A facile one-pot synthesis of 2-pyrazolyl-4-aryl-thiazoles in a threecomponent reaction

Article abstract of DOI:10.3184/030823408X314707

A one-pot multi-component reaction of phenacylbromide, thiosemicarbazide and acetyl acetone or ethyl acetoacetate is described for the preparation of the title compounds. The key features of this methodology are its operational simplicity, mild reaction conditions, and good yields.

Full text of DOI:10.3184/030823408X314707

JOURNAL OF CHEMICAL RESEARCH 2008
APRIL, 195–197
RESEARCH PAPER 195
A facile one-pot synthesis of 2-pyrazolyl-4-aryl-thiazoles in a three-
component reaction
Guravaiah Nalajam and Rajeswar Rao Vedula*
Department of Chemistry, National Institute of Technology, Warangal 506 004, A.P., India
A one-pot multi-component reaction of phenacylbromide, thiosemicarbazide and acetyl acetone or ethyl acetoacetate
is described for the preparation of the title compounds. The key features of this methodology are its operational
simplicity, mild reaction conditions, and good yields.
Keywords: thiazoles, pyrazoles, phenacyl bromides, thiosemicarbazide, β-ketoesters, β-diketones, multicomponent reactions
Multi component reactions (MCRs) are a promising field of
chemistry because the synthesis of complicated molecules
can be achieved rapidly and efficiently without the isolation
of intermediates. As a result, laboratory effort is reduced,
minimising the environmental loading, and so is acceptable
from a Green Chemistry point of view. In recent years, the
development of new MCRs has been a popular area of
research in current organic chemistry.1,2
Thiazoles are most generally synthesised by Hantzsch’s
thiazole synthesis from α-halogenoketones and thioureas or
thioamides.3,4 Later, King et al.5,6 and others7,8 synthesised
aminothiazoles by a modification of the method. The method
still remains cumbersome and time-consuming.
Many pyrazole derivatives possess anti-inflammatory
activity.9-11 In continuation of our earlier work12,13 on
the synthesis of heterocyclic systems, we report here the
facile one-pot multi-component reaction forming 4-aryl-2-
pyrazolylthiazoles in a single step from the readily available
starting materials phenacyl bromides, thiosemicarbazide and
acetyl acetone or ethyl acetoacetate.
in acetylacetone or ethyl acetoacetate indeed gave a thiazolyl
pyrazole rather than a thiazolo-triazepine (
7, 8) structure. This is
based on our earlier observations16 and also from others in the
literature.17 In order to distinguish between a 5- and 7-membered
ring structure an alternative synthesis was employed. Refluxing
ethanolic solution of an equimolar amounts of 3,5-dimethyl-
1-carbamylpyrazole18 and 5-hydroxy-3-methylpyrazole-1-
thiocarboxamide19 with 1 gave 4 and 6 respectively. The
products obtained by both the methods were identical from
mixed melting-point measurements, co-TLC and IR spectra.
According to a recent observation by Peet et al.,20 synthetic
design of seven membered ring system should require a careful
consideration of the competitive five or six membered ring
closures which are usually favoured from acyclic precursors.
The IR spectrum of 4a showed prominent peaks at 1216
(C–S) and 1619 cm-1 (C=N), consistent with the assigned
structure. The 1H NMR (CDCl3) spectrum of 4a showed signals
at δ 2.30 (s, 3H, C3–CH3), 2.77 (s,3 H, C5–CH3),3.85 (s, 3H,
OCH3),6.0(s,1H,pyrazoleproton),7.06(s,1H,thiazoleproton).
In the 13C NMR spectrum 4a showed signals at δ 13.5 and
13.78 (CH3 of pyrazole) and 55.3 (OCH3). Further support
for the presence of the pyrazole ring was provided by the
signals at ca 151, 109 and 142 ppm, in excellent agreement
with the values reported for C-3, C-4 and C-5 respectively
of pyrazoles.21 The newly synthesised compounds were
characterised by their analytical and spectral data.
Results and discussion
We report here the Hantzsch thiazole synthesis and
concomitant formation of pyrazolothiazoles in a single-step
reaction. The procedure involves refluxing an equimolar
mixture of phenacyl bromides, thiosemicarbazide, and acetyl
acetone or ethyl acetoacetate in dry ethanol for 4–6 hours.
