Waste-free and environment-friendly uncatalyzed synthesis of dithiocarbamates under solvent-free conditions

Article abstract of DOI:10.1055/s-2007-991085

A mild, convenient, and practical one-pot procedure for the direct synthesis of dithiocarbamates has been developed by condensation of amines, CS₂, and a Michael acceptor, under solvent-free conditions at room temperature in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991085

LETTER
2797
Waste-Free and Environment-Friendly Uncatalyzed Synthesis of
Dithiocarbamates under Solvent-Free Conditions
Synthesisof
Dithi
a
ocarbamate
j
s
medin Azizi,*b Forogh Ebrahimi,a Elham Aakbari,a Fezzeh Aryanasab,a Mohammad R. Saidi*a
a
Department of Chemistry, Sharif University of Technology, 11365 Tehran, Iran
Fax +98(21)66012983; E-mail: saidi@sharif.edu
b
Chemistry and Chemical Engineering Research Center of Iran, 14335 Tehran, Iran
Received 24 January 2007
as urethane in alcoholic medium. Furthermore, their reac-
tions require toxic reagents and harmful organic solvents
such as DMF and DMSO with limited substrate and
moderate yields.
Abstract: A mild, convenient, and practical one-pot procedure for
the direct synthesis of dithiocarbamates has been developed by con-
densation of amines, CS2, and a Michael acceptor, under solvent-
free conditions at room temperature in good to excellent yields.
Key words: amines, dithiocarbamates, solvent-free, carbon disul- In continuation of our research interest for developing
green organic chemistry by using water10 as reaction
fide, waste-free
medium or by performing organic transformations under
solvent-free conditions,11 recently, we have reported the
use of water as reaction medium and activator to produce
dithiocarbamate in efficient manner, from amine, CS2,
and enones.10b Although this methodology is very mild
and novel, the yields are low and in a few cases organic
solvent was used. We have decided to investigate an alter-
native synthesis of dithiocarbamates by performing the
process in the absence of any organic solvent.
The development of solvent-free organic synthetic meth-
ods has become an important research area, since it pre-
serves the environment and develops procedures that are
both environmentally and economically feasible.1 Among
the most promising ways to reach this goal, solvent-free
techniques hold a strategic position, since solvents are
very often toxic, expensive, and problematic to use and to
remove after the reaction. So it is the main reason for the
development of such techniques, especially in the context
of current green chemistry.2
As a model reaction, chalcone was reacted with CS2 and
diethyl amine with different loading of starting materials.
It was found that by simple mixing of chalcone (4 mmol),
CS2 (5 mmol) and diethyl amine (4.5 mmol), the corre-
sponding dithiocarbamate was afforded in 97% yield
(Scheme 1).
Dithiocarbamates are ubiquitous in many biologically im-
portant compounds,3 and have a variety of applications in
agriculture4 as pesticides, as well as in the rubber indus-
tries as vulcanization accelerators and antioxidants.5 Be-
cause they have strong metal-binding capacity, they can
act as inhibitors of enzymes and have a profound effect on
biological systems, and are widely used in medicinal
chemistry and cancer treatment.6 The biological activities
of dithiocarbamates are increased when they are in the
form of heavy-metal salts as versatile classes of ligands
with the ability to stabilize transition metals in a wide
range of oxidation states and efficient ligands in surface
science and nanomaterial chemistry.7
S
Ph
O
H
O
N
CS2, neat
+
Ph
N
S
Ph
Ph
0 °C to r.t., 8 h
97%
Scheme 1
To explore the scope of this new three-component cou-
pling, we investigated different amines and Michael
acceptor. This procedure is quite general, and a wide
range of structurally varied amines such as primary, allyl-
ic, benzylic, hindered and unhindered secondary and ter-
tiary alkyl primary amines were used in this protocol with
excellent results. Generally, secondary amines such as
pyrrolidine, piperidine, and diethylamine show higher
yields compared with the primary amines. Primary amines
such as benzylamine and n-butylamine, sec-butylamine
and hindered amine such as tert-butylamine undergo
efficient addition with Michael acceptors to give the cor-
respondinding dithiocarbamate with excellent results.
