A facile and eco-friendly synthesis of diarylthiazoles and diarylimidazoles in water

Article abstract of DOI:10.1016/j.tetlet.2011.02.069

A simple, efficient and high yielding greener protocol for the synthesis of substituted thiazoles and imidazoles is described that utilizes the reaction of readily available α-tosyloxy ketones with variety of thioamides/amidines in water.

Full text of DOI:10.1016/j.tetlet.2011.02.069

Tetrahedron Letters 52 (2011) 1983–1986
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile and eco-friendly synthesis of diarylthiazoles and diarylimidazoles
in water
Dalip Kumar a, , N. Maruthi Kumar a, Gautam Patel a, Sudeep Gupta a, Rajender S. Varma b,
⇑
⇑
a Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
b Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443, Cincinnati, OH 45268, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient and high yielding greener protocol for the synthesis of substituted thiazoles and imi-
Received 7 January 2011
Revised 15 February 2011
Accepted 16 February 2011
Available online 22 February 2011
dazoles is described that utilizes the reaction of readily available
amides/amidines in water.
a-tosyloxy ketones with variety of thio-
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Thiazoles
Imidazoles
Greener synthesis
Water
Thiazoles and imidazoles are important heterocycles known for
their broad spectrum of biologicalactivities.1,2 Natural and synthetic
molecules containing thiazole scaffold play a significant role in
pharmaceutical industry due to their anti-inflammatory,3 anti-
HIV,4 anti-bacterial5, and anti-schizophrenia6 properties. The
aminothiazoles are ligands for estrogen receptors7 and studied for
their anti-cancer activity.8 This structural unit is a part of many
agro-chemicals9 and natural products such as vitamin B1 (thiamine).
Cystothiazole and its analogues, isolated from Mycobacterium
culture broth of Cystobacter fuscus, show anti-bacterial activity.
Mycothiazole, isolated from the Indo-Pacific sponge Spongia myco-
fijiensis, displays anthelmintic activity and selective cytotoxicity
against lung cancer,10 some indole-based secondary metabolites
containing thiazole nucleus are known to display interesting anti-
cancer activity.11 Similarly, analogues bearing imidazole moiety is
an active pharmacophore in several natural and synthetic drug
molecules. Diarylimidazoles are well documented for their wide
range of biological activities12–14 and imidazole containing natural
products such as topsentine, nortopsentine, and analogues show
prominent anticancer activity.15
generation of unwanted side-products, and the use of moisture sen-
sitive and expensive reagents.16 To overcome these problems and to
find new alternatives for simple and environmentally benign proto-
cols, chemists have adopted water as solvent of choice in the organic
synthesis. Usage of water addresses the several concerns of green
chemistry such as easy availability, safe handling, simple workups
and cost effective for small and bulk scale process industries. Water
due to its high hydrophobic nature can enhance the rates and affect
the selectivity of various organic transformations.17 In the recent
years a variety of organic transformations such as aldol reaction,
allylation reaction, Diels–Alder reaction, Michael reaction,
Mannich-type reaction, Henry reaction, and Pd catalyzed coupling
reactions have been reported in aqueous media.17,18 In continuation
of our efforts for the development of novel and eco-friendly proto-
cols to synthesize biologically active molecules, we have explored
solvent-free synthesis, the use of alternative solvent media such as
PEG-400, ionic liquids, aqueous media, polymer supported sulfonic
acid reagents and microwave-assisted organic reactions.19
In this Letter, we report a facile synthesis of various thiazoles
and imidazoles in water. There are several synthetic routes to con-
struct diarylthiazoles and diarylimidazoles. Hantzsch synthesis
In view of immense biological significance of these five-
membered azoles, many synthetic protocols have been reported.
However, in recent years the key constraints for the synthetic
chemists are the use of hazardous solvents, multi-step protocols,
involving the reaction of
a-haloketones with various thioamides
is the most prominent method of choice,20 however, this method
suffers from longer reaction times, harsh reaction conditions and
the use of lachrymatory reagents. Subsequent efforts to improve
efficiency of this method entails the use of solvents such as DMF,
1,4-dioxane and chlorinated solvents.21 Some recent reports have
focused on the use of alternative solvents such as PEG-400 and io-
nic liquids.22 Many improved results have been reported for the
⇑
Corresponding authors. Tel.: +91 1596 245073 279 (D.K.), +1 513 487 2701
(R.S.V.).
E-mail addresses: dalipk@bits-pilani.ac.in (D. Kumar), varma.rajender@epa.gov
(R.S. Varma).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.069

