A convenient synthesis of dihydrocoumarins from phenols and cinnamic acid derivatives

Article abstract of DOI:10.1016/j.tet.2005.07.062

A facile procedure for synthesis of dihydrocoumarin derivatives was described. Although the yield of the products in the reaction of phenols with acrylates in trifluoroacetic acid in the presence of Pd(OAc)₂ giving coumarins was found to be very low, dihydrocoumarin derivatives were obtained in good to high yields in the absence of Pd(OAc)₂ when ethyl cinnamates bearing electron-donating groups were employed in this reaction.

Full text of DOI:10.1016/j.tet.2005.07.062

Tetrahedron 61 (2005) 9291–9297
A convenient synthesis of dihydrocoumarins from phenols
and cinnamic acid derivatives
*
Shinya Aoki, Chie Amamoto, Juzo Oyamada and Tsugio Kitamura
Department of Chemistry and Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi, Saga 840-8502, Japan
Received 27 June 2005; revised 16 July 2005; accepted 19 July 2005
Available online 9 August 2005
Abstract—A facile procedure for synthesis of dihydrocoumarin derivatives was described. Although the yield of the products in the reaction
of phenols with acrylates in trifluoroacetic acid in the presence of Pd(OAc)2 giving coumarins was found to be very low, dihydrocoumarin
derivatives were obtained in good to high yields in the absence of Pd(OAc)2 when ethyl cinnamates bearing electron-donating groups were
employed in this reaction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
employed in the hydroarylation reaction.9 This procedure
provides a very mild and convenient method for synthesis of
4-aryl-3,4-dihydrocoumarins. Here we wish to report our
findings concerning the synthesis of 4-aryl-3,4-dihydrocou-
marins from phenols and electron-rich cinnamic acids and
esters.10
4-Aryl-3,4-dihydrocoumarins are of synthetic interest
because they are present in a number of natural molecules,
such as 4-aryl-3,4-dihydrocoumarins (neoflavonoids),1
complex flavonoids,2 and 1-arylbenzo[f]chroman-3-ones.3
Although many synthetic methods for 4-aryl-3,4-dihydro-
coumarins have been reported up to the present, most of
the procedures based on the condensation of phenols with
cinnamic acids have been conducted in strong acidic media
and at high temperature.4 Consequently, a mild and simple
procedure is strongly desired.
(1)
Recently, it has been found that hydroarylation of alkynes
takes place in the presence of a palladium or platinum
catalyst under mild conditions in trifluoroacetic acid (TFA)
(Eq. 1).5 This hydroarylation reaction efficiently proceeds
intramolecularly to afford heterocycles, such as coumarins,
quinolines, and thiocoumarins.5,6 Interestingly, this hydro-
arylation reaction has been applied to direct synthesis of
coumarins from phenols and propiolic acids or esters
(Eq. 2).7 However, the palladium-catalyzed reaction of
phenols with ethyl acrylates does not afford dihydro-
coumarins via hydroarylation but coumarins derived
from the Heck-type coupling reaction followed by
intramolecular cyclization (Eq. 3).8 During the course of
our study on hydroarylation reactions, we found that
dihydrocoumarins were formed without palladium catalysts
when electron-rich cinnamic acids and esters were
(2)
(3)
2. Results and discussion
2.1. Reaction of ethyl 4-methoxycinnamate (1a) with
phenols 2
First, the reaction of ethyl 4-methoxycinnamate (1a) as an
electron-rich substrate with 2-naphthol (2a) was examined
(Table 1). After dissolving 1a and 2a in TFA, the mixture was
stirred for 24 h at rt. Workup (neutralization and extraction)
Keywords: Dihydrocoumarins; Phenols; Cinnamic acid derivatives;
Trifluoroacetic acid.
*
Corresponding author. Tel.: C81 952288550; fax: C81 952288548;
e-mail: kitamura@cc.saga-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.062

9292
S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297
followed by purification (column chromatography on silica
gel) gave 1,2-dihydro-1-(4-methoxyphenyl)-3H-naphtho-
[2,1-b]pyran-3-one (3aa) quantitatively. This reaction is a
very simple and useful method that provides a sophisticated
dihydrocoumarin derivative in high yield.
