Suzuki-Miyaura cross-coupling of benzylic bromides under microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2011.08.096

A procedure for benzylic Suzuki-Miyaura cross-coupling under microwave conditions has been developed. These conditions allowed for heterocyclic compounds to be coupled. Optimum conditions found were Pd(OAc)₂, JohnPhos as the catalyst and ligand

Full text of DOI:10.1016/j.tetlet.2011.08.096

Tetrahedron Letters 52 (2011) 5656–5658
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Suzuki–Miyaura cross-coupling of benzylic bromides under
microwave conditions
⇑
Steven W. McDaniel, Charles M. Keyari, Kevin C. Rider, Nicholas R. Natale, Philippe Diaz
Core Laboratory for Neuromolecular Production, Dept. of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59803, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A procedure for benzylic Suzuki–Miyaura cross-coupling under microwave conditions has been devel-
oped. These conditions allowed for heterocyclic compounds to be coupled. Optimum conditions found
were Pd(OAc)2, JohnPhos as the catalyst and ligand, potassium carbonate as base, and DMF as the solvent.
Using these conditions, a library of structurally diverse compounds was synthesized.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 July 2011
Revised 16 August 2011
Accepted 16 August 2011
Available online 23 August 2011
Keywords:
Suzuki–Miyaura
Cross-coupling
Microwave
Palladium
System xÀc (SxÀc ) is a membrane transporter that functions as an
obligate exchanger of -glutamate (
-Glu) and cystine.1 The high
concentration of -Glu within cells drives the export of -Glu and
oxazole-3-carboxylate derivatives. Our previous attempts at this
coupling have resulted in low yields in our series of compounds.
We developed a protocol that is useful for the coupling of water
sensitive compounds. Optimizing this coupling is necessary to cre-
ate a library of SxÀc inhibitors. In this Letter, we report a method
for the palladium-catalyzed benzylic arylation of isoxazole and
benzoate derivatives with arylboronic acids.
The isoxazole was prepared using previously reported synthetic
strategy.14,15 In our initial attempt at the benzylic coupling, phenyl
boronic acid was used, but the compound resulting from Suzuki
coupling was only separable from the starting material by HPLC.
In order to have a better monitoring of the reaction, 3-methoxy-
benzeneboronic acids and the isoxazole were used for the optimi-
zation of the Suzuki coupling under microwave conditions.
Microwave was used instead of classical heating to shorten the
reaction time. Yields were comparable between conventional and
microwave heating. Details on the experimental protocol used
are mentioned in Tables 1 and 2.
L
L
L
L
the import of cystine in a 1:1 molar ratio.2 SxcÀ transporter has
emerged as a very promising target for CNS disorders, such as drug
addiction,3 viral pathology,4 and brain tumor growth because of its
role in oxidative protection,5 blood–brain barrier operation, neuro-
transmitter release, and synaptic organization.6 We recently re-
ported a novel series of SxÀc inhibitors based on an isoxazole
scaffold.7 Inhibition of SxÀc reduces the tumor cell’s ability to pro-
tect itself from oxidative stress.
To further explore structure–activity relationships of this series
we sought to introduce an aromatic cycle at the benzylic C5 posi-
tion of an isoxazole. One straightforward approach to introduce
the aromatic ring at the benzylic C5 position of an isoxazole would
be to use a Suzuki–Miyaura cross-coupling reaction. There are
very few examples in the literature of Suzuki couplings at the ben-
zylic position and no examples involving heteroaryl benzylic bro-
mide. Benzylic carbonates have been coupled using [Pd]-DPPPent
with K2CO3 and DMF.8 McLaughlin coupled benzylic phosphates
with Pd(OAc)2/PPh3.9 Burns et al. coupled heteroarylboronic acids
with benzylic carbons.10 Molander et al. developed a protocol
Conversion yields were determined by LC–MS analysis. A low
yield, approximately 10%, was achieved when coupling 3-meth-
oxybenzeneboronic acid to the isoxazole using Pd(PPh3)4 as a cat-
alyst, Cs2CO3 as a base, and with dioxane as a solvent.
using potassium organotrifluoroborates as the nucleophilic bor-
To improve the yield of this reaction, several modifications were
explored. Increasing the time or the temperature did not improve
the yield (Table 1, entries 1–3). We then studied the impact of
the solvent on the yield. Using DMF slightly increased the yield
compared to dioxane and THF (Table 1, entry 5). Changes to the
base had no effect on the yield. It has been proposed that silver
oxide increases the rate of boron to palladium transfer step of
the catalytic cycle.16,17 Use of silver oxide (Table 1, entry 8) had
13
on.11 Chowdhury et al.12 and Ines et al. also used water in their
´
protocols. Unfortunately, this route fails in using previously
described protocols because of the water sensitivity of ethyl 1,2-
⇑
Corresponding author.
E-mail addresses: philippe.diaz@umontana.edu, philippe.diaz@mso.umt.edu
(P. Diaz).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.096

S. W. McDaniel et al. / Tetrahedron Letters 52 (2011) 5656–5658
5657
Table 1
Condition screen for benzylic Suzuki–Miyaura cross-coupling reactions under micro-
t-Bu
wave conditionsa
PCy2
OMe
P
PCy2
MeO
t-Bu
O
O
N
Br
OEt
O
N
O
L1 (SPhos)
L2 (JohnPhos)
L3 (Cyclo JohnPhos)
OEt
Pd(PPh3)4, 140o C
O
Figure 1. Buchwald phosphine ligands.
O
O
O
O
O
B
HO
OH
Table 3
Entry
Base
Solvent
Yield (%)
Cross-coupling of benzylic bromides with arylboronic acidsa
1
2b
3c
4
5
6
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaHCO3
K2CO3
Dioxane
Dioxane
Dioxane
THF
DMF
DMF
10
10
10
10
15
15
15
15
R
R
Pd(OAc)2, JohnPhos
Ar
Ar
O
Br
O
K2CO3, DMF, microwave
B
HO
OH
7
DMF
DMF
O
8d
K2CO3
O
N
a
Reaction conditions: boronic acid (1.5 mmol), isoxazole bromide (1.0 mmol),
base (3.0 mmol), Pd (PPh3)4 (5 mol %), solvent (2 mL), 20 min.
OEt
N
OEt
OEt
b
Duration was 60 min.
Temperature 160 °C.
Ag2O (2.5 mmol) was added.
O
c
O
O
O
O
d
O
O
2 (60.9%)
1 (50.4%)
F3C
Table 2
O
N
Condition screen for benzylic Suzuki–Miyaura cross-coupling reactions under micro-
O
N
wave conditionsa
OEt
O
O
O
O
O
O
O
N
Br
OEt
O
N
O
OEt
3 (68.9%)
reaction conditions
4 (20.1%)
O
O
O
O
O
O
O
O
B
HO
OH
O
O
O
O
Entry
Catalyst System
Base
Temp (°C)
Yield (%)
9
10b
11
12
13
14
15
16c
17
18
19
PdCl2(dppf)
PdCl2(dppf)
Pd(OAc)2, L1
Pd(OAc)2, L2
Pd(OAc)2, L2
Pd(OAc)2, L2
Pd(OAc)2, L2
Pd(OAc)2, L2
Pd(OAc)2, L3
Pd(OAc)2, L2
Pd(OAc)2, L3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
140
140
140
140
150
130
80
15
15
5 (63.0%)
7 (74.6%)
6 (66.7%)
F3C
25
50.4d
40
O
O
O
44d
10
O
80
15
25
25
25
8 (34.7%)
140
140
140
a
Reaction conditions: boronic acid (1.5 mmol), bromide (1.0 mmol), K2CO3
(3.0 mmol), Pd(OAc)2 (5 mol %), L2 (10 mol %), DMF (2 mL), 140 °C, 20 min. Isolated
Et3N
a
yields are shown.
Reaction conditions: boronic acid (1.5 mmol), bromide (1.0 mmol), base
(3.0 mmol), catalyst (5 mol %), ligand (10 mol %), DMF (2 mL), 20 min.
b Ag2O (2.5 mmol) was added.
Using Table 2, entry 12 protocol, we coupled a small series of
isoxazoles and benzoates to show the effects of electron donating
and electron withdrawing groups, as well as the versatility of this
protocol (Table 3). The phenylboronic acid had the highest yield
with 75% for the benzoate derivative and 69% for the isoxazole
derivative. Electron withdrawing groups such as 4-trifluorobenzen-
eboronic acid had the lowest yields with 35% and 20%. As expected,
better yields were obtained with electron donating groups like 4-
methoxybenzene boronic acid. Although the 4-methoxybenzene
boronic acid would be expected to have a much higher yield com-
pared to the 3-methoxybenzeneboronic acid, yet the 4-methoxy-
benzeneboronic acid only had a slightly better yield than the
3-methoxybenzeneboronic acid. This can be attributed to the boro-
nic acids being used as the 4-methoxybenzeneboronic acid that was
of much lower purity than the 3-methoxybenzeneboronic acid as
determined by NMR analysis (data not shown). Comparable moder-
ate to good yields were obtained in the benzyl bromide series.
c
Duration was 60 min.
Isolated yield.
d
no effect on the yield. We decided to use the pre-catalyst
PdCl2(dppf) because of its chelating biphosphine with a large ‘‘bite’’
angle18 even though b-hydride elimination cannot compete with
reductive elimination in our case. The use of PdCl2(dppf) had no ef-
fect on the yield. Several bulky, electron-rich Buchwald phosphine
ligands were chosen (Fig. 1). These ligands have been shown to
accelerate the oxidative addition and reductive elimination pro-
cesses due to their bulky electron-rich phosphine groups.19,20 Use
of these phosphine ligands and Pd(OAc)2 as the catalysts resulted
in the greatest increase of the yield (Table 2). The conditions that
provided the greatest yield of 50% were L2 as shown in Table 2,
entry 12.

5658
S. W. McDaniel et al. / Tetrahedron Letters 52 (2011) 5656–5658
The current protocol is superior to two other routes to C5 aryl
References and notes
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To conclude, few examples of Suzuki couplings at a benzylic
position and even less with heteroaromatic rings such as isoxaz-
oles have been described in the literature. Our study provides a
protocol for achieving benzylic Suzuki coupling with moderate
to good yields. Our study also provides a method that is useful
for the synthesis of water sensitive compounds using a catalyst
system commercially available. Furthermore, our method is quick
and versatile with these findings; the synthesis of new class of
water sensitive isoxazoles was possible. Our study allowed us
to obtain the desired compounds to explore the SARs in this
series.
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Acknowledgment
This work was supported by NIH Grant P30-NS055022.
Supplementary data
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Supplementary data associated (experimental procedures for
synthesis, characterization data of new compounds, and 1H and
13C NMR spectra for all compounds prepared) with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.08.096.