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

Article abstract of DOI:10.1002/jhet.897

The Knoevenagel reactions of malononitrile with acetophenone or 4-substituted acetophenons were carried to give the corresponding 2-(1-aryle thylidene)malononitriles, which was further cyclized with sulfur using NaHCO₃ as catalysts to generate

Full text of DOI:10.1002/jhet.897

July 2012
Synthesis of Thieno[2,3-b]quinolinone Derivatives
909
*
Guang-Fan Han, Ming Wang, Li-Zhuang Chen, and Xiao-Lei Hu
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 January 17, 2011
DOI 10.1002/jhet.897
View this article online at wileyonlinelibrary.com.
Ar
O
CN
CN
O
H3C
CN
CN
S
NH4Ac
CN
+
Ar
CH3
NH2
toluene
NaHCO3/THF
Ar
S
2
1
O
NH2
O
Ar
Ar
CN
R1
R2
R1
R2
THF
K2CO3/Cu2Cl2
O
R1
R2
N
TsOH/toluene
S
S
N
H
4a-4i
3a-3i
3a: Ar=C6H5, R1=Ph, R2=H;
3d: Ar=4-ClPh, R1=H, R2=H;
3g: Ar=4-MeOPh, R1=H, R2=H;
4a: Ar=C6H5, R1=Ph, R2=H;
4d: Ar=4-ClPh, R1=H, R2=H;
4g: Ar=4-MeOPh, R1=H, R2=H;
3b: Ar=C6H5, R1=CH3, R2=CH3;
3e: Ar=4-ClPh, R1=CH3, R2=CH3;
3h: Ar=4-MeOPh, R1=CH3, R2=CH3;
4b: Ar=C6H5, R1=CH3, R2=CH3;
4e: Ar=4-ClPh, R1=CH3, R2=CH3;
4h: Ar=4-MeOPh, R1=CH3, R2=CH3;
3c: Ar=C6H5, R1=H, R2=H;
3f: Ar=4-ClPh, R1=Ph, R2=H;
3i: Ar=4-MeOPh,R1=Ph, R2=H;
4c: Ar=C6H5, R1=H, R2=H;
4f: Ar=4-ClPh, R1=Ph, R2=H;
4i: Ar=4-MeOPh,R1=Ph, R2=H.
The Knoevenagel reactions of malononitrile with acetophenone or 4-substituted acetophenons were car-
ried to give the corresponding 2-(1-aryle thylidene)malononitriles, which was further cyclized with sulfur us-
ing NaHCO3 as catalysts to generate 2-amino-5-arylthiophene-3-carbonitrile 2. The intermediate enamines 3
were prepared by refluxing of 2 with 5-substituted-1,3-cyclohexanedione using p-toluenesulfonic acid as cat-
alyst. The title compounds 4-amino-3-aryl -7-substituted-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-one were
synthesized by cyclization of 3 in the presence of K2CO3 and Cu2Cl2. The structures of all compounds were
1
characterized by elemental analysis, IR, MS, and H-NMR spectra.
J. Heterocyclic Chem., 49, 909 (2012).
INTRODUCTION
In view of the above information and to continue our re-
search program concerned with structural modification of
certain biologically active heterocyclic nuclei with the pur-
pose of enhancing their biological activity, we report here
the synthesis of several novel analogs of thieno[2,3-b]qui-
nolinone derivatives hoping that they can have some chem-
ical and biological interests.
The substantial growth in the number of investigations in the
field of the organosulfur compounds observed in recent years,
in particular, for condensed heteroaromatic systems including a
thiophene ring, has been due to an expanded application in the
medical field and has been shown to exert diverse biological
effects such as antioxidant effects, anti-inflammatory proper-
ties, inhibition of platelet aggregation, reduction of systolic
blood pressure, reduction of cholesterol levels, and anticardio-
vascular disease [1,2]. Rashad reported several novel analogs
of dihydronaphthothiophenes, naphthothiophenes, thieno
[2,3-d]pyrimidines, and their fused heterocyclic thienotria-
zolo[4,3-a] pyrimidine derivatives, which including a thio-
phene ring showed higher anti-H5N1 activity [3].
Quinolines and their derivatives are very important com-
pounds because of their wide occurrence in natural products
and biologically active compounds. Quinoline derivatives
are utilized as potential antitumoral, antituberculosis, anti-
convulsant, antibreast cancer, and anti-HIV agents [4–8].
