Heck arylation of styrenes promoted by an air-stable phosphinito complex with palladium(II); Synthesis of resveratrol

Article abstract of DOI:10.1055/s-0031-1289664

An air-stable phosphinito complex of palladium(II) was found to be an efficient catalyst in the Heck reaction of a variety of aryl halides and styrenes. Resveratrol was concisely synthesized in 63% overall yield; the reactions were performed under conventional and microwave heating. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289664

446
PAPER
Heck Arylation of Styrenes Promoted by an Air-Stable Phosphinito Complex
with Palladium(II); Synthesis of Resveratrol
Synthesis
o
of Resveratro
s
l
é Antonio Morales-Serna, Armando Zúñiga-Martínez, Manuel Salmón, Rubén Gaviño, Jorge Cárdenas*
Instituto de Química, Universidad Nacional Autónoma de México Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, México, D.F.,
México
Fax +52(55)56162217; E-mail: rjcp@unam.mx
Received 12 September 2011; revised 21 November 2011
reaction12c,14,15 for the Z-isomer and the Wittig–Horner
Abstract: An air-stable phosphinito complex of palladium(II) was
reaction14a,d,16 for the E-isomer. Other strategies used in
found to be an efficient catalyst in the Heck reaction of a variety of
the synthesis of stilbenes involve palladium-catalyzed
aryl halides and styrenes. Resveratrol was concisely synthesized in
Heck17 and Suzuki18 coupling reactions. Additionally, ru-
63% overall yield; the reactions were performed under conventional
and microwave heating.
thenium-catalyzed cross-metathesis,19 the Perkin reac-
tion,20 Diels–Alder/Wittig reaction,21 Ramberg–Bäcklund
reaction,22 and lithiation condensation23 have been used.
Key words: Heck reaction, palladium, homogeneous catalysis, ha-
lides, coupling
Ph
Ph
Pd
Ph
Ph
Pd
Ph
Ph
O
O
P
P
P
O
Cl
Cl
1
In recent years, derivatives of stilbenes have attracted at-
tention because of their wide range of biological activity
and potential therapeutic value.1 Resveratrol (trans-
3,4¢,5-trihydroxystilbene, Figure 1) is perhaps the most
recognized polyhydroxylated stilbene (naturally occur-
ring), as it is easily found in vine bark, leaves, grapes, and
other plants.2 Resveratrol is usually synthesized in grapes
in response to microbial infections or stress. However, it
is also produced after exposure to chemical treatments,
such as herbicide or fungicide application, and by UV
light.3 Recently, resveratrol has been thought to be the
causative agent involved in the ‘French paradox’ and the
molecule most responsible for the Mediterranean diet ef-
fect in which high fat intake coupled with moderate wine
consumption leads to abnormally low rates of heart dis-
ease and cancer.4 The use of resveratrol has also been im-
plicated in the treatment of heart disease,5 Alzheimer’s
disease,6 platelet anti-aggregation,7 cancer,1b,e,8 and estro-
genic activity,9 as it acts as an anti-inflammatory10 and an-
tiviral agent.11 Additionally, resveratrol has shown radical
scavenging activity.12 Interestingly, from the same family
of stilbenes, Sale and co-workers have demonstrated the
strong anti-cancer activity of DMU-212 (trans-3,4,4¢,5-
tetramethoxystilbene).
H
H
P
O
Ph
Ph
Figure 2 Phosphinito complex of palladium(II)
In this article, we wish to enrich this diverse range of strat-
egies for stilbene synthesis using an air-stable phosphinito
complex of palladium(II) 1 (Figure 2). As part of our in-
terest in the preparation and application of this complex,
we have recently demonstrated that complex 1 is useful in
the Heck coupling of aryl halides with primary and sec-
ondary allylic alcohols24 and in the Heck arylation of elec-
tron-deficient and electron-rich alkenes.25 Complex 1 was
first synthesized by Dixon in 1971,26 and then later, the
crystalline structure was reported by several groups27 and
used in the methoxycarbonylation of iodobenzene and in
the cross-coupling of bromobenzene with butyl acrylate.28
Similar platinum and palladium compounds containing
hydrogen-bonded P–O–H–O–P ligands have also been
prepared, and they have been used in the syntheses of
amides and for the hydrophosphinylation of alkynes.
