Ruthenium-catalyzed synthesis of indoles from anilines and epoxides

Article abstract of DOI:10.1002/chem.201304432

A general synthetic route to indoles from readily available anilines and epoxides by using ruthenium catalysis is described. This straightforward transformation allows a variety of indoles to be obtained in good yields by using [Ru₃(CO)₁₂]/1,1-bis(diphenylphosphino)ferrocene as the catalytic system. Water and hydrogen are formed as the only stoichiometric by-products, making this process highly atom efficient.

Full text of DOI:10.1002/chem.201304432

DOI: 10.1002/chem.201304432
Communication
&
Ring-Opening Reactions
Ruthenium-Catalyzed Synthesis of Indoles from Anilines and
Epoxides
Miguel PeÇa-Lꢀpez, Helfried Neumann, and Matthias Beller*[a]
from less expensive and more available reagents, such as ani-
Abstract: A general synthetic route to indoles from readily
lines. For example, the Bischler–Mçhlau synthesis allows the
available anilines and epoxides by using ruthenium cataly-
preparation of indoles from anilines and a-haloketones,[5]
sis is described. This straightforward transformation allows
whereas the more recently developed Larock procedure makes
a variety of indoles to be obtained in good yields by
use of modified aniline derivatives, such as ortho-haloanilines,
using [Ru3(CO)12]/1,1’-bis(diphenylphosphino)ferrocene as
in the presence of palladium catalysts (Scheme 1b and c).[6]
the catalytic system. Water and hydrogen are formed as
More recently, Glorius and co-workers have developed a pal-
the only stoichiometric by-products, making this process
ladium-catalyzed oxidative cyclization of N-aryl enamines de-
highly atom efficient.
rived from anilines and ketones to afford the corresponding in-
doles (Scheme 1d).[7] Alternatively, the research groups of
Yoshikai,[8] Jiao,[9] Cacchi,[10] Zhao,[11] and Liang[12] have explored
The indole moiety constitutes one of the most important het-
erocycles in nature. It is present in many natural products,
pharmaceutical agents, and agrochemicals,[1] and binds to
many receptors with high affinity.[2] Despite the significant
number of powerful methodologies for the synthesis of in-
doles,[3] the development of new, efficient, versatile, and regio-
selective strategies is still a field of great interest.
the use of different metals, oxidants, and reaction conditions
to improve the substrate scope. From our point of view, the
ideal synthesis of indoles would be one that involves the
direct connection of anilines with C2 fragments, such as al-
kenes or alkynes (Scheme 1e).[13] Herein, we propose the use
of epoxides, which are easily available from olefins, for the syn-
thesis of indoles through metal-catalyzed dehydrogenation
reactions.
To date, the Fischer indole synthesis from aryl hydrazines
and carbonyl compounds represents the most general synthet-
ic route due to its operational simplicity and acceptance of
a wide range of compatible functional groups (Scheme 1a).[4]
However, the common instability and toxicity of hydrazines
has led to the development of alternative syntheses starting
Over the last two years, the synthesis of heterocycles by se-
quential dehydrogenative coupling processes has been devel-
oped by several research groups. Interestingly, the groups of
Kempe and Milstein published the iridium- and ruthenium-cat-
alyzed synthesis of pyrroles and pyridines from secondary alco-
hols and 1,2- or 1,3-aminoalcohols, respectively.[14] At the same
time, our research group reported the ruthenium-catalyzed
three-component synthesis of pyrroles by using benzylic ke-
tones, vicinal diols, and amines.[15] Based on this work, we con-
sidered the synthesis of indoles by using a similar dehydrogen-
ative methodology, starting from anilines and epoxides. To the
best of our knowledge, only two precedents exist for such
transformations.[16] Unfortunately, several limitations, such as
the requirement for high temperatures, high catalyst loading,
and high amine/epoxide ratios, meant that only a small
number of indoles could be prepared in low and moderate
yields. Notably, the reactions of anilines with related substrates,
such as diols,[17] alkanolammonium chlorides,[18] or 1,2-dibro-
moalkanes,[19] proceeded in most cases under harsh conditions,
but proved to lack versatility.
In agreement with well-known “hydrogen autotransfer” pro-
cesses,[20] the indole synthesis should proceed by the following
domino sequence (Scheme 2). First, the ring opening of the
epoxide with the aniline provides the corresponding 1,2-ami-
noalcohol A. This intermediate is transformed into the final
indole through ketone B by ruthenium-catalyzed dehydrogen-
ation, followed by condensation with aniline to give the imine
C. Subsequent intramolecular cyclization provides the desired
Scheme 1. Traditional syntheses of indoles.
[a] Dr. M. PeÇa-Lꢀpez, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304432.
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Communication
Scheme 2. Ruthenium-catalyzed synthesis of indoles from anilines and epox-
ides.
product. Advantageously, water and hydrogen would be the
only by-products of this synthesis, and the aniline is used in
catalytic amounts in the second step of this transformation.
With these premises in mind, we present herein a general
study into the ruthenium-catalyzed synthesis of indoles from
anilines and epoxides.
