Synthesis of alkyl dithiocarbamates by using thiuram disulfide reagents: A metal-free C(sp3)-S bond formation

Article abstract of DOI:10.1016/j.tetlet.2019.01.044

An efficient and environmentally benign protocol for the synthesis of S-alkyl dithiocarbamates has been achieved. By reacting tetraalkylthiuram disulfides with alkyl halides, the desired products could be obtained in good to excellent yields. The methodol

Full text of DOI:10.1016/j.tetlet.2019.01.044

Accepted Manuscript
Synthesis of Alkyl Dithiocarbamates by Using Thiuram Disulfide Reagents: a
Metal-free C(sp3)-S Bond Formation
Yu Cheng, Han-Ying Peng, Zhi-Bing Dong
PII:
S0040-4039(19)30070-X
https://doi.org/10.1016/j.tetlet.2019.01.044
TETL 50577
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
13 November 2018
7 January 2019
22 January 2019
Please cite this article as: Cheng, Y., Peng, H-Y., Dong, Z-B., Synthesis of Alkyl Dithiocarbamates by Using
Thiuram Disulfide Reagents: a Metal-free C(sp3)-S Bond Formation, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.01.044
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Synthesis of Alkyl Dithiocarbamates by
Using Thiuram Disulfide Reagents:a
Metal-free C(sp3)-S Bond Formation
Leave this area blank for abstract info.
Yu Chenga, Han-Ying Penga, Zhi-Bing Donga,b*

1
Tetrahedron Letters
Synthesis of Alkyl Dithiocarbamates by Using Thiuram Disulfide Reagents: a
Metal-free C(sp3)-S Bond Formation
Yu Chenga, Han-Ying Penga, Zhi-Bing Donga,b*
aSchool of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, China.
bDepartment of Chemistry, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 München, Germany.
Email: dzb04982@wit.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and environmentally benign protocol for the synthesis of S-alkyl
dithiocarbamates has been achieved. By reacting tetraalkylthiuram disulfides with
alkyl halides, the desired products could be obtained in good to excellent yields. The
methodology features efficiency, transition-metal-free, nice yields and easy
performance, illustrating it practical synthetic value for the convenient preparation of
some potential biologically active molecules.
Available online
Keywords:
alkyl
2009 Elsevier Ltd. All rights reserved.
dithiocarbamate
C-S coupling
synthesis
metal-free
1. Introduction
between tosylates and carbon disulfide under Triton-B catalyzed
conditions as well as between mercaptans and isothiocyanates are
optional ways for their preparation.[14-15] In addition,
1-(methyldithiocarbonyl)imidazole could be applied as
thiocarbonyl transfer reagent to react with amines to give alkyl
dithiocarbamates.[16] There is also a procedure involving the
reaction of tetramethylthiuram disulfide with organozinc or
organolithium reagents which are sensitive to air and moisture.[17]
However, these methods suffer from the utilization of irritating
and flammable dialkyl amines, volatile and flammable carbon
disulfide, smelling mercaptans, as well as pre-synthesized
organozinc reagents (Scheme 2).
Organic dithiocarbamates are very important compounds and
ubiquitous structural motifs found in biologically active
molecules.[1-4] Among these, alkyl dithiocarbamates have
received much attention by synthetic chemists since they have
many applications in pharmaceuticals and agrochemicals
(Scheme 1),[5] serving as repellents,[6] herbicides,[7] and
fungicides.[8] Alkyl dithiocarbamates acting as ligand can be
complexed with gold(I) and gold(III) to give gold complexes,
which are potential antineoplastic agents.[9] In addition, alkyl
dithiocarbamates are also applied as models for drug metabolites
in the area of bioanalytical chemistry.[10]
Scheme 2. Existing methods for the synthesis of alkyl
Scheme 1. Applications of alkyl dithiocarbamates.
dithiocarbamates.
Due to the potential of the alkyl dithiocarbamates, various
methods have been reported for their preparation (Scheme 2).
General methods are one-pot (three-component) reactions of
amines, carbon disulfide with electrophiles, such as alkyl boronic
acids, alkyl halides, and allyl acetates.[11-13] The reactions
To develop a more practical and economic methodology for
the synthesis of dithiocarbamates, we previously reported the
C(sp2)-S formation by the S-arylation of tetramethylthiuram
disulfide (TMTD) with aryl halides, aryl boronic acids or
diaryliodonium salts.[18] Based on our longstanding interests in

2
the research of organosulfur compounds and relevant
applications,[19] we herein demonstrate an efficient and practical
method for the synthesis of S-alkyl dithiocarbamates via C(sp3)-S
coupling (Scheme 3).
13
14
15
16
17
18
19
20
21
22
23
24
-
-
-
-
-
-
-
-
-
-
-
-
Cs2CO3
Cs2CO3
KOH
CH3CN
H2O
57
13
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
65
K2CO3
NaOH
t-BuOK
CH3ONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
-
56
74
trace
37
32c
77d
62e
85f
-
Scheme 3. Synthesis of alkyl dithiocarbamates: C(sp3)-S
formation (this work).
2. Results and discussions
We began our investigations by using chlorobutane (1a) and
tetramethylthiuram disulfide (2a, TMTD) to carry out the model
reaction, and the results are summarized in Table 1. Optimization
of the reaction conditions included screening of solvents, bases,
catalysts, temperature, loading of base. For the first trial, the
desired product (3a) was obtained with moderate yield by using
CoCl2 as catalyst (Table 1, entry 1). Subsequently, a broad
screening of copper, iron, cobalt and nickel catalysts was
performed (entries 2-9), and Co(acac)2 was proved to be the best
one (entry 4). To our delight, product was obtained in good yield
(86%, entry 10) without Co(acac)2, which demonstrated that
catalyst was not crucial for the reaction. Further screening of
solvent (entries 10-14) revealed that DMSO was the most
suitable solvent, giving the desired product in 86% yield (entry
10). Then, a series of bases, such as K2CO3, t-BuOK, KOH,
NaOH and CH3ONa were surveyed (entries 15-19), the results
showed that all of these bases are not as active as Cs2CO3 (1.0
equiv). Decreasing the loading of the base would dramatically
decrease the yields (entry 20), while increasing the base loading
had no help for the yield (entry 21). The reaction could not
proceed with no addition of base (entry 24). Finally, the effect of
the temperature was checked (entries 22-23), and the results
showed that the reaction should be performed at 60oC (entry 10).
aReaction condition: 1a (1.0 mmol), 2a (1.0 mmol), catalyst (10 mol%), base
(1.0 equiv), DMSO (2mL), stirred at 60 C for 12 h. Isolated yields. With
0.5 equiv of Cs2CO3. dWith 1.2 equiv of Cs2CO3. ePerformed at room
temperature. fPerformed at 80 oC.
o
b
c
Under the optimized reaction conditions, various substituted
S-alkyl dithiocarbamates were synthesized smoothly by reacting
tetraalkylthiuram disulfides with a series of alkyl halides, and the
results are summarized in Table 2. Generally, tetraalkylthiuram
disulfides reacted with chain alkyl halides well. There is almost
no big difference for the reactivity between alkly bromides and
alkyl chlorides in this reaction. The dithiocarbamate sources
(TETD: tetraethylthiuram disulfide, TBTD: tetrabutylthiuram
disulfide) did not show obvious steric hindrance. In addition, the
cyclohexyl bromide was submitted to react with TMTD and
TETD under the standard reaction conditions and the desired
products (3z and 3zc) could be furnished in 54% and 61%,
respectively. Substrates bearing alkene, methoxyl groups all
reacted well with thiuram disulfide to give the desired products
(3za, 3zb, 3zd) in 58-83% yields, demonstrating the versatility of
our protocol.
Table 1. Optimization of the reaction conditions. a
Table 2. Synthesis of aryl dithiocarbamates starting from
alkyl halides and tetraalkylthiurams disulfides. a
Entry
1
Catalyst
CoCl2
CoBr2
Co(OAc)2
Co(acac)2
CuBr2
CuCl
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
67
39
51
85
63
74
71
70
59
86
85
57
Entry
Alkyl halide
Thiuram reagent
Product b
2
3
2a
4
1
2
1a
5
3a: 86%
6
7
Cu2O
Fe(OAc)3
NiBr2
-
2a
2a
8
1b
1c
3b: 70%
3c: 75%
9
10
11
12
3
-
-
THF

3
4
5
2a
2a
20
21
2b
2b
1i
3t: 78%
3u: 62%
1d
1e
3d: 79%
3e: 65%
1j
22
23
24
2b
2c
6
7
2a
2a
2a
1k
3v: 58%
3w: 76%
1f
3f: 57%
3g: 83%
1g
1f
8
9
2c
2c
1c
1h
1l
3h: 88%
3i: 89%
1h
1i
3x: 80%
3y: 90%
2a
2a
25
26
2a
2a
10
11
3j: 71%
3z: 54%
1j
27
28
2a
2b
2b
1m
1k
3za: 83%
3zb: 78%
3k: 62%
3l: 62%
2a
2b
1n
12
13
1f
29
30
1l
3zc: 61%
3zd: 58%
1b
1c
3m: 75%
3n: 73%
2b
1n
14
15
2b
2b
aReaction conditions: alkyl halides (1.0 mmol), tetraalkylthiuram disulfide
(1.0 mmol), Cs2CO3 (1 mmol), DMSO (2 mL), stirred at 60°C for 12 h.
bIsolated yields.
1d
1e
A control experiment was performed to investigate the reaction
mechanism (Scheme 4). It was found that the reaction was not
inhibited by radical scavengers such as TEMPO (TEMPO =
2,2,6,6-tetramethylpiperidinooxy), indicating that the mechanism
was not a radical one. The detailed reaction mechanism and the
related applications of this protocol are under research in our lab.
3o: 66%
16
17
2b
2b
3p: 71%
3q: 65%
1f
Scheme 4. Control experiment by using TEMPO as radical
scavenger.
18
19
2b
2b
1g
3r: 69%
3s: 72%
3. Conclusion
To summarize, we presented a simple and efficient method for
the preparation of alkyl dithiocarbamates. The desired products
1h

4
were furnished with good to excellent yields by treating
tetraalkylthiuram (alkly=Me, Et, nBu) disulfides with alkyl
halides in the presence of Cs2CO3/DMSO. A variety of alkyl
(propyl, butyl, sec-butyl, iso-butyl, cyclohexyl, heptyl) halides,
or substrates bearing alkene, methoxyl groups all reacted well
with thiuram disulfide to give S-alkyl dithiocarbamates smoothly.
The reaction has advantages of transition metal-free, easy
performance, versatility, nice yield and environmental
friendliness, which is expected to be useful for the preparation of
some potential biologically active molecules.
evaporated under vacuum. The residue was purified by flash
column chromatography to give the desired product.
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Acknowledgments
We thank the foundation support from National Natural
Science Foundation of China (21302150), foundation of
Chen-Guang program from Hubei Association for Science and
Technology, foundation of Chutian distinguished fellow from
Hubei Provincial Department of Education, foundation of
Highend Talent Cultivation Program from Wuhan Institute of
Technology. Z.-B. D. acknowledges the Humboldt Foundation
and China Scholarship Council for a fellowship. We thank Prof.
Dr. Aiwen Lei at Wuhan University (China) for generous NMR
analysis support.
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Experimental
All starting materials were purchased from commercial
suppliers and used without further purification unless otherwise
stated. Yields refer to isolated compounds estimated to be >95%
pure as determined by 1H NMR and capillary GC analysis. NMR
spectra were recorded on a Bruker AM400 NMR instrument in
CDCl3 using TMS as an internal standard. Chemical shifts are
given in ppm and coupling constants (J) are given in Hz.
High-resolution mass spectra (HRMS) were recorded on a
Finnigan MAT 95Q or Finnigan 90 mass instrument (ESI). TLC
was performed using aluminum plates coated with SiO2 (Merck
60, F-254) and visualized with UV light at 254 nm. Column
chromatography was performed on silica gel (200-300 mesh)
with PE (petroleum ether)-EtOAc as eluent.
Typical Procedure for the Preparation of Alkyl dithiocarbamate
(TP).
Alkyl halide (1; 1.0 mmol), tetraalkylthiuram disulfide (2;
1.0 mmol), and Cs2CO3 (1.0 mmol) were added to a dried sealed
tube equipped with a septum and magnetic stirring bar, DMSO (2
mL) was then added. The mixture was stirred at 60°C, and the
reaction progress was checked by TLC until the starting material
was finished (around 12 h). The mixture was then cooled to room
temperature and the reaction was quenched with sat. NH4Cl
solution (5 mL), extracted with ethyl acetate. The organic phase
was dried over anhydrous Na2SO4, and the solvents were
19. (a) Xu W, Zeng MT, Liu M, Liu X, Chang CZ, Zhu H, Li YS, Dong ZB.
Chem. Lett. 2017; 46: 641-643. (b) Zhu H, Liu X, Chang CZ, Dong ZB.
Synthesis 2017; 49: 5211-5216. (c) Dong ZB, Wang M, Zhu H, Liu X,
Chang CZ. Synthesis 2017; 49: 5258-5262. (d) Liu M, Zeng MT, Xu W,
Wu L, Dong ZB. Tetrahedron Lett. 2017; 58: 4352-4356. (e) Xu W,
Zeng MT, Liu SS, Li YS, Dong ZB. Tetrahedron Lett. 2017; 58:
4289-4292.

5
*Highlights:
●30 Alkyl Dithiocarbamate derivatives are synthesized in good to excellent yields.
● The substrates are cheap and environmentally benign.
●The methodology features efficiency, transition-metal-free and easy performance.