dihydrocoumarin (3aj), quite differing from the elec-
tron-rich phenols. However, it is expected that the
reaction at an elevated temperature for a longer time
increases the yield of dihydrocoumarins 3, as observed
in the literature.10
Similar reactions with 3,4-methylenedioxyphenol (2b),
3,5-dimethoxyphenol (2c), and 3-methoxyphenol (2d)
gave the corresponding dihydrocoumarins 3ab, 3ac, and
3ad in high yields, respectively. However, the reaction
with 4-methoxyphenol (2e) afforded 6-methoxy-4-(4-
methoxyphenyl)-3,4-dihydrocoumarin (3ae) only in 32%
yield. The methoxy group of 2e deactivates the reaction
site, the ortho position to the hydroxyl group, by an
inductive effect. In the reaction of 1a with 3,4-
dimethylphenol (2f) and 3,5-di-methylphenol (2g), the
corresponding dihydrocoumarins 3af and 3ag were
obtained in high yields, respectively. The reactions with
cresols, such as 3-methylphenol (2h) and 4-methylphenol
(2i), gave dihydrocoumarins 3ah and 3ai in 60 and 71%
yields, respectively. An electron-deficient phenol, 4-bro-
mophenol (2j), afforded only 8% yield of
2.2. Substituent effect on the formation of dihydro-
coumarins 3 in the reaction of ethyl cinnamates 1 with
phenols 2
To apply the reaction to the synthesis of several substituted
dihydrocoumarins 3, various substituted ethyl cinnamates 1
were employed in the reaction with 2-naphthol (2a) (Table 2
and Fig. 1). In the case of 1 bearing electron-rich aryl groups
such as 4-methoxyphenyl (1a), 3,4-dimethoxyphenyl (1b),
and 3-hydroxy-4-methoxyphenyl (1c), dihydrocoumarins
3aa, 3ba, and 3ca were obtained quantitatively, whereas the
reaction of ethyl 4-methylcinnamate (1d) afforded only 43%
yield of dihydrocoumarin 3da. In the cases of the substrates
bearing a methyl group at the ortho position such as ethyl
2,5-dimethycinnamate (1g) and 2,4,6-trimethycinnamate
(1h), no dihydrocoumarins 3 were obtained and the starting
Table 1. Reaction of 1a with phenols 2a
Run
Phenol 2
Product 3
Yield
(%)
Run
Phenol 2
Product 3
Yield
(%)
2a
1
100
6
100
3af
3aa
3ab
2f
2
3
4
100
86
7
8
9
98
60
71
2g
3ag
2b
2c
2d
3ah
3ai
2h
3ac
3ad
71
2i
5
32
10
8
3aj
3ae
2e
2j
a A solution of 1a (1 mmol) and 2 (1 mmol) in TFA (1 mL) was stirred at rt for 24 h.

S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297
Table 2. Substituent effect of cinnamate 1 on the formation of dihydrocoumarins 3a
9293
Entry
1
Cinnamate 1, Ar
Phenol 2
Dihydrocoumarin
3 (%)
1b:
2a
3ba 100
3bf 100
2
1b
2f
3
4
1b
3bg 100
3ca 100
2g
2a
1c:
5
6
1c
1c
2f
2g
3cf 100
3cg 97
1d:
7
8
2a
2b
3da 43
3db 9
1d
1e:
1f:
9
2a
2a
3ea 20
10
3fa 100
a A solution of 1 (1 mmol) and 2 (1 mmol) in TFA (1 mL) was stirred at rt for 24 h.
materials were recovered. The parent ethyl cinnamate (1i)
also did not undergo any reaction under the same conditions.
2.3. Reaction in a mixed solvent of TFA and
1,2-dichloroethane
On the other hand, the combination of electron-rich
cinnamates 1b,c and electron-rich phenols 2f,g gave almost
quantitative yields of dihydrocoumarins 3bf, 3bg, 3cf, and
3cg, respectively.
Although the reaction proceeded efficiently in TFA solvent
at rt, we examined a decrease of the amount of TFA in a
mixed solvent of TFA and 1,2-dichloroethane (Table 3).
When the reaction of 1a with 2g was conducted in a 1:1
Figure 1. Dihydrocoumarins 3 listed in Table 2.

9294
S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297
Table 4. Reaction of 4-methoxycinnamic acid 4 with phenols 2a
Table 3. Effect of the amount of TFA
Solvent
Yield (%)
TFA (mL)
ClCH2CH2Cl (mL)
1
0
98
93
58
5
0.5
0.3
0.1
0.5
0.7
0.9
Entry
Phenol 2
Dihydrocou-
marin 3
Isolated yield
(%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2k
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ak
85
99
90
72
mixture (v/v) of TFA and 1,2-dichloroethane, dihydro-
coumarin 3ag was obtained in 93% yield. Further decrease
in the ratio of TFA resulted in a significant decrease in the
yield of 3ag, as seen from Table 3.
38
100
100
47
13b
a A solution of 4 (1 mmol) and 2 (1 mmol) in TFA (1 mL) and CH2Cl2
(0.5 mL) was stirred at rt for 24 h.
2.4. Reaction of 4-methoxycinnamic acid (4) with
phenols 3
b 3-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)propionic acid (5) was also
formed in 85% yield
To extend the above reaction, we examined the reaction
of 4-methoxycinnamic acid (4) instead of ethyl ester 1a
(Table 4).10 On the basis of the reaction in a mixture of TFA
and 1,2-dichloroethane, we conducted the reaction of 4 in a
2:1 mixture (v/v) of TFA and CH2Cl2. When the reaction of
4 with 3,5-dimethylphenol (2g) was carried out in a mixed
solvent of TFA (1 mL) and CH2Cl2 (0.5 mL) at rt for 24 h,
dihydrocoumarin 3ag was obtained quantitatively.
Similarly, the reaction with 3,4-dimethyphenol (2f) gave
dihydrocoumarin 3af quantitatively, while the reaction with
3-methylphenol (2h) decreased the yield of dihydro-
coumarin 3ah (47%). Apparently, the reaction with
electron-rich phenols, such as 2-naphthol (2a), 3,4-methyl-
enedioxyphenol (2b), 3,4-dimethoxyphenol (2c), and
3-methoxyphenol (2d), afforded the corresponding
dihydrocoumarins 3 in high yields. In the case of the
reaction with 4-methoxyphenol (2e), however, a lower yield
(38%) of dihydrocoumarin 3ae was observed for the reason
similar to the reaction of 1a with 2e. When the reaction of 4
with phenol (2k) was conducted under similar conditions,
dihydrocoumarin 3ak was obtained in 13% yield, together
with 85% yield of 3-(4-hydroxyphenyl)-3-(4-methoxy-
phenyl)propionic acid (5).
.
2.5. Mechanistic consideration
The role of TFA is important in the reaction of cinnamates 1
with phenols 2, as seen from Table 3. Scheme 1 shows a
possible mechanism of the formation of dihydrocoumarins
3, where the reaction is promoted by protonation of 1 with
TFA. Accordingly, electron-donating groups on 1 stabilize
the resulting cationic intermediate 6 and facilitate the
further reaction. However, an unsubstituted phenyl group is
not enough to react with phenols 2. Since the phenyl groups
with the ortho methyl substituent cannot participate in the
stabilization of the cationic intermediate 6 because of steric
hindrance, no products are formed. A similar substituent
Scheme 1.

S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297
9295
effect is also observed in the case of phenols 2. As expected,
the reaction with 4-bromophenol (2j) results in the low yield
of 3. The electrophilic substitution of phenol 2 by the
cationic intermediate 6 gives 3-(2-hydroxyphenyl)propiol-
ate 7, which immediately undergoes intramolecular
transesterification to lead to dihydrocoumarin 3. The
electrophilic substitution of phenol (2k) occurs at the para
position to afford 3-(4-hydroxyphenyl)propionic acid (5)
predominantly. The behavior of the cationic intermediate
6 toward the phenol is very close to the result of the
Friedel–Crafts alkylation of phenol that shows the pre-
dominant formation of para products.11
NMR (CDCl3, 75.5 MHz) d 36.64, 37.45, 55.02, 114.43,
117.37, 117.90, 122.95, 125.09, 127.29, 127.86, 128.58,
129.65, 130.83, 130.93, 132.42, 149.52, 158.75, 167.15.
4.2.2. 4-(4-Methoxyphenyl)-6,7-methylenedioxy-3,4-
dihydrocoumarin (3ab). Mp 136.5–137.5 8C (CH2Cl2/
hexane) (lit.6 mp 134.6–135.2 8C). 1H NMR (CDCl3,
300 MHz) d 2.91 (dd, JZ15.8, 8.0 Hz, 1H, CH), 3.00 (dd,
JZ15.7, 6.0 Hz, 1H, CH), 3.79 (s, 3H, OMe), 4.16 (app. t, JZ
6.8 Hz, 1H, CH), 5.93 (s, 2H, CH2), 6.38 (s, 1H, ArH), 6.63 (s,
1H, ArH), 6.86 (app. d, JZ8.7 Hz, 2H, ArH), 7.05 (app. d, JZ
8.7 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.14,
39.82, 55.26, 99.06, 101.64, 107.21, 114.48, 118.38, 128.49,
132.35, 144.36, 146.10, 147.41, 158.99, 167.67.
3. Conclusion
4.2.3. 5,7-Dimethoxy-4-(4-methoxyphenyl)-3,4-dihydro-
coumarin (3ac). Mp 133.3–133.8 8C (CH2Cl2/hexane). H
1
Duringthe course of study onour hydroarylation reactions, we
found a convenient and efficient synthesis of 4-aryl-3,4-
dihydrocoumarins. This process is conducted under very mild
conditions by using electron-rich cinnamic acid derivatives 1
(or 4) and electron-rich phenols 2. The convenient procedure
involves only a simple mixing of 1 (or 4) and 2 in TFA at rt,
followed by separation by column chromatography. Because
of the simplicity and mildness, this procedure is applicable for
a variety of 4-aryl-3,4-dihydrocoumarins, along with the
previously reported methods (Table 4).
NMR (CDCl3, 300 MHz) d 2.97 (d, JZ4.2 Hz, 2H, CH2),
3.74 (s, 6H, 2OMe), 3.81 (s, 3H, OMe), 4.50 (t, JZ4.5 Hz,
1H), 6.27 (d, JZ2.1 Hz, 1H, ArH), 6.31 (d, JZ2.4 Hz, 1H,
ArH), 6.78 (d, JZ8.4 Hz, 1H, ArH), 7.02 (d, JZ8.7 Hz, 1H,
ArH). 13C NMR (CDCl3, 75.5 MHz) d 33.67, 37.25, 55.18,
55.53, 55.79, 93.94, 95.08, 106.41, 114.17, 127.74, 133.57,
153.00, 157.36, 158.57, 160.58, 167.74. Anal. Calcd for
C18H18O5: C, 68.78; H, 5.77. Found: C, 68.89; H, 5.81.
4.2.4. 7-Methoxy-4-(4-methoxyphenyl)-3,4-dihydro-
coumarin (3ad).4o Mp 143.6–144.9 8C (CH2Cl2/hexane).
1H NMR (CDCl3, 300 MHz) d 2.94 (dd, JZ15.8, 8.0 Hz,
1H, CH), 3.03 (dd, JZ15.8, 5.9 Hz, 1H, CH), 3.786 (s, 3H,
OMe), 3.794 (s, 3H, OMe), 4.23 (app. t, JZ6.6 Hz, 1H,
CH), 6.63 (dd, JZ8.4, 2.4 Hz, 1H, ArH), 6.66 (d, JZ
2.1 Hz, 1H, ArH), 6.85–6.88 (m, 3H, ArH), 7.06 (app. d, JZ
8.7 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.47,
39.30, 55.26, 55.51, 102.48, 110.68, 114.43, 118.04, 128.51,
128.81, 132.70, 152.39, 158.92, 159.94, 167.72.