However, aromatic amines such as aniline did not partici-
pate in this reaction and give the corresponding products
in very low yields (Table 1). With regard to Michael ac-
ceptors, the reactions proceeded smoothly with electron-
Therefore, the syntheses of biologically important thio-
carbamates have received considerable attention, and
there are few reports for the synthesis of dithiocarbamate
derivatives in the literature. Among them, reaction of
amine with costly and toxic reagents, such as thiophos-
gene and isothiocyanate, is reported as a general route.8 A
one-pot reaction of amines with carbonyl sulfide and
Michael acceptor in organic solvent has also been devel-
oped.9 However, many isothiocyanates are hazardous and
tedious to prepare and display poor long-term stability and
they are associated with formation of side products such
SYNLETT 2007, No. 18, pp 2797–2800
x
x
.x
x
.2
0
0
7
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-991085; Art ID: D02407ST
© Georg Thieme Verlag Stuttgart · New York

2798
N. Azizi et al.
LETTER
Table 1 One-Pot Synthesis of Dithiocarbamates Under Solvent-Free
deficient olefins such as methyl vinyl ketone, chalcone,
methyl acrylate, and acrylonitrile to afford the corre-
sponding Michael adducts in good to excellent yields.
Conditions13 (continued)
S
R3
CS2, 0 °C to r.t.
1–12 h
X
X
R1R2N
S
R1R2NH
+
R3
Table 1 One-Pot Synthesis of Dithiocarbamates Under Solvent-Free
Conditions13
80–97%
X = COOMe, COPh, COMe, CONH2, CN
S
R3
CS2, 0 °C to r.t.
1–12 h
X
X
Entry Michael acceptor
Amine (R1R2NH)
Yield (%)
90
R1R2N
S
R1R2NH
+
R3
Me
80–97%
NH
19
X = COOMe, COPh, COMe, CONH2, CN
O
Entry Michael acceptor
1
Amine (R1R2NH)
Yield (%)
97
NH
20
21
82
92
NH
NH
NH
2
3
90
97
CN
22
23
82
76
NH2
NH
Ph
NH2
NH2
24
25
76
94
4
5
6
84
90
80
NH2
NH2
NH2
NH2
NH2
26
27
84
92
7
8
84
90
Ph
NH2
NH2
NH2
O
NH
28
96
92
92
9
80
Ph
Ph
NH
NH
29
30
NH2
10
11
12
13
14
84
97
94
97
82
NH
OMe
NH
O
21
32
80
84
Ph
NH2
NH
NH2
33
34
35
36
37
80
90
84
82
12
NH
NH2
NH2
NH2
NH
O
15
16
85
92
Ph
NH2
NH
NH2
NH2
NH
17
18
88
78
OMe
PhNH2
O
NH
Synlett 2007, No. 18, 2797–2800 © Thieme Stuttgart · New York

LETTER
Synthesis of Dithiocarbamates
2799
(4) (a) Chen-Hsien, W. Synthesis 1981, 622. (b) Mizunom, T.;
Nishiguchi, I.; Okushi, T.; Hirashima, T. Tetrahedron Lett.
1991, 32, 6867. (c) Chen, Y. S.; Schuphan, I.; Casida, J. E.
J. Agric. Food Chem. 1979, 27, 709. (d) Rafin, C.; Veignie,
E.; Sancholle, M.; Postal, D.; Len, C.; Villa, P.; Ronco, G. J.
Agric. Food Chem. 2000, 48, 5283.
(5) (a) Nieuwenhuizen, P. J.; Ehlers, A. W.; Haasnoot, J. G.;
Janse, S. R.; Reedijk, J.; Baerends, E. J. J. Am. Chem. Soc.
1999, 121, 163. (b) Thorn, G. D.; Ludwig, R. A. The
Dithiocarbamates and Related Compounds; Elsevier:
Amsterdam, 1962. (c) Nice, H. R. Org. React. 1962, 12, 57;
and references cited therein.
Generally, the reaction is experimentally simple and pro-
ceeding well under solvent-free conditions without using
a catalyst at room temperature and generating virtually no
byproducts. This methodology is compatible with various
a,b-unsaturated ketones, esters, nitriles, amides, and dif-
ferent substituted amines under mild reaction conditions.
Equally important is the wide scope, high selectivity, and
nearly quantitative yields of this transformation, which
lead to significant structural diversity in the products, that
is not possible with the older procedures.
In summary, we have described a novel system that is
quite effective and entirely green procedure for the
synthesis of dithiocarbamates at room temperature. The
mild reaction conditions, enhanced reaction rates, clean
reaction profiles, operational and experimental simplicity,
and with options of further transformations of the
resulting dithiocarbamates into synthetically interesting
biologically active compounds, this synthetic methodolo-
gy is ideally suited for automated applications in organic
synthesis.
