Formation of coumarins by palladium(II)-catalyzed reaction of phenols with ethyl acrylates

Article abstract of DOI:10.1246/bcsj.78.468

The reaction of phenols with ethyl acrylates in the presence of a Pd(OAc)₂ catalyst in trifluoroacetic acid did not yield dihydrocoumarins but gave coumarins, in contrast to the reaction of phenols with propiolates. The addition of K₂S₂O₈ as an oxidant increased the yield of coumarins. The reaction of several phenols with ethyl cinnamate, ethyl crotonate, or ethyl acrylate gave the corresponding coumarin derivatives in moderate to good yields. The coumarin formation competed with the oxidative coupling of electron-rich phenols, which reduced the product yield.

Full text of DOI:10.1246/bcsj.78.468

4
68 Bull. Chem. Soc. Jpn., 78, 468–472 (2005)
Ó 2005 The Chemical Society of Japan
Formation of Coumarins by Palladium(II)-Catalyzed
Reaction of Phenols with Ethyl Acrylates
ꢀ
Shinya Aoki, Juzo Oyamada, and Tsugio Kitamura
Department of Chemistry and Applied Chemistry, Faculty of Science and Engineering, Saga University,
Honjo-machi, Saga 840-8502
Received September 21, 2004; E-mail: kitamura@cc.saga-u.ac.jp
The reaction of phenols with ethyl acrylates in the presence of a Pd(OAc)2 catalyst in trifluoroacetic acid did not
yield dihydrocoumarins but gave coumarins, in contrast to the reaction of phenols with propiolates. The addition of
K2S2O8 as an oxidant increased the yield of coumarins. The reaction of several phenols with ethyl cinnamate, ethyl cro-
tonate, or ethyl acrylate gave the corresponding coumarin derivatives in moderate to good yields. The coumarin forma-
tion competed with the oxidative coupling of electron-rich phenols, which reduced the product yield.
2
Activation or functionalization of C–H bonds is one of the
protonation and cyclization. In analogy with the coumarin
synthesis from phenols and propiolates, it is expected that an
(2-arylethyl)palladium intermediate is formed when an acry-
late is employed instead of the propiolate in the Pd(II)-cata-
lyzed reaction of phenols, as shown in Scheme 1. If the (2-
arylethyl)palladium similarly undergoes the protonation fol-
lowed by cyclization, a dihydrocoumarin may be formed. On
the other hand, the elimination of ‘‘PdH’’ on the (2-arylethyl)-
most important reaction processes. The process is challenging
since the C–H bonds of hydrocarbons are stable for most
chemical transformations because of their relatively strong
bonds. The reactions via C–H bond activation are noted as
an environment-friendly process because such processes do
not require toxic halogens for chemical transformations. One
can reduce the reaction steps due to the direct use of hydrocar-
bons as the substrates instead of halogenated substrates that are
usually used for synthetic reactions. Direct metalation of aro-
matic substrates can functionalize the C–H bond of aromatic
hydrocarbons. To date, many reviews on aromatic C–H bond
5
palladium will give rise to ethyl cinnamates, which undergo
the cyclization to afford coumarins. Thus, we examined the re-
action of phenols with acrylates in the presence of Pd(OAc)2 to
learn the behavior of the (2-arylethyl)palladium species in an
acidic medium, TFA.
1
activation or functionalization have been reported. If such
reactions via C–H bond activation can proceed catalytically
and perform functional transformations of simple or complex
molecules, they become useful and straightforward processes
for synthesis of valuable compounds and functional materials.
Recently, it has been found that hydroarylation of alkynes
takes place in the presence of a palladium catalyst under mild
conditions in trifluoroacetic acid (TFA). This hydroarylation
reaction efficiently proceeds intramolecularly to afford hetero-
cycles, such as coumarins, quinolinones, and thiocouma-
Results and Discussion
In order to find the difference of the reactivity between ethyl
phenylpropiolate and ethyl cinnamate, reaction of 3,5-dime-
thoxyphenol (1a) with ethyl cinnamate (2a) was carried out
in TFA in the presence of Pd(OAc)2 (0.02 molar amount) at
room temperature for 20 h. The product was 5,7-dimethoxy-
4-phenylcoumarin (3a) but the yield was only 7% (Table 1,
Entry 1). Most of 2a was recovered unchanged. The elongation
of the reaction time (70 h) improved the yield of 3a up to 19%
2
2
a,3
rins.
Interestingly, this reaction has been applied to direct
4
ꢁ
synthesis of coumarins from phenols and propiolates. The
coumarin synthesis explains that an in situ-generated arylpalla-
dium species adds to the triple bond of the propiolate to give
an (2-arylvinyl)palladium intermediate, which is subject to
(Entries 2, 3). The reactions at 40 C were not effective (En-
tries 4–6). No products were formed in the absence of Pd-
(OAc)2 (Entry 4). We examined the reaction conditions to in-
crease the yield of the product but the yield was less than 20%.
Scheme 1.
Published on the web March 11, 2005; DOI 10.1246/bcsj.78.468

S. Aoki et al.
Table 1. The Reaction of 3,5-Dimethoxyphenol with Ethyl Cinnamate
Bull. Chem. Soc. Jpn., 78, No. 3 (2005)
469
aÞ
bÞ
Entry
1a/mmol
2a/mmol
Pd(OAc)2/mmol
Additive/mmol
Time/h
Yield/%
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
1
0.02
0.02
0.02
0
—
—
—
—
—
—
20
40
70
20
20
20
40
40
40
40
40
70
70
70
7
17
19
0
cÞ
cÞ
cÞ
0.02
0.05
0.02
0.02
0.02
0.02
0.05
0.05
0.05
0.05
16
18
24
17
32
43
46
50
52
58
Cu(OAc)2/0.5
dÞ
OXONE /0.25
K2S2O8/0.5
K2S2O8/1
K2S2O8/1
K2S2O8/1
K2S2O8/1
K2S2O8/1
1
1
1
1
1
a) The reaction of 1a with 2a in TFA (1 mL) was carried out in the presence of Pd(OAc)2 at room temper-
ꢁ
ature. b) Isolated yields based on the least amount of the substrate. c) At 40 C. d) 2KHSO5–KHSO4–
K2SO3.
The present reaction using cinnamate 2a gave no 3,4-dihy-
dro-5,7-dimethoxy-4-phenylcoumarin that was expected to be
formed when the reaction proceeded in a similar manner to
the reaction using ethyl phenylpropiolate. Therefore, this result
suggests that the reaction using cinnamate 2a predominantly
takes place via elimination of ‘‘PdH’’ on the intermediate pal-
ladium species generated by addition of arylpalladium species
to cinnamate 2a. Since the in situ-generated palladium hydride
species readily undergoes reductive transformation to Pd(0),
the Pd(0) species is required to be re-oxidized to a Pd(II)
species to maintain the catalytic cycle. Then, we examined
the addition of oxidizing agents, such as Cu(OAc)2, OXONE
(1d), and 3-methylphenol (1e) with cinnamate 2a afforded 5,7-
dimethyl-4-phenylcoumarin (3c), 6,7-dimethyl-4-phenylcou-
marin (3d), and 7-methyl-4-phenylcoumarin (3e) in 46, 11,
and 46% yields, respectively.
Furthermore, the reactions with ethyl crotonate (2b) and
with ethyl acrylate (2c) were conducted. The reactions of ethyl
crotonate (2b) with 3,5-dimethoxyphenol (1a) and with 3-me-
thoxyphenol (1b) gave 5,7-dimethoxy-4-methylcoumarin (4a)
and 7-methoxy-4-methylcoumarin (4b) in 25 and 32% yields,
respectively. In the reaction of ethyl acrylate (2c) with 3,5-di-
methoxyphenol (1a), 5,7-dimethoxycoumarin (5) and 8-[2-
(ethoxycarbonyl)ethyl]-5,7-dimethoxycoumarin (6) were ob-
tained in 40 and 6% yields, respectively. However, no couma-
rins were obtained when 4-methoxyphenol (1f), 3,4-methyl-
enedioxyphenol (1g), and 2-naphthol (1h) were employed in
this reaction. Particularly, the reactions using phenols 1g and
1h gave a complex mixture.
(Monopersulfate compound, 2KHSO5–KHSO4–K2SO4), and
K2S2O8.
Cu(OAc)2 was effective as the oxidizing agent but OXONE
was not (Entries 7, 8). Among three oxidizing agents, K2S2O8
was the best additive; it gave coumarin 3a in 43% yield when 1
mmol of K2S2O8 was added (Entries 7–10). The use of 0.05
mmol of Pd(OAc)2 slightly increased the yield of 3a. The best
result (58% yield) was obtained when the reaction was carried
out using 1a (2 mmol), 2a (1 mmol), Pd(OAc)2 (0.05 mmol),
K2S2O8 (1 mmol), and TFA (1 mL) at room temperature for 70
h (Entry 14).
A possible mechanism for the formation of coumarins in the
reaction of phenols with acrylates in the presence of Pd(OAc)2
in TFA is shown in Scheme 2. The mildness of this reaction is
attributable to an increased reactivity of Pd(OAc)2 by replac-
ing acetate with trifluoroacetate, compared with a Pd(II)-cata-
5
lyzed reaction of aromatics with alkenes in acetic acid. The
In order to examine the scope and limitations on the cou-
marin formation, we carried out the reaction of various phenols
reaction of an in situ-generated positive palladium species with
a phenol followed by addition to an acrylate produces a phe-
nol-substituted alkylpalladium species. Elimination of a palla-
dium hydride takes place to give a phenol-subsitituted acrylate,
which readily cyclizes intramolecularly to a coumarin.
On the other hand, the palladium hydride species undergoes
reductive elimination to produce TFA and Pd(0), which is re-
oxidized by K2S2O8 in TFA to regenerate Pd(OCOCF3)2.6
In conclusion, we have demonstrated the coumarin forma-
tion in the Pd(II)-catalyzed reaction of phenols with acrylates
in TFA. In contrast to the similar type of reactions with propio-
1
with ethyl cinnamate (2a). The reaction of several phenols 1
with ethyl cinnamate 2a in the presence of Pd(OAc)2 and
K2S2O8 was carried out in TFA for 40 h. The results are given
in Table 2.
The reaction of 3-methoxyphenol (1b) with ethyl cinnamate
2a) in the presence of K2S2O8 gave 7-methoxy-4-phenylcou-
(
marin (3b) in 75% yield. In addition to the methoxy-subsituted
phenols, methyl-substituted phenols reacts with cinnamate 2a.
The reactions of 3,5-dimethylphenol (1c), 3,4-dimethylphenol

4
70 Bull. Chem. Soc. Jpn., 78, No. 3 (2005)
Table 2. Pd(II)-Catalyzed Reaction of Phenols with Acrylates
Coumarin Formation by Pd(II)-Catalyzed Reaction
aÞ
bÞ
Phenol 1
Acrylate 2
Coumarin 3
Yield/%
75
1
1
b
c
2a
3b
3c
2a
2a
2a
46
11
1
1
d
e
3d
3e
4a
4b
5
46
25
32
40
1
a
2b
1
b
a
2b
1
2c
6
6
a) The reaction of 1 (1 mmol) with 2 (1 mmol) in TFA (1 mL) was carried out in the presence of
Pd(OAc)2 and K2S2O8 (1 mmol) at room temperature for 40 h. b) Isolated yields.
lates, it is considered that an arylpalladium species undergoes
addition to the double bond of an acrylate and the subsequent
elimination of a palladium hydride instead of protonation by
TFA. Therefore, the present reaction requires an oxidant to re-
generate a palladium(II) species. The competition with the ox-
idative coupling of phenols takes place and reduces the yield
of coumarins 3 when phenols are highly electron-rich.
the Presence of Pd(OAc)2 in TFA. Palladium acetate, 3,5-dime-
thoxyphenol, and ethyl cinnamate were placed in a test tube,
sealed with a septum, and cooled in an ice/water bath. To a cold
mixture was added TFA (1 mL) and then the mixture was stirred
at room temperature for 20 h. The reaction mixture was neutral-
ized with aqueous NaHCO3, extracted with CH2Cl2, dried with
anhydrous Na2SO4, and concentrated. The product was separated
by column chromatography on silica gel.
In the case of the reaction with an oxidant, TFA was added to a
cold mixture of 3,5-dimethoxyphenol, ethyl cinnamate, Pd(OAc)2,
and an oxidant.
Experimental
General. Melting points were measured with a Yanaco micro-
1
4b
ꢁ
melting apparatus and are not corrected. H NMR spectra were re-
5,7-Dimethoxy-4-phenylcoumarin (3a).
Mp 168–170 C
1
corded on a JEOL AL 300 spectrometer (300 MHz); chemical
shifts (ꢀ) are reported in parts per million relative to tetramethyl-
silane. 13C NMR spectra were recorded on a JEOL AL 300 spec-
trometer (75 MHz); chemical shifts are reported in parts per mil-
lion relative to tetramethylsilane with the solvent resonance as the
internal standard (CDCl3; ꢀ 77.00). Mass spectrum was recorded
on a Shimadzu GCMS-QP5050A. Column chromatography was
carried out on silica gel (Silica Gel 60, spherical, Kanto Chemical
Co.).
(CH2Cl2/hexane); H NMR (300 MHz, CDCl3) ꢀ 3.42 (s, 3H,
OMe), 3.87 (s, 3H, OMe), 6.00 (s, 1H, =CH), 6.23 (d, J ¼ 2:4
Hz, 1H, ArH), 6.52 (d, J ¼ 2:4 Hz, 1H, ArH), 7.23–7.29 (m,
2H, ArH), 7.34–7.38 (m, 3H, ArH); 13C NMR (75 MHz, CDCl3)
ꢀ 55.36, 55.71, 93.61, 95.75, 103.55, 112.65, 127.07, 127.31,
127.84, 139.76, 155.63, 157.15, 158.23, 160.78, 163.36.
General Procedure for the Reaction of Phenols with Acry-
lates in the Presence of Pd(OAc)2 in TFA. A phenol (1 mmol),
an ethyl acrylate (1 mmol), Pd(OAc)2 (0.05 mmol), and K2S2O8
(1 mmol) were placed in a test tube, sealed with a septum, and
Reaction of 3,5-Dimethoxyphenol with Ethyl Cinnamate in

S. Aoki et al.
Bull. Chem. Soc. Jpn., 78, No. 3 (2005)
471
Scheme 2.
the mixture was cooled in an ice/water bath. To the cooled mix-
ture was added TFA (1 mL) and then the mixture was stirred at
room temperature for 40 h. The reaction mixture was neutralized
with aqueous NaHCO3, extracted with CH2Cl2, dried over anhy-
drous Na2SO4, and concentrated. The product was isolated by col-
umn chromatography on silica gel with hexane and ethyl acetate
as an eluent.
155.62, 160.95.
5,7-Dimethoxy-4-methylcoumarin (4a).4b
ꢁ
Mp 174
C
(CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3) ꢀ 2.46 (s, 3H,
Me), 3.78 (s, 3H, OMe), 3.79 (s, 3H, OMe), 5.88 (s, 1H, =CH),
6.22 (d, J ¼ 2:4 Hz, 1H, ArH), 6.36 (d, J ¼ 2:4 Hz, 1H, ArH);
13
C NMR (75 MHz, CDCl3) ꢀ 24.03, 55.56, 55.61, 93.31, 95.28,
104.75, 111.22, 154.32, 156.86, 159.02, 160.91, 162.68.
7-Methoxy-4-methylcoumarin (4b).7
Mp 155–158 C
ꢁ
4
b
ꢁ
7
-Methoxy-4-phenylcoumarin (3b).
1
Mp 108 C (CH2Cl2/
hexane); H NMR (300 MHz, CDCl3) ꢀ 3.80 (s, 3H, OMe), 6.14
(CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3) ꢀ 2.33 (d, J ¼
0:9 Hz, 3H, Me), 3.81 (s, 3H, OMe), 6.07 (d, J ¼ 0:9 Hz, 1H,
=CH), 6.75 (d, J ¼ 2:4 Hz, 1H, ArH), 6.79 (dd, J ¼ 2:4, 8.8
(
s, 1H, =CH), 6.72 (dd, J ¼ 2:7, 8.9 Hz, 1H, ArH), 6.82 (d, J ¼
2
2
5
1
:7 Hz, 1H, ArH), 7.30 (d, J ¼ 8:9 Hz, 1H, ArH), 7.34–7.38 (m,
13
13
H, ArH), 7.42–7.45 (m, 3H, ArH); C NMR (75 MHz, CDCl3) ꢀ
5.75, 101.10, 111.85, 112.27, 112.51, 127.95, 128.34, 128.78,
29.54, 135.57, 155.77, 156.01, 161.15, 162.80.
Hz, 1H, ArH), 7.43 (d, J ¼ 8:8 Hz, 1H, ArH); C NMR (75
MHz, CDCl3) ꢀ 18.53, 55.65, 100.79, 111.80, 112.10, 113.47,
125.45, 152.49, 155.19, 161.13, 162.58.
,7-Dimethyl-4-phenylcoumarin (3c).4b 1H NMR (300 MHz,
5,7-Dimethoxycoumarin (5).
4b
Mp 148–150 C (CH2Cl2/
ꢁ
5
1
CDCl3) ꢀ 1.71 (s, 3H, Me), 2.31 (s, 3H, Me), 6.09 (s, 1H, =CH),
hexane); H NMR (300 MHz, CDCl3) ꢀ 3.79 (s, 3H, OMe), 3.82
(s, 3H, OMe), 6.08 (d, J ¼ 9:5 Hz, 1H, =CH), 6.21 (d, J ¼ 2:4
Hz, 1H, ArH), 6.34 (d, J ¼ 2:4 Hz, 1H, ArH), 7.89 (d, J ¼ 9:5
Hz, 1H, =CH); 13C NMR (75 MHz, CDCl3) ꢀ 55.69, 55.86,
92.77, 94.66, 103.88, 110.77, 138.60, 156.71, 156.90, 161.36,
163.64.
6
7
2
1
.75 (s, 1H, ArH), 7.00 (s, 1H, ArH), 7.18–7.21 (m, 2H, ArH),
1
3
.34–7.38 (m, 3H, ArH); C NMR (75 MHz, CDCl3) ꢀ 21.16,
3.17, 115.37, 115.66, 115.98, 127.23, 128.44, 128.61, 129.39,
36.96, 139.48, 142.23, 155.08, 156.66, 160.35.
1
6
,7-Dimethyl-4-phenylcoumarin (3d).4b H NMR (300 MHz,
CDCl3) ꢀ 2.23 (s, 3H, Me), 2.35 (s, 3H, Me), 6.28 (s, 1H, =CH),
8-[2-(Ethoxycarbonyl)ethyl]-5,7-dimethoxycoumarin
(6).
1
7
7
2
1
.18 (s, 1H, ArH), 7.20 (s, 1H, ArH), 7.42–7.47 (m, 2H, ArH),
3
H NMR (300 MHz, CDCl3) ꢀ 1.18 (t, J ¼ 7:2 Hz, 3H, Me),
1
.50–7.54 (m, 3H, ArH); C NMR (75 MHz, CDCl3) ꢀ 19.31,
0.14, 114.14, 116.66, 117.85, 126.93, 128.40, 128.80, 129.50,
2.46 (t, J ¼ 8:0 Hz, 2H, CH2), 3.01 (t, J ¼ 8:0 Hz, 2H, CH2),
3.84 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.05 (q, J ¼ 7:2 Hz, 2H,
OCH2), 6.06 (d, J ¼ 9:6 Hz, 1H, =CH), 6.24 (s, 1H, ArH), 7.91
32.90, 135.62, 142.00, 152.63, 155.62, 161.24.
1
-Methyl-4-phenylcoumarin (3e).3
H NMR (300 MHz,
(d, J ¼ 9:6 Hz, 1H, =CH); C NMR (75 MHz, CDCl3) ꢀ 14.19,
13
7
CDCl3) ꢀ 2.37 (s, 3H, Me), 6.22 (s, 1H, =CH), 6.96 (d, J ¼ 8:1
Hz, 1H, ArH), 7.12 (s, 1H, ArH), 7.28 (d, J ¼ 8:1 Hz, 1H,
ArH), 7.33–7.38 (m, 2H, ArH), 7.41–7.45 (m, 3H, ArH);
17.88, 33.53, 55.88, 55.92, 60.29, 90.21, 103.65, 108.59, 110.70,
138.83, 153.80, 155.66, 161.15, 161.53, 173.11; MS (EI) m=e
306 (M ), 232 (M ꢂ HCO2Et), 219 (Mþ ꢂ CH2CO2Et). This
compound contained a small amount of impurities that could not
be separated out and removed.
þ
þ
1
3
C NMR (75 MHz, CDCl3) ꢀ 21.54, 113.99, 116.52, 117.40,
25.30, 126.34, 128.36, 128.77, 129.55, 135.38, 143.14, 154.26,
1

4
72 Bull. Chem. Soc. Jpn., 78, No. 3 (2005)
Coumarin Formation by Pd(II)-Catalyzed Reaction
4
a) J. Oyamada, C. Jia, Y. Fujiwara, and T. Kitamura,
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6
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2
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