Solvent-free microwave-assisted Suzuki-Miyaura coupling catalyzed by PEPPSI-iPr

Article abstract of DOI:10.1055/s-0029-1217359

We have developed a new method for Suzuki coupling using an NHC-stabilized palladium catalyst under solvent-free conditions using microwave activation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217359

LETTER
1761
Solvent-Free Microwave-Assisted Suzuki–Miyaura Coupling Catalyzed by
PEPPSI-iPr
PEPPSI-iPr
C
a
i
talyze
e
r
iyaura
C
r
ouplingick Nun, Jean Martinez, Frédéric Lamaty*
Institut des Biomolécules Max Mousseron UMR 5247, CNRS, Université Montpellier 1 et Université Montpellier 2,
Place Eugène Bataillon, 34095 Montpellier Cedex 05, France
Fax +33(0)46144866; E-mail: frederic.lamaty@univ-montp2.fr
Received 25 February 2009
tions, solvents and bases. The main advances we can
quote here are the use of palladium supported on char-
coal,3 KF/Al2O3 or polymers, the use of trihydroxyborate
or trifluoroborate instead of boronic acid and diazonium
salts in place of aryl halides.4,5 Microwaves were also
used as an activation technique for Suzuki coupling,6 es-
pecially with water as solvent7 or under solvent-free con-
ditions using a solid support8,9 or hypervalent iodonium
salt and sodium tetraphenylborate.10
Abstract: We have developed a new method for Suzuki coupling
using an NHC-stabilized palladium catalyst under solvent-free con-
ditions using microwave activation.
Key words: Suzuki reaction, N-heterocyclic carbene catalyst, biar-
yls, green chemistry, cross-coupling
Palladium-catalyzed cross-coupling reactions are one of
the most powerful tools for the formation of carbon–
carbon bonds and the Suzuki reaction is certainly the most
used among them.1,2 The coupling of an aryl boronic acid
with an aryl halide in the presence of a base provides a
simple method to synthesize a large variety of com-
pounds. In recent years, many modifications have been
described including the use of diverse catalysts, condi-
One of the main objectives of our research group is to de-
velop clean processes and solvent-free reactions when
possible.11
Using the reaction of bromobenzene with 4-methoxyben-
zeneboronic acid, in the presence of potassium carbonate
(3 equiv), we investigated diverse conditions in order to
Table 1 Optimization of the Reaction Conditions
Entry
Time (min)
Temp (°C)
60
Catalyst (mol%)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (1)
PEPPSI (0.5)
Pd/C 10% (5)
Pd/C 10% (2)
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Conversion (%)
Homocoupling (%) Yield (%)a
b
b
b
b
b
b
b
b
b
b
c
1
45
45
45
45
45
30
20
10
5
71
93
–
–
–
–
–
–
–
–
–
–
–
–
c
2
90
3
110
130
150
110
110
110
110
110
110
110
110
110
100
100
100
100
100
100
90
91
89
80
80
80
88
4
5
6
7
8
c
9
–
c
10
10
10
10
10
10
93
–
c
11
98
6.8
9.4
9.8
6.7
–
c
12
97
–
c
13
100
97
–
c
14
–
a Isolated product.
b No homocoupling observed by 1H NMR.
c Not measured with an incomplete conversion.
SYNLETT 2009, No. 11, pp 1761–1764
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217359; Art ID: G07709ST
© Georg Thieme Verlag Stuttgart · New York

