Synthesis of 1,2-disubstituted 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one derivatives

Article abstract of DOI:10.1007/s00706-014-1171-3

A facile and efficient method for the synthesis of 1,2-dihydropyrrolo[3,4- b]indol-3(4H)-one derivatives via a two-step reaction has been developed. The starting materials of 1H-indole-2-carboxylic acid, aldehyde, and amine are mixed and refluxed in ethanol to generate Mannich products, which are dehydrated in the presence of 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium to form the desired products, 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-ones. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-014-1171-3

Monatsh Chem
DOI 10.1007/s00706-014-1171-3
ORIGINAL PAPER
Synthesis of 1,2-disubstituted 1,2-dihydropyrrolo[3,4-b]indol-
3(4H)-one derivatives
•
Fei Ma Lei Ma Min Lei Lihong Hu
•
•
Received: 20 November 2013 / Accepted: 27 January 2014
Ó Springer-Verlag Wien 2014
Abstract A facile and efficient method for the synthesis
of 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one derivatives
via a two-step reaction has been developed. The starting
materials of 1H-indole-2-carboxylic acid, aldehyde, and
amine are mixed and refluxed in ethanol to generate
Mannich products, which are dehydrated in the presence of
2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
to form the desired products, 1,2-dihydropyrrolo[3,4-b]indol-
3(4H)-ones.
as mGluR1 antagonists [13], cannabinoid 2 receptor ago-
nists [14], potent inhibitors of purified human renin [15],
and therapeutic agents for the treatment of osteoporosis
[16]. Due to the importance of these heterocyclic com-
pounds, several methods for the synthesis of 1,2-
dihydropyrrolo[3,4-b]indol-3(4H)-ones have been reported,
which include a cyclization reaction [13], an isomerisation
reaction [17], an acyl radical-based route [18], reaction of
halogenactive maleimides with sodium azide [19], and
reductive condensation via hydrogen [15]. However, many
of these reported methods have drawbacks such as long
reaction times, low yields of products, harsh reaction
conditions, the use of stoichiometric reagents, and diffi-
culties in work-up. Therefore, the development of facile
and eco-friendly methods for the synthesis of 1,2-dihy-
dropyrrolo[3,4-b]indol-3(4H)-one and its derivatives is still
a demanding task in organic synthesis.
Keywords Aldehyde Á Amine Á
1H-Indole-2-carboxylic acid Á Mannich reaction
Introduction
In recent years, many studies focused on the modification
of indole scaffolds for synthesis of indole derivatives via
hydrogenation [1–5], oxidation [6–9], and heterocycliza-
tion [10–12]. Among all the derivatives from indole
scaffolds, 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one and
its derivatives are a vital class of pharmaceutical moieties
due to their pharmacological and biological activities, such
In continuation of our ongoing studies aimed at devel-
oping mild and practical protocols for the synthesis of
useful building blocks and/or biologically active com-
pounds, herein we wish to report a facile and efficient
method for the synthesis of 1,2-dihydropyrrolo[3,4-b]in-
dol-3(4H)-one derivatives. The starting materials of 1H-
indole-2-carboxylic acid, aldehyde, and amine are mixed
and refluxed in EtOH to generate Mannich products, which
are dehydrated in the presence of 2-(7-aza-1H-benzotria-
zole-1-yl)-1,1,3,3-tetramethyluronium (HATU) to form the
desired products, 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-
ones (Scheme 1).
F. Ma Á L. Ma
School of Pharmacy, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237,
People’s Republic of China
M. Lei (&) Á L. Hu
Shanghai Research Center for Modernization of Traditional
Chinese Medicine, Shanghai Institute of Materia Medica,
Shanghai 201203, People’s Republic of China
e-mail: mlei@simm.ac.cn
Results and discussion
Initially, we combined the mixture of 1H-indole-2-car-
boxylic acid (1a), benzaldehyde (2a), and benzylamine
L. Hu
e-mail: lhhu@simm.ac.cn
123

F. Ma et al.
Scheme 1
Table 1 Condensation of 1H-indole-2-carboxylic acid (1), aldehyde
(2), and 3-amine (3)
starting materials proceeded smoothly to give the corre-
sponding 4 in good yields (Table 1, entries 1–3).
Moreover, moderate to good yields of the corresponding
products 4 were obtained when using alkyl amines as
substrates (Table 1, entries 4–7). In order to study the steric
effects on this three-component condensation reaction,
amines, including isopropylamine, cyclopentylamine, and
tert-butylamine were investigated (Table 1, entries 4, 7, 8).
The results revealed that the reaction could proceed
smoothly when using isopropylamine and cyclopentyl-
amine as starting materials to obtain the desired products
4d and 4g in 90 and 49 % yields, respectively. However,
the reaction was sluggish when using tert-butylamine as a
substrate, and the desired product 4h was not determined
by LC–MS. Furthermore, we also carried out the reaction
with an aromatic amine under similar reaction conditions;
unfortunately, no products were observed (Table 2,
entry 9).
