Carbonylative Suzuki-Miyaura coupling catalyzed by palladium supported on aminopropyl polymethylsiloxane microspheres under atmospheric pressure of CO

Article abstract of DOI:10.1016/j.molcata.2016.03.017

Carbonylative Suzuki-Miyaura cross-coupling reactions of various aryl iodides with phenylboronic acids were catalyzed by palladium supported on amino-modified silica microspheres. Reactions performed with a very low concentration of Pd, under the atmospheric pressure of CO, led to high/moderate yields of multiple benzophenones.

Full text of DOI:10.1016/j.molcata.2016.03.017

Accepted Manuscript
Title: Carbonylative Suzuki–Miyaura coupling catalyzed by
palladium supported on aminopropyl polymethylsiloxane
microspheres under atmospheric pressure of CO
´
Author: Wojciech Zawartka Piotr Pospiech Marek Cypryk
Anna M. Trzeciak
PII:
S1381-1169(16)30084-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.03.017
MOLCAA 9816
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
5-12-2015
27-2-2016
5-3-2016
´
Please cite this article as: Wojciech Zawartka, Piotr Pospiech, Marek Cypryk,
Anna M.Trzeciak, Carbonylative SuzukindashMiyaura coupling catalyzed by
palladium supported on aminopropyl polymethylsiloxane microspheres under
atmospheric pressure of CO, Journal of Molecular Catalysis A: Chemical
http://dx.doi.org/10.1016/j.molcata.2016.03.017
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Carbonylative Suzuki–Miyaura coupling catalyzed by palladium
supported on aminopropyl polymethylsiloxane microspheres
under atmospheric pressure of CO
Wojciech Zawartka1, Piotr Pośpiech2, Marek Cypryk2, Anna M. Trzeciak1*
1Faculty of Chemistry University of Wrocław, 14 F. Joliot-Curie St., 50-383 Wrocław, Poland
2Centre of Molecular and Macromolecular Studies Polish Academy of Sciences 112
Sienkiewicza, 90-363 Łódź, Poland

Graphical abstract
Ar1X + Ar2B(OH)2
CO
O
Ar1
Ar2
R Si
Si R
Si R
R
O
R
O
OEt
EtO
O
H
H
R Si
Si
OEt
Si
N
H
N
H
O
O
O
EtO
R Si
Si R
R
R
O
O
R Si
Si R
R
R
Highlights
 High catalytic activity of palladium supported on polysiloxane microspheres in Suzuki
reaction.
 High catalytic efficiency at low amount of Pd.
 Good selectivity to different substituted benzophenones at low CO pressure.

Abstract
Carbonylative Suzuki–Miyaura cross-coupling reactions of various aryl iodides with
phenylboronic acids were catalyzed by palladium supported on amino-modified silica
microspheres. Reactions performed with a very low concentration of Pd, under the atmospheric
pressure of CO, led to high/moderate yields of multiple benzophenones.
key words: palladium; silica microspheres; carbonylative coupling; benzophenones.
1. Introduction
Palladium-catalyzed cross-coupling reactions have become one of the most popular tools for
the synthesis of novel bio-active compounds and advanced materials. Among the different C–
C cross-coupling reactions, three substrate-type carbonylations have also been developed[1].
While the carbonylations of aryl halides are well established, the carbonylative coupling
reactions of such compounds have been investigated much less. Benzophenones, which are
usually formed in these reactions, are important building blocks for a large number of
pharmaceuticals and natural products. Hence, there is still a need to develop convenient and
more general methodologies for the synthesis of products of this class.
Carbonylative Suzuki reactions generally proceed in the presence of typical homogeneous
palladium precursors such as PdCl2, Pd(OAc)2, [Pd(acac)2], [Pd(tmhd)2], [Pd2(dba)3][2–5],
palladium complexes containing phosphine ligands [6–18], or N-heterocyclic carbenes (NHC)
[19, 20], which makes the recovery of the metal from the reaction mixture almost impossible
and may result in the unacceptable contamination of the product with palladium. The high cost
combined with the toxic effects of Pd have led to an increased interest in immobilizing the
catalysts on supports. There are a few examples of carbonylative S–M coupling with silica-
supported phosphine complexes[21], Pd nanoparticles immobilized on supported ionic liquid-
like phases[22], in situ generated Pd nanoparticles[23], Pd on carbon[24], or even Pd supported

on hollow magnetic mesoporous spheres[25]. This class of supported precursors facilitate both
the isolation and the recycling of the catalysts by simple filtration, leading to an
environmentally cleaner process.
Microspheric-supported palladium catalysts reported in this article have previously been
successfully used in the Suzuki–Miyaura coupling[26]. The main goal of the studies was to
switch the catalytic activity from the standard Suzuki–Miyaura coupling to the carbonylative
Suzuki–Miyaura reaction by a simple change of the reaction conditions[25].
2. Results and Discussion
2.1 Catalyst
The preparation of the catalyst and its structural studies shown in Figure 1 have been reported
previously[26].
2.2 Carbonylative Suzuki–Miyaura cross-coupling reactions
The carbonylative Suzuki–Miyaura reaction of aryl iodides with substituted phenylboronic
acids was selected as a model reaction for investigations (Fig. 2).
The general reaction conditions were adapted with small changes from previous similar
studies[24]. Anisole was chosen as a solvent, because a base K2CO3 was the best choice. CO
proceeded from a balloon equipped with a capillary under continuous flow atmospheric
pressure. Due to the heterogeneous nature of the catalyst, the reaction was performed for 5 h to
reach max. 96% conversion of iodide. A longer reaction time only resulted in the increase of
the amount of the secondary product (biphenyl). Since there are two competitive reactions, the
palladium concentration had to be lowered from the initial 2 mol% to 0.05 mol% to reduce the
homocoupling reaction speed, and to increase the saturation of the solution with CO due to its
low solubility under these conditions.
The obtained results are presented in Table 1.
Reactions of different aryl iodides with phenylboronic acid show conversions from 0% for 4-
iodophenole to over 90%. The highest conversions, up to 91%, were obtained for 4-iodoanisole.
There is a strong correlation between the activity and the position of the substituent in the aryl

ring. For a substrate with a methoxy group in position 4, the conversion is the highest, reaching
91%. The substituents in positions 3 and 2 decrease the activity of the substrate, allowing for
conversion at the level of 80% and 46%. Good results were also obtained for 1-iodonaphtalene,
82%. 4-Nitro- and 4-methyl-substituted iodides showed a moderate and a low activity of 40%
and 24%. 2-Iodotiophene was almost not active in this reaction and gave only a trace of the
product. Attempts 1a and 4a were carried out with the catalyst reduced before the reaction. No
significant change in activity was observed. The differences were in the range from 1% to 2%
of the total substrate conversion.
For further study, 4-iodoanisole was selected as a representative halide. Reactions with
substituted boronic acids showed conversions from 51% for 1-naphtylboronic acid to 0% for 4-
formylboronic acid, phenylboronic acid pinacol ester, and 4-carboxyphenylboronic acid. 4-
Methyl-1-naphtyl and 3,5-dimethoxyboronic acid show moderate reactivity with conversions
from 50% to 47%. 4-Vinyl, 4-tertbutyl, and 4-acethylboronic acids showed low or very low
activity in these reactions, with conversions from 30% to 2%. It should also be noted that,
during all the performed reactions, the product of the homo-coupling of boronic acid was
formed in small to moderate quantities as a result competing reactions. This can be prevented
by raising the pressure of CO or reducing the concentration of the catalyst. Interestingly,
lowering the concentration of the catalyst does not influence the carbonylative S–M reaction
rate, but it reduces the amount of the unwanted product. Thus, in our opinion, the reaction rate
limiting factor is the concentration of CO in the reaction solution.
In order to prove this theory, two model reactions were carried out in a steel autoclave with a
CO pressure of 5 bar. Both showed a significant increase in conversion to the carbonyl product,
with a slight increase of the total substrate conversion (Table 2). In most cases the amount of
byproduct (product b) was reduce by half or even more. It was therefore clearly shown that the
selectivity of the carbonylative S-M reaction was significantly improved already at CO pressure
of 5 bar. For example, excellent selectivity was achieved for 4-iodoanisole and
dimethoxyboronic acid (Table 2). In this case the yield of product a increased from 44% to
60% after increase of CO pressure from 1 bar to 5 bar. Similarly, in carbonylative coupling of
4-iodoanisole with 1-naphtylboronic acid increase of the yield of product a from 15% to 38%
was noted (Table 2). Thus, in our system the suppression of S-M coupling reaction was
achieved just by small increase of the CO pressure. Such modification of the reaction conditions
is in our opinion simpler than application of pivalic acid as an agent inhibiting S-M reaction
[23].

2.3 Carbonylative Suzuki-Miyaura coupling of di-halogenated benzenes.
In the course of studies, carbonylation reactions with di-halogenated benzenes have also been
conducted. The expected products, diketones, may be of interest for the synthesis of functional
materials [27].
Two substrates, 1,4-diiodobenzene, and 1-bromo-4-iodobenzene were used and difference in
their activity has been observed (Table 3).
The conversion of 1-bromo-4-iodobenzene was 60% and increased to 75% when amount of
phenylboronic acid increased from 1.2 to 2.4 equivalents. The mono-carbonylation product, 4-
bromo-benzophenone (c) was formed as the main one (50%) together with 4-bromo-biphenyl
(e) (10%), which is a normal product of the Suzuki-Miyaura coupling reaction. When 1,4-
diiodobenzene was used as a substrate, the main products were 1,4-dibenzoylbenzene (d)
(30%), and 4-iodobiphenyl (e), approximately 10%. Other two products c and f were also
observed in in small quantities not exceeding 5%.
2.3 Catalyst recycling
The most important feature of heterogeneous catalysts is the ability to re-use, or recycle, them.
During the research, such tests were also carried out for the [Pd] catalyst according to the
procedure described in the experimental section. The tests showed a slow reduction of activity
of the catalyst from 96% in the first to 60% in the fourth reaction (Fig. 3). In the same time
selectivity changed and amount of biphenyl (b) increased. This may be caused by the
modification of the catalyst structure.
On the other hand, ICP studies of the reaction mixture and the post-reaction product extracts
were also done in order to assess the possible presence of the palladium leached from the
support. The contents of palladium in the reaction products were below of the detection limit,
which confirms a very strong interaction between the microspheres and palladium.
3. Experimental
Chemicals and procedures
Commercially available reagents were purchased and used without purification.
All synthetic manipulations were carried out under air atmosphere.

GC-FID and GC/MS
Spectra of the organic products were obtained using the HP 5890 (Hewlett Packard) instrument
with mass detector 5971 A. Capillary column HP 5 was used with a non-polar liquid phase
containing 95% of dimethyl- and 5% of diphenylpolysiloxane.
ICP
Measurements of the palladium content were performed using spectrometer ARL model 3410.
Carbonylative Suzuki–Miyaura reaction procedure
Reactions were performed in a Schlenk tube. Weighed amounts of the solid reactants:
phenylboronic acids (1.1 mmol), base (3.0 mmol), catalyst (5.00 mg), aryl iodide (1 mmol), and
5 mL of solvent (anisole) were introduced to the Schlenk tube. Next, the Schlenk tube was
sealed with a glass septum equipped with capillary connected to a balloon with CO and
introduced into an oil bath preheated to 100 °C. The continuous flow of gas (aprox. 0.5 l/h) was
made possible by the use of a fine needle inserted in the septum. The reaction mixture was
magnetically stirred at a given temperature for 5 h, and after this time it was left for several
minutes to cool down. The inorganic side product were removed by the addition of 5 ml of 5%
HCl. The organic products were separated by extraction with 5 mL of DEE. The extracts (10
ml) were GC-FID analyzed with dodecane (0.050 mL) as an internal standard to determine the
conversion of aryl iodide. The products of the reaction were determined by GC-MS.
Catalyst procedure recycling
Reactions were performed in 10 times larger scale (10 mmol) in order to avoid problems with
separation of a very small amount of catalyst.
After reaction performed as described above, reaction mixture was filtered using G4 Schott
glass filter, and washed several times with DEE. Catalyst was dried in 1000C under reduced
pressure, and used for the next run. A new portion of reactants was added to the Schlenk tube,
and the reaction was carried out under conditions described above. Recycling was performed
4 times in a row for 50 mg portion of [Pd].
Catalyst reduction procedure
200 mg of the prepared catalyst was placed in a round-bottom 50 ml flask on a magnetic stirrer.
Next, 10 ml of methanol was added, followed by 0,1 ml of trimethylamine. The catalyst was

left overnight at room temperature. The next day, a white solid was filtered and washed with
methanol and DEE. The catalyst was dried under vacuum.
4. Conclusions
It was demonstrated previously that palladium supported on a siloxane polymer functionalized
with propylamine groups efficiently catalyzed the Suzuki–Miyaura reaction in an
environmentally friendly mixture of solvents (2-propanol/water)[26].
In the case of a carbonylative Suzuki–Miyaura reaction, the presented catalyst shows good
activity compared to the amount of palladium used in one reaction cycle. Lowering the catalyst
concentration made it possible to obtain the main product with only a small amount of biphenyl.
It was also shown that raising the CO pressure to 5 bar can further increase the conversion of
substrates to the desired carbonyl product. The efficient suppression of undesired S-M reaction
was achieved by small incrase of the CO pressure, without introduction of additional agents
such as pivalic acid [23].
In reaction of di-halogenated benzenes with arylboronic acid 1,4-dibenzoylbenzene, and 4-
bromo-benzophenone were formed. These products can be used as a building blocks for
synthesis of more structurally complex compounds.
The catalyst showed moderate recyclability in this reaction. However, it was recycled four times
with some loss of activity.
Also, in this study, there was no leaching of palladium from the support to the solution at the
time of the reaction. Despite some setbacks, the catalyst has a high potential for use in
carbonylative Suzuki–Miyaura-type reactions.
Acknowledgement
Financial support of National Science Centre (NCN) with grant 2014/15/B/ST5/02101 (W.Z.,
A.M.T.) is gratefully acknowledged.

5. References
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3025
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[5] D. K. Paluru, S. Dey, K. R. Chaudhari , M. V. Khedkar, B. M. Bhanage, V. K. Jain,
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[6] A. Petz, G. Peczely, Z. Pinter , L. Kollar, J. Mol. Catal. A: Chemical 255 (2006) 97–102
[7] X. Wu, H. Neumann, M. Bellera, Adv. Synth. Catal. 3532 (2011) 788 – 792
[8] P. Gautam, B. M. Bhanage, J. Org. Chem. 80 (2015) 7810−7815
[9] L. Bartali, A. Guarna, P. Larini, E. G. Occhiato, Eur. J. Org. Chem. (2007) 2152–2163
[10] S. Sumino, T. Ui, I. Ryu, Org. Chem. Front. 2 (2015) 1085–1087
[11] T. Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N. Miyaura, J. Org. Chem. 63 (1998) 4726-
4731
[12] S. Couve-Bonnaire, J. Carpentier, A. Mortreux, Y. Castanet, Tetrahedron 59 (2003) 2793–
2799
[13] X. Wu, H. Neumann, M. Beller, Tetrahedron Lett. 51 (2010) 6146–6149
[14] L. Kaganovsky , D. Gelman, K. Rueck-Braun, J. Organomet. Chem. 695 (2010) 260–266
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[20] S. Zheng, L. Xu, C. Xia1, Appl. Organometal. Chem. 21 (2007) 772–776
[21] M. Cai, G. Zheng, L. Zha, J. Peng, Eur. J. Org. Chem. (2009) 1585–1591
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[23] Q. Zhou, S. Wei, W. Han, J. Org. Chem. 79 (2014) 1454−1460
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6981–6986
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Figure 1. Catalyst [Pd] surface SEM (left) and proposed molecular structure (right)

O
R'
R
R
R
R'
R'
CO, [Pd], anisole, K2CO3
1000C, 5 h
+
+
OH
I
B
product a
product b
OH
Figure 2. Carbonylative Suzuki–Miyaura coupling

Fig.3. Recycling of catalyst.
96
100
90
80
70
60
50
40
30
20
10
0
80
77
70
60
60
conversion
product a
product b
45
30 30
25
20
19
1
2
3
4
Reaction conditions: 4-iodoanisole(10 mmol), phenylboronic acid(24 mmol), [Pd](0.05 mol%),
base(30 mmol), solvent(anisole 50 mL), temperature 1000C, time 5h CO(atm).

Table 1. Carbonylative Suzuki–Miyaura C–C coupling of aryl iodides with arylboronic acids
O
R'
R
R
R'
R
R'
CO, [Pd], solv. base
+
+
OH
I
B
a
b
OH
Entry R
R’
H
H
H
H
H
H
H
H
H
H
H
Conv. [%]
a [%]
85
81
64
32
37
41
53
22
20
1
b [%]
6
1
4-OMe
4-OMe
3-OMe
2-OMe
91
90
80
46
82
80
66
40
24
1
1a
2
9
16
13
45
38
13
18
4
3
4
Naphtalene
Naphtalene
H
4a
5
6
4-NO2
7
4-Me
8
Tiophene
4-OH
0
9
0
0
0
10
11
12
13
14
15
16
17
18
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
3,5-OMe
4-CHO
47
0
44
0
3
0
1-Nap
59
50
30
2
15
20
25
1
45
30
5
4-Me, 1-Nap
4-Vinyl
4-Ac
1
4-tBu
26
0
22
0
4
4-COOH
H, Pinacol ester
0
0
0
0
Reaction conditions: aryl halide(1 mmol), arylboronic acid(1.2 mmol), [Pd](0.05 mol%, 0.02
mmol Pd), base(3 mmol), solvent(anisole 5mL), temperature 1000C, time 5h, CO(atm).

Table 2. Carbonylative Suzuki–Miyaura reaction of aryl iodides with arylboronic acids under
a CO pressure of 5 bar.
O
R'
R
R
R'
R
R'
[Pd], anisole, K2CO3
+
+
OH
0
100 C, 5 hours, CO 5 bar
I
B
product a
product b
OH
Entry R
R’
Conv. [%]
a [%]
b [%]
1
4-OMe
Naphtalene
H
H
90
90
65
40
70
70
10
0
88
69
60
38
61
68
9
2
2
H
21
5
3
H
4
4-Me
H
2
5
4-NO2
3-OMe
4-Ac
H
9
6
H
2
7
H
1
8
4-OH
H
0
0
9
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
3,5-OMe
4-CHO
2-iPr, 6-O-Me
4- Ac
60
0
60
0
0
10
11
12
13
14
15
16
0
0
0
0
0
0
0
1-Nap
4-Me, 1-Nap
4-Vinyl
4-tBu
40
40
30
30
38
30
29
29
2
10
1
1
Reaction conditions: aryl halide(1 mmol), arylboronic acid(1.2 mmol), [Pd](0.05 mol%, 0.02
mmol Pd), base(3 mmol), solvent(anisole 5mL), temperature 1000C, time 5h, CO(5 bar).

Table 3. Carbonylative Suzuki-Miyaura C-C coupling reaction of di-halogenated benzenes
with arylboronic acid.
O
O
+
X
X
[Pd], anisole, K2 CO3
product d
product c
O
+
OH
1000C, 5 hours, CO (atm.)
I
B
OH
X
+
product e
product f
Entry X
Conv. [%]
c [%]
50
d [%]
trace
30
e [%]
f [%]
trace
5
1
Br
60
50
75
50
10
5
2
I
10
3*
4*
Br
I
50
5
20
5
trace
5
10
30
Reaction conditions: aryl halide(1 mmol), arylboronic acid(1.2 mmol), [Pd](0.05 mol%, 0.02
mmol Pd), base(3 mmol), solvent(anisole 5 mL), temperature 1000C, time 5h, CO(atm.).
*- arylboronic acid(2.4 mmol)