Substituted quinolinones, part 10: Synthesis of angular tetracyclic thieno and thiopyrano[3,2-c]benzo[h]quinolinones under PTC conditions as novel enzymatic enhancers

Article abstract of DOI:10.1080/10426500601047511

4-Chlorobenzo[h]quinolin-2(1H)-one (4) and its 4-sulfanyl derivative 6 were smoothly obtained via chlorination, hydrolysis, and sulfurization starting with 4-hydroxybenzo-[h]quinolin-2(1H)-one (1). Heterocyclization reaction of compound 6 with chloroacetaldehyde diethylacetal, phenacylbromide, chloroacetonitrile, ethyl chloroacetate, and bromomalononitrile under phase transfer catalysis (PTC) conditions was described affording benzo[h]thieno[3,2- c]quinolinones 7-9, 11, 12, and 14. The PTC-nucleophilic substitution of compound 4 with malononitrile gave quinolinylmalononitrile 15, which subsequently cyclized with sulfur/triethylamine (TEA) to afford benzo[h]thieno[2,3-c]quinolinone 16. The PTC reaction of compound 6 with CS2 and malononitrile gave benzo[h]thiopyrano[3,2-c]quinolinone 18. Similarly, cyclization of compound 4 with thiosalicylic acid furnished benzo[h] thiochromeno[3,2-c]quinolinedione 20. Thermal condensation of compound 6 with ethyl 2-cyano-3-ethoxyacrylate or ethyl 2-cyano-3,3-di(methylsulfanyl)acrylate afforded benzo[h]thiopyrano[3,2-c]quinolinones 22 and 24, respectively. The effect of new 14 products on α-amylase activity was examined. Thienoquinolinones 9, 11, 14, and 16 were the most potent enhancers in which these compounds multiplicate the activity of the enzyme to produce α-D-glucose up to eightfold. Copyright Taylor & Francis Group, LLC.

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Substituted Quinolinones,
Part 10: Synthesis of Angular
Tetracyclic Thieno and
Thiopyrano[3,2- c ]benzo[
h ]quinolinones Under PTC
Conditions as Novel Enzymatic
Enhancers
Mohamed Abass a
a Department of Chemistry , Ain Shams University ,
Cairo, Egypt
Published online: 24 Feb 2007.
To cite this article: Mohamed Abass (2007) Substituted Quinolinones, Part 10:
Synthesis of Angular Tetracyclic Thieno and Thiopyrano[3,2- c ]benzo[ h ]quinolinones
Under PTC Conditions as Novel Enzymatic Enhancers, Phosphorus, Sulfur, and Silicon
and the Related Elements, 182:4, 735-748, DOI: 10.1080/10426500601047511
To link to this article: http://dx.doi.org/10.1080/10426500601047511
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Phosphorus, Sulfur, and Silicon, 182:735–748, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601047511
Substituted Quinolinones, Part 10: Synthesis
of Angular Tetracyclic Thieno and
Thiopyrano[3,2-c]benzo[h]quinolinones Under PTC
Conditions as Novel Enzymatic Enhancers
Mohamed Abass
Department of Chemistry, Ain Shams University, Cairo, Egypt
4-Chlorobenzo[h]quinolin-2(1H)-one (4) and its 4-sulfanyl derivative 6 were
smoothly obtained via chlorination, hydrolysis, and sulfurization starting with 4-
hydroxybenzo-[h]quinolin-2(1H)-one (1). Heterocyclization reaction of compound 6
with chloroacetaldehyde diethylacetal, phenacylbromide, chloroacetonitrile, ethyl
chloroacetate, and bromomalononitrile under phase transfer catalysis (PTC)
conditions was described affording benzo[h]thieno[3,2-c]quinolinones 7–9, 11,
12, and 14. The PTC-nucleophilic substitution of compound 4 with malonon-
itrile gave quinolinylmalononitrile 15, which subsequently cyclized with sul-
fur/triethylamine (TEA) to afford benzo[h]thieno[2,3-c]quinolinone 16. The PTC
reaction of compound 6 with CS and malononitrile gave benzo[h]thiopyrano[3,2-
2
c]quinolinone 18. Similarly, cyclization of compound
4 with thiosalicylic
acid furnished benzo[h]thiochromeno[3,2-c]quinolinedione 20. Thermal conden-
sation of compound 6 with ethyl 2-cyano-3-ethoxyacrylate or ethyl 2-cyano-3,3-
di(methylsulfanyl)acrylate afforded benzo[h]thiopyrano[3,2-c]quinolinones 22 and
24, respectively. The effect of new 14 products on α-amylase activity was examined.
Thienoquinolinones 9, 11, 14, and 16 were the most potent enhancers in which
these compounds multiplicate the activity of the enzyme to produce α-D-glucose up
to eightfold.
Keywords Benzo[h]quinolinone; enzymatic activity; phase transfer catalysis;
thieno[3,2-c]quinolinone; thiopyrano[3,2-c]quinolinone
Received July 12, 2006; accepted August 23, 2006.
This work is dedicated to Prof. Dr. Ali L. Ibrahim with best wishes of his recovery
soon.
The author would like to thank Asst. Prof. Usama F. Ali, Department of Microbiology,
Faculty of Education, Ain Shams University, Cairo, Egypt, for evaluation of the enzymatic
activity.
Address correspondence to Mohamed Abass, Department of Chemistry, Faculty
of Education, Ain Shams University, Roxy, Helipolis, Cairo, 11757 Egypt. E-mail:
m.abass@chemist.com
735

736
M. Abass
INTRODUCTION
Recently we reviewed the literature of azoloquinolines, includ-
ing thienoquinolines,1 and noticed that although this category of
fused heterocyclic compounds is associated with important biological
properties,2−5 limited synthetic research work has been directed to
these compounds.6−10 Similarly, thiopyranoquinolines rarely appeare
in literature.1 On the other side, even 4-hydroxybenzo[h]quinolin-
2(1H)-one is readily available via facile high yield condensation of 1-
aminonaphthalene with diethyl malonate in the presence of polyphos-
phoric acid (PPA),11 barely very few cyclization reactions have been
reported with this compound.12 This encouraged us to continue our
previous work on fused quinolinones.13−15 In the present work we de-
scribe convenient methodology to obtain the hitherto unreported angu-
lar sulfur-containing S-shaped tetracyclic heteroaromatic compounds,
e.g., thieno- and benzo[h]thiopyrano[3,2-c]quinolinones, which are of
expected biological activity. The reported studies on enzymatic effect of
quinolinones revealed their importance in the economical production
of glucose via stimulation of α-amylase enzyme,16 so that the effect of
new compounds on activity of α-amylase was examined.
RESULTS AND DISCUSSION
Chemistry
4-hydroxybenzo[h]quinolin-2(1H)-one (1)11 was chosen as starting ma-
terial to obtain its isomeric 4-sulfanyl derivative 6, using a facile unam-
biguous synthesis, as depicted in Scheme 1. The synthetic route includes
SCHEME 1

Substituted Quinolinones, Part 10
737
chlorination of the starting material 1, using a mixture of phospho-
ryl chloride and phosphorus pentachloride to obtain the 2,4-dichloro
derivative 217 in a 68% yield. Hydrolysis of compound 2 was attempted
in both acid and alkaline media. In an alkaline medium, tary mate-
rial was obtained. Even after long-term work up, no definite product
was isolated, as indicated by the very broad melting point and crowded
1H NMR and IR spectra. Anyhow, only acid media was useful to hy-
drolyze compound 2 into the desired quinolinone 4. The possibility of
hydrolysis into either the hydroxybenzoquinolinone 1 and/or 2-chloro-4-
hydroxybenzoquinoline 3 was excluded on the basis of the spectral and
chemical properties of the product. Elemental analysis data showed
that only one chlorine atom was replaced in this nucleophilic substitu-
tion. Since spectral data are not cut off to decide which is which, with
respect to 3 and 4 possibilities, the reaction of the product with sodium
azide was carried out, in which the substitution process took place with
a chlorine atom. IR spectrum of the azido product 5 showed the charac-
teristic band of N3 group at ν 2115 cm–1. The later reaction evidently
proved the given structure 4 as the product of hydrolysis (Scheme 1).
Sulfurization of compound 4 was achieved via the well-known method-
ology of formation of the corresponding isothiourea by nucleophilic sub-
stitution using thiourea followed by in situ alkaline hydrolysis to afford
the desired 4-sulfanyl derivative 6 (Scheme 1).
Compound 6 was subjected to react with some α-halo active methy-
lene compounds viz. chloroacetaldehyde diethyl acetal, phenacyl bro-
mide, chloroacetonitrile, ethyl chloroacetate, and 2-bromomalononitrile
in the presence of potassium carbonate as the base. The reaction is
conveniently carried out under solid-solution Phase Transfer Cataly-
sis (PTC) conditions using Tetrabutylammonium Iodide (TBAI) as the
PTC catalyst in dry dimethylformamide (DMF). Even the expected open
chain S-alkylated products were not isolated in all cases except for ethyl
chloroacetate, and it is obvious that alkylation took place selectively at
the sulfur atom followed by cyclization in rest of the cases to afford the
corresponding benzo[h]thieno[3,2-c]quinolinones 7–9 (Scheme 2). The
formation of the acetate ester 10 was simply confirmed via the existence
of the ethyl set of protons in its 1H NMR spectrum (cf. the Experimen-
tal Section). Despite that there is no apparent reason for this dissimilar
behavior of the later reagent under the same conditions for cyclization
compared to previous ones, this highlights that the reaction may re-
quire an alternate condition that can be affected by ring closure. Hence,
the acetate ester 10 was treated with PPA, a strong acidic catalyst, to
give tetracyclic benzo[h]thieno[3,2-c]quinolinone 11. The structure of
compound 11 was confirmed with no doubt via its elemental and spec-
tral analyses. The 1HNMR spectrum did not show any indication for the

738
M. Abass
SCHEME 2
ethyl protons set. Moreover, as indicated by 1H NMR, the ketonic form of
compound 11 was not seen, and the compound assumed enolic structure,
which may be explained by the stabilities gained by both intramolec-
ular H-bonding with the neighboring carbonyl group and aromticity of
thiophene in the enolic form. Thermal reaction of acetate ester 10 with
Dimethylformamide Dimethylacetal (DMF-DMA) led smoothly to the
formation of the tetracyclic benzothienoquinoline-2-carboxylate 12, in

Substituted Quinolinones, Part 10
739
a high yield (88%). The results emphasize again that the carboxylate
group was not involved in the cyclization process (Scheme 2).
Similar to the previously discussed results, the reaction of compound
6 with 2-bromomalononitrile furnished directly 1-amino-11-oxo-10,
11-dihydrobenzo[h]thieno[3,2-c]quinoline-2-carbonitrile (14). Herein
again, the S-alkylated intermediate 13 was non-isolable (Scheme 3).
Interestingly, isomeric 2-amino-11-oxo-10,11-dihydrobenzo[h]thieno
[2,3-c]quinoline-3-carbonitrile (16) was prepared in a two-step route
starting with 4-chloro derivative 4. Nucleophilic replacement of the
chlorine atom using malononitrile, in the presence of potassium car-
bonate under the same previously described PTC conditions, gave the
quinolinylmalononitrile 15. The structure of compound 15 was verified
from its 1H NMR spectrum that revealed a singlet signal at δ 5.80 due
to CH(CN)2 and another singlet at δ 6.80 due to the proton at position
3. In addition, its IR spectrum revealed two sharp absorption bands at
–1
ν 2204 and 2175 cm characteristic for a CH(C N)2 system. A mod-
ified Gewald’s method was followed to affect a thiophene ring closure
by treating compound 15 with elemental sulfur and triethylamine as
a base catalyst, affording the tetracyclic compound 16, in a 78% yield
(Scheme 3).
SCHEME 3
Under the same PTC condition as previously cited (K2CO3, TBAI,
DMF), the one-pot synthesis of tetracyclic benzothiopyranoquinoline
18 was accomplished. Thus, the chloro derivative 4 was treated with
a mixture of carbon disulfide and malononitrile. The intermediacy of
dithioate 17 was expected in such reactions via the first formation of
dicyanodithioacetate anion, which consequently substituted a chlorine
atom in compound 4. The process was completed by an intramolecu-
lar exo-dig nucleophilic addition affording compound 18 (Scheme 4).
The PTC reaction of thiosalicylic acid with the chloro derivative 4

740
M. Abass
SCHEME 4
furnished the thio-ether 19, in an 82% yield. Cyclization of compound
19 was affected using PPA to afford the hitherto unreported pentacyclic
benzothiochromenoquinolinedione 20 (Scheme 4).
The condensation of 4-sulfanyl derivative 6 with ethyl 2-cyano-
3-ethoxyacrylate led to the formation of tetracyclic imino-ester 22
(Scheme 5). The possibility of the formation the corresponding oxo-
carbonitrile 25, as a product for the expected thio-ether intermediate
21, was absolutely excluded, whereas the IR spectrum of the product
1
lacked the C N specific bands. Additionally, the H NMR spectrum
SCHEME 5

Substituted Quinolinones, Part 10
741
indicated the presence of the ethyl ester set of protons and the imino
proton, exchangeable on addition of D2O (cf. Experimental Section).
Similarly, in the reaction of the compound 6 with ethyl 2-cyano-3,3-
di(methylsulfanyl)-acrylate, the possible conversion of the intermediate
23 to either the ester 24 or its competitor carbonitrile 25 was considered.
However, herein again the only product afforded was the ester 24 as
1
evidenced by elemental microanalysis and IR and H NMR spectral
data (Scheme 5).
Enzymatic Results
The effect of fourteen new compounds, 4–9, 11, 12, 14, 16, 18, 20, 22,
and 24, on the activity of α-amylase in the hydrolysis of starch was
indicated by monitoring production of α-D-glucose. Screening of the
new compounds showed that compounds 14, 16, 9, and 11 are the most
potent enzyme enhancer candidates as these compounds multiplicate
the activity of the enzyme to 8, 7.4, 6.3, Sixfold, respectively (Table I).
It is noted that all the tested compounds have a stimulation effect on α-
amylase except for compound 8, which revealed an inhibition effect and
reduced the activity to half. The remark on the structure of compound 8
is that it possesses a phenyl group, which increases its hydrophobicity.
This hypothesis is confirmed by replacing this phenyl group with more
polar groups, such as amino and hydroxyl functions in compounds 9 and
11, respectively, where we received high stimulation effect as previously
cited. Likewise, the results supported this finding as compounds 14 and
16, which have neighboring two-polar functions in positions 2 and 3,
showed the highest stimulation in this series.
TABLE I Effect of the New Compounds, at a Concentration of
100 μg/mL, on the Activity of α-Amylase at 40◦C as Indicated by
then Amount of Produced Glucose
Compound
no.
Produced α-D-Glucose
Compound
no.
Produced α-D-Glucose
(mg/L)
(mg/L)
4
5
6
7
8
860
1370
1300
910
14
15
16
18
19
2880
—
2680
1540
—
180
9
2270
—
2150
1830
20
22
24
Control
1010
2030
2100
360
10
11
12

742
M. Abass
EXPERIMENTAL
Melting points are uncorrected and were determined on a digital
Gallen-kamp MFB-595. IR spectra were taken on Perkin-Elmer FT-IR
1650 or Nicolet FT-IR 710 spectrophotometers, using samples in KBr
disks. 1H NMR spectra were recorded on Varian Gemini 200 (200 MHz)
spectrometer, using DMSO-d6 as the solvent and TMS as an internal
reference. Elemental microanalyses were performed on a Perkin-Elmer
CHN-2400 analyzer, at the Cairo University Microanalytical Centre
(Cairo, Egypt). 4-hydroxybenzo[h]quinolin-2(1H)-one (1) was prepared
according to the reported methods.11
2,4-Dichlorobenzo[h]quinoline (2)
Phosphoryl chloride (93 mL, 1 mol) was added to a mixture of phospho-
rus pentachloride (32 g, 0.15 mol) and compound 1 (10.55 g, 0.05 mol)
and then heated under reflux for 2 h. The excess phosphoryl chloride
was removed in a vacuum, and the residue was poured onto crushed ice
(200 g). The solution that was obtained was neutralized using cold 2N
sodium hydroxide solution to give solid deposits, which were filtered
and crystallized from acetone to yield 8.43 g (68%); m.p. 136–138◦C,
lit.17 m.p. 134–135◦C (52%).
4-Chlorobenzo[h]quinolin-2(1H)-one (4)
A suspension of dichloroquinoline 2 (2.48 g, 10 mmol) in hydrochloric
acid (50 mL, 6N) was heated under reflux for 4 h. Afterward, the solution
that was obtained was diluted with cold water to give white precipitate,
which was filtered and crystallized from acetone to yield 1.95 g (85%);
–1
m.p. 229–231◦C. IR (KBr):νmax 3216 (N–H), 3120, 1668 (C O), 772 cm
(C–Cl); 1H NMR (200 MHz, DMSO-d6): δ 6.94 (s, 1H, 3-H), 7.18–8.09 (m,
6H, Harom), 11.24 (b, 1H, N–H). Anal. calcd. for C13H8ClNO (229.67): C,
67.99; H, 3.51; N, 6.10. Found C, 67.84; H, 3.30; N, 5.96.
4-Azidobenzo[h]quinolin-2(1H)-one (5)
A mixture of chloroquinolinone 4 (1.15 g, 0.005 mol) and sodium azide
(0.65 g, 0.01 mol), in DMF (25 mL), was stirred at 80◦C for 6 h. Then the
mixture was poured onto cold water, and the precipitate material that
was formed was collected by filtration and crystallized from dioxane to
yield 1.04 g (88%); m.p. 253–254◦C (decomp.). IR, ν: 3047, 2115 (N3),
1667 (C O), 1613, 1566, 1528 and 1488 cm–1. 1H NMR, δ: 5.74 (s, 1H,
3-H), 7.12–8.05 (m, 6H, Harom) and 10.85 (b, 1H, N–H). Anal. calcd. for

Substituted Quinolinones, Part 10
743
C13H8N4O (236.23): C, 66.10; H, 3.41; N, 23.72. Found: C, 65.94; H, 3.15;
N, 23.60.
4-Sulfanylbenzo[h]quinolin-2(1H)-one (6)
A mixture of 4-chloroquinolinone 4 (2.30 g, 10 mmol) and thiourea
(1.52 g, 20 mmol) was heated in an oil-bath at 170–190◦C for 1 h. The
reaction mixture was then treated with ethanol (50 mL) and refluxed
for 2 h. After that, the mixture was left to cool and treated with an
aqueous solution of sodium hydroxide (50 mL, 2N), and the solution
that was obtained was filtered off. The clear filtrate was then acidified
by hydrochloric acid (100 mL, 2N) to give a yellow precipitate that fil-
tered and crystallized from DMF to yield 1.45 g (64%); m.p. >300◦C.
IR, ν: 3165 (N-H), 2510 (br S-H), 1666 (C O), 1613 cm–1. H NMR, δ:
1
1.72 (s, 1H, S H), 6.78 (s, 1H, 3 H), 7.21–8.12 (m, 6H, Harom) and 11.12
(b, 1H, N–H). Anal. calcd. for C13H9NOS (227.29): C, 68.70; H, 3.99; N,
6.16; S, 14.11. Found C, 68.62; H, 4.02; N, 6.05; S, 13.94.
General Method for a PTC Reaction of Thiol Derivative 6 With
Halo Compounds
A mixture of anhydrous potassium carbonate (5 g), dry DMF (25 mL),
compound 6 (5 mmol), the appropriate halo reagent (6 mmol), and TBAI
(0.6 g) was stirred in a boiling water bath for 4–6 h. The reaction mixture
was filtered off, and the filtrate was evaporated in vacuum. The solid
residue that was obtained was washed thoroughly with water, dried,
and crystallized from the proper solvent to give compounds 7, 8, 9, 10,
and 14.
Benzo[h]thieno[3,2-c]quinolin-11(10H)-one (7) was obtained ac-
cording to the previously discussed general method from compound 6
(1.14 g) and chloroacetaldehyde diethyl acetal (1.0 mL) and crystallized
from DMF. Yield 0.9 g (72%); m.p. 288–290◦C. IR (KBr):νmax 3245 (N–
H), 3120, 1644 cm–1 (C O); 1H NMR (200 MHz, DMSO-d6): δ 7.12–8.04
(m, 8H, Harom), 11.83 (b, 1H, N–H). Anal. calcd. for C15H9NOS (251.31):
C, 71.69; H, 3.61; N, 5.57; S, 12.76. Found C, 71.56; H, 3.49; N, 5.32; S,
12.50.
1-Phenylbenzo[h]thieno[3,2-c]quinolin-11(10H)-one (8) was
obtained according to the previously discussed general method from
compound 6 (1.14 g) and phenacyl bromide (1.22 g), and crystallized
from DMSO. Yield 1.23 g (75%); m.p. >300◦C. IR (KBr):νmax 3245 (N–
–1
1
H), 3120, 1644 cm (C O); H NMR (200 MHz, DMSO-d6): δ 6.79 (s,
1H, 2-H), 7.20–8.05 (m, 11H, Harom), 11.24 (b, 1H, N–H). Anal. calcd.

744
M. Abass
for C21H13NOS (327.41): C, 77.04; H, 4.00; N, 4.28; S, 9.79. Found C,
76.83; H, 3.93; N, 4.32; S, 9.66.
1-Aminobenzo[h]thieno[3,2-c]quinolin-11(10H)-one (9) was ob-
tained according to the previously discussed general method from com-
pound 6 (1.14 g) and chloroacetonitrile (0.4 mL) and crystallized from
dioxane. Yield 0.9 g (68%); m.p. >300◦C. IR (KBr):νmax 3224 (N–H),
–1
1
3145, 1654 cm (C O); H NMR (200 MHz, DMSO-d6): δ 6.04 (b, 2H,
NH2), 6.55 (s, 1H, 2-H), 7.18–7.99 (m, 6H, Harom), 10.88 (b, 1H, N–H).
Anal. calcd. for C15H10N2OS (266.32): C, 67.65; H, 3.78; N, 10.52; S,
12.04. Found C, 67.40; H, 3.64; N, 10.31; S, 11.84.
Ethyl [(2-Oxo-1,2-dihydrobenzo[h]quinolin-4-yl)sulfanyl] ac-
etate (10) was obtained according to the previously discussed gen-
eral method from compound 6 (1.14 g) and ethyl chloroacetate (0.7
mL), and crystallized from ethanol. Yield 1.31 g (84%); m.p. 208–210◦C.
–1
IR (KBr):νmax 3228 (N–H), 3142, 2940, 2885, 1725 (C O), 1643 cm
(C O); 1H NMR (200 MHz, DMSO-d6): δ 1.38 (t, 3H, OCH2CH ), 3.65 (s,
3
2H, S-CH2-CO), 4.21 (q, 2H, OCH CH3), 6.68 (s, 1H, 3-H), 7.15–8.06 (m,
2
6H, Harom), 10.90 (b, 1H, N–H). Anal. calcd. for C17H15NO3S (313.38):
C, 65.16; H, 4.82; N, 4.47; S, 10.23. Found C, 65.03; H, 4.76; N, 4.59; S,
10.15.
1-Hydroxybenzo[h]thieno[3,2-c]quinolin-11(10H)-one (11)
A mixture of the acetate ester 10 (1.57 g, 5 mmol) and PPA (5.0 g) was
heated at 180◦C for 1 h; after that the temperature was raised gradu-
ally to 200◦C for 1 h. The reaction mixture was left to cool to r.t. and was
poured onto crushed ice. The precipitate that was obtained was filtered
off and dissolved in excess aqueous sodium hydroxide (50 mL, 2N). The
alkaline solution was filtered off, and 2N hydrochloric acid was added
until the solution became acidic to litmus and then was left to settle
down for 2 h. The precipitate that was formed was filtered and crys-
tallized from anisole to yield 0.84 g (63%); m.p. >300◦C. IR (KBr):νmax
3324–2665 (N–H, O–H), 1643 cm–1 (C O); 1H NMR (200 MHz, DMSO-
d6): δ 6.43 (s, 1H, 2-H), 7.09–8.12 (m, 6H, Harom), 11.24 (b, 1H, N–H).
Anal. calcd. for C15H9NO2S (267.31): C, 67.40; H, 3.39; N, 5.24; S, 12.00.
Found C, 67.22; H, 3.41; N, 5.01; S, 11.75.
Ethyl 11-Oxo-10,11-dihydrobenzo[h]thieno[3,2-c]quinoline-2-
carboxylate (12)
A mixture of the acetate ester 10 (1.57 g, 5 mmol) and DMF-DMA
(0.8 mL, 6 mmol), in o-xylene (50 mL) was heated under reflux for 4
h. The reaction mixture was left to cool to r.t., and the precipitate that

Substituted Quinolinones, Part 10
745
was obtained was filtered off and recrystallized from DMF. Yield 1.42
g (88%); m.p. 245–246◦C. IR (KBr):νmax 3242 (N–H), 3045, 2992, 2934,
1727 (C O), 1649 cm–1 (C O); 1H NMR (200 MHz, DMSO-d6): δ 1.44 (t,
3H, OCH2CH ), 4.28 (q, 2H, OCH CH3), 6.98 (s, 1H, 3-H), 7.22-8.02 (m,
3
2
6H, Harom), 11.40 (b, 1H, N–H). Anal. calcd. for C18H13NO3S (323.37):
C, 66.86; H, 4.05; N, 4.33; S, 9.92. Found C, 66.64; H, 3.97; N, 4.42; S,
9.74.
1-Amino-11-oxo-10,11-dihydrobenzo[h]thieno[3,2-c]quinoline-
2-carbonitrile (14)
According to the previously discussed PTC general method, this com-
pound was obtained from compound 6 (1.14 g, 5 mmol) and 2-
bromomalononitrile (0.87 g, 6 mmol), and the product was crystallized
from DMF. Yield 1.15 g (79%); m.p. 290–291◦C. IR (KBr):νmax 3424,
3325 (NH2), 3145, 2224 (C N), 1646 (C O), 1628, 1612 cm–1; 1H NMR
(200 MHz, DMSO-d6): δ 6.15 (b, 2H, NH2), 7.32–8.09 (m, 6H, Harom),
11.23 (b, 1H, N–H). Anal. calcd. for C16H9N3OS (291.33): C, 65.97; H,
3.11; N, 14.42; S, 11.01. Found C, 65.62; H, 3.05; N, 14.30; S, 10.88.
2-(2-Oxo-1,2-dihydrobenzo[h]quinolin-4-yl)malononitrile (15)
To equimolar amounts (5 mmol) of chloroquinolinone 4 (1.15 g) and
malononitrile (0.35 g) in DMF (25 mL), anhydrous potassium carbonate
(4.18 g, 30 mmol) and TBAI (0.6 g) were added. The reaction mixture
was stirred in a boiling water bath for 6 h and then filtered off, and the
filtrate was evaporated in vacuum. The solid residue that was obtained
was washed thoroughly with cold water, dried, and crystallized from
dioxane to yield 0.91 g (70%); m.p. 266–267◦C. IR (KBr):νmax 3267 (N–
H), 3111, 2204, 2175 (C N), 1644 (C O), 1605 cm–1; H NMR (200
1
MHz, DMSO-d6): δ 5.80 (s, 1H, CH(CN)2), 6.80 (s, 1H, 3-H), 7.04–7.70
(m, 6H, Harom), 11.25 (b, 1H, N–H). Anal. calcd. for C16H9N3O (259.27):
C, 74.12; H, 3.50; N, 16.21. Found C, 74.11; H, 3.42; N, 16.09.
2-Amino-11-oxo-10,11-dihydrobenzo[h]thieno[2,3-c]quinoline-
3-carbonitrile (16)
To a solution of compound 15 (1.30 g, 5 mmol) in DMF (50 mL), contain-
ing triethyamine (0.3 mL, 2.1 mmol), elemental sulfur (0.16 g, 5 mmol)
was added. The reaction mixture was heated under reflux for 3 h. The
solid deposits that formed after cooling to r. t. were filtered, washed with
ethanol, dried, and crystallized from acetonitrile to yield 1.14 g (78%);
m.p. 287–288◦C. IR (KBr):νmax 3384, 3335 (NH2), 3145, 2218 (C N),

746
M. Abass
1
1652 (C O), 1620, 1604 cm–1; H NMR (200 MHz, DMSO-d6): δ 5.92
(b, 2H, NH2), 7.22–8.02 (m, 6H, Harom), 11.45 (b, 1H, N–H). Anal. calcd.
for C16H9N3OS (291.33): C, 65.97; H, 3.11; N, 14.42; S, 11.01. Found C,
65.90; H, 2.96; N, 14.23; S, 10.84.
1-Amino-12-oxo-3-thioxo-11,12-dihydro-3H-benzo[h]
thiopyrano[3,2-c]quinoline-2-carbonitrile (18)
To equimolar amounts (5 mmol) of the chloroquinolinone 4 (1.15 g),
malononitrile (0.35 g) in DMF (25 mL), carbon disulfide (0.3 mL), anhy-
drous potassium carbonate (4.18 g, 30 mmol), and TBAI iodide (0.6 g)
were added. The reaction mixture was stirred in a boiling water bath
for 4 h and then filtered off, and the filtrate was evaporated in vacuum.
The solid residue that was obtained was washed thoroughly with cold
water, dried, and crystallized from acetonitrile to yield 1.11 g (66%);
m.p. >300◦C. IR (KBr):νmax 3412, 3297 (NH2), 3121, 2225 (C N), 1638
(C O), 1618, 1604 cm–1; 1H NMR (200 MHz, DMSO-d6): δ 5.80 (s, 2H,
NH2), 7.14–7.95 (m, 6H, Harom), 11.03 (b, 1H, N–H). Anal. calcd. for
C17H9N3OS2 (335.41): C, 60.88; H, 2.70; N, 12.53; S, 19.12. Found C,
60.54; H, 2.61; N, 12.44; S, 19.05.
2-[(2-Oxo-1,2-dihydrobenzo[h]quinolin-4-yl)sulfanyl]benzoic
Acid (19)
To equimolar amounts (5 mmol) of the chloroquinolinone 4 (1.15 g)
and thiosalicylic acid (0.79 g), anhydrous potassium carbonate (4.18 g,
30 mmol) and TBAI (0.6 g) were added. The reaction mixture was stirred
in a boiling water bath for 4 h and then filtered, and the solid residue
that separated was dissolved in hot water (100 mL). The solution that
was obtained was acidified with diluted acetic acid tile for complete pre-
cipitation. The precipitate was filtered, washed with cold water, dried,
and crystallized from DMSO to yield 1.42 g (82%); m.p. >300◦C. IR
–1
(KBr):νmax 3435-2550 (br, COOH), 1712 (C O), 1648 (C O), 1606 cm
;
1H NMR (200 MHz, DMSO-d6): δ 6.80 (s, 1H, 3-H), 7.14–7.95 (m, 10H,
arom), 10.23 (b, 1H, N–H). Anal. calcd. for C20H13NO3S (347.40): C,
H
69.15; H, 3.77; N, 4.03; S, 9.23. Found C, 68.96; H, 3.65; N, 3.90; S, 9.05.
5,6-Dihydro-7H-benzo[h]thiochromeno[3,2-c]quinoline-6,7-
dione (20)
A mixture of acid 19 (1.74 g, 5 mmol) and PPA (5.0 g) was heated at
180◦C for 1 h; after that the temperature was raised gradually to 200◦C

Substituted Quinolinones, Part 10
747
for 1 h. The reaction mixture was left to cool to r.t. and poured onto
crushed ice. The precipitate that was formed was filtered and crystal-
lized from DMSO to yield 1.07 g (65%); m.p. 275–278◦C. IR (KBr):νmax
–1
3224 (N–H), 3125, 1688 (C O), 1642 cm (C O); 1H NMR (200 MHz,
DMSO-d6): δ 7.09–8.02 (m, 9H, Harom), 8.15 (d, 1H, 8-Harom) 11.41 (b,
1H, N–H). Anal. calcd. for C20H11NO2S (329.38): C, 72.93; H, 3.37; N,
4.25; S, 9.73. Found C, 73.02; H, 3.29; N, 4.22; S, 9.62.
Ethyl 3-Imino-12-oxo-11,12-dihydro-3H-benzo[h]thiopyrano
[3,2-c]quinoline-2-carboxylate (22)
A mixture of the compound 6 (1.14 g, 5 mmol) and ethyl 2-cyano-3-
ethoxyacrylate (1.0 g, 6 mmol), in dry DMF (25 mL), was heated under
reflux for 4 h. The reaction mixture was poured onto crushed ice, and
the precipitate that formed was filtered, dried, and crystallized from
absolute ethanol to yield 1.5 g (86%); m.p 268–287◦C. IR (KBr):νmax
3320 (N–H), 3225, 1719 (C O), 1645 (C O), 1622 cm–1 (C N); 1H NMR
(200 MHz, DMSO-d6): δ 1.23 (t, 3H, OCH2CH ), 4.19 (q, 2H, OCH CH3),
3
2
7.09–8.14 (m, 7H, Harom), 8.78 (s, 1H, NHimine), 10.56 (b, 1H, NHlactam).
Anal. calcd. for C19H14N2O3S (350.40): C, 65.13; H, 4.03; N, 7.99; S,
9.15. Found C, 64.97; H, 4.10; N, 7.86; S, 9.04.
Ethyl 3-Imino-2-methylsulfanyl-12-oxo-11,12-dihydro-3H-
benzo[h]thiopyrano[3,2-c]quinoline-2-carboxylate (24)
A mixture of the compound 6 (1.14 g, 5 mmol) and ethyl 2-cyano-
3,3-di(methylsulfanyl)acrylate (1.3 g, 6 mmol), in dry DMF (25 mL),
was heated under reflux for 4 h. The reaction mixture was left to cool
overnight, and the precipitate that formed was filtered, dried, and re-
crystallized from DMF/EtOH to yield 1.65 g (83%); m.p 291–293◦C.
–1
IR (KBr):νmax 3287 (N–H), 3204, 1722 (C O), 1639 (C O), 1621 cm
1
(C=N); H NMR (200 MHz, DMSO-d6): δ 1.24 (t, 3H, OCH2CH ), 2.63
3
(s, 3H, SCH3), 4.18 (q, 2H, OCH CH3), 7.11–8.05 (m, 6H, Harom), 8.62
2
(s, 1H, NHimine), 10.84 (b, 1H, NHlactam). Anal. calcd. for C20H16N2O3S2
(396.49): C, 60.59; H, 4.07; N, 7.07; S, 16.17. Found C, 60.40; H, 3.88; N,
6.95; S, 15.88.
Examination of the Effect on α-Amylase
The procedure of determination of the effect of the tested compounds
on α-amylase activity was based on measuring of the amount of α-D-
glucose (mg/L) that librated from enzymatic hydrolysis of starch using
the standard enzymatic glucose-oxidase method.18,19 The tests were

748
M. Abass
carried out on α-amylase enzyme produced by Thermomyces lanugi-
nosus, a thermophilic fungus which is grown on starch-containing sub-
stances. The tested samples were added as a DMF solution (0.1 mL,
100 μg/mL) to an assay mixture consisting of enzyme solution (0.5 mL),
citrate phosphate buffer (4.5 mL, pH = 5.0), containing 1% starch. Then
it was incubated at 40◦C for 30 min, and the released α-D-glucose was
determined on a Spekol-k colorimeter at λ = 505 nm. Tests were carried
out in triplicates, and the mean reading was recorded. A blank test was
prepared using distilled water instead of the enzyme, and it was used
for zero-setting of the colorimeter. A control test was prepared using
DMF without the addition of the candidate compounds.
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