Synthesis of highly N-substituted indole library via conjugate additions of indoline and their synthetic tool potentials

Article abstract of DOI:10.1016/j.tet.2012.04.066

A comprehensive library of N- or 1-substituted indoles was formed by conjugate additions of indoline with Michael acceptors followed by an oxidation step. Using N-substituted indoles as key Michael donors, the synthesis of 1,3-disubstituted indoles was al

Full text of DOI:10.1016/j.tet.2012.04.066

Tetrahedron 68 (2012) 5619e5630
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Synthesis of highly N-substituted indole library via conjugate additions
of indoline and their synthetic tool potentials
,
,
*
Haydar Kilic a, Sinan Bayindir a b, Esra Erdogan a, Nurullah Saracoglu a
a
€
Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum 25240, Turkey
b
€
€
Department of Chemistry, Faculty of Sciences and Arts, Bingol University, Bingol 12000, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A comprehensive library of N- or 1-substituted indoles was formed by conjugate additions of indoline
with Michael acceptors followed by an oxidation step. Using N-substituted indoles as key Michael do-
nors, the synthesis of 1,3-disubstituted indoles was also accomplished.
Received 10 February 2012
Received in revised form 24 March 2012
Accepted 16 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 27 April 2012
Keywords:
Indoline
Conjugate addition
Michael acceptor
Substitution
Catalyst
4
1. Introduction
3
The indole (1) ring is of great interest and significance since this
sub-unit is found in numerous natural alkaloids.1e7 Therefore, in-
tensive efforts have been devoted to the development of efficient
methods for the synthesis of functionalized indoles. While many
methods for the functionalization of indole at C3 are well establish-
ed,8e11 there is still limited ease of access to C2 and N-functionalized
indoles (Fig. 1). Although N-functionalized indoles also represent an
important subclass, the derivatization of the indole nitrogen atom is
difficult due to its low nucleophilicity.12e17 Both the alkylation of in-
doles and the salts of indoles under extreme conditions usually gives
N- and C-alkylation products with low regioselectively.18e22 Michael
or conjugate additions are one of the most fundamental indole
functionalization reactions.23e27 Recently, we have been communi-
cating our two-step synthesis results to access new N-substituted
indoles via the conjugate addition reaction of indoline with Michael
acceptors.28 Herein, we report our detailed results on the synthesis of
a highly N-substituted indole library.
1
2
7
N
H
1
Fig. 1. Indole (1).
a Michael donor. The first step of the method was the conjugate ad-
dition of indoline with various acceptors, which provided N-alkyl
indolines (Scheme 1). Cyclic unsaturated ketones, acyclic unsaturated
ketones and esters, nitro alkenes, 1,4-naphthoquinone, 1,1-
bis(phenylsulfonyl)ethylene, and N-phenyl maleimide were used as
Michael acceptors (Table 1, entries 1e17). The results for reaction of
the indoline, catalyzed by Lewis acid and base catalysts such as
Bi(NO)3$5H2O, KF/Al2O3, and 4-dimethylaminopyridine (DMAP) are
presented in Table 1. The last step is the oxidation of the alkylated
indolines to N-alkylated indoles in high yields (Scheme 1).
The Michael reaction of the indoline with 1,4-naphthoquinone
(NQ) catalyzed by DMAP or KF/Al2O3 provided the indol-1-yl
substituted naphthoquinone 5q after oxidation with MnO2
(Scheme 2). We also examined the Michael reaction of 3 with indol-
1-yl naphthoquinone 5q. Oxidation of the crude Michael addition
product with MnO2 in situ afforded 6 in 14% yield (Scheme 2).
When p-benzoquinone (PBQ) was employed as a Michael acceptor,
the desired product 7 was obtained in low yield after in situ oxi-
dation with the MnO2 (Scheme 2).
2. Results and discussions
The Michael addition is the cornerstone of our synthesis. In our
synthetic approach, the other cornerstone is the indoline used as
* Corresponding author. Tel.: þ90 442 231 4425; fax: þ90 442 236 0948; e-mail
address: nsarac@atauni.edu.tr (N. Saracoglu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.066

5620
H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
was found that the reaction afforded a mixture of indole (1) and the
O
reduced DEAD 20 instead of the expected Michael adduct 21. This
result indicated that DEAD promoted dehydrogenation of indoline
(3) to indole (1).
To test the developed methodology, we focused our attention on
the enantioselective synthesis of N-substituted indolines/indoles.
catalyst
R2
+
N
O
N
H
R1
R1
R2
2
3
4
We selected the Michael addition of b-nitro styrene with indoline
as a model reaction. The chiral catalysts were obtained from com-
mercial sources, and were used in the asymmetric Michael addi-
[O]
tions. The reaction of b-nitro styrene with indoline in the presence
oxidant s:
DDQ
Mn O2
catalysts:
of 0.2e10 mol % of (S)-(þ)-1,10-binaphthyl-2,20-diyl hydro-
.
Bi(NO3)3 5H2O
KF/Al2O3
DMAP
genphosphate (22),
L-(þ)-tartaric acid (23), and (R,R)-[Al(salen)Cl]
N
O
(24) resulted in excellent yields of the expected Michael product 4l
(93e96%) (Scheme 9). Unfortunately, no enantioselectivity could be
detected by 1H NMR spectroscopy/HPLC in the reactions.
R1
R2
5
The Michael additions to N-alkyl indoles were then carried out
with b-nitro styrene (2l) to yield 1,3-disubstituted indoles. The results
Scheme 1.
are summarized in Table 2 (entries 1e7). The best results were
obtained using zinc triflate (0.1 mmol) as a Lewis acid catalyst. The 1H
and 13C NMR spectra revealed that the products were obtained as
a mixture of the expected diastereomers (Table 2, entries 2, 4e7) and
enantiomers for both entries 1 and 2. In this manner, the Michael
When the reaction of indoline with 1,1,2,2-tetracyanoethylene
(TCNE, 8) was carried out in the presence of bismuth nitrate in
CH2Cl2 at rt for 5 h, the 1H and 13C NMR spectra of the isolated
product 9 with an excellent yield of 95%, indicated that elimination
of hydrogen cyanide from the primary Michael adduct resulted in
the formation of tricyano compound 9 (Scheme 3). Despite all at-
tempts, oxidation of the indoline ring in 9 to give the indole ring
failed. Oxidation was carried out with oxidants such as MnO2, 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ), elemental sulfur, Pd/C,
and bis(trifluoroacetoxy)iodobenzene (PIFA). When the MnO2-
catalyzed oxidation of 9 was performed in presence of indoline (3),
we only observed the oxidation of indoline to indole. We proposed
that the strong electron-withdrawing CN groups increase the oxi-
dation resistance of 9.
reaction of N-vinyl indole derivative 5j with b-nitro styrene did not
occur under the same conditions. The original materials were re-
covered unchanged (Scheme 10). We assume that the resonance
structure5jRstronglyreducedthereactivityoftheindoleringin5j. To
support this hypothesis, the reaction between N-vinyl indoline 4j and
b-nitro styrene was examined under the same conditions
(Scheme 11). Interestingly, this reaction afforded an unexpected
product 26asa single product in highyield. The proposed mechanism
involves the formation of a zwitterionic enolate 4jR and the attack of
the enolate to the acceptor to give a new a-Michael product 26. The
In addition, an intramolecular FriedeleCrafts ring closure of
Michael adduct 4k obtained from indoline with dimethyl acetyle-
nedicarboxylate (DMAD, 2k) in CH2Cl2 (Table 1, entry 11) was ac-
complished using polyphosphoric acid (PPA) or Eaton’s reagent
(P2O5/MeSO3H) as a dehydrating agent to provide the corre-
sponding dihydroquinoline 11 (Scheme 4).29 The FriedeleCrafts
product 11 was oxidized with MnO2 in methylene chloride to give
the corresponding tricyclic system 12 (Scheme 4). Under similar
reaction conditions, many attempts to perform an intramolecular
FriedeleCrafts acylation of N-vinyl indole 5k to 13 under failed, and
only polymeric materials were recovered (Scheme 5).
Furthermore, 1-(2-nitro-1-phenylethyl) indoline (4l) was easily
aromatized with DDQ to afford the corresponding indole 5l in the 95%
yield (Table 1, entry12). Surprisingly, theuseofMnO2 inthisoxidation
resulted in an unexpected product mixture (Scheme 6). The reaction
mixture was separated by silica gel column to give nitro styrene 14
(64%) and N-benzoyl indole (15) (31%). We propose a mechanism as
depicted in Scheme 7. We assume that the indoline ring, which is very
sensitive toward oxidation because of its tendency to be aromatized
into an indole, is firstly oxidized with active MnO2. The mechanism
continues via the formation of a benzylic radical intermediate due to
the stability of the benzylic radical as in Scheme 7. The decomposition
via a six-membered transition state leads tothe formation of isomeric
nitro styrene 14. The hydration of nitro olefins undergoes carbon-
ecarbon cleavage to give N-benzoyl indole (15) and nitro methane.
We assumed that MnO2 acts as a Lewis acid during the addition of
water to the olefin. To verify the hydration-bond cleavage, the hy-
dration of olefins was again examined in the presence of MnO2 and
water in CH2Cl2. ThereactionproceededsmoothlytoaffordN-benzoyl
indole (15). However, the reaction was carried out in the presence of
H2SO4/H2O inCH2Cl2 to give the cleavage product15 asa soleproduct.
Indoline (3) was also reacted with diethyl azodicarboxylate
(DEAD; 19) as a Michael substrate in methylene chloride (Scheme
8). In the presence of bismuth nitrate (0.1 mmol %) as a catalyst, it
geometry of the product 26 (E or Z isomer) was not determined by
NOE H NMR spectroscopy. The reaction of the Michael product 26
1
with DDQ gave 27 in an 87% yield (Scheme 11). Unlike 4j, the same
product from 5j was not obtained. We think that both the indole ring
and the vinyl group resulted through the resonance structures of 5j
not being prone to give the corresponding Michael adduct. We also
examined the enantioselective reaction of the methyl 3-(1H-indol-1-
yl) propanoate (5d) model as a compound with b-nitro styrene in the
presence of (S,S)-2,20-isopropylidene-bis (4-phenyl-2-oxazoline)e
Zn(OTf)2 (Scheme 12). The desired Michael product 29h was obtained
through high chemical yields (85e90%) and low enantioselectivies
(15.6e27.6% ee) (Table 3). The enantiomeric excess (ee) for the
product was determined by chiral HPLC analysis.
3. Conclusions
In summary, we have demonstrated that the Lewis acid/base-
catalyzed conjugate addition reactions of a,b-unsaturated accep-
tors with indoline provides a highly N-substituted indole library
followed by subsequent oxidation. The enantioselective alkylations
for the selected model reactions were not observed here. However,
we hope that further studies will result in highly enantio- and
diastereoselective variants of this reaction.
4. Experimental section
4.1. General
All reagents and solvents were purchased from commercial
suppliers (SigmaeAldrich or Fluka) and used without further pu-
rification. Column chromatography and thin-layer chromatography
(TLC) were performed using Silica gel 60 (70e230 Fluka) and Silica
gel 60 HF254 (Fluka), respectively. Melting points were determined
on Buchi 539 capillary melting apparatus and uncorrected. Infrared

