Facile Synthesis and Anticancer Activity Study of Novel Series of Substituted and Fused Coumarin Derivatives

Article abstract of DOI:10.1002/jhet.3179

Various new substituted and fused coumarin analogues have been synthesized via different synthetic pathways. Among which are variable substituted coumarin derivatives bearing either biologically active side chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10, 12, 13, 16–19, 21, 23–32, 38, and 42–45. In addition, different pyranocoumarin derivatives either substituted as in compounds 2, 3, and 6 or fused as compounds 33–36, pyranoxanthene analogues such as compounds 4 and 46, coumarinotriazolothiadiazine derivative 8, coumarinonaphthodiazocin analogue 39 and coumarinopyrazolone derivative 40 were synthesized. Thirty-eight of the synthesized compounds were subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed that, among the tested compounds, compounds 16, 40, and 43 bearing 4-chlorophenyl-2-aminopyridine-3-carbonitrile attached to C₆ position, fused pyrazolone ring or attached to 4-chlorophenyl-2-oxo-dihydropyridine-3-carbonitrile at C₃ position of the coumarin nucleus, respectively, exhibited moderate to strong activity against both cell lines.

Full text of DOI:10.1002/jhet.3179

Month 2018
Facile Synthesis and Anticancer Activity Study of Novel Series of
Substituted and Fused Coumarin Derivatives
a
b
M. A. El Deeb,b*
c
b
A. Y. Hassan, M. T. Sarg,
A. H. Bayoumi, and S. I. El Rabeb
a
Organic Chemistry Department, Faculty of Science (Girls), Al-Azhar University, Cairo, Egypt
b
c
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls) Al-Azhar University, Cairo, Egypt
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys) Al-Azhar University, Cairo, Egypt
*
E-mail: adel-moshira@outlook.com
Received November 26, 2017
DOI 10.1002/jhet.3179
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Various new substituted and fused coumarin analogues have been synthesized via different synthetic path-
ways. Among which are variable substituted coumarin derivatives bearing either biologically active side
chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10, 12, 13,
1
6–19, 21, 23–32, 38, and 42–45. In addition, different pyranocoumarin derivatives either substituted
as in compounds 2, 3, and 6 or fused as compounds 33–36, pyranoxanthene analogues such as compounds
and 46, coumarinotriazolothiadiazine derivative 8, coumarinonaphthodiazocin analogue 39 and
4
coumarinopyrazolone derivative 40 were synthesized. Thirty-eight of the synthesized compounds were
subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma
MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed
that, among the tested compounds, compounds 16, 40, and 43 bearing 4-chlorophenyl-2-aminopyridine-3-
carbonitrile attached to C
dihydropyridine-3-carbonitrile at C
to strong activity against both cell lines.
6
position, fused pyrazolone ring or attached to 4-chlorophenyl-2-oxo-
3
position of the coumarin nucleus, respectively, exhibited moderate
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
RESULTS AND DISCUSSION
Coumarins and their derivatives comprise a class of
heterocyclic compounds of valuable medicinal
importance. Anticancer [1–3], antibacterial [4], antiviral
Chemistry. Literature survey revealed the significant
anticancer activity of different coumarin derivatives
against various cancer cell lines including HepG2 and
[5], anti-inflammatory [6], anticoagulant [7], acetyl, and
MCF7
cell
lines
[10–18].
Therefore,
Novel
butyryl cholinesterase inhibitory activity [8,9] are widely
reported biological activities of various coumarin
derivatives. Therefore, it was designed to synthesize
different novel substituted and fused coumarin derivatives
and investigate their anticancer activity.
pyranocoumarin-4-carboxylate derivative 2 was prepared
by fusion of the 5-hydroxycoumarin derivative 1 [19] and
dimethyl acetylenedicarboxylate (Scheme 1). The reaction
was suggested to proceed through the interaction of the
activated ortho position of the phenolic coumarin
©
2018 Wiley Periodicals, Inc.

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
Scheme 1. Reagents and conditions: (i) conc.H2SO4, R.T.; (ii) DMAD/fusion; (iii) citric acid/fusion; (iv) Dimedone, 4-chlorobenzaldehyde, piperdine,
C2H5OH/reflux; (v) piperidine, C2H5OH/reflux; (vi) DMSO/reflux; (vii) DMSO/reflux.
function and dimethyl acetylenedicarboxylate triple bond
with the subsequent intramolecular lactonization through
elimination of a methanol moiety. The IR spectrum of
compound 2 was devoid of the characteristic OH
absorption band of its precursor 1.
and 1.06 ppm attributed to the dihydropyranoxanthene-
C -(CH ) protons In addition, three singlet signals at δ
10
3 2
.
2.29, 2.70, and 5.03 ppm due to dihydropyranoxanthene-
C , C , and C protons, respectively, which were not
11
9
7
observed in its precursor compound 1.
Novel pyranocoumarin acetic acid derivative 3 was
obtained by fusion of equivalent amounts of 5-
hydroxycoumarin derivative 1 and citric acid. H NMR
Furthermore,
2-aminopyranocoumarin-3-carbonitrile
derivative 6 was prepared via the reaction of equivalent
amounts of the 2-(4-methoxybenzylidene)malononitrile 5
[21] and 5-hydroxy- coumarin derivative 1 in ethanol
1
spectrum of compound 3 revealed a singlet signal at δ
1
6.59 ppm attributed to the pyranocoumarin C3 proton
containing piperidine as a catalyst. H NMR spectrum of
which was not observed in its precursor compound 1.
Building up a xanthene moiety on the pyran ring in
compound 4 was carried out via the multicomponent
cyclocondensation of equimolar amounts of the
compound 6 displayed a deuterium oxide exchangeable
singlet signal at δ 3.89 ppm due to NH protons and a
2
singlet signal at
δ
4.03 ppm corresponding to
pyranocoumarin-C proton.
4
5
-hydroxycoumarin derivative 1, 4-chlorobenzaldehyde
The reaction of compound 1 with two equivalents of
4-amino-5-trifluromethyl-4H-1,2,4-triazole-3-thiol 7 [22]
in dimethyl sulfoxide under reflux condition led to the
novel coumarinotriazolothiadiazine 8 through the addition
of the bis(o-amino aryl)disulfide on the substituted
hydroxycoumarin accompanied by elimination of a water
molecule. The bis(o-aminoaryl) disulfide was cleaved and
intramolecular cyclization occurred (Fig. 1). The IR
spectrum of compound 8 showed two characteristic
absorption bands at 3427 and 1700 cm due to NH and
carbonyl functions, respectively.
5-Hydroxycoumarin derivative 1 upon heating under
reflux with one equivalent of 3-(4-chlorophenyl)-1H-
1,2,4-triazol-5-amine 9 [23] in dimethyl sulfoxide yielded
and dimedone in ethanol containing piperidine as a
catalyst. A conceivable mechanism for the formation of a
pyranoxanthene system was reported to proceed either
through the knoevenagel condensation between the
aldehyde and dimedone followed by Michael addition of
the α-position of the hydroxy group of the coumarin [20]
or through formation of the intermediate via the
nucleophilic addition of the activated α-position of the
hydroxycoumarin to the aldehyde followed by subsequent
Michael addition of the dimedone [4]. In both cases,
subsequent intramolecular cyclization afforded the
À1
1
corresponding pyranoxanthene derivative 4. The H NMR
spectrum of compound 4 revealed singlet signals at δ 0.87
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
Figure 1. Postulated mechanism for synthesis of compound 8.
the novel (1H-1,2,4-triazol-5-ylamino)coumarin derivative
a deuterium oxide exchangeable singlet signal at δ
12.87 ppm corresponding to OH proton.
1
1
0. The H NMR spectrum of compound 10 displayed
two deuterium oxide exchangeable singlet signals at δ
.12 and 12.24 ppm due to coumarin-C NH and triazole
In
addition,
5-hydroxycoumarin-6-carboxamidine
8
derivative 18 was prepared upon fusion of compund 1
and cyanamide through the nucleophilic addition of the
activated ortho position of the phenolic 5-hydroxy
5
NH protons, respectively.
Furthermore, cinnamoyl-5-hydroxycoumarin derivative
1
1
2 was obtained through fusion of equivalent amounts of
function to the cyano triple bond. H NMR spectrum of
1
cinnamoyl chloride 11 [24] and compound 1. H NMR
spectrum of compound 12 displayed two multiplet signals
at δ 6.56–6.60 and δ 7.07–7.14 due to the vinylic
protons, as well as a deuterium oxide exchangeable
singlet signal at δ 10.49 ppm due to OH proton.
compound 18 showed three deuterium oxide
exchangeable singlet signals at δ 2.53, 6.09, and
10.52 ppm due to NH2, imine NH, and OH protons,
respectively.
Moreover, refluxing equivalent amounts of compound 1
and 1,3-dichloroacetone in ethanolic sodium ethoxide
yielded 2-oxo-propoxycoumarin derivative 19 (Scheme 3).
Our scope was extended to study the anticancer activity
of different substituted coumarines, therefore, bis-
hydroxycoumarin derivative 13 was prepared via heating
The IR spectrum of compound 19 showed broad
À1
4
-methoxybenzaldehyde with two equivalents of 5-
absorption band at 3390 cm
due to tautomeric OH
1
hydroxycoumarin derivative 1 (Scheme 2). The H NMR
spectrum of compound 13 revealed two singlet signals
function, in addition to two characteristic absorption bands
À1
at 1722 and 1681 cm attributed to two carbonyl functions.
at δ 3.68 and 6.03 ppm corresponding to –OCH and
In
our
recent
study,
the
3
–
CH-(coumarin) protons, respectively.
The multicomponent reaction of the acetylcoumarin
chromenyloxyacetylthiosemicarbazide derivative 21 was
obtained by heating equivalent amounts of methyl
coumarinylacetate derivative 20 [25] and thiosemicarb-
2
derivative 15 [18], malononitrile, ammonium acetate, and
-chlorobenzaldehyde in ethanol under reflux condition
1
4
azide in pyridine under reflux. H NMR spectrum of
furnished the target 2-aminocoumarinylnicotinonitrile
derivative 16. The reaction mechanism was postulated to
proceed through initial formation of the coumarin
chalcone followed by the nucleophilic attack of
malononitrile on the chalcone double bond. Ammonium
acetate introduces a nitrogen atom and elimination of a
water molecule occurs followed by subsequent
intramolecular cyclization. The H NMR spectrum of
compound 16 displayed a deuterium oxide exchangeable
singlet signal at δ 7.28 ppm corresponding to OH and
compound 21 showed three deuterium oxide
exchangeable singlet signals at δ 6.81, 6.92, and
10.52 ppm due to NH and two NH protons, respectively.
2
In attempts to develop various side chains attached
to C5 of the coumarin nucleus, the potassium
hydrazincarbodithioate derivative 23 was prepared by
stirring equivalent amounts of the acid hydrazide
derivative 22 [25] and carbon disulfide in presence of
potassium hydroxide which was heated in absolute
ethanol to afford the target oxadiazolethione derivative
1
1
NH protons, in addition to a singlet signal at δ 7.46 ppm
24. H NMR spectrum of compound 24 displayed a
2
corresponding to the pyridine-C proton.
deuterium oxide exchangeable singlet signal at
6.47 ppm due to NH proton.
However, the target 1,3,4 thiadiazole derivative 25 was
obtained via stirring the potassium salt 23 with
concentrated sulfuric acid in ethanol at room temperature.
δ
5
The target 1,3-diketone derivative 17 was prepared via
heating an equimolar mixture of compound 15 and
benzoyl chloride in pyridine containing potassium
1
hydroxide. H NMR spectrum of compound 17 revealed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
Scheme 2. Reagents and conditions: (i) fusion; (ii) 4-methoxybenzaldehyde/fusion; (iii) AC2O/reflux; (iv) AlC13/fusion; (v) 4-chlorobenzaldehyde,
malononitrile, NH4OAc, C2H5OH/reflux; (vi) PhCOC1, KOH, pyridine/reflux; (vii) cyanamide/fusion.
1
H NMR spectrum of compound 25 displayed a deuterium
oxide exchangeable singlet signal at δ 12.99 ppm attributed
to NH proton.
exchangeable singlet signal at
tautomeric OH half proton.
The reaction of compound 22 with ethyl cyanoacetate by
heating under reflux in dimethyl formamide afforded the
δ
10.51 due to
Fusion of the potassium salt 23 with hydrazine hydrate
led to formation of 4-amino[1,2,4]triazole-5-thione
derivative 26. The IR spectrum of compound 26 revealed
absorption bands at 3394, 3356, 3336, and 1700 cm
attributed NH, NH , and carbonyl functions, respectively.
corresponding
amino
pyrazolyloxoethoxycoumarin
1
derivative 29. H NMR spectrum of compound 29
displayed two deuterium oxide exchangeable singlet
signals at δ 3.75 and 10.28 ppm corresponding to NH2
and OH protons, respectively. However, a singlet signal
À1
2
Furthermore,
coumarinyloxyhydroxyethylacetamide
derivative 27 was obtained by fusion of the methyl
coumarinylacetate derivative 20 with ethanolamine. IR
spectrum of compound 27 revealed broad absorption
appeared at 7.92 ppm due to pyrazole-C proton.
Furthermore, the target pyrazolyloxoethoxychromenone
derivative 30 was prepared by fusion of equivalent
amounts of the compound 22 and ethyl acetoacetate. H
4
À1
1
bands at 3421 and 3300 cm corresponding to OH and
NH functions, in addition to two absorption bands at
NMR spectrum of compound 30 revealed a singlet signal
À1
1743 and 1685 cm due to two carbonyl functions.
at δ 7.34 ppm attributed to pyrazole-C proton and a
4
Acetylacetone was utilized in the synthesis of
deuterium oxide exchangeable singlet signal at
δ
dimethyl pyrazolyloxoethoxycoumarinone derivative 28
10.49 ppm corresponding to OH proton.
via fusion with the acetohydrazide derivative 22
In addition, the target 3,5-dioxopyrazolidine derivative
1
(Scheme 4). H NMR spectrum of compound 28
31 was prepared by fusion of equivalent amounts of the
1
revealed two singlet signals at δ 2.52 and 2.58 ppm
corresponding to pyrazole-C3 and pyrazole-C5 CH3
protons, respectively, in addition to a deuterium oxide
acetohydrazide derivative 22 and diethyl malonate.
H
NMR spectrum of compound 31 displayed two deuterium
oxide exchangeable singlet signal at δ 9.61 and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
Scheme 3. Reagents and conditions: (i) 1,3-dichloroacetone, NaOC2H5, C2H5OH/reflux; (ii) methyl bromoacetate, K2CO3, acetone/reflux; (iii)
thiosemicarbazide, pyridine/reflux; (iv) NH2NH2 99%, C2H5OH/R.T.; (v) CS2, KOH, C2H5OH/R.T.; (vi) C2H5OH/reflux; (vii) conc.H2SO4,
C2H5OH, R.T.; (viii) NH2NH2 99%/fusion; (ix) ethanolamine/fusion.
1
0.23 ppm each integrated for half proton attributed to
nucleophilic attack of the lone pair of the formamide
amino group on the electrophilic nitrile carbon. IR
tautomeric OH and NH proton, respectively.
The acetohydrazide derivative 22 afforded its
corresponding acetyl benzohydrazide derivative 32 upon
fusion with one equivalent of benzoyl chloride. IR
spectrum of compound 34 revealed absorption bands at
À1
3309 and 3163 cm
absorption band at 1680 cm attributed to the carbonyl
function.
attributed to NH2 function and
À1
spectrum of compound 32 absorption bands at 1743,
À1
1680, and 1658 cm
attributed to the carbonyl
Furthermore, refluxing a mixture of compound 6 and
carbon disulfide in absolute ethanol containing potassium
hydroxide afforded pyranochromenopyrimidinedithione
derivative 35 (Fig.3). IR spectrum of compound 35
functions.
Iminopyranochromenopyrimidine-2-thione derivative
3 was synthesized by heating equimolar amounts of the
-aminopyranocoumarin-3-carbonitrile derivative 6 and
3
2
À1
showed absorption bands at 3390 and 3292 cm due to
À1
phenyl isothiocyanate in refluxing pyridine (Scheme 5).
IR spectrum of compound 33 revealed absorption bands
two NH functions and absorption band at 1654 cm
attributed to the carbonyl function.
À1
at 3380, 3360, and 1716 cm corresponding to two NH
Friedlander cyclocondensation [26] of compound 6 and
cyclohexanone in refluxing dimethyl formamide
containing anhydrous zinc chloride as a lewis acid atalyst
yielded the target tetrahydropyranochromenoquinoline
and the carbonyl functions, respectively, in addition to
À1
absorption bands at 1543, 1438, 1253, and 1029 cm
due to the four bands of –N–C═S function (Fig. 2).
In addition, the target 4-aminopyranochromenopyrimidine
derivative 34 was formed by refluxing compound 6 in
excesss formamide first through o-cyanoformamidine
formation followed by intramolecular cyclization via
1
derivative 36. H NMR spectrum of compound 36
displayed the tetrahydropyranochromenoquinoline-C8,9
and tetrahydropyranochromenoquinoline-C7,10 multiplets
at 1.19–1.29 and 1.55–1.72 ppm, respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
Scheme 4. Reagents and conditions: (i) acetylacetone/fusion; (ii) ethyl cyanoacetate, DMF/reflux; (iii) ethyl acetoacetate/fusion; (iv) diethyl malonate/
fusion; (v) PhCOC1/fusion.
Scheme 5. Reagents and conditions: (i) PhNCS, pyridine/reflux; (ii) excess formamide/reflux; (iii) CS2, KOH, C2H5OH/reflux; (iv) cyclohexanone,
ZnCl2, DMF/reflux.
Moreover, heating equimolar amounts of the ethyl ester
derivative 37 [27] and 5-bromosalicylaldehyde in absolute
ethanol containing a catalytic amount of potassium
hydroxide led to the formation of 2-formylphenylchromene-
3-carboxylate 38 (Scheme 6). H NMR spectrum of
compound 38 lacked signals due to ethyl ester protons.
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
Figure 2. Postulated mechanism for synthesis of compound 33.
However, it displayed a singlet signal at δ 7.81 ppm attributed
to CHO proton.
In our investigation, the target chromenonaphthodiazocine
derivative 39 was prepared by fusion of the ester derivative
3
7 with one equivalent of 1,8-diaminonaphthalene. IR
spectrum of compound 39 lacked the absorption band of
the coumarin carbonyl function and displayed absorption
À1
bands at 3446 and 3387 cm due to tautomeric OH and
NH functions, respectively, as well as absorption band at
À1
1
685 cm attributed to the amidic carbonyl function.
The reaction of equivalent amounts of compound 37 and
hydrazine hydrate in absolute ethanol yielded the
chromenopyrazolone derivative 40 via the initial
formation of the hydrazide intermediate which undergoes
subsequent intramolecular condensation to yield the
Figure 3. Postulated mechanism for synthesis of compound 35.
Scheme 6. Reagents and conditions: (i) pipridine, gl.AcOH, C2H5OH/reflux; (ii) 5-bromosalicylaldehyde, KOH, C2H5OH/reflux; (iii) 1,8-
diaminonaphthalene/fusion; (iv) NH2NH2 99%, C2H5OH/reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
cyclic compound 40. IR spectrum of compound 40 lacked
the absorption band characteristic for the coumarin
carbonyl functions and revealed absorption bands at 3383
Ethyl coumarin-2,4-dioxobutanoate derivative 44 was
prepared via Claisen condensation of equivalent amounts
of the acetylcoumarin derivative 41 and diethyl oxalate
by fusion. However, compound 44 upon reflux with
excess hydrazine hydrate yielded the pyrazole-3-
carbohydrazide analogue 45. IR spectrum of compound
À1
and 1685 cm due to NH and amidic carbonyl function,
respectively.
1
While the H NMR spectrum of compound 40 revealed
À1
a deuterium oxide exchangeable singlet signal at δ
44 showed absorption bands at 1732 and 1693 cm
11.10 ppm due to NH proton.
corresponding to carbonyl functions. While the IR
In continuation for our study of different C -substituted
spectrum of compound 45 showed absorption bands
3
À1
coumarin derivatives, we carried out the synthesis of the
oxiranylpropanoylcoumarin derivative 42 by refluxing
equimolar amounts of epichlorohydrin and acetylcoumarin
derivative 41 [28] in dimethylformamide in presence of
potassium hydroxide (Scheme 7). IR spectrum of
3390, 3367, and 3128 cm due NH and NH functions.
2
1
H NMR spectrum of compound 45 revealed three
deuterium oxide exchangeable singlet signals at δ 6.98,
7.11, and 7.23 ppm due to NH , amide NH, and pyrazole
2
NH protons, respectively.
compound 42 revealed absorption bands at 3402 and
In addition, pyranoxanthene derivative 46 was prepared
via refluxing equivalent amounts of the 5-
À1
1725 cm due to tautomeric OH and carbonyl functions,
respectively.
hydroxycoumarin derivative
1
and acetylcoumarin
However, the target coumarinylpyridinone-3-carbonitrile
derivative 43 was synthesized through the multicomponent
condensation reaction of the acetylcoumarin derivative 41,
derivative 41 in methanolic sodium methoxide (Fig. 4).
H NMR spectrum of compound 46 revealed a multiplet
1
signal at δ 2.68–2.73 ppm corresponding to CH proton,
2
ethyl
cyanoacetate,
4-chlorobenzaldehyde,
and
in addition to a deuterium oxide exchangeable singlet
signals at δ 2.27 ppm due to tautomeric OH half proton.
Finally, pentynoylcoumarin derivative 47 was prepared
1
ammonium acetate in refluxing ethanol. H NMR
spectrum of compound 43 revealed a singlet signal at
δ 7.00 ppm due to pyridine C5 proton and two
deuterium oxide exchangeable singlet signals at δ 8.15
and 9.80 ppm each integrated for half proton attributed
to tautomeric OH and NH proton, respectively.
via heating equimolar amounts of compound 41 and
1
propargyl bromide in ethanolic sodium ethoxide.
H
NMR spectrum of compound 47 displayed a singlet
signal at δ 2.25 ppm due to the terminal acetylenic
Scheme 7. Reagents and conditions: (i) piperidine, R.T.; (ii) epichlorohydrin, KOH, DMF/reflux; (iii) 4-chlorobenzaldehyde,ethyl cyanoacetat, NH4OAc,
C2H5OH/reflux; (iv) diethyl oxalate/fusion; (v) excess NH2NH2 99%/reflux; (vi) NaOCH3, CH3OH/reflux; (vii) propargyl bromide, NaOC2H5,
C2H5OH/reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
Figure 4. Postulated mechanism for synthesis of compound 46.
Table 1
Six dose growth inhibition percent and IC50 values of the tested compounds against HepG2 cell line.
Sample
Growth inhibition (%)
concentration
(
μg/mL)
Compound no.
500
79.18
250
125
62.5
31.25
15.6
10.49
0
0
IC50 (μg/mL)
1
2
3
4
6
8
65.75
5.35
54.36
1.27
41.81
0
8.53
7.69
63.51
3.63
1.28
38.46
6.96
75.44
56.09
23.61
9.33
15.81
14.77
61.11
0.24
23.77
11.51
7.55
8.57
7.64
27.37
0
103
>500
344
395
25.1
449
>500
112
16.14
69.11
63.07
81.24
58.28
37.51
74.29
68.46
91.98
85.53
70.58
57.82
76.06
80.22
91.66
24.86
78.63
63.26
68.22
59.35
57.04
71.66
61.84
69.35
89.76
86.18
88.64
70.39
38.58
31.83
76.98
17.94
15.29
61.82
30.38
87.69
76.11
56.09
31.04
61.37
64.74
84.02
12.02
67.94
39.08
35.71
36.82
27.18
30.88
53.62
51.74
78.61
71.24
79.42
51.71
21.04
15.35
71.09
10.72
7.65
53.05
14.87
81.33
62.75
38.52
18.52
32.72
31.53
72.88
5.88
40.82
25.83
18.34
20.96
14.81
11.53
21.96
20.38
69.18
60.92
68.21
20.87
2.75
1.56
57.65
0.59
0
25.81
1.22
67.21
35.46
14.58
1.75
7.63
5.98
30.75
0
10.43
5.93
1.37
1.24
1.29
0.22
4.87
2.58
35.82
14.78
38.73
7.65
0
38.07
0
0
16.94
0
61.28
18.55
8.65
0
1.96
2.76
12.69
0
5.88
2.38
0
0
0
0
1.28
0
21.35
6.86
27.87
1.38
10
12
13
16
17
18
19
21
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
379
7.65
53.3
207
427
200
195
51.1
>500
167
363
360
396
441
367
236
243
54.6
106
52.4
243
5.84
13.59
9.87
54.77
25.83
55.37
13.96
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
Table 1
(
Continued)
Sample
Growth inhibition (%)
concentration
(
μg/mL)
Compound no.
500
84.17
250
125
62.5
31.25
15.6
10.88
61.93
52.74
9.64
50.36
1.41
0
IC50 (μg/mL)
39
40
41
42
43
44
45
46
47
75.94
87.66
84.11
61.69
84.17
37.09
29.84
79.02
87.06
95.69
67.21
83.72
76.39
50.35
76.28
24.15
15.09
73.83
75.39
93.25
51.84
77.37
68.28
31.52
67.03
16.83
7.63
65.42
65.44
87.61
27.13
68.02
59.46
18.36
61.59
7.24
60.2
6.89
13.6
124
15.5
360
93.04
90.53
82.18
90.86
66.38
63.75
85.94
94.63
96.92
0.52
399
51.67
52.32
77.02
36.52
27.61
68.13
29.5
29.7
3.67
Cisplatin
Table 2
Six dose growth inhibition percent and IC50 values of the tested compounds against MCF7 cell line.
Sample
Growth inhibition (%)
concentration
(
μg/mL)
Compound no.
500
75.43
250
125
62.5
31.25
15.6
4.53
0
0
0
7.51
0
IC50 (μg/mL)
1
2
3
4
6
8
61.53
2.15
47.07
0
18.02
8.57
51.37
3.93
0.79
25.62
45.04
77.63
54.78
30.59
27.82
26.06
60.38
76.09
5.97
29.18
0
9.33
1.33
37.66
0.16
13.85
0
1.96
0
21.85
0
0
8.26
8.52
61.25
18.57
4.87
3.59
1.94
18.53
32.18
0
150
>500
382
484
119
>500
>500
299
162
23.8
111
264
212
215
60.5
48.3
>500
224
>500
236
385
57
382
495
399
148
97
7.63
63.51
51.94
69.18
27.19
14.86
63.11
79.58
90.38
78.64
61.27
78.26
70.52
86.15
93.72
35.19
69.75
40.33
68.46
62.11
91.69
73.03
50.48
58.33
72.14
89.26
82.11
61.26
73.66
91.25
91.21
78.4
34.88
20.72
60.25
10.48
6.13
10
12
13
16
17
18
19
21
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
0
0
46.79
61.83
85.44
65.82
49.32
59.63
59.15
71.26
85.64
19.38
57.41
18.52
52.72
35.85
83.24
24.38
25.81
37.66
60.33
78.13
73.57
43.15
62.19
85.11
81.96
63.43
82.18
30.12
52.87
14.87
19.37
69.58
32.71
11.28
10.44
10.85
52.11
64.77
0.24
9.33
1.24
10.96
5.92
54.98
4.64
2.02
1.24
37.62
9.33
1.08
0
0
4.78
15.84
0
0
0
0.53
0
10.3
0
0
0
7.94
5.82
13.59
0
8.58
53.22
38.68
1.28
29.41
0
21.88
3.77
1.87
0
28.04
13.77
67.52
13.77
10.47
18.05
47.66
65.38
59.15
18.58
54.81
77.64
73.25
25.72
73.27
12.79
29.71
3.77
0.35
26.71
0.58
0.59
1.48
15.69
20.44
29.08
2.02
20.44
60.47
50.75
5.74
52.75
0.14
4.78
3.22
7.63
29.15
31.07
47.12
7.63
37.62
68.16
61.59
12.85
64.72
2.96
77.5
345
108
14
30.2
205
29.4
401
235
89.06
63.08
67.44
13.88
0.53
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
Table 2
(
Continued)
Sample
Growth inhibition (%)
concentration
(
μg/mL)
Compound no.
500
83.21
90.17
96.28
250
125
62.5
31.25
15.6
28.76
17.57
65.38
IC50 (μg/mL)
4
4
6
7
76.25
79.52
95.02
71.44
72.31
92.17
60.37
60.15
85.32
47.62
39.29
76.21
37.1
47.3
5.71
Cisplatin
proton and a multiplet due to two CH2 protons at δ
chain attached to C position of the coumarine backbone
6
3
.20–3.58 ppm.
Anticancer screening. Thirty eight of the synthesized
exhibited nearly half potency of the reference drug
Cisplatin against HepG2 cell line and good anticancer
activity against MCF7 cell line. Moreover, attachment of
4-chlorophenyl-2-hydroxypyridine-3-carbonitrile moiety
compounds were subjected to in vitro anticancer
screening and six dose growth inhibition percent and IC50
values were calculated against mammalian hepatocellular
carcinoma HepG2 and breast carcinoma MCF7 cell lines.
Cytotoxicity evaluation using viability assay [29,30] was
carried out in the Regional Center for Mycology and
Biotechnology, Al-Azhar University, Cairo, Egypt. Cis-
platin was used as the reference drug in this study.
at C position of coumarin skeleton as in compound 43
3
resulted in strong activity against HepG2 and moderate
activity against MCF7 cell lines, respectively. However,
other substituted coumarin derivatives showed either very
weak potency or inactivity against both cancer cell line.
As revealed from the anticancer screening results
presented in Tables 1 and 2, the 5-hydroxycoumarin
derivative 1 did not exhibit anticancer activity against
HepG2 and MCF7 cell lines. However, fusion of
substituted pyran ring to the 5-hydroxycoumarin
backbone as in compounds 2, 3, and 6 showed only weak
anticancer activity of compound 6 against liver cancer
HepG2 cell line. While attachment of another chromene
nucleus to the coumarin backbone as in compounds 4 and
CONCLUSIONS
It could be concluded that, among the tested compounds,
compound 16, 40, and 43 bearing 2-amino-4-(4-
chlorophenyl)nicotinonitrile side chain attached to C6
position, fused pyrazolone ring or 4-(4-chlorophenyl)-2-
oxo-1,2-dihydropyridine-3-carbonitrile
side
chain
attached at C3 position of the coumarin backbone,
respectively, exhibited moderate to highly potent
anticancer activity against both HepG2 with IC50 values
6.89–15.5 μg/mL and MCF7cell lines with IC50 values
14–29.4 μg/mL.
46 led only to the moderate to weak anticancer agent 46
against both cell lines. However, triazolothiadiazine
moiety attached to the 5-hydroxycoumarin skeleton as in
compound 8 diminished the anticancer activity against
both cell lines. Structure modification of the moderately
active pyranocoumarin derivative 6 by fusion with
different substituted pyrimidine rings as in compounds
EXPERIMENTAL
33–35 or tetrahydroquinoline as in compound 36 was
found to diminish the anticancer activity against both
HepG2 and MCF7 cell lines. Furthermore, attachement of
a naphthodiazinone moiety to the chromene back bone led
to very weak anticancer activity against both cell lines.
However, fusion of substituted pyrazolone nucleus to the
coumarin backbone in compound 40 led to highly potent
anticancer activity against HepG2 cell line which showed
nearly half potency of the reference drug Cisplatin and
strong anticancer activity against MCF7 cell line. Finally,
our attempts were extended to study the anticancer
activity of compounds having different side chains or
rings attached at 5, 6, or 3 positions of the coumarin
nucleus as in compounds 10, 12, 13, 16–19, 21, 23–32,
Chemistry. All melting points were taken on Electro
thermal LA 9000 SERIS, Digital Melting Point
Apparatus and were uncorrected. IR Spectra were
determined using KBr disk technique on Nikolet IR 200
FT IR Spectrophotometer at Pharmaceutical Analytical
Unit, Faculty of Pharmacy, Cairo University, and values
are represented in cm . The H NMR Spectra was
recorded in Varian Gemini EM-300 MHz, NMR
Spectrometer at laboratories of the nuclear magnetic
resonance, Chemical Warfare Department, Ministry of
À1
1
Defense, DMSO-d was used as a solvent and Chemical
6
shifts were measured in δ ppm, relative to TMS as
internal standard. Mass Spectra were recorded at 70 ev
on DI-50 unit of Schimadzu GC/MS-QP5050A
Spectrometer at Regional Center for Mycology and
38, and 42–45. It has been revealed that only compound
6 bearing 2-amino-4-(4-chlorophenyl)nicotinonitrile side
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
(s,
Biotechnology, Al-Azhar University. Microanalyses were
dihydropyranoxanthene-C –CH );
2.70
6
3
carried out at Regional Center for Mycology and
2H, dihydropyranoxanthene-C –H); 5.03 (s, 1H,
9
Biotechnology, Al-Azhar University.
dihydropyranoxanthene-C –H);
6.33
7.06
(s,
(s,
1H,
1H,
7
Methyl 5,10-dimethyl-2,8-dioxo-2H,8H-pyrano[3,2-e]chromen-
dihydropyranoxanthene-C –H);
2
4
1
(
5
-carboxylate (2). A mixture of 5-hydroxycoumarin derivative
(0.19 g, 1 mmol) and dimethyl acetylenedicarboxylate
0.21 g, 0.18 mL, 1.5 mmol) was fused at 200–210°C for
h. The reaction mixture was allowed to cool then
dihydropyranoxanthene-C –H); 7.19 (d, 2H, J = 8 Hz,
5
4
-Cl–C H –C –H); 7.29 (d, 2H, J = 8 Hz, 4-Cl–
6 4 2,6
C H –C –H).
6
4
3,5
2
-Amino-5,10-dimethyl-4-(4-methoxyphenyl)-8-oxo-4H-pyrano
[2,3-f]chromen-3-carbonitrile (6). An equimolar mixture of
compound (0.19 g, mmol) and 2-(4-
triturated with ethanol. The obtained precipitate was
filtered, washed with ethanol, dried, and crystalized from
ethanol/acetone mixture (3:1) to yield compound 2.
Brown powder; yield: 0.25 g (83%); m.p.: >300°C. Anal.
Calcd. (%) for C H O (300.26): C, 64.00; H, 4.03.
1
1
methoxybenzylidene)malononitrile 5 (0.18 g, 1 mmol)
was heated under reflux in absolute ethanol (20 mL) in
presence of a catalytic amount of piperidine (3 drops)
for 3 h. The reaction mixture was left to cool, the
obtained precipitate was filtered, washed with ethanol,
and crystallized from ethanol to yield compound 6.
Yellow crystals; yield: 0.13 g (35%); m.p.: 260-262°C.
Anal. Calcd. (%) for C H N O (374.39): C, 70.58; H,
1
6 12 6
À1
Found (%): C, 64.36; H, 3.96. IR (KBr, cm ): 3003,
954 (CH-aromatic); 2848 (CH-aliphatic); 1735, 1720
2
+.
(
1
C═O); 1560 (C═C). Mass spectrum, m/z (%): 300 (M ,
+.
.67); 299 (M À1, 6.2); 43(100).
5,10-Dimethyl-2,8-dioxo-2H,8H-pyrano[3,2-e]chromen-4-acetic
22 18 2 4
acid (3). An equimolar mixture of compound 1 (0.19 g,
4
.85; N, 7.48. Found (%): C, 70.81; H, 4.92; N, 7.76.
1
2
mmol) and citric acid (0.19 g, 1 mmol) was fused at
00–210°C for 3 h. The reaction mixture was allowed to
À1
IR (KBr, cm ): 3444, 3390 (NH ); 3068, 3051, 3030
2
(CH-aromatic); 2929, 2820 (CH-aliphatic); 2222 (CN);
cool, then triturated with ethanol, the precipitated solid
was filtered, washed with ethanol, and crystallized from
dimethyl formamide to yield compound 3. Dark brown
powder; yield: 0.09 g (30%); m. p.: > 300°C. Anal.
Calcd. (%) for C H O (300.26): C, 64.00; H, 4.03.
1
1690 (C═O); 1604 (C═C). H NMR (DMSO-d , δ
6
ppm): 2.28 (s, 3H, pyranocoumarin-C –CH ); 2.55 (s,
1
0
3
3
H, pyranocoumarin-C –CH ); 3.25 (s, 3H, OCH , under
5 3 3
DMSO); 3.89 (s, 2H, NH , D O exchangeable); 4.03 (s,
2
2
1
6 12 6
1H,
pyranocoumarin-C -H);
6.03
(s,
1H,
4
À1
Found (%): C, 63.95; H, 4.11. IR (KBr, cm ): 3406
broad OH); 3070, 2924 (CH-aromatic); 2854 (CH-
aliphatic); 1720, 1700, 1674 (C═O); 1616 (C═C); 1273,
pyranocoumarin-C –H); 6.58 (s, 1H, pyranocoumarin-C –
9
6
(
H); 7.18 (d, 2H, J = 8.5 Hz, 4-OCH –C H –C –H);
3
6
4
3,5
7
.98 (d, 2H, J = 8.5 Hz, 4-OCH –C H –C –H).
3 6 4 2,6
1
1
3
087 (C–O–C). H NMR (DMSO-d , δ ppm): 2.25 (s,
6
1,6-Dimethyl-10-(trifluoromethyl)chromeno[5,6-e][1,2,4]triazolo
[3,4-b][1,3,4]thiadiazin-3(12H)-one (8).
H, pyranocoumarin-C –CH ); 2.50–2.53 (m, 5H,
A mixture of
5
3
pyranocoumarin-C –CH
3
&
CH2); 6.02 (s, 1H,
compound 1 (0.19 g, 1 mmol) and the amino triazole
derivative 7 (0.37 g, 2 mmol) was heated under reflux in
dimethylsulfoxide (15 mL) for 10 h. The precipitated
solid was filtered while hot, washed with various
solvents, and dried to yield compound 8. Dark brown
powder; yield: 0.3 g (86%); m. p.: >300°C. Anal. Calcd.
1
0
pyranocoumarin-C –H); 6.55 (s, 1H, pyranocoumarin-
9
C –H); 6.59 (s, 1H, pyranocoumarin-C –H); 10.49 (s,
6
3
1
3
H, OH, D O exchangeable). Mass spectrum, m/z (%):
2
00 (M , 1.38); 162 (100).
7
+.
-(4-Chlorophenyl)-1,6,10,10-tetramethyl-10,11-dihydropyrano
2,3-c]xanthene-3,8(7H,9H)-dione (4). An equimolar mixture
of compound 1 (0.19 g, 1 mmol), dimedone (0.14 g,
mmol), and 4-chlorobenzaldehyde (0.14 g, 1 mmol) in
[
(
%) for C H F N O S (354.31): C, 47.46; H, 2.56; N,
14 9 3 4 2
1
5.81; S, 9.05. Found (%): C, 47.69; H, 2.54; N, 16.07;
1
À1
S, 9.17. IR (KBr, cm ): 3427 (NH); 2924 (CH-
absolute ethanol (20 mL) was heated under reflux in
presence of a catalytic amount of piperidine (2 drops) for
aromatic); 2852, 2810 (CH-aliphatic); 1700 (C═O); 1618
(
(
C═N); 1570 (C═C). Mass spectrum, m/z (%): 356
12 h. The reaction mixture was left to cool, the obtained
+.
+.
M +2, 3.95); 354 (M , 7.35); 55 (100).
precipitate was filtered, washed with ethanol, and
crystallized from ethanol to yield compound 4. Yellow
crystals; yield: 0.15 g (35%); m.p.: 253-255°C. Anal.
Calcd. (%) for C H ClO (434.91): C, 71.80; H, 5.33.
5-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-ylamino)-4,7-dimethyl-
2H-chromen-2-one (10).
A mixture of compound 1
(0.19 g, 1 mmol) and the aminotriazole derivative 9
(0.19 g, 1 mmol) was heated under reflux in dimethyl
sulfoxide (15 mL) for 10 h. The reaction mixture was
allowed to cool, then triturated with ethanol. The
precipitated solid was filtered, washed with various
solvents, and dried to yield compound 10. Yellow
powder; yield: 0.08 g (22%), m.p.: >300°C. Anal. Calcd.
(%) for C H ClN O (366.8): C, 62.21; H, 4.12; N,
26
23
4
À1
Found (%): C, 72.07; H, 5.35. IR (KBr, cm ): 3070,
3061, 3045 (CH-aromatic); 2922, 2899 (CH-aliphatic);
1
1716, 1666 (C═O); 1614, 1591 (C═C). H NMR
(DMSO-d6,
δ
ppm):
0.87
1.06
2.18
2.29
(s,
(s,
(s,
(s,
3H,
3H,
3H,
2H,
3H,
dihydropyranoxanthene-C –CH );
10
3
dihydropyranoxanthene-C –CH );
10
3
19 15
4 2
dihydropyranoxanthene-C –CH );
15.27. Found (%): C, 62.44; H, 4.20; N, 15.56. IR (KBr,
1
3
À1
dihydropyranoxanthene-C –H);
2.63
(s,
cm ): 3400, 3240 (NH); 3060, 2932 (CH-aromatic);
11
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
2
1
880, 2840 (CH-aliphatic); 1700 (C═O); 1600 (C═N);
absolute ethanol (20 mL) for 30 h. The reaction mixture
was left to cool and poured onto crushed ice; the
obtained precipitate was filtered, washed with water, dried,
and crystallized from ethanol to yield compound 16.
Brown powder; yield: 1.5 g (72%); m.p.: 228–230°C.
Anal. Calcd. (%) for C H ClN O (417.84): C, 66.11; H,
1
570 (C═C). H NMR (DMSO-d , δ ppm): 1.23 (s, 3H,
6
coumarin-C –CH ); 2.03 (s, 3H, coumarin-C –CH );
4
3
7
3
7
4
.55–7.70 (m, 3H, coumarin-C3,6,8–H); 7.92–8.00 (m,
H, 4-Cl–C H ); 8.12 (s, 1H, coumarin-C –NH, D O
6
4
5
2
exchangeable); 12.24 (s, 1H, triazole-NH, D O
exchangeable). Mass spectrum, m/z (%): 368 (M +2,
2
23 16
3 3
+.
3.86; N, 10.06. Found (%): C, 66.42; H, 3.89; N, 10.40.
+.
À1
1.80); 366 (M , 3.59); 71 (100).
IR (KBr, cm ): 3428 (OH); 3342, 3214 (NH ); 3000,
2
6
12).
-Cinnamoyl-5-hydroxy-4,7-dimethyl-2H-chromen-2-one
2950 (CH-aromatic); 2880, 2860 (CH-aliphatic);
2205 (CN); 1700 (C═O); 1638 (C═N); 1549 (C═C). H
1
(
An equimolar mixture of compound 1 (0.19 g,
1
mmol) and cinamoyl chloride 11 (0.17 g, 1 mmol) was
NMR (DMSO-d , δ ppm): 1.23 (s, 3H, coumarin-C –
6
4
fused at 190–205°C for 10 h. The reaction mixture was
allowed to cool, then triturated with ethanol and the
obtained solid was filtered, washed with ethanol, dried,
and crystallized from dimethyl formamide to yield
compound 12. Dark brown powder; yield: 0.1 g (31%); m.
p.: >300°C. Anal. Calcd. (%) for C H O (320.34): C,
CH ); 2.30 (s, 3H, coumarin-C –CH ); 6.90 (s, 1H,
3 7 3
coumarin-C –H); 7.28 (s, 3H, OH & NH , D O
3
2
2
exchangeable); 7.36 (s, 1H, coumarin-C –H); 7.46 (s, 1H,
8
pyridinyl-C –H); 7.50 (d, 2H, J = 8.7 Hz, 4-Cl–C H –
5
6 4
C3,5–H); 7.58 (d, 2H, J = 8.7 Hz, 4-Cl–C H –C –H).
6
4
2,6
+.
+.
Mass spectrum, m/z (%): 419 (M +2, 1.77); 417 (M ,
2
0 16 4
7
4.99; H, 5.03. Found (%): C, 75.23; H, 5.08. IR (KBr,
4.43); 81 (100).
À1
cm ): 3427 (broad OH); 3000, 2990 (CH-aromatic);
1
-(5-Hydroxy-4,7-dimethyl-2oxo-2H-chromen-6-yl)-3-
1
2924 (CH-aliphatic); 1732, 1716 (C═O); 1614 (C═C). H
phenylpropane-1,3-dione (17). Equimolar amounts of
NMR (DMSO-d , δ ppm): 2.21 (s, 3H, coumarin-C –
compound 15 (0.23 g, 1 mmol) and benzoyl chloride
(0.14 g, 0.12 mL, 1 mmol) were heated under reflux in
pyridine (15 mL) in presence of potassium hydroxide
(0.084 g, 1.5 mmol) for 10 h. The reaction mixture was
left to cool and poured onto crushed ice; the obtained
precipitate was filtered, washed with water, dried, and
recrystallized from hexane to yield compound 17. White
crystals; yield: 0.25 g (74%); m.p.:136–138°C. Anal.
Calcd. (%) for C H O (336.34): C, 71.42; H, 4.79.
6
4
CH ); 2.27 (s, 3H, coumarin-C –CH ); 6.02 (s, 1H,
3
7
3
coumarin-C –H); 6.32 (s, 1H, coumarin-C –H); 6.56–6.60
3
8
(
m, 1H, –CH═CH–C H ); 7.07–7.14 (m, 1H, –CH═CH–
6 5
C H ); 7.20–7.40 (m, 3H, C H –C3,4,5–H); 7.42–7.59 (m,
6
5
6 5
2
H, C H –C –H); 10.49 (s, 1H, OH, D O exchangeable).
6 5 2,6 2
+
.
Mass spectrum, m/z (%): 320 (M , 3.75); 44 (100).
‚
6
,6 -((4-Methoxyphenyl)methylene)bis(5-hydroxy-4,7-dimethyl-
2H-chromen-2-one) (13). A mixture of compound 1 (0.38 g,
20 16 5
À1
2
1
mmol) and 4-methoxybenzaldehyde (0.14 g, 0.13 mL,
mmol) was fused at 200–210°C for 5 h. The reaction
Found (%): C, 71.68; H, 4.87. IR (KBr, cm ): 3400
(broad OH); 3070, 3012, 2956 (CH-aromatic); 2883,
2837 (CH-aliphatic); 1710, 1685 (C═O); 1610 (C═C).
mixture was allowed to cool, then triturated with ethanol.
The precipitated solid was filtered, washed with ethanol,
dried, and crystallized from dimethyl formamide to yield
compound 13. Dark brown powder; yield: 0.4 g (40%); m.
p.: >300°C. Anal. Calcd. (%) for C H O (498.52): C,
1
H NMR (DMSO-d , δ ppm): 1.23 (s, 3H, coumarin-C –
6
4
CH ); 2.40 (s, 3H, coumarin-C –CH ); 3.27 (s, 2H, CH ,
3
7
3
2
under DMSO); 7.40–7.56 (m, 2H, coumarin-C3,8–H);
7.59–7.64 (m, 3H, C H –C3,4,5–H); 7.91 (d, 2H,
30
26
7
6 5
7
2.28; H, 5.26. Found (%): C, 72.49; H, 5.34. IR (KBr,
J = 8.1 Hz, C H –C –H); 12.87 (s, 1H, OH, D O
6 5 2,6 2
+.
À1
cm ): 3406 (broad OH); 3066, 2951 (CH-aromatic);
exchangeable). Mass spectrum, m/z (%): 337 (M +1,
1
+.
2927, 2860 (CH-aliphatic); 1720 (C═O); 1604 (C═C). H
3.43); 336 (M , 10.78); 71 (100).
NMR (DMSO-d , δ ppm): 1.16 (s, 6H, two coumarin-C –
6
4
5-Hydroxy-4,7-dimethyl-2-oxo-2H-chromene-6-carboxamidine
CH ); 2.26 (s, 6H, two coumarin-C –CH ); 3.68 (s, 3H,
(18).
An equimolar mixture of compound 1 (2.35 g,
3
7
3
OCH ); 6.03 (s, 1H, -CH-(coumarin)); 6.56 (s, 2H, two
12.4 mmol) and cyanamide (1.04 g, 24.8 mmol) was
fused at 200–210°C for 12 h. The reaction mixture was
allowed to cool, then triturated with ethanol and the
obtained solid product was filtered, washed with ethanol,
dried, and crystallized from dimethyl formamide to yield
compound 18. Brown powder; yield: 1.9 g (66%); m.p.:
>300°C. Anal. Calcd. (%) for C H N O (232.24): C,
3
coumarin-C –H); 6.60 (s, 2H, two coumarin-C –H); 6.98–
3
8
7.05 (m, 2H, 4-OCH –C H –C3‚5–H); 7.41–7.60 (m, 2H,
3 6 4
4
-OCH –C H –C2‚6–H); 10.14 (s, 1H, OH, D O
3
6
4
2
exchangeable); 10.51 (s, 1H, H-bonded-OH, D O
2
+.
exchangeable). Mass spectrum, m/z (%): 498 (M , 1); 162
(100).
12 12 2 3
6
2.06; H, 5.21; N, 12.06. Found (%): C, 62.23; H, 5.27;
2
-Amino-4-(4-chlorophenyl)-6-(5-hydroxy-4,7-dimethyl-2-oxo-
À1
2
H-chromen-6-yl)nicotine-nitrile (16).
A mixture of 6-
N, 12.19. IR (KBr, cm ): 3417 (OH); 3334, 3200, 3130
acetyl-5-hydroxy-coumarin derivative 15 (1.16 g,
mmol), malononitrile (0.33 g, mmol), 4-
(NH & NH ); 1680 (C═O); 1622 (C═N); 1548 (C═C).
2
1
5
5
H NMR (DMSO-d , δ ppm): 1.90 (s, 3H, coumarin-C –
6
4
chlorobenzaldehyde (0.7 g, 5 mmol), and ammonium
CH ); 2.27 (s, 3H, coumarin-C –CH ); 2.53 (s, 2H, NH ,
3 7 3 2
acetate (0.77 g, 10 mmol) was heated under reflux in
D O exchangeable); 6.04 (s, 1H, coumarin-C –H); 6.09
2 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
(
s, 1H, imine NH, D O exchangeable); 6.57 (s, 1H,
filtered while hot and the filtrate was concentrated. The
filtrate was allowed to stand overnight to yield a
precipitate that was collected, washed with ethanol,
dried, and crystallized from dimethyl formamide to
yield compound 24. White powder, yield: 0.12 g (40%);
m.p.: >300°C. Anal. Calcd. (%) for C H N O S
2
coumarin-C –H); 10.52 (s, 1H, OH, D O exchangeable).
8
2
5
-(3-Chloro-2-oxopropoxy)-4,7-dimethyl-2H-chromen-2-one
(19).
An equimolar mixture of compound 1 (0.19 g,
mmol) and 1,3-dichloroacetone (0.13 g, 1 mmol) was
1
heated under reflux in ethanolic sodium ethoxide
prepared by dissolving (0.05 g, 2 mmol) of sodium
14 12 2 4
[
(
5
2
304.32): C, 55.25; H, 3.97; N, 9.21. Found (%): C,
5.38; H, 4.11; N, 9.43. IR (KBr, cm ): 3250 (NH);
958, 2927 (CH-aromatic); 2885 (CH-aliphatic); 1720
À1
metal in 5 mL ethanol] for 24 h. The reaction mixture
was allowed to cool, then poured onto crushed ice. The
formed precipitate was filtered, washed with water, dried,
and crystallized from toluene/ethanol mixture (3:1) to
yield compound 19. Brown powder; yield: 0.15 g (54%);
(
9
C═O); 1620 (C═N); 1570 (C═C); 1570, 1492, 1296,
41 (I, II, III, IV bands of N–C═S). H NMR (DMSO-
1
d , δ ppm): 1.69 (s, 3H, coumarin-C –CH ); 2.35 (s, 3H,
6
4
3
m.p.: > 300°C. Anal. Calcd. (%) for C H ClO
1
4
13
4
coumarin-C –CH ); 5.15 (s, 2H, CH ); 6.12 (s, 1H,
7 3 2
(280.70): C, 59.90; H, 4.67; Found (%): C, 60.27; H,
coumarin-C –H); 6.47 (s, 1H, NH, D O exchangeable);
3
2
À1
4
.78. IR (KBr, cm ): 3390 (broad OH); 2960, 2926
6
.82 (s, 1H, coumarin-C –H); 6.95 (s, 1H, coumarin-C –
6 8
+.
(CH-aromatic); 2854 (CH-aliphatic); 1722, 1681 (C═O);
H). Mass spectrum, m/z (%): 305 (M +1, 2.49); 304
+.
+.
1
8
620 (C═C). Mass spectrum, m/z (%): 282 (M +2, 0.
(M , 6.32); 162 (100).
+.
5); 280 (M , 4.58); 78 (100).
4,7-Dimethyl-5-((5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)
1
-(2-(4,7-Dimethyl-2-oxo-2H-chromen-5-yloxy)acetyl)
methoxy)-2H-chromen-2-one (25). Compound 23 (0.38 g,
1 mmol) was stirred at room temperature for 20 h in
absolute ethanol/concentrated sulfuric acid mixture (8:2)
(10 mL). The reaction mixture was poured onto distilled
water and the obtained precipitate was filtered, washed
with water, dried, and crystallized from dimethyl
formamide to yield compound 25. White powder; yield:
0.22 g (69%); m.p.: >300°C. Anal. Calcd. (%) for
C H N O S (320.39): C, 52.48; H, 3.78; N, 8.74.
thiosemicarbazide (21).
An equimolar mixture of the
methyl acetate derivative 20 (0.26 g, 1 mmol) and
thiosemicarbazide (0.09 g, 1 mmol) was heated under
reflux in pyridine (15 mL) for 5 h. The reaction mixture
was allowed to cool, then poured onto crushed ice; the
obtained precipitate was filtered, washed with water, dried,
and crystalized from dimethyl formamide to yield
compound 21. Brown powder; yield: 0.18 g (56%); m.p.:
300°C. Anal. Calcd. (%) for C H N O S (321.35): C,
2.33; H, 4.70; N, 13.08. Found (%): C, 52.61; H, 4.79;
N, 13.34. IR (KBr, cm ): 3363, 3300, 3280, 3213 (NH &
14 12 2 3 2
À1
>
5
Found (%): C, 52.76; H, 3.72; N, 8.98. IR (KBr, cm ):
3220 (NH); 2927 (CH-aromatic); 2854 (CH-aliphatic);
1720 (C═O); 1640 (C═N); 1620 (C═C); 1555, 1485,
1
4 15 3 4
À1
1
NH ); 2974, 2924 (CH-aromatic); 2854 (CH-aliphatic);
1280, 940 (I, II, III, IV bands of N–C═S). H NMR
2
1
1
724, 1670 (C═O); 1604 (C═C). H NMR (DMSO-d , δ
(DMSO-d , δ ppm): 2.33 (s, 3H, coumarin-C –CH );
6
6
4
3
ppm): 1.33 (s, 3H, coumarin-C –CH ); 2.27 (s, 3H,
2.58 (s, 3H, coumarin-C –CH ); 4.80 (s, 2H, CH ); 6.12
4
3
7 3 2
coumarin-C –CH ); 4.55 (s, 2H, CH ); 6.03 (s, 1H,
(s, 1H, coumarin-C –H); 6.74 (s, 1H, coumarin-C –H);
3 6
7
3
2
coumarin-C –H); 6.56 (s, 1H, coumarin-C –H); 6.60 (s,
6.80 (s, 1H, coumarin-C –H); 12.99 (s, 1H, NH, D O
8 2
3
6
+
.
1
H, coumarin-C –H); 6.81 (s, 2H, NH2, D O
exchangeable). Mass spectrum, m/z (%): 321 (M +1,
8
2
+.
exchangeable); 6.92 (s, 1H, –CS–NH, D O exchangeable);
15.24); 320 (M , 28.73); 313 (100).
2
5-((4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy)-
1
0.52 (s, 1H, –NHCO, D O exchangeable). Mass
2
+
.
+.
4,7-dimethyl-2H-chromen-2-one (26).
Compound 23
spectrum, m/z (%): 322 (M +1, 6.14); 321 (M , 18.89);
(0.38 g, 1 mmol) was fused with hydrazin hydrate (0.03 g,
5
4 (100).
Potassium2-(2-(4,7-dimethyl-2-oxo-2H-chromen-5-yloxy)-
0.03 mL, 1 mmol) at 230–240°C for 5 h. The reaction
mixture was allowed to cool, then triturated with ethanol,
the formed precipitate was filtered, washed with ethanol,
and boiled in different solvents to yield compound 26.
Dark brown powder; yield: 0.25 g (78%); m.p.: >300°C.
Anal. Calcd. (%) for C H N O S (318.35): C, 52.82; H,
acetyl)hydrazinecarbodithioate (23).
A mixture of the
acetohydrazide derivative 22 (0.26 g, 1 mmol) in absolute
ethanol (15 mL) containing potassium hydroxide (0.06 g,
1
0
1
mmol) was treated with carbon disulfide (0.07 g,
.06 mL, 1 mmol) and stirred at room temperature for
2 h. The obtained precipitate was filtered, washed with
14 14 4 3
4.43; N, 17.60. Found (%): C, 53.07; H, 4.52; N, 17.89. IR
À1
ethanol, and dried to yield compound 23 that was used as
(KBr, cm ): 3394, 3356, 3336 (NH & NH ); 3032, 3012
2
such in the next steps. White powder; yield: 0.15 g
(CH-aromatic); 2924, 2854 (CH-aliphatic); 1700 (C═O);
1640 (C═N); 1600 (C═C). Mass spectrum, m/z (%): 318
(
39%); m.p.: >300°C.
+.
4
,7-Dimethyl-5-((5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
(
M , 4.11); 42 (100).
methoxy)-2H-chromen-2-one (24).
A solution of the
potassium salt of the hydrazinecarbodithioate derivative
3 (0.38 g, 1 mmol) in absolute ethanol (20 mL) was
heated under reflux for 20 h. The reaction mixture was
2
-(4,7-Dimethyl-2-oxo-2H-chromen-5-yloxy)-N-(2-hydroxyethyl)
acetamide (27).
A mixture of compound 20 (1.37 g,
2
5 mmol) and ethanolamine (0.037 g, 0.37 mL, 6 mmol)
was fused at 140–145°C for 10 h. The reaction mixture
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
was allowed to cool, then poured onto crushed ice; the
obtained precipitate was filtered, washed with water,
dried, and washed with different solvents to yield
compound 27. Yellow powder; yield: 0.6 g (40%); m.
p.: >300°C. Anal. Calcd. (%) for C H NO (291.30):
acetoacetate (0.13 g, 0.13 mL, 1 mmol) was fused at 170–
180°C for 5 h. The reaction mixture was allowed to cool,
then triturated with ethanol, the obtained precipitate was
filtered, washed with ethanol, dried, and boiled in
different solvents to yield compound 30. Dark brown
powder; yield: 0.21 g (64%); m.p.: >300°C. Anal. Calcd.
(%) for C H N O (328.32): C, 62.19; H, 4.91; N, 8.53.
1
5
17
5
C, 61.85; H, 5.88; N, 4.81. Found (%): C, 62.17; H,
À1
5
.92; N, 4.89. IR (KBr, cm ): 3421 (broad OH); 3300
17 16 2 5
À1
(NH); 2924 (CH-aromatic); 2854 (CH-aliphatic); 1743,
Found (%): C, 62.43; H, 4.98; N, 8.71. IR (KBr, cm ):
3421 (broad OH); 3097, 3062 (CH-aromatic); 2924, 2854
1
2
685 (C═O); 1595 (C═C). Mass spectrum, m/z (%):
92 (M +1, 2.29); 291 (M , 2.59); 43 (100).
+.
+.
(CH-aliphatic); 1716, 1685 (C═O); 1612 (C═N); 1565
1
5
-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethoxy)-4,7-dimethyl-
H-chromen-2-one (28). A mixture of compound 22 (0.26 g,
mmol) and acetylacetone (0.2 g, 0.2 mL, 2 mmol) was
(C═C). H NMR (DMSO-d
, δ ppm): 1.20 (s, 3H,
6
2
1
coumarin-C –CH ); 2.25 (s, 3H, coumarin-C –CH ); 2.31
4 3 7 3
(s, 3H, pyrazole-C –CH ); 4.87 (s, 2H, CH ); 6.11 (s, 1H,
3 3 2
fused for 5 h. The reaction mixture was allowed to cool,
then triturated with ethanol to precipitate a solid that was
filtered, washed with ethanol, dried, and crystalized from
dimethyl formamide to yield compound 28. Dark brown
powder; yield: 0.2 g (61%); m.p.: >300°C. Anal. Calcd.
coumarin-C –H); 6.54 (s, 1H, coumarin-C –H); 6.79 (s,
3 6
1H, coumarin-C –H); 7.34 (s, 1H, pyrazole-C –H); 10.49
8
4
(s, 1H, OH, D O exchangeable). Mass spectrum, m/z (%):
2
+.
+.
329 (M +1, 1.01); 328 (M , 1.58); 276 (100).
1-(2-(4,7-Dimethyl-2-oxo-2H-chromen-5-yloxy)acetyl)
(
%) for C H N O (326.35): C, 66.25; H, 5.56; N,
pyrazolidine-3,5-dione (31). An equimolar mixture of the
1
8 18 2 4
8
.58. Found (%): C, 66.13; H, 5.67; N, 8.90. IR (KBr,
acetohydrazide derivative 22 (0.26 g, 1 mmol) and
diethyl malonate (0.16 g, 0.15 mL, 1 mmol) was fused at
170–180°C for 5 h. The reaction mixture was allowed to
cool, then triturated with ethanol, the obtained precipitate
was filtered, washed with ethanol, dried, and crystalized
from dimethyl formamide to yield compound 31. Yellow
powder; yield: 0.23 g (70%); m.p.: >300°C. Anal. Calcd.
(%) for C H N O (330.29): C, 58.18; H, 4.27; N,
À1
cm ): 3420 (broad OH tautomer); 3097, 3066 (CH-
aromatic); 2924, 2854 (CH-aliphatic); 1716, 1678 (C═O);
1
1612 (C═N); 1590 (C═C). H NMR (DMSO-d , δ ppm):
6
2.26 (s, 3H, coumarin-C –CH ); 2.33 (s, 3H, coumarin-
4
3
C –CH ); 2.52 (s, 3H, pyrazole-C –CH ); 2.58 (s, 3H,
pyrazole-C –CH ); 4.79 (s, 1H, CH ); 6.03 (s, ½ H,
7
3
3
3
5
3
2
–CH═C(OH) tautomer); 6.12 (s, 1H, coumarin-C –H);
3
16 14 2 6
6
.55 (s, 1H, coumarin-C –H); 6.60 (s, 1H, coumarin-C –
8.48. Found (%): C, 58.40; H, 4.31; N, 8.65. IR (KBr,
cm ): 3402 (NH); 3070, 2974 (CH-aromatic); 2924,
6
8
À1
H); 6.74 (s, 1H, pyrazole-C –H); 10.51 (s, ½H, OH
4
tautomer, D O exchangeable). Mass spectrum, m/z (%):
2854 (CH-aliphatic); 1724, 1697, 1658 (C═O); 1620
2
+.
1
326 (M , 5.57); 43 (100).
(C═N); 1600 (C═C). H NMR (DMSO-d , δ ppm): 2.33
6
5
-(2-(5-Amino-3-hydroxy-1H-pyrazol-1-yl)-2-oxoethoxy)-4,7-
(s, 3H, coumarin-C –CH ); 2.57 (s, 3H, coumarin-C –
4 3 7
dimethyl-2H-chromen-2-one (29). An equimolar mixture of
CH ); 4.75 (s, 2H, CH ); 4.82 (s, 2H, pyrazole-CH );
3
2
2
compound 22 (0.26 g, 1 mmol) and ethyl cyanoacetate
6.13 (s, 1H, coumarin-C –H); 6.74 (s, 1H, coumarin-C –
3
6
(0.11 g, 0.11 mL, 1 mmol) in dimethyl formamide (10 mL)
H); 6.82 (s, 1H, coumarin-C –H); 9.61 (s, ½H, OH, D O
8 2
was heated under reflux for 5 h. The reaction mixture was
allowed to cool, the obtained precipitate was filtered while
hot, washed with ethanol, dried, and crystalized from
dimethyl formamide to yield compound 29. Brown
powder; yield: 0.25 g (76%); m.p.: >300°C. Anal. Calcd.
exchangeable); 10.23 (s, ½H, NH, D O exchangeable).
2
Mass spectrum, m/z (%): 330 (M , 1.13); 43 (100).
N-(2-(4,7-dimethyl-2-oxo-2H-chromen-5-yloxy)acetyl)
benzohydrazide (32). An equimolar mixture compound 22
(0.26 g, 1 mmol) and benzoyl chloride (0.14 g, 0.12 mL,
1 mmol) was fused at 170–180°C for 5 h. The reaction
mixture was allowed to cool, then triturated with ethanol,
the obtained precipitate was filtered, washed with ethanol,
dried, and boiled in different solvents to yield compound
32. Dark brown powder; yield: 0.22 g (59%); m.p.:
+.
(
%) for C H N O (329.31): C, 58.36; H, 4.59; N,
16 15 3 5
1
2.76. Found (%): C, 58.64; H, 4.67; N, 13.02. IR (KBr,
À1
cm ): 3406 (OH); 3300, 3200 (NH ); 3020, 2924 (CH-
2
aromatic); 2854 (CH-aliphatic); 1727, 1654 (C═O); 1616
1
(
C═N); 1570 (C═C). H NMR (DMSO-d , δ ppm): 2.33
6
(
s, 3H, coumarin-C –CH ); 2.56 (s, 3H, coumarin-C –
>300°C. Anal. Calcd. (%) for C20H N O (366.37): C,
18 2 5
4
3
7
CH ); 3.75 (s, 2H, NH , D O exchangeable); 4.75 (s, 2H,
65.57; H, 4.95; N, 7.65. Found (%): C, 65.82; H, 4.89;
N, 7.89. IR (KBr, cm ): 3429 (OH); 3300, 3220 (NH);
3
2
2
À1
CH ); 6.13 (s, 1H, coumarin-C –H); 6.73 (s, 1H,
2
3
coumarin-C –H); 6.82 (s, 1H, coumarin-C –H); 7.92 (s, 1H,
3059, 3032, 2978 (CH-aromatic); 2854 (CH-aliphatic);
1743, 1680, 1658 (C═O); 1597 (C═N); 1577 (C═C). H
6
8
1
pyrazole-C –H); 10.28 (s, 1H, OH, D O exchangeable).
4
2
+
.
Mass spectrum, m/z (%): 329 (M , 1.06); 72 (100).
NMR (DMSO-d , δ ppm): 2.70 (s, 3H, coumarin-C –
6
4
CH ); 2.86 (s, 3H, coumarin-C –CH ); 4.28 (s, 2H,
5
-(2-(5-Hydroxy-3-methyl-1H-pyrazol-1-yl)-2-oxoethoxy)-4,7-
3
7
3
dimethyl-2H-chromen-2-one (30). An equimolar mixture of
CH
2
); 7.32 (s, 1H, coumarin-C –H); 7.40–750 (m, 4H,
3
the acetohydrazide derivative 22 (0.26 g, 1 mmol) and ethyl
coumarin-C6,8–H & two NH); 7.51–7.68 (m, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
C H –C –H); 7.85–8.00 (m, 2H, C H –C –H). Mass
cyclohexanone (0.98 g, 1 mL, 10 mmol) was heated under
reflux in dimethyl formamide (10 mL) containing zinc
chloride (0.68 g, 5 mmol) for 5 h. The reaction mixture was
allowed to cool, poured onto crushed ice, and triturated
with few drops of dilute hydrochloric acid (10%); the
obtained solid was filtered, washed with water, dried, and
crystallized from dimethyl formamide to yield compound
6
5
3,4,5
6
5
2,6
+
.
+.
spectrum, m/z (%): 367 (M + 1, 11.51); 366 (M ,
+
.
2
1.58); 365 (M À1, 7.21); 43 (100).
4-Imino-6,11-dimethyl-5-(4-methoxyphenyl)-9-oxo-3-phenyl-
À
À
pyrano[2 ,3 :2,3]chromeno [2,3-d]-pyrimidine-2-(1H,5H)thione
33).
(
An equimolar mixture of the 2-aminopyrano-
coumarin-3-carbonitrile derivative 6 (0.37 g, 1 mmol) and
phenyl isothiocyanate (0.14 g, 0.13 mL, 1 mmol) was
heated under reflux in pyridine (10 mL) for 10 h. The
reaction mixture was allowed to cool, poured onto crushed
ice, and triturated with few drops of dilute hydrochloric
acid (10%), the precipitated solid was filtered, washed
with water, dried, and boiled in different solvents to yield
compound 33. Dark brown powder; yield: 0.27 g (53%);
m.p.: >300°C. Anal. Calcd. (%) for C H N O S
36. Brown powder; yield: 3.5 g (77%); m.p.: >300°C.
Anal. Calcd. (%) for C H N O (454.52): C, 73.99; H,
28 26 2 4
5
.77; N, 6.16. Found (%): C, 74.23; H, 5.85; N, 6.42. IR
À1
(KBr, cm ): 3392, 3213 (NH ); 3070 (CH-aromatic);
2
2
1
4
854, 2926 (CH-aliphatic); 1674 (C═O); 1616 (C═N);
1
585 (C═C). H NMR (DMSO-d , δ ppm): 1.19–1.29 (m,
6
H, tetrahydropyranochromenoquinoline-C –H); 1.55–1.72
8,9
2
9 23 3 4
(m, 4H, tetrahydropyranochromeno-quinoline-C7,10–H);
(
509.58): C, 68.35; H, 4.55; N, 8.25; S, 6.29. Found (%):
2
2
2
.28 (s, 3H, tetrahydropyranochromenoquinoline-C –CH );
À1
4 3
C, 68.57; H, 4.51; N, 8.49; S, 6.34. IR (KBr, cm ) 3380,
.54 (s, 3H, tetrahydropyranochromenoquinoline-C –CH );
13
3
3
360 (NH); 3062, 2924 (CH-aromatic); 2854 (CH-
aliphatic); 1716 (C═O); 1625 (C═N); 1597 (C═C); 1543,
438, 1253, 1029 (I, II, III, IV bands of N–C═S). Mass
.89 (s, 3H, OCH3); 4.15 (s, 1H, tetrahydro-
6.03 (s, 1H,
tetrahydropyranochromenoqunoline-C –H); 6.57 (s, 1H,
pyranochromenoquinoline-C –H);
12
1
+
.
3
spectrum, m/z (%): 509 (M , 1); 57 (100).
tetrahydropyranochromeno-quinoline-C –H);
7.62–7.78
–C3,5–H); 7.90–7.99 (m, 2H, 4-
OCH –C H –C –H); 10.52 (s, 2H, NH2, D O
14
4
-Amino-6,11-dimethyl-5-(4-methoxyphenyl)-9-oxo-5H-pyrano
À
À
(m, 2H, 4-OCH –C H
3 6 4
[
2 ,3 :2,3]chromeno[2,3-d] pyrimidine (34).
Compound 6
3
6
4
2,6
2
(0.37 g, 1 mmol) was heated under reflux in excess
+.
exchangeable). Mass spectrum, m/z (%): 454 (M , 2.1);
4 (100).
formamide solution (5 mL) for 2 h. The reaction mixture
was allowed to cool, then triturated with ethanol and the
precipitated solid was filtered, washed with ethanol, boiled
in different solvents to yield compound 34. Dark brown
powder; yield: 0.3 g (75%); m.p.: >300°C. Anal. Calcd.
4
4
-Bromo-2-formylphenyl 6-bromo-2-oxo-2H-chromene-3-
carboxylate (38).
An equimolar mixture of ethyl
coumarin-3-carboxylate 37 (0.3 g, mmol) and
-bromosalicylaldehyde (0.2 g, 1 mmol) was heated under
1
5
(
%) for C H N O (401.41): C, 68.82; H, 4.77; N, 10.47.
23 19 3 4
À1
reflux in absolute ethanol (10 mL) containing potassium
hydroxide (0.06 g, 1 mmol) for 20 h. The reaction
mixture was allowed to cool and poured onto crushed ice;
the formed precipitate was filtered, washed with water,
dried, and crystallized from dimethyl formamide to yield
compound 38. Yellow powder; yield: 0.32 g (71%) m.p.:
Found (%): C, 69.04; H, 4.85; N, 10.69. IR (KBr, cm ):
3
309, 3163 (NH ); 3088, 3066, 3014 (CH-aromatic); 2900,
2
2
882 (CH-aliphatic); 1680 (C═O); 1640 (C═N); 1595
+.
(C═C). Mass spectrum, m/z (%): 401 (M , 1); 69 (100).
À
À
6
,11-Dimethyl-5-(4-methoxyphenyl)-9-oxo-pyrano[2 ,3 :2,3]
chromeno[2,3-d]pyrimidine-2,4(1H,3H,5H)dithione (35).
To
>
300°C. Anal. Calcd. (%) for C H Br O (452.05): C,
a solution of compound 6 (0.37 g, 1 mmol) in absolute
ethanol (15 mL), carbon disulfide (0.08 g,
17 8 2 5
4
5.17; H, 1.78. Found (%): C, 45.41; H, 1.89. IR (KBr,
À1
cm ): 3053, 2960 (CH-aromatic); 1734, 1716, 1695
0
1
.06 mL,1 mmol) and potassium hydroxide (0.06 g,
mmol) were added. The reaction mixture was heated
1
(C═O); 1616 (C═C). H NMR (DMSO-d , δ ppm): 7.26
6
(
s, 1H, coumarin-C –H); 7.29 (s, 2H, coumarin-C –H &
under reflux for 20 h. The reaction mixture was allowed
to cool and then poured onto crushed ice; the precipitated
solid was filtered, washed with water, dried, and
crystallized from ethanol to yield compound 35. Yellow
powder; yield: 0.34 g (76%); m.p.: 260–262°C. Anal.
Calcd. (%) for C H N O S (450.53): C, 61.32; H,
4
5
4
4
7
-Br–C H –C –H); 7.62–7.65 (m, 2H, coumarin-C –H &
6 3 3 8
-Br–C H –C –H); 7.66–7.77 (m, 1H, coumarin-C –H);
6
3
6
7
.81 (s, 1H, CHO); 7.93–7.96 (m, 1H, 4-Br–C H –C –H).
6
3
5
+.
Mass spectrum, m/z (%): 456 (M +4, 2.21); 453
+.
+.
(M +1, 32.2); 452 (M , 11); 155 (100).
2
3 18 2 4 2
1
1-Bromochromeno[2,3-f]naphtho[1,8-bc][1,5]diazocin-8(7H)
one (39). An equimolar mixture of compound 37 (0.3 g,
mmol) and 1,8-diaminonaphthalene (0.16 g, 1 mmol) was
4
6
3
.03; N, 6.22; S, 14.23. Found (%): C, 61.47; H, 4.01; N,
.30; S, 14.37. IR (KBr, cm ): 3390, 3292 (NH); 3049,
014 (CH-aromatic); 2887, 2872 (CH-aliphatic); 1654
À1
1
fused at 145–150°C for 3 h. The reaction mixture was
allowed to cool, then triturated with ethanol and the formed
precipitate was filtered, washed with ethanol, dried, and
crystallized from toluene/dimethyl formamide mixture (3:1)
to yield compound 39. Dark brown powder; yield: 0.3 g
(
1
C═O); 1612 (C═N); 1558 (C═C); 1512 1448, 1296,
099 (I, II, III, IV bands of N–C═S). Mass spectrum, m/z
+.
+.
(%): 452 (M +2, 5.80); 450 (M , 6.18); 73 (100).
1
1-Amino-4,13-dimethyl-12-(4-methoxyphenyl)-7,8,9,10-tetrahydro-
-
-
2
-oxo-12H-pyrano[2 ,3 :2,3]chromeno[2,3-b]quinoline (36). An
(
77%) m.p.: >300°C. Anal. Calcd. (%) for C H BrN O
equimolar mixture of compound 6 (3.7 g, 10 mmol) and
20 11 2 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Facile Synthesis and Anticancer Activity Study of Some Novel Substituted and
Fused Coumarin Derivatives
(
2
391.22): C, 61.40; H, 2.83; N, 7.16. Found (%): C, 61.59; H,
.88; N, 7.34. IR (KBr, cm ): 3446 (OH tautomer); 3387
C H); 7.22–7.31 (m, 1H, coumarin-C –H); 7.32–7.39 (m,
5À 7
2H, 4-Cl–C H –C –H); 7.40–7.50 (m, 3H, coumarin-C –
6 4 3,5 5
À1
(
(
7
NH); 3049, 2924 (CH-aromatic); 1685 (C═O); 1627
C═N); 1558 (C═C). Mass spectrum, m/z (%): 391 (M ,
.33); 298 (100).
H & 4-Cl–C H –C –H); 8.04 (s, 1H, coumarin-C –H);
6 4 2,6 4
+.
8.15 (s, ½ H, OH tautomer, D O exchangeable); 9.80 (s, ½
2
H, NH, D O exchangeable). Mass spectrum, m/z (%): 457
2
+.
+.
+.
6-Bromochromeno[2,3-c]pyrazol-3(2H)one (40).
An
(M + 4, 0.99); 455 (M + 2, 1.48); 453 (M , 13.97); 44 (100).
Ethyl 4-(6-bromo-2-oxo-2H-chromen-3-yl)-2,4-dioxobutanoate
equimolar mixture of compound 37 (0.3 g, 1 mmol)
and hydrazine hydrate (0.032 g, 0.03 mL, 1 mmol) was
heated under reflux in absolute ethanol for 3 h. The
formed precipitate was filtered, washed with ethanol,
dried, and crystallized from dimethyl formamide to
yield compound 40. Yellow powder; yield: 0.2 g (74%)
m.p.: >300°C. Anal. Calcd. (%) for C H BrN O
2 2
(
4
3
(44). An equimolar mixture of compound 41 (0.27 g,
1
mmol) and diethyl oxalate (0.15 g, 0.14 mL, 1 mmol)
was fused at 200–210°C for 10 h. The reaction mixture
was allowed to cool, then triturated with ethanol, and the
obtained solid product was filtered, washed with ethanol,
dried, and crystallized from dimethyl formamide to yield
compound 44. Dark brown powder; yield: 0.19 g (51%);
1
0
5
265.06): C, 45.31; H, 1.90; N, 10.57. Found (%): C,
À1
m.p.: >300°C. Anal. Calcd. (%) for C15
H11BrO
6
5.48; H, 1.87; N, 10.76. IR (KBr, cm ): 3383 (NH);
(
367.15): C, 49.07; H, 3.02. Found (%): C, 49.31; H,
007, 2954, 2924 (CH-aromatic); 1685 (C═O); 1624
À1
1
3.11. IR (KBr, cm ): 3059 (CH-aromatic); 2890 (CH-
(C═N); 1564 (C═C). H NMR (DMSO-d , δ ppm):
6
aliphatic); 1732, 1693 (C═O); 1624 (C═C); 1265, 1068
6
7
7
.96 (d, 1H, J = 8.8 Hz, chromenopyrazolone-C –H);
8
(
(
C–O–C); 817 (C–Br). Mass spectrum, m/z (%): 370
.55 (d, 1H, J = 8.8 Hz, chromenopyrazolone-C –H);
7
+.
+.
+.
M +3, 1.00); 368 (M +1, 1.51); 367 (M , 2.07); 43 (100).
.91 (s, 1H, chromenopyrazolone-C –H); 8.95 (s, 1H,
4
5-(6-Bromo-2-oxo-2H-chromen-3-yl)-1H-pyrazole-3-carbohydrazide
chromenopyrazolone-C –H); 11.10 (s, 1H, NH, D O
exchangeable).
5
2
(45). The ethyl butanoate derivative 44 (0.37 g, 1 mmol)
was fused with excess hydrazine hydrate (1 mL) for 10 h.
The reaction mixture was allowed to cool, triturated with
ethano; and the obtained solid product was filtered,
washed with several solvents, and dried to yield
compound 45. Dark brown powder; yield: 0.27 g (77%);
m.p.: >300°C. Anal. Calcd. (%) for C H BrN O
4 3
3
-(3-(Oxiran-2-yl)propanoyl)-6-bromo-2H-chromen-2-one
(
42).
An equimolar mixture of the acetylcoumarin
derivative 41 (0.27 g, 1 mmol) and epichlorohydrin
0.09 g, 0.08 mL, 1 mmol) was heated under reflux in
(
dimethyl formamide (5 mL) containing potassium
hydroxide (0.06 g, 1 mmol) for 10 h. The reaction
mixture was allowed to cool, poured onto crushed ice,
and the obtained solid product was filtered, washed with
water, dried, and crystallized from dimethyl formamide to
yield compound 42. Brown powder; yield; 0.21 g (65%),
m.p.: >300°C. Anal. Calcd. (%) for C H BrO
4
13
9
(
4
3
349.14): C, 44.72; H, 2.60. N, 16.05. Found (%): C,
5.05; H, 2.57; N, 16.37. IR (KBr, cm ): 3390, 3367,
À1
128 (NH & NH ); 3032, 2935 (CH-aromatic); 1678
2
1
(C═O); 1625 (C═N); 1600 (C═C). H NMR (DMSO-d ,
6
δ ppm): 6.87 (d, 1H, J = 6.4 Hz, coumarin-C –H); 6.98 (s,
8
1
4
11
2
H, CONHNH , D O exchangeable); 7.11 (s, 1H,
2 2
(
323.14): C, 52.04; H, 3.43; Found (%): C, 52.31; H,
CONHNH , D O exchangeable); 7.23 (s, 1H, pyrazole-
2
2
À1
3
2
1
5
.50. IR (KBr, cm ): 3402 (broad OH tautomer); 3040,
NH, D O exchangeable); 7.26 (s, 1H, pyrazole-C –H);
2
4
927 (CH-aromatic); 2877 (CH-aliphatic) 1725 (C═O);
7
.31 (d, 1H, J = 6.4 Hz, coumarin-C –H); 7.93 (s, 1H,
7
+.
589 (C═C). Mass spectrum, m/z (%): 325 (M +2,
coumarin-C –H); 8.07 (s, 1H,coumarin-C –H). Mass
5
4
+.
.61); 323 (M , 11.36); 55 (100).
+.
+.
spectrum, m/z (%): 351 (M +2, 1.33); 349 (M , 3.97);
3 (100).
6-(6-Bromo-2-oxo-2H-chromen-3-yl)-4-(4-chlorophenyl)-2-oxo-
4
1
,2-dihydropyridine-3-carbonitrile (43).
A
mixture of
compound 41 (1.3 g, 5 mmol), ethyl cyanoacetate (0.57 g,
.53 mL, 5 mmol), 4-chlorobenzaldehyde (0.7 g, 5 mmol),
9
-Bromo-1,6-dimethyl-7-(2-oxopropyl)pyrano[2,3-c]xanthen-
3(7H)-one (46). An equimolar mixture of compound 41
(0.27 g, 1 mmol) and 5-hydroxycoumarin derivative 1
(0.19 g, 1 mmol) was heated under reflux in methanolic
sodium methoxide [prepared by dissolving 0.07 g,
3 mmol of sodium metal in absolute methanol (10 mL)]
for 60 h. The reaction mixture was allowed to cool,
poured onto crushed ice; and the obtained solid product
was filtered, washed with water, dried, and crystallized
from toluene/ethanol mixture (4:1) to yield compound 46.
Brown powder; yield: 0.25 g (61%), m.p.: >300°C. Anal.
Calcd. (%) for C H BrO (413.26): C, 61.03; H, 4.15.
0
and ammonium acetate (0.77 g, 10 mmol) was heated under
reflux in absolute ethanol (20 mL) for 60 h. The reaction
mixture was allowed to cool and poured onto crushed ice.
The obtained solid product was filtered, washed with water,
dried, and crystallized from ethanol to yield compound 43.
Yellow powder; yield: 1.5 g (66%); m.p.: >300°C. Anal.
Calcd. (%) for: C H BrClN O (453.67): C, 55.60; H,
21
10
2 3
2
.22; N, 6.17. Found (%): C, 55.89; H, 2.18; N, 6.34. IR
À1
(KBr, cm ): 3390 (broad OH tautomer); 3277 (NH); 3080,
2
1
17
4
À1
2
980 (CH-aromatic); 2220 (CN); 1732 (C═O); 1645
Found (%): C, 61.29; H, 4.19. IR (KBr, cm ): 3442
(broad OH tautomer); 3084, 3066, 3034 (CH-aromatic);
2872, 2854 (CH-aliphatic); 1701, 1685 (C═O); 1608
1
(C═N); 1575 (C═C). H NMR (DMSO-d , δ ppm): 6.75
6
(d, 1H, J = 9 Hz, coumarin-C –H); 7.00 (s, 1H, pyridine-
8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, M. A. El Deeb, A. H. Bayoumi, and S. I. El Rabeb
Vol 000
1
(
C═C). H NMR (DMSO-d , δ ppm): 1.17 (t, 1H,
[6] Chougala, B. M.; Samundeeswari, S.; Holiyachi, M.; Shastri,
L. A.; Dodamani, S.; Jalalpure, S.; Dixit, S. R.; Joshi, S. D.; Sunagar, V.
A. Eur J Med Chem 2017, 125, 101.
[7] Abdelhafez, O. M.; Amin, K. M.; Batran, R. Z.; Maher, T. J.;
Nada, S. A.; Sethumadhavan, S. Bioorg Med Chem 2010, 18, 3371.
6
pyranoxanthene-C –H); 1.23 (s, 3H, pyranoxanthene-C –
CH ); 1.98 (s, 3H, pyranoxanthene-C -CH ); 2.27 (s, ½
H, OH tautomer, D O exchangeable); 2.30 (s, 3H, CH –
C═O); 2.68–2.73 (m, 1H,CH –CO–CH ); 2.89 (s, ½H, –
7
1
3
6
3
2
3
[8] Ebrahimi, S. E. S.; Ghadirian, P.; Emtiazi, H.; Yahya-
3
2
Meymandi, A.; Saeedi, M.; Mahdavi, M.; Nadri, H.; Moradi, A.; Sameem,
B.; Vosooghi, M.; Emami, S.; Foroumadi, A. Med Chem Res 2016, 25,
1831.
C(OH)═CH tautomer); 6.04 (s,1H, pyranoxanthene-C2–
H); 6.57 (s, 1H, pyranoxanthene-C –H); 6.62 (s,1H,
pyranoxanthene-C -H);
pyranoxanthene-C –H);
5
[9] Shaik, J. B.; Palaka, B. K.; Penumala, M.; Eadlapalli, S.; Mark,
7.10–7.20
7.21–7.30
(m,
(m,
1H,
1H,
8
M. D.; Ampasala, D. R.; Vadde, R.; Gangaiah, D. A. Chem Biol Drug Des
11
2016, 88, 43.
pyranoxanthene-C –H). Mass spectrum, m/z (%): 415
[10] Keerthy, H. K.; Mohan, C. D.; Siveen, K. S.; Fuchs, J. E.;
Rangappa, S.; Sundaram, M. S.; Li, F.; Basappa, B. A.; Rangappa, K. S.
J Biol Chem 2014, 46, 31879.
1
0
+.
+.
(
M +2, 0.75); 413 (M , 2.26); 111 (100).
6
-Bromo-3-(pent-4-ynoyl)-2H-chromen-2-one (47).
An
[11] Yeh-Long, C.; Tai-Chi, W.; Cherng-Chyi, T. Helv Chim Acta
equimolar mixture of compound 41 (0.27 g, 1 mmol) and
propargyl bromide (0.12 g, 0.08 mL, 1 mmol) was heated
under reflux in ethanolic sodium ethoxide [prepared by
dissolving 0.07 g, 3 mmol of sodium metal in absolute
ethanol (10 mL)] for 10 h. The reaction mixture was
allowed to cool and poured onto crushed ice; the
obtained solid product was filtered, washed with water,
dried, and crystallized from toluene/ethanol mixture (4:1)
to yield compound 47. Brown powder; yield: 0.2 g
1
999, 82, 191.
[12] Kempen, I.; Papapostolou, D.; Thierry, N.; Pochet, L.;
Counerotte, S.; Masereel, B.; Foidart, J. M.; Reboud-Ravaux, M.; Noël,
A.; Pirotte, B. BJC 2003, 88, 1111.
[13] Ranganatha, V. L.; Zameer, F.; Meghashri, S.; Rekha, N. D.;
Girish, V.; Gurupadaswamy, H. D.; Khanum, S. A. Arch Pharm Chem
Life Sci 2013, 346, 901.
[14] Avin, B. R. V.; Thirusangu, P.; Ranganatha, V. L.;
Firdouse, A.; Prabhakar, B. T.; Khanum, S. A. Eur J Med Chem 2014,
7
7
5, 211.
[15] Nasr, T.; Bondock, S.; Youns, M. Eur J Med Chem 2014,
6, 539.
16] Sandhu, S.; Bansal, Y.; Silakari, O.; Bansal, G. Bioorg Med
(
67%); m.p.: >300°C. Anal. Calcd. (%) for C H BrO
14 9 3
[
(
305.12): C, 55.11; H, 2.97; Found (%): C, 55.38; H,
.94. IR (KBr, cm ): 3410 (broad, OH tautomer); 3032,
Chem 2014, 22, 3806.
À1
2
2
1
2
[17] Salem, M. A. I.; Marzouk, M. I.; El-Kazak, A. M. Molecules
2016, 21, 249.
958, 2927 (CH-aromatic); 2873 (CH-aliphatic) 1725,
1
[18] Garazd, Y.; Garazd, M.; Lesyk, R. Saudi Pharma J 2017, 25,
14.
685 (C═O); 1600 (C═C). H NMR (DMSO-d , δ ppm):
6
2
.25 (s, 1H, –C≡CH); 3.20–3.58 (m, 4H, –CO–CH2–
[19]
Intermed 2015, 41, 1591.
20] Pradhan, K.; Paul, S.; Das, A. R. Tetrahedron Lett 2013, 54,
105.
21] Zhuo, C.; Xian, D.; Jian-wei, W.; Hui, X. ISRN Org Chem,
2011, Article ID 676789, 1.
22] Hasssan, A. Y.; Kadh, M. S.; Saleh, N. M.; Abuo-Amra, E. S.
J Adv Res 2016, 4, 335.
23] Hoggarth, E. J Chem Soc (resumed) 1950 612.
EL-Gogary, S.; Hashem, N.; Khodeir, M. N. Res Chem
CH –); 6.60–7.10 (m, 1H, coumarin-C –H); 7.20–7.70
2
8
[
(
m, 2H, coumarin-C5,7–H); 7.77 (s, 1H, coumarin-C –H).
4
3
+
.
+.
Mass spectrum, m/z (%): 307 (M +2, 0.93); 305 (M ,
.86); 43 (100).
[
0
[
[
Acknowledgments. We would like to thank the Regional Center
for Mycology and Biotechnology, at Al-Azhar University, Cairo,
Egypt, for performing the anticancer screening.
[24] Li, B.; Yan, W.; Zhang, C.; Zhang, Y.; Liang, M.; Chu, F.;
Gong, Y.; Xu, B.; Wang, H.; Lei, P. Molecules 2015, 20, 4307.
[
[
[
[
25] Alwahaibi, L. H. Int J Res 2016, 4, 1477.
26] singh, S. K.; singh, K. N J Hetercyclic Chem 2011, 48, 397.
27] Song, A.; Wang, X. A Tetrahydron Lett 2003, 44, 1755.
28] Vijesh, A. M.; Isloor, A. M.; Prabhu, V.; Ahmad, S.; Malladi,
REFERENCES AND NOTES
S. Eur J Med Chem 2010, 45, 5460.
[29] Mosmann, T. J Immunol Methods 1983, 65, 55.
[
1] Xiao-Qin, W.; Huang, C.; Ying-Ming, J.; Bao-An, S.; Jun, L.;
Xin-Hua, L. Eur J Med Chem 2014, 74, 717.
2] Benci, K.; Mandic, L.; Suhina, T.; Sedic, M.; Klobucar, M.;
Pavelic, S. K.; Pavelic, K.; Wittine, K.; Mintas, M. Molecules 2012, 17,
1010.
3] Vaarla, K.; Kesharwani, R. K.; Santosh, K.; Vedula, R. R.;
Kotamraju, S.; Toopurani, M. K. Bioorg Med Chem Lett 2015, 25, 5797.
[30] Gomha, S. M.; Riyadh, S. M.; Mahmmoud, E. A.; Elaasser,
M. M. Heterocycles 2015, 91, 1227.
[
1
[
SUPPORTING INFORMATION
[
[
4] Jardosh, H. H.; Patel, M. P. Med Chem Res 2013, 22, 905.
5] Zavrsnik, D.; Muratovic, S.; Makuc, D.; Plavec, J.; Cetina, M.;
Additional Supporting Information may be found online
in the supporting information tab for this article.
Nagl, A.; Clercq, E. D.; Balzarini, J.; Mintas, M. Molecules 2011, 16, 6023.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet