Short-step synthesis of a resveratrol derivative from commercially available1,3-dimethoxybenzene and 4-vinylanisole

Article abstract of DOI:10.1271/bbb.90462

An efficient synthesis of tri-O-methylated resveratrol is presented using an advanced Heck reaction promoted by Pd(dba)₂ in the presence of P(t-Bu)₃.

Full text of DOI:10.1271/bbb.90462

Biosci. Biotechnol. Biochem., 73 (11), 2547–2548, 2009
Note
Short-Step Synthesis of a Resveratrol Derivative from Commercially Available
1,3-Dimethoxybenzene and 4-Vinylanisole
y
Takashi IIJIMA and Hidefumi MAKABE
Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University,
8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan
Received June 30, 2009; Accepted July 21, 2009; Online Publication, November 7, 2009
[doi:10.1271/bbb.90462]
An efficient synthesis of tri-O-methylated resveratrol
is presented using an advanced Heck reaction promoted
by Pd(dba)2 in the presence of P(t-Bu)3.
Karade et al.,12) and 3,5-dimethoxylation of 1,3,5-
tribromobenzene by using NaOMe.13) However, in all
cases, our achieved yield of 2 was very poor.
Resveratrol derivative 3 was prepared by using the
advanced Heck reaction developed by Fu et al.,14) except
that Pd(dba)2 was used as the catalyst. As shown in
Table 2, P(t-Bu)3 was a suitable ligand. The amounts of
catalyst, ligand, and the base were extremely important.
The combination of 5 mol% of Pd(dba)2, 12 mol% of
P(t-Bu)3, and 1.5 eq. of Cs2CO3 gave 3 in an 88% yield
with 100% E selectivity.
Key words: resveratrol; Heck reaction; polyphenolic
stilbenes
Resveratrol (1) is a naturally occurring phytoalexin
compound that has been isolated from grape skin, vine
bark and many other plants. This compound has
attracted attention in recent years due to its remarkable
biological activities as a chemopreventive agent against
cancer, inflammation, aging, obesity, cardiovascular
diseases and neurodegeneration.1) Antioxidative, anti-
bacterial, and antifungal activities have also been
attributed to this molecule. The O-methylated analogues
of resveratrol (1) possess higher lipophilicity and a
pharmacological profile that is comparable or even
superior to that of resveratrol.2) Resveratrol (1) has also
recently been shown to extend the life of yeast by
activating sirtuin (SIRT-1,2) an NAD dependent histone
deacetylase that has been found to be directly correlated
with cellular longevity.3) Many synthetic approaches
have been reported through Wittig-type reactions4,5) and
Heck-type reactions.6–9) However, in the case of the
Wittig reaction, difficulty in controlling the stereo-
selectivity has been found. In the case of the Heck
reaction, preparation of the required precursor took
several steps. Therefore, the development of an alter-
native strategy to synthesize 1 is necessary. We report
here a 2-step synthesis of resveratrol derivative 3, using
an advanced Heck reaction from commercially available
1,3-dimethoxybenzene and 4-vinylanisole.
1-Bromo-3,5-dimethoxybenzene (2) was prepared
from 1,3-dimethoxybenzene by the Ir-catalyzed arene
borylation method developed by Hartwig et al.10) with a
slight modification. As shown in Table 1, 0.7 mol% of
[Ir(COD)(OMe)]2, 1.5 mol% of dtbpy, and 0.8 eq. of
B2pin2 gave a good result. Although compound 2 is
commercially available, it is rather expensive. This
method is useful for a large-scale preparation and can be
applied to synthesize some precursors for cross-coupling
methods applicable to the synthesis of various natural
products. We attempted to synthesize 2 by using the
Sandmyer reaction from 3,5-dimethoxyaniline with
CuBr and HBr,11) (deacetoxyiodo)benzene-mediated
oxidative nuclear halogenation of arene developed by
Compound 3 can be converted to resveratrol (1) by
using a known procedure.5,7) The synthesis of other
analogues of resveratrol (1) is currently underway.
Experimental
All reactions were carried out in an Ar atmosphere. Silica gel
column chromatographic separation was performed on 70–230-mesh
silica gel 60. 1H- and 13C-NMR spectra were measured in CDCl3 with
a Bruker Avance DRX 500 FT-NMR (500 MHz) spectrometer, and IR
spectra were taken with a Jasco FT/IR 480 Plus infrared spectrometer.
1-Bromo-3,5-dimethoxybenzene (2).12) [Ir(COD)(OMe)]2 (9.3 mg,
14 mmol), dtbpy (8 mg, 30 mmol), and B2pin2 (406 mg, 1.6 mmol) were
combined in a Schlenk tube that was evacuated and refilled three times
with argon. Under a positive flow of argon, dry THF (3.0 ml) and
1,3-dimethoxybenzene (276 mg, 2.0 mmol) were added. The tube was
then sealed and heated overnight in an oil bath at 80 ꢀC. After this
overnight heating, the volatiles were removed under vacuum, and
MeOH (25 ml) and CuBr2 (1.35 g, 6.0 mmol) in H2O (25 ml) were
added. The tube was then resealed and heated again in an oil bath at
80 ꢀC for 4 h. The reaction mixture was then cooled to room
temperature and extracted with Et2O (3 ꢁ 40 ml). The organic solution
was successively washed with water and brine, dried over MgSO4, and
concentrated. The crude product was purified by preparative TLC
(hexane/CH2Cl2 ¼ 5=2) to give 2 (238 mg, 55%) as a colorless
amorphous compound. IR ꢀmax (film) cmꢂ1: 3080, 3004, 2968, 2936,
2838, 1580, 1471, 1429, 1300, 1201, 1160, 1037, 855, 821, 795, 684.
1H-NMR (CDCl3, Me4Si) ꢁ: 3.79 (6H, s), 6.38 (1H, t, J ¼ 2:3 Hz),
6.65 (2H, d, J ¼ 2:3 Hz) ppm. 13C-NMR (CDCl3, Me4Si) ꢁ: 55.5, 99.8,
109.8, 122.9, 161.1 ppm.
Trans-3,5,40-trimethoxystilbene (3).5,7) In an atmosphere of argon, a
solution of 2 (82 mg, 0.38 mmol) in dioxane (1.0 ml) and a solution of
P(t-Bu)3 (9.1 mg, 0.045 mmol) in dioxane (0.5 ml) were added in turn
to a Schlenk tube charged with Pd(dba)2 (10.4 mg, 1.7 mmol) and
Cs2CO3 (184 mg, 0.57 mmol). 4-Vinylanisole (56 mg, 0.42 mmol) was
then added, and the Schlenk tube was sealed, placed at 120 ꢀC in an oil
bath and stirred for 7 h. The reaction mixture was cooled to room
temperature, diluted with Et2O, filtered through a Celite pad, and
concentrated. The crude product was purified by preparative TLC
(hexane/EtOAc ¼ 5=1) to give 3 (89 mg, 88%) as a pale yellow oil. IR
ꢀmax (film) cmꢂ1: 3030, 3000, 2968, 2935, 2836, 1592, 1511, 1457,
y
To whom correspondence should be addressed. Fax: +81-265-77-1700; E-mail: makabeh@shinshu-u.ac.jp
Abbreviations: COD, cyclooctadienyl; dtbpy, 4,40-di-tert-butyl-2,20-bipyridyl-hexafluorobenzene; B2pin2, bis(pinacolato)diboron

2548
T. IIJIMA and H. MAKABE
Table 1. Iridium-Catalyzed Arene Borylation
Scheme 1. Known Transformation of 3 to 1.
Table 2. Advanced Heck Reaction of 2 with 4-Vinylanisole
1300, 1277, 1252, 1151, 1065, 961, 831. 1H-NMR (CDCl3, Me4Si) ꢁ:
3.80 (9H, s), 6.38 (1H, t, J ¼ 1:5 Hz), 6.66 (2H, d, J ¼ 1:5 Hz), 6.90
(1H, d, J ¼ 16:0 Hz), 6.91 (2H, d, J ¼ 8:5 Hz), 7.05 (1H, d,
J ¼ 16:0 Hz), 7.46 (2H, dt, J ¼ 8:5 Hz) ppm. 13C-NMR (CDCl3,
Me4Si) ꢁ: 55.4 (3 ꢁ C), 99.6, 104.3, 114.1, 126.5, 127.8, 128.7,
130.3, 139.7, 159.4, 160.9 ppm.
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