The progress of the reaction was monitored by TLC. After
completion of the reaction, the mixtures were cooled to room
temperature. The solids that separated out were filtered off
and dried to obtain the corresponding title compounds. The
solid product was recrystallised from a suitable solvent and
The main fragmentation in the mass spectrum of 4f involves
fission of the thiazole moiety resulting in an abundant ion at
m/z 134,which undergoes cleavage via several pathways. In
a competing process, the pyrazole ring also suffers cleavage,
and methyl cyanide is lost from the molecular ion. The
molecular ion undergoes rearrangement yielding a prominent
ion at m/z 107. This process involves the loss of C8H6NS from
the molecular ion in one or several steps. The appearance of
the same ion in the mass spectrum of 4d (where the phenyl
ring carries a chlorine atom) shows that the aryl ring does not
participate in the formation of this ion. An obvious pathway
involves ring expansion of the pyrazole moiety, and the ion
may thus be formulated as 2,4-dimethylpyrimidinium. From
the mass spectral fragmentation it is evident that the product 4
has a pyrazole structure rather than a triazepine structure.
The IR spectrum 6a showed prominent peaks at 1216 (C–
S) and 1616 cm-1 (C=N) and 3400 cm-1 (OH). In the NMR
spectra a singlet at d 2.1 is due to CH3 of pyrazole, and one at
d 3.83 (s) to OCH3 group. The pyrazole and thiazole protons
show as singlets at d 6.05 and 7.6 respectively. The PMR
spectra of 6 in neutral or basic solvent (CDCl3 or DMSO-d6)
displayed signals at 6.06 and 12.4 integrating for one proton
each, assignable to 4H and OH respectively, besides the other
signals.24 This observation showed that 6 exists in the enol
form in CDCl3 or DMSO-d6. It may be inferred that in basic or
neutral solvent due to strong hydrogen bonding the enol form
exists. The 13C NMR spectrum of 6a in CDCl3 showed signals
at d 19.1 (CH3 of pyrazole) and 55.4 (methoxy group).
1
fully characterised by IR, H NMR and mass spectrometry
and elemental analysis.
In the literature,14,15 it has been reported that the synthesis
of the title compounds requires a multi step process. The first
step involves in the preparation of N-acetyl thiosemicarbazide.
This on reaction with various phenacylbromides gives the
corresponding 2-N-acetylhydrazino-4-phenylthiazoles. These
are deacetylated to yield the corresponding 2-hydrazino-4-
phenylthiazoles, which on reaction with acetylacetone or
ethyl acetoacetate lead to the formation of the polycyclic ring
system. Though the above methodologies are quite useful,
they have some limitations, such as the requirement of the
isolation of intermediates and longer reaction times, and the
overall yields are lower.
It is thus evident that there remains scope for the development
of clean and efficient methodologies involving single step
reactions for the preparation of the title compounds. We have
developed a one-pot synthesis of these compounds in good
yields when compared to alternative available methods. The
condensation of phenacyl bromides with thiosemiarbazide
* Correspondent. E-mail: vrajesw@yahoo.com
PAPER: 07/4977

196 JOURNAL OF CHEMICAL RESEARCH 2008
CH3
O
N
O
H2N
H2N
R
N
H3C
NH
CH2
O
a
R
N
+
+
CH2Br
S
H3C
S
CH3
1
2
3
4
CH3
O
N
R
H3C
CH2
N
a
N
1
2
+
+
O
EtO
S
OH
O
5
6
1, 4, 6 a, R = OMe
b, R = Me
c, R = Ph
CH3
N
CH3
NH
H3C
d, R = Cl
N
N
e, R = Br
R
R
N
N
f, R = H
S
S
8
7
Scheme 1 Synthesis of pyrazolythiazoles. Conditions: a, dry EtOH/HCl, reflux.
4-(4-Bromophenyl)-2-(3,5-dimethylpyrazol-1-yl)thiazole (4e): Yield
85%, m.p.151–152°C, (lit.14 m.p. 149–150°C).
2-(3,5-Dimethylpyrazol-1-yl)-4-phenylthiazole (4f): Yield 92%,
m.p. 100–102°C (lit.14 102–104°C) (from ethanol). MS (70eV): m/z
(%) 255 (M+,100), 214 (M–CH3–CN, 5), 213 (M–CH3–CN–H, 7),
134 (40), 107 (10), 102 (19) and 89 (12).
Experimental
Melting points were determined in open capillaries with a Cintex
melting point apparatus Mumbai, India. CHN analysis was done on a
Carlo Erba EA 1108 automatic elemental analyser. The purity of the
compounds was checked by TLC plates (E.Merck, Mumbai, India),
IR spectra (KBr) were recorded on a BrukerWM-4(X) spectrometer
(577 model). 1H NMR spectra were recorded on a Bruker WM-
300 spectometer using TMS as internal standard. Mass spectra
(EI-MS) were determined on Perkin Elmer (SCIEX API-2000,ESI) at
12.5eV and at 70eV on MS12 mass spectrometer fitted with a direct
inlet system; source temperature was kept at about 165°C. Phenacyl
bromides were procured from Aldrich, Mumbai, India. Acetyl
acetone, ethyl acetoacetate and thiosemicarbazide were procured
from Loba chemicals, Mumbai, India.
Synthesis of pyrazolols 6 from phenacyl bromides: general procedure
The phenacyl bromide (1 mmol), thiosemicarbazide (0.091 g,
1 mmol) and ethyl acetoacetate (0.13 g, 1 mmol) were refluxed for
4–6 hours in dry ethanol containing a catalytic amount of conc.
HCl. The mixture was cooled to room temperature and the solid that
separated was filtered off, dried and recrystallised.
2-[4-(4-Methoxyphenyl)thiazol-2-yl]-5-methyl-2H-pyrazol-3-ol
(6a): Yield 96%, m.p. 206–208°C (from ethyl acetate/hexane). IR:
νmax 1215 (C–S), 1616 (C=N), 3400 cm-1 (OH). NMR (CDCl3),
Synthesis of pyrazolylthiazoles 4 from phenacyl bromides: general
procedure
The phenacyl bromide (1 mmol), thiosemicarbazide (0.091 g,
1 mmol) and acetylacetone (0.090 g, 1 mmol) were refluxed for
4–6 hours in dry ethanol containing a few drops of conc. HCl.
The mixture was cooled to room temperature and the solid which
separated was filtered off, dried and recrystallised.
d
H 2.1 (s, 3H, CH3) 3.83 (s, 3H, OMe), 6.5 (s, 1H, pyrazole), 7.6 (s,
1H, thiazole) and 12.4 (OH, D2O exchangeable). EI-MS 287 (M+).
Anal. calcd. for C14H13N3O2S: C, 58.52; H, 4.56; N, 14.62. Found: C,
58.60; H, 4.50; N,14.54%.
5-Methyl-2-[4-(4-tolyl)thiazol-2-yl]-2H-pyrazol-3-ol (6b): Yield
94%, m.p. 214–216°C (from ethyl acetate/hexane). IR: νmax 1215
(C–S),1620 (C=N), 3409 cm-1 (OH). NMR (CDCl3) dH 2.3
(s, 3H, CH3 of pyrazole), 2.78 (s, 3H, Me) 6.0 (s, 1H, pyrazole),7.3
(s, 1H, thiazole) and 7.2–7.8 (m, 4H, ArH), 15.75 (OH, 1H, D2O,
exchangeable); dC 19.0, 21.3, 24.8, 99.6, 124.6, 125.4, 130.5,
140.4, 140.6, 159.1, 169.5. EI-MS: m/z 271 (M+). Anal. Calcd. for
C14H13N3OS: C, 61.97; H, 4.83; N, 15.49. Found: C, 61.91; H, 4.80;
N, 15.42%.
2-[4-(Biphenyl-4-yl)thiazol-2-yl]-5-methyl-2H-pyrazole-3-ol (6c):
Yield 92%,m.p. 200–202°C (from ethyl acetate/hexane). IR: νmax
1216 (C–S), 1565 (C=N), 3432 cm-1 (OH). NMR (CDCl3): dH 2.0
(s, 3H, CH3), 6.9 (s, 1H, pyrazole) 7.8 (s, 1H, thiazole) and 7.3–7.7
(m, 9H, ArH), 15.85 (OH, 1H, D2O, exchangeable). EI-MS: m/z 333
(M+). Anal. Calcd. for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60.
Found: C, 68.40; H, 4.50; N, 12.54%.
2-(3,5-Dimethylpyrazol-1-yl)-4-(4-methoxyphenyl)thiazole (4a):
Yield 95%, m.p. 122–124°C (from ethyl acetate/hexane). IR: νmax
1247 (C-S), 1607 cm-1 (C=N). NMR (CDCl3) dH 2.30 (s, 3H, CH3),
2.77 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 6.0 (s, 1H pyrazole), 7.06 (s,
1H, thiazole), 6.94–6.97 (d, 2H, ArH), and 7.81–7.84 (d, 2H, ArH);
dC 13.5, 13.8, 55.3, 106.5, 109.4, 114.0, 127.2, 127.3, 141.6, 151.3,
152.0, 159.5, 161.7. EI-MS 285 (M+). Anal. calcd. for C15H15N3OS:
C, 63.13: H, 5.3; N, 14.72. Found: C, 63.00; H, 5.41; N, 14.64%.
2-(3,5-Dimethylpyrazol-1-yl)-4-(4-tolyl)thiazole (4b): Yield 90%,
m.p. 96–98°C (from ethyl acetate/hexane). IR: νmax 1214 (C–S),1616
cm-1 (C=N). NMR (CDCl3): dH 2.09 (s,3H, pyrazole CH3), 2.17 (s,
3H, CH3), 2.36 (s, 3H, CH3), 6.64 (s, 1H, pyrazole), 7.54 (s, 1H,
thiazole) and 7.23–7.26 (m, H, ArH), 7.54–7.57 (m, 2H, ArH); dC
13.5, 13.8, 21.2, 107.6, 109.4, 124.7, 126.9, 129.3, 137.9, 139.0,
141.0, 151.4, 152.0. EI-MS 269 (M+). Anal. Calcd.for C15H15N3S: C,
66.88; H, 5.61; N, 15.60. Found: C, 66.81; H, 5.68; N, 15.54%.
4-Biphenyl-4-yl-2-(3,5-dimethylpyrazol-1-yl)thiazole (4c): Yield
88% m.p. 146–148°C (from ethyl acetate/hexane). IR: νmax 1216
(C-S), 1619 cm-1 (C=N). NMR (CDCl3): dH 2.25 (s, 3H, CH3
of pyrazole), 2.8 (s, 3H, CH3), 6.05 (s, 1H pyrazole), 8.0 (s, 1H,
thiazole), and 7.3–7.7 (m, 9H, ArH). EI-MS 331 (M+). Anal. Calcd.
for C20H17N3S: C, 72.48; H, 5.17; N, 12.68. Found: C, 72.41; H,
5.12; N,12.62%.
2-[4-(4-Chlorophenyl)thiazol-2-yl]-5-methylpyrazol-3-ol (6d): Yield
87%, m.p. 192–194°C (lit.19 m.p. 191°C).
2-[4-(4-Bromophenyl)thiazol-2-yl]-5-methylpyrazol-3-ol (6e): Yield
85%, m.p. 206–208°C (lit.19 m.p. 208°C).
5-Methyl-2-(4-phenylthiazol-2-yl)pyrazol-3-ol (6f): Yield, 90%,
m.p. 192–194°C (lit.19,22,23 m.p. 193°C).
The authors are thankful to Head of the Analytical Division,
IICT Hyderabad, for analytical and spectral data. Further, the
authors are very thankful to CSIR, New Delhi for the sanction
of the project (No.01 (2062) 06/EMR-II).
4-(4-Chlorophenyl)-2-(3,5-dimethylpyrazol-1-yl)thiazole
(4d):
Yield 88%, m.p. 151–152°C (lit.14 m.p. 151–152°C) (from ethanol).
MS (70eV), m/z (%) 289 (100), 288 (8), 274 (6), 248 (5), 247 (6), 167
(24), 107 (15).
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JOURNAL OF CHEMICAL RESEARCH 2008 197
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Received 7 December 2007; accepted 17 April 2008
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