1984
D. Kumar et al. / Tetrahedron Letters 52 (2011) 1983–1986
R1
R2
have replaced highly toxic and lachrymatory a-haloketones to pre-
O
X
pare variety of heterocycles.28,29 Thioamides were synthesized
from the reaction of corresponding arylnitiriles with NaSH in
R2
OTs
heat
N
R1
+
R3
NH2
R3
Water
DMF.30 Our initial attempts involving the reaction of
a-tosyloxy
X
2
1
acetophenone 1 with thiobenzamide in water at ambient temper-
ature were unsuccessful to produce desired product and hence, the
reaction was investigated at various temperatures. We found 60 °C
was optimum temperature and affords desired product in good
yield (Scheme 1). Pure products were isolated by simple filtration
or recrystallization of the ensuing products. To understand the
unprecedented role of water as a solvent and reaction promoter,
we have conducted the synthesis of diarylthiazoles in various or-
ganic solvents. A comparative study was made using organic sol-
vents, such as polar–protic (ethanol and methanol) and polar–
aprotic (acetonitrile, THF and DMF) which has the drawbacks such
as prolonged reaction times, incompletion of the reaction and re-
sulted in poor yields (Table 1). In nonpolar solvents toluene and
xylene reaction needs higher temperatures and yields are moder-
ate. Results were not satisfactory in chlorinated solvents such as
CHCl3 and CH2Cl2. Further, a model reaction was studied at our
optimized reaction conditions and results were compared with
the water and organic solvents (Table 1). Encouraged by the favor-
able results in water, the scope of the reaction was investigated by
3a-s X = S
4a-i
X = NH
Scheme 1. Synthesis of thiazoles 3 and imidazoles 4.
Table 1
Yields of diarylazoles 3a and 4a in various solventsa
Entry
Solvent
3ab (%)
4ab (%)
1
2
3
4
5
6
7
8
9
EtOH
MeOH
DMF
CH3CN
THF
Xylene
Toluene
CHCl3
47
40
15
27
18
23
20
30
35
87
84
23
18
10
No product
30
No product
No product
55
25
70
68
CH2Cl2
Distilled water
Tap water
10
11
a
Reaction conditions:
zamidine (1 mmol) and solvent (0.5 mL); 3a stirred at 60 °C for 5 h/4a stirred at
80 °C for 3 h.
a-tosyloxyacetophenone (1 mmol), thiobenzamide/ben-
reacting a variety of
a-tosyloxyketones 1 having electron-with-
drawing and electron-donating groups, and aryl and heteroaryl
thioamides 2 to generate a library of disubstituted thiazoles 3 (Ta-
ble 2).31 In the case of heteroaryl thioamides yields were less when
compared with aryl systems. In several aspects usage of water is
advantageous, as it is environmentally benign and due to its high
hydrogen bonding capacity it can stabilize the intermediates
formed in Hantzsch thiazole synthesis to promote the reaction
(Fig. 1).
b
Isolated yields.
synthesis of thiazoles using KF-10 clay,23 ammonium 12-molybdo-
phosphate,24 b-cyclodextrin,25 and microwave-assisted synthe-
sis.26 Despite these reports, there is a vast scope to develop
eco-friendly alternatives that preclude the use of any catalysts or
hazardous solvents, high temperatures and improving the yields.
-Tosyloxyketones were prepared from enolizable ketones
using hydroxyl(tosyloxy)iodobenzene as reported in literature.27
-Tosyloxyketones are one of the versatile intermediates which
Synthesis of imidazoles is often reported from the reaction of
glyoxal with a variety of aldehydes in the presence of ammonium
acetate.32 Synthesis of imidazole ring is also achievable by reacting
a
a
-haloketones with amidines in organic solvents such as chloro-
form, DMF, acetonitrile, and alcohols.33
a
Table 2
Synthesis of diarylthiazoles 3 and diarylimidazoles 4
Compound
R1
R2
R3
Yielda (%)
Time (h)
Mp (°C)
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
C6H5
4-ClC6H4
NH2
87
90
92
82
80
70
65
85
85
90
90
88
93
80
85
90
87
75
86
70
65
65
70
63
55
55
60
50
5.0
6.0
1.0
5.0
4.0
4.0
5.0
4.0
5.0
3.0
3.0
3.0
3.0
4.0
3.0
4.0
4.0
6.0
5.0
3.0
3.5
2.5
3.0
3.0
2.0
3.0
2.5
3.5
89–90 (90–91)24
104 (104–105)25
148–149 (149–150)24
64–65 (64)30
CH3
4-OCH3C6H4
3-Indolyl
4-Pyridyl
1-Methyl-3-indolyl
C6H5
4-ClC6H4
4-OCH3C6H4
C6H5
4-ClC6H4
NH2
C6H5
4-ClC6H4
3-Indolyl
C6H5
1-Methyl-3-indolyl
C6H5
4-ClC6H4
4-Pyridyl
C6H5
4-ClC6H4
4-Pyridyl
4-ClC6H4
4-Pyridyl
C6H5
99–100 (98–99)25
278–279
108–109
90–91
CH3
CH3
CH3
COCH3
COCH3
COCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
68–70 (70–71)25
113–114 (114)25
89 (88–89)25
3j
3k
3l
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
1-PhSO2-3-indolyl
1-PhSO2-3-indolyl
C6H5
126–127 (127–129)24
140–141(139–140)25
205–206 (206–208)24
130–132 (131–132)24
144–145 (145)25
248–249
3m
3n
3o
3p
3q
3r
3s
4a
4b
4c
4d
4e
4f
182–184
156–158
166–167 (168)24
264–265 (263–265)29
238–240 (237–240)29
277–279 (278–279)29
190–191
C6H5
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
227–229
233–235
4g
4h
4i
H
H
H
246–248
177–179 (178–179)29
a
Isolated yields.

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δ
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δ
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Figure 1. Proposed water mediated construction of diarylazoles 3 and 4.
Reported protocols are plagued by poor yields and require-
ments of higher temperatures. We report the formation of diary-
limidazoles 4 by reacting a-tosyloxyketones 1 with amidines 2 in
benign solvent, water. Our initial attempts to achieve this conden-
sation reaction in aqueous medium were unsuccessful at room
temperature. However, reactions proceeded smoothly at 80 °C
and further increase of temperature resulted only in the formation
of undesired products. Syntheses of diarylimidazoles were also
investigated in different organic solvents, such as THF, CHCl3, and
DMF (Table 1). Under similar reaction conditions in organic sol-
vents poor yields and prolonged reaction timings were observed.
We have synthesized a library of diarylimidazoles 4 (Table 2) using
the optimized reaction conditions. Reaction of pyridylamidine with
19. (a) Ju, Y.; Varma, R. S. Tetrahedron Lett. 2005, 46, 6011; (b) Kumar, D.; Reddy, V.
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50, 2065.
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a-tosyloxyketones having electron-donating groups resulted in
lower yields. Over all, yields are lower in case of diarylimidazoles
as compared to diarylthiazoles, possibly due to the enhanced
nucleophilicity of sulfur in thioamides when compared to nitrogen
amidines. All the synthesized compounds were characterized by IR,
1H NMR and Mass spectral data.31
In conclusion, we have developed a simple and greener ap-
proach for the synthesis of bioactive molecules, diarylthiazoles
and diarylimidazoles in good yields. Protocol is highly efficient
and facile in water as solvent and reaction promoter. The advan-
tages of the reaction conditions include no metal reagents, avoid-
ance of toxic, volatile, and corrosive organic solvents and the
relative ease of safe experimental procedures. This method is a
useful and attractive strategy to generate a diverse array of bioac-
tive thiazoles and imidazoles under eco-friendly conditions.
29. Zhang, P.; Chen, Z. Synth. Commun. 2001, 31, 415.
30. Manaka, A.; Sato, M. Synth. Commun. 2005, 35, 761.
31. General experimental procedure: To a stirred solution of aryl thioamide or
amidine (1 mmol) in 5 mL distilled water was added
a-tosyloxyketone
(1 mmol) and the reaction mixture stirred at 60 °C or 80 °C till completion.
Progress of the reaction was monitored by thin layer chromatography. After
completion of the reaction, product was readily filtered and recrystallized
from ethanol (3a–k, 3p–o and 4a–e). In some cases (3l–m and 4f–i) product
was extracted with dichloromethane (25 mL), washed with brine (25 mL),
the organic layers were combined, dried over anhydrous Na2SO4 and
distilled off in vacuum. The residue so obtained was purified by column
chromatography on silica gel (100–200 mesh) (EtOAc/Hexane) to give pure
product. Analytical data for some representative compounds. 3f: Off-white
Acknowledgments
solid; IR (KBr): 3132, 1595;1539, 1435, 1340, 734, 679 cmÀ1
;
1H NMR
Authors acknowledge financial support from UGC-SAP (level-1),
New Delhi and M.K. is thankful to the Council of Scientific and
Industrial Research, New Delhi for Senior Research Fellowship.
(400 MHz, CDCl3): d 11.80 (s, 1H), 8.34–8.31 (m, 1H), 8.16 (d, J = 2.8 Hz, 1H),
8.09 (d, J = 8.03, 1H), 7.94 (s, 1H), 7.52–7.47 (m, 3H), 7.26–7.21 (m, 2H), 7.13
(d, J = 7.8 Hz, 2H); MS (FAB) m/z calculated for
observed 276.30. 3h: Pale yellow solid; IR (KBr): 3032, 1623, 1580, 1484,
1325, 734 cmÀ1 1H NMR (400 MHz, CDCl3): d 8.28 (s, 1H), 7.97–7.94 (m,
2H), 7.74 (s, 1H), 7.40–7.36 (m, 3H), 7.26–7.16 (m, 4H), 3.74 (s, 3H); MS
(FAB) m/z calculated for
18H14N2S (M+H)+ 291.10, observed 291.0. 3q:
White solid; IR (KBr): 3145, 1650, 1426, 1380, 690 cmÀ1 1H NMR (400 MHz,
C
17H12N2S (M)+ 276.07,
;
References and notes
C
;
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(m, 1H), 8.00 (s, 1H), 7.59–7.47 (m, 2H), 7.27–7.21 (m, 2H), 7.12 (d,
J = 7.8 Hz, 2H); MS (FAB) m/z calculated for
observed 310.06. 3r: Off-white solid; IR (KBr) 3130, 1625, 1460, 1176,
979, 688 cmÀ1 1H NMR (400 MHz, CDCl3): d 8.09 (s, 1H), 8.05 (d, J = 9.1 Hz,
C
17H11ClN2S (M)+ 310.03,
;
1H), 7.98–8.01 (m, 3H), 7.87 (d, J = 3.4 Hz, 1H), 7.89 (s, 1H), 7.48–7.38 (m,
5H), 7.37 (s, 1H), 7.32–7.28 (m, 3H); MS (FAB) m/z calculated for
C
23H16N2O2S2 (M+Na)+ 439.05, observed 439.1. 4f: White solid; IR (KBr)
3213, 1607, 1534, 1488, 1315, 692 cmÀ1 1H NMR (400 MHz, CDCl3): d 8.06–
;
8.01 (m, 2H), 7.94 (d, J = 8.7 Hz, 2H), 7.47–7.40 (m, 4H), 7.34–7.30 (m, 2H),
MS (FAB) m/z calculated for C14H10ClN3 (M+H)+ 256.06, observed 255.8. 4g:

1986
D. Kumar et al. / Tetrahedron Letters 52 (2011) 1983–1986
White solid; IR (KBr) 3195, 1660, 1520, 1465, 1245, 827, 692 cmÀ1
;
1H NMR
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Chen, Z.-C. Synthesis 2001, 2075; (e) Makoto, U.; Hideo, T. Synthesis 2004, 2673.
(400 MHz, CDCl3): d 7.78 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.42–7.28
(m, 3H), 7.24 (s, 1H), 6.92 (d, J = 8.20 Hz, 2H), 3.75 (m, 3H); MS (FAB) m/z
calculated for
C
16H13ClN2O (M+H)+ 285.08, observed 285.08. 4h: White
solid; (KBr) 3150, 1660, 1580, 1470, 1280, 690 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d 7.96 (d, J = 9.6 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.41–7.36 (m, 3H),
7.27 (s, 1H), 6.90 (d, J = 9.2 Hz, 2H), 3.79 (s, 3H); MS (FAB) m/z calculated for
C
15H13N3O (M+H)+ 252.1, observed 252.4.