A re-investigation of resveratrol synthesis by Perkins reaction. Application to the synthesis of aryl cinnamic acids

Article abstract of DOI:10.1016/S0040-4020(03)00405-8

A re-investigation of resveratrol synthesis by Perkins reaction allowed to improve this method and to determine the configuration of the intermediates. The results were applied to the synthesis of several aryl cinnamic acids for biological evaluation.

Full text of DOI:10.1016/S0040-4020(03)00405-8

Tetrahedron 59 (2003) 3315–3321
A re-investigation of resveratrol synthesis by Perkins reaction.
Application to the synthesis of aryl cinnamic acids
a
Guy Solladie, Yacine Pasturel-Jacope and Jean Maignan
a
b
,
*
´
´
a
´ ´ ´ ´
Laboratoire de Stereochimie associe au CNRS, Universite Louis Pasteur, ECPM, 25 Rue Becquerel, F-67087 Strasbourg Cedex 2, France
L’Oreal Recherche, 1 av. E. Schueller, F-93601 Aulnay sous Bois, France
b
´
Received 7 January 2003; revised 12 February 2003; accepted 13 March 2003
Abstract—A re-investigation of resveratrol synthesis by Perkins reaction allowed to improve this method and to determine the configuration
of the intermediates. The results were applied to the synthesis of several aryl cinnamic acids for biological evaluation. q 2003 Elsevier
Science Ltd. All rights reserved.
Resveratrol is a natural polyphenol which has been isolated
from more than 70 plant species. In 1992 it was reported
that resveratrol had antioxidant and antimutagenic
properties,1a–c a result which is probably at the origin of a
tremendous amount of work to synthesize many resveratrol
analogues.1d
who purified a small sample of the resulting trimethoxy-
stilbene carboxylic acid 1 by sublimation and after
decarboxylation they isolated the trimethyl ether of
resveratrol which was identical to the natural product
derivative reported by Takoaka (Scheme 1).
In this reaction the configuration of 1 was not
determined. After decarboxylation the product could not
be crystallized and finally the trimethyl ether of
resveratrol (trans configuration) was isolated by crystal-
lisation in 48 h from a mixture of MeOH and conc. HCl,
experimental conditions which could isomerise cis to trans
resveratrol.
The first synthesis of resveratrol with identification of the
synthetic material by comparison with the natural product
was reported in 1941 by Spath and Kromp.1e This synthesis
¨
was indeed based on a report of Takaoka2 who isolated
resveratrol from roots of Veratrum grandifluorum. It
described a synthesis of resveratrol dimethyl and trimethyl
ether but the synthetic material could not be compared with
the natural product derivatives because it never crystallized.
This synthesis, a Perkins type condensation of p-anisyl
Later on, this Perkins type reaction was described in
presence of a base for the synthesis of cis-stilbene from
benzaldehyde and phenylacetic acid.3 cis-Stilbene was
obtained by decarboxylation of the adduct and this result
acetic acid sodium salt with 1,3-dimethoxy benzaldehyde in
1
¨
acetic anhydride, was reinvestigated by Spath and Kromp
Scheme 1.
Keywords: cinnamic acid; cis–trans isomerization; Perkins reaction.
*
Corresponding author. Tel.: þ33-3-90-24-26-03; fax: þ33-3-90-24-27-42; e-mail: solladie@chimie.u-strasbg.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00405-8

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G. Solladie et al. / Tetrahedron 59 (2003) 3315–3321
3316
Scheme 2.
Scheme 3.
Table 1. Temperature effect on the decarboxylation of 1
allowed the authors to assume that the carboxylic acid
intermediate had also the same configuration (Scheme 2).
Wood and Mallory4 applied also the method to
p-anisaldehyde.
Catalyst
Solvent
T (8C) (time)
cis–trans ratio (GPC)
Cu Chromite
Quinoline
210 (1 h)
57:43
75:25
86:14
79:21
No reaction
210 (1 h 30 min)
230 (1 h)
230 (1 h)
We report in this paper a re-investigation of the Perkins
reaction for application to the synthesis of resveratrol and
analogues. We also report the synthesis of several
Cu powder
No catalyst
Quinoline
Quinoline
230 (4 h)
Scheme 4.
Table 2. Isomerization of cis and trans resveratrol in the NMR tube in
acetone D6
substituted aryl cinnamic acids, the first intermediate
isolated in the Perkins condensation, for biological
evaluation.
Time
cis–trans ratio
We started our study with Perkins condensation of p-anisyl
acetic acid to 3,5-dimethoxybenzaldehyde in presence of
acetic anhydride and triethylamine at 908C. We obtained in
72% yield only one isomer of the resulting carboxylic acid
0
72:28
59:41
55:45
26:74
12 h
36 h
3 days

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G. Solladie et al. / Tetrahedron 59 (2003) 3315–3321
3317
Scheme 5.
Table 3. Synthesis of aryl cinnamic acids by Perkins condensation
Aryl acetic acid
Aromatic aldehyde
Perkins adduct R¼i-Pr
After deprotection with BCl3, R¼H
45 min at 08C; 4, 98%
5
9
7
6
6
5
5
8
9
1 h at 258C; 12b, 86%
9
Degradation
10
11
10
10
30 min at 258C; 15b, 89%
30 min at 2108C; 63%; isomerization trans–cis: 80:20
2 h at 258C; 17b, 97%
4 h at 08C; 18b, 90%

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G. Solladie et al. / Tetrahedron 59 (2003) 3315–3321
3318
1. However the configuration of 1 was not determined in this
experiment (Scheme 3).
phenol groups on the aromatic rings, an experimental
observation which is difficult to explain at the present time
(Scheme 6).
The decarboxylation was then carried out in presence of
copper chromite3 and we found a clear temperature effect as
shown in Table 1: cis–trans mixtures were obtained from a
single carboxylic acid isomer and the cis isomer was always
¨
the main product. With the catalyst used by Spath and
Kromp, copper powder, we isolated a 79:21 cis–trans
mixture at 2308C showing that the pure trans isomer
isolated by the authors resulted from isomerization during
the acidic treatment they used.
Scheme 6.
It must be pointed out that decarboxylation of the acid 12a,
followed by deprotection with BCl3 in the conditions
described in Scheme 4, gave the mono-methoxy resveratrol
19 only in the trans configuration and not the usual cis–
trans mixture; the isomerization occuring during the acidic
cleavage of the i-propyl ethers (methyl ethers being stable in
these conditions).
Aware of the difficulties of resveratrol purification after
cleavage of the methyl ethers due to degradation products,
we decided to use isopropyl ethers which are known5 to be
cleaved at lower temperature than methyl ethers and should
avoid the isomerization of the product.
Condensation of isopropyl ethers of p-hydroxyphenyl acetic
acid and 3,5-dihydroxybenzaldehyde in the previous
Perkins conditions (Scheme 4) led in 72% yield to only
one isomer of the carboxylic acid 2 which was identified by
RMN NOESY as the cis isomer. Gas chromatography
analysis of the corresponding methyl ester showed the
absence of the trans isomer. Decarboxylation with copper
chromite at 2308 afforded in 96% yield a 95:5 cis–trans
mixture of the substituted stilbenes 3. cis–trans Isomeriza-
tion of this mixture in refluxing THF with phenyldisulfide
led in 94% yielded the pure trans substituted stilbene; the
isopropyl ethers were cleaved in high yield with BCl3 below
08C.
In conclusion, our results showed that resveratrol and
analogues can be readily obtained by Perkins condensation.
All the compounds listed in Table 3 are under biological
evaluation.
1. Experimental
1.1. Data for compounds
1.1.1. 4-Isopropoxyphenylacetic acid (5). 10 g of
4-hydroxyphenylacetic acid, 30 g of potassium carbonate
(3.3 equiv.) and 28 mL of isopropyl bromide (4.6 equiv.) in
100 mL of DMF were heated to reflux during 29 h. After
cooling down to room temperature, 100 mL of water were
added in order to dissolve the carbonate and 100 mL of HCl
2 M to acidify the solution. The aqueous layer was extracted
by ethyl acetate (3£50 mL). The organic layer was dried
over MgSO4, filtered, and evaporated. 20 g of LiOH
(14 equiv.), 100 mL of water and 100 mL of THF were
added. After refluxing for 15 h, THF was evaporated. 50 mL
of ether were added and the solution was acidified to pH¼1
at 08C by HCl 2 M (150 mL). The aqueous layer was
extracted with ether (4£100 mL), dried over MgSO4,
filtered and concentrated. The solid was recrystallized in
hexane/ethyl acetate (9:1) to give 10.5 g of a colourless
solid. Yield for the two steps: 85%. Rf¼0.35 (hexane/ethyl
Attempts to isolate pure cis-resveratrol from the isopropyl
ether 95:5 cis–trans mixture 3 in the same conditions and
below 2108C failed giving always a 60:40 cis–trans
mixture of resveratrol (Scheme 4). This results confirms
the easy cis–trans isomerization6 of resveratrol in presence
of Lewis acid.
We also observed in the NMR tube a slow isomerization of
cis resveratrol. We however, could not completely
isomerise the cis isomer to the trans because of degradation
in presence of acid at room temperature (Table 2).
However, the cleavage of i-propyl ethers in acid 2 with BCl3
below 08 worked quantitatively without any isomerization.
1
It is clear that the use of i-propylether was an improvement
in the purification of resveratrol which can be now obtained
in four high yield steps.
acetate 1:1). Mp: 57–618C. H NMR (CDCl3):7.00 (AB,
4Harom, JAB¼8.6 Hz, Dn¼66.6 Hz), 4.52 (sept., 1HCH
,
J¼6 Hz), 3.58 (s, 2Hbenz.), 1.32 (d, 6H(CH3) , J¼6 Hz). 13C
2
NMR (CDCl3): 178.2, 157.3, 130.5, 125.1, 118.0, 70.0,
40.2, 22.1.
We then applied this method to the preparation of analogues
of phenyl-cinnamic acid. The starting materials used for the
Perkins reaction (in the conditions used in the Scheme 4) are
shown in Scheme 5, and yields in Table 3.
1.1.2. 3-Isopropoxyphenylacetic acid (8). The title com-
pound was prepared following the same procedure as for
4-isopropoxyphenylacetic acid 5 from 3-hydroxyphenyl-
acetic acid. Yield for two steps: 73% (2.6 g). Rf¼0.37
The deprotection conditions with BCl3 were adapted to each
compound with reaction times and temperatures between
30 min at 2108C and 2 h at 258C (Table 3). The results
listed in this Table 3 showed that the stability of the
polyhydroxy cinnamic acids after cleavage of the protecting
isopropyl ethers is strongly depending on the position of the
1
(hexane/ethyl acetate 1:1). Oil at 258C, solide at 68C. H
NMR (CDCl3): 7.21 (m, 1Harom), 6.83 (m, 3Harom), 4.55
(sept., 1HCH–iPr, J¼6.1 Hz), 3.61 (s, 2Hbenzylique), 1.33 (d,
6HCH3–iPr, J¼6.1 Hz). 13C NMR (CDCl3): 177.4, 157.9,
134.7, 129.5, 121.4, 116.9, 114.5, 69.7, 40.2, 22.1.

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G. Solladie et al. / Tetrahedron 59 (2003) 3315–3321
3319
1.1.3. 3,5-Diisopropoxybenzaldehyde (9). To 1 g of 3,5-
(AB, 4Harom, JAB¼8.6 Hz, Dn¼90 Hz), 6.46 (AB, 2Hvinylic
,
dihydroxybenzaldehyde in DMF (10 mL) isopropyl
bromide (3.1 mL, 4.5 equiv.) and then anhydrous potassium
carbonate (3.3 g, 3.3 equiv.) were added at room tempera-
ture. The mixture was heated for 2.5 h at 558C, cooled to
room temperature, and quenched with water (15 mL). The
organic layer was extracted with ethyl acetate (3£15 mL),
dried over MgSO4, filtrated and concentrated. The resulting
deep red oil was purified by chromatography on silica gel
(hexane/ethyl acetate 9:1) to give a pale yellow oil (1.5 g).
JAB¼12.2 Hz, Dn¼15 Hz), 6.38 (d, 2Harom, J¼2.2 Hz), 6.28
(t, 1Harom, J¼2.2 Hz), 4.50 (sept, 1H(1£iPr), J¼6.0 Hz), 4.34
(sept, 2H(2£iPr), J¼6.0 Hz), 1.31 (d, 6H(1£iPr), J¼6.0 Hz),
1.23 (d, 12H(2£iPr), J¼6.0 Hz). 13C NMR (CDCl3): 158.9,
157.0, 139.5, 130.3, 130.0, 129.6, 129.0, 115.6, 108.4,
103.4, 69.9, 22.1. For C23H30O3 were calculated 77.96 %C,
8.47 %H and found 77.73 %C, 8.71 %H.
1.4. General procedure for isopropyl ether cleavage
1
Yield: 94%. Rf¼0.67 (hexane/ethyl acetate 1:1). H NMR
(CDCl3): 9.77 (s, 1H(–COH)), 6.85 (d, 2H, J¼2.4 Hz), 6.56
(t, 1Harom, J¼2.3 Hz), 4.49 (sept., 2H(iPr), J¼6 Hz), 1.25 (d,
12HCH3(iPr), J¼6 Hz). 13C NMR (CDCl3): 192.1, 159.6,
138.4, 118.6, 110.3, 70.3, 22.0.
1.4.1. a-(p-Hydroxyphenyl)-m,m-dihydroxycinnamic
acid (4). To 450 mg of acid 2 in 8 mL of dichloromethane,
were added at 2788C, 7.4 mL of BCl3 (1 M in CH2Cl2). The
mixture was maintained 1.5 h between 230 and 2608C then
45 min at 08C. After addition of the borane, a deep yellow
precipitate appeared and remained during all the reaction.
By quenching with water (10 mL), the colour disappeared.
15 mL of ethyl acetate were added at 08C, (to dissolve the
precipitate) and 10 mL of 2 M sodium hydroxide were
added (pH¼1). The aqueous layer was extracted with ethyl
acetate (3£10 mL), the organic layer was dried over MgSO4
and concentrated. 330 mg of a colourless powder were
obtained. Yield: 98%. Mp: 254–2578C. 1H NMR (CDCl3):
8.50 (bs, 1H), 8.30 (bs, 2H), 7.55 (s, 1Hvinylic), 6.85 (AB,
1.1.4. 4-Isopropoxybenzaldehyde (10). The title com-
pound was prepared following the same procedure as for
3,5-diisopropoxybenzaldehyde 9. Pale yellow oil (2.2 g).
