Special Issue Reviews and Accounts ARKIVOC 2009 (i) 150-197

Hydrazinecarbothioamide group in the synthesis of heterocycles

Ashraf A. Aly,a* Alan B. Brown,b

Talaatt I. El-Emary,c Ashraf M. Mohamed Ewas,d and Mohamed Ramadane

a
Chemistry Department, Faculty of Science, El-Minia University, 61519-El-Minia, Egypt
b
Chemistry Department, Florida Institute of Technology, Melbourne, FL 32901, U.S.A.
c
Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
d
Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo-12622, Egypt
e
Medicinal Chemistry Department, Faculty of Pharmacy, El-Minia University,
61519-El-Minia, Egypt
E-mail: ashrafaly63@yahoo.com

Abstract
The review summarizes recent literatures dealing with hydrazinecarbothioamide group in
thiocarbohydrazides and other derivatives including their physical and chemical properties along
with their applications in the synthesis of heterocycles.

Keywords: Hydrazinecarbothioamides, heterocycles

Contents

Introduction

1. Synthesis of thiocarbohydrazides
1.1. Hydrazinolysis of thiophosgene
1.2. Hydrazinolysis of carbon disulfide
1.3. Hydrazinolysis of dialkyl xanthates
1.4. General procedure for the preparation of 1,5-diacyl thiocarbohydrazides
1.5. From acid hydrazides
1.6. By phase-transfer catalysis
1.7. From 1,3,4-oxadiazole-2-thione
1.8. Action of periodic acid
2. Biological activities of thiocarbohydrazide derivatives
3. Reactions of thiocarbohydrazides
3.1. Thermolysis of thiocarbohydrazides

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3.2. Reactions of thiocarbohydrazides with acetylenic compounds

4.Thiocarbohydrazides in synthesis of heterocycles
5. Reactions of thio(semi)carbohydrazides with -acceptors p-CHL, DCHNQ, CNIND,
TCNE, DDQ, DCNQ, DEM and DECF
6. Heterocycles via metal complexation
References

Introduction

Carbohydrazide and thiocarbohydrazide are hydrazine derivatives of carbonic and thiocarbonic

acids. Although in general thiocarbohydrazides are more widely used in heterocyclic synthesis
than thioureas, both types contain the functional group RNHCSNHR. Substituted thiobiureas
(RNHCONHNHCSNHR) are key to the synthesis of many organic heterocyclic ring systems.
Several authors have investigated under various conditions the heterocyclization of 1-
acylthiobiurea,1 1,6-disubstituted 2,5-dithiobiureas,2 and 1-aryl/alkyl-2-thiobiureas.3 Also, the
heterocyclization of compounds having an extended urea-like chain such as 1,4- and 2,4-
disubstituted thiosemicarbazides have been reported.4,5 Thiocarbohydrazide derivatives have
attracted much attention in recent years due to their applications in the synthesis of heterocyclic
compounds,6 synthesis of transition metal complexes,7,8 and pharmacological studies.3 Moreover,
carbohydrazide derivatives were widely used as an oxygen scavenger (metal passivator) for
water treatment systems, particularly for boiler-feed systems.9 The chemistry of carbohydrazides
has grown fast, and has not been reviewed in more than three decades. Accordingly, it is
important to shed more light on the recent literature dealing with that chemistry, especially in the
field of heterocycles.

1. Synthesis of Thiocarbohydrazides

Syntheses of carbohydrazide and thiocarbohydrazide of preparative value are exclusively

variations of one basic reaction, viz. the hydrazinolysis of carbonic and thiocarbonic acid
derivatives. The individual variants of this general synthesis differ from one another in their
applicability and relative merit and are discussed separately below.

1.1. Hydrazinolysis of thiophosgene

Reaction of thiophosgene (1) with hydrazine afforded directly thiocarbohydrazide (2) as shown
in Scheme 1.10

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S
S
H 2N NH 2
+ 2NH2NH2 N N + 2HCl
Cl 1 Cl H H
Scheme 1 2

Scheme 1

1.2. Hydrazinolysis of carbon disulfide

The reaction of hydrazine with carbon disulfide is no doubt the cheapest and most useful method
for the preparation of thiocarbohydrazide (2) in quantity.11
CS2 + 2NH2NH2 NH2NHCSNHNH2 (2)+ H2S

1.3. Hydrazinolysis of dialkyl xanthates

The hydrazinolysis of dialkyl xanthates 3 is a possible route to thiocarbohydrazide (2). By
warming the two reactants, high yields of thiocarbohydrazide are claimed to be obtainable; the
effluent gases, ethanol and ethanethiol, are ignited as they leave the reaction vessel (Scheme
2).12,13
S

R R + 2NH 2NH2 2 + ROH + RSH

O S
3
Scheme 2

Scheme 2

1.4. General procedure for the preparation of 1,5-diacyl thiocarbohydrazides

Thiocarbohydrazide (2) was dissolved in aqueous NaOH solution, which was added dropwise to
a solution of acid chloride in tetrahydrofuran at 0-5 oC. The reaction mixture was then stirred at
room temperature for 2 h to give products 4 in 71-80% yield (Scheme 3).14

O O
O
aq NaOH
2 H H
2 + N N
Ar N N Ar
Ar Cl H H

Scheme 3 S 4

Scheme 3

1.5. From acid hydrazides

Varma15 reported the synthesis of benzamidothiosemicarbazides (N-aroyl thiocarbohydrazides) 5
by treating successively the acid hydrazides prepared by the hydrazinolysis of the acid methyl
ester with carbon disulphide, sodium monochloroacetate and hydrazine hydrate (Scheme 4).15

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-CH3OH 1) CS2
ArCOOCH3 + NH2.NH2 ArCONHNH2
O
2)ClCH2CO2-Na+
3) NH2NH2
H H
N N
Ar N NH2
H

S
Scheme 4 5

Scheme 4

1.6. By phase-transfer catalysis

1,5-Diacyl thiocarbohydrazides 4 were efficiently synthesized in high yield (89-95%) by the
reactions of thiocarbohydrazide 2 with a variety of aroyl chlorides at room temperature using
PEG-400 as a phase-transfer catalyst (Scheme 5).16

NaOH/PEG-400
4
Ar Cl + 2
CH 2Cl 2/H 2O, r.t.
Scheme 5

Scheme 5

1.7. From 1,3,4-oxadiazole-2-thione

The reaction of 5-(2-hydroxyphenyl)-1,3,4-oxadiazole-2(3H)-thione (6) and salicyloyl hydrazide
(7) led to the formation of disalicyloyl thiocarbohydrazide (8) (Scheme 6).17

H
N O
N
S
OH HO
O H2NHN S
+ H H
N N
OH 6 HO N N
H H
7 8
Scheme 6 O O

Scheme 6

1.8. Action of periodic acid

1,5-Diacyl thiocarbohydrazides 4 were expeditiously transformed into the corresponding 1,5-
diacyl carbohydrazides 9 with periodic acid by room temperature grinding under solvent free
conditions. This protocol has the advantages of mild conditions, fast reaction rate, high yield, and
simple work-up procedure (Scheme 7).18

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O O

HIO4.2H2O H H
N N
4 solvent f ree Ar N N Ar
r.t. grinding H H
3-5 min, 88-96% 9
O
Scheme 7

Scheme 7

2. Biological activities of thiocarbohydrazide derivatives

Thiocarbohydrazide is the closest structural analog of thiosemicarbazide, derivatives of which

are recommended as effective antitubercular18,19 and antiviral preparations.20 Thiocarbazides of
the aromatic series also exhibit high antiviral21 and antimicrobial activity.22 Macrocycles
synthesized in the reactions of thiocarbohydrazide (2) with polycarbonyl compounds and their
complexes with the salts of divalent metals are effective fungistatic agents,23 while the
cytotoxicity of the carbohydrazones and thiocarbohydrazones of some ketones is commensurable
with or even exceeds the cytotoxicity of the well-known product melphalan.24

3. Reactions of thiocarbohydrazides

3.1. Thermolysis of thiocarbohydrazides

Thermolysis of dithiocarbohydrazides offers monomeric and dimeric aliphatic and aromatic N-
isothiocyanatoamines. An example is shown in Scheme 8.25

N N
heat
N N N +
N HN C HN
S

Scheme 8

Scheme 8

3.2. Reactions of thiocarbohydrazides with acetylenic compounds

1-Benzoyl-2-phenylacetylene (10a) and 1-(2-thienoyl)-2-phenylacetylene (10b) with
thiocarbohydrazides in acetic acid/water or ethanol/water, with the reagents in an equimolar
ratio, led to the formation of the corresponding 1-carbothiohydrazinoyl-5-hydroxy-3-phenyl-5-R-
2-pyrazolines 11 with yields of 60-88% (Scheme 9).26

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R O R Ph R Ph

HN NH2
O NH O N
+ S
HN HN
HN R1

Ph R S NHR1 S NHR1
Ph B
10a,b A
HO
N N
S
Scheme 9 11
NHR1

Scheme 9

The structure of the compounds 11 so obtained demonstrated that the process takes place
selectively through the intermediate formation of the enamine A, which is in tautomeric
equilibrium with the hydrazone form B; at the second stage of the reaction attack by the amide
nitrogen atom on the electron-deficient carbonyl carbon atom is accompanied by closure of the
pyrazoline ring (Scheme 9).26 By contrast, 1-acetyl-2-phenylacetylene 10c reacted with
thiocarbohydrazide (2) in (i) DMSO or (ii) AcOH at room temperature only through the carbonyl
moiety to furnish N2-(Z-s-trans)- and N3-(Z-s-cis)-bis(1-methyl-3-phenyl-2-propynylidene)-
carbonothioic dihydrazides 12 in 76 or 92% yield, respectively (Scheme 10).27

H3C O S

HN NH 2
i or ii H3C N N CH3
S N N
+ -H2O H H
HN NH 2
2
Ph
(i) DMSO, rt
10c 12
(ii) AcOH, rt
Ph Ph
Scheme 10

Scheme 10

4. Thiocarbohydrazides in the synthesis of heterocycles

4.1. Synthesis of pyrazoles

As previously mentioned, 1-benzoyl-2-phenylacetylene (10a) and 1-(2-thenoyl)-2-
phenylacetylene (10b) reacted with thiocarbohydrazides to give 1-carbothiohydrazinoyl-5-
hydroxy-3-phenyl-5-R-2-pyrazolines 11 with yields of 60-88% (Scheme 9).26 The reaction of
ketene dithioacetals 13a,b with thiocarbohydrazide (2) in hot ethanol afforded the corresponding
pyrazole derivatives 14a,b, respectively (Scheme 11).28a The reaction of ,-acetylenic -

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hydroxy nitriles with thiosemicarbazide, under mild conditions (rt, no catalyst, in 1:1 aqueous
ethanol, 414 h), proceeds chemo-, regio- and stereoselectively to give hitherto inaccessible tri-
functionalized (amino, hydroxylalkyl and thioamide groups) pyrazoles 15 in 5391% yields. The
hydroxyl function is easily protected by using the corresponding acetals of the starting acetylenic
hydroxynitriles (Scheme 11).28b

H3CS X
H 3CS X

C C (NH 2NH)2CS
or NH 2NHCSNH2 N
H 3CS CN N NH 2
13a,b
a; X= CN
S NHNH2
b; X= CONH2
14a; X= CN
b; X=CONH2
R2
HO

R1
R1
NC R2 + NH2CSNHNH2
N
OH
N NH2
15
S NHNH2
Scheme 11

Scheme 11

Reaction of 2,4,6-triphenylpyrylium tetrafluoroborate with 2 at room temperature in ethanol

in the presence of triethylamine gave 5-(2-oxo-2-phenylethyl)-3,5-diphenylethyl)-3,5-diphenyl-
4,5-dihydro-1H-pyrazole-1-carbothiohydrazide (16, Scheme 12).29

Ph Ph

O
Ph
+ 2
N CSNHNH2
Ph O Ph
BF4- N
Ph 16
Scheme 12

Scheme 12

Heating of 3-methyl-5-oxo-1-phenyl-2-pyrazoline-4-thiocarbohydrazide (17) with phenyl

isothiocyanate in absolute ethanol afforded N1-(4,5-dihydro-3-methyl-5-oxo-1-phenylpyrazol-4-
yl)thiocarbonyl-N4-phenylthiosemicarbazide (18, Scheme 13).30 Treatment of 17 with sodium
nitrite in acetic acid yielded 4-azidothiocarbonyl-3-methyl-1-phenyl-2-pyrazolin-5-one (19).
Compound 17 underwent facile condensation with cyclohexanone and benzaldehyde in absolute
ethanol giving N1-cyclohexylidine-3,4-dihydro-3-methyl-5-oxo-1-phenylpyrazole-4-
thiocarbohydrazide (20) and N1-benzylidine-3,4-dihydro-3-methyl-1-phenylpyrazole-4-

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thiocarbohydrazide (21), respectively (Scheme 13). Compound 17 reacted with CS2 in KOH to
give 4-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)-3-methyl-1-phenyl-2-pyrazolin-5-one
(22, Scheme 13).31

H3C CSNHN=CHPh H3C CSNHN

N N
N O N O
21 20
Ph Ph
O
PhCHO

H3C CSNHNHCSNHPh H3C CSNHNH2 H3C CSN3

PhNCS NaNO2
N N N
EtOH AcOH
N O N O N O
18 17
19
Ph Ph Ph
N NH CS2/ KOH
H3C EtOH
S S
N
N O
22 Ph
Scheme 13

Scheme 13

4.2. Synthesis of thiazoles and thiazolidines

Reaction of 2 with aryl isothiocyanates gave 1,5-di(arylamidothiocarbo)-thiocarbohydrazides 23
(Scheme 14). Oxidation of 23 with potassium ferrocyanide afforded symmetrical bis-
benzothiazoles (24, Scheme 14).31 Surprisingly, reaction proceeds via migration of alkyl
substitutent to form the thionylated product 24 (Scheme 14).13

2 + 2 RC6H4NCS RC6H4NHCSNHNH
CS
RC6H4NHCSNHNH
23
K3[Fe(CN)]6
S S

N N C N N

N 24 SR N
H

Scheme 14

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Allowing compound 25 to react with -halocarbonyl compounds such as phenacyl bromide,

chloroacetone, 2-bromomethyl propionate, chloroacetic acid, and bromo- diethylmalonate
afforded the thiazolines 26a-c and thiazolidinones 27a,b, respectively (Scheme 15).32

Me
S
Me
N NHSO2 C
N NNH C NH2
Ph 25

(iii)- (iv) (i), (ii)

Me
Me
Me
Me
N NHSO2 C NN S R
N N NHSO 2 C NN S
N
Ph HN
26a-c Ph HN
O 27a,b R
26a, R = Me (i) = PhCOCH2Br
(ii) = CH3COCH2Cl 27a, R = Ph
26b, R = H 27b, R = Me
26c, R = COOC2H5 (iii) = CH3CH(Br)COOMe
(iv) = ClCH 2COOH
(v) = BrCH(COOEt) 2

Scheme 15

When thiocarbohydrazide (2) was treated with an equivalent of -bromo--butyrolactone

(28) in boiling ethanol, a 1,3-thiazolidine dimer (29) was provided in low yield (Scheme 16).33

Br

+ 2 S
NHNH2 S
HO H2NHN
O O OH
28 N
HO N
NH2
O O H2N
O

O
H2N
S N NH2
N
OH
H
N
N S
S N
N
HO
NHNH2
S N NH2 N
O NH2
29
O

HO Scheme 16

Scheme 16

4.3. Synthesis of 1,2,4-triazolethiones

4-Amino-3-substituted-l,2,4-triazol-5-thiones have proven to possess high cytotoxicity in vitro
against thymocytes.34a 1-Acyl thiocarbohydrazides 5 were cyclized with aqueous NaOH to 4-
amino-3-aryl(H)-l,2,4-triazol-5-thione (30, Scheme 17).34b Several derivatives of compound 5

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have been similarly cyclized by aqueous NaOH.34c Additional syntheses of bis-[4-N-amino-5-

mercapto-1,2,4-triazol-3-yl]alkanes were reported.34d Moreover, 4-amino-5-mercapto-5-[(1H-
indol-3-yl)methyl]-1,2,4-triazole has been synthesized by heating thiocarbohydrazide with 1H-
indol-3-acetic acid.34e

O
H H N NH
N N
aq alkali
Ar N NH 2
H Ar S
N
5 S
30
NH2

Scheme 17

Reactions of 2-methyl-4-phenylthiosemicarbazide with ethyl orthoformate in boiling xylene

led to the formation of 2-methyl-4-phenyl-1,2,4-triazolium-5-thiolate (31) and 1-methyl-4-
phenyl-1,2,4-triazoline-5-thione (32, Scheme 18).35 The formation of these mesoionic
compounds resulted from the rearrangements of 2,4-disubstituted thiosemicarbazides to 1,4-
derivatives, which helped to depict the structure quite convincingly.35

R R
NRNH2 N N N N
HC(OEt)3 +
S Xylene,
S
NHR1 N S N
R = Me; R1= Ph
Scheme 18 31 R 32 R1
1

Scheme 18

Hydrazine reacted with acetylhydrazine-carbothioamide to afford 4-amino-3-methyl-2-

1,2,4-triazoline-5-thione (33), whereas two molecules of 2 reacted together in presence of
hydrazine to form 4-amino-3-hydrazino-2-1,2,4-triazoline-5-thione (34, Scheme 19).36

NHNHCOCH3 HN N
N2H 4. H2O
S

NH2 S N CH3
33 NH 2
NHNH2 HN N
N 2H4. H2O
2eq. S
2 S N NHNH 2
NHNH2
34
Scheme 19 NH2

Scheme 19

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N-Methyl hydrazinecarbothioamide reacted with phenyl isocyanide to yield only 4-methyl-

2
-1,2,4-triazoline-5-thione (35), whereas N-phenyl-hydrazine-carbothioamide afforded
2-phenylamino-1,3,4-thiadiazole (36) in addition to 4-phenyl-2-1,2,4-triazoline-5-thione (37,
Scheme 20).37

NHNH2 PhNC HN N
S
NHMe
S N 35
Me
NHNH2
PhNC N N HN N
S
NHPh +
PhHN S S N
Scheme 20 36 37
Ph

Scheme 20

Reactions of N-phenyl-hydrazine-carbothioamide with ethylphenylimidate hydrochloride at

pH > 7 illustrated the formation of 3,4-diphenyl-2-1,2,4-triazoline-5-thione (38, Scheme 21).38

NHNH2 HN N
EtOC(Ph)=NH.HCl
S
NHPh PH 7
S N Ph
Scheme 21 38
Ph

Scheme 21

Compound 2 reacted with two equivalents of diphenylcarbodiimide in DMF to yield

3-anilino-4-(N,N-diphenylguanidino)-2-1,2,4-triazoline-5-thione (39, Scheme 22).39 On the
contrary, 1-phenylthiocarbohydrazide reacted with one equivalent of diphenylcarbodiimide in
DMF to yield 3,4-bis(phenylamino)-2-1,2,4-triazoline-5-thione (40, Scheme 22).40

HN N
2eq. PhN=C=NPh
2
+ PhNH 2
S N NHPh

HN
NHPh
39
NPh
NHNHPh 1eq. PhN=C=NPh HN N
S + PhNH2
NHNH2
S N NHPh
Scheme 22 40
NHPh

Scheme 22

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Similarly, Kurzer and Secker reported the formation of 3-hydroxy-2-1,2,4-triazoline-5-

thione (41) from 1,4-bis(ethoxycarbonyl) thiosemicarbazide under alkaline conditions (Scheme
23).41

NHNHCO 2Et - OH
HN N
S
NHCO 2Et
S 41 N OH
Scheme 23 H

Scheme 23

Compounds like 3-(2,6-difluorophenyl)-1-phenyl-2-1,2,4-triazoline-5-thiones 43 having

insecticidal properties were prepared by heating thiosemicarbazones 42 in ethanolic hydrochloric
acid (Scheme 24).42

R1
R1
NN=CR2R3 N N
HCl
S
NHCOR EtOH, , 1h

S N R
42: R= 2,6-F2C6H3; R1=Ph; R2,R3= Me H
43
S h 24

Scheme 24

Equimolar quantities of thiocarbohydrazide (2) and aroyl isothiocyanates reacted in DMF at

room temperature, affording excellent yields of the monoadducts, i.e. l-amino-thiocarbamoyl-4-
aroyl-3-thiosemicarbazides (44, R = C6H5, p-ClC6H4, or p-MeOC6H4, Scheme 25).43 The action
of two moles of benzoyl isothiocyanate readily gave the linear di-adduct, e.g. (45; R = R' = Ph).
Boiling of compound 44 in alkali gave rise to cyclization, forming 3-mercapto-5-phenyl-1,2-4-
triazole (R = C6H5) as shown in Scheme 25.43

HN NCS.NHNH2 N N
NH2.NH.CS.NH.NH 2

RCONCS S N R HS N R
H

R'CONCS
RCO.NH.CSNHNH.CS.NH.NH 2 RCONHCSNHNHCSNHNHCSNHCOR'
44 45
S h 25

Scheme 25

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4-Methylthiophenyl acetonitrile (46) was converted into 4-methylthiophenyl acetic acid (47)
by alkaline hydrolysis (Scheme 26).43 The acid 47 was fused with thiocarbohydrazide (2) to get
4-amino-5-(4-methylthio)benzyl)-4H-1,2,4-triazole-3-thiol (48) as illustrated in Scheme 26.44 In
this procedure, an equimolar mixture of 47 and 2 was heated in an oil bath till the contents
melted. The reaction mixture was maintained at this temperature for 3 h. Then it was allowed to
cool and treated with dilute sodium bicarbonate solution in order to remove any unreacted acid.
The solid was filtered, washed with water, dried and recrystallized from ethanol to obtain the
pure triazole.44

SH
NC HOOC
N
N NH2
N
1. KOH. EtOH 2
2. HCl
fusion
48

SCH3 SCH3
46 47
H3CS
Scheme 26

Scheme 26

Various 4-amino-2,3-dihydro-4H-triazoles with aromatic, aliphatic and heterocyclic

substituents at the C(5) positions were synthesized from corresponding acids 49 and/or acid
esters 50 and thiocarbohydrazide (2, Scheme 27).44 This method allows the synthesis of these
heterocycles in a short time and at reduced expense.45

RCO2H 2, C
H
49 3 ON
a, C
HO
3 H
, re H
f lu N
x N
S

at N
2, he R
RCO 2R1
NH 2
50
Scheme 27

Scheme 27

Reaction of carboxylic acids 51 with thiocarbohydrazide (2) at melting temperature afforded

4-amino-5-mercapto-3-aryloxymethyl/anilinomethyl-1,2,4-triazoles 52 (Scheme 28).46

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R
X
+ (NH2NH)2CS
R
2
N N
HO O X
51
51; X= O, NH, SH
R= 2-Cl, 4-Cl, 3-CH3, 2,4-Cl2, 4-Cl, 3-F N
52
Scheme 28 NH2

Scheme 28

Different dicarboxylic acids 53 were fused with 2 to obtain bis-[4-amino-5-mercapto-1,2,4-

triazol-3-yl]alkanes (54, Scheme 29).47

HOOC CH2 COOH + (NH2NH) 2CS

n
(2)
53 Fusion
N N N N

HS N CH2 N SH
n
54
NH2 NH2

Scheme 29

As an extension to the former work, fusing 2,3,5-trichlorobenzoic acid (55) with 2 afforded
the corresponding 3-(2,3,5-trichlorophenyl)-4-amino-1,2,4-triazole-5-thione (56, Scheme 30).48
Synthesized triazolethiols were screened for their antimicrobial and anti-inflammatory activities
such as against Escherichia coli (ATTC-25922), Staphylococcus aureus (ATTC-25923),
Pseudomonas aeruginosa (ATCC-27853) and Klebsiella pneumoniae. Some of the compounds
exhibited promising antimicrobial and anti-inflammatory activities.48

Cl Cl

OH f usion N N

+ (NH2NH)2CS
2 N SH
O
56 NH 2
Cl Cl Cl Cl
55 Scheme 30

Scheme 30

The biologically active 1-(6-methoxy-2-naphthyl)-1-(5-amino-4-mercapto-s-triazol-3-

yl)ethane (58) was synthesized by the fusion of 2-(6-methoxy-2-naphthyl)-propanoic acid (57,
Naproxen) and thiocarbohydrazide (2) as shown in Scheme 31.49 Heterocyclic compound 58
exhibited a remarkable antifungal activity compared with the standard fungicide Mycostatine.

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Radiosterilization of 58 in the dry state proves to be applicable (retaining their structures

unchanged up to 40 kGy).49
The s-triazolosulfonamide derivatives 60 were obtained in good yields by fusion of the tosyl
amino acid derivatives 59 with 2 in an oil bath at 180 oC (Scheme 32).50

Me

f usion
COOH + 2

MeO
57

CH 3 CH3

N N

NH N
N N
MeO MeO H2N
H2N
S SH

58

Scheme 31

R1
O R4 S
H
R2 S N (CH)n H 2N C NH2
+
N N
O COOH H H
R3 59 2

f usion
oil bath, 180 oC
R1
O R4 N NH
R1 H
O R4 N N R2 S N (CH)n
H N S
R2 S N (CH)n O
N SH R3 NH2
O
R3 NH2 60

Scheme 32

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O O

N COOH N COOH
H H
61 63
Cl (NH2NH) 2CS Cl
f usion 2 f usion

O N N
O N N N NH
NH N SH
NH2 NH N SH N S
Cl
NH2 N NH
Cl
O N N

NH N SH
NH2
Cl
62 Cl
Scheme 33 64

Scheme 33

Fusion of 2 with 2-chlorohippuric acid (61) afforded the corresponding triazole derivative
62. In the reaction of 2 with 4-chlorohippuric acid (63), double cyclization occurred to give the
triazolotriazine (64) via the expected triazole derivative (Scheme 33),50 while fusion of bis-
phenoxyacetic acids 65 with thiocarbohydrazide (2) afforded 1,4-bis-[4-amino-5-mercapto-1,2,4-
triazol-3-ylmethoxy]-phenylenes 66 in good yields (Scheme 34).51

R R

2 eq. ClCH2CO2H
OH OH HO2CH2CO OCH2CO2H
NaOH, H2O, heat
65
H2N
R' R'
R 2, heat S
N H

N
O O N

N
N R'
N NH2
66
Scheme 34
SH

Scheme 34

4.3.1. Glycosides of triazolethiols. Refluxing of equimolar amounts of D-glucono- and D-

galactono-1,5-lactones (67 and 68) with thiocarbohydrazide (2) in pyridine for 4 h gave the
respective 4-amino-3-mercapto-1,2,4-triazoles 69 and 70 in good yields. However, under

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microwave irradiation (MW) compounds 69 and 70 were obtained with improved yields (88%)
and shorter reaction times (5-6 min; Scheme 35).52

HS
N
OH
R2 N
N
R1 H 2N
O
Method A: pyridine, ref lux 4 h HC OH
HO + 2
Method B: MW, pyridine HO CH
OH
67,68 O
R2 C R1

69,70 HC OH
Scheme 35
CH2OH

Scheme 35

The synthesis of (1R,2S)-1,2-bis(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)ethane-1,2-diol

(72) has been achieved by the dehydrative cyclization of L-tartaric acid (71) with
thiocarbohydrazide (2) (Scheme 36).53

COOH
S
N N OH NH2
H C OH Pyridine
+ NH2NH C NHNH2
N
HO C H 2 HS SH
N
COOH OH N
NH2 N
71 72
Scheme 36

Scheme 36

4.4. Synthesis of thiadiazoles, thiadiazolines and thiadiazolidines

Glotova et al synthesized 1,3,4-thiadiazole derivatives 74 from 1-benzylidene-
thiocarbohydrazides and 3-bromo-1-phenylprop-2-yn-1-one (73) in acetic acid (Scheme 37).54,55

Ph O
HN NH2
AcOH S H
N
+ S 20-23oC Ph CHR
N
HN N CHR N N
73 O .HBr
Br 74

Scheme 37

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Solvents affect the cyclized products resulting from the reaction of thiocarbohydrazide (2)
with carbon disulfide. In pyridine, reaction of 2 with carbon disulfide afforded the salts 75 and
76.56 In DMF, compound 2 reacted with carbon disulfide and KOH to afford the salt 77 which
can be cyclized on warming to give the corresponding 1,3,4-thiadiazoline-2-thione (Scheme
38).56

CS2 N N
2 N N N
2 +
-S 2
S-
N N N
N -
S N
H+ S
NH2 75 76 H+
NH2

CS2 S N
2
S
KOH/ DMF HN
H2N NHNHCSS-K +
Scheme 38 77
S

Scheme 38

Several 2-phenylimino-1,5-diacyl- and/or-1,5-diaroyl-hydrazine-1,3,4-thiadiazolidines 80

were synthesized by the reaction of 1,5-diaroyl- and/or 1,5-diacyl-3-thiocarbohydrazides 4 with
N-phenyl isocyanodichloride (78). The products 79 obtained on basification with dilute
ammonium hydroxide afforded the free bases 80, which were acetylated using a mixture of
acetic acid and acetic anhydride in 1:1 ratio to afford monoacetyl derivatives 81 (Scheme 39).57

SH
H H Cl
Ar N N Ar
CHCl 3
N N + NPh
H
4 78 -HCl
O O Cl

HN N HN N

NH NH .HCl
O O
O dil NH4OH O
Ar S N Ar S N

Ar Ar
PhN PhN
80 79
CH3COOH:(CH 3CO)2O
1:1 79-81 Ar
HN N COCH 3 a styryl
b o-hydroxy phenyl
N c methyl
O d n-propyl
O
Ar S N e p-hydroxy phenyl

Scheme 39 81 Ar
PhN
Scheme 39

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4.5. Synthesis of dithiazolidines

Choudhari and Berad reported the synthesis of several 3-phenylimino-4-arylidineamino-5-
arylidinehydrazino-1,2,4-dithiazolidines 84 by one step condensation of bis-1,5-arylidine-3-
thiocarbohydrazides 82 and N-phenyl-S-chloro-isothiocarbamoyl chloride (83), followed by
basification of the first-formed hydrochloride salts (Scheme 40).58

S S
CHCl3
H2N NH2 + RCHO N N
N N 1:2 RHC N N CHR
H H -H2O H H
2
S NPh
SH Cl NPh S
Cl
N N CHCl3 N N
+ N N
RHC N N CHR S RHC CHR
H -HCl H
Cl
82 83
-HCl
S
S
NPh
S
N S
N NH 4OH
N NPh
RHC
84 N N N
CHR
N HCl
RHC
Scheme 40 N CHR

Scheme 40

4.6. Synthesis of pyridazines

The reaction of 2-benzylidene-1,2,3,4-tetrahydrocarbazol-1-ones 85 with thiocarbohydrazide (2)
yielded pyridazinocarbazoles 86 and not the thiol-substituted pyrazinocarbazoles as expected
(Scheme 41).59,60

R1 EtOH/KOH R1
+ 2
R2 N O N N N
H R2 H
R3 85 86
R3

Scheme 41

4.7. Synthesis of thiazines

Aly et al recently demonstrated that 1,4-diphenylbut-2-yne-1,4-dione (87) reacted with N-
substituted hydrazinocarbothioamides to form the corresponding N'-[(2E)-6-benzoyl-4-phenyl-
2H-1,3-thiazin-2-ylidene]-substituted hydrazides 88a-e (Scheme 42).61

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88 R Yield of 88 (%)
COR a C6H5- 80
HN b 4-HO-C6H 4- 83
NH c 4-CH3O-C6H4- 86
d 4-Br-C6H 4-CH2- 72
e Ph
H2N S CH3 62
N
PhOC COPh CH 3CN, ref lux
+ RCOHN O
COR 87 1- 2 d N S
88a-e Ph
HN
NH
Ph - H2O
Ph
HN SH O- Ph
NH O OH
HN H
RCONH .. O + N
N S RCONH O
H N S RCOHN O
Ph N S
H Ph
Scheme 42 Ph

Scheme 42

4.8. Synthesis of triazines

A facile synthetic route to triazinones 90 is outlined in Scheme 43.62 The reaction mixture of 2
and oxazolones 89 was refluxed for nearly 2 h and the products separated upon cooling were
collected by filtration.62

CH3
N SH
N N
O
Ar N
2 + Ar NH2

89 O O 90
Scheme43 H

Scheme 43

Reaction of thiocarbohydrazide (2) with dicyandiamides 91 yielded 1-amino-6-hydrazono-4-

imino(or ary1imino)hexahydro-1,3,5-triazine-2-thiones 92 (Scheme 44).63

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RHN-C-NHCN NH 2NH2CNH 2NH2 RNH-C-NH-C-S-C-NHNH2

-HCN
+
NH S NH NH NHNH2
91 2

NNH 2

HN NNH 2

Scheme 44 RN N S
H
92

Scheme 44

4-Amino-6-(aryl-furanylmethyl)-3-mercapto-1,2,4-triazin-5(4H)-ones 94a-f were

synthesized by refluxing the corresponding substituted aryl-furanylpyruvic acids 93a-f with 2 in
ethanolic solution on a steam-bath (Scheme 45).64

O
O
NH2
OH N
R O + 2
O N
O EtOH + H 2O, N SH
94a-f
93a-f

93,94; a, R= p -Cl; b, p -NO 2; c, p -Br; d, o-NO2; e, m-NO2; f , o-Cl R

Scheme 45

Another class of fused triazines, identified as imidazo[4,5-e]triazine-2-ones 96a,b, were

obtained from the interaction of imidazolidineimino-thiones 95a,b with 2 via elimination of both
H2S and NH3 (Scheme 46).30 The isolated products were investigated as antitumor agents.30

O O

R1 N N R2 R1 N N R2
2/ EtOH

-H2S, -NH3
S NH N N

N
95a, R1 = Cl, R2= Cl 96a, R1= Cl, R2= Cl NHNH2
95b, R1 = Br, R2= Cl 96b, R1= Br, R2= Cl

Scheme 46

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4.9. Synthesis of thiadiazines

Thiocarbohydrazide (2) reacted with diethyl bromomalonate (97, DBM) and with 4-bromo-4H-
3-substituted-1,3-disubstituted-pyrzol-5-ones 98 in ethanolic pyridine solution affording 2-
hydrazino-6-carbethoxy-4H,6H-1,3,4-thiadiazin-5-one (99) and 2-hydrazino-5-substituted-4H-
pyrazolo[5,4-e]1,3,4-thiadiazines 100, respectively (Scheme 47).6 Reaction of 2 with 3-bromo-2-
oxoglutaric acid dimethyl ester (101) in methanol gave (2-hydrazino-5-methoxycarbonyl-6H-
1,3,4-thiadiazin-6-yl)acetic acid methyl ester hydrobromide (102, Scheme 48).65

H
NHNH2 Br N
R S CO2Et O
N
EtOH/ pyridine
2 +
N CO2 Et H
R Br
N H 2NHN S
N
X H DBM, 97 COOC2H5
99
100
N
X O
98

98, 100: X= NH, N-Ph, R= CH3, Ph

Scheme 47

CO 2Me
MeO2C
C O N
2 N
CH-Br
23% MeO2C
CH 2 S NHNH 2.HBr
102
CO 2Me
101

Scheme 48

4.10. Synthesis of tetrazinethiones

Interestingly, Mohan and his group demonstrated the synthesis of a series of tetrazinethiones. For
example, reaction of 2 with p-chloro-benzaldehyde proceeded to give successfully the tetrazine-
3(2H)-thione 103 (Scheme 49).66

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HN NH

HN NH O
109

R H
108

HN NH
2 + p-Cl-C6H4-CHO
HN NH

HN NH 103 S R= p -Cl-C6H4
HN NH O
106

S 104 O
107
HN NH

HN NH
Scheme 49 105

Scheme 49

The reaction of 2 with 2-adamantanone (104) in ethanol gave the spiro-[adamantine-2,3'-s-

tetrazine]-6'-thione (105).67 In the same manner, 1',2',4',5'-tetrahydrospiro[fluorene -9,3')-s-
tetrazine]-6'(H)-thione (107) was obtained by the reaction of 9-fluorenone (106) with
thiocarbohydrazide (2).68 Cyclic alkanones such as cyclopentanone (108) reacted with 2 to form
the corresponding tetrazinethione 109 (Scheme 49).69 Isatin (110) reacted with 2 in similar
fashion to give 1',2',4',5'-tetrahydro-3H-2-oxospiro[indole-3,3'-s-tetrazine]-6'-thione (112).70
Reinvestigation of the reaction of 110 with 2 under the same reaction condition (the aqueous
solution of thiocarbohydrazide was stirred without further heating and treated dropwise over 15
min with 110 in ethanol) proved that the obtained compound was isatin--thiocarbohydrazide
(111, Scheme 50).71

NHNHCSNHNH 2

O
S
N
111 H
HN
NH
2 O
HN
NH
2
O O

N N
H 110 H
112
Scheme 50

Scheme 50

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O
+ (NH 2NH)2CS
2
HN NH
CHO
113
HN NH

Scheme 51 114
S

Scheme 51

Mohan reported on another tetrazinethione 114 from the reaction of furfural (113) with 2,
which was identified as 6-(2-furyl)-1,4,5,6-tetrahydro-s-tetrazine-3(2H)-thione (Scheme 51).72 3-
Methylspiro[indane-1,3'-hexahydro-s-tetrazine]-6'-thione (116) was obtained from the reaction
of 3-methylindan-1-one (115) with 2.73 1,7,7-Trimethyl-bicyclo[2.2.1]-heptan-2-one (117)
reacted with 2 in 2N acetic acid to give 1,7,7-trimethyl-spiro[bicycle-[2.2.1]heptane-2,3'-
[1,2,4,5]tetrazinane]-6'-thione (118).74 Treatment of 118 with ethyl chloroacetate and aldehydes
in the presence of pyridine afforded 7-arylidenespiro-[bicycle-heptane-2'-3(4H)-[2H]-
thiazolo[3,2-b]-s-tetrazin]-6-(7H)-ones 119 (Scheme 52).74 1,4-Dioxo-3,4-dihydro-
2(1H)phthalazinecarbothiohydrazide (121) was initially synthesized by reaction of phthalic
anhydride (120) with thiocarbohydrazide (2). Heterocycles 122-126, i.e. 4-substituted-1-thioxo-
1,2-dihydro[1,2,4,5]tetrazino[1,2-b]-phthalazine-6,11-diones, were subsequently synthesized by
cyclocondensation of 121 with trimethyl orthoformate, trimethyl orthoacetate, benzoic
anhydride, cyanogen bromide and carbon disulfide, respectively (Scheme 53).75

Me Me

O HN NH
115
HN NH

116 S
HN
2N acetic acid NH
+ (NH2NH) 2CS
N
HN NH N

117 O O
HN NH
S
118 119
Scheme52 S
CHAr

Scheme 52

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O
S

O + NH 2NHCNHNH2
2

O S 120 O S
O

N NH N NH

N N N NH

CH O S
(O OH
O CH /K O 126 S
122 3 )3 CS 2
N NH
)
H3 3 BrC
OC NH NH2
C( N
CH 3
O S O S
O
121
N NH N NH
(PhCO)2O
N N N N

O CH 3 O S O NH 2
123 125
N NH

N N

Scheme 53
124
O Ph

Scheme 53

4.11. Synthesis of thiaoxadiazines

1,5-Diacyl thiocarbohydrazides 4 were cyclized with iodine to give 1,2,4,5-thiaoxadiazines 127
in 61-80% yields (Scheme 54).17 Iodine solution in ethanol was added with continuous stirring;
the color of iodine gradually disappeared. The addition of iodine was continued till it was in
slight excess indicated by the persistence of its violet color. After keeping the reaction mixture
overnight granular solids were obtained; these were identified as dihydroiodo-1,2,4,5-
thiaoxadiazines, which on basification with dilute ammonium hydroxide gave the free base
(Scheme 54).17

Ar N
NH
4 1. I2/EtOH, r t, overnight H
O N Ar
2. NH4OH S N
Scheme 54 127
O

Scheme 54

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4.12. Synthesis of triazepinothiones

Aly et al reported the synthesis of 1,2,4-triazepine-3-thiones 129-131.76 These products were
obtained in respective reactions of N1-substituted thiosemicarbazides with dimethyl
acetylenedicarboxylate (128, DMAD) and 1,4-diphenylbut-2-yne-1,4-dione (87) under prolonged
reflux in DMF (Schemes 55 and 56).76

S H COCH 3
N
N H H Method B
Method A 1 N N
1 R NH2 + MeO 2C CO2Me
N CO 2Me
R
S 128 S H
N
NH
O 129a-c Method A Method B
1 N
AcOH, ref lux DMF, MW R CO 2Me
10-18 h 5-10 min
129,130 R1 Time (h) Yield of 129 (%) Time (min) Yield of 130 (%)
O 130a -c
a C6H 5- 14 56 5 75
b C6H 5-CH2- 10 60 7 87
c CH 2=CH-CH2- 18 54 10 70

Scheme 55

However, the reaction of the starting materials under microwave irradiation afforded the
same products in higher yields within a few minutes.76 Spectroscopic data excluded the
formation of the regio-isomeric heterocycle 132 (Scheme 56).

H S H
S N N
N N
Method A H H 1
1 N N
1
R N COPh NH2 + PhCO COPh R N Ph
R
or Method B 87
131a-c S PhCO
Ph 132a-c
Method A Method B
DMF, ref lux DMF, MW
24-48 h 10-20 min
131, 132 R1 Time (h) Yield of 131 (%) Time (min) Yield of 132 (%)

a C6H5- 36 82 10 98
b C6H5-CH2- 24 72 12 82
c CH2=CH-CH2- 48 76 20 92

Scheme 56

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4.13. Synthesis of thiadiazepines

NHPhCO Me Ar
.. 2
N NHPh NHPh
HN S N
AcOH Ph
134a-e Ph N S S
10-16 h Ph N CO2Me H
Ar Ar N CO2Me
128
133 CO2Me CO2Me
CO2Me
136
135
Ph
NPh H N H
Ph N Ph N
- H2
134a-e S S
N N
Ar Ar
CO2Me H CH2O2Me
MeO2C
MeO2C
137

Scheme 57. Synthesis of 1,3,5-thiadiazepines 134a-e. a: Ar=4-CH3OC6H4 (84%);

b: Ar=4-CH3C6H4 (80%); c: Ar=4-ClC6H4 (75%); d: 4-O2NC6H4 (65%); e: Ar=Ph (82%).

N-Imidoylthioureas (133, analogous to thiocarbohydrazides) reacted with DMAD (128) to

form 1,3,5-thiadiazepines 134a-e (Scheme 57).77 The reaction mechanism can be simply
described as due to sulfur atoms attacking the triple bond of DMAD in conjugate fashion,
followed by proton transfer and nucleophilic attack of the amidine group on the double bond in
128 to form the intermediates 135.77 Thereafter a nucleophilic attack of the amidine-like nitrogen
on the ethylenic-ester would form the salt 136. Aromatization of 136 is accompanied by the
extrusion of a hydrogen molecule to produce the stable compounds 134a-e (Scheme 57).77 A
similar observation was reported by Alajarn and his group.78

4.14. Synthesis of tetrazepinethiones

Reaction of 2-oxo-2-(3-oxo-5,6-disubstituted-1,2,4-triazin-2(3H)-yl)acetaldehydes 138 with
thiocarbohydrazide (2) in a mixture of acetic acid and sodium acetate produced the
corresponding 1,2,4,5-tetrazepine-3-thiones (139, Scheme 58).79

S
H
CHO N
N
R N NH
N O CH3COONH4 R N
N
+ 2 N
CH3COOH
138
R N O
R N O 139

Scheme 58

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4.15. Synthesis of fused heterocycles

4.15.1. Synthesis of pyrrolo[2,1-b]-1,3,4-oxadiazoles. The Aly group80 described the reaction
of 2,3-diphenylcyclopropenone (140) with arylidene-N-phenylhydrazine-carbothioamides 141a-
e. The formed pyrrolo[2,1-b]-1,3,4-oxadiazoles 142a-e can be described as due to initial
[3+2]cycloaddition, followed by further cyclization with loss of H2S (Scheme 59).80

Ph RH R
R H
H H AcOH H N N Ph Ph
N N CH + N HN N
Ph N O Ph Ph Ph
S
S 140 H+ O Ph HS O Ph
141a-e
141,142 R Yield of 127 (%) - H2S
4-H3CO-C6H4 76
4-HO-C6H4 72 R
4-Cl-C6H4 64
2-Thienyl 60 N N Ph
Phenyl 70 Ph
Scheme 59 O Ph
142a-e

Scheme 59

4.15.2. Synthesis of pyrrolo[2,1-b]-1,3,4-oxadiazoles, 1,2,4-triazolo[4,3-b]pyridazine-thiones

and pyridazinethines. Aly et al81 have also recently reported that cyclopropenone 140 reacted
with two equivalents of either thiosemicarbazide or 1-phenylthiosemicarbazide to afford the
corresponding 1,2,4-triazolo[4,3-b]-pyridazinethiones 143-146.81 However, the reaction of
disubstituted hydrazine-carbothioamides with 140 occurs with stoichiometric amounts of the
starting materials to produce pyridazinethiones 147 (Scheme 60). The reaction mechanism, in
both cases, was described as a formal [3+3]-cycloaddition.81

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MeOH, reflux
H Et3N, 6 h, ref lux (80%)
H 2N N NH 2
NH2 H NH 2 H
2 S N
S S N
N N
N + N
N Ph N
Ph
MeOH, ref lux OH H
Ph Ph
2d 143 (40%) 144 (30%)

H H
N N
H NHR1 NHR1
2 Ph NH 2 H
O S N S N
S N N
N + N
Ph N Ph N
Ph Ph MeOH, ref lux OH H
140 Ph Ph
12-24 h 145 146
Ph
H
N N
Ph NH2 H
S N Ph
S N

Ph NR1 147
MeOH, ref lux
Ph
Scheme 60

Scheme 60

4.15.3. Synthesis of fused triazolo-heterocycles. 3-(3,5-Dimethoxyphenyl)-6-(3,4-

methylenedioxyphenyl)-7H-[1,2,4]triazolo-[3,4-b][1,3,4]-thiadiazines 151 and 6-(3,4-
methylenedioxyphenyl)-7,8-dihydro-3-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo-[4,3-b]-
[1,3,4]triazines 155 were discovered as activators of caspases and inducers of apoptosis so they
may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth
and spread of abnormal cells occurs; accordingly, they may be used as therapeutic anti-cancer
agents.82
Reaction of 3,5-dimethoxybenzoic acid (148) with thiocarbohydrazide (2) produced 4-
amino-5-(3,5-dimethoxyphenyl)-3-mercapto-(4H)-1,2,4-triazole (149), which reacted with 2-
bromo-1-(3,4-methylenedioxyphenyl)ethanone (150) to afford 3-(3,5-dimethoxyphenyl)-6-(3,4-
methylene-dioxyphenyl)-7H-[1,2,4]triazolo-[3,4-b][1,3,4]thiadiazine (151, Scheme 61).82

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OCH 3 OCH3
S
2
NH 2NHCNHNH2
H 2N
HO
N
OCH3 OCH3
HS
O 148 N
N 149

O
Br

150 O

H3CO

OCH3

N
O N
N
151 N
Scheme 61 S

Scheme 61

3-(3,5-Dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)-7H-[1,2,4]triazolo-[3,4-b][1,3,4]-
thiadiazines 151 and 6-(3,4-methylenedioxyphenyl)-7,8-dihydro-3-(3,4,5-trimethoxyphenyl)-
[1,2,4]triazolo-[4,3-b]-[1,3,4]triazines 155 were discovered as activators of caspases and
inducers of apoptosis so they may be used to induce cell death in a variety of clinical conditions
in which uncontrolled growth and spread of abnormal cells occurs; accordingly, they may be
used as therapeutic anti-cancer agents.82

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OCH3
N N
OCH3 H3CO
S

NH2
NH2NHCNH2 S
HO
OCH3 H2SO4 H3CO

O 152 H3CO 153

NH2NH2
O

O N N
O H3CO

150 NH2
N
Br
H3CO
NH2

H3CO 154
OCH3
H3CO

OCH3

N
O
N
N
155 N
N
Scheme 62 H

Scheme 62

On the other hand, reaction of 3,4,5-trimethoxybenzoic acid (152) and thiosemicarbazide

produced 5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazol-2-amine (153) which reacted with
hydrazine hydrate to afford compound 154, which reacted with 2-bromo-1-(3,4-
methylenedioxyphenyl)-ethanone (150) to afford 6-(3,4-methylenedioxyphenyl)-7,8-dihydro-3-
(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo-[4,3-b][1,3,4]triazine (155, Scheme 62).82

4.15.4. Synthesis of fused 1,3,4-thiadiazines. Bromo rhodanine (156) when treated with
thiocarbohydrazide (2) yielded 5H-2-hydrazino-6-thioxo-(1,3)-thiazolo[4,5-e]-1,3,4-thiadiazine
(157) which was then condensed with aromatic aldehydes to obtain the Schiff bases 158.
Similarly, 156 was reacted with thiosemicarbazide to yield 5H-2-amino-6-thioxo-1,3-
thiazolo[4,5-e]-1,3,4-thiadiazine (159). Schiff bases of 159 were also obtained by treating it with
aromatic aldehydes (Scheme 63).83

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Br
SH SH
2 S
NH2NHC=NHNH2 NH 2C=NNH2
(i) O O (i)
N
H
H 156 H
S NHNH 2 S NH2
S S

N N
S N N S N N
H H 159
157

(i) Ar-CHO (i) Ar-CHO

H H
S NHN CH-Ar S N CH-Ar
S S

N N
S N N S N N
H H
158 160
Scheme 63 (i) DMF/Pyridine/MWI

Scheme 63

H3C Br
H3C S NNH2
SH

N NH2NHC=NHNH2
O (i) N NH
N 2
H N N
H 162
161
(i) Ar-CHO

H3C S NN=CH-Ar

(i) DMF/Pyridine/MWI
N NH
Scheme 64 N N
H 163

Scheme 64

Likewise, 3H,5H-2-iminoamino-7-methyl-(1,2)-pyrazolo[4,5-e]-1,3,4-thiadiazine (162) was

formed when 4-bromopyrazole (161) was treated with thiocarbohydrazide (2). This was further
allowed to react with aromatic aldehydes to obtain the corresponding Schiff bases 163 (Scheme
64).83

5. Reactions of thiocarbohydrazides with -acceptors p-CHL, DCHNQ,

CNIND, TCNE, DDQ, DCNQ, DECF and DEM

5.1. Reaction of thiocarbohydrazides with 2,3,5,6-tetrachloro-1,4-benzoquinone

Hassan et al reported84 that addition of tetrahydrofuran (THF) solutions of substituted
thiocarbohydrazides to a solution of 2,3,5,6-tetrachloro-1,4-benzoquinone (p-CHL, 164) in a

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ratio of 1:2 in the same solvent formed, after standing for 48 hours at room temperature,
substituted imidazothiadiazolediones 165 as minor products (21-24%) and substituted benzo-
bisimidazothiadiazoles 166 as major products (48-54%) (Scheme 65).84
Other work was also undertaken to examine the reactions of thiocarbohydrazides derived
from ethylene diamine p-CHL. Thus, two equivalents of thioureidoethylthiourea derivatives
reacted with 164 in THF at room temperature to afford substituted imino-[1,3,6]-thiadiazepane-
2-thiones 167 as minor products (14-19%) and trichloro-7-oxo-quinoxaline-1- carbothioamides
168 as major products (41-49%), in addition to the corresponding dihydrobenzoquinone (Scheme
65).85

O O H
S N R
N
Cl Cl Cl N
HN C NH2 S +
+
HN C NHR N
Cl Cl Cl
S 165
164 O O
Cl NH R
R HN N N

N N
S
S

N N
166
Cl N
RN
Cl N
NHCSNHR NH CSNHR
S
164 +
+
Cl Cl
S N
NHCSNHR H
O 168
167
Scheme 65

Scheme 65

5.2. Reaction of thiocarbohydrazides with 2,3-dichloro-1,4-naphthoquinone

Hassan has also reported that substituted naphthimidazothiadiazolediones 170 and disubstituted
naphthobisimidazo-thiadiazoles 171 were obtained from the reaction of substituted
thiocarbohydrazides with 2,3-dichloro-1,4-naphthoquinone (DCHNQ, 169, Scheme 66).84
O O H
N R
N
S
Cl N
+
S
HN C NH2
+
N N
HN C NHR Cl N
S S
170
S O O NHR
RHN
N N
169 N N

Scheme 66 171

Scheme 66

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5.3. Reaction of thiocarbohydrazides with [1,3-dioxo-2,3-dihydro-1(H)-inden-2-ylidene]-

propanedinitrile
The reaction of substituted thiocarbohydrazides with (1,3-dioxo-2,3-dihydro-1(H)-inden-2-
ylidene)propanedinitrile (CNIND, 172) was carried out in ethyl acetate under reflux, followed by
chromatographic separation. The reaction mixture afforded the products 173-175 (Scheme 67),
and numerous colored byproducts in very small quantities.84

S
O
S N NH C NHR
H
CN N
HN C NH2
+ S
HN C NHR CN

S 172 O CN
NC
S O
173
N
NH C NHR
N S
N
N
S NH C NHR

+
174 CN CN
O 175
Scheme 67 O

Scheme 67

5.4. Reaction of thiosemicarbohydrazides with 1,1,2,2-tetracyanoethylene The reaction of

equimolar quantities of thiocarbohydrazides with 1,1,2,2-tetracyanoethylene (TCNE, 176)
afforded the thiadiazoles 177 and thiadiazine derivatives (178, Scheme 68).84

HN N

Ar C N N S 177,178 Ar
H Ar
a C6H5
b p -C6H4-CH3
N N c p -C6H4-OCH3
d p -C6H4-Cl
Ar C N N S
H H Ar
177
NC CN
+ R NH C NH NH2
H NC CN S
Ar HC N N 176
N
N
178 S
Scheme 68 NC CN Ar

Scheme 66

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Upon addition of doubled molar amounts of 176 to a solution of 4-substituted

thiosemicarbazides in ethyl acetate, with the admission of air, the green color of a transient
charge-transfer complex is observed, which quickly gives way to a brown and finally to a
characteristic reddish orange color. Chromatographic separation of the sublimation residue gave
products 179182 (see Scheme 69).86

NC CN CN
RNHCSNHNH 2 + H2N
CN
CN NC 176 CN

H2N N CN
H N
CN
RN N RN
N
CN
N S
CN CN 179
N
S CN
RN

S N CN
O CN N
180
181 H 2N 182

S CN
Scheme 69 RHN

Scheme 69

5.5. Reaction of acyl thiosemicarbohydrazides with -acceptors

Mixing of two-fold molar amounts of acceptor 164 and/or 2,3-dicyano-5,6-dichloro-1,4-
benzoquinone (DDQ, 183) with one mole of acyl thiosemicarbohydrazides in ethyl acetate, with
admission of air, gave a blue color (max = 573-591 nm).

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O O

Y X Z

RCONHNHCSNH2 +

Y X Z

O 169; Z = Cl O
164; X = Y = Cl 184; Z = CN 169 and 184
183; X = CN, Y = Cl 164 and 183
R
R O
O O
R
N N
NH2 N
N N Cl
N
N O
185
CN
O O
N
Cl
Cl S Cl Cl
OH 186
O
Cl 187 R O
N
Cl S Cl
NNHCOR
188 N
O O O
H H S N
ROCHN N N N N NHCOR
N

S S NH2 O
189
190
CN
191
Scheme 70
OH

Scheme 70

This behavior is explained as being due to initial formation of an unstable charge-transfer

complex (CTC) followed by a chemical reaction which yields substituted oxadiazoles 185 and
heterocycles 186-188. Upon reaction of the same acyl thiosemicarbohydrazides with two
equivalents of acceptors 169 and/or 2,3-dicyano-1,4-naphthoquinone (DCNQ, 184) in ethyl
acetate, the transient CT-complexes underwent conversion into heterocycles 189-191 (Scheme
70).87
Reactions of acyl thiosemicarbohydrazides with 176 in DMF were found to run smoothly,
the conversions of starting materials, in case of phenyl substitutent, in chlorobenzene to 192,
whereas the other derivatives of the target donors gave with 176, heterocycles 193-195 (Scheme
71).88
PhCONHNHCSNHR + 176
NC Ph N
NH
CN
S
NH O
CN
PhOC CN 193
N CN
N CN
192 PhOC
N PhOC
N N
CN N
NHR
H2N CN
CN NC S
194 H2N 195
Scheme 71 CN
CN

Scheme 71

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Reaction of N-substituted-hydrazino-carbothioamides with diethyl maleate (DEM, 196) gave

mainly the corresponding ethyl 7-oxo-3-substituted-7H-[1,2,4]triazolo[3,4-b][1,3]thiazine-5-
carboxylates 200a-e.89 This reaction can be ascribed to nucleophilic attack of the thiol group on
the ester carbon accompanied by elimination of one molecule of ethanol to form the intermediate
197. Thereafter amidine-like nucleophilic attack on the amide is accompanied by water
elimination to give 198. Nucleophilic attack of the terminal NH on the -deficient double-bond
produces the corresponding triazolo-dihydrothiazines 199.

CO2Et
CO2Et CO2Et
R CO2Et CO 2Et R CO 2Et
196 R OH R
COR NH ..
NH O2
HN NH N N
N N .. N N N
SH - EtOH
H N S O -H2O N N
H S O N S O S O
197a-e 199a-e 200a-e
198a-e
time
R O (h)
2 200 R Yield of 200 (%)
COR NH 2
N C6H5- 30 70
HN N a
N S b 4-HO-C6H4- 26 75
H N S CO2Et c 4-CH3O-C6H4- 24 80
d 4-Br-C6H4-CH2- 36 62
201a-e e CH 3- 48 56

Scheme 72. Reaction of N-substituted-hydrazino-carbothioamides with diethyl maleate (196).

Condition: AcOH, reflux, 1-3d.

Ultimately, it was proposed that aerial oxidation of 199 gives the stable heterocyclic
compounds 200 (Scheme 72).89

5.6. Reaction of thiosemicarbazones with selected -acceptors

Acceptor 172 reacted with formohydrazonohydrazide and N-benzylideneformo-
hydrazonohydrazide to respectively form aminoindenopyrazolo-pyridazinone 202 and phenyl-
l,2,3,4-tetraazacyclopenta-fluorene 203 (Scheme 73).84

H2N
O
N
NH

N N
202 172 + R N CH NH NH2

N NH
a, R = NH2
N b, R = C6H5-CH=N
N
203
Ph
Scheme 73

Scheme 73

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Addition of methylene chloride solutions of 2-phenylidene-N-substituted-hydrazine-

carbothioamides to solutions of 183 in the same solvent resulted in the appearance of a green
color, which gradually changed into brown. 5-Substituted N-phenyl-1,3,4-thiadiazole-2-amines
204 (6-11%), together with 3-amino-5,6-dichloro-4,7-dioxo-N-phenyl-4H-indazole-2(7H)-
carbothioamide 205 (71%), were isolated by preparative thin layer chromatography (Scheme
74).88

R O
NH N CHR S N Cl
H 183 N
N S + N
N
S NH Cl
169 204 NHPh H2N 205 O
S
PhHN O O NHPh
N
+ N
N
N
R O 206 207 O Scheme 74
R

Scheme 74

Mixing equimolar amounts of 2-phenylidene-N-substituted-hydrazine-carbothioamides and

169 in ethyl acetate for 72 h led to the formation of substituted benzindazole-4,9-diones 206 as
major products and substituted benzophthalazinediones 207 as minor products (Scheme 74).90
Addition of ethyl acetate solutions of 2-phenylidene-N-substituted-hydrazine-carbothioamides to
solutions of 176 in the same solvent resulted in the formation of heterocycles 208-210 (Scheme
75).91

S NC CN
+
NH
NC 176 CN
NH N CHAr
CHAr Ar
N
PhN N
PhN N
N N
+ + S
CN S HN
S CN
210
208 HN 209 NPh
NH2
Scheme 75 NH2

Scheme 75

5.6.1. Reaction of thiosemicarbazones with diethyl 2,3-dicyanofumarate. Equimolar

solutions of aldehyde 4-phenylthiosemicarbazones and diethyl 2,3-dicyanofumarate (DECF, 211)

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in ethyl acetate formed, on warming to reflux temperature for 1418 h, major (212, 213 in 54
61%) and minor (214, 215 in 2226%) products in each case (Scheme 76).92

S NC CO2Et
+
NH

NH N CHAr EtO2C CN
211
CO2Et R
O CO2Et
O
EtO2C O
NC NC +
Ar + N CSNHPh N
PhHN N
N N PhHNSC N Ar
Ar 214
212 213
S R

EtO2C O

N
Ar N CSNHPh
215

Scheme 76

5.7. Reaction of N-imidoylthioureas with 1,1,2,2-tetracyanoethylene

Aly et al also reported the reaction of N-imidoylthioureas (analogous to thiocarbohydrazides)
with 176 in dry ethyl acetate at room temperature under a stream of N2. Addition of electron
donors to electron acceptor 176 in dichloromethane at room temperature led to complex
formation characterized by CT-bands in the visible region. These CT-complexes gradually
disappeared to give the precipitated thiadiazines 216 (Scheme 77).93

Ar NC CN
NC CN N S Ar
anhy. EtOAc N S
+
Ph N NHPh r.t. 2-6 h Ph
NC CN H Ph N N
176
216 Ar Yield (%)
216a-d
a 4-OCH3-C6H4- 85
b 4-CH3-C6H4- 80
c 4-Cl-C6H4- 75
Scheme 77 d 4-NO2-C6H4- 68

Scheme 77

Aly has also demonstrated a very convenient synthesis of the fused thiazoles 217 (Scheme
78) from the reaction of aroylphenylthioureas (as analogues of thiocarbohydrazides) with -
acceptor quinones (CHL-p, DDQ and DCHNQ).94

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O O 217
O Ar X Yield (%)
Ph
HN Cl X X a 70
N Cl
b Cl 65
HN S + N c Cl 60
Cl X S Ph d CN 68
X
Ar O e CN 65
O f
O CN 63
217a-i g -CH=CH-CH=CH- 78
h -CH=CH-CH=CH- 74
Scheme 78. Synthesis of f used 1,3-thiazoles i -CH=CH-CH=CH- 70

Scheme 78. Synthesis of fused 1,3-thiazoles.

6. Heterocycles via Metal Complexation

A series of complexes 218 of the type [M(TML)X2]; where TML is Tetradentate Macrocyclic
Ligand; M = Co(II), Ni(II), Cu(II), Zn(II)or Cd(II); X = Cl, CH3COO or NO2 have been
synthesized by template condensation of glyoxal and compound 2 in the presence of divalent
metal salts in methanolic medium (Scheme 79).95 The procedure can be summarized as follows:
to a stirring methanolic solution (50 mL) of 2 (10 mmol) was added a divalent cobalt, nickel,
copper, zinc or cadmium salt (5 mmol) dissolved in a minimum quantity of methanol (20 mL).
The resulting solution was refluxed for 0.5 h. After that glyoxal (10 mmol) dissolved in 20 mL
methanol was added to the refluxing mixture and refluxing continued for 610 h, depending
upon the metal salt. The mixture was concentrated to half of its volume and kept in desiccators
for 2 d. The complexes 218 were filtered, washed with methanol, acetone and ether and dried in
vacuo: yield 40%. The complexes are soluble in DMF and DMSO, but are insoluble in common
organic solvents and water.95

C
HN NH

N X
N
HC CH
MeOH M
(NH 2NH)2CS + C2H 2O2 + MX2
6-8h HC CH
2 N X N

HN NH
C
218 [M(TML)X 2]
Where M= Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) S
X=Cl-, NO 3-, CH3COO -
[M(TML)X2] = Tetradentate Macrocyclic Ligand

Scheme 79

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The triple Cu(II) thiocarbohydrazide-2,3-butanedione system in the Cu(II) hexacyanoferrate

gelatin immobilized matrix (219 and 220) has been prepared. The similar process in the
nickel(II)hexacyanoferrate(II) matrices does not occur under such conditions (Scheme 80).96

n Cu2[Fe(CN)6] + 4nOH-1 2[Cu(OH)2]n + n[Fe(CN)6] -4

H2NHN OH NHNH2
S S
O
S Cu
N NH
O N N
[Cu(OH)2] + 2 NH 2NHCNHNH2 + H3C + 3H2O
2
CH3
H 3C CH3
219
H 2NHN NHNH
S OH S 2

O
S Cu
N NH
O N OH N 2H 2O
[Cu(OH)2] + 2NH2NHCNHNH2 + H 3C +
2
CH3
H3C CH3
Scheme 80 220

Scheme 80

Moreover, a series of complexes of the type [M(TML)X2]; 221 where TML is a tetradenate
macrocyclic ligand, M= Co(II), Ni (II), Cu (II); X= Cl-, X= CH3COO- or NO3- have been
synthesized by template condensation of benzil and thiocarbohydraide in the presence of divalent
metal salts in methanolic medium (Scheme 81).96

S
S

NH
HN HN NH
NH 2 NH2 X
2 N
O O N
Ph C C Ph Ph C C Ph
+ MeOH
M
Ph C C Ph MX 2 C Ph
Ph C
O H 2N O N X N
H2N
NH HN NH
HN
2 221
Scheme 81 S
S

Scheme 81

Reactions of formylpodands 222 with carbohydrazide (2b) or thiocarbohydrazide (2a)

afforded macroheterocycles 223 and 224 with a carbo- or thiocarbohydrazone moiety
respectively (Scheme 82).97

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NH2

n NH
O O O

+ X

NH
CH 222 a,b HC

172n = 1(a), 2(b) NH2

O O 2a,b

n X = S (a), O (b)
O O O

CH HC

N N
N N
H H

X
223, X = S; n = 1(a), 2(b)
Scheme 82 224, X = O; n = 1(a), 2(b)

Scheme 82

References

1. Okawara, T.; Tateyama, Y.; Yamasaki, T.; Furukawa, M. J. Heterocycl. Chem. 1988, 25,
1071.
2. Tao, E. V. P.; Rolski, S. Org. Prep. Proc. Int. 1986, 18, 272.
3. Suni, M. M.; Nair, V. A.; Joshua, C. P. Tetrahedron 2001, 57, 2003.
4. Dobosz, M.; Pachuta-Stec, A. Acta Polon. Pharm. 1996, 53, 123.
5. Korzycka, L.; Glowka, M.; Jawicka, J. Polish J. Chem. 1998, 72, 73.
6. Chande, M. S.; Pankhi, M. A.; Ambhaikar, S. B. Indian J. Chem. 2000, 39B, 603.
7. Mikhailov, O. V.; Kazymova, M. A.; Shumilova, T. A.; Chmutova, G. A.; Solovieva, S. E.
Transition Met. Chem. 2005, 30, 299.
8. Saha, G. C.; Khayer, K.; Islam, M. R.; Chowdhury, M. S. K. Indian J. Chem. 1992, 31B,
547.
9. Slovinsky, M. (Nalco Chemical Co.) U. S. Pat. 1980, 4,269,717; Chem. Abstr. 1980, 95,
103118k.
10. Autenrieth, W.; Hefner. H. Ber. Dtsch. Chem. Ges. 1925, 58B, 2151.
11. Petri, N. Z. Naturforsch. 1961, 16B, 769.
12. Beyer, H.; Lassig, W.; Schultz, U. Chem. Ber. 1954, 87, 1401.
13. Sandstrom. J. Arkiv Kemi 1952, 4, 297.
14. Li, Z.; Liu, Z.; Liao, Q-X.; Wei, Z-B.; Long, L-S.; Jiang, Y.-B. C. R. Chim. 2008, 11, 67.
15. Varma, R. S. J. Indian Chem. Soc. 1996, 43, 558.

ISSN 1551-7012 Page 191

ARKAT USA, Inc.
Special Issue Reviews and Accounts ARKIVOC 2009 (i) 150-197

16. Li, Z.; Zhao, Y.; Yang, J. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 79.
17. Brzozowski, Z. Rocz. Chem. 1970, 44, 1309.
18. Donovick, R.; Pansy, F.; Stryker, G.; Bernstein, J. J. Bacteriol. 1950, 59, 667.
19. Popat, K. H.; Purohit, D. H.; Chovatia, P. T.; Joshi, H. S. J. Indian Chem. Soc. 2005, 82,
940.
20. Genova, P.; Varadinova, T.; Matesanz, A. I.; Marinova, D.; Souza, P. Toxicol. Appl.
Pharmacol. 2004, 197, 107.
21. Blumenkopf, T. A.; Harrington, J. A.; Koble, C. S.; Bankston, D. D.; Morrison, R. W., Jr.;
Bigham, E. C.; Styles, V. L.; Spector, T. J. Med. Chem. 1992, 35, 2306.
22. Abu-Hussen, A. A. A.; Emara, A. A. A. J. Coord. Chem. 2004, 57, 973.
23. Naik, A. D.; Annigeri, S. M.; Gangadharmath, U. B.; Revankar, V. K.; Mahale, V. B. J.
Inclusion Phenom. Macrocycl. Chem. 2002, 43, 291.
24. Dimmock, J. R..; Kumar, P.; Allen, T. M.; Kao, G. Y.; Halleran, S.; Balzarini, J.; De Clercq,
E. Pharmazie 1997, 52, 182.
25. Anthoni, U.; Larsen, C.; Nielsen, P. H. Acta Chem. Scand. 1966, 20, 1714.
26. Dvorko, M. Yu.; Albanov, A. I.; Chipanina, N. N.; Sherstyannikova, L. V.; Samoilov, V. G.;
Komarova, T. N.; Glotova, T. E. Chem. Heterocycl. Compd. 2006, 42, 1421.
27. Dvorko, M. Yu.; Glotova, T. E.; Albanov, A. I.; Chipanina, N. N.; Kazheva, O. N.; Shilov,
G. V.; Dyachenko, O. A. Mendeleev Commun. 2008, 18, 48.
28. (a) Hassan, S. M.; Emam, H. A.; Abdelall, M. M. J. Chem. Res. (S) 2000, 544. (b) Trofimov,
B. A.; Malkina, A. G.; Borisova, A. P.; Nosyreva, V. V.; Shemyakina, O. A.; Kazheva, O.
N.; Shilov, G. V.; Dyachenko, O. A. Tetrahedron Lett. 2008, 49, 3104.
29. Molina, P.; Tarraga, A.; Serrano, C. Tetrahedron 1984, 40, 4901.
30. Al-Raqa, S. Y.; ElSharief, A. M. Sh.; Khalil, S. M. E.; Al-Amri, A. M. Heteroatom Chem.
2006, 17, 634.
31. Kandeel, M. M.; Abbady, M. S.; Youssef, M. S. K. Bull. Kor. Chem. Soc. 2002, 23, 41.
32. El-Emary, T. I.; Al-Muaikel, N.; Moustafa, O. S. Phosphorus Sulfur Silicon Relat. Elem.
2002, 177,195.
33. Kabashima, S.; Okawara, T.; Yamasaki, T.; Furukawa, M. Heterocycles 1990, 31, 1129.
34. (a) Mavrova, A. T.; Wesselinova, D.; Tsenov, Y. A.; Denkova, P. Eur. J. Med. Chem. 2009,
44, 63. (b) Kurzer, F.; Wilkinson, M. Chem. Rev. 1970, 70, 111. (c) Mekuskiene, G.;
Burbuliene, M. M.; Jakubkiene, V.; Udrenaite, E.; Gaidelis, P.; Vainilavicius, P. Chem.
Heterocycl. Compd. 2003, 39, 1364. (d) Al-Amin, M.; Islam, M. R. Bangladesh J.
Pharmacol. 2006, 1, 21. (e) Kaplancikli, Z. A.; Turan-Zitouni, G.; zdemir, A.; Revial, G.
Eur. J. Med. Chem. 2008, 43, 155.
35. Buccheri, F.; Cusmano, G.; Gruttadauria, M.; Noto, R.; Werber, G. J. Heterocycl. Chem.
1997, 34, 1447.
36. Saikachi, H.; Kanaoka, M. Yakugaku Zasshi. 1962, 82, 683; Chem. Abstr. 1963, 58, 4543d.
37. Treppendahl, S.; Jakobsen, P. Acta Chem. Scand. Ser. B. 1977, 31, 264.
38. Weidinger, H.; Kranz, J. Chem. Ber. 1963, 96, 1059.

ISSN 1551-7012 Page 192

ARKAT USA, Inc.
Special Issue Reviews and Accounts ARKIVOC 2009 (i) 150-197

39. Kurzer, F.; Wilkinson, M. J. Chem. Soc. C 1968, 2099.

40. Kurzer, F.; Wilkinson, M. J. Chem. Soc. C 1970, 26.
41. Kurzer, F.; Secker, J. L. J. Heterocycl. Chem. 1989, 26, 355.
42. Wegner, P.; Hoemberger, G.; Baumert, D. (Schering A.-G.) Ger. Offen. DE 3717865, 1988;
Chem. Abstr. 1989, 110, 192827j.
43. Kurzer, F. J. Chem. Soc. C 1971, 2932.
44. (a) Prasad, D. J.; Ashok, M.; Karegoudar, P; Poojary, B.; Shivarama, P. H.; Holla, B. S.;
Kumari, N. S. Eur. J. Med. Chem. 2009, 44, 551. (b) Ashok M.; Holla, B. S. J. Pharmacol.
Toxicol. 2007, 2, 256.
45. (a) Smicius, R.; Burbuliene, M. M.; Jakubkiene, V.; Udrenaite, E.; Vainilavicius, P. J.
Heterocyl. Chem. 2007, 44, 279. (b) Bhat, K. S; Prasad, D. J.; Poojary, B; Holla, B. S.;
Phosphorus Sulfur Silicon Relat. Elem. 2004, 179, 1595. (c) Liu, J. L.; Yan, B. J. Phys.
Chem. 2008, 112C, 14168.
46. Holla, B. S.; Rao, B. S.; Sarojini, B. K.; Akberali, P. M.; Kumari, N. S. Eur. J. Med. Chem.
2006, 41, 657.
47. Holla, B. S.; Gonsalves, R.; Shenoy, S. Farmaco 1998, 53, 574.
48. Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.; Poojary, B.; Holla, B. S. Eur. J.
Med. Chem. 2008, 43, 808.
49. Ammar, Y. A.; Ghorab, M. M.; El-Sharief, A. M. Sh.; Mohamed, Sh. I. Heteroatom Chem.
2002, 13, 199.
50. El-Sharief, A. M. Sh.; Ghorab, M. M.; El-Gaby, M. S. A.; Mohamed, Sh. I.; Ammar, Y.
Heteroatom Chem. 2002, 13, 316.
51. Holla, B. S.; Poojary, K. N.; Rao, B. S.; Shivananda, M. K. Eur. J. Med. Chem. 2002, 37,
511.
52. (a) Awad, L. F.; El Ashry, E. S. H. Nucleosides Nucleotides 1999, 18, 557. (b) El Ashry, E.
S. H.; Awad, L. F.; Abdel Hamid, H. M.; Atta, A. I. Nucleosides Nucleotides Nucleic Acids
2005, 24, 427.
53. Moustafa, A. H.; Haggam, R. A.; Younes, M. E.; El Ashry, E. S. H. Nucleosides Nucleotides
Nucleic Acids 2005, 24, 1885.
54. Glotova, T. E.; Dvorko, M. Yu.; Samoilov, V. G.; Ushakov, I. A. Russ. J. Org. Chem. 2008,
44, 866.
55. Glotova, T. E.; Dvorko, M. Yu.; Chipanina, N. N.; Albanov, A. I.; Sherstyannikova, L. V.;
Kazheva, O. N.; Chekhlov, A. N.; Dyachenko, O. A. Russ. J. Org. Chem. 2008, 44, 114.
56. Rudorf, W.-D. J. Sulfur Chem. 2007, 28, 295.
57. Choudhari, J. R.; Berad, B. N. Asian J. Chem. 2007, 19, 4502.
58. Choudhari, J. R.; Berad, B. N. Asian J. Chem. 2005, 17, 495.
59. (a) Hammam, A. E. G.; Abd El-Salam, O. I.; Mohamed, A. M.; Abdel Hafez, N. Indian J.
Chem. 2005, 44B, 1887. (b) Amr, A. E.; Mohamed, A. M.; Mohamed, S. F.; Abdel-Hafez,
N. A.; Hammam, A. E. G. Bioorg. &Med. Chem. 2006, 14, 5481. (c) Abdel-Latif, N. A.;
Sabry, N. M.; Mohamed, A. M.; Abdalla, M. M. Monatsh. Chem. 2007, 138, 715.

ISSN 1551-7012 Page 193

ARKAT USA, Inc.
Special Issue Reviews and Accounts ARKIVOC 2009 (i) 150-197

60. Danish, I. A.; Prasad, K. J. R. Collect. Czech. Chem. Commun. 2005, 70, 223.
61. Aly, A. A.; Hassan, A. A.; Ibrahim, Y. R. J. Chem. Res. 2008, 699.
62. Ashok, M.; Holla, B. S. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 981.
63. Joshua, C. P.; Rajan, V. P. Aust. J. Chem. 1976, 29, 1051.
64. Holla, B. S.; Shivananda, M. K.; Veerendra, B.; Bhat, K. S. Indian J. Chem. 2003, 42B,
2649.
65. Hartenstein, H.; Blitzke, T.; Sicker, D.; Wilde, H. J. Prakt. Chem. 1993, 335, 176.
66. Mohan, J.; Kiran; Dureja, P. Indian J. Chem. 1990, 29B, 148.
67. Mohan, J.; Kataria, S. Indian J. Chem. 1994, 33B, 196.
68. Mohan, J.; Anjaneyulu, G. S. R.; Madan, D. J. Indian Chem. Soc. 1991, 68, 252.
69. Mohan, J.; Malik, N. Indian J. Chem. 1996, 35B, 685.
70. Mohan, J.; Kataria, S. Indian J. Chem. 1998, 37B, 819.
71. (a) Badawy, M. A.; Abdel-Hady, S. A. Arch. Pharm. 1991, 324, 349. (b) Joshi, K. C.; Jain,
R; Dandia, A.; Sharma,V. J. Heterocyl. Chem.1986, 23, 97.
72. Mohan, J. Indian J. Heterocycl. Chem. 1996, 6, 73.
73. Sharma, R.; Kumar, S.; Pujari, H. K. Indian J. Chem. 1990, 29B, 440.
74. Mohan, J.; Khatter, D. Indian J. Heterocyl. Chem. 2002, 12, 169.
75. Amin, A. H.; Bakherad, M. Heterocycl. Commun. 2007, 13, 311.
76. Aly, A. A.; Hassan, A. A.; El-Sheref, E. M.; Mohamed, M. A.; Brown, A. B. J. Heterocycl.
Chem. 2008, 45, 521.
77. Aly, A. A.; El-Shaieb, K. M. J. Chem. Res. 2007, 563.
78. Alajarn, M.; Cabrera, J.; Pastor, A.; Snchez-Andrada, P.; Bautista, D. J. Org. Chem. 2006,
71, 5328.
79. Abdel-Moneim, W. R. Indian J. Heterocycl. Chem. 2004, 13, 379.
80. Aly, A. A.; Hassan, A. A.; Ameen, M. A.; Brown, A. B. Tetrahedron Lett. 2008, 49, 4060.
81. Aly, A. A.; Hassan, A. A.; Gomaa, M. A.-M.; El-Sheref, E. M. ARKIVOC 2007, (xiv), 1.
82. Cai, S. X.; Drewe, J. A.; Zhang, H.-Z.; Kasibhatla, S.; Claassen, G.; Sirisoma, N. S.;
Kemnitzer, W. E. (Cytovia, Inc., USA) WO 2008/011045 A2; Chem. Abstr. 2008, 148,
191966.
83. Dabholkar, V, V.; Gavande, R. P. Indian J. Heterocyl. Chem. 2006, 16, 101.
84. Hassan, A. A.; Mohamed, N. K.; Aly, A. A.; Mourad, A. F. E. Monatsh. Chem. 1997, 128,
61.
85. Hassan, A. A.; Mourad, A.-F. E.; El-Shaieb, K. M.; Abou-Zied, A. H. Molecules 2005, 10,
822.
86. Hassan, A. A.; Mohamed, N. K.; Shawky, A. M.; Dpp, D. ARKIVOC 2003, (i), 118.
87. Hassan, A. A.; Aly, A. A.; El-Sheref, E. M. ARKIVOC 2007, (xiv), 229.
88. Hassan, A. A.; El-Shaieb, K. M.; Shaker, R. M.; Dpp, D. Heteroatom Chem. 2005, 16, 12.
89. Aly, A. A.; Hassan, A. A.; Ibrahim, Y. R.; Abdel-Aziz, M. J. Heterocycl. Chem. 2009 (in
press).
90. Hassan, A. A.; Refaey, S. M.; Shehatta, H. S. ARKIVOC 2007, (xv), 265.

ISSN 1551-7012 Page 194

ARKAT USA, Inc.
Special Issue Reviews and Accounts ARKIVOC 2009 (i) 150-197

91. Gomaa, M. A.-M.; Hassan, A. A.; Shehatta, H. S. Heteroatom Chem. 2006, 17, 261.
92. Hassan, A. A.; Shehata, H. S.; Dpp, D. J. Chem. Res. 2008, 725.
93. Aly, A. A.; El-Shaieb, K. M. J. Chem. Res. 2007, 207.
94. Aly, A. A.; Ahmed, E. K.; El-Mokadam, K. M. J. Sulfur Chem. 2006, 27, 419.
95. Singh, D. P.; Kumar, R.; Tyagi, P. Transition Met. Chem. 2006, 31, 970.
96. Singh, D. P.; Kumar, R.; Malik, V.; Tyagi, P. J. Enzyme Inhibition Med. Chem. 2007, 22,
177.
97. Fedorova, O. V.; Popova, V. A. Russ. J. Gen. Chem. 1995, 65, 593.

Biographical Sketches

Ashraf Abd El-Moneim Aly Shehata (born 1963). He is a Professor of Organic Chemistry in
Chemistry Department, Faculty of Science, Organic Division, El-Minia University, 61519-El-
Minia, Egypt. He was awarded with a channel system program to complete his Ph.D. program
under the supervision of Prof Dr Henning Hopf, in the field of cyclophane chemistry for two
years at TU-Brauschweig, Germany. Awarded with a scientific grant to be a scientific visitor to
TU-Braunschweig, Germany from 28 November 1997 until 31 January 1999. He published about
70 papers in sound international journals. Awarded as a visiting Professor in Sultan of Oman.
Awarded with The States Encouragement National Prize in Organic Chemistry (2004)
from the Academy of Science and Technology, Cairo, Egypt. Awarded with DAAD scholarship
for two months from 12 August 2005 until 12 October 2005 with Prof Dr Henning Hopf. He has
been selected on the boards of referees in the following journals: Journal of Organic
Chemistry, Journals of Royal Society of Chemistry (RSC), and Arkivoc. Acknowledged by
Shoman foundation (in 2006) for his research program and his list of publications. He has joint
research with Dr Alan B. Brown, Chemistry Department, University Blvd, Melbourne, Florida,
U.S.A. He has a prospective cooperation with Prof. Dr. Shinmyozu Teruo, Department of
Applied Molecular Chemistry, Institute for Materials Chemistry and Engineering, Japan. The
research group of Professor Ashraf A Aly is working for a long time on the chemistry of
cyclophanes and he is interested in study of synthetic approaches to new cyclophanes containing
heterocyclic rings. Moreover, his research activity deals with synthesis of heterocycles which
may have prospective biological and/or pharmaceutical activities. In 10-2008, he has been
invited as a visitor Professor in Saudi Arabia, Al-Jouf University, Faculty of Science, Chemistry
Department. E-mail: ashrafaly63@yahoo.com.

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Dr Alan B. Brown (born 1957) was awarded a B. A. in chemistry from Middlebury College and
a Ph.D. in organic chemistry from the University of Wisconsin - Madison. After an N.I.H.
postdoctoral fellowship at Columbia University, he joined Florida Institute of Technology in
1988. His research interests include sensor science, aromaticity, and applied NMR spectroscopy.
E-mail: abrown@fit.edu.

Dr. Talaat Ibrahim Aly El-Emary. Ph.D. Assistant Prof. of Organic Chemistry, Chemistry
Department, Faculty of Science, Assiut University, Assiut, Egypt. Awarded DAAD Grant in
Tubingen University, Institute of Organic Chemistry, Germany at 1998 for 2 months July &
August 1998. He published 37 papers in sound international journals specialized in organic
chemistry and inorganic chemistry journals. E-mail: emary768@hotmail.com.

Dr. Ashraf Metwally Mohamed Ewas was born in 1968, Beni-suef, Egypt. A researcher in
National Research Center, Chemical Industries Research Division, Applied Organic Chemistry
Department., Giza-Dokki, Egypt. His Research interests on the synthesis of heteroorganic
compounds of biological interest, specially as anticancer agents. In 1998, he was awarded many
scientific missions to Poland in order to complete his Ph.D. Program (1997-1998) under
supervision of Professor Marian Mikolajczyk. Awarded another three scientific missions
dated in 1999, 2001 and 2006 to Poland under the same program to elaborate his Post doctoral
research. He participated in the research program on the (Synthesis of enantiomerically pure
cyclopropylphosphonate derivatives via asymmetric cyclopropanation of chiral -
phosphorylvinyl sulfoxides). Awarded a post doctoral scientific grant for supporting a young
researchers (February, 2007) from the Ministry of High Education and Scientific Research in the
Faculty of Organic Chemistry, TU-Dresden, Germany. He participated in the research program
entitled (New domino reactions with sulfones) with Professor Peter Metz. In 09-2008, he has

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been invited as a visitor assistant Professor in Saudi Arabia, Al-Jouf University, Faculty of
Science, Chemistry Department. E-mail: ammewas@yahoo.com.

Mohamed Ramadan Eisa (born 1978) was awarded a B. Pharm. Sci., from Faculty of
Pharmacy, Helwan University in 2000 and a M.Sc., Pharmaceutical Organic Chemistry from
Faculty of Pharmacy, El-Minia University in 2005. His research interests the design of novel
heterocycles which posses anticancer activity. He registries his Ph.D. under the supervision of
Professor Ashraf A. Aly. E-mail: elbashamohammed@yahoo.com.

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