1494
Vol. 58, No. 11
ESI-MS (m/z): 270 (Mϩ), 269.
The procedure has several advantages such as simple opera-
tions, short reaction time and high purity of product. It is
noteworthy that the direct Willgerodt–Kindler rearrangement
of 3,5-dihydoxyacetophenone (1) under identical reaction
conditions has also been investigated but failed to afford 3,5-
General Procedure for the Preparation of cis-Polymethoxystilbene In-
termediates (6) The reaction was carried out under dry nitrogen atmo-
sphere. A solution of 5 (5 mmol), quinoline (15 ml, 100 mmol) and copper
powder (2.56 g, 40 mmol) was stirred at 220 °C for 3 h. Then the copper
power was filtered out, and aqueous HCl (V/Vϭ1 : 1) was added into the fil-
trate, extracted with ethyl acetate, dried over MgSO4, and evaporated. The dihydroxyphenylacetic acid (8).
dark oily substance was extracted with petroleum ether to afford yellow oil
6, which was used without further purification.
Perkin condensations between 3,5-dimethoxyphenylacetic
acid (3) and substituted phenylaldehydes 4a—c in the pres-
ence of acetic anhydride and triethylamine at 120 °C selec-
tively gave E-2,3-diarylcrylic acids 5a—c in yields of 86.3%,
85.1%, and 81.6%, respectively. We can’t detect the Z-isomer
of 5a—c only after single crystallization. The E-configura-
tion with a cis-relationship of phenyl rings can be clearly
cis-3,4Ј,5-Trimethoxystilbene (6a): Yellow oil (1.01 g, 74.2%) 1H-NMR
(CDCl3) d: 3.65 (6H, s), 3.76 (3H, s), 6.29—6.30 (1H, t, Jϭ2.4 Hz), 6.40—
6.43 (1H, d, Jϭ12.0 Hz), 6.41—6.43 (2H, d, Jϭ2.4 Hz), 6.49—6.52 (1H, d,
Jϭ12.0 Hz), 6.73—6.76 (2H, dd, Jϭ8.8, 2.0 Hz), 7.18—7.20 (2H, dd,
Jϭ8.8, 2.0 Hz); IR (KBr) cmϪ1: 3003, 1595, 1425; MS (m/z): 272 (Mϩ),
257, 241.
cis-3,3Ј,4Ј,5-Tetramethoxystilbene (6b): Yellow oil (1.13 g, 75.3%) 1H-
NMR (CDCl3) d: 3.63 (3H, s), 3.66 (3H, s), 3.66 (3H, s), 3.83 (3H, s),
6.29—6.30 (1H, t, Jϭ2.0 Hz), 6.43—6.44 (2H, d, Jϭ2.0 Hz), 6.43—6.46
(1H, d, Jϭ12.4 Hz), 6.48—6.51 (1H, d, Jϭ12.4 Hz), 6.72—6.74 (1H, d,
Jϭ8.0 Hz), 6.81—6.83 (1H, dd, Jϭ8.0, 2.0 Hz), 6.83—6.83 (1H, d,
Jϭ2.0 Hz); IR (KBr) cmϪ1: 3002, 1604, 1460; MS (m/z): 300 (Mϩ), 285.
cis-2Ј,3,4Ј,5-Tetramethoxystilbene (6c): Yellow oil (1.07 g, 70.6%) 1H-
NMR (CDCl3) d: 3.52 (6H, s), 3.58 (3H, s), 3.67 (3H, s), 6.29 (1H, t,
Jϭ2.4 Hz), 6.41 (1H, d, Jϭ9.6 Hz), 6.49 (1H, d, Jϭ9.6 Hz), 6.49 (1H, d,
Jϭ12 Hz), 6.73 (1H, t, Jϭ8.8 Hz), 6.73 (1H, d, Jϭ2.4 Hz), 7.18 (1H, d,
Jϭ8.8 Hz); IR (KBr) cmϪ1: 3002, 1600, 1459; MS (m/z): 300 (Mϩ), 269.
General Procedure for the Preparation of trans-Phenolic Stilbenes (7)
To a solution of AlI3 (20.40 g, 50 mmol) in CH3CN (100 ml) at 82 °C was
added drop wise the solution of 6 (10 mmol) in CH3CN (20 ml), and stirred
1
corroborated by H-NMR spectrum (Fig. 2, for example 5c),
which has been well established in our previous studies.50,51)
The field-effect of carboxyl group in 5a—c resulted in a re-
markable down-field shift of the olefinic proton (Hb):
dϭ7.84 for 5a, dϭ7.83 for 5b, dϭ8.12 for 5c, as compared
with the olefinic proton of cis-isomer (dϷ6.90), suggesting
that the down-field shift of olefinic proton is a typical charac-
ter of E-2,3-diarylcrylic acid (5). Moreover, the 2Ј-methoxy
group of 5c may also exert an additional field-effect to the
olefinic proton, leading to a even higher chemical shift. The
H(2,6) proton of 5c appears as a doublet at d 6.35 ppm and
for 3 h. The resulting mixture was concentrated, and a yellow solid appeared. H(4) as a triplet at d 6.43 ppm with a coupling constant
The remaining solid was added into water, a pale yellow solid was obtained,
Jϭ2.4 Hz. The H(5Ј), H(6Ј) proton signals of B ring appear
at d 6.20 and d 6.74 ppm, respectively, with the triple-bond
coupling constant Jϭ8.8 Hz; d 6.53 ppm corresponds to the
H(3Ј) proton of B ring with a W-type long-range coupling
constant of Jϭ2.4 Hz.
which was recrystallized from EtOH/H2O to afford a white crystal.
trans-3,4Ј,5-Trimethoxystilbene (Resveratrol, 7a): White crystal (1.68 g,
73%). mp 224—226 °C (lit49) 233—235 °C); 1H-NMR (CDCl3) d: 6.27 (1H,
t, Jϭ2.0 Hz), 6.54—6.55 (2H, d, Jϭ2.0 Hz), 6.83—6.85 (2H, d, Jϭ8.8 Hz),
6.87—6.91 (1H, d, Jϭ16.4 Hz), 7.00—7.04 (1H, d, Jϭ16.4 Hz), 7.41—7.43
(2H, d, Jϭ8.8 Hz), 8.20 (2H, s, D2O exchangeable), 8.43 (1H, s, D2O ex-
changeable); IR (KBr) cmϪ1: 3292, 1587, 1444; MS (m/z): 230 (Mϩ). Anal.
Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.46; H, 5.40.
Decarboxylation reactions of 5a—c were carried out in the
presence of Cu/quinoline at 220 °C under the protection of
N2 to give the Z-stilbene intermediates 6a—c in yields of
74.2%, 75.3%, and 70.6%, respectively. Results determined
trans-3,3Ј,4Ј,5-Tetramethoxystilbene (Piceatannol, 7b): White crystal
(1.73 g, 70.9%). mp 231—234 °C; 1H-NMR (DMSO-d6) d: 6.08—6.09 (1H,
t, Jϭ2.0 Hz), 6.35—6.35 (2H, d, Jϭ2.0 Hz), 6.67—6.71 (1H, d, Jϭ16.4 Hz),
6.68—6.70 (1H, d, Jϭ8.0 Hz), 6.80—6.83 (1H, dd, Jϭ8.0, 2.0 Hz), 6.81—
6.85 (1H, d, Jϭ16.4 Hz), 6.93—6.94 (1H, d, Jϭ2.0 Hz), 8.91 (1H, s, D2O
exchangeable), 9.08 (1H, s, D2O exchangeable), 9.17 (2H, s, D2O exchange-
able); IR (KBr) cmϪ1: 3392, 1600, 1481; MS (m/z): 244 (Mϩ), 227.
1
by H-NMR spectrum clearly indicate that, despite the high
reaction temperature, the decarboxylation process maintained
the original cis-relationship of phenyl rings and gave the cor-
responding cis-products 6a—c with a typical coupling con-
stant of Jϭ12.4 Hz.
Demethylation process of 6a—c took place smoothly in
the presence of AlI3 in acetonitrile. Interestingly and fortu-
nately, a simultaneous cis- to trans-isomerization was also
taking place during the demethylation process, giving high
trans-2Ј,3,4Ј,5-Tetramethoxystilbene (Oxyresveratrol, 7c): White crystal
1
(1.67 g, 68.4%). mp 202—205 °C; H-NMR (CD3COCD3) d: 6.21 (1H, t,
Jϭ2.0 Hz), 6.34—6.37 (1H, dd, Jϭ8.4 Hz), 6.41 (1H, d, Jϭ2.0 Hz), 6.49
(2H, d, Jϭ2.0 Hz), 6.83 (1H, d, Jϭ16.4 Hz), 7.27 (1H, d, Jϭ16.4 Hz), 7.35
(1H, d, Jϭ8.4 Hz), 8.57 (2H, s, D2O exchangeable), 8.78 (1H, s, D2O ex-
changeable), 8.96 (1H, s, D2O exchangeable); 13C-NMR (CD3COCD3) d:
102.1, 103.4, 105.2, 108.1, 117.0, 124.3, 126.1, 128.1, 141.5, 156.7, 158.9, yields for the target compounds 7a—c. We tried a number of
159.3; IR (KBr) cmϪ1: 3208, 1590, 1513; MS (m/z): 244 (Mϩ), 226.
Results and Discussion
The Perkin reaction has been characterized as favorable
atom economy, relatively high yields and simple operations.
We therefore based our strategy on Perkin-type reactions to
form the stilbene skeleton. It could be noticed that the 3,5-di-
hydroxyphenyl group (usually referred to as A ring of stil-
bene) is a common subunit for target compounds 7a—c, so a
common intermediate can serve as starting material. 3,5-Di-
hydroxyphenylacetic acid (8) was initially taken into consid-
eration as the starting material but this compound is not com-
mercially available and is difficult to prepare. Therefore we
started with 3,5-dihydoxyacetophenone (1), which was cheap
and readily available, and obtained 3,5-dimethoxyphenyl-
acetic acid (3) as the common intermediate through methyl-
Fig. 2. The 1H-NMR Spectrum of Compound 5c
ation and Willgerodt–Kindler rearrangement in 80.6% yield.