The Convenient Synthesis of 11-Methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione Derivatives

Article abstract of DOI:10.1002/jhet.1930

The 2-arylidene-3-oxobutanenitrile derivatives 2 were prepared by the Knoevenagel condensation between aldehydes and 3-oxobutanenitrile 1, which was obtained by acid hydrolysis of β-aminocrotononitrile. 3-Acetyl-2-amino-4H-chromen-5(6H)-one derivatives 3 were synthesized by reaction of 2-arylidene-3-oxobutanenitrile 2 and 5-substituted-1,3-cyclohexanedione in ethylene glycol. The 11-methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione derivatives 4 were obtained by Friedl?nder reaction of compounds 3 with 5-substituted-1,3-cyclohexanedione, using p-toluenesulfonic acid monohydrate as catalyst. The structures of all novel compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal and molecular structure of compound 4f has been determined by single crystal XRD analysis.

Full text of DOI:10.1002/jhet.1930

Month 2014
The Convenient Synthesis of 11-Methyl-3,8-disubstituted-12-aryl-
3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione
Derivatives
*
Guang-Fan Han, Li-Jun Zhao, Li-Zhuang Chen, Jia-Wei Du, and Zhong-Xia Wang
Department of Applied Chemistry, School of Biological and Chemical Engineering, Jiangsu University of Science and
Technology, Zhenjiang, Jiangsu 212003, China
*
E-mail: gf552002@yahoo.com.cn
Received September 12, 2012
DOI 10.1002/jhet.1930
Published online in 00 Month 2014 Wiley Online Library (wileyonlinelibrary.com).
R
R
O
O
O
O
PTSA, 3~4h
R1
R2
R3
R4
R1
R2
toluene, reflux
O
NH2
O
N
R1=CH3, R2=CH3 or R1=H, R2=C6H5;
R3=C6H5, R4=H or R3=CH3, R4=CH3 or R3=R4=H or R3=H, R4=C4H3O;
R=H, 4-OCH3, 3-NO2 , 4-Cl;
The 2-arylidene-3-oxobutanenitrile derivatives 2 were prepared by the Knoevenagel condensation
between aldehydes and 3-oxobutanenitrile 1, which was obtained by acid hydrolysis of b-aminocrotononitrile.
3-Acetyl-2-amino-4H-chromen-5(6H)-one derivatives 3 were synthesized by reaction of 2-arylidene-3-
oxobutanenitrile 2 and 5-substituted-1,3-cyclohexanedione in ethylene glycol. The 11-methyl-3,8-disubstituted-
12-aryl-3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione derivatives 4 were obtained by
Friedländer reaction of compounds 3 with 5-substituted-1,3-cyclohexanedione, using p-toluenesulfonic
acid monohydrate as catalyst. The structures of all novel compounds were characterized by elemental
1
analysis, IR, MS, and H NMR spectra. The crystal and molecular structure of compound 4f has been
determined by single crystal XRD analysis.
J. Heterocyclic Chem, 00, 00 (2014).
INTRODUCTION
Despite numerous methods have been reported by
Ukawa et al. [6], the Friedländer annulation is the most
simple and straightforward approach for the synthesis of
poly-substituted pyridines and related azaheterocycles.
Among various Friedländer syntheses, cyclocondensation
of o-aminobenzonitrile with different ketones has been
extensively explored. Previous investigation on condensa-
tion of these derivatives required prolonged reaction time,
complex process, and low yield [7,8]. To improve the effi-
ciency of the reaction, search for medicinal compounds,
and enrich the tetracyclic compounds, we undertook the
synthesis of novel six-membered tetracyclic compounds
chromeno[2,3-b]quinolinone derivatives with a methyl group
at the 11-position from 3-acetyl-2-amino-4H-chrome-n-5
(6H)-one derivatives as new synthetic precursors.
The presence of pyranopyridine scaffold in the framework
of several biologically active naturally occurring alkaloids of
plant origin has enthused researchers to synthesize and study
their potential biological activities. They are known to pos-
sess anti-allergic, anti-inflammatory, and estrogenic proper-
ties [1], among which chromeno[2,3-b]quinolinone not
only possess the structure of benzopyran but also contains
a quinoline ring. Parts of benzopyran and quinoline deriva-
tives have already been reported to possess good biological
activity and also exhibit antitumor activity. Tacrine, a potent
and reversible AChE inhibitor, was the first drug approved in
the United States for the palliative treatment of Alzheimer’s
disease. Jose et al. [9] reported some new multipotent tetra-
cyclic tacrine analogs, which had the similar structure to
the title compounds, and these tacrine analogs are modest
AChE inhibitors but proved to be very selective. And some
of them show a significant neuroprotective effect on neuro-
blastoma cells subjected to Ca2+ overload or free radical-
induced toxicity [2]. In addition, chromeno[2,3-b]pyridines
exhibit antiproliferative, cancer chemopreventive, antibacte-
rial (including antitubercular), antimyopic, antihistamic, hypo-
tensive, antirheumatic, and anti-asthmatic activities [3–5].
