Chapter II

58

CERIUM(IV) AMMONIUM NITRATE

Cerium(IV) ammonium nitrate (CAN) is one of the most important reagent,

which is used as one-electron oxidant and Lewis acid catalyst among the Lanthanide(IV)

complexes in organic synthesis.1 The reason for its general acceptance as a one-electron

oxidant and Lewis acid is due to its large reduction potential valve of +1.61 V vs NHE

(Normal Hydrogen Electrode) and low affinity for oxygen as compared to other Lewis

acids.2 CAN has been found chemically superior in many respects to widely employed

manganese triacetate for the generation of radicals.3 CAN has the additional advantages

of having a low toxicity besides being inexpensive, reasonably soluble in many organic

media, air stable, easily handled and allowing for a considerable degree of experimental

simplicity. A large number of research papers and several reviews have been published

for CAN mediated reactions.4-13

Cerium has a property, unique among the lanthanides, which explain its ability

to participate in one-electron transfer reactions, its ability to exist in two stable

adjacent oxidation states +3 and +4. Cerium in its ground state has an electronic

configuration of [Xe]4f26s2, where Xe represents the xenon configuration. The

electronic configuration of the Ce+3 ion is [Xe]4f1, while that of Ce+4 ion is [Xe]4f0.

The enhanced stability of the vacant f shell in Ce+4 accounts for the ability of cerium

to exist in the +4 oxidation state. The large reduction potential value of 1.61V (vs

NHE) makes Ce(IV) a very efficient oxidizing reagents compared to other metal ions.

Cerium(IV) ammonium nitrate is used as a catalyst for several types of

transformations. They are classified into the following categories:

1. Reactions involving the formation of carbon-carbon bond.

2. Reactions involving the formation of carbon-heteroatom bond.

3. Miscellaneous transformations.

Chapter II

59

1. Reactions Involving the Formation of Carbon-Carbon Bond

Initial attempts in this direction were largely due to CAN-mediated

oxidation of 5-hydroxy-2-methoxytropone (1) afforded the two crystalline

dimeric condensates (2 & 3) along with 2,10-dimethoxydicycloheptal[b,d]furan-

3,9-dione (4), p-tropoquinone di-methyl acetal (5) and its methanol adduct (6)

(Scheme 1).14

OMe

HO

O

(1)

CAN, CH3OH

O

OMeO

O

OMe

(2)

O

MeOO

OMeMeO

(4)

+

O

O

MeO OMe

(3)

+

+

O OMeMeO

O

O

OOMeMeO

+

O

O

O

OOMeMeO

OMe

(5) (6)

Scheme 1

4-Ketaldehyde dimethyl acetals (9) were prepared in good yields by the

cerium(IV) ammonium nitrate promoted reaction of ketones (7) with vinyl acetate (8)

respectively (Scheme 2).15

RR

O

(7) (8) (9)

+ OAcCAN, MeOH

reflux R

R OCH3

OCH3

O

R = R1 = CH3, OCH3, ,

Scheme 2

Chapter II

60

Systematic and in-depth investigation of CAN-mediated addition of active

methylene compounds to a range of π-systems including unactivated alkenes has also

been embarked upon. The studies were initiated with the addition of dimedone (10) to

phenylcyclohexene (11) in the presence of CAN in methanol. The reaction afforded the

corresponding dihydrofuran derivative (12) in nearly quantitative yield (Scheme 3).16

O

O

+

PhCAN, MeOH

0 °CO

Ph

O

(10) (11) (12)

Scheme 3

Dihydrofuropyrimidinediones (15) were formed with complete regioselectivity

by the [3+2] cycloaddition of pyrimidine trione (13) with alkenes (14) (Scheme 4).17

Me–N

NO

Me

O

+

O

R3

R4

R1

R2 CH3CN, 0 °CCAN (2 eq.) Me–N

NO

Me

O

O R2

R1R4R3

R1 = Me, R2 = Ph, R3 = R4 = H 15a (66%)R1 = R2 = Ph, R3 = R4 = H 15b (80%)R1 = R2 = R3 = M, R4 = H 15c (52%)R1 = R2 = R3 = R4 = Me 15d (49%)

(13) (14) (15)

Scheme 4

Enamide esters such as (16) were reported to undergo 5-endo cyclization in

the presence of CAN to yield disubstituted γ−lactams (17) in moderate yields. This

method has been used to synthesize the basic heterocyclic ring fragments of natural

products L-755,807, Quinolacticin C, and PI-091 (Scheme 5).18

Chapter II

61

O

MeOOC

N

PMB

MeOH, rtCAN (4 eq)

(16) (17)

NO

MeOOC

PMBOMe

Scheme 5

Synthesis of 2,3,7,8-tetrahydrofuro[3,2-c]oxepin-4-one derivatives (20)

was achieved by reaction of tert-butyl-2-(2-hydroxytetrahydrofuran-2-yl)acetates

(18) with alkenes (19) in the presence of cerium(IV) ammonium nitrate (CAN)

(Scheme 6).19

O OH

OtBu

O

R1

R2 +R3

R4

CAN (2 equiv)CH3CN, 0 °C

R1 = H, Me, Et; R2 = H; R3 = Ph; R4 = Me, Ph

O

O

R3

R4R1

R2

O

(18) (19) (20)

Scheme 6

The synthesis of unsymmetrical bis(indolyl)alkanes (23) was achieved by a

CAN-catalyzed, ultrasound-accelerated reaction between indoles (22) and (1H-indol-

3-yl)(alkyl/aryl)methanol (21) in good to excellent yields (Scheme 7).20

NH

N

R

OH

R1

CANU.S., EtOH

N

R

R1

NH

+

(21) (22) (23)

R = H, Ts; R1 = Ph, n-Nonanyl, n-Octanyl, n-Hexanyl, n-Butanyl; R2 = CH3, H, BnO, Ts

R2R2

Scheme 7

Chapter II

62

Ethylation of a variety of imines (24) at the methine moiety was accomplished

by CAN-promoted coupling of imines with triethyl aluminium to give the

corresponding products (25) (Scheme 8).21

Ar1 NAr2

CAN (1 equiv.), Et3Al (3 equiv.)C6H6, 25 oC, H2O

Ar1

NH

Ar2

(24) (25)

Ar1 = Ar2 = Ph; Ar1 = 4-MeC6H4, Ar2 = Ph; Ar1 = Ph, Ar2 = 4-MeOC6H4Ar1 = 4-ClC6H4, Ar2 = Ph; Ar1 = Ph, Ar2 = 4-ClC6H4; Ar1 = 4-BrC6H4, Ar2 = PhAr1 = 3-HOC6H4, Ar2 = Ph; Ar1 = 2-C5H4N, Ar2 = Ph; Ar1 = Ph, Ar2 = 2-C10H7Ar1 = 4-NCC6H4, Ar2 = Ph

Scheme 8

Perumal et al. has demonstrated that CAN catalyzed 1,4-addition of pyrimidin-

2(1H)-ones (26) with several nucleophiles (27) in methanol to furnish the highly

functionalized 3,4-dihydropyrimidin-2(1H)-ones (28) in very good yields (Scheme 9).22

N

NHR

O

O

Ar

H

Nu HCe(NH2)2(NO3)6 (5 mol%)

MeOH, rt, 1-3 hN

NHR

O

O

Ar

Nu

+

(26) (27) (28)

R = CH3CO, EtOOC; Ar = C6H5, o-O2NC6H4, o-ClC6H4

NH

NH

NCH3CH3

NH

Ph N Ph

NH

Br

,

,, ,Nu = ,

Scheme 9

α-dehydro-β-amino esters (31) were synthesized from acetates of Baylis-

Hillman adducts (29) with amines (30) in the presence of a catalytic amount of CAN

in tetrahydrofuran (THF) at 60-65 °C. (Scheme 10).23

Chapter II

63

ArCOOMe

OAc

R NH2Ar

NHR

COOMe+ CAN (10 mol%)

THF, 60-65 oC, 3 h

(29) (30) (31)

Ar = Ph, 4-MeC6H4, 4-ClC6H4R = Bn, Ph, 4-MeC6H4, 4-MeOC6H4, 3-Cl-4-MeC6H3, 3-O2NC6H4, n-C8H17, n-C16H33, β-Naphthyl, cyclo-C6H11

Scheme 10

The synthesis of 4,4'-(arylmethylene)bis(1H-pyrazol-5-ols) (34) was

accomplished by tandem Knoevenagel–Michael reaction of two equivalents of 5-

methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (32) with various aromatic aldehydes

(33) catalyzed by ceric ammonium nitrate (CAN) in water at room temperature

(Scheme 11).24 All these compounds were evaluated for in vitro antiviral activity

against peste des petits ruminant virus (PPRV).

NN

H3C

O

R H

OCAN (5 mol%)

H2O, rt

NN

H3C

OH

N

N

OH

H3CR

(32) (33) (34)R = C6H5, 3-H3CC6H4, 4-H3CC6H4, 4-CH3OC6H4, 4-FC6H4, 4-O2NC6H4, 3,4-(OCH3)2C6H3, 3-CH3O-4-HOC6H3, 2-Furfuryl, 2-Pyridyl

+

Scheme 11

2. Reactions Involving the Formation of Carbon-Heteroatom Bond

Carbon-heteroatom bond formation assumes much significance, especially

from the vantage point of heterocyclic compound formation. Recently, there has been

a flurry of activity towards developing novel methods for attaining this goal. The

Chapter II

64

utility of CAN in carbon-heteroatom bond formation, particularly C-O, C-S, C-N, C-

Se, C-Br and C-I bonds, is noteworthy in this connection. Mostly these reactions

involve the oxidative addition of heteroatom-centered radicals, formed by the

oxidation of anions by CAN, to alkenes and alkynes.

In his seminal work, which marked the beginning of the use of CAN for the

construction of carbon-heteroatom bonds, Huston has demonstrated that CAN

promotes a facile addition of azide radicals to olefins such as stilbene and

acenaphthene (35) to afford trans-α-azido-β-nitroalkanes (36) (Scheme 12).25

NaN3, CAN

N3

O2NO

CH3CN, rt

(35) (36)

H

H

Scheme 12

Nitration of naphthalene derivatives (37) was carried out with silica gel

supported CAN to give corresponding nitrated products (38) (Scheme 13).26

CAN on silica gel

OR

X2(37) (38)

ORX1

R = H, X1 = H, X2 = NO2; R = CH3, X1 = H, X2 = NO2R = H, X1 = NO2, X2 = H; R = C2H5, X1 = H, X2 = NO2

Scheme 13

Reaction of α,β−unsaturated ketones and esters (39) with iodine and CAN in

methanol, ethanol, or isopropyl alcohol, under reflux conditions afforded the

corresponding β-alkoxy-α-iodoketones and esters (40) in good yields (Scheme 14).27

Chapter II

65

OEt

OCAN, I2, MeOH

OEt

OOMe

I(39) (40)

Scheme 14

Reaction of substituted styrenes (41) with ammonium thiocyanate (NH4CN)

(42) was mediated by CAN as catalyst to give the corresponding dithiocyanates (43)

in acetonitrile at room temperature (Scheme 15).28

R rt, 15 minCAN, CH3CN

R

SCN

SCN

(41) (42) (43)

+ NH4SCN

R = CH3, OCH3, COCOCH3, R-C6H4 = ,

Scheme 15

3-(selenocyanato)-indoles (46) were synthesized by the reaction of indoles

(44) with potassium selenocyanate (KSeCN) (45) in methanol at room temperature

(Scheme 16).29

N

R1

R2

(44) (46)

