Thiocarbonyl Surrogate via Combination of Potassium Sulfide and Chloroform for Dithiocarbamate Construction

Article abstract of DOI:10.1021/acs.orglett.9b02784

An efficient and practical thiocarbonyl surrogate via combination of potassium sulfide and chloroform was established. A variety of dithiocarbamates were afforded along with four new chemical bond formations in a one-pot reaction in which the thiocarbonyl

Full text of DOI:10.1021/acs.orglett.9b02784

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Thiocarbonyl Surrogate via Combination of Potassium Sulfide and
Chloroform for Dithiocarbamate Construction
†
‡
‡
,‡
Wei Tan, Niklas Jansch, Tina Ohlmann, Franz-Josef Meyer-Almes,* and Xuefeng Jiang*,†,§
̈
̈
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 North Zhongshan Road, Shanghai 200062, P.R. China
‡Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Darmstadt 64295, Germany
§State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P.R. China
S
* Supporting Information
ABSTRACT: An efficient and practical thiocarbonyl surro-
gate via combination of potassium sulfide and chloroform was
established. A variety of dithiocarbamates were afforded along
with four new chemical bond formations in a one-pot reaction
in which the thiocarbonyl motif was generated in situ.
Furthermore, these readily accessed molecules showed
promising activity against HDAC8, opening a potential gateway to discover a new type of nonhydroxamate and isoenzyme-
selective HDAC inhibitors.
ithiocarbamate is an important class of molecule with
extensive value in pharmaceuticals, agrochemicals, and
Accordingly, numerous procedures have been developed for
the synthesis of dithiocarbamate. Most of these strategies
revolved around the reactions of volatile and flammable carbon
disulfide6 with electrophiles through a dithiocarbamic acid salt
intermediate7 in which the electrophiles included alkyl
halides,7a epoxides,7b alkynes,7c alkyl vinyl ethers,7d etc.
(Scheme 2). Furthermore, there is an alternative procedure8
involving the reaction of pre-prepared tetramethylthiuram
D
organic materials (Scheme 1).1−5 Disulfiram with a dithio-
Scheme 1. Representative Dithiocarbamates
Scheme 2. Strategies for Dithiocarbamate Construction
carbamate motif is a famous molecule previously applied for
alcoholism treatment1a and recently as a drug candidate for its
anticancer activity in preclinical models.1b Moreover, other
dithiocarbamates are attracting more and more attention based
on their variety of biological activities2 such as antitumor,2a
antibacterial,2b cholinesterase inhibition,2c etc. Sulfallate is a
chlorinated dithiocarbamate derivative that is used as an
herbicide.3 Meanwhile, dithiocarbamate also serves a unique
role in material science, such as a radical chain transfer agent
BDC in reversible addition−fragmentation chain transfer
(RAFT) polymerizations.4 VANLUBE 7723 is a nonnegligible
chemical widely applied as a lubricant additive in the
mechanical industry.5
Received: August 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02784
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
disulfide and organozinc8a or organolithium8b reagents as
nucleophiles that are sensitive to air and moisture. However,
the development of a practical and environmentally friendly
process for dithiocarbamate construction is still highly
desirable. Based on our continuous study on organosulfur
chemistry9 especially in thiocarbonyl chemistry,10 we envi-
sioned that dithiocarbamate can be assembled from a
combination of sulfur, carbon, and amino sources in one pot
along with the direct generation of a thiocarbonyl group in situ,
indicated that odorless S-phenethyl thiosulfate salt 1a had a
distinct advantage not only for the ecofriendly procedure but
also for the chemical “mask” effect.9c When the reaction was
carried out under air atmosphere, the yield decreased (Table 1,
entry 4 vs entry 1). Meanwhile, other inorganic sulfur sources
were examined, and only a trace amount of product could be
observed by substituting elemental sulfur or sodium thiosulfate
for potassium sulfide while potassium thioacetate afford
product in 47% yield (Table 1, entries 5−7). Various polar
solvents were explored, in which the target product 3a could be
afforded in 55% yield with N,N-dimethylformamide (DMF)
(Table 1, entries 8−11). Subsequently, barium hydroxide
octahydrate was employed as a base in the reaction, and the
compound 3a was isolated in 81% yield with a significant
elevation compared to other base usage (Table 1, entries 12−
16). Finally, the product 3a was obtained in 85% yield with a
slight improvement by adjusting the base amount and solvent
concentration (Table 1, entries 17−19).
avoiding the use thiocarbonyl reagents. Following our concept,
•−
potassium sulfide provides trisulfur radical anion (S3
)
11 as an
inorganic sulfur source and chloroform12 provides dichlor-
ocarbene as one carbon source. Herein, we developed a
straightforward method for preparation of dithiocarbamate
with potassium sulfide and chloroform in the presence of
readily available thiosulfate salts9c,13 and organic amines, in
which a library of valuable bioactive molecules was well
established.
