C-3 alkylation of oxindole with alcohols by Pt/CeO2 catalyst in additive-free conditions

Article abstract of DOI:10.1039/c3cy00911d

In a series of transition metal-loaded CeO₂ catalysts and Pt-loaded catalysts on various supports, Pt-loaded CeO₂ shows the highest activity for the selective C-3 alkylation of oxindole with octanol. The catalyst is effective for alkylation of oxindole and N-substituted oxindole with a series of substituted benzyl, linear, hetero-aryl alcohols under additive-free conditions and is recyclable. Our results demonstrate the first additive-free catalytic system for this reaction. Mechanistic studies show that this system is driven by the borrowing-hydrogen pathway. Structure-activity relationship studies show that co-presence of surface Pt⁰ species on Pt metal clusters and basic support is indispensable for this catalytic system. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cy00911d

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C-3 alkylation of oxindole with alcohols by
Pt/CeO2 catalyst in additive-free conditions†
Cite this: Catal. Sci. Technol., 2014,
4, 1064
Chandan Chaudhari,a S. M. A. Hakim Siddiki,b Kenichi Kon,a Atsuko Tomita,c
c
ab
*
Yutaka Tai and Ken-ichi Shimizu
In a series of transition metal-loaded CeO2 catalysts and Pt-loaded catalysts on various supports, Pt-loaded
CeO2 shows the highest activity for the selective C-3 alkylation of oxindole with octanol. The catalyst is
effective for alkylation of oxindole and N-substituted oxindole with a series of substituted benzyl, linear,
hetero-aryl alcohols under additive-free conditions and is recyclable. Our results demonstrate the first
additive-free catalytic system for this reaction. Mechanistic studies show that this system is driven by the
borrowing-hydrogen pathway. Structure–activity relationship studies show that co-presence of surface Pt0
species on Pt metal clusters and basic support is indispensable for this catalytic system.
Received 11th November 2013,
Accepted 24th December 2013
DOI: 10.1039/c3cy00911d
www.rsc.org/catalysis
the presence of strong base (10–20 mol% of KOH or NaOH).
Liu et al.15 developed a support-immobilized Ir complex
Introduction
Oxindole and their derivatives, particularly C-3 functional-
ized oxindoles, are important intermediates in pharmaceuti-
cal industry due to their biological activity. These include
the antiinflammatory Tenidap1 and anti-cancer kinase
inhibitor Sunitinib.2 The conventional C-3 alkylation of
oxindoles with alkyl halides has serious drawbacks such as
poor regioselectivity, the formation of dialkylated products,
formation of salt wastes and use of hazardous reagents.
Recently, much attention has been focused on the use of
alcohols as economic and environmentally benign alkylating
reagents in indirect C–C bond formation reactions3–10
so-called borrowing-hydrogen3 (or hydrogen-autotransfer4)
methodology, where alcohol is initially dehydrogenated,
then undergoes a functionalization reaction, and finally,
re-hydrogenated. Wenkert and Bringi have first described
the C-3 alkylation of oxindole with alcohols in the presence
of excess amount of RANEY® nickel.11 Simig and co-workers
reported the C-3 alkylation of oxindole with alcohols at
150–220 °C with relatively less amount of RANEY® Ni, but
the system was still non-catalytic; substrate/catalyst molar
ratio was 10:17.12 Recently, Madsen and a co-worker13 and
Grigg et al.14 independently reported the first catalytic C-3
alkylation of oxindole with alcohols at 110 °C by homogeneous
catalysts (2 mol% RuCl3/PPh3;13 2.5 mol% [IrCp*Cl2]2 14) in
as reusable catalysts for this reaction. However, the system
has drawbacks such as narrow scope and needs of sub-
stoichiometric amount of strong base (KOH) and an organic
ligand. As a part of our continuing interest in the heteroge-
neous catalysis for hydrogen-transfer reactions16–19 (such as
Pt-catalyzed C-3 alkylation of indoles with alcohols19), we
report herein the first additive-free catalytic system for C-3
selective alkylation of indole with alcohols by Pt-loaded CeO2
as a reusable heterogeneous catalyst.
