Synthesis of N-Alkylated Indolines and Indoles from Indoline and Aliphatic Ketones

Article abstract of DOI:10.1002/jhet.2337

A survey of redox aminations of indoline with aliphatic ketones using bismuth nitrate as catalyst is described. A reaction of an equivalent amount of indoline and aliphatic cyclic and acyclic ketones provides a mixture of excessive alkylated indole derivatives over typically redox isomerization and reductive alkylation pathways while using of the five equivalent of indoline provides N-alkylated indolines as a reductive alkylation product. The desired N-alkyl indoles from the oxidation of N-alkyl indolines were obtained in excellent yields.

Full text of DOI:10.1002/jhet.2337

Month 2015
Synthesis of N-Alkylated Indolines and Indoles from Indoline and
Aliphatic Ketones
a
a
a
a
Sinan Bayindir,a,b Esra Erdogan, Haydar Kilic, Omer Aydin, and Nurullah Saracoglu
*
aDepartment of Chemistry, Faculty of Sciences, Atatürk University, Erzurum, 25240, Turkey
bDepartment of Chemistry, Faculty of Sciences and Arts, Bingöl University, Bingöl, 12000, Turkey
*
E-mail: nsarac@atauni.edu.tr
Additional Supporting Information may be found in the online version of this article.
Received July 11, 2014
DOI 10.1002/jhet.2337
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A survey of redox aminations of indoline with aliphatic ketones using bismuth nitrate as catalyst is described.
A reaction of an equivalent amount of indoline and aliphatic cyclic and acyclic ketones provides a mixture of
excessive alkylated indole derivatives over typically redox isomerization and reductive alkylation pathways
while using of the five equivalent of indoline provides N-alkylated indolines as a reductive alkylation product.
The desired N-alkyl indoles from the oxidation of N-alkyl indolines were obtained in excellent yields.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
have reported independently on the Brønsted acid-catalyzed in-
termolecular redox amination of indoline with benzaldehydes
(or aryl aldehydes) under reflux and microwave irradiation
conditions, respectively, to yield N-benzyl indoles 3 [23–27].
In another set of the research of Pan group, the evaluation of
salicylaldehydes as an electrophile in the standard process gave
N-alkylindolines instead of the expected N-alkyl indoles.
However, the mechanism of these redox aminations is
still controversial. Computational studies conducted at the
second-order Møller–Plesset perturbation theory (MP2)
and density functional theory levels have shown that the
one-step direct 1,3-hydrogen shift, which was proposed
earlier for the redox process, was not valid because of its
very high activation energy requirement [28]. The results
suggest that the process involving the formation of the
acetic acid-assisted azomethine ylide intermediate should
be the most likely process.
Although the previous studies to generate N-alkyl indoles
over the redox amination process from indolines are the pow-
erful method, they are restriction with aryl or nonenolisable
aldehydes. However, the synthetic and mechanistic potentials
of ketones to engage in redox amination reactions of indoline
have not yet been evaluated. Here, we report on our premier
results of the bismuth nitrate-catalyzed redox amination of
the enolisable cyclic and acyclic ketones with indoline.
Many natural and synthetic biologically active compounds
containing indole skeletons are being used as therapeutic agents
[1–5]. Therefore, a great deal of attention have been continued
to develop innovative synthetic strategies for the decoration of
indole cores. Indole is an electron-rich heteroaromatic system,
and although various methods for its alkylation at the
C3-position are well established, its C2-alkylation remains to
be a difficult task [6,7]. As an alternative solution to this prob-
lem, we have developed an indirect two-step protocol for
C2-alkylation, in which the first step is an alkylation of
4,7-dihydroindole as a Michael donor and the second one is
the oxidation of C2-alkylated 4,7-dihydroindole [8,9]. N-Alkyl
indoles are also found in numerous natural products and
pharmaceutical compounds [10–14]. However, regioselective
functionalization at the N-position of indoles is still unexplored
[15,16]. Recently, the redox amination has become a very
powerful trend in C–N bond forming reactions applied to the
synthesis of N-alkyl pyrroles and N-alkyl indoles [17]. The
reactions of aryl aldehydes with indoline (1) and
2-carboxyindoline (2) have been used as precursors of the
N-alkyl indoles (Scheme 1) [18–22]. Pan and Siedel groups
Scheme 1. Present synthesis of N-alkyl indoles via redox amination.
RESULTS AND DISCUSSIONS
To optimize the redox amination feasibility between
aliphatic ketones and indoline, at the start of our
© 2015 HeteroCorporation

S. Bayindir, E. Erdogan, H. Kilic, O. Aydin, and N. Saracoglu
Vol 0000
Table 1
Studies on optimization for the reaction of indoline (1; 1 equivalent) with cyclohexanone (6; 1 equivalent).
Products (yield%)
Entry
Catalyst
Conditions
rt, CH2Cl2
80°C, MeCN
120°C, MeCN (or PhMe)
140°C
5a
6a
7a
8a
9
1
2
3
4
5
6
7
8
Bi(NO3)3·5H2O
—
—
38
35
—
—
30
12
—
—
25
27
—
—
13
15
—
—
21
26
—
—
26
10
—
—
12
21
—
—
25
28
—
—
4
—
—
13
15
—
—
3
15
—
—
2
—
—
4
6
ZrCl4
rt, CH2Cl2
—
—
12
6
—
—
19
8
80°C, MeCN
120°C, MeCN (or PhMe)
140°C
9
Zn(OTf)2
rt, CH2Cl2
10
11
12
80°C, MeCN
120°C, MeCN (or PhMe)
140°C
18
17
No reaction took place in the presence of PhCOOH or TFA as catalyst under same reaction conditions.
investigations, the reaction of indoline (1) with cyclohexa-
none (4a) was selected as a test reaction. In these prelimi-
nary experiments, in addition to N-cyclohexylindole (5a) as
the desired product, four other compounds, which can be as-
sumed to be secondary reaction products, were also isolated
from the reaction mixture using column or thin-layer chroma-
tography (TLC) (Table 1). The formation of the undesired
products 6–9 could not be suppressed under different reaction
conditions in which various Brønsted and Lewis acids such as
Bi(NO3)3·5H2O, ZrCl4, Zn(OTf)2, PhCOOH, or TFA were
employed as catalysts at varying temperatures and in different
solvents (Table 1). Better yield for the desired product 5a was
obtained with Bi(NO3)3·5H2O (0.1mmol) at 120°C (in sealed
tube) in acetonitrile (entry 3).
and cycloheptanone (4c) similarly underwent the redox
amination and alkylation side reactions. In most cases, the
desired N-alkyl indoles were obtained as major products in
a similar product distribution trend. However, the same
reaction conditions, when applied to 2-butanone (4d) as an
acyclic ketone, afforded a separable mixture containing five
products (Scheme 2). In addition to similar alkylation
products observed to cyclic ketones, N-sec-butylindoline
(10d) and 1,5-di-sec-butylindole (11d) were first detected
(Scheme 2).
The formation of the undesired products 6–9 could not
be suppressed under different reaction conditions in
which various Brønsted and Lewis acids were employed
as catalysts at varying temperatures and in different sol-
vents. To probe the effect of varying ratios of starting ma-
terials on product distribution, indoline (1 equivalent) was
reacted with cyclohexanone (5 equivalent) in the presence
Under a similar protocol, we next examined the scope of
the redox amination as summarized in Table 2. Indoline
and aliphatic cyclic ketones such as cyclopentanone (4b)
Table 2
The reaction of indoline (1, 1 equivalent) with ketones 4b–c (1 equivalent) catalyzed by Bi(NO3)3·5H2O (0.1 mmol).
Entry
Ketone 4
Product (yield%)
1
2
Cyclopentanone (4b)
Cycloheptanone (4c)
5b
50
5c
39
6b
7b
—
7c
10
8b
—
8c
26
9
17
9
R = cyclopentyl
R = cycloheptyl
Not isolated
6c
13
3
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N-Alkylated Indolines and Indoles
Scheme 2. Reaction of indoline (1; 1 equivalent) with 2-butanone (4d; 1 equivalent).
Scheme 3. The reaction of indoline (1; 5 equivalent) with cyclohexanone (4a; 1 equivalent).
of Bi(NO3)3·5H2O (0.1 mmol) at 120°C in acetonitrile. In
this reaction, no N-alkyl indole 5a formation was ob-
served. This is possible because of the increased reactivity
of N-alkylation product 5a, allowing for its complete con-
version into 1,3-dialkyl and 1,3,5-trialkylation products.
Alternatively, when 5 :1 equivalent ratio of indoline to
cyclohexanone was used under the same reaction condi-
tions, the product portfolio changed considerably, as shown
in Scheme 3, and the formation of N-cyclohexylindoline
(10a) as a reductive alkylation product first was observed
in a high yield. It was found that no other alkylation
products were formed, and only a trace amount of 5a could
be identified. The improved method was also applied to the
reaction of the other ketones (except for acetone), and the
observed similar results are summarized in Table 3.
However, we noticed that N-alkyl indolines 10a–d easily
tend to oxidize to the corresponding indole compounds
either on standing or during the purification. Therefore,
N-alkyl indolines 10a–d were aromatized with MnO2.
A plausible mechanism for the reaction of indoline with
cyclohexanone is shown in Scheme 4. The mechanism for
the formation of N-cyclohexylindole (5a) involves subsequent
condensation and final isomerization of indoline with cyclo-
hexanone in the presence of bismuth nitrate. According to
the experimental results, we proposed a reductive alkylation
mechanism based on the formation of iminium ion for the for-
mation of the other products. As depicted in Scheme 4, in the
presence of a Lewis acid, the direct substitution of cyclohexa-
none with N-cyclohexylindole (5a) produces 1-(1-cyclohexyl-
indo-lin-3-yl)cyclohexanol, which is subsequently converted
to the iminium ion 12 by eliminating H2O. Intermolecular
Table 3
The reaction of excess indoline (1; 5 equivalent) with ketones 4a–d
(1 equivalent) catalyzed by Bi(NO3)3·5H2O (0.1 mmol).
Product (yield%)
Entry
Ketone 4
10
9
5
1
2
3
4
a
b
c
58
57
59
54
33
35
31
35
Trace
Trace
Trace
Trace
d
hydride transfer from another indoline to the iminium ion 12
led to N-alkylation product 10a. On the other hand, the
deprotonation of the iminium ion generated from indoline
results in the formation of indole (9). Similarly, a mechanism
to 1,3-alkylation could also be suggested for the formation of
both 1,3,5-alkylation and 3-alkylation products (6a, 7a)
(Scheme 5).
Attempts to extend this reaction to acetone failed to give
any of the desired alkylation product under the usual reaction
condition. Therefore, we changed the amount of catalyst and
performed the reaction without any solvent. The reaction of
indoline (4.2 mmol) with acetone (42mmol) in the presence
of Bi(NO3)3·5H2O (0.1mmol) at 120°C in a sealed tube led
to N-alkylindole (5e), 1,3-dialkyl indole 6e, and indole (9).
Additionally, we found that heating of indoline (1 equivalent)
with acetone (10 equivalent) in the presence of 10 mmol of
Bi(NO3)3·5H2O yielded pyrrolo[3,2,1-ij]quinolines (15 and
16) as a result of chain reaction (Scheme 6). This reaction
may proceed via an intermolecular aldol-type reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Bayindir, E. Erdogan, H. Kilic, O. Aydin, and N. Saracoglu
Vol 0000
Scheme 4. Proposed mechanism for Lewis acid (LA)-promoted redox
isomerization and reductive alkylation products 5a, 10a. [Color figure can be
viewed in the online issue,which is available at wileyonlinelibrary.com.]
a Lewis acid-catalyzed dehydration of the alcohol occurs
cationic types (Scheme 7). Finally, the tetra-quinoline and
dihydropyrrolo-quinoline 22 and 23 undergoes a dehydroge-
nation to provide Friedel–Crafts-type alkylation in the same
reaction vessel resulting in the corresponding indole.
CONCLUSIONS
In summary, we have first reported bismuth nitrate-catalyzed
redox aminations of indoline with aliphatic ketones. A possible
formation mechanism for the products is described. Further
studies aimed at examining the redox amination scope of
benzylic ketones with indoline are in progress.
EXPERIMENTAL SECTION
Representative procedure (RP1): reaction of indoline (1; 1
Scheme 5. Formation of the reductive alkylation products 6a, 7a as
secondary product.
equivalent) with cyclohexanone (4a; 1 equivalent).
To a
solution of indoline (1; 500 mg; 4.2 mmol) in MeCN (5 mL) was
added cyclohexanone (4a; 412 mg, 4.2 mmol) and Bi(NO3)3·5H2O
(0.1 mmol, 48 mg). Reaction mixture was stirred magnetically in a
sealed tube at 120°C for 3 h. The reaction was monitored by TLC.
After the completion of the reaction, the mixture was diluted with
ethylacetate (30 mL) and washed with water (3 × 30 mL), and
organic phase was dried over Na2SO4. The crude product (830 mg)
was purified by silica gel column chromatograph (25 g), and
isolated compounds was given according to elution sequence.
1,3,5-Tricyclohexyl-1H-indole (7a). 115 mg, 12%, white solid,
mp = 145–146°C (hexane), eluent: hexane, Rf = 0.88 (254 nm).
1H-NMR (400 MHz, CDCl3): δ 7.46 (s, Ar–H, 1H), 7.27 (d, A part
of AB system, J=8.6Hz, Ar–H, 1H), 7.07 (d, B part of AB system,
J=8.6Hz, Ar–H, 1H), 6.94 (s, Ar–H, 1H), 4.17 (p, J= 5.8 Hz, CH,
1H), 2.84–2.82 (m, CH, 1H), 2.63 (p, J= 5.8 Hz, CH, 1H), 2.13–2.10
between acetone and the iminium intermediate 17 followed
by an intramolecular Friedel–Crafts alkylation of the resulting
ketone 18 and the pyrrolo[3,2,1-ij]quinoline skeleton are
formed (Scheme 7). In the next step of the reaction sequence,
Scheme 6. Reaction of indoline (1; 1 equivalent) with acetone (4e; 10 equivalent).
Scheme 7. Proposed formation mechanism for pyrrolo[3,2,1-ij]quinolines 15 and 16. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
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Month 2015
N-Alkylated Indolines and Indoles
(m, CH2, 4H), 1.97–1.86 (m, CH2, 10H), 1.80–1.65 (m, CH2, 2H),
1.59–1.47 (m, CH2, 10H), 1.44–1.27 (m, CH2, 4H). 13C-NMR
(100 MHz, CDCl3): δ 138.6, 134.7, 127.2, 121.6, 120.7, 119.8,
116.9, 109.3, 55.1, 45.1, 35.8, 35.5, 34.5, 33.8, 27.5, 27.3, 26.9, 26.6,
26.3, 26.0. IR (KBr, cmÀ1): 3374, 2924, 2852, 1672, 1631, 1607,
1437, 1397, 1359, 1322, 1270, 1255, 1456, 1439, 1397, 1356,
1206, 1323, 1163, 1122, 1084, 979, 908, 858, 811. Anal. Calcd
for C26H37N: C, 85.89; H, 10.26; N, 3.85, found: C, 85.87; H,
10.21; N, 3.93.
CDCl3): δ 7.05–7.02 (m, Ar–H, 2H), 6.58 (t, J=7.7Hz, Ar–H,
1H), 6.40 (d, J=7.7Hz, Ar–H, 1H), 3.40–3.36 (m, CH, CH2, 3H),
2.94 (t, J=8.4Hz, CH2, 2H), 1.86–1.84 (m, CH2, 4H), 1.71–1.68
(m, CH2, 2H), 1.39–1.33 (m, CH2, 4H). 13C-NMR (100 MHz,
CDCl3): δ 151.2, 130.1, 127.2, 124.3, 116.5, 106.8, 54.6, 46.7,
28.7, 28.3, 26.1, 26.0. IR (KBr, cmÀ1): 2921, 2851, 1627, 1456,
1439, 1397, 1356, 1206, 1323, 1163, 1122, 1084, 979, 908, 858,
811. Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96, found:
C, 83.47; H, 9.51; N, 6.92.
N-Cyclohexyl-1H-indole (5a) [29,30]. 345 mg, 38%, colorless
liquid, eluent: hexane, Rf = 0.82 (254 nm). 1H-NMR (400 MHz,
CDCl3): δ 7.67 (d, J=7.8Hz, Ar–H, 1H), 7.42 (d, J=7.8Hz,
Ar–H, 1H), 7.26–7.21 (m, Ar–H, 2H), 7.13 (t, J=7.8Hz, Ar–H,
1H), 6.54 (d, J=3.3Hz, Ar–H, 1H), 4.29–4.23 (m, CH, 1H),
2.19–2.16 (m, CH2, 2H), 1.99–1.90 (m, CH2, 2H), 1.84–1.76
(m, CH2, 2H), 1.73–1.48 (m, CH2, 2H), 1.38–1.30 (m, CH2, 2H).
13C-NMR (100 MHz, CDCl3): δ 135.8, 128.8, 124.3, 121.3, 121.2,
119.5, 109.7, 101.3, 55.4, 33.8, 26.3, 25.9. IR (KBr, cmÀ1): 2921,
2851, 1627, 1456, 1439, 1397, 1356, 1206, 1323, 1163, 1122,
1084, 979, 908, 858, 811. Anal. Calcd for C14H17N: C, 84.37; H,
8.60; N, 7.03, found: C, 84.31; H, 8.58; N, 6.98.
Indole (9). 187 mg, 33%.
Indoline (1). 300 mg (2.6 mmol) was recovered.
Representative procedure (RP3): N-Cyclohexyl-1H-indole
(5a).
To a solution of N-cyclohexylindoline (10a; 300 mg,
1.5 mmol) in CH2Cl2 (10 mL) was added the active MnO2
(1.50 g, 15 mmol). The mixture was stirred at rt for 12 h. The
reaction was monitored by TLC. After the completion of the
reaction, the mixture was diluted with ethylacetate (30 mL) and
washed with water (3 × 30 mL), and organic phase was dried
over Na2SO4. N-Cyclohexyl-1H-indole (5a) was eluted on silica
gel column chromatography (25 g) using hexane as colorless
liquid (289 mg, 97%).
1,3-Dicyclohexyl-1H-indole (6a).
122 mg, 13%, colorless
liquid, eluent: hexane, Rf = 0.65 (254 nm). 1H-NMR (400 MHz,
CDCl3): δ 7.90 (d, J=7.7Hz, Ar–H, 1H), 7.47 (d, J=7.7Hz,
Ar–H, 1H), 7.30 (t, J=7.7Hz, Ar–H, 1H), 7.25 (t, J=7.7Hz,
Ar–H, 1H), 7.10 (s, Ar–H, 1H), 4.32–4.24 (m, CH, 1H), 2.97–2.95
(m, CH, 1H), 2.29–2.23 (m, CH2, 4H), 2.09–1.80 (m, CH2, 8H),
1.77–1.61 (m, CH2, 6H), 1.58–1.37 (m, CH, 2H). 13C-NMR
(100 MHz, CDCl3): δ 136.3, 127.4, 121.4, 121.9, 119.8, 119.7,
118.6, 109.7, 55.2, 35.9, 34.6, 33.8, 27.4, 26.9, 26.4, 26.1. IR
(KBr, cmÀ1): 3029, 2978, 2928, 2109, 1509, 1463, 1457, 1401,
1355, 1310, 1300, 1228, 1190, 1163, 1122, 1084, 979, 908, 858,
811. Anal. Calcd for C20H27N: C, 85.35; H, 9.67; N, 4.98, found:
C, 85.37; H, 9.64; N, 4.93.
Acknowledgments. We are greatly indebted to The Scientific and
Technical Research Council of Turkey (TUBITAK, grant no.
TBAG-112T600) and the Department of Chemistry, Ataturk
University for their financial support for this study.
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1
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Representative procedure (RP2): The reaction of indoline
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solvent-free condition. A mixture of indoline (1, 1.00g, 8.4mmol),
cyclohexanone (4a, 165 mg, 1.7 mmol), and Bi(NO3)3·5H2O
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120°C for 1 h under solvent-free condition. The reaction was
monitored by TLC. After the completion of the reaction, the
mixture was diluted with ethylacetate (30 mL) and washed with
water (3 × 30 mL), and organic phase was dried over Na2SO4.
The crude product (1.15 g) was purified by silica gel column
chromatograph (25 g), and isolated compounds was given
according to elution sequence.
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Vol 0000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet