A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one derivatives

Article abstract of DOI:10.1007/s11164-015-2273-1

A simple and concise construction of a series of new quinoline-based isoindolin-l-ones, namely N-substituted-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones, wherein the benzene moiety of isoindolin-l-one is replaced by a quinoline ring has been achieved via

Full text of DOI:10.1007/s11164-015-2273-1

Res Chem Intermed
DOI 10.1007/s11164-015-2273-1
A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one
derivatives
Kai Li1 Xinbo Fu1 Yanan Zhao1 Wentao Gao1
Yang Li1
•
•
•
•
Received: 10 August 2015 / Accepted: 12 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A simple and concise construction of a series of new quinoline-based
isoindolin-l-ones, namely N-substituted-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-
ones, wherein the benzene moiety of isoindolin-l-one is replaced by a quinoline ring
has been achieved via a two-step procedure, involving the one-step synthesis of
ethyl 2-chloromethyl-quinoline-3-carboxylate followed by its one-pot reaction with
various amines in a refluxing EtOH–AcOH (v/v, 10:1) solvent system. These newly
synthesized compounds could be good candidates for the development of lead
compounds for use in medicinal chemistry.
Keywords Quinoline Á Isoindolin-l-one Á Hybrid Á One-pot synthesis Á Amine
Introduction
It is well established that when a number of bioactive heterocyclic compounds are
linked with a quinoline moiety in fused or bonded forms the combination usually
results in new hybrids with potent pharmacological properties, such as anti-ulcer
[1], anti-tubercular [2], antimalarial [3], antimicrobial and anticancer activities [4].
For example, Guo et al. [5] recently found that rhodanine derivatives, upon bearing
a quinoline moiety, are interesting scaffolds for the development of novel Gram-
positive antibacterial agents. A recent review concerning the anticancer potential of
bioactive heterocycle quinoline has been reported [6]. It is, therefore, not surprising
that the design and synthesis of novel quinoline-containing heterocycle hybrids has
attracted much attention and interest in these compounds continues unabated [7–9].
&
Yang Li
bhuzh@163.com
1
Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, China
123

K. Li et al.
On the other hand, isoindolin-1-one (or phthalimidine) is a key structural element
present in many naturally occurring substances like cichorine (1, Fig. 1) [10], and
vitedoamine A (2, Fig. 1) [11], and also in some pharmacologically important
synthetic compounds such as indoprofen (3, Fig. 1) [12] and lenalidomide (4,
Fig. 1) [13] (as shown in Fig. 1). Compounds of this family had earned the status of
a privileged pharmacophore and exhibited a broad spectrum of biological activity,
such as antimicrobial [14], anti-nociceptive [15], antipsychotic [16], and the
inhibitory activities on tumor necrosis factor production and on histone deacetylase
(HDAC) [17]. Moreover, this benzolactam system is also used as important
synthons to access various drugs and natural products [18–20]. Therefore, numerous
efforts have been invested in exploring new structures of isoindolin-l-one analogues
[21, 22]. However, as far as we know, there are very seldom reports on the synthesis
of quinoline-based isoindolin-l-ones wherein the benzene moiety of isoindolin-l-one
is replaced by a quinoline ring. In this context, Isomae et al. [23] reported the
synthesis of quinoline-based isoindolin-l-one T-82 (5, Fig. 1), which exhibited
selective inhibitory activity against acetylcholinesterase. However, the report is of
individual synthesis and no efforts have been made to develop a general synthetic
approach.
On the basis of these observations, and in view of structural diversity playing a
prominent role in medicinal and combinatorial chemistry for a faster and more
efficient route towards new drug discovery [24], the synthesis of structurally novel
quinoline-based isoindolin-l-one derivatives as possible drug-like candidates would
be of synthetic importance. In the context of our ongoing studies concerning the
synthesis of quinoline-based hybrid molecules [25–30], we would like to report
herein a simple and efficient procedure for the synthesis of a series of novel
N-substituted-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones (6, Fig. 1) through the
one-pot reaction between ethyl 2-(chloromethyl)quinoline-3-carboxylate and
amines.
Fig. 1 The structures of compounds 1–6
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A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
Results and discussion
In recent years, a number of synthetic methods have been developed for the
synthesis of isoindolin-1-one derivatives, such as the one-pot reaction of 2-formyl-
benzoic acid with amines and dimethyl phosphate followed by dephosphonylation
reaction [31], palladium(0)-catalyzed carbonylation–amination [32], carbamoyl
radical cyclization [33], the Parham-type cyclization of iodinated benzyldicarba-
mates [34], the condensation of anilines with o-phthalaldehydes [35], and inverse-
electron demand Diels–Alder cycloadditions [36]. These synthetic methodologies
described occur with medium to high yields, but they are not easily extended to the
synthesis of quinoline-based isoindolin-l-ones due to the unavailability of the
required starting materials.
Recently, ethyl 2-halomethyl-quinoline-3-carboxylates have been viewed as an
ideal starting material for the flexible synthesis of a large range of quinoline
derivatives because of the presence of an active halomethyl group [37, 38]. In this
context, we have reported their reaction with various phenols or aromatic aldehydes
in the synthesis of polycyclic systems structurally related to biologically active
alkaloids (Scheme 1) [25, 27]. We have also developed their one-pot reaction with
various salicylaldehydes for the synthesis of 2-benzofuran-containing quinoline-3-
carboxylic acid derivatives [28]. Building on the evolving expertise, we envisioned
Scheme 1 One-pot synthesis of quinoline-based isoindolin-l-ones 6
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K. Li et al.
it might be possible to convert them into the desired quinoline-based isoindolin-l-
one derivatives through a cascade Williamson-type condensation reaction with
amines and subsequent intramolecular C–N bond cyclization of the resulting
intermediates in a single synthetic operation, as shown in Scheme 1.