At the same time, quinoline derivatives are the important
fine chemicals for the synthesis of drug molecules, dyes,
pesticides, etc. [9].
RESULT AND DISCUSSION
As shown in Scheme 1, the intermediates 2-(1-arylethy-
lidene)malononitriles 1 were prepared from acetophenone
or substituted acetophenone, malononitrile in dry toluene
with NH4Ac as catalyst, followed by the cyclization with
sulfur in the presence of NaHCO3 as catalyst in THF to
give the thiophenes 2. This process was achieved in high
yield. 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. 4-Amino-3-aryl-7-substituted-7,8-dihy-
drothieno[2,3-b]quinolin-5(6H)-ones 4 were synthesized by
cyclization of the intermediate enamines 3 in the presence
© 2012 HeteroCorporation

910
G.-F. Han, M. Wang, L.-Z. Chen, and X.-L. Hu
Vol 49
Scheme 1
Ar
O
CN
CN
O
H3C
CN
CN
S
NH4Ac
CN
+
Ar
CH3
NH2
toluene
NaHCO3/THF
Ar
S
2
1
O
NH2
O
Ar
Ar
CN
R1
R2
R1
R2
THF
K2CO3/Cu2Cl2
O
R1
R2
N
TsOH/toluene
S
S
N
H
4a-4i
3a-3i
3a: Ar=C6H5, R1=Ph, R2=H;
3d: Ar=4-ClPh, R1=H, R2=H;
3g: Ar=4-MeOPh, R1=H, R2=H;
4a: Ar=C6H5, R1=Ph, R2=H;
4d: Ar=4-ClPh, R1=H, R2=H;
4g: Ar=4-MeOPh, R1=H, R2=H;
3b: Ar=C6H5, R1=CH3, R2=CH3;
3e: Ar=4-ClPh, R1=CH3, R2=CH3;
3h: Ar=4-MeOPh, R1=CH3, R2=CH3;
4b: Ar=C6H5, R1=CH3, R2=CH3;
4e: Ar=4-ClPh, R1=CH3, R2=CH3;
4h: Ar=4-MeOPh, R1=CH3, R2=CH3;
3c: Ar=C6H5, R1=H, R2=H;
3f: Ar=4-ClPh, R1=Ph, R2=H;
3i: Ar=4-MeOPh,R1=Ph, R2=H;
4c: Ar=C6H5, R1=H, R2=H;
4f: Ar=4-ClPh, R1=Ph, R2=H;
4i: Ar=4-MeOPh,R1=Ph, R2=H.
of K2CO3 and Cu2Cl2 [10]. The melting points and yields of
compounds 3 and 4 are shown in Tables 1 and 2.
at d 7.00 corresponding to the proton attached to thiophene
ring and additional single peak at d 5.98 ascribed to the typ-
ical proton peak olefin proton bonded to the enamine moiety.
In the 1H-NMR spectrum of compound 4a, two broad single
peaks at d 5.39 and d 9.63 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 intra-
molecular 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 9.63. A sharp single peaks
at 7.01 was observed. It was attributed to the C2-H of the
thiophene ring. The structures of these compounds were
further supported by their IR spectra. The spectrum of
compound 3a showed the absorption bands at 2215 and
3452 cmꢀ1 for the cyano group and amino group, respec-
tively. However, an absorption band of cyano group
disappeared in the IR spectrum of compound 4a.
In our initial experiments, we noted that the substituted
functional groups at 4-position of acetophenone, including
electron-donating to electron-withdrawing groups, was tol-
erated under the same conditions. However, the reaction
yields for these compounds differ from each other and cor-
related to electronic effects of their substituents. The pres-
ence of an electron-withdrawing group such as chlorine
atom on an acetophenone tends to speed up the reaction
and gave higher yields. However, if there is an electron-do-
nating group such as methoxyl group on an acetophenone
tends to slow down the reaction and gave lower yields of
the compounds 2. On the other hand, substitutions on the
1,3-cyclohexanedione appear to have effect on the yields.
The presence of two methyl groups or a phenyl group in
1,3-cyclohexanedione appears to have a positive effect on
the yield of the intermediate enamines 3.
1
The data of H-NMR, MS, and IR shown in the Experi-
EXPERIMENTAL
mental section are in accordance with the chemical structures
1
of the target compounds. The H-NMR spectra of com-
All melting points were determined on an electrothermal appa-
ratus and are uncorrected. Microanalysis was performed by the
PerkinElmer 2400 microanalytical service. Infrared spectra were
pounds 3a and 4a were recorded in CDCl3, CD3OD, or
DMSO-d6. The 1H-NMR spectra of 3a showed single signal
Table 1
Table 2
The melting point and yield of 2-amino-5-arylthiophene-3-carbonitrile
derivatives.
The melting point and yield of thieno[2,3-b]quinolinone derivatives.
Entries
R1
R2
Ar
MP (ꢁC)
Yield (%)
Entries
R1
R2
Ar
MP (ꢁC)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
CH3
H
H
CH3
Ph
H
CH3
Ph
H
CH3
H
H
CH3
H
H
CH3
H
Ph
Ph
Ph
4-ClPh
4-ClPh
194–196
226–228
200–202
>270
49.6
50.1
46.4
58.6
64.1
60.2
62.1
65.3
63.1
3a
3b
3c
3d
3e
3f
Ph
CH3
H
H
CH3
Ph
H
CH3
H
H
CH3
H
Ph
Ph
Ph
4-ClPh
4-ClPh
4-ClPh
4-OCH3
4-OCH3
190–192
156–158
146–148
228–230
190–192
178–180
202–204
172–174
85.4
89.5
79.3
92.1
93.1
89.5
90.5
91.3
>270
4-ClPh
216–218
176–178
178–180
204–206
4-OCH3
4-OCH3
4-OCH3
3g
3h
H
CH3
H
CH3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis of Thieno[2,3-b]quinolinone Derivatives
911
recorded as KBr pellets on PerkingElmer 1700 spectrophotometer.
The 1H-NMR spectra were recorded by a Bruker ARX-300 or
VARIAN-400 spectrometer. Sample solutions were prepared in
CDCl3, CD3OD, or DMSO-d6, and the chemical shifts are
expressed d ppm using TMS, as an internal standard. Mass spectra
were recorded by JMS-DX300 at 70eV.
All chemical reagents were commercially available and puri-
fied with standard methods before use. The solvents were dried
in routine ways and redistilled. 5-Substituted-1,3-cyclohexane-
dione were prepared in good yield from aromatic aldehyde, ace-
tone, and diethyl malonate according to the literature [11]
method with slightly modification.
1656 (C=O), 2214 (CꢂN) cmꢀ1; MS (70eV) m/z (%): 371.2
(M+1, 100); Anal. Calcd. for C23H18N2OS: C 74.57, H 4.90, N
7.56; found C 74.60, H 4.91, N 7.44.
2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-4-phenylthiophene-
3-carbonitrile (3b). Yield: 89.5%, m.p. 156–158ꢁC; 1H-NMR
(CD3OD, 400 MHz) d:1.15 (s, 6H, 2ꢃCH3), 2.28 (s, 2H, 60-H),
2.55 (s, 2H, 40-H), 7.44–7.51 (m, 4H, 5-H, and Ph-H), 7.63–7.65
(m, 2H, Ph-H); IR (KBr) u: 3429 (NH), 1685 (C=O), 2232 (CꢂN)
cmꢀ1; MS (70eV) m/z (%): 323.1 (M+1, 100); Anal. Calcd. for
C19H18N2OS: C 70.78, H 5.63, N 8.69; found C 70.71, H 5.58, N
8.64.
2-(3-Oxocyclohex-1-enylamino)-4-phenylthiophene-3-carbonitrile
(3c). Yield: 79.3%, m.p. 146–148ꢁC; 1H-NMR(CD3OD, 300
MHz) d: 2.01–2.10 (m, 2H, 60-H), 2.30–2.39 (m, 2H, 50-H),
2.63–2.67 (m, 2H, 40-H), 5.50 (s, 1H, 20-H), 7.38–7.48 (m, 4H,
5-H, and Ph-H), 7.60–7.62 (d, J = 6.9 Hz, 2H, Ph-H); IR (KBr)
u: 3472 (NH), 1714 (C=O), 2225 (CꢂN) cmꢀ1; MS (70eV) m/z
(%): 295.1 (M+1, 100); Anal. Calcd. for C17H14N2OS: C 69.36,
H 4.79, N 9.52; found C 69.22, H 4.88, N 9.54.