KSeCN (45)N

R1

R2

SeCN

R1 = H, R2 = CH3; R1 = CH3, R2 = H; R1 = H, R2 = C6H5

CAN/MeOH/0 oC

Scheme 16

The reaction of styrene (47) with p-toluenesulfinate (48) was catalyzed by ceric

ammonium nitrate (CAN) to give the corresponding α-sulfinato-β-nitrato product (49)

and β-keto-sulfone (50) in anhydrous acetonitrile at room temperature (Scheme 17).30

Chapter II

66

O2S

ONO2

Me

O2S

Me

O

SO2Na

Me

CAN, CH3CNrt, 40 min

+

(49)

(50)

(47) (48)

+

Scheme 17

3-benzoylisoxazole derivatives (52) were synthesized by the reaction of

alkynes (51) with acetone or acetophenone by using ceric ammonium nitrate (CAN)

(Scheme 18).31

RCAN (IV)Acetone or

Acetophenone

NO

RR1

O(51) (52)

R1 = Me, PhR = n-C3H7, n-C4H9, n-C5H11, n-C6H13, COOEt, cyclo-C6H10OH

Scheme 18

The chemoselective and solvent-free method for the synthesis of acylals (54)

and their deprotection to 4-oxo-4H-1-benzopyran-3-carbaldehydes (53) were

catalyzed by ceric ammonium nitrate (CAN) and acetic anhydride (Ac2O) at room

temperature (Scheme 19).32

OR2

R3

R1

O

O

O

OAc

OAc

R2

R1

R3

O

CAN, Ac2O

(53) (54)

rt

R1 = R2 = R3 = CH3; R1 = R2 = H, R3 = CH3; R1 = R2 = H, R3 = Cl; R1 =R2 = H, R3 = FR1 = R3 = H, R2 = CH3; R1 = CH3, R2 = H, R3 = Cl; R1 = R2 = H, R3 = Br

Scheme 19

Chapter II

67

Ceric ammonium nitrate (CAN) in PEG was used as an efficient and

recyclable solvent system for one-pot three-component Mannich reaction of

acetophenone (55) with aromatic aldehydes (56) and aromatic amines (57) to give the

corresponding β-amino carbonyl compounds (58) at 45 °C (Scheme 20).33

CH3

CHO

R1 R2

NH2HNO

R2

R1

O

+ + CAN (5 mol%)PEG, 45 oC

R1 = H, 4-CH3, 4-OCH3, 4-NO2, 4-Br; R2 = H, 4-CH3, 3,4-(CH3)2, 4-Cl, 4-NO2, 2-NO2

(55) (56) (57) (58)

Scheme 20

2,4,5-Triarylimidazoles (61) were obtained in excellent yields by the one-

pot three-component condensation of benzil/benzoin (59), aldehydes (33) and

ammonium acetate (60) in the presence of catalytic amount of cerium (IV)

ammonium nitrate (CAN) in aqueous media under ultrasound at room temperature

(Scheme 21).34

O

O NH

N

RNH4OAc (60), CAN (5 mol%)Ultrasonication, rt

+

(59) (33) (61)R = C6H5, 2-ClC6H4, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, 4-O2NC6H4, 4-(Me)2NC6H4, 4-HOC6H4, 4-FC6H4, 2-Furyl, 2-Thienyl

RCHO

Scheme 21

Chapter II

68

The one-pot synthesis of N-substituted decahydroacridine-1,8-diones (63) was

reported by the reaction of 1,3-dicarbonyl compounds (62) with aromatic aldehydes

(56) and aromatic amines (57) in the presence of cerium(IV) ammonium nitrate

(CAN) as the catalyst in polyethylene glycol (PEG) at 50 °C (Scheme 22).35

R1

R2

O

N

R1

R2

R1

R2

R4

R3

CHO NH2

R3 R4

CAN (5 mol%), PEG 40050 oC, 4 h

+ +

(62) (56) (57) (63)

R1 = R2 = R3 = R4 = H; R1 = R2 = R4 = H, R3 = 4-OCH3, 4-Cl, 3-NO2; R1 = R2 = CH3, R3 = R4 = H R1 = R2 = R3 = H, R4 = 4-Br, C6H5CH2; R1 = R2 = CH3, R4 = H, R3 = 4-OCH3, 4-Cl, 3-NO2

2

O O

Scheme 22

3. Miscellaneous transformations

The serendipitous discovery of some novel and interesting processes turned

out to be one of the exciting aspects of the pursuit of Ce(IV) chemistry. Such

reactions also provide additional insight into the mechanistic details of several CAN-

mediated transformations.

Dethioacetalisation procedure for the transformation of dithioacetals such as

(64) into the parent carbonyl compound (65) by employing CAN in aqueous

acetonitrile at room temperature was developed (Scheme 23).36

SS

CAN, aq. CH3CNrt, 3 min

O

(64) (65)

Scheme 23

Chapter II

69

Treatment of acetoacetanilides (66) with CAN in methanol, in

anticipation of an intramolecular reaction to derive the oxindole, nevertheless

afforded the corresponding oxamates (67) in good yield. Substantial

enhancement of the overall yield occurred in an atmosphere of oxygen

(Scheme 24).37

NH

O

O

CAN, MeOH, O2rt, 15 min

NH

COOMe

O

(66) (67)

R3

R2

R1 R1

R2

R3

R1 = R2 = R3 = H; R1 =R2 = H, R3 = CH3; R1 = R2 = H, R3 = OCH3; R1 = R2 = H, R3 = ClR2 = R3 = H, R1 = CH3; R1 = OCH3, R2 = R3 = H; R1 = COOCH3, R2 = R3 = H R1 = R3 = H, R2 = Br

Scheme 24

Hwu and co-workers have reported a highly regioselective, silicon directed

C-C bond cleavage of β-(trimethylsilyl)cycloalkanones (68) to afford the

β-alkenyl carboxylic acids (69) in the presence of CAN and acetonitrile

(Scheme 25).38

R1

R2n

O

CAN, CH3CN, H2O60 °C, 30 min, 2 h

OH

n

O

n = 1, R1 = H, R2 = SiMe3; n = 2, R1 = H, R2 = SiMe3 n = 2, R1 = CH2SiMe3, R2 = H; n = 3, R1 = CH2SiMe3, R2 = H

(68) (69)

Scheme 25

Chapter II

70

The reaction of monoterpenes such as (+)-α-pinene (70) with CAN in

acetonitrile afforded the bisamide (71) in good yields (Scheme 26).39

CAN (2.3 equiv)CH3CN, rt, 3 h

HN CH3

NH

CH3

OO

(70)

(71)

Scheme 26

The cerium(IV) ammonium nitrate (CAN) promoted oxidation of 4,5-

diphenyloxazoles (72) in to the corresponding imides (73) in good yields was reported

(Scheme 27).40 This reaction will allow the use of robust oxazole ring system as a

surrogate amide in organic synthesis.

CAN (3.8 eq)CH3CN-H2O Ph N R

H

O O

+

(72) (73) (74)

R = Et, i-Pr, i-Bu, Cy, Bn, t-Bu,

ClMe

,O ,

N

OPh

Ph R PhCOOH

Scheme 27

Three component domino reaction between α,β-unsaturated aldehydes (75),

aromatic amines (76) and ethyl acetoacetate (77) were carried out using CAN as

catalyst in methanol as solvent to give the desired product 1,4-dihydropyridines (78)

at room temperature (Scheme 28).41

Chapter II

71

O

+

R4

NH2

+

CH3

Z

O

O

EtOH, rt, 1 hN CH3

Z

O

R4

CAN (5 mol%)R1

R3

R2

R5

R3

R2

R5

R1

(75) (76) (77)

(78)R1 = R2 = R3 = R4 = R5 = H, Z = OC2H5; R3 = CH3, R1 = R2 = R4 = R5 = H, Z = OC2H5R3 = F, R1 =R2 = R4 = R5 = H, Z = OC2H5; R3 = Cl, R1 =R2 = R4 = R5 = H, Z = OC2H5R2 = CH3, R3 = R1 = R4 = R5 = H, Z = OC2H5; R2 =R3 = CH3, R1 = R4 = R5 = H, Z = OC2H5R2 =Cl, R1 = R3 = R4 = R5 = H, Y = OC2H5; R1 = R2 = R3 = R4 = R5 = H, Y = S-C(CH3)3R1 = R2 = R3 = R4 = R5 = H, Y = O-C(CH3)3

Scheme 28

The oxidation of selected metal anions (M+X-) (80) by 2 equivalent of CAN in

the presence of substituted cyclopropyl alcohols (79) provided a novel approach to β-

functionalized ketones (81) (Scheme 29).42

R OHM+X-(80), solvent,

rt, 30 minR X

O

M = K+, Na+, NH4+; X = Br–, I–, N3

–, SCN–

R = Ph, p-CH3OC6H4, Cyclohexyl, CH3

(79) (81)

2 CAN

Scheme 29

CAN catalyzed sequential, one pot reaction between alkylamines (30),

chalcones (82) and β-ketoesters (83) afforded cis-4,6-disubstituted-2-

alkylaminocyclohexene-1-carboxylic esters (84) with complete diastereoselectivity

(Scheme 30).43

Chapter II

72

R1–NH2 + O

Ph

Ar

+

O

O

OR2

CH3

EtOH, rtCAN (5%)

HO Ar

Ph

OR2O

NH

R1

R1 = n-Bu, n-C6H13, n-C7H15, (±)-2-Me-Bu, (S)-2-Me-Bu, (±)-sec-Bu, (R)-sec-BuR2 = Et, tBu; Ar = Ph, 4-ClC6H4

(30) (82) (83) (84)

Scheme 30

A variety of highly substituted 3,4-dihydroquinoxalin-2-amine derivatives (88)

were efficiently synthesized by the reaction of o-phenylenediamines (85), ketones

(86) and isocyanides (87) using cerium(IV) ammonium nitrate (CAN) as catalyst in

ethanol at room temperature (Scheme 31).44

NH2

NH2

R1

R2 R3

OR4 N C+ +

N

HN R2

R3

NH

R4R1CAN (5 mol%)

EtOH, rt

(85) (86) (87) (88)R1 = H, 4-NO2, 4-C6H5CO, 5-CH3, 2-NO2; R2 = R3 = CH3R4 = t-Butyl, Cyclohexyl, 2,6-Dimethylphenyl, Benzyl, 1,1,3,3-Tetramethylbutyl

Scheme 31

Ceric ammonium nitrate (CAN) was found to catalyze the one-pot synthesis of

2,2,4-trimethyl-1,2-dihydroquinoline derivatives (90) from substituted anilines (57)

and acetone (89) via a modified Skraup reaction at 50-55 °C (Scheme 32).45

HN

H3C CH3

ONH2

R

CH3

CH3

CH3RCAN, 50-55 C

20-24 h°

(57) (89) (90)R = 4-NO2, 4-MeO, 4-F, 4-Me, 4-CF3, 4-Cl, 4-Br

+

Scheme 32

Chapter II

73

Ceric ammonium nitrate (CAN) was found to be an effective catalyst for the

reaction of 1,3-dicarbonyl compounds (62) with aromatic aldehydes (33) and

ammonium acetate (91) by using polyethylene glycol as reaction medium to give the

corresponding decahydroacridine-1,8-diones (92) at 25 °C (Scheme 33).46

R1 H NH

R1

R

R

RR

RR

O

O

O

OO

NH4OAcCAN (5 mol%)

PEG, 25 oC++

(62) (33) (91) (92)R = H, CH3 R1 = C6H5, 2-MeOC6H4, 4-MeOC6H4, 4-ClC6H4, 4-HOC6H4, 2-HOC6H4, 3-O2NC6H4, 2-Thienyl

