An Efficient Synthesis of Benzyl Dithiocarbamates by Base-Promoted Cross-Coupling Reactions of Benzyl Chlorides with Tetraalkylthiuram Disulfides at Room Temperature

Article abstract of DOI:10.1002/ejoc.201801449

A straightforward, mild and efficient protocol for the synthesis of benzyl dithiocarbamates from benzyl chlorides and tetraalkylthiuram disulfides is presented. This protocol is compatible with a wide variety of electron-donating and -withdrawing substituents and enables construction of various dithiocarbamate derivatives from readily available starting materials.

Full text of DOI:10.1002/ejoc.201801449

A Journal of
Accepted Article
Title: An Efficient Synthesis of Benzyl Dithiocarbamates via Base-
Promoted Cross-Coupling Reactions of Benzyl Chlorides with
Tetraalkylthiuram Disulfides at Room Temperature
Authors: Zhiyong Wu, Miao Lai, Siyuan Zhang, Xianyun Zhong, Hao
Song, and Mingqin Zhao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801449
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10.1002/ejoc.201801449
European Journal of Organic Chemistry
COMMUNICATION
An Efficient Synthesis of Benzyl Dithiocarbamates via Base-
Promoted Cross-Coupling Reactions of Benzyl Chlorides with
Tetraalkylthiuram Disulfides at Room Temperature
Zhiyong Wu,*[a] Miao Lai,[a] Siyuan Zhang,[a] Xianyun Zhong,[a] Hao Song,[a] and Mingqin Zhao*[a]
Dedication ((optional))
Abstract: A straightforward, mild and efficient protocol for the
synthesis of benzyl dithiocarbamates from benzyl chlorides and
tetraalkylthiuram disulfides is presented. This protocol is compatible
conventional methods for the preparation of benzyl
dithiocarbamates typically involved the three-component
approachs: (i) the reactions of amines, carbon disulfide with
benzyl halides,[10] methylarenes[11] or benzaldehyde[12]; (ii) the
reactions of N,N-dimethylthiocarbamoyl chloride with the
corresponding thiolates;[13] (iii) the interactions of mercaptans,
amines, with bis(benzotriazolyl)methanethione.[14] Recently,
Alexanian and co-workers developed a general, convergent
approach to site-specific C-H functionalization via hydrogen
atom transfer using N-dithiocarbamates which affording to
various alkyl dithiocarbamates products.[15] Moreover, Knochel et
with
a
wide variety of electron-donating and -withdrawing
substituents and allows for construction of various dithiocarbamate
derivatives from readily available starting materials.
Introduction
In the past decades, organic dithiocarbamates have been
extensively investigated for their outstanding biological
activities,[1] pivotal role in agriculture[2] and controlled radical
polymerization techniques.[3] They have often been used as
vulcanization accelerators in the rubber industry,[4] as linkers in
solid-phase organic synthesis,[5] and recently used in the
synthesis of ionic liquids.[6] Among the compounds containing
dithiocarbamate moieties, the benzyl dithiocarbamates represent
one of the typical scaffolds possessing special activities, as
exemplified in Figure 1. Compound a (4-methoxybenzyl N, N-
diethyldithiocarbamate) showed excellent herbicidal activity
against graminaceous and broad-leaved plants.[7] Compound b
al. described
a
reaction of benzylzinc bromide with
tetramethylthiuram disulfide affording the corresponding benzyl
N, N-dimethyldithiocarbamate in excellent yield (Scheme 1 a).[16]
However, this prefunctionalization route is inevitably
accompanied with problems such as the need of extra
preparation steps for the frequently unstable precursors and the
formation of byproducts. Moreover, the unpleasant smell of the
substrate and the moisture sensitive precursors also limit their
wide application. Therefore, the development of an alternative
approach for the facile and efficient synthesis of benzyl
dithiocarbamate derivatives should be challenging and of great
significance. Based on our previous studies on direct cross-
coupling reactions,[17] we report herein a simple, mild and
efficient base-promoted cross-coupling reactions of benzyl
chlorides with tetraalkylthiuram disulfides (Scheme 1 b).
((3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)-methyl
4-(4-
fluorophenyl)piperazine-1-carbodithioate) exhibited significant
antitumor activity against human myelogenous leukemia K562
cells.[8] Compound c (benzyl N, N-diethyldithiocarbamate) was
used as the iniferter and sur-iniferter for the synthesis of flame
retardant materials.[9]
Figure 1. Examples illustrating the importance of benzyl dithiocarbamates.
Due to the significance of benzyl dithiocarbamates in various
fields, the development of efficient methods that allow for the
easy access to this substructure is of great importance. The
Scheme 1. Previous art and current work on the synthesis of benzyl
dithiocarbamates.
Results and Discussion
[a] College of Tobacco Science, Flavors and Fragrance Engineering &
Technology Research Center of Henan Province, Henan Agricultural
University, 95, Wenhua Road, Zhengzhou 450002, P. R. China
E-mail: smileyongyong062@163.com
http://yancao.henau.edu.cn/a/shiziduiwu/yancaogongchengxi/20171112
/1476.html
E-mail: zhaomingqin118@126.com
http://yancao.henau.edu.cn/a/shiziduiwu/yancaogongchengxi/20171112
/1494.html
We commenced our studies by investigating the reaction of
benzyl chloride (1a) with tetramethylthiuram disulfide (TMTD,
2a). We first attempted the reaction of 1a (0.4 mmol) and 2a
(0.2 mmol) with Cu2O as catalyst and K2CO3 as base in DMSO
at 100 °C. To our delight, the reaction gave the expected
product 3aa (benzyl dimethylcarbamodithioate) in 45% yield
(Table 1, entry 1). Interestingly, an improved yield (60%) of 3aa
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10.1002/ejoc.201801449
European Journal of Organic Chemistry
COMMUNICATION
was observed with this reaction in the absence of Cu2O (Table 1, yields. Ortho, meta and para methyl, isopropyl and tert-butyl-
entry 2). It was found that the inorganic base played a crucial
role in this transformation and no desired product of 3aa was
observed without addition of any base (Table 1, entries 3 and 9).
Subsequently, we evaluated the effect of other bases to further
improve the yield of this transformation (Table 1, entries 4-8)
and the result showed that 1 equivalent of Cs2CO3 provided
product 3aa in the highest yield (82%, Table 1, entry 8). Further
examination of solvents indicated that none of the new screened
solvents such as Toluene, DMF or 1,4-Dioxane et al. benefited
the outcome (58-80%, Table 1, entries 10-18). Gratifyingly, the
modification of the substrate ratio led to an obviously increased
yield of the reaction (89%, Table 1, entry 20). The reaction
afforded slightly higher yield of 3aa when it was conducted at 60
oC (91%, Table 1, entry 21), and further decreasing the reaction
temperature to room temperature resulted in almost the same
reaction yield (91%, Table 1, entry 22). The reaction time was
also examined (Table 1, entries 23-24), and 24 h was found to
be the best choice.
substituted substrates gave the desired products in moderate to
excellent yields. However, only 41% yield of 3aa was detected
when benzyl bromide was used as the substrates. Interestingly,
slightly lower yield (82%) of the product 3ba was observed
Table 2. Substrate Scope for Cross-Coupling Reaction of Benzyl Chlorides
with Tetraalkylthiuram Disulfides.[a,b]
Table 1. Optimization of the Reaction Conditions.[a]
entry
base
solvent
yield (%) [b]
1[c]
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
Toluene
Xylene
DCE
45
60
N.R
72
25
43
46
82
N.R
76
58
61
58
61
80
72
70
72
79
89
91
91
91
83
2
3[c]
4
none
t-BuOK
KOH
5
6
K3PO4
7
Na2CO3
Cs2CO3
none
8
9
10
11
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
12
13
14
15
16
17
18
19d
20e
21e,f
22e,g
23e,g,h
24e,g,i
1,4-Dioxane
DMF
THF
MTBE
Chlorobenzene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.3 mmol), base (1.0 equiv.), solvent
(1.0 mL), room temperature, 24 h. [b] Isolated yields. [c] Starting from benzyl
bromide.
compared with 3aa (91%), 3ca (91%) and 3da (99%), perhaps
due to the steric hindrance. Similar outcomes were observed
when 4-isopropylbenzyl chloride 1e and 4-tert-butylbenzyl
chloride 1f were subjected to the reactions (3ea and 3fa vs. 3da,
36-41% vs. 99%). The coupling reactions of benzyl chlorides
with di- or tri-substituted benzenes were also efficient, and the
disired products (3ga-3ka) were obtained in moderate to good
yields (28%-89%). Electronic effects exerted by the phenyl
group do not influence the reaction results to a large extent, and
benzyl chlorides bearing electron-withdrawing substituents (Br,
Cl, F) also provided the corresponding products (3ma-3sa) in
good to excellent yields (65-99%). The reaction afforded a
slightly lower yield when the α-methylbenzyl chloride 1t
participated the reaction. This was probably due to the steric
effect (3ta vs. 3aa, 71% vs. 90%). The α-naphthylmethyl
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), base (1.0 equiv.),
solvent (1.0 mL), 100 °C, 48 h. [b] Isolated yields. [c] 10 mol % Cu2O was
added. [d] n(1a)/n (2a) = 0.6/0.2. [e] n (1a)/n (2a) = 0.4/0.3. [f] Run at 60 oC. [g]
Run at r.t. [h] 24 h. [i] 12 h.
With the establishment of the optimal reaction conditions, we
turned our attention to the scope of substrates for this
transformation, as shown in Table 2. It was found that benzyl
chlorides with both electrondonating and -withdrawing groups
(such as F, Cl, Br, Me, i-Pr, t-Bu and MeO et al.) at diverse
positions all tolerated in this reaction and afforded the
corresponding cross-coupling products in good to excellent
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10.1002/ejoc.201801449
European Journal of Organic Chemistry
COMMUNICATION
resulting solution was directly filtered and concentrated under reduced
pressure. Purification by flash chromatography (petroleum ether /ethyl
acetate = 8:1) gave 74.3 mg of product 3aa (91% yield). In general, the
identity and purity of the products were confirmed by 1H and 13C NMR
spectroscopy, HRMS and IR.
chloride 1u and 9-anthracenylmethylchloride 1v can be cross-
coupled in 76% (3ua) and 75% (3va) yields, respectively, while
2-(chloromethyl)-6-methylpyridine (1w) and 1-chlorobutane (1x)
resulted the corresponding products 3wa (99%) and 3xa (93%)
in excellent yields, indicating a good compatibility of the
reactions to alkyl chlorides. In addition, N,N,N′,N′-
tetraalkylthiuram disulfides with ethyl and n-butyl groups (TETD,
2b, and TBTD, 2c, respectively) were applicable and the yields
of the resulting benzyl dithiocarbamates were comparable to
those obtained in reactions with TMTD.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the Key Science and Technology
Program of Science and Technology Department of Henan
Province (Nos. 132102210042) and Henan Agricultural
University (30500567, 30500701).
Scheme 2. Gram-Scale Reaction of 1a with 2a.
Keywords: benzyl chlorides • C-S coupling reactions • synthetic
methods
disulfides
•
functional dithiocarbamates • tetraalkylthiuram
We further expanded the reaction of benzyl chloride 1a and
tetramethylthiuram disulfide 2a to 1.51g and 10.00g scale to
demonstrate the synthetic utility of this reaction. In these cases,
product 3aa was obtained in 81% and 79% yields, respectively
(Scheme 2).
Notes and references
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Scheme 3. Proposed Reaction Mechanism.
According to the previous reports,13,18 a plausible reaction
mechanism was described in Scheme 3. Firstly, the thiuram
reagent 2 reacted with Cs2CO3 affording nucleophile A, then,
nucleophile A underwent nucleophilic substitution reactions with
alkyl
chlorides
generating
the
S-alkyl
N,N-
dialkyldithiocarbamates in moderate to excellent yields.
Conclusions
In conclusion, we have disclosed the first example of base-
promoted cross-coupling reactions for the direct synthesis of
benzyl
dithiocarbamates
from
benzyl
chlorides
and
tetraalkylthiuram disulfides under mild conditions. Various benzyl
dithiocarbamate derivatives were selectively prepared in good to
excellent yields. We anticipate further development of the
presented method and its application towards systhesis of
bioactive compounds.
Experimental Section
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Synthesis of benzyl dimethylcarbamodithioate (3aa): To a 10 mL
sealable tube equipped with a magnetic stirring bar was charged with all
solid reaction components, including tetramethylthiuram disulfide 2a (0.3
mmol) and Cs2CO3 (0.4 mmol). After the addition of benzyl chloride 1a
(0.4 mmol) and DMSO (1 mL), the resulting mixture was stirred at room
temperature for 24 h under air atmosphere, then quenched with a sat.
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Entry for the Table of Contents (Please choose one layout)
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Key Topic* C-S bond coupling
Zhiyong Wu,* Miao Lai, Siyuan Zhang,
Xianyun Zhong, Hao Song and Mingqin
Zhao*
Page No. – Page No.
A mild and efficient synthesis of benzyl dithiocarbamates through transition metal
free cross-coupling reactions was developed. This attractive methodology for the
synthesis of benzyl dithiocarbamate derivatives is of great significance due to the
product’s potential utilization in pharmaceutical industry.
An Efficient Synthesis of Benzyl
Dithiocarbamates via Base-Promoted
Cross-Coupling Reactions of Benzyl
Chlorides
with
Tetraalkylthiuram
Disulfides at Room Temperature
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