Efficient synthesis of functionalized dithiocarbamate derivatives through one-pot three-component reaction and evaluation of their antimicrobial activities

Article abstract of DOI:10.1007/s13738-012-0206-0

The one-pot three-component reaction of primary and secondary amines, carbon disulfide and β-nitrostyrene derivatives in neat condition at room temperature afforded functionalized dithiocarbamate derivatives in good to high yields. High bond-forming efficiency and easy work-up are advantages of this reaction. In vitro antimicrobial activities of synthesized compounds were studied against four Gram-positive bacteria, four Gram-negative bacteria and four fungi. The screening for the antimicrobial activity was performed by twofold serial dilution technique. Notably, some synthesized compounds displayed comparable or even better antibacterial and antifungal activities against some tested strains than the reference drugs ampicillin, streptomycin and amphotericin B, respectively. Graphical abstract: A series of novel dithiocarbamates 4a-j have been synthesized via three-component reaction and compared pharmacologically concerning their antimicrobial and antibacterial activities as well as antifungal activity [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-012-0206-0

J IRAN CHEM SOC (2013) 10:725–732
DOI 10.1007/s13738-012-0206-0
ORIGINAL PAPER
Efficient synthesis of functionalized dithiocarbamate derivatives
through one-pot three-component reaction and evaluation
of their antimicrobial activities
•
Elmira Ghabraie Hamid Moghimi
•
•
Saeed Balalaie Morteza Bararjanian
•
•
Frank Rominger Hamid Reza Bijanzadeh
Received: 15 August 2012 / Accepted: 5 December 2012 / Published online: 15 January 2013
ꢀ Iranian Chemical Society 2013
Abstract The one-pot three-component reaction of pri-
mary and secondary amines, carbon disulfide and b-nitro-
styrene derivatives in neat condition at room temperature
afforded functionalized dithiocarbamate derivatives in good
to high yields. High bond-forming efficiency and easy
work-up are advantages of this reaction. In vitro antimi-
crobial activities of synthesized compounds were studied
against four Gram-positive bacteria, four Gram-negative
bacteria and four fungi. The screening for the antimicrobial
activity was performed by twofold serial dilution technique.
Notably, some synthesized compounds displayed compa-
rable or even better antibacterial and antifungal activities
against some tested strains than the reference drugs ampi-
cillin, streptomycin and amphotericin B, respectively.
Keywords One-pot multicomponent reactions (MCRs) Á
b-Nitrostyrene Á Michael addition Á Neat reaction
conditions Á Functionalized dithiocarbamates Á
Antimicrobial activity
Introduction
Multicomponent reactions (MCRs) have gained a wide
interest in organic and medicinal chemistry. The develop-
ment of convenient approaches and selective synthetic
transformations through new one-pot MCRs is a major
challenge in modern organic synthesis [1–5]. Meanwhile,
solvent-free synthetic methods are being discovered for eco-
friendly synthesis of many organic compounds [6–8]. The
reactions under solvent-free conditions are considerably
safe, non-toxic and prevent energy consumption [9–11].
Carrying out one-pot multi-component reactions in solvent-
free conditions is of great importance in the context of green
synthesis.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-012-0206-0) contains supplementary
material, which is available to authorized users.
Dithiocarbamates are important sulfur-containing com-
pounds, which possess broad applications in organic and
medicinal chemistry [12–14]. They have been widely used
in organic synthesis [15–19], and they have a variety of
applications in agriculture [20–22], as well as in the rubber
industry as vulcanization accelerators and antioxidants
[23–25]. Furthermore, some of the dithiocarbamates
have direct antibacterial [26–28] and antitumor [29–32]
functions and are also cell apoptosis inhibitors [33].