Entry R1
R2
Time/h Product Yield/%a
4
1
C6H5
C6H5CH2
4.5
4a
4b
4c
4d
4e
4f
86
88
67
90
70
63
49
0
2
C6H5
4-CH3OC6H4CH2 4.5
3
C6H5
C6H5CH2CH2
(CH3)2CH
5.5
6
4
C6H5
5
C6H5
CH3CH2CH2
7.5
6
C6H5
CH3CH2CH2CH2 10
7
C6H5
Cyclopentyl
(CH3)3C
C6H5
5
4g
4h
4i
8
C6H5
10
10
6
Then, in order to gauge the scope of these conditions,
several aromatic and aliphatic aldehydes were examined
under similar conditions for condensation with 1H-indole-
2-carboxylic acid and benzylamine. As shown in Table 1,
2-, 3-, and 4-chlorobenzaldehydes were chosen for this
three-component condensation, and the desired products 4j,
4k, and 4l were obtained in 64, 71, and 92 % yields,
respectively. The differences in yields may be caused by
steric hindrance. Furthermore, in the reaction using
4-methoxybenzaldehyde as a substrate, the product 4m
could be obtained at 61 % yield after 6 h. On the contrary,
the reaction could proceed smoothly to yield product 4n at
93 % after 1 hour when using 4-nitrobenzaldehyde as a
starting material. Moreover, we also examined the con-
densation reaction using alkyl aldehydes, such as
propionaldehyde and n-butylaldehyde, as starting materials
for 10 h. Unfortunately, in these cases, no desired products
were detected by LC–MS.
9
C6H5
0
10
11
12
13
14
15
16
2-Cl C6H4
3-Cl C6H4
4-Cl C6H4
C6H5CH2
C6H5CH2
C6H5CH2
4j
64
71
92
61
93
0
4
4k
4l
2
4-CH3OC6H4 C6H5CH2
4-NO2C6H4 C6H5CH2
6
4m
4n
4o
4p
1
CH3CH2
C6H5CH2
10
10
CH3CH2CH2 C6H5CH2
0
Conditions 1H-indole-2-carboxylic acid (1) (10 mmol), aldehyde 2
(12 mmol), amine 3 (15 mmol), 20 cm3 EtOH
a
Isolated yields
(3a) in EtOH under catalyst-free conditions. To our delight,
this three-component reaction proceeded smoothly, gener-
ating the corresponding product 4a in 86 % yield under
reflux temperature for 6 h. Encouraged by this result, we
utilized different aromatic aldehydes and amines for the
preparation of Mannich compounds 4, and the results are
summarized in Table 1.
Having synthesized Mannich products 4 successfully,
we turned our attention to the synthesis of compounds 5.
Initially, the reaction of compound 4a was performed in
MeCN at reflux temperature for 10 h in the presence of
Brønsted acid or Lewis acids, such as TsOH, ZnCl2,
Zn(OTf)2, Yb(OTf)3, and CAN. Unfortunately, compound
4a could not be cyclized to form compound 5a.
At first, we carried out the reaction of 1H-indole-2-
carboxylic acid, benzaldehyde, and a series of amines in
EtOH under reflux temperature. In all cases studied, the
three-component reaction using aryl–alkyl amines as
123

Synthesis of 1,2-disubstituted 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one derivatives
Table 2 Optimization of reaction conditions for the cyclization
reaction of 5a
Table 3 Synthesis of 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one
derivatives 5
Entry R1
R2
Time/ Product Yield/%a
Entry
Conditions
Time/h
Yield of 5a/%a
h
5
1
TsOH, 20 mol%
ZnCl2, 20 mol%
Zn(OTf)2, 20 mol%
Yb(OTf)3, 20 mol%
CAN, 20 mol%
HATU, 1.5 eq
10
10
10
10
10
6
0
0
1
C6H5
C6H5CH2
6
5a
5b
5c
5d
5e
5f
95
90
95
88
95
92
94
95
95
93
78
93
2
2
C6H5
4-CH3OC6H4CH2 5.5
3
0
3
C6H5
C6H5CH2CH2
(CH3)2CH
5.5
8
4
0
4
C6H5
5
0
5
C6H5
CH3CH2CH2
CH3CH2CH2CH2
Cyclopentyl
C6H5CH2
3.5
4
6
90
80
88
86
95
88
6
C6H5
7
HBTU, 1.5 eq
6
7
C6H5
6.5
5.5
6
5g
5j
8
PyBop, 1.5 eq
6
8
2-Cl C6H4
3-Cl C6H4
4-Cl C6H4
9
HATU, 1.0 eq
8
9
C6H5CH2
5k
5l
10
11
HATU, 1.2 eq
6
10
11
12
C6H5CH2
6
HATU, 2.0 eq
6
4-CH3OC6H4 C6H5CH2
4-NO2C6H4 C6H5CH2
4.5
8
5m
5n
Conditions compound 4a (3 mmol), 20 cm3 MeCN
a
Isolated yields
Conditions compound 4 (3 mmol), HATU (3.6 mmol, 1.2 eq.),
20 cm3 MeCN, reflux temperature
a
Isolated yields
Subsequently, we carried out the reaction via the use of
dehydration reagents such as HATU, HBTU, and PyBop.
To our delight, the reaction proceeded smoothly to yield
the corresponding product 5a in 88–90 % yields (Table 2,
entries 6–8). As shown in Table 2, the best reaction con-
ditions were obtained by using 1.2 eqiv HATU as the
dehydration reagent in MeCN at reflux temperature.
With the optimal reaction conditions in hand, this
method was applied to different compounds 4 to explore
the substrate scope and limitations of this method, and the
relevant results are summarized in Table 3.
reaction conditions make the strategy useful in synthesiz-
ing these kinds of heterocyclic compounds.
Experimental
Melting points were measured by a WRS-1B micromelting
point apparatus. NMR spectra were recorded on Bruker
AMX 400 and Bruker Avance III/500 instruments as
DMSO-d6 solutions. HR–ESI–MS were determined on a
Micromass Q-Tof Global mass spectrometer, and ESI–MS
were run on a Bruker Esquire 3000 Plus Spectrometer.
TLC was performed on GF254 silica gel plates (Yantai
Huiyou Inc., China). The chemicals used in this work were
obtained from commercial channels and were used without
purification.
As shown in Table 3, the reaction of compound 4 was
carried out in the presence of 1.2 equiv HATU in MeCN
under reflux temperature to synthesize compounds 5
(Table 3). The results revealed that all the compounds 4
synthesized by the Mannich reaction could proceed
smoothly to form compounds 5 in high yields.
In conclusion, we have developed a facile and efficient
method for the synthesis of 3-(aminomethyl)-1H-indole-2-
carboxylic acid derivatives 4 via the three-component
condensation of 1H-indole-2-carboxylic acid (1a), alde-
hyde 2, and amine 3 in EtOH under catalyst-free
conditions. 1,2-Dihydropyrrolo[3,4-b]indol-3(4H)-one deri-
vatives 5 can be obtained from compound 4 by using 1.2
equiv HATU as the dehydration reagent in MeCN at reflux
temperature. The simple work-up, high yields, and mild
General procedure for the synthesis of compounds 4
A mixture of 1H-indole-2-carboxylic acid (1, 10 mmol),
aldehyde 2 (12 mmol), and amine 3 (15 mmol) in 20 cm3
alcohol was stirred under reflux conditions for the appro-
priate time (Table 1). After completion of the reaction
123

F. Ma et al.
7.82 (d, J = 8.1 Hz, 1H), 10.29 (brs, 1H), 11.40 (s, 1H),
14.04 (brs, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 19.29, 19.78, 47.34, 54.99, 112.15, 112.68, 119.47,
119.71, 123.51, 126.92, 128.41, 128.74, 129.19, 132.17,
134.73, 139.22, 165.04 ppm; MS (ESI): m/z = 309
([M ? H]?); HRMS (ESI): calcd for C19H21N2O2
[M ? H]? 309.1598, found 309.1605.
(TLC), the solid was filtered off and washed with ethanol to
yield the pure products 4.
3-[(Benzylamino)(phenyl)methyl]-1H-indole-2-carboxylic
acid (4a, C23H20N2O2)
Yield: 86 %; white solid; m.p.: 256–257 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.95 (d, J = 13.2 Hz, 1H),
4.04 (d, J = 13.2 Hz, 1H), 5.70 (s, 1H), 7.00 (t,
J = 8.1 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.29 (t,
J = 7.4 Hz, 1H), 7.34–7.42 (m, 8H), 7.59 (d,
J = 8.0 Hz, 1H), 7.64–7.68 (m, 2H), 10.15 (brs, 1H),
11.49 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 49.33, 57.15, 112.13, 112.38, 118.93, 119.42, 123.28,
126.47, 127.90, 128.32, 128.34, 128.53, 128.75, 129.42,
131.12, 133.69, 134.62, 138.84, 164.40 ppm; MS (ESI):
m/z = 357 ([M ? H]?); HRMS (ESI): calcd for
C23H21N2O2 [M ? H]? 357.1598, found 357.1606.
3-[Phenyl(propylamino)methyl]-1H-indole-2-carboxylic
acid (4e, C19H20N2O2)
Yield: 70 %; white solid; m.p.: 190–192 °C; 1H NMR
(400 MHz, DMSO-d6): d = 0.88 (t, J = 7.4 Hz, 3H),
1.58–1.72 (m, 2H), 2.77 (brs, 2H), 5.71 (s, 1H), 6.99 (t,
J = 7.5 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.30 (t,
J = 7.3 Hz, 1H), 7.34–7.40 (m, 3H), 7.67 (d,
J = 8.1 Hz, 1H), 7.70–7.74 (m, 2H), 10.09 (brs, 1H),
11.41 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 11.58, 20.04, 47.91, 57.85, 112.16, 112.72, 119.37,
119.72, 123.52, 127.00, 128.38, 128.77, 129.16, 131.92,
134.82, 139.23, 165.12 ppm; MS (ESI): m/z = 309
([M ? H]?); HRMS (ESI): calcd for C19H21N2O2
[M ? H]? 309.1598, found 359.1607.
3-[[(4-Methoxybenzyl)amino](phenyl)methyl]-1H-indole-
2-carboxylic acid (4b, C24H22N2O3)
Yield: 88 %; white solid; m.p.: 235–236 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.77 (s, 3H), 3.89 (d,
J = 13.9 Hz, 1H), 3.98 (d, J = 13.9 Hz, 1H), 5.67 (s,
1H), 6.95 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H),
7.15 (t, J = 7.2 Hz, 1H), 7.27–7.42 (m, 6H), 7.59 (d,
J = 8.1 Hz, 1H), 7.62–7.69 (m, 2H), 10.03 (brs, 1H), 11.45
(s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 49.13,
55.58, 57.32, 112.29, 112.79, 114.33, 119.31, 119.83,
123.64, 125.73, 126.92, 128.34, 128.74, 129.17, 131.42,
131.77, 135.00, 139.25, 159.74, 164.88 ppm; MS (ESI):
m/z = 387 ([M ? H]?); HRMS (ESI): calcd for
C24H23N2O3 [M ? H]? 387.1703, found 387.1711.
3-[(Butylamino)(phenyl)methyl]-1H-indole-2-carboxylic
acid (4f, C20H22N2O2)
Yield: 63 %; white solid; m.p.: 192–193 °C; 1H NMR
(400 MHz, DMSO-d6): d = 0.82 (t, J = 7.2 Hz, 3H),
1.25–1.35 (m, 2H), 1.55–1.70 (m, 2H), 2.75–2.90 (m,
2H), 5.77 (s, 2H), 7.00 (t, J = 7.4 Hz, 1H), 7.15 (t,
J = 7.5 Hz, 1H), 7.29 (t, J = 7.1 Hz, 1H), 7.35 (t,
J = 7.3 Hz, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.69 (d,
J = 8.0 Hz, 1H), 7.75 (d, J = 7.4 Hz, 2H), 10.22 (s,
1H), 11.52 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 13.94, 19.87, 28.61, 45.96, 57.98, 112.15, 112.81,
119.37, 119.80, 123.59, 127.06, 128.44, 128.79, 129.13,
131.92, 134.92, 139.08, 165.50 ppm; MS (ESI): m/z = 323
([M ? H]?); HRMS (ESI): calcd for C20H23N2O2
[M ? H]? 323.1754, found 323.1760.
3-[(Phenethylamino)(phenyl)methyl]-1H-indole-2-
carboxylic acid (4c, C24H22N2O2)
Yield: 67 %; white solid; m.p.: 226–227 °C; 1H NMR
(400 MHz, DMSO-d6): d = 2.91–3.08 (m, 4H), 5.75 (s,
1H), 6.98 (t, J = 7.5 Hz, 1H), 7.11–7.23 (m, 4H),
7.25–7.33 (m, 3H), 7.35–7.40 (m, 3H), 7.62 (d,
J = 8.1 Hz, 1H), 7.67–7.72 (m, 2H), 10.16 (brs, 2H),
11.43 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 32.75, 47.35, 57.78, 112.45, 112.74, 119.40, 119.75,
123.62, 126.94, 127.02, 128.35, 128.80, 128.87, 129.02,
129.20, 131.58, 134.91, 138.10, 139.26, 164.97 ppm; MS
(ESI): m/z = 371 ([M ? H]?); HRMS (ESI): calcd for
C24H23N2O2 [M ? H]? 371.1754, found 371.1749.
3-[(Cyclopentylamino)(phenyl)methyl]-1H-indole-2-
carboxylic acid (4g, C21H22N2O2)
Yield: 49 %; white solid; m.p.: 182–183 °C; 1H NMR
(400 MHz, DMSO-d6): d = 1.41–1.50 (m, 2H), 1.63–1.76
(m, 4H), 1.80–1.87 (m, 1H), 1.92–2.00 (m, 1H), 3.22–3.30
(m, 1H), 5.67 (s, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.13 (t,
J = 7.5 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.34–7.10 (m,
3H), 7.72–7.77 (m, 2H), 10.13 (brs, 1H), 11.41 (s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 23.81, 23.89,
29.88, 30.01, 56.65, 56.88, 112.20, 112.69, 119.41, 119.72,
123.51, 126.94, 128.48, 128.74, 129.13, 132.04, 134.80,
139.20, 165.11 ppm; MS (ESI): m/z = 335 ([M ? H]?);
HRMS (ESI): calcd for C21H23N2O2 [M ? H]? 335.1754,
found 335.1761.
3-[(Isopropylamino)(phenyl)methyl]-1H-indole-2-
carboxylic acid (4d, C19H20N2O2)
Yield: 90 %; white solid; m.p.: 217–218 °C; 1H NMR
(400 MHz, DMSO-d6): d = 1.23 (d, J = 6.5 Hz, 3H), 1.30
(d, J = 6.4 Hz, 3H), 3.02 (brs, 1H), 5.77 (s, 1H), 7.00 (t,
J = 7.5 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.30 (t,
J = 7.3 Hz, 1H), 7.34–7.40 (m, 3H), 7.76–7.78 (m, 2H),
123

Synthesis of 1,2-disubstituted 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one derivatives
3-[(Benzylamino)(2-chlorophenyl)methyl]-1H-indole-2-
carboxylic acid (4j, C23H19ClN2O2)
128.96, 129.82, 129.87, 130.89, 131.64, 134.04, 135.06,
159.65, 165.07 ppm; MS (ESI): m/z = 387 ([M ? H]?);
HRMS (ESI): calcd for C24H23N2O3 [M ? H]? 387.1703,
found 387.1710.
Yield: 64 %; white solid; m.p.: 234–235 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.92 (d, J = 13.6 Hz, 1H),
4.14 (d, J = 13.6 Hz, 1H), 5.97 (s, 1H), 7.00 (t,
J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.29–7.51 (m,
10H), 7.65–7.68 (m, 1H), 8.92 (brs, 1H), 11.68 (s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 49.66, 52.71,
111.28, 113.08, 118.87, 120.18, 124.00, 126.90, 128.35,
128.92, 128.94, 130.12, 130.30, 130.72, 130.82, 132.20,
133.30, 133.71, 135.25, 135.84, 164.74 ppm; MS (ESI):
m/z = 391 ([M ? H]?); HRMS (ESI): calcd for
C23H20ClN2O2 [M ? H]? 391.1208, found 391.1200.
3-[(Benzylamino)(4-nitrophenyl)methyl]-1H-indole-2-
carboxylic acid (4n, C23H19N3O4)
Yield: 93 %; pale yellow solid; m.p.: 255–257 °C; 1H
NMR (500 MHz, DMSO-d6): d = 4.00 (d, J = 13.0 Hz,
1H), 4.05 (d, J = 13.0 Hz, 1H), 5.95 (s, 1H), 7.05 (t,
J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.36–7.42 (m,
6H), 7.73 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.7 Hz, 2H),
8.23 (d, J = 8.6 Hz, 2H), 10.14 (brs, 1H), 11.61 (s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 50.06, 56.90,
112.36, 112.97, 119.49, 120.15, 124.02, 124.35, 126.78,
128.72, 128.95, 129.43, 129.77, 131.24, 134.44, 135.23,
146.84, 147.56, 164.62 ppm; MS (ESI): m/z = 402
([M ? H]?); HRMS (ESI): calcd for C23H20N3O4
[M ? H]? 402.1448, found 402.1442.
3-[(Benzylamino)(3-chlorophenyl)methyl]-1H-indole-2-
carboxylic acid (4k, C22H19ClN2O2)
Yield: 71 %; white solid; m.p.: 240–241 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.98 (d, J = 13.2 Hz, 1H),
4.03 (d, J = 13.2 Hz, 1H), 5.79 (s, 1H), 7.04 (t,
J = 7.5 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.35–7.43 (m,
8H), 7.62 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H),
7.77 (s, 1H), 9.99 (brs, 1H), 11.57 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 49.98, 57.11, 112.18, 112.94,
119.41, 120.06, 123.90, 126.91, 127.07, 128.23, 128.70,
128.77, 128.95, 129.83, 131.08, 131.56, 133.66, 134.16,
135.16, 141.71, 164.93 ppm; MS (ESI): m/z = 391
([M ? H]?); HRMS (ESI): calcd for C23H20ClN2O2
[M ? H]? 391.1208, found 391.1203.
General procedure for the synthesis of compounds 5
A
mixture of compound 4 (2 mmol) and HATU
(2.4 mmol) in 20 cm3 MeCN was stirred under reflux
conditions for the appropriate time (Table 3). After com-
pletion of the reaction (TLC), the solid was filtered off and
purified by column chromatography to yield the pure pro-
ducts 5.
3-[(Benzylamino)(4-chlorophenyl)methyl]-1H-indole-2-
carboxylic acid (4l, C22H19ClN2O2)
2-Benzyl-1-phenyl-1,2-dihydropyrrolo[3,4-b]indol-3(4H)-
one (5a, C23H18N2O)
Yield: 92 %; white solid; m.p.: 250–252 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.96 (d, J = 13.2 Hz, 1H),
4.03 (d, J = 13.2 Hz, 1H), 5.76 (s, 1H), 7.02 (t,
J = 7.5 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.35–7.45 (m,
6H), 7.43 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.1 Hz, 1H),
7.68 (d, J = 8.5 Hz, 2H), 10.20 (brs, 1H), 11.53 (s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 49.86, 56.94,
112.43, 112.91, 119.37, 119.97, 123.83, 126.87, 128.75,
128.95, 129.13, 129.81, 130.29, 131.54, 133.40, 134.21,
135.15, 138.28, 164.97 ppm; MS (ESI): m/z = 391
([M ? H]?); HRMS (ESI): calcd for C23H20ClN2O2
[M ? H]? 391.1208, found 391.1211.
Yield: 95 %; white solid; m.p.: 240–242 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.85 (d, J = 15.6 Hz, 1H),
5.07 (d, J = 15.6 Hz, 1H), 5.54 (s, 1H), 6.98 (t,
J = 7.5 Hz, 1H), 7.14–7.40 (m, 12H), 7.47 (d,
J = 8.7 Hz, 1H), 12.07 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 44.23, 60.10, 113.94, 119.71,
120.53, 121.38, 124.48, 127.58, 127.60, 127.89, 128.64,
129.03, 129.42, 130.66, 133.42, 137.55, 138.33, 141.87,
162.84 ppm; MS (ESI): m/z = 339 ([M ? H]?); HRMS
(ESI): calcd for C23H19N2O [M ? H]? 339.1492, found
339.1496.
2-(4-Methoxybenzyl)-1-phenyl-1,2-dihydropyrrolo-
3-[(Benzylamino)(4-methoxyphenyl)methyl]-1H-indole-2-
carboxylic acid (4m, C24H22N2O3)
[3,4-b]indol-3(4H)-one (5b, C24H20N2O2)
Yield: 90 %; white solid; m.p.: 235–236 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.72 (s, 3H), 3.76 (d,
J = 15.3 Hz, 1H), 5.02 (d, J = 15.3 Hz, 1H), 5.49 (s,
1H), 6.88 (d, J = 8.5 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H),
7.08 (d, J = 8.5 Hz, 2H), 7.19–7.26 (m, 4H), 7.30–7.40
(m, 3H), 7.46 (d, J = 8.5 Hz, 1H), 12.07 (s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 43.60, 55.46, 59.82,
113.92, 114.44, 119.67, 120.50, 121.35, 124.43, 127.56,
128.61, 129.33, 129.43, 130.23, 130.61, 133.46, 137.62,
Yield: 61 %; white solid; m.p.: 249–251 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.70 (s, 3H), 3.93 (d,
J = 13.2 Hz, 1H), 4.02 (d, J = 13.2 Hz, 1H), 5.66 (s,
1H), 6.91 (d, J = 8.7 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H),
7.15 (t, J = 7.5 Hz, 1H), 7.36–7.40 (m, 6H), 7.52–7.57 (m,
3H), 10.35 (brs, 1H), 11.45 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 49.59, 55.58, 57.07, 112.68,
112.79, 114.49, 119.32, 119.77, 123.66, 126.89, 128.77,
123

F. Ma et al.
141.81, 158.88, 162.74 ppm; MS (ESI): m/z = 369
([M ? H]?); HRMS (ESI): calcd for C24H21N2O2
[M ? H]? 369.1898, found 369.1904.
DMSO-d6): d = 13.98, 19.92, 30.71, 40.18, 60.09, 113.90,
119.52, 120.43, 121.38, 124.21, 127.52, 128.54, 129.33,
130.22, 133.92, 138.06, 141.72, 162.62 ppm; MS (ESI):
m/z = 305 ([M ? H]?); HRMS (ESI): calcd for
C20H21N2O [M ? H]? 305.1648, found 305.1644.
2-Phenethyl-1-phenyl-1,2-dihydropyrrolo[3,4-b]indol-
3(4H)-one (5c, C24H20N2O)
Yield: 95 %; white solid; m.p.: 267–268 °C; 1H NMR
(400 MHz, DMSO-d6): d = 2.68–2.76 (m, 1H), 2.86-2.93
(m, 1H), 2.95–3.03 (m, 1H), 3.92–4.00 (m, 1H), 5.63 (s,
1H), 6.99 (t, J = 7.5 Hz, 1H), 7.14–7.29 (m, 9H),
7.31–7.41 (m, 3H), 7.45 (d, J = 8.2 Hz, 1H), 11.98 (s,
1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 34.80,
42.25, 60.41, 113.93, 119.54, 120.49, 121.32, 124.30,
126.68, 127.62, 128.67, 128.84, 128.99, 129.40, 130.12,
133.88, 137.79, 139.41, 141.73, 162.43 ppm; MS (ESI):
m/z = 353 ([M ? H]?); HRMS (ESI): calcd for
C24H21N2O [M ? H]? 353.1648, found 353.1641.
2-Cyclopentyl-1-phenyl-1,2-dihydropyrrolo[3,4-b]indol-
3(4H)-one (5g, C21H20N2O)
Yield: 94 %; white solid; m.p.: 288–289 °C; 1H NMR
(400 MHz, DMSO-d6): d = 1.37–1.79 (m, 7H), 1.88–1.98
(m, 1H), 4.02–4.09 (m, 1H), 5.82 (s, 1H), 6.97 (t,
J = 7.5 Hz, 1H), 7.16–7.21 (m, 2H), 7.26–7.37 (m, 5H),
7.43 (d, J = 8.6 Hz, 1H), 11.90 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 23.69, 23.90, 29.65, 29.89,
55.79, 60.60, 113.85, 119.41, 120.36, 121.24, 124.21,
127.15, 128.24, 129.17, 130.92, 133.81, 139.64, 141.70,
163.28 ppm; MS (ESI): m/z = 317 ([M ? H]?); HRMS
(ESI): calcd for C21H21N2O [M ? H]? 317.1648, found
317.1654.
2-Isopropyl-1-phenyl-1,2-dihydropyrrolo[3,4-b]indol-
3(4H)-one (5d, C19H18N2O)
Yield: 88 %; white solid; m.p.: 290–291 °C; 1H NMR
(400 MHz, DMSO-d6): d = 1.01 (d, J = 6.8 Hz, 3H), 1.29
(d, J = 6.8 Hz, 3H), 4.01–4.09 (m, 1H), 5.80 (s, 1H), 6.96
(t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.18 (t,
J = 7.5 Hz, 1H), 7.26–7.36 (m, 1H), 7.43 (d, J = 8.3 Hz,
1H), 11.90 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.10, 21.49, 45.85, 59.60, 113.85, 119.38, 120.36,
121.24, 124.19, 127.48, 128.33, 129.08, 130.94, 133.95,
139.60, 141.73, 163.06 ppm; MS (ESI): m/z = 291
([M ? H]?); HRMS (ESI): calcd for C19H19N2O
[M ? H]? 291.1492, found 291.1497.
2-Benzyl-1-(2-chlorophenyl)-1,2-dihydropyrrolo[3,4-b]-
indol-3(4H)-one (5j, C23H17ClN2O)
Yield: 95 %; white solid; m.p.: 240–241 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.88 (d, J = 15.6 Hz, 1H),
5.13 (d, J = 15.6 Hz, 1H), 5.90 (s, 1H), 6.96 (d,
J = 8.0 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 7.14 (d,
J = 7.0 Hz, 2H), 7.20–7.37 (m, 7H), 7.48 (d,
J = 8.3 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 12.17 (s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 49.34, 61.08,
118.80, 124.35, 125.55, 125.65, 129.40, 132.51, 132.67,
132.76, 132.76, 133.34, 133.79, 134.78, 135.01, 137.76,
138.14, 139.21, 142.53, 146.55, 167.74 ppm; MS (ESI):
m/z = 373 ([M ? H]?); HRMS (ESI): calcd for
C23H18ClN2O [M ? H]? 373.1102, found 373.1108.
1-Phenyl-2-propyl-1,2-dihydropyrrolo[3,4-b]indol-3(4H)-
one (5e, C19H18N2O)
Yield: 95 %; white solid; m.p.: 270–271 °C; 1H NMR
(400 MHz, DMSO-d6): d = 0.81 (t, J = 7.4 Hz, 3H),
1.41–1.57 (m, 2H), 2.76–2.83 (m, 1H), 3.61–3.69 (m,
1H), 5.77 (s, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.21 (t,
J = 7.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.26–7.40 (m,
5H), 7.45 (d, J = 8.2 Hz, 1H), 11.97 (s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 11.64, 21.98, 42.30,
60.13, 113.90, 119.53, 120.44, 121.38, 124.23, 127.51,
128.54, 129.34, 130.25, 133.91, 138.07, 141.72,
162.69 ppm; MS (ESI): m/z = 291 ([M ? H]?); HRMS
(ESI): calcd for C19H19N2O [M ? H]? 291.1492, found
291.1499.
2-Benzyl-1-(3-chlorophenyl)-1,2-dihydropyrrolo[3,4-b]-
indol-3(4H)-one (5k, C23H17ClN2O)
Yield: 95 %; white solid; m.p.: 245–246 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.95 (d, J = 15.6 Hz, 1H),
5.04 (d, J = 15.6 Hz, 1H), 5.62 (s, 1H), 7.01 (t,
J = 7.5 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 7.20–7.40
(m, 9H), 7.48 (d, J = 8.3 Hz, 1H), 12.12 (s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 44.48, 59.56, 114.00,
119.66, 120.65, 121.21, 124.60, 126.30, 127.35, 127.63,
127.92, 128.65, 129.00, 130.20, 131.31, 133.35, 133.97,
138.20, 140.33, 141.86, 162.83 ppm; MS (ESI): m/z = 373
([M ? H]?); HRMS (ESI): calcd for C23H18ClN2O
[M ? H]? 373.1102, found 373.1107.
2-Butyl-1-phenyl-1,2-dihydropyrrolo[3,4-b]indol-3(4H)-
one (5f, C20H20N2O)
Yield: 92 %; white solid; m.p.: 299–300 °C; 1H NMR
(400 MHz, DMSO-d6): d = 0.84 (t, J = 7.3 Hz, 3H),
1.16–1.28 (m, 2H), 1.40–1.51 (m, 2H), 2.76–2.85 (m,
1H), 3.68–3.76 (m, 1H), 5.76 (s, 1H), 6.99 (t, J = 7.5 Hz,
1H), 7.18–7.24 (m, 2H), 7.26–7.40 (m, 5H), 7.45 (d,
J = 8.3 Hz, 1H), 11.97 (s, 1H) ppm; 13C NMR (125 MHz,
2-Benzyl-1-(4-chlorophenyl)-1,2-dihydropyrrolo[3,4-b]-
indol-3(4H)-one (5l, C23H17ClN2O)
Yield: 93 %; white solid; m.p.: 287–288 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.89 (d, J = 15.6 Hz, 1H),
5.04 (d, J = 15.9 Hz, 1H), 5.59 (s, 1H), 7.00 (t,
J = 7.6 Hz, 1H), 7.17 (d, J = 7.0 Hz, 2H), 7.20–7.36
123

Synthesis of 1,2-disubstituted 1,2-dihydropyrrolo[3,4-b]indol-3(4H)-one derivatives
Acknowledgments This work was supported by the National Natural
(m, 7H), 7.42 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.6 Hz,
1H), 12.10 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 44.30, 59.36, 113.97, 119.67, 120.61, 121.24, 124.57,
127.63, 127.93, 129.03, 129.42, 129.56, 130.33, 133.12,
133.38, 136.70, 138.24, 141.86, 162.77 ppm; MS (ESI):
m/z = 373 ([M ? H]?); HRMS (ESI): calcd for
C23H18ClN2O [M ? H]? 373.1102, found 373.1096.
Science Foundation of China (Grants 30925040, 81102329, 81273397),
the Chinese National Science and Technology Major Project ‘‘Key New
Drug Creation and Manufacturing Program’’ (Grants 2013ZX09508104,
2012ZX09301001-001, 2011ZX09307-002-03), and the Science Foun-
dation of Shanghai (Grant 12XD1405700).
References
2-Benzyl-1-(4-methoxyphenyl)-1,2-dihydropyrrolo-
[3,4-b]indol-3(4H)-one (5m, C24H20N2O2)
1. Clarisse D, Fenet B, Fache F (2012) Org Biomol Chem 10:6587
2. Falini G, Gualandi A, Savoia D (2009) Synthesis 14:2440
3. Tan M-X, Zhang Y-G (2009) Tetrahedron Lett 50:4912
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10. Pudlo M, Csanyi D, Moreau F, Hajos G, Riedl Z, Sapi J (2007)
Tetrahedron 63:10320
Yield: 78 %; white solid; m.p.: 259–260 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.74 (s, 3H), 3.83 (d,
J = 15.6 Hz, 1H), 5.03 (d, J = 15.6 Hz, 1H), 5.48 (s,
1H), 6.92 (d, J = 8.6 Hz, 2H), 6.99 (t, J = 7.6 Hz, 1H),
7.12–7.35 (m, 9H), 7.47 (d, J = 8.3 Hz, 1H), 12.04 (s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 44.01, 55.48,
59.54, 113.92, 114.78, 119.73, 120.48, 121.41, 124.42,
127.57, 127.87, 128.96, 129.03, 129.08, 130.75, 133.51,
138.44, 141.86, 159.55, 162.68 ppm; MS (ESI): m/z = 369
([M ? H]?); HRMS (ESI): calcd for C24H21N2O2
[M ? H]? 369.1598, found 369.1603.
11. Pudlo M, Gerard S, Mirand C, Sapi J (2008) Tetrahedron Lett
49:1066
12. Hynes J, Doubleday WW, Dyckman AJ, Godfrey JD, Grosso JA,
Kiau S, Leftheris K (2004) J Org Chem 69:1368
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18. Bennasar ML, Roca T, Garcia-Diaz D (2008) J Org Chem
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2-Benzyl-1-(4-nitrophenyl)-1,2-dihydropyrrolo[3,4-b]-
indol-3(4H)-one (5n, C23H17N3O3)
Yield: 93 %; white solid; m.p.: 289–290 °C; 1H NMR
(400 MHz, DMSO-d6): d = 3.97 (d, J = 15.6 Hz, 1H),
5.07 (d, J = 15.6 Hz, 1H), 5.78 (s, 1H), 7.00 (t,
J = 7.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 2H), 7.20–7.32
(m, 5H), 7.48 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.6 Hz,
2H), 8.20 (d, J = 8.6 Hz, 2H), 12.17 (s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 44.64, 59.40, 114.03,
119.63, 120.71, 121.11, 124.59, 124.71, 127.68, 128.02,
128.94, 129.03, 129.88, 133.32, 138.04, 141.88, 145.67,
147.70, 162.85 ppm; MS (ESI): m/z = 384 ([M ? H]?);
HRMS (ESI): calcd for C23H18N3O3 [M ? H]? 384.1343,
found 384.1338.
123