Synthesis of oxindoles by tandem heck-reduction-cyclization (HRC) from a single bifunctional, in situ generated Pd/C catalyst

Article abstract of DOI:10.1021/jo802467s

A tandem sequence involving palladium-catalyzed sequential Heck-reduction-cyclization transformations in mild conditions has been developed for the synthesis of oxindoles. The protocol involves inexpensive reagents and does not require any additives such

Full text of DOI:10.1021/jo802467s

become more economically advantageous (time and resource
management benefits) and environmentally friendly (waste
reduction). The unrivalled diversity of transition-metal-catalyzed
reactions available has made them important mediators for the
elaboration of tandem processes.3,4 Among them, palladium has
been intensively studied for tandem transformations of two or
more mechanistically related reactions. However, the use of
palladium complexes for the catalysis of at least two funda-
mentally different reactions is quite unusual5 because of the high
specificity of the catalyst, and these challenging tandem reactions
remain essentially described with other metals such as rhodium,
ruthenium, and copper.6
Synthesis of Oxindoles by Tandem
Heck-Reduction-Cyclization (HRC) from a Single
Bifunctional, in Situ Generated Pd/C Catalyst
Franc¸ois-Xavier Felpin,* Oier Ibarguren,
Luma Nassar-Hardy, and Eric Fouquet
UniVersite´ de Bordeaux, CNRS, Institut des Sciences
Mole´culaires, 351 Cours de la Libe´ration,
33405 Talence Cedex, France
fx.felpin@ism.u-bordeaux1.fr
Palladium metal has been widely used for a century as a
hydrogenation, hydrogenolysis, and hydrodechlorination catalyst
essentially under a heterogeneous form. On the other hand, the
use of homogeneous palladium complexes as catalysts for
carbon-carbon bond formation is more recent with the discov-
ery of Heck,7 Suzuki,8 Stille,9 Sonogashira,10 and other related
reactions11 in the 1970s.
ReceiVed NoVember 4, 2008
Processes based on the exploitation of the dual reactivity of
palladium catalysts (C-C bond formation and hydrogenation)
have, quite surprisingly, rarely been developed in the context
of one-pot reactions.12 In this paper, we report our results related
to the synthesis of C3 benzylated oxindoles by a sequential
tandem Heck-reduction-cyclization (HRC)13 using aryl diazo-
nium salts as “super” electrophiles.
Oxindole-containing heterocycles, particularly those substi-
tuted at the C3 position, are commonly encountered in natural
products14 and pharmaceutical compounds15 (Figure 1).
They display a wide range of biological properties including
antiarthritis,16 antitumoral,17 and antiviral activities.18 As a
A tandem sequence involving palladium-catalyzed sequential
Heck-reduction-cyclization transformations in mild condi-
tions has been developed for the synthesis of oxindoles. The
protocol involves inexpensive reagents and does not require
any additives such as base or ligands.
In recent years, the development of rapid and practical routes
for the production of libraries of small organic molecules in
drug discovery has attracted much attention from the synthetic
community.1 To this end, multiple transformations performed
in a one-pot process, called domino, tandem, or cascade
reactions,2 have become an important area of research in organic
chemistry.3,4 Preparative protocols in which at least two
consecutive transformations are carried out in the same reaction
vessel offer a number of advantages to the organic chemist.
For instance, they allow the elaboration of complex structures
from relatively simple starting materials in a reduced number
of technical operations, and syntheses using such reactions
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10.1021/jo802467s CCC: $40.75
Published on Web 12/29/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1349–1352 1349

