Citric Acid-catalyzed Synthesis of 2,4-Disubstituted Thiazoles from Ketones via C–Br, C–S, and C–N Bond Formations in One Pot: A Green Approach

Article abstract of DOI:10.1002/jccs.201700200

An improved and greener protocol has been developed for the synthesis of 2,4-disubstituted thiazoles via C–Br, C–S, and, C–N bond formations in a single step from readily available ketones, N-bromosuccinimide (NBS), and thiourea catalyzed by citric acid in a mixture of ethanol and water (3:1) under reflux conditions. This method has the advantages of freedom from the isolation of lachrymatory α-bromoketones, ease of carrying out, cleaner reaction profile, broad substrate scope, freedom from chromatographic purification, and suitability for large-scale synthesis.

Full text of DOI:10.1002/jccs.201700200

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Citric Acid-catalyzed Synthesis of 2,4-Disubstituted Thiazoles from Ketones via C–Br,
C–S, and C–N Bond Formations in One Pot: A Green Approach
*
Trivikram Reddy Gundala, Kumar Godugu and Chinna Gangi Reddy Nallagondu
Department of Chemistry, School of Physical Sciences, Yogi Vemana University, Kadapa 516 003, Andhra Pradesh, India
(Received: June 6, 2017; Accepted: August 28, 2017; DOI: 10.1002/jccs.201700200)
An improved and greener protocol has been developed for the synthesis of 2,4-disubstituted thia-
zoles via C–Br, C–S, and, C–N bond formations in a single step from readily available ketones, N-
bromosuccinimide (NBS), and thiourea catalyzed by citric acid in a mixture of ethanol and water
(3:1) under reflux conditions. This method has the advantages of freedom from the isolation of
lachrymatory α-bromoketones, ease of carrying out, cleaner reaction profile, broad substrate
scope, freedom from chromatographic purification, and suitability for large-scale synthesis.
Keywords: Citric acid; Alkyl aryl ketones; α-bromination; Heterocyclization; 2,4-Disubstituted
thiazoles.
INTRODUCTION
Thiazole-based heterocycles are important structural
series of compounds synthesized in this study require
high temperature. However, the use of high tempera-
ture affects the thermal and chemical stability of lactic
acid, which is due to the possibility of its polymeriza-
tion at reflux temperatures. Further, it may not be suit-
able for solid–liquid separation because of the high
viscosity of lactic acid.30 With the objective of finding a
solution to the above problems, we identified citric acid
as an efficient and green catalyst for the synthesis of 2-
amino-4-aryl/naphthyl/coumaryl thiazoles from readily
available ketones, N-bromosuccinimide (NBS), and
thiourea in a one-pot process. Usually, α-bromination
of ketone with NBS proceeds by acid catalysis. Com-
pared to that of lactic acid, the pKa of citric acid is
smaller, which means that citric acid protonates ketones
very easily when compared to the lactic acid. Further-
more, citric acid is a nontoxic, low-cost, biodegradable,
and environmentally benign catalyst, which is also
employed in many organic transformations.31
In this work, we employed a biodegradable citric
acid catalyst for the synthesis of 2-amino-4-aryl/
naphthyl/coumaryl thiazoles (5) via C–Br (α-bromina-
tion), C–S, and C–N bond formations (heterocycliza-
tion) in a one-pot operation from readily available aryl
alkyl ketones (1) NBS (2), and thiourea (4) in a mixture
of ethanol and water (3:1) under reflux conditions
(Scheme 1).
motifs in many naturally occurring products as well as in
synthetic compounds of pharmaceutical interest.1 These
are valuable building blocks2 in the development of lead
molecules and drug candidates. Among them, 2-
aminothiazoles exhibit a wide range of pharmacological
activities.3–10 In addition, these derivatives are also useful
in catalysis,11 fluorescence,12diagnoses,13 dyes,14 solar
cells,15 photovoltaics,16 organic semiconductors,17 etc.
Recently, 2-amino-4-arylthiazoles were explored in detail
as “prodrugs” for the treatment of type-2 diabetes,18
tuberculosis,19 and Parkinson’s disease.20 A variety of
methods have been reported for the synthesis of thiazole
derivatives from α-bromoketones,21 simple ketones,22 and
other substrates.23–29 Most of them suffer from the use of
lacrymatory α-bromoketones and their availability, nar-
row substrate scope, use of volatile and toxic solvents, low
yields, tedious work-up procedures, and identification/
preparation of a suitable catalyst. Hence, the development
of green and sustainable methodologies for the synthesis
thiazole derivatives remains an active area of research.
