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JournaloftheChileanChemicalSocietyversinOnlineISSN07179707

J.Chil.Chem.Soc.v.52n.2Concepcinjun.2007

http://dx.doi.org/10.4067/S071797072007000200006

J.Chil.Chem.Soc,52,N2(2007)pgs.:11451149

SYNTHESISOFNOVELPYRAZOLE,COUMARINANDPYRIDAZINEDERIVATIVESEVALUATEDASPOTENTIALANTIMICROBIALANDANTIFUNGALAGENTS

WAGNATW.WARDAKHAN*AANDNADIAA.LOUCAB

aNationalOrganizationforDrugControl&Research(NODCAR),P.O.29,CairoA.R.Egypt.bHormonesDepartment,NationalResearchCenter,Dokki,A.R.Egypt

Direccinparacorrespondencia

ABSTRACT

ThereactionofcyanoacetylhydrazinewithbromoacetophenonegavetheN[2bromo1phenylethylidene]2isocyanoacetohydrazide(3).Thelattercompoundunderwentreadycyclizationwhentreatedwithpotassiumcyanidetogivethe1(isocyanoacetyl)3phenyl1Hpyrazol5amine(6).Compound6underwentaseriesofheterocyclizationtogiveeithercoumarin,pyridazine,1,2,4triazine



orthiophenederivatives.Theantimicrobialandantifungalactivitiesofthenewlysynthesizedproductsweremeasured,usingtwoGramnegative(EscherichiacoliandPseudomonasaeruginosa),twoGrampositivebacteria(BacillussubtilisandBacilluscereus)andtheantifungalactivityusingCandidaalbicans.

Keywords:Cyanoacetylhydrazine,Pyrazole,Coumarin,Pyridazine

INTRODUCTIONThepyrazoleringisaprominentstructuralmotiffoundinnumerouspharmaceuticallyactivecompounds.Thisismainlyduetotheeasepreparationandtheimportantbiologicalactivity.Pyrazoleframeworkplaysanessentialroleinbiologicallyactivecompoundsandthereforerepresentsaninterestingtemplateforcombinatorialaswellasmedicinalchemistry110Indeed,pyrazolebasedderivativeshaveshownseveralbiologicalactivitiesasseenasanxiolytics,11GABAreceptorantagonistsandinsecticides,12apotentialPETligandforCB1receptors,13antiinflammatoryandantimicrobialagents14andgrowthinhibitionactivity.15

RESULTSANDDISCUSSIONInthisworkwereportanovelmethodforthesynthesisofpyrazolederivativesstartingwithcyanoacetylhydrazine(1)and(0bromoacetophenone(2)followedbyheterocyclizationtothepyrazolederivative.Thus,thereactionbetweenthetworeagentsin1,4dioxanatroomtemperaturegaveasingleproductwithmolecularformulaC11H10N3OBr.Twopossibleisomericstructureswereconsideredforthereactionproductdependingonthewayofcondensationreaction,either3or4.Thepossibilityofstructure4wasruledoutonthebasisofIRspectrumwhichshowedtheabsenceofanyNH2stretching,andthe1HNMRspectrumwhichrevealedthepresenceoftwosingletsat4.48,5.23correspondingtotwoCH2groups,amultipletat7.267.31forthephenylprotonsandasinglet(D2Oexchangeable)at8.31fortheNHgroup.Suchdataareconsistentwiththestructureofthehydrazidehydrazonederivative3.Compound3,reactswithpotassiumcyanidetogivethe1(cyanoacetyl)3phenyl1//pyrazol5amine6viatheintermediateformationoftheacyclicintermediate5.TheIRspectrumofthereactionproductshowedthepresenceofanNH2stretchingat1)3466,3380correspondingtoanNH2groupandonlyoneCNgroupstretchingat2256.Moreover,the1HNMRspectrumshowedthepresenceofasingletat4.67correspondingtoCH2group,asingletat4.88(D2Oexchangeable)correspondingtoNH2group,asingletat6.56forpyrazoleH4andamultipletat7.307.36forphenylprotons.The13CNMRspectrumshowed18.2(CH2),93.4(pyrazolC4),117.1(CN),127.8,128.8,129.1,129.3,130.2,143.2,150.4(C6H5,pyrazoleC3,C5)and198.5(C=O).

Compound6underwentmanychemicaltransformationsduetothepresenceofthe1cyanoacetylmoietyandthe5aminogroup.Thus,thereactionofbenzenediazoniumchloride7withcompound6at05oCgavethephenylhydrazonederivative.Ontheotherhand,withthearomaticaldehydes9acgavethearylidenederivatives10ac,respectively.Theanalyticalandspectraldataofthereactionproductsareconsistentwiththeproposedstructures(seeexperimentalsection).Ontheotherhand,thereactionofcompound6withsalicylaldehyde11gavethecoumarinderivative12.TheIRand1HNMRspectraagreewiththeproposedstructures(Scheme1).Formationofmanycoumarinderivativesbythismethodhasbeenreportedbefore.1618



Theaminogrouppresentincompound6isreadyfordiazotizationinawaysimilarwiththatreportedworkbyElnagdiandRenetal.19,20Thus,asolutionofcompound6inacetic/hydrochloricacidsreactswithsodiumnitriteat05oCtogivethenonisolablediazoniumchloridesalt13.Thereactionoftheintermediatediazoniumsalt13withmalononitrile(14)gavethehydrazonederivative15.Structureofthelatterproductwasbasedontheanalyticalandspectraldata.Thus,IRspectrumshowedthepresenceofNHstretchingat34603327cm1,threeCNgroupsstretchingat2255,22272220cm1.Compound15underwentreadycyclizationwhenheatedinethanolicsodiumhydroxidesolutiontogivethepyrazolo[1,5:1,2]pyrimidino[1,66]1,2,4triazinederivative17.Formationofthelatterproductisexpectedviatheintermediateformationofthepyrazolo[1,5a]pyrimidinederivative16.Structureofcompound17wasestablishedonthebasisofanalyticalandspectraldata(seeexperimentalsection).Moreover,compound15reactedwitheitherhydrazinehydrate(18a)orphenylhydrazine(18b)togivethepyrazolo4yl5azopyrazolederivatives19aand19b,respectively(Scheme2).



Thereactionofcompound15withmalononitrile(14)inethanolcontainingacatalyticamountoftriethylaminegavethe1pyrazol5ylpyridazinederivative21,thereactiontookplacethroughtheintermediateformationoftheacyclicstructure20followedbyMichaelcyclization.Formationofthelatterproductwasbasedontheanalyticalandspectraldata(seeexperimentalsection)besideitssynthesisviaanotherreactionroute.Thus,thereactionofthediazoniumsalt13withPaminoa,ydicyanocrotononitrile(22)at05oCaffordedtheacyclichydrazonederivative20.Heatingofthelatterproductinethanolic/triethylaminesolutiongavethesameproduct21(mixedm.p.andfingerprintIRspectra).

Thereactionofcompound15withphenylisothiocyanate(23)gavethe1pyrazol5yl1,2,4triazinederivative24(Scheme3).Theanalyticalandspectraldataofthelatterproductareconsistentwiththeproposedstructure(seeexperimentalsection).



Compound15coupledwiththediazoniumsalts7,25aand25btogivethehydrazonederivatives26ac,respectively.Analyticalandspectraldataofthelatterproductsareagreewiththeproposedstructures(seeexperimentalsection).Ontheotherhand,compound15reactswithacetophenone(27)inthepresenceofammoniumacetateat140oCtogivethecondensedproduct28.Thelatterproductreactswithelementalsulfurinthepresenceoftriethylaminetoaffordthethiophenederivative29(Scheme4).



INVITROANTIMICTOBIALANDANTIFUNGALACTIVITIESEVALUATIONAnevaluationoftheantibacterialactivityusingtwoGramnegative(EscherichiacoliandPseudomonasaeruginosa)andtwoGrampositivebacteria(BacillussubtilisandBacilluscereus)andtheantifungalactivityusingCandidaalbicansasarepresentativespeciesoffungiwasassessedforcompounds.Theminimalinhibitoryconcentration(MICing/mL)wasdeterminedusinganadaptationofagarstreakdilutionmethodbasedonradialdiffusion.21,22Inthesameconditionsdifferentconcentratedsolutionsofampicillin(antibacterial)andcycloheximide(antifungal)wereusedasstandards.TheMICwasconsideredtobethelowestconcentrationofthetestedcompoundwhichinhibitsgrowthofbacteriaorfungiontheplate.ThediametersoftheinhibitionzonescorrespondingtotheMICsarepresentedin

Table1.ThecompoundstestedarenotactiveagainstPseudomonasaeruginosastartingfromDMSOsolutionsof1000g/mLofeachcompound.

Table1:Theantimicrobialactivityofthenewlysynthesizedproducts

Compound MICing/mL(zoneofinhibitioninmm)

E.coliECT101

B.CereusCECT148

B.subtilisCECT498

C.albicansCECT1394

3 Notactive 25(8) 23(6) 26(3)

6 Notactive 0.05(9) 3.13(10) 0.61(6)

Notactive 6.25(15) 20(8) 30(6)

10a 12.50(6) 20(8) 6.25(4) 8.65(4)



10b Notactive 12.34(7) 6.13(4) 0.40(5)

10c Notactive 18.32(5) 6.22(2) 0.40(10)

12 Notactive 20.15(4) 23.16(9) 100(5)

15 Notactive 12.32(3) 16.32(8) 14.40(4)

17 16.64 0.06(2) 6.33(5) 50(11)

19a Notactive 12.30(4) 4.22(6) 12.55(12)

19b Notactive 6.05(6) 12.42(2) 4.55(10)

20 10.46(4) 8.66(6) 25.33(5) 12.22(8)

21 Notactive 0.08(3) 5.23(8) 8.44(6)

24 Notactive 10.23(6) 2.56(4) 28.60(8)

26a Notactive 7.03(8) 0.68(2) 20.50(5)

26b Notactive 6.22(5) 12.89(4) 18.42(9)

26c Notactive 7.39(4) 4.33(5) 12.77(5)

28 Notactive 0.08(2) 2.22(5) 6.44(8)

29 Notactive 22.01(3) 0.48 25.60(6)

Ampicillin6.25 3.13 12.50(10)

Cycloheximide 12.50

FromtheanalysisofTable1itispossibletoestablishsomeSARs.TheonlyactivecompoundsagainstE.coliintheconcentrationstestedare10a,17and20(MIC12.5g/mL),thesubstitutedpyrazolemoietybeingtheresponsibleforsuchactivity.However,theannulatedderivative17showedthehighestactivity.AgainstGram+bacteriatheMICsfor10caremuchhigherthanthosefor10a.Comparing3with10aand10c(thepyridinederivative),compound3(haloketone)seemedtobemoreactiveagainstB.cereus(MIC3.13g/mL)butlessactiveagainstB.subtilis.AgainstC.albicans10b(4chlorophenyl)and10c(4methoxyphenyl)presentthesameMIC(25g/mL)whichishigherthantheMICobtainedfor3(50g/mL).Compound12(withthecoumaringroup)showedthehighestativityagainstC.albicans.

Comparingcompounds26a,26band26c,onecannoticethat26a(withthephenylhydrazonogroup)showedhighestMICvalueagainstC.albicanswhereas26cshowedtheleastvalue.Fortheinvitroantimicrobialactivity,suspensionsofthemicroorganismwerepreparedtocontainapproximately108



cfu/mLandtheplateswereinoculated.Astocksolutionofthesynthesized

compound(1000|lg/mL)inDMSOwaspreparedandgradeddilutionsofthetestedcompoundswereincorporatedinacavity(depth3mm,diameter4mm)madeinthecenterofthepetridish(nutrientagarforantibacterialactivityandSabouraudvsdextroseagarmediumforantifungalactivity).Theplateswereincubatedat37oC(forbacteria)andat30oC(forfungi)for24hinduplicate.PositivecontrolusingonlyinoculationandnegativecontrolusingonlyDMSOinthecavitywerecarriedout.

CONCLUSION

Theworkdescribedinthisarticleshowedanovelmethodforthesynthesisofpyrazolesandtheirderivativesstartingfromahydrazidehydrazonederivativeobtainedthroughthereactionoffflbromoacetophenoneandcyanoacetylhydrazine.Thus,Uponusingavarietyofahaloketonesasstartingmaterialsanewfieldisopenedthroughwhichanewseriesofpyrazolesthatcanundergoheterocyclizationintoalargenumberoffusedheterocycles.Mostofthesynthesizedproductsshowedantimicrobialandantifungalactivities.

EXPERIMENTALMeltingpointsareuncorrected.IRspectrawererecorded(KBr)onaPyeUnicamSP1000spectrophotometer.1HNMRspectrawereobtainedonaVarianGemini200MHzspectrometerinDMSOd6assolventandTMSasinternalreference.Chemicalshiftsareexpressedasppm.

iV[2bromolphenylethylidene]2isocyanoacetohydrazide(3)

Toasolutionofcyanoacetylhydrazine(1)(0.01mol,1.0g)in1,4dioxan(50mL),fflbromoacetophenone(0.01mol,2.0g)wasadded.Thereactionmixturewasstirredatroomtemperaturefor6hrs.Theformedsolidproductwascollectedbyfiltration.Whitecrystalsfrom1,4dioxan,yield70%(2.23g),m.p.160oC.CalculatedforC11H10BrN3O(280.12):C,47.16H,3.60Br,28.52N,15.00Found:C,46.89H,3.25Br,28.18N,14.74.IR1):34803325(NH),3055(CHaromatic),2875(CH2),2260(CN),1687(C=O),1665(C=N),1632(C=C).1HNMR:4.48,5.23(2s,4H,2CH2),7.267.31(m,5HCH5),8.31(s,1H,NH).

l(isocyanoacetyl)3phenyllffpyrazol5amine(6)

Toasolutionofcompound3(2.80g,0.01mol)inethanol(40mL),asolutionofpotassiumcyanide(2.8g,0.05mol)wasadded.Thereactionmixturewasheatedinawarmwaterbathat60oCfor30min.thenleftwithstirringatroomtemperatureforanadditionalonenight.Thesolidproductformeduponpouringontoice/watercontaininghydrochloricacid(tillpH6)wascollectedbyfiltration.Paleyellowcrystalsfromethanol,yield78%(1.76g),m.p.22022oC.CalculatedforC12H10N4O(226.23):C,63.71H,4.46N,24.77Found:C,64.08H,4.21N,25.09.IR1):34663380(NH2),3050(CHaromatic),2256(CN),1690(C=O),1655(C=N),1634(C=C).1HNMR:4.67(s,2H,CH2),4.88(s,2H,NH2),6.56(s,1H,pyrazoleH4),7.307.36(m,5H,CH5).13CNMR:18.2(CH2),93.4(pyrazolC4),117.1(CN),127.8,128.8,129.1,129.3,130.2,143.2,150.4(C6H5,pyrazoleC3,C5),198.5(C=O).

2(5Amino3phenylliipyrazollyl)2oxoAr"phenylethanehydrazonoylisocyanide(8):

Toacoldsolution(05oC)ofcompound6(2.26g,0.01mol)inethanol(40mL)containingsodiumacetate(8.0g),benzenediazoniumchloride(0.01mol)[preparedbyaddingsodiumnitritesolution(0.7g,0.01mol)toacoldsuspension(05oC)ofaniline(0.94g,0.01mol)intheappropriatequantityofhydrochloricacidwithcontinuousstirring]wasadded.Thereactionmixturewaskeptatroomtemperatureforanadditional1handtheformedsolidproductwascollectedbyfiltration.Orangeredcrystalsfrom1,4dioxan,yield70%(2.31g),m.p.1857oCCalculatedforC18H14N6O(330.34):C,65.44H,4.27N,25.44Found:C,65.92H,4.31N,25.86.IR1):34503321(NH2,NH),3052(CHaromatic),2255(CN),1683(C=O),1658(C=N),1638(C=C).1HNMR:4.90(s,2H,NH2),6.59(s,1H,pyrazoleH4),7.327.39(m,10H,2CH5),8.33(s,1H,NH).

l[2Cyano3phenylprop2enoyl]3phenyllHpyrazol5amine(10a),l[2cyano3(4chlorophenyl)prop2enoyl]3phenyllHpyrazol5amine(10b),l[2Cyano3(4methoxyphenyl)prop2enoyl]3phenyllHpyrazol5amlne(10c)and3[(5amino3phenyllHpyrazollyl)carbonyl]2Hchromen2one(12)

Generalprocedure:Equimolaramountsofcompound6(2.26g,0.01mol)in1,4dioxanecontaining



triethylamine(0.5mL)andeitherbenzaldehyde(1.06g,0.01mol),4chlorobenzaldehyde(1.43g,0.01mol),4methoxybenzaldehyde(1.39g,0.01mol)orsalicyladehyde(1.08g,0.01mol)wereheatedunderrefluxfor2hrsthenlefttocool.Thesolidproductformeduponpouringontoice/watercontainingfewdropsofhydrochloricacidwascollectedbyfiltration.

Compound10a:Paleyellowcrystalsfromethanol,yield66%(2.07g),m.p.12224oC.CalculatedforC19H14N4O(314.12):C,72.60H,4.49N,17.82Found:C,72.32H,4.69N,18.20.IR:3488,3350(NH2),3066(CHaromatic),2256(CN),1688(C=O),1655(C=N),1630(C=C).1HNMR:4.78(s,2H,NH2),6.53(s,1H,pyrazoleH4),7.267.35(m,10H,2C6H5),8.21(s,1H,CH=C).

Compound10b:Paleyellowcrystalsfromethanol,yield82%(2.85g),m.p.18790oC.CalculatedforC19H13ClN4O(348.79):Calcd:C,65.43H,3.76N,16.06Found:C,65.09H,4.16N,15.88.IR:3471,3364(NH2),3060(CHaromatic),2248(CN),1686(C=O),1650(C=N),1636(C=C).1HNMR:4.74(s,2H,NH2),6.58(s,1H,pyrazoleH4),7.257.34(m,9H,C6H5,C6H4),8.14(s,1H,CH=C).

Compound10c:Yellowcrystalsfromethanol,yield72%(2.47g),m.p.1658oC.CalculatedforC20H16N4O2(344.37):C,69.76H,4.68N,16.27Found:C,69.08H,4.25N,16.37.IR:3469,3325(NH2),3051(CHaromatic),2896(CH3),2250(CN),1688(C=O),1653(C=N),1640(C=C).1HNMR:2.89(s,3H,CH3),4.73(s,2H,NH2),6.61(s,1H,pyrazoleH4),7.297.36(m,9H,C6H5,C6H4),8.19(s,1H,CH=C).

Compound12:Orangecrystalsfrom1,4dioxanyield80%(2.64g),m.p.2304oC.CalculatedforC19H13N3O3(331.32):C,68.88H,3.95N,12.68Found:C,69.31H,4.42N,13.09.IR:3423,3310(NH2),3056(CHaromatic),2875(CH3),1690,1693(2C=O),1650(C=N),1631(C=C).1HNMR:4.65(s,2H,NH2),6.60(s,1H,pyrazoleH4),7.307.39(m,9H,C6H5,C6H4),8.21(s,1H,coumarinH4).

{[1(cyanoacetyl)3phenyl1Hpyrazol5yl]hydrazono}malononitrile(15)and2amino3{[1(cyanoacetyl)3phenyl1Hpyrazol5yl]hydrazono}prop1ene1,1,3tricarbonitrile(20)

Acoldsolution(05oC)ofthediazoniumsalt13(0.01mol)[preparedbyaddingsodiumnitritesolution(0.70g,0.01mol)toacoldsolution(05oC)ofcompound6(2.26g,0.01mol)inaceticacid(20mL)andhydrochloricacid(5.0mL)withcontinuousstirring]wasaddedtoasolutionofeithermalononitrile(0.66g,0.01mol)orcompound22(1.32g,0.01mol)inethanol(40mL)containingsodiumacetate(6.0g),withstirring.Aftercompleteadditionofthediazoniumsalt13,thereactionmixturewasstirredforanadditional6hrsatroomtemperatureandtheformedsolidproductwascollectedbyfiltration.

Compound15:reddishbrowncrystalsfromethanolyield68%(2.96g),m.p.15861oC.CalculatedforC15H9N7O(303.28):C,59.40H,2.99N,32.33Found:C,59.11H,3.38N,32.68.IR:34603327(NH),3051(CHaromatic),2870(CH2),2255,22272220(3CN),1690(C=O),1662(C=N).1HNMR:4.29(s,2H,CH2),6.63(s,1H,pyrazoleH4),7.337.36(m,5H,C6H5),8.30(s,1H,NH).

Compound20:reddishbrowncrystalsfrom1,4dioxanyield70%(2.58g),m.p.110oC.CalculatedforC18H11N9O(369.34):C,58.53H,3.00N,34.13Found:C,57.88H,2.68N,33.79.IR(/cm1)=3485,3345(NH2,NH),3058(CHaromatic),2877(CH2),2248,22292220(4CN),1688(C=O),1660(C=N),1633(C=C).1HNMR=4.37(s,2H,NH2),4.66(s,2H,CH2),6.69(s,1H,pyrazoleH4),7.327.36(m,5H,C6H5),8.36(s,1H,NH).

3amino6oxo9phenyl6Hpyrazolo[5,1:2,3]pyrimido[1,6b][1,2,4]triazine2carbonitrile(17)

Asolutionofcompound15(3.03g,0.01mol)inethanolicsodiumhydroxide(5%)washeatedunderrefluxfor4hrsthenpouredontoice/watercontaininghydrochloricacid(tillpH6).Theformedsolidproductwascollectedbyfiltration.Paleyellowcrystalsfromethanolyield56%(1.69g),m.p.>300oC.CalculatedforC15H9N7O(303.28):C,59.40H,2.99N,32.33Found:C,60.08H,3.32N,31.98.IR:3452,3346(NH2),3056(CHaromatic),2225(CN),1686(CO),1660(C=N),1636(C=C).1HNMR:4.72(s,2H,NH2),6.67,6.83(2s,2H,pyrazoleH4,pyrimidineH5),7.307.33(m,5H,C6H5).

3{5[(3,5diamino3Hpyrazol4yl)diazenyl]3phenyl1Hpyrazol1yl}3oxopropanenitrile(19a)and3{5[(3,5diamino1phenyl1Hpyrazol4yl)diazenyl]3phenyl1Hpyrazol1yl}3oxopropanenitrile(19b)



Generalprocedure:Equimolaramountsofcompound15(3.03g,0.01mol)andeitherhydrazinehydrate(0.5g,0.01mol)orphenylhydrazine(1.08g,0.01mol)washeatedunderrefluxfor30min.thenlefttocool.Thereactionmixturewasevaporatedundervacuumandtheremainingproductwastrituratedwithdiethylether.Theformedsolidproductwascollectedbyfiltration.

Compound19a:Whitecrystalsfromethanolyield62%(2.07g),m.p.1968oC.CalculatedforC15H13N9O(335.32):C,53.73H,3.91N,37.59Found:C,54.08H,4.41N,37.93.IR(/cm1)=34663346(2NH2),3062(CHaromatic),2252(CN),1685(CO),1657(C=N),1636(C=C).1HNMR:4.23(s,2H,CH2),4.68,5.31(2s,4H,2NH2),6.33(s,1H,pyrazoleH4),7.317.35(m,5H,C6H5).

Compound19b:Paleyellowcrystalsfromethanolyield55%(2.26g),m.p.130oC.CalculatedforC21H17N9O(411.42):Calcd:C,61.31H,4.16N,30.64Found:C,60.99H,4.53N,30.84.IR(/cm1)=34803328(NH2),3056(CHaromatic),2220(CN),1687(CO),1650(C=N),1639(C=C).1HNMR:4.26(s,2H,CH2),4.65,5.34(2s,4H,2NH2),6.37(s,1H,pyrazoleH4),7.277.38(m,10H,2C6H5).

4amino1[1(cyanoacetyl)3phenyl1Hpyrazol5yl]6imino1,6dihydropyridazine3,5dicarbonitrile(21)

MethodA:Asolutionofcompound15(3.03g,0.01mol)inabsoluteethanol(50mL)containingtriethylamine(0.5mL),malononitrile(0.66g,0.01mol)wasadded.Thereactionmixturewasheatedunderrefluxfor4hrsthenlefttocoolandtheprecipitatedproductwascollectedbyfiltration.

Method(B)Asolutionofcompound20(3.69g,0.01mol)inabsoluteethanol(40mL)containingtriethylamine(0.5mL)washeatedunderrefluxfor2hrsthenpouredontoicewater.Theformedsolidproductwascollectedbyfiltration.Yellowcrystalsfrom1,4dioxanyield66%(2.34g),m.p.2602oC.CalculatedforC18H11N9O(369.34):C,58.53H,3.00N,34.13Found:C,58.33H,3.17N,34.49.IR:3466,3315(NH2,NH),3047(CHaromatic),2890(CH2),2240,22272220(3CN),1691(C=O),1662(C=N),1636(C=C).1HNMR:4.67(s,2H,CH2),5.21(s,2H,NH2),6.67(s,1H,pyrazoleH4),7.307.35(m,5H,C6H5),8.33(s,1H,NH).

2[1(cyanoacetyl)3phenyl1Hpyrazol5yl]5imino4phenyl3thioxo2,3,4,5tetrahydro1,2,4triazine6carbonitrile(24)

Toasolutionofcompound15(2.26g,0.01mol)in1,4dioxan(30mL)containingtriethylamine(0.5mL),phenylisothiocyanate(1.30g,0.01mol)wasadded.Thereactionmixturewasheatedunderrefluxfor12hrsthenevaporatedundervacuum.Theremainingproductwastrituratedwithdiethyletherandthesolidifiedproductwascollectedbyfiltration.Orangecrystalsfromaceticacidyield55%(2.41g),m.p.1803oC.CalculatedforC22H14N8OS(438.47):C,60.26H,3.22N,25.56Found:C,59.99H,2.89N,25.84.IR:34803321(NH),3050(CHaromatic),2888(CH2),2240,2225(2CN),1689(C=O),1668(exocyclicC=N),1642(C=C).1HNMR:4.80(s,2H,CH2),6.64(s,1H,pyrazoleH4),7.327.39(m,5H,C6H5),8.29(s,1H,NH).

({1[2cyano2(phenylhydrazono)acetyl]3phenyl1Hpyrazol5yl}hydrazono)malononitrile(26a),{[1[2cyano2(phenylhydrazono)acetyl]3(3cyano4,5,6,7tetrahydro1benzothien2yl)1Hpyrazol5yl]hydrazono}malononitrile(26b),andethyl2{1[2cyano2(phenylhydrazono)acetyl]5[2(dicyanomethylene)hydrazino]1Hpyrazol3yl}4,5,6,7tetrahydro1benzothiophene3carboxylate(26c).

Generalprocedure:Toacoldsolutionofcompound15(3.03g,0.01mol)inethanol(50mL)containingsodiumhydroxide(10mL,20%g)eitherofbenzenediazoniumchloride(7)(0.01mol),oranyofthe2diazo4,5,6,7tetrahydrobenzo[b]thiophenederivatives25aor25bwasaddedwithcontinuousstirring.Thereactionmixture,ineachcasewaskeptatroomtemperatureforanadditional2hrsandtheformedsolidproduct,ineachcase,wascollectedbyfiltration.

Compound26a:Orangeredcrystalsfrom1,5dioxanyield63%(2.56g),m.p.144oC.CalculatedforC21H13N9O(407.39):C,61.91H,3.22N,30.94Found:C,62.08H,3.64N,31.41.IR:34663310(2NH),3060(CHaromatic),2246,22252220(3CN),1687(C=O),1665(exocyclicC=N),1639(C=C).1HNMR:6.65(s,1H,pyrazoleH4),7.317.36(m,10H,2C6H5),8.20,8.33(2s,2H,2NH).

Compound26b:Orangeredcrystalsfromaceticacidyield70%(3.44g),m.p.2203oC.Calculatedfor



C24H16N10OS(492.12):C,58.53H,3.27N,28.44.Found:C,59.03H,2.87N,28.82.IR:34863318(2NH),3054(CHaromatic),2242,22272220(4CN),1690(C=O),1657(C=N),1643(C=C).1HNMR:2.232.27(m,4H,2CH2),2.332.36(m,4H,2CH2),6.66(s,1H,pyrazoleH4),7.267.35(m,10H,2C6H5),8.21,8.32(2s,2H,NH2).

Compound26c:Orangeredcrystalsfromaceticacidyield70%(3.44g),m.p.2203oC.CalculatedforC26H21N9O3S(539.57):C,57.88H,3.92N,23.36S,5.94.Found:C,58.03H,3.55N,23.72S,6.33.IR:34863318(2NH),3054(CHaromatic),2242,22272220(4CN),1690(C=O),1657(C=N),1643(C=C).[1HNMR:2.232.27(m,4H,2CH2),2.332.36(m,4H,2CH2),6.66(s,1H,pyrazoleH4),7.267.35(m,10H,2C6H5),8.22,8.35(2s,2H,2NH)].

({1[2cyano3phenylbut2enoyl]3phenyl1Hpyrazol5yl}hydrazono)malononitrile(28)

Equimolaramountsofdrysolidofcompound15(3.03g,0.01mol),acetophenone(1.20g,0.01mol)andammoniumacetate(2.0g)wereheatedinanoilbathat140Cfor1hthenlefttocool.Thesolidifiedproductwastrituratedwithdiluteethanolandtheformedsolidproductwascollectedbyfiltration.Paleyellowcrystalsfromethanolyield55%(2.27g),m.p.27780oC.CalculatedforC23H15N7O(405.41):C,68.14H,3.73N,24.18.Found:C,67.77H,3.25N,23.69.IR:34553323(NH),3058(CHaromatic),2240,22292220(3CN),1687(C=O),1650(C=N),1633(C=C).1HNMR:2.89(s,3H,CH3),6.67(s,1H,pyrazoleH4),7.297.38(m,10H,2C6H5),8.24(s,1H,NH).

({1[(4amino2phenyl3thienyl)carbonyl]3phenyl1Hpyrazol5yl}hydrazono)malononitrile(29)

Amixtureofcompound28(4.05g,0.01mol)andelementalsulfur(0.32g,0.01mol)in1,4dioxan(40mL)containingtriethylamine(0.5mL)washeatedunderrefluxfor1hthenlefttocool.Thesolidproductformeduponpouringontoice/watercontainingfewdropsofhydrochloricacidwascollectedbyfiltration.Yallowcrystalsfrom1,4dioxanyield50%(2.18g),m.p.160oC.CalculatedforC23H15N7OS(437.48):C,63.15H,3.46N,22.41S,7.33.Found:C,63.08H,3.40N,22.88S,7.70.

IR:34803330(NH2,NH),3052(CHaromatic),2225,2221(2CN),1689(C=O),1656(C=N),1630(C=C).1HNMR:4.88(s,2H,NH2),6.21,6.64(2s,2H,thiopheneH5,pyrazoleH4),7.267.37(m,10H,2C6H5),8.26(s,1H,NH).

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Journal of the Chilean Chemical Society - Synthesis of Novel Pyrazole, Coumarin and Pyridazine...

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