Scheme 33

An environment friendly method for the synthesis of 2-

oxo/thioxooctahydroquinazolin-5-ones (95) and 2-oxo/thioxo-7,7-

dimethyloctahydroquinazolin-5-ones (96) was reported by the reaction of 5,5-

dimethyl-1,3-cyclohexanedione (10) or 1,3-cyclohexanedione (93) with aldehydes

(33) and urea or thiourea (94) using ceric ammonium nitrate (CAN) as catalyst and

polyethylene glycol (PEG) as solvent at 50 °C (Scheme 34).47

R H H2N NH2

XH3C

H3C

O

O

O

O

O NH

NH

NH

NH

X

X

O

O R

R

H3CH3C

R H H2N NH2

XOCAN (5 mol%)PEG 400, 50 C°

CAN (5 mol%)PEG 400, 50 C°

+ +

++

(93) (33) (94)

(10) (33) (94) (96)

X = O, S; R = C6H5, 4-CH3OC6H4, CH2CH3, C3H8,O

O

(95)

Scheme 34

Chapter II

74

Ceric ammonium nitrate in polyethylene glycol was used as a sustainable,

non-volatile, and ecofriendly catalytic medium for the green synthesis of 2,5-

disubstituted 1,3,4-oxadiazoles (99) by the reaction of benzhydrazide (97) with

aromatic carboxylic acids (98) at 80 °C (Scheme 35).48

NHNH2 R OH

OO

+CAN (5 mol%)

NN

O RPEG 400, 80 C°

(97) (98) (99)R = C6H5, 2-H2NC6H4, 4-HOC6H4, 4-H3CC6H4, 4-ClC6H4, 3-H3COC6H4, 4-CH3OC6H4, 4-O2NC6H4, Furyl, Pyridinyl

Scheme 35

Efficient deprotection of tritylated amines (100) to the corresponding amines

(101) were mediated by 20 mol% ceric ammonium nitrate (CAN), 10 equiv of acetic

acid and 15 equiv of water in acetonitrile (Scheme 36).49

N

O

NH

O

OP

T T

OP

Tr

CAN, AcOHMoist CH3CN

(100) (101)P = t-Butyldiphenylsilyl (TBDPS); T = Thymine

Scheme 36

This is quite remarkable that even in stoichiometric amounts, CAN is an

excellent multipurpose catalyst finding general acceptance for the laboratory scale

synthesis of a variety of organic compounds and it is anticipated that CAN will

continue to find increasing application in organic synthesis.

Chapter II

75

DITHIOCARBAMATES

The discovery of the dithiocarbamates early in the history of organosulfur

compounds50 led to important uses in the rubber industry.51 Their profound effects

on biological systems due to their metal-combining capacity52 and their ability to

interact with sulfhydryl-containing compounds have practical applications in the

fields of medicinal chemistry53 and agriculture.54 Of the many dithiocarbamates

synthesized and studied, mainly by the agricultural chemical industry, a few have

been widely used as fungicides. The biological activity of the dithiocarbamates is

increased when they are in the form of heavy-metal salts as versatile classes of

ligands with the ability to stabilize transition metals in a wide range of their

oxidation states. They are also efficient ligands in surface science and

nanomaterial chemistry.55 Furthermore, they are useful building blocks for the

synthesis of biologically active heterocyclic compounds and solid support grafting

materials.56

S-[4,5-dichloro-6(1H)-pyridazinon-1-ylmethyl]-N,N-dialkyldithiocarbamates

(102) were prepared and tested for their fungicidal and acaricidal activities against

Sclerotiniafructicola and Tetranychusurticae.57

NN

H2C S C

S

NR1

R2

Cl

Cl

O

R1 = R2 = Me, Et

(102)

5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acids or amides (103) was

reported as anti-hypersensitive agents.58

Chapter II

76

N

CH2

S C

S

NMe2

R

O

R = OH, MeO, NH2, NHMe, NMe2

(103)

Sodium salts of N,N-diethyldithiocarbamate (104) were injected into the renal

artery of dogs did not affect tubular resorption but inhibited glomerular filtration and

evaluated as antidiuretic agents.59

N

C

C2H5 C2H5

SHS

Na

(104)

A series of N-((2-methyl-4(3H)-quinazolinon-6-yl)methyl)dithiocarbamates

(105) were synthesized and evaluated for their cytotoxic activity against five human

cancer cell lines.60

HN

N

O

H3C

NH

SR

S

(105)

R = CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, CH3(CH2)2CH2, CH3(CH2)3CH2, CH3(CH2)4CH2, CyclohexylCH2, Ph2C(CN)CH2CH2, PhCH2, 4-H3CC6H4CH2, 4-FC6H4CH2, 4-BrC6H4CH2, 2,4-F2C6H3CH2, F5C6CH2, 4-O2NC6H4CH2, 4-CNC6H4CH2, 4-HO2CC6H4CH2, Ph2CH, 4-EtO2CC6H4CH2, H2C=CHCH2-, HC=CCH2

Synthesis and in vitro antitumor activity of new butenolide-containing

dithiocarbamates (106) were evaluated. These compounds exhibited broad spectrum

anti-cancer activity against five human cancer cell lines with IC50 < 30 lM. Structure-

Chapter II

77

activity relationship analysis showed that the introduction of dithiocarbamate side

chains on the C-3 position of butenolide was crucial for anti-tumor activity.61

OO

S N

R1

R2

S

(106)-NR1R2= CH3NH-, C2H5NH-, (CH3)2N-, (C2H5)2N-, (CH3)2CHNH-,

N

N NMeHN

HN

HN

Me

ClNH

O N

HN

HN, , ,

,,

,

,

The reaction of 2-aminobenzothiazole (107) and carbon disulfide (108) was

carried out using concentrated aqueous sodium hydroxide and N,N-

dimethylformamide (DMF) as solvent at room temperature to give (2-benzothiazolyl)-

dithiocarbamates (109) as intermediate which further react with methyliodide (110) to

give corresponding methyl-N-(2-benzothiazolyl)-dithiocarbamates (111) at room

temperature (Scheme 37).62

N

SNH2X

NaOH(H2O)/DMFCS2 (108), rt

N

SNHX C SNa

S

(107) (109)

N

SNHX C S

S

CH3

CH3I (110), rt

(111)

X = H, 4-Cl, 6-NO2, 6-OCH3

Scheme 37

Chapter II

78

Bis(dithiocarbamate) derivatives of glycerol (114) were obtained by reaction

of dithiocarbamic acid salt (113) with 1,3-dichloro-1,3-dideoxyglycerol (112) in

acetone under reflux condition, which was evaluated as antifungal activity against

Alternaria brassicae, Pseudocercosporella herpotrichoides, Septoria nodorum and

Phytophtora cinnamomi (Scheme 38).63

Cl

Cl

OHR1R2NCSSLi (113) (3 eq.)

Acetone, reflux

N S

S

NR1R2S

S

OH

R1

R2

(112) (114)

R1 = R2 = Ethyl; NR1R2 = Morpho-4-yl; NR1R2 = 1-Piperidyl

Scheme 38

Dithiocarbamate derivatives (117) were prepared by a simple one-pot

procedure from primary or secondary amines (115) carbon disulfide (108) and a

variety of alkyl halides (116) in the presence of anhydrous potassium phosphate under

mild condition in good yields (Scheme 39).64

RNH

R1CS2 R2 X++

K3PO4/CH3COCH310 oC~rt

RNCS2R2

R1

(115) (108) (116) (117)

RR1NH = 1-Methylpiperazine; R2X = C2H5Br, i-C3H7Br, n-C4H9Br, HOCH2CH2Cl, NCCH2Cl, H2C=CHCH2Cl, BrCH2CO2C4H9RR1NH = C6H5CH2NH2; R2X = C2H5Br, C6H5CH2Cl, HOCH2CH2ClRR1NH = 1-Benzoylpiperazine; R2X = 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide

Scheme 39

Chapter II

79

A novel synthesis of functional dithiocarbamates (120) was reported by the

reaction of bis(thiocarbonyl) disulfides (118) with azo-compounds (119) in ethyl

acetate under reflux condition (Scheme 40).65

Z C S S C

S

Z

S+ N N RR

Ethyl acetatereflux, 18 hr Z C S R

S

(118) (119) (120)

Z = C6H5, R = C(CH3)(CN)(CH2CH2COOH), C(CH3)2CN; Z = CH3CH2O, R = C(CH3)2CN

Scheme 40

S-alkyl N,N-dimethyldithiocarbamates (123) were synthesized by the reaction

of N,N-dimethylthiocarbamoyl chloride (121) with the corresponding thiolates (122)

(Scheme 41).66

(H3C)2N Cl

S+ R E M

(H3C)2N ER

S

E = S; M = Li or Na; R = C6H5, C6H5CH2, 4-MeC6H4, 3-MeC6H4, 2-ClC6H4

(121) (122) (123)

Scheme 41

Reactions of 1-(1-hydroxyalkyl)benzotriazoles (125) with alkyl N-

alkyldithiocarbamates (124) gave intermediate N-[1-(benzotriazol-1-yl)alkyl]

dithiocarbamates (126), which further gave N-(1-sulfanylalkyl) dithiocarbamates

(128) or N-[1-(dialkylphosphono)alkyl] dithiocarbamates (130) on treatment with

thiols (127) or trialkyl phosphates (129) respectively, in the presence of zinc bromide

(Scheme 42).67

Chapter II

80

RNH

SR3

SOH

R1 Bt

TsOHToluenefeflux

+R

SR3

Bt R1

S

P(OR2)3 (129)ZnBr2

R2SH(127)

RN S

R3

R1R2S

S

R3

SN

R1P

OR2O

R2O

SR

(124) (125) (126)

(128)

(130)(126): R = Me, R1 = H, R3 = Et; R = Me, R1 = Pr, R3 = Et; R = Et, R1 = H, R3 = Me; R = Et, R1 = Pr, R3 = Me; R = Bu, R1 = Pr, R3 = Et; R = Bu, R1= Pr, R3 = Et(128): R = Me, R1 = Pr, R2 = Ph, R3 = Et; R = Et, R1 = Pr, R2 = Ph, R3 = Me; R = Et, R1 = Pr, R2 = Et, R3 = Me; R = Bu, R1 = Pr, R2 = Ph, R3 = Et; R = Bu, R1 = Pr, R2 = R3 = Et(130): R = R2 = R3 = Et, R1 = Pr; R = Me, R1 = Pr, R2 = i-Pr, R3 = Et; R = Et, R1 = Pr, R2 = Et, R3 = Me; R = Et, R1 = Pr, R2 = i-Pr; R3 = Me

ZnBr2

Scheme 42

A simple protocol was reported for the one-pot synthesis of various

structurally divergent dithiocarbamates (132 & 133) in one-pot reaction of amines

(115), carbon disulfide (108) and styrene oxide (131) without using any solvent and

catalyst at room temperature was described (Scheme 43).68

RR1NHO

Ph+CS2 (108), rt

1-4 h R1RN S

OH

PhR1RN S

OH

PhS S

+

(115) (131) (132) (133)

RR1NH = NH NHNH2

NH2NH2

NH, , , , ,

Scheme 43

An efficient, Amberlite IRA 400 (basic resin) mediated, one-pot synthesis of

dithiocarbamates (135) were accomplished in high yields by the reaction of amines

(115), carbon disulfide (108) and α,β-unsaturated compounds (134) via Michael

addition. (Scheme 44).69

Chapter II

81

R1

NHR2

CS2

R3

EWG++ Amberlite IRA 400, Dry DMSO

rt, 2-4 h

R1

N SEWG

R3R2

S

(115) (108) (134) (135)