(6) (a) Ronconi, L.; Marzano, C.; Zanello, P.; Corsini, M.;
Miolo, G.; Macca, C.; Trevisan, A.; Fregona, D. J. Med.
Chem. 2006, 49, 1648. (b) Walter, W.; Bode, K.-D. Angew.
Chem., Int. Ed. Engl. 1967, 6, 281. (c) Elgemeie, G. H.;
Sayed, S. H. Synthesis 2001, 1747.
(7) (a) Hogarth, P. G. Inorg. Chem. 2005, 53, 7. (b) Zhao, Y.;
Perez-Segarra, W.; Shi, Q.; Wei, A. J. Am. Chem. Soc. 2005,
127, 7328. (c) Griffin, T. S.; Woods, T. S.; Klayman, D. L.
In Advances in Heterocyclic Chemistry, Vol. 18; Katritzky,
A. R.; Boulton, A. J., Eds.; Academic Press: New York,
1975, 99.
(8) (a) Tilles, H. J. Am. Chem. Soc. 1959, 81, 714. (b) Chin-
Hsien, W. Synthesis 1981, 622. (c) Sugiyama, H. J. Synth.
Org. Chem. Jpn. 1980, 38, 555. (d) Walter, W.; Bode, K.-D.
Angew. Chem., Int. Ed. Engl. 1967, 6, 281.
(9) (a) Guo, B.; Ge, Z.; Chang, T.; Li, R. Synth. Commun. 2001,
31, 3021. (b) Ziyaei-Halimjani, A.; Saidi, M. R. J. Sulfur
Chem. 2005, 26, 149.
(10) (a) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649.
(b) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi,
M. R. J. Org. Chem. 2006, 71, 3634. (c) Azizi, N.;
Torkiyan, L.; Saidi, M. R. Org. Lett. 2006, 8, 2079.
(d) Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Biomol.
Chem. 2006, 4, 4275.
(11) (a) Azizi, N.; Saidi, M. R. Eur. J. Org. Chem. 2003, 4630.
(b) Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383.
(c) Azizi, N.; Saidi, M. R. Organometallics 2004, 23, 1457.
(d) Azizi, N.; Yousefi, R.; Saidi, M. R. J. Organomet. Chem.
2006, 691, 817.
General Procedure for the One-Pot Reaction of Amines, CS2,
and Michael Acceptor Under Solvent-Free Conditions
Amine (4.5 mmol) was added slowly to the mixture of CS2 (5
mmol) and the Michael acceptor (4 mmol) into a test tube in an ice
bath12 and the reaction mixture was stirred at 0 °C for 30 min. Then,
the mixture was warmed to r.t. and stirred for another 1–12 h. After
completion of the reaction, the excess of CS2 and amine was re-
moved under reduced pressure to give the dithiocarbamates in the
almost pure form. The crude product was analyzed by 1H NMR and
13C NMR. In some cases, further purification was carried out by re-
crystallization or short-column chromatography on silica gel
(EtOAc–PE). All compounds were characterized on the basis of
1
NMR spectroscopic data (in the case of primary amines, the H
NMR spectra shows mixture of E- and Z-isomers).
(12) The reaction was very exothermic and should be controlled
by slow addition of amine and maintaining the temperature
by using an ice bath.
Acknowledgment
We are grateful to the Sharif University of Technology Research
Council and Chemistry and Chemical Research Center of Iran for
financial support of this research.
(13) Selected Spectroscopic Data
Table 1, Entry 1: 1H NMR (500 MHz, CDCl3): d = 0.92–
0.96 (6 H, m), 2.53 (2 H, t, J = 6.7 Hz), 3.12 (2 H, t, J = 6.2
Hz), 3.42 (2 H, q, J = 6.7 Hz), 3.67 (2 H, t, J = 6.7 Hz).
13C NMR (125 MHz, CDCl3): d = 9.4, 11.7, 18.2, 32.0, 47.2,
49.9, 118.6, 192.7.
References and Notes
Table 1, Entry 2: 1H NMR (500 MHz, CDCl3): d = 1.30–
1.51 (6 H, m), 2.74 (2 H, t, J = 6.2 Hz), 3.39 (2 H, t, J = 6.3
Hz), 3.75 (2 H, m), 4.12 (2 H, m). 13C NMR (125 MHz,
CDCl3): d = 18.5, 25.9, 32.2, 51.9, 53.4, 54.2, 118.7, 193.0.
Anal. Calcd (%) for C9H14N2S2: C, 50.43; H, 6.58; N, 13.07.
Found: C, 50.80; N, 12.92; H, 6.62.
(1) (a) Chakraborti, A. K.; Shivani, G. R. J. Org. Chem. 2006,
71, 5785. (b) Tucker, J. L. Org. Process Res. Dev. 2006, 10,
315. (c) Sikchi, S. A.; Hultin, P. G. J. Org. Chem. 2006, 71,
5888.
(2) (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
(b) Shibahara, F.; Nozaki, K.; Hiyama, T. J. Am. Chem. Soc.
2003, 125, 8555.
(3) (a) Caldas, E. D.; Hosana Conceicüa, M.; Miranda, M. C. C.;
Souza, L.; Lima, J. F. J. Agric. Food Chem. 2001, 49, 4521.
(b) Erian, A. W.; Sherif, S. M. Tetrahedron 1999, 55, 7957.
(c) Wood, T. F.; Gardner, J. H. J. Am. Chem. Soc. 1941, 63,
2741. (d) Beji, M.; Sbihi, H.; Baklouti, A.; Cambon, A. J.
Fluorine Chem. 1999, 99, 17.
Table 1, Entry 3: 1H NMR (500 MHz, CDCl3): d = 1.72–
1.92 (4 H, m), 2.66 (2 H, t, J = 6.5 Hz), 3.29 (2 H, t, J = 6.5
Hz), 3.43 (2 H, t, J = 6.7 Hz), 3.64 (2 H, t, J = 6.7 Hz).
13C NMR (125 MHz, CDCl3): d = 18.6, 24.5, 26.2, 31.6,
51.1, 53.9, 55.5, 118.7, 190.0. Anal. Calcd for C8H12N2S2: C,
47.97; H, 6.04; N, 13.98. Found: C, 48.30; H, 5.82, N, 13.69.
Table 1, Entry 7: 1H NMR (500 MHz, CDCl3): d = 2.82 (2
H, t, J = 6.2 Hz), 3.46 (2 H, t, J = 6.3 Hz), 4.88 (2 H, s),
7.26–7.39 (5 H, m), 8.02 (1 H, br s, NH). 13C NMR (125
MHz, CDCl3): d = 18.9, 31.4, 51.5, 119.0, 128.3, 128.8,
129.7, 136.5, 196.0.
Synlett 2007, No. 18, 2797–2800 © Thieme Stuttgart · New York

2800
N. Azizi et al.
LETTER
Table 1, Entry 10: 1H NMR (500 MHz, CDCl3): d = 0.77 (3
H, t, J = 7.3 Hz), 1.07 (3 H, d, J = 6.4 Hz), 1.41–1.51 (4 H,
m), 2.65 (2 H, t, J = 6.6 Hz), 3.35 (2 H, J = 6.7 Hz), 4.37–
4.38 (1 H, m), 7.73 (1 H, br s, NH). 13C NMR (125 MHz,
CDCl3): d = 10.8, 18.5, 19.4, 29.7, 31.1, 55.1, 55.2, 119.1,
194.3.
MHz, CDCl3): d = 10.6, 20.9, 29.1, 30.9, 34.2, 52.1, 54.7,
54.8, 172.8, 196.0.
Table 1, Entry 19: 1H NMR (500 MHz, CDCl3): d = 1.01–
1.06 (6 H, m), 1.94 (3 H, s), 2.72 (2 H, t, J = 6.6 Hz), 3.23 (2
H, t, J = 6.6 Hz), 3.52 (2 H, q, J = 7.1 Hz), 3.79 (2 H, q,
J = 7.1 Hz). 13C NMR (125 MHz, CDCl3): d = 11.8, 12.7,
30.1, 30.6, 43.3, 46.9, 49.6, 195.2, 206.9.
Table 1, Entry 11: 1H NMR (500 MHz, CDCl3): d = 0.93–
0.99 (6 H, m), 2.47 (2 H, t, J = 6.4 Hz), 3.20 (2 H, t, J = 6.5
Hz), 3.44 (3 H, s), 3.45 (2 H, q, J = 6.9 Hz), 3.70 (2 H, q,
J = 6.9 Hz). 13C NMR (125 MHz; CDCl3): d = 11.7, 12.9,
31.7, 33.9, 46.9, 49.6, 51.6, 171.9, 194.4.
Table 1, Entry 21: 1H NMR (500 MHz, CDCl3): d = 1.38–
1.76 (7 H, m), 2.53 (2 H, t, J = 6.1 Hz), 3.01–3.44 (6 H, m).
13C NMR (125 MHz, CDCl3): d = 23.8, 25.9, 29.9, 43.1,
50.7, 55.1, 191.7, 206.3. Anal. Calcd (%) for C9H15NOS2: C,
49.73; H, 6.96; N, 6.44. Found: C, 49.53; H, 6.82; N, 6.61.
Table 1, Entry 25: 1H NMR (500 MHz, CDCl3–CCl4):
d = 1.58 (3 H, d, J = 6.8 Hz), 2.14 (3 H, s), 2.89 (2 H, t,
J = 6.1 Hz), 3.40 (2 H, t, J = 6.1 Hz), 5.81 (1 H, q, J = 6.8
Hz), 7.26–7.35 (5 H, m), 8.18 (1 H, br s, NH). 13C NMR (125
MHz, CDCl3): d = 21.3, 29.0, 30.4, 43.3, 56.4, 127.0, 128.2,
129.3, 141.7, 196.8, 207.6.
Table 1, Entry 12: 1H NMR (500 MHz, CDCl3): d = 1.41–
1.47 (6 H, m), 2.53 (2 H, t, J = 6.4 Hz), 3.42–4.01 (9 H, m).
13C NMR (125 MHz, CDCl3): d = 24.5, 25.8, 31.8, 34.0,
44.3, 51.5, 51.8, 52.9, 172.1, 194.5. Anal. Calcd (%) for
C10H17NO2S2: C, 48.55; N, 5.66; H, 6.93. Found: C, 48.70;
N, 5.79; H, 6.95.
Table 1, Entry 13: 1H NMR (500 MHz, CDCl3): d = 1.76–
1.86 (4 H, m), 2.57 (2 H, t, J = 6.7 Hz), 3.28–3.46 (7 H, m),
3.64–3.66 (2 H, m). 13C NMR (125 MHz, CDCl3): d = 24.5,
26.3, 31.2, 34.1, 50.8, 51.8, 55.2, 172.3, 191.7.
Table 1, Entry 28: 1H NMR (500 MHz, CDCl3): d = 1.26–
1.31 (6 H, m), 3.68–4.21 (6 H, m), 5.76 (1 H, dd, J = 4.1,
10.2 Hz), 7.24–7.69 (8 H, m), 8.00–8.01 (2 H, m). 13C NMR
(125 MHz, CDCl3): d = 127.9, 128.5, 128.7, 129.1, 129.6,
134.1, 137.6, 140.8, 190.8, 197.4.
Table 1, Entry 15: 1H NMR (500 MHz, CDCl3): d = 2.82 (2
H, t, J = 6.7 Hz), 3.52 (2 H, t, J = 6.7 Hz), 3.67 (3 H, s), 4.90
(2 H, s), 7.33–7.35 (5 H, m), 7.90 (1 H, br s, NH). 13C NMR
(125 MHz, CDCl3): d = 30.3, 34.6, 51.4, 52.3, 128.3, 128.6,
129.3, 135.7, 172.8, 197.7.
Table 1, Entry 30: 1H NMR (500 MHz, CDCl3): d = 1.93–
2.05 (4 H, m), 3.58–4.02 (6 H, m), 5.83 (1 H, dd, J = 4.1, 9.8
Hz), 7.27–7.56 (8 H, m), 8.00 (2 H, d, J = 7.3 Hz). 13C NMR
(125 MHz, CDCl3): d = 24.6, 26.5, 51.0, 54.6, 55.3, 128.0,
128.6, 128.8, 129.0, 129.4, 133.6, 137.0, 140.0, 191.5,
197.4.
Table 1, Entry 17: 1H NMR (500 MHz, CDCl3): d = 0.89 (3
H, t, J = 7.2 Hz), 1.19 (3 H, d, J = 5.3 Hz), 1.51–1.61 (2 H,
m), 2.74 (2 H, t, J = 6.8 Hz), 3.44 (2 H, t, J = 6.8 Hz), 3.66
(3 H, s), 4.52 (1 H, m), 7.38 (1 H, br s, NH). 13C NMR (125
Synlett 2007, No. 18, 2797–2800 © Thieme Stuttgart · New York

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