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EuropeanJournalofChemistry3(1)(2012)5156

EuropeanJournalofChemistry

ISSN21532249(Print)/ISSN21532257(Online)2012EURJCHEMDOI:10.5155/eurjchem.3.1.5156.500

EuropeanJournalofChemistryJournalhomepage:www.eurjchem.com

Cyclocondensation,antimicrobialactivityandsemiempiricalAM1MOcalculationsofbenzopyronederivatives

HafezMohamedElShaaer

DepartmentofChemistry,FacultyofEducation,AinShamsUniversity,Roxy,11711,Cairo,Egypt

*Correspondingauthorat:DepartmentofChemistry,FacultyofEducation,AinShamsUniversity,Roxy,11711,Cairo,Egypt.Tel.:+201.12627069;fax:+202.2581243.Emailaddress:[email protected](H.M.ElShaaer).

ARTICLEINFORMATION ABSTRACTReceived:13August2011Receivedinrevisedform:06September2011Accepted:22September2011Online:31March2012

KEYWORDS

An efficient synthesis of 7amino9hydroxy6oxo6Hbenzo[c]chromene8carbonitrilederivatives (2,6) and 4methyl2oxo2Hchromene3carbonitrile (5) via Claisencondensation of 2hydroxyacetophenones (1,3) withethyl cyanoacetate inthepresenceof

sodiummetalisreported.Reactionof 5withthiosemicarbazidegave1(3cyano4methyl2oxoquinolin1(2H)yl)thiourea(7).Treatmentof 5 with 6,8dichloro4oxo4Hchromene3carboxaldehyde gave 4(2(6,8dichloro4oxo4Hchromen3yl)2hydroxyethyl)2oxo2Hchromene3carbonitrile (9). Further treatment of 5 with ethyl acetate followed bycondensationwith6,8dichloro3formylchromonegave7((6,8dichloro4oxo4Hchromen3yl)methyleneamino)9hydroxy6Hbenzo[c]chromen6one (12). Structures of theproductswereestablishedonthebasisofelementalanalysis,IR,1Hand13CNMR,massspectraand semiempirical AM1MO calculations. The antimicrobial activities of the synthesizedproductswerealsostudied.

SynthesisBenzopyrone4QuinolinoneCyclocondensationAM1MOcalculationAntimicrobialactivity

1.Introduction

Fused coumarins (2H1benzopyran2ones) comprise avery interesting class of compounds due to their significantantibacterial [1] and pharmacological activities [2]. Also,chromone (4H1benzopyran4one) derivatives exhibitsignificant biological activities, such as antifungal [3,4],

antimycobacterial[5,6],antialergic[ 7],antitumour[810],andantiviral[1112].So,andwiththeexpectativetofindbiologicalactivity, I decided to investigate the synthesisof some novelsystems of coumarin derivatives bearing chromone moiety.Recently, the synthesis [13], photochemical [14] andtheoretical [15] properties of chromone derivatives werelargelyinvestigated.

Theaimofthepresentpaperistoinvestigateanefficientsynthesisofcoumarinderivativescontainingactivemethylandcyanogroupsandstudytheircyclocondensationreactionswithethyl cyanoacetate, thiosemicarbazide, ethyl acetate and 6,8dichloro4oxo4Hchromene3carboxaldehyde. The antimicrobial activities for the prepared compounds wereinvestigated.Also,semiempiricalAM1andAbInitio(STO3G)molecular orbital calculations for the new compounds werestudiedandcomparedwiththeirexperimentaldata.

2.Experimental

2.1.Instrumentation

The uncorrected melting points were determined in anopencapillarytubeonadigitalStuartSMP3apparatus. 1H/13CNMRspectrawereobtainedona500/125MHzJeolEcaorona300/75.46MHzVarianMercuryVX300NMR spectrometerinDMSOd6 with tetramethylsilane as an internal standard.Elemental analyses were performed on Vario El Elementarapparatus. IR spectra were recorded on FTIR Nicolet IS10

spectrophotometer(cm1),usingKBrdisks.Massspectrawererecorded on a Gas Chromatographic GCMSqp 1000 exShimadzu instrument at 70 eV. Thermodynamic data wereobtainedfrommolecularmechanicalcalculations onthe basisof the semiempirical AM1 and Ab Initio (STO3G) methodswiththeHyperChem8.03computerprogram.2.2.

Synthesis

6,8Dichloro4oxo4Hchromene3carboxaldehyde (8)

was prepared according to [15]. The other chemicals werepurchasedfromthesuppliersasthehighestpuritygrade.2.2.1.7Amino2,4dichloro9hydroxy6oxo6Hbenzo[c]

chromene8carbonitrile(2)

Asolutionof3,5dichloro2hydroxyacetophenone(1)(4.0g,2mmol)inethylcyanoacetate(22cm3),sodiummetal(2g,8mmol) was added by small portion on the solution and thereactionmixture washeated on waterbath for2 h andthenheated under reflux for 1 h. The product was treated withwater and acidified with acetic acid. The solid obtained wasfiltered, and crystallized from acetic acidto give2 asyellow

crystals(Scheme1).7Amino2,4dichloro9hydroxy6oxo6Hbenzo[c]chromene8carbonitrile(2):Yield:29%.M.p.:270272C.FTIR(KBr,cm1):3350,3260,3197,3064,2981,2209,1736,1682,1616.1HNMR(300MHz,DMSOd6):2.50(m,3H,CH,CH2),4.19(m,2H,NH2,exchangeablewithD2O),8.028.09(m,2H,H1andH3), 8.88 (s, 1H, exchangeable with D2O), 9.19 (s, 1H,exchangeablewithD2O).13CNMR(75.46MHz,DMSOd6):60.0,72.0, 109.2, 117.5, 120.7, 120.9, 121.4, 122.3, 125.1, 129.1,132.5, 146.6, 150.4, 155.8, 163.2, 166.1. MS (EI, m/z (%)):322.4(M+1,15.9),322.8(M+2,18.2).

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52 ElShaaer/EuropeanJournalofChemistry3(1)(2012)5156

Scheme1

Scheme2

Anal. calcd. for C14H6Cl2N2O3: C, 52.36; H, 1.88; N, 8.72.

Found:C,52.54;H,2.00,N,8.72%.

2.2.2.4

Methyl

2

oxo

2H

chromene

3

carbonitrile

(5)

and

7

amino9hydroxy6oxo6Hbenzo[c]chromene8carbonitrile(6)

MethodA: Sodium metal (10 g, 43 mmol) was added insmallportiontoasolutionof2hydroxyacetophenone(3)(20.0g, 15 mmol) in ethyl cyanoacetate (110 cm3). The reactionmixturewasheatedonwaterbathfor3h,andthencooledtoroomtemperature,treatedwithethanol(30cm 3)andrefluxedfor1h.Thesolidobtainedwasfiltered,andcrystallizedfromcyclohexanetogive5asyellowcrystals,Yield:20%.M.p.:192194 C (Scheme 2 and 3). The ethanolic filtrate wasconcentratedtoitshalfamount,acidifiedwith96%aceticacidanddilutedwithwatertogive6as pallyellowcrystals,Yield:30%.M.p.:237238C(aceticacid).

4Methyl2oxo2Hchromene3carbonitrile(5):FTIR(KBr,

cm1

):3060,2920,2228,1723,1600.1

HNMR(500MHz,DMSOd6):2.69(s,3H,CH3),7.447.47(m,2H,H6andH8),7.76(t,J=7.65Hz,1H,H7),7.95(d,J=8.45Hz,1H,H5).13CNMR(125MHz,DMSOd6):18.7(),101.8(quat),114.8(quat),117.5(+),118.6(quat),125.8(+),127.6(+),135.8(+),153.2(quat),157.3(quat),164.2(quat).MS(EI,m/z(%)):184(M1,13.7),185(M,100.0),186(M+1,12.1).Anal.calcd.forC11H7NO2:C,71.35;H,3.81;N,7.56.Found:C,71.70;H,3.50;N,7.76%.

7amino9hydroxy6oxo6Hbenzo[c]chromene8

carbonitrile (6): FTIR (KBr, cm1): 3370, 3282, 3220, 3079,2987,2211,1705,1638,1609.1HNMR(300MHz,DMSOd6):2.47 (m, 3H, CH, CH2), 4.22 (m, 2H, NH2, exchangeable withD2O),7.437.49(m,2H,H2andH3),7.72(dd,J=7.2,1.2Hz,1H, H4), 7.93 (dd, J = 9.0, 1.2 Hz, 1H, H1), 9.00, (s, 1H,

exchangeablewithD2O),9.26(s,1H,exchangeablewithD 2O).13CNMR(75.46MHz,DMSOd6):59.9,72.1,116.5,117.7,118.5,121.0,124.9,126.2,133.2,151.0,152.2,157.1,164.3,166.4.MS

(EI,m/z(%)):252.5(M,5.1).Anal.calcd.forC 14H8N2O3:66.67;H,3.20;N,11.11.Found:C,66.52;H,3.00;N,11.50%.

MethodB:Asolutionofcompound5(0.5g,0.27mmol)inethoxide(0.15 g sodium,10 cm3 absoluteethanol), and thenethylcyanoacetate(1.0cm3)wasaddedandthemixturewasrefluxedonwaterbathfor2h,cooledtoroomtemperatureandacidifiedwith96%aceticacid.Thesolidobtainedwasfiltered,and crystallized from acetic acid to give 6 as pallyellowcrystals(Scheme2).M.p.:237238C.Yield:59%.2.2.3.1(3Cyano4methyl2oxoquinolin1(2H)yl)thiourea

(7)

A mixture of compound 5 (0.25 g, 0.13 mmol) andthiosemicarbazide(0.15g,0.16mmol)inpyridine(2cm 3)wasrefluxed for 5 h. The solid obtained was filtered, and

crystallizedfromethanoltogive7asorangecrystals(Scheme4and5).1(3Cyano4methyl2oxoquinolin1(2H)yl)thiourea (7):

Yield: 73%. M.p.:186187C. FTIR(KBr, cm1): 3368, 3263,3177,3061,2923,2228,1724,1601.1HNMR(300MHz,DMSOd6):2.73(s,3H,CH3),4.47(s,2H,NH2,exchangeablewithD2O),7.457.50(m,2H,H6andH8),7.77(dd,J=7.8,1.8Hz,1H,H5), 7.93 (dd, J = 7.8, 6.3 Hz, 1H, H7), 8.55 (s , 1H, NH,exchangeablewithD2O).13CNMR(75.46MHz,DMSOd6):18.1,101.2, 114.1, 116.9, 118.0, 120.7, 125.2, 127.0, 135.2, 152.6,156.6, 163.6. MS (EI, m/z (%)): 256 (M2, 16.7), 257 (M1,16.7), 258 (M, 13.3). Anal.calcd. for C12H10N4OS: C,55.80;H,3.90;N,21.69;S,12.41.Found:C,55.59;H,4.00;N,21.20;S,12.15%.

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ElShaaer/EuropeanJournalofChemistry3(1)(2012)5156 53

Scheme3

Scheme4

Scheme52.2.4.4(2(6,8Dichloro4oxo4Hchromen3yl)2

hydroxyethyl)2oxo2Hchromene3carbonitrile(9)

MethodA:Amixtureofcompound5(0.5g,0.27mmol)and6,8dichloro4oxo4Hchromene3carboxaldehyde(8)(0.66g,0.27 mmol) in dimethylformamide (10 cm3) was stirred atroomtemperature(25C)for4 h,leaveovernight,filteredoffandcrystallizedfromaceticacidtogive9asawhitecrystals(Scheme6).

4(2(6,8Dichloro4oxo4Hchromen3yl)2hydroxyethyl)

2oxo2Hchromene3carbonitrile (9): Yield: 60%. M.p.: 293294C.FTIR(KBr,cm 1):3743(br),3060,2226,1727,1652.1HNMR(500MHz,DMSOd6):2.07(d,J=6.9Hz,2H,CH2),2.85(br.s,1H,CH),7.397.52(m,2H,ArH),7.80(s,1H,H7),7.94(d,J=8.4Hz,1H,ArH),8.04(s,1H,H5),8.24(dd,J=9.95,6.1Hz,1H,ArH),9.08(s,1H,H2),10.05(s,1H,OH).MS(EI,m/z(%)):410(MH2O,43.3).Anal.calcd.forC21H11Cl2NO5:C,58.90;H,2.59;N,3.27.Found:C,58.75;H,2.23;N,3.56%.

MethodB:Amixtureofcompound5(0.5g,0.27mmol)and6,8dichloro4oxo4Hchromene3carboxaldehyde(8)(0.66g,0.27mmol)indimethylformamide(5cm3)wasrefluxedfor5min.ThesolidobtainedwasfilteredandpurifiedinthesamemannerasinmethodA,Yield:69%.2.2.5.

7

((6,8

Dichloro

4

oxo

4H

chromen

3

yl)methyleneamino)9hydroxy6Hbenzo[c]chromen6one(12)

Asolutionofcompound 5(0.5g,0.27mmol)inethoxide(0.15 g sodium, 10 cm3 absolute ethanol), and then ethylacetate(1.0cm3)wasaddedandthemixturewasrefluxedonwaterbathfor2h,cooledtoroomtemperatureandfilteredoff.The solid obtained (0.27 g) was mixed with acetic acid (2.5cm3), sodium acetate (0.3 g) and 6,8dichloro4oxo4Hchromene3carboxaldehyde (0.26 g, 0.1 mmol) and refluxedfor1h,filteredoffandcrystallizedfromethanoltogive12asapaleorangecrystals(Scheme7).

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Scheme6

7((6,8Dichloro4oxo4Hchromen3yl)methyleneamino)9hydroxy6Hbenzo[c]chromen6one (12): Yield: 65%. M.p.:183184 C. FTIR(KBr, cm1):3431 (br),3075, 1716, 1653,1602. 1HNMR(500MHz,DMSOd6):6.69(s,1H,CH=N),7.25(s,1H,ArH),7.377.43(m,2H,ArH),7.637.72(m,3H,ArH),7.96(s,1H,H5),8.02(s,1H,H2),8.168.22(m,1H,ArH),8.92(s, 1H, OH, exchangeable with D2O). Anal. calcd. forC23H11Cl2NO5:C,61.08;H,2.45;N,3.10.Found:C,61.42;H,2.15;N,2.75%.2.3.Antimicrobialactivity

Thenewlysynthesizedcompoundswerescreened againstGrampositive bacteria: Staphylococcus aureus (ATCC 25923)and Bacillus subtilis (ATCC 6635), Gramnegative bacteria:Salmonella typhimurium (ATCC 14028) and Escherichia coli(ATCC 25922), Yeast: Candida albicans (ATCC 10231) andFungus: Aspergillus fumigatus. The standardized discagardiffusionmethod[16]wasfollowedtodeterminetheactivityof

thesynthesizedcompoundsagainstthetestedmicroorganisms.The tested compounds were dissolved in dimethyl

formamide(DMF)solventandpreparedintwoconcentrations2 and 1 mg/mL. The antibiotic chloramphencol was used asstandard reference in the case of Gramnegative bacteria,Cephalothin was used as standard reference in the case ofGrampositive bacteria and Cycloheximide was used asstandardreferenceinthecaseofyeastsandfungi.3.Resultsanddiscussion

3.1.Chemistry

The Claisen condensation of 2hydroxyacetophenonederivativeswithethylacetateinthepresenceofsodiummetalgavedicarbonyl compoundderivativeswhichwere cyclized

undertheeffectofconc.sulfuricacidtogive2methylchromonederivatives[15].The novel and unexpected Claisen condensation of 3,5

dichloro2hydroxyacetophenone (1) with excess of ethylcyanoacetate in thepresence of sodium metal gave7amino2,4dichloro9hydroxy6oxo6Hbenzo[c]chromene8carbonitrile (2) (Scheme 1), but when unsubstituted 2hydroxyacetophenone (3) reacted under the same conditiongaveamixtureof4methyl2oxo2Hchromene3carbonitrile(5) (20%) and 7amino9hydroxy6oxo6Hbenzo[c]chromene8carbonitrile (6) (30%). When compound 5 wasreacted with ethyl cyanoacetate in the presence of sodiumethoxidegavecompound(6)(59%)(Scheme2).

Theformation of compounds 2 and 6 proceeded via,unsaturatedesterderivatives(4),whichcanbecyclizedunderthe effect of heat to give compound 5, further Claisencondensationonactivemethylgroupofcompound 5followedbynucleophiliccyclizationgavecompounds(2,6)(Scheme3).

The Claisen condensation of 3,5dichloro2hydroxyacetophenone (1) with ethyl cyanoacetate gave onlycyclocondensationproduct 2a 2b, while unsubstituted 2hydroxyacetophenone (3) gave a mixture of condensationproduct5andcyclocondensationproduct6a 6bduetothethermodynamicstabilitiesof 2a 2bthan 6a 6b (Table1).Also,theoreticalthermodynamicdata obtainedfromsemiempirical AM1MO calculations shows that structure 2b ismorestabilizedthan2aand6bthan6a(Table1).

Table 1. Calculated heat of formation of coumarin derivatives by semiempiricalAM1MOmethod.Compound Heat offormation(kcal/mol)2a 13.652b 43.635 2.516a 5.216b 34.779 72.4510 59.69

Thepresenceof cyano group in a 3position of coumarin

moiety facilitate thenucleophilicring additionon C=O groupfollowed by ring fission and recyclization, so the reaction ofthiosemicarbazide with compound 5 in pyridine gave 1(3cyano4methyl2oxoquinolin1(2H)yl)thiourea (7) (Scheme4)andthemechanismofformationofcompound7(Scheme5).

The reaction of compound 5 with 6,8dichloro4oxo4Hchromene3carboxaldehyde (8) in dimethylformamide atroom temperature (25 oC) and/or reflux for 5 min gaveaddition product 9 rather thanthe condensation product 10.Thepreferableformationof 9ratherthan10seemstobedueto the thermodynamic stabilities according to semiempiricalAM1calculationdata,wheretheHf=72.45kcal/molfor 9whichismuchmorestabilizedthanHf=59.69kcal/molof10(Table1) andalso forthe presenceof strong hydrogenbondbetween the C=O and the OHgroupsof chromone moiety ofcompound9(Scheme6).

TheClaisencondensationofcompound5withethylacetateinthepresenceofsodiumethoxidegavethesodiumsaltof7amino9hydroxy6Hbenzo[c]chromen6one (11) asintermediate product which upon treatmentwith 8 inaceticacid and sodium acetate gave 7((6,8dichloro4oxo4Hchromen3yl)methyleneamino)9hydroxy6Hbenzo[c]chromen6one(12)(Scheme7).

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ElShaaer/EuropeanJournalofChemistry3(1)(2012)5156 55

Scheme73.2.Molecularorbitalcalculations

The experimental IR frequencies of C=O groups ofcoumarin derivatives were compared with theoretical bondlengths of C=O groups which were obtained from molecularmechanicalcalculationsonthebasisofthesemiempiricalAM1andAbInitio(STO3G)methodsofHyperChem8.03computerprogram after geometrical optimization of the structures forcompounds(212)(Table2).

Table 2.CalculatedbondlengthsofC=OofcoumarinderivativesbysemiempiricalAM1 andAb Initio(STO3G)methods andtheirexperimentalIRC=Ovaluesforcompounds(2a12).

CompoundBondlengthsofC=O,

ExperimentalC=O(cm1)Semiempirical(AM1)

AbInitio(STO3G)

2a 1.22484a 1.21413 17362a 1.2303b 1.21421 16825 1.228a 1.217 17236a 1.22623a 1.21621 1705

6a 1.2309b 1.21456 16807 1.2353c 1.2208 17249 1.22853a 1.21732 17279 1.23831b 1.44367 165212 1.22777a 1.21652 171612 1.23908b 1.45056 1653rd 0.914 0.987 aCOcoumarinbC=OchromoneorcyclicketonecC=Oquinolinonedr=regressioncoefficient.

ThecalculatedbondlengthsofC=Ogroups()onthebasis

of semiempirical AM1 method are linearly related to themeasured IR C=O groups (cm1) for compounds (212) andfromthelinearrelationbondlength(C=O)=1.470.001C=O,r = 0.9140 except (7), where r is regression coefficient. Thenegativesloperevealsindirectproportionalityofthecalculated

bondlengthswithmeasuredC=Ovalues,whichagreementwithHookeslawandthesesupporttheproposedstructuresforthepreparedcompounds.Ontheotherhand,whenAbInitio(STO3G)methodwasused,thelinearrelationbondlength(C=O)=1.11+6.25x105 C=O, r = 0.9870 except (2a, 7, 9b and 12b)whichislessefficientmethodthanthelastmethod.

Also, thecalculated netcarbonchargesby semiempiricalAM1 and Ab Initio (STO3G) methods after geometricaloptimization were compared with experimental 13C NMR valuesforcompound5(Table3).

The calculated net carbon charges on the basis of semiempiricalAM1methodarelinearlyrelatedtotheexperimental13C NMR ( in ppm) for compound 5 and from the linear

relation charges on carbon atoms = 0.74 + 0.005 13C NMR,r = 0.9200, except (C2 and C10), where r is regression

coefficient.Thepositivesloperevealsdirectproportionalityofthe calculated net carbon charges withmeasured 13CNMR values,whichsupporttheproposedstructureforcompound 5.Also, when Ab Initio (STO3G) method was used, the linearrelation charges on carbon atoms = 0.25 + 0.002 13C NMR,r = 0.8340, except (C2 and C9),which less agreementwithexperimental data than semiempirical AM1 method. Thedependence of 13C NMRshiftson the net carbon charges forcompound5ismorepronouncedthanthatfoundofIR( C=O)and their bond lengths for compounds (212), as indicatedfromslopevaluesofsemiempiricalAM1method.

Table3.CalculatednetcarbonchargesbysemiempiricalAM1andAbInitio(STO3G)methodsandtheirexperimental13CNMRvaluesforcompound5.

Carbonnumber

CalculatednetcarbonchargesExperimental13CNMR(ppm)Semiempirical

(AM1)AbInitio(STO3G)

C2 0.350 0.319 164.24C3 0.125 0.042 118.66C4 0.098 0.066 153.25C5 0.067 0.048 135.86C6 0.159 0.070 117.54C7 0.073 0.043 127.69C8 0.150 0.075 125.89C9a 0.153 0.036 101.85C10a 0.118 0.142 157.32C9 0.086 0.073 114.80C10 0.210 0.189 18.79r* 0.920 0.834 *r=regressioncoefficient.3.3.Antimicrobialactivity

ThenewlysynthesizedcompoundswerescreenedagainstGrampositive bacteria: Staphylococcus aureus (ATCC 25923)and Bacillus subtilis (ATCC 6635), Gramnegative bacteria:Salmonella

typhimurium (ATCC 14028) and Escherichia coli

(ATCC 25922), Yeast: Candida albicans (ATCC 10231) andFungus: Aspergillus fumigatus. The standardized discagardiffusionmethod[11]wasfollowedtodeterminetheactivityofthesynthesizedcompoundsagainstthetestedmicroorganisms.

Compound 12 showed high activities againstAspergillusfumigatesatconcentrationof2mgand1mg,whileitshowedintermediateactivitiesagainstBacillussubtilis,Escherichiacoliand Candida albicans. Compound 9 showed intermediateactivitiesagainstBacillus subtilis,Escherichia coliandCandidaalbicans(Table4).

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Table4.Antimicrobialactivitiesdataofcompounds212.

Sample

Meanofzonediametera,mmGrampositivebacteria Gramnegativebacteria Yeastsb

Staphylococcus

aureus

(ATCC25923)

Bacillus

subtilis

(ATCC6635)

Salmonella

typhimurium

(ATCC14028)

Escherichia

coli

(ATCC25922)

Candida

Albicans

(ATCC10231)

Aspergillus

fumigatus

Conc.g 2 1 2 1 2 1 2 1 2 1 2 12 4Ld 2L 3L c 2L 4L 2L 2L 5 3L 2L 3L 2L 2L 7L 4L 7 6L 4L 3L 9L 5L 2L 6 6L 4L 3L 9L 5L 2L 9 8L 5L 15Ie 11I 18I 12I 18I 13I 8L 5L12 6L 3L 13I 9L 4L 17I 12I 20I 17I 28Hf 20HControlh 42 28 38 30 36 25 38 30 40 28 40 31

aCalculatefrom3values.bIdentifiedonthebasisofroutinecultural,morphologicalandmicroscopicalcharacteristics.c:Noeffect.dL:Lowactivity=Meanofzonediameter1/3ofmeanzonediameterofcontrol.eI:Intermediateactivity=Meanofzonediameter2/3ofmeanzonediameterofcontrol.fH:Highactivity=Meanofzonediameter>2/3ofmeanzonediameterofcontrol.gConcentration,mg/mL.hChloramphencolinthecaseofGrampositivebacteria,CephalothininthecaseofGramnegativebacteriaandcycloheximideinthecaseoffungi.

4.Conclusion

The Claisen condensation of 2hydroxaceophenonederivatives with ethyl cyanoacetate gave condensation and

cyclocondensation products with different nucleophilicreagents and depends on the reactivity of 2hydroxyacetophenone, nucleophilic reagents, and the thermodynamicstabilitiesoftheproducts.Also,theantimicrobialactivitiesforthe prepared compounds indicated that when coumarinderivatives bear a chromone moiety, the biological activitiesareincreasedcomparedwithotherpreparedderivatives.References

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[3]. Ali,T.E.;AbdelAziz,S.A.;ElShaaer,H.M.;Hanafy,F.I.;ElFauomy,A.Z.PhosphorusSulfur2008,183,21392160

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