An efficient synthesis of resveratrol and a hydroxyl derivative via the Perkin reaction: Cis to trans isomerisation in a demethylation process

Article abstract of DOI:10.3184/030823407X266234

Two trans polyphenolic stilbenes, Resveratrol and 3,4,4′,5- trans-tetrahydroxystilbene, were prepared in three steps from 4-methoxy phenylacetic acid and methoxylated benzaldehydes via a Perkin reaction. An interesting cis to trans isomerisation occured in the demethylation process in the presence of AII₃ and acetonitrile to give resveratrol and 3,4,4′,5-trans-tetrahydroxystilbene with overall yields of 51% and 48% respectively.

Full text of DOI:10.3184/030823407X266234

JOURNAL OF CHEMICAL RESEARCH 2007
NOvEMBER, 657–659
RESEARCH PAPER 657
An efficient synthesis of resveratrol and a hydroxyl derivative via the
Perkin reaction: cis to trans isomerisation in a demethylation process
Guoxing Lia,b Yong Zoua* and Xuejing Zhanga
aGuangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou 510650, P.R. China
bGraduate School of Chinese Academy of Sciences, Beijing 100039, P.R. China
Two trans polyphenolic stilbenes, Resveratrol and 3,4,4',5- trans-tetrahydroxystilbene, were prepared in three steps
from 4-methoxy phenylacetic acid and methoxylated benzaldehydes via a Perkin reaction. An interesting cis to trans
isomerisation occured in the demethylation process in the presence of AlI3 and acetonitrile to give resveratrol and
3,4,4',5-trans-tetrahydroxystilbene with overall yields of 51% and 48% respectively.
Keywords: polyphenolic stilbenes, Perkin reaction, resveratrol, 3,4,4',5- trans-tetrahydroxystilbene, isomerisation
OH
Resveratrol (3,4',5-trans-trihydroxystilbene) 1a is an
outstanding polyphenolic stilbene which in recent years has
aroused the attention of not only biologists and chemists, but
also the general public. Resveratrol exerts many effects on
cellular events associated with cancer initiation, promotion and
progression.1 It is an antioxidant, antimutagen, and apoptosis
inducer. It promotes the clearance of Alzheimer's disease
amyloid-peptides and affords neuroprotective properties.2
It has been shown that resveratrol can inhibit cyclooxygenase,
hydroperoxidases, protein kinase C, Bcl-2 phosphorylation,
Akt, focal adhesion kinase, NFκB, matrix metalloprotease-
9, and cell cycle regulators.3 Studies reported by Sinclair and
colleagues have confirmed that resveratrol is a potent lead
compound for a new medicinal category called small molecule
sirtuin activators(STACs) which exerts antiaging properties
through calorie restriction mimic.4 Recently resveratrol
has been shown to extend the lifespan of evolutionarily
distant species including S. cerevisiae, C. elegans and
D. melanogaster in a Sir2-dependent manner, improve health
and extend maximum lifespan by 59% in a vertebrate fish.5
Recent studies have also shown that resveratrol improves the
health and survival of mice on a high-calorie diet.6
OH
HO
HO
HO
OH
OH
1b
1a
Fig.1 The chemical structure of resveratrol and 3,4,4',5-trans-
tetrahydroxystilbene.
Also, we have found that, in demethylation process, the cis-
stilbenes were simultaneously and completely converted to
trans-stilbenes. The one-pot demethylation and isomerisation
process has not been reported in the literature. This is the most
efficient synthetic route for resveratrol 1a and 3,4,4',5-trans-
tetrahydroxystilbene 1b starting from commercial materials.
Results and discussion
The Perkin condensation between 4-methoxyphenylacetic
acid and methoxylated benzaldehydes in the presence of
acetic anhydride and triethylamine at 110°C gave the 1,2-
Hydroxylated resveratrol analogues, which in recent
studies possessed a higher activity than resveratrol, are
important targets.7-9 Hydroxylated resveratrol analogues
showed selective cyclooxygenase-2 inhibition,10 increased
antioxidant, prooxidant activity and cytotoxicity.8 3,4,4',5-
,
diarylacrylic acids 3a–b in 86.4% and 84% yields respectively
in which the cis-stilbene isomer (the E isomer by IUPAC
rules) was the main product (cis-stilbene/trans-stilbene =
11/1). The cis-stilbene configuration was established by the
1H NMR spectrum, in which the field effect of carboxylic
group in the cis-stilbene resulted in a noticeable low-field
shift of the alkene H-atom. This field effect was not found
in trans-stilbene (the Z isomer by IUPAC rules). This can be
confirmed by chemical shift of alkene H-atom of the isomers,
for 3a, δHa = 7.81 ppm, and for trans-stilbene isomer (Z)-3a,
δHa = 6.91 ppm (Figure 2).
The decarboxylation was carried out in the presence of
quinoline and copper powder at 220°C under nitrogen, to
give the polymethoxy stilbenes 4a–b in 70.6% and 70%
yields respectively in which the cis-stilbene was the main
product. The geometrical configuration of 4a and 4b were
also determined by 1H NMR, the Jbc = 12 Hz for cis-stilbene
whereas the Jbc = 16 Hz for trans-stilbene. The last step,
demethylation, was performed in the presence of AlI3 and
acetonitrile, to give polyphenolic stilbenes 1a–b, with a
trans-stilbene structure were obtained in 83.8% and 82%
Trans-tetrahydroxystilbene 1b,
a resveratrol derivative,
exhibits potent growth inhibitory effect against transformed
human cells,11 differentially induces pro-apoptotic p53/Bax
gene expression and inhibits the growth of transformed cells
but not their normal counterparts.12
The most common synthetic method to prepare resveratrol
and its analogues involves a Wittig reaction,13 which forms a
mixture of cis- and trans-stilbenes. Hence the conversion of
cis- to trans- stilbene was needed, which sometimes involved
relatively harsh reaction conditions. A palladium-catalysed
Heck-based route has been reported that utilised 3,5-
dihydroxybenzaldehyde as the starting material, through series
of reactions to form the 3,5-diacetoxy-styrene intermediate,14
but the overall yield was poor. Guy Solladié et al.15 synthesised
resveratrol by Perkin reaction in which i-propyl ethers were
used as protecting groups and an extremely expensive reagent
BCl3 was used to eliminate them in the last stage at low
temperature condition (–78°C). Chromatographic purification
was also required to obtain the final product. Starting from
4-methoxyphenylacetic acid and methoxylated benzaldehydes,
we report a convenient synthetic route for resveratrol 1a and
3,4,4',5-trans-tetrahydroxystilbene 1b via Perkin reaction
methodology in only three steps with good yields (Scheme 1).
.
yields respectively In this step, AlI3 was used to remove
the methyl groups, and to our surprise, when the methyl
groups were removed, the configuration of stilbene was
simultaneously and completely isomerised from cis to trans.
This was novel and made the synthetic process highly efficient.
Several explanations may account for the demethylation and
isomerisation process. (Scheme 2).
* Correspondent. E-mail: zou_ jinan@163.com
PAPER: 07/4921

658 JOURNAL OF CHEMICAL RESEARCH 2007
H
b
Ha
CHO
CH2COOH
AcO2
MeO
R1
H
c
COOH
MeO
Et3N
Cu
Quinoline
+
R1
MeO
OMe
OMe
OMe
R1
R
OMe
OMe
OMe
2a:
2b:
R
R
3a:
3b:
1 =H
1=H
1=OMe
4a: R
1=H
R
1=OMe
R
4b:
1=OMe
OH
HO
R2
CH3CN
AlI3
OH
1a:
1b:
R2
R2
=H
=OH
Scheme 1 Synthesis of polyphenolic stilbenes.
In the Perkin condensation, we took advantage of the fact
that the product is an acid, and used a basification/extraction/
acidification procedure as an easy way to isolate the solid
product and remove any nonacidic impurities in the crude
product. The product was obtained in a yield of 84%.
The yield reported by Guy Solladié et al., in the Perkin
reaction was only 70%.
Ha (7.81ppm)
COOH
OMe
MeO
(6.91ppm)
OMe
Ha
MeO
COOH
OMe
OMe
In the decarboxylation reaction, dark oily byproducts in the
mixture made the purification difficult. In order to purify the
crude product, column chromatography is usually needed.
TLC analysis showed that compounds 4a–b were poorly
lipophilic, whereas the byproducts were highly lipophilic.
Thus, we used petroleum ether to extract compounds 4a–b
from the dark oily reaction mixtures and leaving the byproducts
alone. The product was thus readily purified without using
column chromatography. The crude products 4a–b can also be
purified by vacuum distillation (180–185°C/0.2 mmHg).
In summary, we have developed an effective process for
syntheses of trans polyphenolic stilbenes in good yields.
Starting from 4-methoxyphenylacetic acid and methoxylated
benzaldehydes, resveratrol 1a and 3,4,4',5-tetrahydroxy-
trans-stilbene 1b were successfully prepared in only three
steps with overall yields of 51% and 48.2% respectively.
3a
(Z)-3a
Fig. 2 Chemial shift of alkene H-atom.
Demethylation process occured when 4a undergone
electrophilic attack by AlI3, and at the same time, the
intermediate 5 can rotate around the carbon-carbon single
bond to acquire a more favourable configuration, then with
the loss of MeI and AlI3 to give the more stable trans-stilbene
7, finally, 1a was obtained by hydrolysis.
The reaction temperature (82°C) is perhaps another reason
for the isomerisation of double bond, when cis-stilbene
is heated at certain temperature with sufficient energy to
overcome the activation energy of isomerisation, cis-stilbene
will be converted to the more stable trans-isomer.
AlI2
+
+
-
AlI3
O
OAlI2
MeO
H3C
+
-
AlI2O
I
AlI3
-MeI
+
-
O
AlI3
OMe
H3C
AlI2
+
-
O
OAlI2
I
OMe
H3C
AlI2
-
I
4a
5
6
OAlI2
OH
AlI2O
HO
–AlI3
hydrolysis
OAlI2
OH
7
1a
Scheme 2 Proposed mechanism for demethylation/isomerisation process.
PAPER: 07/4921

JOURNAL OF CHEMICAL RESEARCH 2007 659
3,4',5-Trans-trihydroxystilbene (resveratrol) (1a): a solution of 4a
(2.70 g, 10 mmol) in 5 ml CH3CN was added dropwise to a solution
of AlI3 (15.22 g, 37.3 mmol) and CH3CN (75 ml). The mixture
was stirred at 82°C for 3 h. The resulting mixture was concentrated
to obtain a yellow solid, which was added into water, then filtered
to afford a pale yellow solid which was recrystallised from
EtOH/H2O to yield white crystal 1a (1.91 g, 83.8%). M.p. 263–265°C.
(lit.,13 256–259°) IR (KBr, cm-1): 3291(OH), 3019, 1606, 1587, 1511,
Purification of compounds was improved and the cis to trans
isomerisations in demethylation process made the procedure a
highly efficient one.
Experimental
All reagents were obtained from commercial suppliers and were used
without further purification. The melting points were uncorrected
and determined on Thiele apparatus. IR spectra were recorded on
an Analect RFX-65A IR spectrometer. 1H NMR were obtained from
a Brucker DRX-400 MHz spectrometer with TMS as an internal
standard. EI-MS analysis was performed using a Shimadzu GCMS-
QP5050A mass spectrometer. Elemental analyses were carried out by
Elementar vario EL element analyser.
1
1462, 1444. H NMR (DMSO-d6, 400 MHz) δ 6.10 (t, 1H, 4-ArH,
J = 2.0 Hz), 6.37 (d, 2H, 2,6-ArH, J = 2.0 Hz), 6.74 (d, 2H, 3',5'-ArH,
J = 8.4 Hz), 6.80–6.92 (q, 2H, CH=CH, J = 16 Hz), 7.38 (d, 2H,
2',6'-ArH, J = 8.4 Hz), 9.20 (s, 2H, 2OH, D2O exchangeable), 9.55
(s, 1H, OH, D2O exchangeable). EI-MS: 228 (M+), 211, 199, 181,
152, 91, 76, 55. Anal. Calc. for C14H12O3: C, 73.67; H, 5.30. Found:
C, 73.46; H, 5.40%. It was identified by comparison of the 1H NMR
spectrum.13
3,4,4',5-Trans-tetrahydroxystilbene (1b): To a solution of AlI3
(19.18 g, 47 mmol) and CH3CN (80 ml), a solution of 4b (3.00 g,
10 mmol) in 5 ml CH3CN was added dropwise. The mixture was
stirred at 82°C for 3 h. The resulting mixture was concentrated
to obtain a red solid, which was added into sat. NaCl soln., then
extracted with ethyl acetate. The combined organic layers were
washed with water, dried with anh. MgSO4, and concentrated to
obtain a pale yellow solid, which was recrystallised from EtOH/
H2O to yield white crystals of 1b (2.00 g, 82%). M.p. 258–260°C.
