Hydrazinecarbothioamide group in the synthesis of ... - Arkivoc

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: [email protected]

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 π-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 1acylthiobiurea,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 2,4disubstituted 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

Cl

+

Cl

1

H 2N

2NH2NH2

N H

N H

NH 2

2HCl

+

2

Scheme 1

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 O

Scheme 2

3

+ 2NH 2NH2

2

+

ROH

RSH

+

S

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

2

+

2 Ar

O

aq NaOH Cl

H N Ar

H N

N H

N H S

Scheme 3

Ar

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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ARKIVOC 2009 (i) 150-197 -CH3OH

ArCOOCH3 +

1) CS2

ArCONHNH2

NH2.NH2

2)ClCH2CO2-Na+

O

Ar

3) NH2NH2

H N

H N N H

NH2 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 O NaOH/PEG-400 Cl + 2

Ar

4

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 N

H N

O S

OH

O H2NHN + OH 6

HO S H N

HO

H N N H

7

O

Scheme 6

8

N H O

Scheme 6 1.8. Action of periodic acid 1,5-Diacyl thiocarbohydrazides 4 were expeditiously transformed into the corresponding 1,5diacyl 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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ARKIVOC 2009 (i) 150-197 O

4

O H N

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

H N

N H

N H

Ar

9

O

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 Nisothiocyanatoamines. An example is shown in Scheme 8.25 N

N heat

N

N

HN

N

N

+

C

HN

S 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-R2-pyrazolines 11 with yields of 60-88% (Scheme 9).26

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R

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O

R HN

+

Ph

R

Ph

NH2 O

S

NH

O

HN

NHR1

S

N HN

HN R1 R

Ph 10a,b

S Ph

HO N

B

A

NHR1

N

S 11

Scheme 9

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

S

O HN +

S

10c Scheme 10

i or ii

H3C

N

N N H

-H2O HN

Ph

NH 2

CH3

N H

NH 2

2 (i) DMSO, rt (ii) AcOH, rt

Ph

12

Ph

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)-2phenylacetylene (10b) reacted with thiocarbohydrazides to give 1-carbothiohydrazinoyl-5hydroxy-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 α,β-acetylenic γ-

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hydroxy nitriles with thiosemicarbazide, under mild conditions (rt, no catalyst, in 1:1 aqueous ethanol, 4–14 h), proceeds chemo-, regio- and stereoselectively to give hitherto inaccessible trifunctionalized (amino, hydroxylalkyl and thioamide groups) pyrazoles 15 in 53–91% yields. The hydroxyl function is easily protected by using the corresponding acetals of the starting acetylenic hydroxynitriles (Scheme 11).28b H 3CS C

(NH 2NH)2CS

C

H 3CS

X

H3CS

X

N

or NH 2NHCSNH2

CN

NH 2

N

13a,b a; X= CN b; X= CONH2

S

NHNH2

14a; X= CN b; X=CONH2

R2

HO R1

R1 R2 + NH2CSNHNH2

NC

N

OH

N S

Scheme 11

NH2 15 NHNH2

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-diphenyl4,5-dihydro-1H-pyrazole-1-carbothiohydrazide (16, Scheme 12).29 Ph

Ph

+ Ph

O

BF4-

O

Ph

2

N CSNHNH2

Ph Ph

Scheme 12

16

N

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-4yl)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-4thiocarbohydrazide (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

N

N

O

N

CSNHN

20

21 Ph

O

N Ph

O PhCHO H3C

CSNHNHCSNHPh PhNCS EtOH

N O

N

H3C

N O

N

17

18

H3C

CSNHNH2

Ph

NaNO2 AcOH

N

NH

O

N 19

Ph N

CSN3

Ph

CS2/ KOH

H3C

EtOH S

S N N Scheme 13

22

O

Ph

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 bisbenzothiazoles (24, Scheme 14).31 Surprisingly, reaction proceeds via migration of alkyl substitutent to form the thionylated product 24 (Scheme 14).13 2

+

RC6H4NHCSNHNH

2 RC6H4NCS

CS RC6H4NHCSNHNH 23 K3[Fe(CN)]6

S N N H

N

C

24

SR

N

S N N

Scheme 14

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Allowing compound 25 to react with α-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

N

C

NNH C

NH2

25

Ph

(i), (ii)

(iii)- (iv) Me

Me

Me N

NHSO2

N Ph

C

S

NN

Me

R

N

HN

26a-c

N Ph

O

26a, R = Me 26b, R = H 26c, R = COOC2H5

NHSO 2

C

HN

27a,b

(i) = PhCOCH2Br (ii) = CH3COCH2Cl (iii) = CH3CH(Br)COOMe (iv) = ClCH 2COOH (v) = BrCH(COOEt) 2

S

NN

R

27a, R = Ph 27b, R = Me

Scheme 15 When thiocarbohydrazide (2) was treated with an equivalent of α-bromo-γ-butyrolactone (28) in boiling ethanol, a 1,3-thiazolidine dimer (29) was provided in low yield (Scheme 16).33 Br S

2

+

NHNH2

HO

OH

O

O 28

HO

N

N

N

NH2

O

O

S

S

H2NHN

H2N

O O

H2N

NH2

N OH H

N

S

N

S

N

S

N

HO N

NH2

O

29

NHNH2

N NH2

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

N H

NH 2

5

NH

N

H N

aq alkali Ar

S

N

S

NH2

30

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-4phenyl-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 1,4derivatives, which helped to depict the structure quite convincingly.35 NRNH2 S NHR1

R HC(OEt)3 Xylene,

N S

R = Me; R1= Ph

Scheme 18

N

R N

+ S

N 31 R 1

N

N 32

R1

Scheme 18 Hydrazine reacted with acetylhydrazine-carbothioamide to afford 4-amino-3-methyl-∆21,2,4-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 S

HN

N2H 4. H2O S

NH2 NHNH2 2eq. S Scheme 19

NHNH2

N 2H4. H2O 2

N

N 33

NH 2

HN

N

S

N 34

CH3

NHNH 2

NH2

Scheme 19

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N-Methyl hydrazinecarbothioamide reacted with phenyl isocyanide to yield only 4-methyl∆ -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 2

NHNH2

S

PhNC

HN

N

NHMe S NHNH2

S

N 35 Me

PhNC

N

HN

N

N

+

NHPh PhHN

S

S 36

Scheme 20

N 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 S

NHNH2

HN

EtOC(Ph)=NH.HCl

NHPh

PH

7

S

N

Ph

N 38

Scheme 21

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

2

HN

2eq. PhN=C=NPh S

N

NHPh

N HN

+ PhNH 2

NHPh

39 NPh NHNHPh

HN

1eq. PhN=C=NPh

N + PhNH2

S NHNH2

S

Scheme 22

40

N

NHPh

NHPh

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Similarly, Kurzer and Secker reported the formation of 3-hydroxy-∆2-1,2,4-triazoline-5thione (41) from 1,4-bis(ethoxycarbonyl) thiosemicarbazide under alkaline conditions (Scheme 23).41 NHNHCO 2Et

HN

- OH

S NHCO 2Et

S

Scheme 23

N

OH

N H

41

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 NN=CR2R3 S NHCOR

R1 N

HCl EtOH, ∆, 1h

42: R= 2,6-F2C6H3; R1=Ph; R2,R3= Me

S h

N

S 43

R

N 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-4aroyl-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-1,2-4triazole (R = C6H5) as shown in Scheme 25.43 HN

NH2.NH.CS.NH.NH 2 S

RCONCS

RCO.NH.CSNHNH.CS.NH.NH 2 S h

44 25

R'CONCS

NCS.NHNH2

N

R

N

HS

N

R

N H

RCONHCSNHNHCSNHNHCSNHCOR' 45

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 N

1. KOH. EtOH

2

2. HCl

fusion

SCH3

NH2

48

SCH3 47

46

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 49

2, C H

3 ON

a, C HO 3 H , re

f lu x

N

H N S

RCO 2R1

at 2, he

R

N 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 51

HO

N

O

N

X

51; X= O, NH, R= 2-Cl, 4-Cl, 3-CH3, 2,4-Cl2, 4-Cl, 3-F

SH

N

52

NH2

Scheme 28

Scheme 28 Different dicarboxylic acids 53 were fused with 2 to obtain bis-[4-amino-5-mercapto-1,2,4triazol-3-yl]alkanes (54, Scheme 29).47 HOOC

CH2

COOH

n

53 N

HS

+ (NH2NH) 2CS (2) Fusion

N

N CH2

N

n

54

NH2

N

SH

N 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 + O

Cl

55

N

f usion

N

(NH2NH)2CS N

2

Cl Scheme 30

Cl

Cl

56

SH

NH 2

Scheme 30 The biologically active 1-(6-methoxy-2-naphthyl)-1-(5-amino-4-mercapto-s-triazol-3yl)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 2

COOH +

MeO

57 CH3

CH 3

N

N

N

NH N

N MeO

MeO

H2N

H2N

SH

S 58

Scheme 31 R1 R2

O S

R3

59

O

S

R4 H N (CH)n

H 2N

+

COOH

C N H

2

f usion oil bath, 180 oC R1 R2

O S

R3

O

R4

H N (CH)n

N

R2

O S

R3

SH

NH2

NH2

R1

N

N

N H

O

R4 H N (CH)n

N

NH

N

S

NH2

60

Scheme 32

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O

O COOH

N H Cl

(NH2NH) 2CS

f usion O NH

63

Cl f usion

2 N

COOH

N H

61

N O

SH

N

NH

NH2

Cl O

N NH

Cl

N

N SH

N

NH N

NH2

Cl

N N

N

N

S

NH

SH

NH2 Cl

62

64

Scheme 33

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 bisphenoxyacetic acids 65 with thiocarbohydrazide (2) afforded 1,4-bis-[4-amino-5-mercapto-1,2,4triazol-3-ylmethoxy]-phenylenes 66 in good yields (Scheme 34).51 R

R

OH

OH

2 eq. ClCH2CO2H

HO2CH2CO

OCH2CO2H

NaOH, H2O, heat R'

R' R

2, heat

O

65 H2N S H

N

O

N

N

N N

N Scheme 34

NH2

R' 66

SH

Scheme 34 4.3.1. Glycosides of triazolethiols. Refluxing of equimolar amounts of D-glucono- and Dgalactono-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 H 2N

R1 O OH

67,68

HC

Method A: pyridine, ref lux 4 h

2

+

HO

Method B: MW, pyridine

HO

O

OH

CH

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

H

C

OH

HO

C

H

+

NH2NH C

NHNH2

N

Pyridine

N

HS

2

SH

N

COOH 71

NH2

OH

N

N

OH

NH2

N

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-benzylidenethiocarbohydrazides and 3-bromo-1-phenylprop-2-yn-1-one (73) in acetic acid (Scheme 37).54,55 Ph

O HN

NH2

+ S

20-23oC HN

Br

AcOH

N

N

CHR

73

H N

S Ph O

N

N 74

CHR

.HBr

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 S N

CS2

2

-S

N

N

N NH2

N H+

75

CS2

2

N

+

2 S-

N 2 N

-

S

S

S

N H+

76 NH2

N S

KOH/ DMF NHNHCSS-K +

H2N

Scheme 38

N

HN

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 N

Ar

H N N 4

O HN

Cl

Ar

N H

+ Cl

O

HN NH

O

HN

S

O

N

dil NH4OH

Ar PhN 80 CH3COOH:(CH 3CO)2O 1:1 N COCH 3 N

O Ar Scheme 39 81

-HCl

78

N

Ar

CHCl 3

NPh

S

O

N

PhN

N NH

O Ar

S

.HCl O

N

PhN

Ar

79 79-81 Ar a styryl b o-hydroxy phenyl c methyl d n-propyl e p-hydroxy phenyl

Ar

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4.5. Synthesis of dithiazolidines Choudhari and Berad reported the synthesis of several 3-phenylimino-4-arylidineamino-5arylidinehydrazino-1,2,4-dithiazolidines 84 by one step condensation of bis-1,5-arylidine-3thiocarbohydrazides 82 and N-phenyl-S-chloro-isothiocarbamoyl chloride (83), followed by basification of the first-formed hydrochloride salts (Scheme 40).58 S H2N

N H

S NH2 +

N H

RCHO

CHCl3

N

1:2 -H2O

2

N N H

N H

RHC

CHR S

SH N

N N

RHC

82

N H

CHR

Cl

NPh

+

CHCl3

Cl

S

-HCl

N

N N

RHC

N

N

RHC

84

CHR

-HCl NPh

N

N H

Cl

83

S

S

NPh

S

S

NH 4OH N

NPh N

CHR RHC

Scheme 40

S

N

HCl

N 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

EtOH/KOH R1

R1 R2 R3

N H

O

+

2 N H

R2

85

R3

N N 86

Scheme 41 4.7. Synthesis of thiazines Aly et al recently demonstrated that 1,4-diphenylbut-2-yne-1,4-dione (87) reacted with Nsubstituted hydrazinocarbothioamides to form the corresponding N'-[(2E)-6-benzoyl-4-phenyl2H-1,3-thiazin-2-ylidene]-substituted hydrazides 88a-e (Scheme 42).61

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R

88 COR HN H2N

S +

COR HN

a b c d e

NH

PhOC

Yield of 88 (%)

C6H54-HO-C6H 44-CH3O-C6H44-Br-C6H 4-CH2CH3

80 83 86 72 62 N

CH 3CN, ref lux

COPh 87

Ph

RCOHN

1- 2 d

N

O

S 88a-e

Ph

NH

HN

Ph

SH NH RCONH .. N H

Ph O

+ RCONH N

Ph

Scheme 42

Ph

HN

O

S

- H2O

O-

H

H O

S

RCOHN

Ph

OH

N

N

O

S 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 SH

N N

N O 2 +

Ar

Scheme43

N

Ar

NH2 H

89

O

O

90

Scheme 43 Reaction of thiocarbohydrazide (2) with dicyandiamides 91 yielded 1-amino-6-hydrazono-4imino(or ary1imino)hexahydro-1,3,5-triazine-2-thiones 92 (Scheme 44).63

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NH 2NH2CNH 2NH2

RHN-C-NHCN +

NH

RNH-C-NH-C-S-C-NHNH2

-HCN

S

NH

NH NHNH2

2

91

NNH 2 HN

Scheme 44

RN

NNH 2 N H 92

S

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 OH R

O

N 2

+ O

O

NH2

N N

EtOH + H 2O,

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

2/ EtOH

R1

N

N

R2

-H2S, -NH3 S

NH

N

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

95a, R1 = Cl, R2= Cl 95b, R1 = Br, R2= Cl

NHNH2

Scheme 46

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4.9. Synthesis of thiadiazines Thiocarbohydrazide (2) reacted with diethyl bromomalonate (97, DBM) and with 4-bromo-4H3-substituted-1,3-disubstituted-pyrzol-5-ones 98 in ethanolic pyridine solution affording 2hydrazino-6-carbethoxy-4H,6H-1,3,4-thiadiazin-5-one (99) and 2-hydrazino-5-substituted-4Hpyrazolo[5,4-e]1,3,4-thiadiazines 100, respectively (Scheme 47).6 Reaction of 2 with 3-bromo-2oxoglutaric acid dimethyl ester (101) in methanol gave (2-hydrazino-5-methoxycarbonyl-6H1,3,4-thiadiazin-6-yl)acetic acid methyl ester hydrobromide (102, Scheme 48).65 Br

NHNH2

S

R

2 N N X

R

H N

CO2Et

+

O

N

EtOH/ pyridine

H

CO2 Et

Br

N H

H 2NHN

DBM, 97

S

99

100

COOC2H5

N

98

X

O

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

Scheme 47 CO 2Me C

MeO2C

O

CH-Br

N N

2 23%

MeO2C

CH 2

S 102

NHNH 2.HBr

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 tetrazine3(2H)-thione 103 (Scheme 49).66

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HN

NH S

HN

NH 109

O R

108 + p-Cl-C6H4-CHO

2

HN

HN

NH

HN

NH

NH

HN

H

103 S

R= p -Cl-C6H4

O 106

NH S

104 O

107

Scheme 49

HN

NH

HN

NH

105

S

Scheme 49 The reaction of 2 with 2-adamantanone (104) in ethanol gave the spiro-[adamantine-2,3'-stetrazine]-6'-thione (105).67 In the same manner, 1',2',4',5'-tetrahydrospiro[fluorene -9,3')-stetrazine]-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-β-thiocarbohydrazide (111, Scheme 50).71 NHNHCSNHNH 2

O 111 2

S

N H

HN NH

O

HN NH 2 O

O

N H 110

N H 112

Scheme 50

Scheme 50

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O O

113

+

(NH 2NH)2CS 2

CHO

HN

NH

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 3Methylspiro[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-dihydro2(1H)phthalazinecarbothiohydrazide (121) was initially synthesized by reaction of phthalic anhydride (120) with thiocarbohydrazide (2). Heterocycles 122-126, i.e. 4-substituted-1-thioxo1,2-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 2

115

O

HN

NH

HN

NH

116 S + (NH2NH) 2CS

HN

2N acetic acid

117 O

HN

NH

HN

NH 118

Scheme52

S

N

NH N O

S 119 CHAr

Scheme 52

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O S O

+

NH 2NHCNHNH2 2

O

O 122

120

S

N

NH

N

N

CH (O

O

O

O CH

3

)3

) H3 3 OC C(

O

CH 3

S

N

NH

NH

NH2

OH /K CS 2

S

N

NH

N

NH

O 126

S

O

S

BrC N

S O 121

N

NH

N

N

O

(PhCO)2O

O

CH 3

S

O

123

N

NH

N

N

NH 2

125

Scheme 53

124

N

NH

N

N

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-1,2,4,5thiaoxadiazines, which on basification with dilute ammonium hydroxide gave the free base (Scheme 54).17 N

Ar

NH 4

1. I2/EtOH, r t, overnight 2. NH4OH

H N

O S

Scheme 54

N 127

Ar 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 H N

S 1

R

N

N

COCH 3 Method A CO 2Me

O

129a-c

129,130 a b c

1

R

H N

H N

Method B NH2 + MeO 2C

CO2Me

S

Method A AcOH, ref lux 10-18 h Time (h) R1 14 C6H 510 C6H 5-CH2CH 2=CH-CH2- 18

128

Yield of 129 (%) 56 60 54

H N

S

Method B 1 N DMF, MW R 5-10 min Time (min) Yield of 130 (%) O 5 75 7 87 10 70

NH CO 2Me

130a -c

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). S

H N

S

N

1 R N Ph

Method A COPh

or Method B

131a-c

131, 132 a b c

R1

H 1 N R

H N

NH2 + PhCO

S

COPh

PhCO

82 72 76

10 12 20

N

1 R N

Ph

87

Method A Method B DMF, ref lux DMF, MW 24-48 h 10-20 min Time (h) Yield of 131 (%) Time (min)

C6H536 24 C6H5-CH2CH2=CH-CH2- 48

H N

132a-c

Yield of 132 (%) 98 82 92

Scheme 56

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4.13. Synthesis of thiadiazepines

134a-e

.. HN

AcOH 10-16 h

Ph

NHPhCO Me 2 S

N Ar 133

Ar

N

Ph

NHPh N H

CO2Me 128

S

N

Ph N

Ar MeO2C

S

Ar N CO2Me CO2Me 135

134a-e

NHPh

N

Ph

CO2Me CO2Me 136

NPh

Ph

- H2

S

Ph H N H N S

N H MeO2C Ar

CO2Me

CH2O2Me 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 Alajarín 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 N

CHO N R

N N

R

N

O + 138 O

CH3COONH4 2

R

NH

N

N

N

CH3COOH 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 141ae. 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

H N

H N

N

S 141a-e

Scheme 59

R CH

Ph + O

141,142

AcOH

Ph 140

R 4-H3CO-C6H4 4-HO-C6H4 4-Cl-C6H4 2-Thienyl Phenyl

Ph

H N N

H N

H+

S

RH

O

Yield of 127 (%) 76 72 64 60 70

R Ph

Ph

HN N Ph HS O

Ph

Ph - H2S

R N N Ph

Ph

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 N

H 2N 2

Et3N, 6 h, ref lux (80%) NH2

S

NH 2

H N

S

N

Ph

2 Ph

O

Ph

140

H N

H N

NH 2

S

MeOH, ref lux 12-24 h

N

NHR1 N

N N

Ph 144 (30%)

S N

H N

+

N OH H

Ph

Ph

Ph 145

NHR1 N

N N

Ph Ph 146

Ph

H N

N

NH2

S MeOH, ref lux Scheme 60

H N

NH 2

Ph

Ph 143 (40%)

S Ph

+

N

N OH H

MeOH, ref lux 2d

H N

S

S

H N

N

Ph NR1 147

Ph Ph

Scheme 60 4.15.3. Synthesis of fused triazolo-heterocycles. 3-(3,5-Dimethoxyphenyl)-6-(3,4methylenedioxyphenyl)-7H-[1,2,4]triazolo-[3,4-b][1,3,4]-thiadiazines 151 and 6-(3,4methylenedioxyphenyl)-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 4amino-5-(3,5-dimethoxyphenyl)-3-mercapto-(4H)-1,2,4-triazole (149), which reacted with 2bromo-1-(3,4-methylenedioxyphenyl)ethanone (150) to afford 3-(3,5-dimethoxyphenyl)-6-(3,4methylene-dioxyphenyl)-7H-[1,2,4]triazolo-[3,4-b][1,3,4]thiadiazine (151, Scheme 61).82

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OCH 3

S

OCH3

2

NH 2NHCNHNH2

H 2N

HO

N

OCH3 O

OCH3

HS

148

N

N

149 O Br

O 150

O

H3CO OCH3 O N

O

N N

Scheme 61

151

S

N

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 OCH3

NH2NHCNH2

HO

O

NH2

S

H2SO4

OCH3

N

N

H3CO

S

H3CO

152

H3CO

153

NH2NH2

O

O

O

N

N

H3CO

150

N Br

H3CO

NH2 H3CO

OCH3

H3CO

NH2

154

OCH3 O

N

O

N N

155 Scheme 62

N H

N

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-(3,4methylenedioxyphenyl)-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-1,3thiazolo[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 2

SH

S

NH2NHC=NHNH2

NH 2C=NNH2

(i)

O

N H

H S

(i) H

156

NHNH 2

S

O

NH2

S S

N S

N H (i)

N

N

S

N H 159

157

Ar-CHO

Ar-CHO

(i)

H

N

H NHN

S

CH-Ar

N

S

S

CH-Ar

S N

S

N H

N

N

S

N H

158

Scheme 63

N 160

(i) DMF/Pyridine/MWI

Scheme 63 Br

H3C

H3C

SH N N H 161

O

NH2NHC=NHNH2 2

(i)

S

NNH2

N

NH N H

N 162 (i)

H3C

Ar-CHO

S

NN=CH-Ar

(i) DMF/Pyridine/MWI N

NH N H

Scheme 64

163

N

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 π-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 benzobisimidazothiadiazoles 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]-thiadiazepane2-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

S Cl HN

C

NH2

HN

C

NHR

Cl

Cl

H N

N

R

N

+

S

+ Cl

N

Cl

Cl

S

164 O

165

O R

HN

Cl

NH

N

N

R

N

N

S

S N

N 166 Cl

RN NHCSNHR

Cl

NH

S S

NHCSNHR

CSNHR

Cl

N H 167

Scheme 65

N

+

164

+

N

Cl O

168

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 S

Cl

HN

C

NH2

HN

C

NHR

R

N

+

S

+

N

Cl O

O

169

N

S

170 S

H N

N

RHN

N N

Scheme 66

N

S NHR

N N

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-2ylidene)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 HN

C

NH2

HN

C

NHR

N

H N

CN

NH

C

NHR

S

+ CN 172 O

S

N

NH

N

C

CN

NC

S

O

173

NHR

S

N

N

S

NH

C

NHR

+ CN

CN

174 O

Scheme 67

175

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 N

HN Ar

C H

N

N

S

N Ar

C H

N

N H

Ar

177,178 a b c d

N S 177

Ar

C6H5 p -C6H4-CH3 p -C6H4-OCH3 p -C6H4-Cl

Ar CN

NC Ar

HC

H N

N N

NC N

176

CN

+

R

NH

C

NH

NH2

S

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 179–182 (see Scheme 69).86 NC

CN H2N

H2N NC CN CN

N

RN S 181

CN

+

RNHCSNHNH 2

N

CN

O

176

CN

CN H N

RN

N

CN S

H 2N

Scheme 69

180

CN

N

RN

N

CN

N

RHN

CN

S 179

CN N

CN 182

S

CN

Scheme 69 5.5. Reaction of acyl thiosemicarbohydrazides with π-acceptors Mixing of two-fold molar amounts of acceptor 164 and/or 2,3-dicyano-5,6-dichloro-1,4benzoquinone (DDQ, 183) with one mole of acyl thiosemicarbohydrazides in ethyl acetate, with admission of air, gave a blue color (λmax = 573-591 nm).

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O

O

RCONHNHCSNH2

Y

X

Z

Y

X

Z

+

R

169; Z = Cl 184; Z = CN

O 164 and 183

164; X = Y = Cl 183; X = CN, Y = Cl

R

O

O

N

R

N

NH2 N

O 169 and 184

N

N O

CN

O

Cl

Cl

S

Cl

N

185

O

O

N

N

Cl

Cl

OH Cl Cl

S O

ROCHN

188

H N

N

O R

187

Cl

S

O

N

NNHCOR

N

O H N

186

O N

S

NHCOR

N N NH2

S

189

190

O

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

O

NH

192

N

N

CN

PhOC N

CN CN

CN

193

CN

CN

H2N Scheme 71

NH

CN

S PhOC

N

PhOC

N

N

NHR NC

S CN

194

N CN 195

H2N 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-5carboxylates 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 π-deficient double-bond produces the corresponding triazolo-dihydrothiazines 199. CO2Et CO2Et 196

COR NH HN

N H

SH

COR NH 2 HN

N H

S

O -H2O

S

N

CO2Et .. NH S

CO2Et

S 201a-e

N

O

S 199a-e time (h)

C6H54-HO-C6H44-CH3O-C6H44-Br-C6H4-CH2CH 3-

CO 2Et

R O2

N

N

R

a b c d e

CO 2Et

R

198a-e 200

N N

N

197a-e

O

R N

R

NH N .. N H

- EtOH

2

CO2Et

OH

R

N

N N

O

S 200a-e

O

Yield of 200 (%) 70 75 80 62 56

30 26 24 36 48

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 π-acceptors Acceptor 172 reacted with formohydrazonohydrazide and N-benzylideneformohydrazonohydrazide to respectively form aminoindenopyrazolo-pyridazinone 202 and phenyll,2,3,4-tetraazacyclopenta-fluorene 203 (Scheme 73).84 O

H2N N NH N N

172 + R

202 N

N

CH

NH

NH2

NH N

a, R = NH2 b, R = C6H5-CH=N

N Scheme 73

203

Ph

Scheme 73

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Addition of methylene chloride solutions of 2-phenylidene-N-substituted-hydrazinecarbothioamides 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 O

R NH N

H N

S S

PhHN

CHR

169 O

N

R

O 206

Cl

NH H2N 205 O

Cl

N

+

NHPh

NHPh N N

+

N

S

204

O

N

S

N N

183

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 NC

S NH

N PhN

NH N CHAr PhN

CHAr

176

NC

Ar

+ CN

+ S

S

CN NH2

CN

N N

N

208

CN

+

HN

Scheme 75

209

N S HN 210 NPh

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 14–18 h, major (212, 213 in 54– 61%) and minor (214, 215 in 22–26%) products in each case (Scheme 76).92 NC

S +

NH NH CO2Et

CO2Et

N

EtO2C

CHAr

NC

CN R

CO2Et

O

211

O

EtO2C

NC Ar N

PhHN S

+

N

N

CSNHPh

N N

PhHNSC

N

Ar

212

O

+ Ar

214

213

R

EtO2C

O

N N 215

Ar

CSNHPh

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 NC

Ar NC

CN

S

N +

NC

176

CN

Scheme 77

Ph

anhy. EtOAc

N H

NHPh

216

Ar

N

S

r.t. 2-6 h

Ph Ph

a b c d

CN

Ar

4-OCH3-C6H44-CH3-C6H44-Cl-C6H44-NO2-C6H4-

Yield (%)

N

N

216a-d

85 80 75 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 πacceptor quinones (CHL-p, DDQ and DCHNQ).94

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HN

S +

HN Ar

Ph

O

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O Cl

O X

O

X

217

Ar

N N

Cl

X

S

X

O

O

217a-i

Scheme 78. Synthesis of f used 1,3-thiazoles

Ph

a b c d e f g h i

Yield (%)

X

70 65 60 68 65 63 78 74 70

Cl Cl Cl CN CN CN -CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-CH=CH-

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 6–10 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 S C NH

HN N

HC (NH 2NH)2CS + C2H 2O2 + 2

MX2

MeOH 6-8h

X

N

CH

M

HC

CH

N X N HN

NH C

Where M= Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) X=Cl-, NO 3-, CH3COO -

218

S

[M(TML)X 2]

[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

S

O

S

Cu N

O

N

[Cu(OH)2] + 2 NH 2NHCNHNH2 + H3C 2

CH3

+ 3H2O

CH3

219

NHNH

S OH S

O

2

Cu N

O

[Cu(OH)2] + 2NH2NHCNHNH2 + H 3C 2

NH

N

H 3C H 2NHN

S

NHNH2

S

CH3

N

H3C

Scheme 80

NH

OH N

220

+

2H 2O

CH3

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 NH 2 O Ph

C

Ph

C

2

HN

NH2 O

C H2N

H 2N

Scheme 81

Ph Ph

MeOH

Ph

C

MX 2

Ph

C

O

S

C

Ph

C

Ph

M N

NH

HN

N

N C

+ O

NH X

X

N NH

HN 221

2

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 O

n

O

NH

O

X

+ CH O

NH

HC

222 a,b 172n = 1(a), 2(b) O

NH2 2a,b

O O

n

O

CH

HC

N

N N H

N H

Scheme 82

X = S (a), O (b)

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

Scheme 82

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

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

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29. 30. 31. 32. 33. 34.

35. 36. 37. 38.

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45.

46. 47. 48. 49. 50. 51. 52.

53. 54. 55. 56. 57. 58. 59.

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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-ElMinia, 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 State’s 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: [email protected].

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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: [email protected].

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: [email protected].

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 αphosphorylvinyl 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: [email protected].

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: [email protected].

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