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1
CHAPTER – I
Introduction, synthesis of dithiocarbamates and its application
2
INTRODUCTION
3
1.0 Introduction
Organic dithiocarbamates have attracted a great deal of
importance due to their interesting chemistry and wide utility.1-7
Dithiocarbamates have a wide range of uses and applications and are
produced in great quantities throughout the world. Dithiocarbamate
acid ester (1) is a common class of organic molecules. They exhibit
valuable biological effects, including antibacterial activity, antifungal
activity, antioxidant activity,8 inhibition of cardiac hypertrophy,9 etc.
Dithiocarbamic acid ester represents a new kind of compound with a
novel structure, significant anticancer activity and very low toxicity. A
Dithiocarbamate is a functional group in organic chemistry. It is the
analogue of carbamate in which both oxygen atoms are replaced by
sulfur atoms (figure 1).
N SR3
S
R1
R2
(1)
Figure 1: General formula of the dithiocarbamate
The dithiocarbamate containing two donor sulfur atoms, which
it is prepared from the reaction of primary amine or secondary amine
with base and carbon disulfide.
Sodium diethyl dithiocarbamate is a common ligand in
inorganic chemistry. Lots of primary and secondary amines react with
carbon sulfide and sodium hydroxide to form dithiocarbamates; they
4
are used as ligand when metal salts are added to it. It readily reacts
with many metal salts such as Cu, ferrous, ferric, cobaltous, Ni salts.
They are mostly octahedral complexes.
Despite major breakthroughs in many areas of modern medicine
over the past 100 years, the successful treatment of cancer remains a
significant challenge at the start of the 21st century. Because it is
difficult to discover novel agents that selectively kill tumor cells or
inhibit their proliferation without the general toxicity, the use of
traditional cancer chemotherapy is still very limited. Besides being
widely used as fungicides to protect crops from fungal diseases,10
dithiocarbamic acid esters have a number of other applications such
as in photochemistry,11 catalysis in the sulfur vulcanization of
rubber,12 detection and analysis of biological NO produced
endogenously from NO synthases,13 and polymerization.14
Furthermore, functionalized carbamates are an important class of
compounds and their medicinal and biological properties warrant
study.15 Dithiocarbamic acid esters were recently reported as potent
anticancer agents16 and cell apoptosis inhibitors.17
Organic dithiocarbamates are valuable synthetic
intermediates,18 which are ubiquitously found in a variety of
biologically active compounds. Functionalization of the carbamate
moiety offers an attractive method for the generation of derivatives,
which may constitute interesting medicinal and boilogical properties.19
5
Dithiocarbamates (DTCs) are a group of organosulfur
compounds that have extensively been used as pesticides in
agriculture for more than 50 years with some products being already
introduced in the 1930s. Today, the yearly consumption is between
25,000 and 35,000 metric tones.20 Most of the DTCs are applied as
fungicides and some are classified by the World Health Organization
as being hazardous.21 As a consequence, an array of various methods
has been developed for the analysis of DTCs and their potential
degradation products in environmental samples and in food stuff.
The carbamate moiety is an important structural element in
numerous biologically active compounds22 and has played a crucial
role in the area of synthetic organic chemistry primarily as a novel
protecting group.23 Therefore; functionalization of organic carbamates
offers great potential in the generation of large combinatorial libraries
for rapid screening24 and drug design.25
Dithiocarbamates have received considerable attention due to
their numerous biological activities26 and their pivotal role in
agriculture27 and as linkers in solid phase organic synthesis.28 They
are also used in the rubber industry as vulcanization accelerators29
and in controlled radical polymerization techniques.30 Because they
have a strong metal binding capacity, they can also act as inhibitors of
enzymes and have a profound effect on biological systems.
Dithiocarbamates are also widely used in medicinal chemistry and
have found application in the treatment of cancer31 and have been
6
tested in clinical trials for various indications including HIV.32-35
Furthermore; dithiocarbamates are versatile classes of ligands with
the ability to stabilize transition metals in a wide range of oxidation
states,36 the ability to chelate heavy metals,37-38 to function as NO
scavengers,39 radical chain transfer agents in the reversible addition
fragmentation chain transfer polymerizations,40 for the protection of
amino groups in peptide synthesis,41 as radical precursors 42 and
recently in the synthesis of ionic liquids.43 They have also been widely
used in the synthesis of trifluoromethylamines,44 thioureas,45
aminobenzimidazoles,46 isothiocyanates,47 alkoxyamines,48 2-imino-
1,3-dithiolane,49 and total synthesis of (-)-aphanorphine.50
On the other hand, dithiocarbamates are of growing interest due
to their biological potencies,51 such as antihistaminic,52
antibacterial,53 and anticancer activties.54 Owing to their strong
metal-binding capacity, they can also act as enzyme inhibitors, such
as indoleamine 2,3-dioxygenase, which plays an important role in
tumor growth.55 For these reasons, the synthesis of dithiocarbamate
derivatives with different substitution patterns at the thiol chain by a
convenient and safe method has become a field of increasing interest
in synthetic organic chemistry during the past few years. Traditional
methods for the synthesis of dithiocarbamates involve the use of
costly and toxic reagents, such as thiophosgene, chlorothioformates,
and isothiocyanates.
7
A number of methodologies have been developed; the standard
preparation of carbamates/dithiocarbamates generally involves the
use of toxic and highly reactive phosgene/thiophosgene56 and its
derivatives57, thereby posing environmental and safety problems. As a
result, considerable effort has been made to develop a
phosgene/thiophosgene free route58 for the preparation of carbamates
and thiocarbamates. However, many of these methods suffer from
limitations, such as long reaction times, use of expensive and strongly
basic reagents, use of volatile solvents, tedious work-up, and low
yields.59
Therefore, the synthesis of this type of molecule has received
considerable attention. Furthermore, a one pot reaction of amine with
carbonyl sulfide and alkyl halides in organic solvents in the presence
of a catalyst also has been developed.60 However, there are several
disadvantages to these methods: many isothiocyanates are hazardous
and tedious to prepare and display poor long-term stability with the
formation of side products such as urethane in alcoholic media. Such
intermediates also require high reaction temperatures, give low or
moderate yields of products, and usually entail multistep procedures.
Furthermore, these reactions require very toxic reagents and harmful
organic solvents in the presence of a catalyst.
Structure modification of folic acid led to the discovery of a
number of antifolates as efficient anticancer agents. For example,
Methotrexate (2) (figure 2), an inhibitor of dihydrofolate reductase, has
8
been used clinically for the treatment of leukemia and solid tumors in
children and adults for several decades.61 Raltitrexed (3)62-63 (figure 2),
which is an inhibitor of thymidylate synthase has been registered
widely for the first-line treatment of advanced colorectal cancer.
However, these so-called classical antifolates containing L-glutamic
acid moiety in the molecule have shortcomings such as drug
resistance, which have originated from the defective cell transport by
mutation, and toxicity to the host, which is due to unnecessarily long
retention inside normal cells.64 One strategy to overcome these
shortcomings is to design nonclassical lipophilic inhibitors of folate
requiring enzymes by deleting or modifying L-glutamic acid
component from the folate analogues.65-66
N
NN
N
NH2
H2N
N
CH3
O
NH
COOH
HCOOH
Methotrexate (2)
SN
HN
HN
N
O
H3CCH3
H
COOH
O COOH
Raltitrexed (3)
Figure 2: Structures of Methotrexate (2) and Raltitrexed (3)
Recently, Brassinin (4)67 (figure 3), a dithiocarbamate isolated
from cabbage, was reported to have cancer chemopreventive activity,
and its structural modification led to the design and synthesis of a
9
potential cancer chemopreventive agent (4-methanesulfinyl-butyl)-
dithiocarbamic acid methyl ester (5)68 (figure 2). A steadily increasing
number of studies have been published on dithiocarbamates and their
anticancer activity. 4-Methanesulfinylbutyl dithiocarbamic acid
methyl ester has proved to be a potential cancer chemopreventive
compound as a phase II enzyme inducer.68 More recently, a series of
dithiocarbamate compounds have been synthesized and found to
possess in vitro and in vivo antitumor activity.69-70
NH
SSCH3
Brassinin (4)
S
O
NH
S
S
Sulforamate (5)
Figure 3: Structures of Brasinin (4) and Sulforamate (5)
Furthermore, diarylalkyl thioureas have merged as one of the
promising nonvanilloid TRPV1 antagonists, possessing excellent
therapeutic potentials in pain regulation71 and human CB1 and CB2
cannabinoid receptor affinity.72 For these reasons, 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 few years.
Thiocarbamates73 have received much attention due to their
interesting technological,74 biological,75 and synthetic applications.76
Typically, the thiocarbonyl moiety has been utilized ubiquitously as a
protecting group,77 and as an intermediate in further synthesis.78
10
Their formation employs harsh reaction conditions such as the use of
strong bases, high temperatures, and long reaction times.79 In
addition, modifications have been reported to use chlorothioformates,
which are costly and toxic reagents. Recently, reported a highly
efficient cesium base promoted solution phase synthesis of alkyl
carbonates and carbamates,80 which utilizes non-toxic reagents under
mild conditions. This protocol has been successfully applied to
peptidomimetic synthesis as well as solid phase synthesis.81 As a
complementary approach, this procedure has been extended to the
formation of thiocarbonates and thiocarbamates using carbon
disulfide.
Direct thiocarboxylation of amines with carbon monoxide and
sulfur to form urea derivatives has also been reported.82 Recently, a
one-pot reaction of amines with carbonyl sulfide, alkyl halides, or α, β-
unsaturated compounds also has been developed.83
Recently, it was found by Hirschelman‟s group that and 5-
oxohexyl dithiocarbamic acid methyl ester (6) (figure 4) are potent
phase II enzyme inducers which could be used as cancer
Oxomate (6)
RWJ-025856 (7) 990207 (8)
O
NH
S
SR1
NN
S NMe2
SCl
NC
S
S
N
NH3C
Figure 4. Structures of oxomate (6), RWJ-025856 (7) and 990207 (8)
11
chemopreventive agents.84-86 Another group from Italy also found that
the metal complex of dithiocarbamic acid esters exhibited anticancer
activity. For example, the platinum complexes have similar activity
but less toxicity than the cisplatin.87-89 However, little systematic
research has been reported about anticancer activity of this class of
compounds, although compound RWJ-025856 (7) (figure 4) was
unexpectedly found to have attenuating effects on tumor necrosis
factor a (TNFa)-induced apoptosis in murine fibrosarcoma WEHI 164
cells.90 One of the best compounds is 4-methyl-piperazine-1-
carbodithioic acid 3-cyano-3,3-diphenyl-propyl ester (8) (figure 4) with
79% and 75% inhibition rates against HL-60 and Bel-7402 cell lines
at 33 lM in vitro, respectively. A further in vivo test of its
hydrochloride salt (4.HCl), which has better solubility, indicated that
the inhibition rates against tumor growth of sarcoma 180 (S180),
hepatocyte carcinoma 22 (H22), and implanted human gastric
carcinoma in nude mice were 46.4–59.6% (P < 0.01), 39.3–51.6% (P <
0.05 _ 0.01), and 18.1–59.0% (P < 0.01) at different doses from 50 to
200 mg/kg, respectively. Taking it orally at a dose of 10 g/kg
continuously for 10 days, the rats are neither dead nor damage of
organs observed by visual examination. Furthermore, the body weight
of tested group is similar to that of control group.91 To the best of our
knowledge, dithiocarbamic acid ester (8) represents a new kind of
compound with a novel structure, significant anticancer activity, and
very low toxicity. Compound (8) as a lead compound to further explore
12
the structure–activity relationships with the aim of optimizing potency
and anticancer activity.
A series of alkyl/arylsulfonyl-N,N-diethyldithiocarbamates
display moderate to powerful tumour growth-inhibitory properties
against several cancer cell lines in vitro.92 4(3H)-Quinazolinone
derivatives with a dithiocarbamate side chain exhibit antitumour
activity against human myelogenous leukaemia K562 cells.93-94
Pyrrolidine dithiocarbamate stimulates apoptosis by suppressing the
activation of nuclear factor Jb (NF-jB) in various cancer cells (e.g.,
acute myelogenous leukaemia95 and pancreatic adenocarcinoma96). A
variety of 4-substituted-piperazine-1-carbodithioic acid 3-cyano-3,3-
diphenylpropyl esters have been found to be effective against the HL-
60 and Bel-7402 cell lines.97 Different metal [Pt(II), Pd(II), Au(III),
Cu(II)] complexes of dithiocarbamate derivatives (methyl- and
ethylsarcosinedithiocarbamate, N,N-dimethyldithiocarbamate, S-
methyl-N,N-dimethyldithiocarbamate and diethyldithiocarbamate)
have been prepared and their cytotoxicities were studied.98-100 The
Pt(II) complexes of these sulfur-containing molecules can act as
chemoprotectants in platinum-based chemotherapy, modulating
cisplatin nephrotoxicity.101 Besides the compounds mentioned above,
probably the most interesting group of dithiocarbamates exhibiting
antitumour activity are the phytoalexins from cruciferous plants. The
phytoalexins are a group of structurally diverse, low molecular weight,
generally lipophilic antimicrobial substances formed in plants. They
13
are not present in healthy plant tissue, but are synthesized in
response to pathogen attack or physical or chemical stress; probably
as a result of the de novo synthesis of enzymes.102 Some of the
cruciferae species that have been examined accumulate a series of
specific indole-sulfur compounds. The basic structures are
characterized by an indole ring variably substituted at positions 2
and/or 3 with nitrogen and sulfur containing substituents.103 Typical
representatives of dithiocarbamate and thiazino[6,5-b]indole-type
phytoalexins from cruciferous plants are brassinin (4),1-
methoxybrassinin (9), 4-methoxybrassinin (10), cyclobrassinin (11)
and sinalbin B (12) (figure 5). Among these compounds, brassinin (4)
and cyclobrassinin (11) proved active in inhibiting the formation of
preneoplastic mammary lesions in culture.104 The former also exerts
an antiproliferative effect in human acute T-lymphoblastic leukaemia
cells.105 Brassinin and its derivatives are inhibitors of indolamine 2,3-
dioxygenase, a new cancer immunosuppression target.106 These
compounds can serve as lead compounds for the generation of more
efficient analogues.107
1-Methoxy brassinin (9) 4-Methoxy brassinin (10)
Cyclobrassinin (11) Sinalbin-B (12)
N
HN
S
SCH3
OCH3
NH
HN
S
SCH3
OCH3
NH
S
NSCH3
N
S
NSCH3
OCH3
14
Figure 5: Dithiocarbamate and 1,3-thiazino[6,5-b]indole phytoalexins
from cruciferous plants
A survey of the literature showed that carbamoyl xanthates have
been proposed as intermediates in the reaction between readily
prepared carbamoyl chlorides and xanthate salts, which ultimately
affords the corresponding S substituted thiocarbamates upon loss of
carbon oxysulfide.108
Dithiocarbamates are intensively used as fungicides.109-111 The
mode of action and the metabolism of thiocarbonyl compounds has
been studied. 112-117 Among other possibilities it has been proposed
that the biological active species would be the corresponding sulfines
arising from the cytochrome P-450 monoxygenase mediated oxidation
of the C=S moiety. Moreover, a dithiocarbamate oxide has recently
been evidenced118-120 as the oxidation product of a cruciferous
phytoalexin (brassinin) by Phoma lingam fungi strains.
