PROTOCOL

Practical and convenient synthesis of coumarins from

phenols and propiolic acid esters
Tsugio Kitamura1, Juzo Oyamada1 & Toshiki Tsubota2
1Department of Chemistry and Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi, Saga 840-8502, Japan. 2Department of Materials
Science, Faculty of Engineering, Kyushu Institute of Technology, Sensui-cho, Tobata-ku, Kitakyushu 804-8502, Japan. Correspondence should be addressed to T.K.
(kitamura@cc.saga-u.ac.jp).

Published online 5 April; corrected online 28 June 2007 (details online); doi:10.1038/nprot.2007.103

This protocol describes the synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2
2007 Nature Publishing Group http://www.nature.com/natureprotocols

catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that
have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in
trifluoroacetic acid at room temperature (1520 1C) under atmospheric conditions. This protocol can be completed in 3 d.

INTRODUCTION
Coumarin and its derivatives occur widely in nature, particularly in
plants; many of them show biological activity14. To date, many
procedures for coumarin synthesis have been extensively studied14,
including the Perkin reaction, the Knoevenagel reaction and the
PechmannDuisberg reaction. The latter has been widely applied to
the synthesis of coumarin derivatives5. However, there are still
limitations, such as the requirement of harsh reaction conditions,
the need for a stoichiometric amount of a condensing agent and the
difficulty in obtaining the starting 2-hydroxybenzaldehyde derivatives.
Recently reported coumarin synthesis reactions have focused on
palladium-catalyzed reactions of phenols and their derivatives:
intermolecular and intramolecular reactions of 2-iodophenol or
its O-acyl derivatives in the presence of CO (refs. 6,7), intra-
molecular cyclizations of (2-hydroxyphenyl)alkenes or alkynes8,9,
reactions of phenols and ethyl propiolates10 and reactions of
2-iodophenol and alkynes in the presence of CO11. However, a
Pd(0) species is the actual catalyst in these reactions. To accomplish
a catalytic cycle, these reactions need iodides or triflates as sub-
strates69,11 or formic acid to re-oxidize the Pd(0) species10.
We found earlier that hydroarylations of alkynes by simple arenes
proceed at room temperature using a Pd(OAc)2 catalyst in tri-
fluoroacetic acid (TFA) to give aryl-substituted alkenes (Fig. 1)12.
Furthermore, we found that PtCl2/AgOTf13 and K2PtCl4/AgOTf14
were effective catalysts for the hydroarylation of propiolic acids,
affording the corresponding cinnamic acids selectively. The
K2PtCl4/AgOTf catalyst was the most effective in application to
the hydroarylation of propiolic acid with less reactive benzene.
In the same way, we have demonstrated that the intramolecular
hydroarylation of aryl propiolates provides coumarin derivatives in
high yields (Fig. 2)15. This Pd(II)-catalyzed intramolecular reaction
proceeds with high efficiency under mild conditions. In this
reaction, however, the starting aryl propiolates must be prepared
by the condensation of propiolic acids and phenols.
We have developed a straightforward synthesis of coumarins
from phenols and propiolic acids (Fig. 3)16. This method is much
simpler and more convenient as it does not need aryl propiolates as
a substrate but uses the starting materials of aryl propiolates
directly. It also has the following advantages. (i) The reaction
proceeds at room temperature and does not need any additives
such as re-oxidizing agents, which are usually used for transition
metalcatalyzed coupling reactions. (ii) The preparation does not
require any special conditions such as an inert atmosphere and can
be conducted under atmospheric conditions.
Experimental design
This protocol describes the synthetic procedure for 6,7-methylene-
dioxy-4-phenylcoumarin (3) catalyzed by Pd(OAc)2 (Fig. 4). The
procedure is extremely simple: Just mix all the reagents and stir
them. This protocol is suitable for electron-rich phenols such as
alkoxyphenols but is not applicable for electron-deficient phenols.
TFA is essential as a solvent. As TFA is a strong acid, this protocol
cannot be applied to substrates unstable in the presence of a strong
acid. All reagents and solvents are commercially available and used
as received without further purification.

MATERIALS
REAGENTS . Silica gel (Silica Gel 60, spherical, 63210 mm; Kanto Chemical, cat. no.
. Sesamol (3,4-(methylenedioxy)phenol; Tokyo Chemical Industry, cat. no. 37564-84)
S0418) . TLC aluminum sheets (Silica gel 60F254; Merck, cat. no.
. Palladium(II) acetate (Pd(OAc)2; Sigma-Aldrich, cat. no. 520764) 1.05554.009)
. TFA (Wako, cat. no. 208-02746) . Dichloromethane
. Ethyl phenylpropiolate (Sigma-Aldrich, cat. no. E45309) . Hexane
O O O O
R1 a R1
Catalyst Ar R2
Ar H + R1 R2
R2
TFA, r.t. R1 H R2

Figure 1 | Scheme for hydroarylation of alkynes. Catalyst: Pd(OAc)2, PtCl2/ Figure 2 | Scheme for synthesis of coumarins through intramolecular
AgOTf, K2PtCl4/AgOTf. cyclization. a, Pd(OAc)2, TFA, CH2Cl2 (1520 1C).

NATURE PROTOCOLS | VOL.2 NO.4 | 2007 | 845

 PROTOCOL
OH O OH O O O
a
O O + Ph CO2Et
a O O
R1 + R2 CO2Et R1 2
1 Ph
R2 3

Figure 3 | Scheme for synthesis of coumarins by a direct reaction of phenols Figure 4 | Scheme for synthesis of coumarin 3 catalyzed by Pd(OAc)2.
and ethyl propiolates. Pd(OAc)2, TFA (1520 1C). Pd(OAC)2, TFA (1520 1C).

. Ethyl acetate . Rubber septa (Aldrich)

. Sodium hydroxide (2 M solution) . Reflux condensers
. Sodium hydrogencarbonate (saturated solution) . Hot plate (Corning)
. Sodium sulfate . Pyrex chromatographic column (4.1 cm i.d.
50 cm long)
EQUIPMENT . Rotary evaporator (Shibata-Buchi)
. Ice/water bath . Buchner funnels
. Glass syringes . Filter paper (Whatman no. 2)
2007 Nature Publishing Group http://www.nature.com/natureprotocols

. Reusable injection needles . Vacuum pump (Shimadzu)

PROCEDURE
Synthesis of 6,7-methylenedioxy-4-phenylcoumarin
1| Weigh 2.76 g (0.020 mol) sesamol (1) into a 50-ml round-bottomed flask.
2| Add 0.226 g (0.001 mol) Pd(OAc)2 to the flask.
3| Place a Teflon-coated magnetic stir bar in the flask and cool the flask to 0 1C in an ice/water bath. Turn the
magnetic stirrer on.
4| Add 20 ml TFA gradually to the flask using a glass syringe fitted with an injection needle. Cap the flask with a rubber
septum.
! CAUTION TFA is corrosive and harmful. Special care should be taken when handling it. Alternatively, an addition funnel can
be used.
5| Add 4 ml (0.024 mol) ethyl phenylpropiolate (2) to the flask using a glass syringe fitted with an injection needle.
6| Remove from the ice/water bath and stir the reaction mixture at room temperature (1520 1C) for 48 h.
7| Transfer the reaction mixture to a 1-l beaker and rinse the flask with 60 ml CH2Cl2.
m CRITICAL STEP Ethyl acetate or diethyl ether can be used instead of CH2Cl2.
8| Neutralize the mixture with aqueous NaHCO3 (approximately 500 ml).

9| Transfer the mixture to a separatory funnel.

10| Extract the organic compounds with five 40-ml portions of CH2Cl2 and combine the CH2Cl2 extracts.
m CRITICAL STEP Ethyl acetate or diethyl ether can be used instead of CH2Cl2.

11| Transfer the combined CH2Cl2 extract to a separatory funnel and wash with 200 ml 2 M NaOH solution.
12| Transfer the CH2Cl2 extract to a separatory funnel and wash with 200 ml water.

13| Transfer the CH2Cl2 extract to a separatory funnel, wash with 200 ml saturated NaCl solution and dry by adding anhydrous
sodium sulfate.
PAUSE POINT Can be left overnight at room temperature.
14| Filter the mixture under gravity through cotton on a powder funnel to remove sodium sulfate and collect the filtrate
in a flask.
15| Evaporate solvents using a rotary evaporator at approximately 40 1C. It takes approximately 1 h. Dissolve the product with
the least amount of CH2Cl2 possible.

16| Pack a chromatography column (4.1 cm i.d.
50 cm length) with 80 g silica gel using hexane.
17| Load the product solution on the top of the silica gel layer.

18| Elute the column under gravity (3040 ml min1) with 1:31:2 (vol/vol) ethyl acetate/hexane until no spot of the product
appears on TLC sheets (Rf 0.5, 1:2 (vol/vol) ethyl acetate/hexane).

846 | VOL.2 NO.4 | 2007 | NATURE PROTOCOLS

 PROTOCOL

m CRITICAL STEP If the product partially crystallizes in the column, use 1:31:2 (vol/vol) ethyl acetate/CH2Cl2 as the eluent.
In the beginning, the product mixture is dissolved in CH2Cl2 at a high concentration. When the solvent is replaced with ethyl
acetate/hexane at the high concentration, crystals may form as a result of the lower solubility of the compound.
19| Evaporate solvents from the eluate using a rotary evaporator at 4045 1C.

20| Dissolve the crude crystals with the least amount of ethyl acetate possible (approximately 15 ml) in a 200-ml round-
bottomed flask equipped with a reflux condenser by heating the mixture to the refluxing temperature on a hot plate.
21| Stand at room temperature overnight.

22| Collect the crystals by filtration using a Buchner funnel, wash with 1:3 (vol/vol) ethyl acetate/hexane and dry in a
desiccator using a vacuum pump.
2007 Nature Publishing Group http://www.nature.com/natureprotocols

? TROUBLESHOOTING

 TIMING
Steps 13, 15 min; Step 4, 15 min; Step 5, 15 min; Step 6, 48 h; Step 7, 5 min; Step 8, 30 min; Steps 913, 2 h; Steps 14 and
15, 1 h; Steps 1618, 3 h; Step 19, 30 min; Step 20, 30 min; Step 21, 12 h; Step 22, 1 h

? TROUBLESHOOTING
Troubleshooting advice can be found in Table 1.

TABLE 1 | Troubleshooting table.

Problem Possible reasons Solution
Low yields of coumarin synthesis Low reactivity of reagents Increase the ratio of phenols; for example,
1:2 2:1 (molar ratio)
Low purity of coumarins Contamination with the starting material, Repeat the re-crystallization or purify by column
the hydrated product or by-products chromatography on silica gel. As an alternate
procedure, use phenylpropiolic acid instead of the
ethyl ester 2. It can be removed by washing with
sodium hydroxide solution (see ref. 17)

ANTICIPATED RESULTS
Typical yields
Typical isolated yield of coumarin 3 is 76%. Other examples can be found in ref. 16.

Analytical data
6,7-Methylenedioxy-4-phenylcoumarin (3).
Mp 142144 1C (recrystallized from CH2Cl2/hexane)
1H NMR (300 MHz, CDCl ) d 6.05 (s, 2H, OCH O), 6.24 (s, 1H, CH), 6.83 (s, 1H, ArH), 6.89 (s, 1H, ArH), 7.39-7.42 (m, 2H,
3 2
Ph), 7.49-7.53 (m, 3H, Ph).
13C NMR (75.5 Hz, CDCl ) d 98.45, 102.31, 104.26, 112.09, 112.73, 128.16, 128.82, 129.53, 135.57, 144.75, 151.07, 151.24,
3
155.80, 161.08.

ACKNOWLEDGMENTS This work was supported partially by a grant-in-aid for
scientific research on priority areas, Advanced Molecular Transformations of Carbon
Resources, from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
COMPETING INTERESTS STATEMENT The authors declare that they have no
competing financial interests.
Published online at http://www.natureprotocols.com
Reprints and permissions information is available online at http://npg.nature.com/
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 CORRIGENDUM

Corrigendum: Practical and convenient synthesis

of coumarins from phenols and propiolic acid esters
Tsugio Kitamura, Juzo Oyamada & Toshiyuki Tsubota
Nat. Protoc. 2, 845848 (2007); doi:10.1038/nprot.2007.103; published online 5 April; corrected online 28 June 2007.
In the version of this article initially published online, the third authors name appeared as Toshiyuki Tsubota instead
of Toshiki Tsubota. The name has been corrected in all versions of the article.

NATURE PROTOCOLS