Consequently, the synthesis of dithiocarbamate derivatives
with different substitution patterns at the thiol chain has
become a field of increasing interest in synthetic organic
chemistry during the past years. A survey of the literature
revealed relatively few methods for the synthesis of
dithiocarbamate derivatives in one-pot fashion, [34–48]
E. Ghabraie Á S. Balalaie (&) Á M. Bararjanian
Peptide Chemistry Research Center, K. N. Toosi University
of Technology, P. O. Box 15875-4416, Tehran, Iran
e-mail: balalaie@kntu.ac.ir
H. Moghimi
Microbial Biotechnology Lab, Department of Microbiology,
School of Biology, College of Science, University of Tehran,
Tehran, Iran
F. Rominger
Organisch-Chemisches Institut, der Universitat Heidelberg,
¨
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
H. R. Bijanzadeh
Department of Chemistry, Tarbiat Modares University,
P. O. Box 141115-175, Tehran, Iran
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J IRAN CHEM SOC (2013) 10:725–732
while some bases such as NaOH, NaOC2H5, Et3N, and
Cs2CO3 in different organic solvents were used for this
goal. In addition, some of the reported methods require
toxic reagents in the presence of a catalyst. Recently,
Michael addition of electron-deficient alkenes with aryl
amines and CS2 in solid media alkaline Al2O3 was used for
the preparation of dithiocarbamic acid esters [49]. In this
regard, b-nitrostyrene and its derivatives which are
important synthetic intermediates and starting materials for
the synthesis of a variety of useful building blocks [50–54]
are considered attractive candidates, as Michael acceptor,
for the synthesis of dithiocarbamates.
Table 1 Solvent effect on the formation of dithiocarbamate 4c
Entry
Solvent
Yield %
1
2
3
4
Neat
95
73
55
–
CH2Cl2
MeOH
Ionic liquid
reaction time (8 h) to obtain its corresponding adduct.
Furthermore, b-nitrostyrenes are more reactive toward
secondary amines such as diallylamine compared to the
primary ones. In general, this methodology provided good
to high yields for the substrates.
In continuation of our research, interest for developing
novel domino reactions [55–59], herein we have presented a
new and one-pot three-component methodology for the
synthesis of functionalized dithiocarbamates containing
nitro group via the reaction of carbon disulfide, primary or
secondary amines, and b-nitrostyrene derivatives
(Scheme 1).
In order to extend the scope of the our protocol, we
scaled-up the reaction using 20 mmol of b-nitrostyrene 3a
in the presence of carbon disulfide and diallylamine at
room temperature. The reaction proceeded without diffi-
culty to obtain a high yield of product 4a (95 %). The
products are nitro dithiocarbamates which may be con-
verted to various valuable products. Nitro compounds are
versatile precursors of diverse functionalities, for example,
they could be converted into carbonyl group through Nef
reaction, [61] or into amine group via reduction, etc. [51].
Results and discussion
We began our investigations with the synthesis of b-nitro-
styrene 3a (Ar = Ph), which could be synthesized according
to the reported methods [60]. The reaction of 3a with piper-
idine and carbon disulfide was chosen as the model reaction.
Stirring of the mixture in the ionic liquid [bmim][BF4]
(n-butyl-1-methylimidazoium tetra-fluoro borate) did not
provide any product. Therefore, other solvents such as MeOH
and CH2Cl2 were used and the desired product 4c was
obtained at room temperature in 55, and 73 % yields,
respectively. But, we were pleased to find that the reaction
under neat condition provided the desired dithiocarbamate 4c
in 95 % yield. The results are summarized in Table 1.
A
proposed reaction mechanism is depicted in
Scheme 2. In the first step, in the synthetic sequence, the
reaction of primary or secondary amines with carbon
disulfide leads to thiocarbamates as S-nucleophiles. Addi-
tion of S-nucleophiles to the synthesized b-nitrostyrenes
leads to the desired products.
The formation of dithiocarbamates was confirmed by an
X-ray diffraction study of single crystals of 4c. The
molecular structure of the compound is shown in Fig. 1.
The structures of the products were determined from
spectroscopic data and high-resolution mass spectrometry
(HR-Mass-ESI). Characteristic resonances for the com-
pounds 4a-j in the 1H-NMR spectra are three distinguished
doublet of doublet peaks for the three different magnetic
non-equivalent hydrogen atoms S–CH–CH2–NO2. The
geminal coupling for hydrogens (H1 and H2) in compound
3c is 13.3 Hz and coupling constant JH1H3 = 10.5 Hz,
which is in accordance with the dihedral angle. The X-ray
crystallographic data could confirm the dihedral angle in
the crystal structure. (J12 = 13.3 Hz, J13 = 10.5 Hz,
J23 = 4.9 Hz).
To explore the generality and scope of this reaction, a
series of amines 1a-f and b-nitrostyrenes were studied for
the synthesis of dithiocarbamates 4a-j and the results are
illustrated in Table 2. The results showed that the reaction
time varied according to the nature of substituents on the
b-nitrostyrenes. For example, b-nitrostyrene, bearing the
electron-donating group such as methyl, required longer
R1
N
R2
Finally, the antimicrobial activity of some synthesized
compounds on standard fungi and bacterial strains was
evaluated.
S
R1
NO2
neat
r.t.
S
NO2
NH
R2
CS2
Ar
Minimum inhibitory concentration (MIC) values of four
synthesized dithiocarbamate (4a, 4b, 4c and 4d) were
determined using agar dilution method as recommended by
national committee on clinical laboratory standards
(NCCLS) [62, 63]. Some Standard and clinically isolated
Ar
1 a-f
3 a-c
2
4a-j
Scheme 1 Synthesis of functionalized dithiocarbamates using one-
pot three-component reaction
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J IRAN CHEM SOC (2013) 10:725–732
727
Table 2 Synthesis of dithiocarbamates using three-component reaction of b-nitrostyrene, primary or secondary amines, and carbon disulfide
Entry
Aryl
Amine
Product
Entry
Aryl
Amine
Product
Bn
HN
S
S
NO2
N
S
S
NO2
Ph
4-Br-C6H4
1
6
Ph
1f
Br
1a
4a(95%, 2h)
4f(70%, 7h)
O
N
O
N
S
S
NO2
S
S
NO2
Ph
4-Br-C6H4
2
3
7
8
Ph
1b
1b
Br
4b(75%, 2.5h)
4g(65%, 5h)
N
S
N
S
S
S
NO2
NO2
Ph
4-Br-C6H4
Ph
1c
1c
Br
4c(81%, 3h)
4h(77%, 5h)
N
S
S
N
S
NO2
S
NO2
4
Ph
9
4-Br-C6H4
Ph
1d
1d
Br
4d(70%, 2h)
4i(83%, 4h)
N
S
S
S
N
NO2
HN
S
S
Ph
4-H3C-C6H4
5
10
NO2
1c
H3C
1e
Ph
4j(80%, 8h)
4e(68%, 4h)
R1
N
subtilis (ATCC6633), Entrococcus faecalis (PTCC1237),
Staphylococcus aureus (ATCC25923) as gram-positive
bacteria were used to determine antimicrobial activity. A
clinically isolated strain of methicillin-resistant Staphylo-
coccus aureus (MRSA) as well as four fungi including;
Candida albicans (ATCC10231), Candida tropicalis
(ATCC750), Fusarium oxysporum (DSM62060) and
Aspergillus niger (CBS513.88) were also examined ampi-
cillin, streptomycin and amphotericin B were used as the
reference antibiotics. The bacteria and fungi were cultivated
in Mueller–Hinton agar and potato dextrose agar (PDA),
R2
S
NO2
S
R1
R1
NH
R2
S
NO2
N
R2
S
CS2
Ar
Ar
Scheme 2 Plausible mechanism for the synthesis of compounds 4a-j
strains of the bacteria including; Escherichia coli
(ATCC8739), Pseudomonas aeruginosa (ATCC9027),
Salmonella typhi (NCTC5761), and Enterobacter aeroge-
nes (PTCC1221) as Gram-negative bacteria and Bacillus
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Furthermore the MIC values, ranging from 0.5 to 2 lg/mL,
were found for the Gram-positive bacteria (Table 3).
However, the antibacterial activity of compound 4d
against Gram-positive bacteria was comparable to ampi-
cillin as a reference drug (Table 3).
The compounds 4b and 4c were slightly less active than
the compounds 4a and 4d. The screening data revealed that
these compounds have moderate activity against bacteria
(Table 3).
Whileall tested compoundsshoweda weakactivityagainst
drug resistance P. aeruginosa (MIC 128–256 lg/mL), they
had high activity against methicillin-resistant S. aureus.
Methicillin-resistant Staphylococcus aureus was known
to be the most virulent organism that caused a broad array
of problems to hospitalized patients, and showed multi-
drug resistance to numerous currently available agents. The
compound 4b showed the highest anti-MRSA activity
(2 lg/mL) that was twofold more active than Streptomycin
and fourfold active than ampicillin. The MIC value of
compound 4a against MRSA (4 lg/mL) was the same as
Streptomycin and threefold more active than ampicillin.
These results suggested that dithiocarbamate derivatives
have anti-MRSA potential and can be considered as a lead
compound for future study.
