Heterogeneous palladium multi-task catalyst for sequential Heck-reduction-cyclization (HRC) reactions: influence of the support

Article abstract of DOI:10.1016/j.tetlet.2009.06.084

An evaluation study of various palladium supports led to the selection of charcoal as the most efficient system for the preparation of oxindoles by sequential Heck-reduction-cyclization (HRC) reactions. The in situ prepared Pd0/C was not recyclable for further cross-coupling reactions but remains still highly active for reduction processes. The sustainable chemistry described herein allows extremely simple experimental protocol under mild conditions, free of any base, ligand and additive.

Full text of DOI:10.1016/j.tetlet.2009.06.084

Tetrahedron Letters 50 (2009) 5071–5074
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Heterogeneous palladium multi-task catalyst for sequential
Heck-reduction–cyclization (HRC) reactions: influence of the support
Oier Ibarguren a, Cécile Zakri b, Eric Fouquet a, François-Xavier Felpin a,
*
a Université de Bordeaux, CNRS, Institut des Sciences Moléculaires (ISM), 351 Cours de la Libération, 33405 Talence, France
b Université de Bordeaux, CNRS, Centre de Recherche Paul Pascal, Avenue Schweitzer, 33600 Pessac, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An evaluation study of various palladium supports led to the selection of charcoal as the most efficient
system for the preparation of oxindoles by sequential Heck-reduction–cyclization (HRC) reactions. The
in situ prepared Pd0/C was not recyclable for further cross-coupling reactions but remains still highly
active for reduction processes. The sustainable chemistry described herein allows extremely simple
experimental protocol under mild conditions, free of any base, ligand and additive.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 May 2009
Revised 10 June 2009
Accepted 16 June 2009
Available online 21 June 2009
Keywords:
Heterogeneous palladium catalysts
Aryldiazonium tetrafluoroborate salts
Heck reaction
Sustainable chemistry
One-pot reactions
In the context of sustainable chemistry, the development of
transition metal-based heterogeneous multi-task catalysts is a re-
cent concept which shows good promise for carrying out one-pot
reactions.1 Preparative procedures in which two or more consecu-
tive transformations are carried out in the same reaction vessel of-
fer a number of advantages to the organic chemist: especially, they
result in a reduced number of operations, giving significant time-
cost, labour, resource management and waste generation benefits.2
Moreover, they allow the preparation of elaborated structures from
relatively simple starting materials.
Two different approaches have been proposed for executing
several transformations in the same reaction vessel with heteroge-
neous multi-task catalysts. (1) The first approach involves a heter-
ogeneous mono-metallic catalyst in which the metal is able to
promote several consecutive reactions. Conceptually straightfor-
ward to establish for consecutive reactions having a similar mech-
anism,3 this approach remains much more challenging when
different mechanisms are involved in a one-pot process due to
the high specificity of the metal.4 (2) This issue has been addressed,
in a second approach, by using heterogeneous multi-metallic cata-
lysts.5 Such a strategy appears much more convenient and flexible
since each metal plays a specific and often unique role in promot-
ing the one-pot multi-step sequence. However, the preparation of
heterogeneous multi-metallic catalysts is a quite difficult task
and has limited further developments in this area. It should be
noted that while a heterogeneous multi-metallic catalyst consid-
ered as a unique entity could be classified as a multi-task catalyst,
each metal considered independently could not.
We recently reported our own contribution relating the use of
Pd/C as catalyst for the preparation of novel oxindoles by sequen-
tial Heck-reduction–cyclization (HRC) reactions.6 Our strategy
exploited the dual reactivities7 of an in situ-generated Pd/C cata-
lyst with an experimentally simple protocol making use of highly
reactive diazonium salts under base-free, ligand-free and addi-
tive-free conditions.8 We selected charcoal as the support for its
low cost, inertness, stability and high surface area. Moreover, char-
coal is prepared from renewable resources (vegetal or animal), a
crucial point for the development of sustainable chemistry.
However, we were interested in evaluating other kinds of sup-
ports which feature similar advantages to charcoal including low
cost and high surface area. In this Letter we wish to report our
investigations towards the selection of the most efficient support
for the HRC strategy (Scheme 1).
We selected methyl 2-(2-nitrophenyl)acrylate
(methoxycarbonyl)benzene-diazonium tetrafluoroborate
1
and 4-
as
2
coupling partners in our model system (Table 1). Preliminary
experiments showed that the Heck cross-coupling works well
either with or without addition of charcoal. This observation sug-
gests that a quasi-homogeneous catalysis is operating, as already
observed by other groups.9 If such, the active catalyst is soluble
* Corresponding author. Tel.: +33 4000 6285; fax: +33 4000 6286.
E-mail addresses: fx.felpin@ism.u-bordeaux1.fr, fx.felpin@lcoo.u-bordeaux1.fr
(F.-X. Felpin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.084

5072
O. Ibarguren et al. / Tetrahedron Letters 50 (2009) 5071–5074
nanotubes (MWNTs) and activated charcoal. From these three sup-
R2
N2BF4
ports, charcoal gave the highest results while graphite produced
non-negligible quantities of N-hydroxyoxindole due to the partial
reduction of the nitro group along with the expected oxindole 3.
This by-product was also detected in very minor quantity with
MWNT and charcoal at a 5-mol % palladium loading. However,
decreasing the amount of palladium to 2 mol % resulted in the for-
mation of larger quantities of N-hydroxyoxindole (corresponding
to a partial reduction of the nitro group) and, consequently, lower
yields of 3. Charcoal proved to be the best support in our system,
leading to high yield (83%) of oxindoles 3 at 5 mol % Pd. This result
could be explained by the strong affinity of palladium nanoparti-
cles with charcoal as confirmed by ICP-MS analysis of the filtered
solution. Indeed, more than 99.99% of the initial quantity of intro-
duced palladium under the form of Pd(OAc)2 is retained on the
charcoal after the HRC process. Moreover, the HBF4 produced dur-
ing the Heck cross-coupling (1 equiv/diazonium salt) is not detri-
mental to the integrity of the charcoal while an opposite
behaviour has been observed with PANI. We also observed a slight
increase in the yield when one additional equivalent of HBF4 is
added to the reaction mixture10 during the reduction–cyclization
sequence (entry 12). When palladium was omitted no reaction oc-
curred indicating a genuine palladium-catalyzed reaction (entry
13).
Based on the ICP-MS results showing a total adsorption of pal-
ladium on the charcoal, we assume that a 10% w/w Pd/C was gen-
erated in situ. After a simple filtration, the catalyst was separated
from the reaction mixture and dried under vacuum.
TEM analysis showed a wide distribution of the nanoparticles
with an average size of 30 nm and uniform dispersion on the char-
coal (Fig. 1).
We explored the recycling potential of the in situ prepared Pd/C.
Unfortunately, the recycled catalyst showed a strong deactivation
for the Heck cross-coupling (Scheme 2, Eq. 1) involved in the prep-
aration of oxindole 3. This deactivation was also observed with a
Pd(OAc)2
charcoal
CO2Me
+
CO2Me
NO2
MeOH, 40°C
NO2
R1
R2
A
B
Heck
C
R1
R2
R2
H2
Cyclization
CO2Me
O
Reduction
N
NH2
D
R1
H
E
R1
Scheme 1. General strategy of the HRC approach.
Table 1
Screening of various supports
MeO2C
N2BF4
HRC
CO2Me
NO2
+
O
1
N
2
CO2Me
Entrya
3
H
Support
Pd(OAc)2 (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
—
PANI
CeO2
MgO
Zeolite
Graphite
MWNTd
MWNT
Charcoal
Charcoal
Charcoale
Charcoalf
Charcoal
5
5
5
5
5
5
5
2
5
2
2
2
0
52
20
65
c
—
74
65
78
70
83
63
70
75
0
less demanding cross-coupling involving methyl acrylate
5
(Scheme 2, Eq. 2). We attributed these disappointing results to
the reduced form (Pd0) of the reused Pd/C catalyst. Indeed, we have
previously reported that Heck reactions catalyzed by Pd/C require a
PdII pre-catalyst.11 We attempted without success a re-oxidation of
the Pd0/C to the more reactive PdII/C using iodine as reported by de
Vries and co-workers.12 We noticed that the presence of iodine
ions completely inhibited the catalytic activity. However that point
a
Reaction conditions: Acrylate (1 mmol), diazonium salt (1.2 mmol), Pd(OAc)2
(1–5 mol %) and support (90%/Pd, w/w) in MeOH (6 mL) at 40 °C for 0.5–1 h (Heck
coupling), then H2 for 24 h.
b
Yield of isolated product.
Degradation.
MeOH (10 mL) was used.
c
d
e
The reduction was carried out for 48 h.
One equivalent of HBF4 was added.
f
palladium nanoparticles leached in the solvent resulting in similar
mechanism whatever the homogeneous or heterogeneous nature
of the pre-catalyst. However, in the absence of a support the sub-
sequent reduction–cyclization steps proceeded partially, resulting
in a moderate yield of oxindole 3 (entry 1). This result clearly indi-
cated the requirement of a support able to promote smoothly the
reduction stage. The use of polyaniline (PANI) as an organic sup-
port proved to be incompatible with the reaction conditions due
to its extensive decomposition (entry 2). Metallic oxides are not
useful on the whole process although Pd/MgO has been recently
described as an efficient catalyst for sequential Heck-reduction
reactions.7f The use of zeolite led to oxindole 3 along with uniden-
tified by-products (entry 5). Moreover, after filtration of the cata-
lyst, at the end of the HRC process, an important leaching of
palladium was detected in solution leading to an unacceptable
contamination level. We finally screened three different forms of
carbon-based material including graphite, multi-wall carbon
Figure 1. TEM images of the Pd/C catalyst in situ generated.

O. Ibarguren et al. / Tetrahedron Letters 50 (2009) 5071–5074
5073
MeO2C
MeO2C
Eq. 1
MeO2C
N2BF4
Pd(OAc)2
Charcoal
CO2Me
Reused Pd0/C
+
CO2Me
MeOH, 40°C
NO2
CO2Me
NO2
MeOH
40°C, 24 h
O
CO Me
2
NO2
1
2
4
N
H
Fresh : 98% yield
First reuse : 53% yield
3
4
With HBF4 : 88% yield
Without HBF4 : 72% yield
N2BF4
+
Eq. 2
O
Pd(OAc)2
Charcoal
O
Scheme 4. Study of the HBF4 effect.
OCH3
OCH3
MeOH, 40°C
6
MeO2C
CO Me
To our surprise, we noticed a decrease in the conversion in the
absence of HBF4,resulting in a significant drop in the yield. There-
fore, HBF4 could not be considered as a waste of the first step (Heck
cross-coupling) since it acts as a co-catalyst for the subsequent
transformations. This intriguing behaviour has not been reported
previously although a related concept has been recently described
with an indium catalyst for a domino imine formation Diels–Alder
reaction.13
In summary, this work showed that the strong affinity of palla-
dium nanoparticles for robust, inexpensive and non-toxic charcoal
could be efficiently exploited in one-pot sequential reactions. Our
studies demonstrated that the experimental simplicity is not
antagonist to the reaction efficiency. Indeed, the HRC strategy al-
lows the succession of 4 steps in one pot under mild conditions
with a simple in situ-generated Pd/C catalyst and does not require
any base, ligand and additive. We believe that such a research of
experimental simplicity associated to the synthesis of useful bio-
logically relevant heterocycles will be of increased interest in the
context of sustainable chemistry.
2
5
2
Fresh : 93% yield
First reuse : 42% yield
Scheme 2. Recycling studies for the Heck reaction.
does not preclude the overall process as from an industrial point of
view, heterogeneous catalysts are rarely reused directly after filtra-
tion and an inexpensive standard combustion procedure is pre-
ferred for the reactivation.
In order to support our hypothesis, we examined a set of reac-
tions where a Pd0 is required (Scheme 3). Therefore, we exploited
the reductive properties of the recycled catalyst for the reduction
of acrylate 6 (Eq. 1) and 2-nitrobiphenyl 8 (Eq. 2), the debenzyla-
tion of oestrogen 10 (Eq. 3) and the debromination of bromoindole
12 (Eq. 4). In contrast with the recycling experiments conducted on
the Heck reaction, we noticed a high activity of the catalyst in-
volved in reduction processes leading to good to high yield of com-
pounds 7, 9, 11 and 13. These observations confirm that the
prepared Pd0/C remains an active catalyst for reduction purposes
but cannot be used further for the Heck cross-coupling where a
PdII/C would be required.
Acknowledgements
During the optimization studies of the support, we established
the beneficial effect of HBF4 on the rate of the reduction (Table 1,
entry 11). In order to understand in depth the role of HBF4 in the
HRC sequence, we compared the reduction of the Heck intermedi-
ate 4 for the synthesis of oxindole 3 (Scheme 4).
This work was supported by the ‘Université de Bordeaux’ and
the ‘Centre National de la Recherche Scientifique (CNRS).’ We
thank M. Olivier Brugier (Université de Montpellier, UMR Geosci-
ences/Analytical Platform AETE) for ICP-MS analyses. We also
acknowledge Mrs Claire Mouche (CESAMO, Bordeaux) for HRMS
analyses and Dr. Marion Zanese (University of Bordeaux) for fruit-
ful discussions.
Reused Pd0/C
CO2Me
CO2Me
MeOH, 40°C
Eq. 1
MeO2C
MeO2C
6
Supplementary data
7
97% yield
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.084.
Reused Pd0/C
OMe
OMe
MeOH/THF (1:1)
References and notes
Eq. 2
98% yield
NO2
NH2
40°C
8
9
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