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Review Article CODEN: IJPRNK ISSN: 2277-8713 Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218 IJPRBS

Available Online at www.ijprbs.com 197

A COMPREHENSIVE REVIEW ON BIOGENESIS AND SYNTHESIS OF PHARMACOLOGICALLY ACTIVE COUMARINS

ALIM AZIM SAYED*, MUJAHID YUSUFI Department of Chemistry and Post Graduate Research Center Abeda Inamdar Senior College of Arts, Science and

Commerce (Affiliated to Savitribai Phule Pune University), Pune 411 001, Maharashtra, India.

Accepted Date: 31/01/2015; Published Date: 27/02/2015

Abstract: Coumarins are natural products occurring in plants, bacteria, fungi and are

biosynthesized by the Shikimate pathway. This review is based on biogenesis, classic and

recent methods of synthesis along with diverse pharmacological activities of coumarins.

Keywords: Biogenesis, Coumarin, Furanocoumarin, Pyranocoumarin, Biscoumarin

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Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218



INTRODUCTION

Coumarins (2H-1-benzopyran-2one) are naturally occurring secondary metabolites from plants,

bacteria and fungi. They are also found in some essential oils such as lavender oil, cassia oil and

cinnamon bark oil1. As far as distribution in plants is concerned the occurrence of coumarins is

very high in the fruits2, seeds3, roots4 and leaves5.

Coumarins have been classified6 into a) simple coumarins b) furanocoumarins c)

pyranocoumarins and d) biscoumarins and are widely distributed in plant species such as

umbelliferae, rutaceae, and compositae. Numerous coumarins have been isolated since the

first example was reported in 18127. Murray8 et al have written an excellent book that provides

a broad overview of naturally occurring coumarins.

The present review is arranged according to a) Biogenesis of naturally occurring coumarins b)

Classic methods of synthesis of coumarins c) Recent methods of synthesis d) Pharmacological

activity of coumarins.

a) Biogenesis:

In nature simple coumarins are biosynthesized by the Shikimate Pathway9 (Scheme-1) involving

chorismic acid (1), prephenic acid (2) phenylalanine and tyrosine (3). The latter form the

corresponding cinnamic acids (4) on removal of ammonia in the presence of Phenyalanine

ammonia lyase or Tyrosine ammonia lyase (PAL/TAL). Hydroxylation of the cinnamic acid leads

to the formation of 2-coumaric acid or 2,4-dihydroxy cinnamic acid (5) which in turn undergoes

isomerisation and lactonisation to form coumarins (6). Further introduction of second hydroxyl

group at C6 position in umbelliferone gives aesculetin (7) which forms scopoletin (8) on

selective methylation at C6-OH group.



In case of furanocoumarins the main precursor is umbelliferone which undergoes

dimethylallylation at C6 position to form demethylsuberosin (9) (Scheme-2) which further

undergoes epoxidation and ring closure forming the linear furan ring as in marmesin (10),

psoralen (11), bergaptol (12), bergapten (13), xanthotoxol (14), xanthotoxin (15) and

isopimpenelin (16).



Angular furanocoumarin – angelesin (17) can arise by a similar sequence of reactions but these

involve dimethylallylation at the alternative position i.e. C8ortho to phenolic –OH group10

(Scheme-3).

Pyranocoumarins are biosynthesized (Scheme-4) from the same precursor as that of

furanocoumarins i.e. demethylsuberosin, which undergoes epoxidation followed by ring closure

to form six membered pyranring (18), which releases a water molecule forming

pyranocoumarin (19).



O OOH O OO

OH

H

OO O

HO

(18)

H2O_

OO O

(19)

Scheme-4

The most important compound of the biscoumarin series is Dicoumarol i.e. 4,4’-dihydroxy-3,3’-

methylenebiscoumarin (22) which is biosynthesized from 4-hydroxycoumarin (21) and HCHO.

The main precursor of 4-hydroxycoumarin is an ester of 2-coumaric acid and HSCoA (20)

(Scheme-5).

OH

CoSCoA

(20)

OH

CoSCoA

O

lactone formation O O

OH

HCHO

O O

O

OHH

H

O O

O

OO

OH

O

OH

OHO

O

O

dicoumarol (22)Scheme-5

4-hydroxycoumarin (21)

b) Classic Methods of Synthesis:



The classic methods of synthesis of coumarins are i) Perkin reaction ii) Knoevenagel reaction iii)

Pechmann reaction iv) Kostanecki reaction v) Wittig reaction and vi) Reformatsky reaction

i) Perkin Reaction:

An aliphatic anhydride is condensed with salicylaldehyde in presence of sodium acetate to form

coumarins11 (Scheme-6).

ii) Knoevenagel Reaction:

Condensation of o-hydroxybenzaldehydes with active methylene compounds in the presence of

ammonia or amines is known as Knoevenagel reaction (Scheme-7).

O-methoxybenzylidenemalonates, which are available from o-methoxybenzaldehydes and

diethylmalonate were hydrolyzed to the dipotassium malonates12. Treatment of these salts

with trifluoroacetic acid–trifluoroacetic anhydride gave coumarins by demethylative ring

closure reaction in 60-80% yield. Synthesis of 7-dimethylamino-3-ethoxycarbonyl coumarins

derivatives was obtained by this method13.

The reaction of pyridinium-1-[ethoxycarbonylacetyl]methylide with

dialkylacetylenedicarboxylate gave 3-(ethoxycarbonylacetyl)indolizine (23) whose 3-substituent

was smoothly converted to a coumarins skeleton14 by Knoevenagel reaction with

salicylaldehyde (Scheme-8).



N

O

EtOOC

COOR'R'OOC

H2_ N

O

COOR'

COOR'

OH

CHO

N

O

COOR'

COOR'

COOEt

COOEt

OH

N

O

COOR'

COOR'

O

O

3-(ethoxycarbonylacetyl)indolizine (23)

Scheme-8

In Knoevenagel reaction type O-methoxyaryl aldehydes (or ketones) react in solid phase with

Meldrum’s acid and zinc oxide under mild conditions to give benzylidene derivatives (24) which

are cyclized in high yield with cold sulphuric acid to substituted 3-carboxycoumarins15 (Scheme-

9). Thermal decarboxylation by copper powder provided an easy access to numerous

coumarins.

R

OR2

COR1

R1 = H or MeR2 = H or Me

Meldrum's acid

Catalyst

R

OR2

O O

OOH

O

R

R1

COOH

O

O

R

R1

O

Cu

24

Scheme-9

In another Knoevenagel type reaction a solid phase synthesis was carried out in which ethyl

malonate bound to Wang resin16 and orthohydroxyarylaldehydes were used as starting

materials (Scheme-10).



iii) Pechmann Reaction:

It involves condensation of phenols and β-ketoesters in presence of acid catalysts to yield

coumarins (Scheme-11).

R OH

R1

O

O

O

R2

R O O

R2

R1

Scheme-11

The synthesis and structural characterization of coumarins derivatives of some macrocyclic

ethers has been reported. They were obtained from 1,2,3-trihydroxy and 1,2,4-

trihydroxyphenol by reaction with ketoesters17.

Using a similar methodology an improved synthesis of esculetin (6,7-dihydroxycoumarin) and 3-

hydroxy-6,7-dimethoxy coumarins has been described18.

An efficient synthesis of 7-aminocoumarin was performed via the Pechmann reaction by

microwave irradiation of the reactants on solid support (graphite/montmovillonite K10)

(Scheme-12). In this convenient new methodology the strong thermal effect due to graphite-

microwave interaction is associated with the acidic catalyst role of the clay19.



iv) Kostanecki-Robinson Reaction:

The formation of coumarins usually 3 and 4-substituted coumarins by this reaction occurred by

acylation of ortho-hydroxy aryl ketones with aliphatic acid anhydrides followed by cyclization

(Scheme-13)20.

v) Wittig Reaction:

In the Wittig reaction the alkene formation occurs from carbonyl compounds and

phosphoniumylides, proceeding primarily through betaine and /or oxophosphenate

intermediate. This type of olefination of orthohydroxy carbonyl aromatic compounds, followed

by further lactonisation is a well known method for the preparation of coumarin derivatives

(Scheme-14).

The coumarins isolated from Artemesia carvifolia Wall was aproved synthetically to be 7,8-

dimethoxycoumarin. 3,4-dimethoxy and 3,6-dimethoxy salicylaldehydes gave the

corresponding coumarins in good yields by the method using phosphorane reagent and N,N-

dimethylaniline under reflux21(Scheme-15).



Coumarinderivativces having 6-acetyl and 7-hydroxy group have been prepared by the reaction

of 4,6-bis(acetyl)resorcinol and alkoxycabonylalkylidene (triphenyl) phosphorane22.

vi) Reformatsky Reaction:

In this reaction condensation of aldehydes or ketones with organozinc derivatives of α-

haloesters to yield β-hydroxyesters is known as Reformatsky reaction (Scheme-16). In

appropriate reaction conditions, lactonisation could occur with the formation of coumarins23.

c) Recent Methods of Synthesis

Esculetinderivatives, 3-vinyl-6,7-dimethoxycoumarin and 3-bromo-6,7-dimethoxycoumarin on

Heck coupling reaction afford 3-styryl coumarins24 (Scheme-17).



Iodocyclization of 3-ethoxy-1-(2-alkoxyphenyl)-2-yn-1-ols with I2 in DCE or DCM furnishes 3-

iodo-4-substituted coumarins25(Scheme-18).

Palladium catalyzed oxidative cyclocarbonylation of 2-vinylphenol in low pressure of air, CO or

in 1,4-benzoquinone (as oxidant) form 4-substituted coumarins26(Scheme-19).

Salicylaldehydes when reacted with diethylacetylenedicarboxylate or

dimethylacetylenedicarboxylate inPPh3/DMF at 50°C form 4-carbalkoxy-8-

formylcoumarin27(Scheme-20).



The use of TCT and N-methyl morpholine enables an efficient and general protocol for a rapid

synthesis of 3-acylcoumarins. A series of substituted phenylacetic acids have been successfully

reacted with 2-hydroxy-benzaldehyde to afford 3-arylcoumarins in good to excellent yields28

(Scheme-21).

Palladium catalyzed oxidative Heck coupling reaction of coumarins and arylboronic acids allow

a direct synthesis of 4-arylcoumarins in good yields. The raction also showed tolerance towards

functional groups such as hydro, methoxy, ditheylamino, nitro and chloro groups29 (Scheme-

22).

Arylpropionic acid methylesters having a MOM-protected hydroxyl group at the ortho position

underwent hydroarylation with various aryl boronic acids in methanol at ambient temperature

in the presence of a catalytic amount of copper acetate, resulting in the formation of 4-

arylcoumarins in high yields after the acidic workup30 (Scheme-23).



The basic ionic liquid 1-butyl-3-methylimidazolinium hydroxide [bmim]OH efficiently catalyzed

the Knoevenagel condensation of various aliphatic and aromatic aldehydes and ketones with

active methylene at room temperature without requirement of any organic solvent31 (Scheme-

24).Aroylketenedithioacetals react with substituted salicylaldehydes in the presence of

piperidine in THF at 80°C to form 3-aroylcoumarin32 (Scheme-25).

The employment of hydrophobic ionic liquids dramatically enhanced the activity of metal

triflates in Friedel-Crafts alkenylation of aromatic compounds with various alkyl and aryl

substituted alkynes. This is a very good method of forming 4-substituted coumarins33 (Scheme-

26).

Salicylaldehyde when reacted with reactive methylene compounds like diethylmalonate

and ethylacetoacetate in presenece of 1,2-diaminoethane, acetic acid, [bmim]BF4 at room

temperature afford 3-substituted coumarins34(Scheme-27).



An easy method for the synthesis of biscoumarins through a one pot reaction of 4-

hydroxycoumarins and aryl aldehydes under very mild reaction conditions using nanoTiO2as

catalyst in aqueous medium is described35. The products were obtained in short reaction times

with excellent yield under reflux.

An efficient and simple catalyst-free one pot synthesis of biscoumarins by condensing 4-

hydroxycoumarin with aromatic aldehydes in water under ultrasound irradiations at ambient

temperature with excellent yield of the desired product-biscoumarin in shorter reaction time is

described36 (Scheme-28).

CHO

R +

O O

OH

2 H2O

O O

R

OO

Scheme-28

ambient temp.

ultra sound

Reaction of aldehydes and 4-hydroxycoumarin in the presence of catalytic amount of silica-

supported Preyssler nanoparticles led to synthesis of biscoumarins in excellent yields37.

d) Pharmacological activity of Coumarins:

Coumarins have diverse pharmacological activities (Table 1) anti inflammatory (Coumarin 1,

Esculetin 3, 17), antibacterial (Ammoresinol 4, 15, Novobiocin 19, Coumermycin 20), anti-TB,

antimycobacterial (Ostruthin 5), antihypertensive (Imperatorin 10), antihyperglycemic

(Umbelliferone 2), vitiligo treatment (Psoralen 7, Methoxsalen 9) skin pigmentation (Bergapten

8), blood anticoagulant activity (Warfarin 11, Dicoumarol 12, 13) and anticancer activity

(Chartreusin 21, Osthole 6, 14, 16, 18).

Table 1

Sr. No.

Structure Activity

1.

Antiinflammatory38

2.

Antihyperglycemic agent39



3.

Anti inflammatory40

4.

Antibacterial41

5.

Antimycobacterial42

6.

Anticancer43

7.

Vitiligo Treatment44

8.

Skin Pigmentation45

9.

Vitiligo Treatment46

10.

Antihypertensive47



11.

Blood anticoagulant48

12.

or

Blood anticoagulant48

13.

Anticoagulant activity49

14.

Anticancer activity50

15.

Antimicrobial activity51



16.

Antileukemic activity52

17.

Anti inflammatory Activity53

18.

Cytotoxic54

19.

Antibacterial55

20.

Antibacterial56

21.

Anticancer57



CONCLUSION:

Coumarins have played a major role right from the first compound which was reported in 1812.

Over a period of two hundred years, numerous derivatives have been isolated from plants,

essential oils, bacteria and fungi. Moreover, many new synthetic methodologies have been

developed which give better yield of the product in shorter time duration as compared to

classic methods namely Perkin, Pechmann, Reformatsky and Knoevenagel.

As far as pharmacological activities are concerned-coumarins play an important role as

antihypertensive, blood anticoagulant, vitiligo treatment, antihyperglycemic, antibacterial,anti-

TB, anti-inflammatory and anticancer agents. Therefore, they are accepted worldwide as drugs

and medicines.

In this review we have attempted to report classical methods as well as newer approaches of

synthesizing biologically relevant coumarin based structures. This work summarizes the

synthetic approaches and it may help budding research scholars to adopt simpler and useful

strategies for their work.

Recently, new derivatives of coumarins possessing a broad spectrum of pharmacological

activities have been synthesized, however to discuss these in detail will lead to finalization of a

new review on this topic by itself.

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