Based on previous studies from our group,[21] the research
started by analyzing the effect on the reaction of different
phospine ligands in combination with [Ru3(CO)12] as the ruthe-
nium source, a highly active catalytic system for several amina-
tion reactions. For this purpose, we chose, as a model transfor-
mation, the reaction of aniline (1a, 120 mol%) with cyclohex-
ene oxide (2, 100 mol%) in the presence of [Ru3(CO)12]
(1 mol%), a ligand (3 mol%), and para-toluenesulfon-
Scheme 3. Screening of ligands for the ruthenium-catalyzed synthesis of
1,2,3,4-tetrahydrocarbazole (3a) from aniline and cyclohexene oxide. The
yield was determined by GC using hexadecane as an internal standard.
ic acid monohydrate as an additive in tert-amyl alco-
hol at 1508C (Scheme 3).
Table 1. Optimization of the reaction conditions for the synthesis of 3a.[a]
Initially, we observed that the reaction under
ligand-free conditions only provided traces of the
corresponding product, whereas the use of different
monodentate ligands (L1–L7) gave the 1,2,3,4-tetra-
hydrocarbazole (3a) in moderate to low yields (7–
44%, Scheme 3). Gratifyingly, bidentate ligands, such
as 1,4-bis(diphenylphosphino)butane (dppb, L9,
80%), BINAP (L12, 75%), and Xantphos (L13, 91%),
improved the product yield considerably, but the
most effective phosphine was found to be 1,1’-bis(di-
phenylphosphino)ferrocene (dppf, L15). In this case,
the desired indole was obtained in 93% yield
(Scheme 3). It is important to note that in some cases
small amounts of the corresponding diamine were
formed, which is derived from the reduction of the
proposed intermediate imine C (Scheme 2).
After this first approach, we explored different re-
action conditions to improve the efficiency of the
catalytic system. In this way, several catalyst precur-
sors, including RuCl3·H2O, [{RuCl2Ph}2], [{RuCl2(para-
cymene)}2], [RuHCl(CO)(PPh3)3], and even [{IrCl(cod)}2]
(cod=1,5-cyclooctadiene), were tested in combina-
tion with dppf and p-TsOH (p-Ts =para-tosyl) as an
additive, but in all cases the 1,2,3,4-tetrahydrocarba-
zole (3a) was formed in lower yields (67–78%,
Table 1, entries 1–5). Next, we studied the effect of
different additives that are necessary both for the
Entry
Catalyst
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11[c]
12
13
14
15
16[d]
17[e]
18[f]
19[g]
20[h]
RuCl3·H2O
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
–
para-toluic acid
Zn(OTf)2
SnCl2·2H2O
Al(OTf)3
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
DMF
DMSO
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
73
67
78
75
67
–
[{RuCl2Ph}2]
[{RuCl2(para-cymene)}2]
[RuHCl(CO)(PPh3)3]
[{IrCl2(cod)}2]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
–
21
59
63
79
4
39
95
99
77
29
82
81
65
[Ru3(CO)12]
[Ru3(CO)12]
[a] Unless otherwise specified, all reactions were carried out with aniline (1.2 mmol),
cyclohexene oxide (1.0 mmol), the catalyst (0.01 mmol), dppf (0.03 mmol), and an ad-
ditive (0.10 mmol) in a solvent (1 mL) at 1508C for 22 h. [b] GC yields with hexadecane
as the internal standard. [c] p-TsOH (0.05 mmol). [d] Reaction temperature: 1408C.
[e] Catalyst (0.005 mmol) and ligand (0.015 mmol). [f] Reaction time: 18 h. [g] Ratio of
aniline/epoxide=1.1:1. [h] Reaction without an argon atmosphere.
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Communication
ring opening of the epoxide and the cyclization step. We ob-
served no reaction in the absence of p-TsOH. Carboxylic acids
such as para-toluic acid or other Lewis acids [Zn(OTf)2,
SnCl2·2H2O, Al(OTf)3] resulted in low to moderate yields, where-
as the use of only 5 mol% of para-toluenesulfonic acid result-
ed in a higher yield (79%, Table 1, entries 6–11). Reactions in
DMF and DMSO did not provide the corresponding indole in
good yields, but this domino sequence can be performed ef-
fectively in toluene and 1,4-dioxane, and in the last case 3a
was obtained in 99% yield (Table 1, entries 12–15). For further
optimization, we analyzed other critical parameters, and found
that decreasing the temperature, catalyst loading, reaction
time, and ratio of amine to epoxide all resulted in lower yields,
whereas the reaction without the protection of an argon at-
mosphere took place in a moderate 65% yield (Table 1, en-
tries 16–20). Thus, after this exhaustive screening of reaction
conditions, we selected the reaction with [Ru3(CO)12] (1 mol%),
dppf (3 mol%), and p-TsOH (10 mol%) in 1,4-dioxane at 1508C
for 22 h as the best catalytic system.
Table 2. Ruthenium-catalyzed synthesis of substituted 1,2,3,4-tetrahydro-
carbazoles from anilines and cyclohexene oxide.[a]
Entry
Aniline
Product
Yield
[%][b]
1
2
1a
3a
85
R=Me
OMe
OH
F
Ac
1b
1c
1d
1e
1 f
R=Me
OMe
OH
F
Ac
3b
3c
3d
3e
3 f
79
68
67
63
61
43
–
To expand the scope of this methodology, our next step was
to check the reactivity of different substituted anilines in the
reaction with cyclohexene oxide under the previously opti-
mized conditions. We found that amines containing electron-
donating groups, such as para-toluidine (1b), para-anisidine
(1c), and 4-aminophenol (1d), provided the corresponding in-
doles 3b–d in good yields (67–79%, Table 2, entries 2, b–d).
The reactions with the electron-poor 4-fluoroaniline and 4’-
aminoacetophenone also took place efficiently (61–63%,
Table 2, entries 2, e and f), whereas 4-dimethylaminoaniline re-
sulted in 3g in a moderate 43% yield (Table 2, entry 2, g). Un-
fortunately, the desired product was not observed for the reac-
tion of strongly electron-deficient anilines such as 4-nitroani-
line (Table 2, entry 2, h). On the other hand, the sterically hin-
dered 2-toluidine gave the corresponding tetrahydrocarbazole
3i in excellent yield (83%, Table 2, entry 3), and the reaction of
3-toluidine provided a mixture of regioisomers with the major
product in 68% yield (Table 2, entry 4). Different substituted di-
methylanilines afforded the expected indoles in similarly good
yields (71–75%, Table 2, entries 5 and 6), whereas the reaction
with naphthylamine allowed isolation of the tetracyclic com-
pound 3m in 79% yield (Table 2, entry 7). Additionally, this re-
action can be performed with secondary amines, such as N-
methylaniline, obtaining in this case the corresponding N-pro-
tected indole 3n in 60% yield (Table 2, entry 8).
To demonstrate the general applicability of this catalytic
system for the synthesis of indoles, our protocol was tested in
the reaction with different epoxides. Unfortunately, the ruthe-
nium-catalyzed reaction of aniline with styrene oxide (4), under
the previously developed conditions, afforded the 2-phenylin-
dole (5a) in only a low yield (22%, Table 3, entry 1). At this
point, we considered that the strongly acidic conditions, re-
quired for the cyclization step, might not be suitable for the
ring opening of more sensitive epoxides. In fact, we observed
that the aminolysis of cyclohexene oxide with aniline, cata-
lyzed by para-toluenesulfonic acid, gave an 85% yield, but the
same experiment with styrene oxide led to only traces of the
desired aminoalcohol. In the latter case, we found different by-
NMe2
NO2
1g
1h
NMe2
NO2
3g
3h
3
4
5
1i
1j
1k
3i
3j
3k
83
68[c]
71
6
1l
3l
75
7
8
1m
1n
3m 79
3n
60
[a] Unless otherwise specified, all reactions were carried out with the
amine (1.2 mmol), cyclohexene oxide (1.0 mmol), [Ru3(CO)12] (0.01 mmol),
dppf (0.03 mmol), and p-TsOH (0.10 mmol) in 1,4-dioxane (1 mL) at 1508C
for 22 h. [b] Yield of the isolated product. [c] The minor regioisomer was
formed in 17% yield.
products resulting from the elimination of water and secon-
dary reactions of the corresponding enamine.
To solve this problem, we turned our attention to the use of
new additives that should allow the amination of epoxides in
a more effective manner.[22] First, we analyzed the reaction by
using different Lewis acids, which are known to be catalysts in
the ring opening of epoxides with anilines. However, the
ruthenium-catalyzed reaction of aniline with styrene oxide in
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Finally, the reactivity of different epoxides, including aromat-
ic and aliphatic derivatives, was studied. The reaction of four
selected anilines (1a, b, m and n) with 4-(chlorophenyl)oxirane
(6) provided the corresponding indoles 10a, b, m and n with
the para-chlorophenyl group in the 2-position as the major
products (71–86%, Table 4, entries 5–8). It is important to note
that the same reaction, under the conditions described in the
Table 2 with p-TsOH as the only additive, resulted in very low
yields. As in the case of the styrene oxide, the regioselectivity
is controlled by the stabilization of the tertiary carbocation.
Encouraged by these results, we were intrigued about the
reactivity of an aliphatic epoxide. To our delight, the zinc-cata-
lyzed ring opening of 1,2-epoxyhexene (7) with aniline and
para-toluidine at room temperature, followed by ruthenium-
catalyzed cyclization in the presence of p-TsOH as an additive,
took place efficiently to give the corresponding 2-butyl indoles
11 a and b in good yields (71–74%, Table 4, entries 9 and 10).
However, the same reaction with 1-naphthylamine provided
the desired indole 11 m in an excellent yield, but as a mixture
of isomers (84%, 45:55, Table 4, entry 11), probably due to the
higher steric hindrance caused by the naphthyl group during
the ring opening of the epoxide. Analogously, the treatment of
the epoxide with an N-protected amine 1n under the standard
conditions also afforded a mixture of indoles in 43% yield. In
this case, the 3-substituted compound was obtained as the
major product (24:76, Table 4, entry 12).
Table 3. Additive screening for the ruthenium-catalyzed synthesis of
2-phenylindole (5a) from aniline and styrene oxide.