4. Experimental
4.1. General
Melting points were measured with a Yanaco micromelting
apparatus and are not corrected. 1H and 13C NMR spectra were
recorded on a JEOL AL 300 spectrometer; chemical shifts (d)
are reported in parts per million relative to tetramethylsilane.
Column chromatography was carried out on silica gel (Silica
Gel 60, spherical, Kanto Chemical Co.) with hexane and ethyl
acetateasaneluent. Elementalanalyseswere conductedbythe
Service Center of the Elemental Analysis of Organic
Compounds, Faculty of Science, Kyushu University.
4.2.5. 6-Methoxy-4-(4-methoxyphenyl)-3,4-dihydro-
coumarin (3ae). Mp 87.8–89.6 8C (CH2Cl2/hexane). 1H
NMR (CDCl3, 300 MHz) d 2.94 (dd, JZ15.9, 7.8 Hz, 1H,
CH), 3.03 (dd, JZ15.75, 6 Hz, 1H, CH), 3.71 (s, 3H, OMe),
3.79 (s, 3H, OMe), 4.24 (t, JZ6.9 Hz, 1H, CH), 6.49 (d, JZ
6 Hz, 1H, ArH), 6.81 (dd, JZ8.9, 3.2 Hz, 1H, ArH), 6.87
(app. d, JZ8.7 Hz, 2H, ArH), 7.04–7.10 (m, 3H, ArH). 13C
NMR (CDCl3, 75.5 MHz) d 37.11, 40.14, 55.25, 55.57,
113.37, 113.61, 114.46, 117.77, 127.18, 128.57, 132.04,
145.56, 156.27, 158.97, 167.91. Anal. Calcd for C17H16O4:
C, 71.82; H, 5.67. Found: C, 71.86; H, 5.65.
4.2. General procedure for the reaction of cinnamates 1
with phenols 2
In a test tube was placed an ethyl cinnamate 1 (1 mmol), a
phenol 2 (1 mmol), and TFA (1 mL). The mixture was
stirred at rt for 24 h. The reaction mixture was neutralized
with aqueous NaHCO3 and extracted with CH2Cl2. The
product was separated by column chromatography on silica
gel and purified by recrystallization from CH2Cl2/hexane.
A similar procedure was also followed when the reaction
of 4-methoxycinnamic acid (4) was conducted in a mixed
solvent of TFA (1 mL) and CH2Cl2 (0.5 mL).
4.2.6. 4-(4-Methoxyphenyl)-6,7-dimethyl-3,4-dihydro-
coumarin (3af).4j Mp 126.5–127.9 8C (CH2Cl2/hexane).
1H NMR (CDCl3, 300 MHz) d 2.15 (s, 3H, Me), 2.24 (s, 3H,
Me), 2.92 (dd, JZ15.8, 7.4 Hz, 1H, CH), 3.00 (dd, JZ15.6,
6.0 Hz, 1H, CH), 3.78 (s, 3H, OMe), 4.21 (t, JZ6.8 Hz, 1H,
CH), 6.72 (s, 1H, ArH), 6.85 (app. d, JZ9.0 Hz, 2H, ArH),
6.89 (s, 1H, ArH), 7.05 (app. d, JZ8.4 Hz, 2H, ArH). 13C
NMR (CDCl3, 75.5 MHz) d 19.00, 19.50, 37.50, 39.62,
55.23, 114.38, 117.79, 122.94, 128.48, 128.91, 132.76,
132.84, 137.27, 149.59, 158.85, 168.10.
4.2.1. 1,2-Dihydro-1-(4-methoxyphenyl)-3H-naphtho-
[2,1-b]pyran-3-one (3aa).4e Mp 130.0–131.0 8C (CH2Cl2/
1
hexane). H NMR (CDCl3, 300 MHz) d 3.11 (dd, JZ15.6,
2.9 Hz, 1H, CH), 3.20 (dd, JZ15.6, 6.0 Hz, 1H, CH), 3.72
(s, 3H, OMe), 4.90 (dd, JZ6.0, 2.7 Hz, 1H, CH), 6.78 (d,
JZ8.7 Hz, 2H, ArH), 7.03 (app. d, JZ8.4 Hz, 2H, ArH),
7.33 (d, JZ8.7 Hz, 1H, ArH), 7.40–7.49 (m, 2H, ArH), 7.79
(d, JZ8.4 Hz, 1H, ArH), 7.85 (d, JZ8.7 Hz, 2H, ArH). 13C
4.2.7. 4-(4-Methoxyphenyl)-4,7-dimethyl-3,4-dihydrocou-
marin (3ag).4j Mp 170.6–171.2 8C (CH2Cl2/hexane). 1H
NMR (CDCl3, 300 MHz) d 2.14 (s, 3H, Me), 2.32 (s, 3H,

9296
S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297
Me), 2.97 (dd, JZ15.8, 3.2 Hz, 1H, CH), 3.03 (dd, JZ15.3,
5.6 Hz, 1H, CH), 3.74 (s, 3H, OMe), 4.32 (dd, JZ5.6, 3.2 Hz,
1H, CH), 6.79 (d, JZ8.6 Hz, 2H, ArH), 6.83 (br s, 2H, ArH),
6.95 (d, JZ8.6 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d
18.53, 20.99, 37.13, 37.89, 55.15, 114.38, 115.32, 120.43,
127.21, 127.94, 132.28, 136.48, 138.58, 151.97, 158.74, 167.54.
