dike-
tones has been reported to yield thiazolotriazepines [16] instead of
isomeric pyrazoles.
So, in the present investigation, an alternate route has been
explored to prepare some new trifluoromethyl substituted pyr-
azolylthiazoles involving the reaction of 3(5)-trifluoromethyl-5(3)-
substituted-pyrazol-1-thiocarboxamides with phenacyl bromides.
2. Result and discussion
Synthesis of 4-aryl-2-(3-substituted-5-trifluoromethyl-1-pyra-
zolyl)thiazoles 6 and isomeric 4-aryl-2-(5-substituted-3-trifluor-
omethyl-1-pyrazolyl)thiazoles 7 was accomplished by the reaction
of 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarbox-
amides
3 and 3-trifluoromethylpyrazol-1-thiocarboxamides 4,
reaction of 2-hydrazinothiazoles with
b-diketones [15]. But, the
respectively with phenacyl bromides 5 (Scheme 1). The key
intermediates 3 and 4, in turn, were obtained by the cyclo-
condensation of thiosemicarbazide
diketones 2 in equimolar ratio using ethanol as solvent. Whereas
the reaction with aliphatic trifluoromethyl- -diketones 2a–b
1 with trifluoromethyl-b-
* Corresponding author. Tel.: +91 1744 238734; fax: +91 1744 238277.
E-mail address: ranjana67in@yahoo.com (R. Aggarwal).
b
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.07.029

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R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
R1
S
N
EtOH
reflux
H2N
S
N
H2N
HO
N
N
N
N
N
S
NH2
R
N
H
EtOH
F3C
O
R
reflux
or
F3C
N
HB
HA
1
6
Br
3
+
Ph
EtOH, H2SO4
reflux
R1
S
+
O
O
5
N
H2N
N
R
CF3
S
EtOH
reflux
CF3
R
CF3
2
R
4
7
R1
R1
C6H5
p-CH3OC6H4
R
2, 3, 4
R
5
6
R
7
a
b
c
p-CH3OC6H4
C6H5
CH3
CF3
C6H5
p-CH3OC6H4
p-ClC6H4
a
b
c
d
e
a
b
c
d
e
a
b
C6H5
p-CH3OC6H4
p-ClC6H4
CH3
CF3
C6H5
p-CH3OC6H4
p-ClC6H4
C6H5
C6H5
p-CH3OC6H4
Scheme 1. Synthesis of 2-(3/5-trifluoromethylpyrazol-1-yl)thiazoles from thiosemicarbazide and trifluoromethyl-b-diketones.
Table 1
for formation of 5-phenyl-3-trifluoromethylpyrazol-1-thiocarbox-
amide 4c was found to be 4–5 drops of H2SO4 in EtOH (yield 42% as
compared to 15% in neutral medium). To check the scope of the
Ratioa of compounds 3 and 4 in the reaction between 1 and 2.
Compound
3 (%)
4 (%)
reaction, other
b-diketones 2 were also made to react with
a
b
c
100
100
85
0
0
thiosemicabazide 1 under the above said optimized reaction
conditions and a change in regioselectivity was observed (Table 2).
In IR spectra of 3 two absorption bands appeared at about 3400
and 3300 cmꢀ1 due to N–H stretch and two absorption bands at
3504–3574 and 1600-1620 cmꢀ1 indicated the presence of O–H and
C55S stretch, respectively. The 1H NMR spectra of 3a–e displayed one
15
42
35
d
e
58
65
a
The ratio of different products is calculated by 1H NMR spectra of the crude
reaction mixture.
doubletofoneprotonintensityatabout
d
3.3-3.8(JHA–HB = 18-20 Hz)
3.2-3.6
yielded a single product, which was identified as 5-hydroxy-5-
trifluoromethyl-3-substituted-4,5-dihydropyrazol-1-thiocarboxa-
mides 3a–b, the reaction with aromatic trifluoromethyl-b-dike-
and one doublet of quartet of one proton intensity at about
d
4
(JHA–HB = 18-20 Hz, JHB-CF3 = 1-2 Hz). This particular pattern is
expected from the two methylene protons (CHAHB), respectively
(cis and trans to the CF3 group) at position 4 of 5-hydroxy-4,5-
dihydropyrazoles [17–20]. Compound 3 also exhibited three signals
tones 2c–e afforded a mixture of two products, which were
identified as 5-hydroxy-5-trifluoromethyl-3-substituted-4,5-dihy-
dropyrazol-1-thiocarboxamides 3c–e as the major and 3-trifluor-
omethyl-5-substitutedpyrazole-1-thiocaboxamides 4c–e as the
minor product (Scheme 1). 4,5-Dihydropyrazol-1-thiocarboxa-
mides 3 and pyrazol-1-thicarboxamides 4 were purified by column
chromatography and the ratio of these two different products was
measured by 1H NMR spectroscopy of the crude reaction mixture
(Table 1). Formation of thesecompounds was confirmed onthe basis
of their IR, NMR (1H, 13C, 19F), mass spectra and elemental analysis.
It is evident from Table 1 that reaction exhibits high level of
regioselectivity towards the formation of 5-hydroxy-5-trifluoro-
methyl-4,5-dihydropyrazol-1-thiocarboxamides 3. The presence of
eachofone protonintensity at about d6.1-6.6, 7.1-7.7 (NH2) and 7.7-
8.5 (OH) which are exchangeable with D2O indicating the presence
of two thiocarboxamide (CSNH2) protons at position 1 and OH
proton at position 5, respectively. Further support for the structure
of 3 was provided by 13C NMR spectra, which exhibited signals at
d
44–49, 92–93 as a quartet (2JC–F = 33-34 Hz) and 153–157 ppm
corresponding to carbons C4, C5 and C3 (Table 3) respectively. Also,
signal at about
d
177 ppm in the 13C NMR spectra demonstrate the
presence of C55S group. Finally, the 19F NMR spectra showed a signal
Table 2
a trifluoromethyl group on the
b-diketones 2 and the thiocarbox-
The ratio of 3 and 4 in the reaction between 1 and 2 in acidic medium.
