Copper-catalyzed S-arylation of tetramethylguanidine-heterocumulene adducts

Article abstract of DOI:10.1016/j.tetlet.2014.01.006

The synthesis of a novel class of aryl bis(dimethylamino) methylenecarbamodithioates via a copper-catalyzed S-arylation reaction of 1,1,3,3-tetramethylguanidine-heterocumulene adducts is described.

Full text of DOI:10.1016/j.tetlet.2014.01.006

Tetrahedron Letters 55 (2014) 1323–1325
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed S-arylation of tetramethylguanidine–heterocumulene
adducts
⇑
Issa Yavari , Manijeh Nematpour, Tahereh Damghani
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a novel class of aryl bis(dimethylamino)methylenecarbamodithioates via a copper-cat-
alyzed S-arylation reaction of 1,1,3,3-tetramethylguanidine–heterocumulene adducts is described.
Ó 2014 Published by Elsevier Ltd.
Received 6 October 2013
Revised 28 November 2013
Accepted 2 January 2014
Available online 9 January 2014
Keywords:
Ullmann coupling
Carbamodithioates
Copper-catalyzed
Heterocumulenes
S-arylation
Cross-coupling reactions using transition metal catalysis repre-
sent a powerful tool for the formation of carbon–heteroatom
bonds.1–6 Copper-catalyzed coupling reactions were first reported
by Ullmann,7 and have found increasing utility for the construction
of carbon-heteroatom bonds.8–10 Although several copper-catalyzed
reactions have been reported for C(aryl)–N and C(aryl)–O, C(aryl)–S
bond formation is much less investigated. Carbon–sulfur bond
formation is a fundamental approach to introduce sulfur into
organic compounds.11–13 Sulfur is present in many molecules that
are of biological, pharmaceutical, and material interest.14 Thus, the
investigation of new protocols for C–S bond generation, which can
lead to the discovery of less expensive and more efficient synthetic
methods for the preparation of organo-sulfur compounds has
attracted much attention in recent years.15–17
Mild and efficient methods for the synthesis of carbamimido-
thioates and dithiocarbamates have attracted widespread interest
due to their diverse biological activities. Consequently, several
methods have been developed for the construction of these com-
pounds.31–33 The biological and synthetic significance places this
scaffold in a privileged position in medicinal chemistry research.
Thus we have investigated copper-catalyzed C(aryl)–S bond forma-
tion using isothiocyanates or carbon disulfide, 1,1,3,3-tetramethyl-
guanidine, and aryl halides.34
Initially, iodobenzene (1a), phenylisothiocyanate (2a) or carbon
disulfide (2m), and 1,1,3,3-tetramethylguanidine (3) were selected
as the model substrates. Several catalysts including CuI, CuBr, CuCl,
Cu2O, and copper powder were tested with CuI giving the best
Organic dithiocarbamates are important in medicinal18 and
agricultural chemistry.19 These compounds are used in the rubber
industry as vulcanization accelerators,20 in controlled radical poly-
merization techniques,21 and in the synthesis of ionic liquids.22
S-Aryl-isothioureas23,24 are starting materials for the synthesis of
guanidines and heterocyclic systems.25,26 It has been recognized
that they can also serve as remarkably potent inhibitors for a
whole range of enzyme systems.27–29 Inhibition of nitric oxide
synthase has led to their use in the treatment of a range of
life-threatening conditions including septic shock, acute kidney
failure, and organ rejection after transplantation surgery.30
Table 1
Optimization of the reaction conditions for the formation of compound 5a from
iodobenzene (1a), phenylisothiocyanate or CS2, and tetramethylguanidine (3)
Catalysta
Solvent
Yieldb (%)
Catalysta
Solvent
Yieldb (%)
Cu2O
Cu2O
Cu2O
CuCl
CuCl
CuCl
CuIc
DMF
43
32
17
61
54
33
83
70
CuI
CuI
CuI
CuBr
CuBr
CuBr
Cu
Toluene
DMSO
THF
46
41
26
62
31
24
—
MeCN
Toluene
DMF
MeCN
Toluene
DMF
DMF
Toluene
DMSO
DMF
CuI
MeCN
Cu
Toluene
—
a
b
c
10 mol % of catalyst was used unless otherwise stated.
Reaction time = 10 h.
5 mol % of catalyst was used; reaction time = 25 h.
⇑
Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
0040-4039/$ - see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2014.01.006

1324
I. Yavari et al. / Tetrahedron Letters 55 (2014) 1323–1325
NH
S=C=Z
Me2N
NMe2
2
3
CuI (10 mol%)
1,10-phenanthroline (10 mol%)
K2CO3 (1.5 eq)
NMe2
Z
NMe2
Z
Ar
Ar-X
Me2N
N
S
Me2N
N
SH
DMF, reflux, 10 h
5
4
1
5
1,2,4,5
Yield (%) of
83
X
Ar
Z
a
b
c
d
e
f
N-Ph
Ph
I
N-Ph
4-Me-C6H4
4-Br-C6H4
4-Cl-C6H4
4-MeO-C6H4
Ph
I
87
79
77
73
76
72
79
74
65
69
60
82
83
78
75
70
71
N-Ph
I
N-Ph
I
N-Ph
I
N-C6H4-4Cl
I
g
h
i
N-C6H4-4Cl
4-Me-C6H4
Ph
4-Me-C6H4
3-Me-C6H4
3-O2N-C6H4
2-thienyl
Ph
4-Me-C6H4
4-Br-C6H4
4-Cl-C6H4
2-thienyl
3-NO2-C6H4
I
N-C6H4-4NO2
I
N-C6H4-4NO2
I
N-Ph
N-Ph
N-Ph
S
j
Br
Br
Br
I
k
l
m
n
o
p
q
r
S
I
S
I
S
I
S
Br
Br
S
Scheme 1. Copper-catalyzed C–S coupling of aryl halides with 1,1,3,3-tetramethylguanidine and heterocumulenes.
results. Among several solvents screened, N,N-dimethylformamide
(DMF) was the best. Thus, the optimized reaction conditions used
were: 10 mol % of CuI as the catalyst, 10 mol % of 1,10-phenanthro-
line as the ligand, 1.5 mmol of K2CO3 as the base, 1 mmol of
1,1,3,3-tetramethylguanidine, and 1 mmol of isothiocyanate or
1.5 mmol of carbon disulfide in DMF (see Table 1).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.006.
Using the optimized conditions, various carbamimidothioates
were prepared from isothiocyanates, 1,1,3,3-tetramethylguanidine,
aryl iodides and aryl bromides. Aryl bromides served as low yield-
ing substrates compared to aryl iodides (see Scheme 1).
The structures of products 5a–r were assigned from IR, 1H NMR,
13C NMR, and mass spectral data. The 1H NMR spectrum of 5a
exhibited two singlets for the dimethylamino (2.74, 2.86 ppm) pro-
tons, along with characteristic multiplets for the phenyl protons.
The 13C NMR spectrum of 5a exhibited 12 signals in agreement
with the proposed structure. The mass spectrum of 5a displayed
the molecular ion peak at m/z = 326. The NMR spectra of com-
pounds 5b–r were similar to those of 5a, except for the substitu-
ents, which showed characteristic signals in the appropriate
regions of the spectra.
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30 min, and the layers separated. The aqueous layer was extracted with CH2Cl2
(3 ꢀ 3 mL) and the combined organic fractions dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by flash
column chromatography [silica gel (230–400 mesh; Merck), hexane/EtOAc,
5:1] to give the product.
Phenyl N-bis(dimethylamino)methylene-N0-phenylcarbamimidothioate (5a):
Cream powder, mp: 139–141 °C; yield: 0.27 g (83%). IR (KBr) (m
max, cmꢁ1):
2050, 1678, 1580, 1405, 1371, 1172, 1075. 1H NMR (500 MHz, CDCl3): dH = 2.74
(6H, s, NMe2), 2.86 (6H, s, NMe2), 7.12 (2H, d, 3J = 7.4 Hz, Ar), 7.18 (1H, t,
3J = 7.4 Hz, Ar), 7.24 (2H, t, 3J = 7.4 Hz, Ar), 7.35 (2H, d, 3J = 7.5 Hz, Ar), 7.39 (1H,
t, 3J = 7.5 Hz, Ar), 7.65 (2H, t, 3J = 7.5 Hz, Ar). 13C NMR (125 MHz, CDCl3):
dC = 41.8 (NMe2), 44.4 (NMe2), 125.9 (C), 126.1 (2 CH), 127.7 (C), 128.7 (2CH),
130.0 (CH), 131.5 (CH), 133.7 (2CH), 135.4 (2CH), 166.9 (C), 172.0 (C). EI-MS:
m/z (%) = 326 (M+, 5), 282 (6), 217 (12), 212 (16), 114 (100), 109 (21), 77 (51),
44 (31). Anal. Calcd for C18H22N4S (326.16): C, 66.22; H, 6.79; N, 17.16. Found:
C, 66.46; H, 6.75; N, 17.21.
33. Sandin, H.; Swanstein, M. L.; Wellner, E. J. Org. Chem. 2004, 69, 1571.
34. General procedure for the synthesis of compounds 5a–r:
A mixture of 2
(1–1.5 mmol) and 3 (1 mmol) was stirred in DMF (2 mL) for 30 min. Next, a
mixture of aryl halide (1 mmol), CuI (0.1 mmol), 1,10-phenanthroline
(0.1 mmol), and K2CO3 (1.5 mmol) in DMF (3 mL) was slowly added and the
resulting mixture stirred at 110 °C, under an N2 atmosphere. After completion
of the reaction [about 10 h; TLC (EtOAc/hexane, 1:5) monitoring], the mixture
was diluted with CH2Cl2 (2 mL) and aqueous NH4Cl solution (3 mL), stirred for