An efficient synthesis of new aza-substituted indoles via Michael-type addition

Article abstract of DOI:10.1055/s-0029-1219923

An efficient method has been developed for the synthesis of new aza-substituted indoles. The methodology involves a two-step synthesis. The first step involves the Michael addition of indoline with various Michael acceptors. The other includes the oxidation of the indoline ring in the Michael adducts to an indole.

Full text of DOI:10.1055/s-0029-1219923

LETTER
1455
An Efficient Synthesis of New Aza-Substituted Indoles via Michael-Type
Addition
Synthesis of
N
i
ew Az
n
aIndoles n Bayindir, Esra Erdogan, Haydar Kilic, Nurullah Saracoglu*
Department of Chemistry, Faculty of Sciences, Atatürk University, Erzurum 25240, Turkey
Fax +90(442)2360948; E-mail: nsarac@atauni.edu.tr
Received 24 February 2010
agents28 and key precursors for the synthesis of indole de-
rivatives.29–33
Abstract: An efficient method has been developed for the synthesis
of new aza-substituted indoles. The methodology involves a two-
step synthesis. The first step involves the Michael addition of indo-
line with various Michael acceptors. The other includes the oxida-
tion of the indoline ring in the Michael adducts to an indole
Initially, cyclic unsaturated ketones were selected as
Michael acceptors (Table 1, entries 1–3). The reaction of
indoline (1) with cyclohex-2-enone (2) was examined in
the presence of 4-dimethylaminopyridine (DMAP) as a
catalyst in acetonitrile, and reaction was complete after
24 hours to afford 3-(indolin-1-yl)cyclohexanone (3,
Scheme 1). The indoline ring was then oxidized to 3-(1H-
indol-1-yl)cyclohexanone (4)37 with MnO2 in CH2Cl2 in
90% yield (Scheme 1 and Table 1, entry 2). Moreover, we
successfully isolated the corresponding N-alkylated in-
doles by starting with cyclopent-2-enone and cyclohept-
2-enone (entries 1 and 3).
Key words: alkylation, indoline, Michael addition, oxidation, cata-
lyst
Indole subunits are of considerable interest both for the
synthetic organic chemist and the medicinal chemist due
to their remarkable range of biological and medicinal
properties. Indole derivatives have been used to treat cer-
tain kinds of cancer, hypercholesterolemia, to prevent car-
diovascular disease, or act as oral insulin mimics.1–7 Other
indole derivatives show antiviral activity against hepatitis
or have applications as nonsteroidal anti-inflammato-
ries.8–12 This wide range of interesting properties has
prompted the development of an efficient methodology
for the synthesis of substituted indoles. In general, substi-
tuted indole synthesis is accomplished either by the con-
struction of the indole ring from other substrates via
Fischer indolization or by direct functionalizations of an
existing indole via electrophilic substitution.13,14 While
the methods for the preparation of 3-substituted indoles
are well established,15–18 there is still a need for easier ac-
cess to 2-substituted indoles and aza-substituted indoles.
Furthermore, alkylation of indoles and their anions under
extreme conditions usually gives N- and C-alkylation
products nonregioselectively.19–23 Although N-substituted
indoles also represent an important subclass,8,11,12,24,25 the
synthesis of N-substituted indoles is more difficult than
the other substituted indoles because of the low nucleo-
philicity of nitrogen atom. Michael-type addition is one of
the most important indole functionalization reactions.26
Recently, KF/Al2O3-mediated direct aza-Michael addi-
tion of indoles to electron-deficient olefins such as a,b-
unsaturated ketones, amides, and nitriles has been report-
ed.27 However, the reaction failed with unsaturated esters
and aldehydes. We herein report our results on the two-
step synthesis of new aza-substituted indole derivatives
via Michael-type addition reactions of indoline with vari-
ous acceptors. Indoline fragments are both important moi-
eties of a large number of natural products and medicinal
O
N
N
2
MnO2
DMAP
MeCN
r.t., 24 h
CH2Cl2
r.t., 24 h
N
H
O
O
1
3
4
Scheme 1
Next, the scope of the method was broadened to include
the reaction between indoline and acyclic unsaturated ke-
tones and esters (Table 1, entries 4–9). Reaction of chal-
cone with indoline catalyzed by KF–Al2O3 in acetonitrile
provided aza-alkylated indole derivative followed by
MnO2 oxidation (entry 4). Michael addition of the other
acceptors such as (E)-4-phenylbut-3-en-2-one, (E)-meth-
yl but-2-enoate, (E)-pent-3-en-2-one, and methyl propi-
olate with indoline, followed by the oxidation of indoline
rings gave the corresponding aza-substituted indoles in
high yield (Table 1, entries 5–8). NMR spectroscopic
studies allowed the assignment of the configuration of the
vinyl groups for both the Michael adduct obtained from
methyl propiolate and oxidation product (entry 8).34,35
Coupling constants (3J = 13.0 and 13.9 Hz) are in good
agreement with the E-configuration for both compounds.
Michael addition of indoline to nitrostyrene catalyzed by
Bi(NO3)3·5H2O gave 1-(2-nitro-1-phenylethyl)indoline in
high yield. Oxidation of the indoline moiety to indole with
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in CH2Cl2
led to a new alkylated indole derivative in 95% yield (en-
try 10). We also used 1,1-bis(phenylsulfonyl)ethylene as
SYNLETT 2010, No. 10, pp 1455–1458
x
x
.x
x
.2
0
1
0
Advanced online publication: 06.05.2010
DOI: 10.1055/s-0029-1219923; Art ID: D05010ST
© Georg Thieme Verlag Stuttgart · New York

1456
S. Bayindir et al.
LETTER
the alkylation reagent in CH2Cl2 in the presence of bis- ter bismuth nitrate catalyzed reaction of indoline with
muth nitrate for 5 hours. Oxidation of the resultant Micha- DMAD in CH2Cl2, the Michael product was oxidized with
el adduct with DDQ gave the novel N-alkylated indole MnO2 to give N-vinyl-substituted indole derivative (entry
derivative (entry 11).
9).36 The nuclear Overhauser effect difference experiment
for DMAD addition product 5 revealed that vinyl group
has the E-geometry (Figure 1).
After the successful application of this protocol with cy-
clic unsaturated ketones and acyclic unsaturated ketones
and esters, we investigated the conjugate–addition reac- The reaction of indoline with 1,4-naphthoquinone was
tions of indoline to symmetrical Michael acceptors such performed in the presence of catalytic DMAP. Naphtho-
as dimethyl acetylenedicarboxylate (DMAD), 1,4-naph- quinone was used in two equivalents instead of one since
thoquinone, and 1,1,2,2-tetracyanoethylene (TCNE). Af- a complex mixture was formed with a stoichiometric
Table 1 The Catalysts and Oxidation Reagents for the Synthesis of New Aza-Substituted Indoles
catalyst
O
oxidation
N
O
N
O
N
R1
R2
R1
R2
H
R2
R1
Entry
Acceptor
Catalysta
Oxidation reagentb Product
Yield (%)
1
2
3
O
n = 1
n = 2
n = 3
92
90
97
N
DMAP
MnO2
(CH2)n
(CH2)n
O
4
5
6
7
R1 = Ph, R2 = Ph
R1 = Ph, R2 = Me
R1 = Me, R2 = OMe
R1 = Me, R2 = Me
60
96
95
92
O
KF–Al2O3
MnO2
N
O
R1
R2
R1
R2
8
9
R = H
R = CO2Me
95
84
N
Bi(NO3)3·5H2O
Bi(NO3)3·5H2O
Bi(NO3)3·5H2O
MnO2
R
CO2Me
R
MeO2C
10
11
DDQ
95
98
NO2
Ph
N
N
NO2
Ph
PhO2S
SO2Ph
DDQ
SO2Ph
SO2Ph
O
O
N
12
DMAP
MnO2
51
O
O
a Catalyst for Michael addition.
b Reagent for oxidation of Michael adduct to corresponding indole.
Synlett 2010, No. 10, 1455–1458 © Thieme Stuttgart · New York

LETTER
Synthesis of New Aza-Substituted Indoles
1457
In conclusion, a facile, efficient, and regioselective syn-
thesis of N-alkylated indoles has been accomplished in
which the key step involves Michael addition reactions of
indoline.
H
H
N
N
NOE
H
H
H
NOE
CO2Me
MeO2C
MeO2C
CO2Me
5
5
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Figure 1
amount. Examination of the 1H NMR and 13C NMR spec-
tra of the reaction mixture revealed the formation of oxi-
dation product 8, instead of the expected Michael adduct
6 or tautomeric form 7 (Scheme 2). We assume that the
Acknowledgment
We are greatly indebted to The Scientific and Technical Research
Council of Turkey (TUBITAK, Grant No. TBAG-108T433) for
second mol of naphthoquinone oxidizes Michael adduct 6 their financial support for this work.
or tautomer 7 to yield naphthoquinone derivative 8. The
indoline ring of 8 was oxidized with MnO2 to afford the
aza-substituted indole derivative in 51% yield (entry 12).
References and Notes
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CN
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Synlett 2010, No. 10, 1455–1458 © Thieme Stuttgart · New York

1458
S. Bayindir et al.
LETTER
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(m, CH2, 1 H), 2.56–2.50 (m, CH2, 1 H), 2.47–2.41 (m, CH2,
1 H), 2.33–2.25 (m, CH2, 1 H), 2.16–2.07 (m, CH2, 2 H),
1.86–1.70 (m, CH2, 1 H), 1.69–1.60 (m, CH2, 1 H). 13C NMR
(100 MHz, CDCl3): d = 210.0, 150.2, 130.1, 127.6, 124.8,
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mg, 10 mmol). The mixture was then stirred at r.t. for 24 h.
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90%). 1H NMR (400 MHz, CDCl3): d = 7.65 (dd, J = 7.8, 2.0
Hz, =CH, 1 H), 7.35 (d, J = 8.4 Hz, =CH, 1 H), 7.26–7.20
(m, =CH, 2 H), 7.16–7.12 (m, =CH, 1 H), 6.57 (d, J = 2.9
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1 H), 2.90–2.77 (m, CH2, 1 H), 2.56–2.40 (m, CH2, 2 H),
2.35–2.30 (m, CH2, 1 H), 2.25–2.10 (m, CH2, 2 H), 1.85–
1.78 (m, CH2, 1 H). 13C NMR (100 MHz, CDCl3): d = 208.2,
135.7, 128.9, 124.0, 122.0, 121.5, 120.1, 109.6, 102.6, 54.4,
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To a solution of indoline (500 mg, 4.19 mmol) and cyclohex-
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