Ruthenium-catalyzed alkylation of oxindole with alcohols

Article abstract of DOI:10.1021/jo900341w

(Chemical Equation Presented) 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 RuCl ₃·xH₂O and P

Full text of DOI:10.1021/jo900341w

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
rm@kemi.dtu.dk
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
(1) (a) Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata,
M.; Tamaki, K.; Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc.
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.
Chem., Int. Ed. 2007, 46, 8748–8758. (d) Kagata, T.; Saito, S.; Shigemori, H.;
Ohsaki, A.; Ishiyama, H.; Kubota, T.; Kobayashi, J. J. Nat. Prod. 2006, 69,
1517–1521.
(2) (a) Volk, B.; Barko´czy, J.; Hegedus, E.; Udvari, S.; Gacsa´lyi, I.; Mezei,
T.; Pallagi, K.; Kompagne, H.; Le´vay, G.; Egyed, A.; Ha´rsing, L. G., Jr.;
Spedding, M.; Simig, G. J. Med. Chem. 2008, 51, 2522–2532. (b) Fensome, A.;
Adams, W. R.; Adams, A. L.; Berrodin, T. J.; Cohen, J.; Huselton, C.; Illenberger,
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C. C.; Mugford, C. A.; Slayden, O. D.; Yudt, M.; Zhang, Z.; Zhang, P.; Zhu,
Y.; Winneker, R. C.; Wrobel, J. E. J. Med. Chem. 2008, 51, 1861–1873. (c)
Stevens, F. C.; Bloomquist, W. E.; Borel, A. G.; Cohen, M. L.; Droste, C. A.;
Heiman, M. L.; Kriauciunas, A.; Sall, D. J.; Tinsley, F. C.; Jesudason, C. D.
Bioorg. Med. Chem. Lett. 2007, 17, 6270–6273. (d) Jiang, T.; Kuhen, K. L.;
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Bioorg. Med. Chem. Lett. 2006, 16, 2105–2108.
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7415.
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Chem. Commun. 2006, 5000–5002.
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4914. (b) Yamada, Y. M. A.; Uozumi, Y. Tetrahedron 2007, 63, 8492–8498.
(c) Mart´ınez, R.; Ramo´n, D. J.; Yus, M. Tetrahedron 2006, 62, 8988–9001. (d)
Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.; Park, J. Angew.
Chem., Int. Ed. 2005, 44, 6913–6915. (e) Taguchi, K.; Nakagawa, H.;
Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72–73.
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9020–9022.
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A. Tetrahedron 2009, 65, 849–854. (b) Lo¨fberg, C.; Grigg, R.; Whittaker, M. A.;
Keep, A.; Derrick, A. J. Org. Chem. 2006, 71, 8023–8027. (c) Motokura, K.;
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Catal. 2007, 349, 1555–1575. (b) Guillena, G.; Ramo´n, D. J.; Yus, M. Angew.
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(10) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218–4223.
(11) Excess Raney nickel has been shown to mediate the alkylation of
oxindole in alcohol solvent at 150-220 °C; see: Volk, B.; Mezei, T.; Simig, G.
Synthesis 2002, 595–597.
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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

TABLE 2. Influence of Base and Solvent on the Catalytic
Alkylation of Oxindole (1) with Pentan-1-ol (2)a
TABLE 3. Catalytic Alkylation of Oxindole (1) with Various
Alcoholsa
entry
base
solvent
3b (%)
1
2
3
4
5
NaOH
KOH
Na2CO3
K2CO3
Cs2CO3
Et3N
>95
>95
58
80
>95
39
6
7
8
9
10
0
NaOH
NaOH
NaOH
toluene
p-dioxane
water
>95c
92c
58c
a 1 (2.0 mmol) was reacted with 2 (2.2 mmol) under the influence of
RuCl3 ·xH2O (2.0 mol %), PPh3 (4.0 mol %), and base (10 mol %) at
110 °C for 20 h. b Conversion was estimated by 1H NMR spectroscopy
based on 1. c Solvent (1.0 mL) added.
decided to employ the commercially available trivalent iridium
complex [Cp*IrCl2]212 for the first experiments since this catalyst
has previously shown high reactivity in the alkylation of
barbiturates and arylacetonitriles with primary alcohols.6,8a After
surveying a small range of bases and reaction temperatures, it
was found that the alkylation of 1 with 2 proceeded cleanly to
provide the 3-alkylation product in almost quantitative yield
when the reaction was performed under neat conditions at 110
°C. Surprisingly, the catalyst system based on [IrCl(cod)]2 and
PPh3 only provided the desired product in low yield (Table 1,
entries 1 and 2). With these encouraging results in hand, we
decided to examine the performance of a range of different
catalysts in the alkylation reaction in order to find a cheaper
ruthenium-based catalyst system. The in situ generated catalyst
based on [RuCl3 ·xH2O] and PPh3 as well as the preformed
[RuCl2(PPh3)3] complex afforded the desired product in high
yield (entries 3 and 5). The addition of PPh3 proved to be
essential since the absence of PPh3 resulted in complete recovery
of the starting materials. A selection of other ruthenium-based
catalysts were tested in the reaction. [Ru(p-cymene)Cl2]2 and
[Ru(PPh3)3(CO)H2] in combination with Xantphos13 as well as
Shvo’s catalyst14 provided the product in high yields while
[Ru(acac)3] and [Ru(p-cymene)Cl2]2 with no additional ligand
added gave either no reaction or low conversion (entries 6-11).
We did not in any case observe dialkylation of the C-3-position,
nor did we observe any N- or O-alkylation. Based on this initial
screening, we decided to use [RuCl3 ·xH2O] in combination with
PPh3 for the further studies.
a 1 (2.0 mmol) was reacted with 2 (2.2 mmol) under the influence of
RuCl3 ·xH2O (2.0 mol %), PPh3 (4.0 mol %), and base (10 mol %) at
110 °C for 20 h. b Isolated yield. c Toluene (1.0 mL) used as cosolvent.
d Stirred for 48 h with 5 equiv (10 mmol) of the alcohol.
A number of experiments were carried out to investigate the
influence of the base and the solvent (Table 2). Sodium
hydroxide and potassium hydroxide seemed to perform equally
well leading to complete conversion of the starting material
(entries 1 and 2). Lower yields were observed when sodium or
potassium carbonate as well as triethylamine were employed,
while cesium carbonate afforded full conversion of 1 (entries
3-6). Not surprisingly no reaction was observed in the absence
of a base, and the starting materials were recovered quantita-
tively (entry 7). The reaction performed very well in toluene or
dioxane while water gave a slightly lower yield (entries 8-10).
However, for general use we decided to use sodium hydroxide
as the additive under neat reaction conditions.
(12) Fujita, K.-i.; Yamaguchi, R. Synlett 2005, 560–571.
(13) Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J. Tetrahedron Lett.
2006, 47, 6787–6789.
(14) Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F. J. Am. Chem.
Soc. 1986, 108, 7400–7402.
J. Org. Chem. Vol. 74, No. 10, 2009 3991

We then turned our attention to other alcohols in order to
investigate the scope of the 3-alkylation procedure (Table 3).
The reaction proceeded in high yield when benzylic alcohols
with either electron-donating or electron-withdrawing groups
present in the 2-, 3-, or 4-position were employed (entries 2-8
and 11-15). It is interesting that chloro substituents are tolerated
under the reactions conditions (entries 5 and 12) since they will
allow for further functionalization of the alkylated product
through cross-coupling chemistry. The use of 4-bromobenzyl
alcohol or 4-(hydroxymethyl)benzonitrile led to complex product
mixtures probably due to hydrodehalogenation and hydrolysis,
respectively. It should be noted that several protecting groups
such as amide, benzyl, and p-methoxybenzyl were compatible
with the reaction conditions (entries 8-10). Some steric
hindrance ortho to the benzyl alcohol is well-tolerated (entries
11-14 and 16), while the highly congested 2,4,6-trimethylben-
zyl alcohol and 2,6-dimethoxybenzyl alcohol afforded the
desired alkylated product in less than 25% yield as judged by
1H NMR. A variety of pharmacophoric functionalities such as
catechol, thiophene, furan, and unprotected indole also proved
successful in the catalytic alkylation (entries 17-20). Notably,
the attempt to alkylate 1 with 2-hydroxymethylfuran under neat
conditions mainly led to decomposition while the addition of
toluene provided a clean alkylation (entry 18).
lation of unprotected and protected oxindoles with a range of
aromatic, heteroaromatic, and aliphatic alcohols. This catalytic
hydrogen transfer reaction constitutes a highly atom-economical
transformation that can be performed under neat conditions and
only produces water as the byproduct.
Experimental Section
General Procedure for 3-Alkylation of Oxindole.
[RuCl3 ·xH2O] (8.3 mg, 0.04 mmol), PPh3 (21.0 mg, 0.08 mmol),
NaOH (8.0 mg, 0.2 mmol), oxindole (266 mg, 2.0 mmol), and the
alcohol (2.2 mmol) were placed in a 7-mL thick-walled screw-cap
vial. The vial was purged with Ar and sealed with a screw-cap.
The mixture was placed in an aluminum block preheated to 110
1
°C and stirred for 20 h or until H NMR of the crude reaction
mixture showed complete consumption of the oxindole. The reaction
mixture was allowed to cool to room temperature followed by
dilution with CH2Cl2 (10 mL). SiO2 was added, and the suspension
was concentrated under reduced pressure to afford a powder that
was purified by use of silica gel chromatography (3 × 15 cm SiO2,
9:1 f 4:1 f 3:7 n-hexane/EtOAc).
3-Pentyl-1,3-dihydroindol-2-one (3) (Table 3, entry 1). Isolated
1
yield 89%; colorless oil; Rf ) 0.18 (heptane/EtOAc ) 7:3); H
NMR (300 MHz, CDCl3) δ 8.99 (bs, 1H), 7.26-7.17 (m, 2H),
7.08-6.98 (m, 1H), 6.92 (d, J ) 7.6 Hz, 1H), 3.48 (t, J ) 5.9,
1H), 2.28-1.86 (m, 2H), 1.55-1.16 (m, 6H), 0.88 (t, J ) 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 180.8, 141.6, 129.9, 127.7,
124.1, 122.2, 109.7, 46.1, 31.8, 30.5, 25.4, 22.4, 14.0; IR (neat)
3211, 3094, 3060, 3031, 2955, 2928, 2858, 1701, 1620, 1470, 1338,
1219, 1100, 749 cm-1; HRMS (ESI+) calcd for C15H21N2O ([M
+ H + MeCN]+) 245.1654, found 245.1649.
The reaction in entry 21 required longer reaction time and
excess alcohol (5 equiv) to reach full conversion of the oxindole
which shows that secondary alcohols react significantly slower
than the corresponding primary alcohols. Attempts to use
cyclohexanol and cyclopentanol gave inseparable mixtures of
the R,ꢀ-unsaturated aldol product and the desired product. Thus
for secondary alcohols the reduction of the putative intermediate
R,ꢀ-unsaturated carbonyl species seems to be the rate-limiting
step. When 4-penten-1-ol was employed in the alkylation
procedure, a 2:1 mixture of 3 and the corresponding R,ꢀ-
unsaturated oxindole was obtained in a modest 27% yield.
Acknowledgment. We thank the Danish National Research
Foundation for financial support.
Supporting Information Available: General experimental
methods, characterization data, and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed a convenient, cheap, and
very effective catalytic system for the selective mono 3-alky-
JO900341W
3992 J. Org. Chem. Vol. 74, No. 10, 2009