Entry
Additive
Yield [%][a]
1
2
3
4
5
6
7
8
9
p-TsOH
Zn(OCl4)2·6H2O
Zn(OTf)2
Al(OTf)3
SnCl2·2H2O
Zn(OCl4)2·6H2O/p-TsOH
Zn(OTf)2/p-TsOH
Zn(OCl4)2·6H2O/p-TsOH[b]
Zn(OTf)2/p-TsOH[b]
Zn(OTf)2/p-TsOH[b,c]
22
9
12
29
36
41
43
68
79
74
10
[a] GC yields with hexadecane as the internal standard. [b] Sequential re-
action: aniline (1.2 mmol), styrene oxide (1.0 mmol), and zinc salt
(0.02 mmol) were stirred without a solvent at RT for 1 h. This was fol-
lowed by addition of [Ru3(CO)12] (0.01 mmol), dppf (0.03 mmol), p-TsOH
(0.10 mmol), and 1,4-dioxane (1 mL) and stirring at 1508C for 22 h.
[c] Ring-opening reaction was performed at 808C.
the presence of 10 mol% of Zn(OCl4)2·6H2O, Zn(OTf)2, Al(OTf)3,
or SnCl2·2H2O in 1,4-dioxane provided 2-phenylindole in low
yields (9–36%, Table 3, entries 2–5). Although these additives
have been shown to be effective in the amination of epoxides,
they are not acidic enough to carry out the cyclization of the
intermediate species. For this reason, we combined zinc salts
(effective in the first step of the reaction) with a strong acid, in
this case, para-toluenesulfonic acid. Nevertheless, the one-pot
reaction of aniline with styrene oxide in the presence of zinc
perchlorate or triflate (2 mol%) and p-TsOH (10 mol%) in 1,4-
dioxane at 1508C took place in a slightly improved 41 and
43% yield, respectively (Table 3, entries 6 and 7).
After this study with monosubstituted epoxides, we exam-
ined the use of the optimized conditions with internal epox-
ides. The reaction of different anilines with cyclopentene oxide
(8) in the presence of p-TsOH took place in very low yields, al-
though this substrate appears similar to the cyclohexene deriv-
ative. Nevertheless, the sequential transformation with aniline
(1a), para-toluidine (1b), and N-methylaniline (1n) proceeded
in better yields (46–52%, Table 4, entries 13, 14, and 16),
whereas the more electron-rich 1-naphthylamine (1m) provid-
ed the corresponding tetracyclic indole 12m in an excellent
84% yield (Table 4, entry 15).
Performing the sequential reaction of the zinc-catalyzed ring
opening followed by the ruthenium-catalyzed dehydrogena-
tive coupling increased the yield. Hence, treatment of an ani-
line and an epoxide with zinc perchlorate in the absence of
a solvent at room temperature for 1 h, with subsequent addi-
tion of [Ru3(CO)12], dppf, p-TsOH, and 1,4-dioxane, and heating
at 1508C overnight, afforded the desired 2-phenylindole (5a)
in 68% yield as the only regioisomer (Table 3, entry 8). The
yield was further improved by the use of zinc triflate instead
the zinc perchlorate (79%, Table 3, entry 9), but higher temper-
atures in the first step did not result in better reactivity
(Table 3, entry 10). The regioselectivity of this reaction is ex-
plained by the better stabilization of the benzylic carbocation
than the less substituted carbon atom of the epoxide ring.[22f]
Next, we explored the reactivity of different anilines with sty-
rene oxide (4) by following the developed sequential method-
ology. For this purpose, we chose to use para-toluidine (1b), 1-
naphthylamine (1m), and N-methylaniline (1n), obtaining the
corresponding 2-phenylindoles (5b, m, and n) regioselectively
in good yields (68–89%, Table 4, entries 2–4).
Finally, we analyzed the reactivity of the asymmetric 1-phe-
nylpropylene oxide (9). In this case, reactions with selected
amines proceeded effectively under the previously developed
sequential conditions, affording the desired indoles regioselec-
tively in moderate to good yields (46–76%, Table 4, entries 17–
20). The major regioisomer observed in all cases proved to be
the 2-phenyl-substituted indole.
In summary, we have developed a general ruthenium-cata-
lyzed synthesis of indoles from readily available reagents, that
is, anilines and epoxides. This atom-efficient transformation al-
lowed us to obtain a variety of indoles in good yields in the
presence of the commercially available [Ru3(CO)12]/dppf catalyt-
ic system. The use of a sequential addition procedure and non-
sensitive additives in substoichiometric amounts makes the
protocol convenient and easy to use. Water and hydrogen are
formed as the only stoichiometric by-products. Our results
show that anilines and epoxides are valuable reagents for the
synthesis of heteroarenes through metal-catalyzed reactions.
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Communication
(1H), 77.0 ppm (13C)]. All measure-
ments were carried out at room
temperature unless otherwise
stated, and DEPT was used to
assign the types of carbon atom.
Mass spectra were, in general, re-
corded on an AMD 402/3 or an HP
5989A mass-selective detector. Gas
chromatography was performed
on an HP 6890 chromatograph
with an HP5 column. Infrared spec-
tra were taken on a Bruker Vector
22 with attenuated total reflec-
tance (ATR). Unless otherwise
stated, commercial reagents were
used as received.
Table 4. Ruthenium-catalyzed synthesis of indoles from anilines and epoxides by using a sequential reaction.[a]
Entry
1
Aniline
Epoxide
Product[b]
Yield [%][c]
77
4
5a, 99:1
5b, 98:2
2
3
4
68
76
89
5m, 91:9
5n, 97:3
General procedure for the
ruthenium-catalyzed synthesis
of indoles from anilines and
cyclohexene oxide
5
6
7
8
aniline (1a)
10a, 99:1
10b, 98:2
10m, 90:10
10n, 98:2
71
77
77
86
para-toluidine (1b)
1-naphthylamine (1m)
N-methylamine (1n)
6
7
8
9
In a glass pressure tube (25 mL)
under an argon atmosphere,
[Ru3(CO)12] (6.4 mg, 0.01 mmol),
1,1’-bis(diphenylphosphino)ferro-
cene (16.6 mg, 0.03 mmol), para-
toluenesulfonic acid monohydrate
(19.0 mg, 0.10 mmol), the amine
(1a–n, 1.2 mmol), and cyclohexene
oxide (2, 100 mL, 1.0 mmol) were
dissolved in 1,4-dioxane (1 mL).
Next, the pressure tube was closed
and the resulting mixture was
stirred at 1508C in an oil bath for
22 h. After cooling to room tem-
perature, the crude mixture was di-
rectly purified by flash column
chromatography on silica gel, elut-
ing with 10% ethyl acetate/hep-
tanes, to afford, after concentra-
tion and high-vacuum drying, the
corresponding indoles (3a–n) in
the reported yields.
9
10
11
12
aniline (1a)
11 a, 97:3
74
71
84[d]
43[d]
para-toluidine (1b)
1-naphthylamine (1m)
N-methylamine (1n)
11 b, 98:2
11 m, 45:55
11 n, 24:76
13
14
15
16
aniline (1a)
12a
12b
12m
12n
51
46
84
52
para-toluidine (1b)
1-naphthylamine (1m)
N-methylamine (1n)
17
18
19
20
aniline (1a)
13a, 99:1
13b, 91:9
13m, 93:7
13n, 95:5
76
65
63
46
para-toluidine (1b)
1-naphthylamine (1m)
N-methylamine (1n)
[a] Unless otherwise specified, all reactions were carried out in a sequential manner: initially, the amine
(1.2 mmol), epoxide (1.0 mmol), and zinc salt (0.02 mmol) were stirred without a solvent at RT for 1 h. This was
followed by addition of [Ru3(CO)12] (0.01 mmol), dppf (0.03 mmol), p-TsOH (0.10 mmol), and 1,4-dioxane (1 mL)
and stirring at 1508C for 22 h. [b] The regioisomeric ratio by GC-MS is given, generally with 2-substituted in-
doles as the major product. [c] Yield of the isolated major regioisomer. [d] Yield of the mixture of regioisomers,
in these cases, with 3-butyl indoles as the major products.
General procedure for the ruthenium-catalyzed synthesis of
indoles from anilines and epoxides by using a sequential
reaction
Experimental Section
General information
Unless otherwise stated, all of the reactions were conducted under
an argon atmosphere with exclusion of moisture from the reagents
and glassware by using standard techniques for the manipulation
of air-sensitive compounds. Reaction temperatures refer to external
bath temperatures. TLC was effected on silica gel 60 F254 (layer
thickness: 0.2 mm) and components were located by observation
under UV light and/or by treating the plates with a phosphomolyb-
dic acid or para-anisaldehyde followed by heating. Column chro-
matography was performed on silica gel (230–400 mesh) by using
10% ethyl acetate/heptane as the eluent. NMR spectra were per-
formed on a Bruker Avance 400 spectrometer by using the residual
solvent signal as an internal standard [chloroform: d=7.26 ppm
In a glass pressure tube (25 mL) under an argon atmosphere,
Zn(OTf)2 (7.3 mg, 0.02 mmol), the amine (1a–n, 1.2 mmol), and the
epoxide (4–9, 1.0 mmol) were stirred at room temperature for 1 h.
After this time, [Ru3(CO)12] (6.4 mg, 0.01 mmol), 1,1’-bis(diphenyl-
phosphino)ferrocene (16.6 mg, 0.03 mmol), and para-toluenesul-
fonic acid monohydrate (19.0 mg, 0.10 mmol) were added and dis-
solved in 1,4-dioxane (1 mL). Next, the pressure tube was closed
and the resulting mixture was stirred at 1508C in an oil bath for
22 h. After cooling to room temperature, the crude mixture was di-
rectly purified by flash column chromatography on silica gel, elut-
ing with 10% ethyl acetate/heptanes, to afford, after concentration
Chem. Eur. J. 2014, 20, 1818 – 1824
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Communication
H. Ham, J.-H. Jeong, J. Comb. Chem. 2005, 7, 130–135; i) A. M. Schmidt,
P. Eilbracht, J. Org. Chem. 2005, 70, 5528–5535; j) P. Linnepe (nꢃe Kçh-
ling), A. M. Schmidt, P. Eilbracht, Org. Biomol. Chem. 2006, 4, 302–313;
k) H. Chen, L. S. Eberlin, M. Nefliu, R. Augusti, R. G. Cooks, Angew. Chem.
2008, 120, 3470–3473; Angew. Chem. Int. Ed. 2008, 47, 3422–3425;
l) L. E. Kaim, L. Grimaud, C. Ronsseray, Synlett 2010, 2296–2298.
[5] For selected examples of Bischler–Mçhlau indole syntheses, see: a) R.
Mçhlau, Ber. Dtsch. Chem. Ges. 1881, 14, 171–175; b) R. Mçhlau, Ber.
Dtsch. Chem. Ges. 1882, 15, 2480–2490; c) E. Fischer, T. Schmitt, Ber.
Dtsch. Chem. Ges. 1888, 21, 1071–1077; d) A. Bischler, Ber. Dtsch. Chem.
Ges. 1892, 25, 2860–2879; e) A. Bischler, Ber. Dtsch. Chem. Ges. 1893,
26, 1336–1349; f) K. L. Nelson, J. C. Robertson, J. J. Duvall, J. Am. Chem.
Soc. 1964, 86, 684–687; g) H. Galons, J. F. Girardeau, C. C. Farnoux, M.
Miocque, J. Heterocycl. Chem. 1981, 18, 561–563; h) D. S. C. Black, M. C.
Bowyer, P. K. Bowyer, A. J. Ivory, M. Kim, N, Kumar, D. B. McConnell, M.
Popiolek, Aust. J. Chem. 1994, 47, 1741–1750; i) K. Pchalek, A. W. Jones,
M. M. T. Wekking, D. S. C. Black, Tetrahedron 2005, 61, 77–82; j) V. Srid-
haran, S. Perumal, C. AvendaÇo, J. C. Menꢃndez, Synlett 2006, 91–95.
[6] For selected examples of Larock indole syntheses, see: a) R. C. Larock,
E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689–6690; b) R. C. Larock, E. K.
Yum, M. D. Refvik, J. Org. Chem. 1998, 63, 7652–7662; for recent exam-
ples in total syntheses, see: c) J. Garfunkle, F. S. Kimball, J. D. Trzupek, S.
Takizawa, H. Shimamura, M. Tomishima, D. L. Boger, J. Am. Chem. Soc.
2009, 131, 16036–16038; d) T. Newhouse, C. A. Lewis, K. J. Eastman,
P. S. Baran, J. Am. Chem. Soc. 2010, 132, 7119–7137.
[7] For recent reviews on indole syntheses by cross-dehydrogenative cou-
pling, see: a) Z. Z. Shi, F. Glorius, Angew. Chem. 2012, 124, 9354–9356;
Angew. Chem. Int. Ed. 2012, 51, 9220–9222; For recent reports see: b) S.
Wꢂrtz, S. Rakshit, J. J. Neumann, T. Drçge, F. Glorius, Angew. Chem.
2008, 120, 7340–7343; Angew. Chem. Int. Ed. 2008, 47, 7230–7233;
c) J. J. Neumann, S. Rakshit, T. Drçge, S. Wꢂrtz, F. Glorius, Chem. Eur. J.
2011, 17, 7298–7303.
[8] Y. Wei, I. Deb, N. Yoshikai, J. Am. Chem. Soc. 2012, 134, 9098–9101.
[9] Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao, Angew. Chem.
2009, 121, 4642–4646; Angew. Chem. Int. Ed. 2009, 48, 4572–4576.
[10] R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew. Chem. 2009, 121,
8222–8225; Angew. Chem. Int. Ed. 2009, 48, 8078–8081.
and high-vacuum drying, the corresponding indoles (5–13) in the
reported yields.
Acknowledgements
We thank the State of Mecklenburg–Vorpommern and the
Bundesministerium fꢂr Bildung und Forschung (BMBF) for fi-
nancial support. M.P.L. thanks the Alexander von Humboldt
Foundation for a Postdoctoral Researchers Fellowship and the
European Commission for a Marie Curie Intra-European Fellow-
ship within the 7th Framework Programme (PIEF-GA-2012-
328500). We also thank Dr. C. Fischer, S. Buchholz, S. Schareina,
A. Koch, and S. Leiminger (LIKAT) for analytical and technical
support.
Keywords: anilines · epoxides · indole synthesis · ring-opening
reactions · ruthenium catalysis
[1] a) R. J. Sundberg, in Indoles; Academic Press, San Diego, 1996; b) T.
Eicher, S. Hauptmann, in The Chemistry of Heterocycles: Structure, Reac-
tions, Syntheses and Applications, 2nd ed.,Wiley-VCH, Weinheim, 2003;
c) M. d’Ischia, A. Napolitano, A. Peyzella, in Comprehensive Heterocyclic
Chemistry III, Vol. 3 (Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven,
R. J. K. Taylor), Elsevier, Oxford, 2008, pp. 353–358; d) A. J. Kochanow-
ska-Karamyan, M. T. Hamann, Chem. Rev. 2010, 110, 4489–4497; e) M.
Somei, F. Yamada, Nat. Prod. Rep. 2004, 21, 278–311; f) M. Somei, F.
Yamada, Nat. Prod. Rep. 2005, 22, 73–103; g) W. Gul, M. T. Hamann, Life
Sci. 2005, 78, 442–453; h) T. Kawasaki, K. Higuchi, Nat. Prod. Rep. 2005,
22, 761–793; i) B. P. Smart, R. C. Oslund, L. A. Walsh, M. H. Gelb, J. Med.
Chem. 2006, 49, 2858–2860; j) A. Dandia, R. Singh, S. Khaturia, C. Mꢃri-
enne, G. Morgant, A. Loupy, Bioorg. Med. Chem. 2006, 14, 2409–2417.
[2] For selected examples of the biological activities of indoles, see: a) D. A.
Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893–930; b) S.
Petit, Y. Duroc, V. Larue, C. Giglione, C. Leon, C. Soulama, A. Denis, F.
Dardel, T. Meinnel, I. Artaud, ChemMedChem 2009, 4, 261–275; c) V.
Sharma, P. Kumar, D. Pathak, J. Heterocycl. Chem. 2010, 47, 491–502;
d) S. A. Patil, R. Patil, D. D. Miller, Curr. Med. Chem. 2011, 18, 615–637;
e) S. Biswal, S. Sethy, H. K. S. Kumar, M. Banerjee, Asian J. Pharm. Clin.
Res. 2012, 5, 1–6; f) N. A. Ali, B. A. Dar, V. Pradhan, M. Farooqui, Mini-
Rev. Med. Chem. 2012, 12, 1–16; g) H. Johansson, T. B. Jørgensen, D. E.
Gloriam, H. Brꢄuner-Osborne, D. S. Pedersen, RSC Adv. 2013, 3, 945–
960.
[3] For selected reviews on indole synthesis, see: a) G. W. Gribble, J. Chem.
Soc. Perkin Trans. 1 2000, 1045–1075; b) F. Alonso, I. P. Beletskaya, M.
Yus, Chem. Rev. 2004, 104, 3079–3159; c) I. Nakamura, Y. Yamamoto,
Chem. Rev. 2004, 104, 2127–2198; d) S. Cacchi, G. Fabrizi, Chem. Rev.
2005, 105, 2873–2920; e) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006,
106, 2875–2911; f) L. Ackermann, Synlett 2007, 0507–0526; g) K. Krꢂger
(nꢃe Alex), A. Tillack, M. Beller, Adv. Synth. Catal. 2008, 350, 2153–2167;
h) O. Leogane, H. Lebel, Angew. Chem. 2008, 120, 356–358; Angew.
Chem. Int. Ed. 2008, 47, 350–352; i) K. Alex, A. Tillack, N. Schwarz, M.
Beller, Angew. Chem. 2008, 120, 2337–2340; Angew. Chem. Int. Ed. 2008,
47, 2304–2307; j) T. Pei, C.-Y. Chen, P. G. Dormer, I. W. Davies, Angew.
Chem. 2008, 120, 4299–4301; Angew. Chem. Int. Ed. 2008, 47, 4231–
4233; k) S. Cacchi, G. Fabrizi, Chem. Rev. 2011, 111, PR215–PR283; l) R.
Vicente, Org. Biomol. Chem. 2011, 9, 6469–6480; m) D. F. Taber, P. K. Tir-
unahari, Tetrahedron 2011, 67, 7195–7210; n) M. Shiri, Chem. Rev. 2012,
112, 3508–3549; o) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29–41.
[4] For selected examples of Fischer indole syntheses, see: a) E. Fischer, F.
Jourdan, Ber. Dtsch. Chem. Ges. 1883, 16, 2241–2245; b) E. Fischer, O.
Hess, Ber. Dtsch. Chem. Ges. 1884, 17, 559–568; c) B. Robinson, Chem.
Rev. 1963, 63, 373–401; d) B. Robinson, Chem. Rev. 1969, 69, 227–250;
e) B. Robinson, in The Fischer Indole Synthesis; Wiley-Interscience, New
York, 1982; f) D. L. Hughes, Org. Prep. Proced. Int. 1993, 25, 607–632;
g) W. Gribble, Contemp. Org. Synth. 1994, 1, 145–172; h) H.-S. Mun, W.-
[11] W. Yu, Y. Du, K. Zhao, Org. Lett. 2009, 11, 2417–2420.
[12] Z.-H. Guan, Z.-Y. Yan, Z.-H. Ren, X.-Y. Liu, Y.-M. Liang, Chem. Commun.
2010, 46, 2823–2825.
[13] For selected examples of the rhodium-catalyzed synthesis of indoles
from alkynes, see: a) D. R. Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am.
Chem. Soc. 2010, 132, 18326–18339; b) D. Zhao, Z. Shi, F. Glorius,
Angew. Chem. 2013, 125, 12652–12656; Angew. Chem. Int. Ed. 2013, 52,
12426–12429.
[14] a) S. Michlik, R. Kempe, Nat. Chem. 2013, 5, 140–144; b) D. Srimani, Y.
Ben-David, D. Milstein, Angew. Chem. 2013, 125, 4104–4107; Angew.
Chem. Int. Ed. 2013, 52, 4012–4015; c) S. Michlik, R. Kempe, Angew.
Chem. 2013, 125, 6450–6454; Angew. Chem. Int. Ed. 2013, 52, 6326–
6329; d) D. Srimani, Y. Ben-David, D. Milstein, Chem. Commun. 2013, 49,
6632–6634.
[15] a) M. Zhang, X. Fang, H. Neumann, M. Beller, J. Am. Chem. Soc. 2013,
135, 11384–11388; b) M. Zhang, H. Neumann, M. Beller, Angew. Chem.
2013, 125, 625–629; Angew. Chem. Int. Ed. 2013, 52, 597–601.
[16] a) C. S. Cho, J. H. Kim, H.-J. Choi, T.-J. Kim, S. C. Shim, Tetrahedron Lett.
2003, 44, 2975–2977; for a previous reference by using vapor-phase
technology, see: b) T. Nishida, Y. Tokuda, M. Tsuchiya, J. Chem. Soc.
Perkin Trans. 2 1995, 823–830.
[17] a) Y. Tsuji, K.-T. Huh, Y. Watanabe, Tetrahedron Lett. 1986, 27, 377–380;
b) Y. Tsuji, K.-T. Huh, Y. Watanabe, J. Org. Chem. 1987, 52, 1673–1680;
c) C. S. Cho, M. J. Lee, S. C. Shim, M. C. Kim, Bull. Korean Chem. Soc.
1999, 20, 119–121; d) H. Aramoto, Y. Obora, Y. Ishii, J. Org. Chem. 2009,
74, 628–633; e) M. Tursky, L. L. R. Lorentz-Petersen, L. B. Olsen, R.
Madsen, Org. Biomol. Chem. 2010, 8, 5576–5582; f) M. Zhang, F. Xie,
X. T. Wang, F. Yan, T. Wang, M. Chen, Y. Ding, RSC Adv. 2013, 3, 6022–
6029.
[18] a) C. S. Cho, J. H. Kim, S. C. Shim, Tetrahedron Lett. 2000, 41, 1811–1814;
b) C. S. Cho, J. H. Kim, T.-J. Kim, S. C. Shim, Tetrahedron 2001, 57, 3321–
3329.
[19] a) C. S. Cho, D. C. Park, S. C. Shim, Bull. Korean Chem. Soc. 2007, 28,
832–834.
Chem. Eur. J. 2014, 20, 1818 – 1824
www.chemeurj.org
1823
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[20] For reviews on the “borrowing-hydrogen” methodology, see: a) G. E.
Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110, 681–703; b) T. D.
Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 753–762;
c) G. W. Lamb, J. M. J. Williams, Chim. Oggi 2008, 26, 17–19;
d) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth. Catal.
2007, 349, 1555–1575; for reviews on the “hydrogen-autotransfer”
methodology, see: e) G. Guillena, D. J. Ramꢀn, M. Yus, Chem. Rev. 2010,
110, 1611–1641; f) G. Guillena, D. J. Ramꢀn, M. Yus, Angew. Chem. 2007,
119, 2410–2416; Angew. Chem. Int. Ed. 2007, 46, 2358–2364.
[21] a) A. Tillack, D. Hollmann, D. Michalik, M. Beller, Tetrahedron Lett. 2006,
47, 8881–8885; b) A. Tillack, D. Hollmann, K. Mevius, D. Michalik, S.
Bꢄhn, M. Beller, Eur. J. Org. Chem. 2008, 4745–4750; c) S. Bꢄhn, A. Till-
ack, S. Imm, K. Mevius, D. Michalik, D. Hollmann, L. Neubert, M. Beller,
ChemSusChem 2009, 2, 551–557; d) S. Imm, S. Bꢄhn, L. Neubert, H. Neu-
mann, M. Beller, Angew. Chem. 2010, 122, 8303–8306; Angew. Chem.
Int. Ed. 2010, 49, 8126–8129; e) S. Imm, S. Bꢄhn, M. Zhang, L. Neubert,
H. Neumann, F. Klasovsky, J. Pfeffer, T. Haas, M. Beller, Angew. Chem.
2011, 123, 7741–7745; Angew. Chem. Int. Ed. 2011, 50, 7599–7603.
[22] For references on catalytic ring opening of epoxides with anilines, see:
a) L. D. Pachꢀn, P. Gamez, J. J. M. van Brussel, J. Reedijk, Tetrahedron Lett.
2003, 44, 6025–6027; b) A. K. Chakraborti, S. Rudrawara, A. Kondaskar,
Eur. J. Org. Chem. 2004, 3597–3600; c) D. B. G. Williams, M. Lawton, Tet-
rahedron Lett. 2006, 47, 6557–6560; d) S. Rana, B. Pujala, A. K. Chakra-
borti, J. Org. Chem. 2007, 72, 3713–3722; e) G. Mancilla, M. Femenꢅa-
Rꢅos, A. J. Macꢅas-Sꢆnchez, I. G. Collado, Tetrahedron 2008, 64, 11732–
11737; f) B. Pujala, S. Rana, A. K. Chakraborti, J. Org. Chem. 2011, 76,
8768–8780.
Received: November 12, 2013
Published online on January 23, 2014
Chem. Eur. J. 2014, 20, 1818 – 1824
www.chemeurj.org
1824
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim