Facile metal-free synthesis of 3-aryl-4-substituted coumarins from o-hydroxy carbonyl compounds

Article abstract of DOI:10.1080/00397910903222082

The intramolecular cyclization of the esters of salicylaldehyde, O-hydroxyacetophenones, methyl salicylate, and 2'-hydroxy chalcones by potassium hydroxide in pyridine leads to a short and convenient synthesis of 3,4-disubstituted coumarins. Twenty 3-phenyl coumarins were synthesized in 80-90% yields. No other by-product, such as 2-benzylchromone or-diketones, was observed the reactions. The mild reaction condition involves the removal of more acidic benzylic proton, which leads to a relatively cheap, nontoxic, metal-free method for the synthesis of 3-aryl-4-substituted coumarins. Copyrigh

Full text of DOI:10.1080/00397910903222082

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Facile Metal-Free Synthesis of 3-Aryl-4-
Substituted Coumarins from O-Hydroxy
Carbonyl Compounds
Kiran Taksande a , D. S. Borse a & Pradeep Lokhande a
a Center for Advanced Studies, Department of Chemistry, University
of Pune, Pune, India
Published online: 07 Jul 2010.
To cite this article: Kiran Taksande , D. S. Borse & Pradeep Lokhande (2010): Facile Metal-Free
Synthesis of 3-Aryl-4-Substituted Coumarins from O-Hydroxy Carbonyl Compounds, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:15, 2284-2290
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Synthetic Communications1, 40: 2284–2290, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903222082
FACILE METAL-FREE SYNTHESIS OF 3-ARYL-4-
SUBSTITUTED COUMARINS FROM O-HYDROXY
CARBONYL COMPOUNDS
Kiran Taksande, D. S. Borse, and Pradeep Lokhande
Center for Advanced Studies, Department of Chemistry, University of Pune,
Pune, India
The intramolecular cyclization of the esters of salicylaldehyde, O-hydroxyacetophenones,
methyl salicylate, and 20-hydroxy chalcones by potassium hydroxide in pyridine leads to
a short and convenient synthesis of 3,4-disubstituted coumarins. Twenty 3-phenyl coumarins
were synthesized in 80–90% yields. No other by-product, such as 2-benzylchromone or b-
diketones, was observed the reactions. The mild reaction condition involves the removal
of more acidic benzylic proton, which leads to a relatively cheap, nontoxic, metal-free
method for the synthesis of 3-aryl-4-substituted coumarins.
Keywords: Acylation; Dickmann-type cyclization; 4-hydroxy coumarin; O-hydroxyacetophenone;
2-phenylacetoxyester
Coumarins have been attractive research candidates because of their applications as
additives in food, perfumes, and cosmetics; anthelmintics; hypnotics; insecticides;[1–3]
anticoagulants;[4] anti-HIV agents;[5,6] optical brightners;[7] and dispersed fluorescent
and laser dyes.[8,9] Most reports dealing with coumarin synthesis use Pechmann,[10]
Perkin,[11] Knoevenagal,[12] Reformatsky,[13] and Wittig reactions[14,15] or flash
vacuum pyrolysis.[16] Different types of catalysts, namely, hetreopolyacids,[17] nano-
sized sulfated tin oxide (STO)=Al-P,[18] oxalic acid,[19] ZnCl2,[20] para toluene sulfonic
acid (pTSA),[21] Pd(OAc)2,[22] lithium diisopropylamide (LDA),[23] HClO4 ꢀ SiO2,[24]
Al-MCM-41,[25] TiCl4,[26] Bi(NO3)3 ꢀ 5H2O,[27] ionic liquids,[28] Sm(NO3)3 ꢀ 6H2O,[29]
Grubb’s catalyst,[30] and Zn(I2),[31] have been explored to produce coumarins.
Almost all methods suffer drawbacks such as use of active phenols, corrosive pro-
blems, several hours of heating above 150ꢁC, multistep reactions, undesired
by-products, expensive catalysts, and environmental pollution.
Perhaps the most direct method known for 3-aryl coumarin synthesis is Perkin
condensation,[11] which suffers from tedious workup, unsatisfactory yields, harsh
conditions, and corrosive condensing agent (PhPOCl2=Et3N). Deshmukh[32] has
used aryl acetothiomorpholide for condensation with 2-hydroxybenzaldehyde in
the presence of POCl3 to give 3-phenyl coumarins in 30–49% yields. Reaction of
Received May 21, 2009.
Address correspondence to Pradeep Lokhande, Center for Advanced Studies, Department of
Chemistry, University of Pune, Pune 411007, India. E-mail: pdlokhande@chem.unipune.ernet.in
2284

SYNTHESIS OF 3-ARYL-4-SUBSTITUTED COUMARIN
2285
2-hydroxy benzaldehyde with phenyl acetic anhydride in the presence of dry benzene
and triethyl benzyl ammonium chloride (TEBA) as a phase-transfer catalyst has
also been reported to give 3-phenyl coumarin in 50–95% yield.[33] Kamat and
coworkers[34] reported thermal condensation of 20-hydroxy acetophenones with
phenyl acetic acid in refluxing boiling diphenyl ether gives 4-methyl-3-phenyl cou-
marins in 45–89% yield; however, the reaction time was too long (10 to 37 h).
Mukaiyama’s esterification protocol as reported by Mashruqui and coworkers[35]
uses 2-chloro-1-methyl pyridinium iodide-triethyl amine reagent to provide rapid
access to 3-substituted coumarins in satisfactory yields but needs inert reaction con-
ditions and freshly prepared catalyst. Recently, Dittmer and coworkers[36] have
reported the synthesis of 3-phenylcoumarins by the use of sodium telluride with
10% yield, but the method requires costly catalyst, tedious workup, and low reaction
temperature (ꢂ20ꢁC).
Herein, we report a facile two-step methodology for synthesis of 3-aryl-4-
hydroxycoumarins, 3-aryl-4-methyl coumarin, and 3-aryl coumarin by acetylation
of appropriately substituted 2-hydroxycarbonyl compounds with aryl acetic acid
and subsequent Dickmann-type cyclization of aryl acetoxy ester with a base to give
the corresponding 3-aryl-4-substituted coumarins.
The synthesis of 3-phenyl coumarins is shown in Scheme 1. The reaction of
salicylaldehyde 1a–c with aryl acetic acid in the presence of phosphoryl chloride in
pyridine afforded the ester 2-arylacetoxy salicylaldehyde in 82–88% yields. These
esters were stirred with the pulverized potassium hydroxide in pyridine to afford
the 3-phenyl coumarin 4a–c (80–90% yield). Similarly, 20-hydroxy acetophenones
1d–j were acylated with phenyl acetic acid using phosphoryl chloride in pyridine
to give ester 3d–j, which on reaction with pulverized potassium hydroxide in pyri-
dine, gave 3-phenyl-4-methyl coumarins 4d–j (85–98% yield).
Scheme 1. Methodology used for synthesis of 3-phenyl coumarins.

2286
K. TAKSANDE, D. S. BORSE, AND P. LOKHANDE
A literature survey has revealed that the benzoyl derivatives of 20-hydroxy
acetophenones on subjecting to Baker–Venkatraman transformation in pulverized
potassium hydroxide in pyridine gave b-diketones, which could be further cyclized
to flavones or chromones under acidic workup.[37] In the esters 3, the acidity of
benzylic protons is greater than acetyl protons. Thus, the carbanion generated at
benzylic carbon atom, and it undergoes Dickmann-type cyclization rather than
rearrangement of aryl acetyl groups to acetyl anion as in Baker–Venkatraman
rearrangement.
The extension of this reaction using ester of o-hydroxy aryl carboxylic acids
with view toward developing a method for the synthesis of 4-hydroxy-3-phenyl cou-
marins has also been examined. Methyl salicylate 1k–l on acylation with phenyl
acetic acid in the presence of phosphoryl chloride gave ester 3k–l, which on reaction
with pulverized potassium hydroxide in pyridine gave 4-hydroxy-3-phenyl coumar-
ins. For the synthesis of 3-benzyl-4-hydroxy coumarins, a,b-dihydro cinnamic acid
was used as acylating agent for acylation of methyl salicylate. The esters were simi-
larly treated to give 3-benzyl-4-hydroxy coumarin. Similarly, 3-benzyl coumarin was
prepared from salicaldehyde (Scheme 2). 3-Phenyl-4-styrylcoumarins 4m–p were
synthesized in two steps from 20-hydroxy chalcones 1m–p by acylation with phenyl
acetic acid and Dickmann-type cyclization using a base. Results of the formation of
esters and coumarins are given in Table 1. The preparation of 4-styryl coumarins is
reported from 4-acetic acid coumarin by condensation with aryl aldehyde in pyridine
at 130ꢁC and from 20-hydroxy chalcones on condensation with Wittig reagent
Ph3P¼CHCOOEt.[38] The behavior of esters 3a–c toward Dickmann-type cyclization
was also studied. Thus, the ester 3a–c was reacted with potassium carbonate
in dimethylformamide (DMF) or triethyl amine in DMF. The results of formation
of coumarin are recorded in Table 2. These results suggested that the Dickmann-
type cyclization in pulverized potassium hydroxide gives better results than other
two conditions.
Alternatively, 3-phenylcoumarins were prepared in one step by reaction of
salicaldehyde with phenyl acetyl chloride in the presence of potassium carbonate
in DMF (Scheme 3). On acidic workup, it affords 3-phenylcoumarins in moderate
yield. Since we need to prepare phenyl acetyl chloride from phenyl acetic acid,
we did not observe any added advantage over the previous method, and there is
difficulty preparing substituted phenyl acetic chloride because of their short life.
Scheme 2. Methodology used for synthesis of 3-benzyl coumarin from salicaldehyde.

SYNTHESIS OF 3-ARYL-4-SUBSTITUTED COUMARIN
2287
Table 1. Synthesis of aryl acetoxy esters and corresponding 3-aryl-4-substitutedcoumarin
Ester (3)
Coumarin (4)
M. P. Yield
(ꢁC)
M. P.
(ꢁC)
Yield
%
Entry
R1
R2
R3
R4
R5
%
a
b
c
H
H
H
H
H
H
H
H
59
33
82
83
88
90
89
92
78
94
92
82
94
91
84
87
92
90
132
120
140
156
168
142
148
192
178
182
137
81–82
192
181
178
185
80
88
89
90
92
90
88
98
96
92
90
85
86
88
83
75
H
ꢂOCH3
H
H
H
H
H
ꢂOCH3 55–56
d
e
ꢂCH3
ꢂCH3
ꢂCH3
ꢂCH3
ꢂCH3
ꢂCH3
ꢂCH3
ꢂOCH3
ꢂOCH3
H
H
H
43
63
H
H
ꢂCH3
H
H
f
H
ꢂCH3
H
H
42
45
g
h
i
ꢂCH3
H
H
Cl
H
H
Cl
H
58
52
H
H
H
j
Cl
H
H
H
H
H
48
ka
la
m
n
o
p
H
H
70–71
78
88
H
ꢂOCH3
H
H
Cl
H
=
ꢂCH CHꢂAr
H
ꢂOCH3
Cl
=
ꢂCH CHꢂAr
H
H
ꢂCH3
Cl
95
98
=
ꢂCH CHꢂAr
H
H
H
=
ꢂCH CHꢂAr
H
ꢂCH3
H
ꢂOCH3
40
aIn Coumarin R1 is –OH.
Table 2. Synthesis of coumarin under different reaction conditions
Coumarin
Pyridine=KOH
K2CO3=DMF
K2CO3=NEt3
a
b
c
92
81
80
43
45
43
48
43
44
Scheme 3. One-step synthesis of 3-phenyl coumarins from phenyl acetyl chloride.

2288
K. TAKSANDE, D. S. BORSE, AND P. LOKHANDE
Attempt to prepare 3-alkyl substituted coumarin by using acetic acid,
propionic acid, and n-butyric acid as acylating agents were unsuccessful. These
acids, on reaction with 20-hydroxy-5-methyl acetophenones in pyridine, give a
corresponding ester in poor yields. These esters did not undergo Dickmann-type
cyclization by using potassium hydroxide in pyridine to afford 3-substituted
coumarin. Instead, most of the time, starting material was recovered.
The present method offer several advantages: relatively cheap and readily
available starting materials are used, formation of enolate is fast, the reaction com-
pletes within 10–30 min at room temperature, and it is a metal-free reaction with
good atom economy.
EXPERIMENTAL
2-Hydroxy phenyl carbonyl compound 1 (0.01 mol) and phenyl acetic acid
(0.012 mol) in pyridine were stirred, and a solution of phosphoryl chloride
(0.02 mol) in ether was added to it over 30 min. The reaction mixture was stirred
for 1 h and diluted with ice-cold HCl. The solid product thus formed was isolated
and washed with cold water, 10% NaHCO3, and again with water and then crystal-
lized by ethanol. The solution of ester 3 in pyridine was added to pulverized potass-
ium hydroxide (KOH) in pyridine in 30 min. The reaction mixture was stirred for
30–60 min and then diluted with HCl. The solid product obtained was washed with
water, dried, and crystallized by ethanol.
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