Very recently, we reported a lactic acid-mediated,
tandem, one-pot synthesis of 2-aminothiazoles.22a
Unfortunately, the method is not suitable for strong
electron-donating groups such as –OH and −NH2 pre-
sent on the aromatic ring of ketones. In addition, a
*Corresponding author. Email: ncgreddy@yogivemanauniversity.ac.in
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Gundala et al.
of citric acid in the presence of 3:1 ratio of EtOH/H2O
afforded the maximum yield of product (5a) under both
conventional stirring (96%) and ultrasound irradiation
(70%) in a short period (entry 2, Table 2). However, on
further increase in the amount of citric acid to 15 and
20% w/w, the product yield remained the same (entries
3 and 4, Table 2). From the above study, we deter-
mined that the conventional method was superior to
the ultrasound irradiation method in giving the highest
yield of 5a obtained in a short period.
Scheme 1. Synthesis of 2,4-disubstituted thiazoles in
one pot.
RESULTS AND DISCUSSION
The main objective of this work was to develop a
green and sustainable method for the synthesis of ana-
logs of thiazole derivatives (5), as depicted in Scheme 1.
For this purpose, the regioselective α-bromination of
acetophenone (1a) with NBS (2), followed by heterocy-
clization with thiourea (4) in different solvents under
reflux conditions, was used as a model system to opti-
mize the reaction conditions. The obtained results are
summarized in Table 1. The α-bromination and hetro-
cyclization involved in the present process proceeded in
the presence of various biodegradable α-hydroxy acidic
catalysts such as malic acid, mandelic acid, tartaric
acid, and citric acid (5.0% w/w) in water for approxi-
mately 120 min. Low yields of product 5a of 5, 5,
8, and 15% were obtained, respectively. To improve the
yield, the same reaction was repeated by employing var-
ious solvents such as acetone, isopropanol, ethanol, eth-
anol/water (1:1, 2:1, and 3:1 ratio), and the results are
summarized in Table 1. After the examination of vari-
ous α-hydroxy acid catalysts and solvents, it was found
that citric acid (5.0% w/w) in 3:1 ratio of EtOH/H2O
medium was the best option to obtain good yield (85%)
of the product (5a) whereas the other α-hydroxy acid
catalysts and solvents gave low yields. This may be due
to the more acidic nature of citric acid when compared
to the other α-hydroxy acids. The same reaction was
then carried out under ultrasound irradiation in the
presence of various biodegradable α-hydroxy acidic cat-
alysts such as malic acid, mandelic acid, tartaric acid,
and citric acid (5.0% w/w) in different solvents for
approximately 120 min. The obtained results are pre-
sented in Table 1. From this study, we find that citric
acid in 3:1 ratio of EtOH/H2O afforded a moderate
yield (55%) of product 5a, whereas the other catalysts
in various solvents provided low yields under ultra-
sound irradiation. Further, the load of citric acid (5, 10,
15, and 20% w/w) was also varied for optimization of
the reaction conditions, and the obtained results are
shown in Table 2. We found that a loading of 10% w/w
SCOPE OF THE METHOD
Under optimized reaction conditions, the substrate
scope of the present method was examined by using vari-
ous readily available ketones (1a–z), and the obtained
results are summarized in Table 3. The parent acetophe-
none (1a) propiophenone (1b) provided excellent isolated
yields of 95% and 93% of the products 5a and 5b, respec-
tively. Ketones with electron-donating groups on the aryl
ring, such as 4-methyl (1c), 4-ethyl (1d), 2-hydroxy (1e),
3-hydroxy (1f), 4-hydroxy (1g), 4-methoxy (1h), 3-
methoxy (1i), and 2,3-methoxy (1j) groups afforded excel-
lent isolated yields (90–96%) of the products 5c–5j,
respectively. From the above observation, we found that
the electron-donating groups at any position on the aro-
matic ring of ketones are well tolerated. This is due to the
in situ formation of α-bromo ketones in high yields.
Ketones with electron-withdrawing groups on the aryl
ring such as 4-nitro (1k) and 3-nitro (1l) groups gave low
isolated yields (60 and 55%) of the products 5k and 5l
compared to the ketones with electron-donating groups
on the aromatic ring. This may be due to the in situ gener-
ated α-bromo ketones in moderate yields. Halo groups at
different positions on aryl ring of ketones, such as 4-
bromo (1m), 4-chloro (1n), 4-fluoro(1p), 3-bromo (1q), 2-
bromo (1r), 2-chloro (1s), 3,4-chloro (1t), and 2,4-chloro
(1u) groups afforded good to excellent isolated yields
(88–96%) of products 5m, 5n, 5p, 5q, 5r, 5s, 5t, and 5u,
respectively. In the case of acetonaphthones (1v and 1w),
the 2-acetylnaphthalene (1v) provided better isolated yield
(94%) of product 5v when compared to 1-acetyl naphtha-
lene (1w).This may be due to steric effects. Encouraged
by the above results, this methodology was applied for
few heterocyclic systems such as 3-acetylcoumarin (1x),
2-acetylpyridine (1y), and 2-acetylthiophene (1z). The
study revealed that the 3-acetylcoumarin (1x) gave the
product 5x in excellent isolated yield (96%), whereas 2-
2
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Citric Acid-catalyzed Synthesis of Thiazoles
Table 1. Optimization of reaction conditions for the preparation of 2-amino-4-phenylthiazole (5a)(a)
Conventional stirring
Ultrasonic irradiation
Entry
1
Catalyst (5.0% w/w)
Malic acid
Solvent
Product
Time (min)
Yield (%)(b)
Time (min) Yield (%)(b)
H2O
5a
120
60
60
60
60
60
60
120
60
60
60
60
60
60
120
60
60
60
60
60
60
120
60
60
60
60
60
60
5
10
20
30
35
40
45
5
15
25
35
40
45
50
8
15
30
45
50
55
60
15
20
45
60
70
75
85
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
—
—
10
15
18
20
25
—
—
12
20
22
25
28
5
Acetone
Isopropanol
EtOH
EtOH: H2O (1:1 ratio)
EtOH: H2O (2:1 ratio)
EtOH: H2O (3:1 ratio)
H2O
Acetone
Isopropanol
2
3
4
Mandelic acid
Tartaric acid
Citric acid
5a
5a
5a
EtOH
EtOH: H2O (1:1 ratio)
EtOH: H2O (2:1 ratio)
EtOH: H2O (3:1 ratio)
H2O
Acetone
Isopropanol
5
20
35
42
48
56
15
18
36
41
50
52
55
EtOH
EtOH: H2O (1:1 ratio)
EtOH: H2O (2:1 ratio)
EtOH: H2O (3:1 ratio)
H2O
Acetone
Isopropanol
EtOH
EtOH: H2O (1:1 ratio)
EtOH: H2O (2:1 ratio)
EtOH: H2O (3:1 ratio)
(a) Reaction conditions: Acetophenone (1a) (10.0 mmol), N-bromosuccinimide (2) (12.0 mmol), catalyst (5.0%, w/w), thiourea (4)
(12.0 mmol) in solvents at reflux temperature.
(b) Isolated yield.
acetylpyridine (1y) and 2-acetylthiophene (1z) did not
form the desired products 5y and 5z because they might
be undergoing ring bromination instead of α-bromina-
tion. From the above observations, it is found that the
isolated yields of the thiazoles depend on the percentage
of in situ generated α-bromoketones.
(1x), NBS (2), and thiourea (4) in the presence of citric
acid in different gram-scale reactions (1, 5, 10, 15,
20, and 25 g) in a mixture of ethanol and water (3:1)
under reflux conditions, which resulted in 96, 96,
96, 95, 94, and 94%, yields of product 5x, respectively.
From this investigation, it was found that the developed
synthetic route is an alternative for the preparation of
2-amino-4-arylthiazoles in gram-scale production.
Further, to test the scalability of the procedure,
the reaction was carried out with 3-acetylcoumarin
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Table 2. Screening for loading of catalyst(a)
Conventional stirring
Ultrasonic irradiation
Entry
Catalyst (% w/w)
Solvent
Product
Time (min)
Yield (%)(b)
Time (min)
Yield (%)(b)
1
2
3
4
5.0
10.0
15.0
20.0
EtOH: H2O (3:1 ratio)
EtOH: H2O (3:1 ratio)
EtOH: H2O (3:1 ratio)
EtOH: H2O (3:1 ratio)
5a
5a
5a
5a
20
20
20
20
85
96
96
94
120
60
60
55
70
70
66
60
(a) Reaction conditions: Acetophenone (1a) (10.0 mmol), N-bromosuccinimide (2) (12.0 mmol), catalyst (5.0%, w/w), thiourea (4)
(12.0 mmol) in in EtOH/H2O (3:1 ratio) at reflux temperature.
(b) Isolated yield.
EXPERIMENTAL
Materials and methods
in the literature.21,22 Spectroscopic data of these com-
pounds are consistent with those reported previously.
Some of the compounds (5e, 5f, 5g, 5i, 5j, 5r, and 5x)
were characterized by spectroscopic data (1H and13C
NMR and HRMS).
Melting points were determined on an MR-Vis+
instrument (Labindia) and are uncorrected. 1H
(400 MHz) and 13C (100 MHz) NMR spectra were
recorded on a Varian 400 MHz spectrometer with CDCl3
as a solvent and tetramethylsilane (TMS) as the internal
reference compound. Mass spectral data were acquired on
a Exactive Orbitrap mass spectrometer (Thermo Scien-
tific, Waltham, MA, USA). All the reactions were moni-
tored by TLC. All chemicals and solvents were procured
from Acros organics Ltd., Merck, or Sigma-Aldrich and
were used as received. Millipore double-distilled water
was used for the work-up. Supporting information
(Supporting Information) contains the 1H, 13C NMR,
and HRMS spectra of newly synthesized compounds (5).
General experimental procedure for gram-scale (25 g)
synthesis
A mixture of 3-acetylcoumarin (1x) (0.135 mol),
NBS (2) (0.15 mol), and citric acid (10% w/w) was dis-
solved in 100 mL of 3:1 ethanol/water and the reaction
mixture was refluxed for 20 min. The formation of
α-bromoketone (3x) was monitored by TLC. After the
formation of α-bromoketone (3x) as per TLC, thiourea
(4) (0.15 mol) was to the reaction mixture and stirred for
1–2 min under reflux conditions. After completion of the
reaction, as indicated by TLC, the reaction mixture was
slowly cooled down to RT and poured into a beaker con-
taining 500 mL water and stirred well. The obtained
crude product (5) was filtered, washed thoroughly with
double-distilled water, and dried. Finally, the crude
product (5x) was recrystallized from hot ethanol. The
isolated yield of the obtained product (5x) was 96%.
General experimental procedure for the synthesis of 2,4-
disubstituted thiazole derivatives (5)
A mixture of ketones (1) (10.0 mmol), NBS (2)
(12.0 mmol), and citric acid (10% w/w) was dissolved in
10 mL of 3:1 ethanol/water, and the reaction mixture
was either stirred under reflux condition for 15–20 min
or under ultrasound irradiation at 60–70 ꢀC for approx-
imately 60 min. After the formation of α-bromoketones
(3) as monitored by TLC, thiourea (4) (12.0 mmol) was
to the reaction mixture and stirred for 1–2 min under
reflux conditions. After completion of the reaction, as
indicated by TLC, the reaction mixture was slowly
cooled down to RT and poured into a beaker contain-
ing 50 mL of water and stirred well. The obtained
crude product (5) was filtered, washed thoroughly with
double-distilled water, and dried. Finally, the crude
product (5) was recrystallized from hot ethanol. Most
of the synthesized compounds are already characterized
CONCLUSION
A practical and environmentally friendly process
has been demonstrated for the synthesis of 2, 4-
disubstituted thiazoles via C–Br, C–S, and C–N bond
formations in a single step from readily available vari-
ous ketones, NBS, and thiourea catalyzed by biode-
gradable citric acid in a mixture of ethanol and water
(3:1) under reflux conditions. Noteworthy features of
the catalyst are the environmentally benign nature,
regioselectivity, and wide substrate scope. The catalyst
is thus a greener alternative to the previously reported
4
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Citric Acid-catalyzed Synthesis of Thiazoles
Table 3. Synthesis of a series of 2,4-disubtituted thiazoles from readily available ketones
Entry
1
Substrate
Product
Time (min)
20
Yield (%)[Ref.]
9621,22
2
3
20
15
9321,22
9621,22
4
5
20
18
9221,22
9622
6
7
16
16
9222
9022
8
18
9421,22
9
20
18
94
94
10
11
12
25
25
6021,22
5521,22
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Gundala et al.
Table 3. Continued
Entry
13
Substrate
Product
Time (min)
16
Yield (%)[Ref.]
9621,22
14
15
9521,22
15
16
20
18
9221
9421,22
17
18
19
20
9321,22
89
19
20
20
19
9122
9021,22
21
22
20
18
8921,22
9421,22
23
24
20
20
9021,22
96
6
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Citric Acid-catalyzed Synthesis of Thiazoles
Table 3. Continued
Entry
25
Substrate
Product
Time (min)
40
Yield (%)[Ref.]
0
26
40
0
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tones, high yields of products, freedom from chromato-
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logically active, thiazole-based analogs.
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The authors thank DAE-BRNS, Mumbai, India
(Project No. 2011/37C/52/BRNS/2264), for financial
support.
Supporting information
Additional supporting information is available in
the online version of this article.
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