R1 = C2H5, CH2Ph, t-C4H9, PhCH(CH3); R2 = C2H5, H; R1R2NH = Pyrrolidine, Piperidine, Morpholine; R3 = H, CH3 EWG = COCH3, COOCH3, CN, CONH2

Scheme 44

The Ullmann-type coupling reaction of sodium dithiocarbamates (137) with aryl

iodides (136) was catalyzed by CuI/N,N-dimethylglycine proceeds smoothly in DMF at

110 °C to give corresponding dithiocarbamates (138) in good yields (Scheme 45).70

I

R

R1

N S

S

R2Na+

CuI/N,N-dimethylglycineDMF, 110 oC

S

NR1 R2

S

R

(136) (137) (138)

R = H, Cl, Br, Me, MeO; R1 = R2 = CH3; R1 = H, R2 = C6H5; R1R2N = N

Scheme 45

The synthesis of thia-Michael adducts (141) was developed by the reaction of

various organic halides (primary, secondary, tertiary, allylic and benzylic) (116),

structurally diverse electron-deficient alkenes (ketones, esters and acrylonitrile) (140)

and thiourea (139) in the presence of sodium carbonate in wet polyethylene glycol

(PEG 200) at 30-35 °C (Scheme 46).71

R X H2N NH2

S

EWG++ H2O, Na2CO3

PEG 200, 30-35 oC RSEWG

(116) (139) (140) (141)

EWG = OC2H5, OC4H9-n R-X = n-C10H21I, n-C8H17Br, CH3I,

O2N

Br

BrCl

ClClBr

Br

Br, , , ,

,,,

Scheme 46

Chapter II

82

A stereoselective synthesis of [E]- and [Z]-allyl dithiocarbamates (144 & 145)

was accomplished from acetates of Baylis–Hillman (BH) adducts (142) in catalyst-

free one-pot three-component coupling reactions of carbon disulfide (108) and amines

(143) in water under a mild and green procedure with high yields (Scheme 47).72

EWGR

OAc

CS2 (108),HN

H2O, rt, 6-10 h(143)

EWGR

S N

S

(144)

or

EWGS N

S

R

(145)

R = H, Cl, NO2, EWG = CN, COOMe

HN = NHHN H2N Ph, ,

(142)

Scheme 47

One-pot three-component reactions of amines (115) and carbon disulfide (108)

with alkyl vinyl ethers (146) via Markovnikov addition reaction were carried out in

water to give corresponding dithiocarbamates (147) under a mild and green procedure

with excellent yields and complete regiospecificity (Scheme 48).73

RR1NH CS2 OH2Ort+ + R1RN S O

S

(115) (108) (146) (147)

RR1NH =

NH NH

NH NH2NH2

ONH2

NH2

O NH NH

, , , ,

, ,, , ,

Scheme 48

A structural diversity was possible in direct access to functional

dithiocarbamates (149) via one-pot reaction of amines (115), carbon disulfide (108)

and bromoesters (148) in nearly quantitative yields in water (Scheme 49).74

Chapter II

83

R1R2NH

R3

BrOR4

O+

CS2 (108)H2O, rt, 8-14 h R1R2N S

OR4

S

O

R3

(115) (148) (149)

R1R2NH = NH

R3 = H, R4 = Me; R3 = H, R4 = Et; R3 = R4 = Me

NHNH NHPh NH2

, , , ,

Scheme 49

S-allyl-N-aryl dithiocarbamates (152) were synthesized by the reaction of

substituted anilines (150) with carbon disulfide (108) and allyl bromides (151) using

SnCl2 as a catalyst under solvent-free conditions at room temperature (Scheme 50).75

R2

R1

NH2

R3

CS2R4 Br

R2

R1

NH

S

R4S

R3

+ +SnCl2.2H2Ort, 10-30 min

(150) (108) (151) (152)

R1 = R2 = R3 = R4 = H; R1 = R3 = CH3, R2 = R4 = H; R1 = R3 = C2H5, R2 = R4 = HR1 = Cl, R2 = R4 = H, R3 = CH3; R1 = Cl, R2 = CH3, R3 = R4 = H; R1 = C2H5, R2 = R3 = R4 = H

Scheme 50

Chapter II

84

OBJECT OF THE PRESENT WORK

The environmentally benign synthesis of organic compounds without using

hazardous reaction conditions has become several steps closer in recent years. Strict

environmental legislations have forced chemists all over the world to develop

alternatives synthesis of biologically and synthetically important compounds. In view

of the potential biological activity of sulfur-nitrogen containing compounds and

substantial reduction in reaction period under greener techniques, it was of interest to

us to prepare the dithiocarbamate compounds as possible drugs effective against the

tropical diseases.

Dithiocarbamates (DTCs) have received considerable attention due to their

interesting chemistry and biological activity. They have widely been used as

pharmaceuticals76 and agrochemicals77 intermediates for the protection of amino

groups in peptide synthesis78, linkers in solid phase synthesis52a and recently in the

synthesis of ionic liquids.79 In rubber industry, dithiocarbamates have been used as

vulcanization accelerators and antioxidants.80 Because of the strong metal binding

capacity, dithiocarbamates can act as inhibitors of enzymes and have profound effect

on biological system and are widely used in medicinal chemistry as well as in cancer

treatment.81 Dithiocarbamates are also used as ligands for soft metal complexation

and are usually prepared by the addition of an amine with carbondisulfide and halides

or α,β-unsaturated compounds.82 Despite their biological activities, no recent progress

on their synthesis has been made. The present study aimed to devise a novel and

environment friendly method for the synthesis of some dithiocarbamate derivatives

and evaluation of their biological activity as potential antimicrobial and anticancer

agents. Only limited preparative methods have been developed for the synthesis of

dithiocarbamates.80b,83 However, these synthetic approaches suffer from the

Chapter II

85

drawbacks such as low availability of starting materials, harsh reaction conditions,

high temperatures, unsatisfactory yields and use of expensive and hazardous catalysts

with side product formation that may be harmful to be environment or sophisticated

techniques.

The discovery of new green and more efficient synthetic protocols for the

preparation of industrial and biologically active organo-sulfur compounds via C-S

bond formation have attracted a great deal of attention.84 In this context, the use of

green catalytic system, with the replacement of expensive, toxic and flammable

organic solvents is highly required for the development of environmentally benign

methods.85

The preliminary studies have revelated that PEG could be used as green and

recyclable reaction medium for selective reactions.33,86 A number of reviews have also

explained PEG chemistry and its application in biotechnology and medicine.87 To

address the concerns raised by volatile organic medium, polyethylene glycol as an

efficient reaction medium for CAN catalyzed C-S bond formation. Ceric ammonium

nitrate (CAN) act as a water-compatible Lewis acid in aqueous medium.88

Additionally, ceric ammonium nitrate is one of the most inexpensive, ecofriendly and

greener reagents for several reactions33,35,46-48 involving C-C, C-S, C-N, C-Se and C-

Cl bond formation.12,89

In line with our interest for the application of CAN in PEG and water herein,

we have tried to describe a novel, highly efficient and ecofriendly method for the

synthesis of dithiocarbamates using CAN as catalyst in PEG 400-H2O aqueous system

(Scheme 51).

Chapter II

86

RESULTS AND DISCUSSION

Chemistry

In order to investigate the optimum reaction condition, we initiated our study

using diethylamine (1.2 mmol) (153), carbon disulphide (2.5 mmol) (154) and

iodobenzene (1 mmol) (155) as a model reaction. The whole reaction mixture was

stirred at an ambient temperature in ethanol for 15 h, only 45% yield of desired

product was obtained, whereas the same reaction was carried out using PEG 400 as a

green solvent, to give 52% yield of product under similar reaction conditions.

Surprisingly, a significant improvement was observed and the yield of product was

dramatically increased up to 85% when water was added in to the reaction mixture

within 5 h at 50 oC (Table 1, Entry 5).

We have also studied the influence of different solvents (Table 1) on the

reaction rate as well as the yield of products, the best result was obtained with PEG

400-H2O system (Table 1, Entry 5). Minimization of chemical waste, of which 80%

is estimated to be solvents, is a constant challenge as environmental concerns are

increasingly brought into focus. With this purpose, PEG-H2O may be a seemly

choice. However, we used PEG as a reaction medium because it is non-toxic and

thermally stable.

Continuously, to improve the yield of product and also to examine the

catalytic activity of CAN, the same reaction was carried out with similar amount of

reactants in PEG 400-H2O (1:1) system at 50 °C and the yield of product was

increased to 92%, when only 2 mol% of CAN was added in the reaction mixture

(Table 2). Encouraged by this observation, we further analyzed the best reaction

condition by using different amount of CAN. An increase in the quantity of catalyst

from 2 mol% to 5 mol% not only decreased the reaction time from 4 h to 2 h but also

Chapter II

87

increased the product yield from 92 to 95%. This revealed that catalyst concentration

plays a major role during optimization of the product yield. Although the use of 10

mol% of CAN permitted the reaction time to be decreased to 1 h, but the yield

unexpectedly decreased to 70%. A possible explanation for decrease the product

yields is that the starting material or product may have been destroyed during the

reaction when excess amount (10 mol%) of CAN was used in the reaction. It shows

that 5 mol% concentration of CAN is the suitable choice for an optimum yield of

dithiocarbamates (Table 2, Entry 3).

After successful optimization of reaction conditions, we screened a variety of

amines and aryl/alkyl halides including iodide and bromide to afford the desired

products in good to excellent yields (Table 3). In case of amines, we used various

primary and secondary amines. Generally, secondary amines such as diethyl amine,

piperidine, morpholine and pyrrolidine gave higher yields of products in short

reaction times (Table 3, 156a-l) compared with the primary amines (Table 3, 156m

& n).

To exploit this in situ generated dithiocarbamates anion for other useful

reactions, we used different Michael acceptor (α,β-unsaturated alkenes) and amines

for the synthesis of dithiocarbamates via Michael type addition. The reaction works

well with different electron deficient acceptors such as chalcone and methyl acrylate

to produce the desired Michael products in good to excellent yields. However, when

acrylamide was used as Michael acceptor, low yield of products were obtained. In

addition, we found that the use of 1-Phenylpiperazine also gave the desired Michael

adduct in higher yield (Table 4, Entry 158d).

PEG could be recycled with minimum loss and decomposition after

completion of the reaction. The product was isolated from the reaction mixture by

Chapter II

88

extracting with diethyl ether and remaining PEG phase may be used. The solvent

phase was recycled up to 3 runs but approximately 5% weight loss of PEG was

observed from cycle to cycle (Table 5).

Pharmacology

Anticancer Activity

The cytotoxic effects of compounds 156a-n and 158a-l on U87 human glioma

cells were studied. The efficacy of the test compound was compared with control on

the basis of % cytotoxicity. The % cytotoxicity for the compounds at five different

concentrations was calculated as:

% cytotoxicity = (100-test optical density (OD)/control OD) x 100

It was evident from the study that all the dithiocarbamate derivatives had cytotoxic

effect on U87 human glioma cells.

The IC50 values for all the compounds were calculated and tabulated. The IC50

values for compounds 156b, 156d and 158d were found to be similar and lowest amongst

all others. Amongst all the dithiocarbamate derivatives, 156c, 156m, 156n, 158i and 158j

were found to be the most effective and 156a, the least effective (Table 6).