Therefore, the first stage in this strategy involved the preparation of ethyl
2-halomethyl-quinoline-3-carboxylate. Prior to the current investigation, we and
other groups reported the preparation of 2-bromomethylquinoline via the radical
bromination of the corresponding 2-methyquinolines with N-bromosuccinimide
(NBS) [39, 40]. However, the reaction has suffered from both low yields and excess
byproduct, because the desired mono-bromo product is always accompanied by the
gem-dibromo byproduct, which has very close polarity to the mono-bromo product
and cannot be easily separated by recrystallization or column chromatography.
Recently, we also described an efficient synthesis of 2-(chloromethyl)benzoquino-
line by the direct cyclization of 1-naphthylamine with ethyl 4-chloroacetoacetate by
the treatment of a Vilsmeier reagent prepared from dimethylformamide and
phosphorus oxychloride [41]. Unfortunately, our attempts to follow the route using
aniline instead of naphthalen-1-amine were frustrated by poor yields of highly
¨
impure products. Additionally, we also tried the Friedlander reaction [42] of o-
aminobenzaldehyde with ethyl 4-chloroacetoacetate employing microwave irradi-
ation (MW) and a catalytic amount of hydrochloric acid, according to the method
reported by Muscia et al. [43] Although the procedure is very easy and impressive,
this purported approach was ineffective in our hands and the reaction did not
proceed satisfactorily, giving poor yields of highly impure product.
McNaughton and coworker reported a mild and efficient one-step synthesis of
quinolines which employs SnCl2 and ZnCl2 to effect the reaction [44]. On this basis,
we conjecture that this one-step reaction sequence might be extended to the
synthesis of ethyl 2-(chloromethyl)quinoline-3-carboxylate by replacing ketones
with ethyl 4-chloroacetoacetate. Accordingly, our attempt was made by refluxing o-
nitrobenzaldehyde (10) and 1.1 equiv. of ethyl 4-chloroacetoacetate (9) in
˚
anhydrous ethanol, in the presence of 5 equiv of SnCl2 and ZnCl2 as well as 4 A
molecular sieves, as outlined in Scheme 2. To our delight, the use of ethyl
4-chloroacetoacetate (9) was amenable to the one-flask reaction conditions, and
thin-layer chromatography (TLC) did not indicate the formation of any distinct
byproduct. After the usual workup, the crude product was purified by column
chromatography over silica gel, and the desired ethyl 2-(chloromethyl)quinoline-3-
carboxylate (8) was obtained at a good yield of 83 %.
Scheme 2 One-step synthesis of ethyl 2-(chloromethyl)quinoline-3-carboxylate (8)
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A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
Having
established
the
efficient
one-pot
synthesis
of
ethyl
2-(chloromethyl)quinoline-3-carboxylate, our attention was transferred to its
reaction with aromatic amines for building the desired quinoline-based isoindolin-
l-one system. At this stage, we first conducted the reaction of 8 and 1.0 equiv of
aniline (7a) using refluxing ethanol (EtOH) as the solvent in accordance with the
reaction conditions described in the literature [45]. As expected, the desired product
N-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6a) could be obtained, but
this was plagued in our hands by a low yield of 53 %. To further improve the yield
of this synthetic approach, various solvents were applied to promote this
transformation and the results are summarized in Table 1.
As shown in Table 1, solvent choice is critical for this reaction. The usual
organic solvents, such as EtOH, methanol (MeOH), acetonitrile (MeCN), tetrahy-
drofuran (THF), dimethylformamide (DMF), and dioxane proved to be ineffective,
and low yields (37–53 %) of the desired product 6a were obtained (Table 1, entries
1–6). By switching the solvent to H2O or a solvent-free condition, no desired
product was detected (Table 1, entries 7 and 8). Recently, You et al. [46] reported
that by using an EtOH–acetic acid (AcOH) solvent system, the reaction of
phthalaldehydic acid, primary amine, and 2-mercaptobenzimidazole or 2-hydrox-
ybenzimidazole proceeded smoothly to give the targeted products in good yields.
The report prompted us to further experiment using the solvent system. To our
surprise, we found that the EtOH–AcOH solvent system also afforded a significant
amelioration in our preparation of 6a, and the best results were obtained when the
volume ratio of EtOH and AcOH was 10:1 (Table 1, entry 11). The progress of the
reaction was monitored by TLC, which exhibited a spot in the initial stages of the
Table 1 Synthesis of N-phenyl-pyrrolo[3,4-b]quinolin-1-one (6a) using various solvents
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)a
1
EtOH
Reflux
Reflux
Reflux
Reflux
85
36
36
36
36
36
36
36
6
53
43
38
37
40
35
0
2
MeOH
3
MeCN
4
THF
5
DMF
6
Dioxane
85
7
H2O
Reflux
r. t.
8
Solvent-free
0
9
EtOH–AcOH (2:1, v/v)
EtOH–AcOH (5:1, v/v)
EtOH–AcOH (10:1, v/v)
EtOH–AcOH (15:1, v/v)
EtOH–AcOH (20:1, v/v)
Reflux
Reflux
Reflux
Reflux
Reflux
6
62
70
83
76
64
10
11
12
13
6
6
6
6
Reaction conditions: compound 8 (0.5 mmol), aniline (7a; 0.5 mmol), solvent (3 mL)
a
Isolated yield
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K. Li et al.