Experimental section
General
Commercially available organic and inorganic compounds
(from Tokyo Chemical Industry, Wako Pure Chemical Indus-
tries, Kishida Chemical, or Mitsuwa Chemicals) were used
without further purification. The GC (Shimadzu GC-14B) and
GCMS (Shimadzu GCMS-QP2010) analyses were carried out
with Ultra ALLOY capillary column UA+-5 (Frontier Laborato-
ries Ltd.) using nitrogen or helium as the carrier gas.
Catalyst
CeO2 (JRC-CEO-1, 157 m2 g−1), MgO (JRC-MGO-3), TiO2
(JRC-TIO-4) and SiO2–Al2O3 (JRC-SAL-2) were supplied from
Catalysis Society of Japan. ZrO2 was prepared by hydrolysis
of zirconium oxynitrate 2-hydrate by an aqueous NH4OH
solution, followed by filtration, washing with distilled water,
drying at 100 °C for 12 h, and by calcination at 500 °C
for 3 h. γ-Al2O3 was prepared by calcination of γ-AlOOH
(Catapal B Alumina purchased from Sasol) at 900 °C for 3 h.
Precursor of 1 wt% Pt/CeO2 catalyst was prepared by an
a Catalysis Research Center, Hokkaido University, N-21, W-10, Sapporo 001-0021,
Japan. E-mail: kshimizu@cat.hokudai.ac.jp; Fax: +81 11 706 9163
b Elements Strategy Initiative for Catalysts and Batteries, Kyoto University,
Katsura, Kyoto 615-8520, Japan
c Materials Research Institute for Sustainable Development, National Institute of
Advanced Industrial Science and Technology (AIST), Nagoya 463-8560, Japan
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cy00911d
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impregnation method; a mixture of CeO2 and an aqueous
HNO3 solution of Pt(NH3)2(NO3)2 was evaporated at 50 °C,
followed by drying at 90 °C for 12 h. A pre-reduced cata-
lyst (named Pt/CeO2) was prepared by pre-reduction of the
precursor in a pyrex tube under a flow of H2 (20 cm3 min−1)
at 500 °C for 0.5 h. Platinum oxides-loaded CeO2 (PtOx/CeO2),
as a comparative catalyst, was prepared by calcination of the
precursor at 300 °C for 3 h. By using various supports, several
pre-reduced Pt catalysts were prepared by the same method
as Pt/CeO2. CeO2-supported metal catalysts, M/CeO2 (M = Co,
Ni, Cu, Ru, Rh, Pd, Ag, Ir) with metal loading of 1 wt% were
prepared by impregnation method in a similar manner as
Pt/CeO2 using an aqueous solution of metal nitrates (for Co,
Ni, Cu, Ag), RuCl3, IrCl3, or an aqueous HNO3 solution of
Rh(NO3)3 or Pd(NO3)2.
1-octanol (1.1 mmol) in mesitylene (1.5 g) was injected to the
pre-reduced catalyst inside the reactor (cylindrical glass tube)
through a septum inlet, followed by filling N2. Then, the
resulting mixture was magnetically stirred for 24 h under
reflux condition; the bath temperature was 170 °C and reac-
tion temperature was ca. 165 °C. After cooling the mixture,
followed by removal of the catalyst, the mixture was purified
with column chromatography and analyzed by 1H and 13C
NMR and GCMS. For the screening and catalyst recycle studies,
conversion of indole and yield of C-3 alkylated product were
determined by GC using n-dodecane as an internal standard.
Results and discussion
We chose the alkylation of oxindole (1 mmol) with 1-octanol
(1.1 mmol) as a model reaction for optimization of catalysts
and conditions. Table 1 summarizes the results of the initial
catalyst screening test under the same reaction conditions
(reflux in mesitylene under N2 for 24 h) using 1 mol% of
transition metal-loaded CeO2. The Ru and Ir-loaded CeO2
and CeO2 itself were completely inactive. Co, Ni, Cu, Rh, Re,
Ir, and Au catalysts showed low yield of the C-3 alkylated
oxindole (2–16%). In contrast, Pt-loaded CeO2 (Pt/CeO2)
showed 99% yield of the C-3 alkylated oxindole. Then, we
studied the support effect on the activity of Pt-loaded cata-
lysts. Pt/MgO and Pt/CeO2 gave higher yield (99%) than the
other catalysts. Especially, Pt/SiO2–Al2O3 and Pt/Al2O3 gave
low yields (12%, 27%). Combined with a well known classifi-
cation on acid–base character of metal oxides,20 it is
suggested that the basic oxides (MgO and CeO2) are more
effective than acidic oxides (Al2O3 and SiO2–Al2O3). On the
basis of the fact that Pt/CeO2 showed higher yield (96%)
after 6 h than Pt/MgO (73%), we adopted Pt/CeO2 as the
standard catalyst.
XANES/EXAFS
X-ray absorption near-edge structures (XANES) and X-ray
absorption fine structure (EXAFS) at Pt L3-edge were mea-
sured at the BL14B2 in the SPring-8 (proposal no.
2012A1734). The storage ring was operated at 8 GeV. A Si(111)
single crystal was used to obtain a monochromatic X-ray
beam. The spectra of Pt/CeO2 and PtOx/CeO2 were obtained
in the fluorescent mode using a Lytle detector, and that of
Pt foil was obtained in a transmittance mode. The Pt/CeO2
catalyst pre-reduced in a flow of 100% H2 (20 cm3 min−1) for
0.5 h at 500 °C was cooled to room temperature in the flow
of H2 and was sealed in cells made of polyethylene under
N2, and then the EXAFS spectrum was taken at room temper-
ature. The spectra of Pt foil and PtOx/CeO2 were recorded
without the pre-reduction treatment. The EXAFS analysis was
performed using the REX version 2.5 program (RIGAKU).
The parameters for the Pt–O and Pt–Pt shells were provided
by FEFF6.
To discuss the relationship between the structure of Pt
species and catalytic activity, we carried out spectroscopic
characterizations of these catalysts. Fig. 1A and B show
XANES and EXAFS spectra of Pt/CeO2, platinum oxides-
loaded CeO2 (PtOx/CeO2) and a reference compound (Pt foil).
The values of the coordination numbers for Pt–O and Pt–Pt
shells as well as the distances derived from the EXAFS analy-
sis are shown in Table 2. The XANES spectrum of PtOx/CeO2
shows a strong white line peak at 11564 eV, which is gener-
ally observed for platinum oxides. The EXAFS of PtOx/CeO2
consists of a Pt–O contribution (4.9 Pt–O bonds at the dis-
tance of 2.00 Å). The EXAFS result indicates that the domi-
nant Pt species in PtOx/CeO2 is a cationic (oxidic) Pt species
highly dispersed on the support, which is consistent with the
XANES results. In contrast, the XANES spectrum of Pt/CeO2 is
nearly identical to that of Pt foil, which indicates that the
electronic state of the Pt species in Pt/CeO2 is metallic. The
EXAFS of Pt/CeO2 consists of a Pt–Pt contribution (7.7 Pt–Pt
bonds at the distance of 2.73 Å). The Pt–Pt distance less than
that of bulk Pt (2.76 Å) and the Pt–Pt coordination number
lower than that of bulk Pt (12) are characteristic features
of a few nm-sized Pt metal clusters.21 As shown in Table 1,
In situ IR
In situ IR (infrared) spectra were recorded at 40 °C using a
JASCO FT/IR-4200 equipped with a quartz IR cell connected
to a conventional flow reaction system. The sample was
pressed into a 40 mg of self-supporting wafer (ϕ = 2 cm) and
mounted into the quartz IR cell with CaF2 windows. Spectra
were measured accumulating 30 scans at a resolution of 4 cm−1.
A reference spectrum of the catalyst wafer in He taken at
the measurement temperature was subtracted from each
spectrum. Prior to the experiment the disk of Pt/CeO2 was
heated in H2 flow (20 cm3 min−1) at 500 °C for 0.5 h, followed
by cooling to 40 °C and purging with He. Then, the catalyst
was exposed to a flow of CO(5%)/He(20 cm3 min−1) for 180 s,
followed by purging with He (40 cm3 min−1) for 600 s.
Typical procedures of the catalytic test
Pt/CeO2 was used as a standard catalyst. After the pre-
reduction at 500 °C, we carried out catalytic tests using a
batch-type reactor without exposing the catalyst to air as fol-
lows. Typically, the mixture of oxindole (1.0 mmol) and
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Table 1 Alkylation of oxindole by 1-octanol with 1 wt% metal-loaded metal oxides
Entry
Catalyst
Conv. (%)
Yield (%)
1
2
3
4
5
6
7
8
Co/CeO2
Ni/CeO2
Cu/CeO2
Ru/CeO2
Rh/CeO2
Pd/CeO2
Ag/CeO2
Ir/CeO2
13
20
30
0
8
2
21
0
5
40
10
0
8
88
14
0
9
Pt/CeO2
Pt/CeO2–air
PtOx/CeO2
CeO2
Pt/MgO
Pt/TiO2
Pt/ZrO2
Pt/Al2O3
Pt/SiO2–Al2O3
99
99
10
10
99
99
99
99
84
99
75
0
10a
11b
12c
13
14
15
16
17
0
99
94
71
27
12
a
b
Pre-reduced Pt/CeO2 was exposed to air at room temperature for 0.5 h. Tested without pre-reduction. c Catalyst amount was 50 mg.
species on the surface of Pt nanoparticles are the active species
and re-oxidation of them by O2 under ambient conditions results
in the catalyst deactivation. This hypothesis is confirmed by the
following results. IR spectroscopy with CO as a probe molecule
allows monitoring of the changes in the electronic states of
Pt surface. As shown in Fig. 2, the IR spectra of CO adsorbed on
Pt/CeO2 showed a band at 2064 cm−1 assignable to linearly coor-
dinated CO on metallic Pt.18 Upon exposure to air at room tem-
perature for 0.5 h, the intensity of the band due to CO–Pt0
decreased. Combined with the result of the catalytic test, it is
clarified that the surface metallic Pt0 sites are the catalytically
active species. Summarizing the above results, we conclude that
co-presence of surface Pt0 species on Pt metal clusters and basic
support are indispensable elements in this catalytic system.
With the most effective catalyst, Pt/CeO2, we investigated
general applicability of the present catalytic system. Table 3
Fig. 1 Pt L3-edge XANES spectra (A) and EXAFS Fourier transforms (B).
PtOx/CeO2 was inactive for the reaction (entry 11), while
Pt metal clusters on CeO2 showed 99% yield. Combined with
the structural results, it is concluded that oxidic Pt species
are inactive and Pt metal clusters are active species.
The catalyst named Pt/CeO2–air, prepared by exposing
Pt/CeO2 to the ambient conditions for 0.5 h, showed lower yield
than the as-reduced Pt/CeO2. This suggests that the metallic Pt0
Table 2 Curve-fitting analysis of Pt L3-edge EXAFS
Sample
Shell
Na
R/Åb
σ/Åc
Rf/%d
PtOx/CeO2
Pt/CeO2
Pt foil
O
Pt
Pt
4.9
2.00
0.044
0.084
—
3.5
2.3
—
7.7
2.73
(12)e
(2.76)e
Fig. 2 IR spectra of CO adsorbed on Pt/CeO2 (after H2-reduction at
500 °C for 0.5 h) and Pt/CeO2–air (after re-oxidation of Pt/CeO2 under
air at room temperature for 0.5 h) at 40 °C.
a
b
c
Coordination numbers. Bond distance. Debye–Waller factor.
d
Residual factor. e Crystallographic data.
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a
Table 3 Alkylation of oxindole with different alcohols using Pt/CeO2
Entry
1
Alcohols
Products
Yieldb (%)
99 (95)
2
3
4
5
99 (90)
90 (82)
90 (79)
99 (92)
6
99 (90)
7
99 (95)
8c
79
9
60 (54)
10
11
12
99 (89)
99 (92)
99 (85)
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Table 3 (continued)
Entry
Alcohols
Products
Yieldb (%)
13
14
70 (58)
99 (92)
15
99 (94)
a
b
0.01 mmol Pt, 1 mmol oxindole, 1.1 mmol alcohol, 1.5 g mesitylene, 170 °C, 24 h, in N2. GC yield. Isolated yield is in the parentheses.
1 mmol oxindole, 1.5 mmol alcohol, 1.5 g mesitylene, 155 °C, 24 h
c
shows the scope of C-3 alkylation of oxindole with different
As proposed in the previous papers on the C-3 alkylation of
oxindole with alcohols,13,14 the present reaction can proceed
through the hydrogen-borrowing pathway, which is evidenced
by the following results. The reaction of n-octanal and indole
with Pt/CeO2 under N2 resulted in the formation of the aldol
condensation product, alkenyl–oxindole, in a quantitative yield
(eqn 1). The same reaction was catalyzed by CeO2 with higher
reaction rate than Pt/CeO2 (result not shown). Considering
that solid base catalysts catalyze the aldol condensation reac-
tion,17 the result indicates that basic site of the CeO2 support
can be the active site for the aldol condensation of aldehyde
and oxindole. Then, the aldol condensation product was
isolated and underwent the transfer hydrogenation with
1-octanol (1.1 equiv) as a hydrogen donor in the presence of
Pt/CeO2 under N2. As shown in eqn 2, the CC bond in the
alcohols using 1 mol% of the catalyst. Various aliphatic pri-
mary alcohols including linear and branched aliphatic alco-
hols (entries 1–6) were tolerated, giving 100% conversion of
oxindole and good to high yield of the corresponding
C-3 alkylated oxindoles. The reactions of oxindole and
benzylalcohols with an electron-donating or an electron-
withdrawing substituent proceeded in moderate to excellent
yield (entries 7–12). This method was also applicable for the
alcohol with a less stable substituent, o-substituted benzylic
alcohol (entry 8). The catalyst was applicable to a hetero-
cyclic alcohol containing nitrogen atoms (entry 13). The
reactions of a N-alkylated oxindole with benzyl and aliphatic
primary alcohols resulted in excellent yield (entries 14, 15).
Note that the turnover number (TON) for the alkylation of
oxindole with benzylalcohol (entry 7) was 95, which is
higher than those obtained in the previous homogeneous
systems: TON of 45 for RuCl3/PPh3/KOH13 and TON of 36
for [IrCp*Cl2]2/KOH.14
The reaction of oxindole with 1-octanol was completely ter-
minated by removal of the catalyst from the reaction mixture
after 1.5 h; further heating of the filtrate for 24 h under the
reflux condition did not increase the yield. ICP-AES analysis of
the filtrate confirmed that the content of Pt in the solution
was below the detection limit. These results confirm that the
reaction is attributed to the heterogeneous catalysis of Pt/CeO2.
Fig. S1† shows the results of catalyst reuse. After the reaction of
cycle 1 (entry 1, Table 2), the catalyst was separated from the
reaction mixture by centrifugation and was dried at 90 °C at
12 h and then reduced in H2 at 500 °C for 0.5 h. The recovered
catalyst showed nearly quantitative yield at least two times (Fig. 3).
Fig. 3 Catalyst reuse for alkylation of oxindole by 1-octanol with by
Pt/CeO2. Conditions are the same as those in Table 3 (entry 1).
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(5) high TON. Structure–activity relationship studies show
that both surface Pt0 species on Pt metal clusters and basic
support are indispensable elements in this catalytic system.
Acknowledgements
This work was supported by a MEXT program "Elements Strategy
Initiative to Form Core Research Center" (since 2012), Japan.
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alkylated oxindole in a quantitative yield. Molecular hydrogen,
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alcohols, might hydrogenate the alkenyl–oxindole, but the
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alkenyl–oxindole in 30% yield (eqn 3). Based on the above
results, we propose the mechanism for Pt/CeO2-catalyzed alkyl-
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by the generation of Pt–H species. Then, CeO2-catalysed aldol
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Conclusions
We have developed the first additive-free method for catalytic
C3 alkylation of oxindole with various alcohols by Pt-loaded
CeO2 catalyst driven by the borrowing-hydrogen pathway.
Considering the fact that the previous catalytic systems need
sub-stoichiometric amount of strong base and expensive
organic ligands, our method provides a more environmen-
tally benign catalytic system for C-3-alkylated oxindoles from
oxindoles and alcohols because of the following advantages:
(1) no need of basic co-catalyst and organic ligands, (2) easy
catalyst/product separation, (3) catalyst reuse, (4) wide scope
including aliphatic alcohols and N-substituted oxindole, and
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