Dithiocarbamates as an efficient intermediate for the synthesis of 2-(alkylsulfanyl)thiazoles in water

Article abstract of DOI:10.1016/j.tetlet.2016.01.045

A simple, green and high-yielding procedure for the synthesis of 4-substituted-2-(alkylsulfanyl)thiazoles from the reaction of dithiocarbamates and α-halocarbonyl containing compounds in water is described. Also, a one-pot, two-step procedure for the synt

Full text of DOI:10.1016/j.tetlet.2016.01.045

Accepted Manuscript
Dithiocarbamates as an efficient intermediate for the synthesis of 2-(alkylsul-
fanyl)thiazoles in water
Azim Ziyaei Halimehjani, Leila Hasani, M. Ali Alaei, Mohammad R. Saidi
PII:
S0040-4039(16)30045-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.045
TETL 47209
Reference:
Tetrahedron Letters
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Revised Date:
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3 January 2016
Please cite this article as: Halimehjani, A.Z., Hasani, L., Ali Alaei, M., Saidi, M.R., Dithiocarbamates as an efficient
intermediate for the synthesis of 2-(alkylsulfanyl)thiazoles in water, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.01.045
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Dithiocarbamates as an efficient intermediate
for the synthesis of 2-(alkylsulfanyl)thiazoles
in water
Azim Ziyaei Halimehjani, Leila Hasani, Ali Alaei, Mohammad R. Saidi

1
Tetrahedron Letters
Dithiocarbamates as an efficient intermediate for the synthesis of 2-
(alkylsulfanyl)thiazoles in water
Azim Ziyaei Halimehjani,*,a Leila Hasani,b M. Ali Alaei,b Mohammad R. Saidi*,b
a Faculty of Chemistry, Kharazmi University, 49 Mofateh St., Tehran, Iran. Tel.: +98(21)88848949, Fax: +98(21)88820992. Email address: ziyaei@khu.ac.ir
b Department of Chemistry, Sharif University of Technology, P.O. Box 11465-9516, Tehran, Iran.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
simple, green and high-yielding procedure for the synthesis of 4-substituted-2-
(alkylsulfanyl)thiazoles from the reaction of dithiocarbamates and α-halocarbonyl containing
compounds in water is described. Also, a one-pot, two-step procedure for the synthesis of 2-
(alkylsulfanyl)thiazoles from acetophenone and dithiocarbamates was developed.
Available online
Keywords:
Dithiocarbamate
4-Substituted-2-(alkylsulfanyl)thiazole
α-Halocarbonyl compounds
Green chemistry
2009 Elsevier Ltd. All rights reserved.
Water
11
The thiazole motif is an important building block that is
present in the structure of pharmacologically active substances
and natural products.1 Compounds containing thiazole rings have
widespread biological applications as anti-inflammatory,2
antitumural,3 antiviral,4 antifungal,5 antipiron,6 herbicidal,7 and
antimicrobial agents.8 Many routes for the synthesis of thiazoles
are reported in the literature.9 Among them, the Hantzch thiazole
synthesis,9o dehydrative cyclization of α-amidoketones using
Lawesson’s reagent,9j,k reaction of thioureas with α-haloketone
derivatives9a-g,l,m and condensation of thioamides with
epoxides9p,q,r are the most reported methods.
The synthesis of organic compounds using environmentally
benign, mild, and simple procedures has received considerable
attention. Among the different branches of green chemistry,
reducing or eliminating the use of hazardous substances, or the
generation of these materials, and performing reactions in green
reaction medium have found widespread application. In this
context, water is the preferred choice as a solvent because of its
properties such as being environmentally safe, simple to handle,
and low cost.10 In addition, performing multi-step reactions in a
one-pot procedure, without the separation of intermediates which
reduces the final product yield, is in agreement with the goals of
green chemistry. Keeping these goals in mind, herein, we report a
simple one-pot procedure for the synthesis of 2-
(alkylsulfanyl)thiazoles in water with high yields.
cyclodextrin (β-CD) as a catalyst. We proposed that by using
S-alkyldithiocarbamates instead of thioamides/thiourea, 2-
(alkylsulfanyl)thiazoles could be obtained. For this purpose,
alkyldithiocarbamates were synthesized via the one-pot, three-
component reaction of aqueous ammonia, carbon disulfide, and
alkyl halides as described in the literature.12 The reaction of S-
benzyldithiocarbamate with phenacyl bromide was considered as
a model reaction for optimization of the reaction conditions. We
found that the best yield was obtained when equal amounts of
dithiocarbamate and α-bromoacetophenone were heated at reflux
in water for 20 h without any catalyst. After quenching the
reaction mixture with NaHCO3, the corresponding 4-phenyl-2-
benzylsulfanyl-thiazole was obtained by filtration or decanting.
Also, we found that while α-chloroacetophenone needed 2 days
heating at reflux to reach completion, α-bromoacetophenone
needed only 20 h. Temperature screening revealed that the best
yield was obtained at reflux.
Scheme 1. Catalyst-free synthesis of 2-alkylsulfanylthiazoles in
water.
Recently, Rao and co-workers reported an efficient procedure
for the synthesis of thiazoles and aminothiazoles from
phenacylbromide and thioamide/thiourea in water using β-

2
Tetrahedron
Table 1. Synthesis of 2-(alkylsulfanyl)thiazoles in water
Entry Dithiocarbamate α-
Halocarbonyl
Product
Yield Entry Dithiocarbamate α-
Product
Yield
(%)a,b
7516
(%)a,b
9013
Halocarbonyl
1
7
1a
1b
2
8814
78
8
8514
75
1a
1b
3
9
1a
1b
4
5
6
8315 10
8316
80
1a
1a
1a
1b
1b
1b
85
95
11
12
8917
aIsolated yield. bReaction conditions: dithiocarbamate (5 mmol), α-halocarbonyl (5 mmol), water (15 mL), reflux, 20 h.
After optimization of the reaction conditions, the generality
of these conditions was examined using various S-
alkyldithiocarbamates and α-halocarbonyl compounds (Table 1).
A proposed mechanism for this reaction is given in Scheme 3.
It is conceivable that the initial event is nucleophilic substitution
of the halide by the thiocarbonyl sulfur atom of dithiocarbamate
2 to afford intermediate A. Intramolecular addition of the
nitrogen to the carbonyl group furnishes intermediate B, which
then undergoes dehydration to afford the corresponding product
3.
All
dithiocarbamates
gave
high
yields
of
2-
(alkylsulfanyl)thiazoles using α-bromoacetophenone or α-
chloroacetone. The structures of the products were confirmed by
1
1H NMR, 13C NMR and CHN analysis. The H-NMR spectrum
showed a singlet peak around 6.7-7.4 ppm which was related to
the C-5 hydrogen of the thiazole ring. The 13C NMR spectra
clearly confirmed the product structure; the chemical shift for C-
2 of the thiazole ring was assigned to approximately 165 ppm,
while the C-4 and C-5 of the thiazole ring appeared around 155
ppm and 112 ppm, respectively.
After the successful synthesis of 2-(alkylsulfanyl)thiazoles, we
expanded our investigation for the synthesis of these compounds
via a one-pot, two-step procedure starting from acetophenone.
For this purpose, acetophenone was initially converted to the
phenacyl iodide using CuO/I2 in ethanol at reflux, followed by
the addition of S-alkyldithiocarbamates and further heating at
reflux for 2 h. We observed that high yields were obtained using
this protocol (Scheme 2). The second step of this reaction was
complete in 2 h which confirmed that the reaction rate had been
increased by increasing the leaving-group ability of the halogen.
Scheme 3. Proposed mechanism for the synthesis of thiazoles 3
In conclusion, an efficient, environmentally benign and high
yielding procedure for the synthesis of 2-(alkylsulfanyl)thiazoles
from the reaction of dithiocarbamates and α-halocarbonyl
compounds in water is described. Also, a one-pot two-step
procedure for the synthesis of 2-(alkylsulfanyl)thiazoles from
acetophenone and dithiocarbamates was developed. The
reactivity of phenacyl halides in this protocol was assigned in
order of phenacyl iodide>phenacyl bromide>phenacyl chloride.
Acknowledgment
We are grateful to the Research Council of the Sharif University
of Technology for financial support. We also thank the Faculty of
Chemistry of Kharazmi University for supporting this work.
References and notes
Scheme 2. One-pot, two-step procedure for the synthesis of 2-
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D. H. R.; Ollis, W. D., Eds.; Pergamon press; London, 1979, p 961. (b)
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3
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