Review Article Synthetic Methods, Chemistry, and the Anticonvulsant Activity...

Hindawi Publishing CorporationInternational Journal of Medicinal ChemistryVolume 2013 Article ID 348948 16 pageshttpdxdoiorg1011552013348948

Review ArticleSynthetic Methods Chemistry and the AnticonvulsantActivity of Thiadiazoles

Bhawna Sharma1 Amita Verma2 Sunil Prajapati1 and Upendra Kumar Sharma1

1 Institute of Pharmacy Bundelkhand University Jhansi 284128 India2Department of Pharmaceutical Sciences Faculty of Health Sciences Sam Higginbottom Institute of AgricultureTechnology and Sciences-Deemed University Allahabad 211007 India

Correspondence should be addressed to Bhawna Sharma bms1928yahoocom

Received 5 December 2012 Revised 8 February 2013 Accepted 12 February 2013

Academic Editor Hussein El-Subbagh

Copyright copy 2013 Bhawna Sharma et alThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The chemistry of heterocyclic compounds has been an interesting field of study for a long time Heterocyclic nucleus 134-thiadiazole constitutes an important class of compounds for new drug development The synthesis of novel thiadiazole derivativesand investigation of their chemical and biological behavior have gained more importance in recent decades The search forantiepileptic compounds with more selective activity and lower toxicity continues to be an active area of intensive investigationin medicinal chemistry During the recent years there has been intense investigation of different classes of thiadiazole compoundsmany of which possess extensive pharmacological activities namely antimicrobial activity anticonvulsant antifungal antidiabeticanti-inflammatory antioxidant and antituberculosis activities and so forth The resistance towards available drugs is rapidlybecoming a major worldwide problemThe need to design new compounds to deal with this resistance has become one of the mostimportant areas of research today Thiadiazole is a versatile moiety that exhibits a wide variety of biological activities Thiadiazolemoiety acts as ldquohydrogen binding domainrdquo and ldquotwo-electron donor systemrdquo It also acts as a constrained pharmacophore On thebasis of the reported literature we study here thiadiazole compounds and their synthetic methods chemistry and anticonvulsantactivity

1 Introduction

Epilepsy is the name of a brain disorder characterizedpredominantly by recurrent and unpredictable interruptionsof normal brain function called epileptic seizures [1 2]The current therapy of epilepsy with antiepileptic drugs isassociated with side effects dose-related and chronic toxicityand teratogenic effects [3 4] Epilepsy is not a singular diseaseentity but a variety of disorders reflecting underlying braindysfunction that may result from many different causesTherefore there is continuing demand for new anticon-vulsant agents So there is an urgent requirement for thedieovery and development of some novel anticonvulsantagents with more selective activity and lower toxicity forthe effective treatment of epilepsy Several five-memberedaromatic systems having three heteroatoms at symmetricalpositions such as thiadiazoles have been studied extensivelyowing to their interesting pharmacological activities There

is a broad variety of heterocyclic compounds which arehaving medicinal importance and recently much attentionhas been focused on thiadiazole derivatives in view oftheir broad spectrum activities Thiadiazole is one suchheterocyclic nucleusThere are several isomers of thiadiazolethat is 123-thiadiazole 124-thiadiazole 125-thiadiazoleand 134-thiadiazole [5] 134-Thiadiazole is the main iso-mer of thiadiazole series having versatile pharmacologicalactivities

2 Thiadiazole

Thiadiazole is a heterocyclic organic compound that has afive-member ring having one sulphur and twonitrogen atoms[6] 134-Thiadiazoles represent one of the most biologi-cally active classes of compounds possessing a wide spec-trum of activities Thiadiazoles have become very important

2 International Journal of Medicinal Chemistry

Table 1 Physical properties of 134-thiadiazole

Bond length Bond angleType A Type (∘)a 1371 120572 1122b 1302 120573 1146c 1721 120574 864d 1721 120575 1146e 1302 120576 1122

compounds in medicine agriculture and many fields oftechnology A large number of 134-thiadiazoles have beenpatented in the agricultural field as herbicides and bacteri-cides [7]

X-ray analysis shows the following structure parameterfor 134-thiadiazole ring (see Table 1 and Structure (1))

N

S

N

1HH

34

5

ab

cd

e

2

(1)

3 Chemistry of Thiadiazole

A recent literature survey revealed that the 134-thiadiazolemoiety has been widely used by the medicinal chemist inthe past to explore its biological activities The developmentof 134-thiadiazole chemistry is linked to the discoveryof phenylhydrazines and hydrazine in the late nineteenthcenturyThefirst 134-thiadiazole was described by Fischer in1882 but the true nature of the ring systemwas demonstratedfirst in 1890 by Freund and Kuh

Thiadiazole is a five-member heterocyclic compoundhaving one sulphur and two nitrogen atomsThere are severalisomers of thiadiazole that is 123-thiadiazole (2) 125-thiadiazole (4) 124-thiadiazole (3) and 134-thiadiazole (5)There are four possible systems in thiadiazole

(2)123-thiadiazole

N

SN

(3)

N

SN

124-thiadiazole

(4)

N

S

N

125-thiadiazole

(5)

NN

S

134-thiadiazole

4 134-Thiadiazoles

134-Thiadiazole was first described in 1882 by Fischer andfurther developed by Bush and his coworkers but truenature of the ring system was demonstrated first in 1956by Goerdler et al [8] The advent of sulphur drugs and thelater discovery of mesoionic compound greatly acceleratedthe rate of progress in the field of thiadiazole Thiadiazolecarrying mercapto hydroxyl and amino substituents canexist in many tautomeric forms The 134-thiadiazoles areconveniently divided into three subclasses

(a) aromatic systems which include the neutral thiadia-zoles and constitute a major part of this paper

(b) mesoionic systems which are defined as five-membered heterocycles which are not covalent orpolar and possess a sextet of electrons in associationwith the five atoms comprising the ring

(c) nonaromatic systems such as the 134-thiadiazolesand the tetrahydro 134-thiadiazoles In the partiallyreduced systems the position of the double bondis denoted by the prefix Δ with being a Δ2-134-thiadiazole (Structures (6) (7) and (8))

(6)

N

S

NH

(7)

N

S

N

(8)

HN

S

NH

5 Synthetic Procedures of 134-Thiadiazoles

(a) Formation of One Bond The most common proce-dure for the synthesis of 5-substituted 2-amino-thiadiazole

International Journal of Medicinal Chemistry 3

(9) (10)

HN NH

C C

SO

R NH

NN

NHR2 NHR2R1

Scheme 1

S

NNMe2NCHO + Me2N=CHCl

ClCHCNHNHCHO

Me2NCH=CHNMe2SH2

(14)(13)(12)(11)

Scheme 2

is the acylation of a thiosemicarbazide followed by dehydra-tion Sulphuric acid polyphosphoric acid and phosphoroushalides are some of the reagents used The most recentprocedure utilizes 15 moles of methane sulphonic as adehydrating agent and the thiadiazoleare obtained in thehigh yield and good purity 5-Alkyl-2-methyl amino-134-thiadiazoles are prepared from a suitable carboxylic acid andmethyl thio-semicarbazide in the presence of three parts ofpolyphosphoric acid and one part of concentreted sulphuricacid 2-alkylamino-134-thiadiazole 119899 substituted in the 5thposition can be prepared in high yields by the reaction of4-alkylthiosemicarbazides with orthoformate esters in thepresence of small amount of concentreted hydrochloric acid[9] (Scheme 1)

(b) Formation of Two Bonds This is the most widely usedprocedure for the synthesis of thiadiazoles thiazolidines andmesoionic thiadiazoles

(1) Cyclization The parent molecule 134-thiadiazole wassynthesized in 1956 by a four-step reaction sequence startutilizing hydrazine and from thiosemicarbazide A secondprocedure utilizes hydrazine and potassium dithioformateDehydration of DMF with thionyl chloride or phosgenegives the formamide chloride which on treatment withNN1015840Diformylhydrazine gives the dihydrochloride of the freebase which is liberated with sodium ethoxide which thencyclizes to thiadiazole in the presence of hydrogen sulphidein an overall yield of 65 2-Amino 134-thiadiazole is alsoprepared from thiosemicarbazide and a mixture of formicand hydrochloric acid in a tedious procedure with an overallyield of 65 (Scheme 2)

(2) Dipolar Cycloadditions This procedure has been widelyused during the last decade for both synthetic and mechanis-tic reasons

From Diazo Compounds The reaction of aryl sulphonyl-substituted sulfines with diazomethane gives Δ3-134-thia-diazole 1-oxide which however is unstable and rearranged

via an isomerization of the Δ3 to the Δ2-thiadiazole oxideThis is followed by an elimination and readdition of sulfonicacid and loss of water in a pummerer-type aromatization togive the rearranged thiadiazole (Scheme 3)

51 Method of Synthesis of 134-Thiadiazole

(a) From Hydrazine 3-Thiocarbamoyl thione methyl car-bonate on oxidation with H

2O2gave alkoxythiadiazole [10]

(Scheme 4)(I) Thiobenzoyl hydrazine cyclized to produce 134-

thiadiazole-thiobenzoyl hydrazine [11] (Scheme 5)(II) Thione carbazate are cyclized by cyanogens chloride

or bromide to give 13-thiadiazole [12] (Scheme 6)

(b) From Semicarbazide When 4-phenyl-1-(thiobenzole)semicarbazide reacts in the presence of concentretedHCl giv-ing 2-hydroxyl-5-phenyl-134-thiadiazole [13] (Scheme 7)

(c) From Thiosemicarbazide Many syntheses of the 134-thiadiazole proceed from thiosemicarbazide or substitutedthiosemicarbazide

Method 1 Gupta et al have shown that thiosemicarbazidecyclizes directly to 2-amino-5-diazole with acetyl chlorideThis simple route to 2-amino 5-substituted-134-thiadiazoleseems to be quite general In the example shown R maybe methyl17 nor hydnocarpyl benzyl cyclopropyl [14] andmany others (Scheme 8)

(d) From Thiosemicarbazone 2-Amino-5-substituted thiadi-azoles are prepared by oxidative cyclization of thiosemi-carbazones with ferric chloride found 134-thiadiazole [15](Scheme 9)

(e) From Resin Resin with TMSCl MCPBA and R2 R3 NHgave 134-S thiadiazole [16] (Scheme 10)

(f) From Bithioureas Bithiourea and substituted bithioureasehave been converted to 134-thiadiazole by several methods


(18) (19)(17)(16)

NNHH

R1 NN

HR1

NN

HR1

O O

H H

S

NN

R1R2O2S R2O2S R2O2S

RSO2H minusH2OSO2R2

Scheme 3

SH

NN

CH2OHCSNHCSNH2H2O2

NH3H3CO

(21)(20)

Scheme 4

Method 1 Bithiourea when treated with 3 hydrogen perox-ide is cyclized to 25-diamino-134-thiadiazole (Scheme 11)

Method 2 Acetic anhydride acts on bithiourea to forma diacetyl derivative of 25-diamino-134-thiadiazole Theacetyl group I is easily removed by hydrolysis to give theparent thiazole [17]

52 Chemical Properties

521 Reactivity Some of the characteristic reactions of the134-thiadiazole nucleus are ring opening by strong baseease of nucleophilic attack and the formation of mesoioniccompounds by quaternization The substituents in the 2 and5 positions have a large effect in determining the reactivity ofthe molecule as a whole Thus the ambient nucleophilicity of2-aminothiazoles gives rise to electrophilic attack on both theamino group and the nuclear nitrogen atom Ring formationbetween these two nitrogen atoms is also a common reaction2-Mercaptothiazoles react similarly to arenethiols while amethyl group on the thiadiazole ring has reactivity similar tothat in a picoline Nucleophiles easily displace halogen atomfrom the thiadiazole nucleus This is due to the electronega-tivity of the two nuclear nitrogen atoms which impart a lowelectron density to the carbon atom of the nucleus

522 Thermal and Photochemical Reactions Thermal andphotochemical fragmentations of 134-thiadiazole often fol-low the fragmentation pattern observed in the mass spec-trometerThe cis-25-di-t-butyl-25-dihydro-134-thiadiazolegives while photolysis yields the katazine The cis 25-dihydro-134-thiadiazole 11-dioxide (cis-4) undergoes ther-molysis at 50∘C to give the azine The trans isomer (trans-4) however undergoes thermolysis only above 145∘C togive the alkylidine hydrazide plus sulphur monoxide whichdisproportionate into sulphur dioxide Compounds were

independently prepared from dimethylpropanyl and thehydrazole thermolysis of the isomeric 23-dihydro-134-thiazole 11-thiadiazole 11 dioxide also gives rise The con-certed [4 + 1] cycloelimination of sulphur dioxidefrom thetrans isomer cannot take place due to steric hindrance(Scheme 12)

(1) Reaction with Electrophile Because unsaturation ringshave excessive 120587eminus the two nitrogen atoms eminus are pulledtowards them and ring carbon atoms remain with loweminus density and consequently no electrophilic substitutionpossible in unsubstituted 134-thiadiazole ring

(a) Attack at Ring Nitrogen (Quaternization) Ratio of 3 or 4substituted product depends on ring substitution in whichnitrogen has high eminus density (Scheme 13)

(b) Electrophilic Attack at Carbon Due to the electron densityat the carbon atoms in 134-thiadiazole such reaction asnitration acetylation sulphonation halogenations How-ever 2-amino-substituted 134-thiadiazoles (1andashi) heat withbromine in acetic acid to give 5-bromo derivatives (2andashi)Similarly the thiadiazoles (3b) yield (3dndashf) the corresponding5-bromo derivatives (4b) and (4dndashf) (Scheme 14)

(c) Electrophilic Attack at Sulphur Although direct oxidationat sulphur atom in 134-thiadiazoles has not been reportedΔ3 134-thiadiazole 1-oxides and 11 dioxides can be indirect

mean (Scheme 15)

(d) Electrophilic Substitution at Ring Strong eminus donar substi-tuted at ring position 2 activates towards electrophilic agentsunder drastic condition (conc H

2SO4+ fuming HNO

3)

Nitration of 2 ammonia 134-thiadiazoles with fumingnitric acid at 40∘C gave 2-amino-134-thiadiazoles (21A)(Scheme 16)

53 Amination Direct nuclear amination of certain thiadia-zoles is possible illustrating the case of nucleophilic attack(R=H) react with hydroxylamine in the presence of base togive (R=NH

2) presumably via the imine (Scheme 17)

(III) Nucleophilic Attack 134-Thiadiazole ring reacts withstrong nucleophiles treatment of the parent compound withbase leading to ring fission 2-Amino and 2-methylamino 13 4-thiadiazole rearrange in the presence of methylamine tothe triazolinethione (Scheme 18)


CS

NN

Ph

S S

PhCNHNH2 ArOCN+ PhCNHN (NH2 NH2)OAr=

(23)(24)

(22)

Scheme 5

RO

S

S

NN

NH2

(26)(25)

ROCNHNH2 + CICN

Scheme 6

S

NNS

C6H5C6H5

CNHNHCONHC6H5Conc HCl

OH

(27) (28)

Scheme 7

S

N N

SRNH-NH2 NH2

(29) (31)(30)

RCOCl + NH2

Scheme 8

S

NN

NH2(R)CH=NNHCS NH3

Fe+++R1

R = Ar ArCO CH3CO EtCO

(33)(32)

Scheme 9

S NH

S

NH

O

N N

N

(35)(34)

(1) TMSCl

(2) MCPBA(3) R2R3

R1

NH

R1R3

R2

HS

Scheme 10

SS

N N

S

(36) (37)

NH NH NH2

NH2

NH2

H2NH2O2

Scheme 11

(2) Nucleophilic Substitution Due to the electronegativ-ity of the two nitrogen atoms in the ring the carbonatom has low electron density and gives many possiblenucleophilic reactions [18] Halogenate 134-thiadiazoles areimportant intermediates in which the halogen atom is readilyby nucleophiles 5-Chloro-thiadiazole reacts readily withnucleophiles to give a series of 5 substituted-2-aryl-134-thiadiazoles (Scheme 19)

Amino thiadiazoles are rather weak bases they arenucleophilic enough to be readily acetylated by acid chloridesor acetic acids (Scheme 20)

Aminothiadiazole forms diazonium salts and shows thecoupling activity [19] (Scheme 21)

2-Amino-134-thiadiazoles and aromatic aldehydes formshiff bases [20] (Scheme 22)

54 Miscellaneous Reaction Direct introduction of mercaptogroup on 2-phenyl-1 3 4-thiadiazoles is possible by the useof phosphorous pentasulphide [21] (Scheme 23)

541 Reduction of Thiadiazole Ring 2-Amino-134-thia-diazoles reduces to benzaldehyde thio semicarbazone [22](Scheme 24)

542 Reaction Involving Formation On heating 2-aminothiadiazole reacts with many dicarbonyl group containingcompounds and forms various types of rings attached tothiadiazole (Scheme 25)

543 Rearrangement Reaction Various 2-chloro and 2-amino substituted thiadiazoles undergo rearrangement byring opening intermediate formation and again ring closureto form 4N substituted 134-thiadiazole 5(1)-terione [23 24](Scheme 26)

(a) Dimorph Rearrangement See Scheme 27

(b) Under Same Condition See Scheme 28

(c) Acid Catalysed See Scheme 29

(d) Cycloaddition Reaction Aminobenzothiadiazoles are pro-duced when 134-thiadiazoleinethiones (R1=H Me AcR2=Me Ph) are reacted with benzyne most likely by a13-dipolar addition mechanism followed by elimination ofRSCN (Scheme 30)

544 Reaction of Constituents on Carbon Treatment of2-methyl 15 diphenyl-1-134-thiadiazole (R=H) with 119899-butyllithium at minus78∘C gives the lithio derivative (R=Li)


N NX

NN X

S

NN NN

NNN

NH

O

(38) (39) (40)

(41)

(43) (44)

(42)

X = S SO SO2h120584 Δ

Bu1

Bu1 Bu1 Bu1

Bu1Bu1

Bu150∘C

O2

SO2

Cis 4

Trans-4

Bu1gt145∘C + (SO) 1

2S + 12

SO2

Scheme 12

N

S

N N

S

N N

S

N

R1R1 R1R2R2R2

CH3

CH3

I

H3C

+

++

(47)(46)(45)

Scheme 13

which on treatment with methyl iodide gives the expected2-ethyl homologue (R=Me) if (R=Li) is allowed to warmfrom minus78∘C to 25∘C the dimer is formed which on heatingabove 150∘C converts into starting material The dimeriza-tion proceeds via intermediates and not the ketone amine(Scheme 31)

545 Sulphur Substituents The mesoionic 45-diphenyl-1-134-thiadiazole-2-thiolate reacts with methyl azodicarboxy-late to yield the azothiadiazole and not the tetrazine betaine aspreviously claimed from 2-amino-5-phenyl-134-thiadiazoleand nitrosobenzene (Scheme 32)

546 Amino Substituents The reaction of unsubstituted 2-amino-13 and 4-thiadiazole with 13-dicarbonyl compoundsis independent of the nature of the dicarbonyl compoundsThe reaction of pentane-2-4-dione gives the 46-dimethyl 12-thiocyanatepyrimidine The formation may proceed via thecation With ethylacetoacetate however if a mixture formedalso being converted in to on heating

Biological Activities of 134-Thiadiazole Derivatives Duringthe recent years there has been intense investigation ofdifferent classes of thiadiazole compounds many of whichpossess extensive pharmacological activities Among of thesecompounds having 134-thiadiazole nucleus are known toexhibit unique antimicrobial activity [25ndash38] Antifungal[39ndash41] antidiabetic [42] anti-inflammatory [38 43ndash54]antileishmanial activity [55ndash58] antituberculosis activity

[59ndash61] anticancer activity [34 62ndash68] anti-HIV activity [6970] antioxidantradioprotective Activity [71ndash73] Carbonicanhydrase inhibitors [74 75] Anti-Helicobacter pylori activity[76 77] This paper focuses on the therapeutic importanceof novel thiadiazole derivatives as anticonvulsant agents forfuture

Anticonvulsant Activity of Thiadiazole Derivatives A seriesof 3-aryl aminoamino-4-aryl-5-imino-D2-124-thiadiazolehas been synthesized and screened for anticonvulsant activityAll the synthesized compounds were evaluated against maxi-mal electroshock-induced seizure (MES) and subcutaneous-pentylenetetrazole- (ScPTZ-) induced seizure models inmice Among the compounds tested all showed protectionfrom MES seizures whereas only (104) (105) was found tobe active in the ScPTZ test The present results revealed thata number of 3-aryl aminoamino-4-aryl-5-imino-D2-124-thiadiazoles exhibit a range of activities in anticonvulsantscreen [78]

(104)

N S

NArndashHN

Ar

NH

(105)N S

NNHH2N

Ar

Ar=C2H5O

N

NAr=


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1

(a) R2 = H(b) R2 =Me(c) R2 = NO(d) R2 = COMe(e) R2 = COPh(f) R2 = Br

(a) R2 = R3 = H(b) R2 = H R3 =Me(c) R2 = R3 = NO(d) R2 =H R3 = COMe(e) R2 = H R3 = COPh(f) R2 = R3 =Me(g) R2 =Me R3 = NO(h) R2 =Me R3 = COMe(i) R2 =Me R3 = COPh

(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16

A series of new substituted 124-thiadiazoles were syn-thesized by appropriate route and screened for anticon-vulsant neurotoxic and sedative-hypnotic activities Thestructures of the synthesized compounds were confirmedby IR spectroscopy C-13 NMR and elemental (nitro-gen and sulphur) analysis After ip injection of thecompounds to mice or rate at doses of 30 100 and300mgkg body weights were examined in the maxi-mal electroshock-induced seizure (MES) and subcutaneous-pentylenetetrazole- (scPTZ-) induced seizure models after05 and 4 h All the compounds showed protection againstMES screen after 05 h Compounds were active at the dosesof 100mgkg and 300mgkg dose ip It may be concludedthat the synthesized compounds were potent against MES-induced seizures than ScPTZ-induced seizures [79] (Struc-ture (106))

N

NHN

N S

N HN

N

N

(106)

A series of five-membered heterocyclics were synthesizedby the reaction between isoniazid and various substitutedisothiocyanates and tested for their anticonvulsant activityby determining their ability to provide protection againstconvulsions induced by electroconvulsiometer Among thesynthesized compounds (107f) 2-(4-chlorophenyl) amino-5-(4-pyridyl)-134-thiadiazole and (108f) 2-(4-chlorophe-nyl)amino-5-(4-pyridyl)-134-oxadiazole were found prom-ising compounds of the series [80]

N

S

NN

NH

(107andashf)

Compound R

107a 108a107b 108b OndashCH3107c 108c pndashCH3107d 108d O-OCH3107e 108e PndashOCH3107f 108f PndashCl

ndashH

NO

NN

NH

R

(108andashf)

A series of aromatic aldehyde imine derivative of 2-thiobezyl-134-thiadiazole were synthesized These deriva-tives 109(andashe) 110(iandashie) 110(iiandashiie) show good anticon-vulsant activity Among these compounds chlorobenzyl sub-stituted compound shows the potent anticonvulsant activityagainst MES method [81]


N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)

Compounds R109a 110ia 110iia

109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)

A variety of new 3-[5-substituted phenyl-134-thiadiazol-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized andevaluated for anticonvulsant activity b Compounds wereexamined in the maximal-electroshock- (MES-) inducedseizures and subcutaneous-pentylenetetrazole- (scPTZ-)induced seizure models Compounds (111a) (111b) and(111c) showed good anticonvulsant activity in the test models[82]

N

N

O

S

N N

R

Ar

111a = R = C6H5 Ar = 4-ClC6H4111b = R = 3-ClC6H4 Ar = 4-ClC6H4111c = R = 4-ClC6H4 Ar = pyridyl

Two new series of 25-disubstituted-134-thiadiazoleswere synthesized for their possible anticonvulsant antibac-terial and antifungal activities The degree of protectionafforded by these compounds at a dose of 100mgkgip against pentylenetetrazole-induced convulsions in miceranged from 0 to 90 Among these compounds 112a(90) and 112g (70) showed maximum protection [83]

S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)

Cl3COCl(CH3CO)2O NHCOCH3NH2

Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN

3-[(2-Methyl-1H-3-indolyl)methyl]-4-aryl-4 5-dihydro-1H-124-triazole-5-thiones and their respective N-5-[(2-methyl-1H-3-indolyl)methyl]-134-thiadiazol-2-yl-N-aryl-amines have been prepared Behavioral effects inducedby the members of both series in conjunction with theiractivity in some specific tests (forced swim pentetrazolconvulsions) on mice show that these derivatives cross theblood-brain barrier and could develop an antidepressantactivity comparable to that of imipramine Blood-brainbarrier penetration is also supported by the lipophilicity dataobtained for all analogs [84] (Structure (113))

N

NS

HN

(113)

NH

Several novel 2-amino-5-[4-chloro-2-(2-chlorophe-noxy)phenyl]-134-thiadiazole derivatives 4andashdwere synthe-sized and their anticonvulsant activity was determined byevaluation of the ability of these compounds to protectmice against convulsion induced by lethal doses of pen-tylenetetrazole (PTZ) and maximal electroshock (MES)The result of anticonvulsant data shows that among thesynthesized compounds 5-[4-chloro-2-(2-chlorophen-oxy)phenyl]-N-ethyl-134-thiadiazol-2-amine (114 115 116)was the most active compound in both MES and PTZ testswith an ED50 of 2011 and 3533mgkg respectively [85]

S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2

NaNO2HCl (0ndash5∘C) N

+

2

NHndashNH NH2ndashNH

Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)

The present study describes the synthesis and anti-convulsant activity evaluation of 6-substituted-[1 2 4]tri-azolo[3 4-b][1 3 4]thiadiazole derivatives and their par-tially dehydrogenated products 56-dihydro-6-substituted-[1 2 4]triazolo[3 4-b][1 3 4]thiadiazole derivatives Thebioevaluation demonstrated that most compounds in theseries exhibited potent anticonvulsant activity in themaximalelectroshock test Among which 6-(4-chlorophenyl)-[1 24]triazolo[34-b][1 3 4]thiadiazole (117) emerged as themost promising candidate on the basis of its favorableED50 value of 237mgkg and PI value of 108 In additionthe potency of compound 117 against seizures induced bypentylenetetrazole 3-mercaptopropionic acid and bicu-culline in the chemical-induced seizure tests suggested thatcompound 117 displayed broad-spectrum activity in severalmodels and it may exert its anticonvulsant activity throughaffecting the GABAergic system [86]

S

ClN N

N

N

(117)

Synthesis and pharmacological evaluation of a numberof substituted 134-thiadiazole the first member of the series2-(aminomethyl)-5-(2-biphenyl)-134-thiadiazole (118) wasfound to possess potent anticonvulsant property in rats andmice and compared favourable with the standard anticon-vulsant drug phenytoin Phenobarbital and carbamazepine ina number of test situations The potency of compound wasmaintained on alkylation of the side chain nitrogen atomhowever aryl substitution on chain lengthening caused adrop in potency replacement of the two biphenyl group byphenyl or benzyl also lead to inactive compound [87]

S

NN

(118)

NH2

Various N-(5-chloro-6-substituted-benzothiazol-2-yl)-N1015840-(substituted phenyl)-[1 3 4]thiadiazole-25-diamineswere designed and synthesized starting from substitutedacetophenones Structures of all the compounds wereconfirmed on the basis of spectral and elemental analysesAll the newly synthesized compounds were screened for theiranticonvulsant activity and were compared with the standarddrug phenytoin sodium Interestingly all the compoundsshowed protections against seizures in the range 50ndash100indicative of the promising nature of the compounds againstseizure spread Compound 119 showed complete protectionagainst MES-induced seizures [88]


N

S

N N

S

NH

Ph

Na(Hg)X H

ArC6H5CH=NndashNHCSNH2NH2 NH2

(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2

A series of 124-thiadiazoles (120andashe) were preparedand evaluated for anticonvulsant activity by Siddiqui et alThe compound with para-chloro substitution (120c) showedmaximal activity inMES test and blocked strychnine seizuresto some extent whereas other compounds of the series wereless active [89]

HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3

A series of 1-(substituted phenyl)-3-[(5-substitutedphenyl)-134-thiadiazol-2-yl]-2-thioxodihydropyrimidine-46 (1H5H)-diones 121(andashw) were designed synthesizedin good yields The compounds were evaluated foranticonvulsant activity The compounds were potent inMES test and were less neurotoxic as compared to standarddrug phenytoin [90]

RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)

A series of thiadiazole derivatives were synthesized withdifferently substituted benzoic acids which were cyclizedto give differently substituted thiazolidin-4-one Elementalanalysis IR HNMRC NMR and mass spectral data con-firmed the structure of the synthesized compounds Thederivatives of these moieties were evaluated for anticonvul-sant activity by MES model and neurotoxicity by rotarodmethodThe synthesized compounds showed good potentialfor anticonvulsant activity besides this and the compoundsalso showed neurotoxic effect It was observed that com-pounds withOCH3 at 3 4 position of phenyl ring showed lessprotection against convulsions as compared to compoundshaving unsubstituted phenyl ring [91]

The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-134-thiadiazoles are described The com-bination of preferred aromatic substituents in the 2-positioncoupled with alkyl substitution on the hydrazine moietyled to a number of potent compounds lacking sedationataxia or lethality 5-(2-Biphenylyl)-2-(1-methylhydrazino)-134-thiadiazole (4m) represents a new class of anticonvul-sant agent and compares favorably with the standard drugsphenytoin phenobarbital and carbamazepine [92] (Structure(122))


N

S

N N

S

N

Cl

N

N

NH

SH

Rearranged product(82) (83) (84)

+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH

Large excessof hydrazine

R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2

A novel series of NN1015840-5-[(1H-indol-3-ylmethyl)-134-thiadiazol]-2-yl-N4-(4-substituted benzaldehyde) semicar-bazones N1-5-[(1H-indol-3-ylmethyl)-134-thiadiazol-2-yl-N4-[1-(4-substituted phenyl)ethanone]-semicarbazonesand N1-5-[(1H-indol-3-ylmethyl)-134-thiadiazol-2-yl-N4-[1-(4-substituted phenyl) (phenyl) methanone]-sem-icarbazones were synthesized and evaluated for their anti-convulsant potential using maximal electroshock seizure(MES) and subcutaneous pentylenetrtrazole (scPFZ)models The minimal motor impairment (neurotoxicity) wasdetermined by rotarod test The results of the present studyconfirmed the requirements of various structural features offour binding site pharmacophore model for anticonvulsantactivity [93]

Treatment of 2-bromoacetylbenzofuran with 1H-benzo-triazole afforded 1-(benzofuran-2-yl)-2-(benzotriazol-1-yl)ethanone which reacted with phenylisothiocyanate to givethe corresponding thioacetanilide derivatives Treatment ofthe latter ethanone and thioacetanilide derivatives withhydrazonoyl chlorides afforded the corresponding pyrazoleand 134-thiadiazolederivatives The thioacetanilide deriva-tive reacted with 120572-haloketones and 120572-halodiketones toafford thiophene and thiazole derivatives respectively Thenewly synthesized compounds were found to possess anti-convulsant and anti-inflammatory activities with the samemechanism of action of selective COX-2 inhibitors [94]

References

[1] W Loscher ldquoNew visions in the pharmacology of anticonvul-sionrdquo European Journal of Pharmaceutical Sciences vol 342 pp1ndash13 1998

[2] A Gringauz John Wiley amp Sons New York NY USA 1stedition 1997

[3] M J Brodie ldquoMonotherapy trials prerequisite datardquo EpilepsyResearch vol 45 no 1ndash3 pp 61ndash64 2001

[4] R H Mattson ldquoEfficacy and adverse effects of established andnew antiepileptic drugsrdquo Epilepsia vol 36 supplement 2 ppS13ndashS26 1995

[5] A Demirbas D Sahin N Demirbas and S A Karaoglu ldquoSyn-thesis of some new 134-thiadiazol-2-ylmethyl-124-triazolederivatives and investigation of their antimicrobial activitiesrdquoEuropean Journal of Medicinal Chemistry vol 44 no 7 pp2896ndash2903 2009

[6] R T Morrison and R N Boyd Organic Chemistry PrenticeHall New Delhi India 6th edition 2005

[7] T-BWei H Liu J-H Hu et al ldquoMicrowave promoted efficientsynthesis of 25-disubstituted 134-thiadiazolerdquo Indian Journalof Chemistry B vol 45 pp 2754ndash2756 2006

[8] J Goerdler J Ohm and O Tegmeyer ldquoDarstellung undEigenschaften des 124- und des 134-Thiodiazolsrdquo ChemischeBerichte vol 89 pp 1534ndash1543 1956

[9] A R Katritzky and R Charlews in Comprehensive HeterocyclicChemistry vol 6 pp 568ndash575 Ist edition 1984

[10] E Formm E Layer and K Nerz Advances in HeterocyclicChemistry vol 9 p 188 1968

[11] H B Koing andH A OfleChemical Abstracts vol 53 p 102531957

[12] British Patent Chemical abstract 59 1650 916061 1963[13] F Kurzer ldquoThiadiazoles Part XI Synthesis and cyclisation of N-

(thiobenzamido)guanidines and related compoundsrdquo Journal ofthe Chemical Society vol 1961 pp 1617ndash1625 1961

[14] R R Gupta M Kumar and V Gupta Heterocyclic ChemistrySpringen vol 2 pp 566ndash573 2005

[15] G Young and W Eyne ldquoIIImdashOxidation of benzalthiosemicar-bazonerdquo Journal of the Chemical Society Transactions vol 79pp 54ndash60 1901

[16] J Y Hweng H Choi D H Lee and Y D Gong ldquoSolid-phasesynthesis of 134-oxadiazole and 134-thiadiazole derivativesvia selective reagent-based cyclization of acyldithiocarbazateresinsrdquo Journal of Combinatorial Chemistry vol 7 pp 816ndash8192005

[17] P C Guha ldquoRing closure of hydrazodithio- and -monothio-dicarbonamides with acetic anhydriderdquo Journal of the AmericanChemical Society vol 45 pp 1036ndash1042 1923


[18] T A Bachetti and B J Banieli Advances in HeterocyclicChemistry vol 9 p 1711 1968

[19] J Goerdeler and H Hanbrich ldquoUber die Kupplungsak-tivitat einiger heterocyclischer Diazoverbindungenrdquo ChemischeBerichte vol 93 pp 397ndash405 1960

[20] M Otha H Oya and A J Miture Charm Soc Japan ChemicalAbstract vol 48 p 10006 1953

[21] C J Anisworth ldquoThe investigation of some substituted 134-thiadiazolesrdquo Journal of the American Chemical Society vol 80no 19 p 5201 1958

[22] F F Medovschikowa and I Y Postovskii Journal of HeterocyclicChemistry vol 9 p 197 1968

[23] H Sai Kachi and M Kanaka Yakugakuzasthi Chemi Abstractvol 58 p 4543 1963

[24] H Sai Kachi and M Kanaka Yakugakuzasthi vol 58 p 73041962

[25] S N Swamy Basappa B S Priya et al ldquoSynthesis of pharma-ceutically important condensed heterocyclic 46-disubstituted-124-triazolo-134-thiadiazole derivatives as antimicrobialsrdquoEuropean Journal of Medicinal Chemistry vol 41 no 4 pp 531ndash538 2006

[26] S Hussain J Sharma and M Amir ldquoSynthesis and antimicro-bial activities of 124-triazole and 134-thiadiazole derivativesof 5-amino-2-hydroxybenzoic acidrdquo E-Journal of Chemistryvol 5 no 4 pp 963ndash968 2008

[27] A A Aly and R E Sayed ldquoSynthesis and biological activity ofnew 134-thiadiazole derivativesrdquo Chemical Papers vol 60 no1 pp 56ndash60 2006

[28] R Dua and S K Srivastava ldquoSynthesis characterization andantimicrobial activityrdquo International Journal of Pharma and BioSciences vol 1 no 2 2010

[29] F Hadizadeh and R Vosooghi ldquoSynthesis of 120572-[5-(5-amino-134-thiadiazol-2-yl)-2-imidazolylthio] acetic acidsrdquo Journal ofHeterocyclic Chemistry vol 45 no 5 pp 1477ndash1479 2008

[30] J Salimon N Salih A Hameed H Ibraheem and EYousif ldquoSynthesis and antibacterial activity of some new 134-oxadiazole and 134-thiadiazole derivativesrdquo Journal of AppliedSciences Research vol 6 no 7 pp 866ndash870 2010

[31] A M Qandil H N Tumah and M A Hassan ldquoSynthe-sis and antibacterial activity of N4-benzoyl-N 1-dihydrox-ybenzoylthiosemicarbazides and their cyclic 134-thiadiazolederivativesrdquo Acta Pharmaceutica Sciencia vol 48 no 2 pp 95ndash107 2006

[32] R S Lamani N S Shetty R R Kambl and A M KhazildquoSynthesis and antimicrobial studies of novel methylenebridged benzisoxazolyl imidazo[21-b][134]thiadiazole deriva-tivesrdquo European Journal of Medicinal Chemistry vol 44 pp2828ndash2833 2008

[33] A Foroumadi S Emami A Hassanzadeh et al ldquoSynthesisand antibacterial activity of N-(5-benzylthio-134-thiadiazol-2-yl) and N-(5-benzylsulfonyl-134-thiadiazol-2-yl)piperazinylquinolone derivativesrdquo Bioorganic and Medicinal ChemistryLetters vol 15 no 20 pp 4488ndash4492 2005

[34] T Onkol D S Doruer L Uzun S Adak S Ozkan and M FAhin ldquoSynthesis and antimicrobial activity of new 124-triazoleand 134-thiadiazole derivativesrdquo Journal of Enzyme Inhibitionand Medicinal Chemistry vol 23 no 2 pp 277ndash284 2008

[35] N Siddiqui and M S Alam ldquo5-(1H-indol-3-ylmethyl)-N-(sub-stituted phenyl)-1 2 4-thiadiazol-2-amine derivatives synthe-sis and biological screeningrdquo Biosciences Biotechnology ResearchAsia vol 6 no 1 pp 261ndash264 2009

[36] P Karegoudar D J Prasad M Ashok M MahalingaB Poojary and B S Holla ldquoSynthesis antimicrobial andanti-inflammatory activities of some 124-triazolo[34-b][134]thiadiazoles and 124-triazolo[34-b][134]thiadiazines bearingtrichlorophenyl moietyrdquo European Journal of Medicinal Chem-istry vol 43 no 4 pp 808ndash815 2008

[37] T Karabasanagouda A V Adhikari andN S Shetty ldquoSynthesisand antimicrobial activities of some novel 124-triazolo[34-b]-134-thiadiazoles and 124-triazolo[34-b]-134-thiadiazinescarrying thioalkyl and sulphonyl phenoxy moietiesrdquo EuropeanJournal of Medicinal Chemistry vol 42 no 4 pp 521ndash529 2007

[38] VMathew J Keshavayya V P Vaidya andD Giles ldquoStudies onsynthesis and pharmacological activities of 36-disubstituted-124-triazolo[34-b]-134-thiadiazoles and their dihydro ana-loguesrdquo European Journal of Medicinal Chemistry vol 42 no6 pp 823ndash840 2007

[39] C J Chen B A Song S Yang et al ldquoSynthesis and antifun-gal activities of 5-(345-trimethoxyphenyl)-2-sulfonyl-134-thiadiazole and 5-(345-trimethoxyphenyl)-2-sulfonyl-134-oxadiazole derivativesrdquo Bioorganic and Medicinal Chemistryvol 15 pp 3981ndash3989 2007

[40] H S Chen H S LI H S Z Y F Han and Z W WangldquoNew fungicidally active pyrazolyl-substituted 134-thiadiazolecompounds and their preparationrdquo Chinese Chemical Lettersvol 10 no 5 pp 365ndash366 1999

[41] M Barboiu M Cimpoesu C Guran and C T Supumn ldquo13 4-thiadiazole derivatives Part 91 Synthesis and biologicalactivity of metal complexes of 5-(2-aminoethyl)-2-amino-134-thiadiazolerdquoMetal Based Drugs vol 3 no 5 pp 227ndash232 1996

[42] S R Pattan P kekare N S Dighe et al ldquoSynthesis andbiological evaluation of some 134-thiadiazolesrdquo Journal ofChemical and Pharmaceutical Research vol 1 no 1 pp 191ndash1982009

[43] M Amir H Kumar and S A Javed ldquoCondensed bridgeheadnitrogen heterocyclic system Synthesis and pharmacologicalactivities of 124-triazolo-[34-b]-134-thiadiazole derivativesof ibuprofen and biphenyl-4-yloxy acetic acidrdquo European Jour-nal of Medicinal Chemistry vol 43 no 10 pp 2056ndash2066 2008

[44] M Amir H Kumar and S A Javed ldquoSynthesis and pharma-cological evaluation of condensed heterocyclic 6-substituted-124-triazolo[34-b]-134-thiadiazole derivatives of naproxenrdquoBioorganic and Medicinal Chemistry Letters vol 17 pp 4504ndash4508 2007

[45] L S Varandas C A M Fraga A L P Miranda and E JBarreiro ldquoDesign synthesis and pharmacological evaluationof new nonsteroidal antiinflammatory 134-thiadiazole deriva-tivesrdquo Letters in Drug Design and Discovery vol 2 no 1 pp 62ndash67 2005

[46] M Moise V Sunel L Profire M Popa J Desbrieres and CPeptu ldquoSynthesis and biological activity of some new 134-thia-diazole and 124-triazole compounds containing a phenylala-nine moietyrdquoMolecules vol 14 no 7 pp 2621ndash2631 2009

[47] H Kumar S A Javed S A Khan and M Amir ldquo134-Oxadiazolethiadiazole and 124-triazole derivatives ofbiphenyl-4-yloxy acetic acid Synthesis and preliminary eval-uation of biological properties rdquo European Journal of MedicinalChemistry vol 43 no 12 pp 2688ndash2698 2008

[48] S Schenone C Brullo O Bruno et al ldquoNew 134-thiadiazolederivatives endowed with analgesic and anti-inflammatoryactivitiesrdquo Bioorganic and Medicinal Chemistry vol 14 no 6pp 1698ndash1705 2006


[49] S G Kucukguzel I Kucukguze I E Tatar et al ldquoSynthesisof some novel heterocyclic compounds derived from diflunisalhydrazide as potential anti-infective and anti-inflammatoryagentsrdquo European Journal of Medicinal Chemistry vol 42 no7 pp 893ndash901 2007

[50] M A Hilfiker N Wang X Hou et al ldquoDiscovery of novelaminothiadiazole amides as selective EP3 receptor antagonistsrdquoBioorganic and Medicinal Chemistry Letters vol 19 no 15 pp4292ndash4295 2009

[51] A K Gadad M B Palkar K Anand M N Noolvi T SBoreddy and J Wagwade ldquoSynthesis and biological eval-uation of 2-trifluoromethylsulfonamido-56-diaryl substi-tuted imidazo[21-b]-134-thiadiazoles a novel class of cycloox-ygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry vol16 no 1 pp 276ndash283 2008

[52] U S Goksen N G Kelekci O Goktas et al ldquo1-Acylthi-osemi-carbazides 124-triazole-5(4H)-thiones 134-thiadiazoles andhydrazones containing 5-methyl-2-benzoxazolinones synthe-sis analgesic-anti-inflammatory and antimicrobial activitiesrdquoBioorganic and Medicinal Chemistry vol 15 no 17 pp 5738ndash5751 2007

[53] A S Kalgutar A BMarnett B C Crews R P Remmel and L JMarnett ldquoEster and Amide derivatives of the nonsteroidal anti-inflammatory drug indomethacin as selective cyclooxygenase-2 inhibitorsrdquo Journal of Medicinal Chemistry vol 43 no 15 pp2860ndash2870 2000

[54] M Duflos M R Nourrisson J Brelet et al ldquoN-Pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential sys-temic and topical inflammation inhibitorsrdquo European Journal ofMedicinal Chemistry vol 36 no 6 pp 545ndash553 2001

[55] V J Ram A Goel and M Kandpal ldquoTetraazaacenaphthenetetraazaphenalene and 134-thiadiazole derivatives as potentialleishmanicidesrdquo Bioorganic and Medicinal Chemistry Lettersvol 7 no 6 pp 651ndash656 1997

[56] E F da Silva M M Canto-Cavalheiro V R Braz L Cysne-Finkelstein L L Leon and A Echevarria ldquoSynthesis and bio-logical evaluation of new 134-thiadiazolium-2-phenylaminederivatives against Leishmania amazonensis promastigotes andamastigotesrdquo European Journal of Medicinal Chemistry vol 37no 12 pp 979ndash984 2002

[57] M Behrouzi-Fardmoghadam F Poorrajab S K ArdestaniS Emami A Shafiee and A Foroumadi ldquoSynthesis and invitro anti-leishmanial activity of 1-[5-(5-nitrofuran-2-yl)-134-thiadiazol-2-yl]- and 1-[5-(5-nitrothiophen-2-yl)-134-thiadiazol-2-yl]-4-aroylpiperazinesrdquo Bioorganic and MedicinalChemistry vol 16 no 8 pp 4509ndash4515 2008

[58] A Foroumadi S Emami S Pournourmohammadi AKharazmi and A Shafiee ldquoSynthesis and in vitro leish-manicidal activity of 2-(1-methyl-5-nitro-1H- imidazol-2-yl)-5-substituted-134-thiadiazole derivativesrdquo European Journal ofMedicinal Chemistry vol 40 no 12 pp 1346ndash1350 2005

[59] S Karakus and S Rollas ldquoSynthesis and antituberculosis activityof new N-phenyl-N1015840-[4-(5-alkylarylamino-134-thiadiazole-2-yl)phenyl]thioureasrdquo Il Farmaco vol 57 no 7 pp 577ndash5812002

[60] E E Oruc S Rollas F Kandermirli N Shvets and A SDimoglo ldquo134-thiadiazole derivatives Synthesis structureelucidation and structureminusantituberculosis activity relation-ship investigationrdquo Journal of Medicinal Chemistry vol 47 pp6760ndash6676 2004

[61] A Foroumadi Z Kargar A Sakhteman et al ldquoSynthesisand antimycobacterial activity of some alkyl [5-(nitroaryl)-13

4-thiadiazol-2-ylthio]propionatesrdquo Bioorganic and MedicinalChemistry Letters vol 16 no 5 pp 1164ndash1167 2006

[62] S Karakus U Coruh B Barlas-Durgun et al ldquoSynthesis andcytotoxic activity of some 124-triazoline-3-thione and 25-disubstituted-134-thiadiazole derivativesrdquo Marmara Pharma-ceutical Journal vol 14 no 2 pp 84ndash90 2010

[63] J Matysiak and A Opolski ldquoSynthesis and antiproliferativeactivity of N-substituted 2-amino-5-(24-dihydroxyphenyl)-134-thiadiazolesrdquo Bioorganic and Medicinal Chemistry vol 14no 13 pp 4483ndash4489 2006

[64] V Padmavathi G Sudhakar Reddy A Padmaja P Kondaiahand Ali-Shazia ldquoSynthesis antimicrobial and cytotoxic activi-ties of 134-oxadiazoles 134-thiadiazoles and 124-triazolesrdquoEuropean Journal of Medicinal Chemistry vol 44 no 5 pp2106ndash2112 2009

[65] MXWei L Feng XQ Li X Z Zhou Z-H Shao andH ShaoldquoSynthesis of new chiral 25-disubstituted 134-thiadiazolespossessing 120574-butenolide moiety and preliminary evaluation ofin vitro anticancer activityrdquo European Journal of MedicinalChemistry vol 44 no 8 pp 3340ndash3344 2009

[66] D A Ibrahim ldquoSynthesis and biological evaluation of 36-disubstituted [124]triazolo[34-b][134]thiadiazole derivativesas a novel class of potential anti-tumor agentsrdquo EuropeanJournal of Medicinal Chemistry vol 44 pp 2776ndash2781 2009

[67] J Matysiak A Nasulewicz M Pelczynska M Switalska IJaroszewicz and A Opolski ldquoSynthesis and antiproliferativeactivity of some 5-substituted 2-(24-dihydroxyphenyl)-134-thiadiazoles rdquo European Journal of Medicinal Chemistry vol 41pp 475ndash482 2006

[68] A T Mavrova D Wesselinova Y A Tsenov and P DenkovaldquoSynthesis cytotoxicity and effects of some 124-triazole and134-thiadiazole derivatives on immunocompetent cellsrdquo Euro-pean Journal of Medicinal Chemistry vol 44 no 1 pp 63ndash692009

[69] P Zhan X Liu Z Li et al ldquoNovel 123-thiadiazole derivatives asHIV-1 NNRTIs with improved potency synthesis and prelimi-nary SAR studiesrdquo Bioorganic and Medicinal Chemistry vol 17pp 5920ndash5927 2009

[70] P Zhan X Liu Z Fang Z Li C Pannecouque and E DClercq ldquoSynthesis and anti-HIV activity evaluation of 2-(4-(naphthalen-2-yl)-123-thiadiazol-5-ylthio)-N-acetamides asnovel non-nucleoside HIV-1 reverse transcriptase inhibitorsrdquoEuropean Journal of Medicinal Chemistry vol 44 pp 4648ndash4653 2009

[71] C Kus G A Kilcigil S Ozbey et al ldquoSynthesis and antioxidantproperties of novel N-methyl-134-thiadiazol-2-amine and 4-methyl-2H-124-triazole-3(4H)-thione derivatives of benzimi-dazole classrdquo Bioorganic and Medicinal Chemistry vol 16 pp4294ndash4303 2008

[72] S Dhanya A M Isloor P Shetty K Satyamoorthy and A SBharath Prasad Arabian Journal of Chemistry In press

[73] D Cressier C Prouillac P Hernandez et al ldquoSynthesis antiox-idant properties and radioprotective effects of new benzoth-iazoles and thiadiazolesrdquo Bioorganic and Medicinal Chemistryvol 17 no 14 pp 5275ndash5284 2009

[74] V Dudutien L Baranauskien and D Matulis ldquoBenzim-idazo[12-c][123]thiadiazole-7-sulfonamides as inhibitors ofcarbonic anhydraserdquo Bioorganic and Medicinal Chemistry Let-ters vol 17 pp 3335ndash3338 2007

[75] G L Almajan A Innocenti L Puccetti et al ldquoCarbonicanhydrase inhibitors Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I II and IX with


a series of 134-thiadiazole- and 124-triazole-thiolsrdquo Bioor-ganic and Medicinal Chemistry Letters vol 15 no 9 pp 2347ndash2352 2005

[76] J Mirzaei F Siavoshi S Emami et al ldquoSynthesis andin vitro anti-Helicobacter pylori activity of N-[5-(5-nitro-2-heteroaryl)-134-thiadiazol-2-yl]thiomorpholines and relatedcompoundsrdquo European Journal of Medicinal Chemistry vol 43no 8 pp 1575ndash1580 2008

[77] A Foroumadi A Rineh S Emami et al ldquoSynthesis and anti-Helicobacter pylori activity of 5-(nitroaryl)-134-thiadiazoleswith certain sulfur containing alkyl side chainrdquo Bioorganic andMedicinal Chemistry Letters vol 18 no 11 pp 3315ndash3320 2008

[78] A Gupta P Mishra S K Kashaw V Jatav and J P StablesldquoSynthesis and anticonvulsant activity of some novel 3-arylaminoamino-4-aryl-5-imino-Δ2-124-thiadiazolinerdquo Euro-pean Journal of Medicinal Chemistry vol 43 no 4 pp 749ndash7542008

[79] A Gupta P Mishra S N Pandeya S K Kashaw V Kashawand J P Stables ldquoSynthesis and anticonvulsant activity of somesubstituted 124-thiadiazolesrdquo European Journal of MedicinalChemistry vol 44 no 3 pp 1100ndash1105 2009

[80] M S Yar and M W Akhter ldquoSynthesis and anticonvulsantactivity of substituted oxadiazole and thiadiazole derivativesrdquoActa Poloniae Pharmaceutica vol 66 no 4 pp 393ndash397 2009

[81] B Ahamad andM Yusuf ldquosynthesis of aromatic aldehyde iminederivative of 2-thiobenzyl-134-thiadiazole and evaluation oftheir anticonvulsant activityrdquo Indian Journal of Chemistry B vol49 pp 241ndash246 2010

[82] V Jatav P Mishra S Kashaw and J P Stables ldquoCNS depressantand anticonvulsant activities of some novel 3-[5-substituted134-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-onesrdquo Euro-pean Journal of Medicinal Chemistry vol 43 pp 1945ndash19542008

[83] H N Dogan A Duran S Rollas G Sener M K Uysal and DGulen ldquoSynthesis of new 2 5-disubstituted-1 3 4-thiadiazolesand preliminary evaluation of anticonvulsant and antimicrobialactivitiesrdquo Bioorganic amp Medicinal Chemistry vol 10 no 9 pp2893ndash2898 2002

[84] A Varvaresou T Siatra-Papastaikoudi A Tsotinis A TKakoulidou and A Vamvakides ldquoSynthesis lipophilicity andbiological evaluation of indole-containing derivatives of 134-thiadiazole and 124-triazolerdquo Il Farmaco vol 53 no 5 pp 320ndash326 1998

[85] A Foroumadi V Sheibani A Sakhteman et al ldquoSynthesisand anticonvulsant activity of novel 2-amino-5-[4-chloro-2-(2- chlorophenoxy) phenyl]-134-thiadiazole derivativesrdquoDaruJournal of Pharmaceutical Sciences vol 15 no 2 pp 89ndash932007

[86] X Q Deng Z Q Dong M X Song B Shu S B Wang andZ S Quan ldquoSynthesis and anticonvulsant activities of sometriazolothiadiazole derivativesrdquo Archiv der Pharmazie vol 345no 7 pp 565ndash573 2012

[87] M R Stillings P W Anthony and S W Donald ldquoSubstituted134-thiadiazoles with anticonvulsant activity 2 Aminoalkylderivativesrdquo Journal of Medicinal Chemistry vol 29 no 11 pp2280ndash2284 1986

[88] N Siddiqui A Rana S Khan et al ldquoSynthesis and preliminaryscreening of benzothiazol-2-yl thiadiazole derivatives for anti-convulsant activityrdquo Acta Pharmaceutica vol 59 no 4 pp 441ndash451 2009

[89] N Siddiqui S Ali S A Khan S Drabu A Rana andM Alam ldquoSynthesis of 3-arylamino-4-aryl-5-(N-arylthiocar-bonylimino)-4 5-dihydro-124-thiadiazoles as anticonvulsantagentsrdquo Indian Journal of Heterocyclic Chemistry vol 14 no 2pp 159ndash160 2004

[90] N SiddiquiM F Arshad S A Khan andWAhsan ldquoSynthesisanticonvulsant and neurotoxicity screening of 1-(substitutedphenyl)-3-[(5-substituted phenyl)-134-thiadiazole-2-yl]-2-thioxodihydro pyrimidine-46 (1H 5H)-dionesrdquo Journal ofPharmaceutical Research vol 7 no 2 pp 122ndash125 2008

[91] P Mullick S A Khan S Verma and O Alam ldquoThiadiazolederivatives as potential anticonvulsant agentsrdquo Bulletin of theKorean Chemical Society vol 32 no 3 pp 1011ndash1016 2011

[92] C B Chapleo P L Mayers J F Saville et al ldquoSubstituted 134-thiadiazoles with anticonvulsant activity 1 Hydrazinesrdquo Journalof Medicinal Chemistry vol 29 no 11 pp 2273ndash2280 1986

[93] H Rajak C K Behera R S Pawar P K Singour andM D Kharya ldquoSynthesis and anticonvulsant evaluationof some novel 25-disubstituted 134-thiadiazoles pharma-cophore model studiesrdquo Acta Poloniae Pharmaceutica vol 67no 5 pp 503ndash510 2010

[94] M D Kamal H A Gawad E A Rageb M Ellithey and H AMohamed ldquoSynthesis anticonvulsant and anti-inflammatoryevaluation of some new benzotriazole and benzofuran-basedheterocyclesrdquo Bioorganic and Medicinal Chemistry vol 14 no11 pp 3672ndash3680 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


Table 1 Physical properties of 134-thiadiazole

Bond length Bond angleType A Type (∘)a 1371 120572 1122b 1302 120573 1146c 1721 120574 864d 1721 120575 1146e 1302 120576 1122

compounds in medicine agriculture and many fields oftechnology A large number of 134-thiadiazoles have beenpatented in the agricultural field as herbicides and bacteri-cides [7]

X-ray analysis shows the following structure parameterfor 134-thiadiazole ring (see Table 1 and Structure (1))

N

S

N

1HH

34

5

ab

cd

e

2

(1)

3 Chemistry of Thiadiazole

A recent literature survey revealed that the 134-thiadiazolemoiety has been widely used by the medicinal chemist inthe past to explore its biological activities The developmentof 134-thiadiazole chemistry is linked to the discoveryof phenylhydrazines and hydrazine in the late nineteenthcenturyThefirst 134-thiadiazole was described by Fischer in1882 but the true nature of the ring systemwas demonstratedfirst in 1890 by Freund and Kuh

Thiadiazole is a five-member heterocyclic compoundhaving one sulphur and two nitrogen atomsThere are severalisomers of thiadiazole that is 123-thiadiazole (2) 125-thiadiazole (4) 124-thiadiazole (3) and 134-thiadiazole (5)There are four possible systems in thiadiazole

(2)123-thiadiazole

N

SN

(3)

N

SN

124-thiadiazole

(4)

N

S

N

125-thiadiazole

(5)

NN

S

134-thiadiazole

4 134-Thiadiazoles

134-Thiadiazole was first described in 1882 by Fischer andfurther developed by Bush and his coworkers but truenature of the ring system was demonstrated first in 1956by Goerdler et al [8] The advent of sulphur drugs and thelater discovery of mesoionic compound greatly acceleratedthe rate of progress in the field of thiadiazole Thiadiazolecarrying mercapto hydroxyl and amino substituents canexist in many tautomeric forms The 134-thiadiazoles areconveniently divided into three subclasses

(a) aromatic systems which include the neutral thiadia-zoles and constitute a major part of this paper

(b) mesoionic systems which are defined as five-membered heterocycles which are not covalent orpolar and possess a sextet of electrons in associationwith the five atoms comprising the ring

(c) nonaromatic systems such as the 134-thiadiazolesand the tetrahydro 134-thiadiazoles In the partiallyreduced systems the position of the double bondis denoted by the prefix Δ with being a Δ2-134-thiadiazole (Structures (6) (7) and (8))

(6)

N

S

NH

(7)

N

S

N

(8)

HN

S

NH

5 Synthetic Procedures of 134-Thiadiazoles

(a) Formation of One Bond The most common proce-dure for the synthesis of 5-substituted 2-amino-thiadiazole


(9) (10)

HN NH

C C

SO

R NH

NN

NHR2 NHR2R1

Scheme 1

S


ClCHCNHNHCHO

Me2NCH=CHNMe2SH2

(14)(13)(12)(11)

Scheme 2




















(18) (19)(17)(16)

NNHH

R1 NN

HR1

NN

HR1

O O

H H

S

NN

R1R2O2S R2O2S R2O2S

RSO2H minusH2OSO2R2

Scheme 3

SH

NN

CH2OHCSNHCSNH2H2O2

NH3H3CO

(21)(20)

Scheme 4











mean (Scheme 15)


2SO4+ fuming HNO

3)






CS

NN

Ph

S S


(23)(24)

(22)

Scheme 5

RO

S

S

NN

NH2

(26)(25)

ROCNHNH2 + CICN

Scheme 6

S

NNS

C6H5C6H5


OH

(27) (28)

Scheme 7

S

N N

SRNH-NH2 NH2

(29) (31)(30)

RCOCl + NH2

Scheme 8

S

NN

NH2(R)CH=NNHCS NH3

Fe+++R1


(33)(32)

Scheme 9

S NH

S

NH

O

N N

N

(35)(34)

(1) TMSCl

(2) MCPBA(3) R2R3

R1

NH

R1R3

R2

HS

Scheme 10

SS

N N

S

(36) (37)

NH NH NH2

NH2

NH2

H2NH2O2

Scheme 11















N NX

NN X

S

NN NN

NNN

NH

O

(38) (39) (40)

(41)

(43) (44)

(42)

X = S SO SO2h120584 Δ

Bu1

Bu1 Bu1 Bu1

Bu1Bu1

Bu150∘C

O2

SO2

Cis 4

Trans-4

Bu1gt145∘C + (SO) 1

2S + 12

SO2

Scheme 12

N

S

N N

S

N N

S

N

R1R1 R1R2R2R2

CH3

CH3

I

H3C

+

++

(47)(46)(45)

Scheme 13







(104)

N S

NArndashHN

Ar

NH

(105)N S

NNHH2N

Ar

Ar=C2H5O

N

NAr=


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1



(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16


N

NHN

N S

N HN

N

N

(106)


N

S

NN

NH

(107andashf)

Compound R


ndashH

NO

NN

NH

R

(108andashf)



N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(9) (10)

HN NH

C C

SO

R NH

NN

NHR2 NHR2R1

Scheme 1

S


ClCHCNHNHCHO

Me2NCH=CHNMe2SH2

(14)(13)(12)(11)

Scheme 2




















(18) (19)(17)(16)

NNHH

R1 NN

HR1

NN

HR1

O O

H H

S

NN

R1R2O2S R2O2S R2O2S

RSO2H minusH2OSO2R2

Scheme 3

SH

NN

CH2OHCSNHCSNH2H2O2

NH3H3CO

(21)(20)

Scheme 4











mean (Scheme 15)


2SO4+ fuming HNO

3)






CS

NN

Ph

S S


(23)(24)

(22)

Scheme 5

RO

S

S

NN

NH2

(26)(25)

ROCNHNH2 + CICN

Scheme 6

S

NNS

C6H5C6H5


OH

(27) (28)

Scheme 7

S

N N

SRNH-NH2 NH2

(29) (31)(30)

RCOCl + NH2

Scheme 8

S

NN

NH2(R)CH=NNHCS NH3

Fe+++R1


(33)(32)

Scheme 9

S NH

S

NH

O

N N

N

(35)(34)

(1) TMSCl

(2) MCPBA(3) R2R3

R1

NH

R1R3

R2

HS

Scheme 10

SS

N N

S

(36) (37)

NH NH NH2

NH2

NH2

H2NH2O2

Scheme 11















N NX

NN X

S

NN NN

NNN

NH

O

(38) (39) (40)

(41)

(43) (44)

(42)

X = S SO SO2h120584 Δ

Bu1

Bu1 Bu1 Bu1

Bu1Bu1

Bu150∘C

O2

SO2

Cis 4

Trans-4

Bu1gt145∘C + (SO) 1

2S + 12

SO2

Scheme 12

N

S

N N

S

N N

S

N

R1R1 R1R2R2R2

CH3

CH3

I

H3C

+

++

(47)(46)(45)

Scheme 13







(104)

N S

NArndashHN

Ar

NH

(105)N S

NNHH2N

Ar

Ar=C2H5O

N

NAr=


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1



(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16


N

NHN

N S

N HN

N

N

(106)


N

S

NN

NH

(107andashf)

Compound R


ndashH

NO

NN

NH

R

(108andashf)



N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(18) (19)(17)(16)

NNHH

R1 NN

HR1

NN

HR1

O O

H H

S

NN

R1R2O2S R2O2S R2O2S

RSO2H minusH2OSO2R2

Scheme 3

SH

NN

CH2OHCSNHCSNH2H2O2

NH3H3CO

(21)(20)

Scheme 4











mean (Scheme 15)


2SO4+ fuming HNO

3)






CS

NN

Ph

S S


(23)(24)

(22)

Scheme 5

RO

S

S

NN

NH2

(26)(25)

ROCNHNH2 + CICN

Scheme 6

S

NNS

C6H5C6H5


OH

(27) (28)

Scheme 7

S

N N

SRNH-NH2 NH2

(29) (31)(30)

RCOCl + NH2

Scheme 8

S

NN

NH2(R)CH=NNHCS NH3

Fe+++R1


(33)(32)

Scheme 9

S NH

S

NH

O

N N

N

(35)(34)

(1) TMSCl

(2) MCPBA(3) R2R3

R1

NH

R1R3

R2

HS

Scheme 10

SS

N N

S

(36) (37)

NH NH NH2

NH2

NH2

H2NH2O2

Scheme 11















N NX

NN X

S

NN NN

NNN

NH

O

(38) (39) (40)

(41)

(43) (44)

(42)

X = S SO SO2h120584 Δ

Bu1

Bu1 Bu1 Bu1

Bu1Bu1

Bu150∘C

O2

SO2

Cis 4

Trans-4

Bu1gt145∘C + (SO) 1

2S + 12

SO2

Scheme 12

N

S

N N

S

N N

S

N

R1R1 R1R2R2R2

CH3

CH3

I

H3C

+

++

(47)(46)(45)

Scheme 13







(104)

N S

NArndashHN

Ar

NH

(105)N S

NNHH2N

Ar

Ar=C2H5O

N

NAr=


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1



(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16


N

NHN

N S

N HN

N

N

(106)


N

S

NN

NH

(107andashf)

Compound R


ndashH

NO

NN

NH

R

(108andashf)



N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


CS

NN

Ph

S S


(23)(24)

(22)

Scheme 5

RO

S

S

NN

NH2

(26)(25)

ROCNHNH2 + CICN

Scheme 6

S

NNS

C6H5C6H5


OH

(27) (28)

Scheme 7

S

N N

SRNH-NH2 NH2

(29) (31)(30)

RCOCl + NH2

Scheme 8

S

NN

NH2(R)CH=NNHCS NH3

Fe+++R1


(33)(32)

Scheme 9

S NH

S

NH

O

N N

N

(35)(34)

(1) TMSCl

(2) MCPBA(3) R2R3

R1

NH

R1R3

R2

HS

Scheme 10

SS

N N

S

(36) (37)

NH NH NH2

NH2

NH2

H2NH2O2

Scheme 11















N NX

NN X

S

NN NN

NNN

NH

O

(38) (39) (40)

(41)

(43) (44)

(42)

X = S SO SO2h120584 Δ

Bu1

Bu1 Bu1 Bu1

Bu1Bu1

Bu150∘C

O2

SO2

Cis 4

Trans-4

Bu1gt145∘C + (SO) 1

2S + 12

SO2

Scheme 12

N

S

N N

S

N N

S

N

R1R1 R1R2R2R2

CH3

CH3

I

H3C

+

++

(47)(46)(45)

Scheme 13







(104)

N S

NArndashHN

Ar

NH

(105)N S

NNHH2N

Ar

Ar=C2H5O

N

NAr=


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1



(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16


N

NHN

N S

N HN

N

N

(106)


N

S

NN

NH

(107andashf)

Compound R


ndashH

NO

NN

NH

R

(108andashf)



N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N NX

NN X

S

NN NN

NNN

NH

O

(38) (39) (40)

(41)

(43) (44)

(42)

X = S SO SO2h120584 Δ

Bu1

Bu1 Bu1 Bu1

Bu1Bu1

Bu150∘C

O2

SO2

Cis 4

Trans-4

Bu1gt145∘C + (SO) 1

2S + 12

SO2

Scheme 12

N

S

N N

S

N N

S

N

R1R1 R1R2R2R2

CH3

CH3

I

H3C

+

++

(47)(46)(45)

Scheme 13







(104)

N S

NArndashHN

Ar

NH

(105)N S

NNHH2N

Ar

Ar=C2H5O

N

NAr=


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1



(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16


N

NHN

N S

N HN

N

N

(106)


N

S

NN

NH

(107andashf)

Compound R


ndashH

NO

NN

NH

R

(108andashf)



N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

S

N N

S

N Me

NHR(1) R = H(2) R = Br

(3) R = H(4) R = Br

NR2R3R1

1

1

1

1

R1



(48)(49)

Scheme 14

O SNH

Me

Me

N N

O

Me

MeR1

R1+

R2

R2

(52)(51)(50)

Scheme 15

N

S

N N

S

NFuming HNO3

40∘CNH2

NH2O2N

(53) (54)

Scheme 16


N

NHN

N S

N HN

N

N

(106)


N

S

NN

NH

(107andashf)

Compound R


ndashH

NO

NN

NH

R

(108andashf)



N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

S

N

R

N

S

N

R

N

S

N

R

N

S

N

RNH2 NH2

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

NH2OH+

NHOH

Scheme 17

(59) (60)

N

S

N N

N

NH

SNHR2R1 R1

R2

Scheme 18

S

NNSH

N

R(109andashe)


109b 110ib 110iib

109c 110ic 110iic

109d 110id 110iid

109e 110ie 110iie

2-Cl

4-Cl

2-NO24-NO24-F

S

N N

N

R

S

(110iandash8ie)

S

N N

N

R

S Cl

(110iiandash15iie)


N

N

O

S

N N

R

Ar



S

NN

OH

NH

(112a)

SNN

OH

NH

(112b)

NH

OH

S

NN

(112c)

OH

NHS

NN

Br(112d)

OH

NHS

NN

F

(112e)


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


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Physical Chemistry



Journal of

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Journal of

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CatalystsJournal of


N

S

N

NHOHArCO ArCO ArCO

N

S

N

Cl

N

S

N

Na

N

SArCO ArCO

N

S

NHNH

S S

(61)

(64) (65)

(62) (63)

Nu+Nu+

Nu+ Nu+

Scheme 19

N

S

N N

S

N

(66) (67)


Scheme 20

O(112f)

OH

NHS

NN

Cl(112g)

OH

NHS

NN

F(112h)

OH

NHS

NN


N

NS

HN

(113)

NH


S

NN

OCl

Cl

NH2

(114)

S

NNNH

OCl

Cl

(115)


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

S

N N

S

N

RR

Diazo compound

N

S

N N

S

N

R

Mxylene Mesitylene

(71)(70)

(69)(68)

NH2


+

2


Scheme 21

N

S

N N

S

N

RR

(72) (73)

NH2 N=CHAr+ ArCHO

Scheme 22

N

S

N N

S

N

Ph SHPh

(75)(74)

P2S5

Scheme 23

S

NNNH

OClCl

(116)


S

ClN N

N

N

(117)


S

NN

(118)

NH2



N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

S

N N

S

NH

Ph

Na(Hg)X H


(76) (77) (78)

Scheme 24

N

S

N N

S

NO

O

O O N

S

NN

HO

ONH2

(81)(80)(79)

COC2H5

COC2H5H2C+

NHCCHCHOndashC2H5

H+ +

Δ

Scheme 25

S

NNN

(119)

NH2


HN

N S

NN

R

R

S

NH

(120andashe)

R = H 2-Cl 4-Cl 4-NO2 2-CH3


RN

NS

NNO

O

S

R = 3-NO2 4-F 2-Cl

R998400

R998400

= H 2-CH3 3-CH3 4-CH3 2-Cl 3-Cl 4-Cl

(121andashw)




N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

S

N N

S

N

Cl

N

N

NH

SH


+

CH2C6H5

NHCH2C6H5

NH2CH2C6H5

Scheme 26

N

S

N N

N

NH

ClSH


R R

(85)(86)

NH3

Scheme 27

N

S

N

N

N

N

N N

N

NH

SH SR

SS

(89)

(87)

(88)

(90)

NH

NH

2

NH2

H2N

H2N

H2N

H2NHN+Large excess

of hydrazine

Scheme 28

(91) (92)

N

S

N N

NN SR RNH2

H2N

Dil HClCH2Ph

NndashCH2Ph

Scheme 29

(93) (94) (95)

N

S

N

S

S

S

NR2R1S

R2

R1SCN+ +

Scheme 30

(99)(98)(97)(96)

PhPh Ph

PhPh

Ph

N

S

N N

S

N NLi

S

N

Me Me

HN

S

NNN

S S

NndashN=C=CH2

Sli CH2R

Scheme 31


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

Ph Ph

N

N

N

S

N

N

N

N

(103)

(100) (101) (102)

PhN

PhN

SSminus

Sminus

COMe2

COMe2

N=NPh

+

+

Scheme 32

S

NNN

(122)

NH2



References













































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




























































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Review Article Synthetic Methods, Chemistry, and the Anticonvulsant Activity...

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Transcript of Review Article Synthetic Methods, Chemistry, and the Anticonvulsant Activity...