Synthesis and characterization of benzochromeno[2,3-b]tetrahydroquinolinone derivatives

Article abstract of DOI:10.1002/jhet.1101

We report on a novel method for the preparation of a new series of benzochromeno[2,3-b]tetrahydroquinolin-1-one derivatives. The title compounds are prepared by the 5-substituted-1,3 -cyclohexanedione and 3-amino-1-aryl-1H- benzo[f]chromene-2-carbonitrile

Full text of DOI:10.1002/jhet.1101

Month 2013
Synthesis and Characterization of Benzochromeno[2,3-b]
tetrahydroquinolinone Derivatives
,*
Guang-Fan Han Ming Wang, Yan Jin, and Li-Zhuang Chen
Biological and Chemical Engineering Institute, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212003, China
*
E-mail: gf552002@yahoo.com.cn
Received June 16, 2011
DOI 10.1002/jhet.1101
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
R1
CN
CHO
OH
NH2
CN
CN
(A)
H2C
R1
O
2
3
1
4a-4c
O
R2
R3
O
(B)
5
R1
R1
NH2
O
O
(C)
CN
R2
R3
R2
R3
N
H
O
N
O
7a-7g
6a-6g
(A): CH3CH2OH, K2CO3, Reflux;
(B): H2O, HCl;
(C): THF, K2CO3/Cu2Cl2.
4a:R1=H;
4b:R1=4-OCH3;
6b,7b:R1=H, R2=R3=H;
4c:R1=2-Cl;
6c,7c: R1=4-OCH3, R2=R3=CH3;
6a,7a: R1=H, R2=R3=CH3;
6d,7d:R1=4-OCH3, R2=R3=H; 6e,7e: R1=2-Cl, R2=R3=CH3; 6f,7f:R1=2-Cl; R2=R3=H.
6g,7g:R1=H, R2=H, R3=Furyl;
We report on a novel method for the preparation of a new series of benzochromeno[2,3-b]tetrahydroquinolin-
1-one derivatives. The title compounds are prepared by the 5-substituted-1,3 -cyclohexanedione and 3-amino-1-
aryl-1H-benzo[f]chromene-2-carbonitrile or 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitrile using dilute
HCl, K2CO3, and Cu2Cl2 as catalysts. The method has the advantages of simple operation, high efficiency, and
low toxicity. The structures of all compounds are characterized by elemental analysis, IR, MS, and 1H NMR spec-
tra. Two single crystals are characterized by using X-ray diffraction.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
resulted in a number of side effects, especially hepatotoxicity
[5]. Even though, considerable amount of THA derivatives
and its analogues were synthesized to find compounds with
reduced side effects [6]. This study is focused to analogues
of THA.
Herein, we tried to use 1,3-cyclohexanedione and
chromenes for the synthesis of benzochromeno-[2,3-b]
tetrahydroqu-inolin-1-one derivatives.
Hydrochloric acid has emerged as an inexpensive, non-
toxic, nonmetallic, readily available and environmental
catalyst for various organic transformations, which has been
reviewed recently. Designing organic reaction in aqueous
media is another attractive area in chemistry [7]. Herein, we
Alzheimer’s disease is the most prevalent of the neurode-
generative diseases and main cause of dementia in elderly
people [1]. Various therapeutic approaches have now been
attempted to treat Alzheimer’s disease by using agents such
as acetylcholinesterase inhibitors, muscarinic agonists, or
acethylcholine releasers [2]. Particularly, clinical trials of
many acetylcholinesterase inhibitors have been conducted.
Among them, 9-amino-1,2,3,4-tetrahydroacridine(Tacrine,
THA) is the first cholinesterase inhibitor approved in the
USA for symptomatic treatment of Alzheimer’s disease [3].
It is a centrally acting reversible cholinesterase inhibitor [4],
but the poor selectivity of this drug for acetylcholinesterase
© 2013 HeteroCorporation

G.-F. Han, M. Wang, Y. Jin, and L.-Z. Chen
Vol 000
tried to use hydrochloric acid as a catalyst to synthesize
benzochromeno[2,3-b]tetrahydroquinolin-1-one derivatives
in aqueous media.
in Tables 1. and 2. We have noted that the reaction tempera-
ture should be higher than 80ꢀC. We guessed that there were
two types of 5-substituted-1,3-cyclohexanedione in the
water: ketenes and enol. When the reaction temperature was
higher than 80ꢀC, 5-substituted-1,3-cyclo-hexanedione was
in the type of enol. It has also been observed that the amount
and concentration of catalyst played a crucial role in the
success of the reaction in terms of the rate and the yields.
The reaction could not be carried out in the absence of the cat-
alyst. It was found that the best conditions were at 80–100ꢀC
and the ratio of 5-substituted-1,3-cyclohexanediones (mmol) :
compound 4a (mmol):50 mmol/L HCl (mmol) was 5:5:2.
Under the optimized conditions, various substituted aro-
matic aldehydes were reacted with malononitrile and naph-
thol to obtain the corresponding products (Tables 3. and 4.),
and the reactions were all successful. From these observa-
tions, we may conclude that the nature of the substituent
on the aromatic rings does not have any significant role in
determining the course of the reaction.
RESULTS AND DISCUSSION
Initially, a one-pot synthesis of 3-amino-1-aryl-1H-benzo
[f]chromene-2-carbonitrile 4 was achieved when aromatic
aldehydes, malononitrile, and 2-naphthol were heated at
80ꢀC using K2CO3 as catalyst in ethanol [8]. Thus, compound
4 reacted with 5-substituted-1,3-cyclohexanedione using
dilute hydrochloric acid (50 mmol/L) as catalyst in aqueous
media to give compound 6. And the title compound 7 was
obtained in THF using K2CO3/Cu2Cl2 as catalysts. The
synthetic pathways are shown in Scheme 1.
Then, we extended our investigations by using 1-naphthol
as the starting materials instead of 2-naphthol. We found
that it also easily reacted with aromatic aldehydes and malono-
nitrile in good yields. The compounds 60 and 70 were prepared
following the method given for 6 and 7. The synthetic
pathways are shown in Scheme 2.
Crystal structure. A summary of the crystal data and
structure refinement is presented in Table 5. A perspective
view of compound 6c with atomic numbering scheme is
shown in Figure 1. In compound 6c, The dihedral angle
between the bond lengths and bond angles are generally
normal in the phenyl and quinoline ring, and the quinoline
5-Substituted-1,3-cyclohexanedione
reacted
with
compound 4 using dilute HCl as catalyst in water. Taking
7a for example, various trial reactions were investigated to
choose the best reaction conditions; the result is summarized
Scheme 1. The synthetic route of benzo[f]chromeno[2,3-b]tetrahydroquinolin-1-one derivatives.
R1
CN
CHO
OH
NH2
CN
CN
(A)
H2C
R1
O
2
3
1
4a-4c
O
R2
R3
O
(B)
5
R1
R1
NH2
O
O
(C)
CN
R2
R3
R2
R3
N
H
O
N
O
7a-7g
6a-6g
(A): CH3CH2OH, K2CO3, Reflux;
(B): H2O, HCl;
(C): THF, K2CO3/Cu2Cl2.
4a:R1=H;
4b:R1=4-OCH3;
6b,7b:R1=H, R2=R3=H;
4c:R1=2-Cl;
6c,7c: R1=4-OCH3, R2=R3=CH3;
6a,7a: R1=H, R2=R3=CH3;
6d,7d:R1=4-OCH3, R2=R3=H; 6e,7e: R1=2-Cl, R2=R3=CH3; 6f,7f:R1=2-Cl; R2=R3=H.
6g,7g:R1=H, R2=H, R3=Furyl;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Synthesis and Characterization of Benzochromeno[2,3-b]tetrahydroquinolinone Derivatives
Scheme 2. The synthetic route of benzo[h]chromeno[2,3-b]-tetrahydroquinolin-1-one derivatives.
NH2
OH
CHO
CN
O
CN
(A)
H2C
R1
R1
CN
2
1
3
4'a-4'c
O
R2
R3
O
5
(B)
R1
R1
O
NH2
O
CN
(C)
R2
R3
R2
R3
O
N
H
O
N
6'a-6'd
7'a-7'd
(A): CH3CH2OH, K2CO3, Reflux;
(B): H2O, HCl;
(C): THF, K2CO3/Cu2Cl2.
4'a:R1=H;
6'a,7'a: R1=H, R2=R3=CH3;
6'd,7'd:R1=2-Cl, R2=R3=H;
4'b:R1=4-OCH3;
6'b,7'b:R1=H, R2=R3=H;
4'c:R1=2-Cl;
6'c,7'c: R1=4-OCH3, R2=R3=H;
Table 3
Table 1
The melting point and yield of benzochromene derivatives.
The reaction temperature of synthesis of compound 7a.
Entry
R1
R2
R3
mp (ꢀC)
Yield (%)
Entry
Reaction temperature (ꢀC)
Time (h)
Yield (%)
4a
4b
4c
H
H
/
/
/
/
/
/
/
/
/
/
>260
91.4
90.8
92.2
90.6
88.6
91.6
60.6
62.8
57.6
58.2
60.6
63.6
46.6
55.8
56.2
54.8
58.6
1
2
3
4
5
6
7
40
50
60
70
80
4
4
4
4
4
4
4
3.8
8.8
190–192
256–258
206–208
188–190
238–240
218–220
236–238
190–192
216–218
242–244
206–208
224–226
246–248
238–240
214–216
256–258
4-OCH3
H
H
4-OCH3
H
H
4-OCH3
4-OCH3
2-Cl
2-Cl
H
12.8
30.6
50.4
50.6
50.6
40a
40b
40c
6a
6b
6c
/
/
90
100
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
Furyl
CH3
H
6d
6e
6f
6g
60a
60b
60c
60d
H
Table 2
H
H
CH3
H
Compound 7a synthesis catalyzed by the various amount of hydrochloric
4-OCH3
2-Cl
H
H
H
H
acid(50 mmol/L HCl).
Entry
Amount of HCl (mL)
Time (h)
Yield (%)
1
2
3
4
5
6
7
0
20
30
40
50
60
70
4
4
4
4
4
4
4
0
ring [C(7), C(8), C(9), C(10), C(11), C(12), C(13), C(14), N
(1), N(2)] with plane equation 4.0780 (0.0027)x + 10.7892
(0.0071) y + 4.6691 (0.0053) z = 8.9674. The benzene ring
a [C(1), C(2), C(3), C(4), C(5), C(6)] with plane equation
10.4240 (0.0095) x + 3.3441 (0.0130) y ꢁ 7.1571 (0.0059)
z = 11.7828 is 88.76ꢀ. The benzene ring b [C(15), C(16), C
36.8
42.8
50.6
45.6
42.2
39.8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-F. Han, M. Wang, Y. Jin, and L.-Z. Chen
Vol 000
Table 4
The melting point and yield of benzochromene[2,3-b]quinolinone
derivatives.
Entry
R1
R2
R3
mp (ꢀC)
Yield (%)
7a
7b
7c
7d
7e
H
H
CH3
H
CH3
H
CH3
H
H
CH3
H
H
CH3
H
CH3
H
CH3
H
Furyl
CH3
H
>260
>260
50.6
51.8
48.6
49.8
51.6
51.8
36.8
50.8
52.8
47.8
51.2
4-OCH3
4-OCH3
2-Cl
2-Cl
H
256–258
202–204
248–250
192–194
234–236
226–228
196–198
232–234
202–204
7f
7g
70a
70b
70c
70d
H
H
4-OCH3
2-Cl
H
H
H
Figure 1. ORTEP plot of compound 6c. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Table 5
Crystallographic data for crystallographic data for complex 6c.
these molecular interactions play the role of further
stabilizing the structure. The bond lengths and bond
angles of primary hydrogen bonds are listed in Table 6.
Complex
C
29H26N203.C2H5OH
Empirical formula
Formula weight
Wavelength (Å)
Space group
Crystal system
a (Å)
b (Å)
c (Å)
a (º)
b (º)
C31 H32 N2 O4
496.59
0.71073
P 21/c
1
The data of H NMR, MS, and IR shown in the experi-
mental section were in accordance with the chemical struc-
tures of the target compounds. And finally, the structures as
well as the relative stereochemistry of compounds 6c
(Fig. 1.) and 7d (Fig. 3.) were confirmed by X-ray crystal-
lographic analysis. From the structure, it was found that the
cyclohexyl ring adopted a half-boat conformation in case
of compound 6c. The existence of the solvent ethanol
moleculars in the crystal links all molecules into a three-
dimensional supermolecular structure by the intermolecular
N—HꢂꢂꢂO and O—HꢂꢂꢂO hydrogen bonds. And compound
7d is a plane structure.
triclinic
10.969(2)
15.260(3)
18.208(3)
90.00
120.213(10)
90.00
2633.8(9), 4
1.252
0.931
g (º)
Volume (Å3), Z
Dcalc (g/cm3)
Absorption coefficient
F(0 0 0)
407
Crystal size (mm3)
Transmission max/min
θ range for data collection (º)
Limiting indices
0.25 ꢃ 0.15 ꢃ 0.10
0.986/0.991
2.2-26.8
ꢁ13 ≤ h ≤13, -18 ≤ k ≤16, -
13 ≤ l ≤22
5177
CONCLUSION
Reflection collected
In summary, a novel methodology is reported for the
synthesis of new benzochromeno[2,3-b]tetrahydroquino-
lin-1-one derivatives. Although it needs two steps, we used
nontoxic solvent and catalyst in the first step, and there was
no need to handle intermediates 6 for the next step.
Compared with the methods in the past, the new method
has many advantages such as reduced pollution, good
yields, and lower cost. In addition, the optimum conditions
are under investigation here. The reaction temperature
should be higher than 80ꢀC, and the most suitable ratio of
5-substituted-1, 3-cyclohexanediones (mmol) : compound
4a (mmol) : 50 mmol/L HCl (mL) is 5: 5: 2.
Independent reflections
3932
0.0365
1.004
0.0455, 0.0570
0.1359, 0.1418
0.19 and ꢁ0.31
(Rint
)
Goodness-of-fit(GOF)on F2
R1
wR2
Largest difference in peak and
hole (e Å-3)
(17), C(18), C(19), C(20)] is coplanar with the conjunction C
(14), whose plane equation is ꢁ2.5083 (0.0140) x+ 11.9234
(0.0087) yꢁ 4.1769 (0.0084) z = 0.8635. The dihedral
angles between the benzene ring b and quinoline ring plane
is 59.09ꢀ. The packing diagram of the 6c in a unit cell is
shown in Figure 2. X-ray analysis reveals that there are
intramolecular and intermolecular hydrogen bonds in the
crystal. The intermolecular hydrogen bond N(1)-H(1)ꢂꢂꢂO
(2) is 2.861(4) Å; the structural analysis indicates that
EXPERIMENTAL
Melting points were determined on an electrothermal apparatus,
and the temperature was not calibrated. Micro-analysis was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Synthesis and Characterization of Benzochromeno[2,3-b]tetrahydroquinolinone Derivatives
Table 6
Inter- and intramolecular interaction distances (Å) for the compound 6c.
D–HꢂꢂꢂA
D–H
HꢂꢂꢂA
DꢂꢂꢂA
D–HꢂꢂꢂA
Symmetry
N(1) ꢁ H(1A)ꢂꢂꢂO(4)
O(4) ꢁ H(4B)ꢂꢂꢂO(2)
0.86
0.82
1.92
1.84
2.7732
2.6548
174.9
177.0
x, y, z
x,-y + 1/2,z + 1/2
performed by the Perkin-Elmer (Waltham, Massachusetts) 2400 Mi-
croanalytical Service. Infrared spectra were recorded as thin films on
40a–40c were synthesized according to the method of the
compounds 4a–4c.
KBr using
a Perkin-Elmer (Waltham, Massachusetts) 1700
General procedure for the synthesis of 3-(5-substituted-
3-oxocyclohex-1-enylamino) 1-aryl-1H-benzo[f]-chromene-
spectrophotometer. The 1H NMR spectra were recorded by a Bruker
(Switzerland) ARX-300 spectrometer. Sample solutions were pre-
pared in CDCl3 or DMSO-d6 containing TMS as an internal standard.
Mass spectra were recorded by Agilent-6110 (Santa Clara, California).
2-carbonitrile (6a–6g).
3-Amino-1-aryl-1H-benzo[f]chromene-
2-carbonitrile (5mmol) and 5-substituted-1,3-cyclo-hexan- edione
(6mmol) were suspended in water (1 mL/mmol) containing
50mmol/L HCl. The mixture was refluxed for 4 h. At the end of
the reaction, the mixture was chilled to room temperature, and the
compound was filtered off. The yellow powder was recrystallized
from ethyl acetate.
General procedure for the synthesis of 2-(5-substituted-
3-oxocyclohex-1-enylamino)-4-aryl-4H- benzo-[h]chromene-3-
carbonitrile(60a–60d). The compounds 60a–60d were synthesized
according to the method given for the compounds 6a–6d.
General procedure for the synthesis of 14-amino-2,3,4,13-
tertrahydro-3-substituted-13-aryl-1H -benzo-[f]chromene[2,3-
b]quinolin-1-one (7a–7g). The mixture of the last step was
added to THF (1mL/mmol) that contains K2CO3 (2.5mmol)
and Cu2Cl2 (1.25 mmol). The reaction mixture was refluxed for
2 h. Then, the precipitate was filtered off and washed with
ethanol. The yellow powder was purified by silica gel flash
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-cyclo-hexanedione 1 were
obtained from aromatic aldehyde, acetone, and dimethyl molanate
according to the literature method with slight modification.
General procedure for the synthesis of 3-amino-1-aryl-1H-
benzo[f]chromene-2-carbonitrile (4a–4c). To a solution of cor-
responding aldehyde (10 mmol), malononitrile (10 mmol) and
2-naphthol (10 mmol) in ethanol (50mL) were added K2CO3
(0.0828g) at room temperature. The mixture was stirred at 80ꢀC
for 4 h, and then, the reaction mixture was cooled to room
temperature. The solid was isolated by filtration, washed with cold
ethanol, and recrystallized from methanol.
General procedure for the synthesis of 2-amino-4-aryl-
4H-benzo[h]-chromene-3-carbonitrile (40a–40c). The compounds
Figure 2. Packing diagram of compound 6c in unit-cell. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-F. Han, M. Wang, Y. Jin, and L.-Z. Chen
Vol 000
Figure 3. ORTEP plot of compound 7d. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
chromatography using ethyl acetate/hexane mixture (1:2, v/v) as
eluent to give pure compounds.
4H, Ph-H), IR (KBr) υ: 3356 (NH), 2138 (CꢄN); MS (ESI) m/z:
329.2 (M+ 1). Anal. Calcd for C21H16N2O2: C 76.81, H 4.91, N
8.53; found C 76.47, H 4.93, N 8.57.
General procedure for the synthesis of 14-amino-2,3,4,13-
2-Amino-4-(2-chlorophenyl)-4H-benzo[h]-chromene-3-carbonitrile
(40c). Yield: 91.6%, mp 238–240ꢀC; 1H NMR (CDCl3, 300 Hz) d:
5.57 (s, 1H, 4-H), 7.06–7.19 (m, 4H, Ph-H), 7.20 (br s, 2H, NH2),
7.27–7.81 (m, 6H, Ph-H), IR (KBr) υ: 3368 (NH), 2098 (CꢄN);
MS (ESI) m/z: 333.1 (M + 1). Anal. Calcd for C20H13ClN2O: C
72.18, H 3.94, N 8.42; found C 71.88, H 3.98, N 8.48.
3-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-1-phenyl-1H-benzo
[f]chromene-2-carbonitrile (6a). Yield: 60.6%, mp 218–220ꢀC;
1H NMR (CDCl3, 300MHz) d: 1.13, 1.14 (each s, each 3H,
CH3), 2.28–2.34 (m, 2H, 40-H), 2.38–2.43 (m, 2H, 60-H), 5.33
(s, 1H, 1-H), 5.99 (s, 1H, 20-H), 6.39 (brs, 1H, NH), 7.19–7.89
(m, 11H, Ph-H), IR (KBr) υ: 3285 (NH), 1619 (C=O), 2216
(CꢄN); MS (ESI) m/z: 421.1 (M + 1). Anal. Calcd for
C20H24N2O2: C 79.98, H 5.75, N 6.66; found C 79.89, H
5.83, N 6.71.
tertrahydro-3-substituted-13-aryl-1H-benzo-[h]chromene[2,3-b]
quinolin-1-one (70a–70d).
The compounds 70a–70d were syn
thesized following the method given for the compounds 7a–7g.
Data of compounds are shown in the succeeding sections.
3-Amino-1-phenyl-1H-benzo[f]-chromene-2-carbonitrile (4a).
Yield: 91.4%, mp > 260ꢀC; 1H NMR (DMSO-d6, 300 Hz) d:
5.29 (s, 1H, 4H), 6.97–7.14 (m, 3H, Ph-H), 7.17 (br s, 2H, NH2),
7.19–7.95 (m, 8H, Ph-H), IR (KBr) υ: 3340 (NH), 2183 (CꢄN);
MS (ESI) m/z: 299.1 (M +1). Anal. Calcd for C20H14N2O: C
80.52, H 4.73, N 9.39; found C 80.40, H 4.74, N 9.41.
3-Amino-1-(4-methoxy-phenyl)-1H-benzo[f]chromene-2-
1
carbonitrile (4b).
Yield: 90.8%, mp 190–192ꢀC; H NMR
(CDCl3, 300Hz) d: 3.74 (s, 3H, OCH3), 5.21 (s, 1H, 4-H), 6.77–
7.13 (m, 4H, Ph-H),7.19 (br s, 2H, NH2), 7.23–7.86 (m, 10H, Ph-
H), IR (KBr) υ: 3323 (NH), 2193 (Cꢄ N); MS (ESI) m/z: 329.1
(M + 1). Anal. Calcd for C21H16N2O2: C 76.81, H 4.91, N 8.53;
found C 76.45, H 4.94, N 8.56.
3-Amino-1-(2-chlorophenyl)-1H-benzo[f]chromene-2-carbonitrile
(4c). Yield: 92.2%, mp 256–258ꢀC; 1H NMR (DMSO, 300 Hz)
d: 5.71 (s, 1H, 4-H), 6.97–7.05 (m, 4H, Ph-H), 7.17–7.21 (m, 4H,
NH2 + Ph-H), 7.32–7.99 (m, 5H, Ph-H), IR (KBr) υ: 3348 (NH),
2179 (CꢄN); MS (ESI) m/z: 333.0 (M +1). Anal. Calcd for
C20H13ClN2O: C 72.18, H 3.94, N 8.42; found C 71.89, H
3.99, N 8.47.
3-(3-Oxocyclohex-1-enylamino)-1-phenyl-1H-benzo[f]chromene-2-
carbonitrile (6b).
Yield: 62.8%, mp 236–238ꢀC; 1H NMR
(CDCl3, 300MHz) d: 2.03–2.12 (m, 2H, 50-H), 2.39–2.46 (m, 2H,
60-H), 2.51–2.61 (m, 2H, 40-H), 5.32 (s, 1H, 1-H), 5.95 (s, 1H,
20-H), 6.54 (brs, 1H, NH), 7.19–7.96 (m, 11H, Ph-H), IR (KBr)
υ: 3213 (NH), 1658 (C=O), 2257 (CꢄN); MS (ESI) m/z: 393.2
(M + 1). Anal. Calcd for C26H20N2O2: C 79.57, H 5.14, N 7.14;
found C 79.45, H 5.17, N 7.19.
3-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-1-(4-methoxy-
phenyl)-1H-benzo[f]chromene-2-carbonitrile (6c).
Yield:
57.6%, mp 190–192ꢀC; 1H NMR (CDCl3, 300 MHz) d: 1.13
(m, 6H, CH3), 2.28–2.43 (m, 4H, 40 + 60-H), 3.73 (s, 3H,
OCH3), 5.27 (s, 1H, 1-H), 5.98 (s, 1H, 20-H), 6.47 (brs, 1H,
NH), 6.82–7.87 (m, 10H, Ph-H), IR (KBr) υ: 3318 (NH),
1582 (C=O), 2263 (CꢄN); MS (ESI) m/z: 451.2 (M + 1).
Anal. Calcd for C29H26N2O3: C 77.31, H 5.82, N 6.22;
found C 77.19, H 5.89, N 6.30.
2-Amino-4-phenyl-4H-benzo[h]-chromene-3-carbonitrile
(40a).
Yield: 90.6%, mp 206–208ꢀC; 1H NMR (CDCl3,
300 MHz) d: 4.89 (s, 1H, 4-H), 7.08–7.33 (m, 8H, NH2 +Ph-H),
7.54–8.23 (m, 11H, Ph-H), IR (KBr) υ: 3385 (NH), 2179 (CꢄN);
MS (ESI) m/z: 299.1 (M +1). Anal. Calcd for C20H14N2O: C
80.52, H 4.73, N 9.39; found C 80.41, H 4.74, N 9.43.
2-Amino-4-(4-methoxy-phenyl)-4H-benzo[h]-chromene-3-
carbonitrile (40b).
Yield: 88.6%, mp 188–190ꢀC; 1H NMR
3-(3-Oxocyclohex-1-enylamino)-1-(4-methoxy-phenyl)-1H-
benzo[f]chromene-2-carbonitrile (6d).
Yield: 58.2%, mp
(CDCl3, 300 MHz) d: 3.79 (s, 3H, OCH3) 4.84 (s, 1H, 4-H),
6.84–7.16 (m, 6H, Ph-H), 7.18 (br s, 2H, NH2), 7.52–8.19 (m,
1
216–218ꢀC; H NMR (CDCl3, 300MHz) d: 2.04–2.14 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Synthesis and Characterization of Benzochromeno[2,3-b]tetrahydroquinolinone Derivatives
50-H), 2.41–2.46 (m, 2H, 60-H), 2.48–2.61 (m, 2H, 40-H), 3.74
(M+ 1). Anal. Calcd for C26H19ClN2O2: C 73.15, H 4.49, N 6.56;
found C 72.97, H 4.57, N 6.63.
(s, 3H, OCH3), 5.32 (s, 1H, 1-H), 5.93 (s, 1H, 20-H), 6.52
(brs, 1H, NH), 7.19–8.06 (m, 11H, Ph-H), IR (KBr) υ: 3238
(NH), 1668 (C=O), 2287 (CꢄN); MS (ESI) m/z: 423.2
(M+ 1). Anal. Calcd for C27H22N2O3: C 76.76, H 5.25, N
6.63; found C 76.52, H 5.32, N 6.69.
14-Amino-2,3,4,13-tertrahydro-3,3-dimethyl-13-phenyl-1H-benzo
[f]chromene[2,3-b]quinolin-1-one (7a). Yield: 50.6%, mp >260ꢀC;
1H NMR (CDCl3, 300 MHz) d: 1.09,1.10 (each s, each 3H, 6H, CH3),
2.46 (s, 2H, 2-H), 2.87 (s, 2H,4-H), 5.58 (s, 1H, 13-H), 6.43 (br s,
1H, NH), 7.10–8.12 (m, 11H, Ph-H), 9.21 (br s, 1H, NH), IR
(KBr) υ: 3296, 1561, 1142, 1093; MS (ESI) m/z: 421.2 (M + 1).
Anal. Calcd for C20H24N2O2: C 79.98, H 5.75, N 6.66; found C
79.82, H 5.85, N 6.70.
3-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-1-(2-chlorophenyl)-
1H-benzo[f]chromene-2-carbonitrile (6e).
Yield: 60.6%, mp
242–244ꢀC; 1H NMR (CDCl3, 300 MHz) d: 1.14, 1.15 (each s, each
3H, CH3), 2.30–2.46 (m, 4H, 40 +60-H), 5.94 (s, 1H, 1-H), 6.06
(s, 1H, 20-H), 6.74 (brs, 1H, NH), 7.06–7.49 (m, 10H, Ph-H), IR
(KBr) υ: 3264 (NH), 1654 (C=O), 2263 (CꢄN); MS (ESI) m/z:
455.2 (M + 1). Anal. Calcd for C28H23ClN2O2: C 73.92, H 5.10, N
6.16; found C 73.78, H 5.18, N 6.23.
14-Amino-2,3,4,13-tertrahydro-13-phenyl-1H-benzo[f]
chromenequinolin-1-one (7b).
Yield: 51.8%, mp >260ꢀC;
1H NMR (CDCl3, 300 Hz) d: 1.24–2.13 (m, 2H, 4-H), 2.55–2.64
(m, 2H,3-H), 2.92–3.10 (m, 2H, 2-H), 5.57 (s, 1H, 13-H), 6.45
(br s, 1H, NH), 7.10–8.13 (m, 11H, Ph-H), 9.23 (br s, 1H, NH),
IR (KBr) υ: 3286, 1568, 1146, 1112; MS (ESI) m/z: 393.2
(M+ 1). Anal. Calcd for C26H20N2O2: C 79.57, H 5.14, N 7.14;
found C 79.43, H 5.19, N 7.17.
3-(3-Oxocyclohex-1-enylamino)-1-(2-chlorophenyl)-1H-benzo
[f]chromene-2-carbonitrile (6f). Yield: 63.6%, mp 206–208ꢀC;
1H NMR (CDCl3, 300MHz) d: 2.06–2.14 (m, 2H, 50-H), 2.41–2.45
(m, 2H, 60-H), 2.53–2.54 (m, 2H, 40-H), 5.98–6.01 (m, 2H, 1 + 20-
H), 6.41 (brs, 1H, NH), 6.92–7.86 (m, 10H, Ph-H), IR (KBr) υ:
3228 (NH), 1638 (C=O), 2247 (CꢄN); MS (ESI) m/z: 427.1
(M + 1). Anal. Calcd for C26H19ClN2O2: C 73.15, H 4.49, N 6.56;
found C 72.98, H 4.57, N 6.62.
14-Amino-2,3,4,13-tertrahydro-3,3-dimethyl-13-(4-methoxy-
phenyl)-1H-benzo[f]chromene[2,3-b]-quinolin-1-one (7c).
Yield:
48.6%, mp 256–258ꢀC; 1H NMR (CDCl3, 300 MHz) d: 1.08,1.09
(each s, each 3H, 6H, CH3), 2.46 (s, 2H, 2-H), 2.88 (s, 2H,4-H),
3.68 (s, 3H, OCH3), 5.53 (s, 1H, 13-H), 6.41 (br s, 1H, NH),
7.27–8.11 (m, 10H, Ph-H), 9.20 (br s, 1H, NH), IR (KBr) υ:
3336, 1581, 1152, 1098; MS (ESI) m/z: 451.3 (M + 1). Anal.
Calcd for C29H26N2O3: C 77.31, H 5.82, N 6.22; found C 77.17,
H 5.89, N 6.29.
3-(50-Furanly-3-oxocyclohex-1-enylamino)-1-phenyl-1H-benzo
[f]chromene-2-carbonitrile (6g). Yield: 46.6%, mp 224–226ꢀC;
1H NMR (CDCl3, 300 MHz) d: 2.05–2.87 (m, 4H, 60-H, 40-H),
3.49–3.59 (m, 1H, 50-H), 5.32 (s, 1H, 1-H), 5.99 (s, 1H,
50 + 500-H), 6.09–6.12 (m, 1H, 50 + 400-H), 6.12–6.33 (50 + 300-H),
6.47 (brs, 1H, NH-H), 7.18–7.89 (m, 11H, Ph-H), IR (KBr) υ:
3228 (NH), 1638 (C=O), 2247 (CꢄN); MS (ESI) m/z: 459.2
(M + 1). Anal. Calcd for C30H22N2O3: C 78.59, H 4.84, N 6.11;
found C 78.40, H 4.91, N 6.19.
2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-4-phenyl-4H-benzo
[h]chromene-3-carbonitrile (60a). Yield: 55.8%, mp 226–228ꢀC;
1H NMR (CDCl3, 300 MHz) d: 1.13, 1.14 (each s, each 3H, CH3),
2.33 (s, 2H, 40-H), 2.44 (s, 2H, 60-H), 4.97 (s, 1H, 1-H), 6.08 (s,
1H, 20-H), 6.90 (brs, 1H, NH-H), 7.22–7.83 (m, 11H, Ph-H), IR
(KBr) υ: 3325 (NH), 1719 (C=O), 2256 (CꢄN); MS (ESI) m/z:
421.2 (M+ 1). Anal. Calcd for C20H24N2O2: C 79.98, H 5.75, N
6.66; found C 79.87, H 5.81, N 6.73.
14-Amino-2,3,4,13-tertrahydro-13-(4-methoxy-phenyl)-1H-
benzo[f]chromene[2,3-b]quinolin-1-one (7d).
Yield: 49.8%,
1
mp 202–204ꢀC; H NMR (CDCl3, 300Hz) d: 2.07–2.11 (m, 2H,
4-H), 2.60–2.64 (m, 2H,3-H), 3.01–3.05 (m, 2H, 2-H), 3.69
(s, 3H, OCH3), 5.54 (s, 1H, 13-H), 6.65 (br s, 1H, NH),
7.27–8.09 (m, 10H, Ph-H), 9.25 (brs, 1H, NH), IR (KBr) υ:
3296, 1608, 1186, 1120; MS (ESI) m/z: 423.2 (M + 1). Anal.
Calcd for C27H22N2O3: C 76.76, H 5.25, N 6.63; found C 76.50,
H 5.30, N 6.67.
14-Amino-2,3,4,13-tertrahydro-3,3-dimethyl-13-(2-chlorophenyl)-
1H-benzo[f]chromene[2,3-b]-quinolin-1-one (7e). Yield: 51.6%,
mp 248–250ꢀC; 1H NMR (CDCl3, 300 MHz) d: 1.42 (d, 6H,
CH3), 2.29–2.47 (m, 4H, 2-H, 4-H), 5.90 (m, 1H, 13-H), 6.46 (br
s, 1H, NH), 7.08–7.83 (m, 10H, Ph-H), 9.18 (br s, 1H, NH), IR
(KBr) υ: 3316, 1602, 1182, 1068; MS (ESI) m/z: 455.1 (M + 1).
Anal. Calcd for C28H23ClN2O2: C 73.92, H 5.10, N 6.16; found C
73.77, H 5.20, N 6.25.
14-Amino-2,3,4,13-tertrahydro-13-(2-chlorophenyl)-1H-benzo[f]
chromene[2,3-b]quinolin-1-one (7f). Yield: 51.8%, mp 192–194ꢀC;
1H NMR (CDCl3, 300 Hz) d: 2.08–2.11 (m, 2H, 4-H), 2.58–2.64
(m, 2H,3-H), 3.00–3.05 (m, 2H, 2-H), 5.54 (s, 1H, 13-H), 6.68 (br
s, 1H, NH), 7.17–8.11 (m, 10H, Ph-H), 9.26 (brs, 1H, NH), IR
(KBr) υ: 3316, 1668, 1192, 1108; MS (ESI) m/z: 423.2 (M + 1).
Anal. Calcd for C26H19ClN2O2: C 73.15, H 4.49, N 6.56; found C
72.95, H 4.57, N 6.65.
2-(3-Oxocyclohex-1-enylamino)-4-phenyl-4H-benzo[h]chromene-
3-carbonitrile (6b0).
Yield: 56.2%, mp 238–240ꢀC; 1H NMR
(CDCl3, 300MHz) d: 2.06–2.14 (m, 2H, 50-H), 2.43–2.47 (m,
2H, 60-H), 2.56–2.61 (m, 2H, 40-H), 4.96 (s, 1H, 1-H), 6.02 (s,
1H, 20-H), 6.82 (brs, 1H, NH-H), 7.00–8.15 (m, 11H, Ph-H), IR
(KBr) υ: 3283 (NH), 1658 (C=O), 2287 (CꢄN); MS (ESI) m/z:
393.2 (M+ 1). Anal. Calcd for C26H20N2O2: C 79.57, H 5.14, N
7.14; found C 79.42, H 5.18, N 7.18.
2-(3-Oxocyclohex-1-enylamino)-4-(4-methoxy-phenyl)-4H-benzo
[h]chromene-3-carbonitrile (6c0). Yield: 54.8%, mp 214–216ꢀC;
1H NMR (CDCl3, 300 MHz) d: 1.14–1.15 (m, 6H, CH3),
2.24–2.43 (m, 4H, 40 + 60-H), 3.75 (s, 3H, OCH3), 5.23 (s,
1H, 1-H), 5.61 (s, 1H, 20-H), 6.57 (brs, 1H, NH),
6.78–7.86 (m, 10H, Ph-H), IR (KBr) υ: 3358 (NH), 1587
(C=O), 2268 (CꢄN); MS (ESI) m/z: 451.1 (M + 1). Anal.
Calcd for C27H22N2O3: C 76.76, H 5.25, N 6.63; found C
76.50, H 5.31, N 6.69.
14-Amino-2,3,4,13-tertrahydro-3-furanly-13-(2-chlorophenyl)-
1H-benzo[f]chromene[2,3-b]-quinolin-1-one (7g).
Yield:
1
36.8%, mp 234–236ꢀC; H NMR (CDCl3, 300MHz) d: 2.53–3.28
(m, 4H, 60-H, 40-H), 3.58–3.61 (m, 1H, 50-H), 5.34 (s, 1H, 1-H),
5.89 (s, 1H, 50 +500-H), 6.13–6.18 (m, 1H, 50 +400-H), 6.57 (brs, 1H,
NH-H), 7.18–7.89 (m, 11H, Ph-H), 7.21–7.33 (m, 1H, 50 +300-H),
IR (KBr) υ: 3336, 1678, 1216, 1138; MS (ESI) m/z: 459.1 (M + 1).
Anal. Calcd for C30H22N2O3: C 78.59, H 4.84, N 6.11; found C
78.38, H 4.93, N 6.19.
2-(3-Oxocyclohex-1-enylamino)-4-(2-chlorophenyl)-4H-benzo
[h]chromene-3-carbonitrile (6d0). Yield: 58.6%, mp 256–258ꢀC;
1H NMR (CDCl3, 300MHz) d: 2.09–2.17 (m, 2H, 50-H), 2.45–2.50
(m, 2H, 60-H), 2.58–2.61 (m, 2H, 40-H), 5.64 (s, 1H, 1-H), 6.08 (s,
1H, 20-H), 6.73 (brs, 1H, NH), 7.01–7.63 (m, 10H, Ph-H), IR (KBr)
υ: 3325 (NH), 1678 (C=O), 2247 (CꢄN); MS (ESI) m/z: 426.4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G.-F. Han, M. Wang, Y. Jin, and L.-Z. Chen
Vol 000
14-Amino-2,3,4,13-tertrahydro-3,3-dimethyl-13-phenyl-1H-
Yield:
for the crystal structure measurement. The X-ray diffraction
intensities were recorded by a Bruker SMART APEX CCD
automatic diffractometer with graphite-monochromatized Mo
Ka radiation (l = 0.071073 nm) at 291(2) K. In the range of
2.2 < θ < 26.8, 3932 independent reflections were obtained in
compound 6c, and 3495 independent reflections were obtained
in compound 7d. The structures were solved by direct methods
using SHELXL-97 program. All the nonhydrogen atoms were
refined on F2 anisotropically with the full-matrix least squares
method. Hydrogen atoms were added according to the
theoretical methods. In the compound 6c, the final convergence
indices were R = 0.0570, wR= 0.1418, w = 1/[s2(F0)2+ (0.0964P)2],
P = (F20 + 2F2c)/3, S = 1.004. The maximum and the minimum
difference peak holes were 0.19 and ꢁ0.31eÅꢁ3, respectively. In
the compound 7d, the final convergence indices were R= 0.1529,
wR = 0.3696, w=1/[s2(F0)2 + (0.11542000P)2+ 8.000P], P=(F02 +2F2c)/
3, and S= 1.031. The maximum and the minimum difference peak
holes were 0.77 and ꢁ0.24 eÅꢁ3, respectively.
benzo[h]chromene[2,3-b]quinolin-1-one
(70a).
50.8%, mp 226–228ꢀC; 1H NMR (CDCl3, 300 MHz) d: 1.10,
1.11 (each s, each 3H, 6H, CH3), 2.47 (s, 2H, 2-H), 2.85
(s, 2H,4-H), 5.54 (s, 1H, 13-H), 6.49 (br s, 1H, NH), 7.15–8.11 (m,
11H, Ph-H), 9.23 (br s, 1H, NH), IR (KBr) υ: 3298, 1611, 1172,
1090; MS (ESI) m/z: 421.1 (M + 1). Anal. Calcd for C26H20N2O2:
C 79.57, H 5.14, N 7.14; found C 79.41, H 5.20, N 7.19.
14-Amino-2,3,4,13-tertrahydro-13-phenyl-1H-benzo[h]chromene
[2,3-b]quinolin-1-one (70b).
Yield: 52.8%, mp 196–198ꢀC; 1H
NMR (CDCl3, 300 Hz) d: 1.18–2.13 (m, 2H, 4-H), 2.55–2.64
(m, 2H,3-H), 2.92–3.19 (m, 2H, 2-H), 5.91 (s, 1H, 13-H), 6.45 (br s,
1H, NH), 7.15–8.63 (m, 11H, Ph-H), 9.25 (br s, 1H, NH), IR (KBr)
υ: 3316, 1618, 1186, 1113; MS (ESI) m/z: 392.5 (M + 1). Anal.
Calcd for C26H20N2O2: C 79.57, H 5.14, N 7.14; found C 79.39, H
5.20, N 7.19.
14-Amino-2,3,4,13-tertrahydro-13-(4-methoxy-phenyl)-1H-
benzo[h]chromene-[2,3-b]quinolin-1-one (70c). Yield: 47.8%,
mp 232–234ꢀC; 1H NMR (CDCl3, 300 Hz) d: 2.06–2.17 (m, 2H,
4-H), 2.61–2.66 (m, 2H,3-H), 3.06–3.10 (m, 2H, 2-H), 3.75
(s, 3H, OCH3), 5.10 (s, 1H, 13-H), 6.68 (br s, 1H, NH),
7.17–8.60 (m, 10H, Ph-H), 9.26 (br s, 1H, NH), IR (KBr) υ:
3306, 1638, 1176, 1108; MS (ESI) m/z: 423.2 (M + 1). Anal.
Calcd for C27H22N2O3: C 76.76, H 5.25, N 6.63; found C
76.49, H 5.33, N 6.69.
REFERENCES AND NOTES
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Cynthia, M. S.; Carlton, C.; Stefan, K. Neuroimage 2010, 51, 1405.
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6093; (b) Marco, C.; Cristina, G.; Giulia, L. Arch Gerontol Geriat 2009, 49, e6.
[3] Svensson, A. L. Behav Brain Res 2000, 113, 193.
[4] (a) Lygia, A. M.; Jeroen, K.; Fransde, K. J Pharmaceut Biomed
2010, 53, 609; (b) Kenneth, G.; Shuangteng, H.; Yungao, Y. Pharmacol
Biochem Be 2009, 94, 169.
[5] Cuider, A.; Eric, L.; Marie, A. T. Eur J Pharmacol 1998,
348, 191.
[6] (a) Patocka, J.; Jun, D.; Kuca, K. Curr Drug Met 2008, 9,
332; (b) Meng, Q.; Rua, J. H.; Zhang, G. L. Toxicol Lett 2007,
168, 140.
14-Amino-2,3,4,13-tertrahydro-13-(2-chlorophenyl)-1H-benzo
[h]chromene[2,3-b]quinolin-1-one (70d).
Yield: 50.8%, mp
202–204ꢀC; 1H NMR (CDCl3, 300 Hz) d: 2.08–2.13 (m, 2H, 4-H),
2.60–2.65 (m, 2H, 3-H), 3.01–3.06 (m, 2H, 2-H), 5.57 (s, 1H,
13-H), 6.74 (br s, 1H, NH), 7.17–8.23 (m, 10H, Ph-H), 9.28 (br s,
1H, NH), IR (KBr) υ: 3322, 1676, 1202, 1102; MS (ESI) m/z:
423.2 (M + 1). Anal. Calcd for C26H19ClN2O2: C 73.15, H 4.49, N
6.56; found C 72.95, H 4.57, N 6.65.
[7] (a) Herrerias, C. I.; Yao, X.; Li, Z. C. Chem Rev 2007, 107,
2546; (b) Chan, T. H.; Yang, Y. J Am Chem Soc 1999, 121, 3228.
[8] Ren, Y. M.; Cai, C. Catal Commun 2008, 9, 1017.
Determination of crystal structure.
A
colorless
transparent crystal of size 0.25 ꢃ 0.15 ꢃ 0.10 mm was selected
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet