Ruthenium-catalyzed regioselective synthesis of 2-substituted indoles via ring-opening of epoxides by anilines

Article abstract of DOI:10.1016/S0040-4039(03)00396-4

Anilines react with epoxides in dioxane at 180°C in the presence of a catalytic amount of a ruthenium catalyst along with tin(II) chloride to afford 2-substituted indoles in moderate to good yields.

Full text of DOI:10.1016/S0040-4039(03)00396-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2975–2977
Ruthenium-catalyzed regioselective synthesis of 2-substituted
indoles via ring-opening of epoxides by anilines
Chan Sik Cho,a,* Jun Ho Kim,b Heung-Jin Choi,b Tae-Jeong Kimb and Sang Chul Shimb,*
aResearch Institute of Industrial Technology, Kyungpook National University, Taegu 702-701, South Korea
bDepartment of Industrial Chemistry, Kyungpook National University, Taegu 702-701, South Korea
Received 26 December 2002; revised 7 February 2003; accepted 7 February 2003
Abstract—Anilines react with epoxides in dioxane at 180°C in the presence of a catalytic amount of a ruthenium catalyst along
with tin(II) chloride to afford 2-substituted indoles in moderate to good yields. © 2003 Elsevier Science Ltd. All rights reserved.
Indoles have been known as pharmacologically and
biologically active compounds. Thus, many conven-
tional named and transition metal-catalyzed synthetic
methods have been developed and documented for the
indole framework formation.1 In connection with this
report, during the course of our ongoing studies on
homogeneous ruthenium catalysis,2–5 we have also
reported on the formation of indoles via a ruthenium-
catalyzed C2-fragment transfer from alkanolamines to
N-atom of anilines (amine exchange reaction).2,6 Fur-
thermore, though not yet clear, it was suggested that
such an amine exchange reaction produces a 2-anili-
noalkanol as an initial intermediate (Scheme 1, route
a). Watanabe et al. also proposed the formation of the
2-anilinoalkanol as an intermediate on ruthenium-cata-
lyzed synthesis of indoles from anilines and ethylene
glycols (Scheme 1, route b).7 Actually, in separate
experiments made by both groups, it was confirmed
that these 2-anilinoalkanols react with anilines to form
indoles under their ruthenium catalyst systems. On the
other hand, although it is known that epoxides are
introduced for the indole synthesis over heterogeneous
catalysts,8 the version is of little synthetic use since the
reaction is carried out under severe conditions and gives
low regioselectivity. In these regards, we have directed
our attention to transition metal-catalyzed in situ for-
mation route of 2-anilinoalkanols for eventual indole
framework construction. Herein we disclose a regio-
selective synthesis of 2-substituted indoles via ruthe-
nium- and SnCl2-catalyzed ring-opening of epoxides by
anilines.
Table 1 shows optimization of the conditions for the
ring-opening and heteroannulation between aniline (1a)
and propylene oxide (2a) leading to 2-methylindole (3a)
and 3-methylindole (4a). Under these circumstances,
the reaction selectively gives rise to 3a in preference to
4a in the range of 7.3–16.5 selectivities. The product
yield was considerably affected by the molar ratio of
1a/2a, increasing with the increase of the molar ratio up
to 1a/2a=10 without significant change of the product
selectivity (entries 1–4). The addition of SnCl2 was
essential for the effective formation of 3a and 4a (entry
5).9 When the reaction was carried out in the absence of
SnCl2, 3a and 4a were produced in only 12% yield with
similar selectivity of 3a/4a. However, the use of a
catalytic amount of SnCl2 (0.1 mmol) under the condi-
tion of entry 5 in Table 1 afforded 3a and 4a in 29%
yield (3a/4a=8.6). Among the activity of various ruthe-
nium precursors examined RuCl3·nH2O/3PPh3 and
RuCl2(PPh3)3 in terms of overall yield revealed to be
the catalysts of choice (entries 4 and 6). However,
performing the reaction under RuCl2(PPh3)3 was
accompanied by many by-products which gives
difficulty in separation comparing with that under
RuCl3·nH2O/3PPh3. Other ruthenium complexes such
as RuH2(PPh3)4 and Ru3(CO)12 were moderately effec-
tive for the formation of 3a and 4a (entries 7 and 8).
Scheme 1.
Keywords: anilines; epoxides; indoles; ring-opening; ruthenium cata-
lyst.
* Corresponding authors. Fax: +82-53-959-5586; e-mail: scshim@
knu.ac.kr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00396-4