3.12 (dd, JZ2.7, 10.6 Hz, 1H, CH), 3.19 (dd, JZ4.0,
10.6 Hz, 1H, CH), 3.76 (s, 3H, OMe), 4.89 (dd, JZ2.7,
4.0 Hz, 1H, CH), 5.52 (s, 1H, OH), 6.60–6.62 (m, 2H, ArH),
6.77–6.80 (m, 1H, ArH), 7.32–7.51 (m, 3H, ArH), 7.79–
7.82 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 37.20,
37.58, 55.69, 109.17, 114.79, 117.31, 117.82, 119.68,
122.96, 125.14, 127.32, 128.59, 129.74, 130.88, 130.96,
132.37, 144.94, 146.96, 149.51, 167.31.
4.2.8.
4-(4-Methoxyphenyl)-7-methyl-3,4-dihydro-
coumarin (3ah).12 Mp 85–87 8C (CH2Cl2/hexane). 1H
NMR (CDCl3, 300 MHz) d 2.34 (s, 3H, Me), 2.93 (dd,
JZ15.2, 8.1 Hz, 1H, CH), 3.01 (dd, JZ15.6, 6.6 Hz, 1H,
CH), 3.77 (s, 3H, OMe), 4.23 (app. t, JZ6.9 Hz, 1H, CH),
6.84–6.92 (m, 5H, ArH), 6.95 (app. d, JZ9.0 Hz, 2H, ArH).
13C NMR (CDCl3, 75.5 MHz) d 20.97, 37.30, 39.51, 55.21,
114.38, 117.38, 123.01, 125.33, 127.93, 128.49, 132.47,
138.94, 151.44, 158.86, 168.08.
4.2.14. 1,2-Dihydro-1-(4-methylphenyl)-3H-naphtho-
[2,1-b]pyran-3-one (3da). Mp 108.5–109.5 8C (CH2Cl2/
hexane). H NMR (CDCl3, 300 MHz) d 2.26 (s, 3H, Me),
1
3.13 (dd, JZ15.9, 2.7 Hz, 1H, CH), 3.20 (dd, JZ15.9,
6.6 Hz, 1H, CH), 4.92 (app. d, JZ3.9 Hz, 1H, CH), 6.99–
7.08 (m, 4H, ArH), 7.34 (d, JZ9.0 Hz, 1H, ArH), 7.40–7.49
(m, 2H, ArH), 7.79 (d, JZ7.8 Hz, 1H, ArH), 7.85 (d, JZ
9.0 Hz, 2H, ArH). 13C NMR (CDCl3, 75.5 MHz) d 20.87,
37.19, 37.44, 117.45, 117.80, 123.01, 125.12, 126.71,
127.34, 128.64, 129.71, 129.80, 130.95, 131.01, 137.12,
137.49, 149.67, 167.12. Anal. Calcd for C20H16O2: C,
83.31; H, 5.59. Found: C, 83.41; H, 5.58.
4.2.9.
4-(4-Methoxyphenyl)-6-methyl-3,4-dihydro-
coumarin (3ai).12 Mp 120.2–120.6 8C (CH2Cl2/hexane). H
NMR (CDCl3, 300 MHz) d 2.24 (s, 3H, Me), 2.93 (dd, JZ15.2,
7.5 Hz, 1H, CH), 3.00 (dd, JZ15.6, 7.5 Hz, 1H, CH), 3.77
(s, 3H, OMe), 4.22 (t, JZ6.8 Hz, 1H, CH), 6.77 (s, 1H, ArH),
6.86 (app. d, JZ8.7 Hz, 2H, ArH), 6.99 (d, JZ8.4 Hz, 1H,
ArH), 7.03–7.07 (m, 3H, ArH). 13CNMR(CDCl3, 75.5 MHz)d
20.71, 37.28, 39.92, 55.24, 114.34, 116.77, 125.74, 128.54,
128.56, 129.15, 132.43, 134.22, 149.57, 158.92, 167.91.
1
4.2.15. 4-(3,4-Dimethoxyphenyl)-6,7-dimethyl-3,4-di-
hydrocoumarin (3bf). Mp 141.7–142.8 8C (CH2Cl2/
1
hexane). H NMR (CDCl3, 300 MHz) d 2.15 (s, 3H, Me),
2.24 (s, 3H, Me), 2.94 (dd, JZ15.8, 7.4 Hz, 1H, CH), 3.01
(dd, JZ15.8, 5.9 Hz, 1H, CH), 3.82 (s, 3H, OMe), 3.85
(s, 3H, OMe), 4.21 (t, JZ6.6 Hz, 1H, CH), 6.66–6.68 (m,
2H, ArH), 6.74 (s, 1H, ArH), 6.81 (app. d, JZ8.7 Hz, 1H,
ArH), 6.89 (s, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d
18.87, 19.37, 37.33, 39.91, 55.75 (2OMe), 110.45, 111.43,
117.63, 119.34, 122.70, 128.78, 132.76, 133.17, 137.19,
148.22, 149.20, 149.42, 168.05. Anal. Calcd for C19H20O4:
C, 73.06; H, 6.45. Found: C, 73.00; H, 6.46.
4.2.10. 7-Bromo-4-(4-methoxyphenyl)-3,4-dihydro-
coumarin (3aj). Mp 149.5–150.5 8C (CH2Cl2/hexane). H
1
NMR (CDCl3, 300 MHz) d 2.96 (dd, JZ16.1, 8.3 Hz, 1H,
CH), 3.04 (dd, JZ15.8, 6.2 Hz, 1H, CH), 3.81 (s, 3H, OMe),
4.26 (app. t, JZ7.2 Hz, 1H, CH), 6.89 (app. d, JZ8.7 Hz,
2H, ArH), 7.00 (d, JZ8.4 Hz, 1H, ArH), 7.05–7.09 (m, 3H,
ArH), 7.40 (dd, JZ8.7, 2.4 Hz, 1H, ArH). 13C NMR
(CDCl3, 75.5 MHz) d 36.78, 39.82, 55.32, 114.69, 117.29,
118.84, 128.44, 128.57, 131.02, 131.26, 131.72, 150.72,
159.22, 166.94. Anal. Calcd for C16H13BrO3: C, 57.68; H,
3.93. Found: C, 57.77; H, 3.94.
4.2.16. 4-(4-Hydroxy-3-methoxyphenyl)-6,7-dimethyl-3,
4-dihydrocoumarin (3cf). Mp 141.7–142.8 8C (CH2Cl2/
1
hexane). H NMR (CDCl3, 300 MHz) d 2.15 (s, 3H, Me),
2.24 (s, 3H, Me), 2.92(dd, JZ16.1, 7.4 Hz, 1H, CH), 3.00 (dd,
JZ15.9, 6.0 Hz, 1H, CH), 3.82 (s, 3H, OMe), 4.19 (t, JZ
6.8 Hz, 1H, CH), 6.62–6.63 (m, 2H, ArH), 6.74 (s, 1H, ArH),
6.85 (d, JZ8.7 Hz, 1H, ArH), 6.89 (s, 1H, ArH). 13C NMR
(CDCl3, 75.5 MHz) d 18.91, 19.41, 37.45, 40.00, 55.82,
139.77, 114.71, 117.66, 120.26, 122.82, 128.85, 132.55,
132.83, 137.23, 144.88, 146.86, 149.44, 168.24. Anal. Calcd
for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.56; H, 6.12.
4.2.11. 4-(4-Methoxyphenyl)-3,4-dihydrocoumarin
(2ak).12 Mp 136.9–138.1 8C (CH2Cl2/hexane). 1H NMR
(CDCl3, 300 MHz) d 2.98 (dd, JZ16.2, 7.8 Hz, 1H, CH),
3.53 (dd, JZ17.4, 6.0 Hz, 1H, CH), 3.79 (s, 3H, OMe), 4.30
(t, JZ6.8 Hz, 1H), 6.87 (app. d, JZ8.7 Hz, 2H, ArH), 6.98
(d, JZ7.5 Hz, 1H, ArH), 7.06–7.13 (m, 4H, ArH), 7.29 (td,
JZ7.8, 1.8 Hz, 1H, ArH). 13C NMR (CDCl3, 75.5 MHz) d
37.19, 39.90, 55.28, 114.48, 117.08, 124.60, 126.20, 128.26,
128.60, 128.68, 132.20, 151.66, 159.00, 167.73.
4.2.17. 4-(3,4-Dimethoxyphenyl)-5,7-dimethyl-3,4-di-
hydrocoumarin (3bg).15 Mp 137.9–138.9 8C (CH2Cl2/
hexane). H NMR (CDCl3, 300 MHz) d 2.16 (s, 3H, Me),
1
4.2.12.
1,2-Dihydro-1-(3,4-dimethoxyphenyl)-3H-
naphtho[2,1-b]pyran-3-one (3ba).13 Mp 156–159 8C
(CH2Cl2/hexane). H NMR (CDCl3, 300 MHz) d 3.14 (dd,
2.34 (d, 3H, Me), 2.94–3.08 (m, 2H, CH2), 3.80 (s, 3H,
OMe), 3.82 (s, 3H, OMe), 4.29–4.32 (m, 1H, CH), 6.52 (d,
JZ8.1 Hz, 1H, ArH), 6.59 (s, 1H, ArH), 6.73 (d, JZ8.1 Hz,
1H, ArH), 6.83 (br s, 2H, ArH). 13C NMR (CDCl3,
75.5 MHz) d 18.54, 20.98, 37.55, 37.87, 55.79 (2OMe),
110.16, 111.51, 115.28, 118.96, 120.25, 127.23, 132.83,
136.51, 138.64, 148.25, 149.30, 151.93, 167.59.
1
JZ3.0, 15.3 Hz, 1H, CH), 3.20 (dd, JZ5.7, 15.3 Hz, 1H, CH),
3.78 (s, 3H, OMe), 4.90 (dd, JZ3.0, 5.7 Hz, 1H, CH), 6.57–
6.60 (m, 1H, ArH), 6.69–6.72 (m, 2H, ArH), 7.33–7.51 (m, 3H,
ArH), 7.80–7.88 (m, 3H, ArH). 13C NMR (CDCl3, 75.5 MHz)
d 37.14, 37.49, 55.70, 55.74, 110.05, 11.56, 117.34, 117.76,
118.94, 122.94, 125.13, 127.32, 128.61, 129.75, 130.88,
130.95, 132.97, 148.34, 149.39, 149.55, 167.15.
4.2.18. 4-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethyl-3,
4-dihydrocoumarin (3cg). Mp 176.8–177.6 8C (CH2Cl2/
1
hexane). H NMR (CDCl3, 300 MHz) d 2.16 (s, 3H, Me),
4.2.13. 1,2-Dihydro-1-(4-hydroxy-3-methoxyphenyl)-
3H-naphtho[2,1-b]pyran-3-one (3ca).14 Mp 150.4–
151.4 8C (CH2Cl2/hexane). H NMR (CDCl3, 300 MHz) d
2.34 (s, 3H, Me), 2.97 (dd, JZ3.0, 15.6 Hz, 1H, CH), 3.03
(dd, JZ5.7, 15.6 Hz, 1H, CH), 3.79 (s, 3H, OMe), 4.30 (dd,
1

S. Aoki et al. / Tetrahedron 61 (2005) 9291–9297
9297
Chapman and Hall: London, 1993; p 239. (c) Wagner, H.;
Seligmann, O.; Chari, M. V.; Wollenweber, E.; Dietz, V.;
Donnelly, D. M. X.; Donnelly, M. J. M.; O’Donnell, B.
Tetrahedron Lett. 1979, 4269–4272.
JZ3.0, 5.7 Hz, 1H, CH), 5.53 (s, 1H, OH), 6.50–6.53 (m,
2H, ArH), 6.77–6.83 (m, 3H, ArH). 13C NMR (CDCl3,
75.5 MHz) d 18.56, 21.02, 37.68, 38.00, 55.83, 109.25,
114.71, 115.33, 119.82, 120.34, 127.28, 132.24, 136.57,
138.68, 144.89, 146.91, 151.97, 167.69. Anal. Calcd for
C18H18O4: C, 72.47; H, 6.08. Found: C, 72.46; H, 6.08.
2. (a) Asai, F.; Iinuma, M.; Tanaka, T.; Takenaka, M.; Mizuno,
M. Phytochemistry 1992, 31, 2487 and references cited
therein. (b) Asai, F.; Iinuma, M.; Tanaka, T.; Mizuno, M.
Phytochemistry 1991, 30, 3091. (c) Asai, F.; Iinuma, M.; Tanaka,
T.; Mizuno, M. Chem. Pharm. Bull. 1990, 38, 1079–1081.
3. Speranza, G.; Di Meo, A.; Manitto, P.; Monti, D.; Fontana, G.
J. Agric. Food Chem. 1996, 44, 274.
4.2.19. 6,7-Methylenedioxy-4-(4-methylphenyl)-3,4-
dihydrocoumarin (3db). Mp 131.6–132.4 8C (CH2Cl2/
1
hexane). H NMR (CDCl3, 300 MHz) d 2.33 (s, 3H, Me),
2.93 (dd, JZ15.9, 7.8 Hz, 1H, CH), 3.01 (dd, JZ15.8,
6.15 Hz, 1H, CH), 4.17 (t, JZ6.9 Hz, 1H, CH), 5.93 (s, 2H,
CH2), 6.38 (s, 1H, ArH), 6.64 (s, 1H, ArH), 7.03 (d, JZ
8.1 Hz, 2H, ArH), 7.15 (d, JZ8.0 Hz, 2H, ArH). 13C NMR
(CDCl3, 75.5 MHz) d 20.97, 37.01, 40.24, 99.06, 101.64,
107.26, 118.26, 127.31, 129.77, 137.37, 137.39, 144.37,
146.16, 147.43, 167.66. Anal. Calcd for C17H14O4: C,
72.33; H, 5.00. Found: C, 72.38; H, 4.99.
4. (a) Liebermann, C.; Hartmann, A. Ber. Dtsch. Chem. Ges.
1891, 24, 2582. (b) Liebermann, C.; Hartmann, A. Ber. Dtsch.
Chem. Ges. 1892, 25, 957. (c) Simpson, J. D.; Stephen, H.
J. Chem. Soc. 1956, 1382. (d) Koelsch, C. F. J. Am. Chem. Soc.
1936, 58, 1326. (e) Anjaneyulu, A. S. R.; Row, L. R.; Krishna,
C. S.; Scrinivasulu, C. Curr. Sci. 1968, 37, 513–515; Chem.
Abstr. 1969, 70, 68062x. (f) Hasebe, N. Nippon Kagaku Zasshi
1961, 82, 1728. (g) Hasebe, N. Nippon Kagaku Zasshi 1961,
82, 1730. (h) Hasebe, N. Nippon Kagaku Zasshi 1962, 83, 224.
(i) Reichel, L.; Proksch, G. Liebigs Ann. Chem. 1971, 745, 59.
(j) Chenault, J.; Dupin, J.-F.E. Heterocycles 1983, 20, 437–443.
(k) Dupin, J.-F.E.; Chenault, J. Heterocycles 1983, 20, 2401. (l)
Starkov, S. P. Zh. Obshch. Khim. 1983, 53, 2098; Chem. Abstr.
1984, 100, 67956t. (m) Matsui, T. Kogakubu Kenkyu Hokoku
(Miyazaki Daigaku) 1984, 30, 141; Chem. Abstr. 1985, 102,
95441f. (n) Talapatra, B.; Deb, T.; Talapatra, S. K. Indian
J. Chem. 1985, 24B, 561. (o) Talapatra, B.; Deb, T.; Talapatra,
S. Indian J. Chem. 1986, 25B, 1122–1125. (p) Kirtany,
J. K. Indian J. Chem. 1993, 32B, 993. (q) Das Gupta, A. K.;
Das, K. R.; Das Gupta, A. Indian J. Chem. 1972, 10, 32. (r)
Das Gupta, A. K.; Das, K. R. Indian J. Chem. 1973, 11, 1245.
(s) Suresh, R. V.; Rukmani Iyer, C. S.; Iyer, P. R. Heterocycles
1986, 24, 1925.
4.2.20. 1,2-Dihydro-1-(2,3,4-trimethoxyphenyl)-3H-
naphtho[2,1-b]pyran-3-one (3fa). Mp 178.0–178.4 8C
(CH2Cl2/hexane). H NMR (CDCl3, 300 MHz) d 3.08 (dd,
1
JZ17.0, 3.6 Hz, 1H, CH), 3.15 (dd, JZ15.9, 6.6 Hz, 1H,
CH), 3.75 (s, 3H, OMe), 3.90 (s, 3H, OMe), 4.09 (s, 3H,
OMe), 5.23 (app. d, JZ4.2 Hz, 1H, CH), 6.35 (d, JZ
8.7 Hz, 1H, ArH), 6.40 (d, JZ8.7 Hz, 1H, ArH), 7.32 (d,
JZ9.0 Hz, 1H, ArH), 7.40–7.49 (m, 2H, ArH), 7.76 (d, JZ
8.1 Hz, 1H, ArH), 7.85 (d, JZ8.7 Hz, 2H, ArH). 13C NMR
(CDCl3, 75.5 MHz) d 31.59, 36.44, 55.72, 60.63, 60.98,
107.13, 117.34, 117.64, 121.89, 122.98, 125.05, 125.95,
127.27, 128.56, 129.58, 130.87, 130.97, 142.11, 150.03,
150.69, 153.22, 167.44. Anal. Calcd for C22H20O5: C,
72.51; H, 5.53. Found: C, 72.30; H, 5.48.
5. (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1192. (b) Jia, C.; Lu, W.;
Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y.
J. Am. Chem. Soc. 2000, 122, 7252.
4.2.21. 1,2-Dihydro-1-(3,4,5-trimethoxyphenyl)-3H-
naphtho[2,1-b]pyran-3-one (3ea). Mp 181.9–182.6 8C
(CH2Cl2/hexane). 1H NMR (CDCl3, 300 MHz) d 3.10–
3.24 (m, 2H, CH2), 3.72 (s, 6H, OMe), 3.77 (s, 3H, OMe),
4.87–4.90 (m, 1H, CH), 6.33 (s, 2H, ArH), 7.33–7.53 (m,
3H, ArH), 7.81–7.88 (m, 3H, ArH). 13C NMR (CDCl3,
75.5 MHz) d 37.56, 37.97, 56.06, 60.72, 103.96, 117.42,
117.51, 123.02, 125.31, 127.50, 128.75, 130.04, 131.00,
131.07, 136.30, 137.40, 149.71, 153.72, 167.14. Anal. Calcd
for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.15; H, 5.55.
6. Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem.
2000, 65, 7516.
7. (a) Oyamada, J.; Jia, C.; Fujiwara, Y.; Kitamura, T. Chem.
Lett. 2002, 31, 380. (b) Kitamura, T.; Yamamoto, K.; Kotani,
M.; Oyamada, J.; Jia, C.; Fujiwara, Y. Bull. Chem. Soc. Jpn.
2003, 76, 1889. (c) Kotani, M.; Yamamoto, K.; Oyamada, J.;
Fujiwara, Y.; Kitamura, T. Synthesis 2004, 1466–1470.
8. Aoki, S.; Oyamada, J.; Kitamura, T. Bull. Chem. Soc. Jpn.
2005, 78, 468–472.
4.2.22. 3-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)pro-
pionic acid (5). H NMR (CD3OD, 300 MHz) d 2.93 (d,
1
9. A preliminary report was presented at the 34th Congress of
Heterocyclic Chemistry, Japan, 2004; pp 347–348, abstract.
10. During the preparation of this manuscript, we found a paper
that reports 4-aryl-3,4-dihydrocoumarin formation from
cinnamic acids and phenols. See, Li, K.; Foresee, L. N.;
Tunge, J. A. J. Org. Chem. 2005, 70, 2881–2883.
JZ7.8 Hz, 2H, CH2), 3.73 (s, 3H, OMe), 4.35 (t, JZ8.0 Hz,
1H, CH), 6.68 (app. d, JZ6.5 Hz, 2H, ArH), 6.80 (app. d,
JZ6.6 Hz, 2H, ArH), 7.04 (d, JZ8.1 Hz, 2H, ArH), 7.13 (d,
JZ8.4 Hz, 2H, ArH). 13C NMR (CD3OD, 75.5 MHz) d
42.12, 46.92, 55.65, 114.79, 116.15, 129.60, 136.54, 137.86,
156.80, 159.57, 175.94. Anal. Calcd for C16H16O4: C,
70.58; H, 5.92. Found: C, 70.29; H, 6.01.
11. Nagai, M.; Yoda, T.; Omi, S.; Kodomari, M. J. Catal. 2001,
201, 105–112.
12. Buu-Hoi, N. P.; Le Bihan, H.; Binon, F.; Maleyran, P. J. Org.
Chem. 1952, 17, 1122–1127.
13. Das, B.; Venkataiah, B.; Ravindranath, N. J. Chem. Res.
Synop. 2000, 556–557.
References and notes
14. Ramesh, C.; Ravindranath, N.; Das, B. J. Org. Chem. 2003, 68,
7101–7103.
1. (a) Donnelly, D. M. X.; Boland, G. M. Nat. Prod. Rep. 1995,
321. (b) Donnelly, D. M. X.; Boland, G. M. In The Flavonoids.
Advances in Research Since 1986; Harborne, J. B., Ed.;
15. Shukla, M. R.; Patil, P. N.; Wadgaonkar, P. P.; Joshi, P. N.;
Salunkhe, M. M. Synth. Commun. 2000, 30, 39–42.