An efficient and mild synthesis of tetrahydro-4 h -indol-4-one derivatives via a domino reaction in water

Article abstract of DOI:10.1055/s-0033-1338526

An efficient domino approach for the synthesis of tetrahydro-4H-indol-4-one derivatives has been established. The use of catalytic amount of l-proline in water at 60 °C makes it quite simple, more convenient, and environmentally benign. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338526

PAPER
▌3007
paper
An Efficient and Mild Synthesis of Tetrahydro-4H-indol-4-one Derivatives via
a Domino Reaction in Water
Synthesis of Tetrahydro-4H-indol-4-one Derivatives
Furen Zhang, Chunmei Li, Chenze Qi*
School of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process,
Shaoxing University, Shaoxing, Zhejiang Province 312000, P. R. of China
Fax +86(575)88345862; E-mail: qichenze@usx.edu.cn
Received: 01.07.2013; Accepted after revision: 12.08.2013
multiple C–C bond formations are achieved in a single op-
Abstract: An efficient domino approach for the synthesis of tetra-
eration using simple experimental procedures, have
hydro-4H-indol-4-one derivatives has been established. The use of
served as a powerful tool for the efficient assembly of
catalytic amount of L-proline in water at 60 °C makes it quite sim-
complex structures with minimized waste production. Re-
cently, L-proline and its derivatives have been used in
domino cyclizations.15 In view of the above perceptions,
the development of a benign and organocatalytic domino
cyclization process for the synthesis of tetrahydroindole
derivatives is desirable.
ple, more convenient, and environmentally benign.
Key words: tetrahydro-4H-indol-4-one, amines, cyclization, domi-
no reaction, catalysis
There is continuing interest in the development of im-
proved methods for the synthesis of indole and its deriva-
tives owing to their importance as ‘privileged
pharmacological structures’ in natural bioactive products
and marketed drugs. As a result, many powerful method-
ologies for the synthesis of these compounds have been
developed,1 the majority of them involve Fischer-type in-
dole synthesis,2 reductive cyclization,1j,r metal-catalyzed
coupling/condensation cascades,3 and electrophilic acti-
vation of N-aryl amides.4 Recently, the utility of enamines
in metal catalysis or under microwave irradiation for the
formation of valuable indoles has also been reported.5 In
spite of a large number of methods reported for the syn-
thesis of indole derivatives, there remains considerable
demand to explore more convenient, practical, and benign
reagents for their synthesis, especially for tetrahydroin-
doles that display a wide spectrum of biological activity
and are important intermediates in the synthesis of highly
functionalized indoles.3d Therefore, the development of
concise approaches to indole and its derivatives by sim-
ple, convenient, and practical procedures and from inex-
pensive starting materials is of great importance and a
challenging endeavor.
Nitroolefins are building blocks for generating molecules
of biological and pharmaceutical relevance.16 Several
groups have reported the base-dependent chemoselective
reactions of cyclohexane-1,3-dione (1a) and nitroolefins
2, and for the generation of bicyclic oximes 3,17 nitro com-
pound 4,18c or hydrobenzofuran 5 or 618 (Scheme 1). In ad-
dition, Arai et al. also reported synthesis of 4-
oxohydroindoles 7 from 4-oxohydrobenzofuran with ex-
cessive benzylamine at 130 °C.18c
O
O
R1
NO2
KOAc
R1
R2
R
2 = Me
O
O
2
1a
6
amine base
2 = H
BnNH2
(3 equiv)
R2 = alkyl
NaOEt
R2 = H
130 °C
O
R
KOt-Bu
KF
R1
O
O
R1
R1
O
R1
NO2
R2
NOH
N
Ph
O
O
O
Recently, organocatalysis has become a major, intensive-
ly active field in chemical synthesis due to its environ-
mental friendliness.6 Particularly, L-proline, as a readily
available commercial catalyst, has received much atten-
tion due to its dual role as a ligand and a catalyst.7 Accord-
ingly, the wide application range of L-proline and its
derivatives has been described though various organic
transformations with excellent yields, such as enamine-
based direct asymmetric aldol,8 Mannich,9 Michael,10
Diels–Alder,11 α-amination,12 and Knoevenagel-type re-
actions,13 as well as unsymmetric Biginelli reactions.14 In
addition, organocatalytic domino cyclizations, where
3
4
5
7
Scheme 1 The reported reaction pathways between cyclohexane-
1,3-dione and nitroalkenes
NO2
O
O
R1
R1
R2
R4
L-proline (10 mol%)
H2O, 60 °C
R4
R2
O
R4
R3 NH2
N
R3
R4
1
8
9
Scheme 2 Synthesis of tetrahydro-4H-indol-4-ones
SYNTHESIS 2013, 45, 3007–3017
Advanced online publication: 05.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338526; Art ID: SS-2013-H0447-OP
© Georg Thieme Verlag Stuttgart · New York

3008
F. Zhang et al.
PAPER
In continuation of our efforts to develop new methods for
the synthesis of useful heterocyclic blocks from common
starting materials,19 herein, we wish to report a domino
multicyclization reaction for the synthesis of new tetra-
hydro-4H-indol-4-one derivatives using L-proline as the
catalyst in water (Scheme 2). Desired aromatic or aliphat-
ic substituents can be introduced to 1- and 3-positions of
the indole skeleton through this domino reaction. To the
best of our knowledge, this convenient procedure for the
efficient synthesis of tetrahydro-4H-indol-4-one deriva-
tives using L-proline as the catalyst in water has not been
previously reported in the literature.
Table 1 Optimization of Reaction Conditions for the Synthesis of
9ca
Cl
NO2
O
O
NH2
catalyst
solvent, 12 h
N
O
Cl
1c
8c
2c
9c
Entry
Solvent
Catalyst (mol%)
T (°C)
Yieldb (%)
We initially evaluated the domino reaction of 5,5-dimeth-
ylcyclohexane-1,3-dione (1c), nitroolefin 2c, which was
derived from the reaction of nitroethane with 4-chloro-
1
EtOH
toluene
EtOH
CH2Cl2
THF
DMF
toluene
i-PrOH
MeOH
H2O
–
60
–
benzaldehyde, and aniline 8c. The reaction mixture, 2c
–
130
60
trace
49
11
31
25
25
85
88
87
69
40
46
10
21
29
53
25
88
62
33
86
85
29
18
–
which was composed of a 1:1:1 mixture of 1c, 2c, and 8c,
was tested under various conditions; the results are pre-
sented in Table 1.
3
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
DL-alanine (10)
DMAP (10)
Et3N (10)
4
reflux
60
The optimization process revealed that none of the desired
product was detected under catalyst-free conditions (Ta-
ble 1, entry 1) and only a trace amount of product was ob-
served, even at an enhanced temperature of 130 °C in
toluene for 36 hours (entry 2). Interestingly, when the re-
action was conducted in the presence of L-proline (10
mol%) as an abundant and inexpensive catalyst in ethanol,
the desired product was obtained in 49% yield (entry 3).
To improve the yield, the effect of the solvent was first
studied and the results indicate that under the catalysis of
L-proline (10 mol%) and heating at 60 °C for 12 hours in
water, the desired product 9c was isolated in 87% yield
(entry 10). Similar results were observed when the solvent
was changed to methanol and isopropyl alcohol (entries 8
and 9). However, poor yields were obtained when the re-
action was carried out in non-protonic solvents, such as
dichloromethane, N,N-dimethylformamide, tetrahydrofu-
ran, and toluene. Then, the efficacies of several other or-
ganic and inorganic catalysts were examined for the
reaction (entries 11–18); in all cases, 10 mol% of the cat-
alyst was used and the reaction was carried out in water at
60 °C. L-Proline provided a superior catalytic effect to DL-
alanine, 4-(dimethylamino)pyridine, triethylamine, pyrro-
lidine, N-methylmorpholine, pyridine, acetic acid, and po-
tassium carbonate (entries 10–18), indicating that the
presence of both secondary nitrogen and carboxylic acid
group may be essential for better catalytic activity. Next,
the effect of catalyst loading on the reaction was evaluated
and the results revealed that increasing the amount of L-
proline from 1 to 10 mol% led to an increase in the yield
from 33% to 87% (entries 20, 21, and 10), but a further in-
crease to 20% did not improve the yield significantly (en-
try 19). Finally, a strong dependence of the domino
reaction on the temperature was observed. Upon varying
the temperature of the reaction from 50 °C to room tem-
perature, the yield also decline significantly (entries 24–
26). When the temperature ranges from 40 to 50 °C, the
reaction gave only poor yields of product 9c, even after
longer reaction times. Instead, the intermediate 10, of
5
6
60
7
60
8
60
9
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
25c
26
60
H2O
60
H2O
60
H2O
60
H2O
pyrrolidine (10)
NMM (10)
60
H2O
60
H2O
pyridine (10)
K2CO3 (10)
AcOH
60
H2O
60
H2O
60
H2O
L-proline (20)
L-proline (5)
L-proline (1)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
60
H2O
60
H2O
60
H2O
80
H2O
reflux
50
H2O
H2O
40
H2O
r.t.
a Reaction conditions: 1c (0.5 mmol), 2c (0.5 mmol), 8c (0.5 mmol),
solvent (3 mL), 12 h.
b Isolated yields.
c Reaction time: 36 h.
