Synthesis and characterization of 11-amino-3-methoxy-8-substituted-12-aryl- 8,9-dihydro-7H-chromeno[2,3-b]quinolin-10(12H)-one derivatives

Article abstract of DOI:10.1002/jhet.2010

A series of 2-amino-7-methoxy-4-aryl-4H-chromene-3-carbonitrile compounds 2 were obtained by condensation of 3-methoxyphenol with β-dicyanostyrenes 1 in absolute ethanol containing piperidine. The intermediate enamines 3 were prepared by compounds 2 with

Full text of DOI:10.1002/jhet.2010

Month 2014 Synthesis and Characterization of 11-Amino-3-methoxy-8-substituted-12-
aryl-8,9-dihydro-7H-chromeno[2,3-b]quinolin-10(12H)-one Derivatives
a
a
a
a
*
Guangfan Han, Jiawei Du, Lizhuang Chen, and Lijun Zhao
School of Biological and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu
212003, China
*
E-mail: gf552002@yahoo.com.cn
Received January 19, 2013
DOI 10.1002/jhet.2010
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A series of 2-amino-7-methoxy-4-aryl-4H-chromene-3-carbonitrile compounds 2 were obtained by
condensation of 3-methoxyphenol with b-dicyanostyrenes 1 in absolute ethanol containing piperidine.
The intermediate enamines 3 were prepared by compounds 2 with 5-substituted-1,3-cyclohexanedione using
p-toluenesuflonic acid (TsOH) as catalyst. The title compounds 11-amino-3-methoxy-8-substituted-12-aryl-8,
9-dihydro-7H-chromeno[2,3-b]quinolin-10(12H)-one 4 were synthesized by cyclization of the intermediate
enamines 3 in THF with K2CO3 1/Cu2Cl2 as catalyst. The structures of all compounds were characterized by
elemental analysis, IR, MS, and H NMR spectra. The crystal structure of compound 4i was determined by
single-crystal X-ray diffraction analysis.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
widely occur in nature. Their derivatives have been ap-
proved to possess good biological activity [4,5]. Quinoline
derivatives are also utilized as potential antitumoral,
anti-tuberculosis, anticonvulsant, anti-breast cancer, and
anti-HIV agents [6–10].
To search for biologically interesting compounds, and
enrich the tetracyclic compounds, we used 4H-chromenes
as building blocks to synthesize a series of new
chromeno[2,3-b]quinolinone derivatives in this article.
Chromeno[2,3-b]quinolinone derivatives display various
pharmacological activities [1]. For example, Jose reported
some new multipotent tetracyclic tacrine compounds that
belonged to chromeno[2,3-b]quinolinone derivatives,
and these compounds are modest AChE inhibitors but
proved to be very selective [2]. Some of them show a
significant neuroprotective effect on neuroblastoma cells
subjected to Ca2+ overload or free radical induced toxicity.
Chromeno[2,3-b]quinolinone derivatives not only possess
the structure of chromene but also contain a quinoline
ring. Parts of chromene and quinoline derivatives have
already been reported for possessing good biological
activity. For example, chromene derivatives are biologically
interesting compounds known for treatment of Alzheimer’s
disease and Schizophrenia disorder [3]. As the parent
ring of many natural products, quinoline and its derivatives
RESULT AND DISCUSSION
Various synthesis methods of chromeno[2,3-b]quinolinone
analogues using different building blocks have been reported
in previous literatures. 11-Amino-12 -aryl-2,3,4,7,8,9,10,12-
octahydro-3,3-dimethyle-1H-chromeno[2,3-b]quinoline-1-one
derivatives have been accessed using 2-amino-3-cyano-4-aryl-
5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-chromene
© 2014 HeteroCorporation

G. Han, J. Du, L. Chen, and L. Zhao
Vol 000
Scheme 1
compounds as synthetic precursors and AlCl3 as cata-
lyst in 1,2-dicholonethane [2]. Chromanone[2,3-b]
quinolinone derivatives were prepared using 2-amino-
3-formyl-chromanone compounds as building blocks
via the Friedländer reaction [11]. Stimulated by these
findings, we were particularly interested in developing
a series of 4H-chromenes. Then, using 4H-chromenes as
building blocks, the title compounds were obtained via two
reaction steps of condensation and cyclization.
As shown in Scheme 1, the intermediates b-dicyanostyrenes
1 were prepared from aromatic aldehyde, malononitrile
in ethanol with KF ꢀ 2H2O as catalyst. And 2-amino-7-
methoxy-4-aryl-4H-chromene-3-carbonitrile compounds
2 were obtained by condensation of 3-methoxyphenol
with b-dicyanostyrenes 1 in absolute ethanol containing
piperidine. The intermediate enamines 3 were synthesized
by condensation of compounds 2 with 5-substituted-
1,3-cyclohexanedione using TsOH as catalyst in toluene.
The title compounds 11-amino-3-methoxy-8-substituted-12-
aryl-8,9-dihydro -7H-chromeno[2,3-b]quinolin-10(12H)-one
4 were synthesized by cyclization of the intermediate
enamines 3 in THF with K2CO3/Cu2Cl2 as catalyst [12].
During our investigation, the effect of the temperature on
the reactions of 3-methoxyphenol with b-dicyanostyrenes 1
was probed. It was found that the reaction temperature
should be below 70ꢁC in the presence of piperidine;
otherwise, the side reactions would be significantly in-
creased. In addition, it was found that the byproducts would
be reduced via the pre-dried process of the solvent, catalyst,
and raw materials before preparation of compounds 3.
The data of 1H NMR, MS, and IR shown in the
Experimental section are in accordance with the chemical
1
structures of the target compounds. The H NMR spectra
1
were recorded with CDCl3 as solvent. In the H NMR
spectrum of compound 2a, the single peak at d 3.79 was
the typical proton peak of methoxy group. The broad
single peak at d 4.68 was the characteristic absorption
proton peak of the amino group. In the 1H NMR spectrum
of compound 3a, the single peak at d 3.80 was the typical
proton peak of methoxy group. The single peak at d 5.95
1
was the typical proton peak of the vinyl group. In the H
NMR spectrum of compound 4a, two broad single peaks
at d 5.07 and d 9.24 were observed. They disappeared
after D2O exchange and therefore were attributed to the
two N–H of the amino group. Because of the existence of
intramolecular hydrogen bond between one proton of the
amino group and the oxygen atom of the carbonyl group
nearby, its proton peak was drifted to d 9.24.
The structures of these compounds were further
supported by their IR spectra. Typical absorption band
at 2187 cmꢂ1 for 2a (ꢂCN) was observed. The spectrum
of compound 3a showed the absorption at 2204 and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Characterization of 11-amino-3-methoxy-8-substituted-12-aryl-8,
9-dihydro-7H-chromeno[2,3-b]quinolin-10(12H)-one Derivatives
3172 cmꢂ1 for –CN and –NH2, respectively. However, an
absorption of –CN group disappeared in the IR spectrum
of compound 4a. The single-crystal structure of 4i was
determined by X-ray diffraction analysis (Fig. 1).
ring C1-C2-C3-C4-C5-C6-C7-C8-C13-N1-O2-C15-C16)
is about 87.842(65)ꢁ.
EXPERIMENTAL
Melting points were determined on an electro-thermal appara-
tus, and the temperature was uncorrected. Micro-analysis was
performed by the Perkin-Elmer 2400 Microanalytical Service.
Infrared spectra were recorded as thin films on KBr using a
Perkin-Elmer 1700 spectrophotometer. The NMR spectra were
recorded by a Bruker ARX-300 or Bruker AVANCE II-400
spectrometer. Sample solutions were prepared in CDCl3 containing
TMS as an internal standard. Mass spectra were recorded by
AGILENT 6460C with ESI ionization. The X-ray single-crystal
diffraction was performed on SMART APEX II instrument. All
chemical reagents were commercially available and purified with
standard methods before use. Solvents were dried in routine ways
and redistilled. 5-Substituted-1,3-cyclohexanediones were obtained
from aromatic aldehyde, acetone, and diethyl malonate according to
the literature [11] with slight modification.
CRYSTAL STRUCTURE
A summary of the crystal data and structure refinement
is presented in Table 1. Single-crystal X-ray analysis
reveals that compound 4i crystallizes in the monoclinic
space group P21/n. A perspective view of compound 4i
with atomic numbering scheme is shown in Figure 1. The
six-membered ring of the pyrano (C4-C5-C6-C14-O2-C15)
adopts a slight boat conformation. In the the six-membered
ring of the cyclohexane (C8-C9-C10-C11-C12-C13), C11
obviously divates the plane by C8-C9-C10-C12-C13.
The angle between two planes (the benzene ring C17-
C18-C19-C20-C21-C22 and the chromeno[2,3-b]pyridine
General procedure for the synthesis of b-dicyanostyrene
(1).
To a solution of the corresponding aldehyde (Aladdin
Chemistry Co., Ltd, Shanghai, China) (0.01 mol) in ethanol
(Chinasun Specialty Products Co., Ltd, Changshu, China)
(30 ml), malonodinitrile (Aladdin Chemistry Co., Ltd, Shanghai,
China) (0.01 mol) and
a
catalytic amount of KF ꢀ 2H2O
(Sinopharm Chemical Reagent Co., Ltd, Shanghai, China) [13]
were added. The mixture was stirred at 60ꢁC till the complete
consumption of raw materials as monitored by TLC. Then, the
reaction mixture was cooled to rt. To this mixture was added
100 mL water, and the precipitate was isolated by suction
filtration, washed with cold ethanol (Chinasun Specialty
Products Co., Ltd , Changshu, China), and recrystallized from
95% ethanol (Sinopharm Chemical Reagent Co., Ltd, Shanghai,
China) to give 1.
General procedure for the synthesis of 2-amino-7-methoxy-4-
aryl-4H-chromene-3-carbonitrile (2a–d).
A catalytic amount
Figure 1. Molecular structure of compound 4i. [Color figure can be
of piperidine (Sinopharm Chemical Reagent Co., Ltd, Shanghai,
China) was added to a solution of the corresponding b-
dicyanostyrene (0.01mol) and 3-methoxyphenol (Aladdin
Chemistry Co., Ltd, Shanghai, China) (0.01 mol) in absolute
ethanol (Chinasun Specialty Products Co., Ltd, Changshu, China).
The mixture was stirred at 60ꢁC till the complete consumption of
raw materials as monitored by TLC. Then, the resultant mixture
was cooled to rt. The precipitate was isolated by suction filtration
and recrystallized from ethanol to yield 2 (Table 2).