amide group on the dinucleophile (thiosemicarbazide) were the
determining factors to control the regiochemistry of the reaction
along with substituents present on aryl ring of the diketones, which
are in accordance with our earlier results [17]. It has also been
observed earlier by us that the acidic medium causes the change in
the regioselectivity of the reaction. So in the present study, reaction
Effect of different reaction condition on
Ratio of 3 and 4 using 4–5
the ratio of 4c
drops of H2SO4 in EtOH
Different reaction conditions
4c (%)a
Compound
3 (%)a
4 (%)a
EtOH
15
17
42
33
a
b
c
91
100
58
9b
0
2 drops HCl in EtOH
4–5 drops H2SO4 in EtOH
AcOH
42
60
54
of thiosemicarbazide and
b-diketones 2 was also studied in acidic
d
e
40
mediumto achieve 3-trifluoromethylpyrazol-1-thiocarboxamides 4
as major product. A set of different experiments was carried out by
using different acids taking 4,4,4-trifluoro-1-phenylbutane-1,3-
dione 2c as a reference compound (Table 2). The optimum condition
46
The ratio of different products is calculated by 1H NMR spectra of the crude
a
reaction mixture.
b
4a cannot be isolated because of poor yields.

R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
967
Table 3
13C NMR data for 5-hydroxy-5-trifluoromethyl-3-substituted-4,5-dihydropyrazol-1-thiocarboxamides 3.
Compound
3a
3b
3c
3d
3e
Pyrazole carbons
C-3
155.41
156.67
153.43
152.96
153.95
43.87
2
(q, JC–F = 33.25 Hz)
C-4
C-5
48.03
92.53
49.11
93.33
44.12
92.71
44.52
92.96
92.87
2
2
2
2
2
(q, JC–F = 33.75 Hz)
(q, JC–F = 33.75 Hz)
(q, JC–F = 33.25 Hz)
(q, JC–F = 33.75 Hz)
(q, JC–F = 33.50 Hz)
Aryl carbons
C-10
C-20,60
C-30,50
C-40
134.21
128.08
128.84
131.66
121.66
128.68
114.49
162.49
129.45
127.52
128.92
136.51
Others
C5S
177.11
123.31
178.16
125.35
178.76
122.42
177.06
123.49
178.01
124.34
5-CF3
1
1
1
1
1
(q, JC–F = 288.00 Hz)
(q, JC–F = 288.00 Hz)
(q, JC–F = 285.05 Hz)
(q, JC–F = 275.25 Hz)
(q, JC–F = 275.75 Hz)
3-CF3
119.27
1
(q, JC–F = 275.25 Hz)
CH3
15.63
OCH3
55.49
Table 4
the CF3 is bonded to double bond and located at position 3. These are
in accordance with the data described in literature [17–20].
Subsequent reaction of 5-hydroxy-5-trifluoromethyl-3-substi-
tuted-4,5-dihydropyrazol-1-thiocarboxamides 3 and 3-trifluoro-
13C NMR data for 5-substituted-3-trifluoromethylpyrazol-1-thiocarboxamides 4.
Compound 4c
4d
4e
Pyrazole carbons
methyl-5-substitutedpyrazole-1-thiocarboxamides
4
with
C-3
157.73
175.71
177.58
2
2
2
(q, JC–F = 33.5 Hz)
(q, JC–F = 36 Hz)
(q, JC–F = 36.98 Hz)
phenacyl bromides 5 provided corresponding 4-aryl-2-(3(5)-
substituted-5(3)-trifluoromethyl-1-pyrazolyl)thiazoles 6 and 7,
respectively as exclusive products (Scheme 1). Formation of 6
indicates the formation of thiazole ring is accompanied by
simultaneous dehydration of 5-hydroxy-5-trifluoromethyl-4,5-
dihydropyrazole ring to 5-trifluoromethylpyrazole ring under
the reaction conditions. This observation was substantiated by the
isolation of intermediate 4-phenyl-2-(5-hydroxy-3,5-bis(trifluor-
C-4
C-5
101.33
145.10
91.53
92.32
144.25
145.94
Aryl carbons
C-10
C-20,60
C-30,50
C-40
133.47
127.51
129.35
128.12
125.48
130.00
114.40
164.64
131.32
128.93
129.43
140.64
Others
C5S
176.15
186.18
184.88
omethyl)-4,5-dihydro-1-pyrazolyl)thiazole
8 obtained by the
3-CF3
120.24
119.27
118.95
1
1
1
(q, JC–F = 275.25 Hz) (q, JC–F = 275.25 Hz) (q, JC–F = 283 Hz)
reaction of 5-hydroxy-3,5-bis(trifluoromethyl)-4,5-dihydropyra-
zol-1-thiocarboxamide 3b with phenacyl bromide 5a, which was
further dehydrated in EtOH–H2SO4 to afford corresponding
pyrazolylthiazole 6b as the sole product (Scheme 2). Isolation of
the intermediate 8 confirms that there is initial formation of the
thiazole ring which is followed by the dehydration of the 4,5-
dihydropyrazole ring with the acid (HBr) generated in situ during
the reaction. Also it was observed in our earlier studies that during
the dehydration of 5-hydroxy-5-trifluoromethyl-1-(3-methylqui-
noxalin-2-yl)-4,5-dihydropyrazoles in acidic medium formation of
triazolo[4,3-a]quinoxalines took place through ring opening of the
5-hydroxy-4,5-dihydropyrazole [17], however, no such observa-
tion was noticed in the present study.
OCH3
55.58
in the range
d
ꢀ78.44 to ꢀ79.11 ppm, which is typical for CF3 bound
to a saturated carbon [17–20].
In contrast, the 1H NMR spectra of 4 showed a singlet of one
proton intensity appearing in the range
pyrazole C4–H. Also, a broad signal at
intensity, exchangeable with D2O, showed the presence of
thiocarboxamide (CSNH2) group. In the 13C NMR spectra of 4,
signals at about
145 ppm correspond to C4, C3 and C5 (Table 4) respectively which
provide the firm evidence in support of the formation of aromatic
d
d
6.5–6.8 corresponding to
7.15 ppm of two proton
2
d
91–101, 157–177 (q, JC–F = 33–37 Hz) and
It is interesting to note that, in the present study, the reaction of
system. Signal at about
d
176–186 ppm shows the presence of C55S
3 or 4 with phenacyl bromides did not afford any trace of a-
group. Further support to the position of CF3 in 3-trifluoromethyl-
thiocyanatoketone due to C–N bond cleavage, as was reported
earlier in the reaction of (3,5-dimethylpyrazol-1-yl)thiocarbox-
amide with phenacyl bromides and phenacyl chlorides (Scheme 3)
pyrazoles 4 was provided by 19F NMR spectra. A sharp singlet for CF3
appearedintherange
d
ꢀ62.26toꢀ62.58 ppmthusestablishingthat
Ph
Ph
N
S
N
O
EtOH
H2N
HO
N
N
N
N
EtOH, H2SO4
S
Br
N
+
CF3
N
S
reflux
HO
reflux
Ph
CF3
CF3
F3C
F3C
F3C
HA
3b
5a
HB
6b
8
Scheme 2. Isolation of 2-(5-trifluoromethyl-4,5-dihydropyrazol-1-yl)thiazole and its conversion to 2-(5-trifluoromethylpyrazol-1-yl)thiazole.

968
R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
R
S
N
O
O
N
H2N
H3C
N
X
EtOH
N
+
N
S
SCN
R
and/or
R
CH3
CH3
H3C
X = Cl, Br
R = aryl, heteroaryl
Scheme 3. Formation of
a-thiocyanatoketones and 2-(3,5-dimethylpyrazol-1-yl)thiazoles.
Table 5
13C NMR data for 4-aryl-2-(3(5)-trifluoromethyl-5-substituted-pyrazol-1-yl)thiazoles 6 and 7.
Compound 6a
6b
6c
6d
6e
7a
7b
7c
Thiazole
C-2
C-4
159.78
158.92
133.84
110.42
157.93
138.47
112.12
158.98
152.53
110.21
158.56
152.53
113.11
159.54
152.47
112.45
159.52
152.56
111.45
159.22
152.44
112.19
158.66
110.21
C-5
Pyrazole
C-30
152.46
152.69
151.67
152.78
152.78
144.54
144.45
143.20
2
2
2
2
(q, JC–F = 38.75 Hz)
(q, JC–F
(q, JC–F
(q, JC–F
= 39.00 Hz)
106.23
= 39.00 Hz)
107.12
= 38.33 Hz)
106.57
C-40
C-50
108.10
109.19
109.34
108.80
109.81
134.25
133.19
132.81
133.07
133.07
147.52
146.23
146.53
2
2
2
2
2
(q, JC–F = 33.25 Hz) (q, JC–F = 41.25 Hz)
(q, JC–F = 40.75 Hz) (q, JC–F = 41.25 Hz) (q, JC–F = 41.25 Hz)
Aryl carbons
C-100
126.88
127.36
114.14
162.71
130.63
128.94
126.06
128.45
132.54
128.51
125.25
127.32
131.94
128.74
124.35
127.01
128.37
127.50
126.05
123.32
133.91
128.79
114.33
160.69
133.54
128.48
113.92
162.04
128.37
127.50
126.05
123.32
130.90
128.01
127.06
128.01
131.34
128.89
125.99
129.22
121.04
131.28
125.97
128.37
133.64
128.68
113.56
160.65
120.78
130.99
125.76
128.12
128.37
127.55
127.09
122.59
C-200,600
C-300,500
C-400
C-1000
C-2000,6000
C-3000,5000
C-4000
Others
CH3
13.44
55.33
OCH3
30-CF3
55.34
55.45
55.43
119.44
122.65
120.73
120.78
1
1
1
1
(q, JC–F = 267.75 Hz)
(q, JC–F
(q, JC–F
(q, JC–F
= 265.75 Hz) = 267.75 Hz) = 262.85 Hz)
50-CF3
115.72
122.45
118.45
119.49
119.22
1
1
1
1
1
(q, JC–F
(q, JC–F
(q, JC–F
(q, JC–F
(q, JC–F
= 297.75 Hz)
= 267.75 Hz)
= 281.25 Hz)
= 267.75 Hz)
= 287.25 Hz)
[21,22]. This observation suggests that C–N bond cleavage is
dependent not only on the nature of R1 and leaving group in
phenacyl bromides 5 but also on nature of ring system attached to
the thiocarboxamide group as well as on the substitutents present
on pyrazole and pyrazoline rings.
the basis of quartet for carbon attached to CF3 group, which is
about 10 ppm downfield in 7 as compared to that in 6. This shows
that CF3 is present at C3 and C5 of pyrazole ring in 7 and 6,
respectively. The 13C NMR data of both the regioisomeric pyrazoles
are given in Table 5. Further support to the position of CF3 in 3-
trifluoromethylpyrazoles 7 was provided by 19F NMR spectra, a
In the 1H NMR spectra of compounds 6, two singlets of one proton
intensity appeared at about
corresponding to protons at position-4 of pyrazole and position-5
of thiazole ring, respectively. In the 13C NMR spectraof compounds 6,
d
6.6-7.1 and 7.1-7.3 ppm thus,
sharp singlet for CF3 appeared at about
d
ꢀ62 ppm showing that
CF3 is bonded to double bond and located at position-3 [17–20].
A plausible mechanism for the formation of these products is
given in Scheme 4. Initially, nucleophilic attack of nitrogen (NAH2)
2
signals at about
d
109, 133 (q, JC–F = 33-41 Hz) and 152 ppm
correspondtocarbonsC4, C5 andC3 ofpyrazole(Table 5)respectively.
In the 19F NMR spectra of 6, a singlet at about
on either carbonyl (path a or b) gave the corresponding
d
ꢀ59 ppm confirms
thiosemicarbazones 1a and 1b. Relative possibility of this attack
depends upon the ratio of two enol forms of the diketones 2 in
equilibrium. As established earlier in our previous reports, with
aliphatic substituents present on diketones, initial attack of
nitrogen takes place entirely on carbonyl remote to trifluoro-
methyl group. However, with aromatic substituents possibility of
attack on trifluoromethyl carbonyl begins to increase. Thiosemi-
carbazones 1a and 1b further cyclized by the nucleophilic attack of
other nitrogen (NBH) on the other carbonyl centre to give the
corresponding 5-hydroxy-4,5-dihydropyrazoles 3 and 5-hydroxy-
4,5-dihydropyrazoles 40. Later undergoes ready dehydration in
reaction medium to give the corresponding pyrazoles 4. However,
dehydration of 5-hydroxy-4,5-dihydropyrazoles 3 is not so facile
that CF3 is located at position-5 of the pyrazole ring [17–20].
The 1H NMR spectra of compounds 7 displayed a singlet of one
proton intensity in the range of d 6.6–6.7 ppm corresponding to the
pyrazole 4-position, which is about 0.4 ppm upfield as compared to
the corresponding proton in the regioisomer 6 [17–20]. An another
signal of one proton intensity in the range
d 7.3–7.4 ppm
(sometime merge with protons of aryl ring) was also observed
in the 1H NMR spectra of compound 7 which shows the formation
of thiazole nucleus. Also, in 13C NMR spectra, signals at about
d 106,
143 (q, 2JC–F = 38-39 Hz) and 146 ppm were assigned to the C4, C3
and C5 positions of the pyrazole ring of 7, respectively (Table 5).
The two regioisomeric pyrazoles 6 and 7 can be distinguished on

R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
969
O
OH
a
R
R
CF3
CF3
S
O
O
S
B
B
N
H2N
N
H2N
S
a
N
H2N
N
b
H
O
b
H
A
O
-H2O
B
NH2
CF3
-H2O
R
N
OH
O
H
R
1a
1b
F3C
1
R
N
CF3
2
S
S
S
N
H2N
HO
N
N
H2N
N
H
N
H2N
+
-H2O
R
R
CF3
CF3
R
F3C
HO
3
4
H
4'
Scheme 4. Plausible mechanism for the formation of 3 and 4.
due to presence of electron-withdrawing trifluoromethyl group
and these intermediates were isolated in all cases.
3.1. In vitro antibacterial assay
Mechanism of further cyclization of thiocarboxamide group
with phenacyl bromides 5 involves three steps as established for
Hantzsch thiazole synthesis. There is initial nucleophilic dis-
placement of bromide by the attack of sulphur with the loss of
HBr, cyclization in the second step by the attack of nitrogen on
the carbonyl carbon and in last step; dehydration to give the
corresponding thiazoles 6 and 7. Acid (HBr) formed during the
first step of reaction acts as a catalyst for the in situ dehydration of
5-hydroxy-4,5-dihydropyrazole 8 to give the corresponding
pyrazolylthiazoles 6 (Scheme 5).
The newly synthesised compounds 3a–e, 6a and 6c were
screened for their antibacterial activity against Gram-positive
bacteria i.e. Bacillus pumilus (MTCC 7411) and Gram-negative
bacteria i.e. Escherichia coli (MTCC 1652) using disc diffusion assay
technique [23,24] and minimum inhibition concentration (MIC)
method. Standard antibiotics Gentamicin, Ciprofloxacin were used
for the comparison against the antibacterial activities shown by
the compounds (Tables 6 and 7). Compounds 3a, 3b and 3e were
found to be active against B. pumilus at 4 mg/ml concentration.
However, no compound showed any activity against E. coli at this
concentration. The zone of inhibition of compounds 3a, 3b and 3e
against B. pumilus were 15 mm, 12 mm and 6 mm, respectively and
the zone of inhibition of standard antibiotics Gentamicin and
Ciprofloxacin were 27 mm and 38 mm, respectively against B.
pumilus and 28 mm and 25 mm against E. coli. The MIC of
3. Biological assay
Medium used for the antibacterial testing was nutrient agar
media(NAM)of thefollowingcomposition:peptone5 g;beefextract
3 g; sodium chloride 5 g; agar 2% and final volume of the media was
adjusted to 1 l with distilled water and autoclave at 15 lbs/in2.
compounds 3a, 3b and 3e was found to be 400
m
g/ml, 400
mg/ml
and 500
mg/ml, respectively against the B. pumilus where as no
R1
R1
N
N
N
H+
(from HBr)
N
H
N
S
H2O
N
S
HO
R
R
O
F3C
F3C
Hantzsch Thiazole
3
8
H
synthesis
or
Br
+
R1
-HBr,-H2O
-H2O, -H+
R1
4
R1
5
N
R
N
N
N
S
N
N
S
CF3
R
F3C
7
6
Scheme 5. Plausible mechanism for the formation of 6, 7 and 8.

970
R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
Table 6
5.1. General procedure for the preparation of 5-hydroxy-5-
trifluoromethyl-3-alkyl-4,5-dihydropyrazol-1-thiocarboxamides
3a–b
In vitro antibacterial activity of 3 and 6 by disc diffusion method.
S. no.
Compound
Diameter of growth of inhibition zone
(mm)a
An ethanolic solution (30 ml) of thiosemicarbazide 1 (0.9 g
Bacillus pumilus
Escherichia coli
10 mmol) and trifluoromethyl-b-diketones 2a–b (10 mmol) was
1
2
3
4
5
6
7
3a
15
12
–
–
refluxed for 6 h. The progress of reaction was monitored with the
help of TLC. When the reaction was complete, solvent was distilled
off under vacuum. 1H NMR spectra and TLC of reaction mixture
showed the presence of single product 3a–b.
