Copper-Catalyzed C(sp2)-S Coupling Reactions for the Synthesis of Aryl Dithiocarbamates with Thiuram Disulfide Reagents

Article abstract of DOI:10.1021/acs.orglett.7b02911

An efficient protocol for the copper-catalyzed preparation of aryl dithiocarbamates from aryl iodides and inexpensive, environmentally benign tetraalkylthiuram disulfides was developed. The features of mild reaction conditions, high yields, and broad substrate scope render this new approach synthetically attractive for the preparation of potentially biologically active compounds.

Full text of DOI:10.1021/acs.orglett.7b02911

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Copper-Catalyzed C(sp2)−S Coupling Reactions for the Synthesis of
Aryl Dithiocarbamates with Thiuram Disulfide Reagents
Zhi-Bing Dong,*,†,‡ Xing Liu,† and Carsten Bolm*,‡
†School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, China
‡Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany
S
* Supporting Information
ABSTRACT: An efficient protocol for the copper-catalyzed preparation of aryl dithiocarbamates from aryl iodides and
inexpensive, environmentally benign tetraalkylthiuram disulfides was developed. The features of mild reaction conditions, high
yields, and broad substrate scope render this new approach synthetically attractive for the preparation of potentially bio-
logically active compounds.
Scheme 1. Synthetic Challenge and Presented Solution
hiuram reagents 1 are cheap and commercially avail-
T
able organosulfur compounds with broad applications as
fungicides, animal repellants, and vulcanization accelerators.1
Because they are so readily available, we regard them as inter-
esting reagents for the development of new synthetic trans-
formations.
Organic dithiocarbamates 2 have received considerable atten-
tion because of their occurrence in a variety of biologically
active compounds,2 their pivotal role in agriculture,3 and their
use as versatile intermediates in organic synthesis.4 The classical
approach toward dithiocarbamates involves the use of thio-
phosgene or its derivatives,5 which is critical with respect to the
negative environmental impact that such toxic reagents have.
In addition, one-pot reactions starting from amines, carbon disul-
fide, and alkyl halides are known.6 In general, these methods
suffer from low or moderate yields and lead to S-alkyl
dithiocarbamates, while S-aryl derivatives are more difficult to
access.7−9 Thus, the development of new procedures for
practical syntheses of dithiocarbamates, in particular those with
S-aryl groups, that employ inexpensive and environmentally
benign reagents is highly desirable.
Knochel and co-workers were the first to describe the
applications of thiuram disulfides in the preparation of
dithiocarbamates.10 The procedures worked well, but they
required stoichiometric amounts of organozinc or organo-
magnesium. Inspired by these reports, we wondered about
catalytic approaches. Here we report on a copper catalysis
providing S-aryl dithiocarbamates from thiuram reagents
(Scheme 1).
Unfortunately, neither at room temperature nor at 80 °C for 48 h
was dithiocarbamate 2a detected. However, upon addition
of 5 mol % CuBr, 2a was obtained in 22% yield (Table 1,
entry 2). Encouraged by this result, base effects were
evaluated (Table 1, entries 3−7). The presence of Cs2CO3
proved optimal, providing 2a in 75% yield. Next, the metal
source was varied. Palladium did not catalyze the reaction
(Table 1, entries 8 and 9). Several copper reagents other than
CuBr proved catalytically active, but generally, the yield of 2a
was low to moderate (Table 1, entries 10−17). The excep-
tion was Cu2O, which in combination with Cs2CO3 gave 2a
in 92% yield (Table 1, entry 18). Varying the catalyst loading
(Table 1, entries 19−21) showed 5 mol % to be the most
suitable. In the absence of the metal, no reaction occurred.
For full conversion, 2.0 equiv of the base had to be used
(Table 1, entries 18, 23, and 24). A reaction temperature of
80 °C and DMSO as the solvent proved best (Table 1,
entries 15−28). The optimal parameters are summarized in
entry 18 of Table 1. An experiment on a 30 mmol scale gave 2a
in 94% yield.
The initial investigation focused on applying tetramethylth-
iuram disulfide (TMTD, 1a) as representative thiuram reagent
and the use of phenyl iodide (3a) as the aryl source under
“superbase” conditions for C−S couplings (Table 1, entry 1).11
Received: September 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
a
b
Reaction conditions: TMTD (1a, 2.0 mmol), phenyl iodide (3a, 3.0 mmol), [Cu], base, solvent (5 mL), 18 h. Use of a 5 mol % loading of the
c
d
metal salt, unless noted otherwise. Use of 2.0 equiv of base, unless noted otherwise. Mixture of unidentified products (under “superbase” reaction
conditions, 48 h). GC yield. Performed on a 30 mmol scale. Use of 1 mol % Cu2O. Use of 10 mol % Cu2O. Use of 15 mol % Cu2O. Use of
1.5 equiv of base. Use of 1.0 equiv of base.
e
f
g
h
i
j
k
Next, the scope of the reaction was examined by varying both
the aryl iodide and the thiuram disulfide. The results are shown
in Table 2. In general, all of the aryl iodides tested reacted well,
independently furnishing aryl dithiocarbamates in moderate to
very good yields. Neither electronic factors induced by sub-
stituents nor the position of the groups had a significant effect.
Both electron-donating and electron-withdrawing substituents
were tolerated. As expected, halo-bearing aryl iodides reacted
at the iodo group, allowing subsequent cross-couplings at the
remaining reactive site (Table 2, entries 2−5). Aryl iodides
with fused rings and heterocycles (Table 2, entries 17 and 18
and entries 19−23, respectively) led to the corresponding
products equally well. Also N,N,N′,N′-tetraalkylthiuram dis-
ulfides with ethyl and n-butyl groups (TETD, 2b, and TBTD,
2c, respectively) were applicable (Table 2, entries 24−26
and 27−29), and the yields of the resulting aryl dithio-
carbamates were comparable to those obtained in reactions
with TMTD.
Scheme 2. Plausible Reaction Mechanisms
On the basis of the aforementioned results, two possible
coupling mechanisms can be proposed. In the first (Scheme 2,
top), intermediate A is formed by oxidative addition of a copper
species into the aryl−iodine bond of 3. Upon reaction with the
base and probably by metal ion support, the thiuram reagent 1
gives nucleophile B,12,13 which leads to intermediate C by
ligand exchange of A. Reductive elimination of C furnishes the
observed product 2, and the catalytic cycle is closed by regen-
eration of the copper catalyst at its original oxidation state.
Alternatively (Scheme 2, bottom), the coupling involves aryl
radical D (or ion thereof). That intermediate would be gen-
erated from aryl iodide 3 by electron-transfer processes initi-
ated by copper species present in the reaction mixture.13,14
Once formed, it could add to the thiuram reagent 115 and sub-
sequently provide product 2 by S−S bond cleavage.
In summary, we have developed a copper-catalyzed cross-
coupling for the synthesis of aryl dithiocarbamates using inex-
pensive, environmentally benign thiuram disulfide reagents.
A wide range of substrates can be applied, leading to the cor-
responding products in high yields. The catalytic system is
derived from readily available reagents (Cu2O and Cs2CO3),
and no additional ligand is required. A scaled-up reaction
(30 mmol) confirmed the practicability of the process.
B
DOI: 10.1021/acs.orglett.7b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Synthesis of Phenyl Dithiocarbamate Derivatives
a
Reaction conditions: Tetraalkylthiuram disulfide 1 (2.0 mmol), aryl iodide 3 (3.0 mmol), Cu2O (0.15 mmol, 5 mol %), Cs2CO3 (6.0 mmol,
2.0 equiv), DMSO (5 mL), 80 °C, 18 h.
C
DOI: 10.1021/acs.orglett.7b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (b) Krasovskiy, A.; Gavryushin,
A.; Knochel, P. Synlett 2005, 2691. (c) Krasovskiy, A.; Gavryushin, A.;
Knochel, P. Synlett 2006, 792.
(11) (a) Baars, H.; Beyer, A.; Kohlhepp, S. V.; Bolm, C. Org. Lett.
2014, 16, 536. (b) Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett.
2011, 13, 2876.
(12) Copper has a very high binding affinity for dithiocarbamates,
which has been used for metal removal. For example, see: Gallagher,
W. P.; Vo, A. Org. Process Res. Dev. 2015, 19, 1369.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02911.
General procedure for product preparation and analytical
data, including 1H and 13C NMR spectra of the products
(PDF)
(13) Metal dithiocarbamate complexes exhibit a rich coordination
chemistry, and various assemblies with copper in different oxidation
states are known. For details, see: Hogarth, G. Prog. Inorg. Chem. 2005,
53, 71 and references therein. It could be that such complexes play a
role in the catalysis reported here.
(14) For stimulating overviews of mechanistic aspects of Ullmann
couplings, see: (a) Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de
Vries, J. G. Dalton Trans 2010, 39, 10338. (b) Sambiagio, C.; Marsden,
S. P.; Blacker, A. J.; McGowan, P. C. Chem. Soc. Rev. 2014, 43, 3525.
(15) For a review of radical additions to CS bonds to form C−S
bonds, see: Liu, D.; Liu, C.; Lei, A. Chem. - Asian J. 2015, 10, 2040.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: carsten.bolm@oc.rwth-aachen.de.
*E-mail: dzb04982@wit.edu.cn.
ORCID
Zhi-Bing Dong: 0000-0002-3354-8318
Carsten Bolm: 0000-0001-9415-9917
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21302150) for financial support. Z.-B.D. acknowledges the
Humboldt Foundation for a fellowship. We also thank Prof. Dr.
Aiwen Lei (Wuhan University, China) for generous NMR
analysis support.
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■
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D
DOI: 10.1021/acs.orglett.7b02911
Org. Lett. XXXX, XXX, XXX−XXX