Microwave- and ultrasound-assisted Suzuki-Miyaura cross-coupling reactions catalyzed by Pd/PVP

Article abstract of DOI:10.1016/j.tetlet.2008.04.061

Suzuki-Miyaura reactions using Pd/PVP as a catalyst source were carried out in water-ethanol solution. Under MW, sonication or thermal condition yields were very similar, from moderate to very good, in a variety of examples. However, TOFs were very different, 750/h under MW, 250/h under sonication, and 28/h under thermal conditions. Studies carried out under sonication showed that the whole system after product extraction can be re-used at least twice without any noticeable loss of yield.

Full text of DOI:10.1016/j.tetlet.2008.04.061

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3895–3898
Microwave- and ultrasound-assisted Suzuki–Miyaura
cross-coupling reactions catalyzed by Pd/PVP
*
*
´
Andrea Luzia F. de Souza , Lucyane C. da Silva, Bianca L. Oliveira, O. A. C. Antunes
Instituto de Quı´mica, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, CT Bloco A 641,
Cidade Universita´ria, Rio de Janeiro RJ 21941-909, Brazil
Received 3 November 2007; revised 8 April 2008; accepted 9 April 2008
Available online 12 April 2008
Abstract
Suzuki–Miyaura reactions using Pd/PVP as a catalyst source were carried out in water–ethanol solution. Under MW, sonication or
thermal condition yields were very similar, from moderate to very good, in a variety of examples. However, TOFs were very different,
750/h under MW, 250/h under sonication, and 28/h under thermal conditions. Studies carried out under sonication showed that the
whole system after product extraction can be re-used at least twice without any noticeable loss of yield.
Ó 2008 Elsevier Ltd. All rights reserved.
Cross-coupling reactions represent an extremely versa-
tile tool in organic synthesis.1 The Suzuki cross-coupling
reactions of arylboronic acids and aryl halides provide an
effective synthetic route to biaryls.2 The coupling reaction
of arylboronic acid derivatives with arylhalides in the pre-
sence of Pd(PPh3)4 and base to afford biaryls was first
reported in 1981.3
Catalysis with nanoparticles has undergone explosive
growth during the past decade. Because nanoparticles are
attractive catalysts compared to other bulk catalytic mate-
rials due to their high surface tension, nanoparticles in col-
loidal solution, as well as supported nanoparticles, have
been used as catalysts.4 El-Sayed’s group5 has deeply stud-
ied palladium nanoparticles stabilized in polyvinylpirrol-
idone (PVP) and verify that the amount of PVP can
determine the particle size. So, they successfully tested the
activity of Pd/PVP in Suzuki reactions and obtained good
yields.6 Sonogashira cross-coupling reaction was also
investigated using Pd/PVP as a catalyst in a ligandless
and copper free-system with high yields.7 Finally, still with
this system, Heck reactions showed to be conveniently car-
ried out and furnished reaction products with high yields.8
Microwave (MW) as a non-conventional energy source
has become a very popular and useful technology in
organic chemistry.9 The main attraction of using MW is
to short reaction times in cleaner systems10 even under sol-
ventless conditions.11 In addition, presently, there is no
doubt that there is no particular MW effect,12 that is
MW irradiation is just a simple, rapid, and effective way
of energy transfer to a reaction medium provide if it is
polar enough to suffer the absorption of MW energy.13
Consequently, MW irradiation has been vastly applied in
organic synthesis including C–C cross-coupling reactions.14
Other non-thermal way of energy transfer is ultrasound
irradiation,15 where cavitation plays the central role. Under
sonication several examples indicated that high yields and
short reaction times are attainable,16a–d and applications
of this energy transfer process on cross-coupling reactions
have been published in the literature.16e–g
Our group has been expanding the use of microwave17a
and ultrasound17b technologies, as well as, other phos-
phine-free systems in cross-coupling reactions.18 In the
present work, we wish to present new protocols to obtain
biaryls via Suzuki–Miyaura reaction conditions under
microwave and ultrasound irradiation using Pd/PVP as a
catalyst source.
*
Corresponding authors. Tel.: +55 21 25627248; fax: +55 21 2562 7559.
E-mail addresses: andrealuziasouza@yahoo.com.br (A. L. F. de
Souza), octavio@iq.ufrj.br (O. A. C. Antunes).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.061

3896
A. L. F. de Souza et al. / Tetrahedron Letters 49 (2008) 3895–3898
The model reaction afforded 100% of conversion in
X
R'
biphenyl at 80° after 18 h, while under microwave irradia-
tion the same result was obtained in 40 min using a potency
of 220 W (entry 1).20 Other aryl halides were tested in both
the conditions. The reactions of 4-nitroiodobenzene and
the 4-iodoanisole with phenylboronic acid, the furnished
products with high yields (entries 2 and 3). When the boro-
nic acids were changed to 4-bromophenylboronic acid and
4-fluorophenylboronic acid reaction with iodobenzene fur-
nished reasonable yields (entries 4 and 5). In the first case
(entry 4), no homosubstrate reaction was noticed showing
much higher selectivity in the oxidative addition step to 4-
nitroiodobenzene. Reaction between 2-furanboronic acid
and iodobenzene gave Suzuki product with very good yield
(entry 6). The less reactive 4-bromoacetophenone in cou-
pling with phenylboronic acid afforded biaryl also in very
good yield (entry 7). All the compounds were characterized
Pd/PVP (0.2 mol%)
R'-B(OH)2
+
K2CO3, EtOH-H2O 40%
R
R
Scheme 1.
In our initial efforts towardthe use of MW irradiation in
the Suzuki–Miyauracross-coupling reaction, using Pd/PVP
as a catalyst (Scheme 1), we choose not to employ any
ligand but PVP and use a very environmentally correct
solvent mixture, 40% aqueous ethanol,which in previous
examples3,18b–e was shown to be suitable to re-use.
We tested, as a model system, the reaction of iodoben-
zene with phenylboronic acid, using potassium carbonate
as a base, 0.2 mol % Pd/PVP (previously prepared accord-
ing to Narayanan and El-Sayed6b) in aqueous ethanolic
solution under microwave irradiation. In parallel, to com-
pare reaction times, thermal heating was also used. Both
MW and thermal heating furnished the reaction product
in quantitative yield, but in much shorter reaction time
under MW (Table 1).19 Other aryl halides and boronic
acids were also tested under both conditions and the results
are described in Table 1.
1
and analyzed by GC–MS, H NMR, and 13C NMR.21 In
general, the microwave-assisted reactions furnished some-
what better yields than those under thermal conditions in
much lower reaction times. In all the cases, considering
the fact that 0.2% molar of the Pd(0) catalyst is used, turn-
overs between 300 (entry 5) and 500 (entry 1) were obtained
in both the conditions, but TOFs (turnover frequency =
number of mol of productÁmol of catalystÀ1hÀ1) were 27
times better under MW, that is, in entry 1 a TON of 500
was obtained in 40 min, TOF of 750/h, under MW and
in 18 h, TOF of 28/h, under thermal conditions.
Table 1
Suzuki–Miyaura reaction between different aryl halides and boronic acidsa
Table 2
b,c
b,d
Suzuki–Miyaura reaction under ultrasound using Pd/PVPa
Entry Aryl halide
Boronic acid
TC
(%)
MW
(%)
Entry
1
Aryl halide
Boronic acid
Yieldb (%)
83
I
1
100
99
99
62
60
70
78
100
86
85
63
67
81
83
B(OH)2
I
B(OH)2
I
2
3
4
5
6
7
O2N
B(OH)2
B(OH)2
2
3
4
5
6
100c
O2N
I
B(OH)2
B(OH)2
MeO
I
80
99
94
47
86
MeO
I
Br
F
I
B(OH)2
B(OH)2
Br
F
I
I
I
I
B(OH)2
B(OH)2
O
I
B(OH)2
O
B(OH)2
O
B(OH)2
Br
O
7
B(OH)2
Br
a
Reaction condition: aryl halide (1 mmol), boronic acid (1 mmol),
K2CO3 (2 mmol), Pd/PVP solution (0.2 mol %) in 15 mL of EtOH-H2O
40% solution.
a
Reaction condition: aryl halide (1 mmol), (hetero)arylboronic acid
(1 mmol), Pd/PVP (0.2 mol %), K2CO3 (2 mmol), EtOH-H2O 40% solu-
tion (15 mL) under ultrasound irradiation by 5 h.
b
Conversion determined by GC–MS.
Thermal condition: 80 °C, 18 h.
c
d
b
Microwave condition: 220 W, 40 min (Monomode Microwave CEM
Determined by GC–MS.
2 h reaction.
c
Discover).

A. L. F. de Souza et al. / Tetrahedron Letters 49 (2008) 3895–3898
3897
To go further, we start investigating the above reaction
systems under ultrasound irradiation,19,22 Table 2, and
observed very good reaction yields after 5 h reaction. Inter-
estingly, as expected, 4-nitroiodobenzene reacted faster
than iodobenzene, that is, 100% conversion is achieved
with the former in only 2 h (27% conversion after the first
hour) while the latter needs 5 h to complete conversion. In
addition, we did not observe formation of homocoupling
products common in ultrasound-assisted coupling reac-
tion.23 Although better than under thermal condition, in
reaction time terms, sonication was observed to be worse
than MW irradiation, but was successful with all the sub-
strates tested.
In summary, the main advantage of microwave-assisted
production of the biaryls is the shorter reaction times. All
the reactions were successful and furnished good yields.
We showed that very low loadings of Pd/PVP were suffi-
cient to catalyze the reactions. The ultrasound-assisted
Suzuki reaction furnished biaryls with high yields and
shorter reaction time in comparison to thermal condition.
Both MW and sonication can be useful to short reaction
times in these reactions. Very high turnovers were observed
in all the cases. Using MW turnover frequencies of up to
750/h was observed. No particular cavitation effect was
observed in the sonicated systems.
The reason to investigate sonication was based on the
fact that we and other groups24 have previously showed
that normally Pd(0) stabilized nanoparticles are the sources
of soluble Pd(0)/Pd(II) species that would be the actual cat-
alysts in very low loadings25 (Scheme 2). We, therefore,
hypothesized that cavitation would play a role in disaggre-
gating Pd(0) stabilized nanoparticles furnishing very reac-
tive (solvated) Pd(0) mononuclear species which could
improve turnover frequencies.
The fact that reaction under sonication was faster than
thermal reaction but slower than MW assisted reaction
indicated that cavitation only accelerated oxidative addi-
tion on the Pd(0) cluster surface (stabilized in PVP) and
did not furnish free active solvated mononuclear Pd(0) spe-
cies. So, turnover frequency under sonication was between
125 and 250/h keeping the same TONs observed above.
Recycling the whole reaction media showed no notice-
able loss in reaction yields up to 2 cycles with high yields,
that is, the extraction of products with hexane and the
addition of 4-nitroiodobenzene, and phenylboronic acid
under ultrasound furnished 98% and 97% yields, 1st and
2nd re-use, respectively.
Acknowledgment
Financial support from CNPq, CAPES, and FAPERJ,
Brazilian Governmental Financing Agencies, is gratefully
acknowledged.
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Scheme 2.

3898
A. L. F. de Souza et al. / Tetrahedron Letters 49 (2008) 3895–3898
´
´
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128.77, 133.82, 140.88, 159.22; GC–MS: m/z = 115, 141, 169, 184
(M+). 4-Nitrobiphenyl – yellow solid. 1H NMR(CDCl3, 200 MHz) d
8.30 (d, 2H),7.74 (d, 2H),7.64 (d, 2H),7.52–7.44 (m, 3H). 13C
NMR(CDCl3, 50 MHz) d 147.6, 147.1, 138.8, 129.2, 128.9, 127.8,
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s), 7.51–7.41 (3H, m), 7.71–7.62 (4H, m), 8.04 (2H, d); 13C
NMR(50 MHz, CDCl3)
d 26.67, 127.23, 128.27, 28.94, 128.99,
135.87, 139.86, 145.77, 197.77; GC–MS: m/z = 76, 152, 181, 196
(M+). 4-Fluorobiphenyl:White solid. 1H NMR (CDCl3, 200 MHz) d
7.56–7.53 (m, 4H), 7.40 (t, 2H), 7.33 (t, 1H), 7.15 (t, 2H). 13C NMR
(CDCl3, 50 MHz) d 163.7, 161.3, 140.3, 137.4, 137.3, 128.8, 128.7,
128.6,127.3, 127.0, 115.7, 115.5. GC–MS: m/z = 77, 95, 172 (M+). 2-
Phenylfuran:Colorless liquid. 1H NMR (CDCl3, 200 MHz) d 7.68 (t,
2H), 7.44 (d, 1H), 7.39–7.24 (m, 3H), 6.64 (d, 1H), 6.45 (dd, 1H). 13C
NMR (CDCl3, 50 MHz) d 154.2, 142.3, 131.1, 128.9, 127.5, 124.0,
111.8, 105.1. GC–MS: m/z = 65, 77, 115, 144 (M+).
22. Sonication was performed in a thermostatic Branson 1210 ultrasonic
cleaner with a frequency of 47 kHz and a power of 250 W.
´
´
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`
19. General procedure for Suzuki reaction: In a 25 mL reaction flask
containing aryl halide (1 mmol), boronic acid (1 mmol), K2CO3 (2
mmol), Pd/PVP (0.2 mol %) in EtOH/H2O 40% solution (15 mL)
were employing at 80 °C by 24 h, when in microwave heating for 40
min (potency of 220 W) or for 5 h under ultrasound irradiation. After
the reaction was completed, the reaction mixture was extracted with
hexane, dry under sodium sulfate, and the solvent was eliminated by
vaccum. The crude product was analyzed by GC–MS, 1H NMR, and
13C NMR.
20. Monomode microwave CEM Discover. See more details in
<www.cem.com>.
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m), 7.50–7.55 (4H, m), 7.68–7.70 (4H, m); 13C NMR(50 MHz,
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