1762
P. Nun et al.
LETTER
optimize time, temperature and amount of catalyst In a microwave vial, agitation during the reaction was not
(Scheme 1). We chose to use palladium acetate, palladium strong enough to insure a good homogenization of solid
supported on charcoal and a new palladium N-hetero- reactants. In order to observe complete conversion, a good
cyclic carbene catalyst, PEPPSI (Pyridine Enhanced Pre- homogenization is essential so the mixture of PEPPSI,
catalyst Preparation, Stabilization and Initiation; K2CO3 and boronic acid should be ground in a mortar to
Figure 1).12–14 The results are presented in Table 1.
obtain a uniform powder before addition of bromoben-
zene to the microwave vial. Other methods use the addi-
tion of a solvent such as methanol and then its evaporation
before the reaction to assure homogenization.8 By a ‘pre-
grinding’ we can avoid this solvent utilization.
B(OH)2
OMe
Br
Pd
+
+
K2CO3
3 equiv
In order to confirm the applicability of our method to oth-
er boronic acids we prepared a large variety of compounds
starting from bromobenzene and various boronic acids
(Table 2; entries 1–8).
microwaves
OMe
Scheme 1
Table 2 Results Obtained with the Optimized Conditions
N
N
Entry Aryl halide
Product
Isolated
yield (%)
Cl Pd Cl
N
Br
MeO
1
88
85
Cl
1
11
Figure 1 Structure of PEPPSI-iPr
Me
2
3
1
To take complete advantage of solvent-free conditions, a
full conversion of reactants into the expected product is
required in order to avoid an expensive and solvent-con-
suming purification step. Furthermore, the homocoupling
12
13
OMe
1
98
1
side reaction needs to be limited. H NMR spectroscopy
was used to measure the conversion of starting materials
and the ratio of homocoupling. As shown in entry 8, the
best conditions were to use 1 mol% of PEPPSI-iPr at
110 °C for 10 minutes. Reducing the quantity of palladi-
um, reaction time or temperature led to a partial conver-
sion of reactants (entries 1, 2, 9 and 10). The yields given
here were obtained after recovery of the crude mixture
with 5 mL of dichloromethane and filtration in order to
eliminate the resulting catalyst and base. Even with full
conversion (entries 3–8), however, the isolated yield was
slightly lower than 100% because a small quantity of sol-
vent was used in order to recover the product and some of
the product may be still contained in the salts which are
not dissolved in water as in a classical extraction. This ex-
plains why in certain cases (entries 7 and 8), surprisingly,
the yield may be lower after a longer time of reaction be-
cause results were obtained from two different experi-
ments.
Me
4
5
6
1
1
1
99
85
85
14
15
O
OMe
OMe
16
S
7
8
1
1
81
84
17
In order to compare PEPPSI with other catalysts, the same
conditions were applied using Pd/C 10% and Pd(OAc)2
(entries 11–14). We found that, although the results are
good compared to those obtained in solution, full conver-
sion was not observed with 5 mol% of palladium and, as
demonstrated previously using solvent-free condi-
tions,15,16 homocoupling was present as an important side-
reaction.
18
19
OMe
Br
9
81
2
Synlett 2009, No. 11, 1761–1764 © Thieme Stuttgart · New York

LETTER
PEPPSI-iPr Catalyzed Suzuki–Miyaura Coupling
1763
Table 2 Results Obtained with the Optimized Conditions
(continued)
Table 2 Results Obtained with the Optimized Conditions
(continued)
Entry Aryl halide
Product
Isolated
Entry Aryl halide
Product
Isolated
yield (%)
yield (%)
Cl
20
96
92
10
11
12
2
2
2
97
98
97
OMe
Me
NO2
NO2
29
29
7
20
I
21
NO2
NO2
8
O2N
21
22
O2N
22
96
94
30
I
9
I
O
23
13
14
2
2
82
98
10
23
24
31
OMe
OMe
OMe
It is important to note that bromobenzene can be easily re-
moved under reduced pressure and boronic acid can be
eliminated simply by washing the reaction mixture with a
5% NaOH aqueous solution. So, in this case, full conver-
sion is not required in order to obtain the coupled product
in a pure form – the starting materials could be removed
easily without needing more dichloromethane for filtra-
tion. This method could not be used with nonvolatile aryl
bromides.
MeO2C
MeO2C
15
16
17
98
94
88
25
Br
3
3
In order to demonstrate the efficiency of this method, we
also applied it to solid arylbromides such as 2-naphtha-
lene, methyl 4-bromobenzoate, 4-bromothioanisole and
4-bromobenzaldehyde (entries 9–18). With these solid
reactants, the yields were particularly high compared to
those obtained with bromobenzene. We can explain that
by the fact that all the reactants were ground together in a
mortar before the reaction and, thanks to this, no aggre-
gates were observed in the microwave vial after the reac-
tion that could retain the product during the filtration step.
Me
MeO2C
26
MeS
MeS
27
Br
4
OHC
We also investigated the reaction starting from chloro and
iodo-aryls (entries 19–23). Here again the aryl halides are
solid and the yields were very high, even with the less
reactive chloro-aryls 6 and 7. Nevertheless, under our
conditions, only compounds with electron-withdrawing
groups were reactive enough to achieve complete conver-
sion.
Me
OHC
18
19
96
98
28
Br
5
CO2Me
MeO2C
Generally, quantification of the amount of palladium
contained in final products arising from the palladium-
catalyzed transformations is not reported, although this in-
formation is crucial in the field of bio-active molecules.17
25
Cl
6
Synlett 2009, No. 11, 1761–1764 © Thieme Stuttgart · New York

1764
P. Nun et al.
LETTER
Using ICP-MS analysis, the amount of palladium remain-
ing in the final product after a simple filtration of the crude
mixture was 997 ppm. This amount represents 14% of the
initial quantity of palladium used in the reaction, which
compares favorably to the 20% of the initial Pd/C recov-
ered in the final product of the Suzuki reaction,18 and is all
the more significant since the method we have developed
uses only 1 mol% of initial catalyst. This result can also
be compared to the 8000 ppm of palladium and iron re-
maining after the use of PdCl2(dppf)·CH2Cl2, after column
chromatography or washings with tributylphosphine.19
Acknowledgment
We thank the MENRT, CNRS and the Fondation d’Entreprise
EADS for financial support.
References and Notes
(1) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(2) Sakurai, H.; Hirao, T.; Negishi, Y.; Tsunakawa, H.;
Tsukuda, T. Trans. Mater. Res. Soc. Jpn. 2002, 27, 185.
(3) Felpin, F.-X.; Ayad, T.; Mitra, S. Eur. J. Org. Chem. 2006,
2679.
(4) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64,
3047.
(5) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59.
(6) Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem.
2008, 1133.
(7) Leadbeater, N. E.; Smith, R. J. Org. Biomol. Chem. 2007, 5,
2770.
(8) Melucci, M.; Barbarella, G.; Sotgiu, G. J. Org. Chem. 2002,
67, 8877.
(9) Basu, B.; Das, P.; Bhuiyan, M. M. H.; Jha, S. Tetrahedron
Lett. 2003, 44, 3817.
(10) Yan, J.; Hu, W.; Zhou, W. Synth. Commun. 2006, 36, 2097.
(11) Colacino, E.; Nun, P.; Colacino, F. M.; Martinez, J.; Lamaty,
F. Tetrahedron 2008, 64, 5569.
In conclusion, we have developed a microwave-assisted
method for the synthesis of biaryls. The reaction was per-
formed in the absence of solvent, although a small amount
of solvent was used for recovery of the product. This
method was based on the use of a new and powerful cata-
lyst and proved to be efficient with a large variety of bo-
ronic acids and bromo-, chloro- and iodoaryls. Compared
to the existing methods, this methodology is clean, rapid,
and efficient.
General Procedures for the Solvent-Free Microwave-Assisted
Suzuki–Miyaura Coupling
Reactions were performed in sealed vessels with a Biotage Initiator
60 EXP® instrument. The temperature was measured with an IR
sensor on the outer surface of the reaction vial.
(12) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G.
Aldrichimica Acta 2006, 39, 97.
(13) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Hadei, N.;
Nasielski, J.; O’Brien, C. J.; Valente, C. Chem. Eur. J. 2006,
13, 150.
Method A (with liquid halides): The boronic acid (0.5 mmol) was
finely ground in a mortar and pestle with K2CO3 (207 mg, 1.5
mmol, 3 equiv) and PEPPSI-iPr (0.005 mmol, 3.4 mg). The solid
mixture was then charged into a microwave vial before the addition
of the liquid halide (0.5 mmol, 1 equiv). After 10 min at 110 °C,
CH2Cl2 (5 mL) was added and the product was isolated after filtra-
tion and evaporation.
(14) (a) Ray, L.; Shaikh, M. M.; Ghosh, P. Dalton Trans. 2007,
4546. (b) Benakki, H.; Colacino, E.; André, C.; Guenoun, F.;
Martinez, J.; Lamaty, F. Tetrahedron 2008, 64, 5949.
(15) Klingensmith, L. M.; Leadbeater, N. E. Tetrahedron Lett.
2003, 44, 765.
(16) Nielsen, S. F.; Peters, D.; Axelsson, O. Synth. Commun.
2000, 30, 3501.
(17) Garrett, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889.
(18) Tagata, T.; Nishida, M. J. Org. Chem. 2003, 68, 9412.
(19) Chen, C.-Y.; Dagneau, P.; Grabowski, E. J. J.; Oballa, R.;
O’Shea, P.; Prasit, P.; Robichaud, J.; Tillyer, R.; Wang, X.
J. Org. Chem. 2003, 68, 2633.
Method B (with solid halides): The boronic acid (0.5 mmol, 1
equiv) and the halide (0.5 mmol, 1 equiv) were finely ground in a
mortar and pestle with K2CO3 (207 mg, 1.5 mmol, 3 equiv) and
PEPPSI-iPr (0.005 mmol, 3.4 mg). The solid mixture is then
charged into a microwave vial then, after 10 min at 110 °C, CH2Cl2
(5 mL) was added and the product was isolated after filtration and
evaporation.
Synlett 2009, No. 11, 1761–1764 © Thieme Stuttgart · New York