Synthesis of methylated resveratrol and analogues by Heck reactions in organic and aqueous solvents

Article abstract of DOI:10.1016/j.tet.2004.04.076

The Heck reaction under phosphane free conditions using oxime-derived palladacycles or Pd(OAc)₂ as catalysts is a general methodology for the synthesis of methoxylated (E)-stilbene derivatives. Couplings can be performed either with (dicyclohexyl)methylamine as base and TBAB in aqueous DMA or in neat water and with Et₃N as base in DMA in air and under thermal and microwave conditions. The arylation of different styrenes are performed with 3,5-dimethoxyiodobenzene to afford a series of important biologically active (E)-stilbene derivatives containing the 3,5-dimethoxyphenyl moiety, including resveratrol, piceatannol and pinosilvine, which are efficiently prepared with high regioselectivity and total stereoselectivity (TON up to 10⁴).

Full text of DOI:10.1016/j.tet.2004.04.076

Tetrahedron 60 (2004) 5563–5570
Synthesis of methylated resveratrol and analogues by
Heck reactions in organic and aqueous solvents
Luis Botella and Carmen N a´ jera
*
Departamento de Qu ´ı mica Org a´ nica and Instituto de S ´ı ntesis Org a´ nica (ISO), Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 28 February 2004; revised 21 April 2004; accepted 29 April 2004
Dedicated to Professor Jos e´ Luis Soto on occasion of his retirement
Abstract—The Heck reaction under phosphane free conditions using oxime-derived palladacycles or Pd(OAc)
methodology for the synthesis of methoxylated (E)-stilbene derivatives. Couplings can be performed either with (dicyclohexyl)methylamine
as base and TBAB in aqueous DMA or in neat water and with Et N as base in DMA in air and under thermal and microwave conditions. The
2
as catalysts is a general
3
arylation of different styrenes are performed with 3,5-dimethoxyiodobenzene to afford a series of important biologically active (E)-stilbene
derivatives containing the 3,5-dimethoxyphenyl moiety, including resveratrol, piceatannol and pinosilvine, which are efficiently prepared
4
with high regioselectivity and total stereoselectivity (TON up to 10 ).
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
reasons new resveratrol analogues have been designed as
1
4–16
chemotherapeutic agents.
For instance, the trimethyl
ether of resveratrol 2a shows more activity against several
Hydroxylated (E)-stilbenoids are natural polyphenols
widely present in nature, especially in medicinal plants
1
4
human cancer cell lines than resveratrol (1) and
methoxylated stilbenes, such as 2b and 2c are potent
CYP1B1 inhibitors valuable for the development of a
1
and food products, which exhibit a variety of biological and
–15
2
therapeutical properties.
The phytoalexin resveratrol (1,
0
16
Fig. 1), 3,4 ,5-trihydroxy-(E)-stilbene, the biosynthetic
precursor of most oligostilbenoids became the most famous
compound as it was suggested as cancer chemopreventive
agent and due to its antiinflamatory and antioxidative
properties may contribute also as chemoprotective agent.
In addition, it presents in vitro growth inhibition in a number
chemopreventive or therapeutic agent for cancer (Fig. 1).
Therefore, the development of general and simple strategies
for the preparation of methoxylated stilbenoids for biologi-
cal evaluation has became an important task.
2
3
4
5
Several synthetic routes are based mainly on: (a) Wittig-
1f,14–17
6
18
of human cancer cell lines. Resveratrol also prevents heart
diseases due to lipid-lowering-activity and lipid peroxi-
type
and modified Julia olefinations, (b) reaction of
3,5-dimethoxybenzyllithium with 4-methoxybenzaldehyde
7
– 9
19
20
dation-inhibition.
scavenging activity, neuroprotection, antiviral activity
and to promote survival and longevity by activating
Other properties, such as radical
12
followed by dehydration, (c) Perkins reaction (d) cross
21
1
0
11
metathesis of styrenes, (e) Suzuki reaction with b-halo-
2
2
styrenes, (f) decarbonylative Heck reaction between
23
resorcylic acid chloride and 4-acetoxystyrene, (g)
1
3
siruins have also been recently found. For all these
Figure 1.
