chapter i - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/3484/12/12... · 2015-12-04 ·...

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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


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


procedure, from 4-Fluoro aniline (5.0 g, 44.99 mmol), carbon disulfide




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


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


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


procedure, from 4-Nitro aniline (5.0 g, 36.1 mmol), carbon disulfide



(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


procedure, from 3-Fluoro aniline (5.0 g, 44.99 mmol), carbon disulfide



(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


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


procedure, from 3-Methoxy aniline (5.0 g, 40.65 mmol), carbon

36



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


procedure, from 2, 3-Dimethyl aniline (5.0 g, 41.26 mmol), carbon



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


procedure, from 3-Chloro aniline (5.0 g, 39.21 mmol), carbon disulfide




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


procedure, from 3-Trifluoromethyl aniline (5.0 g, 31.03 mmol), carbon



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


procedure, from 2-Amino pyridine (2.0 g, 21.27mmol), carbon



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


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


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


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


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


procedure, from 3, 4-Dimethoxy aniline (5.0 g, 32.64 mmol), carbon



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


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

73

REFERENCES

74

1.6 References

1. (a) Han, C.; Porco Jr, J. A. Org. Lett. 2007, 9, 1517; (b) Ranise, A.;

Spallarossa, A.; Schenone, S.; Burno, O.; Bondavalli, F.; Vargiu, L.,

Marceddu, T.; Mura, M.; Colla, P. L.; Pani, A. J. Med. Chem. 2003,

46, 768; (c) Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G.

Y.; Li, R. T. Bioorg. Med. Chem. Lett. 2005, 15, 1915; (d) Salvatore,

R. N.; Sahab, S.; Jung, K. W. Tetrahedron Lett. 2001, 42, 2055; (e)

Adams, P.; Baron, F. A. Chem. Rev. 1965, 65, 567.

2. (a) Rafin, C.; Veignie, E; Sancholle, M.; Postal, D.; Len, C.; Villa, P.;

Ronco, G. J. Agric. Food. Chem. 2000, 48, 5283; (b) Jager, P.;

Rentzea, C. N.; Kieczka, H. in Ullmann`s Encyclopedia of Industrial

Chemistry, 5th edn. (VCH, Weinheim) 1986, 51.

3. (a) Tsuboi, S.; Takeda, S.; Yamasaki, Y.; Sakai, T.; Utka, M.; Ishida,

S.; Yamada, E.; Hirano, J. Chem. Lett. 1992, 8, 1417; (b) Katrizky,

A. R.; Singh, S.; Mahapatra, P. P.; Clemense, N.; Kirichenko, K.

Arkivoc 2005, 9, 63.

4. Greene, T. W.; Wuts, P. G. M. Protecting Group in Organic Synthesis,

3rd edn. (Wiley Interscience, New York) 1999, 484.

5. (a) Garin, J.; Melandz, E.; Merchain, F. L.; Tejero, T.; Urid, S.;

Ayestaron, J. Synthesis 1991, 147; (b) Chaturvedi, D.; Ray, S.;

Tetrahedron Lett. 2006, 47, 1307.

6. (a) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413; (b) Barton,

D. H. R.; Tetrahedron 1992, 48, 2529; (c) Zard, S. Z. Angew Chem.

Int. Ed. (Engl.) 1997, 36, 672.

75

7. Zhang, D.; Chen, J.; Liang, Y.; Zhou, H. Synth. Commun. 2005, 35,

521.

8. Schreck, R.; Meier, B.; Mannel, D. N.; Droge, W.; Baeuerle, P. A. J.

Exp. Med. 1992, 175, 1181.

9. Ha, T.; Li, Y.; Gao, X.; McMullen, J. R.; Shioi, T.; Izumo, S.; Kelley,

J. L.; Zhao, A.; Haddad, G. E.; Williams, D. L.; Browder, I. W.; Kao,

R. L.; Li, C. Free Radic. Biol. Med. 2005, 39, 1570.

10. (a) Villa, P.; Len, C.; Boulogne-Merlot, A. S.; Postal, D.; Ronco, G.;

Goubert, C.; Jeufrault, E.; Mathon, B.; Simon, H. J. Agric. Food

Chem. 1996, 44, 2856; (b) Len, C.; Postal, D.; Ronco, G.; Villa, P.;

Goubert, C.; Jeufrault, E.; Mathon, B.; Simon, H. J. Agric. Food

Chem. 1997, 45, 3; (c) Schwack, W.; Perz, R. C.; Lishaut, H. J.

Agric. Food Chem. 2000, 48, 792; (d) Len, C.; Villa, P.; Ronco, G. J.

Agric. Food Chem. 2000, 48, 5283; (e) Caldas, E. D.; Conceicao, M.

H.; Miranda, M. C.; Souza, L.; Lima, J. F. J. Agric. Food Chem.

2001, 49, 4521.

11. Plyusnin, V. F.; Grivin, V. P.; Larionov, S. V. Coord. Chem. Rev.

1997, 159, 121.