IR (KBr, cm-1): 3473(OH), 3309, 1604, 1538, 1446. 1H NMR
(400 MHz, CD3COCD3) δ 6.60 (s, 2H, 2,6-ArH), 6.80 (d, 2H, 3',5'-
ArH, J = 8.8 Hz), 6.82 (s, 1H), 6.83 (s, 1H), 7.36(d, 2H, 2',6'-ArH,
J = 8.8 Hz), 7.36 (s, 1H, OH, D2O exchangeable), 7.81 (s, 2H, 2OH,
D2O exchangeable), 8.36 (s, 1H, OH, D2O exchangeable). EI-MS: 244
(M+), 225, 197, 181, 169, 141, 115. Anal. Calc. for C14H12O5·H2O: C,
64.12; H, 5.38. Found: C, 63.86; H, 5.45%.
General procedure for the synthesis of (3a–b): 2a–b (60 mmol),
4-methoxyphenyl-acetic acid (60 mmol), acetic anhydride (16.6 ml,
176 mmol), and triethylamine (25.5 ml, 185 mmol) were added to
a
100 ml three-neck round-bottom flask equipped with a
reflux condenser. The solution was stirred at 120°C for 5 h.
The reaction mixture was poured into ice-water, stirred and stored
for a few hours. A yellow solid was obtained by filtration, and
was dissolved in 5% NaOH-soln.(100 ml), extracted with ethyl
acetate and the organic layers were separated. Hydrochloric acid
(v/v = 1:1) was added to the aqueous phase to pH 2–3,
to precipitate
a pale yellow solid which was filtered, and
recrystallised from EtOH to afford 3a–b. Moreover, in the synthesis
of 3a, a trace amount of (Z)-3a (trans-stilbene isomer of 3a) can
also be obtained by fractional recrystallisation and provides spectral
data for structure identification. Compound 3a: colourless crystal
(86.4% yield); m.p. 140–142°C; IR (KBr, cm-1): 3432 (OH), 3008,
2951, 2851, 1672 (C=O). 1H NMR (CDCl3, 400 MHz) δ3.54 (s, 6H,
2OCH3), 3.80 (s, 3H, OCH3), 6.26 (d, 2H, 2,6-ArH, J = 2.0 Hz),
6.33 (t, 1H, 4-ArH, J = 2.0 Hz), 6.91 (d, 2H, 3',5'-ArH, J = 8.8 Hz),
7.17 (d, 2H, 2',6'-ArH, J = 8.8 Hz), 7.81 (s, 1H, C=CH), 11.53 (s,
1H, COOH, D2O exchangeable). EI-MS: 314 (M+), 283, 269, 254,
239, 224, 148, 120. Anal. Calc. for C18H18O5: C, 68.78; H, 5.77.
Found: C, 68.96; H, 5.80%. Compound (Z)-3a: 1H NMR (CDCl3,
400 MHz) δ 3.76 (s, 6H, 2OCH3), 3.82 (s, 3H, OCH3), 6.41 (t, 1H,
4-ArH, J = 2.0 Hz), 6.60 (d, 2H, 2,6-ArH, J = 2.0 Hz), 6.90 (d, 2H,
3',5'-ArH, J = 8.8 Hz), 6.91 (s, 1H, C=CH), 7.42 (d, 2H, 2',6'-ArH,
J = 8.8 Hz), 11.60 (s, 1H, COOH, D2O exchangeable). Compound
3b: colourless crystal (84% yield); m.p. 208–209°C. IR (KBr, cm-1):
This work was supported by Science and Technology Program
of Guangdong Province and Guangzhou City, P.R. China
(2003B31603, 2006B35604002, 2007J1-C0261).
Received 8 November 2007; accepted 29 November 2007
Paper 07/4921
doi: 10.3184/030823407X266234
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the copper power was filtered off, hydrochloric acid (1:1, V/V)
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yield); IR (cm-1): 3002, 2956, 2835, 1595, 1510, 1458. H NMR
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PAPER: 07/4921