Synthesis and Antioxidant Activity of Some Derivatives of 2 2 Oxo 4 Phenyl 2h Chromen 7 Yloxy Aceto...

7/29/2019 Synthesis and Antioxidant Activity of Some Derivatives of 2 2 Oxo 4 Phenyl 2h Chromen 7 Yloxy Aceto Hydrazide

1/16

J. Atoms and Molecules/ 3(4); 2013 / 537552 Eliwa ME et al

All rights reserved 2011 www.jamonline.in 537

Research Article

Journal of Atoms and MoleculesAn International Online JournalAn International Online JournalAn International Online JournalAn International Online Journal

ISSNISSNISSNISSN 2277227722772277 1247124712471247

SYNTHESIS AND ANTIOXIDANT ACTIVITY OF SOME DERIVATIVES OF 2-(2-OXO-4-

PHENYL-2H-CHROMEN-7-YLOXY) ACETO-HYDRAZIDE

Mahmoud Mohamed Abd El-All1,2

, Ahmed Hamdy Halawa1, Ahmed Abd El-Hameed

Hassan1,3

, Mohamed Ahmed El-Nassag1, Gehad Abd El-Raheem Abd El-Jaleel

4, Essam

Mohamed Eliwa1*

, Ahmed Hammam Bedair1

1Chemistry Department, Faculty of Science, AlAzhar University, 11284, Nasr City, Cairo, Egypt2Chemistry Department, Faculty of Science and Art, Al-Baha University, 1988, Al-Baha, Saudi

Arabia3Chemistry Department, Faculty of Medicine, Jazan University, 82621, Jazan, Saudi Arabia

4Pharmacology Department, National Research Center, 12622, Dokki, Cairo, Egypt

Received on: 03-06-2013 Revised on: 18-07-2013 Accepted on: 28072013

ABSTRACT:

A novel series of compounds containing coumarinyl moiety derivatives from 2-(2-oxo-4-phenyl-

2H-chromen-7-yloxy)-acetohydrazide (2) were synthesized. The formed compounds have been

evaluated by correct elemental analysis and spectral data (IR, MS,1H-NMR and

13C-NMR). The

antioxidant evaluation of some selected compounds indicated that tosyl hydrazide derivative 7revealed promising antioxidant activity.

KEY WORDS: Coumarin acetohydrazide, Schiffs bases, oxadiazole, thiazolidinone, pyrazole,antioxidant activity.

INTRODUCTION:

Coumarin and its derivatives are a class of the

most active heteroaromatic compounds that

have drawn much attention due to theirbiological and pharmaceutical activities [1-9].

Many of these com-pounds have proved to be

active as anticancer [10], antifungal [11],

antibacterial [12, 13], antitumor [14], anti-

HIV [15], anti-inflammatory [16],

anticoagulant [17] and antiviral activities

including human immunodeficiency virus

activities are well known [18].

On the other hand, a large number ofhydrazides have been reported to be of

biological interest [19, 20], while oxadiazole

* Corresponding author

Essam Mohamed Eliwa,

Email:[email protected] : +2.0128.5126895


2/16



derivatives have been reported to possess

antibacterial [21, 22], antifungal [23, 24] and

other biological activities. Furthermore, a

number of substituted pyrazoles were found to

exhibit appreciable biological and

chemotherapeutic activities [25-32]. It was

therefore thought worthwhile to incorporate

the hydrazide, oxadiazole and pyrazole

moieties into the coumarin nucleus.

RESULTS AND DISCUSSION

Chemistry

Applying the hydrazinolysis of ethyl 2-(2-

oxo-4-phenyl-2H-chromen-7-yloxy) acetate

(1) [33]with hydrazine hydrate in ethanol at

refluxing temperature, 2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy) acetohydrazide (2) was

obtained in good yield (Scheme 1).

On the other hand, refluxing 2 in formic acid

for 5 hours affo-rded the N-formyl derivative

3 in high yield. Condensation of 3 with 4-

aminobenzoic acid in acetonitrile as a medium

containing a few drops of acetic acid gave 4-

((2-(2-(2-oxo-4-phenyl-2H-chromen-7-

yloxy)acetyl)hydrazinyl)

methyleneamino)benzoic acid (4) as the sole

product. Acetylation of hydrazide compound

2 by refluxing in acetic acid, afforded N'-

acetyl-2-(2-oxo-4-phenyl-2H-chromen-7-

yloxy) acetohydrazide (5). Also, condensation

of hydrazide 2 with 4-nitrobenzoic acid in the

presence of phosphorousoxychloride under

reflux yielded 7-((5-(4-nitrophenyl)-1, 3, 4-

oxadiazol-2-yl) methoxy)-4-phenyl-2H-

chromen-2-one (6) in moderate yield,

(Scheme 1).

Scheme 1

Treatment of acetohydrazide 2 with p-toluene

sulfonyl chlo-ride in dry dioxane in the

presence of a few drops of triethylamine

(TEA) as a catalyst afforded 4-methyl-N -(2-

(2-oxo-4-phenyl-2H-chromen-

7yloxy)acetyl)benzenesulfonohydrazide (7),

while when 2 reacted with proper substituted

benzoyl chlorides namely (4-chloro and 3,5-dinitrobenzoyl chloride) in refluxing dioxane

in the prese-nce of pyridine yielded 4-chloro-


3/16



N'-(2-(2-oxo-4-phenyl-2H-chrom-en-7-

yloxy)acetyl)benzohydrazide (8a) and 3,5-

dinitro-N'-(2-(2-oxo-4-phenyl-2H-chromen-7-

yloxy)acetyl)benzohydrazide (8b), respe-

ctively. Moreover, when 8a was heated with

phosphorousoxychlo-ride at 1200C, gave 1, 3,

4-oxadiazol derivative 9. Condensation of 2

with D-glucose and p-nitroacetophenone in

refluxing ethanol containing a catalytic

amount of acetic acid afforded the correspo-

nding Schiff bases 10 and 11 respectively,

(Scheme 2).

Scheme 2

Condensation of compound 2 with aromatic

aldehydes in boiling ethanol in the presence

of acetic acid afforded the corresponding

benzylidine hydrazide derivatives as N'-(4-

Substitutedbenzylidene)-2-(2-oxo-4-phenyl-

2H-chromen-7-yloxy)acetohydrazide (12a-c),

respectively.Compound 12c underwent cyclocondensation

with thiogly-colic acid to obtain

thiazolidinone derivative 14, the formation of

this compound was assumed to occur via the

addition of thiaol group of thioglycolic acid to

the activated double bond (CH=N) of

hydrazone 12c to yield the corresponding

acyclic non-isolable intermediate 13 which

undergoes intramolecular cyclization by the

elimination of water molecule to afford the

final product 14.

In contrast to the anticipated formation of

pyrazole derivatives 16 a, b, the reaction of 2

with -cyano-4-(substituted)-phenyl

cinnamonitrile (15 a, b) in boiling ethanol

containing a few drops of acetic acid afforded

a products identical in all aspects (m.p., mixedm.p. and spectral data) with compounds 12a

and 12b, respectively. The formation of these

compounds were assumed to proceed via retro

Michael addition through the elimination of

malononitrile from the non-isolable adduct

17a,b. Reaction of 2 with triethyl

orthoformate in ethanol-acetic acid at reflux

temperature furnished the expected product 4-

(2-oxo-4-phenyl-2H-chromen-7-yloxy)-1H-

pyrazol-3(2H)-one (18) (Scheme 3).


4/16



Scheme 3

The reactivity of 2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy) ace-tohydrazide (2)

towards active methylene compounds was

explo-red. Thus, treatment of compound 2

with malononitrile and/or ethyl cyanoacetate

in ethanol-acetic acid under reflux gave a

novel com-pound proved to be identical (m.p.,

mixed m.p. and spectral data) with 7-(2-(5-

amino-3-hydroxy-1H-pyrazol-1-yl)-2-

oxoethoxy)-4-phenyl-2H-chromen-2-one (21).

The formation of this compound could be

interpreted through nucleophilic

transformation into acyc-lic non-isolable

intermediates 19, 20 followed by

intramolecular cyclization, hydrolysis of

imino function to carbonyl group in 19, while

loss of ethanol molecule in 20 andtautomerization for both under the reaction

conditions to afford the final product 21,

(Scheme 4).

Cyclocondensation of compound 2 with

different diketo com-pounds namely

(acetylacetone, benzoylacetone, ethyl

acetoace-tate and ethyl benzoylacetate) in

dioxane-pyridine under reflux temperature

yielded a pyrazole derivative as a single

product (TLC) in each case. On the basis of

elemental and spectral data, the products were

assigned the structures as 7-(2-(3-dimethyl-5-

substitu-ted-1H-pyrazol-1-yl)-2-oxoethoxy)-

4-phenyl-2H-chromen-2-one (23a,b) and 7-

(2-(5-hydroxy-3-substituted-1H-pyrazol-1-

yl)-2-oxoe-thoxy)-4-phenyl-2H-chromen-2-

one (25a,b), respectively. The formation of

these compounds was probably occurring

through the mechanism outline in scheme 4.


5/16



The diazo-coupling of aryl diazonium

chlorides with ethylace-toacetate in alcoholic

sodium acetate solution resulted in the form-

ation of different 2,3-dioxobutyrate-2-aryl

hydrazones (26a,b)[34-37], which on the

reaction with the Coumarin hydrazide 2 in

refluxing dioxane containing pyridine

furnished the products which identified as

ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-

phenyl-2H-chromen-7-yloxy)acetyl)-1H-

pyrazol-4(5H)-ylidene)-hydrazinyl)be-nzoate

(28a) and 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-

4-phenyl-2H-chromen-7-ylo-xy)acetyl)-1H-

pyrazol-4(5H)-ylidene) hydrazinyl)-benzoic

acid (28b) respectively. Formation of these

compounds may be explained by

condensation of hydrazide 2 with arylazo

compounds 26a,b afforded acyclic

intermediate 27a,b, which undergoes

intramolecular cyclization and

tautomerization through nucleophilic addition

of the (NH) group to the carbonyl ester site

followed by elimination of ethanol yielded the

expected compounds 28a,b, respectively,

(Scheme 4).


6/16



Scheme 4

Moreover, the reaction of hydrazide 2 with

tetracyanoethyl-ene and ethoxymethylene

ethyl cyanoacetate in dioxane-pyridine under

reflux furnished the products which identifiedas: 5-amino-1-(2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy)acetyl)-1H-pyrazole-3,4-

dicarbonitrile (30) and ethyl 5-amino-1-(2-(2-

oxo-4-phenyl-2H-chro-men-7-yloxy)acetyl)-

1H-pyrazole-4-carboxylate (32) respectively.

The reaction pathway is assumed to proceed

via addition of2 to the activated double bond

to form intermediates 29, 31 followed by

intramolecular cyclization through

nucleophilic addition of (NH) to the cyano

group then hydrogen cyanide and/or ethanol

molecules were eliminated and

tautomerization occurs under the reaction

conditions, (Scheme 5).

On the same manner, attempted for

preparation of 5-amino-3-(methylthio)

pyrazole-4-carbonitrile derivative (34) via the

reaction of hydrazide 2 with [bis (methylthio)

methylene] malononitrile in boiling dioxane

was failed. The first surprising property of the

prod-uct of this reaction is the absence of

sulfur element. Secondly, no evidences for the

presence of an amino (NH2) group in both IR

and1H-NMR spectra. In addition,

1H-NMR

spectrum clearly shows the loss of both

methylthio groups leading to 2-(5-((2-oxo-4-

phenyl-2H-chromen-7-yloxy) methyl)-1, 3, 4-

oxadiazol-2(3H)-ylidene) malon-onitrile (35).

The reaction seems to proceed via formation

of the expected acyclic intermediate 33,

which in turn underwent intramo-lecular

nucleophilic cyclization with elimination of

methylthiol mole-cule, (Scheme 5).


7/16



Scheme 5

Pharmacology

Antioxidant Activity

Antioxidant compounds in food play animportant role as a health-protecting factor.

Scientific evidence suggests that antioxidants

reduce the risk for chronic diseases. The role

of antioxidant is to remove free radicals by

donating hydrogen to free radicals in its

reduction to produce non-reactive species.

The effect of the different synthetic

compounds on DPPH radical scavenging was

compared to ascorbic acid using as positivecontrol and appreciated by the determination

of the IC50 values. The results are listed in

Table 1.

Table 1: Values of IC50 exhibited by test compounds.

Entry Cpd.No. Conc. (g/mL) % inhibition IC50(g/mL)

1 5

250 13.69

52838500 20.98

750 20.61

1000 20.61

2 7

250 24.05

950500 37.27

750 43.88

1000 51.62

3 8a

250 13.91

9647500 15.66

750 19.30

1000 24.54

4 10

250 20.90

4126500 24.54750 31.32

1000 33.21

5 11

250 7.50

15535500 12.02

750 14.06

1000 16.17

6 12a

250 28.40

4649500 31.54

750 34.45

1000 38.82

7 14

250 25.05

1816500 32.12

750 38.46

1000 41.59

8 21

250 13.08

1278500 21.24

750 35.30

1000 42.33

9 23a

250 14.64

16440500 15.51750 16.53

1000 24.62


8/16



10 28a

250 20.98

2101500 29.21

750 35.54

1000 38.09

11 32

250 12.16

5723500 18.43750 18.94

1000 26.22

12 35

250 13.26

12639500 15.95

750 17.70

1000 23.53

Std. Ascorbic acid

250 65.55

91.45500 75.89

750 78.22

1000 83.10

DPPH test is a direct and reliable method for

determining radical scavenging action. The

DPPH radical contains an odd electron, which

is responsible for the absorbance at 515-517

nm and also for a visible deep purple color.

When DPPH accepts an electron donated by

an antioxidant compound, the DPPH is

decolorized that can be quantitativelymeasured from the changes in absorbance.

The ratio of antioxidant/DPPH required to

decrease the concentration of DPPH to 50%

of its initial value, denoted as IC50 or Efficient

Concentration (EC50), is an indicator of

antiradical activity [38]. It is clear from the

tabulated results that compound 7 is the most

active promising compound.

Experimental

General

All melting points and antioxidant activities

are uncorrected. IR spectra (KBr) were

recorded on FT-IR 5300 spectrometer and

Perkin Elmer spectrum RXIFT-IR system (,

cm-1

). The1H NMR spectra were recorded in

(CDCl3 & DMSO-d6) at (300) MHz on a

Varian Mercury VX-300 NMR spectrometer(, ppm) using TMS as an internal standard.13

C NMR spectra were recorded on Varian

Mercury VX 300 NMR using DMSO-d6 as

solvent and TMS as an internal standard.

Mass spectrum was obtained on GC Ms-QP

1000 EX mass spectrometer at 70 eV.

Elemental analyses were carried out by the

Microanalytical Research Center, Faculty of

Science, Cairo University and Al-Azhar

University.

Synthesis

2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)

acetohydrazide (2).

A mixture of (1; 0.03 mol) and hydrazine

hydrate (0.06 mol) in ethanol (30 mL) was

refluxed for 8 h. The reaction mixture was

concentrated and left to cool to give colorless

crystals in 80% yield; mp: 188O

C; IR (vcm-

1): 3340, 3254 (NH2, NH), 1716 (C=O,

lactone) and 1690 (C=O, amide);1H-NMR (

ppm): 4.36 (s, 2H, NH2 exchangeable with

D2O), 4.63 (s, 2H, OCH2), 6.25 (s, 1H, H-3),

6.96-7.58 (m, 8H, Ar-H) and 9.43 (s, 1H, NH

exchangeable with D2O); MS m/z (%): 310

(77); Anal. calcd. for C17H14N2O4: C 65.80, H

4.55, N 9.03. Found: C 65.74, H 4.53, N 9.00.


9/16



N'-formyl-2-(2-oxo-4-phenyl-2H-chromen-7-

yloxy) acetohydrazide (3).

A solution of 2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy)aceto-hydrazide (2; 0.002

mol) in formic acid (20 ml) was refluxed for 1h.The solvent was evaporated and residue was

recrystallized from ethanol to give compound

3 in 82% yield; mp: 160OC; IR (vcm

-1): 3390

(NH), 3076 (CH-aromatic) and 1732, 1664

(C=O);1H-NMR ( ppm): 4.84 (s, 2H,

OCH2), 6.25 (s, 1H, H-3), 6.92-7.56 (m, 8H,

Ar-H) and 7.58, 8.00, 10.06 (3s, 3H, 2NH and

CHO exchangeable with D2O); Anal. calcd.

for C18

H14

N2O

5: C 63.90, H 4.17, N 8.28.

Found: C 63.87, H 4.15, N 8.25.

4-((2-(2-(2-oxo-4-phenyl-2H-chromen-7-

yloxy) acetyl) hydrazinyl) methyleneamino)

benzoic acid (4).

4-aminobenzoic acid (0.004 mole) was added

to a mixture of compound 3 (0.004 mole) in

acetonitrile (15-20 mL) containing a few

drops of acetic acid. The reaction mixture was

vigorously stirred with the refluxing for 5hours. Excess solvent was then removed

under reduced pressure, the precipitate

resulting after cooling was collected by

filtration and recrystallized from

dimethylformamide to give compound 4 in

70% yield; mp: 298OC; IR (vcm

-1): 3366

(OH), 3262 (NH) and 1692 (C=O);1H-NMR

( ppm): 4.84 (s, 2H, OCH2), 6.26 (s, 1H, H-

3), 7.01-8.10 (m, 12H, Ar-H), 9.24 (s, 1H,CH=N) and 10.48, 13.01 (2s, 2H, NH and

OH exchangeable with D2O); Anal. calcd. for

C25H19N3O6: C 65.64, H 4.19, N 9.19. Found:

C 65.63, H 4.16, N 9.18.

N'-acetyl-2-(2-oxo-4-phenyl-2H-chromen-7-

yloxy) acetohydrazide (5).

Compound 2 (0.002 mol) was refluxed in

acetic acid (20 ml) for 5 h. The precipitate

formed after cooling was collected byfiltration and recrystallized from dioxane to

give compound 5 in 77% yield; mp: 210OC;

IR (vcm-1

): 3372, 3234 (2NH) and 1704

(C=O);1H-NMR ( ppm): 1.87 (s, 3H, CH3),

4.79 (s, 2H, OCH2), 6.22 (s, 1H, H-3), 6.25-

7.56 (m, 8H, Ar-H) and 9.84, 10.29 (2s, 2H,

2NH); Anal. calcd. for C19

H16

N2O

5: C 64.77,

H 4.58, N 7.95. Found: C 64.74, H 4.55, N

7.93.

7-((5-(4-nitrophenyl)-1, 3, 4-oxadiazol-2-yl)

methoxy)-4-phenyl-2H-chro-men-2-one (6).

2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)

acetohydrazide (2; 0.002 mol) was refluxed

with p-nitrobenzoic acid (0.002 mol) in

dioxane (20 ml) in the presence of POCl3 (0.6

ml) for 3 h. The reaction mixture was slowlyquenched into crushed ice with stirring and

neutralized it with 5% NaOH. The solid

which separated after standing overnight was

filtered, washed with cold water, dried and

recrystallized from ethanol/benzene, to give

compound 6 in 74% yield; mp: 128OC; IR

(vcm-1

): 1720 (C=O); MS m/z (%): 441 (43);

Anal. calcd. for C24H15N3O6: C 65.31, H 3.43,

N 9.52. Found: C 65.29, H 3.40, N 9.49.

4-methyl-N'-(2-(2-oxo-4-phenyl-2H-chromen-

7-yloxy) acetyl) benzene-sulfonohydrazide (7).

A mixture of 2-(2-oxo-4-phenyl-2H-chromen-

7-yloxy)aceto-hydrazide (2; 0.002 mol) and p-

toluene sulfonyl chloride (0.002 mol) in dry

dioxane (10 ml) and a catalytic amount of

triethyl amine (TEA) was refluxed for 3 h,

then the reaction mixture left to cool. The

white solid was filtered off, washed withethanol several times and recrystallized from

a mixture of ethanol-benzene. Compound 7

was obtained in 70% yield; mp: 224OC; IR

(vcm-1

): 3290 (NH) and 1720 (C=O);1H-

NMR ( ppm): 2.32 (s, 3H, CH3), 4.62 (s, 2H,

OCH2), 6.25 (s, 1H, H-3), 6.82-7.77 (m, 12H,

Ar-H) and 9.90, 10.39 (2s, 2H, 2NH); Anal.

calcd. for C24H20N2O6S: C 62.06, H 4.34, N

6.03. Found: C 62.05, H 4.30, N 6.01.


10/16



General procedure for the preparation of

Substituted-N'-(2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy) acetyl) benzohydrazide (8a,

b).

A mixture of 2-(2-oxo-4-phenyl-2H-chromen-7-yloxy) aceto-hydrazide (2; 0.002

mol) and benzoyl chloride derivatives namely

(p-chlorobenzoyl chloride and 3, 5-

dinitrobenzoyl chloride) (0.002 mol) in dry

dioxane (10 ml) and a catalytic amount of

pyridine was refluxed for 2 h, the resulting

solid on heating was collected by filtration,

washed with ethanol several times and

recrystallized from dimethylformamide to

give compounds 8a, b.

4-chloro-N'-(2-(2-oxo-4-phenyl-2H-chromen-

7-yloxy) acetyl) benzohydr-azide (8a).

Yield: 90%; mp: 225OC; IR (vcm

-1): 3300

(NH), 3074 (CH-aromatic) and 1692 (C=O);1H-NMR ( ppm): 4.83 (s, 2H, OCH2), 6.27

(s, 1H, H-3), 7.02-7.91 (m, 12H, Ar-H) and

10.35, 10.53 (2s, 2H, 2NH); MS m/z (%): 448

(50); Anal. calcd. for C24H17ClN2O5: C 64.22,H 3.82, N 7.90. Found: C 64.18, H 3.80, N

7.87.

3, 5-dinitro-N'-(2-(2-oxo-4-phenyl- 2H-

chromen -7-yloxy) acetyl) benzo-hydrazide

(8b).


-1): 3340

(NH) and 1696 (C=O); MS m/z (%): 504 (79);


N 11.11. Found: C 57.13, H 3.18, N 11.08.

7-((5-(4-chlorophenyl)-1, 3, 4-oxadiazol-2-yl)

methoxy)-4-phenyl-2H-chromen-2-one (9).

4-chloro-N'-(2-(2-oxo-4-phenyl-2H-chromen-

7-yloxy) acetyl)-benzohydrazide (8a; 0.7

mmol) was fused with POCl3 (3 ml) at 120OC

for 1 h. The reaction mixture was slowly

quenched into crushed ice with stirring and

neutralized with 5% NaOH. The solid whichseparated after standing overnight was

filtered, washed with cold water, dried and

recrystallized from ethanol/benzene to give

compound 9 in 80% yield; mp: 132OC; IR

(vcm-1

): 1693 (C=O); MS m/z (%): 430 (100);

Anal. calcd. for C24H15ClN2O4: C 66.91, H

3.51, N 6.50. Found: C 66.88, H 3.50, N 6.48.

2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)-N'-

(2, 3, 4, 5, 6-pentahydroxy-hexylidene)

acetohydrazide (10).

A mixture of 2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy) aceto-hydrazide (2; 0.002

mol) and D-glucose (0.002 mol) in ethanol

(30 ml) and a catalytic amount of acetic acid

was heated at 800C for 1h. The precipitate

formed was filtered off hot, washed with etha-nol several times, dried and recrystallized

from ethanol/benzene, to give compound 10

in 90% yield; mp: 140OC; IR (vcm

-1): 3435

(OH), 3346 (NH) and 1756, 1706 (2C=O);13

C-NMR ( ppm): 171.25, 166.94, 160.58,

160.48, 155.72, 135.50, 135.39, 130.22,

129.40, 128.94, 113.22, 113.14, 112.16,

102.59, 91.18, 78.57, 77.86, 71.57, 71.34,

70.81, 70.64, 66.64 and 61.87; MS m/z (%):

472 (54); Anal. calcd. for C23H24N2O9: C

58.47, H 5.12, N 5.93. Found: C 58.42, H

5.08, N 5.90.

N'-(1-(4-nitrophenyl) ethylidene)-2-(2-oxo-4-

phenyl-2H-chromen-7-yloxy) acetohydrazide

(11).



mol) and p-nitroacetophenone (0.002 mol) inethanol (30 ml) in the presence of acetic acid

(1 ml) was refluxed for 1h, the resulting solid

on heating was collected by filtration and

recrystallized from dioxane to give compound

11 in 95% yield; mp: 222OC; IR (vcm

-1):

3150(NH) and 1720(C=O);1H-NMR ( ppm):

2.34 (s, 3H, CH3), 4.63 (s, 2H, OCH2), 6.24

(s, 1H, H-3), 6.98-8.27 (m, 12H, Ar-H) and

11.15 (s, 1H, NH); Anal. calcd. forC25H19N3O6: C 65.64, H 4.19, N 9.19. Found:

C 65.62, H 4.16, N 9.15.


11/16



General procedure for the preparation of N'-

(4-Substitutedbenzylidene)-2-(2-oxo-4-phenyl-

2H-chromen-7-yloxy) acetohydrazide (12a-c).


7-yloxy)aceto-hydrazide (2; 0.002 mol) andbenzaldehyde derivatives namely (p-

chlorobenzaldehyde, p-methoxybenzaldehyde

and p-nitrobenz-aldehyde) (0.002 mol) in

ethanol (30 ml) in the presence of acetic acid

(1 ml) was refluxed for 1h, the resulting solid

on heating was collected by filtration and

recrystallized from dioxane to give

compounds 12a-c.

N'-(4-chlorobenzylidene)-2-(2-oxo-4-phenyl-2H-chromen-7-yloxy) aceto-hydrazide (12a).


-1): 3164

(NH), 1706 (C=O) and 1606 (CH=N);1H-

NMR ( ppm): 5.31 (s, 2H, OCH2), 6.24 (s,

1H, H-3), 7.49-8.01 (m, 12H, Ar-H), 8.38 (s,

1H, CH=N) and 11.62 (s, 1H, NH); Anal.

calcd. for C24H17ClN2O4: C 66.59, H 3.96, N

6.47. Found: C 66.54, H 3.93, N 6.45.

N'-(4-methoxybenzylidene)-2-(2-oxo-4-

phenyl-2H-chromen-7-yloxy)-acetohydrazide

(12b).


-1): 3188

(NH), 1720, 1684 (2C=O) and 1608 (CH=N);1H-NMR ( ppm): 3.80 (s, 3H, OCH3), 4.80

(s, 2H, OCH2), 6.24 (s, 1H, H-3), 6.95-7.96

(m, 12H, Ar-H), 8.26 (s, 1H, CH=N) and

11.51 (s, 1H, NH); Anal. calcd. for

C25H20N2O5: C 70.08, H 4.71, N 6.54. Found:

C 70.06, H 4.70, N 6.50.

N'-(4-nitrobenzylidene)-2-(2-oxo-4-phenyl-

2H-chromen-7-yloxy) aceto-hydrazide (12c).


-1): 3128

(NH) and 1710 (C=O); MS m/z (%): 443 (46);


N 9.48. Found: C 65.00, H 3.84, N 9.43.

N-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)-2-

(2-oxo-4-phenyl-2H-chro-men-7-yloxy)

acetamide (14).

A mixture of N'-(4-nitrobenzylidene)-2-(2-

oxo-4-phenyl-2H-chromen-7-yloxy)acetohydrazide (12c; 0.002) and

thioglycolic acid (0.002 mol) in DMF

containing a few drops of pyridine was

refluxed for 24h, cooled and the reaction

mixture was poured into crushed ice

containing a few drops of dil. HCl. The solid

obtained was filtered off and recrystallized

from a mixture of ethanol-benzene.

Compound 14 was obtained in 85% yield;

mp: 194OC; IR (vcm

-1): 3200(NH) and

1715(C=O);1H-NMR ( ppm): 4.87 (s, 2H,

OCH2), 5.36 (s, 2H, CH2-thiazolidinone),

6.24 (s, 1H, H-3), 6.98-8.43 (m, 13H, Ar-H

and CH- thiazolidinone) and 11.93 (s, 1H,

NH); MS m/z (%): 517 (35); Anal. calcd. for

C26H19N3O7S: C 60.34, H 3.70, N 8.12.

Found: C 60.30, H 3.64, N 8.09.

4-(2-oxo-4-phenyl-2H-chromen-7-yloxy)-1H-

pyrazol-3(2H)-one (18).



mol) and triethylorthoformate (0.002 mol) in

ethanol (20 ml) in the presence of acetic acid

(2 ml) was refluxed for 8h, then the reaction

mixture left to cool. The white solid was

filtered off, and crystallized from ethanol to

give compound18

in 82% yield; mp: 98

O

C;IR (vcm-1

): 3300 (NH) and 1716 (C=O); MS

m/z (%): 319 (14); Anal. calcd. for

C18H12N2O4: C 67.50, H 3.78, N 8.75. Found:

C 67.49, H 3.76, N 8.72.

7-(2-(5-amino-3-hydroxy-1H-pyrazol-1-yl)-2-

oxoethoxy)-4-phenyl-2H-chromen-2-one (21).


7-yloxy)aceto-hydrazide (2; 0.002 mol) and

malononitrile and/or ethyl cyano-acetate(0.002 mol) in ethanol (30 ml) in the presence

of acetic acid (1 ml) was refluxed for 8h, the


12/16



resulting solid on heating was collected by

filtration and recrystallized from dioxane to

give com-pound 21 in 85% yield; mp: 245OC; IR (vcm

-1): 3415 (OH), 3320, 3258

(NH2) and 1714, 1672 (2C=O);

1H-NMR (

ppm): 4.79(s, 2H, OCH2), 6.27 (s, 1H, H-3),

6.99-7.56 (m, 11H, Ar-H, CH-pyrazole and

NH2 exchangeable with D2O) and 10.31 (s,

1H, OH exchan-geable with D2O);13

C-NMR

( ppm): 166.67, 161.26, 160.45, 155.75,

155.58, 135.43, 130.24, 129.42, 128.97,

128.36, 113.53, 112.87, 112.26, 102.60 and

66.77; Anal. calcd. for C20H15N3O5: C 63.66,

H 4.01, N 11.14. Found: C 63.62, H 4.00, N

11.10.

General procedure for the preparation of 7-

(2-(3-methyl-5-substituted-1H-pyrazol-1-yl)-

2-oxoethoxy)-4-phenyl-2H-chromen-2-one

(23a, b).



acetylacetone or benzoylacetone (0.002 mol)

in 1,4-dioxane (10 ml) and a catalytic amount

of pyridine was refluxed for 6 h, then the

reaction mixture left to cool. The solid

product was filtered off, washed with ethanol

and recrystallized from ethanol/benzene, to

give compounds 23a, b.

7-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-

oxoethoxy)-4-phenyl-2H-chromen-2-one

(23a).

Yield: 80%; mp: 156O

C; IR (vcm-1

): 1756,1706 (2C=O);

1H-NMR ( ppm): 2.22 (s, 3H,

CH3), 2.23 (s, 3H, CH3), 5.64 (s, 2H, OCH2),

6.26 (s, 1H, H-3), 6.99-7.58 (m, 9H, Ar-H and

CH-pyrazole); Anal. calcd. for C22H18N2O4: C

70.58, H 4.85, N 7.48. Found: C 70.52, H

4.80, N 7.45.

7-(2-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-2-


(23b).


-1): 1754,

1708 (2C=O); MS m/z (%): 436 (64); Anal.calcd. for C27H20N2O4: C 74.30, H 4.62, N

6.42. Found: C 74.28, H 4.59, N 6.40.

General procedure for the preparation of 7-

(2-(5-hydroxy-3-substituted-1H-pyrazol-1-yl)-

2-oxoethoxy)-4-phenyl-2H-chromen-2-one

(25a,b).



mol) and ethyl acetoacetate or ethyl benzo-

ylacetate(0.002 mol) in 1,4-dioxane (10 ml)

and a catalytic amount of pyridine was

refluxed for 6 h, then the reaction mixture left

to cool. The white solid was filtered off and

recrystallized from DMF to give compounds

25a, b.

7-(2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)-2-


(25a).


-1): 3188

(OH) and 1716 (C=O);1H-NMR ( ppm):

1.99 (s, 3H, CH3), 4.79 (s, 2H, OCH2), 6.26

(s, 1H, H-3), 6.99-7.56 (m, 9H, Ar-H and CH-

pyrazole) and 10.29 (s, 1H, OH); MS m/z (%):

376 (12); Anal. calcd. for C21H16N2O5: C

67.02, H 4.28, N 7.44. Found: C 67.00, H

4.25, N 7.40.

7-(2-(5-hydroxy-3-phenyl-1H-pyrazol-1-yl)-2-


(25b).


-1): 3410

(OH) and 1704 (C=O); MS m/z (%): 438 (58);


N 6.39. Found: C 71.19, H 4.11, N 6.35.


13/16



General procedure for the preparation of

ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-

phenyl-2H-chromen-7-yloxy)acetyl)-1H-

pyrazol-4(5H)-ylidene)hydrazinyl)benzoate

(28a) and 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-

4-phenyl-2H-chromen-7-yloxy)-acetyl)-1H-

pyrazol-4(5H)-ylidene)hydra-zinyl)benzoic

acid (28b).



ethyl 4-((1-ethoxy-1,3-dioxobutan-2-

yl)diazenyl)benzoate or 4-((1-ethoxy-1,3-

dioxobutan-2-yl)diazenyl)-benzoic acid

(0.002 mol) in dioxane (10 ml) and a catalytic

amount of pyridine was refluxed for 6 h, then

the reaction mixture left to cool for 28a, while

28b, the solid obtained on heating. The solid

product was filtered off, washed with ethanol

several times and recrystallized from the

proper solvent to give compounds 28a,b.

Ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-

phenyl-2H-chromen-7-yloxy)-acetyl)-1H-

pyrazol-4(5H)-ylidene) hydrazinyl) benzoate

(28a)


-1):

3248(NH) and1706 (C=O);1H-NMR ( ppm):

1.32 (t, 3H, CH3), 2.16 (s, 3H, CH3), 4.26 (q,

2H, CH2), 4.63 (s, 2H, OCH2), 6.26 (s, 1H, H-

3), 6.97-8.00 (m, 12H, Ar-H) and 10.29 (s,

1H, NH); Anal. calcd. for C30H24N4O7: C

65.21, H 4.38, N 10.14. Found: C 65.19, H

4.35, N 10.13.4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-phenyl-

2H-chromen-7-yloxy)-acetyl)-1H-pyrazol-

4(5H)-ylidene) hydrazinyl) benzoic acid

(28b).


-1): 3250

(NH) and 1728, 1702, 1690 (3C=O);1H-

NMR ( ppm): 2.10 (s, 3H, CH3), 4.88 (s, 2H,

OCH2), 6.23 (s, 1H, H-3), 7.05-7.80 (m, 12H,

Ar-H), 10.70 (s, 1H, NH) and 12.38 (s, 1H,OH); Anal. calcd. for C28H20N4O7: C 64.12, H

3.84, N 10.68. Found: C 64.11, H 3.82, N

10.65.

5-amino-1-(2-(2-oxo-4-phenyl-2H-chromen-

7-yloxy) acetyl)-1H-pyra-zole-3, 4-

dicarbonitrile (30).


chromen-7-yloxy) aceto-hydrazide (2; 0.002

mol) and tetracyanoethelyene (0.002 mol) in

1,4-dioxane (10 ml) and a catalytic amount of

pyridine was refluxed for 2 h. The precipitate

formed was filtered off hot, washed with

ethanol several times, dried and recrystallized

from DMF to give compound 30 in 80%

yield; mp: 330O

C; IR (vcm-1

): 3327 (NH2),2214 (CN) and 1700 (C=O); MS m/z (%): 411

(23); Anal. calcd. for C22H13N5O4: C 64.23, H

3.19, N 17.02. Found: C 64.19, H 3.15, N

17.00.

Ethyl 5-amino-1-(2-(2-oxo-4-phenyl-2H-

chromen-7-yloxy) acetyl)-

1H-pyrazole-4-carboxylate (32).

A mixture of 2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)aceto-hydrazide (2; 0.002 mol) and

ethoxymethylene ethyl cyanoacetate (0.002

mol) in 1,4-dioxane (10 ml) and a catalytic

amount of pyridine was refluxed for 7 h, then

the reaction mixture left to cool. The white

solid was filtered off, washed with ethanol

and recrystallized from a mixture of ethanol-

benzene. Compound 32 was obtained in 79%

yield; mp: 154OC; IR (vcm

-1): 3378 (NH2)

and 1700 (C=O); 1H-NMR ( ppm): 1.27 (t,

3H, CH3), 4.21 (q, 2H, CH2), 5.29 (s, 2H,

OCH2), 5.58 (s, 2H, NH2), 6.25 (s, 1H, H-3),

7.01-7.65 (m, 8H, Ar-H) and 7.85 (s, 1H, CH-

pyrazole); Anal. calcd. for C23H19N3O6: C

63.74, H 4.42, N 9.70. Found: C 63.71, H

4.40, N 9.67.


14/16



2-(5-((2-oxo-4-phenyl-2H-chromen-7-yloxy)

methyl)-1, 3, 4-oxadiazol-2(3H)-ylidene)

malononitrile (35).


7-yloxy)aceto-hydrazide (2; 0.002 mol) and 2-(bis(methylthio)methylene)-malononitrile

(0.002 mol) in 1,4-dioxane (10 ml) and a

catalytic amount of pyridine was refluxed for

2 h, the resulting solid on heating was

collected by filtration, washed with ethanol

several times and recrystallized from DMF to

give compound 35 in 75% yield; mp: 252OC;

IR (vcm-1

): 3248(NH), 2210 (CN) and

1702(C=O);1H-NMR ( ppm): 4.79 (s, 2H,

OCH2), 6.26 (s, 1H, H-3), 6.99-7.57 (m, 8H,

Ar-H) and 10.28 (s, 1H, NH); Anal. calcd. for

C21H12N4O4: C 65.62, H 3.15, N 14.58.

Found: C 65.59, H 3.13, N 14.54.

Pharmacology

(2,2-diphenyl-1-picrylhydrazyl) (DPPH)

Radical Scavenging Activity

In the DPPH assay, antioxidants reduce the

free radical 2, 2-diphenyl-1- picrylhydrazyl.

In the presence of an antioxidant, the purple

color of DPPH

fades and the change of

absorbance can be followed

spectrophotometrically at 515 nm [39].

Test compounds are dissolved in N, N-

dimethylformamide (DMF) solution to

specific concentrations and each sample was

mixed with DPPH in DMF solution, the blank

sample contains the same amount of DMF

and DPPH. The mixtures were left for 15 min

at 25 C then the absorbance measured at 517

nm using the UV-VIS spectrophotometer.

Generally, the results are reported as the

percent of inhibition, mean that, the amount

of antioxidant necessary to decrease the initial

DPPH

concentration by 50 %. The

percentage of DPPH radical scavenger was

calculated using this equation: [(A0At)/A0]x100, where A0 is the absorbance value of

blank sample, at a particular time and At is the

absorbance value of the tested sample. The

IC50 (concentration causing 50% inhibition of

DPPH) values of each test compound are

determined. Ascorbic acid can be used as

positive controls.

References

1) S. L. El-ansary, S. E. Abbas, A. N.Mikhael and H. A.El-Banna, Eygpt. J.

Pharm. Sci., (1992), 33 (4), 639-650.

2) L. W. Wattenberg, L. K. T. Lam and A.V. Fladmoe, Cancer Reserch, (1979), 39,

1651-1654.

3) Y. Kashman, K. Gustalleon, R. Fuller, J.Cardellina II, J. McMahon, M. Currens,R. Buckheit Jr, S. Hughes, G. Cragg,

M.Boyd,J. Med. Chem., (1992), 35, 2735.

4) T. C. McKee, R. W. Fuller, C. Covington,J. Cardellina II, R. Gulakowski, B.

Krepps, J. McMahon and M. Boyd, J. Nat.

Prod., (1996), 59, 754.

5) T.K. Rao, M. S. Raju and K. M. Raju, J.Indian. Chem. Soc., (1981), 58, 1021-

1023.

6) R. S. Moffet, J. Med. Chem., (1964), 7,446.

7) J. Jung, J. Kin and O. Park, Synth.Commun., (1999), 29 (20), 3587-3595.

8) M. A. Hermodson, W. M. Barker and K.P. Link,J. Med. Chem., (1971), 14, 167.

9) J. Raboin, M. Beley and G. Kirsch,Tetrahedron Lett. 2000, 41, 1175-1177.

10)Kulkarni MV, Kulkarni GM, Lin CH, SunCM (2006) Recent advances in coumarins

and 1-azacoumarins as versatile biody-

namic agents. Curr Med Chem

13(23):2795-2818.

11)Bistra, S.; Voislava, J.; Boris, S.;Nikolova, P.; Goran, S.; Bozhna, M.;

Emil, P. Experimental and theoretical

investigation of the structure and

nucleophilic properties of 4-

aminocoumarin.ARKIVOC(2010), x, 62-76.


15/16



12)Jianwei, H.; Yong, X.; Jingwei, Z.;Shizheng, Z. l-Proline catalyzed

condensationcyclization tandem process:

Facile and effective synthesis of 3-

polyfluoroalkanesulfonyl coumarin. J.

Fluorine Chem. (2011), 132, 409-413.

13)Musicki, B.; Periers, P.; Laurin, D.;Ferroud, Y.; Bendetti, S.; Lachaud, F.;

Chatreaux, J.; Haesslein, L.; Iltis, A.;

Pierre, C.; Khider, J.; Tessot, N.; Airault,

P.; Bonnefoy, A.; Vicat, P.; Klich, M.

Bioorg. Med. Chem. Lett. (2000), 10,

1695-1699.

14)Nofal, Z.M.; El-Zahar, M.; Abd El-Karim,S. Novel coumarin derivatives with

expected biological activity. Molecules

(2000), 5, 99-113.

15)Kotali, A.; Lafazanis, I.; Harris, P.ChemInform Abstract: Synthesis of 6,7-

Diacylcoumarins via the Transformation

of a Hydroxy into a Carbonyl Group.

Synth. Commun. (2008), 38, 3996-4006.

16)Garazd, M.M.; Muzychka, O.V.; Voyk,A.I.; Nagorichna, I.V.; Ogorodniichuk,A.S. Synthesis and antioxidant activity of

3-substituted 5,7-dihydroxy-4-

methylcoumarins. Chem. Nat. Compd.

(2007), 43, 19-23.

17)Edmont, V.; Jochen, M. PechmannReaction Promoted by Boron Trifluoride

Dihydrate.Molecules(2005), 10, 76276.

18)Al-Zghoul KHA, Salih KSM, AyoubMT, Mubarak MS (2005) Aconvenient

procedure for the synthesis of substituted

4-methylaminocoumarins. Heterocycles

65(12):2937.

19)Wkrner, W. Antitubercular Agents.Derivatives of pyridinecarboxylic acid

hydrazides. J. Org. Chem. (1953), 18,

1333-1337.

20)Parmer, S. S.; Kumar, R. Substitutedquinazolinone hydrazides as possible

antituberculous agents. J. Med. Chem.(1963), 11, 635-636.

21)Bhamaria, R. P.; Bellare, R. A.; Deliwala,C. V. In intro effect of 1-acyl-4-alkyl-(or

aryl)-thiosemicarbazides 1-(5-

chlorosalicylid-ine)-4-alkyl-(or aryl)-

thiosemicarbazones and some hydrazones

of 5-chlorosalicylaldehyde against

pathogenic bacteria including

Mycobacterium tuberculosis (H37Rv).

Indian J. Exp. Biol. (1968), 6, 62-63.

22)Abdel-Al, E. H.; Al-Ashamawi, M. I.;Abd El-Fattah, B. Synthesis and

antimicrobial testing of certain

oxadiazoline and triazole derivatives. Die

Pharmazie (1983), 38, 833-838.

23)Gupta, A. K. S.; Garg, M.; Chandra, U.Synthesis of some new Mannich bases

derived from substituted benzimidazole,

benzoxazol-2-one, benzoxazol-2-thione,

oxadiazol-2-thiones and their biological

activities.J. Indian Chem. Soc. (1979), 56,

1230-1232.

24)Mansour, A. K.; Eid, M. M.; Khalil, N. S.A. M. Synthesis and reactions of some

new heterocyclic carbohydrazides andrelated compounds as potential anticancer

agents.Molecules (2003), 8, 744-755.

25)Taylor. E. C, Harkte. K. S.; J.AM. Chem.Soc., 81, 2456 (1959).

26)A. I. Rutavichyus, S. P. Valyulene, V. V.Mozolisv, J. Org. Chem. Ussr., 1083

(1978).

27)S. P. Singh, D. Kumer; Heterocyclese, 31,855 (1990).

28)K. G. Langenscheid, Luduing., Germanpatent 2508 (1975), Chem. Abs. 85,

78127 (1976); Chem. Abs. 84, 44041e

(1976).

29)H. E. Anderson., J. E. Lasey, L. C.Greene, J. L. Lafferty, H. E.Reiff. J. Med.

Chem., 7, 259 (1946).

30)S. K. Mohant, R. Sriakar, S.Y.Padmanvan, A. A. Mittra.,Indian. J.

Chem., 15B, 1146 (1977).31)L. M. Strnbaach., Prog. Drug. Res., 22,

229 (1978).


16/16


All rights reserved 2011 www jamonline in 552

32)R. Jain, A. J. Shukla; Indian. J. Chem.Soc., 67B, 575 (1990).

33)M. M. Garazd, Ya. L. Garazd, M. N.Smirnov, and V. P. Khilya , Chemistry of

Natural Compounds, VoL 35, No. 4,

(1999).

34)P.V. Ramana, L.K. Ravindranath, J. IndChem. Soc. 76 (1999) 112113.

35)M.S.Y. Khan, M. Akhtar, Indian. J. Chem.42B (2003) 900904.

36)V. Dhingra, R. Bhatawdekar, L. Agarwal,J. Indian Chem. Soc. 68 (1991) 672673.

37)U. Gupta, V. Sareen, V. Khatri, S. Chugh,Indian J. Heterocycl. Chem. 13 (2004)

351354.

38)Brand-Williams W, Cuvelier ME, BersetC. Use of free radical method to evaluate

antioxidant activity. Lebensm- Wiss u-

Technol (1995); 28: 25-30.

39)Schlesier K., Harwat, M.; Bhm, V.;Bitsch, R. (2002). Assessment of

antioxidant activity by using different in

vitro methods. Free Radic.Res., 36, 177-

187.

How to cite this article:

Mahmoud Mohamed Abd El-All , Ahmed Hamdy Halawa , Ahmed Abd El-Hameed Hassan ,

Mohamed Ahmed El-Nassag , Gehad Abd El-Raheem Abd El-Jaleel , Essam Mohamed Eliwa,

Ahmed Hammam Bedair Synthesis and antioxidant activity of some derivatives of 2-(2-oxo-4-

phenyl-2H-chromen-7-yloxy) aceto-hydrazideJ. Atoms and Molecules, 3(4), 2013 : 537 552.

Date post:	14-Apr-2018
Category:	Documents
Upload:	jamonline
View:	216 times
Download:	0 times

Synthesis and Antioxidant Activity of Some Derivatives of 2 2 Oxo 4 Phenyl 2h Chromen 7 Yloxy Aceto...

Documents