With this background, we channeled our efforts to demon-
strate that complex 1 (Figure 2) can be useful in the
palladium-catalyzed, highly chemo-, regio-, and stereo-
selective synthesis of trans-stilbene derivatives. Thus, we
studied the use of 1 in the Heck reaction between iodoben-
zene (2a) and styrene (3) and compared its performance
under standard and microwave conditions. After evaluat-
ing several solvent systems, we identified acetonitrile as
the best solvent (Table 1, entries 7–9). Additionally, 1.0
mol% of 1 was sufficient to obtain a quantitative yield of
trans-stilbene (4a) in 12 hours. Unfortunately, further at-
tempts to decrease the amount of 1 to 0.1 or 0.01 mol%
was reflected in lower yields (entries 10 and 11). Further-
more, the yield was lower still when sodium acetate was
used as the base (entries 1, 4, and 7). Notably, in both pro-
Carbon–carbon double bond formation is the key step in
the synthesis of (Z)- and (E)-stilbenes.13 Principal meth-
ods for the syntheses of these bonds involve the Wittig
OH
HO
OH
Figure 1 Resveratrol
SYNTHESIS 2012, 44, 446–452
x
x
.x
x
.2
0
1
1
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1289664; Art ID: M89011SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Resveratrol
447
Table 1 Heck Reaction between Iodobenzene and Styrenea
cedures, under standard and microwave conditions, the E-
isomer was observed as the sole product. Interestingly,
complex 1 is also known to be stable for up to two years
when stored at room temperature without any special con-
ditions. 31P NMR also showed that the complex was stable
in the presence of water or methanol for five or ten hours,
respectively. However, when the reactions were per-
formed with styrene, it was necessary to use an argon at-
mosphere to avoid styrene polymerization.
I
1
base, solvent
2a
3
4a
Entry
1 (mol%) Base
Solvent
Yieldb (%)
Ac
Bd
22
87
90
25
80
80
38
95
95
70
57
1
2
1
NaOAc
toluene
toluene
toluene
DMF
20
85
85
20
76
78
32
90
90
70
55
Using the optimized reaction conditions, we next exam-
ined the application of 1 for the cross-coupling of a variety
of aryl halides 2 and styrene (3) under 1.0 mol% catalyst
loading (Table 2). The results indicate that 1 constituted a
simple, yet efficient catalyst system for the Heck reactions
of aryl halides. Both electron-rich (entries 1–4) and elec-
tron-poor (entries 5, 7, and 8) aryl iodides and bromides
were efficiently converted into the desired products 4b–e
in high yields. However, when the reaction was carried
out with aryl chlorides, the desired products were not ob-
served (entries 6 and 9). The reaction is compatible with a
variety of functional groups and gives the corresponding
products 4f–h with excellent yields (entries 10–12). Addi-
tionally, when the reactions were performed using a mi-
crowave irradiation conditions, the yields obtained were
comparable to the thermal results, but they required short-
er reaction times (Table 2). However, when the reaction
was performed with 2- and 3-bromopyridines, complex 1
was active only with 3-bromopyridine (entry 14).
1
Et3N
3
1
K2CO3
NaOAc
Et3N
4
1
5
1
DMF
6
1
K2CO3
NaOAc
Et3N
DMF
7
1
MeCN
MeCN
MeCN
MeCN
MeCN
8
1
9
1
K2CO3
K2CO3
K2CO3
10
11
0.1
0.01
a Reaction conditions: 2a (1 mmol), 3 (1.2 mmol), base (2 mmol).
b Yield of isolated product after chromatographic purification.
c Conventional heating 80 °C under argon, 12 h.
d Microwave heating 200 °C, 20 min.
Table 2 Scope of the Palladium-Catalyzed Aryl Halide Heck Reactiona
X
1
R
R
+
K2CO3
MeCN
2
3
4
Entry
Ar-X
Stilbene
Yieldb (%)
Ac
Bd
88
I
1
2
3
4
5
2b
2c
2d
2e
2f
4b
4c
4b
4c
4d
85
MeO
MeO
HO
I
86
75
77
90
89
80
82
95
HO
Br
MeO
HO
MeO
HO
Br
Br
O2N
O2N
© Thieme Stuttgart · New York
Synthesis 2012, 44, 446–452

448
J. A. Morales-Serna et al.
PAPER
Table 2 Scope of the Palladium-Catalyzed Aryl Halide Heck Reactiona (continued)
X
1
R
R
+
K2CO3
MeCN
2
3
4
Entry
Ar-X
Stilbene
Yieldb (%)
Ac
Bd
–
Cl
6
7
2g
2h
–
–
I
4e
90
95
95
O
O
Br
Cl
8
2i
4e
87
O
O
O
9
2j
–
–
–
I
10
2k
4f
90
95
NC
NC
I
11
2l
4g
90
95
EtO
EtO
O
O
I
12
14
2m
2n
4h
4i
88
90
90
95
Cl
Cl
Br
N
N
a Reaction conditions: 2 (1 mmol), 3 (1.2 mmol), 1 (1 mol%), K2CO3 (2 mmol).
b Yield of isolated product after chromatographic purification.
c Conventional heating 80 °C under argon, 12 h.
d Microwave heating 200 °C, 20 min.
To illustrate the potential and efficiency of the described potassium carbonate, using toluene as solvent and micro-
methodology, a concise synthesis of resveratrol was per- wave heating (85%) after demethylation31 with the boron
formed. As shown in Scheme 1, treatment of commercial trichloride/tetrabutylammonium iodide. However, when
phloroglucinol (6) with ammonia/ammonium hydrox- the reaction was performed with sodium acetate as the
ide,29 followed by Sandmeyer reaction,30 provided iodo- base, only the starting material was recovered (entries 1
diphenol 7 (75% yield). Next, the cross-coupling reaction and 4), and with a longer reaction time, decomposition
between iododiphenol 7 and methoxystyrene 8 was per- was observed in the crude reaction mixture. Furthermore,
formed. This reaction took place under standard thermal similar yields were obtained when the Heck reaction was
and microwave conditions using triethylamine, sodium performed using the microwave conditions and shorter re-
acetate, or potassium carbonate as the base, and the sol- action times (see Table 3). Finally, with these results in
vent used was either toluene or acetonitrile. As shown in hand, we can affirm that this procedure provides an effi-
Table 3 (entry 6), a higher yield of resveratrol was ob- cient access to resveratrol with full regioselectivity, with-
tained when the reaction was performed in the presence of
Synthesis 2012, 44, 446–452
© Thieme Stuttgart · New York

PAPER
Synthesis of Resveratrol
449
1)
OH
I
OH
NH2
1) NH3/NH4OH
r.t., 30 min
1) NaNO2, H2SO4
0 °C, 15 min
HO
8
OMe
2) HCl (5 M)
1
, MeCN, K2CO3
80 °C, 12 h
2) KI, 0 °C, 7 h
HO
OH
HO
OH
HO
OH
resveratrol
7
5
6
OH
2) BCl3, TBAI, CH2Cl2
0 °C, 1 h
75% (two steps)
85% (two steps)
Scheme 1 Synthesis of resveratrol
Dipalladium Complex 1
Table 3 Heck Reaction between Iododiphenol 7 and Styrene 8 To
Give Resveratrola
A soln of Ph2PCl (0.75 mL, 4.05 mmol) in THF (5 mL) was added
dropwise with stirring to a Schlenk flask containing a soln of
[PdCl2(PhCN)2] (0.76 g, 2.0 mmol) in THF (10 mL) at r.t. When the
complete formation of the dichlorophosphane complex had been
confirmed by 31P NMR spectroscopy (d = 87 ppm), H2O (0.5 mL)
was added to the mixture and it was stirred at r.t. After 48 h, 31P
NMR analysis of an aliquot exclusively showed one signal at d =
78.6 ppm. The solvent was removed under vacuum to give the com-
plex 1 (1 g, 92%) as a yellow crystalline powder; mp 113–116 °C.
IR: 3441 (m) (O–H–O), 1435 (Ph), 1479 (w), 1023 cm–1 (m) (P–O).
1H NMR (300 MHz, CDCl3): d = 7.2–7.7 (Ph).
31P NMR (121.4 MHz, CDCl3): d = 78.6.
Entry
Base
Solvent
Yieldb (%)
Ac
Bd
–
1
2
3
4
5
6
NaOAc
Et3N
toluene
toluene
toluene
MeCN
MeCN
MeCN
–
50
60
–
60
62
–
K2CO3
NaOAc
Et3N
60
75
80
85
K2CO3
Method A: Catalytic Reaction
In all Heck reactions, aryl halide (1 mmol), styrene (1.0 mmol), base
(2 mmol), and catalyst 1 (1 mol%) in MeCN (3 mL) was heated in
a 80 °C oil bath equipped with a condenser system for 12 h. When
the reaction was complete, the mixture was cooled to r.t., diluted
with EtOAc (15 mL), washed with brine (10 × 3 mL), dried
(Na2SO4), and concentrated under vacuum. The resulting residue
was purified via flash column chromatography (silica gel, 25 × 2.5
cm, EtOAc–hexane, 30:70).
a Reaction conditions: 7 (1 mmol), 8 (1.2 mmol), 1 (1 mol%), base (2
mmol).
b Yield of isolated product after elimination of the protecting group
and chromatographic purification.
c Conventional heating 80 °C under argon, 12 h.
d Microwave heating 200 °C, 20 min.
out the use protecting groups in the aryl halide 7, which is
an important advantage in organic synthesis.
Method B: Microwave Reaction
Sealed vessels containing the mixture were placed in an Anton Paar
In conclusion, we have demonstrated that complex 1 is a
highly efficient catalyst in chemo-, regio-, and stereose-
lective syntheses of stilbenes. Moreover, our synthetic ap-
proach afforded resveratrol in three steps in 63% overall
yield. Finally, in all the examples, the use of microwave
irradiation reduced the reaction time significantly. There-
fore, we believe that this methodology will be of use for
the efficient preparation of polymethoxylated stilbenes of
biological interest.
Monowave 300 system heated at 200 °C/27 bars for 20 min.
trans-Stilbene (4a)32,33
Following the general procedure, the Heck reactions were carried
out with 2a (200 mg, 0.980 mmol), 3 (122 mg, 1.176 mmol), K2CO3
(270 mg, 1.961 mmol), and catalyst 1 (10 mg, 1 mol%). Yield: 159
mg (90%, method A), 168 mg (95%, method B).
1H NMR (300 MHz, CDCl3): d = 7.11 (s, 2 H), 7.23–7.27 (m, 2 H),
7.36 (t, J = 7.5 Hz, 4 H), 7.51 (d, J = 7.7 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 126.7, 127.8, 128.8, 128.9, 137.5.
Anal. Calcd for C14H12: C, 93.29; H, 6.71. Found: C, 93.22; H, 6.69.
All chemicals were purchased from Aldrich Chemical Co and used
without further purification unless stated otherwise. Yields refer to
the chromatographically and spectroscopically (1H and 13C) homo-
geneous materials, unless otherwise stated. All glassware utilized
was flame-dried before use. Reactions were monitored by TLC car-
ried out on 0.25-mm Macherey Nagel silica gel plates. Developed
TLC plates were visualized under a short-wave UV lamp and by
heating plates that were dipped in Ce(SO4)2. Flash column chroma-
tography was performed using flash silica gel (230–400 mesh) and
employed a solvent polarity correlated with TLC mobility. Micro-
wave reactions were performed in an Anton Paar Monowave 300 in
sealed reaction vessels. NMR experiments were conducted on
Bruker-Avance 300 MHz instruments using CDCl3 (99.9% D) as
the solvent referenced to internal standards CHCl3 (1H, d = 7.26
ppm; 13C, d = 77.0 ppm) or TMS as an internal reference (d = 0.00
ppm).
trans-4-Methoxystilbene (4b)32,33
Following the general procedure, the Heck reactions were carried
out with 2b (200 mg, 0.855 mmol), 3 (107 mg, 1.026 mmol), K2CO3
(236 mg, 1.709 mmol), and catalyst 1 (9 mg, 1 mol%). Yield: 153
mg (85%, method A), 158 mg (88%, method B).
1H NMR (300 MHz, CDCl3): d = 3.83 (s, 3 H), 6.90 (d, J = 8.7 Hz,
2 H), 6.98 (d, J = 16.4 Hz, 1 H), 7.08 (d, J = 16.4 Hz, 1 H), 7.23 (t,
J = 7.0 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.44–7.50 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 55.5, 114.3, 126.4, 126.8, 127.3,
127.9, 128.4, 128.8, 130.3, 137.8, 159.5.
Anal. Calcd for C15H14O: C, 85.68; H, 6.71. Found: C, 85.61; H,
6.68.
trans-4-Hydroxystilbene (4c)32,33
Following the general procedure, the Heck reactions were carried
out with 2c (200 mg, 0.909 mmol), 3 (113 mg, 1.091 mmol), K2CO3
© Thieme Stuttgart · New York
Synthesis 2012, 44, 446–452

450
J. A. Morales-Serna et al.
PAPER
(251 mg, 1.818 mmol), and catalyst 1 (10 mg, 1 mol%). Yield: 153
mg (86%, method A), 159 mg (89%, method B).
1H NMR (300 MHz, acetone-d6): d = 6.85 (d, J = 7.7 Hz, 2 H), 7.05
(d, J = 16.4 Hz, 1 H), 7.16 (d, J = 16.4 Hz, 1 H), 7.19–7.21 (m, 1 H),
7.34 (t, J = 7.6 Hz, 2 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.55 (d, J = 7.9
Hz, 2 H), 8.44 (s, 1 H).
trans-4-Chlorostilbene (4h)32,33
Following the general procedure, the Heck reactions were carried
out with 2m (200 mg, 0.840 mmol), 3 (105 mg, 1.008 mmol),
K2CO3 (232 mg, 1.681 mmol), and catalyst 1 (9 mg, 1 mol%).
Yield: 158 mg (88%, method A), 162 mg (90%, method B).
1H NMR (300 MHz, CDCl3): d = 7.07 (s, 2 H), 7.26–7.41 (m, 5 H),
7.44 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 7.4 Hz, 2 H).
13C NMR (75 MHz, acetone-d6): d = 116.5, 126.5, 127.0, 127.8,
128.8, 129.4, 129.5, 130.0, 138.9, 158.3.
13C NMR (75 MHz, CDCl3): d = 126.5, 127.3, 127.6, 127.8, 128.7,
128.8, 129.3, 133.1, 135.8, 136.9.
Anal. Calcd for C14H12O: C, 85.68; H, 6.16. Found: C, 85.65; H,
6.12.
Anal. Calcd for C14H11Cl: C, 78.32; H, 5.16. Found: C, 78.29; H,
5.12.
trans-4-Nitrostilbene (4d)32,33
Following the general procedure, the Heck reactions were carried
out with 2f (200 mg, 0.990 mmol), 3 (124 mg, 1.188 mmol), K2CO3
(273 mg, 1.980 mmol), and catalyst 1 (11 mg, 1 mol%). Yield: 200
mg (90%, method A), 212 mg (95%, method B).
1H NMR (300 MHz, CDCl3): d = 7.14 (d, J = 16.5 Hz, 1 H), 7.27 (d,
J = 16.5 Hz, 1 H), 7.33–7.43 (m, 3 H), 7.55 (d, J = 7.8 Hz, 2 H),
7.64 (d, J = 8.8 Hz, 2 H), 8.22 (d, J = 8.8 Hz, 2 H).
trans-3-Styrylpyridine (4i)32,33
Following the general procedure, the Heck reactions were carried
out with 2n (200 mg, 1.266 mmol), 3 (158 mg, 1.519 mmol), K2CO3
(349 mg, 2.532 mmol), and catalyst 1 (14 mg, 1 mol%). Yield: 206
mg (90%, method A), 218 mg (95%, method B).
1H NMR (300 MHz, CDCl3): d = 7.06 (d, J = 16.4 Hz, 1 H), 7.16 (d,
J = 16.3 Hz, 1 H), 7.26–7.40 (m, 4 H), 7.53 (m, 2 H), 7.85 (d, J = 9.0
Hz, 1 H), 8.48 (m, 1 H), 8.72 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 124.3, 126.5, 127.0, 129.0, 129.1,
133.5, 136.4, 144.0, 147.0.
13C NMR (75 MHz, CDCl3): d = 123.5, 124.9, 126.7, 128.2, 128.4,
128.8, 130.8, 132.6, 133.0, 136.7, 148.6.
Anal. Calcd for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found: C,
74.60; H, 4.88; N, 6.20.
Anal. Calcd for C13H11N: C, 86.15; H, 6.12; N, 7.73. Found: C,
86.12; H, 6.09; N, 7.70.
trans-4-Acetylstilbene (4e)32,33
Following the general procedure, the Heck reactions were carried
out with 2h (200 mg, 0.813 mmol), 3 (101 mg, 0.976 mmol), K2CO3
(224 mg, 1.626 mmol), and catalyst 1 (9 mg, 1 mol%). Yield: 157
mg (87%, method A), 171 mg (95%, method B).
1H NMR (300 MHz, CDCl3): d = 2.61 (s, 3 H), 7.14 (d, J = 16.4 Hz,
1 H), 7.22 (d, J = 16.4 Hz, 1 H), 7.25–7.38 (m, 3 H), 7.55 (d, J = 7.9
Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H).
5-Iodobenzene-1,3-diol (7)30
Concd NH4OH (30 mL) was added to phloroglucinol (5 g, 39.68
mmol) at 0 °C. Upon completion of the addition a stream of NH3
was bubbled into the mixture for 60 min. The cooling bath was re-
moved and stirring was continued at r.t. for 72 h. Vacuum concen-
tration of the clear brown soln gave a solid, to which was added 5
M HCl (20 mL), and the mixture was concentrated under vacuum to
afford a yellow solid. This solid was used directly in the next step.
13C NMR (75 MHz, CDCl3): d = 26.7, 126.6, 126.9, 127.6, 128.4,
128.9, 129.0, 131.6, 136.1, 136.8, 142.1, 197.6.
To an ice-salt cooled soln of 5-aminoresorcinol hydrochloride (4 g,
24.84 mmol) in H2O (50 mL) was added concd H2SO4 (5 mL). After
addition of a soln of NaNO2 (4.85 g, 69.8 mmol) in H2O (20 mL),
the mixture was stirred for 15 min at 0 °C and then EtOAc (25 mL)
was added. A soln of KI (15 g, 90 mmol) in H2O (15 mL) was added
slowly to control the evolution of N2. After 7 h, the layers were sep-
arated, and the aqueous layer was extracted with additional EtOAc
(3 × 30 mL). The organic layers were washed with 25% Na2S2O3
soln (3 × 25 mL), 1 M HCl (3 × 25 mL), and brine (3 × 25 mL), then
dried (MgSO4), filtered, and concentrated to a brown oil. The crude
mixture was purified by chromatography (silica gel, gradient
EtOAc–hexane) to yield 7 (4.3 g, 75%) as a white solid.
Anal. Calcd for C16H14O: C, 86.45; H, 6.35. Found: C, 86.42; H,
6.32.
trans-4-Cyanostilbene (4f)32,33
Following the general procedure, the Heck reactions were carried
out with 2k (200 mg, 0.873 mmol), 3 (109 mg, 1.048 mmol), K2CO3
(241 mg, 1.747 mmol), and catalyst 1 (9 mg, 1 mol%). Yield: 161
mg (90%, method A), 170 mg (95%, method B).
1H NMR (300 MHz, CDCl3): d = 7.08 (d, J = 6.4Hz, 1 H), 7.20 (d,
J = 16.3 Hz, 1 H), 7.31–7.40 (m, 3 H), 7.51–7.64 (m, 6 H).
1H NMR (300 MHz, acetone-d6): d = 6.72 (s, 1 H), 6.33 (s, 2 H),
8.40 (br s, 2 OH),
13C NMR (75 MHz, CDCl3): d = 110.6, 119.1, 126.8, 126.9, 127.0,
128.7, 128.9, 132.5, 132.5, 136.4, 141.9.
13C NMR (75 MHz, acetone-d6): d = 93.8, 106.8, 116.3, 159.3.
Anal. Calcd for C15H11N: C, 87.77; H, 5.40; N, 6.82. Found: C,
87.73; H, 5.36; N, 6.80.
Anal. Calcd for C6H5IO2: C, 30.53; H, 2.14. Found: C, 30.50; H,
2.12.
Ethyl trans-Stilbene-4-carboxylate (4g)32,33
Resveratrol17
Following the general procedure, the Heck reactions were carried
out with 2l (200 mg, 0.725 mmol), 3 (90 mg, 0.870 mmol), K2CO3
(200 mg, 1.449 mmol), and catalyst 1 (8 mg, 1 mol%). Yield: 164
mg (90%, method A), 173 mg (95%, method B).
1H NMR (300 MHz, CDCl3): d = 1.41 (t, J = 7.2 Hz, 3 H), 4.39 (q,
J = 7.2 Hz, 2 H), 7.12 (d, J = 16.2 Hz, 1 H), 7.23 (d, J = 16.2 Hz, 1
H,), 7.29–7.33 (m, 1 H), 7.34–7.43 (m, 2 H), 7.53–7.59 (m, 4 H),
8.03 (d, J = 8.4 Hz, 2 H).
Following the general procedure, the Heck reactions was carried out
with 5-iodobenzene-1,3-diol (7, 100 mg, 0.423 mmol), 8 (68 mg,
0.508 mmol), K2CO3 (116 mg, 0.846 mmol), and catalyst 1 (4 mg,
1 mmol%). The crude product was used directly in the next step.
To the mixture of the crude product and TBAI (936 mg, 2.538
mmol) in anhyd CH2Cl2 (4 mL), 1 M BCl3 in CH2Cl2 (2.5 mL) was
added dropwise at 0 °C under an argon atmosphere. Stirring was
continued for 7 h, while the mixture was allowed to warm to r.t.
Then, sat. aq NaHCO3 (5 mL) was added dropwise at 0 °C and the
resulting suspension stirred for 1 h at r.t., followed by extraction
with EtOAc (3 × 15 mL). The organic phases were combined, dried
13C NMR (75 MHz, CDCl3): d = 14.8, 60.9, 126.2, 126.7, 127.6,
128.2, 128.7, 129.3, 129.9, 131.1, 136.7, 141.7, 166.3.
Anal. Calcd for C17H16O2: C, 80.93; H, 6.39. Found: C, 80.89; H,
6.35.
Synthesis 2012, 44, 446–452
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Synthesis of Resveratrol
451
(MgSO4), and filtered. The solvent was removed under reduced
pressure and the product was purified by flash chromatography (sil-
ica gel, gradient EtOAc–hexane) to yield resveratrol as a white solid
[method A: 72 mg (75%); method B: 81 mg (85%)].
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1H NMR (300 MHz, acetone-d6): d = 7.39 (d, J = 8.1 Hz, 2 H), 6.98
(d, J = 16.2 Hz, 1 H), 6.87 (d, J = 16.2 Hz, 1 H), 6.82 (d, J = 8.1 Hz,
2 H), 6.52 (d, J = 2.2 Hz, 2 H), 6.24 (t, J = 2.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 159.3, 158.1, 140.6, 129.8, 128.9,
128.5, 126.6, 116.2, 105.5, 102.5.
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Acknowledgment
We wish to thank Eréndira García Ríos and Itzel Chacón, for their
technical assistance.
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