On the basis of the optimized conditions, the scope of
amines was examined as shown in Scheme 3. First, various
We commenced our studies with S-phenethyl thiosulfate
sodium salt 1a and morpholine 2a as the model substrate in
combination with potassium sulfide and chloroform. The
desired product 3a could be obtained in 56% yield by using
lithium hydroxide as a base and N-methylpyrrolidone (NMP)
as a solvent at 80 °C under nitrogen atmosphere (Table 1,
entry 1). When the odorous phenylethyl mercaptan or S-
phenethylethanethioate was employed in the corresponding
conditions, the product 3a was only formed in 38% or 13%
yields, respectively (Table 1, entries 2 and 3). The results
a
Scheme 3. Scope of Amines
Table 1. Optimization for the Synthesis of
a
Dithiocarbamate
b
entry
1
“S”
K2S
K2S
K2S
K2S
S8
Na2S2O3
KSAc
K2S
K2S
K2S
K2S
K2S
K2S
K2S
K2S
K2S
K2S
K2S
K2S
base
solvent
NMP
yield (%)
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
KOH
56
38
13
c
2
NMP
NMP
NMP
NMP
NMP
NMP
DMF
MeCN
DMSO
1,4-dioxane
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
d
3
e
4
47
5
6
7
8
trace
trace
47
55
trace
19
nd
17
41
53
9
10
11
12
13
14
15
16
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), K2S (0.4 mmol),
K3PO4
tBuOLi
tBuOK
CHCl3 (2 mmol), and Ba(OH)2·8H2O (0.9 mmol) in NMP (2 mL)
was stirred at 80 °C for 8−12 h under nitrogen atmosphere. Isolated
yields.
33
Ba(OH)2·8H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
81
81
76
85
f
17
18
cyclic amines (3a−3k) were tested, and the corresponding
products were formed in moderate to good yields, in which the
hydrolyzable lactam (3g), amide (3j), and sulfone groups (3k)
under alkaline conditions were tolerable in the reaction system.
Meanwhile, the structure of product 3a was further confirmed
through X-ray crystallographic analysis. Noncyclic amines
could also perform as amino sources (3l−3o). Diethylamine
could give the related product 3l in 52% yield, while
dibenzylamine (3m) and N-methylbenzylamine (3n) afforded
their respective products in good yields. Moreover, N-
g
f h
19 ,
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), “S” (0.4 mmol),
CHCl3 (2 mmol), and base (1.2 mmol) in solvent (1 mL) was stirred
at 80 °C for 12 h under nitrogen atmosphere. Isolated yields. nd =
not detected. Phenylethyl mercaptan is instead of 1a. S-
Phenethylethanethioate is instead of 1a. Air is instead of nitrogen
atmosphere. Ba(OH)2·8H2O (0.9 mmol). Ba(OH)2·8H2O (0.6
mmol). NMP (2 mL).
b
c
d
e
f
g
h
B
DOI: 10.1021/acs.orglett.9b02784
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Organic Letters
Letter
methylaniline as an aromatic amine could be efficiently
transformed to the desired product 3o in moderate yield,
and it seems that the yield of the product with N-arylamine
was slightly lower than those of the N-alkyl-supplied product.
On the other hand, when the primary amine was employed in
the reaction, the target product could not be obtained.14
Subsequently, various thiosulfate salts were successfully
employed, as shown in Scheme 4. When the electron-
Scheme 5. Gram-Scale Preparation and Further Exploration
a
Scheme 4. Scope of Thiosulfate Salts
Afterward, control experiments were carried out (Scheme
6). When the model reaction was carried out in the absence of
Scheme 6. Control Experiments
potassium sulfide or chloroform, no desired product could be
detected. The results indicated that potassium sulfide and
chloroform are indispensable in the transformation for
thiocarbonyl motif construction. Moreover, if the reaction
was performed in the absence of S-alkyl thiosulfate salt 1a, the
thioamide 5 could be formed in 24% H NMR yield, which
implied that a thiolcarbonyl byproduct could be generated
from reaction intermediates on certain conditions.
a
The reaction conditions: 1 (0.2 mmo l), 2a (0.4 mmol), K2S (0.4
mmol), CHCl3 (2 mmol), and Ba(OH)2·8H2O (0.9 mmol) in NMP
(2 mL) was stirred at 80 °C for 8−12 h under nitrogen atmosphere.
