An Efficient One-Pot Synthesis of New Coumarin Derivatives as Potent Anticancer Agents under Microwave Irradiation

Article abstract of DOI:10.1002/jhet.2975

An efficient and rapid synthesis of coumarin derivatives was accomplished via reactions of 3-(3-(4-methoxyphenyl)acryloyl)-2H-chromen-2-one (3) with different carbon nucleophiles such as ethyl acetoacetate, ethyl cyanoacetate, malononitrile, and ethyl benzoylacetate via conventional heating and microwave irradiation conditions and were used as source of pyran and pyridine derivatives bearing coumarin moiety 4–11. Compound 9a was condensed with different carbon electrophiles triethylorthoformate, phenylisothiocyanate, carbon disulfide, benzoylchloride, and acetylchloride that afforded the corresponding chromen derivatives 12–16. All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of synthesized compounds were tested for in vitro cytotoxicity. The preliminary screening results showed that most of the compounds had moderate cytotoxic activity against HCT-116 and MCF-7 cell lines. Nevertheless, compound 10 exhibited potent activity against the two cell lines, which was comparable with the standard drug 5-fluorouracil.

Full text of DOI:10.1002/jhet.2975

Month 2017
An Efficient One-Pot Synthesis of New Coumarin Derivatives as Potent
Anticancer Agents under Microwave Irradiation
*
Abeer M. El-Naggar,
Magdy M. Hemdan, and Saad R. Atta-Allah
Department of Chemistry, Faculty of Science, Ain Shams University, 11566, Abbassia, Cairo, Egypt
*
E-mail: elsayedam@sci.asu.edu.eg
Received May 5, 2017
DOI 10.1002/jhet.2975
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and rapid synthesis of coumarin derivatives was accomplished via reactions of 3-(3-(4-
methoxyphenyl)acryloyl)-2H-chromen-2-one (3) with different carbon nucleophiles such as ethyl
acetoacetate, ethyl cyanoacetate, malononitrile, and ethyl benzoylacetate via conventional heating and
microwave irradiation conditions and were used as source of pyran and pyridine derivatives bearing couma-
rin moiety 4–11. Compound 9a was condensed with different carbon electrophiles triethylorthoformate,
phenylisothiocyanate, carbon disulfide, benzoylchloride, and acetylchloride that afforded the corresponding
chromen derivatives 12–16. All the newly synthesized compounds were characterized by elemental and
spectroscopic evidences. All of synthesized compounds were tested for in vitro cytotoxicity. The preliminary
screening results showed that most of the compounds had moderate cytotoxic activity against HCT-116 and
MCF-7 cell lines. Nevertheless, compound 10 exhibited potent activity against the two cell lines, which was
comparable with the standard drug 5-fluorouracil.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
Therefore, the synthesis of such compounds has attracted
strong interest.
Cancer is a disease that still intrigues the scientific
community, stimulating their interest in finding novel
chemotherapeutic agents effective for the management
and remediation of this life-threatening ailment [1]. Many
factors compromise the rate of success of cancer
chemotherapy, with the emergence of drug resistance to
currently clinically useful agents being the most
worrisome in the fight against cancer [2]. Heterocycle-
based chemical entities have been explored as backbone
scaffolds for the design of novel antiproliferative agents.
Pyridine heterocycles have a considerable attention
because of their pharmacological properties. Literature
has demonstrated the ability of synthetic pyridine-
containing compounds to elicit a wide spectrum of
biological activities with emphasis on their usefulness as
anticancer therapeutic agents [3]. The 4H-pyran nucleus
is a fertile source of biologically important molecules
Coumarins, also known as benzopyran-2-ones, form an
important class of naturally occurring compounds that
possess promising therapeutic perspectives [10]. Its
unique structure has a special ability that allows its
derivatives to readily interact with a diversity of enzymes
and receptors in organisms through weak bond
interactions and thereby exhibit wide potentiality as
medicinal drugs [11]. Especially coumarin-based
compounds have been investigated as potential candidates
for cancer therapy. Encouraged by the above findings on
coumarin (allows its derivatives to readily interact with a
diversity of enzymes and receptors in organisms), pyran,
and pyrimidine (anticancer properties), we planned to
integrate all these necessary subunits into one structure,
so that the combination of all these units might exhibit
synergetic effect in enhancing the bioactivity of the
compound. However, this hypothesis needs further
investigation.
possessing
a
wide spectrum of biological and
pharmacological activities, such as antimicrobial [4],
antiviral [5,6], antitumor [7], and cancer therapy [8,9].
In today’s world, the most fundamental obstacles in
developing technologies are used to minimize the energy
© 2017 Wiley Periodicals, Inc.

A. M. El-Naggar, M. M. Hemdan, and S. R. Atta-Allah
Vol 000
consumption and to eliminate or minimize the use of
hazardous solvents and, most expensive of all, time [12].
Hence, to synthesize the desired compounds, microwave-
irradiation technique was employed, because the most
noticeable advancement in microwave-assisted organic
synthesis is that it dramatically reduces reaction times,
typically from days or hours to minutes or even seconds
[13]. Further, when compared with classical methods,
microwave-assisted reactions are efficient energy source
for synthetic chemistry and have gained importance
because of the simplicity in operation, increase in
reaction rates, improving reaction yields, and formation
of pure products [14]. Influenced by this innovation, we
describe in this paper an efficient and facile synthesis of
some pyran and pyridine derivatives bearing coumarin
moiety (4–11)—of potential biological importance in
excellent yields under microwave irradiation, through
which the yields of the compounds were improved
drastically in very short reaction time as compared with
conventional method. We believe that the present
methodology addresses the current devise toward green
chemistry.
were synthesized by Claisen–Schmidt condensation
reaction [18]. Cyclic condensation of 3 with different
carbon nucleophiles such as ethyl acetoacetate, ethyl
cyanoacetate, malononitrile, and ethyl benzoylacetate
afforded chromen-2-one derivatives (4–11) under both
conventional and microwave irradiation method. The
synthesis of the target compounds was carried out as
outlined in Schemes 1 and 2). It was observed that the
microwave approach proved to be extremely fast
providing good to excellent yields (85–93%) as compared
with the conventional method (54–68%). Here, the most
noticeable advancement was the speed at which the
reaction proceeded; i.e., the reaction was completed
within 4–6 min, being 40–42 times faster than the
conventional method. The results are summarized in
Table 1.
Reaction of coumarin derivative of 3 with ethyl
acetoacetate in ethanol and in the presence of a catalytic
amount of piperidine or under microwave irradiation
afforded pyran derivative 4 (Scheme 1). On the other
hand, treating of the reaction mixture of 3 and ethyl
acetoacetate under conventional or microwave heating in
the presence of ammonium acetate afforded the
corresponding pyridine derivative 5. The structures of
RESULT AND DISCUSSION
Continuing our efforts [15–17] directed toward the
synthesis of new heterocyclic compounds with
anticipated biological activities, we report in this study a
highly efficient method for the synthesis of a series of
pyran and pyridine derivatives bearing coumarin moiety.
The substituted chalconated coumarin derivatives 3a,b
compounds
4 and 5 were confirmed from their
microanalytical and spectral data. Their IR spectra
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
New Coumarin Derivatives as Potent Anticancer Agents under
Microwave Irradiation
Scheme 2
Table 1
Comparison between conventional and microwave irradiation method.
Yield (%)
Time (min)
Comp.
Ar
X
Y
Z
Ca
Mb
Ca
Mb
4
5
6
7
p-C6H4-OCH3
p-C6H4-OCH3
p-C6H4-OCH3
p-C6H4-OCH3
p-C6H4-OCH3
p-C6H4-OCH3
p-C6H4-Cl
O
N
O
N
N
O
O
O
N
OH
CH3
OH
OH
OH
NH2
NH2
NH2
OH
COCH3
COOC2H5
COOC2H5
CN
COOC2H5
CN
CN
CN
COPh
59
69
57
68
63
54
65
67
60
85
93
86
91
89
88
91
92
88
360
480
420
480
360
540
480
420
360
3
4
3
4
4
6
4
4
4
8
9a
9b
10
11
p-C6H4-OCH3
p-C6H4-OCH3
aC, conventional.
bM, microwave.
showed the absorption frequencies for the C=O groups,
beside the N–H group for compound 5. The H NMR
acetate yielded pyridine derivative 8 (Scheme 2). The
spectral properties of the new products 6–8 are in
agreement with their proposed structures. Thus, their
carbonyl groups produced absorption bands at
1676–1726 cmÀ1, and in addition to NH groups of
compounds 7 and 8 that they give rise to bands in the
range 3108–3349 cmÀ1, beside an absorption band at
2211 cmÀ1 corresponds to the CN group for compound
1
spectra displayed signals for aliphatic and aromatic
protons as well as acidic NH proton in the downfield
region that were exchangeable with D2O for
compound 5.
Treatment of α-enone 3 with ethyl cyanoacetate in
boiling ethanol and in the presence of a catalytic
amount of piperidine produced pyran derivative 6.
