Facile one pot multicomponent synthesis of novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives

Article abstract of DOI:10.1080/00397911.2018.1440600

An efficient base catalyzed one pot multicomponent reaction of aryl/hetryl chalcones, thiosemicarbazide and 1-(benzofuran-2-yl)-2-bromoethan-1-one was developed to synthesize the novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives.

Full text of DOI:10.1080/00397911.2018.1440600

Synthetic Communications
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Facile one pot multicomponent synthesis of
novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-
(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole
derivatives
Varun Arandkar, Krishnaiah Vaarla & Rajeswar Rao Vedula
To cite this article: Varun Arandkar, Krishnaiah Vaarla & Rajeswar Rao Vedula (2018) Facile one
pot multicomponent synthesis of novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-
dihydro-1H-pyrazol-1yl)thiazole derivatives, Synthetic Communications, 48:11, 1285-1290, DOI:
10.1080/00397911.2018.1440600
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 11, 1285–1290
https://doi.org/10.1080/00397911.2018.1440600
Facile one pot multicomponent synthesis of novel
4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-
dihydro-1H-pyrazol-1yl)thiazole derivatives
Varun Arandkar, Krishnaiah Vaarla, and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, Telangana, India
ABSTRACT
ARTICLE HISTORY
Received 23 December 2017
An efficient base catalyzed one pot multicomponent reaction of
aryl/hetryl chalcones, thiosemicarbazide and 1-(benzofuran-2-yl)-2-
bromoethan-1-one was developed to synthesize the novel
4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-
1H-pyrazol-1yl)thiazole derivatives.
KEYWORDS
1-(Benzofuran-2-yl)-2-
bromoethan-1-one;
dihydropyrazolylthiazoles;
multicomponent reaction
GRAPHICAL ABSTRACT
Introduction
In organic synthesis, target oriented method development has a long history and the
academia and industries have been focusing on method development to achieve the desired
molecule. The current organic synthetic methods have focused on stereo and regio selective
approaches to achieve structural complex molecules with drug-like properties through
simple reaction conditions with high efficiency. Multicomponent reactions (MCRs) are
among the best synthetic methods to achieve the target molecule libraries and interest in
MCRs has surged during recent years. MCRs are organic chemical transformations in
which three or more reactants combine to generate a single product in a one pot reaction
and in a single operation under mild reaction conditions, in an efficient way with high
atom economy. MCRs have several advantages over conventional linear step synthesis.[1]
MCRs are widely used for the synthesis of natural products,[2–4] organic materials,
polymers,[5–7] and bioactive molecules.[8,9]
Thiazoles are the important organic molecules containing sulfur and nitrogen hetero
atoms in a five-membered hetero cyclic system. Thiazoles are widely distributed in natural
and synthetic medicines and have wide therapeutic applications[10–16] and that makes them
one of the best studied compounds. Some of the thiazoles are available as therapeutic drugs
CONTACT Rajeswar Rao Vedula
rajeswarnitw@gmail.com
Department of Chemistry, National Institute of
Technology, Warangal, Telangana 506004, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

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V. ARANDKAR ET AL.
Figure 1. Design strategy adopted for the synthesis of 4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives.
in the market these being antineoplastic (dasatinib, tiazofurin), anti-inflammatory (fentia-
zac, meloxicam), antiulcer (nizatidine), antifungal (ravuconazole), antiviral (ritonavir), and
these thiazoles are also widely used in agriculture (insecticides, fungicides, and herbicides)
and material applications. Pyrazoles are also well studied heterocyclic compounds with
huge therapeutic value.[17–25] Pyrazoles were found to possess antibacterial, antifungal,
antiviral, antitubercular, antitumor, and analgesic activities. Some of the potential thera-
peutic agents are shown in Figure 1.
In recent years, molecular hybridization technique has been used to generate potential
therapeutic molecules. In view of the important applications of these heterocyclic
compounds in the field of medicinal and material chemistry, we became interested in an
efficient one pot multicomponent approach to synthesize 4-(benzofuran-2-yl)-2-(3-(aryl/
heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives under mild reaction
conditions with high yields.
Results and discussion
In the present study, the target 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-
dihydro-1H-pyrazol-1yl)thiazole derivatives were synthesized using aryl/hetryl chalcones,
thiosemicarbazide and 1-(benzofuran-2-yl)-2-bromoethan-1-one as shown in Scheme 1.
Scheme 1. Synthesis of 4a–k.

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Table 1. A model reaction for the synthesis of compound 4e.
Entry
Solvent
Base
Yield (%)
Reaction time (h)
1
2
NaOH (0.5 equiv.)
KOH (0.5 equiv.)
NaOH (1.0 equiv.)
KOH (1.0 equiv.)
NaOH (1.5 equiv.)
KOH (1.5 equiv.)
NaOH (2.0 equiv.)
KOH (2.0 equiv.)
NaOH (0.5 equiv.)
KOH (0.5 equiv.)
NaOH (1.0 equiv.)
KOH (1.0 equiv.)
NaOH (1.5 equiv.)
KOH (1.5 equiv.)
NaOH (2.0 equiv.)
KOH (2.0 equiv.)
30
38
46
45
55
54
55
50
44
46
55
48
93
12
12
8
3
4
Methanol
8
5
6
6
6
7
6
8
6
9
12
12
8
10
11
12
13
14
15
16
Ethanol
8
4
64
62
57
4
4
4
Bold values indicate the optimized condition to get the compound 4e.
The starting materials aryl/hetryl chalcones were prepared by the Claisen–Schmidt
condensation[26,27] of aryl/hetryl aldehyde with aryl/hetryl ketones using 10% aq. NaOH in
ethanol at room temperature, 1-(benzofuran-2-yl)-2-bromoethan-1-one[28] was prepared as
per the procedure given in literature using 2-acetyl benzofuran and bromine in presence
of chloroform.
In the preliminary study, we performed the reaction of the desired products
4-(benzofuran-2-yl)-2-(3,5-diaryl/heteryl-4,5-dihydro-1H-pyrazol-1yl)thiazoles in presence
of methanol/ethanol by quantifying the base equivalents as shown in Table 1. Initially we
tried the reaction at 60 °C with 0.5 equiv. of NaOH, but the reaction time was high and the
yields of the products were poor. In the next trials, the concentration of NaOH was
increased to 1.0, 1.5, and 2.0 equiv. and it was observed that the yields increased and
the reaction time was minimized. Similarly, the reaction was performed with KOH and
the results are shown in Table 1. It was observed that increasing the concentration of base
beyond 2.0 equiv. did not increase the yield. After several trials of base concentration
modifications, the base concentration (NaOH 1.5 equiv.) was optimized to synthesize
the target compounds through a one pot multicomponent approach in short reaction time
with good yields as shown in Table 2.
Table 2. Yield of compounds 4a–k.
S. no.
Compounda
R1
R2
Yield (%)b
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
Benzofuran-2-yl
Benzofuran-2-yl
4-Fluorophenyl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
4-Methoxyphenyl
Thiophen-2-yl
Thiophen-2-yl
4-Bromophenyl
4-Methoxyphenyl
Furan-2-yl
4-Chlorophenyl
Phenyl
3,4,5-Trimethoxyphenyl
4-Bromophenyl
4-Fluorophenyl
Furan-2-yl
N,N-Dimethylaniline
4-Methoxyphenyl
82
76
85
81
93
88
82
75
91
89
78
3
4
5
6
7
8
9
10
11
4j
4k
aReaction conditions: chalcone (1 equiv.), thiosemicarbazide (1 equiv.), 2-(bromo acetyl) benzofuran (1 equiv.), sodium
hydroxide (1.5 equiv.) in ethanol solvent at 60 °C.
bIsolated yields.

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V. ARANDKAR ET AL.
The newly synthesized compounds were characterized by their physical and analytical
data. The proton NMR spectrum of the compounds exhibited characteristic ABX pattern
for the three protons present in dihydropyrazole ring at fourth and fifth position and
displayed three double doublets (dd). The 1H NMR of compound 4a showed characteristic
peaks at δ 3.38 (dd, J ¼ 17.6 Hz, 6.4 Hz, 1H, HA), 3.97 (dd, J ¼ 17.2 Hz, 12 Hz, 1H, HB),
5.68 (dd, J ¼ 12 Hz, 6.8 Hz, 1H, HX) ppm integrating for one proton each were assigned
to HA, HB, HX protons of dihydropyrazole ring while the aromatic protons appeared at
δ 6.85–7.62 ppm. In 13C NMR of compound 4a the methylene carbon and methine carbon
atoms of dihydropyrazole appeared at δ 42.99 and 63.87 ppm respectively. The remaining
sp2 hybridized carbons appeared from 102.90 to 154.79 ppm. The most down fielded peak
is due to C-2 carbon of thiazole at 164.75 ppm. The mass spectrum for compound 4a
displayed (MþH)þ at 540.25.
Experimental
The reagents used in the present study were purchased from commercial sources and
used without any further purification. The progress of the reaction was monitored through
thin layer chromatography on silica plate (Merck Kieselgel 60 F254 aluminum plates) and
visualization of spots was done under UV–Visible light (254 and 356 nm). Melting points
were identified using Stuart melting point apparatus (SMP-30). The NMR characterization
(1H and 13C) was done using Bruker AV-400 spectrometer. The mass spectral characteri-
zation was done using Water Micromass Quattro API technique. CHN analysis was done
using Carlo Erba 1108 elemental analyzer.
General procedure for the synthesis of 4-(benzofuran-2-yl)-2-(3,5-diaryl/ heteryl-
4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives
A mixture of chalcone (1a–k, 1 mmol), thiosemicarbazide (2, 1 mmol) and 1-(benzofuran-
2-yl)-2-bromoethan-1-one (3, 1 mmol) was taken in a round bottom flask. To this 5 mL of
ethanol was added and stirred at room temperature for about 10 min. Then the reaction
mixture was treated with NaOH (1.5 equiv.) and heated at 60 °C for about 4 h. The pro-
gress of the reaction was monitored through thin layer chromatography using ethyl acetate
and hexane (1:1) as mobile phase. After completion of the reaction the reaction mixture
was cooled to room temperature, solid separated was filtered, washed with ethanol, dried
and recrystallized from ethanol.
4-(Benzofuran-2-yl)-2-(3-(benzofuran-2-yl)-5-(4-bromophenyl)-4,5-dihydro-1H
pyrazol-1-yl) thiazole (4a)
A
mixture of 1-(benzofuran-2-yl)-3-(4-bromophenyl)prop-2-en-1-one (1a, 0.327 g,
1 mmol), thiosemicarbazide (2, 0.091 g, 1 mmol) and 1-(benzofuran-2-yl)-2-bromoethan-
1-one (3, 0.239 g, 1 mmol) was taken in a round bottom flask. To this 5 mL of ethanol
was added and stirred at room temperature for about 10 min. Then the reaction mixture
was treated with NaOH (0.060 g, 1.5 mmol) and heated at 60 °C for about 4.5 h. The
progress of the reaction was monitored through thin layer chromatography using ethyl
acetate and hexane (1:1) as mobile phase. After completion of the reaction the reaction
mixture was cooled to room temperature, solid separated was filtered, washed with ethanol,
1
dried and recrystallized from ethanol. Yellow solid, mp: 256–258 °C, H NMR (400 MHz,

SYNTHETIC COMMUNICATIONS®
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CDCl3, ppm): δ 3.38 (dd, J ¼ 17.6, 6.4 Hz, 1H, pyrazole-HA), 3.97 (dd, J ¼ 17.2, 12 Hz, 1H,
pyrazole-HB), 5.68 (dd, J ¼ 12, 6.8 Hz, 1H, pyrazole-HX), 6.85 (s, 1H, Ar-H), 7.07
(d, J ¼ 9.6 Hz, 2H, Ar-H), 7.18–7.23 (m, 2H, Ar-H), 7.36–7.45 (m, 5H, Ar-H), 7.54–7.62
(m, 5H, Ar-H), 13C NMR (100 MHz, CDCl3): δ 42.99, 63.87, 102.90, 106.44, 108.32,
111.00, 111.76, 121.21, 121.63, 124.28, 125.18, 126.24, 130.05, 130.46, 143.10, 143.22,
143.49, 148.08, 152.22, 154.79, 155.55, 164.75 ppm; MS (ESI m/z %): 540.25 [MþH]þ; Anal.
Calcd. for C28H18BrN3O2S: C, 62.23; H, 3.36; N, 7.78; S, 5.93%. Found: C, 62.29; H, 3.42; N,
7.73; S, 5.87%.
Conclusion
In summary, we have developed an efficient protocol for simultaneous formation of
two potential heterocyclic rings like thiazole and dihydropyrazole derivatives through a
multicomponent reaction approach of deferent aryl/hetryl chalcones, thiosemicarbazide
and 1-(benzofuran-2-yl)-2-bromoethan-1-one in ethanol in presence of aqueous NaOH
in a shorter reaction time.
Acknowledgments
The authors acknowledge the Director, National Institute of Technology-Warangal for providing
the research facilities. One of the authors, Varun Arandkar acknowledges University Grants
Commission, New Delhi for providing him with research fellowship.
Funding
This work was supported by University Grants Commission-New Delhi: [Grant number F. 2-9/2005
(SA)].
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