α,α-Dibromoketone precursors in the synthesis of some new thiazole derivatives: Thiazol-2-yl hydrazonobutanoates, thiazol-2-yl pyrazole-4-carboxylates and acids

Article abstract of DOI:10.1002/jhet.3937

In the present study, α,α-dibromoacetophenones are used as efficient precursors for the facile synthesis of several new hydrazonothiazoles, ethyl 3-((4-arylthiazol-2-yl)hydrazono)butanoates, which undergo Vilsmeier-Haack cyclization to obtain thiazolylpyrazole esters, ethyl 3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazole-4-carbxylates, basic hydrolysis of which gives the corresponding acids, 3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazole-4-carbxylic acids. All these compounds are tested for antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis; Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa and antifungal activity against Saccharomyces cerevisiae and Candida albicans.

Full text of DOI:10.1002/jhet.3937

Received: 11 October 2019
DOI: 10.1002/jhet.3937
Revised: 4 January 2020
Accepted: 31 January 2020
A R T I C L E
α,α-Dibromoketone precursors in the synthesis of some
new thiazole derivatives: Thiazol-2-yl hydrazonobutanoates,
thiazol-2-yl pyrazole-4-carboxylates and acids
Vijay Kiran1 | Radhika Joshi2 | Rashmi Pundeer1
1Department of Chemistry, Kurukshetra
Abstract
University, Kurukshetra, India
2Department of Microbiology,
Kurukshetra University, Kurukshetra,
India
In the present study, α,α-dibromoacetophenones are used as efficient precursors
for the facile synthesis of several new hydrazonothiazoles, ethyl 3-((4-arylthiazol-
2-yl)hydrazono)butanoates, which undergo Vilsmeier-Haack cyclization to obtain
thiazolylpyrazole esters, ethyl 3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazole-4-
carbxylates, basic hydrolysis of which gives the corresponding acids,
3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazole-4-carbxylic acids. All these com-
pounds are tested for antibacterial activity against Gram-positive bacteria Staph-
ylococcus aureus and Bacillus subtilis; Gram-negative bacteria Escherichia coli
and Pseudomonas aeruginosa and antifungal activity against Saccharomyces
cerevisiae and Candida albicans.
Correspondence
Rashmi Pundeer, Department of
Chemistry, Kurukshetra University,
Kurukshetra 136119, Haryana, India.
Email: dr.rashmip@gmail.com
Funding information
University Grants Commission
1 | INTRODUCTION
N-containing heterocycle, the pyrazole core in a single
hybrid structure are expected to impart distinct and interest-
Use of α,α-dibromoketones as efficient precursors for
the synthesis of heterocyclic compounds is gaining
increasing attention because of their stability and
selectivity in the reactions.[1–13] In the present study,
α,α-dibromoacetophenones are used for the construc-
tion of thiazole nucleus applying modified Hantzsch
thiazole synthesis (HTS).[14–19] Among the several syn-
thetic methods available for thiazoles, HTS is one of the
most common approaches which classically involve the
open-chain reactants, α-functionalized carbonyl compounds
like α-bromoketones (C C) and thioamides etc. (N C S)
to construct the nucleus. However, due to handling prob-
lems associated with α-bromoketones such as low melting,
toxicity and lachrymosity, the use of α,α-dibromoketones in
modified HTS is appreciable. Synthesis of new derivatives of
thiazoles is encouraged as (a) the wonder motif is endowed
with remarkable biological activities particularly antimicro-
bial and antitumor,[20–29] (b) there is continuous need
for new antibiotics because the disease causing microbes
become resistant to existing antibiotic arsenal.[30–33] Com-
bining thiazole with another five-membered diheteroatomic
ing structural and biological characteristics.[34,35] Among
the important methods available for the formation of
pyrazole nucleus, reaction of hydrazone or semicarbazone
with Vilsmeier reagent is significant as it involves reactive
halomethyleniminium intermediate which is capable of
generating iminium species from nitrogen (carbon or
oxygen) nucleophiles. Cyclization of these species pro-
vides a facile entry into heterocyclic systems including
pyrazoles.[36–40]
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
Initially, we started the work with the treatment of α,α-
dibromoacetophenone 1a with ethyl-3-thiosemicarbazide
2 in ethanol solvent while stirring at ambient tempera-
ture. The reaction occurred according to expectation to
form the thiazole compound, ethyl 3-[(4-phenylthiazol-
2-yl)hydrazono]butanoate 3a in 69% yield (Scheme 1).[41]
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

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KIRAN ET AL.
Further, the reaction was carried out with variously
1H NMR of 4a displayed a new downfield singlet at δ
8.85 due to pyrazolyl proton. Also, the singlet of methy-
lene protons at δ 3.43, present in the reactant 3a, was
lost. 13C NMR, molecular mass, and elemental data were
also found corresponding to the product 4a. Similarly,
other hydrazones 3b-f were converted to the corres-
ponding pyrazole esters 4b-f on reaction with V-H
reagent in 69% to 77% yield.
substituted α,α-dibromoacetophenones 2b-f to afford the
corresponding thiazole derivatives 3b-f in 67% to 72%
yield (Table 1). The chemical structure of 3b was
established on the basis of spectral data (NMR, IR) and
elemental analysis. The 1H NMR spectrum revealed a
triplet signal at δ 1.31 and a quartet at δ 4.21 due to
methyl and methylene protons of the ethoxy group, in
addition to the singlets at δ 2.30, 2.40, 3.42, and 6.69
assigned to two methyl, methylene and thiazole-5H pro-
tons respectively. The 13C NMR spectrum showed signals
at δ 14.14, 18.67, 43.95, 61.52, 101.28, 125.61 to 140.61,
140.61, 155.49, 168.46 and 170.01 in accordance with the
expected structure.
Subsequently, the esters 4 were made to undergo hydro-
lysis to the corresponding acids in presence of NaOH while
refluxing for 6 hours in ethanol. Neutralization of the
sodium salts with HCl, afforded the acids 5, 3-methyl-
1-(4-arylthiazol-2-yl)-1H-pyrazole-4-carboxylic in excellent
1
yield. In H NMR spectra of 5, peaks due to methylene
The multifunctional thiazolyl hydrazones 3, thus
obtained, were made to undergo Vilsmeier-Haack (V-H)
reaction in an effort to obtain pyrazole motif of the bicyclic
thiazolylpyrazole products. Accordingly, the hydrazone 3a
was subjected to POCl3-DMF at 60ꢀC to 65ꢀC. There was
possibility for the formation of two sets of pyrazole
products because of two different types of α-H present
in the hydrazones in the form of methyl and methylene
(Scheme 2).
and methyl protons of the ester group were dis-
appeared providing firm support to the hydrolysis.
α,α-Dibromoacetophenones 1 needed herein, were pre-
pared by the bromination of different acetophenones with
excess of bromine.[43] Ethyl 3-thiosemicarbazidobutanoate,
required for the work was prepared by the condensation of
ethyl acetoacetate with thiosemicarbazide in ethanol con-
taining catalytic amount of glacial acetic acid.[44]
Thin-layer chromatography (TLC) of the reaction mix-
ture indicated the formation of single product. Usual
workup of the reaction mixture followed by purification of
the crude product by recrystallization from ethanol afforded
the expected pyrazole 4a, ethyl 3-methyl-1-(4-phenylthiazol-
2-yl)-1H-pyrazole-4-carboxylate through the involvement of
more reactive α-H (methylene) of the hydrazone. Methylene
carbon is readily attacked by the strongly electrophilic
chloromethyleniminium salt followed by cyclization to fur-
nish the desired pyrazole product 4a (Scheme 3).[41,42]
2.2 | Biological screening
All the synthesized chemical compounds (3-5) were
screened for their antibacterial and antifungal activity.
The title compounds were tested for the antibacterial activ-
ity against the Gram-positive bacteria Staphylococcus
aureus and Bacillus subtilis; Gram-negative bacteria
Escherichia coli and Pseudomonas aeruginosa and antifun-
gal activity against Saccharomyces cerevisiae and Candida
R
O
N
EtOH
O
NNHCSNH2
CH3
O
N NH
CH3
C
CHBr2
S
stir
+
C2H5O
C2H5O
R
3
2
1
R
R
10% NaOH
DMF-POCl3
N
N
S
N
N
N
N
H3C
HOOC
H3C
C2H5OOC
S
4
5
SCHEME 1 α,α-Dibromoacetophenone precursors (1) in the synthesis of thiazol-2-yl hydrazonobutanoates (3), thiazol-2-yl pyrazole-
4-carboxylates (4) and acids (5)

KIRAN ET AL.
3
TABLE 1 Physical data of
thiazolylhydrazones 3, thiazolylpyrazole
esters 4, and thiazolylpyrazole acids 5
Compd.
3a
R
Mol. formula
M.p. (ꢀC)
% Yield
C6H5
C15H17N3O2S
148 to 150
(lit. m.p. 150)[41,42]
69
3b
3c
3d
3e
3f
4-CH3 C6H5
4-ClC6H5
4-BrC6H5
4-FC6H5
C16H19N3O2S
C15H16ClN3O2S
C15H16BrN3O2S
C15H16FN3O2S
C15H16N4O4S
C16H15N3O2S
C17H17N3O2S
C16H14ClN3O2S
C16H14BrN3O2S
C16H14FN3O2S
C16H14N4O4S
C14H11N3O2S
C15H13N3O2S
C14H10ClN3O2S
C14H10BrN3O2S
C14H10FN3O2S
C14H10N4O4S
180 to 182
191 to 192
200 to 202
173 to 174
229 to 230
138 to 140
109 to 110
112 to 114
121 to 122
131 to 132
196 to 198
169 to 170
210 to 212
195 to 196
225 to 226
206 to 208
288 to 290
72
71
67
74
70
66
70
76
69
73
77
92
88
93
91
87
91
4-NO2C6H5
C6H5
4a
4b
4c
4d
4e
4f
4-CH3 C6H5
4-ClC6H5
4-BrC6H5
4-FC6H5
4-NO2C6H5
C6H5
5a
5b
5d
5e
5c
5f
4-CH3 C6H5
4-ClC6H5
4-BrC6H5
4-FC6H5
4-NO2C6H5
Ar
N
N
N
H3C
S
C2H5OOC
4
Ar
N
O
N NH
CH3
DMF
S
Ar
POCl3
C2H5O
N
N
3
N
S
X
C2H5OOC
4'
SCHEME 2 Regioselective Vilsmeier-Haack cyclization of thiazolylhydrazones 3
albicans. Positive controls produced significantly sized
inhibition zones against the tested bacteria and fungi,
however, negative control produced no observable inhibi-
tory effect against any of the test organism as shown in
Tables 2 and 3.
On the basis of maximum inhibitory activity shown
against Gram-positive bacteria, compounds 3a and 3e
were found to be most effective against S. aureus with
zone of inhibition 21.6 mm and the compounds 4a, 4e,
and 4d were found to be best against B. subtilis, with the
zone of inhibition of 22.6, 21.6, and 21.6 mm, respec-
tively, whereas in case of Gram-negative bacteria, com-
pounds 4a (18.3 mm), 4e (18.6 mm), and 5d (18.6 mm)
were found to be best against E. coli and compound 16e
was found to be most effective against P. aeruginosa with
zone of inhibition of 17.6 mm. Further, compounds 4d
and 4e showed inhibition zone of 16.3 mm each against
S. cerevisiae and 15.6 and 15.0 mm against C. albicans,
respectively (Table 3).In the whole series, the MIC of vari-
ous tested chemical compounds ranged between 8 and

4
KIRAN ET AL.
Cl
O-POCl2
H
Cl
H
Me2N
Me2N-CHO
Ar
POCl3
Me2N
OPOCl2
Ar
Ar
N
N
S
N
S
H
S
N N
H
Cl
N N
N N
-HCl
H
O-POCl2
NMe2
COOC2H5
Me2N
H3C
H3C
H3C
N(CH3)2
COOC2H5
COOC2H5
3
Ar
Ar
N
N
S
-HOPOCl2
-HNMe2
S
N N
N N
H3C
C2H5OOC
H3C
C2H5OOC
N(CH3)2
H
4
SCHEME 3 Mechanistic pathway for the V-H cyclization of hydrazones 3 to pyrazoles 4
TABLE 2 In vitro antimicrobial
activity of the title compounds (3-5)
through agar well diffusion method
Diameter of growth of inhibition zone (mm)a
Compound
Sa
Bs
22.6
Ec
Pa
16.3
-
Sc
Ca
3a
21.6
16.3
17.0
15.6
21.6
16.3
17.6
16.3
14.6
15.0
15.6
13.6
16.3
14.3
18.3
19.6
17.6
15.6
26.6
28.6
Nt
18.3
14.6
15.6
14.3
16.3
16.3
15.3
15.6
-
14.3
14.6
15.3
3b
18.3
19.6
17.6
20.6
18.3
19.3
18.0
15.3
13.6
16.3
14.3
17.6
17.3
19.3
21.6
19.6
18.6
24.0
26.0
Nt
-
3c
15.6
14.3
-
3d
-
15.6
15.0
14.3
13.6
-
3e
18.6
17.0
15.6
15.3
17.6
15.6
13.6
14.0
-
3f
4a
4b
4c
-
-
-
-
13.6
-
14.6
-
4d
-
4e
-
-
-
4f
-
-
-
5a
14.3
15.6
-
14.0
-
13.6
-
5b
-
5c
15.3
18.6
16.3
15.0
25.0
25.3
Nt
15.6
16.3
15.3
14.6
22.0
21.6
Nt
14.3
14.6
-
13.6
15.6
-
5d
5e
5f
13.6
Nt
14.3
Nt
Ciprofloxacin
Gentamycin
Amphotericin-B
Nt
Nt
19.3
16.6
Note: “-” represents no activity.
Abbreviations: Sa, Staphylococcus aureus; Bs, Bacillus subtilis; Ec, Escherichia coli; Pa, Pseudomonas
aeruginosa; Sc, Saccharomyces cerevisiae; Ca, Candida albicans.
aValues, including diameter of the well (8 mm), are means of three replicates.
Good activities are highlighted.

KIRAN ET AL.
5
TABLE 3 Minimum inhibitory
concentration (MIC) (in μg/mL) of the
compounds 3a-f, 4a-f, and 5a-f
determined through agar well diffusion
method
MIC (μg/mL)
Compound
Sa
Bs
32
Ec
64
-
Pa
128
-
Sc
Ca
3a
32
128
128
3b
128
128
128
32
64
64
128
3c
64
128
-
256
-
128
-
64
3d
128
32
64
64
64
3e
64
-
64
-
128
3f
128
128
128
256
128
128
256
128
256
64
128
64
-
4a
128
128
-
256
256
-
64
128
4b
64
-
-
4c
128
256
128
256
128
128
64
128
-
128
4d
-
-
-
4e
-
-
-
-
4f
-
-
-
-
5a
256
-
128
-
128
-
128
-
5b
5c
128
64
128
128
5
128
256
128
256
5
128
128
-
128
5d
64
32
64
5e
128
128
5
64
-
5f
64
128
128
Ciprofloxacin
Gentamycin
Amphotericin-B
5
Nt
Nt
20
Nt
5
5
5
5
Nt
20
Nt
Nt
Nt
Nt
Note: Good activities are highlighted.
Abbreviation: Nt, not tested.
FIGURE 1 Comparison of MIC of compounds 3-5 with standard antibiotic drugs

6
KIRAN ET AL.
256 μg/mL against Gram-positive bacteria and between
32 and 256 μg/mL against Gram-negative bacteria. How-
ever, in case of yeast, MIC ranged between 4 and 128 μg/
mL. Compounds 3a and 3e were found to be best as they
exhibited the lowest MIC of 32 μg/mL against S. aureus
and B. subtilis and 64 μg/mL against E. coli whereas the
compound 3e showed lowest MIC of 64 μg/mL against
P. aeruginosa. However, in case of yeast, compounds 3d
showed lowest MIC of 64 μg/mL against both the yeasts
S. cerevisiae and C. albicans (Table 3, Figure 1).
5 | SYNTHESIS OF ETHYL-
3-[(4-ARYLTHIAZOL-2-YL)
HYDRAZONO]BUTANOATE (3a-3f)
5.1 | General procedure
A solution of α,α-dibromoacetophenone (2, 5 mmol) in ethanol
(20 mL) was mixed with ethyl-3-thiosemicarbazidobutanoate
(1, 5 mmol) and stirred at room temperature for about
30 minutes. After completion of the reaction as monitored by
TLC, a solid was separated out. The solid product was filtered
in vacuo and washed with cold ethanol. The crude prod-
uct, so obtained, was recrystallized from methanol and
petroleum ether (1:1) to obtain the pure thiazolyl
hydrazones 3a-f in good % yield.
3 | CONCLUSIONS
The present study provides α,α-dibromoacetophenones
mediated efficient and facile synthesis of several new
ethyl 3-((4-arylthiazol-2-yl)hydrazono)butanoates (3).
The thiazolyl hydrazones 3 are used effectively for the
smooth conversion to thiazolyl pyrazole esters, ethyl
3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazole-4-carboxylates
(4) via V-H reaction, which in turn, are converted to
the corresponding acids, 3-methyl-1-(4-arylthiazol-2-yl)-1H-
pyrazole-4-carboxylic acids (5). The newly synthesized thia-
zole and pyrazole derivatives 16, 17, and 19 seem to be suit-
able candidates for further chemical modifications and may
be useful as ligands in coordination chemistry. The title com-
pounds showed variable growth inhibitory effects on the
tested Gram-positive and Gram-negative bacterial strains.
Meanwhile, few compounds exhibited moderate antifungal
activity against the yeasts, S. cerevisiae and C. albicans.
5.2 | Ethyl 3-[(4-phenylthiazol-2-yl)
hydrazono]butanoate (3a)[41]
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (CDCl3): δ 1.32 (t, J = 7.2 Hz, 3H, CH2CH3),
2.31 (s, 3H, CH3), 3.43 (s, 2H, CH2), 4.24 (q, J = 7.2 Hz, 2H,
OCH2CH3), 6.75 (s, 1H, C5-H, thiazolyl), 7.49 to 7.75 (m,
5H, Ar-H).
13C NMR (CDCl3): δ 14.14, 18.67, 43.95, 61.52, 101.28,
125.61, 126.45, 127.12, 129.05, 129.60, 130.48, 140.61,
155.49, 168.46, 170.01.
5.3 | Ethyl 3-[{4-(4-methylphenyl)
thiazol-2-yl}hydrazono]butanoate (3b)
4 | EXPERIMENTAL SECTION
Melting points were taken in open capillaries with elec-
trical melting point apparatus and are uncorrected. H
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (CDCl3): δ 1.31 (t, J = 7.2 Hz, 3H, CH2CH3),
2.30 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.42 (s, 2H, CH2),
4.21 (q, J = 7.2 Hz, 2H, OCH2CH3), 6.69 (s, 1H, C5-H,
thiazolyl), 7.28 to 7.62 (m, 4H, Ar-H), 12.6 (s, 1H, NH).
13C NMR (CDCl3): δ 14.15, 18.66, 21.37, 43.95, 61.51, 100.32,
124.37, 125.50, 130.23, 140.68, 140.86, 155.29, 168.49, 169.89.
Anal. Calcd. for C16H19N3O2S: C, 60.54; H, 6.03; N,
13.24. Found: C, 60.48; H, 6.08; N, 13.15. m/z 317.12.
1
NMR and 13C NMR spectra were recorded on a Bruker
300 MHz instrument using tetramethylsilane as an inter-
nal standard with δ = 0 ppm. Infrared (IR) spectra were
recorded on a Perkin-Elmer 1800 FT-IR spectrophotome-
ter. All the new compounds gave satisfactory analytical
results (within 0.4 of the theoretical values). The purity
of the synthesized compounds was tested by TLC. The
α,α-dibromoacetophenones needed for the present study
were prepared by stirring different acetophenones with
bromine (2.5 eq.) in CHCl3 for 24 hours and ethyl-
3-thiosemicarbazidobutanoate
were
synthesized
by
5.4 | Ethyl 3-[{4-(4-chlorophenyl)thiazol-
refluxing ethylacetoacetate with thiosemicarbazide in
EtOH according to the literature procedure and was con-
firmed by comparison with literature mp. All chemicals
used were taken from the commercial suppliers and are
used as such without further purification.
2-yl}hydrazono]butanoate (3c)
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (CDCl3): δ 1.32 (t, J = 7.2 Hz, 3H, CH2CH3),
2.31 (s, 3H, CH3), 3.44 (s, 2H, CH2), 4.22 (q, J = 7.2 Hz, 2H,

KIRAN ET AL.
7
OCH2CH3), 6.75 (s, 1H, C5-H, thiazolyl), 7.48 to 7.70 (m,
4H, Ar-H).
6 | SYNTHESIS OF ETHYL-
3-METHYL-1-(4-ARYLTHIAZOL-
2-YL)-1H-PYRAZOLE-
13C NMR (CDCl3): δ 14.11, 18.59, 43.94, 61.55, 101.69,
125.72, 127.42, 128.26, 132.49, 134.61, 140.38, 155.78, 168.49,
170.05.
4-CARBOXYLATES (4a-4f)
Anal. Calcd. for C15H16ClN3O2S: C, 53.33; H, 4.77; N,
12.44. Found: C, 53.39; H, 4.75; N, 12.42. m/z 337.07.
6.1 | General Procedure
To a cold solution (0ꢀC-5ꢀC) of DMF (20 mL) was added
phosphourous oxychloride (5 mmol), stirred for
30 minutes and then 3 (5 mmol) were added in one por-
tion. The reaction mixture was allowed to rise to room
temperature for 5 minutes and refluxed on water-bath for
2 hours. After completion of the reaction as monitored by
TLC, the reaction mixture was cooled and poured into
crushed ice. The solid product separated out was filtered,
washed with water, dried and the crude product, so
obtained, was recrystallized from ethanol to obtain the
pure products 4a-f.
5.5 | Ethyl 3-[{4-(4-bromophenyl)thiazol-
2-yl}hydrazono]butanoate (3d)
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
(NH) cm−1
1H NMR (CDCl3): δ 1.32 (t, J = 7.2 Hz, 3H, CH2CH3),
2.31 (s, 3H, CH3), 3.44 (s, 2H, CH2), 4.22 (q, J = 7.2 Hz,
2H, OCH2CH3), 6.76 (s, 1H, C5-H, thiazolyl), 7.60 to 7.82
(m, 4H, Ar-H), 12.6 (s, 1H, NH).
13C NMR (CDCl3): δ 14.17, 18.66, 43.98, 61.60, 101.63,
124.92, 126.10, 127.07, 132.89, 139.79, 155.73, 168.45,
170.02.
Anal. Calcd. for C15H16BrN3O2S: C, 47.13; H, 4.22; N,
10.99. Found: C, 47.08; H, 4.20; N, 11.07. m/z 381.01.
6.2 | Ethyl 3-methyl-1-(4-phenylthiazol-
2-yl)-1H-pyrazole-4-carboxylate (4a)
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (CDCl3): δ 1.41 (t, J = 7.2 Hz, 3H, CH2CH3),
2.58 (s, 3H, CH3), 4.37 (q, J = 7.2 Hz, 2H, OCH2CH3),
7.30 (s, 1H, C5-H, thiazolyl), 7.38 to 7.93 (m, 5H, Ar-H),
8.85 (s, 1H, C5-H, pyrazole).
5.6 | Ethyl 3-[{4-(4-fluorophenyl)thiazol-
2-yl}hydrazono]butanoate (3e)
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (CDCl3): δ 1.31 (t, J = 7.2 Hz, 3H, CH2CH3),
2.31 (s, 3H, CH3), 3.43 (s, 2H, CH2), 4.24 (q, J = 7.2 Hz,
2H, OCH2CH3), 6.70 (s, 1H, C5-H, thiazolyl), 7.18 to 7.77
(m, 4H, Ar-H).
13C NMR (CDCl3): δ 13.59, 14.37, 60.39, 109.78,
115.24, 126.11, 128.48, 128.79, 131.21, 133.77, 152.89,
153.86, 159.84, 162.99.
Anal. Calcd. for C16H15N3O2S: C, 61.32; H, 4.82; N,
13.41. Found: C, 61.25; H, 4.85; N, 13.32. m/z 313.09.
13C NMR (CDCl3): δ 14.13, 18.58, 43.92, 61.53, 101.20,
116.68, 116.98, 123.49, 123.54, 127.71, 127.83, 139.53,
155.61, 162.05, 168.43, 169.99.
Anal. Calcd. for C15H16FN3O2S: C, 56.06; H, 5.02; N,
13.08. Found: C, 56.16; H, 4.99; N, 12.96. m/z 321.09.
6.3 | Ethyl 3-methyl-
1-{4-(4-methylphenyl)thiazol-2-yl}-1H-
pyrazole-4-carboxylate (4b)
5.7 | Ethyl 3-[{4-(4-nitrophenyl)thiazol-
2-yl}hydrazono]butanoate (3f)
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (DMSO-d6): δ 1.22 (t, J = 7.2 Hz, 3H,
CH2CH3), 1.98 (s, 3H, CH3), 3.34 (s, 2H, CH2), 4.13 (q,
J = 7.2 Hz, 2H, OCH2CH3), 7.67 (s, 1H, C5-H, thiazolyl),
8.09 to 8.29 (m, 4H, Ar-H), 11.02 (s, 1H, NH).
(NH) cm−1
1H NMR (CDCl3): δ 1.41 (t, J = 7.2 Hz, 3H, CH2CH3),
2.41 (s, 3H, CH3), 2.57 (s, 3H, CH3), 4.37 (q, J = 7.2 Hz,
2H, OCH2CH3), 7.23 (s, 1H, C5-H, thiazolyl), 7.24 to 7.81
(m, 4H, Ar-H), 8.84 (s, 1H, C5-H, pyrazole).
13C NMR (DMSO-d6): δ 14.14, 18.67, 43.95, 61.52,
101.28, 125.61, 127.43, 129.22, 140.34, 140.61, 155.49,
168.46, 170.01.
13C NMR (CDCl3): δ 13.65, 14.62, 21.30, 60.60, 111.55,
115.17, 126.34, 129.80, 131.16, 131.52, 138.34, 152.14,
153.38, 159.50, 162.58.
Anal. Calcd. for C15H17N4O4S: C, 51.71; H, 4.63; N,
16.08. Found: C, 51.78; H, 4.60; N, 15.98. m/z 348.09.
Anal. Calcd. for C16H15N3O2S: C, 61.32; H, 4.82; N,
13.41. Found: C, 61.25; H, 4.85; N, 13.32. m/z 313.09.

8
KIRAN ET AL.
6.4 | Ethyl 3-methyl-
1-[{4-(4-chlorophenyl)thiazol-2-yl}-1H-
pyrazole-4-carboxylate (4c)
6.7 | Ethyl 3-methyl-1-[{4-(4-nitrophenyl)
thiazol-2-yl}-1H-pyrazole-4-carboxylate (4f)
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
IR (υmax
,
KBr): 1605 (C N), 1728 (C O), 3315
(NH) cm−1
(NH) cm−1
.
1H NMR (DMSO-d6): δ 1.32 (t, J = 7.2 Hz, 3H,
CH2CH3), 2.45 (s, 3H, CH3), 4.28 (q, J = 7.2 Hz, 2H,
OCH2CH3), 8.23 to 8.31 (m, 5H, Ar-H, C5-H, thiazolyl),
8.91 (s, 1H, C5-H, pyrazole).
1H NMR (CDCl3): δ 1.41 (t, J = 7.2 Hz, 3H, CH2CH3),
2.58 (s, 3H, CH3), 4.37 (q, J = 7.2 Hz, 2H, OCH2CH3),
7.28 (s, 1H, C5-H, thiazolyl), 7.41 to 7.87 (m, 4H, Ar-H),
8.82 (s, 1H, C5-H, pyrazole).
13C NMR (DMSO-d6): δ 13.59, 14.37, 60.39, 109.78,
115.24, 126.11, 127.42, 128.87, 130.56, 130.88, 131.21,
133.77, 152.89, 153.86, 159.84, 162.99.
Anal. Calcd. for C16H14N4O4S: C, 53.62; H, 3.94; N,
15.63. Found: C, 53.69; H, 3.92; N, 15.52. m/z 358.07.
13C NMR (CDCl3): δ 13.61, 14.59, 60.59, 113.10,
115.23, 128.08, 129.19, 131.49, 132.62, 133.40, 150.73,
153.42, 159.70, 162.49.
Anal. Calcd. for C16H14ClN3O2S: C, 55.25; H, 4.06; N,
12.08. Found: C, 55.17; H, 4.05; N, 12.21. m/z 347.05.
7 | SYNTHESIS OF 3-METHYL-
1-(4-ARYLTHIAZOL-2-YL)-1H-
PYRAZOLE-4-CARBOXYLIC ACIDS
(5a-5f)
6.5 | Ethyl 3-methyl-
1-[{4-(4-bromophenyl)thiazol-2-yl}-1H-
pyrazole-4-carboxylate (4d)
7.1 | General Procedure
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
(NH) cm−1
To a solution of 4 (5 mmol) in ethanol (20 mL) was added
5 mL of 10% sodium hydroxide solution in water and the
reaction mixture was kept in microwave for about
2 minutes. After completion of the reaction as monitored
by TLC, the reaction mixture was neutralized with dilute
HCl and the solid was separated out. The solid product
obtained was filtered, washed with water, dried and the
crude product, so obtained, was recrystallized from etha-
nol to obtain the pure products 5a-f.
1H NMR (CDCl3): δ 1.41 (t, J = 7.2 Hz, 3H, CH2CH3),
2.58 (s, 3H, CH3), 4.37 (q, J = 7.2 Hz, 2H, OCH2CH3),
7.30 (s, 1H, C5-H, thiazolyl), 7.57 to 7.81 (m, 4H, Ar-H),
8.83 (s, 1H, C5-H, pyrazole).
13C NMR (CDCl3): δ 13.63, 14.39, 60.47, 110.23,
115.39, 122.53, 127.66, 131.22, 131.94, 132.67, 151.73,
154.00, 160.06, 162.96.
Anal. Calcd. for C16H14BrN3O2S: C, 48.99; H,
3.60; N, 10.71. Found: C, 49.08; H, 3.58; N, 10.58. m/z
391.00.
7.2 | 3-Methyl-1-(4-phenylthiazol-2-yl)-
1H-pyrazole-4-carboxylic acid (5a)
IR (υmax, KBr): 1605 (C N), 1720 (C O), 3315 (NH) cm−1.
1H NMR (DMSO-d6): δ 2.45 (s, 3H, CH3), 7.38 (s, 1H,
C5-H, thiazolyl), 7.45 to 8.02 (m, 5H, Ar-H), 8.87 (s, 1H,
C5-H, pyrazole).
6.6 | Ethyl 3-methyl-
1-[{4-(4-fluorophenyl)thiazol-2-yl}-1H-
pyrazole-4-carboxylate (4e)
13C NMR (DMSO-d6): δ 13.59, 112.2, 115.97, 126.33,
128.90, 129.26, 131.62, 133.73, 152.00, 153.66, 159.73, 164.05.
Anal. Calcd. for C14H11N3O2S: C, 58.93; H, 3.89; N,
14.73. Found: C, 58.84; H, 3.86; N, 14.84. m/z 285.06.
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
(NH) cm−1
1H NMR (CDCl3): δ 1.41 (t, J = 7.2 Hz, 3H, CH2CH3),
2.58 (s, 3H, CH3), 4.38 (q, J = 7.2 Hz, 2H, OCH2CH3),
7.23 (s, 1H, C5-H, thiazolyl), 7.12 to 7.92 (m, 4H, Ar-H),
8.83 (s, 1H, C5-H, pyrazole).
7.3 | 3-Methyl-1-[{4-(4-methylphenyl)
thiazol-2-yl}-1H-pyrazole-4-carboxylic
acid (5b)
13C NMR (CDCl3): δ 13.59, 14.37, 60.39, 109.78,
115.24, 126.11, 127.48, 128.45, 129.12, 130.60, 130.89,
131.21, 133.77, 152.89, 153.86, 159.84, 162.99.
Anal. Calcd. for C16H14FN3O2S: C, 57.99; H,
4.26; N, 12.68. Found: C, 57.88; H, 4.25; N, 12.77. m/z
331.08.
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (DMSO-d6): δ 2.33 (s, 3H, CH3), 2.44 (s, 3H,
CH3), 7.83 (s, 1H, C5-H, thiazolyl), 7.24 to 7.86 (m, 4H,
Ar-H), 8.75 (s, 1H, C5-H, pyrazole).

KIRAN ET AL.
9
13C NMR (DMSO-d6): δ 13.74, 21.26, 110.79, 119.84,
126.23, 129.74, 131.27, 138.16, 151.99, 153.49, 160.13,
7.7 | 3-Methyl-1-{4-(4-nitrophenyl)
thiazol-2-yl}-1H-pyrazole-4-carboxylic
acid (5f)
164.15.
Anal. Calcd. for C15H13N3O2S: C, 60.18; H, 4.48; N,
14.04. Found: C, 61.25; H, 4.85; N, 13.32. m/z 299.07.
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
(NH) cm−1
1H NMR (DMSO-d6): δ 2.42 (s, 3H, CH3), 8.18 to 8.27
(m, 5H, Ar-H, C5-H, thiazolyl), 8.82 (s, 1H, C5-H,
pyrazole).
7.4 | 3-Methyl-1-[{4-(4-chlorophenyl)
thiazol-2-yl}-1H-pyrazole-4-carboxylic
acid (5c)
13C NMR (DMSO-d6): δ 13.50, 111.80, 115.97, 124.31,
127.08, 128.32, 128.43, 130.38, 131.45, 139.57, 147.10,
149.57, 153.68, 160.10, 164.04.
IR (υmax
, KBr): 1605 (C N), 1728 (C O), 3315
.
(NH) cm−1
Anal. Calcd. for C14H10N4O4S: C, 50.91; H, 3.05; N,
16.96. Found: C, 50.84; H, 3.06; N, 17.06. m/z 330.04.
1H NMR (DMSO-d6): δ 2.41 (s, 3H, CH3), 7.45 to 7.89
(m, 5H, Ar-H, C5-H, thiazolyl), 8.72 (s, 1H, C5-H, pyrazole).
13C NMR (DMSO-d6): δ 13.70, 112.07, 115.92, 121.87,
127.97, 129.10, 131.40, 132.73, 133.16, 150.52, 153.52,
160.39, 164.02.
7.8 | Test microorganisms
Anal. Calcd. for C14H10ClN3O2S: C, 52.59; H, 3.15; N,
13.14. Found: C, 52.66; H, 3.14; N, 13.05. m/z 319.02.
Total six microbial strains were selected on the basis of
their clinical importance in causing diseases in humans.
Two Gram-positive bacteria (Staphylococcus aureus
MTCC 96 and Bacillus subtilis MTCC 121); two Gram-
negative bacteria (Escherichia coli MTCC 1652 and Pseu-
domonas aeruginosa MTCC 741) and two yeast, Candida
albicans (MTCC 227), and Saccharomyces cerevisiae
(MTCC 170) were screened for evaluation of antibacterial
and antifungal activity of the chemical compounds. All
the microbial cultures were procured from Microbial
Type Culture Collection (MTCC), IMTECH, Chandigarh.
The bacteria were sub-cultured on Nutrient agar whereas
yeast on Malt yeast agar.
7.5 | 3-Methyl-1-[{4-(4-bromophenyl)
thiazol-2-yl}-1H-pyrazole-4-carboxylic
acid (5d)
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (DMSO-d6): δ 2.45 (s, 3H, CH3), 7.65 to 7.99
(m, 4H, Ar-H), 8.06 (s, 1H, C5-H, thiazolyl), 8.88 (s, 1H,
C5-H, pyrazole).
13C NMR (DMSO-d6): δ 13.66, 113.13, 116.18, 122.04,
128.39, 131.69, 132.15, 133.02, 150.77, 153.66, 159.90,
160.91, 164.07.
Anal. Calcd. for C14H10BrN3O2S: C, 46.17; H,
2.77; N, 11.54. Found: C, 46.08; H, 2.75; N, 11.66. m/z
362.97.
7.9 | In vitro antimicrobial assay
The antimicrobial activity of the title compounds was
evaluated by the agar well diffusion method. All the
microbial cultures were adjusted to 0.5 McFarland stan-
dard, which is visually comparable to a microbial suspen-
sion of approximately 1.5 × 108 cfu/mL. 20 mL of agar
medium was poured into each Petri plate and plates were
swabbed with 100 μL inocula of the test microorganisms
and kept for 15 minutes for adsorption. Using sterile cork
borer of 8 mm diameter, wells were bored into the seeded
agar plates and these were loaded with a 100 μL volume
with concentration of 2.0 mg/mL of each compound rec-
onstituted in the dimethylsulphoxide (DMSO). All the
plates were incubated at 37ꢀC for 24 hours. Antimicrobial
activity of each compound was evaluated by measuring
the zone of growth inhibition against the test organisms
with zone reader (HiAntibiotic zone scale). DMSO was
used as a negative control whereas Ciprofloxacin and
Gentamycin were used as positive control for bacteria
7.6 | 3-Methyl-1-[{4-(4-fluorophenyl)
thiazol-2-yl}-1H-pyrazole-4-carboxylic
acid (5e)
IR (υmax, KBr): 1605 (C N), 1728 (C O), 3315 (NH) cm−1.
1H NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 7.96 (s, 1H,
C5-H, thiazolyl), 7.29 to 8.07 (m, 4H, Ar-H), 8.85 (s, 1H,
C5-H, pyrazole).
13C NMR (DMSO-d6): δ 13.60, 111.88, 116.13, 124.35,
127.11, 128.36, 128.47, 130.36, 130.40, 131.46, 139.59,
150.89, 153.55, 159.74, 164.16.
Anal. Calcd. for C14H10FN3O2S: C, 55.44; H,
3.32; N, 13.85. Found: C, 55.38; H, 3.33; N, 13.94. m/z
303.05.

10
KIRAN ET AL.
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7.10 | Determination of minimum
inhibitory concentration of chemical
compounds
Minimum inhibitory concentration (MIC) is the lowest
concentration of an antimicrobial compound that will
inhibit the visible growth of a microorganism after over-
night incubation. MIC of the various compounds against
bacterial and yeast strains was tested through a modified
agar well diffusion method.[47] In this method, a 2-fold
serial dilution of each chemically synthesized compound
was prepared by first reconstituting the compound in
DMSO followed by dilution in sterile distilled water to
achieve a decreasing concentration range of 256 to
0.5 μg/mL. A 100 μL volume of each dilution was intro-
duced into wells (in triplicate) in the agar plates already
seeded with 100 μL of standardized inoculum (106 cfu/
mL) of the test microbial strain. All test plates were incu-
bated aerobically at 37ꢀC for 24 hours and observed for
the inhibition zones. MIC, taken as the lowest concentra-
tion of the chemical compound that completely inhibited
the growth of the microbe, showed by a clear zone of
inhibition, was recorded for each test organism. Cipro-
floxacin and amphotericin B was used as positive control
while DMSO as negative control.
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ACKNOWLEDGMENTS
We are indebted to UGC for providing research fellow-
ship to Ms. Vijay Kiran for carrying out this work.
ORCID
Rashmi Pundeer https://orcid.org/0000-0002-5359-
344X
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How to cite this article: Kiran V, Joshi R,
Pundeer R. α,α-Dibromoketone precursors in the
synthesis of some new thiazole derivatives:
Thiazol-2-yl hydrazonobutanoates, thiazol-2-yl
pyrazole-4-carboxylates and acids. J Heterocyclic
Chem. 2020;1–11. https://doi.org/10.1002/jhet.3937