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 1
Crystallographic data for compound 4i (CCDC 926181).
Empirical formula
C25H24N2O3
Formula weight
400.46
General procedure for the synthesis of 2-N-(5-substituted-
3-oxocyclohex-1-enylamino)-7-methoxy-4-aryl-4H-chromene-
3-carbonitrile (3a–i). The corresponding 2-amino-7-methoxy-
4-aryl-4H-chromene-3-carbonitrile (0.01 mol) and 5-substituted-
Wavelength/nm
Crystal system
Space group
a/nm
0.71073
Monoclinic
P21/n
11.600(4)
b/nm
10.337(3)
c/nm
16.782(5)
90.00
94.345(4)
90.00
a/(o)
b/(o)
Table 2
g/(o)
Synthesis of 2-amino-7-methoxy-4-aryl-4H-chromene-3-carbonitrile (2a–d).
Volume/nm3
2006.5(11)
Z
4
Entry
R
Yield (%)
Calculated density/g cmꢂ3
Absorption coefficient/mmꢂ1
F (000)
1.326
0.088
848
2a
2b
2c
2d
2-Cl
4-Cl
4-CH3
H
93
90
88
92
Final R indices [I > 2sigma(I )]
R indices (all data)
R1 = 0.0470, wR2 = 0.1174
R1 = 0.1027, wR2 = 0.1590
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. Han, J. Du, L. Chen, and L. Zhao
Vol 000
1,3-cyclohexanedione (0.01 mol) were suspended in toluene
(Sinopharm Chemical Reagent Co., Ltd, Shanghai, China)
containing TsOH (Aladdin Chemistry Co., Ltd, Shanghai,
China) (0.002 mol). The mixture was refluxed for 3 h, and the
water was collected in a Dean–Stark water separator. The
solvent was removed under reduced pressure, and to the residue
was added 20 mL ethyl acetate (Chinasun Specialty Products
Co., Ltd, Changshu, China), then washed with the potassium
carbonate (Sinopharm Chemical Reagent Co., Ltd, Shanghai,
China) aqueous solution. The organic layer was separated, dried
by anhydrous sodium sulfate (Sinopharm Chemical Reagent
Co., Ltd, Shanghai, China), filtered, and evaporated using a
rotary evaporator. The residue was purified by silica gel flash
chromatography using ethyl acetate/hexane (Chinasun Specialty
Products Co., Ltd, Changshu, China) (1:2) as eluent to give
pure compounds 3 (Table 3).
Ltd, Changshu, China). The yellow powder was purified by silica
gel flash chromatography using ethyl acetate/ hexane (Chinasun
Specialty Products Co., Ltd , Changshu, China) (1:3) as eluent to
give pure compounds 4 (Table 4).
Data of compounds
2-Amino-4-(2-chlorophenyl)-7-methoxy-4H-chromene-3-
carbonitrile (2a).
Yield: 93%, m.p. 178–180ꢁC; 1H NMR
(CDCl3, 400 MHz) d: 3.79 (s, 3H, OCH3), 4.68 (br s, 2H, NH2),
5.36 (s, 1H, 4-H), 6.55 (d, J = 2.4 Hz, 1H, 8-H), 6.61
(dd, J = 8.4 Hz, 2.4 Hz, 1H, 6-H), 6.93 (d, J = 8.4 Hz, 1H, 5-H),
7.16–7.23 (m, 4H, Ph-H); IR (KBr) υ: 3472, 2187 cmꢂ1; MS (ESI)
m/z (%): 335.0 (M + 23, 100); Anal. Calcd for C17H13ClN2O2: C
65.29, H 4.19, N 8.96; found C 65.33, H 4.20, N 8.90.
2-Amino-4-(4-chlorophenyl)-7-methoxy-4H-chromene-3-
carbonitrile (2b).
Yield: 90%, m.p. 166–168ꢁC; 1H NMR
(CDCl3, 300 MHz) d: 3.80 (s, 3H, OCH3), 4.63 (br s, 2H, NH2),
4.78 (s, H, 4-H), 6.56 (d, J= 2.4 Hz, 1H, 8-H), 6.62 (dd, J=8.4Hz,
J= 2.4 Hz, 1H, 6-H), 6.82 (d, J= 8.4 Hz, 1H, 5-H), 7.13–7.31
(m, 4H, Ph-H); IR (KBr) υ: 3399, 2214 cmꢂ1; MS (ESI) m/z (%):
335.1 (M + 23, 100); Anal. Calcd for C17H13ClN2O2: C 65.29,
General procedure for the synthesis of 11-amino-3-methoxy-
8-substituted-12-aryl-8,9-dihydro-7H-chromeno[2,3-b]quinolin-
10(12H)–one (4a–i).
2-N-(5-Substituted-3-oxocyclohex-1-
enylamino)-7-methoxy-4-aryl-4H-chromene-3-carbonitrile (0.01 mol)
was added to dry tetrahydrofuran (Sinopharm Chemical Reagent
Co., Ltd, Shanghai, China) (30 mL) containing potassium
carbonate (0.005 mol; Sinopharm Chemical Reagent Co., Ltd,
Shanghai, China) and cuprous chloride (Sinopharm Chemical
Reagent Co., Ltd , Shanghai, China) (0.0025 mol) under nitrogen
atmosphere. The reaction mixture was refluxed for 6 h, and the
hot mixture was filtered into hexane. The precipitate was filtered
off and washed with ethanol (Chinasun Specialty Products Co.,
H 4.19, N 8.96; found C 65.40, H 4.22, N 8.83.
