Journal of The Chilean Chemical Society - Synthesis of Novel Pyrazole, Coumarin and Pyridazine Derivatives Evaluated As Potential Antimicrobial and Antifungal Agents

7/25/2015 JournaloftheChileanChemicalSocietySYNTHESISOFNOVELPYRAZOLE,COUMARINANDPYRIDAZINEDERIVATIVESEVALUATEDASPO
JournaloftheChileanChemicalSociety
versinOnlineISSN07179707
J.Chil.Chem.Soc.v.52n.2Concepcinjun.2007
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J.Chil.Chem.Soc,52,N2(2007)pgs.:11451149
SYNTHESISOFNOVELPYRAZOLE,COUMARINANDPYRIDAZINE
DERIVATIVESEVALUATEDASPOTENTIALANTIMICROBIALAND
ANTIFUNGALAGENTS
WAGNATW.WARDAKHAN*AANDNADIAA.LOUCAB
a NationalOrganizationforDrugControl&Research(NODCAR),P.O.29,CairoA.R.Egypt. bHormones
Department,NationalResearchCenter,Dokki,A.R.Egypt
Direccinparacorrespondencia
ABSTRACT
ThereactionofcyanoacetylhydrazinewithbromoacetophenonegavetheN
[2bromo1
phenylethylidene]2isocyanoacetohydrazide(3).Thelattercompoundunderwentreadycyclization
whentreatedwithpotassiumcyanidetogivethe1(isocyanoacetyl)3phenyl1Hpyrazol5amine(6).
Compound6underwentaseriesofheterocyclizationtogiveeithercoumarin,pyridazine,1,2,4triazine
http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S071797072007000200006
1/12
orthiophenederivatives.Theantimicrobialandantifungalactivitiesofthenewlysynthesizedproducts
weremeasured,usingtwoGramnegative(EscherichiacoliandPseudomonasaeruginosa),twoGram
positivebacteria(BacillussubtilisandBacilluscereus)andtheantifungalactivityusingCandida
albicans.
Keywords:Cyanoacetylhydrazine,Pyrazole,Coumarin,Pyridazine
INTRODUCTION
Thepyrazoleringisaprominentstructuralmotiffoundinnumerouspharmaceuticallyactive
compounds.Thisismainlyduetotheeasepreparationandtheimportantbiologicalactivity.Pyrazole
frameworkplaysanessentialroleinbiologicallyactivecompoundsandthereforerepresentsan
interestingtemplateforcombinatorialaswellasmedicinalchemistry110Indeed,pyrazolebased
derivativeshaveshownseveralbiologicalactivitiesasseenasanxiolytics,11GABAreceptorantagonists
andinsecticides,12apotentialPETligandforCB1receptors,13antiinflammatoryandantimicrobial
agents14andgrowthinhibitionactivity.15
RESULTSANDDISCUSSION
Inthisworkwereportanovelmethodforthesynthesisofpyrazolederivativesstartingwith
cyanoacetylhydrazine(1)and(0bromoacetophenone(2)followedbyheterocyclizationtothepyrazole
derivative.Thus,thereactionbetweenthetworeagentsin1,4dioxanatroomtemperaturegavea
singleproductwithmolecularformulaC11H10N3OBr.Twopossibleisomericstructureswereconsidered
forthereactionproductdependingonthewayofcondensationreaction,either3or4.Thepossibilityof
structure4wasruledoutonthebasisofIRspectrumwhichshowedtheabsenceofanyNH2stretching,
andthe1HNMRspectrumwhichrevealedthepresenceoftwosingletsat4.48,5.23correspondingto
twoCH2groups,amultipletat7.267.31forthephenylprotonsandasinglet(D2Oexchangeable)at
8.31fortheNHgroup.Suchdataareconsistentwiththestructureofthehydrazidehydrazone
derivative3.Compound3,reactswithpotassiumcyanidetogivethe1(cyanoacetyl)3phenyl1//
pyrazol5amine6viatheintermediateformationoftheacyclicintermediate5.TheIRspectrumofthe
reactionproductshowedthepresenceofanNH2stretchingat1)3466,3380correspondingtoanNH2
groupandonlyoneCNgroupstretchingat2256.Moreover,the1HNMRspectrumshowedthe
presenceofasingletat4.67correspondingtoCH2group,asingletat4.88(D2Oexchangeable)
correspondingtoNH2group,asingletat6.56forpyrazoleH4andamultipletat7.307.36forphenyl
protons.The 13CNMRspectrumshowed18.2(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).
Compound6underwentmanychemicaltransformationsduetothepresenceofthe1cyanoacetyl
moietyandthe5aminogroup.Thus,thereactionofbenzenediazoniumchloride7withcompound6at
05oCgavethephenylhydrazonederivative.Ontheotherhand,withthearomaticaldehydes9ac
gavethearylidenederivatives10ac,respectively.Theanalyticalandspectraldataofthereaction
productsareconsistentwiththeproposedstructures(seeexperimentalsection).Ontheotherhand,the
reactionofcompound6withsalicylaldehyde11gavethecoumarinderivative12.TheIRand1HNMR
spectraagreewiththeproposedstructures(Scheme1).Formationofmanycoumarinderivativesby
thismethodhasbeenreportedbefore.1618
2/12
Theaminogrouppresentincompound6isreadyfordiazotizationinawaysimilarwiththatreported
workbyElnagdiandRenetal.19,20Thus,asolutionofcompound6inacetic/hydrochloricacidsreacts
withsodiumnitriteat05 o Ctogivethenonisolablediazoniumchloridesalt13.Thereactionofthe
intermediatediazoniumsalt13withmalononitrile(14)gavethehydrazonederivative15.Structureof
thelatterproductwasbasedontheanalyticalandspectraldata.Thus,IRspectrumshowedthe
presenceofNHstretchingat34603327cm1,threeCNgroupsstretchingat2255,22272220cm1.
Compound15underwentreadycyclizationwhenheatedinethanolicsodiumhydroxidesolutiontogive
thepyrazolo[1,5:1,2]pyrimidino[1,66]1,2,4triazinederivative17.Formationofthelatterproductis
expectedviatheintermediateformationofthepyrazolo[1,5a]pyrimidinederivative16.Structureof
compound17wasestablishedonthebasisofanalyticalandspectraldata(seeexperimentalsection).
Moreover,compound15reactedwitheitherhydrazinehydrate(18a)orphenylhydrazine(18b)togive
thepyrazolo4yl5azopyrazolederivatives19aand19b,respectively(Scheme2).
3/12
Thereactionofcompound15withmalononitrile(14)inethanolcontainingacatalyticamountof
triethylaminegavethe1pyrazol5ylpyridazinederivative21,thereactiontookplacethroughthe
intermediateformationoftheacyclicstructure20followedbyMichaelcyclization.Formationofthe
latterproductwasbasedontheanalyticalandspectraldata(seeexperimentalsection)besideits
synthesisviaanotherreactionroute.Thus,thereactionofthediazoniumsalt13withPaminoa,y
dicyanocrotononitrile(22)at05oCaffordedtheacyclichydrazonederivative20.Heatingofthelatter
productinethanolic/triethylaminesolutiongavethesameproduct21(mixedm.p.andfingerprintIR
spectra).
Thereactionofcompound15withphenylisothiocyanate(23)gavethe1pyrazol5yl1,2,4triazine
derivative24(Scheme3).Theanalyticalandspectraldataofthelatterproductareconsistentwiththe
proposedstructure(seeexperimentalsection).
4/12
Compound15coupledwiththediazoniumsalts7,25aand25btogivethehydrazonederivatives26a
c,respectively.Analyticalandspectraldataofthelatterproductsareagreewiththeproposed
structures(seeexperimentalsection).Ontheotherhand,compound15reactswithacetophenone(27)
inthepresenceofammoniumacetateat140 o Ctogivethecondensedproduct28.Thelatterproduct
reactswithelementalsulfurinthepresenceoftriethylaminetoaffordthethiophenederivative29
(Scheme4).
5/12
INVITROANTIMICTOBIALANDANTIFUNGALACTIVITIESEVALUATION
AnevaluationoftheantibacterialactivityusingtwoGramnegative(EscherichiacoliandPseudomonas
aeruginosa)andtwoGrampositivebacteria(BacillussubtilisandBacilluscereus)andtheantifungal
activityusingCandidaalbicansasarepresentativespeciesoffungiwasassessedforcompounds.The
minimalinhibitoryconcentration(MICing/mL)wasdeterminedusinganadaptationofagarstreak
dilutionmethodbasedonradialdiffusion.21,22Inthesameconditionsdifferentconcentratedsolutionsof
ampicillin(antibacterial)andcycloheximide(antifungal)wereusedasstandards.TheMICwas
consideredtobethelowestconcentrationofthetestedcompoundwhichinhibitsgrowthofbacteriaor
fungiontheplate.ThediametersoftheinhibitionzonescorrespondingtotheMICsarepresentedin
Table1.ThecompoundstestedarenotactiveagainstPseudomonasaeruginosastartingfromDMSO
solutionsof1000g/mLofeachcompound.
Table1:Theantimicrobialactivityofthenewlysynthesizedproducts
Compound
E.coli
ECT101
MICing/mL(zoneofinhibitioninmm)
B.Cereus
CECT148
B.subtilis
CECT498
C.albicans
CECT1394
Notactive
25(8)
23(6)
26(3)
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)
6/12
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),thesubstitutedpyrazolemoiety
beingtheresponsibleforsuchactivity.However,theannulatedderivative17showedthehighest
activity.AgainstGram+bacteriatheMICsfor10caremuchhigherthanthosefor10a.Comparing3
with10aand10c(thepyridinederivative),compound3(haloketone)seemedtobemoreactive
againstB.cereus(MIC3.13g/mL)butlessactiveagainstB.subtilis.AgainstC.albicans10b(4
chlorophenyl)and10c(4methoxyphenyl)presentthesameMIC(25g/mL)whichishigherthanthe
MICobtainedfor3(50g/mL).Compound12(withthecoumaringroup)showedthehighestativity
againstC.albicans.
Comparingcompounds26a,26band26c,onecannoticethat26a(withthephenylhydrazonogroup)
showedhighestMICvalueagainstC.albicanswhereas26cshowedtheleastvalue.Fortheinvitro
antimicrobialactivity,suspensionsofthemicroorganismwerepreparedtocontainapproximately108
7/12
cfu/mLandtheplateswereinoculated.Astocksolutionofthesynthesized
compound(1000|lg/mL)inDMSOwaspreparedandgradeddilutionsofthetestedcompoundswere
incorporatedinacavity(depth3mm,diameter4mm)madeinthecenterofthepetridish(nutrient
agarforantibacterialactivityandSabouraudvsdextroseagarmediumforantifungalactivity).The
plateswereincubatedat37oC(forbacteria)andat30oC(forfungi)for24hinduplicate.Positive
controlusingonlyinoculationandnegativecontrolusingonlyDMSOinthecavitywerecarriedout.
CONCLUSION
Theworkdescribedinthisarticleshowedanovelmethodforthesynthesisofpyrazolesandtheir
derivativesstartingfromahydrazidehydrazonederivativeobtainedthroughthereactionofffl
bromoacetophenoneandcyanoacetylhydrazine.Thus,Uponusingavarietyofahaloketonesasstarting
materialsanewfieldisopenedthroughwhichanewseriesofpyrazolesthatcanundergo
heterocyclizationintoalargenumberoffusedheterocycles.Mostofthesynthesizedproductsshowed
antimicrobialandantifungalactivities.
EXPERIMENTAL
Meltingpointsareuncorrected.IRspectrawererecorded(KBr)onaPyeUnicamSP1000
spectrophotometer.1HNMRspectrawereobtainedonaVarianGemini200MHzspectrometerinDMSO
d6assolventandTMSasinternalreference.Chemicalshiftsareexpressedasppm.
iV[2bromolphenylethylidene]2isocyanoacetohydrazide(3)
Toasolutionofcyanoacetylhydrazine(1)(0.01mol,1.0g)in1,4dioxan(50mL),ffl
bromoacetophenone(0.01mol,2.0g)wasadded.Thereactionmixturewasstirredatroom
temperaturefor6hrs.Theformedsolidproductwascollectedbyfiltration.Whitecrystalsfrom1,4
dioxan,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(CH
aromatic),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(2.8
g,0.05mol)wasadded.Thereactionmixturewasheatedinawarmwaterbathat60oCfor30min.
thenleftwithstirringatroomtemperatureforanadditionalonenight.Thesolidproductformedupon
pouringontoice/watercontaininghydrochloricacid(tillpH6)wascollectedbyfiltration.Paleyellow
crystalsfromethanol,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(CH
aromatic),2256(CN),1690(C=O),1655(C=N),1634(C=C).1HNMR:4.67(s,2H,CH2),4.88(s,2H,
NH 2),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)containingsodium
acetate(8.0g),benzenediazoniumchloride(0.01mol)[preparedbyaddingsodiumnitritesolution(0.7
g,0.01mol)toacoldsuspension(05oC)ofaniline(0.94g,0.01mol)intheappropriatequantityof
hydrochloricacidwithcontinuousstirring]wasadded.Thereactionmixturewaskeptatroom
temperatureforanadditional1handtheformedsolidproductwascollectedbyfiltration.Orangered
crystalsfrom1,4dioxan,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(CH
aromatic),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(4
chlorophenyl)prop2enoyl]3phenyllHpyrazol5amine(10b),l[2Cyano3(4
methoxyphenyl)prop2enoyl]3phenyllHpyrazol5amlne(10c)and3[(5amino3phenyllH
pyrazollyl)carbonyl]2Hchromen2one(12)
Generalprocedure:Equimolaramountsofcompound6(2.26g,0.01mol)in1,4dioxanecontaining
8/12
triethylamine(0.5mL)andeitherbenzaldehyde(1.06g,0.01mol),4chlorobenzaldehyde(1.43g,0.01
mol),4methoxybenzaldehyde(1.39g,0.01mol)orsalicyladehyde(1.08g,0.01mol)wereheated
underrefluxfor2hrsthenlefttocool.Thesolidproductformeduponpouringontoice/watercontaining
fewdropsofhydrochloricacidwascollectedbyfiltration.
Compound10a:Paleyellowcrystalsfromethanol,yield66%(2.07g),m.p.12224 o C.Calculatedfor
C19H14N4O(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.18790 o C.Calculatedfor
C19H13ClN4O(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.1658 o C.Calculatedfor
C20H16N4O2(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). 1H
NMR: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.2304 o C.Calculatedfor
C19H13N3O3(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(05 o C)ofthediazoniumsalt13(0.01mol)[preparedbyaddingsodiumnitritesolution
(0.70g,0.01mol)toacoldsolution(05 o C)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,thereactionmixturewasstirred
foranadditional6hrsatroomtemperatureandtheformedsolidproductwascollectedbyfiltration.
Compound15:reddishbrowncrystalsfromethanolyield68%(2.96g),m.p.15861 o C.Calculatedfor
C15H9N7O(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.110 o C.Calculatedfor
C18H11N9O(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),7.32
7.36(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%)washeatedunder
refluxfor4hrsthenpouredontoice/watercontaininghydrochloricacid(tillpH6).Theformedsolid
productwascollectedbyfiltration.Paleyellowcrystalsfromethanolyield56%(1.69g),m.p.>300
o C.CalculatedforC H N O(303.28):C,59.40H,2.99N,32.33Found:C,60.08H,3.32N,31.98.
15 9 7
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}3
oxopropanenitrile(19b)
9/12
Generalprocedure:Equimolaramountsofcompound15(3.03g,0.01mol)andeitherhydrazinehydrate
(0.5g,0.01mol)orphenylhydrazine(1.08g,0.01mol)washeatedunderrefluxfor30min.thenleftto
cool.Thereactionmixturewasevaporatedundervacuumandtheremainingproductwastrituratedwith
diethylether.Theformedsolidproductwascollectedbyfiltration.
Compound19a:Whitecrystalsfromethanolyield62%(2.07g),m.p.1968 o C.Calculatedfor
C15H13N9O(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.130 o C.Calculatedfor
C21H17N9O(411.42):Calcd:C,61.31H,4.16N,30.64Found:C,60.99H,4.53N,30.84.IR(/cm
1)=34803328(NH
2),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]6imino1,6dihydropyridazine3,5
dicarbonitrile(21)
MethodA:Asolutionofcompound15(3.03g,0.01mol)inabsoluteethanol(50mL)containing
triethylamine(0.5mL),malononitrile(0.66g,0.01mol)wasadded.Thereactionmixturewasheated
underrefluxfor4hrsthenlefttocoolandtheprecipitatedproductwascollectedbyfiltration.
Method(B)Asolutionofcompound20(3.69g,0.01mol)inabsoluteethanol(40mL)containing
triethylamine(0.5mL)washeatedunderrefluxfor2hrsthenpouredontoicewater.Theformedsolid
productwascollectedbyfiltration.Yellowcrystalsfrom1,4dioxanyield66%(2.34g),m.p.2602 o C.
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),7.30
7.35(m,5H,C6H5),8.33(s,1H,NH).
2[1(cyanoacetyl)3phenyl1Hpyrazol5yl]5imino4phenyl3thioxo2,3,4,5tetrahydro
1,2,4triazine6carbonitrile(24)
Toasolutionofcompound15(2.26g,0.01mol)in1,4dioxan(30mL)containingtriethylamine(0.5
mL),phenylisothiocyanate(1.30g,0.01mol)wasadded.Thereactionmixturewasheatedunderreflux
for12hrsthenevaporatedundervacuum.Theremainingproductwastrituratedwithdiethyletherand
thesolidifiedproductwascollectedbyfiltration.Orangecrystalsfromaceticacidyield55%(2.41g),
m.p.1803 o C.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(3cyano4,5,6,7tetrahydro1benzothien
2yl)1Hpyrazol5yl]hydrazono}malononitrile(26b),andethyl2{1[2cyano2
(phenylhydrazono)acetyl]5[2(dicyanomethylene)hydrazino]1Hpyrazol3yl}4,5,6,7
tetrahydro1benzothiophene3carboxylate(26c).
Generalprocedure:Toacoldsolutionofcompound15(3.03g,0.01mol)inethanol(50mL)containing
sodiumhydroxide(10mL,20%g)eitherofbenzenediazoniumchloride(7)(0.01mol),oranyofthe2
diazo4,5,6,7tetrahydrobenzo[b]thiophenederivatives25aor25bwasaddedwithcontinuousstirring.
Thereactionmixture,ineachcasewaskeptatroomtemperatureforanadditional2hrsandthe
formedsolidproduct,ineachcase,wascollectedbyfiltration.
Compound26a:Orangeredcrystalsfrom1,5dioxanyield63%(2.56g),m.p.144 o C.Calculatedfor
C21H13N9O(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,2C H ),8.20,8.33(2s,2H,2NH).
6 5
Compound26b:Orangeredcrystalsfromaceticacidyield70%(3.44g),m.p.2203 o C.Calculatedfor
10/12
C24H16N10OS(492.12):C,58.53H,3.27N,28.44.Found:C,59.03H,2.87N,28.82.IR:3486
3318(2NH),3054(CHaromatic),2242,22272220(4CN),1690(C=O),1657(C=N),1643(C=C). 1H
NMR: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.2203 o C.Calculatedfor
C26H21N9O3S(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,pyrazoleH
4),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.The
solidifiedproductwastrituratedwithdiluteethanolandtheformedsolidproductwascollectedby
filtration.Paleyellowcrystalsfromethanolyield55%(2.27g),m.p.27780 o C.Calculatedfor
C23H15N7O(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(40
mL)containingtriethylamine(0.5mL)washeatedunderrefluxfor1hthenlefttocool.Thesolid
productformeduponpouringontoice/watercontainingfewdropsofhydrochloricacidwascollectedby
filtration.Yallowcrystalsfrom1,4dioxanyield50%(2.18g),m.p.160 o C.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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