S. Cardinal, N. Voyer / Tetrahedron Letters 54 (2013) 5178–5180
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cross-coupling of gem-dibromoalkene 3 with two molecules of the
functionalized arylboronic acid 4. The dibromoalkene is formed in
four steps from commercially available 4-hydroxy-3-methoxy-
mandelic acid 5, including a Corey–Fuchs type reaction on an
a-
ketoester precursor. The arylboronic acid is obtained in two steps
from commercially available 4-bromo-3-methoxyphenol 6.
Figure 4. Preparation of the arylboronic acid 4.
Results
Preparation of ethyl 3,3-dibromo-2-(4-benzyloxy-3-
methoxyphenyl)propenoate 3
The preparation of the gem-dibromoalkene substrate 3 (Fig. 3)
uses the commercially available 4-hydroxy-3-methoxymandelic
acid 5 as starting material.
First, the ethyl ester functionality was introduced by selectively
producing the cesium carboxylate salt, which then reacted with
bromoethane in DMF to give 7.14 Once the ester was formed, the
phenol functionality was protected with a benzyl group to give ethyl
4-benzyloxy-3-methoxymandelate 8. Prior to the formation of the
gem-dibromoalkene, the benzylic hydroxyl group was oxidized
using Dess-Martin periodinane. The
a-ketoester 9 obtained was
then treated with PPh3 and CBr4 under Corey–Fusch type reaction
conditions. Only few examples of the applications of these condi-
tions have been previously reported on such systems.15–17 Knochel’s
work, in which ethyl 3,3-dibromo-2-phenylpropenoate is prepared
by this strategy, was of particular interest and allows us to obtained
the desired gem-dibromoalkene 3 with satisfying yields.16
Figure 5. Suzuki–Miyaura cross-coupling leading to tetrasubstituted olefin pre-
cursor 2.
ety of functional groups and the low toxicity of boron compounds.
Some cases of double Suzuki–Miyaura cross-coupling on gem-dib-
romoalkene systems have been precendently reported and they
used different catalytic systems and conditions.17,20–25
Preparation of 4-benzyloxy-3-methoxyphenylboronic acid 4
The needed substituted arylboronic acid was prepared in two
steps from commercially available 4-bromo-3-methoxyphenol 6
(Fig. 4). Firstly, phenol was protected by a standard benzylation
protocol to give the compound 10.18 Secondly, the boronic acid
functionality was installed by an halogen-metal exchange/trans-
metallation/hydrolysis sequence. The conditions reported by
Diederich with this procedure for the preparation of multiple
methoxysubstitued arylboronic acids were used with good success
for this reaction.19
Arylboronic acid 4 was prepared with an overall yield of 67%
starting from the bromophenol precursor. With the two cross-cou-
pling partners in hand, we were able to investigate the double Su-
zuki–Miyaura reaction to unite the three aromatic rings of the
target compound.
In our case, we decided to use and adapt conditions inspired by
our previous work on the synthesis of o-aminomethylbiaryl sys-
tems.26,27 For those couplings, Pd2(dba)3 serves as the catalyst
and dicyclohexylphosphino-20,60-dimethoxybiphenyl (Buchwald’s
SPhos ligand) promotes coupling for those hindered systems.28
The preparation of the desired tetrasubstituted olefin 2 is pre-
sented in Figure 5. A 85% yield was obtained when using
2.5 equiv of the arylboronic acid 4. It is forseeable that a higher
yield could have been obtained using 3 equiv because the opti-
mized conditions in our initial work for single coupling required
1.5 equiv of boronic acid. Nevertheless, we were very much satis-
fied with this result considering the efficient consumption of both
reactants.
Preparation of quebecol 1 from ethyl 2,3,3-tri-(4-benzyloxy-3-
methoxyphenyl)propenoate 2
Double Suzuki–Miyaura reaction for the preparation of ethyl
2,3,3-tri-(4-benzyloxy-3-methoxyphenyl)propenoate 2
The preparation of quebecol from the
a,b-unsaturated ester
precursor 2 implies the reduction of the ester moiety, the hydroge-
nation of the double bond and the deprotection of phenolic func-
tionalities. The reactions used are illustrated in Figure 6.
The Suzuki–Miyaura cross-coupling reaction is one of bond two
sp2 centers due to its high efficiency and compatibility with a vari-
Due to a potential hydrogenolysis problem with allylic alcohol,
we decided to proceed with hydrogenation on the a,b-unsaturated
ester precursor 2 first. The use of high-pressure of hydrogen (286
psi) and heating (50 °C) was necessary to reduce the double bond
in addition to removing the benzyl protecting groups, giving 11
with an excellent yield. The ester functionality on the polyphenol
compound 11 was then reduced with LiAlH4. Few precedents were
found concerning the reduction of an ester function on the poly-
phenolic compound.29 A large excess of reducing agent, combined
with reflux heating and extended reaction time gave the target
compound quebecol 1 in a satisfying 84% yield. Interestingly, even
if harsh conditions are used for the final step, no traces of decom-
positions of precursor 11 or side reactions were visible while mon-
itoring the reaction.
Figure 3. Preparation of gem-dibromoalkene cross-coupling partner 3.