The high radicophilicity of the thiocarbonyl group has resulted
in a long association with synthetic free radical chemistry. Radicals
typically add reversibly at the sulfur of the thiocarbonyl group leading
to a new carbon-centered radical, which can in turn undergo further
free-radical processes. This reactivity forms the basis of a number of
important functional group transformations.
The dithiocarbamates are mainly used in agriculture as
insecticides, herbicides and fungicides. In industry, they are used as
slimicides in water-cooling system, in sugar and paper manufacturing.
15
Some are used for the treatment of alcoholism in medicine. Because of
their chelating properties, they are also used as scavengers in water-
waste treatment.121-127 Additional several applications in chemistry
such as supramolecular chemistry due to the fact that the
dithiocarbamate ligand is an attractive structural motif for metal-
directed self_assembly to polymetallic including cages, helicages,
ladders, racks and grids have been constructed. The optical and
electrochemical properties of dithiocarbamate complexes can be used
to construct sensors for the guest molecules.128-130 Recently
dithiocarbamate metal complexes have been used to prepare
nanoparticles and nanowires of a variety of semiconducting materials
including CdS, CuS, ZnS, PbS and EuS.131-137
16
LITERATURE SURVEY
17
1.1 Literature Survey
A). Synthesis of dithiocarbamates
Saidi et al.,138 have been reported one pot synthesis of
dithiocarbamates based upon amines, CS2, and alkyl halides without
using a catalyst under solvent-free conditions.
CS2, rt
3-12 hR1R2NH R1X
S
R2R1N SR1
Mohammad Reza Saidi et al.,139 have been synthesized
dithiocarbamates using amines and carbon disulfide with α,β-
unsaturated compounds were carried out in water.
Water
rt
HN
CS2 COOCH3
N S
S
COOCH3
Kyung Woong Jung et al.,140 have been developed a protocol
for a one-pot, three-component coupling of various amines with an
alkyl halide via a carbon disulfide bridge using Cs2CO3 and TBAI.
RNH2
CS2, Cs2CO3, TBAI
DMF, 0 C, rtR
HN S
S
R1R1X
°
Kyung Woon Jung et al.,141 were developed a three way
coupling was performed to combine diols, diamines, and amino
alcohols with carbon disulfide and halides in the presence of a cesium
base and TBAI, leading to the synthesis of dithio derivatives.
18
Y Zn
RX, Cs2CO3, CS2
TBAI, DMF, 0 C, rtY Zn SR
S
1.Y = Z = NH22. Y = OH, Z = NH2
3. Y = NH2, Z = NH 4. Y= OH, Z = NH
°
Runtao Li et al.,142 have been synthesized a variety of 4-N
atom substituted derivatives with a variety of 1-N-substituted
piperazines, were reacted with carbon disulfide and 3-cyano-3,3-
diphenyl-propyl bromide in the presence of anhydrous potassium
phosphate at room temperature.
CS2Acetone, rt
HN NH
NC
Br
K3PO4
NC
SN
S
HN
Run-Tao Li et al.,143 have been designed and synthesized a
series of 4(3H)-quinazolinone derivatives with dithiocarbamate side
chains.
CH3CSNH2
135-150 C
2 h
NBS, (PhCO)2O2
CHCl3, 3h
CS2, K3PO4
DMF, rt, 2h
HO2C
H2N
CH3 HN
NH3C
O
CH3
HN
NH3C
O
CH2BrHN
NH3C
O
S
S
NR1
R2
°
Lajos Fodor et al.,144 were prepared indolylmethyl
dithiocarbamates and some analogues, using C-(1H-Indol-2-yl)-
methylamine.
19
R1 = CH3I, benzyl bromide
CHCl3, Et3N, DMAP
CS2, 0 C, rt, 2h
°
NH
H2N
° NH
NH
S
S
R1
Krishna Nand Singh et al.,145 have been exploited the
combined role of microwave superoxide and the synthesis of organic
dithiocarbamates under non-aqueous medium employing amines,
carbon disulfide and methyl iodide.
RNH2 CS2
KO2/Et4NBr
CH3I, DMF
MW
R
HN S
S
CH3
Weiliang Bao et al.,146 have been reported a method for the
synthesis of aryl and vinyl dithiocarbamates under Ullmann coupling
reaction of sodium dithiocarbamates with aryl iodides and vinyl
bromides catalyzed by CuI/N,N-dimethylglycine proceeds in DMF at
110 ºC to give corresponding dithiocarbamates.
CuI/ligand/base
solvent/22 h
I
N S Na
S
S N
S
Run-tao Li et al.,147 have been developed a method for the
preparation of dithiocarbamic acid esters by Michael addition of
electron-deficient alkenes with amines and CS2 in solid media alkaline
Al2O3.
20
ArNH2 CS2
alkaline Al2O3
10-30 hR3
R4Ar
HN S
R4
S R3
Akram Ashouri et al.,148 have been shown a procedure for one-
pot synthesis of dithiocarbamates with Markovnikov addition reaction
in water.
CS2NH OH2O
N
S
S
O
Mohammad R. Saidi et al.,149 have been described a procedure
for the synthesis of dithiocarbamates at room temperature.
CS2, neat
0 C to rt, 8hPh
O
Ph
HN
°N
S
S
Ph O
Ph
A.N. Vasiliev et al.,150 have been reported a method of
preparing potassium (1,1-dioxothiolan-3-yl)-dithiocarbamate and
optimized.
CS2 C2H5O-C2H5OHS
NH2
O OS
HN
O O
S
S
B). Application of Dithiocarbamates
Bhisma K. Patel et al.,151 have been developed a method for
the preparation of isothiocyanates from the corresponding
Dithiocarbamic acid salts by using molecular iodine.
21
S
HN S . Et3NH NCSIodine
Et3N
Manas Chakrabarty et al.,152 have been synthesized 2-
alkylthio-6-benzene sulfonyl thiazolo[5,4-e]indoles using N-(1‟-
benezensulfonylindol-3‟-yl)dithiocarbamates.
NBS (1 equiv),CH2Cl2,
-10 0C, 5–10min
DBU (2 equiv), stir, 30minN
HNRS
S
SO2Ph
N
SO2Ph
S
N
RS
Manas Chakrabarty et al.,153 have been synthesised novel 2-
alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and
their 6-alkyl and 8-alkyl derivatives in a three-step route involving the
regioselective cyclisation of thioureidoindazoles and indazolyl
dithiocarbamates as the key steps.
Br2–AcOH, THF
rt, 30–45 min
R = 5-NH2
R = 6-NH2
5
6
Py–Et3N
CS2,RIBr2–AcOH, THF
rt, 30–45 min
NH
NR
NH
HNRS
S
NH
NH
RS
S
NH
NH
N
S
S
N
RS
RS
Lajos Fodor et al.,154 have been synthesized 2-methylthio-1,3-
thiazino[5,6-b]indole and their analogues using 2-(S-
methyldithiocarbamoylaminomethyl)indole.
Et3N, rt 10 min
CH2Cl2, PhMe3NBr3, rt 5 min
NH
HN
S
S
R1NH
NS
SR1
22
Bhisma K. Patel et al.,155 have been developed a method for
the preparation of cyanamides from their corresponding
dithiocarbamic acid salts.
S
HN S . Et3NH I2/Et3N, EtOAc
aq. NH3
HN
N
Patrick Metzner et al.,156 have been investigated the oxidation
reaction of various dithiocarbamates demonstrated that the
corresponding sulfines are formed.
m-CPBA
NaHCO3, CH2Cl2
0 C, 24 h
R2R1N
S
SR3 R2R1N
S
SR3
O
°
Tamejiro Hiyama et al.,157 have been prepared trifluoromethyl
aminopyridines and pyrimidines starting from dithiocarbamates.
DBH, TBAH2F3
CH2Cl2, reflux
DBH, TBAH2F3
CH2Cl2, 0 C
N
X
N
R
S
SCH3
°
N
X
N
X
Br
N
R
CF3
N
R
CF3
Bhisma K. Patel et al.,158 have been demonstrated the
multifaceted use of diacetoxyiodobenzene (DIB) for various
synthetically useful organic transformations. The desulfurization
ability of diacetoxyiodobenzene has been explored in the preparation
of isothiocyanates from the corresponding dithiocarbamate salt.
S
HN S . Et3NH NCS
PhI(OAC)2
Et3N
23
RESULTS AND DISCUSSION
24
1.2 Results and Discussion
Synthesis of Dithiocarbamates:
The reactions were carried out between simple aniline and
various substituted anilines in presence of NaOH, CS2, alkyl halides
and DMSO. Stirring continued for 1-2 hours at room temperature and
then followed by 0 ºC (Sceme 1). These reaction conditions are proved
to be good synthetic procedure for various dithiocarbamates (Table 1)
with 65-95% isolated yield.
Yield: 65-95%
NH2
R CS2
CS2/R1I
DMF/(20N) NaOH
rt, 0 C°
NH
S
SR1
R
R = CH3, OCH3, Cl, F,CF3,NO2 etc
R1 = alkyl
Scheme 1
25
Table 1: Synthesis of dithiocarbamates
S. No.
Aniline
Dithiocarbamate
Time (h)
1
NH2
NH
S
SCH3
2
2
NH2
Cl
NH
S
SCH3
Cl
2
3
NH2
F
NH
S
SCH3
F
2
4
NH2
Cl
Cl
NH
S
SCH3
Cl
Cl
2
5
NH2
Cl
F3C
NH
S
SCH3
Cl
F3C
2
6
NH2
O2N
NH
S
SCH3
O2N
2
7
NH2
F
NH
S
SCH3
F
2
8
NH2
O
NH
S
SCH3
O
2
9
NH2
O
NH
O
S
SCH3
2
10
NH2
NH
S
SCH2CH3
2
26
11
NH2
Cl
NH
S
SCH3
Cl
2
12
NH2
CF3
NH
S
SCH3
CF3
2
13
N NH2
N NH
S
SCH3
2
14
NH2
O
O
NH
S
SCH3
O
O
2
15
NH2
C8H17
NH
S
SCH3
C8H17
2
16
NH2
HN
O
NH
S
SCH3
HN
O
2
17
NH2
O
O
NH
O
OS
SCH3
2
18
NH2
NH
S
SCH2CH3
2
27
CONCLUSION
28
1.3 Conclusion
We have developed an efficient and novel procedure for the
direct synthesis of dithiocarbamates employing amines, CS2, and alkyl
halides, in one-pot, without the use of any catalyst in aqueous
condition having functional groups like methyl, methoxy, nitro, halo
and CF3 from commercially available anilines and prepared some
various substituted anilines with morpholine, 1-Methyl piperazine,
cyclopropane carboxylic acid amide etc. The present method can be
used for the synthesis of biological active compounds and their diverse
functionalized analogues. This methodology has several advantages
including simple reaction conditions, operational, experimental
simplicity combined with high functional group tolerance.
29
EXPERIMENTAL SECTION
30
1.4 Experimental Section
General: All reactions were performed using oven-dried glassware.
Organic solutions were concentrated under reduced pressure using
Buchi rotary evaporator. All other reagents and solvents were obtained
from commercial suppliers and were used without further purification.
Reactions and chromatographic fractions were monitored by thin layer
chromatography. TLC Silica gel-60 F254, Merck was used for TLC and
silica gel (100-200 mesh, SRL, India) was used for column
chromatography.
General experimental procedure for preparation of
dithiocarbamates:
To a stirring solution of aniline (1.0 eq) and DMSO (20 ml) in
250 ml round bottomed flask, 20 N NaOH (1.2 eq) solution was added
drop wise, and followed by addition of CS2 (2.5 eq), the stirring was
continued for 1 hour at room temperature. Then the reaction mixture
was cooled to 0 ºC. To this alkyl halide (2.0 eq) was added drop wise
and the stirring was continued for 1 hour at 0 ºC. The completion of
the reaction was monitored by TLC, then the reaction mixture was
poured into stirring ice cold water, solid was obtained was filtered and
dried under vaccum and the solid compound was purified by column
and confirmed by spectral data.
31
Phenyl-dithiocarbamic acid methyl ester (1a)
NH
S
SCH3
The compound was prepared according to the general
procedure, from simple aniline (5.0 g, 53.76 mmol), carbon disulfide
(8.95 ml, 134.40 mmol) and methyl iodide (5.10 ml, 80.64 mmol) in
the presence of NaOH (2.58 g, 64.51 mmol) in DMSO (20 ml) to give
9.35 g (95%) of the product as a solid; mp: 87-88 ºC; 1H NMR (400
MHz, DMSO-d6): δ 11.66 (s, 1H, NH), 7.60 (br s, 2H), 7.41-7.37 (m,
2H), 7.25-7.22 (m, 1H), 2.57 (s, 3H); Mass (ESI): 184.0 [M+H]+.
(4-Chloro-phenyl)-dithiocarbamic acid methyl ester (1b)
NH
S
SCH3
Cl
The compound was prepared according to the general
procedure, from 4-Chloro aniline (5.0 g, 39.21 mmol), carbon disulfide
(5.89 ml, 98.03 mmol) and methyl iodide (3.72 ml, 58.82 mmol) in the
presence of NaOH (1.88 g, 47.05 mmol) in DMSO (20 ml) to give 7.91 g
(93%) of the product as a solid; mp: 108-109 ºC; 1H NMR (400 MHz,
32
DMSO-d6): δ 11.74 (s, 1H, NH), 7.68 (br s, 2H), 7.46-7.7.44 (m, 2H),
2.58 (s, 3H); Mass (ESI): 217.5 [M+H]+.
(4-Fluoro-phenyl)-dithiocarbamic acid methyl ester (1c)
NH
S
SCH3
F
The compound was prepared according to the general
procedure, from 4-Fluoro aniline (5.0 g, 44.99 mmol), carbon disulfide
(6.78 ml, 112.0 mmol) and methyl iodide (5.57 ml, 89.9 mmol) in the
presence of NaOH (2.15 g, 53.9 mmol) in DMSO (20 ml) to give 8.25 g
(91%) of the product as a solid; mp: 108-109 ºC; 1H NMR (400 MHz,
DMSO-d6): δ 11.64 (s, 1H, NH), 7.61 (br s, 2H), 7.25-7.20 (m, 2H),
2.57 (s, 3H); Mass (ESI): 202.2 [M+H]+.
(3, 4-Dichloro-phenyl)-dithiocarbamic acid methyl ester (1d)
NH
S
SCH3
Cl
Cl
The compound was prepared according to the general
procedure, from 3,4-Dichloro aniline (5.0 g, 30.8 mmol), carbon
disulfide (4.65 ml, 77.1 mmol) and methyl iodide (3.85 ml, 61.7 mmol)
in the presence of NaOH (1.48 g, 37.0 mmol) in DMSO (20 ml) to give
33
6.20 g (80%) of the product as a solid; mp: 132-133 ºC; 1H NMR (400
MHz, DMSO-d6): δ 11.84 (s, 1H, NH), 8.10 (s, 1H), 7.69-7.64 (m, 2H),
2.59 (s, 3H); Mass (ESI): 250.1 [M-H]+.
(4-Chloro-3-trifluoromethyl-phenyl)-dithiocarbamic acid methyl
ester (1e)
NH
S
SCH3
Cl
F3C
The compound was prepared according to the general
procedure, from 4-Chloro-3-trifluoromethyl aniline (5.0 g, 25.56
mmol), carbon disulfide (3.84 ml, 63.51 mmol) and methyl iodide (2.42
ml, 38.3 mmol) in the presence of NaOH (1.22 g, 30.67 mmol) in
DMSO (20 ml) to give 5.50 g (76%) of the product as a solid; mp: 141-
142 ºC; 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H, NH), 8.32 (s,
1H), 8.06-8.04 (m, 1H), 7.76-7.74 (m, 1H), 2.61 (s, 3H); Mass (ESI):
284.1 [M-H]+.
(4-Nitro-phenyl)-dithiocarbamic acid methyl ester (1f)
NH
S
SCH3
O2N
34
The compound was prepared according to the general
procedure, from 4-Nitro aniline (5.0 g, 36.1 mmol), carbon disulfide
(5.45 ml, 90.4 mmol) and methyl iodide (4.51 ml, 72.0 mmol) in the
presence of NaOH (3.47 g, 43.4 mmol) in DMSO (20 ml) to give 7.25 g
(88%) of the product as a solid; 1H NMR (400 MHz, DMSO-d6): δ 12.03
(s, 1H, NH), 8.76 (s, 1H), 8.12-8.06 (m, 2H), 7.70-7.66 (m, 1H), 2.62 (s,
3H); Mass (ESI): 227.2 [M-H]+.
(3-Fluoro-phenyl)-dithiocarbamic acid methyl ester (1g)
NH
S
SCH3
F
The compound was prepared according to the general
procedure, from 3-Fluoro aniline (5.0 g, 44.99 mmol), carbon disulfide
(6.78 ml, 112.0 mmol) and methyl iodide (5.57 ml, 89.9 mmol) in the
presence of NaOH (2.15 g, 53.9 mmol) in DMSO (20 ml) to give 7.60 g
(84%) of the product as a solid; 1H NMR (400 MHz, DMSO-d6): δ 11.64
(s, 1H, NH), 7.61 (br s, 2H), 7.25-7.21 (m, 2H), 2.57 (s, 3H); Mass
(ESI): 200.2 [M-H]+.
35
(4-Methoxy-phenyl)-dithiocarbamic acid methyl ester (1h)
NH
S
SCH3
O
The compound was prepared according to the general
procedure, from 4-Methoxy aniline (5.0 g, 40.65 mmol), carbon
disulfide (6.12 ml, 101.62 mmol) and methyl iodide (5.07 ml, 81.30
mmol) in the presence of NaOH (1.95 g, 48.78 mmol) in DMSO (20 ml)
to give 6.43 g (74%) of the product as a solid; mp: 101-102 ºC; 1H
NMR (400 MHz, DMSO-d6): δ 11.50 (br s, 1H, NH), 7.53 (br s, 2H),
6.95-6.93 (d, J = 8.40 Hz, 2H), 3.76 (s, 3H), 2.55-2.49 (m, 3H); Mass
(ESI): 214.1 [M+H]+.
(3-Methoxy-phenyl)-dithiocarbamic acid methyl ester (1i)
NH
S
SCH3
O
The compound was prepared according to the general
procedure, from 3-Methoxy aniline (5.0 g, 40.65 mmol), carbon
36
disulfide (6.12 ml, 101.62 mmol) and methyl iodide (5.07 ml, 81.30
mmol) in the presence of NaOH (1.95 g, 48.78 mmol) in DMSO (20 ml)
to give 6.80 g (79%) of the product as a solid; mp: 120-122 ºC; 1H
NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H, NH), 7.34 (s, 1H), 7.29 (t, J
= 8.0 Hz, 1H), 7.22-7.18 (m, 1H), 6.82 (d, J = 7.56 Hz, 1H), 3.77 (s,
3H), 2.56 (s, 3H); Mass (ESI): 214.0 [M+H]+.
(2,3-Dimethyl-phenyl)-dithiocarbamic acid ethyl ester (1j)
NH
S
SCH3
The compound was prepared according to the general
procedure, from 2, 3-Dimethyl aniline (5.0 g, 41.26 mmol), carbon
disulfide (6.22 ml, 103.15 mmol) and methyl iodide (5.14 ml, 82.52
mmol) in the presence of NaOH (1.98 g, 49.51 mmol) in DMSO (20 ml)
to give 8.15 g (88%) of the product as a solid; 1H NMR (400 MHz,
CDCl3): δ 8.85 (br s, 1H, NH), 7.3-7.12 (m, 3H), 3.3 (q, J = 8.0 Hz, 2H),
2.38 (s, 3H), 2.18 (s, 3H), 1.3 (t, J = 3.6 Hz, 3H); Mass (ESI): 226.0
[M+H]+.
(3-Chloro-phenyl)-dithiocarbamic acid methyl ester (1k)
37
NH
S
SCH3
Cl
The compound was prepared according to the general
procedure, from 3-Chloro aniline (5.0 g, 39.21 mmol), carbon disulfide
(5.89 ml, 98.03 mmol) and methyl iodide (3.72 ml, 58.82 mmol) in the
presence of NaOH (1.88 g, 47.05 mmol) in DMSO (20 ml) to give 7.91 g
(93%) of the product as a solid; mp: 91-93 ºC; 1H NMR (400 MHz,
DMSO-d6): δ 11.77 (s, 1H, NH), 7.85 (s, 1H), 7.58 (d, J = 7.88 Hz, 1H),
7.41 (t, J = 8.04 Hz, 1H), 7.28 (d, J = 7.56 Hz, 1H); Mass (ESI): 217.5
[M+H]+.
(3-Trifluoromethyl-phenyl)-dithiocarbamic acid methyl ester (1l)
NH
S
SCH3
CF3
The compound was prepared according to the general
procedure, from 3-Trifluoromethyl aniline (5.0 g, 31.03 mmol), carbon
disulfide (3.74 ml, 62.07 mmol) and methyl iodide (3.77 ml, 46.55
mmol) in the presence of NaOH (1.48 g, 37.24 mmol) in DMSO (20 ml)
38
to give 6.74 g (82%) of the product as a solid; mp: 71-72 ºC; Mass
(ESI): 252 [M+H]+.
Pyridin-2-yl-dithiocarbamic acid methyl ester (1m)
N NH
S
SCH3
The compound was prepared according to the general
procedure, from 2-Amino pyridine (2.0 g, 21.27mmol), carbon
disulfide (3.20 ml, 53.19 mmol) and methyl iodide (3.99 ml, 63.8
mmol) in the presence of NaOH (1.02 g, 25.53 mmol) in DMSO (20 ml)
to give 2.79 g (71%) of the product as a solid; mp: 88-89 ºC; Mass
(ESI): 185.1 [M+H]+.
Benzo[1,3]dioxol-5-yl-dithiocarbamic acid methyl ester (1n)
NH
S
SCH3
O
O
39
The compound was prepared according to the general
procedure, from Benzo[1,3]dioxol-5-ylamine (5.0 g, 36.45 mmol),
carbon disulfide (5.49 ml, 91.14 mmol) and methyl iodide (4.54 ml,
72.91 mmol) in the presence of NaOH (1.75 g, 43.75 mmol) in DMSO
(20 ml) to give 6.62 g (80%) of the product as a solid; 1H NMR (400
MHz, DMSO-d6): δ 11.51 (s, 1H, NH), 6.96-6.91 (m, 3H), 6.05 (s, 2H),
2.50 (s, 3H); Mass (ESI): 228.0 [M+H]+.
(3-Octyl-phenyl)-dithiocarbamic acid ethyl ester (1o)
NH
S
S
The compound was prepared according to the general
procedure, from 3-Octyl-phenylamine (5.0 g, 36.45 mmol), carbon
disulfide (5.49 ml, 91.14 mmol) and ethyl iodide (4.54 ml, 72.91
mmol) in the presence of NaOH (1.75 g, 43.75 mmol) in DMSO (20 ml)
to give 5.77 g (78%) of the product as a solid; 1H NMR (400 MHz,
CDCl3): δ 8.82 (br s, 1H, NH), 7.40-7.15 (m, 4H), 3.30 (q, J = 1.2 Hz,
2H), 2.61 (t, J = 8.80 Hz, 3H), 1.69-0.89 (m, 17H); Mass (ESI): 310.0
[M+H]+.
[4-(Cyclopropanecarbonyl-amino)-phenyl]-dithiocarbamic acid
methyl ester (1p)
40
NH
S
SCH3
HN
O
The compound was prepared according to the general
procedure, from Cyclopropanecarboxylic acid (4-amino-phenyl)-amide
(2.0 g, 11.36 mmol), carbon disulfide (1.70 ml, 28.40 mmol) and
methyl iodide (1.43 ml, 22.72 mmol) in the presence of NaOH (0.54 g,
13.63 mmol) in DMSO (20 ml) to give 2.13 g (70%) of the product as a
solid; 1H NMR (200 MHz, DMSO-d6): δ 11.56 (br s, 1H, NH), 10.27 (br
s, 1H, NH), 7.61-7.56 (m, 4H), 2.55 (s, 3H), 1.79-1.70 (m, 1H) 0.81-
0.78 (m, 4H); Mass (GC-LC/MS): 219.0 [M+-SCH3].
(3, 4-Dimethoxy-phenyl)-dithiocarbamic acid methyl ester (1q)
NH
S
SCH3
O
O
The compound was prepared according to the general
procedure, from 3, 4-Dimethoxy aniline (5.0 g, 32.64 mmol), carbon
disulfide (4.92 ml, 81.60 mmol) and methyl iodide (3.05 ml, 48.96
mmol) in the presence of NaOH (1.56 g, 39.16 mmol) in DMSO (20 ml)
to give 7.0 g (88%) of the product as a solid; Mass (ESI): 244.0 [M+H]+.
41
m-Tolyl-dithiocarbamic acid ethyl ester (1r)
NH
S
S
The compound was prepared according to the general
procedure, from 3-Methyl aniline (5.0 g, 46.72 mmol), carbon disulfide
(7.04 ml, 116.82 mmol) and methyl iodide (5.91 ml, 93.45 mmol) in
the presence of NaOH (2.24 g, 56.07 mmol) in DMSO (20 ml) to give
8.34 g (85%) of the product as a solid; mp: 62-63 ºC; Mass (ESI):
212.3 [M+H]+.
42
SPECTRA
43
1.5 Spectra
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
REFERENCES
74
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