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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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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.
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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.
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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].
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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].
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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].
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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.
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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.
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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].
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: 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)
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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.
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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).
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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SPECTRAS
Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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Chapter3: Synthesis of Coumarin-3-carboxylic Acid
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Chapter3: Synthesis of Coumarin-3-carboxylic Acid
121
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