Microwave assisted Suzuki reaction in N-butylpyridinium salts/water systems

Article abstract of DOI:10.1016/j.tetlet.2011.06.009

A solvent mixture containing the ionic liquid derived from 4-picoline (C₄MPyBF₄) and water was tested for the Suzuki-Miyaura reaction under microwave irradiation. This solvent system led to very high conversions and clean reactions. When compared with the other more common ionic liquid, such as C₄MImBF₄, C₄MPyBF₄ proved to be superior.

Full text of DOI:10.1016/j.tetlet.2011.06.009

Tetrahedron Letters 52 (2011) 4168–4171
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted Suzuki reaction in N-butylpyridinium salts/water systems
Kelly L. dos Santos Castro a, Paulo G. de Lima a, Leandro S. M. e Miranda b, Rodrigo O. M. A. de Souza a,
⇑
a Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro CEP22941-909, Brazil
b Instituto Federal de Educação Ciência e Tecnologia do Rio de Janeiro, Campus Maracanã, Rio de Janeiro CEP20270021, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A solvent mixture containing the ionic liquid derived from 4-picoline (C4MPyBF4) and water was tested
for the Suzuki–Miyaura reaction under microwave irradiation. This solvent system led to very high con-
versions and clean reactions. When compared with the other more common ionic liquid, such as C4MIm-
BF4, C4MPyBF4 proved to be superior.
Received 7 May 2011
Revised 30 May 2011
Accepted 2 June 2011
Available online 13 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Microwave irradiation
Ionic liquids
Suzuki reaction
Cross coupling
1. Introduction
Ionic liquids due to their low vapor pressure, high dielectric con-
stant, and high thermal stability, show to be suitable solvent for
Transition metals, especially palladium-catalyzed cross-
coupling reactions have become a very important protocol since
its development in the 70’s with versatile application in organic
synthesis.1 Among these reactions, the Suzuki–Miyaura reaction
is a prominent exponent.2–4 The Suzuki–Miyaura reaction is the
Pd-catalyzed reaction between organoboron reagent and an organ-
ic halide and has become undoubtedly the most important
approach for the biaryls synthesis, which can have numerous
applications in natural product synthesis, pharmaceutical interme-
diates, pesticides, and covalent organic frameworks (COFS).5 The
generally mild reaction conditions and the availability and easy
preparation of organoboron coupling are behind its wide accep-
tance in the community of synthetic chemists.
In agreement with current search for greener process, several
protocols concerning Suzuki–Miyaura reaction in non-conventional
media have been published, such as aqueous medium,3,4 ionic liq-
uids6, and their simultaneous use.7 Among the ionic liquids available
and specifically developed, the 1-alkyl-3-methylimidazolium salts
(CnMImX) are the most used in palladium catalyzed C–C cross cou-
pling.8,9 These ionic liquids have been recognized as substrates10,11
and in situ precursors12,13 of palladium N-heterocyclic-carbene
complexes, which are involved in Pd-activation4,14 On the other
hand, N-alkylpyridinium ionic liquids (CnPyX) are supposed to be
non-carbenogenic salts.15,16
high temperature reactions promoted by microwave,18,19 however,
little efforts have been spent in the simultaneous use of ionic liq-
uids and microwave on Suzuki–Miyaura reactions.20 These short
reaction times can lead to a cleaner reaction, with the suppression
of side reactions, such as homocoupling, deboronation, and
dehalogenation.21
The N-alkyl-4-methyl pyridinium salts (CnMPyX) are long
known ionic liquids that find application in other areas of chemis-
try such as extraction media for organic–inorganic compounds and
electrochemistry.22–24 In the field of Pd catalyzed reactions these
ionic liquids have already found applications in hydrogenation
and carbonylation reactions and proved to be superior than
CnMImX.25–27 To the best of our knowledge ionic liquids derived
from 4-methyl pyridine were never used for Suzuki–Miyaura cross
coupling and here we report our results on the evaluation of
C4MPyBF4 on the microwave assisted Suzuki reaction compared
with other ionic liquid sources.
2. Results and discussion
The ionic liquid C4MPyBF4 was synthesized through N-alkylation
of 4-picoline with bromobutane under conventional heating fol-
lowed by anion metathesis reaction with NaBF4 in aqueous medium
(see Supplementary data). Initially C4MPyBF4 was tested as a solvent
in a series of reactions between phenylboronic acid (1, 1.5 mmol)
and 4-bromoacetophenone (2, 1.5 mmol) catalyzed by Pd(OAc)3
(3% mol) under microwave activation (150 °C for 5 min) in the pres-
ence of triethylamine as base (3 mmol) (Table 1). The model reaction
in neat C4MPyBF4 led only to poor conversion of the substrates to the
Another strategy adopted in Green Chemistry concerns the uti-
lization of microwave irradiation to enable short reaction times.17
⇑
Corresponding author. Fax: +55 2125627001.
E-mail address: rodrigosouza@iq.ufrj.br (R.O.M.A. de Souza).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.009

K. L. dos Santos Castro et al. / Tetrahedron Letters 52 (2011) 4168–4171
4169
Table 2
Table 1
Microwave assisted Suzuki reaction between several aryl halides (4–8) and phenyl-
boronic acid (1) using C4MPyBF4/water system at different proportions
Microwave assisted Suzuki reaction using C4MPyBF4/water system at different
proportions
B(OH)2
O
B(OH)2
O
Y
Y
Pd(OAc)3 (3%mol)
+
Pd(OAc)3 (3%mol)
+
Solvent (3 mL)
X
Solvent (3 mL)
Et3N, 150 ºC
5 minutes, MW
Br
Et3N, 150 ºC
5 minutes, MW
1
4-8
9-12
3
1
2
4- X=I, Y=4-NO2
Entry
C4MPyBF4/water
Conversiona (%)
5
6
- X=I, Y=4-OMe
- X=Br, Y=4-OMe
1
2
3
4
5
1:0
1:1
1:2
1:3
0:1
30
94
97
93
68
7- X=I, Y=2-Me
- X=Br, Y=3-Me
8
Entry
Arylhalide
C4MPyBF4/water
Yielda (Conv.)b (%)
1
2
3
4
5
6
7
8
4
5
6
4
5
6
7
8
1:1
1:1
1:1
1:3
1:3
1:3
1:3
1:3
95 (>99), 9
73 (77), 10
35 (43), 10
70 (77), 9
49 (54), 10
46 (53), 10
75 (78), 11
53 (60), 12
a
Determined by GC–MS analysis using benzonitrile as the internal standard.29
desired cross coupling product 3 (Table 1, entry 1), while the
addition of water to the reaction mixture rendered more active cat-
alytic systems, whichever proportion of ionic liquid/water was
investigated (Table 1, entries 2–4). Nevertheless the presence of
the ionic liquid seems to be crucial because a drop in the catalytic
activity was verified when water was used as the unique solvent (Ta-
ble 1, entry 5). Water was chosen because of the described beneficial
effects on the Suzuki reaction. Other reason for high performances
obtained in C4MPyBF4/H2O system may stem from an increase in
the fluidity of the reaction media allowing energy and mass transfer-
ence between organic (substrates) and aqueous-ionic (catalytic sys-
tem) and easy the work-up of the product.
The synergy of water and ionic liquid upon model reaction was
confirmed through an internal temperature increasing profile mea-
sured by a ruby thermometer (Fig. 1). The presence of water or
C4MPyBF4 as unique solvents led to a slow heating rate of the reac-
tion mixture and overshooting of the desired temperature, respec-
tively. When using different proportions of C4MPyBF4/H2O the
reaction temperature (150 °C) was reached faster and no over-
shooting is observed.
a
Isolated yields.
Determined by GC–MS analysis using benzonitrile as the internal standard.23
b
poor and electron rich aryl halides keeping the same conditions of
the model reaction. The results are presented in Table 2.
As can be seen in Table 2 the solvent system has a very impor-
tant influence on the catalytic performance. The system C4MPyBF4/
H2O 1:1 rendered higher conversions than the system C4MPyBF4/
H2O 1:3, mainly for iodoarenes 4 and 5 (Table 2, entries 1, 2, 4,
and 5). On the other hand, in the case of the bromoarene 6 a more
acceptable result was reached in the 1:3 mixture of solvents (Table
2, entries 3 and 6). Considering reactions in the latter solvent sys-
tem, the ortho-methyl group did exhibit some deactivating effects
upon catalytic activity (Table 2, entries 4 and 7), unlike the pres-
ence of a bromo substituent in the benzene ring (Table 2, entries
6 and 8). The details behind the influence of the ionic liquid con-
centration are not clear at the present moment. The lipophilic
The two faster heated solvent systems, namely C4MPyBF4/H2O
1:3 and 1:1, were also evaluated on their scope with other electron
Figure 1. Temperature behavior of Suzuki reactions presented in Table 1.

4170
K. L. dos Santos Castro et al. / Tetrahedron Letters 52 (2011) 4168–4171
Figure 2. Counter ion effect on heating ramp of Suzuki reaction between phenyl boronic acid (1) and bromo-anisole (2).
Table 3
Such results can be explained from the influence of the counter
ion in C4MPyX upon heating rate of the reaction mixture (Fig. 2).
The reaction performed in aqueous solution of C4MPyNO3 (50% v/
v) showed a completely different temperature increasing profile
when compared with C4MPyBF4 and C4MPyNTf2 based solvent
systems. Therefore, the drop in conversion observed in the latter
ionic liquid can be attributed to its poor solubility in water,
although C1MImNTf2 and C4MImNTf2 exhibited high temperature
increasing rate, even in toluene mixtures.28
Microwave assisted Suzuki reaction using ionic liquid/water system at different
proportions
O
B(OH)2
O
Pd(OAc)3 (3%mol)
+
Solvent (3 mL)
Et3N, 150 ºC
5 minutes, MW
Br
3
1
2
Yielda (Conv.)b (%)
3. Conclusion
Entry
Ionic liquid/water (1:1)
1
2
3
4
5
6
C4MImBF4
C4PyBF4
C4MImNO3
C4MPyNO3
C4MPyBF4
C4MPyNTf2
61 (65)
87 (92)
5 (3)
16 (21)
92 (94)
68 (74)
In conclusion we report that the ionic liquid C4MPyBF4, derived
from 4-picoline, is a very efficient solvent when mixed with water
for the Suzuki–Miyaura cross coupling promoted by microwave
irradiation. The resulting phosphine-free catalytic system was able
to activate both iodo and bromoarenes toward reaction conditions
(150 °C, 5 min). That high performance was indicated to arise from
the influence of the ion pair on the temperature increasing profile
during the dielectric heating of the reaction medium.
a
Isolated yields.
Determined by GC–MS analysis using benzonitrile as the internal standard.23
b
behavior of such ionic liquids may increase the solubility of the
starting materials favoring the interaction between the reactants.
On the other hand the presence of micelles cannot be discarded
at the present moment.
In order to evaluate the influence of the cation and anion of the
ionic liquid on catalytic activity, the model reaction as depicted in
Table 1 was performed in aqueous mixtures 1:1 composed by other
ionic liquids (Table 3).
Acknowledgments
We thank CAPES, CNPq, FAPERJ, and FINEP for the financial
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.009.
The results presented in Table 3 highlight the excellent behavior
of the pyridinium based ionic liquids in this reaction condition
when compared to the imidazolium salts (Table 3, entries 1–5),
indicating that formation of palladium N-heterocyclic-carbene
complexes can be deleterious to the catalytic activity as already re-
ported.24 The influence of the anion is also evident, once reactions
in the ionic liquids bearing tetrafluoroborate anion led to better
conversions than in nitrate based ones, which are more hydro-
philic. However the high performance was not maintained when
C4MPyBF4 was replaced by the water insoluble ionic liquid
C4MPyNTf2 (Table 3, entry 6).
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