Table 2 Yields and physical properties of the compounds 6a–o
Entry
1
Product
6a–o
6a
M.p./oC
Yielda (%)
84
239–240b
2
6b
251–252
80
3
4
6c
262–263
230–232
87
90
6d
5
6e
254–255
83
6
7
6f
237–238
267–268
85
82
6g
8
6h
6i
258–260
278–279
184–185
71
74
90
9
10
A1
11
12
A2
201–202
125–127
88
77
6l
123

A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
Table 2 continued
Entry
13
Product
6a–o
6m
M.p./oC
199–200
Yielda (%)
81
14
15
6n
6o
151–152
187–189
76
87
a
Isolated yields
b
Lit [45]. 240–241 °C
reaction, probably due to the formation of the intermediate ethyl 2-((pheny-
lamino)methyl)quinoline-3-carboxylate, which gradually disappeared with the
appearance of a new dark spot arising from the formation of the desired product
6a. Due to the good yield obtained and in order to retain the simplicity of the
procedure, no further optimization in reaction conditions was necessary and the
above mentioned condition was chosen for the following work.
Thereafter, we extended the reaction to various substituted aromatic amines 7b–k
in a similar fashion. The results of this series of experiments are compiled in
Table 2. Our results demonstrated that the reaction proceeded smoothly in good
yields in the presence of a variety of functional groups, including methyl, ethyl,
methoxy, t-butyl, and halogen atoms (Entries 1–9, Table 2), except in cases of
entries 10 and 11, wherein the reaction of 8 with 2-ethylaniline (7j) and 2,5-
dimethoxyaniline (7k) did not afford the desired cyclized products as determined by
liquid chromatography–mass spectrometry (LC–MS), but only the intermediates A1
and A2, respectively. This phenomenon might be due to the steric hindrance effect
by the presence of an ortho substituent which makes the coplanar form of the lactam
ring difficult to obtain during the intramolecular cyclization reaction. When R was
an electron-withdrawing group in the para-position, such as in fluoride and bromide,
the corresponding products were obtained in slightly lower yields of 71 and 74 %,
respectively (entries 8 and 9, Table 2). While as R was strong electron-withdrawing
groups, such as in NO2 and CN, the reaction was found to be very complex and we
could not separate and obtain any of the desired products in appreciable yields in
these cases. Instead, intractable complex mixtures were observed on TLC.
Further, due to the simplicity of the one-pot synthesis, we decided to extend its
scope to ammonia and some aliphatic amines such as methanamine, ethanamine,
and benzylamine (entries 12–15, Table 1). Fortunately, all of these amine were
equally amenable to the reaction process without any experimental difficulties,
furnishing the corresponding pyrrolo[3,4-b]quinolin-1-ones 6l–o in comparable
yields.
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K. Li et al.
The structures of all the newly-synthesized compounds were easily established
based on spectral data elemental analyses, which were in good agreement with the
compounds expected. As an example, the infrared (IR) spectrum of 6a exhibited the
disappearance of the ester carbonyl group at 1715 cm-1, and the appearance of the
lactam C=O stretching frequency at a decreased wave number of 1693 cm-1, which
were clear evidence for cyclization having occurred. Its proton nuclear magnetic
resonance (1H NMR) spectrum exhibited a singlet sharp line at 5.07 parts per
million (ppm), readily recognizable as arising from methylene protons, supporting
the signal of its carbon-13 (13C) NMR spectrum at 48.3 ppm. Moreover, the
presence of 10 aromatic protons in the range of the aromatic region of
7.19–8.77 ppm exactly matches its structure as well. Further, the structure assigned
to 6a was fully supported by its elemental analysis, which established its molecular
formulae in accordance with the suggested molecular structure. The other
synthesized compounds exhibited similar spectral characteristics, except the
substituents, which exhibited characteristic signals with appropriate chemical shifts.
On the basis of these experiments, a proposed mechanism portraying the
probable sequence of events for the formation of the title compounds is outlined in
Scheme 3. The Williamson-type reaction of the two fragments involves the
formation of intermediate A in the first step, which undergoes subsequent
intramolecular nucleophilic cyclization with participation of the N atom and the
ester C=O group to form a five-membered cyclic system B. After this cyclization,
the elimination of an equiv. of EtOH led to the formation of pyrrolo[3,4-b]quinolin-
1-one ring 6. It is worth mentioning that an example particularly relevant to the
present discussion is described in the literature [47], wherein 7-isopropyl-1-
methylazulen-4-amine undergoes intromolecular ring annulation reactions with a
3-position ester group to yield tricyclic d-lactams with the elimination of methanol
without the need for a catalyst.
Scheme 3 Possible mechanistic pathway of formation of pyrrolo[3,4-b]quinolin-1-ones 6
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A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
Conclusions
In conclusion, we have provided an easy access to the one-pot synthesis of
structurally novel and biologically intriguing quinoline-based isoindolin-l-one
derivatives in a relatively environmentally benign EtOH–AcOH (v/v, 10:1) solvent
system. These newly synthesized compounds would likely possess significant
biological activities and could be potentially applied for the development of
biologically and pharmaceutically important drugs. Further investigation concerning
the bioactive properties of the generated products as well as their application in the
synthesis of more complex heterocycles are currently under investigation in our
laboratory and will be reported in due course.
Experimental
All chemicals were analytical reagent (AR)-grade, commercially available and used
without further purification. The melting points were determined by using a WRS-
1B melting point apparatus and were uncorrected. The IR spectra were obtained
using potassium bromide (KBr) pellets in the range of 400–4000 cm-1 on a
Shimadzu Fourier transform (FT)-infrared spectrophotometer (FTIR-8400S, Shi-
1
madzu, Japan). H NMR and 13C NMR spectra were recorded on a Bruker Avance
NMR spectrometer using deuterated chloroform (CDCl3) as the solvent. The
reported chemical shifts (d values) are given in ppm downfield from tetramethyl-
silane (TMS) as the internal standard. The mass spectra were determined using an
MSD VL ESI1 spectrometer. The progress of reactions was monitored by TLC on
silica gel GF254 using a hexane/ethyl acetate mixture (4:1, v/v) as the eluent.
Procedure for the preparation of ethyl 2-(chloromethyl)quinoline-3-
carboxylate (8)
To a stirred solution of o-nitrobenzaldehyde (10; 1.51 g, 10.0 mmol) in 60 mL of
anhydrous ethanol was added anhydrous ZnCl2 (6.81 g, 50.0 mmol), SnCl2 (9.48 g,
˚
50.0 mmol) and approximately 1.6 g of 4 A molecular sieves at room temperature.
The resulting mixture was heated at refluxing temperature under an atmosphere of
N2 for 5 h. Ethyl 4-chloroacetoacetate (9; 1.82 g, 11.0 mmol) was then added
dropwise to the mixture, and the reaction was continued for another 10 h. After
completion, the reaction was cooled to room temperature and rendered basic (pH 8)
with 10-% sodium bicarbonate (aq). EtOAc (3 9 100 ml) was added to the reaction
mixture and organic phase was washed thoroughly with saturated NaCl (aq),
separated and dried over anhydrous Na2SO4. The residue was subjected to column
chromatography over silica gel eluting with hexane/ethyl acetate (12:1, v/v) to
afford compound 8. Yield 83 %, m.p. 117–118 °C. IR (KBr, m, cm-1): 3048, 2985,
1715 (C=O), 1617, 1562, 1492, 1429, 1389, 1273, 1257, 1133; 1H NMR (400 MHz,
CDCl3) (d, ppm): 1.48 (t, J = 7.2 Hz, 3H, OCH2CH3), 4.50 (q, J = 7.2 Hz, 2H,
OCH2CH3), 5.28 (s, 2H, Cl-CH2-Ar), 7.62 (t, J = 7.8 Hz, 1H, ArH), 7.83 (t,
123

K. Li et al.
J = 8.4 Hz, 1H, ArH), 7.91 (d, J = 8.4 Hz, 1H, ArH), 8.12 (d, J = 8.4 Hz, 1H,
ArH), 8.82 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) (d, ppm): 14.2, 46.6, 61.9,
123.2, 126.7, 127.9, 128.5, 129.3, 132.1, 140.9, 148.3, 155.7, 165.7; EI-MS m/z (%):
250.3, 252.1 [M?H]?. Anal. Calcd for C13H12ClNO2: C, 62.53; H, 4.84; N, 5.61.
Found: C, 62.74; H, 4.90; N, 5.75.
General procedure for synthesis of N-substituted-2,3-dihydro-1H-
pyrrolo[3,4-b]quinolin-1-ones (6a–o)
A mixture of ethyl 2-(chloromethyl)quinoline-3-carboxylate (8; 0.25 g, 1.0 mmol)
and the respective amine (7; 1.0 mmol) was refluxed in EtOH–AcOH (5 mL, v/v,
10:1). After the reaction was completed, as inferred through TLC studies (complete
disappearance of the starting materials), the reaction was cooled to room
temperature and the solvent was removed under reduced pressure. The residue
was purified by column chromatography using hexane/EtOAc (90:10) as the eluent,
affording the pure products 6a–o.
2-Phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6a)
White solid. IR (KBr, m, cm-1): 1693 (C=O), 1617, 1597, 1499, 1447, 1387, 1342,
1297, 1270, 1205; 1H NMR (CDCl3, 400 MHz) (d, ppm): 5.07 (s, 2H, CH2),
7.19–7.25 (m, 5H, ArH), 7.85 (t, J = 7.6 Hz, 1H, ArH), 8.03–8.06 (m, 2H, ArH),
8.38 (d, J = 8.4 Hz, 1H, ArH), 8.77 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) (d,
ppm): 48.3, 107.7, 110.5, 113.4, 116.2, 118.3, 121.8, 124.1, 126.7, 127.4, 128.7,
129.7, 135.3, 155.2, 164.0. MS (ESI, m/z): 261.0 [M?H]?. Anal. Calcd. for
C17H12N2O: C, 78.44; H, 4.65; N, 10.76. Found: C, 78.68; H, 4.91; N, 10.48.
2-(m-Tolyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6b)
White solid, IR (KBr, m, cm-1): 1695 (C=O), 1621, 1574, 1518, 1491, 1444, 1375,
1342, 1291, 1207; 1H NMR (CDCl3, 400 MHz) (d, ppm): 2.37 (s, 3H, Me), 4.98 (s,
2H, CH2), 6.99 (d, J = 7.6 Hz, 1H, ArH), 7.29 (t, J = 7.6 Hz, 1H, ArH), 7.58–7.61
(m, 2H, ArH), 7.71 (s, 1H, ArH), 7.80 (t, J = 8.4 Hz, 1H, ArH), 7.97 (d,
J = 8.4 Hz, 1H, ArH), 8.13 (d, J = 8.4 Hz, 1H, ArH), 8.64 (s, 1H, ArH); 13C NMR
(CDCl3, 100 MHz) (d, ppm): 19.7, 50.5, 115.0, 118.6, 122.6, 123.9, 125.0, 125.5,
126.9, 127.0, 127.6, 129.7, 131.1, 136.8, 137.1, 148.1, 157.2, 163.3; MS (ESI, m/z):
275.1 [M?H]?. Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.99; H, 4.99; N, 10.33.
2-(p-Tolyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6c)
White solid. IR (KBr, m, cm-1): 1690 (C=O), 1635, 1580, 1508, 1454, 1418, 1393,
1
1372, 1298, 1270, 1191; H NMR (CDCl3, 600 MHz) (d, ppm): 2.40 (s, 3H, Me),
5.05 (s, 2H, CH2), 7.29 (d, J = 8.4 Hz, 2H, ArH), 7.66 (t, J = 7.8 Hz, 1H, ArH),
7.80 (d, J = 8.4 Hz, 2H, ArH), 7.89 (t, J = 7.8 Hz, 1H, ArH), 8.05 (d, J = 7.8 Hz,
1H, ArH), 8.20 (d, J = 8.4 Hz, 1H, ArH), 8.72 (s, 1H, ArH); 13C NMR (CDCl3,
123

A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
150 MHz) (d, ppm): 20.9, 52.6, 120.0, 124.8, 127.1, 127.7, 129.1, 129.6, 129.8,
131.7, 133.1, 135.0, 136.5, 150.2, 159.4, 165.3; MS (ESI, m/z): 275.1 [M?H]?.
Anal. Calcd. for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C, 79.03; H, 4.96;
N, 9.97.
2-(4-Methoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6d)
White solid. IR (KBr, m, cm-1): 1689 (C=O), 1619, 1511, 1437, 1373, 1340, 1250,
1205; 1H NMR (CDCl3, 600 MHz) (d, ppm): 3.86 (s, 3H, OMe), 5.02 (s, 2H, CH2),
7.02 (d, J = 8.4 Hz, 2H, ArH), 7.67 (t, J = 7.8 Hz, 1H, ArH), 7.81 (d, J = 8.4 Hz,
2H, ArH), 7.88 (t, J = 7.8 Hz, 1H, ArH), 8.03 (d, J = 7.8 Hz, 1H, ArH), 8.19 (d,
J = 8.4 Hz, 1H, ArH), 8.70 (s, 1H, ArH); 13C NMR (CDCl3, 150 MHz) (d, ppm):
52.9, 55.5, 114.5, 121.8, 124.7, 127.0, 127.8, 129.2, 129.7, 131.6, 132.2, 133.0,
157.1, 159.4, 165.2; MS (ESI, m/z): 290.8 [M?H]?; Anal. Calcd for C18H14N2O2:
C, 74.47; H, 4.86; N, 9.65. Found: C, 74.31; H, 4.97; N, 9.78.
2-(Benzo[d][1, 3]dioxol-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one
(6e)
White solid, IR (KBr, m, cm-1): 1683 (C=O), 1617, 1589, 1494, 1453, 1417, 1373,
1
1332, 1291, 1263, 1201; H NMR (CDCl3, 400 MHz) (d, ppm): 5.04 (s, 2H, CH2),
5.96 (s, 2H, OCH2O), 6.83 (d, J = 8.0 Hz, 1H, ArH), 7.08 (d, J = 8.4 Hz, 1H,
ArH), 7.56 (s, 1H, ArH), 7.66 (t, J = 8.4 Hz, 1H, ArH), 7.87 (t, J = 8.0 Hz, 1H,
ArH), 8.03 (d, J = 8.4 Hz, 1H, ArH), 8.25 (d, J = 8.4 Hz, 1H, ArH), 8.73 (s, 1H,
ArH); 13C NMR (CDCl3, 100 MHz) (d, ppm): 52.5, 102.5, 105.7, 109.2, 117.2,
122.1, 126.9, 127.5, 129.1, 130.3, 133.5, 138.0, 142.4, 143.5, 148.6, 148.9, 157.1,
164.7; MS (ESI, m/z): 305.0 [M?H]?. Anal. Calcd for C18H12N2O3: C, 71.05; H,
3.97; N, 9.21. Found: C, 71.17; H, 3.90; N, 9.03.
2-(4-Ethylphenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6f)
White solid. IR (KBr, m, cm-1): 1695 (C=O), 1617, 1516, 1437, 1374, 1340, 1301,
1272, 1205; 1H NMR (CDCl3, 600 MHz) (d, ppm): 1.28 (t, J = 7.8 Hz, 3H,
CH3CH2), 2.70 (q, J = 7.8 Hz, 2H, CH3CH2), 5.05 (s, 2H, CH2), 7.31 (d,
J = 8.4 Hz, 2H, ArH), 7.66 (t, J = 7.8 Hz, 1H, ArH), 7.82 (d, J = 8.4 Hz, 2H,
ArH), 7.87 (t, J = 7.8 Hz, 1H, ArH), 8.04 (d, J = 7.8 Hz, 1H, ArH), 8.19 (d,
J = 8.4 Hz, 1H, ArH), 8.71 (s, 1H, ArH); 13C NMR (CDCl3, 150 MHz) (d, ppm):
15.6, 28.4, 52.6, 120.1, 124.8, 127.1, 127.7, 128.7, 129.1, 129.6, 131.6, 133.1,
136.7, 141.3, 150.2, 159.4, 165.3; MS (ESI, m/z): 289.1 [M?H]?. Anal. Calcd. for
C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C, 79.35; H, 5.65; N, 9.86.
2-(4-(tert-Butyl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6g)
White solid, IR (KBr, m, cm-1): 1692 (C=O), 1617, 1514, 1449, 1374, 1340, 1298,
1
1267, 1204; H NMR (CDCl3, 400 MHz) (d, ppm): 1.33 (s, 9H, t-Bu), 5.02 (s, 2H,
CH2), 7.48 (d, J = 7.2 Hz, 2H, ArH), 7.62 (t, J = 8.0 Hz, 1H, ArH), 7.81 (d,
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J = 7.2 Hz, 2H, ArH), 7.85 (t, J = 8.0 Hz, 1H, ArH), 8.00 (d, J = 8.4 Hz, 1H,
ArH), 8.15 (d, J = 8.4 Hz, 1H, ArH), 8.68 (s, 1H, ArH); 13C NMR (CDCl3,
100 MHz) (d, ppm): 29.2, 32.4, 50.4, 117.6, 122.6, 125.0, 125.5, 126.9, 127.5,
129.6, 131.1, 134.2, 146.1, 147.9, 157.2, 163.2; MS (ESI, m/z): 317.2 [M?H]?.
Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 79.50; H, 6.54;
N, 9.03.
2-(4-Fluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6h)
Yellow solid, IR (KBr, m, cm-1): 1682 (C=O), 1613, 1510, 1436, 1378, 1343, 1291,
1264, 1220, 1176; 1H NMR (CDCl3, 400 MHz) (d, ppm): 5.00 (s, 2H, CH2),
7.11–7.14 (m, 2H, ArH), 7.61 (t, J = 8.0 Hz, 1H, ArH), 7.81–7.83 (m, 3H, ArH),
7.99 (d, J = 8.4 Hz, 1H, ArH), 8.15 (d, J = 8.4 Hz, 1H, ArH), 8.67 (s, 1H, ArH);
13C NMR (CDCl3, 100 MHz) (d, ppm): 52.6, 110.0, 115.9, 116.2, 121.6, 121.7,
125.2, 125.6, 127.4, 128.8, 129.7, 132.1, 133.6, 158.8, 164.3; MS (ESI, m/z): 279.1
[M?H]?. Anal. Calcd for C17H11FN2O: C, 73.37; H, 3.98; N, 10.07. Found: C,
73.14; H, 4.12; N, 10.16.
2-(4-Bromophenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6i)
Yellow solid; IR (KBr, m, cm-1): 1691 (C=O), 1618, 1584, 1492, 1433, 1367, 1339,
1292, 1264, 1203; 1H NMR (CDCl3, 600 MHz) (d, ppm): 4.96 (s, 2H, CH2), 7.37 (d,
J = 8.4 Hz, 2H, ArH), 7.60 (t, J = 7.8 Hz, 1H, ArH), 7.80–7.84 (m, 3H, ArH), 7.97
(d, J = 7.8 Hz, 1H, ArH), 8.12 (d, J = 8.4 Hz, 1H, ArH), 8.65 (s, 1H, ArH); 13C
NMR (CDCl3, 150 MHz) (d, ppm): 52.4, 120.9, 124.3, 127.3, 127.7, 129.2, 129.3,
129.7, 130.3, 131.9, 133.4, 137.7, 150.4, 158.9, 165.5; MS (ESI, m/z): 339.0, 341.1
[M?H]?. Anal. Calcd for C17H11BrN2O: C, 60.20; H, 3.27; N, 8.26. Found: C,
60.06; H, 3.38; N, 8.39.
Ethyl 2-(((2-ethylphenyl)amino)methyl)quinoline-3-carboxylate (A1)
Yellow crystals, IR (KBr, m, cm-1): 3396 (NH), 1720 (C=O), 1596, 1510, 1452,
1375, 1315, 1257, 1209, 1137, 1056; 1H NMR (CDCl3, 600 MHz) (d, ppm): 1.41 (t,
J = 7.2 Hz, 3H, CH2CH3), 1.51 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.77 (q,
J = 7.2 Hz, 2H, CH2CH3), 4.50 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.00 (s, 2H,
CH2), 6.73 (t, J = 7.2 Hz, 1H, ArH), 6.91 (d, J = 7.2 Hz, 1H, ArH), 7.13 (d,
J = 7.2 Hz, 1H, ArH), 7.18 (td, J = 7.8, 1.2 Hz, 1H, ArH), 7.62 (d, J = 7.2 Hz,
1H, ArH), 7.86 (td, J = 7.8, 1.2 Hz, 1H, ArH), 7.93 (d, J = 7.8 Hz, 1H, ArH), 8.16
(d, J = 8.4 Hz, 1H, ArH), 8.87 (s, 1H, ArH), 9.63 (s, 1H, NH); 13C NMR (CDCl3,
150 MHz) (d, ppm): 13.0, 14.4, 24.3, 48.8, 61.6, 122.4, 125.2, 126.1, 127.1, 127.2,
128.0, 128.6, 129.0, 132.0, 135.4, 137.9, 139.0, 139.6, 140.7, 147.9, 165.7; MS
(ESI, m/z): 335.2 [M?H]?. Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38.
Found: C, 75.21; H, 6.74; N, 8.47.
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A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
Ethyl 2-(((2,5-dimethoxyphenyl)amino)methyl)quinoline-3-carboxylate (A2)
Yellow solid, IR (KBr, m, cm-1): 3445 (NH), 1H NMR (CDCl3, 600 MHz) (d, ppm):
1.32 (t, J = 7.2 Hz, 3H, OCH2CH3), 3.63 (s, 3H, OMe), 3.70 (s, 3H, OMe), 4.33 (q,
J = 7.2 Hz, 2H, OCH2CH3), 4.57 (s, 2H, CH2), 6.86 (s, 1H, ArH), 7.05 (d,
J = 7.2 Hz, 1H, ArH), 7.17 (d, J = 7.2 Hz, 1H, ArH), 7.66 (td, J = 8.4, 1.8 Hz,
1H, ArH), 7.85 (td, J = 8.4, 1.8 Hz, 1H, ArH), 7.94 (d, J = 8.4 Hz, 1H, ArH), 8.13
(d, J = 7.8 Hz, 1H, ArH), 8.85 (s, 1H, ArH), 9.61 (s, 1H, NH); 13C NMR (CDCl3,
150 MHz) (d, ppm): 14.2, 48.6, 55.9, 56.0, 61.7, 121.3, 124.6, 125.2, 126.6, 127.8,
128.1, 128.6, 129.3, 131.9, 132.1, 133.4, 139.6, 140.3, 148.1, 149.8, 165.8; MS
(ESI, m/z): 367.2 [M?H]?. Anal. Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65.
Found: C, 69.06; H, 6.23; N, 7.50.
2,3-Dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6l)
White solid, IR (KBr, m, cm-1): 3459 (NH), 1702 (C=O), 1621, 1514, 1472, 1437,
1
1346, 1241; H NMR (CDCl3, 400 MHz) (d, ppm): 4.49 (s, 2H, CH2), 7.70 (t,
J = 7.6 Hz, 1H, ArH), 7.91 (t, J = 8.0 Hz, 1H, ArH), 8.12 (d, J = 8.4 Hz, 1H,
ArH), 8.22 (d, J = 8.4 Hz, 1H, ArH), 8.77 (s, 1H, ArH), 8.98 (s, 1H, NH); 13C
NMR (CDCl3, 100 MHz) (d, ppm): 47.1, 124.4, 127.0, 127.4, 128.9, 130.2, 131.7,
132.5, 149.6, 163.5, 168.2; MS (ESI, m/z): 185.2 [M?H]?. Anal. Calcd for
C11H8N2O: C, 71.73; H, 4.38; N,15.21. Found: C, 72.05; H, 4.30; N, 15.40.
2-Methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6m)
White solid, IR (KBr, m, cm-1): 1685 (C=O), 1621, 1508, 1449, 1402, 1381, 1336,
1286, 1240; 1H NMR (CDCl3, 400 MHz) (d, ppm): 3.23 (s, 3H, N-Me), 4.51 (s, 2H,
CH2), 7.57 (t, J = 8.4 Hz, 1H, ArH), 7.76 (t, J = 8.4 Hz, 1H, ArH), 7.92 (d,
J = 8.4 Hz, 1H, ArH), 8.06 (d, J = 8.8 Hz, 1H, ArH), 8.52 (s, 1H, ArH); 13C NMR
(CDCl3, 100 MHz) (d, ppm): 29.6, 53.6, 124.1, 126.9, 127.4, 128.9, 129.6, 131.4,
132.3, 149.5, 160.2, 166.5; MS (ESI, m/z): 199.1 [M?H]?. Anal. Calcd for
C12H10N2O: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.83; H, 5.20; N, 13.95.
2-Ethyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6n)
White solid, IR (KBr, m, cm-1): 2937, 2934, 1675 (C=O), 1621, 1581, 1511, 1463,
1406, 1379, 1320, 1239; 1H NMR (CDCl3, 400 MHz) (d, ppm): 1.30 (t, J = 7.2 Hz,
3H, CH2CH3), 3.73 (q, J = 7.2 Hz, 2H, CH2CH3), 4.53 (s, 2H, CH2), 7.57 (d,
J = 8.4 Hz, 1H, ArH), 7.78 (t, J = 8.0 Hz, 1H, ArH), 7.94 (t, J = 8.4 Hz, 1H,
ArH), 8.09 (t, J = 8.4 Hz, 1H, ArH), 8.54 (s, 1H, ArH); 13C NMR (CDCl3,
100 MHz) (d, ppm): 11.3, 35.1, 48.8, 107.9, 122.3, 124.8, 126.8, 127.4, 129.2,
130.2, 147.5, 158.3, 163.9; MS (ESI, m/z): 213.3 [M?H]?. Anal. Calcd for
C13H12N2O: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.41; H, 5.60; N, 13.34.
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2-Benzyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (6o)
White solid, IR (KBr, m, cm-1): 1681 (C=O), 1619, 1515, 1450, 1407, 1384, 1338,
1234; 1H NMR (CDCl3, 400 MHz) (d, ppm): 4.40 (s, 2H, CH2), 4.82 (s, 2H,
NCH2Ph), 7.22–7.28 (m, 5H, ArH), 7.54 (t, J = 8.0 Hz, 1H, ArH), 7.75 (t,
J = 8.4 Hz, 1H, ArH), 7.93 (d, J = 8.4 Hz, 1H, ArH), 8.04 (d, J = 8.8 Hz, 1H,
ArH), 8.58 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) (d, ppm): 46.5, 51.0, 120.7,
124.0, 127.0, 127.4, 127.9, 128.2, 128.9, 129.4, 131.1, 131.8, 132.0, 132.1, 132.8,
136.2, 149.6, 160.3; MS (ESI, m/z): 275.2 [M?H]?. Anal. Calcd for C18H14N2O: C,
78.81; H, 5.14; N, 10.21. Found: C, 79.24; H, 5.19; N, 10.45.
Acknowledgments The authors would like to thank the Scientific Research Foundation of the National
Natural Science Foundation of China (Grant Nos. 21402011 and 21476028) for financial support.
References
1. K.V. Sashidhara, S.R. Avula, V. Mishra, G.R. Palnati, L.R. Singh, N. Singh, Y.S. Chhonker, P.
Swami, R.S. Bhatta, G. Palit, Eur. J. Med. Chem. 89, 638 (2015)
2. A. Nayyar, S.R. Patel, M. Shaikh, E. Coutinho, R. Jain, Eur. J. Med. Chem. 44, 2017 (2009)
3. S.C. Teguh, N. Klonis, S. Duffy, L. Lucantoni, V.M. Avery, C.A. Hutton, J.B. Baell, L. Tilley, J.
Med. Chem. 56, 6200 (2013)
4. C.B. Sangani, J.A. Makawana, X. Zhang, S.B. Teraiya, L. Lin, H.-L. Zhu, Eur. J. Med. Chem. 76,
549 (2014)
5. M. Guo, C.-J. Zheng, M.-X. Song, Y. Wu, L.-P. Sun, Y.-J. Li, Y. Liu, H.-R. Piao, Bioorg. Med.
Chem. Lett. 23, 4358 (2013)
6. O. Afzal, S. Kumar, M.R. Haider, M.R. Ali, R. Kumar, M. Jaggi, S. Bawa, Eur. J. Med. Chem. 97,
871 (2015)
7. K.D. Thomas, A.V. Adhikari, I.H. Chowdhury, T. Sandeep, R. Mahmood, B. Bhattacharya, E.
Sumesh, Eur. J. Med. Chem. 46, 4834 (2011)
8. S.I. Pretorius, W.J. Breytenbach, C. de Kock, P.J. Smith, D.D. N’Da, Bioorg. Med. Chem. 21, 269
(2013)
9. M.I. Abdullah, A. Mahmood, M. Madni, S. Masood, M. Kashif, Bioorg. Chem. 54, 31 (2014)
10. A. Stierle, J. Hershenhorn, G. Strobel, Phytochemistry 32, 1145 (1993)
11. M. Ono, Y. Nishida, C. Masuoko, J.-C. Li, M. Okawa, T. Ikeda, T. Nohara, J. Nat. Prod. 67, 2073
(2004)
12. V. Ventafridda, G. Martino, V. Mandelli, A. Emanueli, Clin. Pharmacol. Ther. 17, 284 (1975)
13. J.B. Bartlett, K. Dredge, A.G. Dalgleish, Nat. Rev. Cancer 4, 314 (2004)
14. J.C. Breytenbach, S. van Dyk, I. van den Heever, S.M. Allin, C.C. Hodkinson, C.J. Northfield, M.I.
Page, Bioorg. Med. Chem. Lett. 10, 1629 (2000)
15. T. Nishiyama, S. Chiba, Y. Yamada, Eur. J. Pharmacol. 596, 56 (2008)
16. Z.-P. Zhuang, M.-P. Kung, M. Mu, H.F. Kung, J. Med. Chem. 41, 157 (1998)
17. H.J. Schmahl, L. Dencker, C. Plum, I. Chahoud, H. Nau, Arch. Toxicol. 11, 749 (1996)
18. J.K. Kim, Y.H. Kim, H.T. Nam, B.T. Kim, J.N. Heo, Org. Lett. 10, 3543 (2008)
19. Z. Guo, A.G. Schultz, J. Org. Chem. 66, 2154 (2001)
20. H.S. Lim, Y.L. Choi, J.N. Heo, Org. Lett. 15, 4718 (2013)
21. C.S. Cho, W.X. Ren, Tetrahedron Lett. 50, 2097 (2009)
22. D.M. Shacklady-McAtee, S. Dasgupta, M.P. Watson, Org. Lett. 13, 3490 (2011)
23. K. Isomae, S. Morimoto, H. Hasegawa, K. Morita, J. Kamei, Eur. J. Pharmacol. 465, 97 (2003)
24. R.E. Dolle, K.H. Nelson Jr, J. Comb. Chem. 1, 235 (1999)
25. W. Gao, X. Xing, Y. Li, Tetrahedron 70, 2180 (2014)
26. Y. Li, W.T. Gao, Heterocycl. Commun. 19, 405 (2013)
27. Y. Li, G.H. Lin, W.T. Gao, Poly. Arom. Compd. 32, 469 (2012)
28. W. Gao, C. Zhang, Y. Li, J. Braz. Chem. Soc. 21, 806 (2010)
123

A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one…
29. Y. Li, W.T. Gao, Beilstein J. Org. Chem. 6, 966 (2010)
30. Y. Li, C. Zhang, M. Sun, W. Gao, J. Heterocycl. Chem. 46, 1190 (2009)
´
31. M. Ordon˜ez, G.D. Tibhe, A. Zamudio-Medina, J.L. Viveros-Ceballos, Synthesis 44, 569 (2012)
´
´
´
32. D. Marosvo¨lgyi-Hasko, A. Takacs, Z. Riedl, L. Kollar, Tetrahedron 67, 1036 (2011)
´
´
33. G. Lopez-Valdez, S. Olguın-Uribe, A. Millan-Ortız, R. Gamez-Montan˜o, Tetrahedron 67, 2693
´
(2011)
34. M. Lamblin, A. Couture, E. Deniau, P. Grandclaudon, Tetrahedron 63, 2664 (2007)
35. J. Wan, B. Wu, Y. Pan, Tetrahedron 63, 9338 (2007)
´
36. R.J. Huntley, M. Gurram, J.R. Walker, D.M. Jenkins, E.J. Robe, F. Ahmed, Tetrahedron Lett. 55,
2286 (2014)
ˆ
´
´
37. R. Aspiotis, D. Deschenes, D. Dube, Y. Girard, Z. Huang, F. Laliberte, S. Liu, R. Papp, D.W.
Nicholson, R.N. Young, Bioorg. Med. Chem. Lett. 20, 5502 (2010)
38. L.H. Wu, D.Q. Yang, Chin. J. Org. Chem. 29, 1122 (2009)
39. Y. Li, Res. Chem. Intermed. 41, 4977 (2015)
40. L.D. Bratton, B. Strzelbicka, R.A. Bartsch, ARKIVOC 7, 80 (2003)
41. W.T. Gao, Y. Jiang, Y. Li, F. Li, Y. Yan, Chin. J. Chem. 30, 822 (2012)
´
42. J. Marco-Contelles, M.E. Perez-Mayoral, A. Samadi, M.C. Carreiras, E. Soriano, Chem. Rev. 109,
2652 (2009)
43. G.C. Muscia, M. Bollini, J.P. Carnevale, A.M. Bruno, S.E. Asıs, Tetrahedron Lett. 47, 8811 (2006)
´
44. B.R. McNaughton, B.L. Miller, Org. Lett. 5, 4257 (2003)
45. A. Cappelli, G. Giuliani, S. Valenti, M. Anzini, S. Vomero, G. Giorgi, C. Sogliano, E. Maciocco, G.
Biggio, A. Concas, Bioorg. Med. Chem. 16, 3428 (2008)
46. H. You, F. Chen, M. Lei, L. Hu, Tetrahedron Lett. 54, 2972 (2013)
47. A. Kiriazis, I.B. Aumu¨ller, J. Yli-Kauhaluoma, Tetrahedron Lett. 52, 1151 (2011)
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