SCHEME 1. Synthesis of Dithiocarbamate
One-Pot Synthesis of Dithiocarbamates
Accelerated in Water
Najmodin Azizi, Fezzeh Aryanasab, Lalleh Torkiyan,
Azim Ziyaei, and Mohammad Reza Saidi*
field of increasing interest in synthetic organic chemistry during
the past few years.
Department of Chemistry, Sharif UniVersity of Technology,
P.O. Box 11465-9516 Tehran, Iran
In fact, few methods for the synthesis of dithiocarbamate
derivatives have been reported in the literature, and among them,
reactions of amines with costly and toxic reagents, such as
thiophosgene and isothiocyanate, have been reported as the
general routes.6 Direct thiocarboxylation of amines with carbon
monoxide and sulfur to form urea derivatives has also been
reported.7 Recently, a one-pot reaction of amines with carbonyl
sulfide, alkyl halides, or R,â-unsaturated compounds also has
been developed.8 However, these reactions require very toxic
reagents and harmful organic solvents such as DMF, DMSO,
and methanol in the presence of a catalyst.
ReceiVed January 9, 2006
With the increasing interest in developing environmentally
benign reactions, the atom-economic catalytic processes, or
reactions without using any catalyst, and the use of green
solvents are ideal processes in organic chemistry. As a continu-
ation of our research devoted to the development of green
organic chemistry by using water as the reaction medium or by
performing organic transformations under solvent-free condi-
tions,9 herein we report an efficient, novel, and entirely green
procedure for the Michael-type addition of dithiocarbamate to
R,â-unsaturated compounds in water without using catalyst at
room temperature. The results of the present work show the
desired product in excellent yield (Scheme 1).
To study the Michael reaction in water, we tested the reaction
of piperidine, methyl acrylate, and carbon disulfide as a simple
model substrate and the results are shown in Table 1. It was
found that simple mixing of amine (5 mmol), carbon disulfide
(8 mmol), and methyl acrylate (6 mmol) gave the desired
product in high yields in water without any catalyst at room
temperature.
After optimizing the conditions, we next examined the
generality of these conditions to other substrates using several
amines and R,â-unsaturated compounds. The results are sum-
marized in Table 1. A variety of R,â-unsaturated carbonyl
compounds or nitriles such as methyl acrylate, acrylonitrile,
methyl vinyl ketone, and cyclohexenone underwent 1,4-addition
with a wide range of aliphatic, aromatic, primary, secondary,
and hindered amines in water at room temperature to give the
Highly efficient one-pot reactions of amines and carbon
disulfide with R,â-unsaturated compounds were carried out
in water under a mild and green procedure with high yields.
The organic reactions in aqueous media have attracted much
attention in synthetic organic chemistry, not only because water
is one of the most abundant, cheapest, and environmentally
friendly solvents but also because water exhibits unique
reactivity and selectivity, which is different from those in
conventional organic solvents. Thus, development of novel
reactivity as well as selectivity that cannot be attained in
conventional organic solvents is one of the challenging goals
of aqueous chemistry.1
Organic dithiocarbamates are valuable synthetic intermedi-
ates,2 which are ubiquitously found in a variety of biologically
active compounds.3 Functionalization of the carbamate moiety
offers an attractive method for the generation of derivatives,
which may constitute interesting medicinal and biological
properties.3 Furthermore, diarylalkyl thioureas have merged as
one of the promising nonvanilloid TRPV1 antagonists, pos-
sessing excellent therapeutic potentials in pain regulation4 and
human CB1 and CB2 cannabinoid receptor affinity.5 For these
reasons, the synthesis of dithiocarbamate derivatives with
different substitution patterns at the thiol chain has become a
* To whom correspondence should be addressed. Fax: 98-21-66005718.
Phone: 98-21-66012983.
(1) (a) Grieco, P. A. Organic Synthesis in Water; Blackie Academic and
Professional: London, 1998. (b) Demko Z. P.; Sharpless, K. B. J. Org.
Chem. 2001, 66, 7945. Li, C.-J. Chem. ReV. 2005, 105, 3095.
(2) (a) Boas, U.; Jakobsen, M. H. J. Chem. Soc., Chem. Commun. 1995,
1995. (b) Elgemeie, G. H.; Sayed, S. H. Synthesis 2001, 1747. (c) Mukerjee,
A. K.; Ashare, R. Chem. ReV. 1991, 91, 1. (d) Boas, U.; Gertz, H.;
Christensen, J. B.; Heegaard, P. M. H. Tetrahedron Lett. 2004, 45, 269.
(3) (a) Dhooghe, M.; De Kime, N. Tetrahedron 2006, 62, 513. (b)
Fernandez, J. M. G.; Mellet, C. O.; Blanco, J. L. J.; Mota, J. F.; Gadelle,
A.; Coste-Sarguet, A.; Defaye, J. Carbohydr. Res. 1995, 268, 57.
(4) Suh, Y.-G.; Lee, Y.-S.; Min, K.-H.; Park, O.-H.; Kim, J.-K.; Seung,
H.-S.; Seo, S.-Y.; Lee, B.-Y.; Nam, Y.-H.; Lee, K.-O.; Kim, H.-D.; Park,
H.-G.; Lee, J.; Oh, U.; Lim, J.-O.; Kang, S.-U.; Kil, M.-J.; Koo, J.-y.; Shin,
S. S.; Joo, Y.-H.; Kim, J. K.; Jeong, Y.-S.; Kim, S.-Y.; Park, Y.-H. J. Med.
Chem. 2005, 48, 5823.
(6) (a) Tilles, H. J. Am. Chem. Soc. 1959, 81, 714. (b) Chin-Hsien, W.
Synthesis 1981, 622.
(7) (a) Franz, R. A.; Applegath, F. J. Org. Chem. 1961, 26, 3304. (b)
Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F. J. Org. Chem
1961, 26, 3306. (c) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron 2005, 61,
9157.
(8) (a) Salvatore, R. N.; Sahaba, S.; Junga, K. W. Tetrahedron Lett. 2001,
42, 2055. (b) Buess, C. M. J. Am. Chem. Soc. 1955, 77, 6613. (c) Guo, B.;
Ge, Z.; Chang, T.; Li, R. Synth. Commun. 2001, 31, 3021. (d) Ziyaei-
Halimjani, A.; Saidi, M. R. J. Sulfur Chem. 2005, 26, 149. (e) Busque, F.;
March, P.-D.; Figueredo, M.; Font, J.; Gonzalez, L. Eur. J. Org. Chem.
2004, 1492.
(9) (a) Azizi, N.; Saidi, M. R. Organometallics 2004, 23, 1457. (b) Azizi,
N.; Saidi, M. R. Tetrahedron 2004, 60, 383. (c) Azizi, N.; Saidi, M. R.
Eur. J. Org. Chem. 2003, 4630. (d) Azizi, N.; Saidi, M. R. Org. Lett. 2005,
7, 3649.
(5) Muccioli, G. G.; Wouters, J.; Scriba, G. K. E.; Poppitz, W.; Poupaert,
J. H.; Lambert, D. M. J. Med. Chem. 2005, 48, 7486.
10.1021/jo060048g CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/16/2006
3634
J. Org. Chem. 2006, 71, 3634-3635