NaOH-promoted one-pot aryl isothiocyanate synthesis under mild benchtop conditions

Article abstract of DOI:10.1080/10426507.2021.1927031

In this work, we have established a green synthesis of aryl isothiocyanates promoted by the low-cost and readily available NaOH from aryl amines and carbon disulfide in a one-pot procedure. The developed protocol features no extra desulfurating reagents and mild benchtop conditions, in which NaOH serves as both the base and the desulfurating reagent to decompose the dithiocarbamate intermediate. Fourteen examples of aryl amines bearing electronic neutral, rich and poor substituents, as well as benzylamine, have proved to be compatible substrates in the developed method to furnish the corresponding isothiocyanates. The reaction has been performed on a gram scale to further demonstrate its synthetic utility. Compared to the reported base-promoted synthesis of aryl isothiocyanates that requires the use of special equipment, such as the ball mill or the microwave reactor, the simplicity in operation and scalability enables this method to efficiently access a variety of aryl isothiocyanates.

Full text of DOI:10.1080/10426507.2021.1927031

Phosphorus, Sulfur, and Silicon and the Related Elements
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NaOH-promoted one-pot aryl isothiocyanate
synthesis under mild benchtop conditions
Xinyun Liu, Hang Li & Xiaogang Yin
To cite this article: Xinyun Liu, Hang Li & Xiaogang Yin (2021): NaOH-promoted one-pot aryl
isothiocyanate synthesis under mild benchtop conditions, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2021.1927031
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2021.1927031
SHORT COMMUNICATION
NaOH-promoted one-pot aryl isothiocyanate synthesis under mild
benchtop conditions
a
b
b
Xinyun Liu
, Hang Li
, and Xiaogang Yin
a
b
School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, China; Key Laboratory of Functional Materials Chemistry of
Guizhou Province, School of Chemistry and Materials Science, Guizhou Normal University, Guiyang, China
ABSTRACT
ARTICLE HISTORY
In this work, we have established a green synthesis of aryl isothiocyanates promoted by the low-
cost and readily available NaOH from aryl amines and carbon disulfide in a one-pot procedure.
The developed protocol features no extra desulfurating reagents and mild benchtop conditions, in
which NaOH serves as both the base and the desulfurating reagent to decompose the dithiocarba-
mate intermediate. Fourteen examples of aryl amines bearing electronic neutral, rich and poor
substituents, as well as benzylamine, have proved to be compatible substrates in the developed
method to furnish the corresponding isothiocyanates. The reaction has been performed on a
gram scale to further demonstrate its synthetic utility. Compared to the reported base-promoted
synthesis of aryl isothiocyanates that requires the use of special equipment, such as the ball mill
or the microwave reactor, the simplicity in operation and scalability enables this method to effi-
ciently access a variety of aryl isothiocyanates.
Received 15 January 2021
Accepted 4 May 2021
KEYWORDS
Isothiocyanates; benchtop
synthesis; sodium
hydroxide; aryl amines;
desulfurating reagents
GRAPHICAL ABSTRACT
Introduction
utility of this approach. Alternatively, the “dithiocarbamate
desulfurization” approach is a two-step process: the amine
starting material is first treated with carbon disulfide in the
presence of a base to afford a dithiocarbamate intermediate,
which then decomposes to provide the ITC product via
desulfurization. A plethora of diverse desulfurating reagents
have been developed, including uronium and phosphonium-
Naturally found in Brassicale vegetables, isothiocyanates
(
ITCs) possess a wide range of biological activities such as
[
1]
[2]
[3]
anticancer,
antibacterial,
anti-inflammatory.
Even
ITCs bearing simple phenyl and benzyl groups are identified
[
4]
as effective anticancer agents. In organic synthesis, aryl
ITCs are versatile synthetic intermediates for the synthesis
of thioureas and a variety of nitrogen- and sulfur-containing
[
9]
[10]
based peptide coupling reagents,
tosyl chloride,
copper salts,
iod-
iron
[7] ine,[
11]
[12]
[13]
[
5]
[6]
di-tert-butyl dicarbonate,
heterocycles,
thiohydantoins.
i8n] cluding benzimidazoles,
benzoxazoles,
[
14]
[15]
[
salts,
persulfate salts,
and recently reported organofluorides.
Despite the wide variety, the use of extra desulfurating
the phase transfer catalyst Triton
[
16]
[17]
B,
Arising from the importance of aryl ITCs to synthetic
and medicinal chemistry, a number of methods that mainly
utilize readily available amines as starting materials have
been established to synthesize ITCs. In general, two
approaches are exploited to prepare ITCs from amines
reagents, mostly in stoichiometric amounts, unavoidably
impairs eco-friendliness and complicates reaction conditions.
Therefore, greener and operationally simpler protocols for
(
Scheme 1). In the “thiocarbonyl transfer” approach, amines ITC preparation are expected to eliminate the need of extra
react with thiophosgene, or its less toxic alternatives, to dir- desulfurating reagents. So far, very few reports have investi-
ectly deliver ITC products via thiocarbonylation. Although gated base-promoted ITC synthesis from amines without
efficient, high toxicity and difficult preparation of the thio- extra desulfurating reagents (Scheme 2). In the mid-1970s,
carbonyl transfer reagents remarkably limit the synthetic Sakai and coworkers reported a stepwise ITC synthesis from
CONTACT Xiaogang Yin
m13885115516@163.com
Key Laboratory of Functional Materials Chemistry of Guizhou Province, School of Chemistry and
Materials Science, Guizhou Normal University, Guiyang, China.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2021.1927031
ß 2021 Taylor & Francis Group, LLC

2
X. LIU ET AL.
Table 1. Optimization of NaOH-promoted synthesis of mesityl ITC from 2,4,6-
trimethylaniline.
a
Entry
Base
Et
CO
NaHCO
NaOAc
NaOH
KOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Solvent
Time (h)
Yield
1
2
3
4
5
6
7
8
9
3
N
3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dried MeCN
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
6
9
12
45%
33%
14%
16%
66%
64%
58%
50%
15%
10%
7%
22%
36%
50%
21%
73%
81%
62%
K
2
Scheme 1. Two general approaches to ITC synthesis.
3
MeCN:H
2
OO ¼ 9:1
H
2
1
1
1
1
1
1
1
1
1
a
0
1
2
3
4
5
6
7
8
EtOAc
DCM
THF
DMSO
MeOH
EtOH
MeCN
MeCN
MeCN
Isolated yields.
[
18]
primary amines promoted by n-butyllithium
Grignard reagent.
and a
[
19]
Although the strongly basic organo-
lithium and organomagnesium reagents effectively desulfur-
ate the dithiocarbamate intermediate, the very forcing
conditions have severely restricted the substrate scope and
limited its synthetic utility. One-pot base-promoted prepar-
ation of ITCs has not been disclosed until within the last
decade. In 2013, Zhang and coworkers reported KOH-pro-
moted aryl ITC synthesis under mechanical ball milling con-
ditions. Employing KOH as both the base and the
desulfurating reagent, a series of aryl ITCs were prepared at
[
20]
room temperature.
More recently, Gajda and coworkers
studied microwave-assisted ITC synthesis promoted by trie-
ꢀ
[21]
thylamine at 90 C.
In both cases, special equipment, a
ball mill or a microwave reactor together with sealed vessels,
is required for the implementation of the reactions. To our
knowledge, benchtop base-promoted ITC synthesis has not
been disclosed. Herein, we report NaOH-promoted synthesis
of ITCs under mild benchtop conditions in the absence of
extra desulfurating reagents. In this method, ITCs are syn-
thesized via the dithiocarbamate desulfurization approach,
wherein the dithiocarbamate intermediate undergoes decom-
position with the low-cost and readily available NaOH serv-
ing as the base as well as the desulfurating reagent. Various
aryl and benzyl ITCs are prepared at room temperature
without special equipment.
Results and discussion
We commenced our investigation by screening a series of
bases for the desired benchtop synthesis of mesityl ITC 2a
(
Table 1). When the organic base triethylamine was
[
21]
employed as reported by Gajda,
2a was obtained in 45%
Scheme 2. Base-promoted ITC synthesis.
yield (entry 1). Switching to weak inorganic bases failed to

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
[
10,23,24]
Table 2. Optimization of carbon disulfide and NaOH loading.
Table 3. The substrate scope of aryl amines.
a
Entry
NaOH (equiv.)
CS
2
(equiv.)
Time (h)
Yield
1
2
3
4
5
6
7
a
1.0
2.0
3.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
1.0
2.0
3.0
4.0
3
3
3
9
9
9
9
48%
66%
65%
24%
77%
81%
76%
Isolated yields.
2
a
2b
70% yield
2c
[23]
[10]
[10]
[10]
8
1% yield
74% yield
provide comparable yields (entry 2–4, 14%–33% yield). The
strong inorganic bases NaOH (entry 5) and KOH (entry 6)
furnished the product in 66% and 64% yield, respectively.
These results were surprising in that NaOH and KOH are
known to hydrolyze the solvent acetonitrile, but yet they
afforded the target ITC in the highest yields. It was evident
that such difference in reaction yields unlikely resulted from
the hydrolysis of acetonitrile, since the reaction with the
hydrolysis product (in the case of NaOH), NaOAc, afforded
the product in only 16% yield (entry 4). These findings
motivated us to perform a detailed solvent study using
NaOH as the base. In our attempt to probe the effect of the
potential hydrolysis of acetonitrile, both dried and wet
acetonitrile were subjected to the reaction conditions, but no
superior yields were achieved (entry 7 and 8, 58% and 50%
yield, respectively). In addition, water was tested as the sole
solvent for the reaction to give the target ITC in 15% yield
2
d
2e
82% yield
2f
[24]
7
7
7% yield
56% yield
2g
2h
70% yield
2i
[24]
[10]
1% yield
74% yield
2
j
2k
78% yield
2l
[10]
6
0% yield
70% yield
(entry 9), indicating that an organic solvent was necessary
for dissolving the 2,4,6-trimethylaniline starting material. A
recent study suggested that the hydrolysis of acetonitrile by
NaOH required the presence of a significant amount of
water as well as remarkably higher temperature than room
2
m
2n
72% yield
2o
23% yield
[10]
[10]
7
4% yield
Note: Isolated yields.
[
22]
temperature.
Herein, with entry 5 as an example, we
postulated that the trace amount of water in the solvent
would not cause considerable hydrolysis of acetonitrile
under basic conditions at room temperature, but to the con-
trary, increased the solubility of NaOH in the reaction mix-
The effect of carbon disulfide and NaOH loading on the
ture for improved reaction efficiency. Next, a series of reaction was also examined and the results are summarized
aprotic solvents were screened. To our disappointment, only in Table 2.
poor yields were obtained (entry 10–13, 7%–36% yield).
With optimized reaction conditions in hand, we set out
Alcohols were also tested in the solvent study. While the to explore the substrate scope of the developed ITC synthe-
reaction with methanol was promising (entry 14, 50% yield), sis. A variety of aryl amines were subjected to the developed
much reduced yield was observed with ethanol (entry 15, conditions (Table 3). With unsubstituted aniline provided
2
1% yield). With NaOH as the base and acetonitrile as the 2b in 70% yield, introducing methyl groups at the ortho
solvent, extending the reaction time to 6 h improved the (2c) and the para (2d) positions increased the yield to 74%
yield to 73% (Table 1, entry 16). Further extending the reac- and 77%, respectively. Submitting the disubstituted 3,5-
tion time to 9 h, to our satisfaction, 2a was obtained in 81% dimethylaniline to the reaction conditions afforded 2e in
yield (entry 17). However, a decrease in reaction efficiency excellent yield. Apparently, the steric effect did not play a
was observed when the substrates were allowed to react for significant role in the cases of the mono- and di-methyl sub-
1
2 h (entry 18, 62% yield).
stituted anilines tested. Substrates containing electron-

4
X. LIU ET AL.
withdrawing groups were also tolerated. Notable electronic when benzylamine was subjected to the reaction conditions,
effects were observed in fluorine to bromine substitution benzyl ITC 2o was furnished notwithstanding that the yield
(2f–2i, 56%–74% yield), which was consistent with the was not ideal. Aryl amines with strongly electron-withdraw-
increased nucleophilicity of the corresponding aryl amines. ing groups, such as 4-nitroaniline, and aliphatic primary
Quite unexpectedly, 5-chloro-2-methylaniline delivered the amines were also subjected to the optimal conditions, but
product 2j with much diminished reaction efficiency. unfortunately,
they
failed
to
provide
respective
Electron-sufficient aryl amines proved to be compatible sub- ITC products.
strates as well. Ortho, meta and para-methoxy anilines
afforded the targeted ITCs in generally good yields (2k–2m, the developed method, we performed a gram-scale synthesis
0%–78% yield). The para-substituted aniline bearing an of the mesityl ITC 2a (Scheme 3). To our delight, the reac-
In order to further demonstrate the synthetic utility of
7
ethoxy group provided ITC 2n in 72% yield. Once again, tion remained efficient at large scale.
steric hindrance did not exhibit obvious effects in the cases
of aryl amines possessing electron-donating groups. Finally,
Proposed mechanism
Control experiments were performed to propose a mechan-
ism for the developed ITC synthesis (Scheme 4). In the
absence of NaOH, the reaction from 2,4,6-trimethylaniline
1
a to ITC 2a did not proceed (Scheme 4a), suggesting that
NaOH was necessary for the reaction to take place. The
insignificant effect of atmosphere (oxygen and nitrogen) on
reaction efficiency (Scheme 4b and 4c, respectively) indi-
cated that the dithiocarbamate desulfurization was unlikely
an oxidative decomposition promoted by the oxygen in air
or the dissolved oxygen in the solvent.
Scheme 3. Gram-scale synthesis of mesityl ITC.
Scheme 4. Control experiments.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
Scheme 5. Proposed mechanism.
Given the above results, the proposed mechanism Disclosure statement
[
14b,21,25]
(
Scheme 5) is based on literature precedents
and
The authors declare no potential conflict of interest.
supported by the formation of sodium sulfide, which was
observed during the reaction course as a yellow precipitate
in acetonitrile, but well soluble in water. It is proposed that Funding
aniline derivative 1 first reacts with carbon disulfide to pro-
This work was supported by Guizhou Provincial Natural Science
Foundation under Grant [2020]1Y030; Guizhou Medical University
vide the key dithiocarbamate intermediate 3. Under the
alkaline conditions, 3 undergoes deprotonation to form the Ph.D. Research Foundation under Grant J[2019]007.
dianion 4. Finally, in the presence of NaOH, the dianion 4
decomposes, expelling a sulfide anion to produce the
sodium sulfide precipitate, whose formation serves as a
plausible driving force for the reaction.
ORCID
Xinyun Liu
Hang Li
http://orcid.org/0000-0002-2525-1944
http://orcid.org/0000-0003-4060-4215
Conclusion
In conclusion, we have developed an operationally-simple,
economical and environmentally-friendly protocol for ITC
synthesis under benchtop conditions at room temperature.
Notably this is the first benchtop ITC synthesis promoted
solely by a base. The readily available NaOH functioned
both as a base and a desulfurating reagent. Sterically and
electronically diverse aryl amines and benzylamine were tol-
erated under the reaction conditions. Future work in our
laboratory will focus on the detailed mechanistic study of
NaOH-promoted desulfurating decomposition of the dithio-
carbamate intermediate.
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