Multicomponent Synthesis of Biologically Relevant S-Aryl Dithiocarbamates Using Diaryliodonium Salts

Article abstract of DOI:10.1021/acs.orglett.1c02220

A transition-metal-free one-pot three-component annulation between diaryliodonium triflates, cyclic and acyclic aliphatic amines, and carbon disulfide providing a convenient and efficient access to biologically relevant S-aryl dithiocarbamates is developed. The reaction does not require metal, base, or any other additive and operates under mild and ambient conditions. This methodology is robust, scalable, and exhibits a broad substrate scope. The in silico analysis revealed that the majority of the compounds have a drug-likeness and good ADMET characteristics.

Full text of DOI:10.1021/acs.orglett.1c02220

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Letter
Multicomponent Synthesis of Biologically Relevant S‑Aryl
Dithiocarbamates Using Diaryliodonium Salts
Sushanta K. Parida, Sonal Jaiswal, Priyanka Singh,* and Sandip Murarka*
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ABSTRACT: A transition-metal-free one-pot three-component annula-
tion between diaryliodonium triflates, cyclic and acyclic aliphatic amines,
and carbon disulfide providing a convenient and efficient access to
biologically relevant S-aryl dithiocarbamates is developed. The reaction
does not require metal, base, or any other additive and operates under mild
and ambient conditions. This methodology is robust, scalable, and exhibits
a broad substrate scope. The in silico analysis revealed that the majority of
the compounds have a drug-likeness and good ADMET characteristics.
Scheme 1. Biologically Active Dithiocarbamates and
Multicomponent Methods for the Synthesis of Aryl
Dithiocarbamates
ver the years organic dithiocarbamates have received
much attention owing to their diverse applications across
O
the fields. They serve as linkers in solid phase synthesis,1
important intermediates in the synthesis of a variety of building
blocks,2 and protecting groups in peptide synthesis.3 More-
over, several biologically active compounds and pharmaceut-
icals embedded with this structural framework have been
reported to act as anticancer agents,4 antimethicillin-resistant
Staphylococcus aureus (MRSA) agents,5 and monoacylglycerol
lipase (MAGL) inhibitors,6 to name a few (Scheme 1).
Accordingly, their synthesis has attracted interest of the
synthetic community and several methods allowing access to
this class of compounds have been developed.
Conventional methods for the synthesis of aryl dithiocarba-
mates either involve use of stoichiometric and toxic organo-
metallic reagents with tetramethylthiuram disulfide7 or are
driven by copper-catalyzed cross-coupling between iodoar-
enes8 or aryl boronic acids9 with sodium salt of dithiocarbamic
acid. Recently, copper-catalyzed S-arylation of tetraalkylthiur-
am disulfides using iodoarenes,10 aryl boronic acids,11 and
diaryliodonium salts12 was reported. All these transition-metal-
catalyzed methods were carried out in the presence of
expensive and toxic copper catalysts, and at elevated
temperature. The presence of a strong base and an expensive
ligand was indispensable for the success of some of these
transformations. The corresponding transition-metal-free two
component couplings involving sodium salt of dithiocarbamic
acid with either aryldiazonium chloride13 or hypervalent
iodine14 have been developed as well. However, sodium salt
of dithiocarbamic acid is potentially toxic, is difficult to
prepare, and limits the substrate scope with regard to
amines.13,15
Received: July 2, 2021
In this regard multicomponent reaction (MCR) is note-
worthy and desirable, as it represents step economic and cost-
efficient tool and enables rapid construction of structurally
diverse compound library.16 Additionally, a MCR obviating the
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© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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a
need of any transition metal is even more beneficial as it
reduces toxicity, improves cost efficiency, sidelines the hassle
during purification, and enables smooth scale-up of the
process. A one-pot method for the preparation of alkyl
dithiocarbamate through reaction of amines with carbon
disulfide and alkyl halide was reported.17 But this method is
mostly restricted to alkyl dithiocarbamates. A strongly
activated arene system, such as pentafluorobenzonitrile that
is suitable for a SNAr-type reaction was required for such a
reaction to be applicable for the preparation of corresponding
aryl counterpart.18 A three-component one-pot coupling
reaction between amines, carbon disulfide, and aryl/styryl
halide catalyzed by a copper nanoparticle at high temperature
was reported (Scheme 1a).19 A similar copper-mediated
process utilizing (hetero)aryl/alkyl boronic acids was also
documented (Scheme 1b).20 The Ranu group described a
metal-free coupling between amines, carbon disulfide and aryl
diazonium tetrafluoroborates allowing access to the corre-
sponding aryl dithiocarbamates (Scheme 1c).26 However, the
hazardous and explosive nature of the diazonium salts limited
the applicability of the process. Therefore, considering diverse
applications of aryl dithiocarbamates, it is highly desirable to
develop straightforward, easily diversifiable, metal-free, and
environmentally benign reaction technologies utilizing bench-
stable and nontoxic reagents for the synthesis of this scaffold.