Antibacterial Activity

Screening of all the synthesized compounds for their antibacterial activity was

performed by employing Broth Microdilution MIC method.90 Using sterile microtitre

plates, 0.2 ml of Mueller Hinton Broth was added to each of the 96 wells. By

doubling the dilution of each compound were made in the wells, a plate contained 0.5-

100 μg/ml dilution of 21 different compounds and that of ampicillin. In each plate one

well was kept as positive control (broth + inoculum) and another as negative control

(broth only). The inoculum was adjusted to a turbidity equivalent to McFarland 0.5

turbidity standard. The inoculum was suitably diluted so as to get a final concentration

Chapter II

89

of approximately 5 x 105 cfu/ml of bacteria in each well. Each well was inoculated

with 0.01 ml of prepared inoculum using a multichannel micropipette and the plates

were incubated overnight at 37 oC. The MICs of these compounds and ampicillin

were determined by using the standard protocol of NCCLS Broth Microdilution MIC

method (Table 7).

Chapter II

90

NH + CS2CAN (5 mol%)ice-bath, 5 min N S

S

N S

S

R

N S

SY

R XR= Alkyl, ArylX= I, Br

PEG 400-H2O, 50 oC

YR1 = H, C6H5 Y= COOMe, CONH2, COPh

PEG 400-H2O, 50 oC

(153) (154)

(155)

(156a-n)

(157)

(158a-l)

R1

R1

Scheme 51: CAN catalyzed synthesis of dithiocarbamates.

Chapter II

91

EXPERIMENTAL

Chemistry

General procedure for the synthesis of dithiocarbamates

Carbon disulphide (2.5 mmol) was added drop by drop to the stirred mixture

of amines (1.2 mmol) in PEG 400-H2O system (3 mL) at 0-5 °C. This mixture was

stirred for 5 min and ceric ammonium nitrate (CAN) (5 mol%) and aryl/alkyl

halides/α,β-unsaturated alkenes (1 mmol) was added. The reaction mixture was stirred

at 50 °C for an appropriate time. The progress of reaction was monitored by TLC. On

completion of reaction, the reaction mixture was cooled in dry ice-acetone bath to

precipitate the PEG 400 and extracted with ether (3 x 10 ml) (PEG being insoluble in

ether). The upper organic layer was washed with water, brine and dried over

anhydrous sodium sulfate (Na2SO4). The solvent was removed under reduced pressure

to afford the crude products, which was further purified by silica gel column

chromatography using hexane:ethylacetate (80:20) as an eluent to yield the desired

products (156a-n & 158a-l). The structure of all the products was unambiguously

established on the basis of their spectral analysis (IR, 1H NMR, 13C NMR and mass

spectral data).

Pharmacology

(Anticancer Activity)

Cell Culture

U87 human glioma cells and Human Embryonic Kidney 293 (HEK-293) cells

were obtained from the Department of Biocybernatics, Institute of Nuclear Medicine

and Allied Sciences, Defense Research and Development Organization, Delhi, India.

U87 human glioma cells were cultured in low glucose (1 g/l) DMEM (Dulbecco’s

modified Eagle’s medium, Himedia, India) supplemented with 10% fetal bovine

Chapter II

92

serum and a mixture of penicillin (100 U/ml) and streptomycin (50 μg/ml) of medium,

under a humidified 5% CO2 atmosphere at 37 °C. Cells were cultured to

approximately 50% confluence at 37 °C with 5% CO2 overnight to insure complete

attachment of cells to the culture matrix. The next day, cells were treated with or

without compounds.

In vitro Cytotoxicity Assay

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay91

was performed in order to examine the cytotoxic effects of the compounds on U87

cells. 5 x 103 cells per well were seeded in 96 flat bottom well plates. The appropriate

concentrations (μg/ml for U87 cells) of the compounds were then added to the cells.

The cells were continuously treated for 24 h. The cytotoxicity was measured by

adding 10μl of 5 mg/ml of MTT (Sigma-Aldrich Inc., U.S.A.) to each well and

incubated for another 2 h in CO2 incubator. The purple formazan crystals were

dissolved by adding 100 μl of dimethyl sulfoxide (DMSO) to each well. The

absorbance was read at 570 nm in a spectrophotometer (Biotek Synergy HT, U.S.A.).

The cell death was calculated as follows:

% cytotoxicity = (100-test OD/control OD) x 100

The test result is expressed as the concentration of a test compound which

inhibits the cell growth by 50% (IC50).

Chapter II

93

Table 1: Screening of solvent.a

Entry Solvent Time (h) Yield (%)b

1 EtOH 15 45

2 H2O 15 15

3 EtOH-H2O (1:1) 10 60

4 PEG 400 15 52

5 PEG 400-H2O (1:1) 5 85

6 PEG 200-H2O (1:1) 5 82

aReaction conditions: diethylamine (1.2 mmol); CS2 (2.5 mmol); iodobenzene (1 mmol); solvent (3 mL); temperature 50 °C. bIsolated yields.

Table 2: Catalytic activity evaluation of CAN for the synthesis of dithiocarbamates.a

Entry CAN (mol%) Time (h) Yield (%)b

1 0 5 85

2 2 4 92

3 5 2 95

4 10 1 70

aReaction conditions: diethylamine (1.2 mmol); CS2 (2.5 mmol); iodobenzene (1 mmol); catalyst CAN (x mol%); solvent PEG 400-H2O (1:1, 3 mL); temperature 50 °C. bIsolated yields.

Chapter II

94

Table 3: CAN catalyzed coupling of dithiocarbamate anions to alkyl/aryl halides.a

R X+ CS2 +NH CAN (5 mol%)PEG 400-H2O, 50 oC

RSN

S

(153) (154) (155) (156a-n)

Entry R X Amines Time (h) Product Yield (%)b

1 C6H5 I (C2H5)2NH 2 156a 95

2 C6H5 I Piperidine 2 156b 92

3 C6H5 I Morpholine 2.5 156c 89

4 C6H5 I Pyrrolidine 2 156d 88

5 4-H3CC6H4 I Piperidine 3 156e 82

6 4-H3COC6H4 I Piperidine 3.5 156f 79

7 4-H3COCC6H4 I Pyrrolidine 3 156g 81

8 C6H5CH2 I Piperidine 2.5 156h 92

9 4-HOC6H4 I Pyrrolidine 3.5 156i 78

10 C2H5 I Piperidine 2 156j 96

11 C2H5 Br Pyrrolidine 3 156k 95

12 C4H9 Br (C2H5)2NH 3.5 156l 91

13 C2H5 I Benzylamine 4 156m 75

14 C4H9 I Benzylamine 4.5 156n 72

aReaction conditions: amines (1.2 mmol); CS2 (2.5 mmol); aryl/alkyl halides (1 mmol); catalyst CAN (5 mol%); solvent PEG 400-H2O (1:1, 3 mL); temperature 50 °C.

bIsolated yields.

Chapter II

95

Table 4: CAN catalyzed nucleophilic addition of dithiocarbamate anions to Michael acceptor.a

+ CS2 +NH CAN (5 mol%)PEG 400-H2O, 50 oC SN

S

R1 Y

R1

Y

R1 = H, Ph; Y = COOMe, COPh, CONH2

(153) (154) (157) (158a-l)

Entry Michael acceptor Amines Time

(h) Product Yield

(%)b

16 OMe

O (C2H5)2NH 2 158a 92

17 Piperidine 2.5 158b 81

18 Pyrrolidine 2.5 158c 94

19 1-Phenylpiperazine 3.5 158d 82

20 NH2

O (C2H5)2NH 3 158e 88

21 Piperidine 3 158f 86

22 Pyrrolidine 3.5 158g 81

23

Ph Ph

O

(C2H5)2NH 2.5 158h 95

24 Piperidine 2.5 158i 93

25 Pyrrolidine 3 158j 92

26 Benzylamine 4 158k 81

27 n-Butylamine 4.5 158l 83

aReaction conditions: amines (1.2 mmol); CS2 (2.5 mmol); α,β-unsaturated alkenes (1 mmol); catalyst CAN (5 mol%); solvent PEG 400-H2O (1:1, 3 mL); temperature 50 °C. bIsolated yields.

Chapter II

96

Table 5: Recyclability of PEG 400.a

No of Cyclesa Fresh Run 1 Run 2 Run 3

Yield (%)b 95 95 94 92

Time (h) 2 2 2 2 aReaction conditions: diethylamine (1.2 mmol); CS2 (2.5 mmol); iodobenzene (1 mmol); catalyst CAN (5 mol%); solvent PEG 400-H2O (1:1, 3 mL); temperature 50 °C. bIsolated yields.

Table 6: Percentage viability at different concentrations and IC50 in μg/ml of compounds (156a-n and 158a-l).

Compd Viability (%) IC50

(µg/ml) 2500 1250 625 312 156 78 39 19 9.8 4.9 2.5

156a 35.333 48.8 49.688 55.822 67.844 81.444 89.35 91.77 100 100 100 625

156b 30.177 42.244 47.822 51.133 63.083 79.111 83.87 97.011 99.11 100 100 312

156c 3.921 3.137 2.549 18.627 19.974 21.568 23.779 37.549 43.581 51.773 78.894 4.9

156d 13.555 13.377 14.177 53.711 65.022 73.511 87.755 99.487 100.6 100 100 312

156e 27.523 32.19 36.19 43.904 47 54.238 91.619 96.761 100 100 100 78

156f 6.686 11.686 17.469 17.988 18.9 20.11 20.542 22.65 93.614 98.795 100 14

156g 4.215 7.352 7.993 8.0 8.0 14.117 44.803 47.45 66.887 100 100 19

156h 1.911 2.556 12.998 24.057 35.113 41.335 55.507 97.246 100 100 100 39

156i 4.215 5.392 6.443 8.443 10.444 10.98 14.705 32.843 53.137 62.549 77.566 98

156j 13.714 17.476 22.904 23.047 74.809 110.666 109.952 91.285 87.476 78.142 80.142 184

156k 2.221 12.667 13.875 17.112 19.443 21.776 25.115 27.407 81.666 91.296 99.259 14.9

156l 36.38 39.285 43 47.619 49.991 51.047 79.523 89.333 99.047 101.809 100 78

156m 15.889 18.666 22.134 28.778 31.011 33.889 39 43.931 47.111 47.988 53.109 2.5

156n 18.11 22.134 23.401 33.89 37 41.556 43.277 49 54.457 88.734 90.06 9.8

158a 35.048 35.998 37.66 40.853 46.999 51.99 69.77 70.331 83.412 87.9620 100 78

158b 30.161 33.838 40.731 47.012 54.301 89.838 96.973 104.30 100 100 100 156

158c 28.104 31.455 39.99 47.882 53.696 86.303 98.704 100 100 100 100 156

158d 36.101 36.909 47.011 53.672 93.686 93.99 100 100 100 100 100 312

158e 32.204 32.904 39.111 39.903 47.873 55.107 93.446 100 100 100 100 78

158f 30.053 37.389 37.998 41.904 56.881 91.047 100 100 100 100 100 156

158g 40.094 41.838 41.989 47.99 49 50.383 88.223 99.44 100 100 100 78

158h 3.887 12.776 13.1324 13.983 15.332 18.223 21.993 24.074 72.407 88.665 100 14.9

158i 8.382 7.205 10.443 19.331 23.556 31.227 37.112 43.778 49.71 72.898 85.797 9.8

158j 8.676 10.823 13.546 19.665 21.11 27.112 31.998 37.391 45.112 51.739 98.443 4.9

158k 33.677 37 41.33 41.99 47.401 49 49.91 52.8 84.463 97.377 100 19

158l 21.871 22.951 32.444 39.55 41 43.367 49 49.834 53.996 74.457 76.385 19

Chapter II

97

Table 7: Antibacterial activity of compounds on E. coli, P. aeruginosa, S. epidermidis and S. aureus (MIC in μg) of (156a-n and 158a-l).

Compound

E. coli

(MIC in μg) P. aeruginosa (MIC in μg)

S. epidermidis (MIC in μg)

S. aureus (MIC in μg)

156a 15.6 15.6 15.6 15.6

156b 62.5 250 250 12.5

156c 15.6 15.6 15.6 31.5

156d 250 250 - 250

156e 15.6 31.5 31.5 15.6

156f 15.6 62.5 31.5 15.6

156g 62.5 62.5 62.5 62.5

156h 250 250 250 12.5

156i 15.6 15.6 31.5 31.5

156j 15.6 31.5 15.6 15.6

156k 15.6 15.6 31.5 31.5

156l 15.6 15.6 15.6 15.6

156m 15.6 15.6 15.6 15.6

156n 15.6 15.6 250 31.5

158a 15.6 15.6 15.6 15.6

158b 15.6 15.6 250 15.6

158c 15.6 15.6 15.6 15.6

158d 250 250 31.5 12.5

158e 15.6 15.6 15.6 15.6

158f 15.6 15.6 62.5 15.6

158g 15.6 15.6 15.6 15.6

158h 15.6 62.5 125 31.5

158i 15.6 62.5 125 31.5

158j 31.5 125 250 31.5

158k 250 250 250 250

158l 250 250 250 31.5

Chapter II

98

Spectroscopic data of synthesized dithiocarbamates (156a-n and 158a-l)

Diethyl-1-dithiocarbamic acid-n-phenyl ester (156a): IR (KBr/cm-1): νmax = 2978,

1501, 1421, 1271, 1065, 732, 686; 1H NMR (CDCl3, 400 MHz): δ = 7.30-7.69 (m,

5H), 3.99 (q, J = 6.92 Hz, 2H), 3.72 (q, J = 6.92 Hz, 2H), 1.24-1.47 (m, 6H); 13C

NMR (CDCl3, 100 MHz): δ = 196.4, 137.3, 130.2, 130.1, 129.4, 129.3, 127.4, 52.3,

52.5, 12.6, 12.5; m/z 226.0679 (M+1, C11H15NS2 requires 225.0646).

Piperidine-1-carbodithioic acid-n-phenyl ester (156b): IR (KBr/cm-1): νmax =

2918, 1459, 1252, 740, 650; 1H NMR (CDCl3, 400 MHz): δ = 7.05-7.65 (m, 5H), 4.16

(br, 2H), 3.80 (br, 2H), 1.67 (br, 6H); 13C NMR (CDCl3, 100 MHz): δ = 198.8, 135.2,

129.6, 129.5, 129.2, 129.1, 125.6, 50.7, 50.6, 24.5, 24.4, 24.1; m/z 238.0679 (M+1,

C12H15NS2 requires 237.0646).

Morpholine-1-carbodithioic acid-n-phenyl ester (156c): IR (KBr/cm-1): νmax =

2918, 1466, 1267, 1216, 1113, 756, 667; 1H NMR (CDCl3, 400 MHz): δ = 7.49-6.70

(m, 5H), 4.30 (br, 4H), 3.79-3.85 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ = 198.2,

136.3, 131.2, 131.1, 130.6, 130.4, 125.2, 66.5, 66.3, 51.7, 51.6; m/z 240.0472 (M+1,

C11H13NOS2 requires 239.0439).

Pyrrolidine-1-carbodithioic acid-n-phenyl ester (156d): IR (Film/cm-1): νmax =

2920, 1441, 1217, 756, 667; 1H NMR (CDCl3, 400 MHz): δ = 7.07-7.39 (m, 5H), 3.56

(t, J = 6.8 Hz, 2H), 3.43 (t, J = 6.7 Hz, 2H), 1.95-2.02 (m, 2H), 1.84-1.91 (m, 2H); 13C

NMR (CDCl3, 100 MHz): δ = 197.6, 134.7, 129.5, 129.4, 128.6, 128.2, 125.2, 53.3,

53.1, 25.2, 25.1; m/z 224.0523 (M+1, C11H13NS2 requires 223.0489).

Piperidine-1-carbodithioic acid-4-methyl-phenyl ester (156e): IR (KBr/cm-1):

νmax = 2945, 1480, 1279, 1134, 948, 851, 755, 666; 1H NMR (CDCl3, 400 MHz): δ =

7.23-7.48 (m, 4H), 4.21 (br, 2H), 3.94 (br, 2H), 2.38 (s, 3H), 1.74 (br, 6H); 13C NMR

Chapter II

99

(CDCl3, 100 MHz): δ = 198.4, 135.2, 131.6, 131.4, 131.3, 129.2, 129.1, 50.5, 50.4,

25.7, 24.3, 24.2, 22.1; m/z 252.0836 (M+1, C13H17NS2 requires 251.0802).

Piperidine-1-carbodithioic acid-4-methoxy-phenyl ester (156f): IR (KBr/cm-1):

νmax = 2960, 1486, 1458, 1286, 913, 819, 744, 670; 1H NMR (CDCl3, 400 MHz): δ =

7.55 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 4.22 (br, 2H), 3.76 (br, 2H), 1.75

(br, 6H); 13C NMR (CDCl3, 100 MHz): δ = 196.8, 159.3, 138.3, 138.1, 126.3, 116.3,

116.2, 55.2, 52.5, 52.3, 24.8, 24.5, 24.0; m/z 268.0785 (M+1, C13H17NOS2 requires

267.0752).

Pyrrolidine-1-carbodithioic acid-4-acetyl-phenyl ester (156g): IR (KBr/cm-1):

νmax = 2953, 2865, 1685, 1438, 1264, 1153, 1009, 955, 820, 748, 607; 1H NMR

(CDCl3, 400 MHz): δ = 7.80 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 3.93 (br,

2H), 3.75 (br, 2H), 2.56 (s, 3H), 2.14-2.18 (m, 2H), 1.97-2.01 (m, 2H); 13C NMR

(CDCl3, 100 MHz): δ = 197.5, 195.2, 135.8, 131.9, 129.8, 129.7, 128.3, 128.2, 54.2,

52.6, 52.5, 24.6, 24.2; m/z 266.0629 (M+1, C13H15NOS2 requires 265. 0595).

Piperidine-1-carbodithioic acid-benzyl ester (156h): IR (KBr/cm-1): νmax = 2919,

1426, 1292, 1180, 934, 809, 709; 1H NMR (CDCl3, 400 MHz): δ = 7.47-7.60 (m, 5H),

4.55 (s, 2H), 4.16 (br, 2H), 3.65 (br, 2H), 1.76 (br, 6H); 13C NMR (CDCl3, 100 MHz):

δ = 197.5, 136.4, 130.1, 129.2, 128.4, 127.4, 52.1, 51.5, 43.2, 29.6, 24.7, 24.1; m/z

252.0836 (M+1, C13H17NS2 requires 251.0802).

Pyrrolidine-1-carbodithioic acid-4-hydroxy-phenyl ester (156i): IR (KBr/cm-1):

νmax = 3441, 2953, 1436, 1250, 1154, 1038, 957, 856, 753, 683; 1H NMR (CDCl3,

400 MHz): δ = 7.63 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 5.25 (s, 1H), 3.94

(br, 2H), 3.61 (br, 2H), 2.09-2.14 (m, 2H), 1.96-2.02 (m, 2H); 13C NMR (CDCl3, 100

MHz): δ = 189.5, 158.6, 136.7, 133.3, 127.2, 123.7, 122.6, 56.9, 50.9, 26.5, 24.1; m/z

240.0473 (M+1, C11H13NOS2 requires 239.0440).

Chapter II

100

Piperidine-1-carbodithioic acid-n-ethyl ester (156j): IR (Film/cm-1): νmax = 2917,

1431, 1243, 1108, 1006, 908, 851, 731; 1H NMR (CDCl3, 400 MHz): δ = 4.21 (br,

2H), 3.85 (br, 2H), 3.14 (q, J = 7.0 Hz, 2H), 1.74 (br, 6H), 1.10 (t, J = 2.1 Hz, 3H);

13C NMR (CDCl3, 100 MHz): δ = 198.4, 52.8, 51.6, 31.4, 26.5, 25.2, 24.5, 14.8; m/z

190.0679 (M+1, C8H15NS2 requires 189.0646).

Pyrrolidine-1-carbodithioic acid-n-ethyl ester (156k): IR (Film/cm-1): νmax =

2918, 1435, 1251, 1155, 1002, 910, 731, 646; 1H NMR (CDCl3, 400 MHz): δ = 3.93

(br, 2H), 3.61 (t, J = 6.8 Hz, 2H), 3.27 (q, J = 7.3 Hz, 2H), 2.10-2.15 (m, 2H), 1.95-

2.06 (m, 2H), 1.32 (t, J = 9.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ = 192.6, 50.9,

50.4, 30.6, 26.5, 25.9, 13.9; m/z 177.0447 (M+1, C7H13NS2 requires 175.0489).

Diethyl-1-dithiocarbamic acid-n-butyl ester (156l): IR (Film/cm-1): νmax = 2932,

1418, 1270, 1143, 1007, 914, 732, 646; 1H NMR (CDCl3, 400 MHz): δ = 4.04 (br,

2H), 3.75 (br, 2H), 3.28 (t, J = 7.3 Hz, 2H), 1.64-1.72 (m, 2H), 1.42-1.48 (m, 2H),

1.27-1.30 (m, 6H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ = 195.9,

51.9, 49.1, 36.8, 30.5, 22.0, 13.6, 11.5, 11.3; m/z 206.0992 (M+1, C9H19NS2 requires

205.0959).

Benzylamine-1-carbodithioic acid-n-ethyl ester (156m): IR (Film/cm-1): νmax =

3263, 2927, 2093, 1638, 1506, 1454, 1383, 1329, 1253, 1073, 1002, 912, 740, 699,

648; 1H NMR (CDCl3, 400 MHz): δ = 8.82 (br, 1H, NH), 7.33-7.36 (m, 5H), 4.93 (d,

J = 5.1 Hz, 2H, PhCH2N), 3.26 (q, J = 6.8 Hz, 2H), 1.22 (t, J = 6.8 Hz, 3H); 13C NMR

(CDCl3, 100 MHz): δ = 198.1, 137.4, 128.9, 128.8, 128.2, 127.9, 126.7, 33.5, 25.6,

14.3; m/z 212.0523 (M+1, C10H13NS2 requires 211.0489).

Benzylamine-1-carbodithioic acid-n-butyl ester (156n): IR (Film/cm-1): νmax =

3246, 2959, 2093, 1601, 1508, 1455, 1347, 1278, 1127, 1028, 909, 733, 698, 648; 1H

NMR (CDCl3, 400 MHz): δ = 7.90 (br, 1H, NH), 7.30-7.39 (m, 5H), 4.70 (d, J = 6.2

Chapter II

101

Hz, 2H, PhCH2N), 3.19 (t, J = 6.9 Hz, 2H), 1.66-1.80 (m, 2H), 1.35-1.48 (m, 2H),

0.92 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ = 197.5, 134.0, 128.9, 128.3,

128.0, 126.8, 126.1, 48.6, 35.2, 31.8, 21.6, 13.3; m/z 240.0836 (M+1, C12H17NS2

requires 239.0802).

3-Diethylthiocarbamoylsulfanyl-propionic acid methyl ester (158a): IR (Film/cm-1):

νmax = 2935, 1735, 1421, 1355, 1202, 1147, 1008, 909, 732, 648; 1H NMR (CDCl3,

400 MHz): δ = 4.0 (br, 2H, CH2N), 3.67 (br, 2H, CH2N), 3.65 (s, 3H), 3.53 (t, J = 6.9

Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 1.22-1.58 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ

= 194.6, 172.5, 51.9, 51.7, 49.3, 33.8, 31.5, 12.3, 11.4; m/z 236.0736 (M+1,

C9H17NO2S2 requires 235.0702).

3-(Piperidine-1-carbothiosulfanyl)-propionic acid methyl ester (158b): IR

(Film/cm-1): νmax = 2919, 1654, 1439, 1217, 1020, 953, 709; 1H NMR (CDCl3, 400

MHz): δ = 4.25 (br, 2H), 3.84 (br, 2H), 3.67 (s, 3H), 3.55 (t, J = 7.1 Hz, 2H), 2.79 (t, J

= 7.1 Hz, 2H), 1.67 (br, 6H); 13C NMR (CDCl3, 100 MHz): δ = 195.2, 172.4, 52.6,

51.8, 51.3, 34.6, 31.8, 25.8, 25.6, 24.3; m/z 248.0734 (M+1, C10H17NO2S2 requires

247.0701).

3-(Pyrrolidine-1-carbothiosulfanyl)-propionic acid methyl ester (158c): IR

(Film/cm-1): νmax = 2917, 1735, 1437, 1221, 1156, 1007, 909, 732, 647; 1H NMR

(CDCl3, 400 MHz): δ = 3.98 (t, J = 6.8 Hz, 2H, CH2N), 3.70 (s, 3H), 3.63 (t, J = 7.2

Hz, 2H, CH2N), 3.57 (t, J = 6.9 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 1.96-2.16 (m, 4H);

13C NMR (CDCl3, 100 MHz): δ = 191.9, 172.4, 54.9, 51.7, 50.9, 33.8, 30.9, 26.5,

24.1; m/z 234.0578 (M+1, C9H15NO2S2 requires 233.0544).

3-(4-Phenylpiperazine-1-carbothiosulfanyl)-propionic acid methyl ester (158d):

IR (Film/cm-1): νmax = 3017, 2917, 2850, 1734, 1599, 1492, 1420, 1215, 1145, 1015,

925, 755, 667; 1H NMR (CDCl3, 400 MHz): δ = 7.24-7.29 (m, 2H), 6.84-6.93 (m,

Chapter II

102

3H), 4.54 (br, 2H), 4.45 (br, 2H), 3.38 (s, 3H), 3.18 (t, J = 6.5 Hz, 2H), 3.08-3.10 (m,

4H), 2.85 (t, J = 6.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ = 193.4, 172.5, 151.1,

129.3, 129.1, 120.3, 116.2, 52.4, 51.3, 49.1, 45.2, 31.8, 29.6; m/z 325.1245 (M+1,

C15H20N2O2S2 requires 324.0976).

3-Diethylcarbamodithioic acid-3-amino-3-oxopropyl ester (158e): IR (KBr/cm-1):

νmax = 3411, 2920, 1667, 1271, 1202, 1147, 1006, 908, 733, 649; 1H NMR (CDCl3,

400 MHz): δ = 5.70 and 5.34 (together, br, 2H, NH2), 4.06 (br, 2H, CH2N), 3.72 (q, J

= 7.3 Hz, 2H, CH2N), 3.56 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 1.25 (t, J = 7.3

Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ = 196.2, 172.1,

53.8, 52.3, 34.1, 33.5, 13.6, 12.8; m/z 221.0738 (M+1, C10H16N2OS2 requires

220.0704).

3-(Piperidine-1-carbodithioic acid)-3-amino-3-oxopropyl ester (158f): IR

(KBr/cm-1): νmax = 3340, 2917, 1645, 1208, 1154, 1042, 913, 744; 1H NMR (CDCl3,

400 MHz): δ = 7.23 (br, 2H, NH2), 4.21 (br, 2H, CH2N), 3.75 (br, 2H, CH2N), 3.58 (t,

J = 7.1 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 0.85-1.73 (m, 6H); 13C NMR (CDCl3, 100

MHz): δ = 194.3, 173.5, 52.6, 52.2, 34.7, 33.2, 24.3, 24.1, 21.3; m/z 233.0738 (M+1,

C9H16N2OS2 requires 232.0704).

3-(Pyrrolidine-1-carbodithioic acid)-3-amino-3-oxopropyl ester (158g): IR

(Film/cm-1): νmax = 3431, 2979, 1647, 1442, 1216, 1154, 1038, 955, 757, 667; 1H

NMR (CDCl3, 400 MHz): δ = 4.13 and 4.11 (together, br, 2H, NH2), 3.93 (t, J = 6.8

Hz, 2H, CH2N), 3.63 (t, J = 6.9 Hz, 2H, CH2N), 3.54 (t, J = 6.6 Hz, 2H), 2.13 (t, J =

6.6 Hz, 2H), 1.98-2.03 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ = 206.5, 189.1, 56.9,

50.9, 32.1, 30.9, 26.5, 24.2; m/z 219.0581 (M+1, C8H14N2OS2 requires 218.0548).

Diethyl-1-carbamodithioic acid-3-oxo-1,3-diphenylpropyl ester (158h): IR (Film/cm-

1): νmax = 3017, 2981, 1663, 1578, 1450, 1216, 1178, 1018, 916, 754, 689; 1H NMR

Chapter II

103

(CDCl3, 400 MHz): δ = 8.00-8.03 (m, 2H), 7.39-7.65 (m, 8H), 4.89 (dd, J = 4.4, 4.4 Hz,

1H), 3.45-4.03 (m, 6H), 1.25-1.47 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 192.3,

190.2, 144.6, 137.9, 134.6, 132.6, 130.4, 129.6, 129.1, 128.8, 128.4, 128.3, 128.2, 52.1,

47.2, 29.5, 13.2, 11.2; m/z 358.1255 (M+1, C20H23NOS2 requires 357.1221).

Piperidine-1-carbodithioic acid-3-oxo-1,3-diphenylpropyl ester (158i): IR

(Film/cm-1): νmax = 3060, 2940, 1664, 1606, 1576, 1449, 1216, 1134, 1016, 748, 689;

1H NMR (CDCl3, 400 MHz): δ = 8.00-8.02 (m, 4H), 7.39-7.64 (m, 8H), 4.87 (dd, J =

4.4 Hz, 4.4 Hz, 1H), 4.21 (br, 2H, CH2N), 3.72 (br, 2H, CH2N), 3.57-3.63 (m, 2H),

1.62-2.31 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 202.4, 199.2, 138.1, 134.8,

132.7, 130.5, 128.9, 128.7, 128.5, 128.4, 128.3, 128.0, 127.8, 127.6, 52.8, 45.0, 39.1,

25.3, 24.8, 24.1; m/z 370.1255 (M+1, C21H23NOS2 requires 369.1221).

Pyrrolidine-1-carbodithioic acid-3-oxo-1,3-diphenylpropyl ester (158j): IR (KBr/cm-

1): νmax = 3062, 2923, 1664, 1577, 1440, 1215, 1178, 1017, 909, 753, 689; 1H NMR

(CDCl3, 400 MHz): δ = 7.26 -8.03 (m, 10H), 5.75 (dd, J = 4.5, 4.5 Hz, 1H), 3.59-4.15 (m,

6H), 2.01-2.17 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ = 197.2, 190.3, 137.6, 134.6,

130.4, 128.8, 128.6, 128.4 128.3, 128.2, 128.1, 126.5, 126.3, 126.1, 52.9, 52.8, 48.5, 38.7,

26.3, 24.1; m/z 356.1098 (M+1, C20H21NOS2 requires 355.1065).

Benzyl-1-carbamodithioic acid-3-oxo-1,3-diphenylpropyl ester (158k): IR

(Film/cm-1): νmax = 3018, 2918, 2850, 1638, 1664, 1605, 1450, 1336, 1215, 1177,

1016, 747; 1H NMR (CDCl3, 400 MHz): δ = 8.02 (d, J = 7.3 Hz, 2H), 7.82-7.91 (m,

3H), 7.22-7.65 (m, 10H), 4.86 (dd, J = 5.8, 5.8 Hz, 1H), 6.20 (br, 1H, NH), 3.74-3.86

(m, 2H), 4.70 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ = 196.2, 196.1, 144.8, 138.0,

134.7, 133.7, 132.7, 130.5, 128.9, 128.8, 128.5, 128.4, 128.2, 128.0, 127.7, 127.5,

127.3, 126.7, 126.4, 50.5, 48.5, 42.4; m/z 392.1099 (M+1, C23H21NOS2 requires

391.1067).

Chapter II

104

Butyl-1-carbamodithioic acid-3-oxo-1,3-diphenylpropyl ester (158l): IR (Film/cm-

1): νmax = 3065, 2918, 2850, 1663, 1605, 1577, 1450, 1336, 1216, 1178, 1017, 908;

1H NMR (CDCl3, 400 MHz): δ = 8.0 (d, J = 7.3 Hz, 2H), 7.39-7.64 (m, 8H), 4.86 (dd,

J = 6.6, 6.6 Hz, 1H), 4.62 (br, 1H, NH), 3.73-3.83 (m, 2H), 3.59 (t, J = 6.8 Hz, 2H),

1.51-1.58 (m, 2H), 1.30-1.38 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100

MHz): δ = 202.0, 198.9, 138.1, 134.8, 132.7, 128.9, 128.6, 128.4, 127.7, 127.5, 50.4,

48.2, 38.7, 29.5, 15.1; m/z 357.7302 (M+1, C20H23NOS2 requires 357.1221).

Chapter II

105

REFERENCES

1. T. L. Ho, Synthesis, 1973, 347.

2. T. Imamoto, M. Nishiura, Y. Yamanoi, H. Tsuruta and K. Yamaguchi, Chem.

Lett., 1996, 25, 875.

3. V. Nair, J. Mathew and K. V. Radhakrishnan, J. Chem. Soc., Perkin Trans. 1,

1996, 1487.

4. T. L. Ho, Organic Synthesis by Oxidation with Metal Compounds; W. J. Mijs,

C. R. H. I de Jonge, Eds; Plenum Press: New York, 1986, 569.

5. H. B. Kagan and J. L. Namy, Tetrahedron, 1986, 42, 6573.

6. G. A. Molander, Chem. Rev., 1992, 92, 29.

7. T. Imamoto, Lanthanides in organic synthesis, Academic Press: London,

1994, chapter 4.

8. V. Nair, J. Mathew and J. Prabhakaran, Chem. Soc. Rev., 1997, 127.

9. J. R. Hwu and K. -Y. King, Curr. Sci., 2001, 81, 1043.

10. V. Nair, S. B. Panicker, L. G. Nair, T. G. George and A. Augustine, Synlett,

2003, 156.

11. V. Nair, L. Balagopal, R. Rajan and J. Mathew, Acc. Chem. Res., 2004, 37, 21.

12. V. Nair and A. Deepthi, Chem. Rev., 2007, 107, 1862.

13. V. Sridharan and J. C. Menendez, Chem. Rev., 2010, 110, 3805.

14. A. Mori, Y. Isayama and H. Takeshita, Bull. Chem. Soc. Jpn., 1986, 59, 511.

15. E. Baciocchi, G. Civitarese and R. Ruzziconi, Tetrahedron Lett., 1987, 28,

5357.

16. A. Citterio, L. Pesce, R. Sebastiano and R. Santi, Synthesis, 1990, 142.

17. K. Kobayashi, H. Tanaka, K. Tanaka, K. Yoneda, O. Morikawa and H.

Konishi, Synth. Commun., 2000, 30, 4277.

Chapter II

106

18. A. J. Clark, C. P. Dell, J. M. McDonagh, J. Geden and P. Mawdsley, Org.

Lett., 2003, 5, 2063.

19. K. Kobayashi, H. Umakoshi, K. Hayashi, O. Morikawa and H. Konishi, Chem.

Lett., 2004, 33, 1588.

20. X. -F. Zeng, S. -J. Ji and S. -Y. Wang, Tetrahedron, 2005, 61, 10235.

21. D. Tsvelikhovsky, H. Schumann and J. Blum, Synthesis, 2006, 1819.

22. P. Shanmugam, P. Boobalan and P. T. Perumala, Tetrahedron, 2007, 63,

12215.

23. M. Paira, S. K. Mandal and S. C. Roy, Tetrahedron Lett., 2008, 49, 2432.

24. K. Sujatha, G. Shanthi, N. P. Selvam, S. Manoharan, P. T. Perumal and M.

Rajendran, Bioorg. Med. Chem Lett., 2009, 19, 4501.

25. J. L. Huston, J. Am. Chem. Soc., 1971, 93, 5256.

26. H. M. Chawla and R. S. Mittal, Synthesis, 1985, 70.

27. C. A. Horiuchi, K. Ochiai and H. Fukunishi, Chem. Lett., 1994, 23, 185.

28. V. Nair and L. G. Nair, Tetrahedron Lett., 1998, 39, 4585.

29. V. Nair, A. Augustine and T. G. George, Eur. J. Org. Chem., 2002, 2363.

30. V. Nair, A. Augustine, S. B. Panicker, T. D. Suja and S. Mathai, Res. Chem.

Intermed., 2003, 29, 213.

31. K. -I. Itoh and C. A. Horiuchi, Tetrahedron, 2004, 60, 1671.

32. S. S. Shindalkar, B. R. Madje, R. V. Hangarge and M. S. Shingare, Indian J.

Chem., 2005, 44B, 2409.

33. M. Kidwai, D. Bhatnagar, N. K. Mishra and V. Bansal, Catal. Commun.,

2008, 9, 2547.

34. K. F. Shelke, S. B. Sapkal and M. S. Shingare, Chin. Chem. Lett., 2009, 20,

283.

Chapter II

107

35. M. Kidwai and D. Bhatnagar, Tetrahedron Lett., 2010, 51, 2700.

36. T. -L. Ho, H. C. Ho and C. M. Wong, J. Chem. Soc., Chem. Commun., 1972,

791.

37. V. Nair and V. Sheeba, J. Org. Chem., 1999, 64, 6898.

38. J. R. Hwu, S. -S. Shiao and S. -C. Tsay, J. Am. Chem. Soc., 2000, 122, 5899.

39. V. Nair, R. Rajan, L. Balagopal, S. Thomas and K. Narasimlu, Tetrahedron

Lett., 2002, 43, 8971.

40. D. A. Evans, P. Nagorny and R. Xu, Org. Lett., 2006, 8, 5669.

41. V. Sridharan, P. T. Perumal, C. Avendano and J. C. Menendez, Tetrahedron,

2007, 63, 4407.

42. J. Jiao, L. X. Nguyen, D. R. Patterson and R. A. Flowers, Org. Lett., 2007, 9,

1323.

43. V. Sridharan and J. C. Menendez, Org. Lett., 2008, 10, 4303.

44. J. Li, Y. Liu, C. Li and X. Jia, Tetrahedron Lett., 2009, 50, 6502.

45. S. Durgadasa, V. K. Chatare, K. Mukkanti and S. Pal, Lett. Org. Chem., 2010,

7, 306.

46. M. Kidwai and D. Bhatnagar, Chem. Papers, 2010, 64, 825.

47. M. Kidwai, D. Bhatnagar, R. Kumar and P. M. Luthra, Chem. Pharm. Bull.,

2010, 58, 1320.

48. M. Kidwai, D. Bhatnagar and N. K. Mishra, Green Chem. Lett. Rev., 2010, 3, 55.

49. S. Pattanayak and S. Sinha, Tetrahedron Lett., 2011, 52, 34.

50. M. Delepine, Compt. Rend., 1907, 144, 1125.

51. (a) Y. S. Chen, I. Schuphan and J. E. Casida, J. Agric. Food. Chem., 1979, 27,

709; (b) T. Mizuno, I. Nishiguchi, T. Okushi and T. Hirashima, Tetrahedron

Lett., 1991, 32, 6867.

Chapter II

108

52. (a) P. J. Nieuwenhuizen, A.W. Ehlers, J. G. Haasnoot, S. R. Janse, J. Reedijk

and E. J. Baerends, J. Am. Chem. Soc., 1999, 121, 163; (b) G. D. Thorn and R.

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

Amsterdam, New York, 1962.

53. H. G. Guy, J. Econ. Entomol., 1936, 29, 467.

54. (a) W. Walter and K. D. Bode, Angew. Chem., Int. Ed. Eng., 1967, 6, 281; (b)

G. H. Elgemeie and S. H. Sayed, Synthesis, 2001, 1747; (c) C. Ronconi, C.

Marzano, P. Zanello, M. Corsini, G. Miolo, C. Macca, A. Trevisan and D.

Fregona, J. Med. Chem., 2006, 49, 1648.

55. (a) A. Ivachtchenko, S. Kovalenko, O. V. Tkachenko and O. Parkhomenko, J.

Comb. Chem., 2004, 6, 573; (b) Y. Zhao, W. Perez-segarra, Q. Shi and A.

Wei, J. Am. Chem. Soc., 2005, 127, 7328.

56. (a) T. S. Griffin, T. S. Woods and D. L. Klayman, In Advances in Heterocyclic

Chemistry; A. R. Katritzky, A. J. Boulton, (Eds.); Academic Press: New York,

1975; 18, 99; (b) S. Goubert-Renaudin, R. Schneider and A. Walcarius,

Tetrahedron Lett., 2007, 48, 2113.

57. K. Vaclav, Chem. Abstr., 1974, 80, 117181.

58. I. Matsumoto, J. Yoshizawa and H. Hidaka, JP51105073, 76, 1976; Chem.

Abstr., 1977, 86, 89610v.

59. M. V. Korablev and M. A. Evets, Farmakol. Toksikol., 1977,40, 603 (in

Russian); Chem. Abstr., 87, 1977, 87, 177859j.

60. S. -L. Cao, Y. Wang, L. Zhu, J. Liao, Y. -W. Guo, L. -L. Chen, H. -Q. Liu and

X. Xu, Eur. J. Med. Chem., 2010, 45, 3850.

61. X. -J. Wang, H. -W. Xu, L. -L. Guo, J. -X. Zheng, B. Xu, X. Guo, C. -X.

Zheng and H. M. Liu, Bioorg. Med. Chem. Lett., 2011, 21, 3074.

Chapter II

109

62. F. Merchan, J. Garin and E. Melendez, Synthesis, 1982, 590.

63. C. Len, A. -S. Boulogne-Merlot, D. Postel, G. Ronco, and P. Villa, J. Agric.

Food Chem., 1996, 44, 2856.

64. R. -T. Li, P. -Y. Ding, M. Han and M. -S. Cai, Synth. Commun., 1998, 28, 295.

65. S. H. Thang, (Bill) Y. K. Chong, R. T. A. Mayadunne, G. Moad and E.

Rizzardo, Tetrahdron Lett., 1999, 40, 2435.

66. M. Koketsu, T. Otsuka and H. Ishihara, Phosphorus Sulfur and Silicon, 2004,

179, 443.

67. A. R. Katritzky, S. Singh, P. P. Mohapatra, N. Clemens and K. Kirichenko,

Arkivoc, 2005, (ix), 63.

68. N. Azizi, B. Pourhasan, F. Aryanasab and M. R. Saidi, Synlett, 2007, 1239.

69. D. Chaturvedi, N. Mishra and V. Mishra, J. Sulfur Chem., 2007, 28, 39.

70. Y. Liu and W. Bao, Tetrahedron Lett., 2007, 48, 4785.

71. H. Firouzabadi, N. Iranpoor and M. Abbasi, Tetrahedron, 2009, 65, 5293.

72. L. D. S Yadav, R. Patel, Vishnu and P. Srivastava, Tetrahedron Lett., 2009,

50, 1335.

73. A. Z. Halimehjani, K. Marjani and A. Ashouri, Green Chem., 2010, 12, 1306.

74. N. Azizia, F. Aryanasab, L. Tourkian and M. R. Saidi, Synth. Commun., 2011,

41, 94.

75. O. M. Singh and N. S. Devi, Synh. Commun., 2011, 41, 516.

76. A. R. Katritzky, S. Singh, P. P. Mohapatra, N. Clemens and K. Kirichenko,

Arkivoc, 2005, (ix), 63.

77. P. G. M. Wuts, T. P. Greene and T. W. Greene’s Protecting Groups in

Organic Synthesis, 4rd ed.; Wiley Interscience; New York, 2006, Chap. 4.

78. D. Zhang, J. Chen, Y. Liang and H. Zhou, Synth. Commun., 2005, 35, 521.

79. L. Ronconi, C. Marzano, P. Zanello, M. Corsini, G. Miolo, C. Macca, A.

Trevisan and D. Fregona, J. Med. Chem., 2006, 46, 1648.

Chapter II

110

80. (a) B. C. Ranu, A. Saha and S. Banerjee, Eur. J. Org. Chem., 2008, 519; (b) A.

Ziyaei-Halimjani and M. R. Saidi, J. Sulfur Chem., 2005, 26, 149.

81. (a) A. Thuillier and P. Metzner, Sulfur Reagents in Organic Synthesis;

Academic: New York, 1994; (b) E. Fujita and Y. Nagao, Bioorg. Chem., 1977,

6, 287.

82. N. Azizi, F. Ebrahimi, E. Aakbari, F. Aryanasab and M. R. Saidi, Synlett,

2007, 2797.

83. A. Ziyaei-Halimajani and M. R. Saidi, Can. J. Chem., 2006, 84, 1515.

84. Y. Quin, G. -Y. Ma, Y. Yang, K. Cheng, Q. -Z. Zheng, W. J. Mao, L. Shi, J.

Zhao and H. L. Zhu, Bio. Org. Med. Chem., 2010, 18, 4310.

85. (a) M. C. Pirrung and K. D. Sarma, J. Am. Chem. Soc., 2004, 126, 444; (b) H.

Firouzabadi, N. Iranpoor and A. Garzan, Adv. Synth. Catal., 2005, 347, 1925;

(c) H. Firouzabadi, N. Iranpoor and A. Khoshnood, J. Mol. Catal. A: Chem.,

2007, 274, 109.

86. M. Kidwai, A. Jahan and D. Bhatnagar, J. Chem. Sci., 2010, 122, 607.

87. (a) J. Chen, S. K. Spear, J. G. Huddleston, R. D. Rogers, Green. Chem., 2005, 7,

64; (b) G. Molineux, Cancer Treat. Rev., 2002, 28, 13; (c) F. M. Veronese, P.

Caliceti, O. Schiavon and M. Sergi, Adv. Drug Delivery Rev., 2002, 54, 587.

88. (a) S. V. More, M. N. V. Sastry and C. -F. Yao, Green Chem., 2006, 8, 91; (b)

A. Dhakshinamoorthy and K. Pitchumani, Catal. Commun., 2009, 10, 872.

89. L. Wang, H. Jing, X. Bu, T. Chang, L. Jin and Y. Liang, Catal. Commun.,

2007, 8, 80.

90. (a). M. Kidwai, S. Saxena, M. K. R. Khan and S. S. Thukral, Eur. J. Med.

Chem., 2005, 40, 816; (b). M. Kidwai, R. Poddar, S. Bhardwaj, S. Singh and

P. M. Luthra, Eur. J. Med. Chem., 2010, 45, 5031.

91. E. Liu, J. Wu, W. Cao, J. Zhang, W. Liu, X. Jiang and X. Zhang, J.

Neurooncol., 2007, 85, 263.