COMMUNICATION
DOI: 10.1002/chem.201302464
General and Selective C-3 Alkylation of Indoles with Primary Alcohols by
Reusable Pt Nanocluster Catalyst
S. M. A. Hakim Siddiki,[a] Kenichi Kon,[b] and Ken-ichi Shimizu*[a, b]
The indole scaffold is one of most relevant structures
found in natural products, pharmaceuticals ingredients, func-
tional materials and agro-chemicals.[1] C-3 substituted in-
doles are of particular importance for the construction of
various biologically active molecules.[2–3] Conventional meth-
odologies for the generation of C-3 substituted indoles re-
quire stoichiometric amount of Lewis acids, which have seri-
ous drawbacks such as poor regioselectivity, formation of
salt wastes and use of hazardous reagents.[4–6] Recently de-
veloped methods for the generation of C-3-alkylated indoles
are based on Friedel–Crafts reactions in the presence of
Lewis and Brønsted acids or organocatalysts, which suffer
from necessities of additives and limited substrate
scopes.[7–11] C-3 alkylation of indoles using propargylic or ar-
omatic alcohol[12–16] or benzylmethyl carbonate[17] have been
recently developed as more environmentally benign meth-
ods, though they suffer from limited scope of alcohols. Very
recently, Yus and co-workers showed non-catalytic C-3 alky-
lation by alcohol through a hydrogen-autotransfer strategy
with a stoichiometric amount of base (130 mol% KOH).
However this method only worked with activated (aromatic)
alcohols.[18] In contrast to these alkylations, transition-metal
catalyzed methodologies have rarely been exploited. There
are two examples of C-3 alkylation of indoles by homogene-
ous transition-metal catalysts.[19,20] Grigg and co-workers
demonstrated the first example with [Cp*IrCl2]2 catalyst and
benzylic alcohols as alkylating reagents.[19] Beller and co-
workers reported the Ru-catalyzed system with benzylic and
aliphatic amines.[20] Among these methods, the Grigg
method is the most atom efficient way to form C-3-alkylated
indoles, because water is the only byproduct. However, it
has serious drawbacks such as limited scope (inapplicability
to less activated aliphatic alcohols), low turnover number
(TON), difficulties with the reuse of the homogeneous Ir
catalyst, the necessity of a basic co-catalyst (20 mol%
KOH) and the excess alkylating agent. Mechanistically, the
Grigg method is based on the so-called borrowing-hydro-
gen[21,22] (or hydrogen-autotransfer[23,24]) methodology, in
which the alcohol is initially dehydrogenated, then under-
goes a functionalization reaction, and is re-hydrogenated.
Herein, as a part of our continuing interest in heterogeneous
catalysis for hydrogen-transfer reactions,[25–27] we report the
first general heterogeneous catalytic system for C-3 selective
alkylation of indole with alcohols by a Pt nanocluster-loaded
q-Al2O3 catalyst.
According to our previous method,[27] q-Al2O3-supported
Pt nanoclusters (1 wt%) with an average Pt particle size of
1.5 nm, designated Pt/q-Al2O3-1.5 nm, was prepared by an
impregnation method with PtACTHNUTRGNE(UNG NH3)4(OH)2·H2O solution and
q-Al2O3, followed by calcination in air at 3008C and by re-
duction under H2 at 5008C. X-ray diffraction (XRD) pattern
of Pt/q-Al2O3 was essentially the same as that of the q-
Al2O3 support, and no lines due to Pt metal were observed,
which indicates the absence of large Pt particles. X-ray ab-
sorption near-edge structure (XANES) for Pt/q-Al2O3-
1.5 nm was similar to that of Pt foil, which indicates that Pt
species in the catalyst is in a metallic state (Figure S1A in
the Supporting Information). The X-ray absorption fine
structure (EXAFS) results (Figure S1B, Table S1 in the Sup-
porting Information) show that the spectrum of Pt/q-Al2O3-
À
1.5 nm mainly consists of a Pt Pt bond with a length of
2.70 ꢀ and coordination number of 7.1 and minor contribu-
À
tion (coordination number=0.4) of a Pt O bond with
À
a length of 2.00 ꢀ. The Pt Pt distance, which is less than
À
that of bulk Pt (2.76 ꢀ) and the Pt Pt coordination number
lower than that of bulk Pt (12) are characteristic features of
Pt metal clusters with a diameter smaller than 2.4 nm.[28]
These features are consistent to with the average diameter
of Pt metal estimated by CO adsorption experiments
(1.5 nm). From these results, it is revealed that the dominant
Pt species in Pt/q-Al2O3-1.5 nm are metallic Pt nanoclusters
with surface Pt atoms in unsaturated coordination environ-
ments.
We performed reaction of equimolar amount of 1-octanol
and indole as a model system in order to optimize the reac-
tion parameters. Table 1 summarizes the results of the initial
catalyst screening under the same reaction conditions
(reflux in o-xylene for 22 h under inert atmosphere) using
various transition metal (Co, Ni, Cu, Ru, Rh, Pd, Ag, Re, Ir,
Pt, Au) catalysts supported on g-Al2O3. Note that the reac-
tion can result in N- and C-alkylated products. Among the
catalysts tested, Pt/g-Al2O3 showed the highest yield of the
[a] Dr. S. M. A. H. Siddiki, Dr. K.-i. Shimizu
Elements Strategy Initiative for Catalysts and Batteries
Kyoto University, Katsura, Kyoto 615-8520 (Japan)
[b] Dr. K. Kon, Dr. K.-i. Shimizu
Catalysis Research Center, Hokkaido University
N-21, W-10, Sapporo 001-0021 (Japan)
Fax : (+81)11-706-9163
Supporting information for this article is available on the WWW
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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