12. Nieuwenhuizen, P. J. Appl. Catal. A: Gen. 2001, 207, 55.

13. Fujii, S.; Yoshimura, T. Coord. Chem. Rev. 2000, 198, 89.

14. (a) Mayadunne, R. T. A.; Rizzardo, E.; Chiefari, J. Macromolecules

1999, 32, 6977; (b) Schilli, C.; Lanzendorfer, M. G.; Muller, A.

H. E. Macromolecules 2002, 35, 6819.

15. Dhooghe, M.; Kimpe, N. D. Tetrahedron 2006, 62, 513.

76

16. (a) Zhang, Y.; Talalay, P. Cancer Res. 1994, 54, 1976; (b) Hecht,

S. S. J. Nutr. 1999, 129, 768s; (c) Conaway, C. C.; Yang, Y. M.;

Chung, F. L. Curr. Drug Metab. 2002, 3, 233; (d) London, S. J.;

Yuan, J. M.; Chung, F. L. Lancet 2000, 356, 724; (e) Spitz, M. R.;

Duphorne, C. M.; Detry, M. A. Cancer Epidemiol. Biomark. Prev.

2000, 9, 1017; (f) Lin, H. J.; Zhou, H.; Dai, A. Pharmacogenetics

2002, 12, 175; (g) Callaway, E. C.; Zhang, Y. S.; Chew, W. D.;

Chow, H. H. Cancer Lett. 2004, 204, 23; (h) Macca, C.; Trevisan,

A.; Fregona, D. J. Med. Chem. 2006, 49, 1648; (i) Cao, S. L.; Feng,

Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R. T. Bioorg. Med.

Chem. Lett. 2005, 15, 1915; (j) Li, R. T.; Hou, X. L.; Ge, Z. M.

Bioorg. Med. Chem. Lett. 2006, 16, 4214.

17. (a) Wolfe, J. T.; Ross, D.; Cohen, G. M. FEBS Lett. 1994, 352,

58; (b) Bessho, R.; Matsubara, K.; Kubota, M. Biochem. Pharmacol.

1994, 48, 1883; (c) Verhaegen, S.; McGowan, A. J.; Brophy, A. R.

Biochem. Pharmacol. 1995, 50, 1021; (d) Nobel, C. S. I.; Kimland,

M.; Lind, B. J. Biol. Chem. 1995, 270, 26202; (e) Tsai, J. C.; Jain,

M.; Hsieh, C. M. J. Biol. Chem. 1996, 271, 3667; (f) Wu, M.; Lee,

H.; Bellas, R. E. EMBO J. 1996, 15, 4682.

18. (a) Boas, U.; Jakobsen, M. H. J. Chem. Soc., Chem. Commun.

1995; (b) Elgemeie, G. H.; Sayed, S. H. Synthesis 2001, 1747; (c)

Mukerjee, A. K.; Ashare, R. Chem. Rev. 1991, 91, 1; (d) Boas, U.;

Gertz, H.; Christensen, J. B.; Heegaard, P. M. H. Tetrahedron Lett.

2004, 45, 269.

77

19. (a) Dhooghe, M.; De Kime, N. Tetrahedron 2006, 62, 513; (b)

Fernandez, J. M. G.; Mellet, C. O.; Blanco, J. L. J.; Mota, J. F.;

Gadelle, A.; Coste-Sarguet, A.; Defaye, J. Carbohydr. Res. 1995,

268, 57.

20. WHO, Dithiocarbamate Pesticides, Ethylenethiourea and

Propylenethiourea: A General Introduction, WHO, Geneva, 1988.

21. WHO, The WHO Recommended Classification of Pesticides by

Hazardand Guidelines to Classification, WHO/IPCS/IOMC 2005.

22. Vauthey, I.; Valot, F.; Gozzi, C.; Fache, F.; Lemaire, M.

Tetrahedron Lett. 2000, 41, 6347.

23. Greene, T. W.; Wuts, P. G. M. Protective Grooups in Organic

Synthesis, 3rd ed.; J.W. Wiley and Sons: New York, 1999, 503 and

references cited therein.

24. Warrass, R.; Weismuller, K. H.; Jung, G. Tetrahedron Lett.

1998, 39, 2715.

25. (a) Li, Z.; Bitha, P.; Lang Jr, S. A.; Lin, Y. Biol. Med. Chem. Lett.

1997, 7, 2909; (b) Bundgaard, H. Drugs Future 1991, 16, 443.

26. (a) Caldas, E. D.; Hosana Conceicu¨a, M.; Miranda, M. C. C.;

Souza, L.; Lima, J. F. J. Agric. Food Chem. 2001, 49, 4521; (b)

Erian, A. W.; Sherif, S. M. Tetrahedron 1999, 55, 7957; (c) Wood,

T. F.; Gardner, J. H. J. Am. Chem. Soc. 1941, 63, 2741; (d)

Bowden, K.; Chana, R. S. J. Chem. Soc., Perkin Trans. 1990, 2,

2163; (e) Beji, M.; Sbihi, H.; Baklouti, A.; Cambon, A. J. Fluorine

Chem. 1999, 99, 17; (f) Goel, A.; Mazur, S. J.; Fattah, R. J.;

78

Hartman, T. L.; Turpin, J. A.; Huang, M.; Rice, W. G.; Appella,

E.; Inman, J. K. Bioorg. Med. Chem Lett. 2002, 12, 767.

27. (a) Chen-Hsien, W. Synthesis 1981, 622; (b) Mizuno, T.;

Nishiguchi, I.; Okushi, T.; Hirashima, T. Tetrahedron Lett. 1991,

32, 6867; (c) Chen, Y. S.; Schuphan, I.; Casida, J. E. J. Agric. Food

Chem. 1979, 27, 709; (d) Rafin, C.; Veignie, E.; Sancholle, M.;

Postal, D.; Len, C.; Villa, P.; Ronco, G. J. Agric. Food Chem. 2000,

48, 5283; (e) Len, C.; Postal, D.; Ronco, G.; Villa, P.; Goubert, C.;

Jeufrault, E.; Mathon, B.; Simon, H. J. Agric. Food Chem. 1997,

45, 3.

28. (a) Morf, P.; Raimondi, F.; Nothofer, H. G.; Schnyder, B.; Yasuda,

A.; Wessels, J. M.; Jung, T. A. Langmuir 2006, 22, 658; (b)

McClain, A.; Hsieh, Y. L. J. Appl. Polym. Sci. 2004, 92, 218; (c)

Bongar, B. P.; Sadavarte, V. S.; Uppalla, L. S. J. Chem. Res. (S)

2004, 9, 450; (d) Dunn, A. D.; Rudorf, W. D. Carbon Disulphide in

Organic Chemistry; Ellis Horwood: Chichester, U. K.; 1989, 226.

29. (a) Nieuwenhuizen, P. J.; Ehlers, A. W.; Haasnoot, J. G.; Janse, S.

R.; Reedijk, J.; Baerends, E. J. J. Am. Chem. Soc. 1999, 121, 163;

(b) Thorn, G. D.; Ludwig, R. A. The Dithiocarbamates and Related

Compounds; Elsevier: Amsterdam, 1962; (c) Nice, H. R. Org. React.

1962, 12, 57 and references cited therein.

30. (a) Wood, M. R.; Duncalf, D. J.; Rannard, S. P.; Perrier, S. Org.

Lett. 2006, 8, 553 and references therein; (b) Crich, D.; Quintero,

L. Chem. Rev. 1989, 89, 1413; (c) Barton, D. H. R. Tetrahedron

79

1992, 48, 2529-2552; (d) Zard, S. Z. Angew. Chem. Int. Ed. 1997,

36, 672.

31. (a) Ronconi, L.; Marzano, C.; Zanello, P.; Corsini, M.; Miolo, G.;

Macca, C.; Trevisan, A.; Fregona, D. J. Med. Chem. 2006, 49,

1648; (b) Walter, W.; Bode, K. D. Angew. Chem. Int. Ed. Engl.

1967, 6, 281; (c) Elgemeie, G. H.; Sayed, S. H. Synthesis 2001,

1747.

32. AIDS Res. Hum. Retrov. 1993, 9, 83.

33. Hersh, E. M.; Brewton, G.; Abrams, D.; Bartlett, J.; Galpin, J.;

Gill, P.; Gorter, R.; Gottlieb, M.; Jonikas, J. J.; Landesman, S.

JAMA 1991, 265, 1538.

34. Kaplan, C. S.; Petersen, E. A.; Yocum, D.; Hersh, E. M. Life Sci.

1989, 45, iii.

35. Lang, J. M.; Touraine, J. L.; Trepo, C.; Choutet, P.; Kirstetter, M.;

Falkenrodt, A.; Herviou, L.; Livrozet, J. M.; Retornaz, G.; Touraine,

F. Lancet 1988, 2, 702.

36. Hogarth, G. Prog. Inorg. Chem. 2005, 53, 7.

37. Hidaka, S.; Funakoshi, T.; Shimada, H.; Tsuruoka, M.; Kojima, S.

J. Appl. Toxicol. 1995, 15, 267.

38. Tandon, S. K.; Singh, S.; Jain, V. K.; Prasad, S. Fundam. Appl.

Toxicol. 1996, 31, 141.

39. Lai, C. S.; Vassilev, V. P.; Wang, T. M. US 5847004.

40. (a) Lai, J. T.; Shea, R. J. Polym. Sci. Part A: Polym. Chem. 2006,

80

44, 4298; (b) Dure´aault, A.; Gnanou, Y.; Taton, D.; Destarac, M.;

Leising, F. Angew. Chem. Int. Ed. 2003, 42, 2869; (c) Bathfield,

M.; D‟Agosto, F.; Spitz, R.; Charreyre, M. T.; Delair, T.; J. Am.