2-Amino-7-methoxy-4-p-tolyl-4H-chromene-3-carbonitrile
(2c). Yield: 88%, m.p. 162–164ꢁC; 1H NMR (CDCl3, 300 MHz)
d: 2.32 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 4.59(br s, 2H, NH2), 4.66
(s, H, 4-H), 6.55 (d, J = 2.4Hz, 1H, 8-H), 6.60 (dd, J = 8.4 Hz,
J = 2.4Hz, 1H, 6-H), 6.86 (d, J = 8.4 Hz, 1H, 5-H), 7.07–7.14 (m,
4H, Ph-H); IR (KBr) υ: 3442, 2205 cmꢂ1; MS (ESI) m/z (%):
315.1 (M + 23, 100); Anal. Calcd for C18H16N2O2: C 73.95,
H 5.52, N 9.58; found C 73.88, H 5.61, N 9.60.
2-Amino-7-methoxy-4-phenyl-4H-chromene-3-carbonitrile
(2d) [14].
Yield: 92%, m.p. 196–198ꢁC; 1H NMR (CDCl3,
Table 3
300 MHz) d: 3.79 (s, 3H, OCH3), 4.58 (br s, 2H, NH2), 4.70
(s, H, 4-H), 6.56 (d, J = 2.4Hz, 1H, 8-H), 6.61 (dd, J = 8.2 Hz,
J = 2.4Hz, 1H, 6-H), 6.87 (d, J = 8.2Hz, 1H, 5-H), 7.19–7.33
(m, 5H, Ph-H); IR (KBr) υ: 3460, 2210cmꢂ1; MS (ESI) m/z (%):
301.0 (M+ 23, 100); Anal. Calcd for C17H14N2O2: C 73.37,
Synthesis of 2-N-(5-substituted-3-oxocyclohex-1-enylamino)-7-methoxy-
4-aryl-4H-chromene-3-carbonitrile (3a–i).
Entry
R
R1
R2
Yield (%)
H 5.07, N 10.07; found C 73.28, H 5.15, N 9.99.
3a
3b
3c
3d
3e
3f
3g
3h
3i
2-Cl
4-Cl
4-CH3
H
2-Cl
4-Cl
4-CH3
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
CH3
H
H
H
H
H
H
H
H
81
86
83
85
75
72
78
71
75
4-(2-Chlorophenyl)-7-methoxy-2-(3-oxocyclohex-1-enylamino)-
4H-chromene-3-carbonitrile (3a). Yield: 81%, m.p. 160–162ꢁC;
1H NMR(CDCl3, 300 MHz) d: 1.98–2.12 (m, 2H, 50-H), 2.40ꢂ2.56
(m, 4H, 60-H, 40-H), 3.80 (s, 3H, OCH3), 5.42 (s, 1H, 4-H), 5.95
(s, 1H, 20-H), 6.63 (d, J= 2.4 Hz, 1H, 8-H), 6.70(br s, 1H, NH), 6.75
(dd, J=8.2Hz, J= 2.4 Hz, 1H, 6-H), 6.88 (d, J= 8.2 Hz, 1H, 5-H),
7.15ꢂ7.40 (m, 4H, Ph-H); IR (KBr) υ: 3172, 1665, 2204 cmꢂ1; MS
(ESI) m/z (%): 429.0 (M + 23, 100); Anal. Calcd for C23H19ClN2O3:
H
CH3
C 67.90, H 4.71, N 6.89; found C 67.86, H 4.80, N 6.92.
4-(4-Chlorophenyl)-7-methoxy-2-(3-oxocyclohex-1-enylamino)-
4H-chromene-3-carbonitrile (3b). Yield: 86%, m.p 198–200ꢁC;
1H NMR (CDCl3, 300 MHz) d: 1.97–2.10 (m, 2H, 50-H),
2.37–2.54 (m, 4H, 60-H, 40-H), 3.81 (s, 3H, OCH3), 4.77 (s, 1H,
4-H), 5.94 (s, 1H, 20-H), 6.65 (d, J = 2.4 Hz, 1H, 8-H), 6.70 (dd,
J = 8.3Hz, J = 2.4 Hz, 1H, 6-H), 6.83 (d, J = 8.3Hz, 1H, 5-H),
7.01 (br s, 1H, NH), 7.11–7.32 (m, 4H, Ph-H); IR (KBr) υ: 3460,
1672, 2210 cmꢂ1; MS (ESI) m/z (%): 429.0 (M+ 23, 100); Anal.
Calcd for C23H19ClN2O3: C 67.90, H 4.71, N 6.89; found
Table 4
Synthesis of 11-amino-3-methoxy-8-substituted-12-aryl-8,9-dihydro -7H-
chromeno[2,3-b]quinolin-10(12H)-one (4a–i).
Entry
R
R1
R2
Yield (%)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
2-Cl
4-Cl
4-CH3
H
2-Cl
4-Cl
4-CH3
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
CH3
H
H
H
H
H
H
H
H
81
86
83
85
75
72
78
71
75
50
48
52
41
44
47
49
44
47
C 67.84, H 4.84, N 6.92.