Keywords: Resveratrol; Heck reaction; Palladacycles; Stilbenes; Styrenes.
*
Corresponding author. Tel.: þ34-965-90-3728; fax: þ34-965-90-3549; e-mail address: cnajera@ua.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.076

5564
L. Botella, C. N a´ jera / Tetrahedron 60 (2004) 5563–5570
Scheme 1.
2
4
one-pot sequential Heck arylation–desilylation of vinyl-
trimethylsilane followed by Heck arylation of styrene
derivatives formed in situ and (h) by arylation of 3,5-
For subsequent studies between methoxylated partners
commercially available 3,4-dimethoxystyrene and
4-methoxyiodobenzene were chosen as model substrates.
For the couplings in aqueous DMA the presence of TBAB
improved the efficiency of the catalyst 3a (0.01 mol% Pd)
(Table 1, entry 11) and Cy NMe as base gave better yields
2
than Et N (Table 1, compare entries 11 and 12). On the
3
other hand, under these reaction conditions, Pd(OAc) led to
2
2
5
dimethoxystyrene with 4-(benzyloxy)iodobenzene. The
main inconvenient for the palladium-catalyzed arylation of
styrenes is the low reactivity of electron-rich styrenes and
2
6
iodides. Thus, the last two processes require the use of
2
4
inert atmosphere and high loadings (2 mol%) of Pd(dba)2
or the addition of silver nitrate at 120 8C during one week
2
5
the same results as complex 3a (Table 1, compare entries 11
and 13). Couplings performed in neat DMA took place in
shorter times in the presence of Et N instead of Cy NMe as
to afford the corresponding resveratrol derivatives. As part
of our project about the use of oxime-derived palladacycles
3
2
2
7
3
in C–C bond-forming reactions in organic and aqueous
base (Table 1, compare entries 14 and 15). In this case both
palladacycles 3 and Pd(OAc) were employed as catalysts,
2
8
media we have focussed our attention on the possible
applications of these catalysts for the synthesis of
methoxylated stilbenes by Heck couplings of substituted
aryl halides and styrenes.
2
the former being the most active source of Pd (Table 1,
entries 15–17). However, the coupling under water reflux
and with Cy NMe as base failed. When 3,4-dimethoxy-
2
styrene was arylated with 4-methoxybromobenzene in
DMA/H O, Cy NMe as base and TBAB as additive the
amount of 3a has to be increased to 0.5 mol% Pd to afford
2
2
2
. Results and discussion
high conversions in 19 h. However, Pd(OAc) failed as
2
catalyst under these conditions (Table 1, compare entries 18
and 19). For couplings in DMA the presence of TBAB was
necessary either with Cy NMe or Et N as base (Table 1,
We first tested the arylation reaction of the rather reactive
-chlorostyrene with activated 4-chlorophenyl and deacti-
4
2
3
vated 4-methoxyphenyl iodides and bromides (Scheme 1
and Table 1) using 4-hydroxyacetophenone oxime-derived
palladacycle 3a as catalyst. However, under the reaction
conditions established for arylation of acrylates, such as
water reflux and (dicyclohexyl)methylamine as base the
reaction was rather slow even with aryl iodides (Table 1,
entries 1 and 4). When the process was performed in
entries 20–22) and both catalysts 3a and Pd(OAc) gave
2
similar results (Table 1, compare entries 21 and 23). Finally
this coupling was carried out under Jeffery’s conditions, so
in the presence of K CO as base the reaction was slower
2
8c
2
3
than with organic amines and Pd(OAc) gave slightly better
2
yields than palladacycle 3a (Table 1, entries 24 and 25).
From these studies we deduced that for the couplings of
methoxylated styrene and aryl halides two method can be
used, Method A: DMAc/H O, Cy NMe as base and TBAB
aqueous N,N-dimethylacetamide (DMA/H O: 4/1) at
2
1
20 8C (bath temperature) reaction times decreased,
especially if 1 equiv of TBAB was added (Table 1, entries
, 3 and 5, 6). For 4-chlorophenyl bromide the same effect
was observed in aqueous DMA and TBAB as additive
Table 1, entries 7 and 8). Deactivated 4-methoxyphenyl
2
2
as additive and either catalyst 3a or Pd(OAc) as catalysts
2
2
except for aryl bromides, which required the use of 3a and
Method B: DMAc and Cy NMe or Et N as base, the
2
3
(
presence of TBAB being required in the case of aryl
bromides as arylating components. The regioselectivity was
lower with 3,4-dimethoxystyrene than with 4-chlorostyrene
and higher with aryl bromides than iodides.
bromide was coupled with 4-chlorostyrene under these
conditions with palladacycle 3a (0.5 mol% of Pd) in longer
2
9
reaction times (1 d) and with Pd(OAc)2 as catalyst only
% conversion was observed (Table 1, entries 9 and 10). In
2
all cases (E)-stilbene derivatives 2d and 2e with very low
amounts of 1,1-diarylstyrenes 4 were observed and pure
compounds 2 were isolated after flash chromatography.
For the preparation of biologically active 3,5-dimethoxy-
(E)-stilbenes the use of different, commercially available or
prepared by Wittig reaction, aryl and heteroarylethylenes
3
0
Scheme 2.

a
Table 1. Reaction conditions optimization for the Heck reaction
Entry ArX Styrene
Cat. (mol% Pd)
Amine
Solvent
Additive
t (h)
Product
b
No.
Yield (%)
2
2
)
1
3a (1.1£10
Cy
2
NMe
H
2
O
—
30
2d
96 [16:1] (79)
2
2
2
2
3
3a (10
3a (10
)
)
Cy
Cy
2
2
NMe
NMe
DMA/H
DMA/H
2
O
O
—
TBAB
20
9
2d
2d
99 [15:1]
99 [19:1]
2
2
2
e
4
3a (0.1)
3a (0.1)
3a (9.1£10
Cy
2
NMe
H
2
O
—
72
89 [8.9:1] (75)
5
6
Cy
Cy
2
NMe
NMe
DMA/H
DMA/H
2
O
O
—
TBAB
48
9
2e
2e
86 [9.2:1]
99 [12:1]
2
2
)
2
2
7
8
9
3a (0.52)
Cy
Cy
Cy
Cy
Cy
2
2
2
2
NMe
NMe
NMe
NMe
NMe
DMA/H
DMA/H
DMA/H
DMA/H
DMA/H
2
2
2
2
O
O
O
O
O
—
38
15
24
24
19
2d
2d
2e
2e
2f
99 [24:1] (89)
94 [25:1]
87 [18:1] (81)
2
22
3a (10
)
TBAB
TBAB
TBAB
TBAB
3a (0.5)
1
0
1
Pd(OAc)
2
(0.5)
2
2
1
3a (10
3a (10
)
2
2
99 [5.7:1]
22
12
13
14
15
16
17
)
Et
3
N
NMe
NMe
N
N
N
DMA/H
DMA/H
DMA
2
O
O
TBAB
TBAB
—
—
—
20
19
24
3.5
6
2f
2f
2f
2f
2f
2f
43 [7.3:1]
98 [6.1:1]
99 [4.9:1]
95 [4.6:1]
91 [4.4:1]
86 [4.6:1]
22
Pd(OAc)
3a (10
2
(1.5£10
)
Cy
Cy
2
2
2
2
2
)
2
2
3a (1.1£10
)
3
Et
Et
Et
3
DMA
DMA
DMA
2
3b (9.1£10
)
3
3
2
2
Pd(OAc)
2
(10
)
—
3.5
1
8
3a (0.5)
Cy
2
NMe
DMA/H
2
O
O
TBAB
19
2f
84 [9.2:1]
19
20
21
22
23
24
25
Pd(OAc)
3a (0.5)
3a (0.5)
3a (0.5)
Pd(OAc)
3a (0.5)
Pd(OAc)
2
(0.5)
Cy
2
Cy
2
Cy
2
NMe
NMe
NMe
DMA/H
DMA
DMA
DMA
DMA
DMA
DMA
2
TBAB
—
19
24
2f
2f
2f
2f
2f
2f
2f
0
75 [7:1]
99 [10:1]
80 [11.3:1]
99 [14.3:1]
82 [10.3:1]
99 [9.9:1]
TBAB
TBAB
TBAB
TBAB
TBAB
3.5
3.5
3.5
7.5
7.5
3
Et N
2
2
(0.5)
(0.5)
Cy
2
NMe
K
K
2
CO
CO
3
2
3
a
22
Reaction conditions: ArX (1 mmol), styrene (1.5 mmol), amine (1.5 mmol), TBAB (1 mmol), H
ArX (2 mmol), styrene (3 mmol), amine (3 mmol), TBAB (2 mmol).
Conversion determined by GC based on ArX using decane as an internal standard. In brackets, regioisomers ratio of crude product (determined by GC). In parenthesis, isolated yield of the (E)-stilbene after flash
2 2
O (3 mL) or DMA/H O (4/1, 5 mL) or DMA (3 mL), 120 8C (bath temperature), pressure tube. For 10 mol% Pd:
b
chromatography (hexane/EtOAc).

Table 2. Synthesis of methoxylated (E)-stilbene derivatives
a
Entry
ArX
Styrene
Cat. (mol% Pd)
Reaction conditions
t
Product
b
No.
Yield (%)
2
1
)
1
3a (10
Method A
14 h
2a
99 [8.4:1] (77)
2
2
2
3
4
3a (1.1£10
)
Method A
Method A
Method A
24 h
24 h
14 h
2a
2a
2a
77 [8:1]
88 [7.9:1]
99 [10.5:1]
2
2
)
Pd(OAc)
3a (0.5)
2
(1.1£10
5
6
7
Pd(OAc)
3a (0.5)
3a (1.1£10
2
(0.5)
Method A
Method A
Method A
14 h
10 min
13 h
2a
2a
2a
2
c
99 [6.3:1]
96 [8.5:1] (85)
2
2
)
2
2
2
2
8
9
1
1
1
Pd(OAc)
2
2
(10
)
Method A
Method B
Method B
Method C
Method A
13 h
5 h
5 h
23 h
14 h
2a
2a
2a
2a
2b
93 [10:1]
95 [6:1]
99 [6.1:1]
99 [9:1]
75 [14:1] (67)
2
3a (10
Pd(OAc)
)
0
1
2
2
(10
)
3a (0.1)
3a (0.15)
1
3
4
3a (0.5)
3a (0.1)
Method A
Method A
8 h
2b
2c
98 [16:1] (64)
98 [9.6:1] (75)
1
14 h
15
3a (0.1)
Method A
14 h
2g
99 [4.2:1] (47)

L. Botella, C. N a´ jera / Tetrahedron 60 (2004) 5563–5570
5567
3
1
and 3,5-dimethoxyiodobenzene as partners could be the
most general strategy for combinatorial chemistry. How-
ever, for initial studies for methylated resveratrol (2a) two
approaches were studied: (I) the arylation of 3,5-dimethoxy-
3
0,32
styrene
(
with 4-methoxyphenyl iodide and bromide and
II) the coupling of 4-methoxystyrene with 3,5-dimethoxy-
iodobenzene (Scheme 2 and Table 2). Both strategies gave
good conversions when the reactions were performed
following Method A–C (Table 2, entries 1–11) either
under thermal or microwave conditions. There are some
exceptions, such as using of Pd(OAc)2 as catalyst the
coupling of 4-methoxybromobenzene and 3,5-dimethoxy-
styrene failed (Table 2 entries 5) also under microwave
conditions. The second strategy gave very low conversions
under microwave conditions either with complex 3 or with
Pd(OAc) as catalysts.
2
Considering aryl iodides, strategy II occurred faster and
with higher conversion than strategy I, it means that 3,5-
dimethoxyiodobenzene is more reactive than 4-methoxy-
iodobenzene (Scheme 3, Table 2, compare entries 2 and 7 or
3
and 8). Following Method B (DMA, Et N) this second
3
procedure occurred faster but with lower regioselectivity
Table 2, entries 9 and 10). Trimethylated resveratrol 2a can
(
also be prepared in water with (dicyclohexyl)methylamine
as base and TBAB as additive (Method C) under thermal
conditions although in longer reaction times than using
Method A and B (Table 2, entry 11). However under
microwave conditions the reaction took place with much
lower conversion (20%). Conditions of Method A were used
in the preparation of other methoxylated stilbenes because
of the higher regioselectivity observed in the synthesis
of resveratrol 2a. In the case of stilbene 2b 2-iodo and
2
-bromothiophene were coupled efficiently with 3,5-
dimethoxystyrene and with high regioselectivity (Table 2,
entries 12 and 13, respectively).
For the rest of methoxylated stilbenes 2c, 2g–2i, 3,5-
dimethoxyiodobenzene was coupled with the corresponding
styrene (Scheme 3 and Table 2, entries 14–17). 2,4-
3
3
30
Dimethoxystyrene was prepared by Wittig reaction and
the rest of styrenes are commercially available. Compounds
2
1
2
g and 2i along with 2a–c present human cytochrome P450
1
6
B1 inhibitory activity. By demethylation of stilbenes 2a,
1
9,24
g and 2h by standard methods
natural products, such as
resveratrol, piceatannol and pinosilvine, respectively can be
obtained.
3. Conclusion
In conclusion, we have found appropriate reaction con-
ditions to perform the Heck reaction between deactivated
aryl halides and styrenes using oxime-derived palladacycle
3a or Pd(OAc) as catalysts in air and under phosphane and
2
silver salt-free conditions. The reactions can be performed
using (dicyclohexyl)methylamine in aqueous DMA or in
neat water and TBAB as additive and in DMA with Et N as
3
base. The former reaction conditions allowed the coupling
between 3,5-dimethoxyiodobenzene and styrenes with the
best regioselectivity. This methodology is an efficient regio
and stereoselective way for the preparation of biologically
active methoxylated stilbenes.

5568
L. Botella, C. N a´ jera / Tetrahedron 60 (2004) 5563–5570
Scheme 3.
4. Experimental
Method B. A 15 mL Ace pressure tube was charged with
aryl halide (2 mmol), styrene (3 mmol), triethylamine
(0.42 mL, 3 mmol), catalyst (102 mol% Pd) and DMA
2
4
.1. General
(3 mL). The solution was stirred at 120 8C in air and the
All reagents and solvents were obtained from commercial
sources and were generally used without further
reaction progress was analyzed by GC. After the reaction
was completed or stopped the same extractive work-up as
before was performed.
purification. Palladacycle
3 was purchased from
MEDALCHEMY S. L. Microwave reactions were per-
formed with a CEM Discover Synthesis Unit (CEM Corp.,
Matthews, NC) in glass vessels (10 mL) sealed with a
septum under magnetic stirring. The catalysts were weighed
out in an electronic microscale (Sartorius, XM1000P) with a
Method C. A 15 mL Ace pressure tube was charged with
aryl iodide (1 mmol), styrene (1.5 mmol), (dicyclohexyl)-
methylamine (0.32 mL, 1.5 mmol), tetra-n-butylammonium
bromide (0.32 mg, 1 mmol), 3a (292 mg, 0.001 mmol Pd)
and water (2 mL). The mixture was stirred at 120 8C in air
and the reaction progress was analyzed by GC. After the
reaction was completed or stopped, the same extractive
work-up as before was performed.
precision of 1 mg. Thin liquid chromatography for R was
f
w
performed on Polygram Silica Gel 60 UV254 plates,
purchased from Merck. Mp were measured in a Reichert
Thermovar apparatus. Gas chromatographic analyses were
performed on an HP-5890 instrument equipped with a
WCOT HP-1 fused silica capillary column using decane as
internal standard. IR data were collected on a Nicolet
All compounds have been previously reported and were
characterized by comparison with their reported physical
and spectroscopic data:
1
Impact 400D-FT. H NMR spectra were recorded on a
1
3
Bruker AC-300 MHz spectrometer and C NMR spectra
were recorded at 75 MHz with CDCl3 as the internal
reference. Mass spectra (MS) were obtained at 70 eV on a
Hewlett Packard HP 6890 series GC system with a 5973
network mass selective detector.
(E)-1-(3,5-Dimethoxyphenyl)-2-(4-methoxyphenyl)-
6
ethene (2a). Mp 53–56 8C (lit. 55–57 8C).
1
(
(
(
E)-1-(3,5-Dimethoxyphenyl)-2-(2-thiophenyl)ethene
16
2b). Oil.
E)-1-(3,4-Dimethoxyphenyl)-2-(3,5-dimethoxyphenyl)-
4.2. Heck reactions. General procedures for the
preparation of compound 2
16
ethene (2c). Mp 67–68 8C (lit. 66–67 8C).
(
(
(
(
(
E)-1,2-Di(4-chlorophenyl)ethene (2d). Mp 175–178 8C
3
4
lit. 177–178 8C).
E)-1-(4-Chlorophenyl)-2-(4-methoxyphenyl)ethene
Method A. A 15 mL Ace pressure tube was charged with
aryl halide (1 mmol), styrene (1.5 mmol), (dicyclohexyl)-
methylamine (0.32 mL, 1.5 mmol), tetrabutylammonium
bromide (0.32 g, 1 mmol), catalyst (0.1–0.5 mol % Pd),
35
2e). Mp 181–184 8C (lit. 185 8C).
E)-1-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)-
36
ethene (2f). Mp 136–138 8C (lit. 133–135 8C).
(E)-1-(2,4-Dimethoxyphenyl)-2-(3,5-dimethoxyphenyl)-
2
2
DMA (4 mL) and water (1 mL). Reactions with 10 mol %
Pd were performed at 2 mmol scale with the same amount of
solvents. The solution was stirred at 120 8C in air and the
reaction progress was analyzed by GC. After the reaction
was completed or stopped, the reaction mixture was poured
into ethyl acetate (20 mL) and washed with 2 M HCl
16
ethene (2g). Mp 82–83 8C (lit. 78–79 8C).
E)-1-(3,5-Dimethoxyphenyl)-2-phenylethene (2h). Mp
(
5
37
4–55 8C (lit. 59–60 8C).
(
Mp 69–70 (lit. 139–144 8C).
E)-1-(3,5-Dimethoxyphenyl)-2-(4-pyridyl)ethene (2i).
38
16
(
dried over Na SO and evaporated (15 Torr). The sub-
2£10 mL) and water (2£10 mL). The organic phase was
2
4
sequent residue was purified by flash chromatography on
silica gel to obtain the corresponding styrene. Only in the
preparation of compound 2i, the reaction mixture was
poured into water (40 mL) and extracted with ethyl acetate
Acknowledgements
(
2£15 mL). The combined organic phases were washed
This work has been supported by the Direcci o´ n General de
Investigaci o´ n of the Spanish Ministerio de Ciencia y
Tecnolog ´ı a (MCyT) (BQU2001-0724-CO2-01). L. B.
thanks the Generalitat Valenciana for a predoctoral
fellowship.
with aqueous saturated NaHCO solution (3£10 mL), dried
3
over Na SO and evaporated (15 Torr) to obtain a residue
2
4
which was purified by flash column chromatography on
silica gel.

L. Botella, C. N a´ jera / Tetrahedron 60 (2004) 5563–5570
5569
References and notes
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