68
Published on the web December 12, 2009
Synthesis of Substituted Stilbenes via Direct Decarboxylative Coupling
of Cinnamic Acids with Arylboronic Acids under Palladium Catalysis
Mana Yamashita, Koji Hirano, Tetsuya Satoh,* and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
(Received October 30, 2009; CL-090964; E-mail: satoh@chem.eng.osaka-u.ac.jp, miura@chem.eng.osaka-u.ac.jp)
R3
R2
CO2H
+
R3
R2
Ar
Readily available cinnamic acids possessing a hydroxy
Pd(acac)2
group including ferulic acid efficiently undergo direct decar-
boxylative arylation under palladium catalysis to form hydroxy-
lated stilbenes. The reaction of related acids is also described.
ArB(OH)2
ð1Þ
•
Cu(OAc)2 H2O
2a-n
LiOAc
R1
R1
1a-d
3a-q
Table 1 also summarizes the results for the couplings of
various cinnamic acids 1a-1d with arylboronic acids 2a-2n. A
series of 4-substituted phenylboronic acids 2b-2l reacted with 1a
to selectively produce the corresponding stilbenes 3b-3l (Entries
2-12). 3-Methylphenylboronic acid (2m) and 2-naphthylboronic
acid (2n) efficiently coupled with 1a to give 3m and 3n, respec-
tively (Entries 13 and 14). Not only ferulic acid but also sinapinic
acid (1b) and coumaric acid (1c), which are also present in plants,
reacted with 2a to afford the corresponding hydroxylated stil-
benes 3o and 3p (Entries 15 and 16). Cinnamic acids possessing
an electron-donating group at their 4-position are known to
readily undergo decarboxylation.1b,8 As expected, 4-(dimethyl-
amino)cinnamic acid (1d) underwent the decarboxylatve cou-
pling to give 4-dimethylaminostilbene (3q) in 71% yield (Entry
17). In contrast, the reaction of unsubstituted cinnamic acid was
sluggish even at 120 °C to form stilbene in only 14% yield.
It was found that 5-phenyl-2,4-pentadienoic acid (4) also
underwent the decarboxylative coupling at 40 °C to afford 1,4-
diphenyl-1,3-butadiene (5) in 77% yield (eq 2).
Hydroxylated cinnamic acids including ferulic acid are
widely present in plants and are readily available from biomass
as building blocks for high-volume manufacturing.1 However,
the derivatization methods of such sustainable starting marerials
have been less explored and thus their development is strongly
desired. Although decarboxylation and amidation reactions to
form styrenes and cinnamamides have been described,1b,1c there
are only a few examples of direct cross-coupling involving C-C
bond formation.2
Meanwhile, we have continuously conducted research on
developing new coupling methods for the synthesis of relatively
complicated molecules from readily available, small molecules.3
Recently we reported the couplings of simple benzoic and
acrylic acids with alkynes under Rh-, Ir-, or Pd-catalysis to
construct fused aromatic and heteroaromatic molecules.4 During
our further study of the catalytic reactions of organic acids, it has
been revealed that the coupling of the hydroxylated cinnamic
acids with arylboronic acids can smoothly proceed under Pd-
catalysis accompanied by decarboxylation to form the corre-
sponding hydroxylated stilbenes. Such stilbenes have been
of considerable interest due to their interesting biological5
and photophysical properties.6 Compared with a conventional
synthetic method involving the reaction sequence of the
decarboxylative bromination of cinnamic acids (path a in
Scheme 1) and the subsequent Suzuki-Miyaura coupling of
the resulting bromostyrenes with arylboronic acids (path b),7
the present halogen-free process is straightforward and atom-
economical (path c).
CO2H
+
2a
(0.48 mmol)
4 (0.4 mmol)
Pd(acac)2 (0.02 mmol)
Cu(OAc)2•H2O (0.8 mmol)
ð2Þ
LiOAc (1.6 mmol)
5, 77%
DMF, 40 °C, 12 h
A plausible mechanism for the present coupling is illus-
trated in Scheme 2. Initial transmetalation of the added Pd(II)
species with arylboronic acids 2 followed by ligand exchange
with cinnamic acids 1 gives arylpalladium carboxylate inter-
mediates A.2 The subsequent decarboxylation and reductive
elimination afford stilbenes 3. The resulting Pd(0) species may
be reoxidized with the added Cu(II) compound.
Another possible reaction sequence may involve the
initial decarboxylation of 1 to form the corresponding styrenes
which then undergo arylation with 2 (oxidative Mizoroki-Heck
reaction).9 It was confirmed that during the reaction of 1a with
2a at an elevated temperature of 120 °C, a small amount of 4-
hydroxy-3-methoxystyrene (6) was detected by GC-MS,8 while
not at all at 60 °C. The reaction of 6 with 2a at 60 °C proceeded
to give 3a in a meaningfully lower yield (62% GC yield) than
that from 1a and 2a (Entry 1 in Table 1), part of 6 being
consumed by unidentified side reactions (eq 3).
In an initial attempt, the reaction of ferulic acid (1a)
with phenylboronic acid (2a) was examined under various
reaction conditions (see the Supporting Information). As a result,
it was found that their decarboxylative coupling proceeded
smoothly by using Pd(acac)2 (acac = acetylacetonate; 5 mol %),
Cu(OAc)2¢H2O (2 equiv), and LiOAc (4 equiv) as catalyst,
oxidant, and additive, respectively, in DMF at 60 °C under N2 to
produce stilbene 3a in 90% yield (R1 = OMe, R2 = OH,
R3 = H, Ar = Ph in eq 1; Entry 1 in Table 1).
Br
NBS
base
ArB(OH)2
a
b
Ar
CO2H
R
c
Pd(acac)2 (0.02 mmol)
Cu(OAc)2•H2O (0.8 mmol)
ArB(OH)2
+
2a
3a, 62%
ð3Þ
R
R
HO
LiOAc (1.6 mmol)
(0.48 mmol)
OMe
DMF, 60 °C, 3 h
6 (0.4 mmol)
Scheme 1.
Chem. Lett. 2010, 39, 68-69
© 2010 The Chemical Society of Japan
Yamashita, Mana
