Highly efficient dehydrogenation of indolines to indoles using hydroxyapatite-bound Pd catalyst

Article abstract of DOI:10.1016/S0040-4039(03)01550-8

A hydroxyapatite-bound palladium catalyst was found to be effective for the dehydrogenation of various types of indolines to give the corresponding indoles. Moreover, the catalyst was readily recovered from the reaction mixture, and could be reused without any loss of its catalytic activity.

Full text of DOI:10.1016/S0040-4039(03)01550-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6207–6210
Highly efficient dehydrogenation of indolines to indoles using
hydroxyapatite-bound Pd catalyst
Takayoshi Hara, Kohsuke Mori, Tomoo Mizugaki, Kohki Ebitani and Kiyotomi Kaneda*
Department of Chemical Science and Engineering, Graduate School of Engineering Science, Osaka University,
1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
Received 2 June 2003; revised 19 June 2003; accepted 20 June 2003
Abstract—A hydroxyapatite-bound palladium catalyst was found to be effective for the dehydrogenation of various types of
indolines to give the corresponding indoles. Moreover, the catalyst was readily recovered from the reaction mixture, and could be
reused without any loss of its catalytic activity.
© 2003 Elsevier Ltd. All rights reserved.
Indole and its myriad derivatives often possess physio-
logical activities, and have served as important and
versatile intermediates for the synthesis of pharmaceuti-
cals, agrochemicals, and finechemicals.1 A large number
of methodologies for indole ring syntheses have been
developed and this trend is still ongoing.2 Among them,
direct dehydrogenation of indolines to indoles is a
promising protocol for accessing a wide variety of
indole derivatives.3 Although various oxidizing
reagents, such as MnO2,4 Fremy’s salt (potassium
nitrosodisulfonate),5 CuCl2–pyridines,6 azasulfonium
hols,11 and for the deprotection of N-benzyloxy-
carbonyl group from amino acids using molecular
hydrogen.12 During the course of our studies, the dehy-
drogenation of various indolines in the presence of
PdHAP can also proceed efficiently. In addition to
advantages such as simple work-up procedures and the
ability to recycle the catalyst, the catalytic system
described herein exhibits high catalytic activities as
compared to other reported methods.
Calcium hydroxyapatite (HAP), Ca10(PO4)6(OH)2, was
synthesized according to procedures described in the
previous literature.13 HAP (2.0 g) was stirred in a
PdCl2(PhCN)2 (2.67×10−4 M) solution in acetone (150
mL) at room temperature for 3 h. The resulting slurry
was filtered, washed with acetone and dried under
vacuum, yielding the PdHAP (2.01 g, Pd content: 0.02
mmol g−1) as a pale yellow powder. Characterization by
elemental analysis, XPS, EDAX, and Pd–K edge XAFS
revealed that a monomeric PdCl2 species was grafted by
chemisorption on the HAP surface.11
salts,7
N-tert-butylsulfinimidoyl
chloride,8
and
trichlorocyanuric acid,9 are generally available to
accomplish this direct dehydrogenation, these reagents
are often harmful and toxic, and require considerable
amounts. Consequently, with respect to the environ-
mental concerns, there is a strong demand for a clean
and highly efficient catalytic methodology for the con-
version of indolines to indoles.
Hydroxyapatites, the main component of bones and
teeth, are of considerable interest in view of their
potential use as biomaterials, adsorbents, and ion-
exchangers.10 To date, however, only a few applications
as catalysts or as catalyst supports have emerged. Most
recently, we have reported that a hydroxyapatite-bound
Pd catalyst (PdHAP) can act as a highly efficient het-
erogeneous catalyst for the aerobic oxidation of alco-
A typical reaction procedure is as follows: into a reac-
tion vessel equipped with a reflux condenser were
placed the PdHAP (0.05 g, Pd: 1 mmol), indoline (2.38
g, 20 mmol), and toluene (25 mL). After stirring the
heterogeneous mixture at 120°C under an argon atmo-
sphere for 6 h, the PdHAP was separated by filtration.
GC analysis of the filtrate showed 99% yield of indole.
Removal of the solvent under the reduced pressure,
followed by recrystallization from n-hexane solution
afforded pure indole (2.16 g, 92% isolated yield).
Keywords: dehydrogenation; indoline; indole; heterogeneous Pd cata-
lyst; hydroxyapatite.
* Corresponding author. Tel./fax: +81-6-6850-6260; e-mail:
kaneda@cheng.es.osaka-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01550-8

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T. Hara et al. / Tetrahedron Letters 44 (2003) 6207–6210
Table 2. Dehydrogenation of indoline derivatives catalyzed
Initially, the dehydrogenation of indoline 1 to indole 2
was examined as a model reaction using various Pd
catalysts. As shown in Table 1, the PdHAP exhibited
the highest catalytic activity in toluene under an argon
atmosphere to give 2 in almost quantitative yield after
1 h (entry 1). Other conventional heterogeneous Pd
catalysts such as Pd/carbon (5 wt%) and Pd/activated
carbon (10 wt%) were found to be less effective under
similar reaction conditions (entries 3 and 4). The use of
by PdHAPa
homogeneous
Pd
catalysts,
e.g.
Pd(OAc)2,
PdCl2(PhCN)2, and Pd2(dba)3CH3Cl also resulted in
low yields, accompanied with the formation of palla-
dium black (entries 5–8). Among the solvents exam-
ined, the use of DMF and 1,4-dioxane provided
favorable results (94 and 80% yields, respectively),
whereas chlorobenzene, nitromethane, and DMSO were
not effective at all. It is notable that dehydrogenation
under an oxygen atmosphere was significantly retarded
(entry 2).14
The results of PdHAP-catalyzed dehydrogenation of
various indolines are summarized in Table 2. All methyl
substituted indolines were dehydrogenated to give the
corresponding indoles in high yields (entries 3–7) with-
out the influence of substituted positions except for
2,3-dimethylindoline (entry 8).15 Remarkably, even ster-
ically hindered indolines such as carbazoline,16 N-ben-
zylindoline, and 2-phenylindoline were converted to the
corresponding indoles in 94, 92, and 92% yields, respec-
tively (entries 9–11). Among the indoline derivatives,
6-nitroindoline and 5-bromoindoline were scarcely oxi-
dized under the above conditions.
To highlight the applicability of the present protocol, a
20 mmol scale reaction of 1 was undertaken using
5×10−3 mol% of the Pd catalyst. Dehydrogenation was
completed within 6 h to afford 2 in 99% yield, in which
the TON based on Pd approached up to 20 000 with an
excellent TOF of approximately 2800 h−1. These TON
Table 1. Dehydrogenation of indoline using various Pd
catalystsa
Entry
Catalyst
Convn (%)b
Yield (%)b
and TOF values are significantly higher than those
reported for other catalytic systems, such as tetra-
propylammonium perruthenate (TPAP)/NMO (TON=
15, TOF=4 h−1),17 Co(salen)/O2 (TON=9, TOF=2
h−1),18 and the conventional Pd/carbon (TON=100,
TOF=50 h−1).1a From the viewpoint of recent environ-
mental consciousness, it is desirable to use water
instead of organic solvents as the reaction medium.19 It
is noteworthy that the PdHAP was proved to be an
efficient catalyst even under aqueous conditions. For
example, dehydrogenation of 1, 2-methylindoline, and
carbazoline proceeded smoothly to give 2, 2-methylin-
dole, and 1,2,3,4-tetrahydrocarbazole in excellent yields
for 3 h, respectively (Scheme 1).20
1
PdHAP
PdHAP
>99
15
28
>99
15
28
2c
3
Pd/carbon (5 wt%)d
Pd/activated carbon
(10 wt%)d
4
49
49
5
6
7
8
Pd(OAc)2
48
45
48
45
48
43
47
43
PdCl2(PhCN)2
Pd2(dba)3CHCl3
Pd(acac)2
a Reaction conditions: Pd catalyst (Pd: 0.6 mol%), indoline (1 mmol),
toluene (5 mL), 100°C, Ar, 1 h.
b Determined by GC using an internal standard technique.
c Under O2 atmosphere.
d Purchased from Wako Pure Chemical Industries, Ltd.

T. Hara et al. / Tetrahedron Letters 44 (2003) 6207–6210
6209
Scheme 1. Dehydrogenation of indolines catalyzed by PdHAP in water.
Upon completion of the reaction, the catalyst was
easily separated from the reaction mixture. ICP analysis
of the filtrate confirmed that no leaching of the Pd
species occurred during the above dehydrogenation.
Subsequently, it was shown that the recovered PdHAP
could be reused without any loss of its catalytic activity
(Table 2, entry 2). In the reaction of 1, the PdHAP was
removed after 40% conversion. The filtrate was further
reacted at 100°C for 1 h and no dehydrogenation was
occurred. TEM images for the isolated PdHAP revealed
the presence of Pd nanoparticles with diameters of ca. 9
nm, showing that the monomeric Pd(II) species on
HAP are reduced to Pd(0) under the reaction condi-
tions, and the dehydrogenation occurs on the Pd parti-
cles located on the HAP surface.
D.; Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979;
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11. Mori, K.; Yamaguchi, K.; Hara, T.; Mizugaki, T.; Ebi-
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We here propose a possible mechanism for this indoline
dehydrogenation. Initially, a nitrogen atom of indoline
coordinated to the Pd(0) species, followed by oxidative
addition at the C–H bond adjacent to the nitrogen
atom to give a s-alkyl Pd species.21 Subsequently, this
intermediate species undergoes b-hydride elimination to
afford the corresponding indole and Pd(0), along with
the evolution of molecular hydrogen.22 Vide supre, the
stereoselective dehydrogenation of 2,3-dimethylindoline
shows that the b-elimination occurs in a syn manner.
In conclusion, the PdHAP was demonstrated to be an
efficient heterogeneous palladium catalyst for the dehy-
drogenation of indolines to indoles. The present cata-
lytic system can offer significant benefits in achieving
the simple and clean synthesis of indoles.
Acknowledgements
14. Generally, indoles are sensitive to oxygen, and conse-
quently, the decrease in the catalytic activity may be
attributed to the deactivation of PdHAP by the over-oxi-
dized products.
15. In the case of 2,3-dimethylindoline (cis:trans=1:3), only
the cis isomer was exclusively dehydrogenated to 2,3-
dimethylindole, whereas the trans isomer remained intact.
16. Gribble, G. W.; Hoffman, J. H. Synthesis 1977, 859
Dehydrogenation of the trans isomer hardly occurred
under the same reaction conditions.
We thank Dr. T. Akita (AIST) for TEM measurements.
K.M. thanks the JSPS Research Fellowships for Young
Scientists. K.M. expresses his special thanks for the
center of excellence (21COE) program ‘Creation of
Integrated Ecochemistry’ of Osaka University.
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20. Typical work-up procedures for the dehydrogenation
under aqueous conditions are as follows: the reaction
mixture was extracted with ethyl acetate, and then the
organic layer was dried over MgSO4. Removal of ethyl
acetate under the reduced pressure, followed by recrystal-
lization from n-hexane solution afforded pure 2 (0.112 g,
93% isolated yield).
22. The evolution of hydrogen gas was measured by the
following experiment: PdHAP (Pd: 0.6 mol%) was placed
in a sidearmed flask attached to a gas buret. The system
was evacuated and filled with Ar, followed by the addi-
tion of toluene (5 mL) and 1 (1 mmol), and then reacted
for 1 h at 100°C. The molar ratio of evolved H2 gas to 2
was ca. 1:1.
21. For the a-CꢀH-bond activation mechanism in the alkyl