Synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones via Pd-catalyzed cross-coupling reaction and cyclization

Article abstract of DOI:10.1039/c3ob41629a

Biologically active 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones have been synthesized in an efficient and concise manner utilizing readily available 4-hydroxyquinolin-2(1H)-ones as the starting material. The key strategy relies on the construction of the pyrrole ring through the palladium catalyzed sequential cross-coupling reaction and cyclization process.

Full text of DOI:10.1039/c3ob41629a

Organic &
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Synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones via
Pd-catalyzed cross-coupling reaction and cyclization†
Zhiyong Wang,*a Xiaoxiao Xing,a Lijun Xue,a Fang Gaoa and Ling Fang*b
Cite this: Org. Biomol. Chem., 2013, 11,
7334
Received 10th August 2013,
Biologically active 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones have been synthesized in an efficient and concise
manner utilizing readily available 4-hydroxyquinolin-2(1H)-ones as the starting material. The key strategy
relies on the construction of the pyrrole ring through the palladium catalyzed sequential cross-coupling
reaction and cyclization process.
Accepted 2nd September 2013
DOI: 10.1039/c3ob41629a
www.rsc.org/obc
Introduction
Drug discovery research constantly calls for large collections of
small molecules to look for lead structures active in biological
assays. Thus, the pursuit of practical and efficient approaches
for rapid chemical synthesis of natural product-like com-
pounds is in great demand and attractive.1 Tremendous efforts
have been devoted by organic chemists to the development of
new methodologies for the synthesis of the intriguing mole-
cules individually; however, it is highly desirable to develop
even more effective and flexible synthetic methodologies for
heterocycle formation in order to build up complex natural
product-like molecules in a combinatorial format.2
Nitrogen-containing heterocycles are of great importance in
the pharmaceutical industry since they often exhibit interest-
ing biological activities. The pyrrole moiety constitutes the key
structure of a wide range of compounds that have shown a
diverse range of bioactivities.3,4 For example, ningalin B and
lamellarin D are two members of novel marine natural pro-
ducts containing a highly substituted coumarin[3,4-b]pyrrolo
core (Fig. 1).3b Ningalin B4a–d has been reported to act as a
nontoxic inhibitor of MDR in various cancer cell lines. Lamel-
Fig. 1 Natural coumarin[3,4-b]pyrroles (left) and proposed pyrrolo[2,3-c]quino-
lin-4-one analogue (right).
For instance, 4-arylquinolin-2(1H)-one derivatives have been
larin D4e–n is a potent inhibitor of human topoisomerase I and reported to be lead compounds or are currently in clinical
trials (Fig. 2, compounds A,5a–c B5d–e and C5f). 3-(1H-Indol-2-yl)-
was recently shown to act on mitochondria to induce apopto-
sis. As coumarin isosteres, quinolin-2(1H)-ones are ubiquitous
quinolin-2(1H)-one D5g–l has been identified by Merck as
subunits of a range of pharmaceuticals and natural products potent KDR kinase inhibitors useful for cancer therapy. More-
with myriad biological activities.5 A number of analogues of
over, quinolin-2(1H)-ones are also valuable intermediates
this family have wide applications in medical chemistry, being
in organic synthesis because they can be easily converted into
used as anticancer, antiviral, and antihypertensive agents. 2-haloquinolines, which can undergo further functionalization.6
As part of our continuing efforts at construction of libraries of
quinolin-2(1H)-one compounds used in different biological
assays,7 we proposed to construct ningalin B and lamellarin D
analogues with the coumarin core modified into a quinolin-2-
(1H)-one scaffold of type 1 (Fig. 1).
aSchool of Chemistry and Chemical Engineering, Chongqing University,
Chongqing 400044, China. E-mail: zwang@cqu.edu.cn
bSchool of Environmental and Biological Engineering, Chongqing Technology and
Business University, Chongqing 400067, China. E-mail: lynnf@163.com;
Fax: +86 23 65102531; Tel: +86 23 65102531
Although a number of approaches are available for the
generation of quinolin-2(1H)-one derivatives with broad
structural diversity,8 synthetic pathways for the efficient and
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all new compounds. See DOI: 10.1039/c3ob41629a
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Results and discussion
As described above, to verify the practicability of the projected
route as shown in Scheme 1, initial model studies for the syn-
thesis of 1 were carried out using the readily available 4-hydoxy-
quinolin-2(1H)-one
2
as the starting material.11 The
Sonogashira coupling precursor 4 was easily synthesized in
high yield (82%) by treatment of 4-hydoxyquinolin-2(1H)-one 2
with HNO3/AcOH and trifluoromethanesulfonic anhydride
subsequently.12 Thus, we started to explore the possibility of
Sonogashira coupling reaction; 3-nitro-4-trifloxyquinolin-
2(1H)-one 4 and 1-hexyne were used as the model substrates
(Table 1). The reaction was initially performed in the presence
of 5 mol% Pd(PPh3)2Cl2/CuI in THF at room temperature,
using K2CO3 as the base. Gratifyingly, we observed the for-
mation of desired product 5a although the yield was low (30%,
Table 1, entry 1). The result was dramatically improved when
the amount of catalyst loading was increased to 10 mol%
(88%, Table 1, entry 2). A lower yield was obtained at higher
reaction temperature (Table 1, entry 3). Further screening
revealed that attempts to change the palladium catalysts or
using other solvents and bases were ineffective and led to a
lower yield (Table 1, entries 4–8).
With the optimized conditions identified, we started to
investigate the reaction scope with 3-nitro-4-trifloxyquinolin-
2(1H)-one 4 and various alkynes. It was found that aliphatic
alkynes are excellent partners in the reactions, leading to the
desired alkynyl derivatives 5a–c in moderate to good yields.
Conversely, no product was detected when aromatic alkynes
were employed in the reaction of 3-nitro-4-trifloxyquinolin-
2(1H)-one 4. We also screened this reaction with various
palladium catalysts, ligands, bases and solvents. However,
Fig. 2 Biologically active molecules with quinolin-2(1H)-one subunit.
straightforward construction of 3H-pyrrolo[2,3-c]quinolin-
4(5H)-one units have been scarce.9 It is well-known that tran-
sition metal catalyzed cyclization of alkynes with a nucleophile
in proximity to the triple bond is an important method to con-
struct various heterocycles in an efficient and atom-economic
way.10 For instance, 2-substituted indoles can be formed
through palladium-10a–d or copper-catalyzed10e intramolecular
cyclization of o-alkynylanilines. Inspired by these results, we
envisioned that the construction of the pyrrole ring in 1 could
be realised by intramolecular cyclisation of the key intermedi-
ate 6 (Scheme 1). In turn, 6 could be generated from the
corresponding 1-methyl-3-nitro-4-trifloxyquinolin-2(1H)-one 4
by Sonogashira coupling and reduction of the nitro group.
Finally 4 could be synthesised by means of a two step pro-
cedure from the easily available 4-hydroxy-1-methylquinolin-2-
(1H)-one 2. Herein, we describe a novel and flexible synthetic
protocol for the synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-
one derivatives utilizing the palladium-catalyzed sequential
coupling–cyclization strategy.
Table 1 Condition screening for Sonogashira couplinga
Catalytic system
Entry (mol%)
Yieldb
Solvent T (°C) (%)
Base
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2/CuI (5)
Pd(PPh3)2Cl2/CuI (10)
Pd(PPh3)2Cl2/CuI (10)
Pd(OAc)2/PPh3/CuI (10) K2CO3
Pd(PPh3)4/CuI (10)
Pd(PPh3)2Cl2/CuI (10)
Pd(PPh3)2Cl2/CuI (10)
Pd(PPh3)2Cl2/CuI (10)
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
THF
r.t.
r.t.
50
r.t.
r.t.
r.t.
r.t.
r.t.
30
88
77
46
49
20
Trace
Trace
K2CO3
Cs2CO3 THF
K2CO3
K2CO3
DMF
MeCN
a All of the reactions were carried out with 4 (0.3 mmol), 1-hexyne
(0.36 mmol), metal catalyst, and base (3.0 equiv.) in solvent (5.0 mL)
under argon. b Isolated yield based on 3-nitro-4-trifloxyquinolin-2(1H)-
one 4.
Scheme 1 Proposed synthetic route for generation of diverse 3H-pyrrolo[2,3-c]-
quinolin-4(5H)-ones 1.
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Table 3 Condition screening for intramolecular hydro-aminationa
Scheme 2 Sonogashira coupling with aliphatic alkynes and reduction.
the results were inferior. This might be due to the inefficient
transmetallation of aromatic copper(I) acetylide with Pd(0)
species. Subsequently, mediated by iron powder in AcOH/H2O
at room temperature, the reduction reaction was performed to
generate the 4-alkynyl-3-amino-quinolin-2(1H)-ones in excel-
lent yield (Scheme 2).
Moreover, to install the desired aromatic substituents at the
alkynes moiety at the C4 of the quinolinone core, 6c was desi-
lylatied giving rise to compound 6d (84% yield, in two steps
from 5c) which in turn was subjected to Sonogashira coupling
with aryl iodides. To our delight, the cross-coupling reactions
proceeded smoothly to furnish the desired 3-amino-4-aryl-
ethynyl-quinolin-2(1H)-ones in high yields when various aryl
iodides were used under the standard Sonogashira coupling
conditions (2 mol% Pd(PPh3)4, 2 mol% CuI, 3.0 equiv. of Et3N,
THF, rt) (Table 2).
Entry
[M] (mol%)
Solvent
T (°C)
t (h)
Yieldb (%)
1
2
3
4
5
6
7
Pd(PPh3)2Cl2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
CuI (20)
CuI (100)
PdCl2 (10)
PdCl2 (10)
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
160
160
160
160
160
100
80
3
3
2
3
3
2
3
87
22
95
78
67
89
76
a All of the reactions were carried out with 6f (0.3 mmol) and metal
catalyst in solvent (2.0 mL) under argon. b Isolated yield based on
4-acetylenyl-3-aminoquinolin-2(1H)-one 6f.
With a variety of 3-amino-4-arylethynylquinolin-2(1H)-ones
in hand, we turned our attention to the key cyclization for
constructing the corresponding pyrrolquinolinone backbone.
The intramolecular hydroamination reaction of 3-amino-4-aryl-
ethynylquinolin-2(1H)-one 6f was initially optimized. To find
the optimum reaction conditions, 6f was subjected to different
metal-catalysts, solvents and reaction temperatures. The results
of condition screening are shown in Table 3. A good result
was obtained when the reaction took place in DMF under
reflux, in the presence of PdCl2 (Table 3, entry 3). Com-
pound 1f was characterized by 1H NMR, 13C NMR and mass
spectral data analysis.
The scope of this palladium-catalyzed intramolecular cycli-
zation reaction of 3-amino-4-arylethynylquinolin-2(1H)-ones 6
was then examined under optimized conditions (10 mol%
PdCl2, DMF, reflux). The results are summarized in Table 4.
We noticed that all reactions worked well to generate the
desired product in moderate to good yields. The reactions were
very clean and usually completed in three hours. For instance,
reactions of the 3-amino-4-arylethynylquinolin-2(1H)-ones
6a–b with an alkyl group attached to the triple bond gave rise
to the corresponding 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones in
excellent yields (Table 4, entries 1 and 2). Moreover, it was
found that the arylacetylenic substrates with electron-with-
drawing groups on the R position were less reactive to some
extent than those with the electron-donating groups. For
example, reaction of 6h or 6i afforded the desired products 1
in 76% or 65% yield, respectively (Table 4, entries 6 and 7). For
the 4-methoxy- or 2-methyl-substituted substrates 6f or 6j, the
corresponding yield was 95% or 93%, respectively (Table 4,
entries 4 and 8).
Table 2 Synthesis of 3-amino-4-arylethynylquinolin-2(1H)-ones 6aa
Entry
Ar
6
Yieldb (%)
1
2
3
4
5
6
7
C6H5
6e
6f
6g
6h
6i
6j
6k
86
96
97
90
98
94
83
4-MeOC6H4
4-MeC6H4
4-ClC6H4
3-FC6H4
2-MeC6H4
2-ClC6H4
To make our strategy more attractive and straightforward as
a synthetic methodology, we also tested the one-pot (stepwise)
reaction of 3-amino-4-ethynylquinolin-2(1H)-one 6d with
p-iodoanisole for the synthesis of 3H-pyrrolo[2,3-c]quinolin-4-
(5H)-ones 1f.13 Gratifyingly, the reaction also proceeded well to
generate the desired product in 71% yield (Scheme 3).
a All of the reactions were carried out with 6d (0.3 mmol), aryl iodide
(0.36 mmol), Pd(PPh3)4 (0.015 mmol), CuI (0.015 mmol), and Et3N (3.0
equiv.) in THF (3 mL) under argon at room temperature. b Isolated
yield based on 3-amino-4-ethynylquinolin-2(1H)-one 6d.
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Table 4 Synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones 1a
out with standard Schlenk techniques under an inert atmos-
phere of argon. All commercial materials were used without
further purification. Column chromatography was performed
using silica gel (300–400 mesh).
Preparation of 1-methyl-3-nitro-2-oxo-1,2-dihydroquinolin-4-yl
trifluoromethanesulfonate (4)
To a solution of 4-hydoxyquinolin-2(1H)-one 2 (875 mg,
5 mmol) in acetic acid (10 mL) was added concentrated nitric
acid (13.5 mmol) and sodium nitrite (28 mg, 0.4 mmol) at
room temperature. The mixture was left for 0.5 h under stir-
ring at room temperature. Then it was poured slowly onto ice-
water under vigorous stirring to give a yellow precipitate.
The precipitate was washed with water and dried to give crude
compound 3. The crude compound 3 (ca. 5 mmol), Et3N (1.01 g,
10 mmol) and DCM (50 mL) were combined in a 100 mL
round-bottom flask with a magnetic stir bar and allowed to
cool to 0 °C. With vigorous magnetic stirring, Tf2O (2.11 g,
7.5 mmol) was added dropwise from a syringe. After the
mixture was stirred overnight at room temperature, ethyl
acetate was added, the organic layer was washed with aqueous
HCl (1 M), dried over Na2SO4, and concentrated under
vacuum. The crude product was purified by column chromato-
graphy on silica gel to yield 4 as a yellow solid (1.44 g, 82%).
1H NMR (500 MHz, CDCl3) δ 8.03–8.02 (m, 1H), 7.89–7.85 (m,
1H), 7.55–7.50 (m, 2H), 3.83 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 154.2, 144.6, 139.3, 135.2, 134.2, 125.2, 124.6, 118.2
(q, J = 319 Hz), 115.2, 113.3, 30.9. HRMS (ESI) calcd for
C11H8F3N2O6S [M + H]+ 353.0055, found 353.0048.
Entry
6
R
1
Yieldb (%)
1
2
3
4
5
6
7
8
9
6a
6b
6e
6f
6g
6h
6i
CH3(CH2)3
t-Bu
C6H5
4-MeOC6H4
4-MeC6H4
4-ClC6H4
3-FC6H4
2-MeC6H4
2-ClC6H4
1a
1b
1e
1f
1g
1h
1i
89
89
90
95
85
76
65
93
78
6j
6k
1j
1k
a All of the reactions were carried out with 6 (0.3 mmol) and PdCl2
(0.03 mmol) in DMF (2.0 mL) under argon for 2–3 h under reflux.
b Isolated yield based on 4-acetylenyl-3-aminoquinolin-2(1H)-one 6.
General procedure for synthesis of 4-acetylenyl-3-
nitroquinolin-2(1H)-ones 5
Scheme 3 Synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one 1f from 6f under
one-pot conditions.
To a mixture of 3-nitro-4-trifloxyquinolin-2(1H)-one 4 (106 mg,
0.3 mmol), Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), CuI (6 mg,
0.03 mmol), K2CO3 (124 mg, 0.9 mmol) in a Schlenk flask
under an argon atmosphere was added 5 mL of freshly dis-
tilled THF and terminal alkyne (0.36 mmol). The mixture was
stirred for 24 hours until TLC indicated completion of reac-
tion. The reaction solution was concentrated under vacuum
and the residue was purified by column chromatography on
silica gel to afford product 5a–5c.
Conclusions
In conclusion, this paper presented an efficient and novel
route for the synthesis of an interesting class of pyrroloquino-
linone compounds 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones via
palladium catalyzed cross-coupling reaction and cyclization
process, starting from 4-hydoxyquinolin-2(1H)-one. A wide sub-
strate scope with good functional group tolerance has been
demonstrated. Introducing more diversity in the scaffold and
evaluation of all these small molecules for biological effects
are currently underway in our laboratory.
4-(Hex-1-yn-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one 5a. 1H
NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.0 Hz, 1H), 7.73–7.70 (m,
1H), 7.42–7.37 (m, 2H), 3.76 (s, 3H), 2.58 (t, J = 7.0 Hz, 2H),
1.68–1.64 (m, 2H), 1.52–1.48 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 154.0, 143.8, 138.9, 133.0, 129.0,
125.7, 123.5, 117.8, 114.6, 110.8, 70.1, 30.0, 29.8, 21.9, 19.6,
13.4; HRMS (ESI) calcd for C16H17N2O3 [M + H]+ 285.1239,
found 285.1236.
Experimental section
General information
4-(3,3-Dimethylbut-1-yn-1-yl)-1-methyl-3-nitroquinolin-2(1H)-
NMR spectra were recorded using a 500 or 600 spectrometer one 5b. 1H NMR (500 MHz, CDCl3) δ 8.03–8.01 (m, 1H),
(500 or 600 MHz for H, 125 or 150 MHz for 13C) with chloro- 7.73–7.70 (m, 1H), 7.41–7.38 (m, 2H), 3.75 (s, 3H), 1.39 (s, 9H);
1
form-d or dimethyl sulfoxide-d6 as a solvent at 20–25 °C. High- 13C NMR (125 MHz, CDCl3) δ 154.0, 143.7, 138.9, 133.1, 128.9,
resolution mass spectra (HRMS) were obtained with a Q-TOF 125.7, 123.5, 118.2, 117.7, 114.6, 69.0, 30.1, 30.0, 28.8; HRMS
MS spectrometer. All anaerobic manipulations were carried (ESI) calcd for C16H17N2O3 [M + H]+ 285.1239, found 285.1237.
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1-Methyl-3-nitro-4-((trimethylsilyl)ethynyl)quinolin-2(1H)-one 120.9, 113.9, 98.8, 89.9, 77.0, 30.0; HRMS (ESI) calcd for
5c. 1H NMR (500 MHz, CDCl3) δ 8.09–8.07 (m, 1H), 7.74–7.71 C12H11N2O [M + H]+ 199.0871, found 199.0873.
(m, 1H), 7.42–7.38 (m, 2H), 3.76 (s, 3H), 0.33 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 154.0, 144.2, 139.0, 133.3, 129.1, 124.6,
General procedure for synthesis of 3-amino-4-
arylethynylquinolin-2(1H)-ones (6e–6k)
123.8, 117.4, 115.9, 114.7, 92.4, 30.2, −0.8; HRMS (ESI) calcd
for C15H17N2O3Si [M + H]+ 301.1008, found 301.1022.
To a mixture of 3-amino-4-ethynyl-1-methylquinolin-2(1H)-one
6d (198 mg, 0.3 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), CuI
(3 mg, 0.015 mmol), Et3N (91 mg, 0.9 mmol) in a Schlenk flask
General procedure for synthesis of 4-acetylenyl-3-
aminoquinolin-2(1H)-ones (6a–6b)
under an argon atmosphere were added 3 mL of freshly dis-
To a solution of 4-acetylenyl-3-nitroquinolin-2(1H)-ones 5a or tilled THF and aryl iodide (0.36 mmol). After TLC indicated
5b (0.20 mmol) in DCM (1 mL) were added HOAc (1 mL), H2O completion of reaction, the reaction solution was concentrated
(1 mL) and reduced iron powder (56 mg, 1 mmol). After TLC under vacuum and the residue was purified by column chromato-
indicated completion of reaction, the reaction solution was graphy on silica gel to afford products 6e–6k.
poured into water. Na2CO3 was added into the solution
3-Amino-1-methyl-4-(phenylethynyl)quinolin-2(1H)-one 6e. 1H
portion by portion until the pH of the solution became weak NMR (500 MHz, CDCl3) δ 7.95–7.93 (m, 1H), 7.62–7.60 (m, 2H),
basic (pH = 8–9). The neutralized solution was filtered, and 7.41–7.26 (m, 6H), 5.18 (s, 2H), 3.80 (s, 3H); 13C NMR
the filtrate was extracted with EtOAc. The combined organic (125 MHz, CDCl3) δ 157.1, 138.7, 133.4, 131.5, 128.7, 128.4,
layers were dried over Na2SO4 and concentrated under 125.8, 124.5, 122.9, 122.7, 121.0, 113.9, 102.2, 100.4, 82.2, 30.0;
vacuum. The residue was purified by column chromatography HRMS (ESI) calcd for C18H15N2O [M + H]+ 275.1184, found
on silica gel to afford product 6a or 6b.
275.1174.
3-Amino-4-(hex-1-yn-1-yl)-1-methylquinolin-2(1H)-one 6a. 1H
3-Amino-4-((4-methoxyphenyl)ethynyl)-1-methylquinolin-
NMR (500 MHz, CDCl3) δ 7.85 (d, J = 7.5 Hz, 1H), 7.34–7.24 (m, 2(1H)-one 6f. 1H NMR (500 MHz, CDCl3) δ 7.93–7.91 (m, 1H),
3H), 4.99 (s, 2H), 3.77 (s, 3H), 2.61 (t, J = 6.5 Hz, 2H), 1.71–1.68 7.53 (d, J = 8.5 Hz, 2H), 7.36–7.24 (m, 3H), 6.90 (d, J = 8.5 Hz,
(m, 2H), 1.57–1.53 (m, 2H), 0.99 (t, J = 6.5 Hz, 3H); 13C NMR 2H), 5.14 (s, 2H), 3.83 (s, 3H), 3.77 (s, 3H); 13C NMR (125 MHz,
(125 MHz, CDCl3) δ 157.3, 138.5, 133.5, 125.7, 124.6, 122.7, CDCl3) δ 160.0, 157.2, 138.4, 133.5, 133.0, 125.8, 124.7, 122.8,
121.6, 113.8, 104.0, 101.8, 73.5, 31.0, 30.0, 22.1, 19.7, 13.6; 121.2, 114.8, 114.1, 113.9, 102.4, 101.0, 80.9, 55.3, 30.0; HRMS
HRMS (ESI) calcd for C16H19N2O [M + H]+ 255.1497, found (ESI) calcd for C19H17N2O2 [M + H]+ 305.1290, found 305.1287.
255.1495.
3-Amino-1-methyl-4-(p-tolylethynyl)quinolin-2(1H)-one 6g.
3-Amino-4-(3,3-dimethylbut-1-yn-1-yl)-1-methylquinolin-2(1H)- 1H NMR (500 MHz, CDCl3) δ 7.91–7.90 (m, 1H), 7.47 (d, J =
one 6b. 1H NMR (500 MHz, CDCl3) δ 7.83–7.81 (m, 1H), 8.0 Hz, 2H), 7.34–7.30 (m, 1H), 7.26–7.23 (m, 2H), 7.17 (d, J =
7.36–7.32 (m, 1H), 7.29–7.24 (m, 2H), 4.96 (bs, 2H), 3.78 (s, 8.0 Hz, 1H), 5.16 (s, 2H), 3.75 (s, 3H), 2.37 (s, 3H); 13C NMR
3H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 157.3, 138.2, (125 MHz, CDCl3) δ 157.1, 138.9, 138.6, 133.4, 131.3, 129.2,
133.5, 125.7, 124.6, 122.7, 121.5, 113.8, 112.4, 101.7, 72.0, 31.2, 125.8, 124.6, 122.8, 121.1, 119.7, 113.8, 102.5, 100.7, 81.6, 30.0,
30.0, 28.7; HRMS (ESI) calcd for C16H19N2O [M + H]+ 255.1497, 21.5; HRMS (ESI) calcd for C19H17N2O [M + H]+ 289.1341,
found 255.1493.
found 289.1337.
Preparation of 3-amino-4-ethynyl-1-methylquinolin-2(1H)-
3-Amino-4-((4-chlorophenyl)ethynyl)-1-methylquinolin-2(1H)-
one 6d. To a solution of 4-acetylenyl-3-nitroquinolin-2(1H)-one one 6h. 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 6.5 Hz, 1H),
5c (301 mg, 1 mmol) in DCM (2 mL) were added HOAc (4 mL), 7.53 (d, J = 7.5 Hz, 1H), 7.37–7.29 (m, 5H), 5.19 (s, 2H), 3.80 (s,
H2O (4 mL) and reduced iron powder (280 mg, 5 mmol). After 3H); 13C NMR (125 MHz, CDCl3) δ 157.1, 138.9, 134.8, 133.5,
TLC indicated completion of reaction, the reaction solution 132.7, 128.9, 126.0, 124.5, 123.0, 121.2, 120.9, 114.0, 101.0,
was poured into water. Na2CO3 was added into the solution 100.1, 83.2, 30.1; HRMS (ESI) calcd for C18H14ClN2O [M + H]+
portion by portion until the pH of the solution became weak 309.0794, found 309.0783.
basic (pH = 8–9). The neutralized solution was filtered, and
3-Amino-4-((3-fluorophenyl)ethynyl)-1-methylquinolin-2(1H)-
the filtrate was extracted with EtOAc. The combined organic one 6i. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 7.5 Hz, 1H),
layers were concentrated under vacuum to afford crude 6c. The 7.40–7.29 (m, 6H), 7.12–7.09 (m, 1H), 5.21 (s, 2H), 3.82 (s, 3H);
crude 6c was added to a solution of K2CO3 (207 mg, 1.5 mmol) 13C NMR (125 MHz, CDCl3) δ 162.4 (d, JCF = 245 Hz), 157.1,
in CH3OH–DCM (5 mL/2 mL). After stirring for another 139.1, 133.5, 130.1 (d, JCF = 9 Hz), 127.4, 126.0, 124.6, 124.5,
30 min, the reaction solution was poured into water and 123.0, 120.9, 118.2 (d, JCF = 22 Hz), 116.0 (d, JCF = 21 Hz),
extracted with EtOAc. The combined organic layers were dried 114.0, 100.8, 99.8, 83.2, 30.1; HRMS (ESI) calcd for
over Na2SO4 and concentrated under vacuum. The residue was C18H14FN2O [M + H]+ 293.1090, found 293.1087.
1
3
2
2
purified by column chromatography on silica gel to afford 6d
3-Amino-1-methyl-4-(o-tolylethynyl)quinolin-2(1H)-one
6j.
as a pale yellow solid (167 mg, 84%). 1H NMR (500 MHz, 1H NMR (500 MHz, CDCl3) δ 7.98–7.96 (m, 1H), 7.59 (d, J =
CDCl3) δ 7.81 (d, J = 7.5 Hz, 1H), 7.33–7.30 (m, 1H), 7.26–7.22 7.5 Hz, 1H), 7.40–7.28 (m, 5H), 7.25–7.21 (m, 1H), 5.18 (s, 2H),
(m, 2H), 5.18 (s, 2H), 3.86 (s, 1H), 3.74 (s, 3H); 13C NMR 3.81 (s, 3H), 2.60 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 157.2,
(125 MHz, CDCl3) δ 157.0, 140.1, 133.2, 125.8, 124.3, 123.0, 139.6, 138.6, 133.6, 131.9, 129.7, 128.8, 125.9, 125.8, 124.6,
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123.0, 122.7, 121.1, 114.0, 101.3, 100.9, 86.1, 30.1, 21.2; HRMS 127.2, 127.0, 125.6, 123.5, 122.8, 121.9, 117.8, 115.5, 99.5, 28.8,
(ESI) calcd for C19H17N2O [M + H]+ 289.1341, found 289.1336. 20.9; HRMS (ESI) calcd for C19H17N2O [M + H]+ 289.1341,
3-Amino-4-((2-chlorophenyl)ethynyl)-1-methylquinolin-2(1H)- found 289.1337.
one 6k. 1H NMR (500 MHz, CDCl3) δ 8.01–7.99 (m, 1H),
2-(4-Chlorophenyl)-5-methyl-3H-pyrrolo[2,3-c]quinolin-4(5H)-
7.67–7.65 (m, 1H), 7.50–7.48 (m, 1H), 7.39–7.29 (m, 5H), 5.37 one 1h. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.03 (d,
(s, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 157.1, 139.5, J = 8 Hz, 3H), 7.56–7.45 (m, 5H), 7.31 (t, J = 7.5 Hz, 1H), 3.74 (s,
135.3, 133.4, 132.9, 129.6, 129.3, 126.7, 125.9, 124.6, 123.0, 3H); 13C NMR (125 MHz, DMSO-d6) δ 154.6, 138.2, 136.7,
122.8, 120.7, 114.0, 99.7, 98.9, 87.9, 30.1; HRMS (ESI) calcd for 132.4, 130.4, 129.0, 127.4, 127.2, 123.6, 123.5, 122.1, 117.9,
C18H14ClN2O [M + H]+ 309.0794, found 309.0788.
115.6, 100.6, 29.0; HRMS (ESI) calcd for C18H14ClN2O [M + H]+
309.0794, found 309.0790.
2-(3-Fluorophenyl)-5-methyl-3H-pyrrolo[2,3-c]quinolin-4(5H)-
one 1i. 1H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.04 (d,
General procedure for synthesis of 3H-pyrrolo[2,3-c]quinolin-
4(5H)-one 1 via PdCl2-mediated cyclization
A mixture of PdCl2 (5.3 mg, 0.03 mmol) and 6 (0.30 mmol) in J = 7.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H),
DMF (2 mL) was stirred at 160 °C under a nitrogen atmos- 7.55 (d, J = 8.5 Hz, 1H), 7.51–7.47 (m, 3H), 7.32 (t, J = 7.5 Hz,
phere. After completion of the reaction as monitored by TLC, 1H), 7.18–7.14 (m, 1H), 3.73 (s, 3H); 13C NMR (125 MHz,
the reaction mixture was poured into water and extracted with DMSO-d6) δ 162. 7 (d, 1JCF = 241 Hz), 154.6, 138.0, 136.6, 133.7,
3
ethyl acetate. The organic layer was washed with water and 133.7, 130.9 (d, JCF = 9 Hz), 127.2, 127.1, 123.5, 122.1, 121.7,
2
2
brine, dried over MgSO4, and concentrated in vacuo. The 117.7, 115.5, 114.5 (d, JCF = 21 Hz), 112.1 (d, JCF = 22 Hz),
residue was purified by flash column chromatography on silica 101.0, 28.9; HRMS (ESI) calcd for C18H14FN2O [M + H]+
gel to give the corresponding product 1.
293.1090, found 293.1089.
5-Methyl-2-(o-tolyl)-3H-pyrrolo[2,3-c]quinolin-4(5H)-one 1j.
2-Butyl-5-methyl-3H-pyrrolo[2,3-c]quinolin-4(5H)-one 1a. 1H
NMR (500 MHz, CDCl3) δ 11.12 (s, 1H), 7.98–7.96 (m, 1H), 7.91 1H NMR (500 MHz, CDCl3) δ 12.36 (s, 1H), 8.08 (d, J = 7.5 Hz,
(d, J = 7.0 Hz. 1H), 7.44 (s, 2H), 7.28 (s, 1H), 6.53 (s, 1H), 3.87 1H), 7.57–7.46 (m, 3H), 7.33–7.27 (m, 4H), 7.04 (s, 1H), 3.74 (s,
(s, 3H), 2.86 (t, J = 7.5 Hz. 2H), 1.79–1.76 (m, 2H), 1.44–1.41 3H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 154.5, 139.3,
(m, 2H), 0.95 (t, J = 7.0 Hz. 3H); 13C NMR (125 MHz, CDCl3) δ 136.5, 135.8, 131.8, 130.6, 129.7, 128.1, 126.8, 126.6, 125.8,
155.5, 142.9, 136.5, 127.7, 126.5, 123.6, 122.1, 121.5, 118.9, 123.5, 122.4, 121.8, 117.9, 115.4, 102.7, 28.8, 20.8; HRMS (ESI)
115.1, 99.6, 31.6, 29.7, 27.9, 22.4, 13.8; HRMS (ESI) calcd for calcd for C19H17N2O [M + H]+ 289.1341, found 289.1336.
C16H19N2O [M + H]+ 255.1497, found 255.1486.
2-(2-Chlorophenyl)-5-methyl-3H-pyrrolo[2,3-c]quinolin-4(5H)-
2-(tert-Butyl)-5-methyl-3H-pyrrolo[2,3-c]quinolin-4(5H)-one 1b. one 1k. 1H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.06 (d,
1H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.98–7.96 (m, J = 7.5 Hz, 1H), 7.75–7.73 (m, 1H), 7.61–7.55 (m, 2H), 7.49–7.41
1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43–7.40 (m, 1H), 7.25 (t, J = 7.0 (m, 3H), 7.29 (t, J = 7.0 Hz, 1H), 7.25 (s, 1H), 3.74 (s, 3H);.
Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 3.70 (s, 3H), 1.37 (s, 9H); 13C 13C NMR (125 MHz, DMSO-d6) δ 154.5, 136.5, 136.1, 131.5,
NMR (125 MHz, DMSO-d6) δ 162.4, 154.5, 151.1, 136.3, 126.5, 131.5, 130.6, 130.2, 129.6, 127.2, 126.9, 126.2, 123.5, 122.7,
125.8, 123.3, 121.7, 118.2, 115.3, 97.3, 32.0, 29.9, 28.7; HRMS 121.9, 117.8, 115.4, 103.7, 28.8; HRMS (ESI) calcd for
(ESI) calcd for C16H19N2O [M + H]+ 255.1497, found 255.1494.
5-Methyl-2-phenyl-3H-pyrrolo[2,3-c]quinolin-4(5H)-one 1e.
1H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.06 (d, J =
7.5 Hz, 1H), 8.02 (d, J = 7.0 Hz, 2H), 7.55 (d, J = 8.5 Hz, 1H),
7.49–7.44 (m, 3H), 7.41 (s, 1H), 7.35–7.30 (m, 2H), 3.74 (s, 3H);
C18H14ClN2O [M + H]+ 309.0794, found 309.0794.
Acknowledgements
13C NMR (125 MHz, DMSO-d6) δ 154.5, 139. 5, 136.5, 131.3, We thank Professor Jie Wu for his invaluable advice during the
128.8, 127.8, 127.1, 127.0, 125.6, 123.5, 123.1, 121.9, 117.8, course of this research. Financial support from the National
115.4, 100.0, 28.8; HRMS (ESI) calcd for C18H15N2O [M + H]+ Science Foundation Project of CQ (CSTC, 2011BB4054 to Z.W.),
275.1184, found 275.1185.
Fundamental Research Funds for the Central Universities
2-(4-Methoxyphenyl)-5-methyl-3H-pyrrolo[2,3-c]quinolin- (CDJRC11220001 to Z.W,), Foundation of Chongqing Edu-
4(5H)-one 1f. 1H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), cational Committee (KJ130701 to L.F.), and the Innovative
8.04 (d, J = 7.0 Hz. 1H), 7.96 (d, J = 8.5 Hz. 2H), 7.55–7.45 (m, Research Team Development Program in University of Chongq-
2H), 7.32–7.29 (m, 2H), 7.02 (d, J = 8.5 Hz. 2H), 3.81 (s, 3H), ing (KJTD 201314 to L.F.) is gratefully acknowledged. Z.W. also
3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.1, 154.4, thanks the Sharing Fund of Chongqing University’s Large-
139.569, 136.5, 127.2, 127.0, 126.8, 124.0, 123.4, 122.6, 121.8, scale Equipment for the financial support.
117.8, 115.4, 114.2, 98.8, 55.2, 28.7; HRMS (ESI) calcd for
C19H17N2O2 [M + H]+ 305.1290, found 305.1281.
5-Methyl-2-(p-tolyl)-3H-pyrrolo[2,3-c]quinolin-4(5H)-one 1g.
Notes and references
1H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.05 (d, J =
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7.36–7.25 (m, 4H), 3.73 (s, 3H), 2.34 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 154.5, 139.7, 137.3, 136.5, 129.4, 128.6,
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3-amino-4-ethynylquinolin-2(1H)-one 6d with p-iodoanisole
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the reaction mixture and the mixture was stirred at 160 °C
for another 2 hours.
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