1
Yield: 82%. Rf¼0.71 (hexane/ethyl acetate 1:1). H NMR
(CDCl3): 9.70 (s, 1H(–COH)), 7.49 (AB, 4Harom, JAB¼9 Hz,
Dn¼225 Hz), 4.65 (sept., 1H(H–OiPr), J¼6 Hz), 1.37 (d,
6H(CH3–OiPr), J¼6 Hz). 13C NMR (CDCl3): 190.2, 162.9,
131.7, 129.4, 115.4, 70.0, 21.6.
1.2. General procedure for the Perkins reaction
4Harom
,
JAB¼8.5 Hz, Dn¼52 Hz), 6.15 (t, 1Harom
,
J¼2.1 Hz), 6.04 (d, 2Harom
,
J¼2.1 Hz). 13C NMR
1.2.1. a-(p-Isopropoxyphenyl)-m,m-diisopropoxy-
cinnamic acid (2). Under argon, 2.12 g of 3,5-diisopro-
poxybenzaldehyde (1 equiv.), 1.85 g of 4-isopro-
poxyphenyl-acetic acid (1 equiv.), 1.62 mL of acetic
anhydride (1.8 equiv.) and 0.94 mL of triethylamine
(0.7 equiv.) were heated at 1108C during 12 h, cooled at
room temperature, diluted in 50 mL of water and 50 mL of
ethyl acetate. The aqueous layer was extracted with ethyl
acetate (3£30 mL). The organic layer was washed with
brine (50 mL), dried over MgSO4 and concentrated. A deep
yellow solid (4.24 g) was purified by chromatography on
silica gel (hexane/ethyl acetate 9:1). 300 mg (16%) of the
aldehyde were recovered and 3 g of solid were recrystal-
lized in hexane to give 2.38 g of acid 2. Yield: 72%.
**Rf¼0.46 (hexane/ethyl acetate 1:1). Mp: 168–1718C. 1H
(CDCl3): 168.9, 158.6, 157.4, 139.8, 137.4, 133.1, 131.4,
127.6, 115.5, 109.4, 103.9.
1.4.2. trans 3,40,5-Triisopropoxystilbene (3b). 2.5 g of cis-
triisopropoxystilbene 3a in THF (40 mL) and diphenyl-
disulfide (0.34 g, 0.2 equiv.) were heated under reflux for
4 h. The THF was evaporated, 2.94 g were purified by
chromatography on silica gel (ethyl acetate/hexane 1:19), to
give 2.4 g of a yellow oil. Yield: 96%. Rf¼0.33 (hexane/
1
ethyl acetate 2:1). H NMR (CDCl3): 7.14 (AB, 4Harom
JAB¼8.8 Hz,
,
,
Dn¼108 Hz),
6.93
(AB,
2Hvinylic
JAB¼16.2 Hz, Dn¼26.4 Hz), 6.61 (d, 2Harom, J¼2.1 Hz),
6.34 (t, 1Harom, J¼2.1 Hz), 5.57 (sept, 2H(1£iPr), J¼6.0 Hz),
5.56 (sept, 1H(2£iPr), J¼6.0 Hz), 1.33 (d, 18H(3£iPr)
,
J¼6.0 Hz). 13C NMR (CDCl3): 159.3, 157.7, 139.7, 129.9,
NMR (CDCl3): 7.79 (s, 1Hvinylic), 7.02 (AB, 4Harom
,
128.6, 127.8, 126.7, 116.1, 106.3, 103.0, 70.0, 22.2.
JAB¼8.5 Hz, Dn¼51.7 Hz), 6.30 (t, 1Harom, J¼2 Hz), 6.23
(d, 2Harom, J¼2 Hz), 4.52 (sept., 1H(1£iPr), J¼6 Hz), 4.16
(sept., 1H(2£iPr), J¼6 Hz), 1.32 (d, 6H(1£iPr), J¼6 Hz), 1.17
(d, 6H(2£iPr), J¼6 Hz). 13C NMR (CDCl3): 173.7, 158.7,
157.8, 142.6, 136.2, 131.5, 131.1, 127.5, 115.9, 110.2,
106.2, 69.9, 69.8, 22.2, 22.1. For C24H30O5 were calculated
72.36 %C, 7.54 %H and found 72.34 %C, 7.81 %H.