Fig. 1 ORTEP structure of compound 4c
respectively. The synthesized dithiocarbamate and antibiotics
were dissolved in DMSO before mixing with Mueller–Hinton
Agar or PDA. Final concentrations of the test compounds in
the medium were 512, 265, 128…0.0.01 lg/mL. The lowest
concentration, in which no visible growth was detected, was
taken as the MIC. The control of experiments was done using
DMSO. Each measurement was repeated three times.
Moreover, synthesized dithiocarbamate compounds
showed strong to moderate antifungal activity (Table 4).
These compoundsexhibitedstrong antifungalactivity against
pathogenic yeast and moderate activity against pathogenic
mould. The compound 4d showed the highest antifungal
activity with the MIC values ranging from 2 to 32 lg/mL
(Table 4).
Tables 3 and 4 represent antimicrobial activity of some
synthesized dithiocarbamates which show significant
activity against bacterial and fungal strains. It was also
found that Gram-positive microorganisms were more sen-
sitive than Gram-negative bacteria and fungi. The com-
pound 4d demonstrated the highest potency against tested
strains while 4b exhibited the lowest activity.
Experimental section
The compound 4a exhibited highly antibacterial activ-
ity. Moreover, the MIC of compound 4d against most
tested microorganisms was comparable or superior to
standard antibiotics. The MIC value for the Gram-negative
bacteria was 32 lg/mL except for P. aeruginosa.
General
Commercially available materials were used without further
purification. Melting points were determined on an Electro-
thermal 9100 apparatus and were uncorrected. IR spectra
Table 3 Minimum inhibitory concentration (MIC) against some Gram-negative and Gram-positive bacteria
MIC (lg/mL)
Compound
B. subtilis
ATCC 6633
E. faecalis
PTCC 1237
S. aureus
ATCC 25923
MRSA E. coli P. aeruginosa
ATCC 8739 ATCC9027
S. typhi E. aerogenes
NCTC 5761 PTCC1221
4a
2
16
64
16
2
2
4
64
128
64
32
4
128
256
128
128
R
64
128
64
32
8
64
128
64
32
256
2
4b
64
16
0.5
2
64
32
1
128
64
2
4c
4d
Ampicillin
Streptomycin
4
0.5
1
16
4
1
128
0.5
16
0.5
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729
Table 4 Minimum inhibitory concentration (MIC) against some fungi
MIC (lg/mL)
Compound
C. albicans ATCC10231
C.tropicalis ATCC750
F.oxysporum DSM62060
A. niger CBS513.88
4a
8
32
32
2
8
32
8
64
128
64
64
128
64
4b
4c
4d
4
32
16
Amphotericin B
2
1
4
4
were obtained on an ABB FT-IR FTLA 2000 spectrometer.
1HNMR and 13CNMR spectra were recorded on a Bruker
DRX-500 AVANCE spectrometer at 500 or 300 MHz for
1HNMR, and 125 or 75 MHz for 13CNMR. CDCl3 was used
as solvent. HRMS was recorded on Mass-ESI-POS (Apex
Qe-FT-ICR instrument) spectrometer. CCDC 818603 for
compound 4c contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
2H, 2-CH), 4.29 (brs, 2H, 2-CH), 4.90 (dd, 1H, J = 13.3,
10.5 Hz, –CH), 5.31 (dd, 1H, J = 13.3, 4.9 Hz, –CH), 5.79
(dd, 1H, J = 10.5, 4.9 Hz, –CH), 7.27–7.39 (m, 5H, H–
Ar), 13C-NMR (75 MHz, CDCl3): d 51.5, 66.1, 77.6, 128.4,
129.0, 129.2, 134.7, 193.6, HR- Mass (ESI) Calc. for
C13H16NaN2O3S2 [M?Na]? 335.05006, found 335.04992.
2-Nitro-1-phenylethyl piperidine-1-carbodithioate(4c)
(81 %)
Mp: 86–88 ꢁC, IR (KBr, cm-1): m 1,557, 1,375, 1,020, 1H-
NMR (500 MHz, CDCl3): d 1.60–1.70 (m, 6H, 3CH2), 3.83
(brs, 1H, –CH), 3.77 (brs, 1H, –CH), 4.18 (brs, 1H, –CH),
4.32 (brs, 1H, –CH), 4.88 (dd, 1H, J = 13.3, 10.5 Hz,
–CH), 5.33 (dd, 1H, J = 13.3, 4.9 Hz, –CH), 5.74 (dd, 1H,
J = 10.5, 4.9 Hz, –CH), 7.25–7.40 (m, 5H, H–Ar),
13C-NMR(125 MHz, CDCl3):d 24.6, 25.8, 52.0, 53.4,
78.3,128.8, 129.3, 129.5, 135.4, 192.1, HR-Mass (ESI)
Calc. for C14H19N2O2S2 [M?H]? 311.08866, found
311.08856.
General procedure for the synthesis of 4a-j
Carbon disulfide (83.6 mg, 1.1 mmol) and the unsubstituted
or substituted b-nitrostyrene (1 mmol;1.0 eq.) werestirred at
room temperature; after 10 min amine (1 mmol) was added
slowly. The progress of the reaction was monitored by TLC
(Eluent:petroleum ether:ethyl acetate, 1:1). After completion
of the reaction (2–8 h), the excess CS2 was removed in vac-
uum and the residue was further purified by recrystallization
in a mixture of petroleum ether –CH2Cl2 (3:1).
Colorless crystal (polyhedron), dimensions 0.31 9
0.21 9 0.07 mm3, crystal system monoclinic, space group
˚
P21/n, Z = 4, a = 13.3431(16) A, b = 6.3809(8) A, c =
˚
˚
2-Nitro-1-phenylethyl diallylcarbamodithioate(4a)
(95 %)
18.117(2) A, alpha = 90ꢁ, beta = 90.037(3)ꢁ, gamma =
3
3
˚
90ꢁ, V = 1,542.5(3) A , rho = 1.337 g/cm , T = 200(2) K,
Thetamax = 28.32ꢁ, radiation Mo Kalpha, lamb-
da = 0.71073 A, 0.3ꢁ omega-scans with CCD area detector,
Mp: 60–62 ꢁC, IR (KBr, cm-1): m 1,555, 1,406, 1,175,
1H-NMR (300 MHz, CDCl3): d 4.27 (d, 2H, J = 4.3 Hz,
2-CH),4.57–4.69 (m, 2H, 2-CH), 4.9 (dd, 1H, J = 13.3,
10.5 Hz, –CH), 5.20(dd, 2H, J = 12.9, 4.3 Hz, –CH), 5.28
(d, 2H, J = 12.9 Hz, =CH), 5.32 (dd, 1H, J = 12.9, 4.9 Hz),
5.74 (dd, 1H, J = 10.5, 4.9 Hz, –CH), 5.79–5.94 (m, 2H,
2-CH), 7.27–7.4 (m, 5H, H–Ar), 13C-NMR (75 MHz,
CDCl3): d 51.9, 53.7, 56.5, 77.6, 119.0, 128.4, 128.9, 129.1,
129.9, 130.5, 134.7, 194.2, HR-Mass (ESI) Calc. for
C15H18N2O2S2 [M?H]? 323.08850, found 323.08844.
˚
covering a whole sphere in reciprocal space, 15,454 reflec-
tions measured, 3,836 unique (R(int) = 0.0462), 3,225
observed (I [ 2(I)), intensities were corrected for Lorentz
and polarization effects, an empirical absorption correction
was applied using SADABS [61] based on the Laue symmetry
of the reciprocal space, mu = 0.35 mm-1, Tmin = 0.90,
Tmax = 0.98, structure solved by direct methods and refined
against F2 with a Full-matrix least-squares algorithm using the
SHELXTL (Version 2008/4) software package [64, 65], 181
parameters refined, hydrogen atoms were treated using
appropriate riding models, goodness of fit 1.16 for observed
reflections, final residual values R1(F) = 0.072, wR(F2) =
0.142 for observed reflections, residual electron density
2-Nitro-1-phenylethyl morpholine-4-carbodithioate(4b)
(75 %)
MP: 87–90 ꢁC, IR(KBr, cm-1): m 1,555, 1,370,1,113, H-
NMR (300 MHz, CDCl3): d 3.77(s, 4H, 2 –CH2), 3.88 (brs,
-0.37–0.50 eA-3. CCDC 818603 contains the supplementary
1
˚
crystallographic data forthis paper. These data can be obtained
123

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J IRAN CHEM SOC (2013) 10:725–732
free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
–CH2N), 4.30 (brs, 2H, 2-CH), 4.85 (dd, 1H, J = 13.3,
10.5 Hz, –CH), 5.26 (dd, 1H, –CH, J = 13.3, 4.9 Hz), 5.76
(dd, 1H, J = 10.5, 4.9 Hz, –CH), 7.26 (d, 2H, J = 8 Hz,
2-CH, H–Ar,), 7.495(d, 2H, J = 8 Hz, 2-CH, H–Ar), 13C-
NMR (75 MHz, CDCl3): d 50.8, 65.9, 77.0, 123.1, 130.0,
132.3, 133.8, 192.9. HR-Mass (ESI) Calc. for
C13H16N2O3S729Br [M?H]?392.31043, found 392.31035;
Calc.for C13H16N2O3S821Br [M?H] ?394.22365, found
394.22357.
2-Nitro-1-phenylethyl pyrrolidine-1-carbodithioate
(4d) (70 %)
Mp: 110–112 ꢁC, IR(KBr, cm-1): m 1,555, 1,370, 1,165, 1H-
NMR (300 MHz, CDCl3) : d 1.94–2.11 (m, 4H, 2-CH2),
3.54–3.64 (m, 2H, 2-CH), 3.84–3.94 (m, 2H, 2-CH), 4.9 (dd,
1H, J = 10.5, 4.9 Hz, –CH), 5.32 (dd, 1H, J = 13.3, 4.9 Hz,
–CH), 5.78 (dd, 1H, J = 13.3, 10.5 Hz, –CH), 7.27–7.41 (m,
5H, H–Ar), 13C-NMR (75 MHz, CDCl3): d 24.2, 26.1, 50.7,
50.9, 55.1, 77.7, 128.3, 128.8, 129.1, 135.0, 189.0.HR-Mass
(ESI) Calc. for C13H17N2O2S2 [M?H]? 297.41433, found
297.41425.
1-(4-Bromophenyl)-2-nitroethylpiperidine-1-
carbodithioate(4h) (77 %)
1
Mp: 90–92 ꢁC, IR (KBr,cm-1): m 1,550, 1,380, 1,113, H-
NMR (300 MHz, CDCl3): d 1.75 (s, 6H, 3-CH2), 3.8 (brs,
2H, 2-CH), 4.18 (d, 1H, J = 15.3 Hz, –CH), 4.34 (d, 1H,
J = 15.3 Hz, –CH), 4.835 (dd, 1H, J = 13.5, 10.5 Hz,
–CH), 5.30 (dd, 1H, J = 13.5, 4.9 Hz, –CH,), 5.75 (dd, 1H,
J = 10.5, 4.9 Hz, –CH), 7.28 (d, 2H, J = 8.5 Hz, 2-CH,
H–Ar), 7.47 (d, 2H, J = 8.5 Hz, 2-CH, H–Ar), 13C-NMR
(75 MHz, CDCl3–): d 24.1, 51.6, 77.6, 122.9, 130.37,
132.25, 134.17, 191.07. HR-Mass (ESI) Calc. for
C14H18N2O2S729Br [M?H]? 390.34086, found 390.34080;
Calc. for C14H18N2O2S821Br [M?H]? 392. 23365, found
392.23350.
2-Nitro-1-phenylethyl benzo[d]thiazol-2-
ylcarbamodithioate(4e) :(68 %)
Mp: 130–133 ꢁC, IR(KBr, cm-1): m 3,209, 1,550, 1,400,
1,110, 1H-NMR (300 MHz, CDCl3): d 4.85 (dd, 1H,
J = 13.0, 5.6 Hz, –CH), 5.09 (dd, 1H, J = 13.0, 6.8 Hz,
–CH), 5.68 (t, 2H, J = 6.6 Hz, –CH2), 7.14 (td, 1H,
J = 6.7, 1 Hz, H–Ar), 7.30 (td, 1H, J = 5.6, 1 Hz, –CH,
H–Ar), 7.36–7.42 (m, 5H, H–Ar), 7.56 (dd, 1H, J = 4.3,
1.0 Hz, –CH, HAr), 7.58 (dd, 1H, J = 4.3, 1.0 Hz, –CH,
1-(4-Bromophenyl)-2-nitroethylpyrrolidine-1-
carbodithioate(4i): (83 %)
13
H–Ar), C-NMR (75 MHz, CDCl3): d 56.8, 78.3, 119.5,
120.9, 122.5, 126.2, 126.6, 129.1, 129.4, 130.5, 136.1,
151.3, 165.3.HR-Mass (ESI) Calc. for C16H14N3O2S3
[M?H]? 376.49875, found 376.49859.
