Synthesis of 3-hydroxyoxindoles by Pd-catalysed intramolecular nucleophilic addition of aryl halides to α-ketoamides

Article abstract of DOI:10.1039/b917958e

Pd/PtBu₃-catalysed intramolecular nucleophilic addition of aryl halides to α-ketoamides in the presence of nBuOH and base has been realized with high yields, providing a new, direct, and efficient synthetic strategy to obtain 3-hydroxyoxindoles

Full text of DOI:10.1039/b917958e

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Synthesis of 3-hydroxyoxindoles by Pd-catalysed intramolecular
nucleophilic addition of aryl halides to a-ketoamideswz
Yi-Xia Jia, Dmitry Katayev and E. Peter Kundig*
¨
Received (in Cambridge, UK) 2nd September 2009, Accepted 7th October 2009
First published as an Advance Article on the web 3rd November 2009
DOI: 10.1039/b917958e
Pd/PtBu3-catalysed intramolecular nucleophilic addition of aryl
halides to a-ketoamides in the presence of nBuOH and base has
been realized with high yields, providing a new, direct, and
efficient synthetic strategy to obtain 3-hydroxyoxindoles.
oxidative addition of the catalyst to the aryl bromide and, more
importantly, facilitate the nucleophilic attack of the Pd–aryl
intermediate on the ketone. Indeed, when 10 mol% PtBu3ꢀ
HBF4 was used as a ligand precursor, the reaction of 1a
proceeded smoothly in the presence of 5 mol% Pd(dba)2,
2 eq. Cs2CO3, and 2 eq. nBuOH in toluene at 50 1C giving
oxindole 2a in 76% isolated yield along with 19% of the
corresponding hydrodehalogenation side product 3a (Table 1,
entry 1). We note that these conditions are milder than those
reported previously for this type of reaction—e.g. 100–150 1C
for intramolecular additions to ketones.3 Solvent examination
revealed toluene to be the best choice as low yields (o15%)
were observed in ether solvents such as THF, DME
(1,2-dimethoxy ethane), and 1,4-dioxane. In DCE (1,2-dichloro-
ethane) product yield was 54% after 20 h, while in DMF the
reaction was completely suppressed. Although the best result
was obtained when nBuOH was used as an additive, MeOH and
EtOH afforded slightly lower yields whereas iPrOH gave a poor
product yield (entries 4–6). In the absence of an additive, the
reaction fails, as has been also reported by the Yamamoto
group.3b Interestingly, instead of an alcohol H2 (1 bar) could be
used to promote this reaction with comparable yield (entry 7).
Moderate yields of 2a were observed when nBu3SnH and
Et3SiH were used and for the former no side product 3a was
detected (entries 8, 9).
The predominantly electrophilic reactivity of aryl and vinyl
organopalladium intermediates derived from the corresponding
halides by an oxidative addition process with a Pd(0) catalyst is
well established.1 Conversely their use as nucleophiles has received
much less attention although literature precedent exists and
includes reactions with aldehydes,2 ketones,3 imines,4 esters and
amides,5 anhydrides6 and nitriles.7 The direct catalytic addition
reaction of aryl and vinyl halides to electrophilic partners is
attractive since no extra organometallic reagents are needed. In
the context of our interest in the synthesis of oxindoles8 we
envisioned that it might be possible to obtain 3-hydroxyoxindoles
by an intramolecular addition of aryl halides to a-ketoamides
using a Pd catalyst. This would provide a direct access to these
compounds avoiding the use of Grignard-, organoborane-, or
organolithium-reagents (Scheme 1).9 Herein, we report the
preliminary results of this new synthetic strategy to oxindoles.
The model substrate 1a was prepared by condensation of
N-methyl o-bromoaniline and 2-oxo-2-phenylacetyl chloride.
Initial attempts to use Pd(PPh3)4 as a catalyst were not efficient
for the transformation 1a - 2a and attempts to improve
results by modifications of base, solvent, and additives were
not successful. The best result was a 17% yield of 2a with
5 mol% Pd(PPh3)4 in toluene at 110 1C for 24 h in the presence
of 2 eq. Na2CO3 and 10 eq. NEt3. Using nBuOH as solvent
afforded 3a and only trace amounts of 2a. We then focused
on the use of electron-rich ligands,10 which should favour
Variation of the base revealed this to be an important
factor. No reactions took place in the presence of Cy2NMe,
KF, KOAc, Li2CO3, and Na2CO3. With K2CO3 as base,
oxindole 2a could be isolated in 23% yield after 24 hours
(entry 10). Finally, K3PO4ꢀH2O was found to be the best base
giving the highest yield of the product albeit a longer reaction
time was needed to achieve full conversion at 50 1C (entry 11).
Increasing the temperature to 80 1C resulted in complete
reaction in 7 hours and 2a was isolated in 88% yield along
with 7% side product 3a (entry 12). Further investigation of the
ligand showed that PCy3 was also suitable (entry 13), while dppe
(1,2-bis(diphenylphosphino)ethane) and 1,3-bis(2,6-diisopropyl-
phenyl)-4,5-dihydroimidazolium chloride (SIPrꢀHCl) as ligand
or ligand precursor were inefficient in this reaction.
Scheme 1 New route to 3-hydroxyoxindoles.
The optimum reaction conditions were then applied to the
substrates shown in Table 2. Yields are generally good
(81–92%). It is noteworthy that the reaction to oxindole 2d
with CF3 as an electron-withdrawing group was complete in
3 h, while 14 h were required for the reaction of substrate 1e
with an o-MeO group. Not only N-Me substrates but also an
N-benzyl amide (2i) could be used, but no reaction took place
for the free N-H substrate (R1 = R2 = H, Ar = Ph).
Department of Organic Chemistry, University of Geneva,
30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
E-mail: peter.kundig@unige.ch;
Web: http://www.unige.ch/sciences/chiorg/kundig/;
Fax: +41 22-379-3215; Tel: +41 22-379-6093
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’t
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details, spectral characterisation and analytical data of reported
compounds. See DOI: 10.1039/b917958e
The reaction is sensitive to the aryl halide used (eqn (1)). In
comparison with 1a, no reaction took place for the analogous
ꢁc
This journal is The Royal Society of Chemistry 2010
130 | Chem. Commun., 2010, 46, 130–132

Table 1 Optimization of reaction conditionsa
Entry
Base
Solvent
Reductant
Temp./1C
Time/h
Yb (%) (2a/3a)
1
2
3
4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4ꢀH2O
K3PO4ꢀH2O
K3PO4ꢀH2O
Toluene
DCE
nBuOH
nBuOH
nBuOH
MeOH
EtOH
50
50
50
50
50
50
100
100
50
80
50
80
80
7
20
20
7
76/19
54/nd
29/nd
69/nd
71/nd
21/nd
62/28
43/0
58/23
23/nd
85/9
88/7
85/7
tBuOMe
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
5
7
6
iPrOH
H2
16
12
24
12
24
30
7
7c
8
nBu3SnH
Et3SiH
nBuOH
nBuOH
nBuOH
nBuOH
9
10
11
12
13d
9
a
b
c
d
0.4 mmol scale in 8 mL solvent. Isolated yield. nd = not determined. With a hydrogen balloon. 10 mol% PCy3 was used instead of
PtBu3ꢀHBF4.
Table 2 Substrate scopea
(1)
Vinyl bromide substrate 1o was synthesized and applied in the
reaction (eqn (2)). Pyrrolidinone product 2m could be obtained;
yields were low (16% for K3PO4ꢀH2O as base, 29% for Cs2CO3).
(2)
Next, experiments designed to shed light on mechanistic aspects
of the reaction were carried out. As shown in eqn (3), oxindole 2a
could be isolated in 92% yield with stoichiometric Pd(0)/PtBu3
complex in the absence of nBuOH, thus demonstrating that Pd(0)
can perform the same role as Mg in Grignard reactions. As
mentioned above, catalytic use of Pd requires an additive and
a
primary alcohols performed best. An earlier study of an intra-
0.4 mmol scale in 8 mL toluene.
molecular aryl addition to ketones, catalysed by Pd with added
1-hexanol,3b reported that the alcohol was recovered. Our findings
are different. Using piperonyl alcohol, as shown in eqn (4),
chloride substrate 1m. Noteworthy, the reaction of the iodo
piperonyl aldehyde was isolated in 95% yield. This confirms the
substrate 1n was slower than that of the bromo substrate 1a
role of the alcohol as reductant in the reaction and thus closing
and 48 h were needed to achieve full conversion. Since the
the catalytic cycle. Also, the deuterated dehalogenation side
reaction of 1a with Cs2CO3 as base was faster than with
product was detected when MeOH-d4 was used (eqn (5)).
K3PO4ꢀH2O, we introduced Cs2CO3 to the reactions of these
two substrates. Product 2a was isolated in 72% yield from 1n
after 6 h at 80 1C and in 33% yield from 1m after 72 h at
110 1C. Interestingly, the reaction of 1a under standard
conditions was suppressed in the presence of 3.0 eq. LiI as
(3)
additive and only traces of oxindole 2a were detected after 48 h.
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 130–132 | 131

Fig. 1 Proposed mechanism.
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(4)
(5)
Based on the above, we propose the mechanism shown in
Fig. 1. The oxindole is formed by intramolecular addition of
the oxidative addition intermediate I to the ketone. Alkoxy-
ligand exchange II (cycle A) liberates product 2a and the Pd(0)
catalyst is regenerated by b-H elimination (aldehyde formation)
followed by base assisted reductive elimination. For the
hydrodehalogenation side product 3a we propose halide–
alcoholate ligand exchange in I to give III (cycle B).
b-Elimination followed by reductive elimination affords 3a
(cycle B). The observation of the deuterated side product
shown in eqn (5) supports this pathway.
7 (a) C. C. Yang, P. J. Sun and J. M. Fang, J. Chem. Soc., Chem.
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Chem., 2002, 67, 9276–9287; (e) Q. P. Tian, A. A. Pletnev and
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9 3-Hydroxyoxindoles can be obtained by addition of aryl Grignard
reagents or aryl lithium reagents (both are prepared from aryl
halides) to isatin: (a) M. A. Sukari and J. M. Vernon, J. Chem.
Soc., Perkin Trans. 1, 1983, 2219–2223; (b) S. J. Angyal,
E. Bullock, W. G. Hanger, W. C. Howell and A. W. Johnson,
J. Chem. Soc., 1957, 1592–1602 and ref. cit. Catalytic asymmetric
synthesis of 3-hydroxyoxindole: Pd catalysed intramolecular aryla-
tion of amides; (c) ref. 8b; M-catalysed addition of aryl boronic
acids to isatin; (d) R. Shintani, M. Inoue and T. Hayashi, Angew.
Chem., Int. Ed., 2006, 45, 3353–3356; (e) H. S. Lai, Z. Y. Huang,
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catalysed asymmetric hydroxylation of oxindoles; (f) T. Ishimaru,
N. Shibata, J. Nagai, S. Nakamura, T. Toru and S. Kanemasa,
J. Am. Chem. Soc., 2006, 128, 16488–16489.
In summary, we have developed a new and efficient
procedure to synthesize 3-hydroxyoxindole compounds in
high yields by applying palladium-catalysed direct addition
of aryl halides to a-ketoamides. Both, electron-rich phosphine
ligands and a reductant (alcohol, H2) are crucial. The forma-
tion of a new stereogenic center in 2 is another important
aspect that is receiving attention in ongoing research.
Notes and references
1 J. Tsuji, Palladium Reagents and Catalysis—New Perspectives for
the 21st Century, Wiley, Weinheim, 2004.
2 (a) R. C. Larock, M. J. Doty and S. Cacchi, J. Org. Chem., 1993,
58, 4579–4583; (b) V. Gevorgyan, L. G. Quan and Y. Yamamoto,
Tetrahedron Lett., 1999, 40, 4089–4092; (c) J. Vicente, J. A. Abad,
B. Lopez-Pelaez and E. Martinez-Viviente, Organometallics, 2002,
10 Although PCy3 has been used as a ligand in a similar addition
reaction of simple ketone substrates (ref. 3b), no reaction took
place from 1a to 2a using the reported conditions (5 mol%
Pd(OAc)2, 10 mol% PCy3, 2 eq. Na2CO3, 5 eq. 1-hexanol in
DMF).
ꢁc
This journal is The Royal Society of Chemistry 2010
132 | Chem. Commun., 2010, 46, 130–132