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Review Article CODEN: IJPRNK ISSN: 2277-8713 Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218 IJPRBS
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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
INTERNATIONAL JOURNAL OF
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Corresponding Author: MR. ALIM AZIM SAYED
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Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218
Review Article CODEN: IJPRNK ISSN: 2277-8713 Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218 IJPRBS
Available Online at www.ijprbs.com 198
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.
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Review Article CODEN: IJPRNK ISSN: 2277-8713 Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218 IJPRBS
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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).
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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).
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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:
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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).
Review Article CODEN: IJPRNK ISSN: 2277-8713 Alim Azim Sayed, IJPRBS, 2015; Volume 4(1): 197-218 IJPRBS
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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).
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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.
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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).
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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).
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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).
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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).
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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).
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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
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3.
Anti inflammatory40
4.
Antibacterial41
5.
Antimycobacterial42
6.
Anticancer43
7.
Vitiligo Treatment44
8.
Skin Pigmentation45
9.
Vitiligo Treatment46
10.
Antihypertensive47
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11.
Blood anticoagulant48
12.
or
Blood anticoagulant48
13.
Anticoagulant activity49
14.
Anticancer activity50
15.
Antimicrobial activity51
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16.
Antileukemic activity52
17.
Anti inflammatory Activity53
18.
Cytotoxic54
19.
Antibacterial55
20.
Antibacterial56
21.
Anticancer57
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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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