7-Methoxy-2-(3-oxocyclohex-1-enylamino)-4-p-tolyl-4H-
chromene-3-carbonitrile (3c). Yield: 83%, m.p. 200–202ꢁC; 1H
NMR (CDCl3, 300 MHz) d: 1.99–2.15 (m, 2H, 50-H), 2.32(s, 3H,
CH3), 2.40–2.53 (m, 4H, 60-H, 40-H), 3.80 (s, 3H, OCH3), 4.74
(s, 1H, 4-H), 5.90 (s, 1H, 20-H), 6.64 (d, J = 2.4 Hz, 1H, 8-H),
6.69 (br s, 1H, NH), 6.75 (dd, J = 8.2Hz, J = 2.4 Hz, 1H, 6-H),
6.88 (d, J = 8.2 Hz, 1H, 5-H), 7.08–7.15 (m, 4H, Ph-H); IR (KBr)
H
CH3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Characterization of 11-amino-3-methoxy-8-substituted-12-aryl-8,
9-dihydro-7H-chromeno[2,3-b]quinolin-10(12H)-one Derivatives
υ: 3472, 1714, 2225 cmꢂ1; MS (ESI) m/z (%): 387.2 (M + 1, 100);
Anal. Calcd for C24H22N2O3: C 74.59, H 5.74, N 7.25; found
C 74.64, H 5.78, N 7.14.
7-Methoxy-2-(3-oxocyclohex-1-enylamino)-4-phenyl-4H-
11-Amino-12-(2-chlorophenyl)-3-methoxy-8,9-dihydro-7H-
chromeno[2,3-b]quinolin-10(12H)-one (4a). Yield: 50%, m.p.
214–216ꢁC; 1H NMR(CDCl3, 300 MHz) d: 1.94–2.15 (m, 2H, 8-
H), 2.49–2.67 (m, 2H, 9-H), 2.83–2.98 (m, 2H, 7-H), 3.77 (s, 3H,
OCH3), 5.07 (br s, 1H, NH), 5.61 (s, 1H, 12-H), 6.57 (dd,
J = 8.2Hz, J = 2.4 Hz, 1H, 2-H), 6.74 (d, J = 2.4Hz, 1H, 4-H),
7.08–7.37 (m, 5H, Ph-H, 1-H), 9.24 (br s, 1H, NH); IR (KBr) υ:
3472, 1640 cmꢂ1; MS (ESI) m/z (%): 407.0 (M+ 1, 100); Anal.
Calcd for C23H19ClN2O3: C 67.90, H 4.71, N 6.89; found
chromene-3-carbonitrile (3d). Yield: 85%, m.p. 188–190ꢁC; 1H
NMR (CDCl3, 300 MHz) d: 1.97–2.15 (m, 2H, 50-H), 2.39–2.52
(m, 4H, 60-H, 40-H), 3.81 (s, 3H, OCH3), 4.78 (s, 1H, 4-H), 5.92
(s, 1H, 20-H), 6.65(d, J = 2.4 Hz, 1H, 8-H), 6.71 (br s, 1H, NH),
6.75 (dd, J = 8.2 Hz, J = 2.4 Hz, 1H, 6-H), 6.89 (d, J = 8.2 Hz, 1H,
5-H), 7.17–7.34 (m, 5H, Ph-H); IR (KBr) υ: 3410, 1655,
2232cmꢂ1; MS (ESI) m/z (%): 395.1 (M+ 23, 100); Anal. Calcd
for C23H20N2O3: C 74.18, H 5.41, N 7.52; found C 74.22,
C 67.86, H 4.82, N 6.82.
11-Amino-12-(4-chlorophenyl)-3-methoxy-8,9-dihydro-7H-
chromeno[2,3-b]quinolin-10(12H)-one (4b). Yield: 48%, m.p.
1
H 5.48, N 7.39.
146–148ꢁC; H NMR (CDCl3, 300MHz) d: 2.01–2.12 (m, 2H,
4-(2-Chlorophenyl)-7-methoxy-2-(3-oxo-5-phenylcyclohex-
8-H), 2.55–2.70 (m, 2H, 9-H), 2.90–3.07 (m, 2H, 7-H), 3.78
(s, 3H, OCH3), 4.78 (br s, 1H, NH), 4.97 (s, 1H, 12-H), 6.59
(dd, J = 8.2 Hz, J = 2.4 Hz,1H, 2-H), 6.73 (d, J = 2.4 Hz, 1H, 4-H),
6.98 (d, J = 8.2 Hz, 1H, 1-H), 7.25–7.27 (m, 4H, Ph-H), 9.21
(br, 1H, NH); IR (KBr) υ: 3450, 1654cmꢂ1; MS (ESI) m/z (%):
407.1 (M + 1, 100); Anal. Calcd for C23H19ClN2O3: C 67.90,
1-enylamino)-4H-chromene-3-carbonitrile (3e).
Yield: 75%,
m.p 122–124ꢁC; 1H NMR (CDCl3, 300 MHz) d: 2.60–2.86
(m, 4H, 60-H, 40-H), 3.37–3.58 (m, 1H, 50-H), 3.81 (s, 3H,
OCH3), 5.42 (s, 1H, 4-H), 6.05 (s, 1H, 20-H), 6.53 (br s, 1H, NH),
6.64 (d, J = 2.4Hz, 1H, 8-H), 6.75 (dd, J = 8.0Hz, J = 2.4 Hz, 1H,
6-H), 6.89 (d, J = 8.0 Hz, 5-H), 7.14–7.38 (m, 9H, Ph-H); IR
(KBr) υ: 3264, 1687, 2219 cmꢂ1; MS (ESI) m/z (%): 483.1
(M+ 1, 100); Anal. Calcd for C29H23ClN2O3: C 72.12, H 4.80,
H 4.71, N 6.89; found C 67.96, H 4.65, N 6.82.
11-Amino-3-methoxy-12-p-tolyl-8,9-dihydro-7H-chromeno
[2,3-b]quinolin-10(12H)-one (4c). Yield: 52%, m.p. 194–196ꢁC;
1H NMR (CDCl3, 400 MHz) d: 2.06–2.13 (m, 2H, 8-H), 2.30 (s, 3H,
CH3), 2.60–2.63 (m, 2H, 9-H), 3.00–3.04 (m, 2H, 7-H), 3.78 (s, 3H,
OCH3), 4.80 (br s, 1H, NH), 4.94 (s, 1H, 12-H), 6.58 (dd, J= 8.8 Hz,
2.8 Hz, 1H, 2-H), 6.60 (d, J= 2.8 Hz, 1H, 4-H), 7.00 (d, J= 8.8Hz,
1H, 1-H), 7.11–7.20 (m, 4H, Ph-H), 9.21 (br s, 1H, NH); IR (KBr)
υ: 3478, 1753 cmꢂ1; MS (ESI) m/z (%): 387.1 (M + 1, 100); Anal.
Calcd for C24H22N2O3: C 74.59, H 5.74, N 7.25; found C 74.65,
N 5.80; found C 72.22, H 4.88, N 5.86.
4-(4-Chlorophenyl)-7-methoxy-2-(3-oxo-5-phenylcyclohex-
1-enylamino)-4H-chromene-3-carbonitrile (3f).
Yield: 72%,
m.p. 124–126ꢁC; 1H NMR (CDCl3, 300 MHz) d: 2.60–2.89
(m, 4H, 60-H, 40-H), 3.37–3.57 (m, 1H, 50-H), 3.82 (s, 3H,
OCH3), 4.78 (s, 1H, 4-H), 6.04 (s, 1H, 20-H), 6.51 (br s, 1H,
NH), 6.65 (d, J = 2.4 Hz, 1H, 8-H), 6.70 (dd, J = 8.0 Hz,
J = 2.4 Hz, 1H, 6-H), 6.87 (d, J = 8.0 Hz, 1H, 5-H), 7.11–7.40
(m, 9H, Ph-H); IR (KBr) υ: 3318, 1696, 2218 cmꢂ1; MS (ESI)
m/z (%): 483.1 (M + 1, 100); Anal. Calcd for C29H23ClN2O3:
H 5.65, N 7.22.
11-Amino-3-methoxy-12-phenyl-8,9-dihydro-7H-chromeno
[2,3-b]quinolin-10(12H)-one (4d). Yield: 41%, m.p. 222–224ꢁC;
1H NMR (CDCl3, 300MHz) d: 2.03–2.14 (m, 2H, 8-H), 2.56–2.72
(m, 2H, 9-H), 2.92–3.02 (m, 2H, 7-H), 3.78 (s, 3H, OCH3), 4.79
(br s, 1H, NH), 4.98 (s, 1H, 12-H), 6.59 (dd, J=8.5Hz, J=2.4Hz,
1H, 2-H), 6.74 (d, J = 2.4 Hz, 1H, 4-H), 7.01 (d, J= 8.5 Hz, 1H,
1-H), 7.28–7.31 (m, 5H, Ph-H), 9.21(br s, 1H, NH); IR (KBr)
υ: 3460, 1735 cmꢂ1; MS (ESI) m/z (%): 373.1 (M + 1, 100);
Anal. Calcd for C23H20N2O3: C 74.18, H 5.41, N 7.52; found
C 72.12, H 4.80, N 5.80; found C 72.02, H 4.78, N 5.92.
7-Methoxy-2-(3-oxo-5-phenylcyclohex-1-enylamino)-4-p-tolyl-
4H-chromene-3-carbonitrile (3g). Yield: 78%, m.p. 128–130ꢁC;
1H NMR (CDCl3, 300MHz) d: 2.33 (s, 3H, CH3), 2.60–2.92
(m, 4H, 60-H, 40-H), 3.38–3.56 (m, 1H, 50-H), 3.81 (s, 3H, OCH3),
4.75 (s, 1H, 4-H), 6.03 (s, 1H, 20-H), 6.47 (br s, 1H, NH), 6.65
(d, J = 2.4 Hz, 1H, 8-H), 6.70 (dd, J = 8.0 Hz, J= 2.4 Hz, 1H, 6-H),
6.87 (d, J = 8.0 Hz, 1H, 5-H), 7.08–7.39 (m, 9H, Ph-H); IR (KBr)
υ: 3453, 1710, 2238 cmꢂ1; MS (ESI) m/z (%): 463.1 (M + 1, 100);
Anal. Calcd for C30H26N2O3: C 77.90, H 5.67, N 6.06; found C
C 74.25, H 5.45, N 7.42.
11-Amino-12-(2-chlorophenyl)-3-methoxy-8-phenyl-8,9-dihydro-
7H-chromeno[2,3-b]quinolin-10(12H)-one (4e). Yield: 44%, m.p.
212–214ꢁC; 1H NMR (CDCl3, 300MHz) d: 2.77–2.93 (m, 2H, 9-H),
3.11–3.33 (m, 2H, 7-H), 3.46–3.57 (m, 1H, 8-H), 3.79 (s, 3H, OCH3),
5.16 (br s, 1H, NH), 5.67 (s, 1H, 12-H), 6.61 (dd, J=8.4Hz,
J= 2.4 Hz, 1H, 2-H), 6.77 (d, J= 2.4 Hz, 1H, 4-H), 7.15–7.61
(m, 10H, Ph-H, 1-H), 9.26 (br s, 1H, NH); IR (KBr) υ: 3484,
1654 cmꢂ1; MS (ESI) m/z (%): 483.1 (M + 1, 100); Anal. Calcd
for C29H23ClN2O3: C 72.12, H 4.80, N 5.80; found C 72.23, H
78.00, H 5.78, N 5.96.
7-Methoxy-2-(3-oxo-5-phenylcyclohex-1-enylamino)-4-phenyl-
4H-chromene-3-carbonitrile (3h). Yield: 71%, m.p. 120–122ꢁC;
1H NMR (CDCl3, 300 MHz) d: 2.58–2.89 (m, 4H, 60-H, 40-H),
3.36–3.57 (m, 1H, 50-H), 3.78 (s, 3H, OCH3), 4.79 (s, 1H, 4-H),
6.05 (s, 1H, 20-H), 6.48 (br s, 1H, NH), 6.65 (d, J = 2.4 Hz, 1H,
8-H), 6.70 (dd, J = 8.2 Hz, J = 2.4 Hz, 1H, 6-H), 6.87
(d, J = 8.2 Hz, 1H, 5-H), 7.19–7.52 (m, 10H, Ph-H); IR (KBr)
υ: 3429, 1685, 2232 cmꢂ1; MS (ESI) m/z (%): 471.1 (M + 23,
100); Anal. Calcd for C29H24N2O3: C 77.66, H 5.39, N 6.25;
4.85, N 5.69.
11-Amino-12-(4-chlorophenyl)-3-methoxy-8-phenyl-8,9-dihydro-
7H-chromeno[2,3-b]quinolin-10(12H)-one (4f). Yield: 47%,
m.p. 228–230ꢁC; 1H NMR (CDCl3, 300 MHz) d: 2.79–2.93 (m,
2H, 9-H), 3.14–3.35 (m, 2H, 7-H), 3.48–3.62 (m, 1H, 8-H), 3.78
(s, 3H, OCH3), 4.81 (br s, 1H, NH), 5.01 (s, 1H, 12-H), 6.61 (dd,
J = 8.4Hz, J = 2.4 Hz, 1H, 2-H), 6.75 (d, J = 2.4Hz, 1H, 4-H), 6.99
(d, J = 8.4 Hz, 1H, 1-H), 7.29–7.39 (m, 9H, Ph-H), 9.21 (br s, 1H,
NH); IR (KBr) υ: 3484, 1656cmꢂ1; MS (ESI) m/z (%): 483.2
(M+ 1, 100); Anal. Calcd for C29H23ClN2O3: C 72.12, H 4.80, N
5.80; found C 72.02, H 4.72, N 5.92.
found C 77.70, H 5.29, N 6.30.
2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-7-methoxy-4-
phenyl-4H-chromene-3-carbonitrile (3i).
Yield: 75%, m.p.
108–110ꢁC; 1H NMR (CDCl3, 400 MHz) d: 1.14 (s, 3H,
CH3), 1.20 (s, 3H, CH3), 2.29–2.37 (m, 4H, 60-H, 40-H), 3.83
(s, 3H, OCH3), 4.79 (s, 1H, 4-H), 6.03 (s, 1H, 20-H), 6.47 (br
s, 1H, NH), 6.55 (d, J = 2.4 Hz, 1H, 8-H), 6.61 (dd, J = 8.4 Hz,
2.4 Hz, 1H, 6-H), 6.89 (d, J = 8.4 Hz, 1H, 5-H), 7.18–7.37
(m, 5H, Ph-H). IR (KBr) υ: 3433, 1675, 2222 cmꢂ1; MS (ESI)
m/z (%): 423.1(M + 23, 100); Anal. Calcd for C25H24N2O3:
C 74.98, H 6.04, N 7.00; found C 75.02, H 6.09, N 6.90.
11-Amino-3-methoxy-8-phenyl-12-p-tolyl-8,9-dihydro-7H-
chromeno[2,3-b]quinolin-10(12H)-one (4g). Yield: 49%, m.p.
226–228ꢁC; 1H NMR (CDCl3, 400MHz) d: 2.32(s, 3H, CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. Han, J. Du, L. Chen, and L. Zhao
Vol 000
REFERENCES AND NOTES
2.84–2.89 (m, 2H, 9-H), 3.19–3.30 (m, 2H, 7-H), 3.46–3.53 (m, 1H,
8-H), 3.78 (s, 3H, OCH3), 4.96 (br s, 1H, NH), 5.16 (s, 1H, 12-H),
6.62 (dd, J = 8.8Hz, J = 2.4 Hz, 1H, 2-H), 6.75 (d, J = 2.4 Hz, 1H, 4-
H), 7.04 (d, J = 8.8 Hz, 1H, 1-H), 7.13–7.40 (m, 9H, Ph-H), 9.17 (br
s, 1H, NH); IR (KBr) υ: 3415, 1649cmꢂ1; MS (ESI) m/z (%): 463.1
(M+ 1, 100); Anal. Calcd for C30H26N2O3: C 77.90, H 5.67, N
[1] Mulakayala, N.; Rambabu, D. Raja, M. R.; Chaitanya
M.; Kumar, C. S.; Kalle, A. M. Rama Krishna, G.; Malla Reddy,
C.; Basaveswara Rao, M. V.; Pal, M. Bioorg Med Chem 2012,
20, 759.
[2] Jose, M. C.; Rafael, L.; Cristobal, R.; Antonio, G. G.;
Manuela, G. L.; Mercedes, V. Bioorg Med Chem 2006, 14, 8176.
[3] Nermien, M. S.; Hany, M. M.; Essam, S. A. E. H. K.; Shymaa,
S. M.; Ahmed, M. E. A. Eur J Med Chem 2011, 46, 765.
[4] Yang, D. Q.; Jiang, K. L.; Li, J. N.; Xu, F. Tetrahedron 2007,
63, 7654.
[5] Huang, X. X.; Hu, W. T. Tetrahedron 2007, 63, 11850.
[6] O’Donnell, F.; Smyth, T. J. P.; Ramachandran, V. N.; Smyt,
W. F. Int J Antimicrob Ag 2010, 35, 30.
[7] Nayyar, A.; Momga, V.; Malde, A.; Coutinhob, E.; Jaina, R.
Bioorg Med Chem 2007, 15, 626.
6.06; found C 77.89, H 5.72, N 5.92.
11-Amino-3-methoxy-8,12-diphenyl-8,9-dihydro-7H-chromeno
[2,3-b]quinolin-10(12H)-one (4h). Yield: 44%, m.p. 206–208ꢁC;
1H NMR (CDCl3, 400 MHz) d: 2.85–2.90 (m, 2H, 9-H), 3.20–3.31
(m, 2H, 7-H), 3.48–3.52 (m, 1H, 8-H), 3.79 (s, 3H, OCH3), 5.00
(br s, 1H, NH), 5.17 (s, 1H, 12-H), 6.60 (dd, J=8.4Hz, J=2.4Hz,
1H, 2-H), 6.76 (d, J= 2.4 Hz, 1H, 4-H), 7.04 (d, J=8.4 Hz, 1H,
1-H), 7.25–7.39 (m, 10H, Ph-H), 9.17 (br s, 1H, NH); IR
(KBr) υ: 3480, 1655 cmꢂ1; MS (ESI) m/z (%): 449.1 (M + 1,
100); Anal. Calcd for C29H24N2O3: C 77.66, H 5.39, N 6.25;
[8] Guo, L. J.; Wei, C. X.; Jia, J. H.; Zhao, L. M.; Quan, Z. S. Eur
J Med Chem 2009, 44, 954.
found C 77.79, H 5.32, N 6.15.
11-Amino-3-methoxy-8,8-dimethyl-12-phenyl-8,9-dihydro-
[9] Shi, A.; Nguyen, T. A.; Battina, S. K.; Rana, S.; Takemoto, D. J.;
Chiangd, P. K.; Huaa, D. H. Bioorg Med Chem Lett 2008, 18, 3364.
[10] Ahmed, N.; Brahmbhatt, K. G.; Sabde, S.; Mitra, D.; Singh,
I. P.; Bhutani, K. K. Bioorg Med Chem 2010, 18, 2872.
[11] Han, G. F.; Wang, J. J.; Jiang, G. J. Chin. J. Org. Chem. 2003,
23, 1004 (in Chinese).
[12] Han, G. F.; Wang, R. H.; Zhang, W. T. Synth. Commun. 2009,
39, 2492.
[13] Dai, G. Y.; Shi, D. Q.; Zhou, L. H. Chinareagent. 1996, 18, 39.
[14] Kemnitzer, W.; Kasibhatla, S.; Jiang, S. C.; Zhang, H. Bioorg
Med Chem Lett 2005, 15, 4745.
7H-chromeno[2,3-b]quinolin-10(12H)-one (4i). Yield: 47%, m.p.
212–214ꢁC; 1H NMR (CDCl3, 400MHz) d: 1.13 (s, 3H, CH3), 1.27
(s, 3H, CH3), 2.07 (s, 2H, 9-H), 2.89 (s, 2H, 7-H), 3.78 (s, 3H, OCH3),
4.99 (s, 1H, 12-H), 5.18 (br s, 1H, NH), 6.59 (dd, J=8.4Hz,
J= 2.4 Hz, 1H, 2-H), 6.74 (d, J= 2.4 Hz, 1H, 4-H), 7.01
(d, J= 8.4 Hz, 1H, 1-H), 7.23–7.33 (m, 5H, Ph-H), 9.14 (br s, 1H,
NH); IR (KBr) υ: 3480, 1655 cmꢂ1; MS (ESI) m/z (%): 401.2
(M + 1, 100); Anal. Calcd for C25H24N2O3: C 74.98, H 6.04, N
7.00; found C 74.89, H 6.07, N 7.02.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet