Iodine mediated direct coupling of benzylic alcohols with dithiocarbamate anions: An easy access of S-benzyl dithiocarbamate esters under neat reaction condition

Article abstract of DOI:10.1016/j.tetlet.2020.152382

An efficient, metal and solvent free synthesis of S-benzylic dithiocarbamate esters has been demonstrated via the iodine mediated direct C-S coupling of benzylic alcohols with dithiocarbamate anions generated in-situ by the reactions of amines and carbon disulphide. All the reactions were very fast (15–30 min) and performed under open air atmosphere. Cyclic and acyclic secondary amines, primary amine, aromatic amine actively participated in the one-pot coupling reactions with different benzylic alcohols. Non benzylic alcohols offer the synthesis of O-thiocarbamate compounds under the identical reaction condition.

Full text of DOI:10.1016/j.tetlet.2020.152382

Tetrahedron Letters 61 (2020) 152382
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Tetrahedron Letters
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Iodine mediated direct coupling of benzylic alcohols with
dithiocarbamate anions: An easy access of S-benzyl dithiocarbamate
esters under neat reaction condition
⇑
Soumya Dutta, Amit Saha
Department of Chemistry, Jadavpur University, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, metal and solvent free synthesis of S-benzylic dithiocarbamate esters has been demonstrated
via the iodine mediated direct C-S coupling of benzylic alcohols with dithiocarbamate anions generated
in-situ by the reactions of amines and carbon disulphide. All the reactions were very fast (15–30 min) and
performed under open air atmosphere. Cyclic and acyclic secondary amines, primary amine, aromatic
amine actively participated in the one-pot coupling reactions with different benzylic alcohols. Non ben-
zylic alcohols offer the synthesis of O-thiocarbamate compounds under the identical reaction condition.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 15 June 2020
Revised 15 August 2020
Accepted 18 August 2020
Available online 26 August 2020
Keywords:
S-Benzyl dithiocarbamate ester
O-Thiocarbamate
Iodine mediated coupling
Neat reaction
Introduction
However, the use of toxic and explosive reagent, diethyl azodicar-
boxylate (DEAD) and the use of dry DMSO solvent make the proce-
Dithiocarbamate compounds have gained immense importance
mainly because of their medicinal values. Dithiocarbamate moi-
eties are often found in many biologically important organic mole-
cules [1] (Fig. 1). They are also useful as important synthetic
intermediates [2], protecting groups [3] in peptide chemistry, rad-
ical chain transfer agents [4], linkers in solid phase organic synthe-
sis [5], vulcanization accelerators [6] in the rubber industry,
chelating ligands [7] and fusarium oxysporum agents [8]. The com-
mon methods for the preparation of organic dithiocarbamates
involve the reaction of amines with thiophosgene [9], nucleophilic
addition of thiols to isothiocyanates [10], nucleophilic substitution
in alkyl halides [11]/tosylates [12]/epoxides [11a,13], reaction of
N-tosylhydrazones [14] with dithiocarbamate anions and addition
reactions [11a,15] in electron deficient alkenes. The modern
method of synthesizing dithiocarbamate compounds is the cross-
coupling reactions using the coupling partners like, aryl/vinyl
halides [16], aryldiazonium cations [17], arylboronic acids [18]
and allylic acetates [19]. However, the use of alcohols as the cou-
pling partner is more advantageous due to their lower price, easy
availability and higher stability. To the best of our knowledge,
there is only one report of using alcohols in S-alkylation of dithio-
carbamic acids [20] following the Mitsunobu coupling strategy.
dure industrially and environmentally less acceptable. In this
article we are demonstrating the direct C(sp3)-S coupling between
benzylic alcohols and dithiocarbamate anions in presence of iodine
under neat reaction condition. Earlier, we have explored dithiocar-
bamate chemistry in the development of useful synthetic protocols
for unsymmetrical thioureas [21], mixed disulfides [22] and diaryl
thioether [23] compounds. In continuation of our previous works,
we are now intended to focus on metal and solvent free one-pot
synthesis of S-benzyl dithiocarbamate esters using various ben-
zylic alcohols as one of the coupling partners. Dithiocarbamate
anions generated in situ by the reactions of amines and carbon
disulfide undergo efficient S-benzylations by the benzylic alcohols
in presence of molecular iodine within very short reaction time
period (15–30 min) at 80 °C (Scheme 1).
Results and discussion
The reaction is very easy to handle. The dithiocarbamate anion
generated in situ by the reaction of amine and carbon disulfide was
heated with benzylic alcohol in presence of iodine at 80 °C under
open aerial condition. Upon completion of reaction (checked by
the TLC) the crude product is purified by usual column
chromatography.
⇑
The reaction condition was optimized by screening of the
various reaction parameters (Table 1). In our initial attempt the
Corresponding author.
E-mail address: amit.saha@jadavpuruniversity.in (A. Saha).
https://doi.org/10.1016/j.tetlet.2020.152382
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
S. Dutta, A. Saha / Tetrahedron Letters 61 (2020) 152382
only in moderate yield (64%) (entry 1, Table 1). Other common
organic solvents like DMF, DMSO, THF, dioxane, toluene and water
(entries 2–7, Table 1) were also found to be ineffective to carry out
the reaction with satisfactory yield. Surprisingly, the reaction was
found to proceed efficiently under the solvent free condition at
80 °C, producing the product 3b with 88% yield within 15 min of
reaction time period (entry 8, Table 1). However, prolongation of
the reaction time (entries 9, 10, Table 1) and elevation of reaction
temperature (entries 12, Table 1) were observed to have an adverse
effect on the yield of the reaction producing some unidentified side
products. The reaction remains incomplete at lower reaction tem-
perature (60 °C) (entry 11, Table 1). Using of other iodinated
reagents such as, NIS and TBAI (entries 13, 14, Table 1) do not pro-
duce the desired product satisfactorily. One equivalent of iodine
was optimized to be suitable for the reaction. To check the crucial
role of iodine we performed the blank experiment which shows the
reaction not to initiate at all in the absence of iodine (entry 17,
Table 1).
The standardized reaction condition was then tested with a
variety of amines and benzylic alcohols. Many cyclic secondary
amines, such as piperidine, pyrrolidine, morpholine, N-methyl
piperazine, 2-methyl piperidine, 4-methyl piperidine have been
used to prepare S-benzyl dithiocarbamates (3b – 3d, 3g – 3i, 3m
– 3p, Table 2) with very good yields. Acyclic secondary amines,
such as dimethyl amine, diethyl amine, dibenzyl amine were also
explored in the preparation of dithiocarabamate esters (3a, 3e,
3f, 3l, Table 2). S-benzylation was performed with the dithiocarba-
mate anion generated from aromatic amine, such as N-methyl ani-
line to obtain the desired product 3j. In this protocol, primary
amine like benzyl amine has participated efficiently to produce
dithiocarbamate product 3k with satisfactory yield (74%). Along
with benzyl alcohol, 4-methoxybenzyl alcohol, 4-chlorobenzyl
Fig. 1. Biologically active organic molecules containing dithiocarbamate
framework.
Scheme 1. Iodine mediated synthesis of dithiocarbamate esters via CAS coupling of
benzylic alcohols and dithiocarbamate anions.
alcohol and
a-methylbenzyl alcohol were found equally reactive
to produce the S-benzylated products.
However, the course of reaction changes in case of S-ethyla-
tion of the dithiocarbamate anion using ethanol and results in
the formation of O-ethyl thiocarbamate (5a, Table 3) under the
identical reaction condition. Allyl alcohol, n-butyl alcohol and
homo propargyl alcohol also reacted following the similar way
dithiocarbamate anion generated by the reaction of piperidine and
carbon disulfide was allowed to react with benzyl alcohol in pres-
ence of 1 equiv. of iodine in acetonitrile solvent at 80 °C under open
air. The desired S-benzyl dithiocarbamate ester (3b) was obtained
Table 1
Optimization of the reaction condition.a
Entry
Reagent (equiv.)
Solvent
Temp (oC)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
NIS (1.0)
TBAI (1.0)
I2 (0.5)
I2 (1.5)
–
MeCN
DMF
DMSO
THF
Dioxane
Toluene
H2O
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
80
80
80
65
80
80
80
80
80
80
60
100
80
80
80
80
80
60
60
60
60
60
60
60
15
40
60
60
60
15
15
15
15
15
64
32
0
26
trace
0
trace
88
82
78
66
74
24
30
56
80
0
9
10
11
12
13
14
15
16
17
a
Reaction condition: All reactions were performed using benzyl alcohol (162 mg, 1.5 mmol), piperidine (85 mg, 1 mmol), carbon disulphide (152 mg, 2 mmol) under aerial
condition. bIsolated yields of the product.