RESULTS AND DISCUSSION
Benzopyranquinolinone analogs have been synthesized
through various processes.11-Amino-3,3-dimethyl-8-
substituted-12-aryl-3,4,7,8,9,12-hexahydro-2H-benzopyran
[2,3-b]quinoline-1,10-dione derivatives were prepared by
reaction of 2-amino-3-cyano-4-aryl-5,6,7,8-tetrahydro-7,
© 2014 HeteroCorporation

G.-F. Han, L.-J. Zhao, L.-Z. Chen, J.-W. Du, and Z.-X. Wang
Vol 000
1
7-dimethyl-5-oxo-4H-benzopyran with 5-substituted-1,3-
cyclohexanedione using p-toluenesulfonic acid (PTSA),
K2CO3, and Cu2Cl2 as catalysts [3]. 11-Amino-12-aryl-
2,3,4,7,8,9,10,12-octahydro-3,3-dimethyl-1H-chromeno
[2,3-b]quinoline-1-one derivatives have been accessed
by reaction of 4-aryl-4H-chromenes with cyclohexanone
using AlCl3 as catalyst in 1,2-dicholonethane [9]. Stimulated
by these findings, we explored the application of 3-acetyl-
2-amino-4H-chromen-5(6H)-one derivatives 3 as synthetic
equivalents of 2-amino-3-cyanobenzopyran derivatives
where a cyano group at the 3-position is replaced by acetyl.
Compared with 2-amino-3-cyanobenzopyran derivatives,
3-acetyl-2-amino-4H-chromen-5(6H)-one derivatives have
many advantages, such as simpler operation, higher effi-
ciency, and less byproducts.
In this study, the 2-arylidene-3-oxobutanenitrile deriva-
tives 2 used for the current studies were easily prepared
by the Knoevenagel condensation between aldehydes and
3-oxobutanenitrile 1 [10], which was obtained by acid
hydrolysis of b-aminocrotononitrile [11,12]. 3-Acetyl-2-
amino-4H-chromen-5(6H)-one derivatives 3 were synthe-
sized by reaction of 2-arylidene-3-oxobutanenitrile 2 and
5,5-dimethyl-1,3-cyclohexanedione in ethylene glycol. The
11-methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-
1H-chromeno[2,3-b]quinoline-1,10(2H)-dione derivatives 4
were obtained by Friedländer reaction of compounds 3
with 5-substituted-1,3-cyclohexanedione using PTSA as
catalyst in toluene.
The data of H NMR, MS, and IR shown in the Experi-
mental section are in accordance with the chemical structures
of the target compounds. In the 1H NMR spectrum of com-
pound 3a, a sharp single peak at d 1.91 was the characteristic
1
absorption proton peak of acetyl at 3-position. In the H
NMR spectrum of compound 4a, a sharp single peak at d
2.58 was the characteristic absorption proton peak of methyl
at 11-position. In the H NMR spectrum of compound 4e,
1
the characteristic absorption proton peak of methyl at
11-position coincides with the solvent residual peak of
deuterated dimethyl sulfoxide (DMSO-d6). We can observe
clearly a sharp single peak at d 2.51 when the CDCl3 was
chosen as a solvent. The structures of these compounds
were further supported by their IR spectra. Several typical
absorption bands at 1671 cmꢁ1 for 3a (C═O), 2212 cmꢁ1
for 2a (CꢂN), and 3364 cmꢁ1 for 3a (N–H) were
observed. The crystal structure of 4f was also proved by
XRD analysis (Fig.1).
CRYSTAL STRUCTURE
A summary of the crystal data and structure refinement is
presented in Table 1. Single-crystal X-ray analysis reveals
that compound 4f crystallizes in the monoclinic system,
space group P21/c. A perspective view of compound 4f with
atomic numbering scheme is shown in Figure 1. In the
compound 4f, the bond lengths and the bond angles are
generally normal. The dihedral angle between the phenyl
and pyrano[2,3-b]pyridine ring and pyrano[2,3-b]pyridine
ring [C(5), C(6), C(7), C(8), C(9), C(10), C(11 ), C(12), N
(1), O(3)] with plane equation 0.8894(3) x ꢁ 0.1149(5) y
0.4424(6) z = 0.6925(107) and the benzene ring [C(19), C
(20), C(21), C(22), C(23), C(24)] with plane equation
0.1703(11) x ꢁ 0.9201(5) y ꢁ 0.3527(11) z = ꢁ22.6108(82)
is 83.668(78)ꢀ. (Scheme 1) The packing diagram of the 4f
in a unit cell is shown in Figure 2.
In our initial experiments, the effect of the temperature
on the reactions of 2-arylidene-3-oxobutanenitrile 2 with
5-substituted-1,3-cyclohexanedione was investigated. It
was found that the reaction temperature should be kept at
70–80ꢀC, otherwise the post-treatment would be very diffi-
cult. In the preparation of compound 4, it was noted that
the amount of the catalyst PTSA has obvious effects on
the reaction. When the amount of PTSA is gradually in-
creasing, the reactivity of compound 4 will have a signifi-
cant improvement. However, in our previous work, when
2-amino-3-cyanobenzopyran derivatives were used as a
precursor, even if we increase the PTSA amount, the reac-
tivity did not have any obvious improvement or even pro-
duced more byproducts. This may be due to the carbonyl
having stronger electrophilicity in acid conditions than
the cyano group. In the following, we will further explore
the synthetic conditions of compound 4 and try to find a
kind of more environmentally friendly, mild acidic system.
Compound 4 should be a diastereomeric mixture. And it
EXPERIMENTAL
All melting points were determined on an electrothermal
apparatus and were uncorrected. Microanalysis was performed
by the Perkin-Elmer 2400 Microanalytical Service. Infrared
spectra were recorded as thin films on KBr using a Perking-
Elmer 1700 spectrophotometer. The 1H NMR spectra were
recorded by a Bruker ARX-300 spectrometer. Sample solutions
were prepared in CDCl3, DMSO-d6, and the chemical shifts are
expressed as d ppm using TMS as an internal standard. Mass
spectra were recorded by JMS-DX300 at 70 eV. 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.
1
was speculated from the H NMR spectrum that when the
yields of the major product were above 90%, the diastereo-
meric was difficult to be isolated. Therefore, we mainly se-
lect some compound 3 with two methyl at 3-position as
synthetic precursors of compound 4. The specific stereo-
structure of the compound with phenyl at 3-position needs
to be further studied.
Synthesis of 3-oxobutanenitrile.
b-Aminocrotononitrile
(Alfa Aesar Co., Ltd. , Tianjin, China) (10.0g, 0.12 mol) was
stirred in water (12.5 mL), and concentrated hydrochloric acid
(Shanghai Chemical Regent Co., Ltd., Shanghai, China) (12.5 mL)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
The Convenient Synthesis of 11-Methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahy-
dro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione Derivatives
Figure 1. Molecular structure of compound 4f.
under reduced pressure to afford crude 3-oxobutanenitrile as a
light brown oil (9.0 g, 90%), which was used in the next step for
the synthesis of compound 1. (Fig. 2)
Table 1
Crystallographic data for complex 4f.
General method for the synthesis of 2-arylidene-3-
oxobutanenitrile (2a–d). To a solution of 3-oxobutanenitrile
(10 mmol) in 40 mL of absolute ethanol (Chinasun Specialty
Products Co., Ltd , Changshu, China) and 10 mL methanol,
L-proline (Aladdin Chemistry Co., Ltd , Shanghai, China)
(0.5 mmol) and aryl aldehyde (Aladdin Chemistry Co., Ltd ,
Shanghai, China) (10 mmol) were successively added. The
resulting reaction mixture was stirred at room temperature for
48 h until the disappearance of starting materials (by TLC).
After the completion of the reaction, the reaction mixture was
added 200 mL ice water, and the precipitate was isolated by
filtration, washed with water, and recrystallized from methanol
(Table 2).
Empirical formula
C
30 H29 N O5
Formula weight
Wavelength (nm)
Crystal system
Space group
a (nm)
b (nm)
483.54
0.71073
Monoclinic
P21/c
11.584(4)
20.494(7)
11.219(4)
c (nm)
a (ꢀ)
90.00
b (ꢀ)
109.783(5)
g (ꢀ)
90.00
Volume (nm3)
2506.4(15)
Z
4
Calculated density (g/cm3)
Absorption coefficient (mmꢁ1
F (000)
1.281
0.087
1024
General method for the synthesis of 3-acetyl-2-amino-4-
)
aryl-7-substituted-4H-chromen-5(6H)-one (3a–j).
To a
solution of the corresponding 2-arylidene-3-oxobutanenitrile
(10 mmol) in ethylene glycol (Sinopharm Chemical Reagent
Co., Ltd, Shanghai, China) (1 mL/mmol), 5-substituted-1,3-
cyclohexanedione (11mmol) was added. The mixture was stirred
at 80ꢀC for 2–4 h, as indicated (by TLC). Then, the resultant
mixture was cooled to RT. To this mixture was added 100 mL
water, and the precipitated solid was isolated by filtration, washed
with water, and recrystallized from methanol (Table 3).
Final R indices [I > 2sigma(I)]
R indices (all data)
R1 = 0.0983, wR2 = 0.2575
R1 = 0.0704, wR2 = 0.2279
was added dropwise below 15ꢀC within 1 h. The reaction mixture
was then heated to 80ꢀC for 2 h. After completion of reaction
(TLC check, chloroform (Hubao Chemical Reagent Co., Ltd.
Yangzhou, China)/methanol (Chinasun Specialty Products Co.,
Ltd , Changshu, China) 9:1), the reaction mixture was cooled to
room temperature and diluted with ethyl acetate (Chinasun
Specialty Products Co., Ltd , Changshu, China) (100 mL). The
insoluble materials were filtered through celite, the biphasic clear
filtrate was separated, and the aqueous layer was extracted twice
with ethyl acetate (100mL ꢃ 2 mL). The combined ethyl acetate
extracts were washed with saturated sodium chloride solution, and
the organic layer was dried over sodium sulfate (Aladdin
Chemistry Co., Ltd , Shanghai, China). The solvent was removed
General method for the synthesis of 11-methyl-3,8-
disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-1H-chromeno[2,3-b]
quinoline-1,10(2H)-dione (4a–k).
3-Acetyl-2-amino-4-aryl-7-
substituted-4H-chromen-5(6H)-one 3 (5 mmol) and 5-substituted-
1,3-cyclohexanedione (6 mmol) were suspended in toluene
(Sinopharm Chemical Reagent Co., Ltd , Shanghai, China)
(1 mL/mmol) containing PTSA (Aladdin Chemistry Co., Ltd ,
Shanghai, China) (3 mmol). The mixture was refluxed for 3–4 h,
and the water was collected in a Dean-Stark water separator, as
indicated (by TLC). At the end of the reaction, the reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-F. Han, L.-J. Zhao, L.-Z. Chen, J.-W. Du, and Z.-X. Wang
Vol 000
Scheme 1
mixture was cooled to room temperature and then alkalined
2-(3-Nitrobenzylidene)-3-oxobutanenitrile (2c).
Yield:
1
using sodium bicarbonate. The aqueous layer was extracted
twice with ethyl acetate (100 mL ꢃ 2 mL), and the solvent was
removed to give crude products, which were further purified
by column chromatography (petroleum ether (Chinasun
Specialty Products Co., Ltd , Changshu, China)/ethyl acetate
5:1) (Table 4).
88.1%, mp 115–116ꢀC; H NMR (CDCl3, 300 MHz) d: 2.65 (s,
3H, COCH3), 7.76–8.42 (m, 4H, Ph-H), 8.77 (s, 1H, 10-H). IR
(KBr) υ: 2213, 1678 cmꢁ1; MS (70 eV) m/z (%): 216.8 (M + 1,
100); Anal. Calcd for C11H8N2O3: C, 61.11; H, 3.73; N, 12.96.
Found: C, 61.13; H, 3.71; N, 12.95.
2-(4-Chlorobenzylidene)-3-oxobutanenitrile (2d).
Yield:
2-Benzylidene-3-oxobutanenitrile (2a).
Yield: 73.2%, mp
82.3%, mp 68–70ꢀC; 1H NMR (CDCl3, 300 MHz) d: 2.7
(s, 3H, COCH3), 7.27–7.94 (m, 4H, Ph-H), 8.07 (s, 1H, 10-H).
IR (KBr) υ: 2218, 1689 cmꢁ1; MS (70 eV) m/z (%): 205.9
(M + 1, 100); Anal. Calcd for C11H8NO: C, 64.25; H, 3.92; N,
6.81. Found: C, 64.27; H, 3.90; N, 6.80.
78–80ꢀC; 1H NMR (DMSO-d6, 300MHz) d: 2.54 (s, 3H,
COCH3), 7.59–8.08 (m, 3H, Ph-H), 8.06–8.08 (m, 2H, Ph-H),
8.42 (s, 1H, 10-H). IR (KBr) υ: 2212, 1691 cmꢁ1; MS (70 eV) m/z
(%): 171.8 (M + 1, 100); Anal. Calcd for C11H9NO: C, 77.17; H,
5.30; N, 8.18. Found: C, 77.15; H, 5.29; N 8.20.
3-Acetyl-2-amino-7,7-dimethyl-4-phenyl-7,8-dihydro-4H-
2-(4-Methoxybenzylidene)-3-oxobutanenitrile (2b).
Yield:
chromen-5(6H)-one (3a).
Yield: 76.4%, mp 152–154ꢀC; 1H
84.6%, mp 113–115ꢀC; 1H NMR (CDCl3, 300 MHz) d: 2.56
(s, 3H, COCH3), 3.91 (s, 3H, OCH3), 7.00–7.28 (m, 2H, Ph-H),
8.02–8.04 (m, 2H, Ph-H), 8.09 (s, 1H, 10-H). IR (KBr) υ: 2221,
1681 cmꢁ1; MS (70 eV) m/z (%): 201.7 (M + 1, 100); Anal.
Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C,
71.65; H, 5.50; N, 6.94.
NMR (DMSO-d6, 300 MHz) d: 0.80 (s, 3H, 7-CH3), 1.02
(s, 3H, 7-CH3), 1.91 (s, 3H, COCH3), 2.04–2.28 (m, 2H, 8-CH2),
2.40–2.55 (m, 2H, 6-CH2), 4.61 (s, 1H, 4-CH), 7.11–7.26 (m, 5H,
Ph-H). IR (KBr) υ: 3364, 1671 cmꢁ1; MS (70 eV) m/z (%): 312.6
(M+ 1, 100); Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N,
4.50. Found: C, 73.28; H, 6.81; N, 4.51.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
The Convenient Synthesis of 11-Methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahy-
dro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione Derivatives
Table 3
Synthesis of 3-acetyl-2-amino-4-aryl-7-substituted-4H-chromen-5(6H)-
one (3a–j).
Entry
R
R1
R2
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
CH3
H
H
CH3
H
H
CH3
CH3
H
CH3
C6H5
H
CH3
C6H5
H
CH3
CH3
C6H5
H
76.4
63.8
70.2
78.3
68.6
72.1
80.5
76.8
65.4
74.3
4-OCH3
3-NO2
3-NO2
3-NO2
4-Cl
4-Cl
4-Cl
3j
H
Table 4
Synthesis of 11-methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahydro-
1H-chromeno[2,3-b]quinoline-1,10(2H)-dione derivatives (4a–k).
Entry
R
R1
R2
R3
R4
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
CH3
H
CH3
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
CH3
H
CH3
H
CH3
H
H
C6H5
C6H5
H
73.0
76.6
70.3
78.1
63.5
76.8
66.8
72.2
80.4
68.5
82.7
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
C4H3O
CH3
C6H5
CH3
C6H5
H
4-Cl
3-NO2
3-NO2
3-NO2
4j
4k
1663 cmꢁ1; MS (70 eV) m/z (%): 360.1 (M + 1, 100); Anal. Calcd
for C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: C, 76.85; H,
5.87; N, 3.91.
3-Acetyl-2-amino-4-phenyl-7,8-dihydro-4H-chromen-5(6H)-
one (3c). Yield: 70.2%, mp 138–140ꢀC; 1H NMR (DMSO-d6,
300 MHz) d: 1.80–1.94 (m, 2H, 7-CH2), 2.18 (s, 3H, COCH3),
2.50–2.55 (m, 2H, 8-CH2), 2.62–2.70 (m, 2H, 6-CH2), 4.32
(s, 1H, 4-CH), 7.25–7.33 (m, 5H, Ph-H). IR (KBr) υ: 3363,
1661 cmꢁ1; MS (70 eV) m/z (%): 284.6 (M + 1, 100); Anal.
Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
72.08; H, 6.04; N, 4.93.
Figure 2. Packing diagram of compound 4f in unit cell.
Table 2
Synthesis of 2-arylidene-3-oxobutanenitrile (2a–d).
3-Acetyl-2-amino-7,7-dimethyl-4-(4-methoxybenzylidene)-
Entry
R
Yield (%)
7,8-dihydro-4H-chromen-5(6H)-one (3d).
Yield: 78.3%, mp
1
147-148ꢀC; H NMR (CDCl3, 300MHz) d: 0.92 (s, 3H, 7-CH3),
1.10 (s, 3H, 7-CH3), 2.07 (s, 3H, COCH3), 2.17–2.22 (m, 2H,
8-CH2), 2.34–2.40 (m, 2H, 6-CH2), 3.78 (s, 3H, OCH3), 4.72
(s, 1H, 4-CH), 6.80–7.28 (m, 4H, Ph-H). IR (KBr) υ: 3391,
1662 cmꢁ1; MS (70 eV) m/z (%): 342.6 (M + 1, 100); Anal.
Calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.38; H, 6.77; N, 4.11.
2a
2b
2c
2d
H
73.2
84.6
88.1
82.3
4-OCH3
3-NO2
4-Cl
3-Acetyl-2-amino-4,7-diphenyl-7,8-dihydro-4H-chromen-5
(6H)-one (3b). Yield: 63.8%, mp 168–170ꢀC; 1H NMR (CDCl3,
300 MHz) d: 2.06 (s, 3H, COCH3), 2.53–2.71 (m, 2H, 8-CH2),
2.71–3.47 (m, 2H, 6-CH2), 3.72–3.74 (m, 1H, 7-CH2), 4.85
(s, 1H, 4-CH), 7.12–7.36 (m, 10H, Ph-H). IR (KBr) υ: 3371,
3-Acetyl-2-amino-7-phenyl-4-(3-nitrobenzylidene)-7,8-dihydro-
4H-chromen-5(6H)-one (3e). Yield: 80.5%, mp 163–164ꢀC; 1H
NMR (CDCl3, 300MHz) d: 2.03 (s, 3H, COCH3), 2.49–2.67
(m, 2H, 8-CH2), 2.71–2.92 (m, 2H, 6-CH2), 3.14–3.59 (m, H, 7-CH),
4.96 (s, 1H, 4-CH), 7.10–8.17 (m, 9H, Ph-H). IR (KBr) υ: 3384,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-F. Han, L.-J. Zhao, L.-Z. Chen, J.-W. Du, and Z.-X. Wang
Vol 000
1665cmꢁ1; MS (70eV) m/z (%): 405.1 (M + 1, 100); Anal. Calcd
for C23H20N2O5: C, 68.31; H, 4.98; N, 6.93. Found C, 68.32;
H, 4.97; N, 6.95.
1664 cmꢁ1; MS (70 eV) m/z (%): 512.1 (M + 1, 100); Anal.
Calcd for C35H29NO3: C, 82.17; H, 5.71; N, 2.74. Found: C,
82.16; H, 5.72; N, 2.73.
3-Acetyl-2-amino-4-(3-nitrobenzylidene)-7,8-dihydro-4H-
chromen-5(6H)-one (3f). Yield: 68.6%, mp 168–170ꢀC; 1H
NMR (CDCl3, 300 MHz) d: 2.03–2.08 (m, 2H, 7-CH2), 2.29
(s, 3H, COCH3), 2.39–2.58 (m, 2H, 8-CH2), 2.64–2.74
(m, 2H, 6-CH2), 4.56 (s, 1H, 4-CH), 7.28–8.15 (m, 4H, Ph-H). IR
(KBr) υ: 3374, 1660 cmꢁ1; MS (70 eV) m/z (%): 329.1 (M +1,
100); Anal. Calcd for C17H16N2O5: C, 62.19; H, 4.91; N, 8.53.
Found: C, 62.18; H, 4.92; N, 8.52.
12-(4-Methoxyphenyl)-3,3,11-trimethyl-3,4,7,8,9,12-hexahydro-
1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4c).
Yield:
70.3%, mp 165–166ꢀC; 1H NMR (DMSO-d6, 300 MHz) d:
0.89 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.99–2.02 (m, 2H,
8-CH2), 2.11–2.31 (m, 2H, 7-CH2), 2.42 (s, 3H,11-CH3),
2.55–2.58 (m, 2H, 4-CH2), 2.60–2.66 (m, 2H, 9-CH2),
2.98–3.99 (m, 2H, 2-CH), 3.67 (s, 3H, OCH3), 5.08 (s, 1H,
12-H), 6.79–7.07 (m, 4H, Ph-H). IR (KBr) υ: 2949,
1662 cmꢁ1; MS (70 eV) m/z (%): 418.1 (M + 1, 100); Anal.
Calcd for C26H27NO4: C, 74.80; H, 6.52; N, 3.35. Found:
C, 74.81; H, 6.51; N, 3.33.