1
Mp: 70–75 ꢁC, IR(KBr, cm-1): m 1,550, 1,370, 1,165, H-
NMR (300 MHz, CDCl3): d 1.95–2.12 (m, 4H, 2-CH2),
3.54–3.64 (m, 2H, 2-CH), 3.9–3.94 (t, 2H, J = 6.7 Hz),
4.83 (dd, 1H, J = 10.5, 13.3 Hz, –CH), 5.29 (dd, 1H,
J = 4.9, 13.3 Hz, –CH), 5.77 (dd, 1H, J = 4.9, 10.5 Hz,
–CH), 7.27(d, 2H, J = 8.3 Hz, H–Ar), 7.48 (d, 2H,
J = 8.3 Hz, H–Ar), 13C-NMR (75 MHz, CDCl3): d 24.2,
26.1, 50.3, 50.7, 55.2, 77.5, 122.9, 129.9, 132.3, 134.3,
188.5.HR-Mass (ESI) Calc. for C13H16N2O2S729Br
[M?H]? 376.31255, found 376.31242; Calc. for
C13H16N2O2S821Br [M?H]? 378. 22415, found 392.22405.
1-(4-Bromophenyl)-2-nitroethyl
benzylcarbamodithioate(4f) (70 %)
Mp: 104–108 ꢁC, IR (KBr, cm-1): m 3,322, 1,550, 1,324,
1,100, 1H-NMR (300 MHz, CDCl3): d 4.85 (brs, 2H, –CH2),
4.82–4.90 (m, 1H, –CH), 5.17 (dd, 1H, J = 13.5,4.9 Hz,
–CH), 5.73 (dd, 1H, J = 10, 4.9 Hz, –CH), 7.07 (brs, 1H,
NH), 7.25 (d, 2H, J = 8.0 Hz, 2-CH, H–Ar), 7.29–7.38 (m,
5H, 5-CH, H–Ar), 7.50 (d, 2H, J = 8.0 Hz, 2-CH, H–Ar),
13C-NMR (75 MHz, CDCl3):d 49.7, 51.5, 77.7, 123.0, 128.4,
128.5, 129.1, 129.8, 132.3, 134.0, 135.4, 193.6. HR-Mass
(ESI) Calc. for C16H16N2O2S729Br [M?H]? 412.34385,
2-Nitro-1-p-tolylethyl piperidine-1-carbodithioate(4j):
(80 %)
found
412.34394;
Calc.
for
C16H16N2O2S821Br
MP: 90–92 ꢁC, IR (KBr, cm-1): m 1,552, 1,377, 1,120, 1H-
NMR (300 MHz, CDCl3): d 1.71 (brs, 6H, 3–CH2), 2.33 (s,
3H, –CH3), 3.8 (d, 2H, J = 17.4 Hz), 4.18 (brs, 1H, –CH),
4.34 (brs, 1H, –CH), 4.87 (dd, 1H, –CH, J = 13.3,
10.5 Hz), 5.36 (dd, 1H, J = 13.3, 4.9 Hz), 5.71 (dd, 1H,
–CH, J = 10.5, 4.9 Hz), 7.16 (d, 2H, J = 8.0 Hz, H–Ar),
7.28 (d, 2H, J = 8.0 Hz, H–Ar), 13C-NMR (75 MHz,
CDCl3): d 21.2, 24.2, 25.4, 26.0, 51.4, 77.81, 128.3, 129.8,
[M?H]?414.33405, found 412.33396.
1-(4-Bromophenyl)-2-nitroethyl morpholine-4-
carbodithioate(4g) (65 %)
Mp: 95–100 ꢁC, IR (KBr, cm-1): m 1,550, 1,421, 1,117,
1H-NMR (300 MHz, CDCl3): d 3.80 (brs, 6H, 2-CH2O,
123

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In conclusion, we report a novel one-pot and three-com-
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simple reaction conditions, inexpensive initial materials,
simple work-up and short reaction time are the advantages
of the presented method, compared to the previously
reported procedures. Moreover, the evaluation of antimi-
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dithiocarbamate has a good potency in inhibiting the growth
of B. subtilis, E. faecalis, S. aureus, MRSA, C.albicans and
C. tropicalis and are less active against E. coli, P.aerugin-
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Acknowledgments S.B gratefully acknowledges Iran National
Science Foundation (INSF) for financial support. We thank Prof.
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