S. Dutta, A. Saha / Tetrahedron Letters 61 (2020) 152382
3
Table 2
I
I
Substrate scope for the synthesis of S-benzyl dithiocarbamatesa,b.
OH
Ar
Ar
S
1
HOI + I
S
N
Ar
3
S
S
Dithiocarbamate ester
N
CS2
NH
+
2
I2
S
R1
S
S
S
S
R1OH
O
N
N
N
4
5
6
O-thiocarbamate
Scheme 2. Proposed reaction mechanism.
isolated from an incomplete reaction of piperidine, CS2 and n-butyl
alcohol (reaction quenched after 5 min) and was characterized by
1H and 13C NMR spectroscopy (spectra included in the Supporting
Information).
Conclusions
a
Reaction condition: The reactions were carried out using 1 (1.5 mmol),
2 (1 mmol), carbon disulphide (2 mmol) under aerial condition. bIsolated
In conclusion, we have developed an efficient and benign proce-
dure to prepare S-benzylic dithicarbamate esters directly from
benzylic alcohols. Neat reaction condition, open air reaction set-
up and use of mild Lewis acid like iodine make the synthetic pro-
tocol environmentally friendly. The protocol also offers a one-pot
synthetic route for the preparation of O-thiocarbamates. Easy
availability of the starting materials, simple operating procedures
and high yields of dithiocarbamate /O-thiocarbamate compounds
are the key features of economic and synthetic advantages.
yields of the products. cFor solid alcohol MeCN (2 ml) was used as solvent.
Table 3
Synthesis of O-thiocarbamatesa,b.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
a
Reaction condition: The reactions were carried out using alcohol (4)
(1.5 mmol), amine (2) (2 mmol), carbon disulphide (3 mmol) under aerial
Acknowledgments
condition. bIsolated yields of the products.
Soumya Dutta is thankful to CSIR, India for his fellowship (JRF).
We are pleased to acknowledge the financial support from UGC-
BSR Start-up-grant (FD Diary No.4855; Dated: 24.09.2018). RUSA
2.0 research grant from Jadavpur University, UGC-CAS program
in Chemistry, Jadavpur University and the DST-PURSE Program at
Jadavpur University are also acknowledged.
to produce the O-thiocarbamate compounds (5b – 5d, Table 3)
with good yields.
Iodine mediated reactions of alcohols are known to follow rad-
ical pathways [24]. In order to understand the mechanism of the
reaction, we conducted the reaction of piperidine, CS2 and benzyl
alcohol in presence of radical quenchers like TEMPO (2,2,6,6-
tetramethylpiperidine-N-oxide) and BHT (butylated hydroxy-
toluene). Both the reactions went smoothly producing the desired
product, 3b with identical yield. Thus, the possibility of radical
pathway was ruled out. We propose the possibility of benzylic car-
bocation intermediacy in presence of molecular iodine (Scheme 2).
Iodine acts as mild Lewis acid [25] and generates benzylic carbo-
cataion intermediate from benzylic alcohol [26]. The dithiocarba-
mate anion generated in situ by the reaction of amine and carbon
disulfide reacts with the benzylic carbocation to produce the
desired dithiocarbamate ester as depicted in Scheme 2. However
in absence of benzylic alcohol, iodine oxidizes dithiocarbamate
anion to the corresponding thiuram disulfide (6) [27] intermediate
(Scheme 2). The nucleophilic attack by non-benzylic alcohol (4) at
the thiocarbonyl carbon of thiuram disulfide [28] produces the O-
thiocarbamate product. The intermediate, thiuram disulfide was
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152382.
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