Moreover, treating of 3 with ethyl cyanoacetate in
boiling ethanol in the presence of an equivalent amount
of ammonium acetate gave pyridine derivative 7. On
the other hand, the reaction of a mixture of chalcone 3,
ethyl cyanoacetate, or malononitrile and ammonium
1
7 in their infrared (IR) spectra. Their H NMR spectra
revealed signals for alkyl and aryl protons in addition
to NH protons in the downfield region for pyridine
derivatives 7 and 8.
Further aspect of reactivity of α,β-unsaturated ketone 3
in the synthesis of the target pyran and pyridine
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A. M. El-Naggar, M. M. Hemdan, and S. R. Atta-Allah
Vol 000
derivatives was gained from its reactions with
CONCLUSION
malononitrile under different conditions and reagents.
Thus, its reaction with malononitrile in refluxing ethanol
or under microwave heating in the presence of a catalytic
amount of piperidine or an equivalent amount of
ammonium acetate leads to pyran and pyridine
derivatives 9a,b and 10, respectively. Moreover, heating
of chalcone 3 with an equivalent amount of ethyl
benzoylacetate in the presence of ammonium acetate
furnished pyridine derivatives 11 (Scheme 2). The
structures of newly synthesized compounds were
elucidated from their IR, NMR, mass spectral studies,
and elemental analysis (see Experimental section). The
formation of the derivatives of pyran and pyridine 4–11
obviously proceeded via Michael addition of the
carbanion formed from the active methylene compound
by the action of bases (piperidine or ammonium acetate)
to the β-carbon atom of chalcone 3 followed by
cyclization to the target heterocycles.
In summary, we have developed a simple, novel, and
ecofriendly synthetic protocols for the synthesis of pyran
and pyridine derivatives bearing coumarin moiety using
microwave irradiation technology that provides higher
yields in shorter reaction time with the simplicity of the
procedures in addition to the anticancer evaluation of
these compounds that afforded good results.
ANTICANCER ACTIVITY
All the newly synthesized compounds (3–16) were
screened for their anticancer activity in vitro against two
representative cell lines of HePG-2 (human hepatocellular
carcinoma) and MCF-7 (human breast cancer). The
results were expressed as growth inhibitory concentration
(IC50) values, which represent the compounds’
concentrations required to produce a 50% inhibition of
cell growth after 72 h of incubation, compared with
untreated controls (Table 2). The pyridine derivative 10
exhibited a promising activity against HCT-116 with
Additionally, in the present work, we synthesized some
new heterocyclic compounds. Compound 9a was
condensed with different electrophiles, namely
triethylorthoformate,
phenylisothiocyanate,
carbon
disulfide, benzoylchloride, and acetylchloride afforded the
corresponding chromen derivatives 12–16, respectively
(Scheme 3).
(IC50 = 9.9
respectively. Compounds
cytotoxic activities against HCT-116 (IC50 = 31.3 2.37
0.82) and MCF-7 (IC50 = 14.1
1.14),
4
and displayed high
5
Scheme 3
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New Coumarin Derivatives as Potent Anticancer Agents under
Microwave Irradiation
Table 2
Mercury VX-300 and Bruker Avance III NMR
spectrometer, respectively, while 13C NMR spectra were
run at 75 MHz. tetramethylsilane was used as an internal
standard in deuterated dimethylsulfoxide (DMSO-d6).
Chemical shifts (δ) are quoted in ppm. The abbreviations
used are as follows: s, singlet; d, doublet; m, multiplet.
All coupling constant (J) values are given in Hertz. The
mass spectra were recorded on Shimadzu GCMS-QP-
1000EX mass spectrometer at 70 eV. Elemental analyses
were performed on CHN analyzer, and all compounds
were within 0.4 of the theoretical values. The reactions
were monitored by thin-layer chromatography (TLC)
using TLC sheets coated with UV fluorescent silica gel
Merck 60 F254 plates and were visualized using UV
lamp and different solvents as mobile phases. All
reagents and solvents were purified and dried by standard
techniques. All the newly synthesized compounds gave
Cytotoxic activity of some compounds against human tumor cells.
In vitro cytotoxicity IC50 (μg/mL)a
Compounds
HCT-116
MCF-7
3
4
5
6
7
8
9
58.8 3.10
31.3 2.37
26.3 2.28
46.3 2.58
86.8 4.15
45.5 2.25
38.9 2.00
9.9 0.82
70.9 3.73
40 0.21
41.4 3.05
27.4 1.97
50.5 3.62
42.5 2.04
72.9 3.76
46 2.33
43.8 2.11
14.1 1.14
>100
10
11
5-FU
38.4 0.17
5-FU, 5-fluorouracil.
aIC50 (μg/mL): 1–10 (very strong), 11–20 (strong), 21–50 (moderate), 51–
100 (weak), and above 100 (noncytotoxic).
satisfactory elemental analysis. Compound
previously reported [19].
3
was
and 26.3
2.28). Compounds 6, 8, and 9 revealed a
General procedure of synthesis of coumarin derivatives
4–11.
moderate activity toward the two cell lines. Pyridine
derivatives 7 gave weak activity against both HCT-116
and MCF-7; on the other hand, pyridine derivative 11
1. Conventional method.
showed
a
weak activity against HCT-116 and
A mixture of chalcone 3 (1 mmol) and active methylene
noncytotoxic activity against MCF-7 cell lines.
Furthermore, chalcone derivative 3 exerts weak activity
against HCT-116 and a moderate activity against MCF-7
(Fig. 1).
compounds,
namely
ethyl
cyanoacetate,
ethyl
benzoylacetate, and malononitrile (1 mmol), in the
presence of piperidine or ammonium acetate as catalyst
was refluxed in (30 mL) ethanol. The reaction mixture
was cooled to room temperature to give solid product that
was collected by filtration, washed with water, and then
recrystallized from a suitable solvent to give compounds
4–11.
EXPERIMENTAL
Chemistry.
All melting points were measured on a
Gallenkamp melting point apparatus (England) and were
uncorrected. The Microwave reactions were carried out
by Microsynth instrument type MA143 (Micro wave
flux). The IR spectra were recorded on a Pye-Unicam SP-
3-300 infrared spectrophotometer (potassium bromide
2. Microwave method.
A mixture of chalcone 3 (1 mmol) and active methylene
2 (1 mmol), namely malononitrile, ethyl cyanoacetate,
ethyl benzoylacetate, and malononitrile, respectively, in
the presence of piperidine or ammonium acetate as
catalyst and 2 mL of ethylene glycol were added to the
reaction vessel of the monomodal Emrys TM Creator
microwave synthesizer and allowed to react under
microwave irradiation at 200–400 W power and 120°C
for several minutes. The automatic mode stirring helped
in mixing and uniform the heating of the reactants. The
reaction vessel was cooled to room temperature. The
solid compound was collected by filtration, washed with
water, and recrystallized from DMF and ethanol mixture
to give pure products 4–11.
1
dicks) and expressed in wavenumber (cmÀ1). H NMR
spectra were run at 300 and 400 MHz, on a Varian
3-(5-Acetyl-4-(4-methoxyphenyl)-6-oxo-6H-pyran-2-yl)-2H–
chromen-2-one (4).
Yield: (i) 85%, (ii) 59%, yellow
crystals; m.p. >300°C; IR (KBr, cmÀ1): 3109 (C–Haryl),
2933 (C–Halkyl), 1721 (C=O chromen), 1676 (C=O
1
amide); H NMR (DMSO-d6): δ = 1.26 (s, 3H, CH3CO),
Figure 1. Anticancer activity of the synthesized compounds. [Color
figure can be viewed at wileyonlinelibrary.com]
3.72 (s, 3H, OCH3), 7.27 (s, 1H, Pyran-H), 7.51–7.65 (m,
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A. M. El-Naggar, M. M. Hemdan, and S. R. Atta-Allah
Vol 000
7H, Ar–H), 8.08 (s, 1H, chromen-H), 8.14 (d, 1H,
J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ = 32.4,
67.1, 115.2 (2), 115.9, 116.7, 118.0, 119.8, 123.9, 125.2,
126.4, 129.1, 129.7, 131.6 (2), 132.8, 133.7, 144.5,
150.4, 155.1, 160.3, 164.4, 171.2; Anal. Calcd for
C23H16O6 (388.4): C, 71.13; H, 4.15; Found: C, 69.89;
H, 4.05%.
3108 (NH), 3046 (C–Haryl), 2929 (C–Halkyl), 1726 (C=O
chromen), 1680 (C=O); 1H NMR (CDCl3): δ = 1.26
(t, 3H, CH3CH2), 3.74 (s, 3H, OCH3), 3.90
(q, 2H, CH3CH2–), 7.40–7.82 (m, 8H, Ar–H), 8.20
(s, 1H, Pyran-H), 8.38 (d, 1H, J = 8.4 Hz), 8.57 (s, 1H,
chromen-H); 11.19 (br. s, 1H, NH, exchangeable with
D2O); 13C NMR (100 MHz, DMSO-d6): δ = 14.9, 55.7,
65.9, 103.4, 115.0 (2), 116.7, 118.0, 126.3, 129.2, 129.5,
131.4 (2), 133.7, 144.5, 150.5, 155.3, 160.2, 168.7; Anal.
Calcd for C24H19NO6: C, 69.06; H, 4.59; N, 3.36. Found:
C, 68.89; H, 4.41; N, 3.28%.
Ethyl 4-(4-methoxyphenyl)-2-methyl-6-(2-oxo-2H-chromen-
3-yl)nicotinate (5).
Yield (i) 93%, (ii) 69%, yellow
crystals; m.p. >300°C; IR (KBr, cmÀ1): 3220 (NH),
3076 (C–Haryl), 2978 (C–Halkyl), 1723 (C=O chromen),
1
1677 (C=O); H NMR (400 MHz, CDCl3): δ = 1.25 (t,
2-Amino-4-(4-methoxyphenyl)-6-(2-oxo-2H-chromen-3-yl)-
3H, CH3CH2), 2.70 (s, 3H, CH3), 3.74 (q, 2H,
CH3CH2) 3.86 (s, 3H, OCH3), 7.37–7.65 (m, 9H,
Ar–H), 8.02 (s, 1H, pyridine-H), 8.08 (s, 1H, chromen-
H), 8.14 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz,
DMSO-d6): δ = 14.9, 20.2, 44.0, 56.4, 65.9, 115.0 (2),
116.7, 118.0, 119.8, 126.4, 129.1, 129.7, 131.6 (2),
132.8, 133.7, 144.5, 150.4, 155.1, 160.3, 165.6, 168.2;
MS (EI, 70 eV): m/z (%) = 418 [M+ + 1, 5], 341 (33),
290 (100); Anal. Calcd for C25H23NO5 (417.45): C,
71.93; H, 5.55; N, 3.36. Found: C, 71.77; H, 5.45; N,
3.23%.
4H-pyran-3-carbonitrile (9).
Yield (i) 88%, (ii) 54%,
yellow crystals; m.p. 267–268°C; IR (KBr, cmÀ1): 3361
(NH), 3036 (C–Haryl), 2924 (C–Halkyl), 2213 (CN), 1724
(C=O chromen), 1676 (C=O); 1H NMR (400 MHz,
DMSO-d6): δ = 3.54 (d, 1H, Pyran-H), 3.83 (s, 3H,
OCH3), 6.94 (d, 1H, Pyran-H), 7.10 (d, 2H, J = 8.4 Hz),
7.42–7.86 (m, 4H, Ar–H), 8.41 (d, 2H, J = 8.4 Hz), 8.60
(s, 1H, chromen-H), 11.21 (br.s, 1H, =NH, exchangeable
with D2O); 13C NMR (100 MHz, DMSO-d6): δ = 30.2,
55.0, 65.9, 102.4, 115.0 (2), 116.7, 118.0, 119.8, 126.4
(2), 129.1, 129.7, 131.6 (2), 132.8, 133.7, 144.5, 150.4,
155.1, 160.3, 165.6; MS (EI, 70 eV): m/z (%) = 372 [M+,
10], 356 (100); Anal. Calcd for C22H16N2O4 (372.4) C,
70.96; H, 4.33; N, 7.52; Found: C, 70.75; H, 4.24; N,
7.44%.
Ethyl 4-(4-methoxyphenyl)-2-oxo-6-(2-oxo-2H-chromen-3-
yl)-2H–pyran-3-carboxylate (6). Yield (i) 86%, (ii) 57%,
yellow crystals; m.p. 287–289°C; IR (KBr, cmÀ1): 3068
(C–Haryl), 2923 (C–Halkyl), 1722 (C=O chromen), 1676
1
(C=O); H NMR (400 MHz, DMSO-d6): δ = 1.25 (t, 3H,
2-Amino-4-(4-chlorophenyl)-6-(2-oxo-2H-chromen-3-yl)-
CH3CH2–), 3.75 (s, 3H, OCH3), 4.23 (q, 2H, CH3CH2–),
7.46–8.40 (m, 8H, Ar–H), 7.59 (s, 1H, Pyran-H), 8.94 (s,
1H, chromen-H); 13C NMR (100 MHz, DMSO-d6):
δ = 14.7, 55.2, 65.0, 114.6, 115.0 (2), 116.7, 118.0, 119.8
(2), 126.4, 126.7, 128.5, 129.3, 131.6, 132.9, 132.8 (2),
146.5, 150.4, 155.1, 160.3, 165.6, 168.4; MS (EI,
70 eV): m/z (%) = 417 [M+-1, 1], 357 (45), 84 (100);
Anal. Calcd for C24H18O7 (418.4): C, 68.90; H, 4.34;
Found: C, 68.76; H, 4.24%.
4H-pyran-3-carbonitrile (9).
Yield (i) 91%, (ii) 65%,
yellow crystals; m.p. 198–200°C; IR (KBr, cmÀ1): 3349,
3242 (NH), 3081 (C–Haryl), 2836 (C–Halkyl), 2218 (CN),
1
1738 (C=O chromen), 1645 (C=O); H NMR (400 MHz,
DMSO-d6): δ = 3.49 (d, 1H, Pyran-H), 6.95 (d, 1H,
Pyran-H), 7.61 (d, 2H, Ar–H, J = 8 Hz), 7.77 (br. s, 2H,
NH2, exchangeable with D2O), 7.91–7.94 (m, 4H, Ar–H),
8.15 (s, 1H, chromen); 13C NMR (100 MHz, DMSO-d6):
δ = 31.9, 60.0, 101.4, 117.6, 116.2, 115.2, 118.9 (2),
120.0, 126.1, 126.7, 128.0, 128.5, 129.8 (2), 134.4 (2),
135.1, 142.7, 154.7, 160.6, 162.8; Anal. Calcd for
C21H13ClN2O3 (376.8): C, 66.94; H, 3.48; N, 7.43;
Found: C, 66.77; H, 3.31; N, 7.35%.
4-(4-Methoxyphenyl)-2-oxo-6-(2-oxo-2H-chromen-3-yl)-1,2-
dihydropyridine-3-carbonitrile (7). Yield (i) 91%, (ii) 68%,
yellow crystals; m.p. over 300°C; IR (KBr, cmÀ1): 3108
(NH), 3046 (C–Haryl), 2929 (C–Halkyl), 1726 (C=O
1
chromen), 1680 (C=O); H NMR (400 MHz, DMSO-d6):
2-Amino-4-(4-methoxyphenyl)-6-(2-oxo-2H-chromen-3-yl)
δ = 3.74 (s, 3H, OCH3), 7.46–8.28 (m, 8H, Ar–H), 8.58
(s, 1H, Pyran-H), 8.98 (s, 1H, chromen-H); 11.40 (br. s,
1H, NH, exchangeable with D2O); MS (EI, 70 eV): m/z
(%) = 370 [M+, 100], 342 (27), 236 (77); 13C NMR
(100 MHz, DMSO-d6): δ = 55.6, 102.5, 115.0 (2), 116.4,
116.9, 118.0 (2), 119.8, 125.2, 126.4 (2), 129.1 (2), 131.6
(2), 132.8, 137.7, 153.6, 155.4, 160.3, 165.6; Anal. Calcd
for C22H14N2O4 (370.36): C, 71.35; H, 3.81; N, 7.56.
Found: C, 71.01; H, 3.76; N, 7.49%.
nicotinonitrile (10).
Yield (i) 92%, (ii) 67%, yellow
crystals; m.p. >300°C; IR (KBr, cmÀ1): 3349, 3239
(NH), 3036 (C–Haryl), 2925 (C–Halkyl), 2205 (CN), 1724
(C=O chromen), 1685 (C=O); 1H NMR (DMSO-d6):
δ = 3.86 (s, 3H, OCH3), 7.54–7.65 (m, 7H, Ar–H),
7.76–7.85 (m, 3H, Ar–H), 8.9 (br. s, 2H, NH2,
exchangeable with D2O); 13C NMR (100 MHz,
DMSO-d6): δ = 30.9, 60.5, 102.4, 117.4, 116.1, 115.3,
118.7 (2), 120.2, 126.4, 126.5, 128.1, 128.7, 129.6 (2),
134.5 (2), 135.3, 142.2, 155.4, 160.1, 162.4; Anal. Calcd
for C22H15N3O3: (369.4) C, 71.54; H, 4.09; N, 11.38.
Found: C, 71.30; H, 4.00; N, 11.25%.
Ethyl 4-(4-methoxyphenyl)-2-oxo-6-(2-oxo-2H-chromen-3-
yl)-1,2-dihydropyridine-3-carboxylate (8).
Yield (i) 89%,
(ii) 63%, yellow crystals; m.p. >300°C; IR (KBr, cmÀ1):
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New Coumarin Derivatives as Potent Anticancer Agents under
Microwave Irradiation
3-Benzoyl-4-(4-methoxyphenyl)-6-(2-oxo-2H-chromen-3-yl)-
3,4-dihydropyridin-2(1H)-one (11).
C28H18ClN3O3S (512.0): C, 65.69; H, 3.54; N, 8.21;
Found: C, 65.44; H, 3.46; N, 8.11%.
Yield (i) 88%, (ii)
60%, yellow crystals; m.p. >300°C; IR (KBr, cmÀ1):
3107 (NH), 3041 (C–Haryl), 2928 (C–Halkyl), 1723
(C=O chromen), 1677 (C=O); 1H NMR (400 MHz,
DMSO-d6): δ = 3.17 (m, 1H), 3.76 (m, 1H), 3.88 (s,
3H, OCH3), 6.94 (s, 1H, pyridine-H), 6.97 (d, 2H,
J = 8.4 Hz), 7.27–8.28 (m, 13H, Ar–H), 9.14 (s, 1H,
chromen-H), 11.40 (br. s, 1H, NH, exchangeable with
D2O); 13C NMR (100 MHz, DMSO-d6): δ = 55.9,
102.3, 115.0 (2), 116.7, 118.0, 119.8, 126.4, 126.9,
129.1, 129.7, 130.4, 131.6 (2), 132.8 (2), 134.5, 133.7,
139.3 (2), 142.8, 144.5, 150.4, 155.1, 160.3, 165.6,
168.2, 192.4; Anal. Calcd for C28H21NO5 (451.47): C,
74.49; H, 4.69; N, 3.10. Found: C, 74.35; H, 4.51; N,
3.01%.
Formation of 3-(5-(4-chlorophenyl)-2,4-dithioxo-1,3,4,5-
tetrahydro-2H-pyrano[2,3-d]pyrimidin-7-yl)-2H-chromen-2-
one (14).
A mixture of 9a (10 mmol), potassium
hydroxide (15 mmol), and excess of carbon disulfide
(0.02 mol) in ethanol (50 mL) were refluxed on water
bath for 7 h. On cooling, the concentrated solution was
poured onto ice water (50 mL) and acidified with conc.
HCl. The crude product was filtered, dried, and
crystallized from ethanol.
Yield 67%, yellow crystals; m.p. 178–180°C; IR (KBr,
cmÀ1): 3036 (C–Haryl), 2847 (C–Halkyl), 2221 (CN), 1739
(CO), 1455 (C=S); 1H NMR (400 MHz, DMSO-d6):
δ = 3.41 (d, 1H, Pyran-H), 6.86 (br. s, 1H, NH,
exchangeable with D2O), 6.95 (d, 1H, Pyran-H),
7.34–7.79 (m, 8H, Ar–H), 8.35 (s, 1H, chromen-H), 8.73
(br. s, 1H, NH, exchangeable with D2O); 13C NMR
(100 MHz, DMSO-d6): δ = 49.7, 93.2, 95.1, 117.4,
118.9, 125.3, 126.0, 126.7, 128.8 (2), 130.1 (2), 130.7,
131.6, 131.9, 142.4, 154.6, 158.1, 160.6, 165.9, 169.2,
185.6; Anal. Calcd for C22H13ClN2O3S2 (452.9): C,
58.34; H, 2.89; N, 6.19; Found: C, 58.07; H, 2.70; N,
6.08%.
Formation of ethyl-N-(4-(4-chlorophenyl)-3-cyano-6-(2-oxo-
2H-chromen-3-yl)-4H-pyran-2-yl)formimidate
(12).
A
mixture of 9a (10 mmol) and triethylorthoformate
(20 mmol) in dry acetic anhydride (20 mL) was heated
under reflux for 10 h. Then, the reaction mixture was
poured onto ice (50 g). The resulting solid was collected
and crystallized from ethanol. Yield 75%, yellow crystals;
m.p. >199–200°C; IR (KBr, cmÀ1): 3036 (C–Haryl),
2852 (C–Halkyl), 2214 (CN), 1719 (CO); 1H NMR
(400 MHz, DMSO-d6): δ = 1.17 (t, 3H, CH3), 4.12 (q,
2H, CH2), 4.13 (s, 1H, Pyran-H), 7.31 (d, 1H,
J = 8.4 Hz), 7.33 (s, 1H, Pyran-H), 8.06 (s, 1H, chromen-
H), 8.07 (s, 1H, CH=), 8.22 (d, 2H, J = 8 Hz), 8.23
(d, 2H, J = 8.4 Hz), 8.25 (d, 2H, J = 8.4 Hz); 13C NMR
(100 MHz, DMSO-d6): δ = 16.9, 31.2, 65.0, 78.4, 101.9,
116.0, 118.7, 126.0, 126.8, 129.4, 130.1, 130.7 (2), 133.6
(2), 134.4, 134.7, 135.5, 142.4, 154.1, 155.6, 156.9,
158.2, 171.6; Anal. Calcd for C24H17ClN2O4 (432.9): C,
66.60; H, 3.96; Cl, 8.19; N, 6.47; Found: C, 66.38; H,
3.78; N, 6.38%.
Formation of N-(4-(4-chlorophenyl)-3-cyano-6-(2-oxo-2H-
chromen-3-yl)-4H-pyran-2-yl)benzamide (15).
A mixture
of 9a (10 mmol) and benzoyl chloride (10 mmol) in dry
acetone (30 mL) was refluxed for 10 h and then left to
cool to room temperature. The formed precipitate was
filtered and crystallized from ethanol to give compound
15. Yield 78%, yellow crystals; m.p. 190–192°C; IR
(KBr, cmÀ1): 3243 (NH), 3041 (C–Haryl), 2928
(C–Halkyl), 2220 (CN), 1723 (C=O chromen), 1677
(C=O amide); 1H NMR (400 MHz, DMSO-d6):
δ = 2.46 (s, 1H, CH3), 3.83 (d, 1H, Pyran-H), 6.95 (d,
1H, Pyran-H), 7.40–8.84 (m, 12H, Ar–H), 8.60 (s, 1H,
chromen-H), 11.20 (br. s, 1H, NH, exchangeable with
D2O); 13C NMR (100 MHz, DMSO-d6): δ = 30.9, 63.2,
101.3, 117.2, 119.5, 120.1, 125.3, 125.8, 126.2, 127.8
(2), 128.5 (2), 130.4 (3), 132.7 (2), 133.1, 135.2, 136.1,
140.7, 142.6, 151.2, 153.6, 155.4, 161.3, 165.2; Anal.
Calcd for C28H17ClN2O4 (480.9): C, 65.96; H, 3.61; N,
6.69; Found: C, 65.78; H, 3.70; N, 6.55%.
Formation of 3-(5-(4-chlorophenyl)-4-imino-3-phenyl-2-
thioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidin-7-yl)-2H-
chromen-2-one (13).
A mixture of 9a (10 mmol) and
phenylisothiocyanate (10 mmol) in dry acetone (30 mL)
containing a catalytic amount of triethylamine (4–6)
drops was refluxed for 10 h. On cooling, the formed
precipitate was filtered and crystallized from ethanol to
afford compound 13. Yield 77%, yellow crystals; m.p.
>223–225°C; IR (KBr, cmÀ1): 3038 (C–Haryl), 2853
Formation of N-(4-(4-chlorophenyl)-3-cyano-6-(2-oxo-2H-
chromen-3-yl)-4H-pyran-2-yl)acetamide (16). A mixture of
1
9a (10 mmol) and acetylchloride (10 mmol) in dry
acetone (30 mL) was refluxed for 10 h and then left to
cool to room temperature. The formed precipitate was
filtered and crystallized from ethanol to give the
corresponding derivative 16. Yield 72%, yellow crystals;
m.p. 153–155°C; IR (KBr, cmÀ1): 3243 (NH), 3041
(C–Haryl), 2928 (C–Halkyl), 2220 (CN), 1723, 1677
(C–Halkyl), 2220 (CN), 1737 (CO); H NMR (400 MHz,
DMSO-d6): δ = 3.23 (s, 1H, Pyran-H), 6.95 (s,
1H, Pyran-H), 7.40–7.84 (m, 12H, Ar–H), 8.32 (d, 1H,
J = 8.4 Hz), 8.57 (s, 1H, chromen-H), 11.18 (br. s, 1H,
NH, exchangeable with D2O); 13C NMR (100 MHz,
DMSO-d6): δ = 30.9, 75.2, 102.0, 116.4, 118.9, 116.0,
126.0, 126.7, 128.8, 129.4, 130.1 (2), 130.7, 131.6 (2),
132.4 (2), 134.7 (2), 135.5, 140.4, 142.6, 146.6, 158.1,
159.6, 156.9, 158.2, 176.6; Anal. Calcd for
1
(C=O); H NMR (400 MHz, DMSO-d6): δ = 2.46 (s, 1H,
CH3), 3.31 (d, 1H, Pyran-H), .6.95 (d, 1H, Pyran-H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. M. El-Naggar, M. M. Hemdan, and S. R. Atta-Allah
Vol 000
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Acknowledgments. Authors are thankful to Mr Ahmed Abbas
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet