TABLE 1. Catalyst Screening for the Alkylation of Oxindole (1)
with Pentan-1-ol (2)a
Ruthenium-Catalyzed Alkylation of Oxindole
with Alcohols
Thomas Jensen and Robert Madsen*
Department of Chemistry, Building 201, Technical UniVersity
of Denmark, DK-2800 Lyngby, Denmark
catalyst loading
entry
catalyst
[Cp*IrCl2]2
(mol %)
ligand
PPh3
3b (%)
1
2
3
4
5
6
7
8
1.0
1.0
2.0
2.0
2.0
1.0
1.0
2.0
2.0
1.0
1.0
>95
32c
>95c
0
ReceiVed February 16, 2009
[IrCl(cod)]2
[RuCl3 ·xH2O]
[RuCl3 ·xH2O]
[RuCl2(PPh3)3]
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(PPh3)3(CO)H2]
[Ru(PPh3)3(CO)H2]
Shvo’s14
PPh3
>95
47
Xantphos
Xantphos
>95d
53
9
10
11
81d
>95
0
[Ru(acac)3]
a 1 (2.0 mmol) was reacted with 2 (2.2 mmol) under the influence of
catalyst (1.0-2.0 mol %) and NaOH (10 mol %) at 110 °C for 20 h.
b Conversion was estimated by 1H NMR spectroscopy based on 1.
c PPh3 (4.0 mol %). d Xantphos (2.0 mol %).
An atom-economical and solvent-free catalytic procedure for
the mono-3-alkylation of oxindole with alcohols is described.
The reaction is mediated by the in situ generated catalyst
from RuCl3 · xH2O and PPh3 in the presence of sodium
hydroxide. The reactions proceed in good to excellent yields
with a wide range of aromatic, heteroaromatic, and aliphatic
alcohols.
such as malonates,5 barbiturates,6 ketones,7 and certain nitriles8
where water is produced as the only byproduct. In all cases,
the pKa value of the methylene group is less than ∼20 and the
alkylation is achieved with a transition-metal catalyst and a base.
The mechanism involves dehydrogenation of the alcohol to the
carbonyl compound followed by addition of the activated
methylene compound, elimination of water, and hydrogenation
of the resulting C-C double bond.9 Since the pKa of the
methylene group in oxindole is 18.2,10 we speculated that this
environmentally friendly alkylation reaction could also be used
for introducing substituents in the 3-position of this motif.11
Herein, we describe an expedient ruthenium-catalyzed procedure
for alkylation of oxindoles with alcohols.
The oxindole ring system is found in many natural products1
and biologically active molecules.2 Usually, the 3-position is
substituted with one or two substituents which can be introduced
from the parent molecule by alkylation with alkyl halides2/allylic
esters3 or by arylation with aryl halides.4 Recently, alcohols
have been used for alkylation of activated methylene compounds
The studies began with investigating the direct catalytic
alkylation of oxindole (1) with pentan-1-ol (2) (Table 1). We
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2008, 130, 2087–2100. (b) Yamada, Y.; Kitajima, M.; Kogure, N.; Takayama,
H. Tetrahedron 2008, 64, 7690–7694. (c) Galliford, C. V.; Scheidt, K. A. Angew.
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3990 J. Org. Chem. 2009, 74, 3990–3992
10.1021/jo900341w CCC: $40.75 2009 American Chemical Society
Published on Web 04/16/2009