4-(4-Chlorophenyl)-2-(3-oxocyclohex-1-enylamino)thiophene-
3-carbonitrile (3d). Yield: 92.1%, m.p. 228–230ꢁC; 1H-NMR
(DMSO-d6, 400 MHz) d: 1.91–1.94 (m, 2H, 60-H), 2.21–2.24 (m,
2H, 50-H), 2.57–2.59 (m, 2H, 40-H), 5.38 (s, 1H, 20-H), 7.57–7.65
(m, 5H, 5-H, and Ph-H); IR (KBr) u: 3464 (NH), 1687 (C=O),
2219 (CꢂN) cmꢀ1; MS (70eV) m/z (%): 329.1 (M+1, 100);
Anal. Calcd. for C17H13ClN2OS: C 62.10, H 3.98, N 8.52; found
C 62.17, H 3.87, N 8.76.
4-(4-Chlorophenyl)-2-(5,5-dimethyl-3-oxocyclohex-1-enylamino)
thiophene-3-carb-onitrile (3e). Yield: 93.1%, m.p. 190–192ꢁC;
1H-NMR(CDCl3, 400 MHz) d: 1.13 (s, 6H, 2ꢃCH3), 2.28 (s, 2H,
60-H), 2.43 (s, 2H, 40-H), 5.87 (s, 1H, 20-H), 6.93 (s, 1H, 5-H),
7.41–7.43 (d, J = 6.8 Hz, 2H, Ph-H), 7.49–7.51 (d, J = 6.8 Hz,
2H, Ph-H); IR (KBr) u: 3418 (NH), 1696 (C=O), 2218 (CꢂN)
cmꢀ1; MS (70eV) m/z (%): 357.1 (M+1, 100); Anal. Calcd. for
C19H17ClN2OS: C 63.95, H 4.80, N 7.85; found C 64.16, H 4.82,
N 7.86.
4-(4-Chlorophenyl)-2-(3-oxo-5-phenylcyclohex-1-enylamino)
thiophene-3-carbonit-rile (3f). Yield: 89.5%, m.p. 178–180ꢁC;
1H-NMR(DMSO-d6, 400 MHz) d: 2.58–2.92 (m, 3H, 6-H, and
4-H), 545 (s, 1H, 20-H), 7.22–7.65 (m, 6H, 5-H, and Ph-H), 7.64
(d, J = 8.8 Hz, 2H, Ph-H), 7.58 (d, J = 8.8 Hz, 2H, Ph-H); IR
(KBr) u: 3439 (NH), 1635 (C=O), 2248 (CꢂN) cmꢀ1; MS (70eV)
m/z (%): 405.1 (M+1, 100); Anal. Calcd. for C23H17ClN2OS: C
68.22, H 4.23, N 6.92; found C 68.50, H 4.30, N 6.89.
General procedure for the synthesis of 2-(1-arylethylidene)
malononitrile (1). Toluene (50 mL) was added to a mixture of 4-
substituted acetophenone (5 mmol), malononitrile (6 mmol), and
ammonium (6 mmol). The solution was stirred at 105ꢁC for 2–3
h. Using a Dean-Stark trap [12], the condensed water was
removed from the reaction system. The solvent was evaporated,
and the resulting solution was cooled to room temperature. The
separated solid was collected, washed with water, and then
recrystallized from 95% ethanol to afford 2-(1-arylethylidene)
malononitrile.
General procedure for the synthesis of 2-amino-4-arylthiophene-
3-carbonitrile (2). 2-(1-Arylethylidene)malononitrile 1 (5 mmol)
and elemental sulfur (6.5 mmol) are suspended in 16 mL THF and
warmed to an internal temperature of 35ꢁC. A solution of sodium
bicarbonate (0.8 g in 16 mL H2O) is added over 1 h [13]. The
mixture is stirred at 35ꢁC for 35 min before the solution is
transferred to a separatory funnel. Then, the organic layers were
separated, and the water phase was extracted with ethyl acetate by
combining the organic phase. After removal of the solvent, the
residue was recrystallized from 95% ethanol to give 2-amino-4-
arylthiophene-3-carbonitrile.
General procedure for the synthesis of 2-(3-oxo-5-substituted-
cyclohex-1-enylamino)-4-arylthiophene-3-carbonitrile(3). To a
three-neck flask with a Dean-Stark trap, 50 mL of dry and
redistilled toluene, p-toluenesulfonic acid (0.1 g) were added. The
mixture was stirred at 110ꢁC for 30 min, then 2-amino-4-
arylthiophene-3-carbonitrile (5 mmol) and 5-substituted-1,3-
cyclohexanedione (7.5 mmol) were added. The reaction was
monitored by TLC. When the reaction was completed, the mixture
was cooled to room temperature, then evaporated under reduced
pressure, and the crude product was recrystallized from 95%
ethanol.
General procedure for the synthesis of 4-amino-3-aryl-7-
substituted-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-one(4). 2-
(3-oxo-5-phenylcyclohex-1-enylamino)-4-phenylthiophene-3-
carbonitrile(5 mmol) was added to THF (1 mL/mmol)
containing potassium carbonate (2.5 mmol) and cuprous
chloride (0.5 mmol). The reaction mixture was refluxed for
6 h, and then the hot mixture was filtered into ice hexane.
The precipitate was collected and washed with ethanol. The
gray powder was purified by silica gel flash chromatography
using ethyl acetate/hexane mixture(1:4) as eluent to afford
pure compounds. Compounds 4a–4i were synthesized by the
same procedure. Data of compounds are shown below.
2-(3-Oxo-5-phenylcyclohex-1-enylamino)-4-phenylthiophene-
3-carbonitrile (3a). Yield: 85.4%, m.p. 190–192ꢁC; 1H-NMR
(CDCl3, 300 MHz) d: 2.64–2.75 (m, 3H, 40-, 60-H), 2.91–2.96
(m, 1H, 40-H), 3.47–3.51 (m, 1H, 50-H), 5.98 (s, 1H, 20-H), 7.00
(s, 1H, 5-H), 7.27–7.60 (m, 10H, Ph-H); IR (KBr) u: 3452 (NH),
4-(4-Methoxyphenyl)-2-(3-oxocyclohex-1-enylamino)thiophene-
3-carbonitrile(3g). Yield: 90.5%, m.p. 202–204ꢁC; 1H-NMR
(CD3OD, 300 MHz) d: 2.03–2.09 (m, 2H, 60-H), 2.34–2.39 (t,
J = 6.3 Hz, J = 6.0 Hz, 2H, 50-H), 2.62–2.66 (t, J = 6.3 Hz, 2H,
40-H), 3.82 (s, 3H, OCH3), 5.54 (s, 1H, 20-H), 6.99–7.01 (d, J = 8.7
Hz, 2H, Ph-H), 7.32 (s, 1H, 5-H), 7.53–7.56 (d, J = 8.7 Hz, 2H,
Ph-H); IR (KBr) u: 3442 (NH), 1654 (C=O), 2223 (CꢂN) cmꢀ1
;
MS (70eV) m/z (%): 325.1 (M+1, 100); Anal. Calcd. for
C18H16N2O2S: C 66.64, H 4.97, N 8.64; found C 66.50, H 4.77, N 8.35.
2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)-4-(4-methoxyphenyl)
thiophene-3-ca-rbonitrile(3h). Yield: 91.3%, m.p. 172–174ꢁC;
1H-NMR(DMSO-d6, 400 MHz) d: 1.02 (s, 6H, 2ꢃCH3), 2.098 (s,
2H, 60-H), 2.43 (s, 2H, 40-H), 3.80 (s, 3H, OCH3), 5.28 (s, 1H, 20-
H), 7.03–7.05 (d, J = 8.8 Hz, 2H, Ph-H), 7.49 (s, 1H, 5-H), 7.52–
7.55 (d, J = 8.8 Hz, 2H, Ph-H); IR (KBr) u: 3453 (NH), 1710
(C=O), 2238 (CꢂN) cmꢀ1; MS (70eV) m/z (%): 353.1 (M+1,
100); Anal. Calcd. for C20H20N2O2S: C 68.16, H 5.72, N 7.95;
found C 68.20, H 5.45, N 7.54.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

912
G.-F. Han, M. Wang, L.-Z. Chen, and X.-L. Hu
Vol 49
4-Amino-3,7-diphenyl-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-
2H, 8-H), 2.87 (s, 2H, 6-H), 3.82 (s, 3H, OCH3) 5.50 (br, s, 1H,
N-H), 7.05–7.07 (d, J = 6.6 Hz, 2H, Ph-H), 7.27 (s, 1H, 2-H),
7.38–7.40 (d, J = 6.6 Hz, 2H, Ph-H), 9.40 (br, s, 1H, N-H); IR
(KBr) u: 3448 (NH), 1741 (C=O) cmꢀ1; MS (70eV) m/z (%):
353.1 (M+1, 100); Anal. Calcd. for C20H20N2O2S: C 68.16, H
5.72, N 7.95; found C 68.24, H 5.75, N 7.86.
one(4a). Yield: 49.6%. m.p. 194–196ꢁC; 1H-NMR(CDCl3, 400
MHz) d: 2.86–2.95 (m, 2H, 8-H), 3.25–3.42 (m, 2H, 6-H), 3.47–
3.54 (m, 1H, 7-H), 5.39 (br, s, 1H, N-H), 7.01 (s, 1H, 2-H), 7.29–
7.48 (m, 10H, Ph-H), 9.63 (br, s, 1H, N-H); IR (KBr) u: 3443
(NH), 1750 (C=O) cmꢀ1; MS (70eV) m/z (%): 371.1 (M+1, 100);
Anal. Calcd. for C23H18N2OS: C 74.57, H 4.90, N 7.56; found C
74.44, H 4.95, N 7.66.
4-Amino-3-(4-methoxyphenyl)-7-phenyl-7,8-dihydrothieno[2,3-b]
1
quinolin-5(6H)-one(4i). Yield: 63.1%. m.p. 204–206ꢁC; H-NMR
4-Amino-7,7-dimethyl-3-phenyl-7,8-dihydrothieno[2,3-b]quinolin-
(DMSO-d6, 300 MHz) d: 2.72–2.78 (m, 2H, 6-H), 2.96–3.05 (m,
2H, 8-H), 3.12–3.17 (m, 1H, 7-H), 3.82 (s, 3H, OCH3), 5.56 (br, s,
1H, N-H), 7.06–7.40 (m, 10H, 2-H, and Ph-H), 9.45 (br, s, 1H, N-
H); IR (KBr) u: 3476 (NH), 1728 (C=O) cmꢀ1; MS (70eV) m/z
(%): 401.1 (M+1, 100); Anal. Calcd. for C24H20N2O2S: C 71.98, H
5.03, N 6.99; found C 71.84, H 5.15, N 6.86.
1
5(6H)-one(4b). Yield: 50.1%. m.p. 226–228ꢁC; H-NMR(CDCl3,
300 MHz) d: 1.02 (s, 6H, 2ꢃCH3), 1.98 (s, 1H, 8-H), 2.88 (s, 3H,
8-H and 6-H), 5.40 (br, s, 1H, N-H), 7.35 (s, 1H, 2-H), 7.50 (s, 5H,
Ph-H), 9.43 (br,s, 1H, N-H); IR (KBr) u: 3426 (NH), 1765 (C=O)
cmꢀ1; MS (70eV) m/z (%): 323.1 (M+1, 100); Anal. Calcd. for
C19H18N2OS: C 70.78, H 5.63, N 8.69; found C 70.64, H 5.65,
N 8.76.
4-Amino-3-phenyl-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-
one(4c). Yield: 46.4%. m.p. 200–202ꢁC; 1H-NMR(DMSO-d6,
300 MHz) d: 1.99–2.08 (m, 2H, 8-H), 2.28–2.26 (m, 2H, 7-H),
2.61–2.65 (m, 2H, 6-H), 5.49 (br, s, 1H, N-H), 7.30 (s, 1H, 2-H),
7.38–7.60 (m, 5H, Ph-H), 9.43 (br, s, 1H, N-H); IR (KBr) u:
3478 (NH), 1753 (C=O) cmꢀ1; MS (70eV) m/z (%): 295.1 (M+1,
100); Anal. Calcd. for C17H14N2OS: C 69.36, H 4.79, N 9.52;
found C 69.44, H 4.75, N 9.66.
CONCLUSIONS
In summary, we have provided a method for the
synthesis of a series of novel compounds 4-amino-
3-aryl-7-substituted-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-
one derivatives. The effect of the temperature on the reactions
of malononitrile with 4-substituted acetophenone was also
investigated. We found that the reaction temperature was
determined to be 35ꢁC in the presence of NaHCO3, signifi-
cantly degrading the byproducts, which is easier to be
removed during the crystallization of the desired product 1.
In addition, the reaction of thiophenes 2 (5 mmol) with 5-
substituted-1,3-cyclo-hexanedione in the presence of
p-toluenesulfonic acid (0.1 g) was also performed in excel-
lent yield. The molar ratio of 5-substituted-1,3-cyclohexane-
diones and compound 2 is 1.5:1, and the optimal reaction
time is 2ꢄ3 h.
4-Amino-3-(4-chlorophenyl)-7,8-dihydrothieno[2,3-b]quinolin-
1
5(6H)-one(4d). Yield: 58.6%. m.p. > 270ꢁC; H-NMR (DMSO-
d6, 300 MHz) d: 2.05–2.08 (m, 2H, 8-H), 2.19–2.22 (m, 2H,
7-H), 2.48–2.56 (m, 2H, 6-H), 5.43 (br, s, 1H, N-H), 7.42–7.44
(d, J = 8.2 Hz, 2H, Ph-H), 7.65 (s, 1H, 2-H), 7.72–7.75 (d,
J = 8.2 Hz, 2H, Ph-H), 9.39 (br, s, 1H, N-H); IR (KBr) u: 3460
(NH), 1735 (C=O) cmꢀ1; MS (70eV) m/z (%): 329.1 (M+1, 100);
Anal. Calcd. for C17H13ClN2OS: C 62.10, H 3.98, N 8.52; found
C 62.24, H 3.95, N 8.66.
4-Amino-3-(4-chlorophenyl)-7,7-dimethyl-7,8-dihydrothieno
[2,3-b]quinolin-5(6H)-one(4e). Yield: 64.1%. m.p. > 270ꢁC;
1H-NMR(DMSO-d6, 300 MHz) d: 1.02 (s, 6H, 2ꢃCH3), 2.18
(s, 2H, 8-H), 2.26 (s, 2H, 6-H), 5.50 (br, s, 1H, N-H), 7.38 (s,
1H, 2-H), 7.48–7.50 (d, J = 8.2 Hz, 2H, Ph-H), 7.55–7.57 (d,
J = 8.2 Hz, 2H, Ph-H), 9.45 (br, s, 1H, N-H); IR (KBr) u: 3466
(NH), 1758 (C=O) cmꢀ1; MS (70eV) m/z (%): 357.1 (M+1,
100); Anal. Calcd. for C19H17ClN2OS: C 63.95, H 4.80, N
7.85; found C 63.64, H 4.75, N 7.96.
4-Amino-3-(4-chlorophenyl)-7-phenyl-7,8-dihydrothieno[2,3-b]
quinolin-5(6H)-on-e(4f). Yield: 60.2%. m.p. 216–218ꢁC; 1H-
NMR(DMSO-d6, 300 MHz) d: 2.73–2.79 (m, 2H, 8-H), 2.97–
3.06 (m, 2H, 8-H), 3.13–3.18 (m, 1H, 6-H), 5.57 (br, s, 1H, N-H),
7.24–7.58 (m, 5H, 2-H, and Ph-H), 9.48 (br, s, 1H, N-H); IR
(KBr) u: 3462 (NH), 1733 (C=O) cmꢀ1; MS (70eV) m/z (%):
405.1 (M+1, 100); Anal. Calcd. for C23H17ClN2OS: C 68.22, H
4.23, N 6.92; found C 68.34, H 4.15, N 6.96.
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4-Amino-3-(4-methoxyphenyl)-7,8-dihydrothieno[2,3-b]quinolin-
5(6H)-one(4g). Yield: 62.1%. m.p. 176–178ꢁC; 1H-NMR(DMSO-
d6, 300 MHz) d: 1.99 (s, 2H, 8-H), 2.59 (s, 2H, 7-H), 2.96 (s,
2H, 6-H), 3.81 (s, 3H, OCH3) 5.50 (br, s, 1H, N-H), 7.05–7.07
(d, J = 7.7 Hz, 2H, Ph-H), 7.26 (s, 1H, 2-H), 7.37–7.39 (d,
J = 7.7 Hz, 2H, Ph-H), 9.44 (br, s, 1H, N-H); IR (KBr) u: 3410
(NH), 1754 (C=O) cmꢀ1; MS (70eV) m/z (%): 325.1 (M+1,
100); Anal. Calcd. for C18H16N2O2S: C 66.64, H 4.97, N 8.64;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet