Synthesis and antimicrobial activity of some novel 4-hydroxyquinolin-2(1H)- ones and pyrano[3,2-c] quinolinones from 3-(1-ethy1-4-hydroxy-2-oxo-1,2- dihydroquinolin-3-yl)-3-oxopropanoic acid

Article abstract of DOI:10.3906/kim-1111-14

Chlorination, bromination, and condensation reactions of 3-(1-ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid (3) were studied. Some novel 4-hydroxyquinolin-2(1H) -ones and pyrano[3,2-c] quinolin-2(1H) -ones were also prepared. The str

Full text of DOI:10.3906/kim-1111-14

Turk J Chem
36 (2012) , 682 – 699.
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˙
c
ꢀ TUBITAK
doi:10.3906/kim-1111-14
Synthesis and antimicrobial activity of some novel
4-hydroxyquinolin-2(1H)-ones and pyrano[3,2-c]
quinolinones from 3-(1-ethy1-4-hydroxy-2-oxo-1,2-
dihydroquinolin-3-yl)-3-oxopropanoic
acid
Hany Mohamed HASSANIN, Magdy Ahmed IBRAHIM∗,
Youssef Abdel-Salam ALNAMER
Department of Chemistry, Faculty of Education, Ain Shams University,
Roxy 11711, Cairo-EGYPT
e-mail: magdy ahmed1977@yahoo.com
Received: 05.11.2011
Chlorination, bromination, and condensation reactions of 3-(1-ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-
3-yl)-3-oxopropanoic acid (3) were studied. Some novel 4-hydroxyquinolin-2(1H)-ones and pyrano[3,2-
c]quinolin-2(1H)-ones were also prepared. The structures of the novel compounds were established by
elemental analyses and spectral data. All the products were also screened in vitro for their antimicrobial
activity.
Key Words: β -Ketoacid, 4-hydroxyquinolin-2(1H)-one, pyrano[3,2-c]quinolinone, condensation reactions
Introduction
Pyranoquinolinones constitute the parent ring structure of pyranoquinoline alkaloids, which occur in the plant
family Rutaceae. These pyranoquinoline alkaloids have gained considerable importance due to their pharma-
ceutical activities like anticoagulant,1 coronary constricting,2 and antifungal.3 Pyrano[3,2-c]quinolinones were
found to be active against certain immuno-reaction diseases, in particular against immediate hypersensitivity
reactions (anaphylaxis).4 In turn, these pyranoquinolinones were used to obtain 4-hydroxyquinolin-2(1H)-ones
∗Corresponding author
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Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
and 3-acetyl-4-hydroxyquinolin-2(1H)-one derivatives.5,6 Moreover, a broad number of important pharmaco-
logical activities have been associated with 3-substituted-4-hydroxyquinolin-2(1H)-ones.7−9 Many derivatives
of this heterocyclic category are biologically active naturally occurring compounds, which were found to be useful
intermediates for many medicinal products.10,11 Heating N -ethylaniline with 2 equivalent diethylmalonate gave
4-hydroxypyrano[3,2-c]quinolin-2(1H)-one 2 in a one-pot double cyclocondensation process.12,13 In our previ-
ous work, 3-(1-ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxo-propanoic acid (3) was prepared (Scheme
1) and its chemical reactivity was studied towards some o-hydroxyaldehydes and o-aminoaldehydes.14 In the
present work, the chemical reactivity of β-ketoacid 3 was studied towards some electrophilic and condensation
reactions, aiming to obtain a new multi-functionalized quinolinone and pyrano[3,2-c]quinolinone derivatives and
the antimicrobial activity of the synthesized products was evaluated.
O
OH
O
O
O
COOEt
O
i) 1N NaOH, 40-50 oC
ii) dil. HCl
OH
COOEt
Fusion
OH
NH
Et
76%
N
Et
N
Et
2
O
1
3
Scheme 1. Formation of β -ketoacid 3.
Experimental
Melting points were determined on a digital Stuart SMP3 apparatus. Infrared spectra were measured on a
Perkin-Elmer 293 spectrophotometer (cm−1), using KBr disks. 1 H-NMR spectra were measured on a Gemini-
200 spectrometer (200 MHz), Mercury-300BB (300 MHz), and/or Jeol Eca-500 MHz using DMSO-d6 as a
solvent and TMS (δ) as the internal standard. Mass spectra were obtained using a GC-2010 Shimadzu Gas
chromatography instrument mass spectrometer (70 eV). Elemental microanalyses were performed on a Perkin-
Elmer CHN-2400 analyzer.
3-(1-Ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxo-propanoic acid (3)
This compound was prepared according to our published method.14
3-(2,2-Dichloroacetyl)-1-ethyl-4-hydroxyquinolin-2(1H)-one (5)
To a suspension of β-ketoacid 3 (0.55 g, 2 mmol) in 1,4-dioxane (30 mL), sulfuryl chloride (2 mmol) was
added portionwise, while the temperature was not allowed to rise above 40 ◦ C. Then the reaction mixture was
stirred for 1 h at room temperature and poured on ice-H2 O (200 mL). The formed precipitate was collected
by filtration and crystallized from ethanol to give compound 5 as yellow crystals, yield (0.39 g, 59%), mp
185 ◦ C (lit. 184-186 ◦ C).15,16 IR (KBr, cm−1): 3390 (OH), 3071 (CHarom. ), 2935, 2895 (CHaliphatic), 1656
(2C=O), 1604 (C=C). 1 H-NMR (DMSO-d6 , δ): 1.17 (t, 3H, J = 6.5 Hz, CH2 CH 3), 4.23 (q, 2H, J = 6.5 Hz,
683

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
CH 2 CH3), 7.35 (t, 1H,J = 7.6 Hz, H-6), 7.62 (d, 1H,J = 7.6 Hz, H-8), 7.83 (t, 1H,J = 7.6 Hz, H-7), 7.87 (s,
1H, CHCl2), 8.14 (d, 1H,J = 7.6 Hz, H-5).
3-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-2,2-dibromo-3-oxopropanoic acid (6)
A solution of bromine (2 mmol) in acetic acid (10 mL) was added dropwise to a solution of β-ketoacid 3 (0.55
g, 2 mmol) in acetic acid (10 mL). The reaction mixture was heated under reflux for 2 h. The solid obtained
after cooling was filtered and recrystallized from ethanol to give 6 as yellow crystals, yield (0.37 g, 43%), mp
240 ◦ C. IR (KBr, cm−1): 3414 (2OH), 3084 (CHarom.), 2980, 2933, 2867 (CHaliphatic), 1719 (C=Oacid), 1672
(C=Oquinoline), 1617 (C=Oketone). 1 H-NMR (DMSO-d6 , δ): 1.27 (t, 3H, J = 7.2 Hz, CH2 CH 3), 4.34 (q,
2H, J = 7.2 Hz, CH 2 CH3), 7.50 (t, 1H, J = 6.4 Hz, H-6), 7.82-7.88 (m, 2H, H-7 and H-8), 8.11 (d, 1H, J
= 7.8 Hz, H-5), 14.42 (br, 2H, 2OH exchangeable with D2 O). Anal. Calcd for C14 H11 Br2 NO5 (433.06): C,
38.83; H, 2.56; N, 3.23; Br, 36.90%. Found C, 38.52; H, 2.65; N, 3.35; Br, 36.55%.
3,3-Dibromo-6-ethylpyrano[3,2-c]quinoline-2,4,5(3H,6H)-trione (8)
Method A
Compound 6 (0.87 g, 2 mmol) in concentrated H2 SO4 (5 mL) was stirred at room temperature for 1 h.
The dark reddish solution was poured onto ice/water, and the precipitate so formed was filtered, washed several
times with water, and crystallized from ethanol to give 8 as yellow crystals, yield (0.46 g, 55%), mp 205 ◦ C.
Method B
A solution of bromine (2 mmol) in acetic acid (10 mL) was added dropwise to a solution of compound
2 (0.51 g, 2 mmol) in acetic acid (10 mL). The reaction mixture was heated under reflux for 2 h. The solid
obtained after cooling was filtered and recrystallized from ethanol to give 8 as yellow crystals, yield (0.34 g,
62%), mp 204-205 ◦ C. IR (KBr, cm−1): 3074 (CHarom. ), 2980, 2934 (CHaliphatic), 1730 (OC=O), 1669 (2C=
O), 1612 (C=C). 1 H-NMR (DMSO-d6 , δ): 1.36 (t, 3H, CH2 CH 3), 4.44 (q, 2H, CH 2 CH3), 7.58 (br, 1H,
Ar-H), 7.93 (br, 2H, Ar-H), 8.16 (br, 1H, Ar-H). M/z (relative intensity): 335 [M-Br; 43], 306 (13), 228 (9), 188
(5), 172 (100), 144 (32), 119 (21), 114 (23), 101 (33), 90 (31), 77 (77), 64 (39). Anal. Calcd for C14 H9 Br2 NO4
(415.04): C, 40.52; H, 2.15; Br, 38.50; N, 3.37%. Found C, 40.28; H, 2.03; Br, 38.01; N, 3.29%.
3-(2,2-Dibromoacetyl)-1-ethyl-4-hydroxyquinolin-2(1H)-one (9)
Compound 8 (0.83 g, 2 mmol) was dissolved in 2 M aqueous sodium hydroxide solution (50 mL) and heated
under reflux for 3 h. The solution obtained after cooling was acidified with conc. hydrochloric acid. The
precipitated so formed was filtered, washed with water, air dried, and crystallized from AcOH to give 9 as
white crystals, yield (0.48 g, 62%), mp 213 ◦ C. IR (KBr, cm−1): 3416 (OH), 3068 (CHarom.), 2922, 2870
(CHaliphatic), 1664 (2C= O), 1605 (C=C). 1 H-NMR (DMSO-d6 , δ): 1.25 (t, 3H, J = 6.9 Hz, CH2 CH 3), 4.44
(q, 2H, J = 6.9 Hz, CH 2 CH3), 6.40 (s, 1H, CHBr2), 7.42 (t, 1H,J = 7.6 Hz, H-6), 7.75-7.83 (m, 2H, H-7 and
H-8), 8.11 (d, 1H,J = 8.4 Hz, H-5). M/z (relative intensity): 317 [M-70; 42], 319 (100), 321 (39), 237 (3), 224
(6), 200 (16), 159 (3), 144 (3), 117 (9), 103 (16), 90 (6). Anal. Calcd for C13 H11 Br2 NO3 (389.05): C, 40.14;
H, 2.85; N, 3.60; Br, 41.08%. Found C, 39.83; H, 2.69; N, 3.43; Br, 40.81%.
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Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
2-Bromo-5-ethyl-3-hydroxyfuro[3,2-c]quinolin-4(5H)-one (10)
Compound 9 (0.78 g, 2 mmol) was dissolved in DMF (10 mL) containing a few drops of triethylamine and heated
under reflux for 4 h. After cooling to room temperature, the reaction mixture was poured onto ice/water. The
precipitated so formed was filtered, washed with water, air dried and crystallized from dioxane/water to give
10 as yellow crystals, yield (0.27 g, 44%), mp 266 ◦ C. IR (KBr, cm−1): 3423 (OH), 3075 (CHarom.), 2972,
2920 (CHaliphatic), 1672 (C= Oquinolinone), 1631 (C=C). 1 H-NMR (DMSO-d6 , δ): 1.13 (t, 3H, J = 6.7 Hz,
CH2 CH 3), 4.20 (q, 2H, J = 6.7 Hz, CH 2 CH3), 7.67 (d, 1H, H-6), 7.78–7.91 (m, 2H, H-7 and H-8), 8.11 (d,
1H, H-9). Anal. Calcd for C13 H10 BrNO3 (308.13): C, 50.67; H, 3.27; N, 4.55; Br, 25.93%. Found C, 50.90;
H, 3.30; N, 4.60; Br, 25.80%.
6-Ethyl-3-[(6-methyl-5-oxo-3-thioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)imino]pyrano[3,2-c]quino-
line-2,4,5(3H,6H)-trione (11)
A mixture of compound 8 (0.41 g, 1 mmol) and 4-amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one
(0.16 g, 1 mmol) in DMF (5 mL) containing a few drops of piperidine was heated under reflux for 4 h. The
solid deposited after cooling was filtered and crystallized from DMF/EtOH to give 11 as yellow crystals, yield
(0.25 g, 61%), mp 178 ◦ C. IR (KBr, cm−1): 3222 (NH), 3085 (CHarom. ), 2978, 2920 (CHaliphatic), 1728
(OC=O), 1672 (3C=O), 1618 (C=N). 1 H-NMR (DMSO-d6 , δ): 1.24 (t, 3H, J = 6.9 Hz, CH2 CH 3), 2.67 (s,
3H, CH3 triazine), 4.33 (q, 2H, J = 6.9 Hz, CH 2 CH3), 7.82 (t, 1H, H-9), 7.85-8.01 (m, 2H, H-7 and H-8), 8.09
(d, 1H, H-10), 13.43 (bs, 1H, NH exchangeable with D2 O). Anal. Calcd for C18 H13 N5 O5 S (411.3): C, 52.55;
H, 3.19; N, 17.02; S, 7.79%. Found C, 52.31; H, 3.02; N, 17.11; S, 7.67%.
2-(6-Ethyl-2,4,5-trioxo-5,6-dihydro-4H-pyrano[3,2-c]quinolin-3-ylidene)-malononitrile (12)
A mixture of compound 8 (0.41 g, 1 mmol) and malononitrile (0.07 g, 1 mmol) in DMF (5 mL) containing
a few drops of piperidine was heated under reflux for 4 h. The solid deposited after cooling was filtered and
crystallized from methanol to give 12 as yellow crystals, yield (0.20 g, 63%), mp 236 ◦ C. IR (KBr, cm−1): 3079
(CHarom. ), 2982, 2937, 2875 (CHaliphatic), 2207 (2C=N), 1737 (OC=O), 1672 (2C=O), 1614 (C=C). 1 H-NMR
(DMSO-d6 , δ): 1.21 (t, 3H, J = 7.2 Hz, CH2 CH 3), 4.24 (q, 2H, J = 6.8 Hz, CH 2 CH3), 7.32 (t, 1H, J =
7.2 Hz, H-9), 7.58 (d, 1H, J = 8.0 Hz, H-7), 7.81 (t, 1H, J = 7.2 Hz, H-8), 8.11 (d, 1H, J = 8.0 Hz, H-10).
Anal. Calcd for C17 H9 N3 O4 (319.28): C, 63.95; H, 2.84; N, 13.16%. Found C, 63.76; H, 2.63; N, 13.02%
6-Ethyl-3,3-bis-phenylsulfanyl-6H-pyrano[3,2-c]quinoline-2,4,5-trione (13)
A mixture of compound 8 (0.41 g, 1 mmol) and thiophenol (0.40 mL, 2 mmol) in DMF (5 mL) containing
a few drops of piperidine was heated under reflux for 4 h. The solid deposited after cooling was filtered and
crystallized from DMF to give 13 as yellow crystals, yield (0.26 g, 55%), mp 155 ◦ C. IR (KBr, cm−1): 3063
(CHarom. ), 2979, 2932, 2868 (CHaliphatic), 1730 (OC=O), 1670 (2C=O), 1610 (C=C). 1 H-NMR (DMSO-d6 ,
δ): 1.13 (t, 3H, CH2 CH 3), 4.28 (q, 2H, CH 2 CH3), 7.16-7.99 (m, 13H, Ar-H), 8.12 (d, 1H, H-10). M/z (relative
intensity): 472 [M-1; 5], 255 (26), 239 (100), 228 (6), 171 (14), 144 (4), 120 (6), 105 (5), 93 (7), 78 (20). Anal.
Calcd for C26 H19 NO4 S2 (473.57): C, 65.94; H, 4.04; N, 2.96; S, 13.54%. Found C, 65.61; H, 3.64; N, 2.68; S,
13.37%.
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Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
6-Ethyl-1-(methylsulfanyl)-3,5,12-trioxo-4,5,6,12-tetrahydro-3H-pyrido [2‘,3‘:4,5] pyrano[3,2-c]qui-
noline-2-carbonitrile (14)
A mixture of β-ketoacid 3 (0.55 g, 2 mmol) and bis(methylthio)methylene-malononitrile and/or bis(methylthio)
methylene-cyanoacetamide (2 mmol) in DMF (10 mL) containing a few drops of DBU was heated under reflux
for 6 h. The solid obtained after cooling was filtered, washed with methanol (10 mL), and crystallized from
DMF/H2 O to give 14 as yellow crystals, mp 201 ◦ C. IR (KBr, cm−1): 3443 (NH), 3083 (CHarom. ), 2943, 2864
(CHaliphatic), 2196 (C≡N), 1743 (OC=O), 1673 (C=Oquinolinone), 1642 (C=Opyridone). 1 H-NMR (DMSO-d6 ,
δ): 1.24 (t, 3H, J = 6.4 Hz, CH2 CH 3), 3.71 (s, 3H, SCH3), 4.32 (q, 2H,J = 6.4 Hz, CH 2 CH3), 7.31 (t, 1H,
H-9), 7.57 (d, 1H, H-7). 7.82–7.89 (m, 1H, H-8), 8.14-8.16 (m, 1H, H-10), 13.59 (b, 1H, NH exchangeable with
D2 O). M/z (relative intensity): 379 (37), 278 (100), 326 (20), 311 (61), 297 (17), 195 (35), 280 (16), 252 (13),
237 (4), 194 (12), 150 (24), 136 (25), 111 (35), 94 (23), 59 (14). Anal. Calcd for C19 H13 N3 O4 S (379.40): C,
60.15; H, 3.45; N, 11.08; S, 8.40%. Found C, 60.32; H, 3.53; N, 11.20, S, 8.37%.
2-[(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]-3-(1H-indol-3-yl)prop-2-enoic acid
(17)
A mixture of compound 3 (0.55 g, 2 mmol) and 3-formylindol (15) (0.30 g, 2 mmol), in glacial acetic acid (10
mL) containing freshly fused sodium acetate (0.2 g), was heated under reflux for 4 h. After cooling, the reaction
mixture was poured onto ice/water, and the solid deposited was filtered and crystallized from AcOH/H2 O to
give 17 as pale brown crystals, yield (0.43 g, 54%), mp 180-181 ◦ C. IR (KBr, cm−1): 3400 (2OH), 3166 (NH),
3095 (CHarom.), 2981, 2929, 2877 (CHaliphatic), 1738 (C=Oacid), 1673 (C=Oquinolinone), 1622 (C=Oketone).
1 H-NMR (DMSO-d6 , δ): 1.27 (t, 3H, CH2 CH 3), 4.38 (q, 2H, CH 2 CH3), 5.61 (s, 1H, methine proton), 7.23-
8.28 (m, 9H, Ar-H), 9.93 (br, 1H, NH exchangeable with D2 O), 12.14 (br, 1H, OHacid exchangeable with D2 O),
13.80 (br, 1H, OHquinolinone exchangeable with D2 O). Anal. Calcd for C23 H18 N2 O5 (402.41): C, 68.65; H,
4.51; N, 6.96%. Found C, 68.89; H, 4.18; N, 6.84%.
2-[(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]-3-(4-oxo-4H-chromen-3-yl)-prop-
2-enoic acid (18)
A mixture of β-ketoacid 3 (0.55 g, 2 mmol) and 3-formylchromone (16) (0.35 g, 2 mmol) in glacial acetic acid
(10 mL) containing freshly fused sodium acetate (0.2 g) was heated under reflux for 4 h. The solid obtained
after cooling was filtered and recrystallized from acetic acid to give 18 as yellow crystals, yield (0.58 g, 67%), mp
252-253 ◦ C. IR (KBr, cm−1): 3456 (2OH), 3081 (CHarom.), 2979, 2932 (CHaliphatic), 1778 (C=Oacid), 1672
(C=Oquinolinone and C=Ochromone), 1620 (C=Oketone). 1 H-NMR (DMSO-d6 , δ): 1.26 (t, 3H, J = 7.2 Hz,
CH2 CH 3), 4.37 (q, 2H, J = 7.2 Hz, CH 2 CH3), 5.68 (s, 1H, methine proton), 7.50 (d, 1H, J = 6.0 Hz, Ar-H),
7.64 (d, 1H, J = 8.4, Ar-H), 7.75-7.85 (m, 3H, Ar-H), 8.04-8.14 (m, 3H, Ar-H), 8.93 (s, 1H, H-2chromone), 13.90
(br, 2H, 2OH exchangeable with D2 O). Anal. Calcd for C24 H17 NO7 (431.41): C, 66.82; H, 3.97; N, 3.25%.
Found C, 66.87; H, 4.20; N, 3.29%.
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Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
6-Ethyl-3-(1H-indol-3-yl)methylidene)pyrano[3,2-c]quinoline-2,4,5(3H,6H)-trione (19)
Method A
Compound 17 (0.80 g, 2 mmol) in concentrated sulfuric acid (5 mL) was stirred at room temperature
for 1 h and left overnight. The dark brown solution was poured onto ice/water and stirred for 1 h. The solid
obtained was filtered, washed with water, and crystallized from ethanol to give 19 as pale brown crystals, yield
(0.54 g, 70%), mp 162 ◦ C.
Method B
A mixture of compound 2 (0.51 g, 2 mmol) and 3-formylindol (15) (0.30 g, 2 mmol) in glacial acetic acid
(10 mL) containing freshly fused sodium acetate (0.2 g) was heated under reflux for 2 h. The solid obtained
after cooling was filtered and crystallized from ethanol to give 19 as pale brown crystals, yield (0.44 g, 57%),
mp 162 ◦ C. IR (KBr, cm−1): 3224 (NH), 3083 (CHarom .), 2983, 2920 (CHaliphatic), 1742 (OC=O), 1664
(C=Oquinoline and C=Oketone). 1 H-NMR (DMSO-d6 , δ): 1.25 (t, 3H, J = 6.4 Hz, CH2 CH3), 4.34 (q, 2H,
J = 6.6 Hz, CH2 CH3), 6.75-7.53 (m, 7H, Ar-H), 7.82 (s, 1H, Ar-H), 7.94 (s, 1H, methine proton), 8.10 (d,
1H, J = 8.0 Hz, H-10), 9.78 (br, IH, NH exchangeable with D2 O). Anal. Calcd for C23 H16 N2 O4 (384.39):
C, 71.87; H, 4.20; N, 7.29%. Found C, 71.58; H, 4.11; N, 7.21%.
6-Ethyl-3-[(4-oxo-4H-chromen-3-yl)methylidene]pyrano[3,2-c]quinoline-2,4,5 (3H,6H)trione (20)
Method A
Compound 18 (0.43 g, 1 mmol) in concentrated sulfuric acid (5 mL) was stirred at room temperature
for 1 h and left overnight. The dark brown solution was poured onto ice/water and stirred for 1 h. The solid
obtained was filtered, washed with water, and crystallized from n-butanol to give 20 as yellow crystals, yield
(0.32 g, 78%), mp 241-242 ◦ C.
Method B
A mixture of compound 2 (0.51 g, 2 mmol) and 3-formylchromone (16) (0.35 g, 2 mmol) in glacial acetic
acid (10 mL) containing freshly fused sodium acetate (0.2 g) was heated under reflux for 2 h. The solid obtained
after cooling was filtered and crystallized from n-butanol to give 20 as yellow crystals, yield (0.58 g, 71%), mp
241-242 ◦ C. IR (KBr, cm−1): 3088 (CHarom .), 2978, 2939 (CHaliphatic), 1744 (OC=O), 1661 (C=Oquinoline
,
C=Oγ−pyrone, and C=Oketone). 1 H-NMR (DMSO-d6 , δ): 1.15 (t, 3H, J = 6.8 Hz, CH2 CH3), 4.09 (q, 2H,
J = 6.8 Hz, CH2 CH3), 7.43-7.77 (m, 8H, Ar-H), 8.35 (s, 1H, methine proton), 8.81 (s, 1H, H-2chromone). M/z
(relative intensity): 413 (15), 386 (4), 358 (4), 330 (3), 316 (10), 288 (8), 257 (58), 229 (87), 201 (21), 171 (100),
145 (47), 132 (54), 117 (28), 92 (38), 77 (78). Anal. Calcd for C24 H15 NO6 (413.39): C, 69.73; H, 3.66; N,
3.39%. Found C, 69.48; H, 3.57; N, 3.41%.
Formation of compounds 22-24: general procedure
A mixture of β-ketoacid 3 (0.55 g, 2 mmol) and some aldehyde derivatives, namely piperonal, 2-formylpyridine,
and 2-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxaldehyde (21) (2 mmol), in DMF (10 mL) containing
a few drops of piperidine was heated under reflux for 4 h. The solid deposited after cooling was filtered and
crystallized from the appropriate solvent to give compounds 22-24, respectively.
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Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
3-(1,3-Benzodioxol-5-ylmethylidene)-6-ethyl-pyrano[3,2-c]quinoline-2,4,5(3H,6H)-trione (22)
Crystallized from DMF/MeOH as yellow crystals, yield (0.46 g, 59%), mp 180-181 ◦ C. IR (KBr, cm−1): 3075
(CHarom. ), 2978, 2883 (CHalipatic), 1737 (OC=O), 1673 (2C=O), 1619 (C=C). 1 H-NMR (DMSO-d6 , δ): 1.25
(t, 3H, J = 6.4 Hz, CH2 CH 3), 4.35 (q, 2H, J = 6.4 Hz, CH 2 CH3), 5.96 (s, 2H, -OCH2 O-), 6.75-7.53 (m,
5H, Ar-H), 7.82 (s, 1H, Ar-H), 7.95 (s, 1H, methine proton), 8.10 (d, 1H, J = 8.0 Hz, Ar-H). Anal. Calcd for
C22 H15 NO6 (389.35): C, 67.86; H, 3.88; N, 3.60%. Found C, 67.65; H, 3.72; N, 3.44%.
6-Ethyl-3-(pyridin-2-ylmethylidene)pyrano[3,2-c]quinoline-2,4,5(3H,6H)-trione (23)
Crystallized from DMF/H2 O as pale brown crystals, yield (0.29 g, 41%), mp 220-221 ◦ C. IR (KBr, cm−1):
3080 (CHarom. ), 2980, 2871 (CHaliphatic), 1739 (OC=O), 1674 (2C=O), 1618 (C=N and C=C). 1 H-NMR
(DMSO-d6 , δ): 1.17 (t, 3H, CH2 CH 3), 4.35 (q, 2H, CH 2 CH3), 7.05-7.86 (m, 8H, Ar-H), 8.17 (s, 1H, methine
proton). M/z (relative intensity): 332 [M-14; 3], 308 (5), 290 (10), 257 (78), 229 (100), 214 (7), 201 (29), 173
(23), 145 (26), 132 (14), 104 (8), 89 (8), 77 (20). Anal. Calcd for C20 H14 N2 O4 (346.33): C, 69.36; H, 4.07; N,
8.09%. Found: C, 69.15; H, 3.89; N, 8.01%.
3-[(2-Chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl) methylidene]-6-ethylpyrano[3,2-c]quinoline-
2,4,5(3H,6H)-trione (24)
Crystallized from DMF as orange crystals, yield (0.52 g, 58%), mp 239-240 ◦ C. IR (KBr, cm−1): 3074
(CHarom .), 2971, 2931, 2864 (CHaliphatic), 1730 (OC=O), 1652 (3C=O). 1 H-NMR (DMSO-d6 , δ): 1.24 (t,
3H, J = 6.8 Hz, CH2 CH 3), 4.31 (q, 2H, J = 7.0 Hz, CH 2 CH3), 7.19-7.33 (m, 3H, Ar-H), 7.39-7.66 (m, 3H,
Ar-H), 7.71-8.09 (m, 3H, 2Ar-H and methine proton). M/z (relative intensity): 445 [M-2; 5], 391 (40), 254 (91),
240 (75), 229 (15), 201 (13), 161 (68), 146 (43), 144 (25), 120 (63), 117 (35), 104 (25), 92 (10), 78 (100). Anal.
Calcd for C23 H14 ClN3 O5 (447.82): C, 61.69; H, 3.15; N, 9.38%. Found C, 61.72; H, 3.24; N, 9.23%.
1-Ethyl-4-hydroxy-3-{5-oxo-4-[(4-oxo-4H-chromen-3-yl)methylidene]-4,5-dihydro-1H-pyrazol-3-yl}
quinolin-2(1H)-one (25)
A mixture of compound 20 (0.82 g, 2 mmol) and hydrazine hydrate (0.1 mL, 2 mmol) in ethanol containing a
few drops of triethylamine (10 mL) was heated under reflux for 2 h. The solid deposited after cooling was filtered
and crystallized from acetic acid to give compound 25 as yellow crystals, yield (0.41 g, 48%), mp 203-204 ◦ C.
IR (KBr, cm−1): 3400, 3285, 3256 (OH, NH), 3072 (CHarom .), 2911, 2833 (CHaliphatic), 1678 (C=Oquinoline
and C=Opyrazole ), 1635 (C=Oγ−pyrone), 1561 (C=N and C=C). 1 H-NMR (DMSO-d6 , δ): 1.23 (t, 3H, J =
7.6 Hz, CH2 CH 3), 4.33 (q, 2H, CH 2 CH3), 5.52 (s, 1H, methine proton), 6.90-6.95 (m, 1H, Ar-H), 7.45-7.49
(m, 2H, Ar-H), 7.61 (d, 1H, J = 6.4 Hz, Ar-H), 7.75-7.86 (m, 2H, Ar-H), 8.03-8.10 (m, 2H, Ar-H), 8.12 (s, 1H,
H-2chromone), 13.78 (s, 2H exchangeable with D2 O, NH and OH). Anal. Calcd for C24 H17 N3 O5 (427.42): C,
67.44; H, 4.01; N, 9.83%. Found C, 67.35; H, 4.05; N, 9.69%.
688

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
1-Ethyl-4-hydroxy-3-{5-[(4-oxo-4H-chromen-3-yl)methylidene]-6-oxo-2-thioxo-1,2,5,6-tetrahyd-
ropyrimidin-4-yl}-quinolin-2(1H)-one (26)
A mixture of compound 20 (0.82 g, 2 mmol) and thiourea (0.15 g, 2 mmol) in ethanol containing a few drops
of triethylamine was heated under reflux for 4 h. The solid deposited after cooling was filtered and crystallized
from methanol to give 26 as yellow crystals, yield (0.58 g, 62%), mp 185 ◦ C. IR (KBr, cm−1): 3425 (OH, NH),
3039 (CHarom.), 2977, 2920 (CHaliphatic), 1654 (3C=O), 1597 (C=N), 1219 (C=S). 1 H-NMR (DMSO-d6 , δ):
1.25 (t, 3H, CH2 CH 3), 4.33 (q, 2H, CH 2 CH3), 5.59 (s, 1H, methine proton), 7.10-8.26 (m, 8H, Ar-H), 8.91
(s, 1H, H-2chromone), 10.77 (s, 1H, NH exchangeable with D2 O), 13.60 (s, 1H, OH exchangeable with D2 O).
Anal. Calcd for C25 H17 N3 O5 S (471.48): C, 63.69; H, 3.63; N, 8.91; S, 6.80%. Found C, 63.57; H, 3.56; N,
8.85; S, 6.72%.
4-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-5-[(4-oxo-4H-chromen-3-yl) methylidene]-6-
oxo-5,6-dihydropyrimidin-2(1H)-ylidene]cyanamide (27)
A mixture of compound 20 (0.82 g, 2 mmol) and cyanoguanide (0.17 g, 2 mmol) in ethanol containing a few
drops of triethylamine was heated under reflux for 4 h. The solid deposited after cooling was filtered and
crystallized from ethanol to give 27 as yellow crystals, yield (0.48 g, 50%), mp 235-236 ◦ C. IR (KBr, cm−1):
3425 (OH, NH), 3030 (CHarom.), 2976, 2928 (CHaliphatic), 2176 (C≡N), 1627 (3C=O). 1 H-NMR (DMSO-d6 ,
δ): 1.16 (t, 3H, CH2 CH 3), 4.18 (q, 2H, CH 2 CH3), 5.83 (s, 1H, methine proton), 6.89-6.92 (m, 2H, Ar-H),
7.19-7.49 (m, 4H, Ar-H), 7.82 (t, 1H, Ar-H), 8.04-8.07 (m, 1H, Ar-H), 8.74 (s, 1H, H-2chromone), 11.93 (s,
1H, NH exchangeable with D2 O), 13.70 (s, 1H, OH exchangeable with D2 O). Anal. Calcd for C26 H17 N5 O5
(479.44); C, 65.13; H, 3.57; N, 14.61 %. Found C, 64.96; H, 4.00; N, 14.34%.
4-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-[(4-oxo-4H-chromen-3-yl) methylidene])-
1,3-dihydro-2H-1,5-benzodiazepin-2-one (28)
A mixture of compound 20 (0.41 g, 1 mmol) and o-phenlyene diamine (0.11 g, 1 mmol) in ethanol containing a
few drops of triethylamine was heated under reflux for 4 h. The solid deposited during heating was filtered and
crystallized from DMF/H2 O to give 28 as yellow crystals, yield (0.27 g, 54%), mp 293-294 ◦ C. IR (KBr, cm−1):
3439 (OH, NH), 3084 (CHarom.), 2982, 2930, 2890 (CHaliphatic), 1640 (2C=O), 1630 (C=O), 1557 (C=N). 1 H-
NMR (DMSO-d6 , δ): 1.13 (t, 3H, CH2 CH 3), 4.17 (q, 2H, CH 2 CH3), 5.83 (s, 1H, methine proton), 6.61 (t,
1H, Ar-H), 7.11-7.85 (m, 11H, Ar-H), 8.80 (s, 1H, H-2chromone), 12.54 (s, 1H, NH exchangeable with D2 O),
13.60 (s, 1H, OH exchangeable with D2 O). M/z (relative intensity): 421 (31), 419 [M-3CO; 3], 403 (24), 390
(91), 375 (10), 359 (58), 331 (23), 305 (49), 290 (27), 277 (48), 214 (30), 202 (24), 188 (60), 174 (17), 161 (44),
146 (60), 130 (82), 120 (50), 104 (35), 92 (47), 77 (100), 65 (55). Anal. Calcd for C30 H21 N3 O5 (503.50): C,
71.56; H, 4.20; N, 8.35%. Found C, 71.60; H, 4.08; N, 8.21%.
689

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
2-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-[(4-oxo-4H-chromen-3-yl) methylidene]-9-
(4-methoxyphenyl)-4,7-dioxo-4,5,6,7-tetrahydropyrido[1,2-b][1,2,4]triazepine-8,10-dicarbonitrile
(31)
A mixture of compound 20 (0.41 g, 1 mmol) and 1,6-diamino-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-
3,5-dicarbonitrile (29) (0.28 g, 1 mmol) in ethanol containing a few drops of triethylamine was heated under
reflux for 4 h. The solid deposited during heating was filtered and crystallized from DMF to give 31 as yellow
crystals, yield (0.38 g, 67%), mp > 300 ◦ C. IR (KBr, cm−1): 3357 (OH, NH), 2973, 2930 (CHaliphatic),
2214 (2C≡N), 1722 (C=O), 1650 (3C=O), 1612 (C=N). 1 H-NMR (DMSO-d6 , δ): 1.24 (t, 3H, J = 6.0 Hz,
CH2 CH 3), 3.80 (s, 3H, CH 3 O), 4.34 (q, 2H, J = 7.4 Hz, CH 2 CH3), 5.59 (s, 1H, methine proton), 6.91-6.98
(m, 3H, Ar-H), 7.32-7.45 (m, 4H, Ar-H), 7.75-7.84 (m, 4H, Ar-H), 8.01 (d, 1H, J = 7.6 Hz, Ar-H), 8.37 (s, 1H,
H-2chromone), 13.46 (s, 1H, NH exchangeable with D2 O), 13.85 (s, 1H, OH exchangeable with D2 O). Anal.
Calcd for C38 H24 N6 O7 (676.65): C, 67.45; H, 3.58; N, 12.42%. Found C, 67.27; H, 3.68; N, 12.02%.
Ethyl 9-(4-chlorophenyl)-3-[(4-oxo-4H-chromen-3-yl)methylidene]-8-cyano-2-(1-ethyl-4-hydroxy-2-
oxo-1,2-dihydroquinolin-3-yl)-)-4,7-dioxo-4,5,6,7-tetrahydropyrido[1,2-b][1,2,4]triazepine-10-car-
boxylate (32)
A mixture of compound 20 (0.41 g, 1 mmol) and ethyl 1,6-diamino-4-(4-chlorophenyl)-5-cyano-2-oxo-1,2-
dihydropyridine-3-carboxylate (30) (0.33 g, 1 mmol) in ethanol containing a few drops of triethylamine was
heated under reflux for 4 h. The solid deposited during heating was filtered and crystallized from DMF to give
compounds 32 as yellow crystals, yield (0.45 g, 62%), mp > 300 ◦ C. IR (KBr, cm−1): 3400 (OH), 3195 (NH),
3087 (CHarom.), 2985, 2925 (CHaliphatic), 2216 (C≡N), 1742 (C=Oester), 1669 (4C=O), 1617 (C=N), 764
(C–Cl). 1 H-NMR (DMSO-d6 , δ): 1.20 (t, 3H, J = 6.8 Hz, CH2 CH 3), 1.29 (t, 3H, J = 7.0 Hz, CH 2 CH3),
4.25 (q, 2H, J = 6.8 Hz, NCH 2 CH3), 4.38 (q, 2H, J = 7.0 Hz, OCH 2 CH3), 5.62 (s, 1H, methine proton),
7.30 (t, 1H,J = 7.4 Hz, Ar-H), 7.49-7.54 (m, 4H, Ar-H), 7.75-7.91 (m, 5H, Ar-H), 8.06-8.12 (m, 2H, Ar-H), 8.84
(s, 1H, H-2chromone), 13.47 (s, 2H, NH and OH exchangeable with D2 O). Anal. Calcd for C39 H26 ClN5 O8
(728.10).C, 64.33; H, 3.60; N, 9.62; Cl, 4.87%. Found C, 64.15; H, 3.68; N, 9.52; Cl, 4.87%.
Results and discussion
In continuation of our previous work on the chemical reactivity of 3-(1-ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-
3-yl)-3-oxopropanoic acid (3),14 chlorination of β-ketoacid 3 using sulfuryl chloride in dioxane afforded 3-
(2,2-dichloroacetyl)-1-ethyl-4-hydroxyquinolin-2(1H)-one (5) via the nonisolable intermediate 4 (Scheme 2).
Compound 5 was found to be identical to the authentic sample obtained from chlorination of 3-acetyl-4-
hydroxyquinolin-2(1H)-one as previously published.15,16 The 1 H-NMR spectrum of compound 5 showed a
characteristic singlet at δ 7.87 ppm attributed to the CHCl2 proton.
On the other hand, bromination of 3 using bromine in acetic acid under reflux afforded only the 2,2-
dibromo-3-oxopropanoic acid derivative 6.17 Structure of the monobromo derivative 7 was ruled out on the
basis of elemental analysis and spectral data (Scheme 3). The 1 H-NMR spectrum of compound 6 confirmed
the absence of the 2 protons of the active methylene group, which appeared at δ 5.56 ppm in the β-ketoacid
690

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
3.14 Moreover, the elemental analysis agrees well with the molecular formula C14 H11 Br2 NO5 , which proves
the presence of 2 bromine atoms.
OH
O
O
OH
O
O
Cl
OH
-CO2
SO2Cl2
3
Cl
Cl
Cl
Dioxane
59%
N
Et
N
Et
O
5
4
Scheme 2. Chlorination of β -ketoacid 3.
O
Br
Br
O
OH
O
O
O
N
Et
8
OH
OH
43%
conc. H2SO4
55%
Br
Br
N
Et
6
O
O
Br2
3
AcOH
OH
O
O
O
Br2
AcOH
62%
2
Br
N
Et
7
Scheme 3. Bromination of compounds 2 and 3.
Dehydration reaction of 6 by stirring in conc. H2 SO4 at room temperature afforded 3,3-dibromo-6-
ethylpyrano[3,2-c]quinoline-2,4,5(3H,6H)-trione (8) (Scheme 3). The latter compound was obtained authenti-
cally in one pot from bromination of pyranoquinolinone 2 under the same reaction conditions [bromine in acetic
acid] (Scheme 3). The broad signal due to the 2OH protons in compound 6 (which appeared at δ 14.42 ppm) did
not appear in the 1 H-NMR spectrum of compound 8. The mass spectrum of the dibromopyrano[3,2-c]quinoline
derivative 8 did not show the molecular ion peak at m/z 415 but showed a peak at m/z 335 corresponding to the
molecular ion after loss of one atom of bromine; this may be attributed to the steric effect between the 2 bromine
atoms. The spectrum also revealed the base peak at m/z 172 assigned to the N -ethylquinolin-2(1H)-one moiety.
Basic hydrolysis of dibromopyrano[3,2-c]quinoline derivative 8 using 2 M aqueous NaOH solution yielded
3-(dibromoacetyl)-1-ethyl-4-hydroxyquinolin-2(1H)-one (9) (Scheme 4). The IR spectrum of compound 9 did
not reveal the α-lactone (OC=O) absorption band that appeared at 1730 cm−1 in the IR spectrum of compound
8. The 1 H-NMR spectrum of the dibromoacetyl derivative 9 showed, in addition to the aromatic and ethyl
protons, a characteristic singlet signal at δ 6.40 ppm due to the dibromoacetyl proton. Formation of compound
9 takes place via the hydrolytic ring opening of the dibromopyran ring system in compound 8 followed by
decarboxylation.16
691

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
Br
OH
O
OH
O
O
i) 2M NaOH
ii) HCl
Br
DMF/TEA
-HBr
44%
8
Br
62%
N
Et
10
O
N
Et
9
Scheme 4. Formation of dibromoacetylquinolinone 9 and furoquinolinone 10.
Heterocyclization of dibromoacetylquinolinone 9 in boiling DMF containing a few drops of triethylamine
(TEA) resulted in loss of one molecule of HBr to produce 2-bromo-5-ethyl-3-hydroxyfuro[3,2-c]quinolin-4(5H)-
one (10) (Scheme 4). The 1 H-NMR spectrum of compound 10 showed the disappearance of the characteristic
singlet signal attributable to the CHBr2 proton, which appeared at δ 6.40 ppm in compound 9.
Compound 8 was used as a good precursor to get some new pyrano[3,2-c]quinoline derivatives via
reactions with a variety of nucleophilic reagents. Thus, condensation of 8 with 4-amino-6-methyl-3-thioxo-
3,4-dihydro-1,2,4-triazin-5(2H)-one18 in boiling DMF containing a few drops of piperidine resulted in the loss
of 2 molecules of HBr to produce 1,2,4-triazinyliminopyrano[3,2-c]quinoline derivative 11 (Scheme 5). The
1 H-NMR spectrum of compound 11 showed a characteristic singlet signal at δ 2.67 ppm assigned to the methyl
protons, in addition to one exchangeable signal at δ 13.43 ppm due to NHtriazine proton.
8
S
H
N
DMF/pip.
CN
H2N
N
O
N
61%
O
2PhSH
O
63%
O
55%
O
CN
Me
S
O
CN
O
H
SPh
N
N
CN
O
N
SPh
O
N
O
O
Me
N
O
N
O
N
O
Et
12
Et
13
Et
11
Scheme 5. Nucleophilic substitution reactions of dibromoquinolinone 8.
Similarly, condensation of 8 with malononitrile under the same reaction conditions gave pyrano[3,2-
c]quinolin-3-ylidenemalononitrile derivative 12. The IR spectrum of compound 12 showed a characteristic
absorption band due to the nitrile functions at 2207 cm−1
.
Furthermore, condensation of dibromo derivative 8 with 2 molecules of thiophenol in boiling DMF
containing a few drops of piperidine gave bis-phenylsulfanyl-pyrano[3,2-c]quinoline derivative 13 (Scheme 5).19
The mass spectrum of compound 13 showed the molecular ion peak at m/z 472 (M-1) and the base peak at
m/z 239. The elemental analysis agrees well with the molecular formula C26 H19 NO4 S2 .
692

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
In the present investigation, we found that the reaction of β-ketoacid 3 with bis(methylthio)methylene-
malononitrile and/or bis(methylthio)methylene-cyanoacetamide in boiling DMF containing a few drops of
1,8-diazabicycle[5.4.0]undec-7-ene (DBU) as a basic catalyst afforded one product, 14 (the same mp, mmp,
and spectral data), and the reaction was expected to proceed as depicted in Scheme 6.20 The reaction takes
place initially via loss of one molecule of CH3 SH to give intermediate A with concomitant cyclization to af-
ford intermediate B. The OH group of the pyrone ring, in intermediate B, undergoes nucleophilic addition
to the nitrile function to yield iminopyran intermediate C, which undergoes Dimorth rearrangement [in the
case of bis(methylthio)methylene-malononitrile] under the reaction conditions to give the final product identi-
fied as 6-ethyl-1-(methylsulfanyl)-3,5,12-trioxo-4,5,6,12-tetrahydro-3H-pyrido[2‘,3‘:4,5]pyrano[3,2-c]quinoline-
2-carbonitrile (14). The IR spectrum of compound 14 showed characteristic absorption bands at 2196, 1743,
1673, and 1642 cm−1 attributed to C≡N, OC=O, C=Oquinolinone , and C=Opyridone , respectively. Moreover,
the mass spectrum of compound 14 showed the molecular ion peak at m/z 379, which is in good agreement
with the formula weight (379.40) and supports the identity of the structure.
OH
SMe
SMe
O
MeS
MeS
CN
CN
CN
CN
O
O
OH
CN
O
OH
N
3
DMF/DBU
42%
N
Et
A
O
N
Et
O
B
O
SMe
O
SMe
O
MeS
MeS
CONH 2
CN
CN
NH
CN
Dimorth Rearrangement
O
O
N
N
H
O
DMF/DBU
51%
O
N
Et
O
Et
C
14
Scheme 6. Formation of pyrido[2‘, 3‘:4,5]pyrano[3,2-c]quinoline 14.
Knoevenagel condensation reactions characterized to the active methylene group in β-ketoacid 3 were
studied towards some heterocyclic aldehydes. Therefore, condensation of compound 3 with 3-formylindole
(15) and 3-formylchromone (16) 21 in glacial acetic acid containing freshly fused sodium acetate yielded the
Knoevenagel condensation products 17 and 18, respectively. The latter compounds gave positive acidity and
FeCl 3 tests indicting the presence of free carboxylic and phenolic OH groups. The 1 H-NMR spectrum of
compound 17 revealed the presence of 3 exchangeable signals at δ 9.93 (NHindole), 12.14 (OHacid), and 13.80
ppm (OHquinolinone), while the 1 H-NMR spectrum of compound 18 revealed the presence of 1 exchangeable
signal at δ 13.90 ppm assigned to OHquinolinone and OHacid , in addition to a characteristic singlet signal at δ
8.93 ppm assigned to the H-2 of the chromone moiety.
Heterocyclization of compounds 17 and 18 via dehydration reactions by stirring in concentrated H2 SO4
at room temperature gave 3-substituted-pyrano[3,2-c]quinoline derivatives 19 and 20, respectively (Scheme
7). Moreover, compounds 19 and 20 were obtained authentically from condensation reactions of pyrano[3,2-
693

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
c]quinoline 2 with 3-formylindole (15) and 3-formylchromone (16), respectively (Scheme 7). The 1 H-NMR
spectrum of compound 20 showed 2 characteristic singlet signals at δ 8.35 and 8.81 ppm due to CHmethine and
H-2chromone , respectively. Furthermore, the mass spectrum of compound 20 showed the molecular ion peak at
m/z 413, which agrees well with the molecular mass and supports the identity of the structure.
O
O
O
N
H
O
16
67%
15
3
gl. AcOH
NaOAc
54%
gl. AcOH
NaOAc
OH
O
O
OH
O
O
COOH
COOH
O
N
Et
N
Et
N
H
O
18
17
conc. H2SO4
conc. H2SO4
70%
O
78%
O
O
O
O
O
N
H
O
O
O
N
Et
O
N
Et
20
19
O
O
O
gl. AcOH
gl. AcOH
N
H
2
O
16
NaOAc
NaOAc
15
71%
57%
Scheme 7. Condensation of compounds 2 and 3 with 3-formylindole (15) and 3-formylchromone (16).
Interestingly, condensation of β-ketoacid 3 with piperonal, 2-formylpyridine, and 2-chloro-4-oxo-4H-
pyrido[1,2-a]pyrimidine-3-carboxaldehyde (21)22 in boiling DMF containing a few drops of piperidine fur-
nished directly the cyclized products, 3-(1,3-benzodioxol-5-ylmethylidene)-6-ethyl-2H-pyrano[3,2-c]quinoline-
2,4,5(3H ,6H)-trione (22), 6-ethyl-3-(pyridin-2-ylmethylidene)-2H-pyrano[3,2-c]quinoline-2,4,5(3H,6H)-trione
(23), and 3-[(2-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methylidene]-6-ethyl-2H-pyrano[3,2-c]quinoline-
2,4,5 (3H ,6H)-trione (24), respectively, in one-step reactions. Under these reaction conditions the Knoevenagel
condensation intermediates were not isolated but underwent intramolecular nucleophilic lactonization to form
the cyclized products 22-24 (Scheme 8). The IR spectra of compounds 22-24 showed characteristic absorption
bands attributed to O-C=O groups at 1737, 1739, and 1730 cm−1 , respectively.
694

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
O
O
O
O
O
O
O
O
59%
O
N
Et
22
O
N
O
O
N
DMF/pip.
O
3
41%
O
N
Et
O
23
O
O
O
N
N
O
N
Cl
N
21
Cl
O
58%
N
O
Et
24
Scheme 8. Condensation of 3 with some aldehyde derivatives.
It is known that23,24 α-pyrones are important synthons for the building of different classes of bioactive
nitrogen heterocyclic compounds that are widely used in pharmaceutics. In the present study, we planned to
prepare 4-hydroxyquinolinones bearing different nitrogen heterocycles linked chromone moiety in one molecular
frame. Therefore, the chemical reactivity of chromenylmethylidene-pyrano[3,2-c]quinoline derivative 20 was
studied towards some bifunctional nitrogen nucleophiles.
Treatment of 20 with hydrazine hydrate in ethanol containing a few drops of triethylamine resulted
in α-pyrone ring opening followed by ring closure (RORC) with loss of one molecule of water leading to
chromenylmethylidene-1H -pyrazolylquinolinone 25 (Scheme 9). The latter compound was found to be iden-
tical to the authentic sample previously prepared from the condensation of pyrazolylquinolinone with 3-
formylchromone.25 The 1 H-NMR spectrum of compound 25 showed exchangeable signal due to NHpyrazole
and OHquinolinone at δ 13.78 ppm.
Reaction of 20 with thiourea and cyanoguanidine as 1,3-binucleophiles in ethanol containing a few drops
of triethylamine afforded the pyrimidine derivatives 26 and 27, respectively (Scheme 9). Herein again, the 1 H-
NMR spectra of compounds 26 and 27 showed characteristic singlet signals assigned to the methine protons and
H-2 of chromone moiety, in addition to the NHpyrimidine and OHquinolinone protons as exchangeable signals.
Moreover, the IR spectrum of compound 26 showed a characteristic absorption band due to the thioxo group
at 1219 cm−1 , while that of compound 27 showed a characteristic absorption band due to the nitrile function
at 2176 cm−1
.
Reaction of 20 with o-phenylenediamine gave a benzodiazepine derivative identified as 4-(1-ethyl-4-
hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-[(4-oxo-4H-chromen-3-yl)methylidene])-1,3-dihydro-2H-1,5-benzo-
695

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
diazepin-2-one (28) (Scheme 10). The 1 H-NMR spectrum of compound 28 showed characteristic singlet signals
assigned to the methine proton and H-2chromone at δ 5.83 and 8.80 ppm, respectively, in addition to the
NHdiazepine and OHquinolinone protons at δ 12.54 and 13.60 ppm, respectively. The mass spectrum of 28 did
not show the molecular ion peak at m/z 503 but showed a peak at m/z 419 corresponding to the molecular ion
after the loss of 3 carbonyl groups.
H
N
N
OH
O
NH2NH2.H2O
48%
O
N
O
Et
25
O
S
S
OH
N
NH
H2N
NH2
EtOH/TEA
O
20
O
62%
N
O
Et
26
O
CN
NH
N
CN
N
OH
N
O
H2N
NH2
O
O
50%
N
Et
O
27
Scheme 9. RORC reactions of compound 20; formation of 25-27.
Herein again, reaction of 20 with 1,6-diaminopyridine derivatives 29 and 3026 as 1,4-bifunctional nu-
cleophiles afforded the pyrido[1,2-b][1,2,4]triazepine derivatives 31 and 32, respectively (Scheme 10). The
reactions proceeds initially via α-pyrone ring opening by the more nucleophilic amino group (N -NH2) followed
by ring closure to produce the desired products 31 and 32.27
Antimicrobial activity
The standardized disk agar diffusion method28 was followed to determine the activity of the synthesized
compounds against the sensitive organisms Staphylococcus aureus as gram-positive bacteria, Proteus vulgaris as
gram-negative bacteria, and Candida albicans as fungal strain. The antibiotics Doxymycin and Fluconazole were
purchased from Egyptian markets and used in concentrations of 100 μg mL−1 as references for antibacterial
and antifungal activities.
The compounds were dissolved in DMSO, which has no inhibition activity, to obtain a concentration of
100 μg mL−1 . The test was performed on medium potato dextrose agars (PDAs) containing an infusion of 200
696

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
OH
N
NH
NH2
H2N
O
O
N
Et
O
54%
Ar
O
28
Ar
CN
CN
NC
O
NC
H2N
O
N
N
N
O
OH
NH
NH2
29
EtOH/TEA
O
20
O
Ar =
OMe
N
Et
67%
Ar
O
31
Ar
CN
CN
EtOOC
OH
O
EtOOC
Ar =
O
N
N
N
NH
H2N
NH2
30
O
O
N
Et
O
Cl
62%
O
32
Scheme 10. RORC reactions of compound 20; formation of 28, 31, and 32.
g of potatoes, 6 g of dextrose, and 15 g of agar.29 The results depicted in the Table showed various activities
against all species of microorganisms, which suggests that the variations in the structures affect the growth of
the microorganisms. Thus, we can conclude from these results:
1. Most of the prepared compounds showed a low to high antimicrobial activity towards gram-positive
bacteria, gram-negative bacteria and the fungal strain (Table).
2. Compounds 3, 11, 18, and 22 showed higher activity than the standard antibiotic Doxymycin against
Staphylococcus aureus as gram-positive bacteria.
3. Compound 17 showed equal activity to the standard antibiotic Doxymycin against Proteus vulgaris as
gram-negative bacteria, while compounds 3, 6, 11, 12, and 22 showed higher activity.
4. Compound 12 showed higher activity than the standard Fluconazole as fungal strain.
697

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
As a result, compounds 3, 6, 11, 12, 17, 18, and 22 may be considered promising for the development
of new antimicrobial agents.
Table. The antimicrobial activity of the newly synthesized compounds.
Diameter of inhibition zone (mm)
conc. (100 μg mL−1
P. vulgaris
(gram +ve) (gram -ve) (Fungal strain)
)
Compound No.
S. aureus
C. albicans
3
20
7
6
-
15
12
8
8
11
-
6
8
9
-
-
10
-
-
-
11
35
-
20
15
-
6
12
17
-
13
-
14
-
-
13
13
9
17
10
18
-
10
7
18
19
8
-
20
-
8
-
22
18
11
-
28
-
9
23
-
24
-
10
-
25
-
-
26
-
-
12
-
27
-
-
28
31
-
-
-
7
-
-
-
32
-
-
Doxymycin
Fluconazole
“-” means no activity
15
-
10
-
-
16
Conclusion
In the present work, some novel 4-hydroxyquinolin-2(1H)-ones and pyrano[3,2-c]quinolin-2(1H)-ones were
successfully synthesized starting from 3-(1-ethy1-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid
(3). The antimicrobial activities of the prepared compounds showed that quinolinone derivatives 3, 6, 11, 12,
17, 18, and 22 have good inhibitory effects towards bacterial and fungal strains.
698

Synthesis and antimicrobial activity of some novel..., H. M. HASSANIN, et al.
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