1.4.3. trans 3,40,5-Trihydroxystilbene (resveratrol). To
200 mg of triisopropoxystilbene, in dichloromethane
(20 mL), at 2788C, were added 3.4 mL of BCl3 1 M in
CH2Cl2. The temperature was allowed to reach 2108C, and
maintained for 1 h at 2108C. The reaction was quenched
with 20 mL of water, the pink solution turned to pale. 20 mL
of ethyl acetate were added and then 8 mL of a 10%
potassium carbonate solution to reach pH¼6. In order to be
in slightly acidic conditions (pH¼1.5), 0.25 mL of HCl 2 M
were added. The aqueous layer was extracted with ethyl
acetate (3£10 mL). After drying over MgSO4, concentrat-
ing, the slightly coloured powder obtained (169 mg) was
dissolved in 4 mL of ethyl acetate. Adding 5 mL of hexane
induced a precipitation. After filtration, 109 mg of a
colourless powder were obtained. Yield: 85%. Mp: 255–
2608C. Rf¼0.24 (hexane/ether 1:3). 1H NMR (CDCl3): 8.50
1.3. General procedure for decarboxylation
1.3.1. cis 3,40,5-Triisopropoxystilbene (3a). To 4.19 g of
the acid 2, were added 15 mL of quinoline (11 equiv.) and
214 mg of copper chromite. The reaction flask was heated at
230–2408C during 1 h. The mixture was then cooled,
filtrated over celite which was washed with 2£20 mL of
ethyl acetate. The organic layer was washed with 2£20 mL
of HCl 2 M, dry over MgSO4 and concentrated. 4.60 g of a
black oil were purified by chromatography on silica gel
(hexane/ethyl acetate 9.5:0.5) to give a pale yellow oil
(3.55 g). Yield: 96%. Rf¼0.38. 1H NMR (CDCl3): 6.97
(s, 1Hphenol), 8.23 (s, 2Hphenol), 7.13 (AB, 4Harom
JAB¼8.6 Hz, Dn¼117 Hz), 6.96 (AB, 2Hvinylic
,
,
JAB¼16.4 Hz, Dn¼26.0 Hz), 6.54 (d, 2Harom, J¼2.1 Hz),

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G. Solladie et al. / Tetrahedron 59 (2003) 3315–3321
3320
6.27 (t, 1Harom, J¼2.1 Hz). 13C NMR (CDCl3): 159.1, 157.6,
133.5, 131.9. IR: 3352, 3210, 1695, 1618, 1600, 1513, 1447,
1370, 1331.
140.4, 129.5, 128.6, 128.3, 126.4, 115.9, 105.2, 102.2.
1.4.4. cis 3,40,5-Trihydroxystilbene. Following the same
procedure as for trans-triisopropoxystilbene, the cis 3,40,5-
triisopropoxystilbene (200 mg) was deprotected to give
114 mg of 3,40,5-trihydroxystilbene-cis and 3,40,5-tri-
hydroxystilbene-trans in 60:40 to 50:50 mixtures. Yield:
1.4.10. a-Phenyl-m,m-diisopropoxycinnamic acid (14).
Yield: 63% (1.35 g). Rf¼0.37 (hexane/ethyl acetate 1:1).
1
Mp: 149–1568C. H NMR (CDCl3): 7.84 (s, 1Hvinyl), 7.37
(m, 3Harom), 7.27 (m, 2Harom), 6.31 (t, 1Harom, J¼2 Hz),
6.20 (d, 2Harom, J¼2 Hz), 4.11 (sept, 2H(2£iPr), J¼6 Hz),
1.15 (d, 12H(2£iPr), J¼6 Hz). 13C NMR (CDCl3): 173.1,
158.6, 142.7, 135.7, 131.5, 129.7, 128.7, 127.9, 110.2,
106.3, 69.8, 22.0. For C21H24O4, calculated 74.09 %C, 7.11
%H, and found 73.96 %C, 7.22 %H.
1
88%. Rf¼0.17 (hexane/ether 1:3). H NMR (CDCl3): 8.40
(s, 1Hphenol), 8.14 (s, 2Hphenol), 6.90 (AB, 4Harom
JAB¼8.8 Hz, Dn¼88.1 Hz), 6.37 (AB, 2Hvinylic
,
,
JAB¼12.3 Hz, Dn¼15.6 Hz), 6.29 (d, 2Harom, J¼2.2 Hz),
6.22 (t, 1Harom, J¼2.2 Hz).
1.4.11. a-(Phenyl)-p-isopropoxycinnamic acid (15a).
Yield: 58% (1.05 g). Rf¼0.42 (hexane/ethyl acetate 1:1).
1.4.5. a-(Methoxyphenyl)-m,m-dimethoxycinnamic acid
(1). The title compound was prepared following the general
Perkins procedure. Yield: 66% (1.25 g). Rf¼0.20 (hexane/
ethyl acetate 1:1). Mp: 171–1748C. 1H NMR (CDCl3): 7.83
(s, 1Hvinyl), 7.06 (AB, 4Harom, JAB¼8.5 Hz, Dn¼50 Hz),
6.35 (t, 1Hpara, J¼2 Hz), 6.27 (d, 2Hortho, J¼2 Hz,), 3.82 (s,
3H(1£OMe)), 3.56 (s, 6H(2£OMe)). 13C NMR (CDCl3): 172.3,
160.3, 159.5, 142.2, 136.2, 131.5, 131.2, 127.6, 114.3,
108.6, 102.6, 55.4. For C18H17O5, calculated 68.94 %C,
5.43 %H, and found 69.20 %C, 5.69 %H.
1
Mp: 148–1568C. H NMR (CDCl3): 7.89 (s, 1Hvinyl), 7.37
(m, 3Harom), 7.25 (m, 2Harom), 6.82 (AB, 4Harom, JAB¼9 Hz,
Dn¼65 Hz), 4.50 (sept, 1H(1£iPr), J¼6 Hz), 1.29 (d,
6H(2£iPr), J¼6 Hz). 13C NMR (CDCl3): 173.5, 159.2,
142.3, 136.0, 132.9, 129.9, 129.0, 128.9, 127.9, 126.6,
115.3, 69.9, 22.0.
1.4.12. a-(Phenyl)-p-hydroxycinnamic acid (15b).
Colourless powder. Yield: (89%). Rf¼0.47 (ether). Mp:
1
190–193.58C. H NMR ((CD3)2CO): 8.79 (bs, 1Hphenol),
7.80 (s, 1Hvinyl), 7.37 (m, 3Harom), 7.23 (m, 2Harom), 6.85
1.4.6. 3,40,5-Trimethoxystilbene-cis. From (1) by the
decarboxylation procedure. Yield: 80% (215 mg). Yellow
(AB, 4Harom
,
JAB¼9 Hz, Dn¼65 Hz). 13C NMR
1
oil. Rf¼0.57 (hexane/ethyl acetate 1:1). H NMR (CDCl3):
((CD3)2CO): 169.0, 159.5, 140.9, 138.1, 133.4, 134.2,
130.7, 129.4, 128.3, 127.1, 116.1.
6.99 (AB, 4Harom, JAB¼8.5 Hz, Dn¼90 Hz), 6.49 (AB,
2Hvinyl
,
JAB¼12.5 Hz, Dn¼20 Hz), 6.44 (d, 2Hortho
,
J¼2 Hz), 6.32 (t, 1Hmeta, J¼2 Hz), 3.78 (s, 3H(OMe)), 3.67
(s, 6H(2£OMe). 13C NMR (CDCl3): 161.1, 159.3, 140.0,
130.8, 130.8, 129.2, 130.7, 114.1, 107.2, 100.2, 55.8. For
C17H17O3, calculated 75.75 %C, 6.31 %H, and found 75.83
%C, 6.58 %H.
1.4.13. a-(p-Isopropoxyphenyl)-cinnamic acid (16a).
Yield: 54% (1.45 g). Rf¼0.36 (hexane/ethyl acetate 1:1).
1
Mp: 142–1498C. H NMR (CDCl3): 7.90 (s, 1Hvinyl), 7.15
(m, 5Harom), 7.04 (AB, 4Harom, JAB¼9 Hz, Dn¼60 Hz),
4.52 (sept, 1H(1£iPr), J¼6 Hz), 1.36 (d, 6H(1£iPr), J¼6 Hz).
13C NMR (CDCl3): 173.5, 157.8, 142.2, 134.7, 131.4, 131.2,
130.9, 129.4, 128.3, 127.1, 116.1, 69.8, 22.0.
1.4.7. 3,40,5-Trimethoxystilbene-trans. Following the
general isomerization procedure, yield: 91% (176 mg).
Rf¼0.48 (hexane/ethyl acetate 1:1). Mp: 54–568C (lit.:
56–578C). 1H NMR (CDCl3): 7.19 (AB, 4Harom, JAB¼9 Hz,
Dn¼110 Hz), 7.03 (AB, 2Hvinyl, JAB¼16.5 Hz, Dn¼25 Hz),
6.68 (d, 2Hmeta, J¼2 Hz), 6.40 (t, 1Hortho, J¼2 Hz), 3.84 (s,
3H(3£OMe). 13C NMR (CDCl3): 161.1, 159.5, 139.8, 128.8,
127.9, 126.7, 114.2, 104.4, 130.0, 99.7, 55.4, 55.4.
1.4.14. a-(p-Hydroxyphenyl)-cinnamic acid (16b).
Colourless powder. Yield: 63%. Mp: 191–1948C/212–
1
2148C. H NMR ((CD3)2CO): cis: 8.52 (bs, 1Hphenol), 7.80
(s, 1Hvinyl), 7.21 (m, 5Harom), 6.96 (AB, 4Harom
JAB¼4.5 Hz, Dn¼40 Hz). trans: 8.66 (bs, 1Hphenol), 7.69
(s, 1Hvinyl), 7.21 (m, 5Harom), 7.01 (AB, 4Harom
,
,
JAB¼4.5 Hz, Dn¼120 Hz). 13C NMR ((CD3)2CO): cis:
168.6, 157.5, 139.4, 135.7, 133.6, 131.4, 130.7, 129.1,
128.5, 127.6, 115.7. trans: 168.6, 157.8, 136.0, 135.9, 133.6,
131.3, 130.5, 128.7, 128.6, 128.4, 116.5.
1.4.8. a-(p-Methoxyphenyl)-m,m-diisopropoxycinnamic
acid (12a). Yield: 70% (3.83 g). Rf¼0.36 (hexane/ethyl
1
acetate 1:1). Mp: 172–1778C. H NMR (CDCl3): 7.81 (s,
1Hvinyl), 7.05 (AB, 4Harom, JAB¼9 Hz, Dn¼50 Hz), 6.31 (t,
1Harom, J¼2 Hz), 6.22 (d, 2Harom, J¼2 Hz), 4.16 (sept,
1.4.15. a-(p-Isopropoxyphenyl)-p-isopropoxycinnamic
acid (17a). Yield: 32% (1.41 g). Rf¼0.36 (hexane/ethyl
acetate 1:1). Mp: 153–156.58C. 1H NMR (CDCl3): 7.84 (s,
1Hvinyl), 7.02 (AB, 4Harom, JAB¼8.8 Hz, Dn¼150 Hz), 6.85
1H(1£iPr), J¼6 Hz), 3.81 (s, 3H(OMe),), 1.17 (d, 12H(2£iPr)
,
J¼6 Hz). 13C NMR (CDCl3): 173.0, 159.8, 159.1, 142.9,
136.4, 131.5, 131.4, 128.1, 114.6, 110.5, 106.5, 70.3, 55.7,
22.4. For C22H26O5, calculated 71.26 %C, 7.02 %H, and
found 71.04 %C, 6.98 %H.
(AB, 4Harom, JAB¼8.5 Hz, Dn¼75 Hz), 4.54 (sept, 2H2£iPr
J¼6.1 Hz), 1.34 (d, 6H1£iPr, J¼6.1 Hz), 1.29 (d, 6H1£iPr
,
,
J¼6.1 Hz). 13C NMR (CDCl3): 173.6, 159.1, 157.6, 142.0,
132.8, 131.1, 128.6, 127.7, 126.8, 116.2, 115.3, 70.0, 69.9,
22.2, 22.0. IR: 2979, 2932, 2624, 1666, 1598, 1564, 1504,
1465, 1421. For C21H24O4, calculated 74.09 %C, 7.11 %H,
and found 73.82 %C, 7.09 %H.
1.4.9. a-(p-Methoxyphenyl)-m,m-dihydroxycinnamic
acid (12b). Yield: 86% (320 mg). Rf¼0.20 (hexane/ether
1:9). Mp: 176–1838C. 1H NMR ((CD3)2CO): 8.27 (bs,
0
2Hphenol), 7.66 (s, 1Hvinyl), 7.03 (AB, 4Harom , JAB¼9 Hz,
Dn¼45 Hz), 6.26 (t, 1Hpara, J¼2.1 Hz), 6.17 (d, 2Hortho
,
J¼2.1 Hz), 3.82 (s, 3H(OMe)). 13C NMR ((CD3)2CO): 169.0,
1.4.16. a-(p-Hydroxyphenyl)-p-hydroxycinnamic acid
(17b). Yield: 97% (260 mg). Rf¼0.18 (hexane/ether 1:5).
129.3, 160.1, 114.5, 159.1, 109.9, 140.6, 104.5, 137.8, 55.7,

´
G. Solladie et al. / Tetrahedron 59 (2003) 3315–3321
3321
Mp: 153.5–1598C. 1H NMR ((CD3)2CO): 8.75 (bs,
1Hphenol), 8.45 (bs, 1Hphenol), 7.74 (s, 1Hvinyl), 6.96 (AB,
13C NMR (CDCl3): 159.0, 159.0, 139.5, 130.3, 129.9, 129.8,
129.1, 113.7, 108.4, 103.4, 69.9, 55.3, 22.2. For C21H26O3,
calculated 77.20 %C, 7.96 %H, and found 76.96 %C, 8.18
%H.
4Harom, JAB¼8.5 Hz, Dn¼40 Hz), 6.85 (AB, 4Harom
,
JAB¼8.8 Hz, Dn¼70 Hz). 13C NMR ((CD3)2CO): 169.4,
159.3, 157.9, 140.4, 133.3, 131.9, 130.6, 128.7, 127.5,
116.3, 116.0. IR: 3217, 1659, 1600, 1509, 1420.
1.4.20. 3,5-Dihydroxy,40-methoxystilbene-trans (19).
Colourless powder. Yield: 90%. Rf: cis Rf¼0.30; trans
Rf¼0.20 (hexane/ether 1:3). Mp: 158–1668C. 1H NMR
1.4.17. a-(m-Isopropoxyphenyl)-p-isopropoxycinnamic
acid (18a). Yield: 30% (1.30 g). Rf¼0.36 (hexane/ethyl
acetate 1:1). Mp: 122.5–1278C. 1H NMR (CDCl3): 7.88 (s,
((CD3)2CO): 8.25 (bs, 2Hphenol), 7.21 (AB, 4Harom
,
JAB¼8.5 Hz, Dn¼115 Hz), 6.99 (AB, 2Hvinyl, JAB¼16 Hz,
0
0
1Hvinyl), 7.30 (t, 1Hmeta , J¼8.2 Hz), 6.90 (ddd, 1Hpara
,
,
Dn¼20 Hz), 6.56 (d, 2Harom, J¼2 Hz), 6.29 (t, 1Harom
,
J¼8.2 Hz, J¼2.4 Hz, J¼0.9 Hz), 6.86 (AB, 4Harom
J¼2 Hz), 3.80 (s, 3H(OMe)). 13C NMR ((CD3)2CO): 159.9,
159.1, 140.2, 130.5, 128.2, 128.0, 127.1, 114.4, 105.2,
102.3, 55.1.
0
JAB¼8.8 Hz, Dn¼25 Hz), 6.82 (dd, 1Hortho , J¼2.4 Hz,
00
J¼0.9 Hz), 6.80 (m, 1Hortho ), 4.52 (sept, 2H2£iPr
,
J¼6.1 Hz), 1.17 (d, 12H2£iPr, J¼6.1 Hz). 13C NMR
(CDCl3): 173.6, 159.3, 158.3, 142.3, 137.2, 133.0, 130.0,
128.9, 126.6, 122.0, 117.0, 116.0, 115.4, 70.0, 69.9, 22.1,
22.0. IR: 2973, 2934, 2549, 1673, 1595, 1564, 1507, 1487,
1470, 1437, 1424, 1383, 1373. For C21H24O4, calculated
74.09 %C, 7.11 %H, and found 74.08 %C, 7.16 %H.
Acknowledgements
´
We gratefully acknowledge L’Oreal for a grant and a
scholarship to Y. P. J.
1.4.18. a-(m-Hydroxyphenyl)-p-hydroxycinnamic acid
(18b). Yield: 90% (340 mg). Rf¼0.16 (hexane/ether 1:9).
1
Mp: 199–2048C. H NMR ((CD3)2CO): 8.80 (s, 1Hphenol),
0
8.38 (s, 1Hphenol), 7.35 (s, 1Hvinyl), 7.23 (t, 1Hmeta ), 6.86
References
(AB, 4Harom, JAB¼6.5 Hz, Dn¼25 Hz), 6.84 (ddd, 1Harom
,
1. (a) Siemann, E. H.; Creasy, L. L. Am. J. Enol. Vitic. 1992, 43,
49–52. (b) Fremont, L. Life Sci. 2000, 66, 663–673. (c) Soleas,
G. J.; Diamandis, E. P.; Goldberg, D. M. Clin. Biochem. 1997,
30, 91–113. (d) Meier, H.; Dullweber, U. J. Org. Chem. 1997,
¨
62, 4821–4826. (e) Spath, E.; Kromp, K. Chem. Ber. 1941, 74,
189–192.
2. Takaoka, M. J. Fac. Sci. Hokkaido Imp. Univ; III 1940, Bd
J¼8.2 Hz, J¼2.4 Hz, J¼1.2 Hz), 6.70 (m, 2Harom). 13C
NMR ((CD3)2CO): 168.4, 158.9, 158.0, 140.1, 138.8, 132.9,
130.1, 130.0, 126.6, 121.2, 116.9, 115.5, 114.8. IR: 3336,
3209, 2952, 2924, 2854, 2627–2511, 2260, 1707, 1660,
1594, 1582, 1510, 1492, 1440, 1415. For C15H12O4,
calculated 77.20 %C, 7.96 %H, and found 76.96 %C, 8.18
%H.
III(1), 13.
3. Buckles, R. E.; Bremer, K. Organic Syntheses, 1963; Collect.
Vol. IV, pp 777–779.
1.4.19. 3,5-Diisopropoxy-40-methoxystilbene-cis. Oil.
Yield: 84% (1.8 g). Rf: cis Rf¼0.54 (hexane/ethyl acetate
4. Wood, C. S.; Mallory, F. B. J. Org. Chem. 1964, 29,
3373–3377.
1
4:1). Trans Rf¼0.46 (hexane/ethyl acetate 4:1). H NMR
(CDCl3): 6.99 (AB, 4Harom, JAB¼8.5 Hz, Dn¼90 Hz), 6.47
5. Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979,
2593–2598.
(AB, 2Hvinyl, JAB¼12 Hz, Dn¼15 Hz), 6.38 (d, 2Harom
,
,
J¼2 Hz), 6.29 (t, 1Harom, J¼2 Hz), 4.35 (sept, 2H(2£iPr)
6. Trela, B. C.; Waterhouse, A. L. J. Agric. Food Chem. 1996, 44,
1253–1257.
J¼6 Hz), 3.78 (s, 3H(OMe)), 1.24 (d, 12H(2£iPr), J¼6 Hz).