Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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,
4

hepatoprotective, anti-thrombotic, anti-viral and anti-carcinogenic activities . In addition to biological activities they are used as additives to food and cosmetics5 and optical brightening agents6.

anti-bacterial and antiviral anti-thrombotic anti-carcinogenic

anti-inflammatory

Coumarins

anti-HIV activities

anti-clotting

hepatoprotective anti-clotting and anti-thrombotic

Fig. 1: Applications of coumarins Hydroxycoumarins are typical phenolic compounds and therefore, act as potent metal chelators and also free radical scavengers7. They are powerful chain-breaking antioxidants. 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

89

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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-hydroxy6,6,10,11-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.

90

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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.

91

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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.
O O CH3 NH2 CS2 I2/Pyridine O O 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

92

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

diacid was transformed in a few steps to high yielding marine sesquiterpene Helianane underscoring the importance of this protocol [Scheme 2].
R1 R2
O O

R1 i. CHCl3, NAOH acetone ii. H+ R2

O CO2H

R3

R3

CO2H

Scheme 2 iii) A direct arylation of 4-hydroxycoumarins by photo induced reaction with aryl 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].
OH Cl OH hv DMSO KOBu-t I Cl

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

+
O O

Scheme 3

Scheme 4 A method for direct arylation of 4-hydroxycoumarins with arylboronic acids via COH 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].

93

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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 -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].

94

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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-pyrone or the benzo--pyrone ring leading to the synthesis of naturally occurring substances. The naturally occurring coumarins have been obtained either i) by the closure

95

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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 Meldrums 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 -ketoester in the presence of an acidic catalyst. Maheswara et al. applied HClO4SiO2 under solvent-free conditions to carry out Pechmann condensation27a [Scheme 10].
OH R O O OEt O R O

H+

Scheme 10 The reaction can also be catalyzed by different Brnsted and Lewis acids viz PPA
27b

, InCl3 27c, ZrCl4 27d, Yb(OTf)327e, p-TsOH27f, BiCl327g, and I2 or AgOTf27h. Because of

recent efforts toward green chemistry, attempts are being made to replace stoichiometric Brnsted 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 ,-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].

96

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

O CHO + R OH O O R O O 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 Meldrums acid in dimethylformamide followed by cyclization [Scheme 12].
O OMe R4 CHO + O R3 R2 R1 O R3 R2 R1 O O O R4 DMF O R3 R2 R1 OMe O O H+ R4 O COOH

Scheme 12 A solid-phase synthesis has also been reported for condensation of 2-methoxy benzaldehyde with Meldrums 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 Meldrums 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-3carboxylic acid, to the best of our knowledge there is no report for the synthesis of coumarin-3-carboxylic acid by Knoevenagel condensation of Meldrums 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

97

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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
29i

between

salicylaldehyde

and diethyl

malonate

by

Shanmuganathan et al.

. carried out synthesis of various coumarins by using a task-

Valizadeh et al.

29j

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.

EtOOC CHO
+

COOEt R O

COOEt O CN R O O

Immobilized organocatalyst

OH

NC

COOEt

IL-OPPh2

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-2Hpyran-2-one via Konevenagel condensation in good yields using [bmim]Br as a catalyst at 90 oC [Scheme 14].
OH

CHO

+
OH
H3C O O

OH

3-acetoacetyl coumarin

Scheme 14

98

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

The stepping stone to the realm of MCRs for organic chemists was a threecomponent coumarin synthesis developed by Nair et al.30b in 1987 [Scheme 15], which proceeds via a domino Knoevenagelhetero-Michael-type addition sequence.

CHO

O O O

OH

OH

+
HO OH

HO

Scheme 15 Singh and co-workers high yields [Scheme16].

CHO O O R' S SMe Urea SnCl2 OH R' O S
30c

carried out reaction of substituted salicylaldehyde and

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

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-2Hchromen-3-yl)carbonyl]amino}-3,4-furandicarboxylates via a one-pot multi-component reaction of salicylaldehyde, Meldrums 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 Meldrums acid to afford the title compound in good to excellent yields. 99

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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].
O OH COR'' R'CH(Br)COBr base O R' COR'' Br M2Te, THF M=Na, Li R'' O O R'

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(-carboxymethylene)phosphorane imidazolide was reported by Upadhyay and his group30 [Scheme 20].
O Ph3P N N OH O R O R' PPh3 R' O R O O

R O

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 21 100

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

Objectives: i) Search for basic catalyst for the synthesis of coumarins from ortho-hydroxy aldehyde and Meldrums acid as it will be the first basic catalyst for the same transformation. ii) iii) The development of a procedure using commercially available, inexpensive mild base. To obtain highly pure coumarin derivatives without using tedious chromatographic techniques.

Present Work: The mechanism of coumarin synthesis follows Knoevenagel condensation of salicylaldehyde with Meldrums acid followed by nucleophilic attack of OH on carbonyl carbon of Meldrums acid. Our group has reported Knoevenagel condensation34 of aldehydes with Meldrums 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 Meldrums 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. 101

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

(a)

(b) Pic.2: Progress of the reaction

(c)

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 Meldrums 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].

102

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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 O O O HO O X H

OH O H H O O O X H O OH

O O O

PO4 + K3 PO4

O O O X O OH O

COOK O O O OH O

O X

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

103

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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 Meldrums acid at room temperature, to afford the corresponding coumarin derivatives.[Scheme 23,Table 2]
O H R 2 OH + O O 1 3 O O K3PO4 C2H5OH/RT R O COOH O

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 ak). Those bearing electrondonating groups at position 5 generally gave better yields than electron-withdrawing group at same position. (Table1, entries ch) 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 Meldrums 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 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 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)

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Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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
13

C-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 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
13

C-NMR spectrum (Fig. 11) at 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).
13

C NMR (Fig. 14) showed sharp signals at 110.51, 116.68,

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

105

Chapter3: Synthesis of Coumarin-3-carboxylic Acid Table 1: Potassium phosphate catalyzed rapid synthesis of 3-carboxycoumarins at ambient temperature
Entry
a
O O
COOH

Product (3)
COOH

Time Yield (min) (%)a,b

45

94

b
OMe
HO

45

89

COOH

c
O O

50

94

Me

COOH O O
COOH

d
O2N

60

91

30
O O
COOH

83

MeO

f
O O

60

93

Br
O

COOH

50
O COOH

85

Cl
O

60
O
COOH

84

Br

i
O O

50
Br
Cl
COOH

90

j
O O

60
Cl

89

k
O
a b

COOH O

60

81

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

106

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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 PerkinElmer FT-IR 783 spectrophotometer. NMR spectra were recorded on a Bruker AC-300 spectrometer in DMSO-d6 using tetramethylsilane as internal standard and values are expressed in ppm. Melting points are uncorrected. Typical Procedure: A mixture of salicylaldehyde (1 mmol), Meldrums 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).

107

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

Spectroscopic Data: 8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (entry 3b, table 1): Mp. 215-217 oC; IR (KBr): 3418, 3057, 2925, 1746,
O OH O H3C O O

1685, 1425, 1227, 1042, 833 cm-1; 1H NMR (400 MHz, DMSO-d6): = 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). Mp. 200 oC; IR(KBr): 3168, 2925, 1731, 1622, 1571, 1435, 1239, 1050, 839 cm-1; 1H NMR (400 MHz,
O

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

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

OH

HO

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): 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): Mp. 224-226 oC; IR(KBr): 3400, 3028, 2959, 1755,
O H3C OH O O

1678, 1576, 1101, 963, 799 cm-1; 1H NMR (400 MHz, DMSO-d6): 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): 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 Br OH O Br O

Mp. 240-242 oC; IR(KBr): 3473, 3065, 2924, 1762, 1696, 1613, 1451, 1216, 991, 804 cm-1; 1H NMR (400 MHz, DMSO-d6): = 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, DMSOd6): 110.51, 116.68, 120.59, 121.35, 132.12, 138.67, 147.28, 150.90, 155.74, 163.88

108

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

SPECTRAS

109

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

110

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

111

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

112

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

113

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

114

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

115

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

116

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

117

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

118

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

119

Chapter3: Synthesis of Coumarin-3-carboxylic Acid

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