Oxidative cyclization of amino alcohols catalyzed by a Cp*lr complex. Synthesis of indoles, 1,2,3,4-tetrahydroquinolines, and 2,3,4,5-tetrahydro-1-benzazepine

Article abstract of DOI:10.1021/ol026200s

A new iridium-catalyzed oxidative cyclization of amino alcohols has been revealed. Indole derivatives are synthesized in good to excellent yields from 2-aminophenethyl alcohols by means of a [Cp*IrCl₂]₂/K₂CO₃ catalytic system. The present catalytic system is also effective for syntheses of 1,2,3,4-tetrahydroquinolines from 3-(2-aminophenyl)propanols and 2,3,4,5-tetrahydro-1-benzazepine from 4-(2-aminophenyl)butanol.

Full text of DOI:10.1021/ol026200s

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2691-2694
Oxidative Cyclization of Amino Alcohols
Catalyzed by a Cp*Ir Complex.
Synthesis of Indoles,
1,2,3,4-Tetrahydroquinolines, and
2,3,4,5-Tetrahydro-1-benzazepine
,†
,‡
Ken-ichi Fujita,* Kazunari Yamamoto,‡ and Ryohei Yamaguchi*
Department of Natural Resources, Graduate School of Global EnVironmental Studies,
and Graduate School of Human and EnVironmental Studies, Kyoto UniVersity,
Kyoto 606-8501, Japan
fujitak@kagaku.h.kyoto-u.ac.jp
Received May 17, 2002
ABSTRACT
A new iridium-catalyzed oxidative cyclization of amino alcohols has been revealed. Indole derivatives are synthesized in good to excellent
yields from 2-aminophenethyl alcohols by means of a [Cp*IrCl2]2/K2CO catalytic system. The present catalytic system is also effective for
3
syntheses of 1,2,3,4-tetrahydroquinolines from 3-(2-aminophenyl)propanols and 2,3,4,5-tetrahydro-1-benzazepine from 4-(2-aminophenyl)butanol.
N-Heterocyclic compounds have attracted considerable at-
tention owing to their functionality in pharmaceutical
chemistry, material chemistry, synthetic organic chemistry,
and dyes.1 In particular, the synthesis of benzo-fused
N-heterocyclic compounds, such as indoles, quinolines,
benzazepines, and their saturated derivatives, is very impor-
tant because their skeletons are found in a variety of natural
products, which exert physiological activities. A number of
methods for synthesis of indoles have been developed and
reviewed.2 Recently, much attention has focused on the
synthesis of indoles by transition-metal-catalyzed N-hetero-
cyclization.3-5 Catalytic systems with palladium,3d,4a,5b,c,e,g
ruthenium,3a,b,4b,5a,f rhodium,3c,5d and other metals2 have been
applied for the synthesis of indoles. On the other hand, the
catalytic synthesis of 1,2,3,4-tetrahydroquinolines or 2,3,4,5-
tetrahydro-1-benzazepines via N-heterocyclization has been
(3) Inter- or intramolecular addition of NH2 to alkyne: (a) Tokunaga,
M.; Ota, M.; Haga, M.; Wakatsuki, Y. Tetrahedron Lett. 2001, 42, 3865.
(b) Kondo, T.; Okada, T.; Suzuki, T.; Mitsudo, T. J. Organomet. Chem.
2001, 622, 149. (c) Burling, S.; Field, L. D.; Messerle, B. A. Organome-
tallics 2000, 19, 87. (d) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron
Lett. 1988, 29, 1799.
(4) Intramolecular oxidative cyclization of amino alcohol: (a) Aoyagi,
Y.; Mizusaki, T.; Ohta, A. Tetrahedron Lett. 1996, 37, 9203. (b) Tsuji, Y.;
Kotachi, S.; Huh, K.-T.; Watanabe, Y. J. Org. Chem. 1990, 55, 580.
(5) Via other routes: (a) Cho, C. S.; Kim, J. H.; Kim, T.-J.; Shim, S. C.
Tetrahedron 2001, 57, 3321. (b) Takeda, A.; Kamijo, S.; Yamamoto, Y. J.
Am. Chem. Soc. 2000, 122, 5662. (c) Larock, R. C.; Yum, E. K.; Refvik,
M. D. J. Org. Chem. 1998, 63, 7652. (d) Dong, Y.; Busacca, C. A. J. Org.
Chem. 1997, 62, 6464. (e) So¨derberg, B. C.; Shriver, J. A. J. Org. Chem.
1997, 62, 5838. (f) Hsu, G. C.; Kosar, W. P.; Jones, W. D. Organometallics
1994, 13, 385. (g) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28,
5291.
† Graduate School of Global Environmental Studies.
‡ Graduate School of Human and Environmental Studies.
(1) ComprehensiVe Heterocyclic Chemistry II; Bird, C. W., Ed.; Perga-
mon: Oxford, 1996.
(2) (a) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry II; Bird,
C. W., Ed.; Pergamon: Oxford, 1996; Vol. 2, pp 119-206. (b) Gribble, G.
W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (c) Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 1999, 2849. (d) Hegedus, L. S. Angew. Chem., Int.
Ed. Engl. 1988, 27, 1113.
10.1021/ol026200s CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/13/2002

hardly explored.6 During the course of our investigation on
the chemistry of pentamethylcyclopentadienyl (Cp*) iridium
complexes,7 we found a catalytic activity of [Cp*IrCl2]2
toward hydrogen-transfer reactions between organic mol-
ecules and reported Oppenauer-type oxidation of primary and
secondary alcohols giving rise to the corresponding carbonyl
compounds.7 In this paper, we wish to report a Cp*Ir
complex-catalyzed synthesis of indoles, 1,2,3,4-tetrahydro-
quinolines, and 2,3,4,5-tetrahydro-1-benzazepine by oxidative
N-heterocyclization of amino alcohols.
At first, we investigated Cp*Ir-catalyzed oxidative N-
heterocyclization of 2-aminophenethyl alcohol (1) under
various conditions. The reactions were performed in the
presence of several iridium complexes and bases in toluene
as a solvent. The results are summarized in Table 1. Indole
catalytic activity (entries 8-10), but the optimum result was
obtained in the reaction with K2CO3. Toluene was the solvent
of choice, since the reactions in other solvents (dioxane or
acetonitrile) gave lower yields of 2 (entries 11 and 12).
The present oxidative N-heterocyclization could be ap-
plicable to various amino alcohols, affording indole deriva-
tives. The results are summarized in Table 2.8 2-Aminophen-
Table 2. Synthesis of Indoles from Various Amino Alcohols
Catalyzed by the [Cp*IrCl2]2/K2CO3 Systema
Table 1. Synthesis of Indole (2) from 2-Aminophenethyl
Alcohol (1) by Various Catalytic Systemsa
entry
catalyst
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrHCl]2
[Cp*Ir(MeCN)3][OTf]2
[IrCl(COD)]2
none
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
base
yieldb (%)
1
2c
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
none
Li2CO3
tBuOK
Et3N
70
90
55
20
22
2
31
42
62
57
50
24
a The reaction was carried out at reflux temperature (111 °C) for 20 h
with amino alcohol (1.0 mmol), [Cp*IrCl2]2 (5.0 mol %/Ir) and K2CO3 (0.10
mmol) in toluene (2 mL). b Isolated yield. c Reaction time was 17 h.
10
11d
12e
K2CO3
K2CO3
ethyl alcohols bearing a substituent on the aromatic ring were
converted into the corresponding indoles in moderate to high
yields (entries 2-4). Indoles bearing a substituent on the
N-heterocyclic ring could be also synthesized in good to
excellent yields by the reaction of 2-aminophenethyl alcohols
with a substituent on the methylene chain (entries 5 and 6).
In the synthesis of indoles, the reaction proceeded with high
selectivity and no indoline product was detected.
Since the complex [Cp*IrCl2]2 exhibits a catalytic activity
toward the reduction of the nitro group to an amino group
with use of alcohols as a hydrogen source,9 we examined
the synthesis of indole from 2-nitrophenethyl alcohol (3) (eq
1). Indole (2) was obtained in the yield of 69% by the
a The reaction was carried out at 100 °C for 17 h with 1 (1.0 mmol),
catalyst (5.0 mol %/Ir), and base (0.10 mmol) in toluene (2 mL).
b Determined by GC. c The reaction was carried out at reflux temperature
(111 °C). d The reaction was carried out in dioxane. e The reaction was
carried out in acetonitrile at reflux temperature (81 °C).
(2) was formed in a yield of 70% when the reaction was
performed at 100 °C for 17 h with use of [Cp*IrCl2]2 (5.0
mol %/Ir) and K2CO3 (10 mol %) (entry 1). The yield of 2
increased up to 90% when the reaction was performed at
reflux temperature (111 °C) (entry 2). Other iridium com-
plexes, [Cp*IrHCl]2, [Cp*Ir(MeCN)3]2+, or [IrCl(COD)]2,
showed some catalytic activity (entries 3-5), but the yields
of 2 were lower than that in the reaction catalyzed by
[Cp*IrCl2]2. We next examined the effect of base. When the
reaction was performed without any base, the yield of 2
declined to 31% (entry 7). Addition of other alkali metal
bases (Li2CO3, tBuOK) or organic base (Et3N) improved the
(6) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
52, 15031 and references therein. (b) Larock R. C.; Berrios-Pena, N. G.;
Fried, C. A.; Yum, E. K.; Tu, C.; Leong, W. J. Org. Chem. 1993, 58, 4509.
(7) Fujita, K.; Furukawa, S.; Yamaguchi, R. J. Organomet. Chem. 2002,
649, 289.
reaction of 3 in 2-propanol at 120 °C for 40 h in a heavy-
walled glass reactor. A small amount of 2-aminophenethyl
alcohol (1) was detected by GC analysis (6%) as a byproduct.
2692
Org. Lett., Vol. 4, No. 16, 2002

Scheme 1
Thus, it is probable that a catalytic reduction of the nitro
aminophenyl)propanol, 1,2,3,4-tetrahydroquinoline was ob-
tained selectively in almost quantitative yield without any
detection of quinoline or dihydroquinolines (entry 1). In this
case, the reaction proceeded readily with smaller amounts
of catalyst (2.0 mol %/Ir). 3-(2-Aminophenyl)propanols
bearing a substituent at the aromatic ring (entries 2-4) or
the methylene chain (entries 5 and 6) were converted into
the corresponding 1,2,3,4-tetrahydroqunolines in moderate
to high yields. In the reactions of entries 5 and 6, small
amounts of 2-methylquinoline and 2-phenylquinoline were
isolated as byproducts. It should be noted that the present
catalytic system was applicable to the synthesis of 2,3,4,5-
tetrahydro-1-benzazepine using 4-(2-aminophenyl)butanol as
a starting material (entry 7).
group to an amino group occurs initially to give 1, which is
then subjected to N-heterocyclization to furnish indole (2).
Synthesis of indole from 3 is significant because nitro
compound 3 as a starting material is more easily available
than amino compound 1. It should be also noted that the
Cp*Ir complex acts as a dual catalyst for both the reduction
of nitro to an amino group and the oxidative N-heterocy-
clization.
We next examined the N-heterocyclization of 3-(2-
aminophenyl)propanols. The results are summarized in Table
3.10 When the present catalytic system was applied to 3-(2-
Although the mechanism for the present reaction is not
completely clear as of yet, possible mechanisms are shown
in Schemes 1 and 2. That for the catalytic synthesis of indoles
is shown in Scheme 1. The first step of the reaction would
involve catalytic oxidation of an alcohol to an aldehyde to
give an intermediate A and a hydrido iridium species. We
have already revealed the catalytic activity of [Cp*IrCl2]2
toward oxidation of primary and secondary alcohols to the
corresponding carbonyl compounds.7 The intermediate A
would readily cyclize to afford indoles via intramolecular
nucleophilic attack of amino group to carbonyl carbon
followed by dehydration, which would be a noncatalytic
process. Release of hydrogen in the reaction of the hydrido
iridium with 2-aminophenethyl alcohol could regenerate the
catalytic active alkoxo iridium species.
Table 3. Synthesis of N-Heterocycles from Various Amino
Alcohols Catalyzed by the [Cp*IrCl2]2/K2CO3 Systema
A possible mechanism for the catalytic synthesis of
1,2,3,4-tetrahydroquinolines and 2,3,4,5-tetrahydro-1-benz-
azepine is shown in Scheme 2. The first step of the reaction
affording an intermediate B would be similar to that for the
synthesis of indoles. The intermediate B would transform
(8) Typical procedure: In a glass reactor under an atmosphere of argon,
[Cp*IrCl2]2 (0.025 mmol) and K2CO3 (0.10 mmol) were suspended in
toluene (2 mL). Then the substrate (1.0 mmol) was added, and the mixture
was stirred under reflux for 20 h. The products were isolated by silica gel
column chromatography (eluent: hexane-ethyl acetate). The products were
identified by NMR analysis.
(9) Reduction of nitrobenzene (1.0 mmol) in 2-propanol (2 mL) catalyzed
by [Cp*IrCl2]2 (0.025 mmol) at 120 °C for 17 h gave aniline in 17% yield.
Unpublished results.
(10) Typical procedure: In a heavy-walled glass reactor under an
atmosphere of argon were suspended [Cp*IrCl2]2 (0.025 mmol) and K2-
CO3 (0.10 mmol) in toluene (2 mL). Then the substrate (1.0 mmol) was
added and sealed, and the mixture was stirred at 111 °C for 20 h. The
products were isolated by silica gel column chromatography (eluent:
hexanes-ethyl acetate). The products were identified by NMR analysis.
a The reaction was carried out in a heavy-walled glass reactor at 111 °C
for 20 h with amino alcohol (1.0 mmol), [Cp*IrCl2]2 (5.0 mol %/Ir), and
K2CO3 (0.10 mmol) in toluene (2 mL). b Isolated yield. The values in
parentheses are GC yield. c 2.0 mol %/Ir of [Cp*IrCl2]2 was used. Reaction
time was 17 h. d Reaction time was 40 h. e 9% of 2-methylquinoline was
also isolated. f 6% of 2-phenylquinoline was also isolated. g The reaction
was carried out in 0.7 mmol scale.
Org. Lett., Vol. 4, No. 16, 2002
2693

Scheme 2
into C via intramolecular nucleophilic addition and dehydra-
knowledge, the first example of the oxidative N-hetero-
cyclization of amino alcohols catalyzed by iridium com-
plexes. The present catalytic system would provide a new
and useful method for the synthesis of various N-heterocyclic
compounds.
tion. Then addition of the hydrido iridium to an iminic
CdN bond of C would occur to give an amido iridium
intermediate D. The intermediate D would react with an
amino alcohol to give a product and regenerate the catalytic
active alkoxo iridium species. The base (K2CO3) would
stimulate the oxidation at the first step as we have already
reported.7
In summary, we have shown a new catalytic system for
the synthesis of indoles, 1,2,3,4-tetrahydroquinolines, and
2,3,4,5-tetrahydro-1-benzazepine, which is, to the best of our
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL026200S
2694
Org. Lett., Vol. 4, No. 16, 2002