Lately, hypervalent iodine(III) (HVI) reagents have
emerged as easily available, nontoxic, bench-stable, and high
functional group tolerant powerful synthetic tool enabling
construction of a range of carbon−carbon and carbon-
heteroatom bonds.21 Diaryliodonium salts have often been
utilized as electrophilic reagents22 and are reported to react
with a range of carbon- and heteroatom-centered nucleophiles
under transition-metal-free conditions.23 We were intrigued by
the possibility of utilizing diaryl iodonium salts as the aryl
source in the three-component coupling with amines and using
carbon disulfide under metal-free conditions. Such a cascade
strategy would be novel, highly efficient, and fascinating from
the perspective of green chemistry and sustainable synthesis.
As part of our program to develop metal-free cascade
annulations24 and driven by our interest in hypervalent
iodine(III) reagents,21c,d we herein disclose a hitherto
unknown metal-free one-pot multicomponent coupling
between diaryliodonium salts, carbon disulfide, and amines
to provide biologically relevant S-aryl dithiocarbamates in an
efficient fashion (Scheme 1d).
Table 1. Optimization of the Reaction Conditions
b
entry
X
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
OTf
OTf
OTf
OTf
OTf
OTf
OTs
Br
DMF
Acetone
HFIP
CH2Cl2
DCE
H2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
2
2
2
2
2
2
0.5
1
4
2
48
57
ND
92
80
55
56
72
68
80
84
91
80
9
BF4
10
11
12
OTf
OTf
OTf
OTf
c
13
a
Reaction conditions: 0.1 mmol scale using 1 (1 equiv), 2a (1.2
equiv), and CS2 (2.5 equiv) in solvent (1 mL). Isolated yield. Using
1.5 equiv of CS2.
b
c
Among the other solvents tested (DCE, H2O), CH2Cl2
remained to be the optimal one (entries 5 and 6). Then we
decided to investigate the role of diaryl iodonium counterion
on the efficacy of the reaction. Notably, the yield plummeted
to 56% upon utilizing tosylate as an counterion (entry 7),
whereas, in case of bromide and tetrafluoroborate, 72% and
68% yields were obtained in a respective manner (entries 8 and
9). Reducing the reaction time to either 0.5 or 1 h delivered
inferior results (entries 10 and 11), and prolonging the
reaction time to 4 h did not improve the yield (entry 12).
Moreover, decreasing the amount of CS2 from 2.5 equiv to 1.5
equiv led to reduced yield (entry 13).
With optimized conditions in hand, we set out to explore the
scope of the three-component reaction manifold through
reacting diphenyliodonium triflate 1a with an array of
electronically and structurally diverse amines 2 (Figure 1).
Pleasingly, a range of cyclic aliphatic amines, such as
piperidine, pyrrolidine, morpholine, N-Boc-protected piper-
azine, tetrahydroisoquinoline, and azepane that are diverse
with regard to ring size and heteroatoms, participated in the
We embarked on optimization studies through reacting
diaryl iodonium triflate 1 (1 equiv), piperidine 2a (1.2 equiv),
and carbon disulfide (CS2, 2.5 equiv) in DMF at room
temperature for 2 h (Table 1). To our delight, the desired aryl
dithiocarbmate 3a was obtained in 48% yield (entry 1).
Typically, an amine 2 was added to a solution/suspension of
CS2 in a given solvent at room temperature and the solution
was stirred for 5 min. Then diaryl iodonium salt 1 was added
over a period of 10−15 min and the reaction mixture was
continued to stir until completion. Importantly, the reactions
were carried out in a screw-cap vial and inert atmosphere or
Schlenck techniques were not required to perform these
reactions. The structure of 3a was confirmed by single-crystal
X-ray analysis (see SI for details). Nevertheless, the yield
increased to 57% upon switching the solvent from DMF to
acetone (entry 2). No product formation was observed in
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solvent (entry 3).
Pleasingly, the yield of 3a jumped to 92% in CH2Cl2 (entry 4).
Figure 1. Substrate scope with regard to amines. Reactions were
performed on 0.25 mmol scale using 1a (1 equiv), 2 (1.2 equiv), and
CS2 (2.5 equiv) in CH2Cl2 (2.5 mL).
B
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transformation providing the corresponding products (3aa−
3af) in moderate to excellent yields (50%−92% yields). The
method was found to be quite robust for several acyclic
secondary aliphatic amines to furnish the corresponding aryl
dithiocarbamates (3ag−3ai) in good yields. Pleasingly, primary
aliphatic amines, which could not be accommodated in earlier
methods,10a,19,20,25 underwent smooth transformation under
the present protocol. Accordingly, benzyl amine and allyl
amine afforded the desired products 3aj and 3ak in 86% and
68% yields, respectively. Unfortunately, the attempt to prepare
phenyl carbamodithioate through MCR of 1a with aqueous
ammonia and CS2 was unsuccessful. Importantly, chiral
primary and secondary amines were tolerated to give the
corresponding coupled products 3al (65%) and 3am (60%) in
good yields.
reaction time (4 h) was required where the aromatic ring was
embedded with electron-rich substituents.
In order to demonstrate the robustness and practicality of
the process, large scale reactions were carried out (Scheme 2).
Scheme 2. Scale-up Synthesis of S-Aryl Dithiocarbamates
Next, we explored the scope of symmetrical diaryliodonium
triflates 1 by varying substitution pattern on the phenyl ring
(Figure 2). The diaryliodonium triflates containing 4-Me and
We were pleased to note that 1 g of HVI reagents 1a and 1i
participated in the three-component coupling through reacting
with piperidine 2a and CS2 to provide the coupling products
3aa and 3ia in 73% and 71% yields, respectively. Importantly,
to address the concern of atom economy of the process, we
decided to isolate the liberated iodoarene derivative.
Pleasingly, as shown in Scheme 2b, besides 71% of desired
3ia, iodoarene derivative 4 was recovered in 50% yield in the
scale-up reaction. Moreover, the recycled 4 was utilized to
prepare the HVI reagent 1i in 80% yield.27
Subsequently, we intended to evaluate the scope of the
process with regard to nonsymmetrical diaryliodonium triflates
(Scheme 3). Importantly, reaction of unsymmetrical diary-
Scheme 3. Chemoselectivity Trends for Unsymmetrical
Diaryliodonium Triflates
Figure 2. Substrate scope with regard to diaryl iodonium salts.
Reactions were performed on 0.25 mmol scale using 1 (1 equiv), 2
(1.2 equiv), and CS2 (2.5 equiv) in CH2Cl2 (2.5 mL).
4-t-Bu substituents on the phenyl ring underwent smooth
transformation providing the corresponding products (3ba−
3ca) in moderate to good yields (50%−72%). Pleasingly, the
reaction was feasible in case of iodine(III) reagents containing
2,5-dimethyl (3da, 73%) and sterically encumbered 2,4,6-
trimethyl substitution pattern on the phenyl ring (3ea, 77%
and 3ec, 60%). Notably, aryl dithiocarbamates containing such
a sterically congested aryl moiety could not be prepared
through earlier metal-free or copper-catalyzed/mediated
protocols.9−12,19,20,26 An electron-rich methoxy functionality
could be accommodated on the phenyl ring to furnish the
desired product (3fa) in 53% yield. Expectedly, the MCR was
found to be quite efficient in case of HVI reagents containing
electron-withdrawing substituents (4-F, 4-Cl, 4-Br, 3-Cl) on
the phenyl ring furnishing the corresponding coupled products
(3ga−3ja) in good yields (60%−86%). Notably, diheteroaryl
iodonium salts, such as di-2-thienyl iodonium trilflate could
not be accommodated in this MCR. In general, the reaction
was faster in the case of HVI reagents with electron-
withdrawing substituents on the phenyl ring and a longer
liodonium salts with nucleophiles is controlled by the
electronic and steric nature as well as the type of nucleophile
plays a crucial role in the chemoselective outcome of the
process.23a In general, it has been observed that under
transition-metal-free conditions, transfer of more electron-
withdrawing and sterically hindered aryl group is preferre-
d.23a,c,d Accordingly, to explore the chemoselectivity of the
transformation, we synthesized four different electronically and
sterically diverse nonsymmetrical diaryliodonium triflates (1k−
1n) and reacted those with piperidine 2a and CS2 under the
standard reaction conditions. When diaryliodonium salts 1k
C
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and 1l were reacted, the selective transfer of phenyl group over
4-t-Bu-Ph group in case of 1k, and 4-nitrophenyl group instead
of the phenyl ring in the latter case (1l) was observed (Scheme
3a and 3b). These facts explicitly demonstrates that transfer of
electron-deficient aryl ring is strongly preferred in this reaction.
When mesityliodonium salt 1m was used, an exclusive transfer
of the sterically congested mesityl group giving rise to the
product 3ea (75%) along the line of so-called “ortho-effect”
was observed (Scheme 3c). In corroboration with previous
reports,23b,c we observed that the thienyl group imparts strong
directing ability and behaved as a perfect “spectator” group
allowing selective transfer of the phenyl ring in case of
iodonium salt 1n (Scheme 3d).
It is well-documented that transition-metal-free arylations
using diaryliodonium salts either proceed through a SET
(single electron transfer) mechanism28 or via formation of a T-
shaped intermediate,23a,29 which then collapses to the product
by ligand coupling between the nucleophile and the equatorial
aryl group. In order to investigate the possibility of a radical
mechanism, 1a, 2a, and CS2 were reacted under optimized
conditions in the presence of TEMPO as the radical scavenger
(Scheme 4a). The multicomponent reaction was found to be
Figure 3. In silico analysis of drug-likeness (a) and ADMET (b)
prediction. (a) Color map indicating percentage compliance of each
drug for L = Lipinski, G = Ghose, V = Veber, E = Egan, and M =
Muegge drug-likeness filters. (b) Bar graph represents average
ADMET-score for each drug. The error bars indicate standard
deviation.
Scheme 4. Control Experiment and Proposed Mechanism
an easy access to a diverse range of S-aryl dithiocarbamates.
The method does not require any expensive and toxic
transition metal, strong base, and high temperature. The
reactions were carried out under environmentally benign
conditions using nonhazardous, bench-stable, easily available,
and inexpensive reacting partners. Furthermore, the present
method is noteworthy as it allows rapid construction of a
potentially biologically active compound library that is
diversified with regard to both the aryl as well the amine
part. This is a major improvement over the earlier protocols,
especially those utilizing either sodium salt of dithiocarbamic
acid or thiuram disulfide reagents as coupling partners, which
drastically limited the scope of the reaction. Importantly, in
silico analysis revealed that the synthesized compounds
accomplished drug-likeness and lead-like properties that are
requisite for drug potency, in turn making them promising
candidates for further exploration of their efficacy using
biological assays.
insensitive toward the radical scavenger and the product 3a
was formed in 81% yield. This experiment ruled out the
possibility of an underlying SET mechanism. Based on our
control experiment and previous reports,23a,d,30 we propose
that an initial reaction between amines 2a and CS2 leads to the
generation of dithiocarbamic acids A, which upon reaction
with diaryliodonium salts 1 form a T-shaped intermediate B
(Scheme 4b). Finally, a ligand coupling between dithiocarba-
mate moiety and the equatorial aryl functionality furnishes the
desired S-aryl dithiocarbmates 3.
ASSOCIATED CONTENT
■
sı
* Supporting Information
Since dithiocarbamates impart diverse biological properties,
we decided to perform in silico studies of the synthesized S-aryl
dithiocarbamates to predict their drug-likeness and lead-like
pharmacokinetic properties. Pleasingly, the compounds were
found to be in good compliance (75%−100%) with different
drug-likeness filters (Lipinski, Ghose, Veber, Egan, and
Muegge) (Figure 3a and SI Tables 1−3). Furthermore, to
our delight, all compounds showed a good range of average
ADMET score (0.76−0.84) with regard to human intestinal
absorption, blood-brain barrier penetration, Caco-2 perme-
ability, Ames mutagenicity, carcinogenicity, and acute oral
toxicity class (Figure 3b and SI Table 4).
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02220.
Experimental procedures, crystal data, tables of SMILES
notations, physiochemical properties, drug-likeness
percentage compliance, and ADMET scores, and NMR
spectral data of all new compounds (PDF)
Accession Codes
CCDC 2083980 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
In summary, we have developed an efficient, robust, and
scalable multicomponent coupling between symmetrical and
unsymmetrical diaryliodonium triflates, cyclic and acyclic
primary and secondary amines and carbon disulfide enabling
D
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pubs.acs.org/OrgLett
Letter
(8) Liu, Y.; Bao, W. A New Method for the Synthesis of
Dithiocarbamates by Cui-Catalyzed Coupling Reaction. Tetrahedron
Lett. 2007, 48, 4785−4788.
AUTHOR INFORMATION
Corresponding Authors
■
Priyanka Singh − Department of Bioscience and
Bioengineering, Indian Institute of Technology Jodhpur,
Karwar 342037 Rajasthan, India; Email: priyankasingh@
iitj.ac.in
Sandip Murarka − Department of Chemistry, Indian Institute
of Technology Jodhpur, Karwar 342037 Rajasthan, India;
orcid.org/0000-0003-1692-0939;
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of Phenyl Dithiocarbamates Starting from Sodium Dialkyldithiocar-
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Coupling Reactions for the Synthesis of Aryl Dithiocarbamates with
Thiuram Disulfide Reagents. Org. Lett. 2017, 19, 5916−5919.
(b) Cao, Q.; Peng, H.-Y.; Cheng, Y.; Dong, Z.-B. A Highly Efficient
CuCl2-Catalyzed C−S Coupling of Aryl Iodides with Tetraalkylth-
iuram Disulfides: Synthesis of Aryl Dithiocarbamates. Synthesis 2018,
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Email: sandipmurarka@iitj.ac.in
Authors
Sushanta K. Parida − Department of Chemistry, Indian
Institute of Technology Jodhpur, Karwar 342037 Rajasthan,
India
(11) Xu, W.; Gao, F.; Dong, Z.-B. Copper-Catalyzed S-Arylation
Starting from Arylboronic Acids and Tetraalkylthiuram Disulfide. Eur.
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B. Copper-Catalyzed S-Arylation of Tetraalkylthiuram Disulfides by
Using Diaryliodonium Salts. Eur. J. Org. Chem. 2017, 2017, 6060−
6066.
Sonal Jaiswal − Department of Bioscience and Bioengineering,
Indian Institute of Technology Jodhpur, Karwar 342037
Rajasthan, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02220
(13) Clifford, A. M.; Lichty, J. G. The Reaction of Diazonium Salts
on Sodium Alkyl Dithiocarbamates. J. Am. Chem. Soc. 1932, 54,
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The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.M. acknowledges CSIR [02(0426)/21/EMR-II] for funding.
P.S. is thankful to SERB (ECR/2017/001410) and DBT (BT/
12/IYBA/2019/02) for the financial support.
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