Chem. Soc. 2006, 128, 2546.

41. Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic

Synthesis, 3rd ed. Wiley Interscience, New York 1999, 484.

42. (a) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413; (b)

Barton, D. H. R. Tetrahedron, 1992, 48, 2529; (c) Zard, S. Z.

Angew. Chem. Int. Ed. Engl. 1997, 36, 672.

43. (a) Blanrue, A.; Wilhelm, R. Synthesis 2009, 583; (b) Zhang, D.;

Chen, J.; Liang, Y.; Zhou, H. Synth. Commun. 2005, 35, 521.

44. Kanie, K.; Mizuno, K.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc.

Jpn. 1998, 71, 1973.

45. (a) Ziyaei-Halimehjani, A.; Porshojaei, Y.; Saidi, M. R. Tetrahedron

Lett. 2009, 50, 32; (b) Sugimoto, H.; Makino, I.; Hirai, K. J. Org.

Chem. 1988, 53, 2263; (c) Takikawa, Y.; Inoue, N.; Sato, R.;

Takizawa, S. Chem. Lett. 1982, 641; (d) Maddani, M.; Prabhu, K.

R. Tetrahedron Lett. 2007, 48, 7151.

46. Das, P.; Kumar, C. K.; Kumar, K. N.; Innus, M. D.; Iqbal, J.;

Srinivas, N. Tetrahedron Lett. 2008, 49, 992.

47. Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969.

48. Guillaneuf, Y.; Couturier, J. L.; Gigmes, D.; Marque, S. R. A.;

Tordo P.; Bertin, D. J. Org. Chem. 2008, 73, 4728.

49. Ziyaei-Halimehjani, A.; Maleki, H.; Saidi, M. R. Tetrahedron Lett.

81

2009, 50, 2747 and references therein.

50. Grainger, R. S.; Welsh, E. J. Angew. Chem. Int. Ed. 2007, 46,

5377.

51. Thorn, G. D.; Ludwig, R. A. The Dithiocarbamates and Related

Compounds, Elsevier, Amsterdam 1962.

52. Safak, C.; Erdogan, H.; Yesilada, A.; Erol, K.; Cimgi, I. Arzneim.

Forsch. 1992, 42, 123.

53. (a) Aboul-Fadl, T.; El-Shorbagi, A. Eur. J. Med. Chem. 1996, 31,

165; (b) Cascio, G.; Lorenzi, L.; Caglio, D.; Manghisi, E.; Arcamone

, F.; Guanti, G.; Satta, G.; Morandotti G.; Sperning, R. Farmaco.

1996, 51, 189; (c) Imamura, H.; Ohtake, N.; Jona, H.; Shimizu,

A.; Moriya, M.; Sato, H.; Sugimoto, Y.; Ikeura, C.; Kiyonaga, H.;

Nakano, M.; Hagano, R.; Abe, S.; Yamada, K.; Hashizume, T.;

Morishima, H. Bioorg. Med. Chem. Lett. 2001, 9, 1571; (d) Nagano,

R.; Shibata, K.; Naito, T.; Fuse, A.; Asano, K.; Hashizume, T.;

Nakagawa, S. Antimicrob. Agents Chemother. 1997, 41, 2278.

54. (a) Gerhauser, C.; You, M.; Liu, J.; Moriarty, R. T.; Hawthorne, M.;

Mehta, R. G.; Moon, R. C.; Pezzuto, J. M. Cancer Res. 1997, 57,

272; (b) Scozzafava, A.; Mastorlorenzo, A.; Supuran, C. T. Bioorg.

Med. Chem. Lett. 2000, 10, 1887; (c) Ge, Z. M.; Li, R. T.; Cheng, T.

M.; Cui, T. M. Arch. Pharm. Med. Chem. 2001, 334, 173; (d) Hou,

X. L.; Ge, Z. M.; Wang, T. M.; Guo, W.; Cui, J. R.; Cheng, T. M.;

Lai, C. S.; Li, R. T. Bioorg. Med. Chem. Lett. 2006, 16, 4214; (e)

Guo, B. G.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Synth. Commun.

82

2001, 31, 3021; (f) Cui, J. L.; Ge, Z. M.; Cheng, T. M.; Li, R. T.

Synth. Commun. 2003, 33, 1969; (g) Wang, Y. Q.; Ge, Z. M.; Hou,

X. L.; Cheng, T. M.; Li, R. T. Synthesis 2004, 675.

55. Gaspari, P.; Banerjee, T.; Malachowski, W. P.; Muller, A. J.;

Prendergast, G. C.; DuHadaway, J.; Bennett, S.; Donovan, A. M. J.

Med. Chem. 2006, 49, 684.

56. Burke, J. T. R.; Bajwa, B. S.; Jacobsen, A. E.; Rice, K. C.; Streaty,

R. A.; Klee, W. A. J. Med. Chem. 1984, 27, 1570.

57. (a) Babad, H.; Zeiler, A. G. Chem. Rev. 1973, 73, 75; (b) Eckert,

H.; Forster, B. Angew Chem. Int. Ed. (Engl.) 1987, 26, 894; (c)

Cotarca, L.; Delogu, P.; Nardelli, A.; Unji, V. Synthesis 1996, 5,

553; (d) Walter, W.; Bode, K. D. Angew Chem. Int Ed (Engl.)

1967, 6, 281.

58. (a) Salvatore, R. N.; Shin, S. I.; Nagle, A. S.; Jung, K. W. J. Org.

Chem. 2001, 66, 1035; (b) Curini, M.; Epifano, F.; Rosati, O.;

Tetrahedron Lett. 2002, 43, 4895; (c) Chaturvedi, D.; Kumar, A.;

Ray, S. Tetrahedron Lett. 2003, 44, 7637; (d) Vauthey, I.; Frederic,

V.; Gozzi, C.; Fache, F.; Lamaire, M. Tetrahedron Lett. 2000, 41,

6347. (e) Inesi, A.; Mucciante, V.; Rossi, L. J. Org. Chem. 1998, 63,

1337; (f) Casadei, M. A.; Moracci, F. M.; Zappia, G. J. Org. Chem.

1997, 62, 6754.

59. Lee, A. W. M.; Chan, W. H.; Wong, H. C.; Wong, M. S. Synth

commn, 1989, 19, 547.

60. (a) Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2006, 47, 1307; (b)

83

Salvatore, R. N.; Sahaba, S.; Jung, K. W. Tetrahedron Lett. 2001,

42, 2055.

61. Curtin, N. J.; Hughes, A. N. Lancet Oncol. 2001, 2, 298.

62. Marsham, P. R.; Hughes, L. R.; Jackman, A. L.; Hayter, A. J.;

Oldfield, J.; Wardleworth, J. M.; Bishop, J. A. M.; O Connor, B.

M.; Calvert, A. H. J. Med. Chem. 1991, 34, 1594.

63. Cunningham, D.; Zalcberg, J.; Maroun, J.; James, R.; Clarke, S.;

Maughan, T. S.; Vincent, M.; Schulz, J.; Baron, M. G.; Facchini, T.

Eur. J. Cancer 2002, 38, 478.

64. Bavetsias, V.; Jackman, A. L.; Kimbell, R.; Gibson, W.; Boyle, F.

T.; Bisset, G. M. F. J. Med. Chem. 1996, 39, 73.

65. Webber, S.; Bartlett, C. A.; Boritzki, T. J.; Hilliard, J. A.; Howland,

E. F.; Johnston, A. L.; Kosa, M.; Margosiak, S. A.; Morse, C. A.;

Shetty, B. V. Cancer Chemother. Pharmacol. 1996, 37, 509.

66. Marsham, P. R.; Wardleworth, J. M.; Boyle, F. T.; Hennequin, L.

F.; Kimbell, R.; Brown, M.; Jackman, A. L. J. Med. Chem. 1999,

42, 3809.

67. Moriarty, R. M.; Mehta, R. G.; Liu, J. Carcinogenesis 1995, 16,

399.

68. Gerhauser, C.; You, M.; Pezzuto, J. M. Cancer Res. 1997, 57, 272.

69. Li, R. T.; Cheng, T. M.; Cui, J. R. CN Patent 01118399 2004, 3.

70. Guo, W.; Ran, F. X.; Wang, R. Q.; Cui, J. R.; Li, R. T.; Cheng, T.

M.; Ge, Z. M. Chin. J. Clin. Pharmacol. Ther. 2004, 9, 59.

71. Suh, Y. G.; Lee, Y. S.; Min, K. H.; Park, O. H.; Kim, J. K.; Seung,

84

H. S.; Seo, S. Y.; Lee, B. Y.; Nam, Y. H.; Lee, K. O.; Kim, H. D.;

Park, H. G.; Lee, J.; Oh, U.; Lim, J. O.; Kang, S. U.; Kil, M. J.;

Koo, J. Y.; Shin, S. S.; Joo, Y. H.; Kim, J. K.; Jeong, Y. S.; Kim, S.

Y.; Park, Y. H. J. Med.Chem. 2005, 48, 5823.

72. Muccioli, G. G.; Wouters, J.; Scriba, G. K. E.; Poppitz, W.;

Poupaert, J. H.; Lambert, D. M. J. Med. Chem. 2005, 48, 7486.

73. Walter, W.; Bode, K. D. Angew. Chem. Int. Ed. Engl. 1967, 6, 281.

74. (a) Raichle, K.; Rossing, L.; Zorn, H. GP 840239 1952

(Badische Anilin & Soda-Fabrik); Chem. Abstr. 1953, 47, 1732; (b)

American Cyanamid Co. BP 700334, 1953; Chem. Abstr. 1955,

49, 2492.

75. (a) Alexander, B. H.; Gertler, S. I.; Oda, T. A.; Bown, R. T.; Ihndris,

R. W.; Beroza, M. J. Org. Chem. 1960, 25, 626; (b) Thorn, G. D.;

Ludwig, R. A. The Dithiocarbamates and Related Compounds;

Elsevier: Amsterdam 1962.

76. Nice, H. R. Org. React. 1962, 12, 57 and references cited therein.

77. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic

Synthesis, 3rd ed.; Wiley-Interscience: New York 1999, 484.

78. For a comprehensive overview using the thiocarbonyl functionality

as an intermediate in organic syntheses, see: Dunn, A. D.; Rudorf,

W. D. Carbon Disulphide in Organic Chemistry; Ellis Horwood:

Chichester, UK, 1989, 226.

79. (a) Lee, A. W. M.; Chan, W. H.; Wong, H. C.; Wong, M. S. Synth.

85

Commun. 1989, 19, 547; (b) Degani, I.; Fochi, R. Synthesis 1978,

365.

80. For our cesium-promoted carbonylations, see: (a) Kim, S. I.; Chu,

F.; Dueno, E. E.; Jung, K. W. J. Org. Chem. 1999, 64, 4578; (b)

Chu, F.; Dueno, E. E.; Jung, K. W. Tetrahedron Lett. 1999, 40,

1847. For our cesium-promoted carbamations, see: (c) Salvatore,

R. N.; Shin, S. I.; Nagle, A. S.; Jung, K. W. J. Org. Chem. 2001, 66,

1035.

81. For our solid-phase carbonylation and carbamation protocols, see:

Salvatore, R. N.; Flanders, V. L.; Ha, D.; Jung, K. W. Org. Lett.

2000, 2, 2797.

82. (a) Franz, R. A.; Applegath, F. J. Org. Chem. 1961, 26, 3304; (b)

Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F. J. Org.

Chem 1961, 3306; (c) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron

2005, 61, 9157.

83. (a) Salvatore, R. N.; Sahab, S.; Jung, K. W. Tetrahedron Lett. 2001,

42, 2055; (b) Buess, C. M. J. Am. Chem. Soc. 1955, 77, 6613; (c)

Guo, B.; Ge, Z.; Chang, T.; Li, R. Synth. Commun. 2001, 31, 3021.

(d) Ziyaei-Halimjani, A.; Saidi, M. R. J. Sulfur Chem. 2005, 26,

149. (e) Busque, F.; March, P. D.; Figueredo, M.; Font, J.;

Gonzalez, L. Eur. J. Org. Chem. 2004, 1492.

84. Hirschelman, W. H.; Song, L. S.; Park, E. J.; Tan, Y.; Yu, R.;

86

Hawthorne, M.; Mehta, R. G.; Grubbs, C. J.; Lubet, R. A.;

Moriarty, R. M.; Pezzuto, J. M. 224th ACS National Meeting:

Division of Medicinal Chemistry 2002, 98.

85. Hirschelman, W. H.; Kosmeder II, J. W.; Song, L. S.; Park, E. J.;

Moriarty, R. M.; Pezzuto, J. M. 224th ACS National Meeting:

Division of Medicinal Chemistry 2002, 178.

86. Hirschelman, W. H. 225th ACS National Meeting: Division of

Medicinal Chemistry, 2003, 86.

87. Fregona, D.; Giovagnini, L.; Ronconi, L.; Marzano, C.; Trevisan, A.;

Sitran, S.; Biondi, B.; Bordin, F. J. Inorg. Biochem. 2003, 93, 181.

88. Marzano, C.; Trevisan, A.; Giovagnini, L.; Fregona, D. Toxicol. Vitro

2002, 16, 413.

89. Faraglia, G.; Fregona, D.; Sitran, S.; Giovagnini, L.; Marzano, C.;

Baccicchetti, F.; Casellato, U.; Graziani, R. J. Inorg. Biochem.

2001, 83, 31.

90. Lee, D. H. S.; Macintyre, J. P.; Taylor, G. R.; Wang, E.; Plante, R.

K.; Tam, S. S. C.; Pope, B. L.; Lau, C. Y. J. Pharmacol. Exp. Ther.

1999, 289, 1465.

91. Guo, W.; Ran, F. X.; Wang, R. Q.; Cui, J. R.; Li, R. T.; Cheng, T.

M.; Ge, Z. M. Chin. J. Clin. Pharmacol. Ther. 2004, 9, 59.

92. Scozzafava, A.; Mastrolorenzo, A.; Supuran, C. T. Bioorg. Med.

Chem. Lett. 2000, 10, 1887.

93. Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R. T.


87

94. Liu, S.; Liu, F.; Yu, X.; Ding, G.; Xu, P.; Cao, J.; Jiang, Y. Bioorg.

Med. Chem. 2006, 14, 1425.

95. Malaguarnera, L.; Pilastro, M. R.; Vicari, L.; Dimarco, R.;

Manzella, L.; Palumbo, G.; Messina, A. Cancer Invest. 2005, 23,

404.

96. Donadelli, M.; Pozza, E. D.; Costanzo, C.; Scupoli, M. T.;

Piacentini, P.; Scarpa, A.; Palmieri, M. Biochim. Biophys. Acta-

Mol. Cell. Res.2006 (accepted manuscript) doi:10.1016/j.bbamcr.2

006.05.015.

97. Hou, X.; Ge, Z.; Wang, T.; Guo, W.; Cui, J.; Cheng, T.; Lai, C.;

Li, R. Bioorg. Med. Chem. Lett. 2006, 16, 4214.

98. Giogvanini, L.; Marzano, C.; Bettio, F.; Fregona, D. J. Inorg.

Biochem. 2005, 99, 2139.

99. Ronconi, L.; Giovagnini, L.; Marzano, C.; Bettio, F.; Graziani, R.;

Pilloni, G.; Fregona, D. Inorg. Chem. 2005, 44, 1867.

100. Viola-Rhenals, M.; Rieber, M. S.; Rieber, M. Biochem. Pharmacol.

2006, 71, 722.

101. Giovagnini, L.; Ronconi, L.; Aldinucci, D.; Lorenzon, D.; Sitran,

S.; Fregona, D. J. Med. Chem. 2005, 48, 1588.

102. Purkayastha, R. P. In Handbook of phytoalexin metabolism and

action. In Progress in Phytoalexin Research During the Past 50

Years; Daniel, M., Purkayasta, R. P.; Eds.; Marcell Dekker: New

York 1995, 1.

103. Pedras, M. S. C.; Okanga, F. I.; Zaharia, I. L.; Khan, A. Q.

88

Phytochemistry 2000, 66, 391.

104. Metha, R. G.; Liu, J.; Constantinou, A.; Thomas, C. F.;

Hawthorne, M.; You, M.; Gerha¨user, C.; Pezutto, J. M.; Moon, R.

C.; Moriarty, M. R. Carcinogenesis 1995, 16, 399.

105. Pilatova, M.; Sarissky, M.; Kutschy, P.; Mezencev, R.;

Curillova, Z.; Suchy, M.; Monde, K.; Mirossay, L.; Mojzis, J. Leuk.

Res. 2005, 29, 415.

106. Gaspari, P.; Banerjee, T.; Malachowski, W. P.; Muller, A. J.;

Prendergast, G. C.; DuHadaway, J.; Bennett, S.; Donovan, A. M.

J. Med. Chem. 2006, 49, 684.

107. Sporn, M. B. Cancer Res. 1999, 59, 4743.

108. Dlamico, J. J.; Schafer, T. Phosphorus Sulfur Silicon Relat. Elem.

1980, 8, 301.

109. Thiocarbamates Pesticides – Ethylenthiourea and

Propylenthiourea: General Introduction; World Health

Organization: Geneva 1988.

110. Cremlyn, R. J. Agrochemicals-Preparation and Mode of Action;

John Wiley: Chichester 1991.

111. Worthing, C. R.; Walker, S. B. The Pesticide Manual; British

Crop Protection Council: Thorton Heath (UK) 1987.

112. Damani, L. A. Sulphur-Containing Drugs and Related

Compounds - Chemistry Biochemistry and Toxicology.

Metabolism of Sulphur Functional Groups; Ellis Horwood:

Chichester, 1989, 1 Part B.

89

113. Madan, A.; Faiman, M. D. Drug Metab. Disp. 1994, 22, 324.

114. Madan, A.; Williams, T. D.; Faiman, M. D. Mol. Pharmacol.

1994, 46, 1217.

115. Hart, B. W.; Faiman, M. D. Biochem. Parmacol. 1992, 43, 403.

116. Madan, A.; Faiman, M. D. J. Pharmacol. Exp. Ther. 1995, 272,

775.

117. Schupan, I.; Segall, Y.; Rosen, J. D.; Casida, J. E. Sulfur in

Pesticide Action and Metabolism; Rosen, J. D.; Magee, P. S.;

Casida, J. E. Ed.; American Chemical Society: Washington

1981, 65.

118. Pedras, M. S. C.; Taylor, J. L. J. Org. Chem. 1991, 56, 2619.

119. Pedras, M. S. C.; Taylor, J. L. J. Nat. Prod. 1993, 56, 731.

120. Pedras, M. S. C.; Okanga, F. I. J. Org. Chem. 1998, 63, 416.

121. Victoria, L. I. Polyhedron 2000, 19, 2269.

122. Baena, J. R.; Gallego, M.; Valcarcel, M. Analyst 2000, 125,

1495.

123. Fabretti, A. C.; Forghier, F.; Giusti, A.; Preti, C.; Tosi, G; Inorg.

Chim. Acta 1984, 86, 127.

124. Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J.;

Deana Jr, A. A.; Gilfillan, J. L.; Huff, J. W.; Novello, F. C.;

Prugh, J. D.; Smith, R. L.; Willard, A. K. J. Med. Chem. 1985,

28, 347.

125. Kumar, S. K. S. Thermochim. Acta 1984, 72, 349.

126. Hulanicki, A.; Talanta 1967, 14, 1371.

90

127. Ali, B. F.; Al-Akramawi, W. S.; Al-Obaidi, K. H.; Al-Karbori, A. H.

Thermochim. Acta 2004, 419, 39.

128. Lai, S. W.; Drew, M. G. B.; Beer, P. D. J. Organomet. Chem.

2001, 89, 637.

129. Webber, P. R. A.; Drew, M. G. B.; Hibbert, R.; Beer, P. D.; Dalton

Tran. 2004, 1127.

130. Wong, W. W. H.; Phipps, D. E.; Beer, P. D. Polyhedron 2004, 23,

2821.

131. Mirkovic, T.; Hines, M. A.; Nair, P. S.; Scholes, G. D. Chem.

Mater. 2005, 17, 3451.

132. Lazell, H. M. R.; O‟Brien, P. Chem. Vapor Depos. 1999, 5, 203.

133. Wang, W. Z.; Geng, Y.; Yan, P.; Liu, F. Y.; Xie, Y.; Qian, Y. T. Inor.

Chem. Commun. 1999, 2, 83.

134. Nomura, R.; Murai, T.; Toyosaki, T.; Matsuda, H. Thin Solid

films 1995, 271, 4.

135. Lazell, M.; O‟Brien, P. Chem. Commun. 1999, 2041.

136. Chunggaze, M.; Malik, M. A.; O‟Brien, P. J. Mater. Chem. 1999,

9, 2433.

137. Barone, G.; Chaplin, T.; Hibbert, T. G.; Kana, A. T.; Maho, M. F.;

Molloy, K. C.; Worsely, I. D.; Parkin, I. P.; Price, L. S. J. Chem.

Soc. Dalton Trans. 2002, 1085.

138. Aziz, N.; Aryanasab, F.; Saidi, R. M.; Org. Lett. 2006, 8, 5275.

139. Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J.

Org. Chem. 2006, 71, 3634.

91

140. Salvatore, R. N.; Sahab, S.; Jung, K. N. Tetrahedron Lett. 2001,

42, 2055.

141. Nagle, S. A.; Salvatore, R. N.; Cross, R. M.; Kapxhiu, E. A.;

Sahab, S.; Yoon, C. H.; Jung, K. W. Tetrahedron Lett. 2003, 44,

5695.

142. Hou, X; Ge, Z.; Wang, T.; Guo, W.; Cui, J.; Cheng, T.; Lai, C.; Li,

R. Bioorg. Med. Chem. Lett. 2006, 16, 4214.

143. Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R.


144. Csomos, P.; Zupko, I.; Rethy, B.; Fodor, L.; Falkay, G.; Bernath,

G. Bioorg. Med. Chem. Lett. 2006, 16, 6273.

145. Singh, S.K.; Verma, M.; Singh, K. N. Indian Journal of

Chemistry 2008, 47B, 1545.

146. Liu, Y.; Bao, W. Tetrahedron Lett. 2007, 48, 4785.

147. Xia, S.; Wang, X.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2009,

65, 1005.

148. Halimehjani, A. Z.; Ashouri, K. M. A. Green Chem. 2010, 12,

1306.

149. Azizi, N.; Ebrahimi, F.; Aakbari, E.; Aryanasab, F.; Saidi, M. R.

Synlett 2007, 18, 2797.

150. Vasiliev, A. N.; Polackov, A. D. Molecules 2000, 5, 1014.

151. Nath, J.; Ghosh, H.; Yella, R.; Patel, B. K. Eur. J. Org. Chem.

2009, 1849.

152. Chakrabarty, M.; Kundu, T.; Arima, S.; Harigay, Y. Tetrahedron

92

Lett. 2005, 46, 2865.

153. Chakrabarty, M.; Kundu, T.; Arima, S.; Harigay, Y. Tetrahedron

2008, 64, 6711.

154. Csomos, P.; Zupko, I.; Rethy, B.; Fodor, L.; Falkay, G.; Bernath,

G. Bioorg. Med. Chem. Lett. 2006, 16, 6273.

155. Nath, J.; Patel, B. K.; Jamir, L.; Sinha, U. B.; Satyanarayana, K.

V. V. V. Green Chem. 2009, 11, 1503.

156. Chevrie, D.; Metzner, P. Tetrahedron Lett. 1998, 39, 8983.

157. Kuroboshi, M.; Mizuno, K.; Kanie, K.; Hiyama, T. Tetrahedron

Lett. 1995, 36, 563.

158. Ghosh, H.; Yella, R.; Nath, J.; Patel, B. K. Eur. J. Org. Chem.

2008, 6189.

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