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C. S. Cho et al. / Tetrahedron Letters 44 (2003) 2975–2977
Table 1. Ruthenium-catalyzed reaction of 1a with 2a under several conditionsa
Entry
Molar ratio (1a/2a)
Ruthenium catalyst
Yield (%)b of 3a+4a
3a/4a
1
2
3
4
6
8
10
10
10
10
10
10
10
RuCl3·nH2O-3PPh3
RuCl3·nH2O-3PPh3
RuCl3·nH2O-3PPh3
RuCl3·nH2O-3PPh3
RuCl3·nH2O-3PPh3
RuCl2(PPh3)3
52
58
68
72
12
77
59
61
23
28
9.0
9.3
8.8
8.2
9.3
8.6
8.2
7.3
16.5
9.5
4
5c
6
7
8
9
10
RuH2(PPh3)4
Ru3(CO)12
Cp*RuCl2(CO)d
RuCl2(=CHPh)(PCy3)2
a Reaction conditions: 2a (1 mmol), ruthenium catalyst (5 mol% based on 2a), SnCl2 (1 mmol), dioxane (10 ml), 180 oC, for 20 h, under argon.
b GLC yield based on 2a.
c In the absence of SnCl2.
d Cp*=h5-C5Me5.
duce 1,2-dianilinoalkane 6,12 and heteroannulation to
Cp*RuCl2(CO) and RuCl2(=CHPh)(PCy)3 were not
give 3b (Scheme 2).2c,7b A variety of catalysts are known
effective for the present reaction, however, the selectiv-
ity of 3a/4a was significantly increased under
Cp*RuCl2(CO) (entries 9 and 10).
to catalyze a nucleophilic ring-opening of epoxides.13 It
appears that ruthenium halides and SnCl2 as Lewis
acids facilitate the initial opening of 2b in the present
Having established suitable reaction conditions, a series
of anilines 1 and epoxides 2 were screened in order to
investigate the reaction scope, and several representa-
tive results are summarized in Table 2. The reactions of
1a with several epoxides (2b–d) also proceed to give the
corresponding indoles (3b–d) with exclusive regioselec-
tivity.10 This result indicates that the bulkiness of sub-
stituent on epoxides dominates the regioselectivity. In
the case of styrene oxide (2d), although 2d was com-
pletely disappeared after the reaction, we obtained 2-
phenylindole (3d) in only 27% yield and could not find
other detectable products. On the other hand, with
cyclohexene oxide the reaction resulted in complicated
mixture on GLC and TLC analyses. Various anilines
(1b–k) were also reacted with (2,3-epoxypropyl)benzene
(2c) to give the corresponding 2-benzylindoles (3e–n) in
the range of 22-98% yields. Here again, exclusive
regioselectivity in favor of 2-substituted isomer was
observed. The indole yield was not significantly affected
by the position and electronic nature of the substituent
on aromatic ring of 1 except for 2-anisidine (1f), which
gave lower yield than that of other anilines. It is known
that catalyst ruthenium is deactivated by coordination
of two adjacent methoxy and amino substituents of 1f
to ruthenium.7b With anilines having two-methyl sub-
stituents (1j and 1k), the product yield was higher than
that when anilines having mono-substituents were
employed (1b–i).
Table 2. Ruthenium-catalyzed synthesis of 2-substituted
indolesa
Anilines 1
Epoxides 2
Indoles 3
Yield (%)b
1a R=H
1a
1a
2a R%=Me
2b R%=Bu
2c R%=benzyl 3c R=H
3a R=H
3b R=H
62c
49
75
27
60
1a
2d R%=Ph
3d R=H
1b R=4-Me
1c R=3-Me
1d R=2-Me
1e R=4-OMe
1f R=2-OMe
1g R=4-Cl
1h R=4-Bu
1i R=4-s-Bu
2c
2c
2c
2c
2c
2c
2c
2c
3e R=5-Me
3f R=4- and 6-Me 62d
3g R=7-Me
3h R=5-OMe
3i R=7-OMe
3j R=5-Cl
59
41
22
54
61
62
98
72
3k R=5-Bu
3l R=5-s-Bu
3m R=4,7-Me2
3n R=4,6-Me2
1j R=2,5-Me2 2c
1k R=3,5-Me2 2c
a Reaction conditions: 1 (10 mmol), 2 (1 mmol), RuCl3·nH2O (0.05
mmol), PPh3 (0.15 mmol), SnCl2 (1 mmol), dioxane (10 ml), 180 oC,
for 20 h, under argon.
As to the reaction pathway, although it is not yet fully
understood, this seems to proceed via a sequence such
as ring-opening of 1,2-epoxyhexane (2b) by 1a to form
2-anilinoalkanol 5,11 N-alkylation of 1a with 5 to pro-
b Isolated yield based on 2.
c Regioisomeric mixture of 2- and 3-methylindoles noted in Table 1.
d Regioisomeric distribution was determined by 1H NMR (400 MHz):
4-Me/6-Me=0.7/1.

C. S. Cho et al. / Tetrahedron Letters 44 (2003) 2975–2977
2977
L. S. Angew. Chem., Int. Ed. 1988, 27, 1113; (c) Sund-
berg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 4, pp. 119–206; (d) Sund-
berg, R. J. In Indoles; Academic Press: London, 1996.
2. (a) Cho, C. S.; Lim, H. K.; Shim, S. C.; Kim, T. J.; Choi,
H.-J. Chem. Commun. 1998, 995; (b) Cho, C. S.; Kim, J.
H.; Shim, S. C. Tetrahedron Lett. 2000, 41, 1811; (c) Cho,
C. S.; Kim, J. H.; Kim, T.-J.; Shim, S. C. Tetrahedron
2001, 57, 3321.
Scheme 2.
reaction. In a careful separate experiment, we isolated
intermediate 6 in 22% yield, whereas intermediate 5 was
not found.14
3. (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett.
1999, 40, 1499; (b) Cho, C. S.; Oh, B. H.; Shim, S. C. J.
Heterocycl. Chem. 1999, 36, 1175; (c) Cho, C. S.; Kim, J.
S.; Oh, B. H.; Kim, T.-J.; Shim, S. C. Tetrahedron 2000,
56, 7747; (d) Cho, C. S.; Oh, B. H.; Kim, J. S.; Kim,
T.-J.; Shim, S. C. Chem. Commun. 2000, 11, 1885; (e)
Cho, C. S.; Kim, T. K.; Kim, B. T.; Kim, T.-J.; Shim, S.
C. J. Organomet. Chem. 2002, 650, 65.
General experimental procedure: a mixture of aniline
(10 mmol), epoxide (1 mmol), RuCl3·nH2O (0.05
mmol), PPh3 (0.15 mmol), and SnCl2 (1 mmol) in
dioxane (10 ml) was placed in a 50 ml stainless steel
autoclave. After the system was flushed with argon, the
mixture was allowed to react at 180°C for 20 h. The
reaction mixture was filtered through a short silica gel
column using ethyl acetate–chloroform as an eluent to
eliminate inorganic salts and the filtrate was concen-
trated. To the residual oily material was added 30 ml of
CHCl3 and washed with 50 ml of aq. 5% HCl solution
to remove excess aniline. The organic layer was dried
over anhydrous Na2SO4. Removal of the solvent left a
crude mixture, which was separated by thin layer chro-
matography (silica gel, ethyl acetate-hexane mixture) to
give indoles.
4. Cho, C. S.; Kim, B. T.; Lee, M. J.; Kim, T.-J.; Shim, S.
C. Angew. Chem., Int. Ed. 2001, 40, 958.
5. (a) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J. Org.
Chem. 2001, 66, 9020; (b) Cho, C. S.; Kim, B. T.; Kim,
T.-J.; Shim, S. C. Chem. Commun. 2001, 2576; (c) Cho, C.
S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Tetrahedron Lett.
2002, 43, 7987.
6. Murahashi, S.-I. Angew. Chem., Int. Ed. 1995, 34, 2443.
7. (a) Tsuji, Y.; Huh, K.-T.; Watanabe, Y. Tetrahedron
Lett. 1986, 27, 377; (b) Tsuji, Y.; Huh, K.-T.; Watanabe,
Y. J. Org. Chem. 1987, 52, 1673.
In summary, we have shown that anilines react with
epoxides in the presence of a ruthenium catalyst and
SnCl2 to afford 2-substituted indoles regioselectively in
moderate to good yields. The present reaction is a novel
regioselective strategy for the synthesis of 2-substituted
indoles from readily available anilines and epoxides.
The exact regioselective mechanism and reductive
cyclization of nitroarenes with epoxide for indoles are
currently under investigation.
8. Nishida, T.; Tokuda, Y.; Tsuchiya, M. J. Chem. Soc.,
Perkin Trans. 2 1995, 823.
9. For catalytic activity of transition metal-tin complexes,
see: Holts, M. S.; Wilson, W. L.; Nelson, J. H. Chem.
Rev. 1989, 89, 11.
10. 1H NMR (400 MHz) analysis of the crude reaction
mixture of 1a and 2b–d, after usual workup prior to
separation, showd no signals for the 2-vinyl protons of
1
3-substituted indoles. See for H NMR data of 3-butylin-
dole and 3-benzylindole: Ito, Y.; Kobayashi, K.; Seko,
N.; Saegusa, T. Chem. Lett. 1979, 1273.
Acknowledgements
11. Rickborn, B. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
pp. 733–775.
12. Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T. J.
Org. Chem. 1996, 61, 4214.
This work was supported by Korea Research Founda-
tion Grant (KRF-2002-070-C00055). C.S.C. gratefully
acknowledges a MOE-KRF Research Professor Pro-
gram (KRF-2001-050-D00015).
13. Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2002,
43, 7891 and references cited therein.
14. The reaction was carried out with the conditions
described in Table 2. 1,2-Dianilinohexane (6): MS m/z
(relative intensity) 268 (M+, 13), 162 (100).
References
1. (a) Remers, W. A.; Spande, T. F. In Indoles; Houlihan,
W. J., Ed.; Wiley: New York, 1979; Vol. 25; (b) Hegedus,