Synthesis of benzopyran[2,3-b]quinolinone derivatives

Article abstract of DOI:10.1002/jhet.470

A series of novel 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 4 were synthesized by 2-amino-3-cyano-4-aryl-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H- benzopyran 2 with 5-substitut

Full text of DOI:10.1002/jhet.470

November 2010
Synthesis of Benzopyran[2,3-b]quinolinone Derivatives
1335
Guangfan Han,* Bin Cui, Lizhuang Chen, and Yan Jin
School of Material Science and Engineering, Jiangsu University of Science and Technology,
Zhenjiang, Jiangsu 212003, China
*E-mail: gf552002@yahoo.com.cn
Received December 29, 2009
DOI 10.1002/jhet.470
Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A
series of novel 11-amino-3,3-dimethyl-8-substituted-12-aryl-3,4,7,8,9,12-hexahydro-2H-benzo-
pyran[2,3-b]quinoline-1,10-dione derivatives 4 were synthesized by 2-amino-3-cyano-4-aryl-5,6,7,8-
tetrahydro-7,7-dimethyl-5-oxo-4H-benzopyran 2 with 5-substituted-1,3-cyclohexanedione using p-tolue-
nesulfonic acid, K2CO3, and Cu2Cl2 as catalysts. The compounds 2 as easily accessible precursors were
obtained from 5,5-dimethyl-1,3-cyclohexanedione by Michael addition with b-dicyanostyrenes 1, pre-
pared by Knoevenagel condensation of different aromatic aldehydes and malononitrile. The synthesis of
the title compounds 4 completed by one-pot reaction of 4-aryl-4H-benzopyran derivatives with 5-substi-
tuted-1,3-cyclohexanediones by refluxing in toluene using TsOH as catalyst. The structures of all com-
1
pounds were characterized by elemental analysis, IR, MS, and H NMR spectra.
J. Heterocyclic Chem., 47, 1335 (2010).
INTRODUCTION
Among which benzopyran[2,3-b]quinolinone not only
possesses the structure of benzopyran but also contains a
quinoline ring. Benzopyran, as the parent ring of many
natural products, are widely found in the nature. Their
derivatives have been approved to possess good biological
activity, and also exhibit antitumor activity. In addition,
benzopyran derivatives could serve as the moderator for
the potassium ion channel [3–5]. Quinoline belongs to the
class benzopyridines (a class with six-membered nitrog-
ened heterocyclic-fused polycyclic rings). The compounds
of quinoline with aromatic or heterocyclic compounds
have rigid planar with a conjugated structure. These com-
pounds exhibit strong fluorescence properties as well as a
variety of biological activities. They can be used by DNA
and other biological macromolecules to embed into the
body, and also can be served as the fluorescent probes
and synthetic drugs. They have been widely used in the
medical and molecular biology [6]. Nitrogen-containing
Many of the multirings occurring products containing
simultaneously oxygen and nitrogen atoms on their car-
bon frameworks display various pharmacological activ-
ities [1]. Tacrine, a potent and reversible AChE inhibi-
tor, was the first drug approved in the United States for
the palliative treatment of Alzheimer’s disease [2]. Jose
[2] reported some new multipotent tetracyclic tacrine
analogs, which had the similar structure with 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 Ca2þ overload or free radical
induced toxicity. In addition, these compounds bind
AChE to the peripheral anionic site of AChE. And, con-
sequently, are potential agents that can prevent the
aggregation of b-amyloid.
C
V
2010 HeteroCorporation

1336
G. F. Han, B. Cui, L. Z. Chen, and Y. Jin
Vol 47
Scheme 1
heterocyclic compounds have shown a strong trend of de-
velopment and broad application prospects in the fields of
sterilization, anti-malaria, and anti-malignant tumor [7].
To search for medicinal compounds, and enrich the
tetracyclic compounds, we first synthesized a series of
new six-membered tetracyclic compounds, benzopyran
[2,3-b]quinolinone derivatives with oxygen and nitrogen
atoms inlaying in the ring.
side reaction and so on. In this study, b-dicyanostyrene
1 were prepared as building block from aromatic alde-
hyde, malononitrile in dry ethanol with KFꢀ2H2O as
catalyst. And 4-aryl-4H-benzopyran derivatives 2 were
synthesized by b-dicyanostyrene and 5,5-dimethyl-1,3-
cyclohexanedione in ethylene glycol. The intermediate
enamines 3 were obtained by condensation reaction of
compounds 2 with 5-substituted-1,3-cyclohexanedione
using p-toluenesulfonic acid as catalyst in toluene. 11-
Amino-3,3-dimethyl-8-substituted-12-aryl-3,4,7,8,9,12-
tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
derivatives 4 were synthesized by cyclization of the in-
termediate enamines 3 in the presence of K2CO3 and
Cu2Cl2 [9,10]. Meanwhile, these series of novel com-
pounds 4 could also be obtained via a one-step reaction
by 4-aryl-4H-benzopyran 2 with 5-substituted-1,3-cyclo-
hexanedione, using p-toluenesulfonic acid as catalyst in
toluene. The synthetic pathway was shown in Scheme 1.
Each of compounds 4a–c, 4f–g should be as a diaster-
RESULTS AND DISCUSSION
11-Amino-12-aryl-2,3,4,7,8,9,10,12-octahydro-3,3-di-
methyl-1H-chromeno[2,3-b]quinoline-1-one derivatives
have been synthesized by 4-aryl-4H-chromenes and
cyclohexanone using AlCl3 as catalyst in 1,2-dicholon-
ethane [2]. Pyrano[2,3-b]pyridines were achieved by
the Friedlander reaction of 2-amino-3-cyano-4H-pyrans
with cyclopentanone/cyclohexanone using SnCl2ꢀ2H2O
under solvent-free condition [8]. Both methods have
been tried in our investigation, but they are found to
suffer from several drawbacks, such as low yield, no
reaction, more byproducts, and long reaction time. Com-
pared with these methods, our method has many advan-
tages, such as higher yield, shorter reaction time, less
1
eomeric mixture. It was speculated from the H NMR
spectrum that the yields of the major product was above
90%. The diastereomeric were difficult to be isolated by
silica gel flash chromatography, and therefore, the major
product was purified by multiple-step crystallizing. As
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of Benzopyran[2,3-b]quinolinone Derivatives
1337
Table 1
vents, and shortened the total reaction time. Both the
method and the benzopyran[2,3-b]quinolinone derivatives
have not been reported. The purpose to enrich the tetracy-
clic heterocyclic compounds was achieved. These com-
pounds contain atoms and groups that they can be modified
according to the need, which can conduct further reaction.
Synthesis of 2-N-(5-Substituted-3-oxo-1-cyclohexanyl)-amino-3-cyano-
4-aryl-5,6,7,8-tetrahydro-5-oxo-benzopyran (compounds 3).
Entry
R1
R2
R
Yield (%)
3a
3b
3c
3d
3e
C6H5
C6H5
C6H5
CH3
H
H
H
H
60.2
45.3
64.8
48.5
50.6
4-OCH3
3,4-(OCH3)2
4-OCH3
4-Cl
CH3
CH3
EXPERIMENTAL
CH3
Melting points were determined on an electrothermal apparatus
and the temperature was not calibrated. Microanalysis was per-
formed by the Perkin-Elmer 2400 Microanalytical Service. Infra-
red spectra were recorded as thin films on KBr using a Perking-
Elmer 1700 spectrophotometer. The NMR spectra were recorded
by a Bruker ARX-300 spectrometer. Sample solutions were pre-
pared in CDCl3 or DMSO containing TMS as an internal refer-
ence. Mass spectra were recorded by JMS-DX300 at 70 eV. 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-cyclohexanedione were obtained
from aromatic aldehyde, acetone and diethyl malonate according
to the literature [1] method with slightly modification.
1
shown in the H NMR spectrum, it was a single peak
for the C12AH. The specific stereostructure of the main
product need to be further studied.
1
The data of H NMR, MS, and IR shown in the ex-
perimental section are in accordant with the chemical
structures of the target compounds. In the 1H NMR
spectrum of compound 3a, the broad single proton peaks
at d 6.38 was the characteristic absorption proton peak
of the amino group. The single peak at d 5.84 was the
1
typical proton peak of the vinyl group. In the H NMR
General method for the synthesis of b-dicyanostyrene(1). To
a solution of the corresponding aldehyde (1 equiv) in dry etha-
nol (1 mL/mmol), malonodinitrile (1 equiv), and a catalytic
amount of KFꢀ2H2O [11] were added. The mixture was stirred
at 60ꢂC for 2–4 h. Then, the reaction mixture was cooled to rt.
To this mixture was added 100 mL water and the precipitated
solid was isolated by filtration, washed with cold ethanol,
recrystallized from 95% ethanol.
spectrum of compound 4a, two broad single peaks at d
5.07 and d 9.14 were observed. They disappeared after
D2O exchange, and therefore, were attributed to the two
NAH of the amino group. Because of the existing 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 9.14. The
structures of these compounds were further supported by
their IR spectra. Server typical absorption bands at 2204
cmꢁ1 for 3a (CBN), 1655 cmꢁ1 for 4a (CAO), and
3410 cmꢁ1 for (NAH) were observed, respectively.
General method for the synthesis of 2-Amino-3-cyano-4-aryl-
a
5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-benzopyran(2). To
solution of the corresponding b-dicyanostyrene (1 equiv) in eth-
ylene glycol (1 mL/mmol), 5,5-dimethyl-1,3-cyclohexanedione
(1 equiv) were added. The mixture was stirred at 80ꢂC for 2–4
h. 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, recrystallized from methanol.
General method for the synthesis of 2-N-(5-substituted-3-
oxo-1-cyclohexenyl)-amino-3-cyano-4-aryl-7,7-dimethyl-5,6,7,8-
tetrahydro-5-oxo-4H-benzopyran (3a–3e). 2-Amino-3-cyano-4-
aryl-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-benzopyran (1
equiv) and 5-substituted-1,3-cyclohexanedione (1.2 equiv)
were suspended in toluene (1 mL/mmol) containing p-
CONCLUSIONS
During our investigate, it is found that the toluene,
TSOH, and raw materials are drier, the corresponding
yields are more excellent and the side reactions are less;
and when the ratio of 4-aryl-4H-benzopyran derivatives
and 5-substituted-1,3-cyclohexanedione is 1:1.2, it can
give the corresponding products in best yields. It is also
found that the intermediate enamines 3 can be obtained
using 4-aryl-4H-benzopyran derivatives and 5-substi-
tuted-1,3-cyclohexanedione in water with catalytic
amount of HCl, and the corresponding yields are also
relatively high, however, the side reactions are more.
Therefore, using this method to synthesize our target
compounds need to be further investigated.
Table 2
Synthesis of 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 (compounds 4).
Entry
R1
R2
R
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
C6H5
C6H5
CH3
H
H
H
H
4-OCH3
3,4-(OCH3)2
4-OCH3
4-Cl
59.6
57.6
40.8
54.5
73.5
65.5
62.3
59.6
56.8
55.4
CH3
CH3
H
In summary, during the synthesis of benzopyran[2,3-
b]quinolinone derivatives, we used two methods and both
could obtain the target compounds. Compared with the two
methods, the method B extended the first step reaction
time based on the method A. But we achieved one-step
ring closure, reduced the kinds of catalysts and organic sol-
CH3
C6H5
C6H5
CH3
4-Cl
2-Cl
H
CH3
CH3
CH3
H
CH3
CH3
3,4-(OCH3)2
2-Cl
4j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1338
G. F. Han, B. Cui, L. Z. Chen, and Y. Jin
Vol 47
toluenesulfonic acid monohydrate (0.2 equiv). The mixture
was refluxed for 4 h and the water was collected in a Dean-
Stark water separator. At the end of the reaction, the reaction
mixture was chilled to rt and the compound was filtered off.
The yellow powder was recrystallized from ethyl acetate.
General method for the synthesis of 11-amino-3,3-dimethyl-
8-substituted-12-aryl-3,4,7,8,9,12-tetrahydro-2H-benzopyran
[2,3-b]quinoline-1,10-dione(4a–4j). Method A. 2-N-(5-Sub-
stituted-3-oxo-1-cyclohexenyl)-amino-3-cyano-4-aryl-5,6,7,8-tet-
rahydro-5-oxo-4H-benzopyran (1 equiv) was added to tetrahy-
drofuran (1 mL/mmol) containing potassium carbonate (0.5
equiv) and cuprous chloride (0.25 equiv). The reaction mixture
was refluxed for 6 h and the hot mixture was filtered into hex-
ane (2 mL/mmol). The precipitated was filtered off and
washed with ethanol. The yellow powder was purified by silica
gel flash chromatography using ethyl acetate/hexane mix-
ture(1:2) as eluent to give purecompounds. The compounds
4a–4e were synthesized by this method.
Method B. In this study, we discovered that these series of
novel compounds 4 could also be obtained via a one-step reac-
tion by 4-aryl-4H-benzopyran 2 with 5-substituted-1,3-cyclohexa-
nedione, using p-toluenesulfonic acid as catalyst in toluene
refluxed for 10 h. Then, the hot mixture was filtered into hexane
(2 mL/mmol). The precipitated was filtered off and washed with
ethanol. The yellow powder was purified by silica gel flash chro-
matography using ethyl acetate/hexane mixture (1:2) as eluent to
give pure compounds. The compounds 4f–j were synthesized by
this method. Data of compounds are shown below.
2-N-(5-phenyl-3-oxo-1-cyclohexenyl)-amino-3-cyano-4-pheny-7,
7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-benzopyran (3a). Yield:
60.2%, m.p. 214–216ꢂC; 1H NMR (CDCl3, 300 MHz) d:
1.03(s, 3H, CH3), 1.15(s, 3H, CH3), 2.51–2.82(m, 6H, 8-, 40-,
and 60-H), 3.38–3.41(m, 1H, 50-H), 4.50(s, 1H, 4-H), 5.84(s,
1H, 20-H), 6.38(br s, 1H, NH), 7.21–7.40(m, 10H, Ph-H); IR
(KBr) t: 3464(NH), 1687(C¼¼O), 2204(CBN); MS (70 eV)
m/z (%): 465.0 (Mþ1, 100); Anal. calcd. for C30H28N2O3: C
77.56, H 6.08, N 6.03; found C 77.50, H 5.98, N 6.15.
2-N-(5-phenyl-3-oxo-1-cyclohexenyl)-amino-3-cyano-4-(4-
methoxy-phenyl)-7,7-dimethyl-5-oxo-5,6,7,8- tetrahydro-4H-
benzopyran (3b). Yield: 55.3%, m.p. 224–226ꢂC; 1H NMR
(DMSO, 300 MHz) d: 1.03(s, 3H, CH3), 1.13(s, 3H, CH3),
2.07–2.22(m, 4H, 6-, and 8-H), 2.27–2.49(m, 4H, 40-, and 60-
H), 3.34–3.45(m, 1H, 50-H), 3.71(s, 3H, OCH3), 4.41(s, 1H, 4-
H), 4.85(s, 1H, 20-H), 5.84(br s, 1H, NH), 6.83–7.11(m, 8H,
Ph-H); IR (KBr) t: 3399(NH), 1719(C¼¼O), 2254(CBN); MS
(70 eV) m/z (%): 495.2 (M þ 1, 100).
3H, CH3), 2.18–2.31(m, 6H, 8-, 40-, and 60-H), 2.54(s, 2H,
6-H), 3.78(s, 3H, OCH3), 4.45(s, 1H, 4-H), 5.79(s, 1H, 20-H),
6.45(br s, 1H, NH), 6.82–7.18(m, 5H, Ph-H); IR (KBr) t:
3460(NH), 1672(C¼¼O), 2210(CBN); MS (70 eV) m/z (%):
447.2 (M þ 1, 100); Anal. calcd. for C27H30N2O4: C 72.62, H
6.77, N 6.27; found C 72.50, H 6.69, N 6.35.
2-N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)-amino-3-cyano-4-(4-
chlorine-phenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
pyran (3e). Yield: 50.6%, m.p. 194–196ꢂC; 1H NMR (CDCl3,
300 MHz) d: 1.04(s, 3H, CH3), 1.12(s, 6H, 2 ꢃ CH3), 1.14(s,
3H, CH3), 2.19–2.32(m, 6H, 8-, 40-, and 60-H), 2.56(s, 2H,
6-H), 4.48(s, 1H, 4-H), 5.82(s, 1H, 20-H), 6.21(br s, 1H, NH),
7.17–7.32(m, 5H, Ph-H); IR (KBr) t: 3385(NH), 1719(C¼¼O),
2238(CBN); MS (70 eV) m/z (%): 449.9 (Mþ, 100).
11-amino-3,3-dimethyl-8,12-diphenyl-3,4,7,8,9,12-tetrahydro-
2H-benzopyran[2,3-b]quinoline-1,10-dione (4a). Yield: 59.6%
1
.m.p. 244–246ꢂC; H NMR (CDCl3, 300 MHz) d: 0.96(s, 3H,
CH3), 1.10(s, 3H, CH3), 2.17–2.30(m, 2H, 4-H), 2.57(s, 2H,
2-H), 2.75–2.92(m, 2H, 9-H), 3.09–3.29(s, 2H, 7-H), 3.39–
3.50(m, 1H, 8-H), 4.85 (s, 1H, 12-H), 5.07(br s, 1H,
NH),7.17–7.38(m, 10H, Ph-H), 9.14(br,s, 1H, N-H); IR (KBr)
t: 3410, 1655, 1167, 1125 cmꢁ1; MS (70 eV) m/z (%): 465.2
(M þ 1, 100); Anal. calcd. for C30H28N2O3: C 77.56, H 6.08,
N 6.03; found C 77.44, H 6.15, N 5.96.
11-amino-3,3-dimethyl-8-phenyl-12-(4-methoxy-phenyl)-
3,4,7,8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-
dione (4b). Yield: 57.6 % , m.p. 210–212ꢂC; 1H NMR
(CDCl3, 300 MHz) d: 0.98(s, 3H, CH3), 1.10(s, 3H, CH3),
2.17–2.30(m, 2H, 4-H), 2.56(s, 2H, 2-H), 2.75–2.93(m, 2H,
9-H), 3.09–3.31(m, 2H, 7-H), 3.39–3.51(m, 1H, 8-H), 3.75(s,
3H, OCH3), 4.81(s, 1H, 12-H), 5.10(br s, 1H, NH),6.79–
7.39(m, 9H, Ph-H), 9.16(br s, 1H, NH); IR (KBr) t: 3450,
1654, 1182, 1029 cmꢁ1; MS (70 eV) m/z (%): 495.2 (M þ 1,
100); Anal. calcd. for C31H30N2O4: C 75.28, H 6.11, N 5.66;
found C 75.21, H 6.21, N 5.58.
11-amino-3,3-dimethyl-8-phenyl-12-(3,4-dimethoxy-phenyl)-
3,4,7,8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-
dione (4c). Yield: 40.8%, m.p. 216–218ꢂC; 1H NMR (CDCl3,
300 MHz) d: 1.03(s, 3H, CH3), 1.11(s, 3H, CH3), 2.16–2.30(m,
2H, 4-H), 2.56(s, 2H, 2-H), 2.76–2.95(m, 2H, 9-H), 3.09–
3.30(m, 2H, 7-H), 3.37–3.51(m, 1H, 8-H), 3.75(s, 3H, OCH3),
3.80(s, 3H, OCH3),4.81(s, 1H, 12-H), 5.16(br s, 1H, NH), 6.89–
7.38(m, 8H, Ph-H), 9.26(br s, 1H, NH); IR (KBr) t: 3430, 1640,
1180, 1025cmꢁ1;MS (70 eV) m/z (%): 525.3 (M þ 1, 100).
11-amino-3,3,8,8-tetramethyl-12-(4-methoxy-phenyl)-3,4,7,8,
9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
(4d). Yield: 54.5%, m.p. 230–232ꢂC; 1H NMR (CDCl3, 300
MHz) d: 1.00(s, 6H, 2 ꢃ CH3), 1.10(s, 6H, 2 ꢃ CH3), 2.14–
2.27(m, 4H, 4-H, 7-H), 2.46(s, 4H, 2-H, 9-H), 3.74(s, 3H,
OCH3), 4.70(s, 2H, 12-H), 5.15(br s, 1H, NH), 6.74–7.22(m,
4H, Ph-H), 9.13(br s, 1H, NH); IR (KBr) t: 3448, 1668, 1195,
1137 cmꢁ1; MS (70 eV) m/z (%): 447.2 (M þ 1, 100).
2-N-(5-phenyl-3-oxo-1-cyclohexenyl)-amino-3-cyano-4-(3,4-
dimethoxy-phenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-
benzopyran (3c). Yield: 64.8%, m.p. 188–190ꢂC; 1H NMR
(CDCl3, 300 MHz) d: 1.07(s, 3H, CH3), 1.15(s, 3H, CH3),
2.27–2.58(m, 2H, 8-H), 2.61–2.76(m, 6H, 6-, 40-, and 60-H),
3.42–3.45(m, 1H, 50-H), 3.84(s, 3H, OCH3), 3.86(s, 3H,
OCH3), 4.44(s, 1H, 4-H), 5.83(s, 1H, 20-H), 5.87(br s, 1H,
NH), 6.71–7.40(m, 8H, Ph-H); IR (KBr) t: 3442(NH),
1682(C¼¼O), 2205(CBN); MS (70eV) m/z (%): 525.3 (M þ 1,
100); Anal. calcd. for C32H32N2O5: C 73.26, H 6.15, N 5.34;
found C 73.39, H 6.22, N 5.20.
2-N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)-amino-3-cyano-4-(4-
methoxy-phenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-benzo-
pyran (3d). Yield: 48.5%, m.p. 192–194ꢂC; 1H NMR (CDCl3,
300 MHz) d: 1.04(s, 3H, CH3), 1.10(s, 6H, 2 ꢃ CH3), 1.26(s,
11-amino-3,3,8,8-tetramethyl-12-(4-chlorine-phenyl)-3,4,7,
8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
(4e). Yield: 73.5%, m.p. 236–238ꢂC; 1H NMR (CDCl3, 300
MHz) d: 0.96(s, 3H, CH3), 1.08(s, 3H, CH3), 1.09(s, 3H,
CH3), 1.10(s, 3H, CH3), 2.16–2.29(m, 2H, 4-H), 2.45(s, 2H,
2-H), 2.56(s, 2H, 9-H), 2.83(s, 2H, 7-H), 4.82(s, 1H, 12-H),
5.09(br s, 1H, NH), 7.22–7.30(m, 4H, Ph-H), 9.10(br s, 1H,
NH); IR (KBr) t: 3484, 1654, 1184, 1126 cmꢁ1; MS (70 eV)
m/z (%): 449.9 (Mþ, 100).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of Benzopyran[2,3-b]quinolinone Derivatives
1339
t: 3415, 1649, 1186,1125 cmꢁ1; MS (70 eV) m/z (%):477.2
(M þ 1, 100).
11-amino-3,3-dimethyl-8-phenyl-12-(4-chlorine-phenyl)-3,4,7,
8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
(4f). Yield: 65.5%, m.p. 230–232ꢂC; 1H NMR (CDCl3, 300
MHz) d: 0.97(s, 3H, CH3), 1.11(s, 3H, CH3), 2.17–2.30(m,
2H, 4-H), 2.57(s, 2H, 2-H), 2.82–2.88(m, 2H, 9-H), 3.14–
3.24(m, 2H, 7-H), 3.44–3.47(m, 1H, 8-H), 4.84(s, 1H, 12-H),
5.10(br s, 1H, NH), 7.23–7.39(m, 9H, Ph-H), 9.17(br s, 1H,
NH); IR (KBr) t: 3484, 1656, 1216, 1168 cmꢁ1; MS (70 eV)
m/z (%): 499.2(M þ 1, 100); Anal. calcd. for C30H27N2O3Cl:
C 72.21, H 5.45, N 5.61; found C 72.13, H 5.36, N 5.70.
11-amino-3,3-dimethyl-8-phenyl-12-(2-chlorine-phenyl)-3,4,7,
8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
(4g). Yield: 62.3%, m.p. 184–186ꢂC; 1H NMR (CDCl3,
300MHz) d: 1.01(s, 3H, CH3), 1.13(s, 3H, CH3), 2.17–2.32(m,
2H, 4-H), 2.63(s, 2H, 2-H), 2.82–2.88(m, 2H, 9-H), 3.08–
3.25(m, 1H, 8-H), 3.37–3.50(m, 2H, 7-H), 5.26(s, 1H, 12-H),
5.73(br s, 1H, NH), 7.15–7.36(m, 9H, Ph-H), 9.39(br s, 1H,
NH); IR (KBr) t:3476, 1655, 1169,1138 cmꢁ1; MS (70eV)
m/z (%): 499.2(M þ 1, 100).
11-amino-3,3,8,8-tetramethyl-12-(2-chlorine-phenyl)-3,4,7,
8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
(4j). Yield: 55.4%, m.p.174–176ꢂC; 1H NMR (CDCl3, 300
MHz) d: 1.12(s, 6H, 2 ꢃ CH3), 1.15(s, 6H, 2ꢃCH3), 2.35(s,
2H, 2-H), 2.54–2.61(m, 2H, 4-H), 2.87(s, 2H, 9-H), 2.93–
2.99(m, 2H, 7-H), 4.75(s, 1H, 12-H), 5.18(br s, 1H, NH),
6.89–7.19(m, 4H, Ph-H), 9.10(br s, 1H, NH); IR (KBr) t:
3484, 1654, 1184, 1126cmꢁ1; MS (70 eV) m/z (%): 449.9
(Mþ, 100).
REFERENCES AND NOTES
[1] Han, G. F.; Wang, J. J.; Jiang, G. J. Chin J Org Chem
2003, 23, 1004 (in Chinese).
[2] Jose, M. C.; Rafael, L.; Cristobal, R.; Antonio, G. G.;
Manuela, G. L.; Mercedes, V. Bioorg Med Chem 2006, 14, 8176.
[3] Isabelle, K.; Marc, H.; Stephane, C. Eur J Med Chem 2008,
43, 2735.
11-amino-3,3,8,8-tetramethyl-12-phenyl-3,4,7,8,9,12-tetrahydro-
2H-benzopyran[2,3-b]quinoline-1,10-dione (4h). Yield: 59.6%,
1
m.p. 246–248ꢂC; H NMR (CDCl3, 300 MHz) d: 0.98(s, 6H, 2
[4] Siegfriend, E.; Drewes, F.; Fatima, K.; Alvaro, K. Eur J
Med Chem 2005, 66, 1812.
ꢃ CH3), 1.10(s, 6H, 2 ꢃ CH3), 2.22–2.24(m, 2H, 4-H), 2.44(s,
2H, 2-H), 2.59(s, 2H, 9-H), 2.86(s, 2H, 7-H), 4.83(s, 1H, 12-
H), 5.09(br s, 1H, NH),7.17–7.36(m, 5H, Ph-H), 9.10(br s, 1H,
NH); IR (KBr) t: 3422, 1660, 1195,1152 cmꢁ1; MS (70 eV)
m/z (%): 417.1 (M þ 1, 100); Anal. calcd. for C26H28N2O3: C
74.97, H 6.78, N 6.73; found C 74.93, H 6.72, N 6.82.
11-amino-3,3,8,8-tetramethyl-12-(3,4-dimethoxy-phenyl)-3,4,7,
8,9,12-tetrahydro-2H-benzopyran[2,3-b]quinoline-1,10-dione
(4i). Yield: 56.8%, m.p. 266-268ꢂC; 1H NMR (CDCl3, 300
MHz) d: 1.01(s, 6H, 2 ꢃ CH3), 1.11(s, 6H, 2 ꢃ CH3), 2.15–
2.28(m, 4H, 4-H, 7-H), 2.46(s, 4H, 2-H, 9-H), 3.80(s, 3H,
OCH3), 3.86(s, 3H, OCH3) 4.71(s, 2H, 12-H), 5.18(br s, 1H,
NH), 6.74–6.91(m, 3H, Ph-H), 9.12(br s, 1H, NH); IR (KBr)
[5] Franco, C.; Bruna, B.; Adriana, B. Photosynth Res 2006,
41, 208.
[6] Noble, S.; Fauldsd, A. Drugs 1998, 31, 115.
[7] Hoock, C.; Reichert, J.; Schmidtke, M. Molecule 1999, 4, 264.
[8] Selvam, N. P.; Babu, T. H.; Perumal, P. T. Tetrahedron
2009, 65, 8524.
[9] Han, G. F.; Wang, R. H.; Zhang, W. T. Synth Commun
2009, 39, 2492.
[10] Shutske, G. M.; Pierrat, F. A.; Kapples, K. J.; Cornfeldt, M.
L.; Szewczak, M. R.; Huger, F. P.; Bores, G. M.; Haroutunian, V.;
Davis, K. L. J Med Chem 1989, 32, 1805.
[11] Dai, G. Y.; Shi, D. Q.; Zhou, L. H. Chinareagent 1996, 18, 39.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet