-:INTRODUCTION:-

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-:INTRODUCTION :Coumarin is first identified in 1820, and is an oxygen heterocyclic compound famous for its vanilla like or freshly mowed hay fragrance. Coumarin contains benzene ring and a -pyrone fused together. Coumarin is generally found in many plants like tonka seeds, sweet clover grass, lavender and licorice. It is also present in fruit bearing plants like apricots, cherries, strawberries and cinnamon. Artificial production of Coumarin started since 1820 and has been used in manufacture of flavoring and perfume since 1868. Coumarin is produced as pesticides by the plants and artificially it is used to manufacture amalgams like anti coagulants and rat poison. Coumarin is the responsible for the smell mown grass and hay. When Coumarin is fermented it generates dicoumarol which present in sweet clover. This is very strong anticoagulant which forms base of rat poison, which creates hemorrhage in the rodents. This discovery in modern days scientists used as anti clouting agent. Coumarin has appetite suppressing properties, suggesting its wide spread occurrence in plants, especially grasses, because of its effect of reducing impact of grazing animal. Coumarin often found in tobacco and artificial vanilla substituents. Coumarin has been used in the treatment of lymph edema. Coumarin used in toxicity and used in foods, beverages, tobacco and cosmetics. Some natural additives containing Coumarin e.g. sweet woodruff are used in alcoholic beverages. In Europe such beverages are very popular f or example maiwein (white wine with woodruff) and zubrowka (wodka flavor with bison grass). Coumarin is also used in flavoring additive in pipe tobacco. Coumarin possesses anti bacterial properties hence it is used to cure goat fever. There are several byproducts of Coumarin they include antifungal umbelliferrone present in umbelliferae or aromatic plant family and in many

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other exclusive medicines. Berapten obtain from bergamot oil applied as sunscreen agent in many suntan lotions. Asculatin is obtaining from horse chest nut (aesculus hippocastanum) as precious vascular therapeutic agent. Coumarin and all its derivative are considered as phenyl propanoids. Similarly coumarin derivatives have been of great interest because of their role in natural and synthetic chemistry. Many products which contain a coumarin subunit exhibit biological activity such as molluscicides, anthelmintic hypnotic insecticidal activity and some are serving as anticoagulant agents and fluorescent brighteners. So coumarins containing a Schiff base are expected to have enhanced antitumor and other biological activities. It is well established that the biological activity associated with the hydrazones compounds attributed to the presence of the active pharmacophore. Hence many hydrazones compounds containing this active moiety showed good anticancer bioactivities according to the literature. Microwave radiation of organic reaction has rapidly gained popularity as it accelerates the reaction towards a variety of synthetic transformation, solvent less procedures without the use of supporting reagents and hence eco-friendly. Chemical transformations that took hours or even days to complete can now be accomplished in minutes. Microwave energy offers numerous benefits for performing synthesis such as increased reaction rates, enhanced yields and cleaner chemistries. Hence, in this paper, we are reporting the synthesis of coumarin analogues with Schiff bases and hetero aromatic aldehydes by conventional and microwave assisted methods, and their characterization through spectral data such as IR, 1HNMR and Mass spectra. Their antimicrobial activity was also evaluated.

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Some derivatives of coumarin as follows :-

Sr.No 1
HO

Structure
O

Derivative Name 2[(4-methyl-2-oxo-2Hchromene-6-yl) oxyl) acetic acid.

HO

Ethyl-7-hydroxy-2-oxo-2h-chromene3-carboxylate.
OC2H5

O
O

O O O

7-hydroxy-4-methyl-2-oxo-2hchromene-8-yl acetate

HO

4
H3CO

8-acetyl-6-hydroxy-7-methoxy-2oxo chromene
O O

HO

H3CO

5-Bromo-7-methoxy-4-methyl-2-oxo2h-chromene

Br

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Chemistry of 7-Methoxy-4-Methyl-2-Oxo-Chromene-6Carbaldehyde:-

1) Structure :H3CO O O

CH3

7-methoxy-4-methyl-2-oxo-2H-chromene-6-carbaldehyde

2) Molecular formula: - C12H10O4 3) Nature: - Yellow solid 4) Percent content of element: It contains % of Carbon = 66 % % of hydrogen = 13 % % of oxygen 5) Melting point = 262 0c 6) Therapeutic use: - Some studies were carried out in order to explore the Anticancer, Antiviral, anticoagulants agent and fluorescent brighteners. 7) Industrial applications: - Its derivatives can be used as enhanced antitumor and other biological activity, and also in dyes building block of synthetic organic semiconductor & florescent material in LED. = 21 %

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Some naturally occurring coumarin derivatives are umbelliferrone, asculatin, herniarin, imperatorin.

HO

HO
O

HO

7-hydroxy-2H-chromen-2-one
Umbelliferrone (7hydroxy coumarin)

6,7-dihydroxy-2H-chromen-2-one
Asculatin (6,7dihydroxy coumarin)

7-methoxy-2H-chromen-2-one
Herniarin (7methoxy coumarin)

4-phenyl-2H-chromen-2-one
Imperatorin (4 phenyl coumarin)

Due to important biological properties & Industrial applications of coumarin & its derivatives we wanted to develop a convenient method for 7-methoxy-4-methyl-2-oxo-chromene carbaldehyde. When we searched the literature we found that Different method available for synthesis of 7-methoxy-4-methyl-2-oxo-chromene carbaldehyde was reported

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-:Reported Methods:-

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Reported Methods:Coumarin Synthesis (7- hydroxy-4-methyl coumarin)

Method I: - Pechmann Condensation reaction

OH

OH

OH

+
O O

H2SO4

Method II: - Zinc Mediated Coumarin Synthesis

HO

OH

+
O

ethyl 3-oxobutanoate resorcinol Zn (0 .2 eq- 0.5 eq) tolune, reflux

HO

CH3

7-hydroxy-4-methyl-2H-chromen-2-one

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Method III: - Nitration reaction.

HO

HO

CAN,NaHCO3
NO2

HO

HO

HNO3, H2SO4
NO2

+
NO2 HO O O

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-: Retro synthetic Analysis:-

H3CO

H3CO

H CH3 CH3 H

Synthon
O

OEt

Synthetic Equivalent
H3CO OH

H3CO

OH O

Synthon
CH3 O O O

FGI

Synthetic Equivalent

HO

OH

Resorcinol

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-: Our Approach:-

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Our Approach:Reaction:Step I:-

HO

OH

HO

+
Resorcinol

Conc. H2SO4
OC2H5

Step II:-

HO

DMS

H3CO

K2CO3
CH3

7-hydroxy-4-methyl-2H-chromen-2-one

CH3 7-methoxy-4-methyl-2H-chromen-2-one

Step III:H3CO O O H3CO O O

DMF POCL3 CH3 7-methoxy-4-methyl-2H-chromen-2-one

H

O CH3 7-methoxy-4-methyl-2-oxo-2H-chromene-6carbaldehyde

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Mechanism:-

Step I:-

HO

OH

HO

Conc. H2SO4
OC2H5

H
HO OH O O

+
O

Conc. H2SO4

O O OH C O

O HO OH C O

-H

H H OH OH

- H2O
O HO OH C O

HO

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Step II:-

H HO H3C S O CH3 O O H3CO O O

(methylsulfinyl) methane

CH3

CH3 7-hydroxy-4-methyl-2H-chromen-2-one

K2CO3

H3CO

H2O CH3 7-methoxy-4-methyl-2-oxo-2H-chromene-6carbaldehyde

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Step III:CH3 O N O H3C N CH3 H Cl P Cl Cl H3C N CH3 H3CO H O O C Cl O H3C C H O P Cl Cl

Cl Cl
H

Cl H3C N CH3 C

CH3

H3CO CH3 N H3C

H3CO CH3 Cl

C H H H3C

N C H

CH3

CH3

H3CO CH3 N H3C

H3CO

Hydrolysis
H

C H

CH3

CH3

7-methoxy-4-methyl-2-oxo-2H-chromene-6-carbaldehyde

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-:

Experimental work :-

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Experiment No:-1
Aim: Preparation of 7-hydroxy- 4-methyl coumarin from resorcinol.

