Mechanistic insights into palladium leaching in novel Pd/C-catalyzed boron-heck reaction of arylboronic acid

Article abstract of DOI:10.1055/s-0032-1318110

For the first time, Pd/C has been used for the Boron-Heck reaction, and the detailed mechanistic aspects of the reaction have been proven experimentally by a leaching test as well as by cyclic voltammetry studies. The results indicate that palladium leaching as a Pd(II) species, by oxidative addition of the arylboronic acid, is responsible for the reaction. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318110

LETTER
▌347
lMetteer chanistic Insights into Palladium Leaching in Novel Pd/C-Catalyzed
Boron-Heck Reaction of Arylboronic Acid
Pd/C-Catalyzed Boron-Heck Reaction
Mahesh G. Dighe, Sachin L. Lonkar, Mariam S. Degani*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India
Fax +91(22)33611020; E-mail: ms.degani@ictmumbai.edu.in
Received: 12.11.2012; Accepted after revision: 30.12.2012
an oxygen atmosphere. The application of heterogeneous
Pd/C is of great interest from the industrial point of view
due to its high catalytic efficiency, low cost, and commer-
cial availability. However, the mechanistic pathway for
Abstract: For the first time, Pd/C has been used for the Boron-
Heck reaction, and the detailed mechanistic aspects of the reaction
have been proven experimentally by a leaching test as well as by cy-
clic voltammetry studies. The results indicate that palladium leach-
ing as a Pd(II) species, by oxidative addition of the arylboronic acid, the heterogeneous Pd/C-catalyzed C–C coupling is still
is responsible for the reaction.
unclear with regard to whether the reaction takes place on
the heterogeneous palladium surface12 or due to palladium
Key words: heterogeneous catalysis, Pd/C, arylboronic acids,
palladium leaching, Boron-Heck reaction
leaching from the catalyst.13 Pd leaching from Pd/C has
been observed in various reactions such as the Heck reac-
tion,14 hydrodechlorination15 and during isobutanol syn-
thesis.16 As compared to classical Heck reaction and
The transition-metal-catalyzed Boron-Heck reaction of
Suzuki reaction, a detailed experimental study of palladi-
um leaching from Pd/C in the Boron-Heck reaction has
not been reported. The objective of this work was to un-
derstand detailed mechanistic aspects of the reaction and
to provide experimental evidence of palladium leaching in
the Pd/C-catalyzed Boron-Heck reaction.
arylboronic acid with olefins is of great interest in chemi-
cal synthesis.1 Apart from arylboronic acids, other arylat-
ing agents2 such as arylstannanes, arylsilanes, aryl-
phosphonic acids, arylbismuth, arylantimony, and aryl-
mercury compounds have also been reported. However,
many of these reagents are unstable and produce highly
toxic byproducts that are difficult to remove from the re-
action mixture. On the contrary, arylboronic acids are
more stable, less toxic, and commercially available. After
the first report of the Boron-Heck reaction of arylboronic
acids by Uemura,3 further investigations were carried out
by various research groups, particularly, Jung,4 Larhed,5
Lautens,6 Brown,7 and Minnaard8 and these have consid-
erably simplified the reaction conditions by screening var-
ious ligands under mild conditions. Various reported
ligands for Boron-Heck reactions are bipyridine, 6,6′-di-
methyl-2,2′-bipyridine,9 1,10-phenanthroline, 2,9-di-
methyl-1,10-phenanthroline (dmphen), bisimines of
acenaphthenequinone (BIAN), 1,3-bis(diphenylphospha-
nyl)propane (dppp) and bisphenyl sulfoxide.10 However,
bipyridine and 1,10-phenanthroline are reported to form
inactive PdL2 complexes; whereas the stability of the dm-
phen ligand is uncertain under oxidative conditions. Phos-
phine ligands such as dppp are quite expensive and are
often prone to rapid oxidation. Moreover, the 6,6′-dimeth-
yl-2,2′-bipyridine ligand is reported to give only a moder-
ate yield with concomitant Pd black formation. Thus all
ligands reported are expensive and/or have stability is-
sues. Ligand-free systems11 are also reported using
Pd(OAc)2 with higher catalyst loadings (5–10 mol%).
Initially, optimization of reaction conditions for the Bo-
ron-Heck reaction using phenylboronic acid and ethyl ac-
rylate as a model reaction was carried out (Scheme 1), but
the reaction failed to proceed under conventional condi-
tions. A low yield was obtained when the reaction was
subjected to high temperature and pressure due to debor-
onation of phenylboronic acid. The final optimized reac-
tion conditions were as follows: pyrrolidine as the base,
N-methyl pyrolidone (NMP) as the solvent, 80 °C, 0.6
mol% Pd loading, O2 gas (3.45 bar; see Table S1, S2 and
S3, Supplementary Data).
O
O
OH
OH
Pd/C (5%)
+
B
O
O
1
(E)-ethyl cinnamate (2)
Scheme 1 Model Boron-Heck reaction
The scope of the optimized system was investigated by
coupling three arylboronic acids with different electron-
rich and electron-poor olefins.17 This system exhibited ex-
cellent activity regardless of the electronic effect of the
olefin substituents, except in the case of 2-cyclohexanone,
where steric effects may be playing a role (Table 1, entries
1–6). When the arylboronic acid had an electron-donating
substitution at the para position, slightly lower yields
were obtained in most cases (Table 1, entries 7–9), while
para-nitrophenylboronic acid gave a higher yield as com-
pared to unsubstituted phenylboronic acid (Table 1,
entries 10–12).
Herein, we report for the first time a mild, cost effective,
Pd/C-catalyzed system for the Boron-Heck reaction of
arylboronic acids with different olefins in the presence of
SYNLETT 2013, 24, 0347–0350
Advanced online publication: 23.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318110; Art ID: ST-2012-D0969-L
© Georg Thieme Verlag Stuttgart · New York

348
M. G. Dighe et al.
LETTER
Table 1 Substrate Study for the Boron-Heck Reactiona
conclude that the solvent alone did not cause leaching
(Table 2, entry 1).
5% Pd/C (0.6 mol%)
pyrrolidine, TBAB
OH
R2
Table 2 Effect of Different Components on Pd Leaching in Boron-
B
+
NMP, 80°C,
Heck Reactiona
R1
R1
R2
OH
O2 gas (3.45 bar)
3
4
Entry
Component added with Pd/C
Isolated yield (%)b
(E)-products
Entry R1
R2
Time Isolated
(h)
1
2
3
4
5
NMP
n.r.
n.r.
91
Yield (%)b
ethyl acrylate
phenylboronic acid
pyrrolidine
TBAB
1
2
H
H
H
H
H
H
CO2CH5
Ph
12
18
10
12
94
88
96
75
70
65
85
83
32
95
89
76
14
3
CN
n.r.
4
CO2(CH2)Me
a Reaction conditions: arylboronic acid (1.0 mmol), olefin (2.0
mmol), 5% Pd/C (Pd loading 0.6 mol%), pyrrolidine (1.5 mmol),
TBAB (0.5 mmol), NMP (10.0 mL), 80 °C, O2 gas (3.45 bar).
b Isolated yield; n.r. = no reaction.
5
CO2CH2C(C2H5)(CH2)3Me 12
6
2-cyclohexenone
12
12
18
12
10
12
10
7
4-OMe CO2CH5
4-OMe Ph
8
Four further experiments were carried out by addition of
each component (ethyl acrylate, phenylboronic acid, pyr-
rolidine, and TBAB) to the mixture of 5% Pd/C (0.6
mol%) in NMP (10 mL). Reactions with ethyl acrylate
and TBAB did not yield the desired product (Table 2, en-
tries 2 and 5) while pyrrolidine resulted in a low yield
(14%, Table 2, entry 4). This indicated that NMP, ethyl
acrylate, and TBAB do not have any effect on the Pd
leaching. In the case of pyrrolidine addition, the low yield
of 14% indicates that this could act as a ligand and leach
Pd to a small extent. In the case of phenylboronic acid,
91% yield was obtained (Table 2, entry 3) which gives a
clear evidence of the existence of a homogeneous
palladium species in the filtrate which catalyzes the reac-
tion.
In the earlier reports by Biffis et al.19 and Conlon et al.20
in the heterogeneously catalyzed classical Heck reaction,
palladium leaching was observed due to oxidative addi-
tion of aryl halides. However, in our experiments, it is in-
teresting to observe that palladium leaching occurs when
phenylboronic acid was added to the mixture of Pd/C in
NMP. In order to investigate whether the palladium leach-
ing occurs due to oxidative addition of phenylboronic ac-
id, we performed cyclic voltammetry studies using a
PGSTAT 30 GPES Interface (Metrohm) instrument.21
The cyclic voltagramms of the phenylboronic acid, Pd-
borate solute (reaction filtrate), and standard PdCl2 were
measured in 0.1 M TBAB–NMP solutions, starting at 0 V
against a platinum reference electrode, in a positive
direction at a scan rate of 5 mV/s (Figure 1).
9
4-OMe 2-cyclohexenone
4-O2N CO2CH5
4-O2N Ph
10
11
12
4-O2N 2-cyclohexenone
a Reaction condition: Arylboronic acid (1.0 mmol), olefin (2.0 mmol),
5% Pd/C (Pd loading 0.6 mol%), pyrrolidine (1.5 mmol), TBAB (0.5
mmol), NMP (10.0 mL), 80 °C, O2 gas (3.45 bar).
b Isolated yield. Products were characterized by 1H NMR
spectroscopy.
In order to understand whether the Pd/C-catalyzed Boron-
Heck reaction takes place on the heterogeneous surface or
due to Pd leaching from Pd/C, we performed leaching
tests to differentiate heterogeneous and homogeneous ac-
tivity based on the comparison of results observed before
and after separation of solid Pd/C18 by filtration. If the re-
action proceeds after separation of Pd/C by filtration, then
it is clear that the leached Pd is responsible for catalyzing
the Boron-Heck reaction. In our leaching study, using the
model Boron-Heck reaction of phenylboronic acid with
ethyl acrylate, various components, which may cause the
palladium leaching, were screened. Components such as
N-methyl pyrrolidone (NMP, solvent), phenylboronic ac-
id, ethyl acrylate, pyrrolidine, and tetrabutylammonium
bromide (TBAB) were screened one at a time. First, the
effect of the solvent on palladium leaching was studied by
addition of 5% Pd/C (Pd 0.6 mol%) to NMP (10.0 mL).
The content was heated to 80 °C for four hours, the hot re-
action mixture was filtered at 80 °C under inert atmo-
sphere to separate solid Pd/C, and then the reaction was
carried out by addition of the ethyl acrylate (2.0 mmol),
pyrrolidine (1.5 mmol), and TBAB (0.5 mmol) to the fil-
trate as in the general reaction procedure. However, this
procedure failed to give the desired product, leading us to
A single reduction peak was observed for phenylboronic
acid at –0.816 V (R1) whereas two reduction peaks were
seen in the case of Pd–borate solute at –0.856 V (R1) and
–1.279 V (R2). The peak at –0.856 V (R1) of Pd–borate
solute corresponds to the reduction peak of phenylboronic
acid indicating the presence of unreacted phenylboronic
acid. The additional peak at –1.279 V (R2) was assigned
to the two electron-reduction process of Pd(II) → Pd(0) as
Synlett 2013, 24, 347–350
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pd/C-Catalyzed Boron-Heck Reaction
349
gives the Pd(0) species and pyrrolidinium hydrogen boro-
nate (12). The Pd(0) species then either becomes re-
deposited on the carbon support or is re-oxidized to Pd(II)
species by molecular oxygen, so that palladium black for-
mation which could hamper the catalytic cycle does not
occur. TBAB plays a crucial role in this reaction by acting
as phase-transfer catalyst and preventing agglomeration
of Pd black.
Thus, in our proposed Pd(0)-catalyzed mechanism, the
palladium leaching due to oxidative addition of arylbo-
ronic acid is the key step for the Boron-Heck reaction. It
is different from other reported Pd(II)-catalyzed mecha-
nisms, in which Pd(II) catalysis involves the transmetala-
tion of arylboronic acid with Pd(II)L2 to form the
organopalladium complex as a key step.22 The application
of the developed catalytic system for various palladium-
catalyzed reactions is under way.
Figure 1 Cyclic voltagramms of phenylboronic acid (red), Pd-borate
solute (blue) and standard PdCl2 (green).
it overlaps with the reduction peak observed by standard
PdCl2 at 1.188 V (R2). Thus, it is confirmed that the Pd(II)
complex is formed in situ due to the oxidative addition of
phenylboronic acid.
In addition, palladium loss in solution was also investigat-
ed for the Boron-Heck reaction of phenylboronic acid
with ethyl acrylate, after completion of the reaction at
room temperature using inductively coupled plasma
atomic emission spectroscopy (ICP-AES). It exhibited no
significant loss of palladium in solution (0.018 ppm), in-
dicating that redeposition of the soluble palladium species
on carbon occurs once the reaction mixture attains ambi-
ent temperature.
In summary, we have demonstrated, for the first time, the
Pd/C-catalyzed Boron-Heck coupling of arylboronic ac-
ids with various olefins. The newly developed, Pd/C-cat-
alyzed system showed excellent activity for Boron-Heck
coupling of arylboronic acids irrespective of electronic
substitution. By studying leaching tests as well as cyclic
voltammetry, we can conclude that oxidative addition of
the arylboronic acid is mainly responsible for the Pd
leaching. In addition, ICP-AES studies indicated that the
loss of Pd is minimal.
Based on this work, we propose a mechanistic pathway as
shown in Scheme 2. Initially, heterogeneous Pd(0) species
leached into the reaction due to oxidative addition of
phenylboronic acid to form Pd(II) complex 6. The next
few steps follow the classical Heck reaction mechanism
which involves the migratory insertion of olefin to the
Pd(II) complex 6, followed by β-hydride elimination to
give the desired product 9 and HPdB(OH)2 (10). Reduc-
tive elimination of 10 in the presence of pyrrolidine (11)
Acknowledgment
I am thankful to the University Grant Commission, Delhi for
financial support for the project and fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Ar B(OH)2
oxidative addition
(causes Pd leaching)
Pd(0)/C
5
redeposition
Pd(II)
Ar
B(OH)2
6
ArB(OH)2
R
alkene
coordination
B(OH)2
Pd(II)
13
Pd
Ar
Pd(0)
O
B
O2
R
7
NH2
H
OH
reductive
pyrrolidinium hydrogen
boronate 12
elimination
migratory
insertion
β-hydride
elimination
••
NH
Ar
Pd(II)
H
B(OH)2
Pd(II)B(OH)2
11
10
R
R
8
Ar
9
Scheme 2 Plausible mechanism for the Boron-Heck reaction
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 347–350

350
M. G. Dighe et al.
LETTER
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the reaction was heated to 80 °C under an oxygen
atmosphere for the desired time. After the completion of the
reaction, it was allowed to cool to r.t., and the palladium was
filtered off for catalyst recovery. The filtrate was poured into
H2O (50 mL), and the crude product was extracted with
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