Synthesis 2013, 45, 3007–3017
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydro-4H-indol-4-one Derivatives
3009
structure D (entries 24, 25 and Scheme 3), was observed aromatic systems, such as 1-nitro-2-thienylethene and 1-
in quantitative yield. When the reaction was performed in furyl-2-nitroethene (entries 8 and 9).
water at room temperature, no desired product was found.
To further expand the scope of the amine substrates, we
employed different nitroolefins and 5,5-dimethylcyclo-
hexane-1,3-dione (1c) as model substrates and examined
various amines, including aniline, 4-chloroaniline, 2-
chloroaniline, o-toluidine, 2,4-dimethylaniline, 1-naph-
thylamine, cyclopropylamine cyclohexanamine, benzyl-
Instead, only hydrobenzofuran of the structure 6 was ob-
tained. Additionally, it is noteworthy that when the R2
substituent was H group, only bicyclic oxime 3 was ob-
tained at room temperature. Moreover, the yield leveled
off when the temperature was further increased to 80 and
100 °C (entries 22 and 23). Extensive screening showed
amine, and pentan-1-amine. In all these cases, the
that the optimal conditions involved the following param-
reactions proceeded smoothly to give the appropriate ex-
eters: 10 mol% L-proline as catalyst, and water as solvent,
pected products in good to excellent yields.
with the reaction temperature at 60 °C.
Finally, with a broad scope of nitroolefins and amines ex-
amined, our attention turned to using other ketones, such
as cyclohexane-1,3-dione (1a) and pentane-2,4-dione
(1b). When cyclohexane-1,3-dione (1a) was used under
With optimal conditions established, we then examined
the scope of the reaction for the construction of various
tetrahydro-4H-indol-4-ones (Table 2). Initially, to test the
scope of the nitroolefins, 5,5-dimethylcyclohexane-1,3-
the optimized conditions, the reactions could be carried
dione (1c) and aniline 8c were used as model substrates,
out smoothly to give the desired products with high yields
(entries 25–39). Surprisingly, open-chain pentane-2,4-di-
one (1b) does not lead to the desired products by this pro-
cedure even after longer reaction times and higher
and the results indicate that a wide range of substituted
groups of nitroolefins all gave the desired products in
good to excellent yields, which include chloro, bromo,
fluoro, nitro, methoxy, or methyl groups. In addition, no
temperatures.
noticeable electronic effects were observed. It should be
noted that good results were also obtained by using other
Table 2 Synthesis of 9 in Watera
O
R1
O
NO2
R2
R4
R2
NH2
R3
L-proline (10 mol%)
H2O, 60 °C
R4
R1
N
R3
O
R4
R4
1
2
8
9
Entry
9
R1
R2
R3
R4
Time (h)
Yieldb (%)
Mp (°C)
1
9a
4-O2NC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
12
10
12
10
8
67
83
87
75
83
89
86
88
80
76
81
83
86
79
75
83
86
106–108
119–120
113–115
95–97
2
9b
9c
9d
9e
9f
3
4
5
140–142
92–94
6
4-MeOC6H4
4-MeC6H4
2-thienyl
2-furyl
8
7
9g
9h
9i
10
10
10
12
12
12
12
12
12
12
12
118–120
107–109
149–150
184–186
169–171
118–120
125–127
136–138
113–115
96–98
8
9
10
11
12
13
14
15
16
17
9j
4-FC6H4
4-ClC6H4
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
9k
9l
9m
9n
9o
9p
9q
4-MeOC6H4
4-MeC6H4
4-FC6H4
Ph
4-MeOC6H4
109–111
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3007–3017

3010
F. Zhang et al.
PAPER
Table 2 Synthesis of 9 in Watera (continued)
O
R1
O
NO2
R4
R2
NH2
R3
L-proline (10 mol%)
H2O, 60 °C
R4
R1
R2
N
R3
O
R4
R4
1
2
8
9
Entry
9
R1
R2
R3
R4
Time (h)
Yieldb (%)
Mp (°C)
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
9r
4-MeC6H4
Me
Me
Me
Me
Me
Me
H
2-MeC6H4
2,4-Me2C6H3
2-MeOC6H4
1-naphthyl
cyclopropyl
cyclopropyl
Ph
Me
Me
Me
Me
Me
Me
Me
H
12
12
12
12
12
12
12
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
12
12
12
82
86
86
75
76
83
85
90
83
92
92
70
79
85
81
78
84
91
84
87
92
77
83
87
85
121–123
110–112
106–108
165–167
148–149
141–142
oil
9s
Ph
9t
Ph
9u
4-ClC6H4
9v
Ph
9w
9x
4-MeOC6H4
Ph
9y
4-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
124–126
110–111
123–124
138–139
143–145
99–101
106–108
164–165
140–141
98–100
122–124
134–136
128–130
107–109
127–129
oil
9z
Ph
Ph
H
9aa
9bb
9cc
9dd
9ee
9ff
4-MeC6H4
Ph
H
2-thienyl
Ph
H
2-furyl
Ph
H
Ph
2-ClC6H4
2-ClC6H4
4-ClC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2,4-Me2C6H3
2,4-Me2C6H3
2-MeOC6H4
1-naphthyl
Cy
H
4-MeOC6H4
H
Ph
H
9gg
9hh
9ii
4-ClC6H4
H
Ph
H
4-MeOC6H4
H
9jj
4-O2NC6H4
H
9kk
9ll
Ph
Ph
Ph
Ph
Ph
Ph
H
H
9mm
9nn
9oo
9pp
H
Me
Me
Me
Bn
156–158
oil
(CH2)4Me
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 8 (0.5 mmol), L-proline (10 mol%), H2O (3 mL), 60 °C.
b Isolated yields.
According to reported literatures,20 a plausible mecha- posed mechanism, intermediate of type A (R3 = Ph, R4 =
nism for the domino cyclization was proposed (Scheme Me) was separately prepared from 5,5-dimethylcyclohex-
3). An initial condensation generated enaminones A, ane-1,3-dione and aniline and when a two-component
which further undergoes in situ a conjugate addition of the coupling reaction of enaminones (intermediate A) and ni-
nitroolefin 2 to give intermediate B. Intermediate B un- troolefin 1c was performed under the same reaction con-
dergoes imine–enamine tautomerization to give radical ditions, the target product 9c was obtained with a yield
intermediate C or D. Finally, intramolecular cyclization similar to that of the one-pot reaction. Additionally, inter-
followed by elimination of H2O and HNO from the inter- mediate 10, of type D, was separated and indentified by
mediate E afford the desired product 9. To test the pro- various spectral data.
Synthesis 2013, 45, 3007–3017
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydro-4H-indol-4-one Derivatives
3011
O
R1
OH
NO2
R2
O
O
O
R1
OH
N
O
N
O
R1
R4
H+
NH2
R3
R4
2
H+
R4
R4
R2
R4
R2
– H2O
NH
R3
O
NH
R3
R4
NH
R3
R4
R4
C
1
8
A
B
O
R1
O
R1
O
R1
NO2
R2
H
R2
– HNO
– H2O
R4
R4
OH
R4
R2
N
NH
R3
N
N
R3
R4
R4
OH
R4
R3
9
D
E
Scheme 3 Proposed mechanism
Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N, 7.48. Found: C,
73.46; H, 5.81; N, 7.61.
In conclusion, we have developed an L-proline-catalyzed
procedure for the facile synthesis of a variety of potential-
ly biologically active tetrahydro-4H-indol-4-ones based
on a novel domino reaction. The ready accessibility of
starting materials and the broad compatibility of nitroole-
fins and amines make these reactions highly valuable for
organic and biomedical fields. The continuing work on
this project will be focused on the development of asym-
metric versions of these reactions.
3-(4-Fluorophenyl)-2,6,6-trimethyl-1-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9b)
Yellow solid; yield: 144.3 mg (83%); mp 119–120 °C.
IR (KBr): 2945, 1645, 1591, 1491, 1485, 1067, 976, 833, 691 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.51 (m, 4 H, HAr), 7.43–
7.39 (m, 2 H, HAr), 7.30 (s, 1 H, HAr), 7.07 (t, J = 8.8 Hz, 2 H, HAr),
2.45 (s, 2 H, CH2), 2.38 (s, 2 H, CH2), 1.99 (s, 3 H, CH3), 1.09 (s, 6
H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.1, 160.4, 142.9, 137.2, 131.9,
131.8, 130.5, 129.6, 128.8, 128.5, 127.8, 119.4, 116.4, 114.5, 114.3,
53.1, 37.0, 35.2, 28.5, 11.0.
All reagents were commercial products without further purification,
unless otherwise stated. Analytical TLC was performed using
Merck silica gel GF254 plates. Flash column chromatography was
performed on silica gel (200–300 mesh). Melting points were mea-
sured on an X-4 melting point apparatus. IR spectra were recorded
with a Nicolet Nexus 670 FT-IR spectrophotometer. 1H NMR spec-
tra were recorded on a 400 MHz instrument (Bruker Avance 400
Spectrometer) relative to TMS as the internal reference. 13C NMR
spectra were recorded at 100 MHz with the internal chloroform sig-
nal at δ = 77.0 as a standard. Elemental analysis was carried out on
EuroEA elemental analyzer. ESI-MS was determined by using the
LCQ Fleet HPLC/MS instrument (Thermo Finnigan). HRMS (ESI)
was measured with a Bruker Daltonics APEXII instrument.
MS (ESI): m/z (%) = 348.25 (100) [M + H]+.
Anal. Calcd for C23H22FNO: C, 79.51; H, 6.38; N, 4.03. Found: C,
79.28; H, 6.49; N, 3.89.
3-(4-Chlorophenyl)-2,6,6-trimethyl-1-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9c)
Yellow solid; yield: 158.2 mg (87%); mp 113–115 °C.
IR (KBr): 2958, 1657, 1591, 1497, 1475, 1061, 995, 802, 721 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.50 (m, 4 H, HAr), 7.40–
7.33 (m, 5 H, HAr), 2.44 (s, 2 H, CH2), 2.38 (s, 2 H, CH2), 2.00 (s, 3
H, CH3), 1.09 (s, 6 H, CH3).
Tetrahydro-4H-indol-4-ones 9; General Procedure
In a 10-mL reaction vial, nitroolefin 2 (0.5 mmol), 1,3-dione 1 (0.5
mmol), amine 8 (0.5 mmol), L-proline (10 mol%), and H2O (3.0
mL) were mixed and then capped. The mixture was stirred for the
given time (Table 2) at 60 °C. Upon completion (TLC monitoring),
the mixture was cooled to r.t. and extracted with EtOAc (3 × 5 mL).
The resulting residue was purified by column chromatography (sil-
ica gel, EtOAc–petroleum ether, 1:20–1:5) to give the pure product.
13C NMR (100 MHz, CDCl3): δ = 193.2, 143.2, 137.1, 133.1, 132.0,
131.7, 129.6, 128.8, 128.7, 127.8, 127.7, 119.2, 116.3, 53.1, 37.0,
35.2, 28.5, 11.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H23ClNO: 364.1463;
found: 364.1458.
3-(4-Bromophenyl)-2,6,6-trimethyl-1-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9d)
Yellow solid; yield: 153.1 mg (75%); mp 95–97 °C.
IR (KBr): 2955, 1651, 1597, 1456, 1431, 1057, 996, 852, 728 cm–1.
2,6,6-Trimethyl-3-(4-nitrophenyl)-1-phenyl-1,5,6,7-tetrahydro-
4H-indol-4-one (9a)
Yellow solid; yield: 125.6 mg (67%); mp 106–108 °C.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.47 (m, 7 H, HAr), 7.32 (d,
J = 8.0 Hz, 2 H, HAr), 2.44 (s, 2 H, CH2), 2.38 (s, 2 H, CH2), 1.99 (s,
3 H, CH3), 1.09 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.2, 143.2, 137.1, 133.6, 132.1,
130.7, 129.7, 128.9, 128.7, 127.8, 120.2, 119.2, 116.2, 53.1, 37.0,
35.2, 28.5, 11.1.
IR (KBr): 2955, 1644, 1590, 1499, 1482, 1451, 1439, 1419, 1066,
1042, 955, 831, 752 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.27–8.20 (m, 4 H, HAr), 7.76 (d,
J = 8.8 Hz, 1 H, HAr), 7.62–7.56 (m, 4 H, HAr), 2.46 (s, 2 H, CH2),
2.41 (s, 2 H, CH2), 2.04 (s, 3 H, CH3), 1.10 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.3, 148.2, 143.9, 142.0, 136.7,
131.0, 129.8, 129.1, 127.7, 127.6, 124.0, 122.9, 116.2, 53.0, 37.0,
35.3, 28.5, 11.3.
MS (ESI): m/z (%) = 408.19 (100) [M + H]+, 410.15.
Anal. Calcd for C23H22BrNO: C, 67.65; H, 5.43; N, 3.43. Found: C,
67.88; H, 5.39; N, 3.61.
MS (ESI): m/z (%) = 375.24 (100) [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3007–3017

3012
F. Zhang et al.
PAPER
2,6,6-Trimethyl-1,3-diphenyl-1,5,6,7-tetrahydro-4H-indol-4-
one (9e)
IR (KBr): 2940, 1655, 1456, 1328, 1056, 975, 821, 734, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.49 (m, 3 H, HAr), 7.43 (s,
1 H, HAr), 7.23–7.21 (m, 2 H, HAr), 7.10 (d, J = 3.2 Hz, 1 H, HAr),
6.48–6.46 (m, 1 H, HAr), 2.39 (s, 2 H, CH2), 2.36 (s, 2 H, CH2), 2.21
(s, 3 H, CH3), 1.05 (s, 6 H, CH3).
Yellow solid; yield: 137.3 mg (83%); mp 140–142 °C.
IR (KBr): 2968, 1651, 1485, 1481, 1112, 975, 889, 830, 738, 691
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.51 (m, 3 H, HAr), 7.47–
7.45 (m, 2 H, HAr), 7.41–7.36 (m, 2 H, HAr), 7.31–7.29 (m, 3 H,
HAr), 2.46 (s, 2 H, CH2), 2.39 (s, 2 H, CH2), 2.02 (s, 3 H, CH3), 1.10
(s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.1, 143.0, 137.3, 134.6, 130.4,
129.6, 128.7, 128.6, 127.8, 127.6, 126.2, 120.3, 116.4, 53.2, 37.1,
35.2, 28.5, 11.2.
13C NMR (100 MHz, CDCl3): δ = 192.8, 140.5, 132.6, 129.7, 129.6,
128.9, 128.0, 127.9, 121.5, 115.8, 111.0, 109.2, 53.3, 37.1, 34.9,
28.4, 12.1.
MS (ESI): m/z (%) = 320.24 (100) [M + H]+.
Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C,
79.16; H, 6.49; N, 4.18.
MS (ESI): m/z (%) = 330.27 (100) [M + H]+, 302.29, 216.28.
1-(4-Chlorophenyl)-3-(4-fluorophenyl)-2,6,6-trimethyl-1,5,6,7-
tetrahydro-4H-indol-4-one (9j)
Anal. Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25. Found: C,
83.53; H, 6.91; N, 4.58.
Yellow solid; yield: 145.2 mg (76%); mp 184–186 °C.
IR (KBr): 2941, 1649, 1457, 1321, 1103, 975, 887, 729, 679 cm–1.
3-(4-Methoxyphenyl)-2,6,6-trimethyl-1-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9f)
1H NMR (400 MHz, CDCl3): δ = 7.55–7.53 (m, 2 H, HAr), 7.40–
7.37 (m, 2 H, HAr), 7.25–7.23 (m, 2 H, HAr), 7.09–7.05 (m, 2 H,
HAr), 2.44 (s, 2 H, CH2), 2.38 (s, 2 H, CH2), 1.99 (s, 3 H, CH3), 1.09
(s, 6 H, CH3).
Yellow solid; yield: 160.2 mg (89%); mp 92–94 °C.
IR (KBr): 2943, 1657, 1497, 1431, 1222, 1113, 975, 856, 731 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.42 (m, 3 H, HAr), 7.30 (d,
J = 8.4 Hz, 2 H, HAr), 7.22–7.21 (m, 2 H, HAr), 6.86 (d, J = 8.8 Hz,
2 H, HAr), 3.77 (s, 3 H, OCH3), 2.36 (s, 2 H, CH2), 2.30 (s, 2 H,
CH2), 1.93 (s, 3 H, CH3), 1.00 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.2, 158.1, 142.8, 137.3, 131.4,
129.5, 128.6, 128.2, 127.8, 126.9, 119.9, 116.4, 113.1, 55.2, 53.2,
37.1, 35.2, 28.5, 11.1.
13C NMR (100 MHz, CDCl3): δ = 193.2, 142.8, 135.6, 134.9, 131.9,
131.8, 130.2, 129.9, 129.1, 128.4, 119.7, 116.6, 114.6, 114.4, 53.1,
37.0, 35.2, 28.5, 11.0.
MS (ESI): m/z (%) = 382.22 (100) [M + H]+.
Anal. Calcd for C23H21ClFNO: C, 72.34; H, 5.54; N, 3.67. Found:
C, 72.09; H, 5.43; N, 3.58.
MS (ESI): m/z (%) = 360.24 (100) [M + H]+, 274.36.
1,3-Bis(4-chlorophenyl)-2,6,6-trimethyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9k)
Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90. Found: C,
80.52; H, 6.89; N, 4.07.
Yellow solid; yield: 161.2 mg (81%); mp 169–171 °C.
IR (KBr): 2940, 1643, 1487, 1223, 988, 851, 739, 669 cm–1.
2,6,6-Trimethyl-1-phenyl-3-(p-tolyl)-1,5,6,7-tetrahydro-4H-in-
dol-4-one (9g)
1H NMR (400 MHz, CDCl3): δ = 7.55–7.52 (m, 2 H, HAr), 7.38–
7.35 (m, 4 H, HAr), 7.27–7.23 (m, 2 H, HAr), 2.43 (s, 2 H, CH2), 2.37
(s, 2 H, CH2), 1.99 (s, 3 H, CH3), 1.09 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.1, 143.0, 135.6, 134.9, 132.8,
132.1, 131.7, 129.9, 129.2, 129.1, 128.6, 127.8, 125.4, 119.5, 116.5,
53.0, 37.0, 35.2, 28.5, 11.1.
Yellow solid; yield: 147.7 mg (86%); mp 118–120 °C.
IR (KBr): 2958, 1655, 1459, 1432, 1130, 997, 853, 802, 729 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.50 (m, 4 H, HAr), 7.36–
7.30 (m, 3 H, HAr), 7.21–7.16 (m, 2 H, HAr), 2.45 (s, 2 H, CH2), 2.39
(s, 3 H, CH3), 2.37 (s, 2 H, CH2), 2.01 (s, 3 H, CH3), 1.09 (s, 6 H,
CH3).
MS (ESI): m/z (%) = 398.23 (100) [M + H]+, 362.41, 324.36.
Anal. Calcd for C23H21Cl2NO: C, 69.35; H, 5.31; N, 3.52. Found: C,
69.26; H, 5.01; N, 3.61.
13C NMR (100 MHz, CDCl3): δ = 192.9, 142.7, 137.4, 135.7, 131.6,
130.2, 129.5, 128.6, 128.3, 127.8, 120.3, 116.5, 111.4, 53.2, 37.1,
35.1, 28.5, 21.2, 11.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO: 344.2009; found:
344.2003.
1-(4-Chlorophenyl)-2,6,6-trimethyl-3-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9l)
Yellow solid; yield: 150.8 mg (83%); mp 118–120 °C.
IR (KBr): 2956, 1658, 1458, 1433, 1228, 975, 837, 809, 726, 684
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.52 (m, 2 H, HAr), 7.44–
7.36 (m, 5 H, HAr), 7.29–7.24 (m, 2 H, HAr), 2.44 (s, 2 H, CH2), 2.38
(s, 2 H, CH2), 2.01 (s, 3 H, CH3), 1.09 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.0, 142.7, 135.8, 134.8, 134.3,
130.4, 129.9, 129.1, 128.7, 128.4, 127.6, 126.3, 120.7, 116.7, 53.1,
37.1, 35.2, 28.5, 11.1.
2,6,6-Trimethyl-1-phenyl-3-(thiophen-2-yl)-1,5,6,7-tetrahydro-
4H-indol-4-one (9h)
Yellow solid; yield: 147.8 mg (88%); mp 107–109 °C.
IR (KBr): 2938, 1649, 1487, 1321, 1221, 1158, 821, 739, 695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.51 (m, 4 H, HAr), 7.33–
7.28 (m, 4 H, HAr), 2.42 (s, 2 H, CH2), 2.37 (s, 2 H, CH2), 2.06 (s, 3
H, CH3), 1.07 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.2, 142.9, 137.2, 134.5, 130.3,
129.6, 128.8, 128.7, 127.8, 124.8, 123.5, 122.7, 116.5, 53.2, 37.1,
35.1, 29.7, 28.5, 11.5.
MS (ESI): m/z (%) = 364.21 (100) [M + H]+, 225.18.
Anal. Calcd for C23H22ClNO: C, 75.92; H, 6.09; N, 3.85. Found: C,
75.56; H, 6.00; N, 3.92.
MS (ESI): m/z (%) = 336.22 (100) [M + H]+, 274.33, 266.31,
231.23.
1-(4-Chlorophenyl)-3-(4-methoxyphenyl)-2,6,6-trimethyl-
1,5,6,7-tetrahydro-4H-indol-4-one (9m)
Anal. Calcd for C21H21NOS: C, 75.19; H, 6.31; N, 4.18. Found: C,
75.40; H, 6.37; N, 4.39.
Yellow solid; yield: 169.2 mg (86%); mp 125–127 °C.
IR (KBr): 2960, 1651, 1436, 1358, 1201, 995, 872, 731, 687 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.4 Hz, 2 H, HAr), 7.36
(d, J = 8.8 Hz, 2 H, HAr), 7.24 (d, J = 8.4 Hz, 2 H, HAr), 6.94 (d,
3-(Furan-2-yl)-2,6,6-trimethyl-1-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9i)
Brown solid; yield: 128.2 mg (80%); mp 149–150 °C.
Synthesis 2013, 45, 3007–3017
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydro-4H-indol-4-one Derivatives
3013
J = 8.8 Hz, 2 H, HAr), 3.85 (s, 3 H, OCH3), 2.43 (s, 2 H, CH2), 2.37
(s, 2 H, CH2), 2.00 (s, 3 H, CH3), 1.09 (s, 6 H, CH3).
OCH3), 2.44–2.32 (m, 3 H, CH2), 2.26–2.19 (m, 1 H, CH2), 2.05 (s,
3 H, CH3), 1.91 (s, 3 H, CH3), 1.08 (d, J = 3.6 Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.1, 158.1, 149.7, 145.2, 142.6,
135.8, 131.4, 129.8, 129.1, 116.7, 113.1, 55.2, 53.1, 37.1, 35.2,
28.5, 11.1.
13C NMR (100 MHz, CDCl3): δ = 193.1, 158.0, 142.6, 136.4, 136.3,
131.4, 131.1, 129.3, 128.4, 127.8, 127.2, 127.0, 119.7, 116.2, 113.1,
55.2, 53.2, 36.7, 35.1, 29.1, 27.9, 17.3, 10.6.
MS (ESI): m/z (%) = 394.24 (100) [M + H]+, 360.32, 274.33.
MS (ESI): m/z (%) = 374.31 (100) [M + H]+, 318.34, 230.27.
Anal. Calcd for C24H24ClNO2: C, 73.18; H, 6.14; N, 3.56. Found: C,
73.40; H, 6.32; N, 3.74.
Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C,
80.03; H, 7.36; N, 3.84.
1-(4-Chlorophenyl)-2,6,6-trimethyl-3-(p-tolyl)-1,5,6,7-tetra-
hydro-4H-indol-4-one (9n)
Yellow solid; yield: 149.2 mg (79%); mp 136–138 °C.
2,6,6-Trimethyl-1-(o-tolyl)-3-(p-tolyl)-1,5,6,7-tetrahydro-4H-
indol-4-one (9r)
Yellow solid; yield: 146.5 mg (82%); mp 121–123 °C.
IR (KBr): 2958, 1659, 1499, 1431, 1325, 1226, 1201, 997, 821, 777,
726 cm–1.
IR (KBr): 2953, 1657, 1552, 1496, 1459, 1413, 1385, 1353, 1299,
1113, 1058, 828, 772, 729 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.52 (m, 2 H, HAr), 7.32 (d,
J = 8.0 Hz, 2 H, HAr), 7.24 (d, J = 8.8 Hz, 2 H, HAr), 7.19 (d, J = 7.6
Hz, 2 H, HAr), 2.43 (s, 2 H, CH2), 2.38 (s, 3 H, OCH3), 2.37 (s, 2 H,
CH2), 2.00 (s, 3 H, CH3), 1.09 (s, 6 H, CH3).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.34 (m, 4 H, HAr), 7.21–
7.18 (m, 4 H, HAr), 2.43–2.29 (m, 6 H, CH2, CH3), 2.18–2.13 (m, 1
H, CH2), 2.00 (s, 3 H, CH3), 1.90 (s, 3 H, CH3), 1.08 (d, J = 4.0 Hz,
6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.0, 142.6, 135.9, 135.8, 134.7,
131.3, 130.2, 129.8, 129.1, 128.4, 128.2, 120.6, 116.7, 53.1, 37.1,
35.2, 28.5, 21.3, 11.1.
13C NMR (100 MHz, CDCl3): δ = 192.9, 142.6, 136.3, 135.6, 131.1,
130.2, 129.5, 129.3, 128.4, 128.3, 128.0, 127.1, 120.1, 116.3, 53.2,
36.7, 35.1, 29.1, 27.9, 21.3, 17.3, 10.6.
HRMS (ESI): m/z [M + H]+ calcd for C24H25ClNO: 378.1619;
MS (ESI): m/z (%) = 358.25 (100) [M + H]+, 274.31, 239.22.
found: 378.1615.
Anal. Calcd for C25H27NO: C, 83.99; H, 7.61; N, 3.92. Found: C,
84.17; H, 7.40; N, 4.13.
3-(4-Fluorophenyl)-2,6,6-trimethyl-1-(o-tolyl)-1,5,6,7-tetra-
hydro-4H-indol-4-one (9o)
Yellow solid; yield: 135.6 mg (75%); mp 113–115 °C.
1-(2,4-Dimethylphenyl)-2,6,6-trimethyl-3-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9s)
Yellow solid; yield: 153.8 mg (86%); mp 110–112 °C.
IR (KBr): 2956, 1658, 1597, 1523, 1497, 1460, 1385, 1222, 1158,
1111, 825, 775, 729 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.35 (m, 5 H, HAr), 7.21 (d,
J = 7.6 Hz, 1 H, HAr), 7.07 (t, J = 8.8 Hz, 2 H, HAr), 2.44–2.32 (m,
3 H, CH2), 2.19–2.15 (m, 1 H, CH2), 2.05 (s, 3 H, CH3), 1.90 (s, 3
H, CH3), 1.09 (d, J = 4.0 Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.1, 142.8, 136.3, 136.2, 131.9,
131.2, 129.4, 128.4, 128.2, 127.2, 116.2, 114.5, 114.3, 111.2, 53.2,
36.7, 35.2, 29.0, 28.0, 17.2, 10.5.
IR (KBr): 2958, 1652, 1549, 1493, 1451, 1428, 1387, 1346, 1295,
1118, 1060, 820, 728 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 6.8 Hz, 2 H, HAr),
7.39–7.35 (m, 3 H, HAr), 7.19 (s, 1 H, HAr), 7.15 (d, J = 8.4 Hz, 1 H,
HAr), 7.08 (d, J = 8.0 Hz, 1 H, HAr), 2.43–2.34 (m, 7 H, CH2, CH3),
1.99 (s, 3 H, CH3), 1.91 (s, 3 H, CH3), 1.07 (d, J = 4.4 Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.0, 143.0, 139.3, 135.9, 134.7,
133.7, 131.8, 131.4, 130.4, 128.7, 128.4, 128.1, 127.8, 127.5, 127.0,
116.1, 53.2, 36.7, 35.2, 29.1, 28.0, 21.2, 17.2, 10.6.
MS (ESI): m/z (%) = 362.23 (100) [M + H]+, 243.19.
Anal. Calcd for C24H24FNO: C, 79.75; H, 6.69; N, 3.88. Found: C,
79.46; H, 6.77; N, 3.69.
MS (ESI): m/z (%) = 358.30 (100) [M + H]+.
Anal. Calcd for C25H27NO: C, 83.99; H, 7.61; N, 3.92. Found: C,
83.62; H, 7.56; N, 3.71.
2,6,6-Trimethyl-3-phenyl-1-(o-tolyl)-1,5,6,7-tetrahydro-4H-in-
dol-4-one (9p)
Yellow solid; yield: 142.8 mg (83%); mp 96–98 °C.
1-(2-Methoxyphenyl)-2,6,6-trimethyl-3-phenyl-1,5,6,7-tetra-
hydro-4H-indol-4-one (9t)
Yellow solid; yield: 154.8 mg (86%); mp 106–108 °C.
IR (KBr): 2955, 1657, 1469, 1452, 1324, 1221, 977, 833, 801, 696
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.48–7.37 (m, 7 H, HAr), 7.29–
7.21 (d, J = 7.6 Hz, 2 H, HAr), 2.45–2.32 (m, 3 H, CH2), 2.19–2.16
(m, 1 H, CH2), 2.05 (s, 3 H, CH3), 1.92 (s, 3 H, CH3), 1.09 (d, J = 4.0
Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.0, 150.4, 142.8, 136.4, 136.3,
134.6, 131.2, 130.4, 129.3, 128.4, 127.5, 127.2, 126.1, 120.2, 116.3,
53.2, 36.7, 35.2, 29.1, 28.0, 17.3, 10.6.
IR (KBr): 2949, 1649, 1541, 1497, 1457, 1420, 1380, 1344, 1295,
1063, 827, 720 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.45 (m, 3 H, HAr), 7.37 (t,
J = 8.0 Hz, 2 H, HAr), 7.26–7.21 (m, 2 H, HAr), 7.11–7.07 (m, 2 H,
HAr), 3,82 (s, 3 H, OCH3), 2.41–2.29 (m, 4 H, CH2), 1.94 (s, 3 H,
CH3), 1.08 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.1, 155.4, 143.9, 134.8, 130.5,
130.4, 129.7, 129.0, 127.4, 126.0, 125.8, 120.9, 119.8, 116.2, 112.2,
55.7, 36.6, 35.1, 28.8, 28.3, 10.6.
MS (ESI): m/z (%) = 344.28 (100) [M + H]+.
Anal. Calcd for C24H25NO: C, 83.93; H, 7.34; N, 4.08. Found: C,
83.78; H, 7.21; N, 3.98.
MS (ESI): m/z (%) = 360.27 (100) [M + H]+, 274.39, 246.22.
Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90. Found: C,
80.37; H, 7.33; N, 3.81.
3-(4-Methoxyphenyl)-2,6,6-trimethyl-1-(o-tolyl)-1,5,6,7-tetra-
hydro-4H-indol-4-one (9q)
Yellow solid; yield: 160.6 mg (86%); mp 109–111 °C.
3-(4-Chlorophenyl)-2,6,6-trimethyl-1-(naphthalen-1-yl)-
1,5,6,7-tetrahydro-4H-indol-4-one (9u)
Red solid; yield: 155.2 mg (75%); mp 165–167 °C.
IR (KBr): 2955, 1648, 1589, 1531, 1490, 1457, 1375, 1231, 1150,
1118, 830, 766, 728 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.35 (m, 5 H, HAr), 7.21 (d,
J = 7.6 Hz, 1 H, HAr), 6.94 (d, J = 8.8 Hz, 2 H, HAr), 3.85 (s, 3 H,
IR (KBr): 2956, 1658, 1596, 1526, 1491, 1430, 1422, 1386, 1367,
1351, 1090, 1013, 966, 826, 742 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3007–3017

3014
F. Zhang et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 8.05–8.00 (m, 2 H, HAr), 7.65–
7.54 (m, 4 H, HAr), 7.48–7.45 (m, 3 H, HAr), 7.37 (d, J = 8.4 Hz, 2
H, HAr), 2.45–2.35 (m, 3 H, CH2), 2.14–2.10 (m, 1 H, CH2), 1.88 (s,
3 H, CH3), 1.05 (s, 3 H, CH3), 1.02 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.2, 144.3, 134.3, 133.7, 133.1,
132.0, 131.8, 130.9, 129.7, 129.0, 128.5, 128.2, 127.9, 127.7, 127.1,
126.1, 125.4, 122.4, 119.1, 116.3, 53.2, 36.4, 35.1, 28.9, 27.8, 10.5.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.49 (m, 5 H, HAr), 7.32–
7.27 (m, 4 H, HAr), 2.59 (t, J = 6.4 Hz, 2 H, CH2), 2.50 (t, J = 6.4
Hz, 2 H, CH2), 2.13–2.06 (m, 2 H, CH2), 1.99 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.7, 144.3, 137.0, 133.7, 132.1,
130.7, 129.6, 128.9, 128.6, 127.7, 120.3, 119.3, 117.3, 39.0, 23.6,
23.0, 11.0.
MS (ESI): m/z (%) = 380.19 (100) [M + H]+, 382.12.
MS (ESI): m/z (%) = 414.24 (100) [M + H]+.
Anal. Calcd for C21H18BrNO: C, 66.33; H, 4.77; N, 3.68. Found: C,
66.59; H, 4.69; N, 3.76.
Anal. Calcd for C27H24ClNO: C, 78.34; H, 5.84; N, 3.38. Found: C,
78.11; H, 5.97; N, 3.29.
2-Methyl-1,3-diphenyl-1,5,6,7-tetrahydro-4H-indol-4-one (9z)
Yellow solid; yield: 125.2 mg (83%); mp 110–111 °C.
1-Cyclopropyl-2,6,6-trimethyl-3-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9v)
White solid; yield: 111.6 mg (76%); mp 148–149 °C.
IR (KBr): 2960, 1728, 1657, 1445, 1367, 1335, 1288, 1205, 1115,
1072, 974, 910, 745 cm–1.
IR (KBr): 2955, 1655, 1543, 1499, 1457, 1426, 1390, 1344, 1289,
1112, 1058, 821, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.33 (m, 4 H, HAr), 7.27–
7.24 (m, 1 H, HAr), 3.02–2.99 (m, 1 H, CH), 2.79 (s, 2 H, CH2), 2.32
(s, 2 H, CH2), 2.28 (s, 3 H, CH3), 1.16–1.14 (m, 8 H, CH2, CH3),
0.99–0.98 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 192.8, 144.1, 134.8, 130.4, 129.9,
127.5, 126.1, 120.0, 115.9, 52.9, 37.6, 35.1, 28.7, 26.0, 11.3, 7.6.
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO: 294.1852; found:
294.1848.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.50 (m, 3 H, HAr), 7.48–
7.43 (m, 4 H, HAr), 7.33–7.27 (m, 3 H, HAr), 2.60 (t, J = 6.0 Hz, 2 H,
CH2), 2.52–2.49 (m, 2 H, CH2), 2.14–2.09 (m, 2 H, CH2), 2.02 (s, 3
H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.7, 144.0, 137.2, 134.7, 130.4,
129.6, 128.7, 128.4, 127.8, 127.6, 126.3, 120.4, 117.5, 39.1, 23.7,
23.1, 11.1.
MS (ESI): m/z (%) = 302.24 (100) [M + H]+.
Anal. Calcd for C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found: C,
83.51; H, 6.24; N, 4.71.
1-Cyclopropyl-3-(4-methoxyphenyl)-2,6,6-trimethyl-1,5,6,7-
tetrahydro-4H-indol-4-one (9w)
Yellow solid; yield: 134.4 mg (83%); mp 141–142 °C.
2-Methyl-1-phenyl-3-(p-tolyl)-1,5,6,7-tetrahydro-4H-indol-4-
one (9aa)
Yellow solid; yield: 145.3 mg (92%); mp 123–124 °C.
IR (KBr): 2958, 1655, 1550, 1499, 1457, 1421, 1380, 1343, 1298,
1118, 829, 699 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m, 2 H, HAr), 6.92–
6.90 (m, 2 H, HAr), 3.83 (s, 3 H, OCH3), 3.02–2.97 (m, 1 H, CH),
2.78 (s, 2 H, CH2), 2.31 (s, 2 H, CH2), 2.26 (s, 3 H, CH3), 1.15–1.13
(m, 8 H, CH3, CH2), 0.99–0.95 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 192.9, 157.9, 143.9, 131.4, 129.5,
128.4, 127.1, 119.6, 115.9, 114.2, 113.0, 55.2, 52.9, 37.6, 35.1,
28.7, 26.0, 11.3, 7.6.
IR (KBr): 2963, 1721, 1669, 1444, 1365, 1321, 1291, 1207, 1119,
1023, 974, 911, 725 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.56–7.49 (m, 3 H, HAr), 7.35–
7.27 (m, 4 H, HAr), 7.20 (d, J = 8.0 Hz, 2 H, HAr), 2.59 (t, J = 6.0 Hz,
2 H, CH2), 2.52–2.48 (m, 2 H, CH2), 2.39 (s, 3 H, CH3), 2.13–2.06
(m, 2 H, CH2), 2.01 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.6, 143.9, 137.3, 135.8, 131.6,
130.2, 129.5, 128.7, 128.4, 128.2, 127.7, 120.3, 117.6, 39.1, 23.7,
23.1, 21.3, 11.1.
MS (ESI): m/z (%) = 324.28 (100) [M + H]+, 274.40, 196.25.
MS (ESI): m/z (%) = 316.29 (100) [M + H]+, 301.30, 188.20.
Anal. Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C,
78.29; H, 7.83; N, 4.19.
Anal. Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C,
83.85; H, 6.83; N, 4.30.
6,6-Dimethyl-1,3-diphenyl-1,5,6,7-tetrahydro-4H-indol-4-one
2-Methyl-1-phenyl-3-(thiophen-2-yl)-1,5,6,7-tetrahydro-4H-in-
dol-4-one (9bb)
Yellow solid; yield: 141.6 mg (92%); mp 138–139 °C.
(9x)
Yellow oil; yield: 134.2 mg (85%).
IR (KBr): 2944, 1641, 1547, 1492, 1438, 1429, 1388, 1351, 1299,
1119, 1057, 728, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.69 (m, 2 H, HAr), 7.55–
7.52 (m, 2 H, HAr), 7.47–7.43 (m, 2 H, HAr), 7.39–7.35 (m, 4 H,
HAr), 6.91 (s, 1 H, CH), 2.68 (s, 2 H, CH2), 2.46 (s, 2 H, CH2), 1.12
(s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.6, 143.4, 138.5, 133.9, 129.6,
128.9, 128.7, 128.0, 127.9, 126.7, 126.6, 125.3, 121.9, 117.2, 53.2,
37.4, 35.3, 28.4.
IR (KBr): 2949, 1704, 1659, 1442, 1361, 1338, 1289, 1208, 1109,
1067, 937, 745 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.50 (m, 3 H, HAr), 7.32–
7.27 (m, 5 H, HAr), 2.59–2.56 (m, 2 H, CH2), 2.52–2.49 (m, 2 H,
CH2), 2.12–2.06 (m, 5 H, CH2, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.8, 144.0, 137.2, 134.6, 130.4,
129.6, 128.8, 128.7, 127.7, 123.6, 122.7, 117.7, 115.1, 39.1, 23.6,
23.1, 11.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NOS: 308.1104; found:
308.1099.
MS (ESI): m/z (%) = 316.25 (100) [M + H]+.
Anal. Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C,
83.99; H, 6.62; N, 4.31.
3-(Furan-2-yl)-2-methyl-1-phenyl-1,5,6,7-tetrahydro-4H-indol-
4-one (9cc)
Brown solid; yield: 102.2 mg (70%); mp 143–145 °C.
3-(4-Bromophenyl)-2-methyl-1-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9y)
Yellow solid; yield: 171.0 mg (90%); mp 124–126 °C.
IR (KBr): 2966, 1728, 1647, 1453, 1359, 1335, 1258, 1211, 1136,
1069, 972,729 cm–1.
IR (KBr): 2943, 1648, 1593, 1500, 1488, 1455, 1437, 1417, 1125,
1069, 1004, 930, 831, 759, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.50 (m, 3 H, HAr), 7.46–
7.45 (m, 1 H, HAr), 7.25–7.27 (s, 2 H, HAr), 7.07–7.06 (m, 1 H, HAr),
Synthesis 2013, 45, 3007–3017
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydro-4H-indol-4-one Derivatives
3015
6.50–6.48 (m, 1 H, HAr), 2.56–2.52 (m, 4 H, CH2), 2.22 (s, 3 H,
CH3), 2.10–2.06 (m, 2 H, CH2).
CH2), 2.13–2.07 (m, 2 H, CH2), 2.05 (s, 3 H, CH3), 1.90 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 193.3, 149.3, 146.2, 144.3, 140.6,
136.9, 129.6, 128.9, 127.9, 120.6, 111.0, 109.2, 39.2, 23.4, 23.2,
12.0.
13C NMR (100 MHz, CDCl3): δ = 193.7, 144.0, 136.3, 136.2, 133.2,
131.7, 131.2, 129.4, 128.3, 127.7, 127.2, 119.1, 117.3, 39.1, 23.6,
22.6, 17.3, 10.5.
MS (ESI): m/z (%) = 292.13 (100) [M + H]+, 266.11.
HRMS (ESI): m/z [M + H]+ calcd for C22H21ClNO: 350.1306;
found: 350.1301.
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.63; H, 5.97; N, 4.89.
2-Methyl-3-phenyl-1-(o-tolyl)-1,5,6,7-tetrahydro-4H-indol-4-
one (9hh)
Yellow solid; yield: 132.6 mg (84%); mp 98–100 °C.
1-(2-Chlorophenyl)-2-methyl-3-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9dd)
Yellow solid; yield: 132.8 mg (79%); mp 99–101 °C.
IR (KBr): 2952, 1721, 1652, 1446, 1358, 1340, 1279, 1206, 1118,
1070, 970, 685 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.38 (m, 7 H, HAr), 7.29–
7.23 (m, 2 H, HAr), 2.51–2.48 (m, 2 H, CH2), 2.40–2.31 (m, 2 H,
CH2), 2.16–2.10 (m, 2 H, CH2), 2.05 (s, 3 H, CH3), 1.92 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 193.6, 143.8, 136.3, 134.7, 131.2,
130.4, 129.3, 128.3, 127.5, 127.1, 126.2, 113.1, 39.1, 23.7, 22.7,
17.3, 10.6.
IR (KBr): 2958, 1657, 1456, 1366, 1331, 1279, 1215, 1119, 1067,
973, 910, 730 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63–7.61 (m, 1 H, HAr), 7.49–
7.44 (m, 4 H, HAr), 7.40–7.37 (m, 3 H, HAr), 7.30–7.29 (m, 1 H,
HAr), 2.52–2.48 (m, 4 H, CH2), 2.16–2.08 (m, 2 H, CH2), 1.95 (s, 3
H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.6, 144.1, 135.1, 134.6, 130.6,
130.4, 130.1, 128.3, 128.0, 127.5, 126.3, 120.4, 117.8, 39.1, 23.5,
22.5, 10.5.
MS (ESI): m/z (%) = 316.17 (100) [M + H]+.
MS (ESI): m/z (%) = 336.19 (100) [M + H]+, 284.38, 222.15.
Anal. Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C,
83.62; H, 6.93; N, 4.18.
Anal. Calcd for C21H18ClNO: C, 75.11; H, 5.40; N, 4.17. Found: C,
74.87; H, 5.29; N, 4.42.
3-(4-Methoxyphenyl)-2-methyl-1-(o-tolyl)-1,5,6,7-tetrahydro-
4H-indol-4-one (9ii)
Yellow solid; yield: 157.4 mg (91%); mp 122–124 °C.
1-(2-Chlorophenyl)-3-(4-methoxyphenyl)-2-methyl-1,5,6,7-tet-
rahydro-4H-indol-4-one (9ee)
Yellow solid; yield: 155.6 mg (85%); mp 106–108 °C.
IR (KBr): 2955, 1720, 1651, 1446, 1361, 1288, 1205, 1121, 1066,
969, 921, 739 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.34 (m, 5 H, HAr), 7.24 (d,
J = 7.6 Hz, 1 H, HAr), 6.94 (d, J = 8.8 Hz, 2 H, HAr), 3.85 (s, 3 H,
OCH3), 2.54–2.47 (m, 3 H, CH2), 2.39–2.32 (m, 1 H, CH2), 2.13–
2.05 (m, 5 H, CH2, CH3), 1.90 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.7, 158.0, 143.6, 136.4, 136.3,
131.4, 131.1, 129.3, 128.3, 127.7, 127.1, 119.8, 117.4, 113.1, 55.2,
39.1, 23.7, 22.7, 17.3, 10.6.
IR (KBr): 2961, 1658, 1440, 1355, 1337, 1289, 1201, 1105, 1070,
974, 726 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m, 1 H, HAr), 7.38–
7.35 (m, 2 H, HAr), 7.30–7.28 (m, 3 H, HAr), 6.84 (d, J = 8.4 Hz, 2
H, HAr), 3.75 (s, 3 H, OCH3), 2.41–2.38 (m, 4 H, CH2), 2.03–2.00
(m, 2 H, CH2), 1.84 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.7, 158.1, 144.0, 135.2, 133.4,
131.5, 130.6, 130.5, 130.1, 128.0, 127.9, 126.9, 117.8, 113.1, 55.2,
39.1, 23.5, 22.5, 10.5.
HRMS (ESI): m/z [M + H]+ calcd for C23H24NO2: 346.1802; found:
346.1806.
MS (ESI): m/z (%) = 366.26 (100) [M + H]+, 274.38, 220.31.
Anal. Calcd for C22H20ClNO2: C, 72.23; H, 5.51; N, 3.83. Found: C,
72.28; H, 5.63; N, 3.69.
1-(2,4-Dimethylphenyl)-2-methyl-3-(4-nitrophenyl)-1,5,6,7-tet-
rahydro-4H-indol-4-one (9jj)
Yellow solid; yield: 157.6 mg (84%); mp 134–136 °C.
1-(4-Chlorophenyl)-2-methyl-3-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9ff)
IR (KBr): 2959, 1718, 1654, 1438, 1355, 1321, 1200, 1109, 1074,
970, 901, 729 cm–1.
Yellow solid; yield: 136.0 mg (81%); mp 164–165 °C.
1H NMR (400 MHz, CDCl3): δ = 8.24–8.21 (m, 2 H, HAr), 7.60 (d,
J = 8.8 Hz, 2 H, HAr), 7.22 (s, 1 H, HAr), 7.17 (d, J = 8.0 Hz, 1 H,
HAr), 7.10 (d, J = 8.0 Hz, 1 H, HAr), 2.53–2.47 (m, 3 H, CH2), 2.43–
2.34 (m, 4 H, CH2, CH3), 2.13–2.10 (m, 2 H, CH2), 2.01 (s, 3 H,
CH3), 1.93 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.9, 145.9, 145.1, 142.3, 139.7,
135.7, 133.1, 132.0, 131.0, 129.6, 128.0, 127.9, 127.5, 124.0, 122.9,
118.4, 117.1, 39.0, 23.5, 22.6, 21.2, 17.2, 10.7.
IR (KBr): 2951, 1655, 1450, 1366, 1339, 1289, 1201, 1082, 973,
917, 728 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.52 (m, 2 H, HAr), 7.43–
7.36 (m, 4 H, HAr), 7.31–7.26 (m, 3 H, HAr), 2.59 (t, J = 6.0 Hz, 2 H,
CH2), 2.50 (t, J = 6.4 Hz, 2 H, CH2), 2.14–2.08 (m, 2 H, CH2), 2.01
(s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.6, 143.8, 135.7, 134.8, 134.4,
130.3, 129.8, 129.1, 128.3, 127.6, 126.4, 120.8, 117.8, 39.0, 23.6,
23.1, 11.0.
MS (ESI): m/z (%) = 375.24 (100) [M + H]+, 274.67, 216.28.
Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N, 7.48. Found: C,
73.85; H, 5.78; N, 7.56.
HRMS (ESI): m/z [M + H]+ calcd for C21H19ClNO: 336.1150;
found: 336.1145.
1-(2,4-Dimethylphenyl)-2-methyl-3-phenyl-1,5,6,7-tetrahydro-
4H-indol-4-one (9kk)
Yellow solid; yield: 143.6 mg (87%); mp 128–130 °C.
3-(4-Chlorophenyl)-2-methyl-1-(o-tolyl)-1,5,6,7-tetrahydro-
4H-indol-4-one (9gg)
Yellow solid; yield: 136.4 mg (78%); mp 140–141 °C.
IR (KBr): 2954, 1717, 1649, 1440, 1366, 1331, 1287, 1209, 1103,
974, 921, 727 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.45 (m, 2 H, HAr), 7.40–
IR (KBr): 2956, 1721, 1652, 1446, 1359, 1289, 1203, 1119, 1070,
973, 900, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.33 (m, 7 H, HAr), 7.22 (d,
J = 7.6 Hz, 1 H, HAr), 2.56–2.48 (m, 3 H, CH2), 2.40–2.31 (m, 1 H,
7.36 (m, 2 H, HAr), 7.29–7.28 (m, 1 H, HAr), 7.20 (s, 1 H, HAr), 7.16–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3007–3017

3016
F. Zhang et al.
PAPER
7.10 (m, 2 H, HAr), 2.54–2.48 (m, 3 H, CH2), 2.42 (s, 3 H, CH3),
2.39–2.32 (m, 1 H, CH2), 2.11–2.06 (m, 2 H, CH2), 2.01 (s, 3 H,
CH3), 1.91 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.6, 144.0, 139.3, 135.9, 134.8,
133.7, 131.8, 130.4, 128.2, 128.0, 127.8, 127.5, 126.1, 120.1, 117.3,
39.1, 23.7, 22.7, 21.2, 17.2, 10.6.
IR (KBr): 2955, 1723, 1636, 1355, 1329, 1220, 1057, 959, 688
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.26 (m, 8 H, HAr), 6.98 (d,
J = 7.6 Hz, 2 H, HAr), 5.11 (s, 2 H, CH2), 2.59 (s, 2 H, CH2), 2.37 (s,
2 H, CH2), 2.12 (s, 3 H, CH3), 1.11 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 192.8, 142.3, 136.7, 134.7, 130.5,
129.0, 127.9, 127.7, 127.5, 126.1, 125.6, 120.6, 116.3, 53.0, 47.2,
36.3, 35.1, 28.6, 10.2.
MS (ESI): m/z (%) = 330.29 (100) [M + H]+, 274.39, 216.22.
Anal. Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25. Found: C,
84.12; H, 7.11; N, 4.38.
MS (ESI): m/z (%) = 343.16 (100) [M + H]+.
Anal. Calcd for C24H25NO: C, 83.93; H, 7.34; N, 4.08. Found: C,
83.79; H, 7.29; N, 4.17.
1-(2-Methoxyphenyl)-2-methyl-3-phenyl-1,5,6,7-tetrahydro-
4H-indol-4-one (9ll)
Yellow solid; yield: 152.6 mg (92%); mp 107–109 °C.
2,6,6-Trimethyl-1-pentyl-3-phenyl-1,5,6,7-tetrahydro-4H-in-
dol-4-one (9pp)
Yellow oil; yield: 137.2 mg (85%).
IR (KBr): 2958, 1719, 1655, 1451, 1366, 1327, 1200, 1070, 966,
745 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.45 (m, 3 H, HAr), 7.40–
7.36 (m, 2 H, HAr), 7.26–7.23 (m, 2 H, HAr), 7.11–7.08 (m, 2 H,
HAr), 3.85 (s, 3 H, OCH3), 2.55–2.48 (m, 4 H, CH2), 2.13–2.08 (m,
2 H, CH2), 1.96 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.7, 155.4, 144.8, 134.9, 130.5,
130.4, 129.6, 128.9, 127.5, 126.1, 125.7, 120.9, 117.4, 112.1, 55.7,
39.1, 23.5, 22.6, 10.5.
IR (KBr): 2958, 1722, 1638, 1351, 1322, 1231, 1055, 931, 667
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.33 (m, 4 H, HAr), 7.27–
7.23 (m, 1 H, HAr), 3.81 (t, J = 7.6 Hz, 2 H, CH2), 2.65 (s, 2 H, CH2),
2.34 (s, 2 H, CH2), 2.21 (s, 3 H, CH3), 1.71–1.66 (m, 2 H, CH2),
1.40–1.37 (m, 4 H, CH2), 1.16 (s, 6 H, CH3), 0.96 (t, J = 7.2 Hz, 3
H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C22H22NO2: 332.1645; found:
332.1640.
13C NMR (100 MHz, CDCl3): δ = 192.6, 141.6, 134.9, 130.5, 127.5,
127.3, 126.0, 120.3, 115.9, 52.9, 44.2, 36.5, 35.0, 30.5, 29.0, 28.7,
22.4, 14.0, 10.2.
2-Methyl-1-(naphthalen-1-yl)-3-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9mm)
Red solid; yield: 135.4 mg (77%); mp 127–129 °C.
MS (ESI): m/z (%) = 323.29 (100) [M + H]+.
Anal. Calcd for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C,
81.36; H, 9.33; N, 4.18.
IR (KBr): 2957, 1721, 1655, 1439, 1366, 1331, 1228, 1062, 980,
917, 684 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.01–7.99 (m, 2 H, HAr), 7.65–
7.50 (m, 6 H, HAr), 7.43–7.39 (m, 2 H, HAr), 7.33–7.29 (m, 2 H,
HAr), 2.54–2.50 (m, 3 H, CH2), 2.36–2.27 (m, 1 H, CH2), 2.10–2.04
(m, 2 H, CH2), 1.90 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 193.7, 145.1, 134.7, 134.3, 133.9,
130.9, 130.5, 129.6, 129.5, 128.4, 127.9, 127.6, 127.0, 126.3, 126.0,
125.4, 122.5, 120.3, 117.6, 39.1, 23.6, 22.6, 10.5.
5,5-Dimethyl-2-(2-nitro-1-phenylethyl)-3-(phenylamino)cyclo-
hex-2-en-1-one (10)
In a 10-mL reaction vial, nitroolefin (0.5 mmol), 5,5-dimethylcy-
clohexane-1,3-dione (1c, 0.5 mmol), aniline (0.5 mmol), L-proline
(0.05 mmol), and H2O (3.0 mL) were mixed and then capped. The
mixture was stirred for 12 h at 45 °C. Upon completion as shown by
TLC monitoring, the mixture was cooled to r.t. and extracted with
EtOAc (3 × 5 mL). The resulting residue was purified by column
chromatography (silica gel, EtOAc–petroleum ether, 1:10) to give
the pure product; yellow oil; yield: 125.6 mg (69%).
MS (ESI): m/z (%) = 352.23 (100) [M + H]+.
Anal. Calcd for C25H21NO: C, 85.44; H, 6.02; N, 3.99. Found: C,
85.18; H, 6.31; N, 3.76.
IR (KBr): 2949, 1710, 1637, 1447, 1356, 1288, 1213, 1106, 981,
929, 718 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.22 (m, 7 H, HAr), 7.24 (t,
J = 7.2 Hz, 1 H, HAr), 6.89 (d, J = 7.6 Hz, 2 H, HAr), 6.78 (s, 1 H,
NH), 5.33–5.28 (m, 1 H, CH2), 5.20–5.15 (m, 1 H, CH2), 5.00–4.96
(m, 1 H, CH2), 2.38–2.24 (m, 4 H, CH3), 0.99 (d, J = 10.4 Hz, 6 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 195.4, 159.0, 139.4, 138.1, 129.4,
129.6, 127.4, 127.3, 126.1, 125.1, 109.6, 50.9, 40.9, 39.6, 32.6,
28.8, 27.8.
1-Cyclohexyl-2,6,6-trimethyl-3-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (9nn)
Yellow oil; yield: 139.0 mg (83%).
IR (KBr): 2951, 1729, 1635, 1361, 1337, 1222, 1060, 919, 681
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.33 (m, 4 H, HAr), 7.25–
7.23 (m, 1 H, HAr), 4.05–3.97 (m, 1 H, CH), 2.79 (s, 2 H, CH2), 2.31
(s, 2 H, CH2), 2.21 (s, 3 H, CH3), 1.97–1.95 (m, 6 H, CH2), 1.81–
1.78 (m, 1 H, CH2), 1.48–1.38 (m, 2 H, CH2), 1.29–1.26 (m, 1 H,
CH2), 1.16 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 192.7, 141.2, 135.2, 131.8, 130.7,
127.5, 127.4, 126.0, 111.5, 57.0, 52.6, 35.1, 32.2, 29.7, 28.7, 25.5,
25.4.
MS (ESI): m/z (%) = 365.23 (100) [M + H]+.
Anal. Calcd for C22H24N2O3: C, 72.51; H, 6.64; N, 7.69. Found: C,
72.39; H, 6.80; N, 7.74.
Acknowledgment
MS (ESI): m/z (%) = 335.24 (100) [M + H]+.
We are grateful to financial support from the Natural Science Foun-
dation of China (No.Y4080450) and the Research Funds of
Shaoxing University (No. 2012LG1006).
Anal. Calcd for C23H29NO: C, 82.34; H, 8.71; N, 4.18. Found: C,
82.57; H, 8.49; N, 4.32.
1-Benzyl-2,6,6-trimethyl-3-phenyl-1,5,6,7-tetrahydro-4H-in-
dol-4-one (9oo)
Yellow solid; yield: 149.2 mg (87%); mp 156–158 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Synthesis 2013, 45, 3007–3017
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydro-4H-indol-4-one Derivatives
3017
(7) (a) Tanimoro, T.; Ueno, M.; Takeda, K.; Kirihata, M.;
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3007–3017