3b
–
3c
–
3d
–
_
3e
6
–
6a
–
–
6c
–
–
5.1.1. 5-Hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydropyrazol-1-
thiocarboxamide 3a
Gentamicin
Ciprofloxacin
27
38
28
25
Mp. 174–176 8C; Yield 92% IR (cmꢀ1): 3403, 3285 (NH2), 3574
(–) indicates no activity at 4 mg/ml.
(O–H), 1605 (C55S), 1477 (C55N); 1H NMR (CDCl3)
d
: 2.09 (s, 3H,
a
Means of three replicates, including diameter of disc.
4
CH3), 3.26 (dq, 1H, JHA–HB = 18.9 Hz, JHB–CF3 = 1.2 Hz 4-HB), 3.37
(d, 1H, JHA–HB = 18.9 Hz, 4-HA), 6.23 (bs, 1H, NH, exchangeable
with D2O), 7.14 (bs, 1H, NH, exchangeable with D2O), 7.95 (bs,
1H, 5-OH, exchangeable with D2O); 19F NMR (CDCl3)
Table 7
Minimum inhibitory concentration (MIC) (
m
g/ml) of 3a–b, e.
d
: ꢀ78.51
(5-CF3); HRMS (m/z): 227.0343 (M+), C6H8F3N3OS requires
S. no.
Compound
Bacillus pumilus
Escherichia coli
227.0340.
1
2
3
3a
400
400
500
10
–
3b
–
3e
_
5.1.2. 5-Hydroxy-3,5-bis(trifluoromethyl)-4,5-dihydropyrazol-1-
thiocarboxamide 3b
Gentamicin
Ciprofloxacin
10
5
5
Mp. 122–125 8C; Yield 91%; IR (cmꢀ1): 3415 (NH2), 3310 (NH2),
3504 (O–H), 1612 (C55S), 1475 (C55N); 1H NMR (CDCl3)
d
: 3.47 (dq,
(–) indicates no activity.
4
1H, JHA–HB = 19.6 Hz, JHB–CF3 = 1.4 Hz, 4-HB), 3.63 (d, 1H, JHA–
HB = 19.6 Hz, 4-HA), 6.55 (bs, 1H, NH, exchangeable with D2O), 7.19
(bs, 1H, NH, exchangeable with D2O), 7.75 (bs, 1H, 5-OH,
exchangeable with D2O); 19F NMR (CDCl3)
zone of inhibition was appeared unless a concentration of 4 mg/ml
was used against in case of E. coli. However, compounds 3c–d, 6a
and 6c did not show any zone of inhibition against either of
bacteria at 4 mg/ml concentration. The MIC of Ciprofloxacin and
d
: ꢀ78.75 (5-CF3),
ꢀ62.42 (3-CF3); Elemental Analysis: Found: C, 25.51; H, 1.84; N,
Gentamicin was 5
m
g/ml and 10
m
g/ml, respectively against both
14.84; C6H5F6N3OS requires C, 25.63; H, 1.79; N, 14.94.
B. pumilus and E. coli.
5.2. General procedure for the preparation of 5-hydroxy-5-
trifluoromethyl-3-aryl-4,5-dihydropyrazol-1-thiocarboxamides 3c–d
and 3-trifluoromethyl-5-arylpyrazol-1-thiocarboxamides 4c–d
4. Conclusion
A regioselective synthesis of isomeric (5(3)-trifluoromethyl-
pyrazol-1-yl)thiazoles 6 and 7 was developed. The highlights of the
present study are: (i) cyclo-condensation of thiosemicarbazide 1
An ethanolic solution (30 ml) of thiosemicarbazide 1 (0.9 g,
10 mmol) and trifluoromethyl-b-diketones 2c–d (10 mmol) was
refluxed for 6 h. The progress of reaction was monitored with the
help of TLC. When the reaction was complete, solvent was distilled
off under vacuum. The 1H NMR spectra and TLC of reaction mixture
showed the presence of two products in the ratio given in Table 1.
Column chromatographic separation using silica gel (100–200
mesh) with petroleum ether:ethyl acetate (99:1) afforded 4,
further elution of column with petroleum ether:ethyl acetate
(97:3) afforded 3.
with trifluoromethyl-b-diketones 2 to form 5-hydroxy-5-trifluor-
omethyl-4,5-dihydropyrazol-1-thiocarboxamides 3 as major prod-
uct in neutral conditions, (ii) reversal of regioselectivity during the
reaction of 1 and 2 in acidic medium afforded pyrazole-1-
thiocarboxamides 4 as significant or major product, (iii) the
reaction of 4,5-dihydropyrazol-1-thiocarboxamides 3 and pyra-
zole-1-thiocarboxamides 4 with phenacyl bromides 5 to give
isomeric (5(3)-trifluoromethylpyrazol-1-yl)thiazoles
6 and 7,
respectively as exclusive product, (iv) isolation of intermediate
2-(5-trifluoromethyl-4,5-dihydropyrazol-1-yl)thiazole 8 provides
an insight in the mechanistic pathway.
5.2.1. 5-Hydroxy-3-phenyl-5-trifluoromethyl-4,5-dihydropyrazol-1-
thiocarboxamide 3c
Mp. 130–132 8C; Yield 65%; IR (cmꢀ1): 3412, 3291 (NH2), 3568
(O–H), 1602 (C55S), 1472 (C55N); 1H NMR (CDCl3)
d
: 3.66 (dq, 1H,
4
JHA–HB = 18.6 Hz, JHB–CF3 = 1.3 Hz, 4-HB), 3.82 (d, 1H, JHA–
HB = 18.6 Hz, 4-HA), 6.28 (bs, 1H, NH, exchangeable with D2O),
7.32 (bs, 1H, NH, exchangeable with D2O), 7.44–7.54 (m, 3H,
30,40,50-H), 7.58 (m, 2H, 20,60-H), 8.00 (bs, 1H, 5-OH, exchangeable
with D2O); 19F NMR (CDCl3) (: ꢀ79.11 (5-CF3); Elemental Analysis:
Found: C, 45.53; H, 3.34; N, 14.32; C11H10F3N3OS requires C, 45.67;
H, 3.48; N, 14.53.
5. Experimental
Melting points were determined in open capillaries in electrical
apparatus and are uncorrected. IR spectra were recorded on a Buck
Scientific IR M500 instrument. The 1H and 13C NMR spectra were
recorded on a Bruker instrument at 300 MHz and 75 MHz,
respectively. 19F NMR spectra were run on DRX 300 and DPX
400 at 282 and 376 MHz, respectively, using deuteriochloroform as
a solvent. The internal standard for 19F spectra was fluorotri-
5.2.2. 5-Phenyl-3-trifluoromethylpyrazol-1-thiocarboxamide 4c
Mp. 100–102 8C; Yield 10%; IR (cmꢀ1): 3012, 1503; 1H NMR
chloromethane, setting the CFCl3 signal at
d 0.0. High resolution
mass spectra (HRMS) were measured in EI mode on a Kratos MS-50
spectrometer at MS Facilities at UCSF, USA. Elemental analysis was
performed at SAIF, Lucknow, India. The compounds gave satisfac-
tory analytical results (within ꢁ0.4 of the calculated values).
(CDCl3)
D2O), 7.34 (m, 3H, 30,40,50-H), 7.61 (m, 2H, 20,60-H); 19F NMR (CDCl3)
: ꢀ62.45 (3-CF3); Elemental Analysis: Found: C, 48.51; H, 2.84; N,
15.77; C11H8F3N3S requires C, 48.70; H, 2.97; N, 15.79.
d: 6.82 (s, 1H, 4-H), 7.16 (bs, 2H, NH2, exchangeable with
d

R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
971
5.2.3. 5-Hydroxy-3-(p-methoxyphenyl)-5-trifluoromethyl-4,5-
dihydropyrazol-1-thiocarboxamide 3d
dried over anhyd. sodium sulphate, filtered and concentrated to
give 6.
Mp. 160–165 8C; Yield 45%; IR (cmꢀ1): 3405, 3275 (NH2), 3578
(O–H), 1614 (C55S), 1476 (C55N); 1H NMR (CDCl3)
d
: 3.56 (dq, 1H,
5.4.1. 4-(p-Methoxyphenyl)-2-(3-methyl-5-trifluoromethylpyrazol-
1-yl)thiazole 6a
4
JHA–HB = 18.6 Hz, JHB–CF3 = 1.2 Hz 4-HB), 3.76 (d, 1H, JHA–
HB = 18.6 Hz, 4-HA), 3.80 (s, 3H, OCH3), 6.19 (bs, 1H, NH,
exchangeable with D2O), 6.89 (dd, 2H, J = 9.0 Hz, J = 1.8 Hz, 30,50-
H), 7.20 (bs, 1H, NH, exchangeable with D2O), 7.58 (dd, 2H,
J = 9.0 Hz, J = 1.8 Hz, 20,60-H), 8.58 (bs, 1H, 5-OH, exchangeable with
Mp. 110–112 8C; Yield 82%; IR (cmꢀ1): 3154, 1497; 1H NMR
(CDCl3)d
: 2.30 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.61 (s, 1H, 40-H),
6.88 (d, 2H, J = 8.7 Hz, 300,500-H), 7.09 (s, 1H, 5-H), 7.84 (d, 2H,
J = 8.7 Hz, 200,600-H); 19F NMR (CDCl3)
Analysis: Found: C, 53.15; H, 3.44; N, 12.48; C15H12F3N3OS requires
C, 53.09; H, 3.56; N, 12.38.
d
: ꢀ58.33 (50-CF3); Elemental
D2O); 19F NMR (CDCl3)
(M+), C12H12F3N3O2S requires 319.0602.
d
: ꢀ78.44 (5-CF3); HRMS (m/z): 319.0611
5.2.4. 5-(p-Methoxyphenyl)-3-trifluoromethylpyrazol-1-
thiocarboxamide 4d
5.4.2. 4-Phenyl-2-(3-phenyl-5-trifluoromethylpyrazol-1-yl)thiazole
6c
Mp. 112–114 8C; Yield 25%; IR (cmꢀ1): 3034, 1512; 1H NMR
Mp. 118–122 8C; Yield 76%; IR (cmꢀ1): 3255, 1482; 1H NMR
(CDCl3)
d
: 3.92 (s, 3H, OCH3), 6.52 (s, 1H, 4-H), 7.0 (dd, 2H,
(CDCl3) d
: 7.11 (s, 1H, 40-H), 7.16 (s, 1H, 5-H), 7.32–7.47 (m, 6H,
J = 6.9 Hz, J = 1.8 Hz, 30, 50-H), 7.14 (bs, 2H, NH2, exchangeable with
D2O), 7.96 (dd, 2H, J = 6.9 Hz, J = 1.8 Hz, 20, 60-H); 19F NMR (CDCl3)
300,400,500,3000,4000,5000-H), 7.78–7.81 (m, 2H, 200,600-H), 7.84–7.86 (m, 2H,
2000,6000-H); 19F NMR (CDCl3)
d
: ꢀ59.01 (50-CF3); Elemental Analysis:
d
: ꢀ62.58 (3-CF3); Elemental Analysis: Found: C, 47.53; H, 3.23; N,
Found: C, 61.22; H, 3.12; N, 11.24; C19H12F3N3S requires C, 61.45;
H, 3.26; N, 11.31.
13.77; C12H10F3N3OS requires C, 47.84; H, 3.35; N, 13.95.
5.2.5. 5-Hydroxy-3-(p-chlorophenyl)-5-trifluoromethyl-4,5-
dihydropyrazol-1-thiocarboxamide 3e
5.4.3. 4-Phenyl-2-(3-(p-methoxyphenyl)-5-trifluoromethylpyrazol-
1-yl)thiazole 6d
Mp. 140–142 8C; Yield 52%; IR (cmꢀ1): 3431, 3264 (NH2), 3573
Mp. 130–132 8C; Yield 86%; IR (cmꢀ1): 3145, 1495; 1H NMR
(O–H), 1610 (C55S), 1463 (C55N); 1H NMR (CDCl3)
d
: 3.57 (dq, 1H,
(CDCl3) d
: 3.89 (s, 3H, OCH3), 7.01 (d, 2H, J = 9.0 Hz, 3000, 5000-H), 7.14
4
JHA–HB = 18.6 Hz, JHB-CF3 = 1.2 Hz 4-HB), 3.71 (d, 1H, JHA–
HB = 18.6 Hz, 4-HA), 6.29 (bs, 1H, NH, exchangeable with D2O),
7.22 (bs, 1H, NH, exchangeable with D2O), 7.37 (dd, 2H, J = 9.0 Hz,
J = 2.3 Hz, 30,50-H), 7.56 (dd, 2H, J = 9.0 Hz, J = 2.3 Hz, 20,60-H), 7.90
(s, 1H, 40-H), 7.36 (s, 1H, 5-H), 7.37–7.40 (m, 1H, 400-H), 7.44–7.49
(m, 2H, 300,500-H), 7.84 (d, 2H, J = 9.0 Hz, 2000, 6000-H), 7.94–7.96 (m,
2H, 200,600-H); 19F NMR (CDCl3)
Analysis: Found: C, 59.52; H, 3.43; N, 10.53; C20H14F3N3S requires
C, 59.84; H, 3.52; N, 10.47.
d
: ꢀ59.13 (50-CF3); Elemental
(bs, 1H, 5-OH, exchangeable); 19F NMR (CDCl3)
Elemental Analysis: Found: C, 40.67; H, 2.64; N, 12.54;
11H9ClF3N3OS requires C, 40.81; H, 2.80; N, 12.98.
d
: ꢀ79.04 (5-CF3);
C
5.4.4. 4-(p-Methoxyphenyl)-2-(3-(p-chlorophenyl)-5-
trifluoromethylpyrazol-1-yl)thiazole 6e
5.2.6. 5-(p-Chlorophenyl)-3-trifluoromethylpyrazol-1-
thiocarboxamide 4e
Mp. 124–126 8C; Yield 82%; IR (cmꢀ1): 3355, 1492; 1H NMR
(CDCl3) d
: 3.88 (s, 3H, OCH3), 6.99 (d, 2H, J = 8.7 Hz, 300, 500-H), 7.18
Mp. 114–116 8C; Yield 24%; IR (cmꢀ1): 3032, 1508; 1H NMR
(s, 1H, 40-H), 7.24 (s, 1H, 5-H), 7.46 (d, 2H, J = 8.4 Hz, 3000, 5000-H), 7.84
(d, 2H, J = 8.4 Hz, 2000, 6000-H), 7.88 (d, 2H, J = 8.7 Hz, 200, 600-H); 19F
(CDCl3)
D2O), 7.46 (d, 2H, J = 8.3 Hz, 30, 50-H), 7.53 (d, 2H, J = 8.3 Hz, 20, 60-
H); 19F NMR (CDCl3)
d: 6.76 (s, 1H, 4-H), 7.13 (bs, 2H, NH2, exchangeable with
NMR (CDCl3)
d
: ꢀ58.97 (50-CF3); Elemental Analysis: Found: C,
d
: ꢀ62.26 (3-CF3); Elemental Analysis: Found:
55.23; H, 2.92; N, 9.45; C20H13ClF3N3S requires C, 55.11; H, 3.01; N,
9.64.
C, 43.12; H, 2.34; N, 13.67; C11H7ClF3N3S requires C, 43.22; H, 2.31;
N, 13.75.
5.5. Preparation of 4-aryl-2-(5-substituted-3-trifluoromethyl-1-
5.3. General procedure for the reaction between thiosemicarbazide 1
pyrazolyl)thiazoles 7a–c
and trifluoromethyl-b-diketones 2 in acidic conditions
To a solution of 4 (1 mmol) in ethanol (20 ml) was added 5
(1 mmol). The reaction mixture was refluxed for 3 h. The progress
of reaction was monitored with the help of TLC. When the reaction
was complete, solvent was evaporated to reduce the volume,
which was neutralized by sodium bicarbonate and extracted with
ethyl acetate (3 ꢂ 20 ml). The combined organic extracts were
dried over anhyd. sodium sulphate, filtered and concentrated to
give 7.
To an ethanolic solution (30 ml) of thiosemicarbazide 1 (0.9 g,
10 mmol) 4–5 drops of H2SO4 were added followed by trifluor-
omethyl-b-diketones 2c–d (10 mmol) and was refluxed for 6 h.
The progress of reaction was monitored with the help of TLC. When
the reaction was complete, solvent was distilled off under vacuum.
Reaction mixture thus obtained by neutralized by aq. NaOH and
was extracted by ethyl acetate (3 ꢂ 20 ml). The combined organic
extracts were dried over anhyd. sodium sulphate, filtered and
concentrated. The 1H NMR spectra and TLC of reaction mixture
showed the presence of two products in the ratio given in Table 2.
Data of compounds 3 and 4 has already been given above.
5.5.1. 4-Phenyl-2-(5-phenyl-3-trifluoromethylpyrazol-1-yl)thiazole
7a
1
Mp. 115–116 8C; Yield 82%; IR (cmꢀ1): 3354, 1497; H NMR
(CDCl3)
H), 7.75–7.83 (m, 4H, 200,600,20006000-H); 19F NMR (CDCl3)
(30-CF3); Elemental Analysis: Found: C, 61.40; H, 3.22; N, 11.45;
19H12F3N3S requires C, 61.45; H, 3.26; N, 11.31.
d
: 6.76 (s, 1H, 40-H), 7.33–7.37 (m, 7H, 5,300,400,500,3000,4000,5000-
5.4. Preparation of 4-aryl-2-(3-substituted-5-trifluoromethyl-1-
d
: ꢀ62.34
pyrazolyl)thiazoles 6a, c–e
C
To a solution of 3 (1 mmol) in ethanol (20 ml) was added 5
(1 mmol). The reaction mixture was refluxed for 3 h. The progress
of reaction was monitored with the help of TLC. When the reaction
was complete, solvent was evaporated to reduce the volume,
which was neutralized by sodium bicarbonate and extracted with
ethyl acetate (3 ꢂ 20 ml). The combined organic extracts were
5.5.2. 4-Phenyl-2-(5-(p-methoxyphenyl)-3-trifluoromethylpyrazol-
1-yl)thiazole 7b
Mp. 110–112 8C; Yield 78%; IR (cmꢀ1): 3352, 1490; 1H NMR
(CDCl3)
J = 8.7 Hz, 3000,5000-H), 7.31–7.36 (m, 4H, 300,400,500,5-H), 7.53 (d, 2H,
d
: 3.89 (s, 3H, OCH3), 6.71 (s, 1H, 40-H), 7.01 (d, 2H,

972
R. Aggarwal et al. / Journal of Fluorine Chemistry 132 (2011) 965–972
J = 8.7 Hz, 2000,6000-H) 7.64–7.67 (m, 2H, 200,600-H); 19F NMR (CDCl3)
d
:
NMR (CDCl3)
d
:
ꢀ58.45 (50-CF3), ꢀ62.25 (30-CF3); Elemental
ꢀ62.44 (30-CF3); Elemental Analysis: Found: C, 59.23; H, 3.92; N,
Analysis: Found: C, 46–51; H, 1.92; N, 11.45; C14H7F6N3S requires
C, 46.29; H, 1.94; N, 11.57.
10.45; C20H14F3N3OS requires C, 59.84; H, 3.52; N, 10.47.
5.5.3. 4-Phenyl-2-(5-(p-chlorophenyl)-3-trifluoromethylpyrazol-1-
yl)thiazole 7c
Acknowledgements
Mp. 124–126 8C; Yield 86%; IR (cmꢀ1): 3357, 1494; 1H NMR
We thank the Council of Scientific and Industrial Research and
University Grants Commission, New Delhi for financial assistance.
Thanks are also due to Sophisticated Analytical Instrument facility,
Central Drug Research Institute, Lucknow, India for providing
elemental analysis. We are also grateful to UCSF Mass Spectrome-
try Facility, University of California, San Fransisco, USA for
providing high resolution mass spectral data. We also thank Prof.
S.P. Singh for helpful suggestions.
(CDCl3) d
: 6.72 (s, 1H, 4-H), 7.42–7.45 (m, 3H, 5, 3000,5000-H), 7.53–
7.58 (m, 4H, 300,500, 2000,6000-H), 7.63–7.66 (m, 400-H), 7.97–8.01 (m,
2H, 200,600-H); 19F NMR (CDCl3)
Analysis: Found: C, 56.55; H, 2.62; N, 10.45; C19H11ClF3N3S
requires C, 56.23; H, 2.73; N, 10.35.
d
: ꢀ62.37 (30-CF3); Elemental
5.6. Preparation of 4-phenyl-2-(3,5-bis-trifluoromethylpyrazol-1-
yl)thiazole 6b via isolation of 4-Phenyl-2-(5-hydroxy-3,5-
bis(trifluoromethyl)-4,5-dihydro pyrazol-1-yl)thiazole 8
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3573 (O–H), 1463 (C55N); 1H NMR (CDCl3)
d: 3.38 (d, 1H, JHA–
HB = 18.6 Hz, 40-HB), 3.56 (d, 1H, JHA–HB = 18.6 Hz, 40-HA), 6.97 (s,
1H, 5-H), 7.10 (bs, 1H, 50–OH, exchangeable with D2O), 7.24–7.29
(m, 1H, 400-H), 7.31–7.35 (m, 2H, 300,500-H), 7.65–7.68 (m, 2H, 200, 600-
H); 13C NMR (CDCl3) : 42.05 (C-40), 93.99 (q, 2JC–F = 34.50 Hz, C-50),
d
1
1
106.38 (C-5), 119.10 (q, JC–F = 271.50 Hz, 3-CF3), 122.81 (q, JC–
F = 270.75 Hz, 5-CF3), 125.96 (C-300, 500), 128.48 (C-400), 128.83 (C-200,
2
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d
: ꢀ78.55 (50-CF3), ꢀ62.18 (30-CF3);
Elemental Analysis: Found: C, 44.12; H, 2.34; N, 11.11;
C
14H9F6N3OS requires C, 44.10; H, 2.38; N, 11.02.
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yl)thiazole 6b
To an ethanolic solution of 8 (0.19 g, 0.0005 mol), 2–3 drops of
H2SO4 were added and refluxed for 5 h. The reaction was monitored
by TLC. On completion, reaction mixture was neutralized using aq.
NaOH and extracted with ethyl acetate (3 ꢂ 20 ml). The combined
organic extracts were dried over anhyd. sodium sulphate, filtered
and concentrated to give 6b. Mp. 114–118 8C; Yield 90%; IR (cmꢀ1):
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3154, 1497; 1H NMR (CDCl3)
d
: 7.17 (s, 1H, 40-H), 7.39–7.43 (m, 1H,
400-H), 7.46–7.50 (m, 3H, 5, 300,500-H), 7.92–7.95 (m, 2H, 200,600-H); 19F