Isolated yields.
1
According to the results of experiments, a possible reaction
mechanism is depicted in Scheme 7. First, dichlorocarbene12
was generated from chloroform in the presence of base and
inserted into the H−N bond of the starting amine to form A,
which provides monochlorinated imine cation B readily. Then
the reaction occurred between imine B and the thiosulfate salt
withdrawing group was connected to the aromatic ring on
substrate at the para position, the yield of the reaction seemed
to decrease (4a−4e). Then S-alkylether thiosulfate salts (4f−
4i) were tested, and notably the acetal group used as a
protective group for aldehydes was compatible in the
multicomponent reaction (4h). Meanwhile, S-alkyl thiosulfate
salts with alkyl chains of different lengths (4j−4p) were
examined, and the corresponding products could be obtained
in similar yields. Moreover, tert-butyl carbonate (4q) and
cyano (4r) groups were tolerable in the reaction as well. In
addition, S-phenyl thiosulfate salts could also be transformed
into the desired product (4u) in a moderate yield, and this
method could be applied to the synthesis of a dithiocarbamate
containing a double thiocarbonyl motif (4v).
Scheme 7. Proposed Mechanism
To further explore the potential practicability of this method
(Scheme 5), the gram-scale operation was performed on a 6
mmol scale for the synthesis of phenethyl morpholine-4-
carbodithioate 3a, and the desired product could be obtained
in 70% yield. On the other hand, (2-bromoethyl)benzene 4
was investigated as a substrate to afford compound 3a in 60%
yield through a multicomponent reaction in one pot, in which
each component was effectively embedded in the target
structure and only inorganic salts as waste materials were
discharged.
C
DOI: 10.1021/acs.orglett.9b02784
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Organic Letters
Letter
to afford another imine cation D via intermediate C. Trisulfur
radical anion (S3•−) could be formed from potassium sulfide in
NMP solvent, which had been demonstrated by detection
experiments in our previous work.10c Herein, trisulfur radical
anion (S3•−) generating from K2S in the solvent of NMP
interacted with imine cation D to produce intermediate E
along with the establishment of the C−S bond. Next, the α-
aminoalkyl radical F was obtained through an intramolecular
hydrogen atom transfer (HAT) process of intermediate E.15
Finally, homolysis of the S−S bond in the intermediate F
provides the target product in the presence of base along with
the generation of disulfur radical anion (S2•−).
The pyrimido[1,2-c][1,3]benzothiazin-6-imine PD-404,182
was recently shown to be a potent and selective inhibitor of the
established cancer target human histone deacetylase 8
(HDAC8).16 However, this compound class turned out to
be unstable in the presence of thiol groups in aqueous solution,
and the reaction of PD-404,182 leads to chemical modifica-
tions of HDAC8 cysteine residues such as cyanylation and the
formation of mixed disulfides.16b What attracted our attention
is that the thiocarbonyl analogues of PD-404,182 still retain
their activity against HDAC8.16a This inspired us to explore
the biological activity of the noncyclic dithiocarbamate
compounds of this study against human HDAC8 and the
catalytic domain of human HDAC4 (cHDAC4). Most
interestingly, some of these compounds exhibited promising
bioactivity against HDAC8 with less activity against cHDAC4,
in which 4n showed impressive activity with an IC50 value in
the low micromolar range (Scheme 8; see the SI for more
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02784.
■
S
Experimental procedures, NMR spectral, X-ray, and
analytical data for all new compounds (PDF)
Accession Codes
CCDC 1935361 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.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: franz-josef.meyer-almes@h-da.de.
*E-mail: xfjiang@chem.ecnu.edu.cn.
ORCID
Franz-Josef Meyer-Almes: 0000-0002-1001-3249
Xuefeng Jiang: 0000-0002-1849-6572
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support provided by the National
Key Research and Development Program of China
(2017YFD0200500), NSFC (21971065, 21722202,
21672069), the S&TCSM of Shanghai (Grant
18JC1415600), Professor of Special Appointment (Eastern
Scholar) at Shanghai Institutions of Higher Learning, and the
National Program for Support of Top-notch Young Profes-
sionals.
a
Scheme 8. IC50 Values on HDAC8 and cHDAC4
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thiocarbonyl surrogate via combination of potassium sulfide
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