Chemicals: 1) Resorcinol 2) Conc. H2SO4 3) Ethyl aceto acetate Reaction:-

OH

OH

OH

+
O O

H2SO4

Procedure: 10 ml. Concentrated sulphuric acid was taken in a conical flask and cooled in the ice bath. To it a mixture of 1.0 gm of resorcinol and 1.4 ml of ethyl acetoacetate was added drop wise manner with constant stirring. This reaction mixture was then kept at room temperature for overnight. This reaction mixture was then poured on crushed ice and stir vigorously with the glass rod solid separates out. Filter this yellow solid. Dissolve this solid in Aq. 10% NaOH and again filter to remove insoluble impurities. Reprecipeted the solid by adding dil.H2SO4 drop wise to the filtrate and then warming on water bath. Filter the crude product, Recrysatalised from ethanol. Dry the product, take the yield and note down the melting point. Run the TLC in suitable solvent.

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Observations:Theoretical yield: Resorcinol 1 gm Practical yield:Practical yield of 7-hydroxy-4-methyl coumarin is = 1.2 gm. = = 7-hydroxy-4-methyl coumarin 1.6 gm

% Practical yield :% Practical yield of 7-hydroxy-4-methyl coumarin = 75 %

Melting point :Melting point of 7-hydroxy-4-methyl coumarin = 184 oC

TLC:-

Rf value of reactant = 0.92 Rf value of product = 0.71

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Solvent used for running TLC is 20 % Ethyl Acetate in Pet Ether.

Result Table:Description Name& structure

HO

Compound
O O

7-hydroxy-4-methyl-2H-chromen-2-one

Time Theoretical yield Practical yield %Practical yield Solvent used Melting point

12 hr. 1.6 gm 1.2 gm 75% EtOH 1840C

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Experiment No:-2
Aim: - Preparation of 4-Methyl 7-Methoxy Coumarin from 4-Methyl 7Hydroxy Coumarin.

Chemicals:1) 4-methyl 7-hydroxy coumarin 2) Acetone 3) Anhydrous K2CO3 4) DMS 5) 10% Na2CO3 6) Sodium sulphate

Reaction:-

HO

DMS

H3CO

K2CO3
CH3

7-hydroxy-4-methyl-2H-chromen-2-one

CH3 7-methoxy-4-methyl-2H-chromen-2-one

Procedure:A solution of 4-methyl 7-hydroxy coumarin (0.5gm) in dry acetone (15 ml) was treated with anhydrous K2CO3 (1.5 gm) and DMS (1.25 ml) is added in three portions. The above mixture was stirred and refluxed for 8 hour. After completion of reaction (TLC) the reaction mixture was then filtered and the residue is washed with hot acetone. The excess of acetone was recovered by distillation. The remaining methylated compound is extracted with

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ether, washed well with 10% Na2CO3 and then with water. The ether layer dried over sodium sulphate and evaporation of ether gave the product.

Observations:Theoretical yield:7-hydroxy-4-methyl coumarin = 7-methoxy -4-methyl coumarin 176gm 0.5gm Practical yield:Practical yield of 6-nitro 7- hydroxy-4-methyl coumarin is = 0.392 gm = = 190gm 0.53gm

% Practical yield:% Practical yield of 6-nitro 7 -hydroxy-4-methyl coumarin = 73.96%

Melting point:Melting point of 6-nitro 7-hydroxy-4-methyl coumarin = 1600C

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TLC :-

a-Reactant of 7-hydroxy-4-methyl coumarin b-Product of 7-methoxy-4-methyl coumarin

Solvent used for TLC- 10%Ethyl acetate in n-hexane Rf values: a b 1)Rf value of Reactant = 0.53 2) Rf value of Product= 0.28

Result Table:Description Name & structure

H3CO

Compound
O O

7-methoxy-4-methyl-2H-chromen-2-one

Time Theoretical yield Practical yield %Practical yield Solvent used Melting point

8 hr. 0.53 gm 0.39 gm 73.96% EtOH 160 0C

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Experiment No:-3

Aim: - Preparation of 4-methyl-7-methoxy, 6-formyl coumarin from 4-methyl7-methoxy coumarin. Chemicals:1) N-N dimethyl form amide 2) POCl3 3) 4-Methyl- 7-methoxy coumarin 4) Sodium acetate Reaction:-

H3CO

H3CO

DMF POCL3 CH3 7-methoxy-4-methyl-2H-chromen-2-one

H

O CH3 7-methoxy-4-methyl-2-oxo-2H-chromene-6carbaldehyde

Procedure :Measure 0.4 ml of N-N dimethyl form amide in a hard glass test tube and cool it in ice bath. To this add constant shaking 0.4 ml of POCl 3. After formation of complex is complete, add 0.5 gm of 4-methyl 7-methoxy coumarin in one portion, put a plastic cover on test tube and for 2 hours. Take care that moist does not enter into test tube. Pour reaction mixture over 7.5ml saturated ice cold solution of sodium acetate and keep it aside for 30 min. Filter the product is obtained , recrystallise by ethanol. Record M.P and TLC.

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Observation:Theoretical yield:7-methoxy 4-methyl coumarin 190gm 0.5gm = = = 0.57gm 6-formyl 7-methoxy 4-methyl coumarin 219gm

Practical yield:Practical yield 4-methyl-7-methoxy-6-formyl coumarin of product = 0.328gm

% Practical yield:%Practical yield 4-methyl-7-methoxy, 6-formyl coumarin of product=56.14%

Melting point:Melting point of methyl-7-methoxy, 6-formyl coumarin = 262 oC TLC :-

a-Reactant of 7-methoxy-4-methyl-2H-chromen-2-one
a
b

b- Product of 7-methoxy-4-methyl-2-oxo-2H-chromene-6-carbaldehyde

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Solvent used for TLC= 10% Ethyl acetate in n-hexane

Rf values= 1) Rf value of reactant= 0.62 2)R f value of product= 0.43

Result Table:-

Description Name & structure

H3CO H O

Compound
O O

7-methoxy-4-methyl-2-oxo-2H-chromene-6carbaldehyde Time Theoretical yield Practical yield %Practical yield Solvent used Melting point 2 hr. 0.57 gm 0.32 gm 56.14% EtOH 262 0C

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-: Spectral data :-

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Conclusion and Result :To conclude, Coumarin showing anti-bacterial properties, anticoagulant properties, and coumarin is widespread naturally occurring aromatic heterocyclic compound. The Coumarin (7-Hydroxy 4-metyl) synthesis by Pechmann condensation method is efficient method giving high yield about 75%, which on methylation by using with DMF,K2CO3 and dry acetone resulted with improved yield of 73% gives product 7-Methoxy 4-Methyl Coumarin as major product, this product is confirmed by T.L.C. and physical method technique. The coumarin (4-methyl-7-hydroxy coumarin)is showing property of fluorescence,hence it is used fluorescent marker. I have synthesized coumarin formylation by various method but coumarin formylation by the approached way proved to be better and efficient method gives high yield about 56.14%.Therefore synthesized 4-methyl 7-methoxy-2-oxo-2H-chromene carbaldehyde is major product, The completion of reaction is confirmed by T.L.C. physical constant and IR spectral analysis data. Spectral data of compound showing following peaks 1745 cm-1 showing presence of lactone ring ,1720 cm-1 showing presence of aldehyde group, 1450-1600 cm-1 showing c=c (unsaturation) aromatic ring, From above we conclusion that, we developed a convenient, simple, efficient and eco-friendly procedure for the synthesis of 4-methyl 7-methoxy-2oxo-2H-chromene carbaldehyde.

H3CO

CH3

7-methoxy-4-methyl-2-oxo-2H-chromene-6-carbaldehyde

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References:
1) Abu-Hussen, A.A.A.J.Coord.Chem.2006, 59,157. 2)Sing, K.; Barwa, M.S; Tyagi, P.Eur.j.Med.chem.2006, 41, 1. 3)Sridhar,S.k;Sarvan,M;Ramesh,Aur.J.Med.Chem.2001,36,615. 4)Khan,S.A;Shashikant,S;Deepak,A.v.Bioorg.Chem.2004,32,211. 5) Vogel text book of practical organic chemistry 6) Tetrahedron letters, 2001 , 42 , 9285-9287 7) Journal of organic chemistry research, Vol-09, 06, June09, PP 339-341 8) Organic chemistry Clayden , Greeves etc 9) Merk index 10) www. sciencedirect.com s 11) www.google.com

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