Microwave-promoted Suzuki-Miyaura coupling reactions in a cycloalkane-based thermomorphic biphasic system

Article abstract of DOI:10.1016/j.tetlet.2005.10.161

Microwave-promoted Suzuki-Miyaura coupling reaction of aryl halides attached to a cycloalkane-soluble platform was accomplished in a cycloalkane-based thermomorphic biphasic system. Following irradiation and subsequent cooling, the monophasic reaction mix

Full text of DOI:10.1016/j.tetlet.2005.10.161

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 171–174
Microwave-promoted Suzuki–Miyaura coupling reactions in
a cycloalkane-based thermomorphic biphasic system
Kanako Hayashi, Shokaku Kim, Yusuke Kono, Mihoko Tamura and Kazuhiro Chiba*
Laboratory of Bio-organic Chemistry, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu 183-8509, Japan
Received 24 September 2005; revised 23 October 2005; accepted 31 October 2005
Available online 16 November 2005
Abstract—Microwave-promoted Suzuki–Miyaura coupling reaction of aryl halides attached to a cycloalkane-soluble platform
was accomplished in a cycloalkane-based thermomorphic biphasic system. Following irradiation and subsequent cooling, the mono-
phasic reaction mixture immediately formed a biphasic solution to allow facile workup and separation of the product.
Ó 2005 Elsevier Ltd. All rights reserved.
Suzuki–Miyaura coupling reaction (palladium-catalyzed
cross-coupling reaction of aryl halides with boronic
acid) is one of the most versatile and utilized reactions
for the selective construction of carbon–carbon bonds,
in particular for the formation of biaryls. To date, sev-
eral palladium-catalyzed Suzuki–Miyaura reactions
using microwave and conventional heating have been
reported.1 Because of reduced reaction time, increased
product yields and allowance of precise control of the
reaction parameters, the use of microwave as a tool
for synthetic chemistry, especially parallel and combina-
torial chemistry, is increasing. In order to facilitate the
sequential process, several methods have been developed
for the Suzuki–Miyaura coupling reaction. For example,
the solid-phase resins possessing aryl halides or boronic
acids offer many advantages with regard to compound
isolation and ease of handling of corresponding
Suzuki–Miyaura coupling.2 The insoluble nature of the
resins has, however, complicated the characterization
of compounds attached to them and led to reagent
accessibility problems. Solution-phase synthesis meth-
ods, including fluorous3 and ionic liquid4 strategies,
have attracted much interest. In these systems, one of
the most important techniques is the relevant phase
labelling of the substrate, catalyst reagents and other
reaction components. An appropriate phase-labelling
system allows purification of the desired products using
simple work-up techniques such as evaporation, extrac-
tion and filtration. Although the introduction of liquid-
phase tags into target compounds which can be isolated
from other reaction components represents an attractive
methodology compared to solid-phase synthesis, many
of the reagents which are currently used for liquid or
solid-phase extraction are expensive, and unusual
treatments are sometimes required.
To overcome the purification difficulties in general solu-
tion-phase reactions, we have decided to explore the use
Table 1. Optimization of solvent combination for Suzuki–Miyaura
coupling reaction of aryl halide 1a with 4-fluorophenylboronic acida
Cycloalkane
Polar
solvent
Solvent
ratio (v/v)
Phase
transition
temp (°C)
Yieldb
(%)
c-Hex
c-Hex
MCH
MCH
MCH
MCH
MCH
MCH
MCH
DMF
DMF
DMF
DMF
DMId
NMPd
DMAcd
DMSOd
NM
1:1
9:1
1:1
9:1
1:1
1:1
1:1
1:1
1:1
45
42
50
44
32
18
20
97
94
98
95c
15
36
31
34
66
e
—
e
—
a Reaction conditions: PdCl2(dppf) (5 mol %), boronic acid (2 equiv),
K3PO4 (3 equiv), under Argon. Microwave-irradiation 150 W,
110 °C, 5 min.
b Isolated yield.
c Reusability of the recovered Pd catalyst was also tested; see Supple-
mentary data.
Keywords: Thermomorphic; Cycloalkane; Microwave; Suzuki–Miya-
ura cross-coupling.
d DMI: 1,3-dimethyl-2-imidazolidinone, NMP: 1-methyl-2-pyrroli-
done, DMAc: dimethylacetamide, DMSO: dimethylsulfoxide.
e Immiscible.
*
Corresponding author. Tel.: +81 42 367 5667; fax: +81 42 360
7167; e-mail: chiba@cc.tuat.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.161

172
K. Hayashi et al. / Tetrahedron Letters 47 (2006) 171–174
Table 2. Microwave-promoted Suzuki–Miyaura coupling reaction in cycloalkane-based thermomorphic biphasic solutiona
2a-2g
X
X
PdCl2(dppf)
Y
O
O
K3PO4, microwave
MCH/DMF (9/1,v/v)
Ar
O
O
1a:X=C, Y=4-Br
1b:X=C, Y=2-I
1c:X=N, Y=5-Br
3a-3j
OC18H37
C18H37
O
O
C18H37
2a : R1=4-F, 2b : R1=3-CN, 2c : R1=3-CHO
2d : R1=4-SMe, 2e : R1=3-NO2, 2f: R1=3-CO2Me
2g : 2-naphthylboronic acid
R1
B(OH)2
Entry
1
Aryl halide
Boronic acid
Productb
Yieldc (%)
98
R2O2C
1a
2a
2b
F
3a
3b
CN
2
3
4
1a
1a
1b
96
98
97
R2O2C
R2O2C
CO2Me
2f
3c
CO2R2
2a
F
3d
CO2R2 CO2Me
3e
5
1b
2f
95
CN
N
3f
6
7
1c
1c
2b
2c
97
98
R2O2C
N
CHO
3g
R2O2C
N
SMe
3h
8
1c
1c
1c
2d
2e
2g
94
97
79
R2O2C
NO2
N
9
3i
3j
R2O2C
N
10
R2O2C
a All reactions were carried out using aryl halide, 2 equiv of boronic acid, 3 equiv of K3PO4 and 5 mol % of PdCl2(dppf) in 4 ml of MCH/DMF (9:1,
v/v). The microwave power was 150 W, irradiation time was 5 min.
b R2: 3,4,5-tris-octadecyloxybenzyl.
c Isolated yield.

K. Hayashi et al. / Tetrahedron Letters 47 (2006) 171–174
173
of a thermomorphic biphasic system,5 which has attrac-
tive features for preparative organic synthesis and prom-
ising options for liquid-phase combinatorial synthesis.
Our studies have previously shown that temperature
can control the phase states of a cycloalkane-based bi-
phasic system that is composed of cyclohexane (c-Hex)
and aprotic polar solvents, such as dimethylformamide
(DMF), nitromethane (NM), acetonitrile or methanol.6
Upon completion of the coupling reaction, the phase
separation of cycloalkane and the aprotic polar solvent
was employed for product separation and purification.
was chosen as the optimal thermomorphic solvent sys-
tem. As listed in Table 2, Suzuki–Miyaura couplings
of various substituted phenylboronic acids with aryl ha-
lides 1a–c in the presence of potassium carbonate and a
catalytic amount of PdCl2(dppf) (5 mol %) in MCH/
DMF (9:1, v/v) were carried out (Table 2, Fig. 1). Using
microwave dielectric heating (150 W, 110 °C), all reac-
tions were completed in 5 min. Subsequently, after cool-
ing and the phase separation, the cycloalkane-soluble
platform-bound substrates 3a–j were selectively recov-
ered in the upper MCH phase. The purity of the prod-
ucts was verified using TLC analysis, which exhibited
a single spot.8,9 The compounds were readily obtained
by evaporation (simple removal of MCH), or by precip-
itation (addition of methanol in the MCH solution fol-
lowed by filtration). Finally, the coupled products
were cleaved from the cycloalkane-soluble platform by
treatment with a catalytic amount of NaOMe in a meth-
anol/MCH solution to afford the corresponding biaryls
in excellent yields.
Although alkanes, because of their low dielectric con-
stants, are not suitable for microwave-irradiated reac-
tions, various polar organic solvents or ionic liquids
are known to be effective for acceleration of Suzuki–
Miyaura coupling reaction. Even in the conventional
heating conditions of biphasic solutions, polar organic
solvents accelerated Suzuki–Miyaura coupling reaction.
This gave us incentive to construct a thermomorphic
reaction system that would enable highly efficient micro-
wave-promoted reactions in a monophasic solutions fol-
lowed by product isolation upon cooling and phase
separation. Herein, we report cycloalkane-based ther-
momorphic systems for microwave-promoted Suzuki–
Miyaura coupling reactions featuring a rapid reaction
purification process.
Initially, various solvents were investigated to determine
the composition that would give the thermomorphic
behaviour necessary for reversible phase transition un-
der microwave-irradiated heating conditions. The ther-
momorphic properties of various combinations of
cycloalkanes and microwave-active organic solvents
are listed in Table 1. As an example, the solvent mixture
of methylcyclohexane (MCH)/DMF (1:1, v/v), which
exists as a monophasic solution at above ca. 45 °C,
immediately separates into two phases upon cooling
the mixture to below ca. 45 °C. Subsequently, Suzuki–
Miyaura coupling reactions were carried out under
microwave-irradiated condition using the optimal sol-
vent combination (Table 1). To selectively partition
the product into the cycloalkane phase following the
reaction, the aryl halides were attached to 3,4,5-tris-
octadecyloxybenzyl alcohol (a cycloalkane-soluble
platform).7
Figure 1. (A) Before heating, with aryl bromide 1a (MCH phase) and
boronic acid 2a, Pd catalyst, base (DMF phase); (B) homogenous
solution after microwave-irradiation (150 W, 110 °C) for 5 min; (C)
after the reaction with biphenyls (MCH phase) and boronic acid, Pd
catalyst, salts (DMF phase).
It is noteworthy that our thermomorphic biphasic
system enables the usage of cycloalkane as a reaction
solvent under microwave-irradiation conditions,
although alkanes, because of their low dielectric
constants, are not suitable for microwave reaction. This
result showed a positive effect of miscibility of the cyclo-
alkane-based thermomorphic system for acceleration of
reactions. Furthermore, although thermal or micro-
wave-irradiated Suzuki–Miyaura coupling reactions
often form small amounts of symmetrical biaryl com-
pounds through self-coupling of the substrates, such
biaryl byproducts were not detected in the MCH phase
of our biphasic system.
As a model reaction, Suzuki–Miyaura coupling was car-
ried out under microwave-irradiated conditions (150 W,
5 min) using 1a and two molar equivalents of p-fluoro-
phenylboronic acid 2a in the presence of potassium
carbonate and a catalytic amount of PdCl2(dppf) (1,10-
bis(diphenylphosphino)ferrocene). In the presence of a
polar solvent, and upon cooling the mixture after the
completion of the reaction, the product was recovered
from the upper cycloalkane layer almost quantitatively.
On the other hand, in the absence of a polar solvent, the
coupling reaction afforded the product in less than 20%
yield. Microwave-irradiation for the mixture of com-
pound 1a and 2a in phase-separated solutions, for exam-
ple, composed of n-tetradecane and DMF (1:1 v/v) gave
product 3a in less than 35% (microwave power: 150 W,
110 °C, 10 min). The mixture of MCH/DMF (9:1, v/v)
In conclusion, our studies have shown that a cyclo-
alkane-based thermomorphic biphasic system allows for
a facile workup and separation in a short reaction time
for the microwave-promoted Suzuki–Miyaura coupling
reactions. We believe that the rapid reaction-separation
methodology using a combination of the microwave-
irradiation and heating technique along with the cyclo-
alkane-based thermomorphic biphasic system holds a
significant potential for parallel synthesis and for the
construction of combinatorial libraries.

174
K. Hayashi et al. / Tetrahedron Letters 47 (2006) 171–174
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Acknowledgments
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This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science, and Technology.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2005.10.161.
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7. More than 99% of product (3a–j) was partitioned in the
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1
8. Pd catalyst was not detected in products by H NMR (less
than 0.05 mol %).
9. A typical procedure: A mixture of PdCl2(dppf) (2.0 mg,
5 mol %), K3PO4 (32 mg, 0.15 mmol) and phenylboronic
acid (0.1 mmol) in 0.4 ml of DMF was treated with aryl
halides attached to the cycloalkane-soluble platform
(55 mg, 0.05 mmol) dissolved in 3.6 ml of methylcyclohex-
ane. The solution was degassed under Ar and irradiated a
microwave (microwave power was 150 W, 110 °C, 5 min).
After cooling, methylcyclohexane layer was separated and
evaporated under vacuum. Methanol was added to the
residue followed by filtration to afford the biaryl product
3a–j. This reaction was achieved in up to 0.1 M scale to give
the products in almost the same yields as the above
condition.