H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
5621
Table 1
The catalysts reagent for the synthesis of new N-substituted indolines and indoles
Entry
Acceptor
Product
Yield (%)
Product
Yield (%)
NR,a 35,b,f 90c,f
NR,a 30,b 94c
NR,a 92,b96c
5a
5b
5c
95,d 92e
92,d 90e
95,d 97e
O
1
2
3
2a
2b
2c
n¼1
n¼2
n¼3
4a
4b
4c
N
N
(CH2)n
(CH2)n
(CH2)n
O
O
O
4
5
6
7
8
9
2d
2e
2f
R1¼H, R2¼Me
R1¼Me, R2¼Me
R1¼Ph, R2¼Me
R1¼Ph, R2¼Ph
R1¼H, R2¼OMe
R1¼Me, R2¼OMe
4d
4e
4f
93,a 97,b 95c
NR,a 92,b 90c
NR,a 87,b,f 86c,f
NR,a 60,b,f 58c,f
97,a 90,b 89c
NR,a 95,b 87c
5d
5e
5f
97,d 95e
92,d 90e
87,d 85e
60,d 65e
96,d 93e
95,d 92e
N
N
O
O
R1
R2
R1
R1
R2
R2
2g
2h
2i
4g
4h
4i
5g
5h
5i
10
11
2j
R¼H
R¼CO2Me
4j
81,a 95,b 87c
85,a 84,b 77c
5j
97,d 95e
85,d 84e
N
R
CO2Me
NO 2
N
2k
4k
5k
R
R
Me O2C
Me O2C
12
13
14
2l
R¼Ph
R¼furan
R¼thiophen
4l
95,a 94,b 87c
96,a,f 95,b,f 83c,f
90,a,f 87,b,f 82c,f
5l
95,d UPe
93,d 65e
94,d de
R
2m
2n
4m
4n
5m
5n
N
R
N
R
NO2
NO2
PhO2S
SO2Ph
98,a 95,b 92c
5o
98,d 56e
N
N
15
2o
4o
SO2Ph
SO2Ph
SO2Ph
SO2Ph
O
O
N
N
16
2p
O
4p
NR,a 87,b 82c
O
5p
47,d 51e
O
O
O
N
N
17
2q
4q
91,a 85,b 81c
5q
79,d 93e
N
Ph
O
O
O
N
N
O
Ph
O
Ph
NR: no reaction.
UP: unexpected product.
a
Bi(NO3)3$5H2O (10 mmol %).
KF/Al2O3 (10 mmol %).
DMAP (10 mmol %).
DDQ (1 mmol).
b
c
d
e
MnO2 (10 mmol).
f
The yield was determined by 1H NMR spectroscopy.

5622
H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
i,ii
O
N
N
N
H
N
N
O
O
N
O
3
CO 2Me
MeO2C
13
CO2Me
O
5k
iii, iv
Scheme 5.
6
5q
i: 3, DMAP; ii: MnO2
iii: PBQ, DMAP; iv: MnO2
N
MnO2
+
O
CH2Cl2
N
N
N
NO2
NO2
O
Ph O
15
Ph
Ph
7
4l
14
Scheme 2.
i or ii
i. MnO2, H2O, CH2Cl2 (95%)
ii. H2SO4, H2O, CH2Cl2 (70%)
NC CN
Scheme 6.
NC CN
8
[O ]
N
N
H
N
-HCN
NC
NC
MnO2
3
CN
CN
CN
CN
- Mn(OH)2
N
N
9
10
NO2
NO 2
Ph
Ph
H
4l
3, MnO2
5l
MnO 2
+
NO2
N
HO Mn=O
N
H
N
NC
H
N
Ph
CN
1
O
O
NO2
CN
Mn
H
Ph
17
16
9
- Mn(OH)2
Scheme 3.
H+/H2O
N
N
NO2
NO2
Ph
Ph
OH
18
14
P2O5-MeSO3H
90%
N
N
15 + CH3NO2
O
CO2Me
CO2Me
Scheme 7.
11
CO2Me
4k
MnO2
92%
CH2Cl2
spectra were recorded on a Mattson 1000 FT-IR spectrophotometer.
1H NMR and 13C NMR spectra were recorded on 400 (100)-MHz
Varian and Bruker spectrometer and are reported in
d units with
SiMe4 as the internal standard. Elemental analyses were carried out
on a Leco CHNS-932 instrument. Enantiomeric purity for enantio-
selective syntheses was determined by chiral HPLC (Hewlett
Packard 1200) analysis using a enantiopure stationary phase (Dai-
cel Chiralcel OD), eluting with i-PrOH/hexane, and using UV de-
tection at 254 nm.
N
O
CO 2Me
12
Scheme 4.

H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
5623
CH2, 1H), 2.16e2.07 (m, CH2, 2H), 1.86e1.70 (m, CH2, 1H), 1.69e1.60
(m, CH2, 1H); 13C NMR (100 MHz, CDCl3):
210.0, 150.2, 130.1, 127.6,
124.8,117.9,107.3, 55.0, 46.7, 43.9, 41.3, 28.5, 28.4, 22.9. Anal. Calcd for
C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 77.90; H, 8.16; N, 6.69. IR
(KBr, cmꢃ1) 3472, 3104, 3052, 2968,1744,1611,1511,1479,1462,1404,
1373, 1313, 1244, 1222, 1175, 1151, 1085, 1014, 979, 888, 848, 744.
EtO2C
N
d
N
19
CO 2Et
CO 2Et
CO2Et
HN
HN
+
N
H
N
H
Bi(NO3)3.5H2O
CH2Cl2
20
3
1
4.2.2. (ꢁ)-3-(Indolin-1-yl)cycloheptanone (4c). DMAP catalyzed
reaction was performed at rt for 24 h in CH2Cl2. (ꢁ)-3-(Indolin-1-yl)
cycloheptanone was obtained as yellow crystals (220 mg, 96%, mp
73e74 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
N
N
d
7.10e7.06 (m, ]CH, 2H), 6.65 (t, J¼7.5 Hz, ]CH, 1H), 6.46 (d,
J¼7.5 Hz, ]CH, 1H), 3.73e3.67 (m, CH, 1H), 3.44e3.39 (m, CH, 1H),
3.28e3.21 (m, CH2, 1H), 2.96e2.87 (m, CH2, 2H), 2.84e2.81 (m, CH2,
1H), 2.63e2.45 (m, CH2, 3H), 2.14e1.97 (m, CH2, 3H), 1.79e1.65 (m,
CH2, 2H), 1.49e1.43 (m, CH2, 1H); 13C NMR (100 MHz, CDCl3):
HN
CO 2Et
CO2Et
21
d
212.8, 150.4, 130.5, 127.7, 124.8, 118.1, 107.9, 53.4, 47.1, 46.1, 44.2,
Scheme 8.
34.7, 28.5, 27.6, 24.5. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N,
6.11. Found: C, 78.40; H, 8.46; N, 6.27. IR (KBr, cmꢃ1) 3376, 3046,
3024, 2931, 2855, 1698, 1606, 1488, 1472, 1459, 1392, 1347, 1331,
1304, 1254, 1202, 1162, 1024, 926, 746.
β
-nitro styrene
catalyst
toluene
N
N
H
3
4.2.3. (ꢁ)-4-(Indolin-1-yl)butan-2-one (4d). KF/Al2O3 catalyzed
reaction was performed at rt for 12 h in CH2Cl2. (ꢁ)-4-(Indolin-1-yl)
butan-2-one was obtained as orange liquid (183 mg, 97%); 1H NMR
NO 2
Ph
*
4l
(400 MHz, CDCl3):
d
7.09e7.05 (m, ]CH, 2H), 6.67 (dd, J¼7.5,
0.7 Hz, ]CH,1H), 6.49 (d, J¼7.5 Hz, ]CH,1H), 3.39 (t, J¼7.0 Hz, CH2,
2H), 3.33 (t, J¼7.0 Hz, CH2, 2H), 2.95 (t, J¼7.0 Hz, CH2, 2H), 2.73 (t,
J¼7.0 Hz, CH2, 2H), 2.20 (s, CH3, 3H); 13C NMR (400 MHz, CDCl3):
OH
O
HO
O
O
OH
P
O
d
207.8, 152.1, 130.2, 127.6, 124.7, 118.0, 107.1, 53.5, 44.1, 41.3, 30.5,
O
OH
23
OH
28.8. Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C,
76.45; H, 8.02; N, 7.52. IR (KBr, cmꢃ1) 3048, 2958, 2919, 2846, 1715,
1607, 1489, 1361, 1266, 1165, 747.
22
4.2.4. (ꢁ)-4-(Indolin-1-yl)pentan-2-one (4e). KF/Al2O3 catalyzed
reaction was performed at rt for 24 h in CH2Cl2. (ꢁ)-4-(Indolin-1-yl)
pentan-2-one was obtained as yellow liquid (187 mg, 92%); 1H NMR
N
N
Al
Cl
t
t
Bu
O
O
Bu
(400 MHz, CDCl3):
d
7.08e7.05 (m, ]CH, 2H), 6.64 (t, J¼7.7 Hz, ]CH,
t
t
1H), 6.48 (d, J¼7.7 Hz, ]CH, 1H), 4.21e4.16 (m, CH, 1H), 3.37 (dd,
J¼16.7, 8.4 Hz, CH2, 1H), 3.27 (dd, J¼16.7, 8.1 Hz, CH2, 1H), 2.97e2.91
(m, CH2, 2H), 2.70 (dd, J¼15.7, 5.9 Hz, CH2,1H), 2.55(dd, J¼15.7, 8.4 Hz,
CH2, 1H), 2.17 (s, CH3, 3H), 1.17 (d, J¼6.8 Hz, CH3, 3H); 13C NMR
Bu
Bu
24
Scheme 9.
(100 MHz, CDCl3):
d 207.7, 150.8, 130.5, 127.6, 124.7, 117.8, 107.4, 47.4,
47.3, 46.6, 30.4, 28.4,16.2. Anal. Calcd for C13H17NO:C,76.83;H, 8.43;N,
6.89. Found: C, 76.67; H, 8.25; N, 6.78. IR (KBr, cmꢃ1) 2968, 2845, 2319,
1713,1607,1488,1460,1389,1361,1259,1157,1022, 868, 748, 714, 549.
4.2. General procedure of Lewis acid/base catalyzed Michael
addition of indoline with -unsaturated systems
a,b
4.2.5. Methyl 3-(indolin-1-yl)propanoate (4h). Bi(NO3)3$5H2O cat-
alyzed reaction was performed at rt for 3 h in CH2Cl2. Methyl 3-
(indolin-1-yl) propanoate was obtained as pale green liquid
To a solution of indoline (1.0 mmol) and Michael acceptor
(1.0 mmol) in CH2Cl2 (10 mL) was added Lewis acid/base
(0.1 mmol). The mixture was stirred until the starting material
disappeared (TLC, hexane/ethyl acetate). After evaporation of the
solvent, the crude product was dissolved with EtOAc (40 mL) and
the organic phase was washed with water (2ꢀ20 mL). The EtOAc
extract was dried over Na2SO4, filtered, evaporated in vacuo, and
the compound was purified by silica gel column chromatography
(hexane/ethyl acetate).
(199 mg, 97%); 1H NMR (400 MHz, CDCl3):
d 7.09e7.06 (m, ]CH,
2H), 6.67 (t, J¼7.4 Hz, ]CH,1H), 6.52 (d, J¼7.4 Hz, ]CH,1H), 3.70 (s,
CH3, 3H), 3.43 (t, J¼7.7 Hz, CH2, 2H), 3.36 (t, J¼7.7 Hz, CH2, 2H), 2.96
(t, J¼7.7 Hz, CH2, 2H), 2.62 (t, J¼7.7 Hz, CH2, 2H); 13C NMR
(100 MHz, CDCl3): d 172.9,152.0,130.1,127.6,124.7,118.1,107.2, 53.3,
52.0, 45.3, 32.6, 28.8. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N,
6.82. Found: C, 70.11; H, 7.23; N, 6.98. IR (KBr, cmꢃ1) 2951, 2925,
1737, 1513, 1484, 1464, 1438, 1399, 1368, 1315, 1262, 1208, 1171,
1062, 1014, 988, 841, 764, 743.
4.2.1. (ꢁ)-3-(Indolin-1-yl)cyclohexanone (4b). DMAP catalyzed re-
action was performed at rt for 24 h in CH2Cl2. (ꢁ)-3-(Indolin-1-yl)
cyclohexanonewasobtained aspaleyellowcrystals (202 mg, 94%, mp
84e85 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
4.2.6. (ꢁ)-Methyl 3-(indolin-1-yl)butanoate (4i). KF/Al2O3 cata-
lyzed reaction was performed at 80 ꢂC for 4 days in CH3CN.
(ꢁ)-Methyl 3-(indolin-1-yl)butanoate was obtained as pale yellow
d
7.08e7.03 (m, ]CH, 2H), 6.64 (t, J¼7.6 Hz, ]CH, 1H), 6.42 (d,
liquid (208 mg, 95%); 1H NMR (400 MHz, CDCl3):
d 7.09e7.05 (m, ]
J¼7.6 Hz, ]CH, 1H), 3.82e3.75 (m, CH, 1H), 3.49e3.43 (m, CH2, 1H),
3.38e3.31 (m, CH2,1H), 2.98(t, J¼8.2 Hz, CH2, 2H), 2.60e2.57 (m, CH2,
1H), 2.56e2.50 (m, CH2, 1H), 2.47e2.41 (m, CH2, 1H), 2.33e2.25 (m,
CH, 2H), 6.64 (td, J¼7.8, 0.7 Hz, ]CH, 1H), 6.51 (d, J¼7.8 Hz, ]CH,
1H), 4.20e4.18 (m, CH, 1H), 3.67 (s, OCH3, 3H), 3.40e3.35 (m, CH2,

