Synthesis of indoles via dehydrogenative N-heterocyclization by supported platinum catalysts

Article abstract of DOI:10.1039/c4ra11893f

We found the first heterogeneous Pt catalysts (Pt/Nb₂O₅ and Pt/HBEA) for the synthesis of indoles via acceptorless dehydrogenative cyclization of 2-(2-aminophenyl)ethanol, showing higher turnover number (TON) than previously reported catalysts. This journal is

Full text of DOI:10.1039/c4ra11893f

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Table of Contents
2 5
Heterogeneous Pt catalysts (Pt/Nb O and Pt/HBEA) show higher turnover number (TON) than
previously reported catalysts for the synthesis of indole via acceptorless dehydrogenative
cyclization of 2-(2-aminophenyl)ethanol.
OH
0
.2 mol% Pt/HBEA
+
H + H O
2 2
o-xylene, reflux
N
NH2
H
90% yield (TON of 450)
1

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Synthesis of indoles via dehydrogenative N-heterocyclization by supported platinum catalysts
a
Sondomoyee Konika Moromi, Abeda Sultana Touchy, S. M. A. Hakim Siddiki, Md. Ayub Ali,
a
b
a
a,b
Ken-ichi Shimizu*
a
Catalysis Research Center, Hokkaido University, N-21, W-10, Sapporo 001-0021, Japan
Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Katsura, Kyoto
b
6
*
15-8520, Japan
Corresponding author
Ken-ichi Shimizu
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
Abstract: We found the first heterogeneous Pt catalysts (Pt/Nb O and Pt/HBEA) for the synthesis
2
5
of indoles via acceptorless dehydrogenative cyclization of 2-(2-aminophenyl)ethanol, showing
higher turnover number (TON) than previously reported catalysts.
Indoles are important organic compounds, which are widely used for the syntheses of
1–6
1–4
pharmaceuticals and agrochemicals. Various methods to prepare indoles were reported.
Oxidative or dehydrogenative N-heterocyclization of 2-(2-aminophenyl)ethanol alcohols is one of
7
-17
the most promising protocols, since the starting alcohol is easily prepared by the condensation
of 2-nitrotoluene with formaldehyde in the presence of bases, followed by the reduction of a nitro
8
functionality to an amino one. Heterogeneous copper catalysts were reported to catalyze the
7
reaction at high temperatures (> 200 °C). Homogeneous transition metal catalysts, such as
8
-10
11-14
15
complexes and a copper/TEMPO system catalyzed the reaction at
ruthenium and iridium
lower temperatures but have problems such as difficulties in catalyst/product separation and
catalyst reuse and needs of additives such as base or acceptor. A supported Au catalyst also
1
6
required basic additives (200 mol% of NaOtBu) and oxidant (O2). From a viewpoint of
5
,6,18-20
sustainable chemistry, acceptorless dehydrogenative coupling methodology
conditions using a reusable catalyst is most attractive. Recently, Wada and co-workers
under neutral
17
developed a new heterogeneous catalyst, Ru/CeO , that was effective for acceptorless
2
dehydrogenative synthesis of indole from 2-(2-aminophenyl)ethanol in the absence of any
additives. As discussed in the previous studies on this reaction, the reaction can proceeds via the
following two step pathway:
, where dehydrogenation of 2-(2-aminophenyl)ethanol by a metal (M) catalyst is followed by
condensation of the amino aldehyde intermediate to give indole. As a part of our continuing
2
interest in heterogeneous Pt catalysts for acceptorless dehydrogenation of alcohols and
1
2
2,23
acceptorless dehydrogenative coupling reactions of alcohols,
we report herein the synthesis of
indoles via acceptorless dehydrogenative N-heterocyclization 2-(2-aminophenyl)ethanol under
additive-free conditions by heterogeneous Pt catalysts, which show higher TON than previous
catalytic systems.
We started the N-heterocyclization of 2-(2-aminophenyl)ethanol under o-xylene reflux
conditions in N as a model system in order to optimize catalytic conditions. Table 1 (entries 1–8)
summarizes the results of the initial catalyst screening test under the same reaction conditions
2
1

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using various transition metal (Pt, Ir, Ru, Re, Pd, Co, Cu, Ag) catalysts supported on Nb O5
2
pre-reduced in H at 300 °C. Cu and Ag catalysts (entries 7,8) showed no activity and Ru, Re, Pd
2
and Co catalysts (entries 3–6) showed low yields. Ir/Nb O (entry 2) gave a good yield of 68%.
5
2
Among the catalysts tested, Pt/Nb O (entry 1) showed the highest yield (82%) of indole. Entries
2
5
1
TiO , ZrO , Al O , SnO ,carbon, SiO ). Pt/Nb O (entry 1) and Pt/HBEA (entry 10) showed
0–19 show the results of Pt catalysts loaded on the other supports (HBEA zeolite, CeO , MgO,
2
2
2
2
3
2
2
2
5
higher yields (82-83%) than the other supported Pt catalysts. Pt/CeO , Pt/MgO, Pt/TiO Pt/ZrO ,
2
2,
2
Pt/Al O , Pt/SiO -Al O , Pt/C and Pt/SiO (entries 11–19) gave low to moderate yields (9–69%).
2
2
3
2
2
3
To study the effect of the oxidation state of Pt species on the activity, we tested the activity of a
pre-oxidized catalyst named PtO /Nb O , that is, a platinum oxides-loaded Nb O catalyst.
x
2
5
2
5
PtO /Nb O (entry 20) showed a lower yield (10%) than with the pre-reduced catalyst, Pt/Nb O
5
x
2
5
2
(
entry 1). Taking into account the result that the activity of the metal-unloaded Nb O was
2 5
negligible (entry 9) and the result that the activity depends strongly on the support, it is suggested
that the co-presence of metallic Pt species and specific support materials (Nb O or HBEA) is
2
5
important factor of highly active catalysts. Note that indole was not produced in the absence of a
catalyst (entry 21).
Table 2 shows the effect of reaction conditions on the yield of indole for the reaction of
2
-(2-aminophenyl)ethanol by Pt/Nb O under reflux conditions for 7 h. The reactions in toluene
2 5
and hexane gave low yield (entries 3,4), and the reaction in mesitylene gave 78% yield (entry 2).
The reaction in reflux of o-xylene gave the highest yield of 93% (entry 1). After the reaction, the
catalyst was removed from the mixture and indole was isolated by column chromatography,
resulting in high isolated yield of indoles (88%). The reaction in o-xylene at lower temperature
(
(
130 °C) gave low yield (29%) of indole (entry 5). The reaction under 1atm O in the gas phase
2
entry 6) gave lower yield (82%) than that under N (93%), indicating that O as a hydrogen
2
2
acceptor does not accelerate the catalytic reaction. For the reaction under N with Pt/Nb O , we
2
2
5
carried out mass spectrometry analysis of the gas phase products after 1 h. As shown in eqn. (1),
the yields of gas phase H (24%) was close to the yield of indole (32%).
2
Using Pt/Nb O and Pt/HBEA as two of the effective catalysts for this reaction, we carried
5
2
out detailed catalytic studies. We checked the time course of the reaction under the standard
conditions (Fig. 1). For Pt/Nb O , the yield of indole increased with time and reached 93% after 7
2
5
h. For Pt/HBEA, the yield of indole reached 95% after 12 h. Fig. 2 shows the results of catalyst
reusability of Pt/Nb O and Pt/HBEA. After completion of the reaction, 2-propanol (1 mL) was
2
5
added to the reaction mixture and the catalyst was separated by centrifugation. The recovered
catalyst was washed with acetone three times, followed by centrifugation and drying in an oven
(
under air) at 90 °C for 12 h and then H reduction at 300 °C for 0.5 h. The recovered Pt/Nb O
2 2 5
catalyst showed high yield for the second and the third cycle. In contrast, the recovered Pt/HBEA
catalyst showed low yields in the second and third cycles. Thus, Pt/Nb O was found to be a
better catalyst in terms of reusability.
2
5
In order to evaluate TON of the catalytic system, next we carried out the reaction with small
amount of the catalysts. As shown in eqn. (2), the reactions with 0.2 mol% of Pt/Nb O and
Pt/HBEA for 52 h resulted in 76% and 90% yields, corresponding to TONs of 380 and 450,
2
5
8
-15
respectively. The TON by Pt/HBEA is 3~25 times larger than those by homogeneous
and
17
heterogeneous catalysts in the literature for the same reaction. ICP-AES analysis of the filtrate
after the reaction with Pt/HBEA showed that the content of Pt in the solution was quite low (3.4
ppm).
2

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Cl
Cl
Pt/HBEA
1 mol%)
OH
OH
(
(3)
o-xylene (1 mL)
NH2
N
reflux, 8 h
H
1
mmol
7
1% isolated yield
Cl
Cl
Pt/HBEA
(1 mol%)
(4)
+
H2
o-xylene (1 mL)
NO2
1 atm
reflux, 12 h
N
H
1
mmol
7
5% isolated yield
Pt/HBEA
(1 mol%)
OH
(5)
+
H2
o-xylene (1 mL)
N
H
NO2
1 atm
reflux, 12 h
1
mmol
68% isolated yield
The present method was also effective for the synthesis of a functionalized indole. As shown
in eq. (3), the 2-aminophenethyl alcohol with a Cl- group on the aromatic ring was converted to
the corresponding indole in 71% isolated yield by 1 mol% of Pt/HBEA.
Since supported Pt catalysts can exhibit a catalytic activity for the reduction of the nitro
group to an amino group with H , we examined the synthesis of indoles from 2-nitrophenthyl
alcohols. As shown in equations (4) and (5), Cl-functionalized 2-nitrophenthyl alcohol and
2
2-nitrophenthyl alcohol were selectively converted to the corresponding indole derivatives in
moderate isolated yields under balloon H pressure for 12 h in the presence of 1 mol% of
Pt/HBEA.
2
In summary, we reported that Pt/Nb O and Pt/HBEA acted as effective heterogeneous
5
2
catalysts for the synthesis of indoles via acceptorless dehydrogenative cyclization of
-(2-aminophenyl)ethanol. These catalysts showed higher TON than previously reported
catalysts, and the Pt/Nb O catalyst was reusable.
2
2
5
Experimental section
Commercially available organic compounds (from Tokyo Chemical Industry) were used without
further purification. The GC (Shimadzu GC-14B) and GCMS (Shimadzu GCMS-QP2010)
3

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DOI: 10.1039/C4RA11893F
+
analyses were carried out with Ultra ALLOY capillary column UA -1 (Frontier Laboratories Ltd.)
using nitrogen and helium as the carrier gas.
+
H -type BEA zeolite (HBEA, SiO /Al O = 25±5, JRC-Z-HB25), CeO (JRC-CEO-3), MgO
2
2
3
2
(JRC-MGO-3), TiO (JRC-TIO-4) and SiO -Al O (JRC-SAL-2, Al O = 13.75 wt%) were
supplied from Catalysis Society of Japan. Nb O was prepared by calcination of niobic acid
2 2 2 3 2 3
2
5
(
Laboratory Co., Ltd.) at 500 °C for 3 h. ZrO was prepared by calcination of a hydroxide of Zr at
CBMMI) at 500 °C for 3 h. SnO was prepared by calcination of H SnO (Kojundo Chemical
2 2 3
2
23
5
from Sasol) at 900 °C for 3 h. Precursor of 5 wt% Pt/Nb O was prepared by an impregnation
00 °C for 3 h. γ-Al O was prepared by calcination of γ-AlOOH (Catapal B Alumina purchased
2
3
2
5
method; a mixture of Nb O and an aqueous HNO solution of Pt(NH ) (NO ) was evaporated at
3 2
2
5
3
3 2
5
prepared by pre-reduction of the precursor in a pyrex tube under a flow of H (20 cm min ) at
0 °C, followed by drying at 90 °C for 12 h. A pre-reduced catalyst, named Pt/Nb O , was
2 5
3
−1
2
3
00 °C for 0.5 h. Platinum oxides-loaded Nb O (PtO /Nb O ), as a comparative catalyst, was
2 5 x 2 5
prepared by calcination of the precursor in air at 300 °C for 3 h. By using various supports,
several pre-reduced Pt catalysts were prepared by the same method as Pt/Nb O . Nb O -supported
metal catalysts, M/Nb O (M = Co, Cu, Ru, Pd, Ag, Re, Ir) with metal loading of 5 wt% were
2
5
2
5
2
5
prepared by impregnation method in a similar manner as Pt/Nb O using an aqueous solution of
2
5
metal nitrates (for Co, Cu, Ag), RuCl , IrCl , NH ReO or an aqueous HNO solution of
3
3
4
4
3
Pd(NO ) .
2
3
Typically, 5 wt% Pt/Nb O5 (39 mg, 0.01 mmol of Pt) was used as a standard catalyst. After the
2
pre-reduction at 300 °C, we carried out catalytic tests using a batch-type reactor without exposing
the catalyst to air as follows. A mixture of 2-(2-aminophenyl)ethanol (1.0 mmol) and n-dodecane
(
(
0.2 mmol) in o-xylene (1 mL) was injected to the pre-reduced catalyst inside the reactor
cylindrical glass tube) through a septum inlet, followed by filling N . Then, the resulting mixture
2
was magnetically stirred for 5 h under reflux condition; the bath temperature was 155 °C and
reaction temperature was ca. 144 °C. The yield of indole was determined by GC using
n-dodecane as an internal standard. The analysis of the gas phase product (H ) was carried out by
2
the mass spectrometer (BELMASS). To determine the isolated yield of indole, indole was isolated
by column chromatography using silica gel 60 (spherical, 63-210 ꢀm, Kanto Chemical Co. Ltd.)
with hexane/ethylacetate (95/5) as the eluting solvent, followed by analyses by GCMS and H and
1
1
3
C NMR (JEOL-ECX 600 operating at 600.17 and 150.92 MHz, respectively) with
tetramethylsilane as an internal standard.
Acknowledgment
This work was supported by Grant-in-Aids for Scientific Research B (26289299) from MEXT
(Japan), a MEXT program "Elements Strategy Initiative to Form Core Research Center" and a
Grant-in-Aid for Scientific Research on Innovative Areas "Nano Informatics" (25106010) from
JSPS.
Notes and references
1
.
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Perkin Trans. 1, 1999, 2849–2866.
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5

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a
Table 1. Catalyst screening for indole synthesis from 2-(2-amino-phenyl)-ethanol.
OH
cat. (1 mol%)
+
H + H O
2 2
o-xylene (1 mL)
reflux, 5 h
N
H
NH2
1
mmol
a
Yield (%)
Entry
Catalyst
Pt/Nb
1
2
3
4
5
6
7
8
2
O
5
82
Ir/Nb
O
5
68
9
2
Ru/Nb
O
2
5
Re/Nb
O
2
2
5
Pd/Nb
Co/Nb
Cu/Nb
Ag/Nb
O
5
1
2
O
2
O
2
O
2
1
5
5
5
0
0
b
9
Nb
Pt/HBEA
Pt/CeO
Pt/MgO
Pt/TiO
Pt/ZrO
Pt/Al
Pt/SiO -Al
2
O
5
1
1
0
1
77
69
69
47
42
22
15
9
1
2
1
1
1
1
1
1
1
1
2
2
2
3
4
5
6
7
8
9
0
1
2
2
O
2
3
O
3
2
2
Pt/SnO
Pt/C
2
15
10
10
0
Pt/SiO
PtO /Nb
blank
2
O
2 5
x
a
Yield was determined by GC.
Catalyst amount was 39 mg.
b
a
Table 2. Indole synthesis from 2-(2-amino-phenyl)-ethanol by Pt/Nb O .
2
5
Entry
Solvent
o-xylene
mesitylene
hexane
Conv.(%)
100
100
74
Yield (%)
1
2
3
4
93
78
5
toluene
65
23
29
82
b
5
o-xylene
o-xylene
44
c
6
99
a
Conditions: 1 mol% Pt/Nb O , 1.0 mmol 2-(2-amino-phenyl)-ethanol, 1 mL solvent, reflux, in
2
5
N , 7 h. Yield was determined by GC.
2
b
T = 130 °C.
in 1 atm O2.
c
6

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100
Pt/Nb O5
2
80
60
40
20
Pt/HBEA
0
5
t / h
10
Fig. 1 Yields of indole vs time for N-heterocyclization of 2-(2-aminophenyl)ethanol under o-xylene
reflux conditions in N by Pt/Nb O () or Pt/HBEA (ꢀ).
2
2
5
100
80
60
40
20
0
1
2
Cycle number
3
Fig. 2. Reuse of
2
P
-(2-aminophenyl)ethanol under o-xylene reflux conditions in N for 7 h
t/Nb O (gray bars) or Pt/HBEA (black bars) for N-heterocyclization of
2 5
.
2
7