3-Acetyl-2-amino-7,7-dimethyl-4-(3-nitrobenzylidene)-7,8-
dihydro-4H-chromen-5(6H)-one (3g).
Yield: 72.1%, mp
1
174–175ꢀC; H NMR (CDCl3, 300 MHz) d: 0.89 (s, 3H, 7-CH3),
1.10 (s, 3H, 7-CH3), 2.01 (s, 3H, COCH3), 2.14–2.30 (m, 2H,
8-CH2), 2.38–2.44 (m, 2H, 6-CH2), 4.88 (s, 1H, 4-CH),
7.28–8.11 (m, 4H, Ph-H). IR (KBr) υ: 3391, 1652 cmꢁ1; MS
(70 eV) m/z (%): 357.1 (M + 1, 100); Anal. Calcd for
C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.05; H,
5.68; N, 7.85.
12-(4-Methoxyphenyl)-3,3,11-trimethyl-8-phenyl-3,4,7,8,9,12-
hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4d).
Yield: 78.1%, mp 228–230ꢀC; 1H NMR (CDCl3, 300 MHz)
d: 0.89 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.12–2.32 (m, 2H,
4-CH2), 2.48 (s, 3H, 11-CH3), 2.56–2.67 (m, 2H, 7-CH2),
3.72–2.78 (m, 2H, 2-CH2), 2.96–3.18 (m, 2H, 9-CH2),
3.44–3.53 (m, 1H, 8-CH), 3.69 (s, 3H, OCH3), 5.11 (s, 1H, 12-H),
6.80–7.37 (m, 9H, Ph-H). IR (KBr) υ: 2959, 1652 cmꢁ1; MS
(70 eV) m/z (%): 494.2 (M + 1, 100); Anal. Calcd for
C32H31NO4: C, 77.87; H, 6.33; N, 2.84. Found: C, 77.88; H,
6.31; N, 2.83.
12-(4-Methoxyphenyl)-3,3,8,8,11-pentamethyl-3,4,7,8,9,12-
hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4e).
Yield: 63.5%, mp 194–195ꢀC; 1H NMR (CDCl3, 300 MHz)
d: 0.89 (s, 3H, CH3), 0.99 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.06
(s, 3H, CH3), 1.99–2.14 (m, 2H, 7-CH2), 2.24–2.30 (m, 2H,
4-CH2), 2.44 (s, 3H, 11-CH3), 2.54–2.66 (m, 2H, 9-CH2),
2.87–2.97 (m, 2H, 2-CH2), 3.68 (s, 3H, OCH3), 5.08 (s, 1H,
12-H), 6.79–7.08 (m, 4H, Ph-H). IR (KBr) υ: 2959,
1662 cmꢁ1; MS (70 eV) m/z (%): 446.2 (M + 1, 100); Anal.
Calcd for C28H31NO4: C, 75.48; H, 7.01; N, 3.14. Found: C,
75.47; H, 7.02; N, 3.15.
3-Acetyl-2-amino-7,7-dimethyl-4-(4-chlorobenzylidene)-7,
8-dihydro-4H-chromen-5(6H)-one (3h).
Yield: 76.8%, mp
135–136ꢀC; 1H NMR (DMSO-d6, 300 MHz) d: 0.89 (s, 3H,
7-CH3), 1.08 (s, 3H, 7-CH3), 2.02 (s, 3H, COCH3), 2.19–2.22
(m, 2H, 8-CH2), 2.28–2.38 (m, 2H, 6-CH2), 4.73 (s, 1H,
4-CH), 6.94–7.28 (m, 4H, Ph-H). IR (KBr) υ: 3356,
1683 cmꢁ1; MS (70 eV) m/z (%): 346.1 (M + 1, 100); Anal.
Calcd for C19H20ClNO3: C, 65.99; H, 5.83; N, 4.05. Found:
C, 65.98; H, 5.85; N, 4.03.
3-Acetyl-2-amino-7-phenyl-4-(4-chlorobenzylidene)-7,8-dihydro-
1
4H-chromen-5(6H)-one (3i). Yield: 65.4%, mp 179–180ꢀC; H
NMR (CDCl3, 300 MHz) d: 2.02 (s, 3H, COCH3), 2.54–2.65 (m,
2H, 8-CH2), 2.70–2.79 (m, 2H, 6-CH2), 3.24–3.50 (m, 1H, 7-CH),
4.82 (s, 1H, 4-CH), 7.12–7.37 (m, 9H, Ph-H). IR (KBr) υ: 3361,
1641 cmꢁ1; MS (70eV) m/z (%): 394.1 (M + 1, 100); Anal. Calcd
for C23H20ClNO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 70.13; H,
5.14; N, 3.55.
8-(Furan-2-yl)-12-(4-methoxyphenyl)-3,3,11-trimethyl-3,4,7,8,9,
12-hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4f).
Yield: 76.8%, mp 223–224ꢀC; 1H NMR (CDCl3, 300 MHz)
d: 0.87 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.19–2.30 (m, 2H,
4-CH2), 2.54 (s, 3H, 11-CH3), 2.54–2.58 (m, 2H, 7-CH2),
2.78–3.05 (m, 2H, 2-CH2), 3.23–3.50 (m, 2H, 9-CH2), 3.54–3.60
(m, 1H, 8-H), 3.73 (s, 3H, OCH3), 5.12 (s, 1H, 12-H), 6.07–6.31
(m, 2H, furyl-H), 6.73–7.35 (m, 4H, Ph-H), 7.35–7.36
3-Acetyl-2-amino-4-(4-chlorobenzylidene)-7,8-dihydro-4H-
1
chromen-5(6H)-one (3j). Yield: 74.3%, mp 165–166ꢀC; H
NMR (DMSO-d6, 300 MHz) d: 1.92–2.17 (s, 2H, 7-CH2), 2.18
(s, 3H, COCH3), 2.26–2.33 (s, 2H, 8-CH2), 2.50–2.68 (m, 2H,
6-CH2), 4.36 (s, 1H, 4-CH), 7.26–7.40 (m, 4H, Ph-H). IR
(KBr) υ: 3358, 1693 cmꢁ1; MS (70 eV) m/z (%): 319.1 (M + 1,
100); Anal. Calcd for C17H16ClNO3: C, 64.26; H, 5.08; N,
4.41. Found: C, 64.24; H, 5.07; N, 4.41.
(m, 1H, furyl-H). IR (KBr) υ: 2958, 1662 cmꢁ1
(70 eV) m/z (%): 484.1 (M + 1, 100); Anal. Calcd for
30H29NO5: C, 74.52; H, 6.04; N, 2.90. Found: C, 74.53;
; MS
3,3,11-Trimethyl-8,12-diphenyl-3,4,7,8,9,12-hexahydro-1H-
chromeno[2,3-b]quinoline-1,10(2H)-dione (4a).
Yield:
C
73.0%, mp 234–236ꢀC; 1H NMR (CDCl3, 300 MHz) d: 0.97
(s, 3H, CH3), 1.12 (s, 3H, CH3), 2.04–2.32 (m, 2H, 4-CH2),
2.48 (s, 3H,11-CH3), 2.56–2.70 (m, 2H, 7-CH2), 2.71–3.03
(m, 2H, 2-CH2), 3.12–3.19 (m, 1H, 8-CH2), 3.45–3.53 (m, 2H,
9-CH), 5.27 (s, 1H, 12-H), 7.16–7.38 (m, 10H, Ph-H). IR
(KBr) υ: 2959, 1671 cmꢁ1; MS (70 eV) m/z (%): 464.5 (M + 1,
100); Anal. Calcd for C31H29NO3: C, 80.32; H, 6.31; N, 3.02.
Found: C, 80.33; H, 6.30; N, 3.01.
H, 6.04; N, 2.91.
12-(4-Chlorobenzylidene)-3,3,8,8,11-pentamethyl-3,4,7,8,9,12-
hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4g).
Yield: 66.8%, mp 184–186ꢀC; 1H NMR (CDCl3, 300 MHz)
d: 0.89 (s, 3H,CH3), 0.99 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.06
(s, 3H, CH3), 2.10–2.32 (m, 2H, 7-CH2), 2.41 (s, 3H, 11-CH3),
2.49–2.61 (m, 2H, 4-CH2), 2.59–2.68 (m, 2H, 9-CH2),
2.85–2.99 (m, 2H, 2-CH2), 5.08 (s, 1H, 12-H), 6.79–7.08
(m, 4H, Ph-H). IR (KBr) υ: 2949, 1652 cmꢁ1; MS (70 eV) m/z
(%): 449.8 (M + 1, 100); Anal. Calcd for C27H28ClNO3: C,
72.07; H, 6.27; N, 3.11. Found: C, 72.09; H, 6.27; N, 3.12.
12-(4-Chlorobenzylidene)-3,3,11-trimethyl-8-phenyl-3,4,7,8,9,12-
hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4h).
Yield: 72.2%, mp 218–220ꢀC; 1H NMR (CDCl3, 300 MHz) d: 0.87
(s, 3H, CH3), 1.04 (s, 3H, CH3), 1.98–2.32 (m, 2H, 4-CH2), 2.44 (s,
11-Methyl-3,8,12-triphenyl-3,4,7,8,9,12-hexahydro-1H-chromeno
[2,3-b]quinoline-1,10(2H)-dione (4b).
Yield: 76.6%, mp
222–224ꢀC; 1H NMR (DMSO-d6, 300 MHz) d: 2.34–2.46
(m, 2H, 7-CH2), 2.62–2.73 (m, 2H, 4-CH2), 2.51 (s, 3H, 11-CH3),
2.79–2.83 (m, 2H, 2-CH2), 2.92–3.12 (m, 2H, 9-CH2), 3.38–
3.46 (m, 1H, 8-CH), 3.50–3.57 (m, 1H, 3-CH), 4.67 (s, 1H,
12-CH), 7.21–7.38 (m, 15H, Ph-H). IR (KBr) υ: 2959,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
The Convenient Synthesis of 11-Methyl-3,8-disubstituted-12-aryl-3,4,7,8,9,12-hexahy-
dro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione Derivatives
3H,11-CH3), 2.49–2.62 (m, 2H, 7-CH2), 2.67–3.02 (m, 2H, 2-CH2),
3.10–3.36 (m, 2H, 9-CH2), 3.40–3.46 (m, 1H, 8-CH), 5.18 (s, 1H, 12-
H), 7.18–7.33 (m, 9H, Ph-H). IR (KBr) υ: 2959, 1655 cmꢁ1; MS
(70 eV) m/z (%): 498.1 (M + 1, 100); Anal. Calcd for
C31H28ClNO3: C, 74.76; H, 5.67; N, 2.81. Found: C, 74.77; H,
5.66; N, 2.80.
2-CH2), 5.09 (s, 1H, 12-H), 6.77–7.05 (m, 4H, Ph-H). IR (KBr)
υ: 2958, 1663 cmꢁ1; MS (70 eV) m/z (%): 433.2 (M + 1, 100);
Anal. Calcd for C25H28N2O5: C, 69.43; H, 5.59; N, 6.48.
Found: C, 69.41; H, 5.58; N, 6.49.
REFERENCES AND NOTES
3,3,8,8,11-Pentamethyl-12-(3-nitrophenyl)-3,4,7,8,9,12-hexahydro-
1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4i).
Yield:
80.4%, mp 202–203ꢀC; 1H NMR (CDCl3, 300 MHz) d: 0.84
(s, 3H, CH3), 0.95 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.05
(s, 3H, CH3), 1.94–2.11 (m, 2H, 7-CH2), 2.23–2.30 (m, 2H,
4-CH2), 2.45 (s, 3H, 11-CH3), 2.52–2.63 (m, 2H, 9-CH2),
2.84–2.96 (m, 2H, 2-CH2), 5.07 (s, 1H, 12-H), 6.78–7.05 (m, 4H,
Ph-H). IR (KBr) υ: 2961, 1655cmꢁ1; MS (70 eV) m/z (%): 461.0
(M+ 1, 100); Anal. Calcd for C27H28N2O5: C, 70.42; H, 6.13; N,
6.08. Found: C, 70.41; H, 6.11; N, 6.09.
[1] Nagarajan, P.S.; Thelagathoti, H.B.; Paramasivan, T.P.
Tetrahedron 2009, 65, 8524.
[2] Han, G.F.; Cui, B.; Chen, L.Z.; Jin, Y. J Heterocyclic Chem
2010, 47, 1335.
[3] Kolokythas, G.; Pouli, N.; Marakos, P.; Pratsinis, H.; Kletsas,
D. Eur J Med Chem 2006, 41, 71.
[4] Azuine, M.A.; Tokuda, H.; Takayasu, J.; Enjyo, F.;
Mukainaka, T.; Konoshima, T.; Nishino, H.; Kapadia, G. J Pharmacol.
Res 2004, 49, 161.
3,3,11-Trimethyl-12-(3-nitrophenyl)-8-phenyl-3,4,7,8,9,12-
hexahydro-1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4j).
Yield: 68.5%, mp 206–207ꢀC; 1H NMR (CDCl3, 300 MHz)
d: 0.84 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.08–2.27 (m, 2H,
4-CH2), 2.44 (s, 3H, 11-CH3), 2.53–2.65 (m, 2H, 7-CH2),
3.72–2.75 (m, 2H, 2-CH2), 2.93–3.15 (m, 2H, 9-CH2),
3.43–3.52 (m, 1H, 8-CH), 5.09 (s, 1H, 12-H), 6.78–7.35
(m, 9H, Ph-H). IR (KBr) υ: 2956, 1654 cmꢁ1; MS (70 eV) m/z
(%): 509.2 (M + 1, 100); Anal. Calcd for C31H28N2O5: C, 73.2;
H, 5.55; N, 5.51. Found: C, 73.5; H, 5.54; N, 5.52.
[5] Srivastava, S.K.; Tripathi, R.P.; Ramachandran, R. J Biol
Chem 2005, 280, 30273.
[6] Ukawa, K.; Ishiguro, T.; Kuriki, H.; Nohara, A. Chem Pharm
Bull 1985, 33, 4432.
[7] Li, J.R.; Zhang, L.J.; Yang, X.Q.; Li, Q.; Wang, D.; Wang, C.X.;
Shi, D.X.; Zhang, Q. Chin Chem Lett 2008, 19, 15.
[8] Leon, R.; Marco-Contelles, J.; Garcia, A.G.; Villarroya, M.
Bioorg Med Chem 2005, 13, 1167.
[9] Jose, M.C.; Rafael, L.; Cristobal, R.; Antonio, G.G.;
Manuela, G.L.; Mercedes, V. Bioorg Med Chem 2006, 14, 8176.
[10] Amancha, P.K.; Lai, Y.C.; Chen, I.C.; Liu, H.J.; Zhu, J.L.
Tetrahedron 2010, 66, 871.
[11] Birari, D.R.; Ghagare, M.G.; Kazi, M.A.; Bagul, S.M.;
Ghotekar, B.K.; Toche, R.B.; Jachak, M.N. Org Prep Preced Int 2009,
41, 515.
[12] Boschelli, D.H.; Wang, D.; Prashad, A.S.; Subrath, J.; Wu, B.
Q.; Niu, C.; Lee, J.; Yang, X.K.; Brennan, A.; Divya, C. Bioorg Med
Chem Lett 2009, 19, 3623.
3,3,11-Trimethyl-12-(3-nitrophenyl)-3,4,7,8,9,12-hexahydro-
1H-chromeno[2,3-b]quinoline-1,10(2H)-dione (4k).
Yield:
1
82.7%, mp 184–186ꢀC; H NMR (DMSO-d6, 300 MHz) d: 0.86
(s, 3H, CH3), 1.05 (s, 3H, CH3), 1.91–2.03 (m, 2H, 8-CH2),
2.13–2.30 (m, 2H, 7-CH2), 2.43 (s, 3H, 11-CH3), 2.52–2.56
(m, 2H, 4-CH2), 2.62–2.66 (m, 2H, 9-CH2), 2.96–3.97 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet