09 chapter 3

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

89

Introduction:

Coumarins occupy an important place in the realm of natural products and

synthetic organic chemistry1,2. Coumarins comprise a group of natural compounds found

in a variety of plant sources in the form of benzopyrene derivatives. Coumarins have

important effects in plant biochemistry and physiology, as they act as antioxidants,

enzyme inhibitors, and precursors of toxic substances. In addition, these compounds are

involved in the actions of plant growth hormones and growth regulators, the control of

respiration, photosynthesis, as well as defense against infection3. Coumarins have long

been recognized to possess anti-inflammatory, anti-oxidant, anti-allergic,

hepatoprotective, anti-thrombotic, anti-viral and anti-carcinogenic activities4. In addition

to biological activities they are used as additives to food and cosmetics5 and optical

brightening agents6.

Hydroxycoumarins are typical phenolic compounds and therefore, act as potent

metal chelators and also free radical scavengers7. They are powerful chain-breaking anti-

oxidants. The very long association of plant coumarins with various animal species and

other organisms throughout evolution may account for the extraordinary range of

biochemical and pharmacological activities of these chemicals in mammalian and other

biological systems8. The coumarins are extremely variable in structure, due to the various

Coumarins

anti-bacterial and antiviral

anti-carcinogenic

anti-clotting hepatoprotective

anti-thrombotic

anti-inflammatory

anti-clotting and anti-thrombotic Fig. 1: Applications of coumarins

anti-HIV activities


90

types of substitutions in their basic structure, which can influence their biological

activity. The interesting biological activities of the coumarins have made them attractive

targets in organic synthesis.

A Special Emphasis on Coumarin Derivatives:

Fig.2: Representative bio-active natural coumarins

(+)- Calanolide A, (Fig.2) (+) -[10R,11S,12S] -10,11- trans-dihydro-12-hydroxy-

6,6,10,11-tetra methyl-4-propyl-2H, 6H-benzo [1,2-b:3,4-b′:5,6-b″] tripyran-2-one is a

novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent activity against

HIV-19-10a. This compound was first isolated from a plant Calophyllum lanigerum in

Malaysia9. Due to low availability of naturally occurring (+)-calanolide A, a total

synthesis of this polycyclic coumarin was developed to provide material for preclinical

and clinical research10a. Only (+)-calanolide A accounted for anti-HIV activity, which

was similar to the data reported for the natural product while (−)-calanolide A was

inactive.


91

Patil et al.10b reported the isolation of (+)-inophyllum B from C. Inophyllum which

is the most active component for inhibition against HIV-reverse transcriptase.

(+)-Cordatolide A, isolated from the light petrol extract of the leaves of C.

cordatooblangum in 198510c, is a novel tetracyclic coumarin. Its structure and properties

are similar to (+)-calanolide A10d.

Pic. 1 Ayapana triplinervis

Ayapin was first discovered in the late 1930s from the plant Ayapana triplinervis,

it was reported to have pronounced blood-thinning or anti-coagulant actions10e. Ayapana

also contains a coumarin named hernarin (7-methoxycoumarin) hence the plant is used in

herbal medicine as an anti-tumor remedy. Recently, it was found that this chemical is

toxic to cancer cells including multi-drug resistant cancer cells and leukemic cells10f.

Carbochromen is a coronary vasodilator drugs and is capable of increasing local

myocardial blood flow and decreasing myocardial metabolic heat production both in the

normal canine myocardium and in the myocardium rendered ischaemic by acute ligation

of a coronary artery10g.


92

Fig. 3: Marine alkaloids containing coumarin skeleton

Pyrrolocoumarins are of considerable pharmacological relevance and occur in a

variety of natural products. A chromeno[3,4-b]pyrrol-4(3H)-one core structure occurs, for

example, in the marine alkaloids Ningalin B and Lamellarin D (Fig. 3) which exhibit

HIV-1 integrase inhibition, immunomodulatory activity and cytotoxicity11.

Coumarin as precursor in Organic transformations:

i) Mulwad et al.12 have reported the facile synthesis of coumarinyl isothiocyanate

from amino coumarins using CS2, iodine and pyridine [Scheme 1]. The attraction of

isothiocyanate as synthons is obviously due to its diverse reactions and easy availability.

It undergoes nucleophilic addition reactions13, cycloaddition to unsaturated systems14,

Diels-Alder reaction15 and reaction with bifunctional compounds to yield heterocyclic

derivatives16. Isothiocyanates have found wide applications in agrochemical17 and

pharmaceutical industries18. They have attracted attention as they are potent and selective

inhibitors of carcinogenesis in various animal models19.

OO

NH2

CH3 CS2

I2/Pyridine

OO CH3

NCS

Scheme 1 ii) Venkateswaran and co-workers20 have described a one-step conversion of

coumarins to usefully functionalized diacids employing the Bargellini condensation. The


93

diacid was transformed in a few steps to high yielding marine sesquiterpene Helianane

underscoring the importance of this protocol [Scheme 2].

O O O

CO2H

CO2H

R1

R2

R3

i. CHCl3, NAOHacetone

ii. H+

R1

R2

R3

Scheme 2

iii) A direct arylation of 4-hydroxycoumarins by photo induced reaction with aryl

halides was reported by Baumgartner21 et al. in good yields (>60%) [Scheme 3].

However, the reaction of 4-hydroxycoumarins with o-dihalobenzenes leads to the

synthesis of ring closure products which bear a tetracyclic aromatic-condensed ring

system with an overall yield of 45 % [Scheme 4].

O O

OH Cl

I

+

O

OH

O

Cl

DMSOKOBu-t

hv

Scheme 3

Scheme 4

A method for direct arylation of 4-hydroxycoumarins with arylboronic acids via

C–OH bond activation catalyzed by PdCl2 operable under mild conditions was reported

by Wu et al.22, to give rise the corresponding 4-arylcouamrins in good to excellent yields

[Scheme 5].


94

Scheme 5

iv) An efficient and straightforward synthesis of functionalized angularly-fused

dihydrofurocoumarins by an efficient multi-component domino process of aromatic

aldehydes, 4-hydroxycoumarin and α-chloroketones in refluxing n-propanol is described

by Altieri et al.23 The products were formed with high diastereoselectivities [Scheme 6].

Scheme 6

v) Yang co-workers24 reported enantioselective Michael reaction of

4-hydrocoumarin, using LiClO4/DPEN as a catalyst (up to 94 % ee) [Scheme 7].

Scheme 7

vi) Langer and his group25 carried out the base-mediated cyclocondensation of

1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin which provided a convenient

approach to various chromeno[3,4-b]pyrrol-4(3H)-ones [Scheme 8].


95

Scheme 8

vii) The synthesis of 2-benzazepine derivatives was reported by Prasad et al.26 from

4-chloro-3-formyl coumarin and benzyl amine under catalyst-free conditions in aqueous

medium [Scheme 9].

Scheme 9

Synthetic Routes for Coumarins:

The occurrence of a large number of coumarin derivatives has led many investigators to

find out general methods for the synthesis of compounds containing either the benzo-α-

pyrone or the benzo-γ-pyrone ring leading to the synthesis of naturally occurring

substances. The naturally occurring coumarins have been obtained either i) by the closure


96

of the lactonic ring with the necessary substituent in the benzene nucleus, or ii) by the

introduction of the substituent in the requisite coumarin.

The synthesis of coumarins has been the subject of extensive study over many

decades and is usually synthesized by several methods viz the von Pechmann27, Perkin28,

Knoevenagel condensation29-30 of ortho-hydroxyaldehydes with Meldrum’s acid, maleic

acid, malonic ester, or cyanoacetic ester, Reformatsky31 and Wittig reactions32,

Cyclocoupling33, etc.

i) Von Pechmann reaction:

The Pechmann condensation27a-k is one of the most common procedures for the

preparation of coumarin and its derivatives. This method involves the reaction between

phenol and β-ketoester in the presence of an acidic catalyst. Maheswara et al. applied

HClO4–SiO2 under solvent-free conditions to carry out Pechmann condensation27a

[Scheme 10].

OH

R

O O

OEt

O O

R+

H+

Scheme 10

The reaction can also be catalyzed by different Brønsted and Lewis acids viz PPA

27b, InCl3 27c, ZrCl4

27d, Yb(OTf)327e, p-TsOH27f, BiCl3

27g, and I2 or AgOTf27h. Because of

recent efforts toward green chemistry, attempts are being made to replace stoichiometric

Brønsted and Lewis acids by nonstoichiometric solid acids, such as montmorillonite

clay27i and cation-exchanged resin27j. Application of ionic liquids was also reported27k.

ii) Perkin reaction:

In 1868, Perkin28a reported the synthesis of coumarin by the reaction of sodium

salt of salicylaldehyde with Ac2O. The Perkin reaction28a-c provides a useful method for

the synthesis of α,β-unsaturated aromatic acids and involves the condensation of a

carboxylic anhydride with an aromatic aldehyde in presence of a weak base such as

sodium or potassium acetate or triethylamine [Scheme 11].


97

OH

CHO

O

O

O

O OR R

+ weak base

Scheme 11

iii) Knoevenagel Condensation:

In 1988, Armstrong et al.29a reported a two step method for the synthesis of

coumarin-3-carboxylic acids via sulphuric acid catalyzed Knoevenagel condensation of

2-methoxybenzaldehyde with Meldrum’s acid in dimethylformamide followed by

cyclization [Scheme 12].

O

O

O

O

OMe

CHO

R1

R2

R3

R4

O

O

O

O

R4

R3

R2

R1

OMe

R1

R2

R3

R4

O

O

COOH

+

DMF H+

Scheme 12

A solid-phase synthesis has also been reported for condensation of 2-methoxy

benzaldehyde with Meldrum’s acid in the presence of an excess of ZnO29b at 80 oC

followed by cyclization in the presence of cold H2SO4. Recently many one-pot methods

have been reported involving condensation of ortho-hydroxyarylaldehyde and Meldrum’s

acid in the presence of a solid acid catalyst under microwave irradiation29c, by grinding a

reaction mixture with ammonium acetate and keeping it overnight29d, and by use of

piperidinium acetate in ethanol under reflux conditions29e. Some uncatalyzed routes have

also been developed involving heating the reaction mixture in an aqueous medium29f-g.

Recently, Salunkhe and co-workers reported synthesis of coumarin-3-carboxylic acid

using [Hmim]Tfa ionic liquid 29h.

Although large number of reports available on the synthesis of Coumarin-3-

carboxylic acid, to the best of our knowledge there is no report for the synthesis of

coumarin-3-carboxylic acid by Knoevenagel condensation of Meldrum’s acid and

salicylaldehyde using basic catalyst.

Knoevenagel condensation of 2-hydroxybenzaldehyde with malonic ester or

cyanoacetic ester results in formation of Coumarins, It was by the influence of


98

organocatalyst 29i, imidazolium-based phosphinite ionic liquid (IL-OPPh2),29j respectively

[Scheme 13].

The catalytic scope of the silica-immobilized piperazine was assessed for the

Knoevenagel condensation between salicylaldehyde and diethyl malonate by

Shanmuganathan et al. 29i.

Valizadeh et al.29j carried out synthesis of various coumarins by using a task-

specific ionic liquid (IL, OPPh2) bearing a phosphinite weak Lewis base group in an

imidazolium cation, which was found to efficiently catalyze the Knoevenagel

condensation of salicylaldehydes with ethyl cyanoacetate.

OH

CHO

COOEtEtOOC

COOEtNC

Immobilized organocatalyst

R

IL-OPPh2

O O

COOEt

O O

CN

R

R

+

Scheme 13

For coumarin synthesis, a series of developments and modifications have also

been reported.

Recently, Shi and co-workers30a have synthesized novel 3-acetoacetylcoumarin

derivatives by reaction between substituted salicylaldehyde and 4-hydroxy-6-methyl-2H-

pyran-2-one via Konevenagel condensation in good yields using [bmim]Br as a catalyst

at 90 oC [Scheme 14].

O O

OH OOH

CHO

O

OH

CH3 O

+

3-acetoacetyl coumarin

Scheme 14


99

The stepping stone to the realm of MCRs for organic chemists was a three-

component coumarin synthesis developed by Nair et al.30b in 1987 [Scheme 15], which

proceeds via a domino Knoevenagel–hetero-Michael-type addition sequence.

O O

OH

OH

CHOOH

OH OH

O O

OO

+ +

Scheme 15

Singh and co-workers30c carried out reaction of substituted salicylaldehyde and

oxodithioesters using SnCl2 as a catalyst for the synthesis of 2H-chromene-2-thiones in

high yields [Scheme16].

R' SMe

SO OH

CHO

O S

R'

O

Urea

SnCl2

Scheme 16

Wardakhan et al.30d synthesized coumarin moiety containing 1,3,4-Thiadiazole

derivatives having anti-microbial activity [Scheme 17].

Scheme 17

Adib co-workers30e reported synthesis of 2-(alkylamino)-5-{alkyl[(2-oxo-2H-

chromen-3-yl)carbonyl]amino}-3,4-furandicarboxylates via a one-pot multi-component

reaction of salicylaldehyde, Meldrum’s acid, cycloyl isocyanide and diethyl

acetylenedicarboxylate [Scheme 18]. The reactive 1:1 zwitterionic intermediate generated

from the addition of isocyanides to dialkyl acetylenedicarboxylates was trapped at room

temperature by coumarin-3-carboxylic acid prepared in situ from a 2-hydroxy aromatic

aldehyde and Meldrum’s acid to afford the title compound in good to excellent yields.


100

Scheme 18

iv) Reformatsky Reaction

Dittmer et al.31 have achieved the sodium telluride-triggered cyclization of the

bromoacetate of salicylaldehyde to coumarin via modified Reformatsky reaction. The

cyclization proceeds by formation of the phenolate ester enolate, elemental tellurium, and

bromide ion. The enolate anion either attacks the ortho carbonyl group leading to

cyclization or eliminates a phenolate ion to give a ketene [Scheme 19].

OH

COR''

R'CH(Br)COBr

COR''

O

O

R'

BrM2Te, THF

O

R''

R'

O

base M=Na, Li

Scheme 19

v) Wittig reaction

Recently, a novel one-pot synthesis of coumarins via intramolecular Wittig

cyclization from the reaction of phenolic compounds containing ortho-carbonyl group

and triphenyl(α-carboxymethylene)phosphorane imidazolide was reported by Upadhyay

and his group30 [Scheme 20].

O O

R'

RN

O

N

Ph3P

OH

R'

O

RO O

R'

PPh3O

R+

Scheme 20

vi) Hua co-workers33 synthesized 3,4,7,8-Tetrahydro-2H-chromene-2,5(6H)-dione

derivatives with excellent selectivity via a [3+2+1] cyclocarbonylative coupling of

1,3-cyclohexanediones, terminal alkynes, and CO catalyzed by Pd(PPh3)4 [Scheme 21].

Scheme 21


101

Objectives:

i) Search for basic catalyst for the synthesis of coumarins from ortho-hydroxy

aldehyde and Meldrum’s acid as it will be the first basic catalyst for the same

transformation.

ii) The development of a procedure using commercially available, inexpensive mild

base.

iii) To obtain highly pure coumarin derivatives without using tedious

chromatographic techniques.

Present Work:

The mechanism of coumarin synthesis follows Knoevenagel condensation of

salicylaldehyde with Meldrum’s acid followed by nucleophilic attack of –OH on

carbonyl carbon of Meldrum’s acid. Our group has reported Knoevenagel condensation34

of aldehydes with Meldrum’s acid using K3PO4 as a catalyst in ethanol medium. In the

preceding chapter, we have carried out synthesis of tetrahydrobenzo[b]pyrans35 via

Knoevenagel condensation of aldehydes and malononitrile followed by Michael attack of

dimedone and cyclodehydration using anhydrous K3PO4 as a mild base in ethanol

medium. The success obtained in performing these reactions prompted us to explore

efficacy of potassium phosphate in the synthesis of coumarin-3-carboxylic acid.

As a trial case, to a well stirred solution of an equimolar amount of salicylaldehyde

and Meldrum’s acid (1 mmol each) in ethanol (5 mL) was added potassium phosphate

(40 mg). A clearly homogeneous system was formed at the beginning of the reaction [Pic.

2(a)], which suddenly changed into pale yellowish precipitate indicating the formation of

Knoevenagel adduct [Pic. 2(b)], followed by white precipitate which shows formation of

3-carboxycoumarins [Pic. 2(c)], these changes were also monitored on TLC. The routine

workup of the reaction mixture [ether 15 mL x 3] followed by neutralization with NH4Cl

yielded desired coumarin-3-carboxylic acid which was characterized on the basis of its

physical data.


102

(a) (b) (c)

Pic.2: Progress of the reaction

In an initial study to examine the catalytic activity of different catalysts generating

K+ ions such as K3PO4, K2HPO4, KH2PO4 and K2CO3, equimolar mixture of 2-hydroxy

benzaldehyde and Meldrum’s acid was stirred in presence of 20 mol % of catalyst in

ethanol medium. The results revealed that potassium phosphate is better suited for the

present transformation for the reasons of low cost, ease of availability, time and yields

[Graph 1].

Graph 1: Effect of catalyst on the synthesis of coumarin-3-carboxylic acid

It is worthy of note that in solvents viz H2O, CHCl3, CH3CN, CH3OH, yields of

product 3 obtained were considerably lower than that in ethanol [Graph 2].


103

Graph 2: Effect of solvent on the synthesis of coumarin-3-carboxylic acid

The plausible mechanism involving the role of K3PO4 in the synthesis of

coumarin-3-carboxylic acid is depicted in Scheme 22.

O

OO

O

H

H

K3PO4

K+

PO4

3-

O

OO

O H

O

OH X

O

O

O

OOH

OH

H

X

O O

COOK

X

O

O

O

OOHX

O

O

O

OOHX

-

+

Scheme 22: Proposed mechanism for synthesis of coumarin-3-carboxylic acid


104

Using optimized reaction conditions, to prove the generality of protocol, we have

carried out the reaction between various substituted salicylaldehydes containing both

electron donating as well as electron withdrawing substituents viz methoxy, methyl,

bromo, chloro, hydroxyl, nitro and naphthyl reacted smoothly with Meldrum’s acid at

room temperature, to afford the corresponding coumarin derivatives.[Scheme 23,Table 2]

OH

H

O

R

O

O

O

O

K3PO4

C2H5OH/RTO O

COOH

R+

2 1 3

Scheme 23: Potassium phosphate catalyzed synthesis of 3-carboxycoumarins

The electronic property of the substituent at the aromatic ring of aldehyde has

considerable effect on yield of product (Table 1, entries a–k). Those bearing electron-

donating groups at position 5 generally gave better yields than electron-withdrawing

group at same position. (Table1, entries c–h) However, in case of electron-withdrawing

groups both at positions 3 and 5 gave excellent yields, as compared to mono-substituted

aldehydes at position 5. The structures of the all synthesized compounds were established

unambiguously using spectral methods.

8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (3b) obtained from the reaction

between 3-methoxy-salicylaldehyde and Meldrum’s acid showed satisfactory

spectroscopic data. IR spectrum (Fig. 4) of the 3b showed prominent peaks at 3418,

1746, 1685 cm-1 corresponding to hydroxy group, lactone group and carboxylic carbonyl

group, respectively.1H-NMR spectrum (Fig. 5) of the same compound exhibited sharp

singlet at δ 3.93 corresponding to three protons of methoxy group. Aromatic protons

appeared as multiplets at 7.33 (1 H) and 7.42 (2 Hs). Olefinic and carboxylic acid group

protons appeared at 8.72 and 13.26, respectively.

IR spectrum (Fig. 6) of compound 3c showed broad peaks at 3400 and 3168 cm-1

marking the presence of aromatic hydroxyl and carboxylic hydroxyl groups, further it

also demonstrated peaks at 1731 (lactone carbonyl), 1669 (carbonyl from carboxyl),

1571, 1239 cm-1. 1H NMR (Fig. 7) spectrum of the same compound exhibited doublet of

doublet at δ 7.15 (J=2.8 Hz, J= 9.2 Hz), doublets at 7.20 (J=2.8 Hz) and 7.29 (J=9.2 Hz)


105

corresponding to three aromatic protons. A singlet observed at 8.66 consequent to

olefinic proton and two broad singlets appeared at 9.89 and 13.19 analogous to

hydroxylic and carboxylic protons, respectively. In 13C-NMR spectrum (Fig. 8) sharp

signals were observed at 114.20, 117.54, 118.84, 118.96, 122.93, 148.29, 148.66, 154.44,

157.70, and 164.59 corresponding to 10 different carbons of the compound. IR and NMR

data is in agreement with the expected structure.

6-Methyl-2-oxo-2H-chromene-3-carboxylic acid (3d) in its IR spectrum (Fig. 9)

exhibited broad O-H stretching band around 3400 cm-1 and -CH stretching bands at

3028, 2959 cm-1. Proton-NMR spectrum (Fig.10) of same compound displayed sharp

singlet at δ 2.37 for three methyl group protons. In aromatic region, doublet at 7.34,

doublet of doublet at 7.55 and singlet at 7.69 for one proton each is observed. Proton

from olefinic functionality appeared at 8.67 and carboxylic functionality appeared at

13.23. Eleven carbons from the same compound showed prominent and sharp peaks in 13C-NMR spectrum (Fig. 11) at δ 21.60, 116.32, 118.11, 118.65, 130.03, 134.58, 135.64,

148.64, 153.03, 157.36, and 164.46. Peak at 164.46 is the characteristic for carbon of

carboxylic acid group.

IR spectrum (Fig. 12) of 6,8-dibromo-2-oxo-2H-chromene-3-carboxylic acid (3i)

exhibited peaks at 3473 (-OH from –COOH), 3065 (C-H), 1762 (lactone), 1696

( carbonyl from –COOH). In 1H-NMR spectrum (Fig. 13) two doublets appeared at 8.18

and 8.25 ppm (J = 2.4 Hz) with respect to two aromatic protons. A sharp singlet was

exhibited by hydroxyl proton at 8.68. A broad singlet at 13.50 marked the presence of

acidic proton (carboxyl). 13C NMR (Fig. 14) showed sharp signals at δ 110.51, 116.68,

120.59, 121.35, 132.12, 138.67, 147.28, 150.90, 155.74, and 163.88.


106

Table 1: Potassium phosphate catalyzed rapid synthesis of 3-carboxycoumarins at ambient temperature

Entry Product (3)

Time (min)

Yield (%)a,b

a

O O

COOH

45

94

b O O

COOH

OMe

45

89

c O O

COOHOH

50

94

d O O

COOHMe

60

91

e

O O

COOHO2N

30

83

f

O O

COOHMeO

60

93

g

O O

COOHBr

50

85

h

O O

COOHCl

60

84

i

O O

COOHBr

Br

50

90

j

O O

COOHCl

Cl

60

89

k

O O

COOH

60

81

a All products showed satisfactory spectroscopic data. (IR, 1H and 13C NMR). b Yields refer to pure, isolated products


107

Conclusion:

In summary, we have described a practical method for the rapid synthesis of

coumarin-3-carboxylic acid using potassium phosphate as an inexpensive catalyst at

ambient temperature. High yields along with simple reaction conditions auger well for

the application of this strategy for the synthesis of coumarin-3-carboxylic acids.

Experimental:

General

IR spectra were recorded on a Perkin–Elmer FT-IR 783 spectrophotometer. NMR

spectra were recorded on a Bruker AC-300 spectrometer in DMSO-d6 using

tetramethylsilane as internal standard and δ values are expressed in ppm. Melting points

are uncorrected.

Typical Procedure:

A mixture of salicylaldehyde (1 mmol), Meldrum’s acid (1 mmol) and K3PO4

(20 mol %) in ethanol (5 mL) was stirred at room temperature for the time indicated in

Table 1. The reaction mixture was neutralized using ammonium chloride solution and

extracted with ether. Ether layer was dried with sodium sulfate and evaporated to yield

corresponding Coumarin-3-carboxylic acid. The residue was purified by recrystalization

in ethanol to provide the desired product 3 (Table 1).


108

Spectroscopic Data:

8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (entry 3b, table 1):

O O

O

OH

OCH3

Mp. 215-217 oC; IR (KBr): 3418, 3057, 2925, 1746,

1685, 1425, 1227, 1042, 833 cm-1; 1H NMR (400 MHz,

DMSO-d6): δ = 3.93 (s, 3H), 7.33 (m, 1H, J = 2.8 Hz, J

= 9.2 Hz), 7.42 (m, 2H, J = 2.8 Hz), 8.71 (s, 1H), 13.26

(bs, 1H, -COOH).

6-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (entry 3c, table 1):

O O

O

OHOH

Mp. 200 oC; IR(KBr): 3168, 2925, 1731, 1622, 1571,

1435, 1239, 1050, 839 cm-1; 1H NMR (400 MHz,

DMSO-d6): δ = 7.15 (dd, 1H, J = 2.8 Hz, J = 9.2 Hz),

7.20 (d, 1H, J = 2.8 Hz), 7.29 (d, 1H, J = 9.2 Hz), 8.66

(s, 1H), 9.89 (s, 1H, -OH), 13.19 (bs, 1H, -COOH); 13C

NMR (100 MHz, DMSO-d6): δ 114.20, 117.54, 118.84,

118.96, 122.93, 148.29, 148.66, 154.44, 157.70, 164.59.

6-Methyl-2-oxo-2H-chromene-3-carboxylic acid (entry 3d, table 1):

O O

O

OHCH3

Mp. 224-226 oC; IR(KBr): 3400, 3028, 2959, 1755,

1678, 1576, 1101, 963, 799 cm-1; 1H NMR (400 MHz,

DMSO-d6): δ 2.37 (s, 3H), 7.34 (d, 1H, J = 8.4 Hz),

7.55 (dd, 1H, J = 2.0 Hz, J = 8.4 Hz), 7.69 (s, 1H), 8.67

(s, 1H), 13.23 (bs, 1H, -COOH); 13C NMR (100 MHz,

DMSO-d6): δ 21.60, 116.32, 118.11, 118.65, 130.03,

134.58, 135.64, 148.64, 153.03, 157.36, 164.46.

6,8-Dibromo-2-oxo-2H-chromene-3-carboxylic acid (entry 3i, table 1):

O O

O

OHBr

Br

Mp. 240-242 oC; IR(KBr): 3473, 3065, 2924, 1762,

1696, 1613, 1451, 1216, 991, 804 cm-1; 1H NMR (400

MHz, DMSO-d6): δ = 8.18 (d, 1H, J = 2.4 Hz), 8.25 (d,

1H, J = 2.4 Hz), 8.68 (s, 1H), 13.50 (bs, 1H, -COOH,

exchangeable with D2O); 13C NMR (100 MHz, DMSO-

d6): δ 110.51, 116.68, 120.59, 121.35, 132.12, 138.67,

147.28, 150.90, 155.74, 163.88


109

SPECTRAS


110


111


112


113


114


115


116


117


118


119


120


121

References:

[1] Murray, R. D. H. Prog. Chem. Org. Nat. Prod. 1991, 58, 84.

[2] Selim, M.Chemical Abstracts 1992, 27(117), 811, XP002053889

[3] Murray R. D. H.; Mendez J.; Brown S. A. The Natural Coumarins: Occurance,

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