5624
H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
Table 2
The new 1,3-disubstituted indoles
Entry
1
Reagent
Product
Yield (%)
85
Ph
4d
R1¼H, R2¼Me
29d
NO2
N
O
2
3
4
4e
4h
4i
R1¼Me, R2¼Me
R1¼H, R2¼OMe
R1¼Me, R2¼OMe
29e
29h
29i
77
91
71
O
N
R1
R2
R2
R1
Ph
5
6
4l
R¼Ph
29l
88
82
NO2
N
N
4m
R¼furanyl
29m
NO2
R
NO2
R
Ph
NO2
N
N
7
4q
29q
93
O
O
N
N
O
Ph
O
Ph
1H), 3.35e3.31 (m, CH2, 1H), 2.95 (br t, J¼8.1 Hz, CH2, 2H), 2.64 (dd,
J¼14.5, 6.6 Hz, CH2, 1H), 2.41 (dd, J¼14.5, 8.1 Hz, CH2, 1H), 1.22 (d,
CH2, 2H); 13C NMR (100 MHz, CDCl3):
d 169.5, 144.3, 140.8 (]CH),
130.7, 128.1 (]CH), 125.7 (]CH), 122.4 (]CH), 108.5 (]CH), 90.0 (]
J¼6.6 Hz, CH3, 3H); 13C NMR (100 MHz, CDCl3):
d
172.7 (CO), 150.9,
CH), 51.0 (OCH3), 48.0 (CH2), 27.8 (CH2). Anal. Calcd for C12H13NO2: C,
130.3, 127.6 (]CH), 124.7 (]CH), 117.7 (]CH), 107.5 (]CH), 51.9
(OCH3), 48.3 (CH), 46.2 (CH2), 38.3 (CH2), 28.4 (CH2), 16.3 (CH3).
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.05;
H, 7.83; N, 6.30. IR (KBr, cmꢃ1) 3025, 2963, 2925, 2850, 1736, 1607,
1489, 1436, 1393, 1260, 1160, 1091, 1018, 799, 745.
70.92; H, 6.45; N, 6.89. Found: C, 70.53; H, 6.46; N, 6.95. IR (KBr, cmꢃ1
3052, 1687, 1633, 1505, 1426, 1310, 1265, 1166, 977, 791, 744.
)
4.2.8. Dimethyl 2-(indolin-1-yl)maleate (4k). Bi(NO3)3$5H2O cata-
lyzed reaction was performed at rt for 3 h in CH2Cl2. Dimethyl 2-
(indolin-1-yl)maleate was obtained as yellow crystals (222 mg,
85%, mp 134e135 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz,
4.2.7. (E)-Methyl 3-(indolin-1-yl)acrylate (4j). KF/Al2O3 catalyzed
reaction was performed at rt for 2 h in CH2Cl2. (E)-Methyl 3-(indolin-
1-yl) acrylate was obtained as yellow crystals (193 mg, 95%, mp
133e134 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
CDCl3):
d
7.17 (d, J¼8.1 Hz, ]CH, 1H), 7.09 (td, J¼8.1, 0.7 Hz, ]CH,
1H), 6.93 (br t, J¼8.1 Hz, ]CH,1H), 6.81 (d, J¼8.1 Hz, ]CH,1H), 5.03
(s, ]CH, 1H), 4.04 (s, OCH3, 3H), 3.86 (t, J¼8.4 Hz, CH2, 2H), 3.69 (s,
OCH3, 3H), 3.16 (t, J¼8.4 Hz, CH2, 2H); 13C NMR (100 MHz, CDCl3):
d
8.08 (d, J¼13.0 Hz, ]CH, 1H), 7.19e7.16 (m, ]CH, 2H), 6.97 (br d,
J¼7.5 Hz, ]CH,1H), 6.91 (t, J¼7.5 Hz, ]CH,1H), 4.87 (d, J¼13.0 Hz, ]
CH,1H), 3.78(t, J¼8.5 Hz,CH2, 2H), 3.73(s,OCH3, 3H), 3.21(t, J¼8.5 Hz,
d 167.8 (CO), 165.6 (CO), 147.4, 142.7, 132.4, 127.9 (]CH), 125.7 (]
CH), 123.1 (]CH), 111.5 (]CH), 91.6 (]CH), 53.3 (OCH3), 51.3
Ph
β
-nitro styrene
NO2
β
-nitro styrene
Zn(OTf)2
N
Ph
N
Zn(OTf)2
91%
N
N
NO2
CO 2Me
CO2Me
CO2Me
CO 2Me
25
5j
26 (E or Z)
4j
DDQ
87%
CH2Cl2
12 h
N
Ph
O
N
Ph
N
NO2
NO2
CO2Me
O
MeO
MeO
5jR
27 (E or Z)
4jR
Scheme 10.
Scheme 11.

H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
5625
87%, mp 129e130 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz,
CDCl3): 8.09e8.06 (m, ]CH, 2H), 7.75e7.71 (m, ]CH, 1H),
Ph
d
catalyst 28 (20 mol%)
*
7.69e7.65 (m, ]CH, 1H), 7.26 (br d, J¼6.6 Hz, ]CH, 1H), 7.19e7.18
(m, ]CH, 2H), 7.05e6.97 (m, ]CH, 1H), 6.70 (s, ]CH, 1H), 4.27 (t,
J¼8.0 Hz, CH2, 2H), 3.15 (t, J¼8.0 Hz, CH2, 2H); 13C NMR (100 MHz,
NO 2
Zn(OTf)2 (20 mol%)
β-nitro styrene
toluene, N2
OMe
N
O
N
O
CDCl3):
d 184.1, 183.1, 148.5, 144.0, 134.3, 134.1, 132.8, 132.7, 132.5,
OMe
127.4, 126.9, 125.8, 125.7, 123.6, 115.5, 112.3, 54.6, 29.3. Anal. Calcd
for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.35; H, 4.81; N,
5.09. IR (KBr, cmꢃ1) 2319, 2297, 1676, 1624, 1547, 1479, 1402, 1339,
1281, 1268, 749, 719.
5d
29h
O
O
N
N
4.2.12. (ꢁ)-3-(Indolin-1-yl)-1-phenylpyrrolidine-2,5-dione
(4q). Bi(NO3)3$5H2O catalyzed reaction was performed at rt for 2 h
in CH2Cl2. (ꢁ)-3-(Indolin-1-yl)-1-phenylpyrrolidine-2,5-dione was
obtained as pale yellow crystals (266 mg, 91%, mp 114e115 ꢂC) in
Ph
Ph
28
Scheme 12.
hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
d 7.51e7.39 (m, ]
CH, 3H), 7.32 (d, J¼8.1 Hz, ]CH, 2H), 7.14e7.07 (m, ]CH, 2H), 6.76
(t, J¼7.5 Hz, ]CH, 1H), 6.48 (d, J¼8.1 Hz, ]CH, 1H), 4.88e4.84 (m,
CH, 1H), 3.54e3.45 (m, CH2, 2H), 3.18 (dd, J¼18.4, 9.3 Hz, CH2, 1H),
3.07 (t, J¼8.2 Hz, CH2, 2H), 2.94 (dd, J¼18.4, 5.7 Hz, CH2, 1H); 13C
Table 3
Enantioselective Michael reaction of methyl 3-(1H-indol-1-yl) propanoate (5d) with
-nitro styrene (2l) catalyzed by the chiral catalyst (S,S)-2,20-isopropylidene-bis (4-
phenyl-2-oxazoline) (28)
NMR (100 MHz, CDCl3):
d 174.7, 173.8, 131.7, 130.5, 129.5, 129.2,
b
129.1, 127.7, 126.6, 125.3, 119.6, 107.6, 56.0, 50.0, 31.4, 28.6. Anal.
Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.87; H,
5.40; N, 9.45. IR (KBr, cmꢃ1) 3473, 3048, 2961, 2849, 1777, 1715,
1606, 1500, 1488, 1458, 1382, 1260, 1177, 1063, 1027, 827, 747, 698.
Entry
Time (h)
Temperature (ꢂC)
Yield (%)
ee (%)
1
2
3
12
24
24
25
ꢃ30
ꢃ70
90
88
85
27.6
19.6
15.6
4.3. 2-(Indolin-1-yl)ethene-1,1,2-tricarbonitrile (9)
To a solution of indoline (119 mg, 1.0 mmol) and TCNE (128 mg,
1.0 mmol) in CH2Cl2 (10 mL) was added Bi(NO3)3$5H2O (47 mg,
0.1 mmol). After the mixture was stirred at rt for 5 h, the solvent
was evaporated under vacuo. The crude product was dissolved with
EtOAc (40 mL) and the organic phase was washed with water
(2ꢀ20 mL). The EtOAc extract was dried over Na2SO4, filtered,
evaporated in vacuo, and the compound was purified by silica gel
column chromatography (hexane/ethyl acetate, 3:1). 2-(Indolin-1-
yl)ethene-1,1,2-tricarbonitrile (9) was obtained as pale green
crystals (209 mg, 95%, mp 143e144 ꢂC) in hexane/ethyl acetate; 1H
(OCH3), 51.3 (CH2), 27.4 (CH2). Anal. Calcd for C14H15NO4: C, 64.36;
H, 5.79; N, 5.33. Found: C, 64.22; H, 5.76; N, 5.26. IR (KBr, cmꢃ1
2952, 2852,1734,1684,1600,1575,1496,1436,1415,1389,130,1214,
1171, 974, 867, 793, 746.
)
4.2.9. (ꢁ)-1-(2-Nitro-1-phenylethyl)indoline (4l). Bi(NO3)3$5H2O
catalyzed reaction was performed at rt for 1 h in CH2Cl2. (ꢁ)-1-(2-
Nitro-1-phenylethyl)indoline was obtained as orange crystals
(255 mg, 95%, mp 125e126 ꢂC) in hexane/ethyl acetate; 1H NMR
(400 MHz, CDCl3):
d
7.38e7.32 (m, ]CH, 3H), 7.30e7.26 (m, ]CH,
NMR (400 MHz, CDCl3):
d
7.71 (d, J¼8.1 Hz, ]CH,1H), 7.38e7.26 (m,
2H), 7.11e7.04 (m, ]CH, 2H), 6.70e6.66 (m, ]CH, 2H), 5.62 (t,
J¼7.6 Hz, CH,1H), 5.01 (dd, J¼12.4, 7.6 Hz, CH2,1H), 4.92 (dd, J¼12.4,
7.6 Hz, CH2, 1H), 3.46e3.41 (m, CH2, 1H), 3.17e3.13 (m, CH2, 1H),
]CH, 3H), 4.51 (t, J¼7.5 Hz, CH2, 2H), 3.34 (t, J¼7.5 Hz, CH2, 2H); 13
C
NMR (100 MHz, CDCl3):
d 140.8, 133.7, 133.6 (2C), 128.7 (]CH),
128.2 (]CH), 126.4 (]CH), 115.5 (]CH), 113.3, 112.9, 110.5, 56.0
(CH2), 29.0 (CH2). Anal. Calcd for C13H8N4: C, 70.90; H, 3.66; N,
25.40. Found: C, 70.67; H, 3.44; N, 25.34. IR (KBr, cmꢃ1) 2922, 2852,
2217, 1550, 1463, 1407, 1329, 1264, 756, 523.
2.96e2.90 (m, CH2, 2H); 13C NMR (100 MHz, CDCl3):
d 150.1, 135.1,
129.8, 129.2 (]CH), 128.8 (]CH), 127.8 (]CH), 127.7 (]CH), 125.0
(]CH), 118.6 (]CH), 107.3 (]CH), 75.6 (CH), 57.7 (CH2), 47.5 (CH2),
28.4 (CH2). Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44.
Found: C, 71.46; H, 6.00; N, 10.47. IR (KBr, cmꢃ1) 3025, 2913, 2846,
2325, 1608, 1555, 1457, 1373, 1309, 1231, 1194, 1083, 742.
4.4. General procedure for the oxidation of Michael addition
products to indole derivatives with MnO2
4.2.10. 1-(2,2-Bis(phenylsulfonyl)ethyl)indoline
(4o). Bi(NO3)3$
To a solution of Michael addition product of indoline (1.0 mmol)
in CH2Cl2 (10 mL) was added activated MnO2 (10.0 mmol). The
mixture was stirred at rt for 24 h. After filtration, the mixture was
evaporated under vacuo and the compound was purified by silica
gel column chromatography (hexane/ethyl acetate).
5H2O catalyzed reaction was performed at rt for 10 h in CH2Cl2. 1-
(2,2-Bis(phenylsulfonyl)ethyl)indoline was obtained as white
crystals (419 mg, 98%, mp 122e123 ꢂC) in hexane/ethyl acetate; 1H
NMR (400 MHz, CDCl3):
d 7.95e7.93 (m, ]CH, 4H), 7.68 (m, ]CH,
2H), 7.50 (m, ]CH, 4H), 7.30e7.00 (m, ]CH, 2H), 6.69 (t, J¼8.0 Hz,
]CH, 1H), 6.39 (d, J¼8.0 Hz, ]CH, 1H), 4.82 (t, J¼6.2 Hz, CH, 1H),
3.95 (d, J¼6.2 Hz, CH2, 2H), 3.19 (t, J¼8.4 Hz, CH2, 2H), 2.71 (t,
4.5. General procedure for the oxidation of Michael addition
products to indole derivatives with DDQ
J¼8.4 Hz, CH2, 2H); 13C NMR (400 MHz, CDCl3):
d 150.6, 138.9, 134.7,
129.6, 129.5, 129.3, 127.6, 124.8, 119.0, 107.3, 82.0, 53.7, 47.7, 28.6.
Anal. Calcd for C22H21NO4S2: C, 61.80; H, 5.95; N, 3.28. Found: C,
61.65; H, 5.78; N, 3.18. IR (KBr, cmꢃ1) 3070, 2930, 2846, 2325, 2297,
1606, 1488, 1446, 1329, 1264, 1153, 1079, 744, 688.
The Michael addition product (1.0 mmol) and DDQ (1.0 mmol)
were dissolved in CH2Cl2 (10 mL). The mixture was stirred at rt for
24 h. After completion of the reaction, it was quenched with a sat-
urated aqueous solution of NaHCO3 (5%, 20 mL). CH2Cl2 layer was
separated and washed with water and brine solution and dried over
anhydrous Na2SO4 and filtered. The solvent was removed in vacuo
and then the compound was purified by silica gel column chro-
matography (hexane/ethyl acetate).
4.2.11. 2-(Indolin-1-yl)naphthalene-1,4-dione (4p). KF/Al2O3 cata-
lyzed reaction was performed at rt for 2 day in CH2Cl2. 2-(Indolin-1-
yl) naphthalene-1,4-dione was obtained as black crystals (240 mg,

5626
H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
4.5.1. (ꢁ)-3-(1H-Indol-1-yl)cyclopentanone (5a). (ꢁ)-3-(1H-Indol-
(400 MHz, CDCl3):
d
7.61 (ddd, J¼7.7, 1.7, 0.9 Hz, ]CH, 1H), 7.34 (dd,
1-yl)cyclopentanone was obtained as yellow oil (189 mg, 95%); 1H
J¼8.3, 0.9 Hz, ]CH, 1H), 7.31e7.20 (m, ]CH, 3H), 7.19e7.11 (m, ]
CH, 4H), 7.09e7.07 (m, ]CH, 1H), 6.55 (dd, J¼3.3, 0.7 Hz, ]CH, 1H),
6.15 (t, J¼7.2 Hz, CH, 1H), 3.46 (dd, J¼16.9, 7.2 Hz, CH2, 1H), 3.41 (dd,
J¼16.9, 7.2 Hz, CH2, 1H), 2.12 (s, CH3, 3H); 13C NMR (100 MHz,
NMR (400 MHz, CDCl3):
d
7.68 (d, J¼7.6 Hz, ]CH, 1H), 7.40 (d,
J¼7.6 Hz, ]CH, 1H), 7.28 (t, J¼7.6 Hz, ]CH, 1H), 7.26e7.16 (m, ]CH,
2H), 6.59 (d, J¼2.9 Hz, ]CH, 1H), 5.12e5.09 (m, CH, 1H), 2.87 (dd,
J¼18.5, 7.4 Hz, CH2,1H), 2.65 (dd, J¼18.5, 7.4 Hz, CH2,1H), 2.61e2.48
CDCl3):
d 205.0, 140.4, 136.2, 129.03 (]CH), 129.0, 128.1 (]CH),
(m, CH2, 4H); 13C NMR (100 MHz, CDCl3):
d
215.0, 136.2, 129.2,
126.5 (]CH), 125.4 (]CH),122.0 (]CH), 121.2 (]CH), 120.0 (]CH),
110.3 (]CH), 102.5 (]CH), 55.3 (CH), 48.9 (CH2), 30.7 (CH3). Anal.
Calcd for C18H17NO: C, 82.13; H, 6.51; N, 5.32. Found: C, 82.09; H,
6.43; N, 5.39. IR (KBr, cmꢃ1) 3048, 2913, 2302, 1715, 1459, 1307,
1013, 742.
123.8, 122.1, 121.5, 120.2, 109.7, 102.6, 53.3, 44.8, 37.4, 29.8. Anal.
Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.28; H,
6.51; N, 6.87. IR (KBr, cmꢃ1) 3472, 3104, 3052, 2968, 1744, 1611, 1511,
1479, 1462, 1404, 1373, 1313, 1244, 1222, 1175, 1151, 1085, 1014, 979,
888, 848, 744.
4.5.7. (ꢁ)-3-(1H-Indol-1-yl)-1,3-diphenylpropan-1-one (5g). (ꢁ)-3-
(1H-Indol-1-yl)-1,3-diphenylpropan-1-one was obtained as white
crystals (211 mg, 65%, mp 106e107 ꢂC) in hexane/ethyl acetate; 1H
4.5.2. (ꢁ)-3-(1H-Indol-1-yl)cyclohexanone (5b). (ꢁ)-3-(1H-Indol-
1-yl)cyclohexanone was obtained as yellow liquid (196 mg, 92%);
1H NMR (400 MHz, CDCl3):
d
7.65 (dd, J¼7.8, 2.0 Hz, ]CH, 1H), 7.35
NMR (400 MHz, CDCl3):
d
7.95e7.92 (m, ]CH, 2H), 7.61 (d, J¼7.5 Hz,
(d, J¼8.4 Hz, ]CH, 1H), 7.26e7.20 (m, ]CH, 2H), 7.16e7.12 (m, ]
CH, 1H), 6.57 (d, J¼2.9 Hz, ]CH, 1H), 4.72e4.66 (m, CH, 1H),
2.94e2.91 (m, CH2, 1H), 2.90e2.77 (m, CH2, 1H), 2.56e2.40 (m, CH2,
2H), 2.35e2.30 (m, CH2, 1H), 2.25e2.10 (m, CH2, 2H), 1.85e1.78 (m,
]CH, 1H), 7.56 (d, J¼7.5 Hz, ]CH, 1H), 7.47e7.37 (m, ]CH, 4H),
7.32e7.22 (m, ]CH, 5H), 7.17 (td, J¼7.5, 1.1 Hz, ]CH, 1H), 7.09 (t,
J¼7.5 Hz, ]CH, 1H), 6.53 (d, J¼3.3 Hz, ]CH, 1H), 6.41 (t, J¼7.0 Hz,
CH, 1H), 3.98 (d, J¼7.0 Hz, CH2, 2H); 13C NMR (100 MHz, CDCl3):
CH2, 1H); 13C NMR (100 MHz, CDCl3):
d
208.2, 135.7, 128.9, 124.0,
d 196.5, 140.6, 136.7, 133.7, 129.0 (2C), 128.6 (2C), 128.3, 128.0, 126.7,
122.0, 121.5, 120.1, 109.6, 102.6, 54.4, 48.4, 41.1, 31.6, 22.5. Anal.
Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.75; H,
7.40; N, 6.48. IR (KBr, cmꢃ1) 3048, 3051, 2950, 1713, 1511, 1476, 1461,
1414, 1310, 1216, 1187, 1014, 972, 884, 744.
125.6, 122.0, 121.2, 120.0, 110.4, 102.4, 55.4, 44.1. Anal. Calcd for
C23H19NO: C, 84.89; H, 5.89; N, 4.30. Found: C, 84.72; H, 5.89; N,
4.10. IR (KBr, cmꢃ1) 2923, 2852, 1685, 1594, 1459, 1306, 1197, 742.
4.5.8. Methyl 3-(1H-indol-1-yl)propanoate (5h). Methyl 3-(1H-
4.5.3. (ꢁ)-3-(1H-Indol-1-yl)cycloheptanone (5c). (ꢁ)-3-(1H-Indol-
Indol-1-yl)propanoate was obtained as pale green liquid (195 mg.
1-yl)cycloheptanone was obtained as pale yellow liquid (220 mg,
96%); 1H NMR (400 MHz, CDCl3):
d
7.66 (d, J¼7.7 Hz, ]CH, 1H), 7.37
97%); 1H NMR (400 MHz, d6-DMSO):
d
7.55e7.50 (m, ]CH, 2H),
(d, J¼8.4 Hz, ]CH, 1H), 7.25 (t, J¼7.7 Hz, ]CH, 1H), 7.16e7.13 (m, ]
CH, 2H), 6.52 (d, J¼3.3 Hz, ]CH,1H), 4.47 (t, J¼7.0 Hz, CH2, 2H), 3.69
(s, OCH3, 3H), 2.85 (t, J¼7.0 Hz, CH2, 2H); 13C NMR (100 MHz,
7.43 (d, J¼2.9 Hz, ]CH, 1H), 7.11 (d, J¼7.4 Hz, ]CH, 1H), 7.00 (d,
J¼7.4 Hz, ]CH, 1H), 6.43 (d, J¼2.9 Hz, ]CH, 1H), 4.78 (br t,
J¼11.2 Hz, CH, 1H), 3.36e3.29 (m, CH2, 1H), 2.68e2.67 (m, CH2, 1H),
2.64e2.48 (m, CH2, 2H), 2.13e2.01 (m, CH2, 2H), 1.95e1.89 (m, CH2,
CDCl3):
d 171.9, 135.9, 129.0, 128.2, 121.9, 121.3, 119.8, 109.3, 101.9,
52.2, 42.0, 35.0. Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.90; H, 6.40; N, 6.98. IR (KBr, cmꢃ1) 2951, 2925, 1737,
1513, 1484, 1464, 1437, 1368, 1315, 1262, 1208, 1171, 1062, 1014, 988,
841, 764, 743.
2H), 1.73e1.61 (m, CH2, 2H); 13C NMR (100 MHz, DMSO-d6):
d 211.1,
135.5, 128.7, 125.8, 121.7, 121.2, 119.8, 110.6, 102.1, 52.7, 50.9, 44.2,
37.9, 27.5, 23.9. Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16.
Found: C, 79.30; H, 7.40; N, 6.44. IR (KBr, cmꢃ1) 2932, 1701, 1609,
1461, 1411, 1305, 1213, 742.
4.5.9. (ꢁ)-Methyl 3-(1H-indol-1-yl)butanoate (5i). (ꢁ)-Methyl 3-
(1H-Indol-1-yl)butanoate was obtained as pale yellow liquid
1
4.5.4. 4-(1H-Indol-1-yl)butan-2-one (5d). 4-(1H-Indol-1-yl)butan-
(206 mg, 95%); H NMR (400 MHz, CDCl3):
d
7.67 (td, J¼7.9, 1.0 Hz,
2-one was obtained as pale green liquid (181 mg, 97%); 1H NMR
]CH, 1H), 7.47 (br d, J¼8.0 Hz, ]CH, 1H), 7.29e7.26 (m, ]CH, 1H),
7.22 (d, J¼3.3, ]CH, 1H), 7.18e7.14 (m, ]CH, 1H), 6.58 (br d,
J¼3.3 Hz, ]CH, 1H), 5.11e5.03 (m, CH, 1H), 3.64 (s, OCH3, 3H), 2.95
(dd, J¼15.5, 6.6 Hz, CH2, 1H), 2.80 (dd, J¼15.5, 7.6 Hz, CH2, 1H), 1.64
(400 MHz, CDCl3):
d
7.62 (d, J¼8.2 Hz, ]CH, 1H), 7.33 (d, J¼8.2 Hz,
]CH,1H), 7.25e7.19 (m, ]CH,1H), 7.13e7.08 (m, ]CH, 2H), 6.47 (d,
J¼2.8 Hz, ]CH, 1H), 4.42 (t, J¼6.4 Hz, CH2, 2H), 2.94 (t, J¼6.4 Hz,
CH2, 2H), 2.10 (s, CH3, 3H); 13C NMR (400 MHz, CDCl3):
d
206.4,
(d, J¼6.8 Hz, CH3, 3H); 13C NMR (100 MHz, CDCl3):
d 171.4, 135.8,
135.9, 128.9, 128.3, 121.8, 121.3, 119.7, 109.2, 101.7, 43.7, 40.8, 30.6.
Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.75;
H, 7.01; N, 7.38. IR (KBr, cmꢃ1) 3053, 2908, 2319, 1715, 1464, 1357,
1314, 1164, 743.
128.9, 124.2 (]CH), 121.8 (]CH), 121.3 (]CH), 119.8 (]CH), 109.8
(]CH), 102.4 (]CH), 52.1 (OCH3), 48.6 (CH), 41.9 (CH2), 21.0 (CH3).
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.69; N, 6.45. Found: C, 71.72;
H, 6.74; N, 6.56. IR (KBr, cmꢃ1) 3053, 2969, 2951, 1736, 1608, 1460,
1410, 1365, 1307, 1217, 1194, 1172, 1088, 1013, 739.
4.5.5. (ꢁ)-4-(1H-Indol-1-yl)pentan-2-one (5e). (ꢁ)-4-(1H-Indol-1-
yl)pentan-2-one was obtained as pale green liquid (184 mg, 97%);
4.5.10. (E)-Methyl 3-(1H-indol-1-yl)acrylate (5j). (E)-Methyl 3-(1H-
Indol-1-yl)acrylate was obtained as white crystals (195 mg, 97%,
mp 80e81 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d
7.63 (d, J¼7.4 Hz, ]CH, 1H), 7.42 (d,
J¼7.4 Hz, ]CH, 1H), 7.22 (br t, J¼7.4 Hz, ]CH, 1H), 7.18 (d, J¼3.3 Hz,
]CH, 1H), 7.11 (br d, J¼7.4 Hz, ]CH, 1H), 6.53 (d, J¼3.3 Hz, ]CH,
1H), 5.08e5.03 (m, CH, 1H), 3.04 (dd, J¼16.9, 5.5 Hz, CH2, 1H), 2.90
(dd, J¼16.9, 5.5 Hz, CH2, 1H), 2.07 (s, CH3, 3H),1.57 (d, J¼6.6 Hz, CH3,
d
8.29 (d, J¼13.9 Hz, ]CH, 1H), 7.62e7.58 (m, ]CH, 2H), 7.38 (d,
J¼3.5 Hz, ]CH, 1H), 7.34 (td, J¼7.5, 1.0 Hz, ]CH, 1H), 7.23 (td, J¼7.5,
1.0 Hz, ]CH, 1H), 6.73 (d, J¼3.5 Hz, ]CH, 1H), 5.95 (d, J¼13.9 Hz, ]
3H); 13C NMR (100 MHz, CDCl3):
d
206.1, 135.6, 128.9, 124.4, 121.8,
CH,1H), 3.82 (s, OCH3, 3H); 13C NMR (100 MHz, CDCl3):
d 168.1 (CO),
121.3, 119.8, 109.8, 102.2, 50.6, 47.6, 30.8, 21.1. Anal. Calcd for
C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.47; H, 7.57; N, 6.97.
IR (KBr, cmꢃ1) 3048, 2976, 2928, 1716, 1611, 1510, 1477, 1461, 1412,
1364, 1308, 1219, 1164, 764, 742.
137.6 (]CH), 136.4, 130.1, 124.2 (]CH), 123.8 (]CH), 122.7 (]CH),
121.7 (]CH), 110.3 (]CH), 109.1 (]CH), 100.4 (]CH), 51.8 (OCH3).
Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.53;
H, 5.31; N, 6.87. IR (KBr, cmꢃ1) 3053, 2969, 2951, 1736, 1608, 1460,
1410, 1365, 1307, 1217, 1194, 1172, 1088, 1013, 739.
4.5.6. (ꢁ)-4-(1H-Indol-1-yl)-4-phenylbutan-2-one (5f). (ꢁ)-4-(1H-
Indol-1-yl)-4-phenylbutan-2-one was obtained as white crystals
(228 mg, 87%, mp 103e104 ꢂC) in hexane/ethyl acetate; 1H NMR
4.5.11. Dimethyl 2-(1H-indol-1-yl)maleate (5k). Dimethyl 2-(1H-
Indol-1-yl)maleate was obtained as pale yellow oil (220 mg, 85%);

H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
5627
1H NMR (400 MHz, CDCl3):
d
7.62 (d, J¼7.1 Hz, ]CH, 1H), 7.57 (dd,
51%, mp 173e174 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz,
CDCl3): 8.22e8.20 (m, ]CH, 1H), 8.17e8.15 (m, ]CH, 1H),
J¼8.3, 0.8 Hz, ]CH, 1H), 7.29 (dd, J¼8.3, 1.5 Hz, ]CH, 1H), 7.23 (d,
J¼7.1 Hz, ]CH, 1H), 7.15 (d, J¼3.7 Hz, ]CH, 1H), 6.69 (dd, J¼3.7,
0.8 Hz, ]CH,1H), 6.25 (s, ]CH,1H), 4.01 (s, OCH3, 3H), 3.81 (s, OCH3,
d
7.84e7.80 (m, ]CH, 2H), 7.65 (br d, J¼7.7 Hz, ]CH, 1H), 7.60 (br d,
J¼8.4 Hz, ]CH, 1H), 7.54 (br d, J¼3.7 Hz, ]CH, 1H), 7.31e7.28 (m, ]
CH, 1H), 7.26e7.21 (m, ]CH, 1H), 7.19 (s, ]CH, 1H), 6.75 (d,
3H);13C NMR(100 MHz, CDCl3):
d166.0 (CO),164.7 (CO),143.7,135.6,
130.9, 126.4 (]CH), 124.2 (]CH), 122.7 (]CH), 122.0 (]CH), 112.3
(]CH), 108.0 (]CH), 107.1 (]CH), 53.6 (OCH3), 52.2 (OCH3). Anal.
Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.63; H,
5.01; N, 5.29. IR (KBr, cmꢃ1) 2952, 2846, 1745, 1717, 1625, 1537, 1458,
1436, 1374, 1292, 1258, 1197, 1166, 1025, 980, 869, 764, 743.
J¼3.7 Hz, ]CH, 1H); 13C NMR (100 MHz, CDCl3):
d 184.7, 181.6,
143.1,135.9,134.7,134.1,132.0,131.9,130.8,129.4, 127.5,126.4,126.0,
123.7, 122.6, 121.8, 112.4, 107.2. Anal. Calcd for C18H11NO2: C, 79.11;
H, 4.06; N, 5.13. Found: C, 79.04; H, 3.95; N, 5.11. IR (KBr, cmꢃ1
)
2924, 1670, 1655, 1593, 1526, 1452, 1365, 1286, 1200, 996, 905, 761,
743, 713.
4.5.12. (ꢁ)-1-(2-Nitro-1-phenylethyl)-1H-indole
(5l). (ꢁ)-1-(2-
Nitro-1-phenylethyl)-1H-indole was obtained as white crystals
(253 mg, 95%, mp 97e98 ꢂC) in hexane/methylene chloride; 1H
4.5.17. (ꢁ)-3-(1H-Indol-1-yl)-1-phenylpyrrolidine-2,5-dione
(5q). (ꢁ)-3-(1H-Indol-1-yl)-1-phenylpyrrolidine-2,5-dione
was
NMR (400 MHz, CDCl3):
d
7.63 (dd, J¼6.9, 0.9 Hz, ]CH, 1H),
obtained as yellow crystals (270 mg, 93%, mp 130e131 ꢂC) in hex-
7.38e7.34 (m, ]CH, 4H), 7.23e7.15 (m, ]CH, 4H), 7.13 (dd, J¼6.9,
0.9 Hz, ]CH, 1H), 6.61 (d, J¼3.3 Hz, ]CH, 1H), 6.44 (dd, J¼9.0,
6.1 Hz, CH, 1H), 5.23 (dd, J¼13.3, 9.0 Hz, CH2, 1H), 5.15 (dd, J¼13.3,
ane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
d
7.68 (br d, J¼7.7 Hz,
]CH, 1H), 7.54e7.51 (m, ]CH, 2H), 7.49e7.43 (m, ]CH, 2H),
7.27e7.16 (m, ]CH, 4H), 7.12 (br d, J¼3.3 Hz, ]CH, 1H), 6.63 (br d,
J¼4.1 Hz, ]CH, 1H), 5.57 (t, J¼4.1 Hz, CH, 1H), 3.51 (dd, J¼18.6,
9.3 Hz, CH2, 1H), 3.15 (dd, J¼18.6, 5.8 Hz, CH2, 1H); 13C NMR
6.1 Hz, CH2, 1H); 13C NMR (100 MHz, CDCl3):
d 136.2, 135.9, 129.6
(]CH), 129.3 (]CH), 129.1, 126.7 (]CH), 124.6 (]CH), 122.6 (]
CH), 121.5 (]CH), 120.6 (]CH), 109.7 (]CH), 103.9 (]CH), 77.4
(CH), 57.3 (CH2). Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N,
10.52. Found: C, 72.08; H, 5.30; N, 10.40. IR (KBr, cmꢃ1) 3025, 2913,
2846, 2325, 1608, 1555, 1457, 1373, 1309, 1231, 1194, 1083, 742.
(100 MHz, CDCl3):
d 172.6, 172.5, 135.4, 131.4, 129.4, 129.3, 129.2,
126.3, 125.9, 122.7, 121.8, 120.6, 108.9, 104.0, 54.7, 35.8. Anal. Calcd
for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.30; H, 4.80;
N, 9.44. IR (KBr, cmꢃ1) 3437, 3448, 2961, 2848, 1777, 1715, 1606,
1500, 1488, 1382, 1260, 1177, 827, 748, 699, 627.
4.5.13. (ꢁ)-1-(1-(Furan-2-yl)-2-nitroethyl)-1H-indole (5m). (ꢁ)-1-
(1-(Furan-2-yl)-2-nitroethyl)-1H-indole was obtained as blue oil
4.6. 2,3-Di(1H-indol-1-yl)naphthalene-1,4-dione (6)
(238 mg, 93%); 1H NMR (400 MHz, CDCl3):
d
7.63 (d, J¼7.3 Hz, ]CH,
1H), 7.45e7.42 (m, ]CH, 2H), 7.26e7.24 (m, ]CH, 1H), 7.17e7.13
(m, ]CH, 2H), 6.58 (d, J¼3.3 Hz¼CH, 1H), 6.44 (t, J¼7.5 Hz, CH, 1H),
6.38 (dd, J¼3.3, 1.8 Hz, ]CH, 1H), 6.33 (d, J¼3.3 Hz, ]CH, 1H), 5.18
(dd, J¼13.4, 7.5 Hz, CH2, 1H), 5.10 (dd, J¼13.4, 7.5 Hz, CH2, 1H); 13C
To
a
solution of 2-(1H-indol-1-yl)naphthalene-1,4-dione
(273 mg, 1.0 mmol) and indoline (119 mg, 1.0 mmol) in CH2Cl2
(10 mL) was added DMAP (122 mg, 0.1 mmol). After the mixture
was refluxed at 80 ꢂC for 12 h, the reaction mixture was cooled to rt.
Then, to a solution of the reaction mixture in CH2Cl2 (10 mL) was
added activated MnO2 (870 mg, 10.0 mmol). The mixture was stir-
red at rt for 12 h. After the filtration, the mixture was evaporated
under vacuo and the crude product was purified by silica gel col-
umn chromatography (hexane/ethyl acetate, 9:1). The product 6
was obtained as brown crystals (54 mg, 14%, mp 222e223 ꢂC) in
NMR (400 MHz, CDCl3):
d 148.3, 143.7, 135.8, 129.1, 125.3, 122.7,
121.6, 120.7, 111.1, 109.6, 109.3, 104.1, 76.0, 51.8. Anal. Calcd for
C14H12N2O3: C, 65.62; H, 4.72; N, 10.93. Found: C, 65.85; H, 4.66; N,
10.72. IR (KBr, cmꢃ1) 3053, 2913, 1646, 1556, 1458, 1373, 1307, 1236,
1194, 1146, 1014, 742.
4.5.14. (ꢁ)-1-(2-Nitro-1-(thiophen-2-yl)ethyl)-1H-indole (5n). (ꢁ)-
1-(2-Nitro-1-(thiophen-2-yl)ethyl)-1H-indole was obtained as red
hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
d 8.29 (m, 2H),
7.87 (m, 2H), 7.40 (d, J¼7.7 Hz, ]CH, 2H), 7.00 (td, J¼8.1, 1.5 Hz, ]
oil (258 mg, 94%); 1H NMR (400 MHz, CDCl3):
d
7.63 (dd, J¼7.0,
CH, 2H), 6.93e6.86 (m, ]CH, 6H), 6.50 (d, J¼3.3 Hz, ]CH, 2H); 13C
0.8 Hz, ]CH, 1H), 7.41 (br d, J¼8.4 Hz, ]CH, 1H), 7.31e7.30 (m, ]
CH, 1H), 7.25e7.22 (m, ]CH, 1H), 7.17e7.13 (m, ]CH, 2H),
7.03e6.98 (m, ]CH, 2H), 6.64 (t, J¼7.5 Hz, CH, 1H), 6.60 (d,
J¼3.3 Hz, ]CH, 1H), 5.25e5.14 (m, CH2, 2H); 13C NMR (400 MHz,
NMR (100 MHz, CDCl3): d 180.9, 135.6, 135.2, 134.8 (]CH), 131.5,
129.3, 128.1 (]CH), 127.4 (]CH), 122.9 (]CH), 121.6 (]CH), 121.1
(]CH), 111.4 (]CH), 107.0 (]CH). Anal. Calcd for C26H16N2O2: C,
80.40; H, 4.15; N, 7.21. Found: C, 80.37; H, 4.12; N, 7.11. IR (KBr,
cmꢃ1) 3420, 1672, 1598, 1571, 1451, 1396, 1344, 1270, 1218, 1116,
1102, 1069, 999, 743, 714.
CDCl3):
d 138.6, 135.9, 129.2, 127.5, 126.8, 126.2, 124.7, 122.8, 121.7,
120.8, 109.5, 104.3, 77.8, 53.5. Anal. Calcd for C14H12N2O2S: C, 61.75;
H, 4.44; N, 10.29. Found: C, 62.01; H, 4.40; N, 10.44. IR (KBr, cmꢃ1
)
3025, 2913, 2846, 2325, 1608, 1555, 1457, 1373, 1309, 1231, 1194,
1083, 743.
4.7. 2-(1H-Indol-1-yl)cyclohexa-2,5-diene-1,4-dione (7)
To a solution of indoline (200 mg, 1.7 mmol) and p-benzoqui-
none (724 mg, 6.7 mmol) in CH3CN (10 mL) was added
Bi(NO3)3$5H2O (47 mg, 0.1 mmol). After the mixture was stirred at
100 ꢂC for 2 days, the reaction mixture was cooled to rt and the
solvent was removed under vacuo. Then the crude product was
dissolved with EtOAc (50 mL) and the activated MnO2 (1.46 g,
16.8 mmol) was added to the solution. The mixture was stirred at rt
for 12 h. After the filtration, the solvent was evaporated under
vacuo and the crude product was purified by silica gel column
chromatography (hexane/ethyl acetate, 20:1). 2-(1H-Indol-1-yl)
cyclohexa-2,5-diene-1,4-dione (7) was obtained as brown crystals
(60 mg, 27%, mp 115e116 ꢂC) in hexane/ethyl acetate; 1H NMR
4.5.15. 1-(2,2-Bis(phenylsulfonyl)ethyl)-1H-indole
(5o). 1-(2,2-
Bis(phenylsulfonyl)ethyl)-1H-indole was obtained as white crys-
tals (417 mg, 98%, mp 150e151 ꢂC) in hexane/ethyl acetate; 1H NMR
(400 MHz, CDCl3):
d 7.79e7.93 (m, ]CH, 4H), 7.64e7.57 (m, ]CH,
2H), 7.56 (d, J¼0.8 Hz, ]CH, 1H), 7.49e7.45 (m, ]CH, 4H),
7.24e7.09 (m, ]CH, 4H), 6.43 (d, J¼2.6 Hz, ]CH, 1H), 5.07 (d,
J¼5.1 Hz, CH2, 2H), 4.69 (t, J¼5.1 Hz, CH, 1H); 13C NMR (400 MHz,
CDCl3):
d 138.1, 135.5, 135.0, 129.5, 129.4, 129.3, 129.2, 122.5, 121.5,
120.5, 109.2, 102.9, 82.7, 42.7. Anal. Calcd for C22H19NO4S2: C, 62.10;
H, 4.50; N, 3.29. Found: C, 62.08; H, 4.74; N, 3.26. IR (KBr, cmꢃ1
)
3062, 2924, 1580, 1513, 1448, 1401, 1332, 1156, 1079, 998, 815, 736,
686, 620.
(400 MHz, CDCl3):
d
7.64 (d, J¼8.1 Hz, ]CH, 1H), 7.55 (d, J¼8.4 Hz,
]CH,1H), 7.42 (d, J¼3.5, ]CH,1H), 7.31e7.21 (m, ]CH, 2H), 6.98 (d,
4.5.16. 2-(1H-Indol-1-yl)naphthalene-1,4-dione (5 p). 2-(1H-Indol-
1-yl)naphthalene-1,4-dione was obtained as red crystals (139 mg,
J¼1.8, ]CH,1H), 6.83e6.86 (m, ]CH, 2H), 6.73 (dd, J¼3.5, 0.7 Hz, ]
CH, 1H); 13C NMR (100 MHz, CDCl3):
d 187.1, 183.4, 141.3, 136.9 (]

5628
H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
CH), 135.9 (]CH), 135.7, 130.8, 129.0 (]CH), 123.8 (]CH), 123.3 (]
CH), 122.7 (]CH), 121.9 (]CH), 112.2 (]CH), 107.5 (]CH). Anal.
Calcd for C14H9NO2: C, 75.33; H, 4.06; N, 6.27. Found: C, 75.24; H,
4.20; N, 6.30. IR (KBr, cmꢃ1) 3149, 3098, 3048, 2919, 2852, 1660,
1593, 1454, 1288, 1231, 1088, 895, 750.
4.11. (1H-Indol-1-yl)(phenyl)methanone (15)
To a solution of (E)- and (Z)-1-(2-nitro-1-phenylvinyl)-1H-indole
(14) (169 mg, 0.6 mmol) in CH2Cl2 (10 mL) was added MnO2 (577 mg,
6.4 mmol) and H2O (1e2 drop). The mixture was stirred at rt for 2 h
and the product 15 was obtained as a pale yellow crystals (mp
58e59 ꢂC) in hexane/ethyl acetate (210 mg, 95%); 1H NMR (400 MHz,
4.8. Methyl 6-oxo-2,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-
4-carboxylate (11)
CDCl3):
d
8.41 (br d, J¼7.6 Hz, ]CH, 1H), 7.75e7.73 (m, ]CH, 2H),
7.63e7.59 (m, ]CH, 2H), 7.55e7.51 (m, ]CH, 2H), 7.39 (t, J¼7.6 Hz, ]
CH, 1H), 7.34e7.25 (m, ]CH, 2H), 6.62 (d, J¼3.7 Hz, ]CH, 1H); 13C
Procedure A: Polyphosphoric acid (18.4 g) was added to dimethyl
2-(indolin-1-yl)maleate (801 mg, 3.1 mmol) and the mixture was
stirred and maintained at 90 ꢂC for 1 h. The resulting dark blue tar
was cooled to 0 ꢂC. After ice water (25 mL) was added, the dark blue
solid was dissolved with ethyl acetate (100 mL). The organic phase
was washed with NaHCO3 solution (5%, 2ꢀ50 mL) and water
(50 mL). The organic phase was dried with NaSO4 and the solvent
was evaporated. The product 11 was obtained as white crystals (mp
226e227 ꢂC) in methanol (180 mg, 26%). Procedure B: Eaton’s re-
agent (5 mL) was added to dimethyl 2-(indolin-1-yl)maleate
(499 mg, 1.9 mmol) and the mixture was stirred at 50 ꢂC for 5 h.
Then ice water (25 mL) was added to the resulting mixture. The
yellow solution was extracted with EtOAc (80 mL) and the organic
phase was washed with NaHCO3 solution (5%, 2ꢀ40 mL) and water
(40 mL). After the ethyl acetate phase was dried with Na2SO4, the
solvent was evaporated. The product 11 was obtained as white
crystals in methanol (395 mg, 90%); 1H NMR (400 MHz, CDCl3):
NMR (100 MHz, CDCl3): d 168.9, 136.3, 134.9, 132.1, 131.0, 129.4, 128.8,
127.8, 125.1, 124.1, 121.1, 116.6, 108.8. Anal. Calcd for C15H11NO: C,
81.43; H, 5.01; N, 6.33. Found: C, 81.30; H, 4.92; N, 6.44. IR (KBr, cmꢃ1
2917, 2849, 1731, 1684, 1450, 1376, 1337, 1178, 1055, 937, 884, 749.
)
4.12. General procedure for reaction of indoline and trans-
nitro styrene with asymmetric catalysts (22e24)
b-
To a flask were added asymmetric catalyst (22e24) (0.1 mmol)
in toluene (2 mL) and the trans- -nitro styrene (1.0 mmol). The
b
mixture was stirred at room temperature for 30 min and indoline
(1.0 mmol) was added. The mixture was stirred until the starting
material disappeared (TLC, hexane/ethyl acetate, 20:1). After
evaporation of the solvent, the crude product was extracted with
EtOAc (2ꢀ20 mL). The EtOAc extracts were dried over Na2SO4, fil-
tered, evaporated in vacuo, and the compound was purified 1-(2-
nitro-1-phenylethyl)indoline as orange crystals by silica gel col-
umn chromatography (hexane/ethyl acetate, 20:1).
d
7.96 (dd, J¼8.2, 1.1 Hz, ]CH, 1H), 7.46 (dd, J¼7.2, 1.1 Hz, ]CH, 1H),
7.28 (dd, J¼8.2, 7.2 Hz, ]CH, 1H), 6.99 (s, ]CH, 1H), 4.83 (t,
J¼7.8 Hz, CH2, 2H), 3.96 (s, CH3, 3H), 3.49 (t, J¼7.3 Hz, CH2, 2H); 13
C
4.13. General procedure for synthesis of 1,3-disubstituted
indole derivatives with Zn(OTf)2
NMR (100 MHz, CDCl3): d 178.7 (CO), 163.2 (CO), 145.5, 137.0, 133.4,
127.2 (]CH), 125.4 (]CH), 125.0, 122.4 (]CH), 115.2 (]CH), 53.4
(OCH3), 52.9 (CH2), 28.3 (CH2). Anal. Calcd for C13H11NO3: C, 68.11;
H, 4.84; N, 6.11. Found: C, 68.05; H, 4.76; N, 6.02. IR (KBr, cmꢃ1
)
To a solution of Michael addition product of indoline (1.0 mmol)
and Michael acceptor (1.0 mmol) in CH2Cl2 (10 mL) was added
Zn(OTf)2 (37 mg, 0.1 mmol). The mixture was stirred until the
starting material disappeared (TLC, hexane/ethyl acetate). After
evaporation of the solvent, the crude product was extracted with
EtOAc (2ꢀ20 mL). The EtOAc extracts were dried over Na2SO4, fil-
tered, evaporated in vacuo, and the compound was purified by
silica gel column chromatography (hexane/ethyl acetate).
3529, 3468, 3020, 2941, 1732, 1622, 1582, 1514, 1449, 1278, 1256,
775.
4.9. Methyl 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-4-
carboxylate (12)
To a solution of methyl 6-oxo-2,6-dihydro-1H-pyrrolo[3,2,1-ij]
quinoline-4-carboxylate (229 mg, 1.0 mmol) in CH2Cl2 (10 mL) was
added activated MnO2 (870 mg, 10.0 mmol). The mixture was stir-
red at rt for 12 h, the product 12 was obtained as pale green crystals
(mp 115e116 ꢂC) in hexane/ethyl acetate (209 mg, 92%); 1H NMR
4.13.1. (ꢁ)-4-(3-(2-Nitro-1-phenylethyl)-1H-indol-1-yl)butan-2-one
(29d). The reaction was performed at rt for 12 h. (ꢁ)-4-(3-(2-Nitro-
1-phenylethyl)-1H-indol-1-yl)butan-2-one was obtained as brown
crystals (286 mg, 85%, mp 92e93 ꢂC) in hexane/ethyl acetate; 1H
(400 MHz, CDCl3):
d
8.39 (d, J¼3.7 Hz, ]CH, 1H), 8.16 (d, J¼7.5 Hz,
NMR (400 MHz, CDCl3):
d
7.44 (br d, J¼7.6 Hz, ]CH, 1H), 7.34e7.20
]CH, 1H), 7.97 (d, J¼7.5 Hz, ]CH, 1H), 7.56 (t, J¼7.5 Hz, ]CH, 1H),
7.15 (s, ]CH, 1H), 6.89 (d, J¼3.7 Hz, ]CH, 1H), 4.04 (s, OCH3, 3H);
(m, ]CH, 7H), 7.07 (t, J¼7.6 Hz, ]CH, 1H), 6.99 (s, ]CH, 1H), 5.16 (t,
J¼8.1 Hz, CH, 1H), 5.04 (dd, J¼12.4, 7.6 Hz, A part of AB system, CH2,
1H), 4.93 (dd, J¼12.4, 7.6 Hz, B part of AB system, CH2, 1H), 4.37 (t,
13C NMR (100 MHz, CDCl3):
d 180.9 (CO), 162.8 (CO), 135.7, 134.9,
J¼6.6 Hz, CH2, 2H), 2.92 (t, J¼6.6 Hz, CH2, 2H), 2.11 (s, CH3, 3H); 13
C
130.1, 128.2 (]CH), 127.9 (]CH), 125.5 (]CH), 123.2, 122.7 (]CH),
120.0 (]CH), 110.4 (]CH), 53.7 (OCH3). Anal. Calcd for C13H9NO3:
C, 68.72; H, 3.99; N, 6.16. Found: C, 68.45; H, 3.73; N, 6.04. IR (KBr,
cmꢃ1) 3165, 3120, 2997, 2947, 2852, 2297, 1732, 1635, 1524, 1441,
1378, 1264, 1240, 1137, 822, 772, 741.
NMR (100 MHz, CDCl3):
d 206.4, 139.5, 136.4, 129.1, 128.0, 127.7,
127.1, 125.9, 122.6, 119.9, 119.5, 113.4, 109.6, 79.8, 43.5, 41.7, 40.8,
30.6. Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C,
71.38; H, 5.80; N, 8.20. IR (KBr, cmꢃ1) 2919, 1716, 1551, 1469, 1454,
1432, 1377, 1165, 745, 702.
4.10. Oxidation of ( )-1-(2-nitro-1-phenylvinyl)-1H-indole
(4l) with MnO2
4.13.2. Diastereomeric mixture of 4-(3-(2-nitro-1-phenylethyl)-1H-
indol-1-yl)pentan-2-one (29e). The reaction was performed at rt for
24 h. A diastereomeric mixture of 4-(3-(2-nitro-1-phenylethyl)-1H-
indol-1-yl)pentan-2-one was obtained as orange crystals in hex-
ane/ethyl acetate (270 mg, 77%, mixture of diastereomers AþB, A/B
ratio¼5.6:4.4, determined by 1H NMR); 1H NMR (400 MHz, CDCl3):
7.44e7.38 (m, ]CH, 2H), 7.34e7.26 (m, ]CH, 3H), 7.24e7.19 (m, ]
CH, 3H), 7.08e7.02 (m, ]CH, 1H), 6.98 (s, ]CH, 1H), 5.20e5.15 (m,
CH, 1H), 5.08e4.90 (m, CH, 3H), 3.03e2.96 (m, A part of AB system,
CH2, 1H), 2.88 (dd, J¼17.0, 7.8 Hz, B part of AB system, CH2, 1H), 2.07
To
a
solution of (ꢁ)-1-(2-nitro-1-phenylethyl)indoline
(1.0 mmol, 268 mg) in CH2Cl2 (10 mL) was added activated MnO2
(870 mg, 10.0 mmol). The mixture was stirred at rt for 12 h. The
solvent was removed in vacuo and then the compound was purified
by silica gel column chromatography (hexane/ethyl acetate, 20:1).
Compound 14 was obtained as a mixture of stereo isomers (169 mg,
64%), the product 15 was obtained as a yellow crystals in hexane/
ethyl acetate (69 mg, 31% yield).

H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
5629
(s, CH3, 3H), 2.06 (s, CH3, 3H), 1.56 (d, J¼4.4 Hz, CH3, 3H); 13C NMR
(400 MHz, CDCl3):
d
7.46 (m, ]CH, 1H), 7.40e7.32 (m, ]CH, 2H),
(100 MHz, CDCl3):
d
205.9, 139.5, 136.2, 129.2, 128.0, 127.8, 127.0,
7.31e7.27 (m, ]CH, 2H), 7.26e7.22 (m, ]CH, 5H), 7.09 (t, J¼7.5 Hz, ]
CH,1H), 7.00 (s, ]CH,1H), 6.41e6.37 (m, ]CH, 2H), 6.31 (m,¼CH,1H),
5.19e5.00 (m, CH2, 3H), 4.99e4.88 (m, CH2, 1H); 13C NMR (100 MHz,
122.5, 122.1, 121.8, 120.0, 119.9, 119.4, 113.8, 110.2, 79.9, 79.8, 50.4,
47.8, 41.9, 30.8, 21.1 (Note: diastereoisomeric mixture 29e must
consist in total 38 carbon signals. But 16 carbon signals for 29e are
coincident.). Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99.
Found: C, 71.84; H, 6.32; N, 7.89. IR (KBr, cmꢃ1) 3422, 3055, 2854,
1717, 1612, 1554, 1463, 1432, 1378, 1314, 1266, 1164, 909, 739, 702.
CDCl3):
d 147.9, 143.9, 143.8, 138.9, 136.4, 129.2, 128.0, 127.9, 127.4,
123.5, 122.9, 122.7, 120.9, 119.9, 119.8, 115.8, 115.7, 111.2, 109.8, 109.7,
79.7, 76.0, 75.8, 52.1, 52.0, 41.7 (Note: diastereoisomeric mixture 29m
must consist in total 40 carbon signals. But 14 carbon signals for 29m
are coincident.). Anal. Calcd for C22H19N3O5: C, 69.18; H, 4.72; N,10.37.
Found: C, 69.12; H, 4.66; N, 10.15. IR (KBr, cmꢃ1) 3030, 2958, 2923,
1554, 1499, 1461, 1431, 1378, 1189, 1015, 742, 702.
4.13.3. (ꢁ)-Methyl
propanoate (29h). The reaction was performed at rt for 10 h. Methyl
3-(3-(2-nitro-1-phenylethyl)-1H-indol-1-yl)propanoate was
obtained as brown crystals (321 mg, 91%, mp 100e101 ꢂC) in hex-
ane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
3-(3-(2-nitro-1-phenylethyl)-1H-indol-1-yl)
4.13.7. Diastereomeric mixture of 3-(3-(2-nitro-1-phenylethyl)-1H-
indol-1-yl)-1-phenylpyrrolidine-2,5-dione (29q). The reaction was
performed at rt for 12 h. A diastereomeric mixture of 3-(3-(2-nitro-
1-phenylethyl)-1H-indol-1-yl)-1-phenylpyrrolidine-2,5-dione was
obtained as pale yellow crystals in hexane/ethyl acetate (409 mg,
93%, mixture of diastereomers AþB, A/B ratio was not determined
d
7.44 (br d, J¼8.0 Hz,
]CH,1H), 7.35e7.21 (m, ]CH, 7H), 7.08 (t, J¼8.0 Hz, ]CH,1H), 6.97
(s, ]CH,1H), 5.17 (t, J¼8.1 Hz, CH,1H), 5.04 (dd, J¼12.4, 7.7 Hz, A part
of AB system, CH2, 1H), 4.93 (dd, J¼12.4, 7.7 Hz, B part of AB system,
CH2, 1H), 4.42 (t, J¼6.8 Hz, CH2, 2H), 3.66 (s, OCH3, 3H), 2.80 (t,
J¼6.8 Hz, CH2, 2H); 13C NMR (100 MHz, CDCl3):
d
171.8, 139.5, 136.5,
by 1H NMR); 1H NMR (400 MHz, CDCl3):
d 7.54e7.43 (m, ]CH, 4H),
129.1, 128.0, 127.7, 127.1, 125.7, 122.7, 120.0, 119.5, 113.7, 109.6, 79.7,
52.1, 42.1, 41.7, 35.0. Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N,
7.95. Found:C, 68.09;H, 5.77; N, 7.88. IR (KBr, cmꢃ1)3028, 2951,1735,
1551, 1469, 1454, 1436, 1378, 1334, 1204, 1173, 744, 702.
7.39e7.33 (m, ]CH, 5H), 7.30e7.24 (m, ]CH, 3H), 7.18e7.11 (m, ]
CH, 2H), 6.95 (m, ]CH, 1H), 5.52e5.47 (m, CH, 1H), 5.20e5.16 (m,
CH,1H), 5.04e5.01 (m, A part of AB system, CH2, 1H), 4.94 (m, B part
of AB system, CH2, 1H), 3.45 (m, A part of AB system, CH2, 1H), 3.13
(m, B part of AB system, CH2, 1H); 13C NMR (100 MHz, CDCl3):
4.13.4. Diastereomeric mixture of methyl 3-(3-(2-nitro-1-
phenylethyl)-1H-indol-1-yl)butanoate (29i). The reaction was per-
formed at rt for 12 h. A diastereomeric mixture of methyl 3-(3-(2-
nitro-1-phenylethyl)-1H-indol-1-yl)propanoate was obtained as
brown crystals in hexane/ethyl acetate (260 mg, 71%, mixture of
diastereomers AþB, A/B ratio¼5.6:4.4, determined by 1H NMR); 1H
d 172.7, 172.4, 138.9, 138.8, 136.3, 136.2, 131.5, 129.6, 129.4, 129.3,
128.0, 127.8, 126.5, 124.0, 123.8, 123.7, 121.0, 120.2, 115.8, 109.5,
109.4, 79.6, 55.1, 41.7, 35.9, 35.8 (Note: diastereoisomeric mixture
29q must consist in total 44 carbon signals. But 18 carbon signals
for 29q are coincident.). Anal. Calcd for C26H21N3O4: C, 71.06; H,
4.82; N, 9.56. Found: C, 70.86; H, 4.70; N, 10.03. IR (KBr, cmꢃ1) 3499,
3056, 2956, 2926, 2856, 2305, 1791, 1724, 1598, 1554, 1499, 1463,
1378, 1265, 1182, 1080, 910, 742, 702.
NMR (400 MHz, CDCl3):
d
7.44 (br d, J¼8.0 Hz, ]CH, 1H), 7.35e7.21
(m, ]CH, 7H), 7.08 (t, J¼8.0 Hz, ]CH, 1H), 6.97 (s, ]CH, 1H), 5.17 (t,
J¼8.1 Hz, CH, 1H), 5.04 (dd, J¼12.4, 7.7 Hz, A part of AB system, CH2,
1H), 4.93 (dd, J¼12.4, 7.7 Hz, B part of AB system, CH2, 1H), 4.42 (t,
J¼6.8 Hz, CH2, 2H), 3.66 (s, OCH3, 3H), 2.80 (t, J¼6.8 Hz, CH2, 2H);
4.14. ( )-(Z)- or (E)-Methyl 2-(indolin-1-ylmethylene)-4-nitro-
3-phenylbutanoate (26)
13C NMR (100 MHz, CDCl3):
d 171.8, 139.5, 136.5, 129.1, 128.0, 127.7,
127.1, 125.7, 122.7, 120.0, 119.5, 113.7, 109.6, 79.7, 52.1, 42.1, 41.7, 35.0
(Note: diastereoisomeric mixture 29i must consist in total 38 car-
bon signals. But 20 carbon signals for 29i are coincident.). Anal.
Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.09; H,
5.77; N, 7.88. IR (KBr, cmꢃ1) 3028, 2951,1735, 1551, 1469, 1454,1436,
1378, 1334, 1204, 1173, 744, 702.
To a solution of (E)-methyl 3-(indolin-1-yl)acrylate (203 mg,
1.0 mmol) and b-nitro styrene (149 mg,1.0 mmol,) in CH2Cl2 (10 mL)
was added Zn(OTf)2 (37 mg, 0.1 mmol). The mixture was stirred at rt
for 12 h, the product 26 was obtained as orange crystals (321 mg,
91%, mp 134e135 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz,
CDCl3): d 8.15 (s, ]CH,1H), 7.35e7.31 (m, ]CH, 4H), 7.29e7.18 (m, ]
CH, 3H), 6.99e6.95 (m, ]CH, 2H), 5.39e5.33 (m, CH, 1H), 5.18e5.11
(m, CH2, 2H), 4.37 (dd, J¼17.5, 9.0 Hz, CH2, 1H), 4.18 (dd, J¼17.5,
4.13.5. Diastereomeric mixture of 1,3-bis(2-nitro-1-phenylethyl)-1H-
indole (29l). The reaction was performed at rt for 12 h. A di-
astereomeric mixture of 1,3-bis(2-nitro-1-phenylethyl)-1H-indole
was obtained as yellow crystals in hexane/ethyl acetate (366 mg,
88%, mixture of diastereomers AþB, A/B ratio was not determined
9.0 Hz, CH2, 1H), 3.69 (s, OCH3, 3H), 3.25 (t, J¼9.0 Hz, CH2, 2H); 13
C
NMR (100 MHz, CDCl3):
d 169.1, 146.2, 140.7, 140.4, 129.8, 128.9,
128.2,127.3,127.2,125.6,123.2,109.9, 99.9, 79.0, 51.5, 50.5, 40.6, 29.1.
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.06;
H, 5.95; N, 7.88. IR (KBr, cmꢃ1) 2957, 2925, 2854, 1686, 1620, 1590,
1548, 1488, 1435, 1380, 1348, 1291, 1256, 1187, 1107, 749, 699.
by 1H NMR); 1H NMR (400 MHz, CDCl3):
d 7.41e7.24 (m, ]CH, 9H),
7.21e7.15 (m, ]CH, 3H), 7.10e7.05 (m, ]CH, 2H), 7.04 (s, ]CH, 1H),
6.37 (t, J¼7.7 Hz, CH, 1H), 5.23e5.12 (m, CH, 3H), 5.06e5.01 (m, A
part of AB system, CH2, 1H), 4.96e4.91 (m, B part of AB system, CH2,
4.15. ( )-(Z)- or (E)-Methyl 2-(indolin-1-ylmethylene)-4-nitro-
3-phenylbutanoate (27)
1H); 13C NMR (100 MHz, CDCl3):
d
138.9, 136.9, 135.5, 129.7, 129.4,
129.3, 129.2, 127.9, 127.3, 126.5, 123.4, 122.5, 120.9, 119.8, 115.5,
110.2, 79.8, 79.7, 77.3, 57.6, 57.5, 41.8 (Note: diastereoisomeric
mixture 29l must consist in total 40 carbon signals. But 18 carbon
signals for 29l are coincident.). Anal. Calcd for C24H21N3O4: C, 69.39;
To a solution of (ꢁ)-(Z)- or (E)-methyl 2-(indolin-1-ylmethylene)-
4-nitro-3-phenylbutanoate (352 mg, 1.0 mmol) in CH2Cl2 (10 mL)
was added DDQ (870 mg,1.0 mmol). The mixture was stirred at rt for
12 h, the product 27 was obtained as white crystals (305 mg, 87%, mp
141e142 ꢂC) in hexane/ethyl acetate; 1H NMR (400 MHz, CDCl3):
H, 5.10; N, 10.11. Found: C, 69.31; H, 5.14; N, 9.98. IR (KBr, cmꢃ1
)
2958, 2918, 2871, 1552, 1494, 1461, 1433, 1378, 1262, 1185, 745, 702.
d
8.44 (s, ]CH, 1H), 7.63 (d, J¼7.8 Hz, ]CH, 1H), 7.50 (d, J¼7.8 Hz, ]
4.13.6. Diastereomeric mixture of 1-(1-(furan-2-yl)-2-nitroethyl)-3-
(2-nitro-1-phenylethyl)-1H-indole (29m). The reaction was per-
formed atrt for 12 h. Adiastereomeric mixtureof1-(1-(furan-2-yl)-2-
nitroethyl)-3-(2-nitro-1-phenylethyl)-1H-indole was obtained as
black crystals in hexane/ethyl acetate (332 mg, 82%, mixture of di-
astereomers AþB, A/B ratiowas not determined by 1H NMR); 1H NMR
CH, 1H), 7.37e7.25 (m, ]CH, 8H), 6.71 (d, J¼3.5 Hz, ]CH, 1H), 5.36
(dd, J¼12.5, 7.2 Hz, CH2, 1H), 5.27 (t, J¼7.2 Hz, CH, 1H), 5.12 (dd,
J¼12.5, 7.2 Hz, CH2, 1H), 3.84 (s, OCH3, 3H); 13C NMR (100 MHz,
CDCl3):
d 169.1, 146.2, 140.4, 136.7, 129.8, 129.4, 128.1, 127.7, 126.2,
124.0, 122.8, 121.6, 110.5, 108.5, 100.0, 78.3, 52.4, 41.9. Anal. Calcd for
C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.42; H, 5.02; N,

5630
H. Kilic et al. / Tetrahedron 68 (2012) 5619e5630
7.82. IR (KBr, cmꢃ1) 2956, 2925, 2854, 1710, 1632, 1555, 1461, 1377,
1265, 909, 740, 705.
References and notes
1. Sundberg, R. J. Indoles; Academic: London, 1996.
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nitro styrene with Zn(OTf)2 and (S)-Ph-bisoxazoline (28) at
different temperatures
To a dried flask were added Zn(OTf)2 (74 mg, 0.2 mmol) and (S)-
Ph-bisoxazoline (66 mg, 0.2 mmol) under N2 atmosphere, followed
by addition of the toluene (5 mL). The solution was stirred at room
temperature (or ꢃ30 ꢂC or ꢃ70 ꢂC) for 1 h under N2 atmosphere,
and the trans-b-nitro styrene (149 mg, 1.0 mmol) was added. The
mixture was stirred for 10 min before the methyl 3-(1H-indol-1-yl)
propanoate (203 mg, 1.0 mmol) was added. The mixture was stirred
until the starting material disappeared (TLC, hexane/ethyl acetate,
20:1). After evaporation of the solvent, the crude product was
extracted with EtOAc (2ꢀ20 mL). The EtOAc extracts were dried
over Na2SO4, filtered, evaporated in vacuo, and the compound was
purified methyl 3-(3-(2-nitro-1-phenylethyl)-1H-indol-1-yl)prop-
anoate (29h) as brown crystals by silica gel column chromatogra-
phy (hexane/ethyl acetate, 20:1).
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Acknowledgements
We are greatly indebted to The Scientific and Technical Research
Council of Turkey (TUBITAK, Grant no. TBAG-108T433) for their fi-
nancial support for this study.
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Supplementary data
Supplementary data includes some experimental details and 1H
and 13C NMR spectra of compounds. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2012.04.066.