SCHEME 1. Overall HRC Strategy
FIGURE 1. Representative oxindole-containing natural products (1 and
2) and drugs (3-5).
consequence, the selective monofunctionalization at C3 by alkyl,
alkenyl, or benzyl groups of N-unsubstituted oxindoles has been
a longstanding issue.19,20 Indeed, base-mediated C3 alkylation
generaly gives a mixture of C- and N-alkylated products as a
consequence of the close acidity of the protons in C3 and N1
positions.21 Thereby, a less direct method is generally preferred
involving the reduction of 3-alkyl or 3-arylideneoxindoles,
prepared by the condensation of unsubstituted oxindoles with
aldehydes or ketones.22 Considering the need for a more
straightforward pathway, we designed a novel approach where
the oxindole core and the C3 functionalization are executed in
the same reaction vessel.
TABLE 1. Preparation of 2-(2-Nitrophenyl)acrylates
Optimization of Reaction Conditions. Our strategy, outlined
in Scheme 1, is based on a Heck cross-coupling of a 2-(2-
nitrophenyl)acrylate A with an aryl diazonium tetrafluoroborate
salt B. We23 and others24 have reported the practical use of
diazonium salts, easily prepared from inexpensive anilines,25
for Heck reactions without any external additive (base or ligand),
TABLE 2. Optimization Studies of the HRC Sequence
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Johnson, D. L.; Kuperman, A. V.; Liston, T. E.; Malloy, D.; Martin, J. J.;
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S. J. Med. Chem. 2006, 49, 3432. (b) Luk, K. C.; So, S. S.; Zhang, J.; Zhang,
Z. WO Patent 2006136606, 2006.
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oxindoles; see: Altman, R. A.; Hyde, A. M.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 9613–9620.
(21) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218–4223.
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reduction-
entry
1
Heck coupling
cyclization yielda (%)
5 mol % Pd(II)/C, MeOH,
40 °C, 0.25 h
5 mol % Pd(II)/C, dioxane,
40 °C, 2 h
5 mol % Pd(0)/BaCO3, MeOH,
40 °C 2 h
5 mol % Pd(0)/BaCO3, dioxane,
40 °C, 2 h
5 mol % Pd(OAc)2, charcoal, MeOH,
40 °C, 0.5 h
5 mol % Pd(OAc)2, MeOH,
40 °C, 0.5 h
5 mol % PdCl2, charcoal, MeOH,
40 °C, 2 h
5 mol % Pd2dba3, charcoal, MeOH,
40 °C, 1 h
H2, 24 h
H2, 48 h
H2, 24 h
H2, 48 h
H2, 24 h
H2, 48 h
H2, 24 h
H2, 24 h
b
2
3
4
5
6
7
8
b
b
b
81
62
b
(24) For selected references, see: (a) Kikukawa, K.; Maemura, K.; Kiseki,
Y.; Wada, F.; Matsuda, T. J. Org. Chem. 1981, 46, 4885–4888. (b) Beller, M.;
Ku¨hlein, K. Synlett 1995, 441–442. (c) Perez, R.; Veronese, D.; Coelho, F.;
Antunes, O. A. C. Tetrahedron Lett. 2006, 47, 1325–1328. (d) Artuso, E.;
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4643.
<50
a Isolated yield. b Complex mixture of products.
making it ideal for tandem transformations. The cross-coupling
could be followed by Pd-mediated reductions of the double bond
and the nitro group, giving the corresponding aniline D, which
(25) Hanson, P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.; Timms, A. W.
J. Chem. Soc., Perkin Trans. 2 2002, 1126–1134.
1350 J. Org. Chem. Vol. 74, No. 3, 2009

TABLE 3. Preparation of Variously Substituted Oxindoles by the HRC Strategy
a Reaction conditions: acrylates (1 mmol), aryldiazonium salt (1.2 mmol), Pd(OAc)2 (5 mol %), charcoal (45 mg), MeOH (5 mL), 40 °C, 15-90 min;
then H2, 40 °C, 24 h. Yields are an average of at least two runs. b 2 equiv of diazonium salt was used.
SCHEME 2. Synthesis of Bis-oxindole 25 by the HRC
Strategy
should spontaneously cyclize to give variously substituted
oxindoles E.
The substituted 2-(2-nitrophenyl)acrylates 6-9 employed in
this study were easily accessed by methylenation of the
corresponding methyl 2-(2-nitrophenyl)acetates in good yields
(Table 1). Acrylates 6-9 proved to be stable for months when
stored in the freezer, rendering their use quite easy.
We selected methyl 2-(2-nitrophenyl)acrylate 6 and 4-(meth-
oxycarbonyl)benzenediazonium tetrafluoroborate 10 as coupling
partners in our model system (Table 2). Unfortunately, com-
mercially available supported catalysts such as Pd(II)/C23 and
12f
Pd(0)/BaCO3 were poorly effective, leading to a mixture of
inseparable products (entries 1 and 3). Close inspection of the
crude reaction mixture after the coupling step showed a large
amount of methyl benzoate (formed by dediazoniation). This
issue could not be addressed with a nonprotic solvent (entries
free of palladium residues as indicated by ICP-MS analyses
(<50 ppb).26This result indicated that virtually all palladium
species remained on the charcoal (>99.9%), rendering the
purification step easier. As indicated in entry 6, it is interesting
2 and 4). Considering that the nature of the Pd source could be
to note that when the charcoal was omitted, the hydrogenation
crucial for the success of the tandem process, we examined the
step never reached full a conversion even under extended time
(>48 h). This observation contrasts with literature precedents12d,e
in which coupling-hydrogenation sequences without charcoal
possibility of forming, in situ, the heterogeneous catalyst by
mixing a well-defined homogeneous Pd complex with charcoal.
To our delight, 5 mol % Pd(OAc)2 smoothly promoted the HRC
were described through the in situ formation of palladium
sequence (entry 5), while PdCl2 and Pd2dba3 were less efficient
nanoparticles.
for the cross-coupling step (entries 7 and 8). To our knowledge,
Scope of the Reaction. Having successfully optimized the
this work is the first example of a catalytically active hetero-
HRC protocol on a model sequence, we next explored its scope
geneous palladium complex prepared in the same reaction vessel
with various coupling partners (Table 3). A variety of diazonium
as the cross-coupling. This unusual approach opens the door
salts were engaged in our newly designed tandem protocol.
for the development of dramatically simplified protocols. From
Pleasingly, the HRC sequence smoothly furnished the required
a synthetic point of view, it should be noted that after the 2-(2-
oxindoles with homogeneous yields (70-80%) whatever the
structure of the coupling partners. We learned from these studies
a number of interesting features. For instance, the electronic
nitrophenyl)acrylate 6 has been consumed, as indicated by
nitrogen evolution (∼30 min), the reaction mixture was stirred
under an H2 atmosphere for 24 h, leading to 11 with a good
yield (81%). Importantly, at the end of the reaction, a simple
(26) Other cross-couplings studied in this work showed metal leaching to a
filtration of the charcoal left the solvent and the product almost
similar extent.
J. Org. Chem. Vol. 74, No. 3, 2009 1351

SCHEME 3. Recycling Tests
reused catalyst was less active for the Heck reaction (eq 2) but
remained still and even more active for the reduction-cyclization
steps (eq 3). It is likely that the reduced form (Pd(0)/C) of the
reused catalyst is detrimental for the success of the Heck reaction
for which a Pd(II) precatalyst is preferred. On the other hand,
the reduction-cyclization sequence requires preferably a pal-
ladium with a low degree of oxidation. We are currently working
to solve this issue.
In summary, we have reported an efficient synthesis of C3
benzylated oxindoles by a novel tandem HRC process. This
work represents one of the few applications in heterocyclic
chemistry of tandem reactions catalyzed by a single heteroge-
neous catalyst.27 We demonstrated, for the first time, that the
preparation of an active heterogeneous catalyst and the tandem
process could be carried out in one pot. The experimental
simplicity associated with the extremely mild conditions render
the method highly competitive over existing procedures. We
believe that such a simple method could be of broad interest
for synthetic and medicinal chemists.
Experimental Section
General Procedure for the Tandem Heck-Reduction-
Cyclization Sequence. To a solution of diazonium salt (1.2 mmol)
in MeOH (5 mL) were added acrylate (1 mmol), charcoal (45 mg),
and Pd(OAc)2 (5 mol %). The reaction was stirred for 15-90 min
at 40 °C and then stirred under H2 for 24 h at 40 °C. After filtration,
the crude material was purified by flash chromatography to give
the corresponding oxindole.
effects of the substituents on the diazonium salts only have a
minor impact on the tandem process. Indeed, diazonium salts
having electron-withdrawing substituents (compounds 11, 15,
19, 20, and 21) react faster with the corresponding acrylate in
the Heck cross-coupling than those having electron-donating
ones (compounds 14, 16, 17, 18, and 23). However, we did not
observe any considerable influence of these electronic effects
on the yields of the reduction-cyclization sequence. On the other
hand, the nature of the acrylates has also a low influence on
both kinetics and yields. The compatibility of the method with
a biphenyl group (compound 12) and hindered diazonium salts
(compounds 14 and 18) is noteworthy.
Interestingly, the protocol could be extended to the preparation
of even more elaborated substrates (Scheme 2). For instance,
the reaction of acrylates 6 with the bis-diazonium salt 24 allows
the creation of four chemical bonds in only one reaction vessel
(i.e., two C-C and two C-N) with 70% yield.
Recycling Tests. Since the catalyst could be easily separated
from the reaction mixture by simple filtration, leaving the solvent
and the product almost free of palladium residues, we examined
its recyclability with a set of key experiments (Scheme 3).
Unfortunately, after the first run, the reused catalyst showed a
strong deactivation leading to lower yield of oxindole 11 (eq
1). Additional experiments unambiguously showed that the
Acknowledgment. This work was supported by the Univer-
site´ de Bordeaux, the CNRS, and the Ligue Nationale contre le
Cancer, Comite´ de la Gironde. We thank M. Olivier Brugier
(University of Montpellier) for ICP-MS, Mrs. Claire Mouche
(CESAMO, Bordeaux) for HRMS analyses, and Mrs. Marion
Zanese (University of Bordeaux) for fruitful discussions. We
thank M. Je´rome Coste and M. Renaud He´raud for preliminary
experiments.
Supporting Information Available: Detailed experimental
procedures, characterization data, and NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802467S
(27) To the best of our knowledge only one report has been previously
disclosed, see: (a) Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358–
4361.
1352 J. Org. Chem. Vol. 74, No. 3, 2009