Synthesis and antimicrobial activities of pyrano[3,2 c]quinoline, pyrimido [5',4':5,6]pyrano[3,2-c]quinoline and [1,2,4]triazolo[2",3":1',6'] pyrimido [5',4':5,6]pyrano[3,2-c]quinoline derivatives

Article abstract of DOI:10.3184/030823409X12509546260155

The synthesis of novel 7-(4-chlorophenyl)-6-hydroxy-3-methoxy-10-methyl-8, 9-dihydro-7H-pyrimido[5', 4' : 5, 6]pyrano- [3, 2-c]quinoline and [1, 2, 4]triazolo[2", 3" : 1', 6']pyrimido[5', 4' : 5, 6]pyrano[3, 2-c]quinoline derivatives has been reported. Th

Full text of DOI:10.3184/030823409X12509546260155

588 RESEARCH PAPER
SEPTEMBER, 588–592
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis and antimicrobial activities of pyrano[3,2-c]quinoline, pyrimido
[5',4':5,6]pyrano[3,2-c]quinoline and [1,2,4]triazolo[2",3":1',6']pyrimido
[5',4':5,6]pyrano[3,2-c]quinoline derivatives
Fatma El Mariah*
Department of Chemistry, Faculty of Girls, Ain Shams University, Cairo, Egypt
The synthesis of novel 7-(4-chlorophenyl)-6-hydroxy-3-methoxy-10-methyl-8, 9-dihydro-7H-pyrimido[5', 4':5, 6]pyrano-
[3,2-c]quinolineand[1,2,4]triazolo[2",3":1',6']pyrimido[5',4':5,6]pyrano[3,2-c]quinolinederivativeshasbeenreported.
The key intermediate 2-amino-4-(4-chlorophenyl)-5-hydroxy-8-methoxy-4H-pyrano[3, 2-c]-quinoline-3-carbonitrile
was obtained by treating 4-hydroxy-7-methoxyquinolin-2(1H)-one with various substituted a-cyanocinnamonitrile in
ethanolic piperidine solution. Antimicrobial activity was shown for most of the synthesised compounds.
Keywords: a-cyano-p-chlorocinnamonitrile, ethyl a-cyano-p-chlorocinnamate, 4-hydroxy-7-methoxyquinolin-2(1 H)-one, pyrano
[3, 2-c]quinoline, pyrimido[5', 4':5, 6]pyrano[3, 2-c]quinoline, [1, 2, 4]triazolo[2", 3":1', 6']pyrimido[5', 4':5, 6]pyrano[3, 2-c]
quinoline
9
Many fused quinolines have exhibited antimicrobial
activities,1-4 antimalarial activity,5 antitumor activity,6
antioxidant,7 antileishmanial8 and antiplatelet activity.9
Encouraged by these findings and as a continuation of
our work in this area,10 I now report the synthesis of some
new 4H-pyrano[3, 2-c]quinolines and related derivatives.
The condensation of 4-hydroxy-7-methoxyquinolin-2(1H)-
one (1)11 with various substituted a-cyanocinnamonitrile
(2a,b) in ethanolic piperidine afforded 1:1 adducts12,13
H3CO
10
8
7
1
O
10a
NH2
X
2
3
10b
6a
N
6
4a
5
4
OH
OH
Ar
(3)
CN
(i)
(3a): Ar =C6H4Cl(p-) X= CN
(3b): Ar =C6H4Cl(p-) X=CO2Et
ArCH=C
+
X
1
H3CO
N
H
O
(Scheme 1). On the basis of H NMR data, structure 4 was
OH
N
Ar
O
(2)
(1)
excluded. Structure 3 was established on the basis of 1H NMR
spectra each of which revealed a one-proton singlet at d 4.47–
4.79 ppm corresponding to the 4H-pyran in 4H-pyrano[3, 2-c]
quinoline derivatives (3a,b), in addition of a –OH group at
d 11.63–11.67 ppm characteristic for structure 3 instead of a
–OH group at d 9.80–9.82 ppm for structure 4.
X
H3CO
O
NH2
H3CO
(4)
NHCOCH3
CN
The interaction of 2-amino-4-(4-chlorophenyl)-5-hydroxy-
8-methoxy-4H-pyrano[3, 2-c]- quinoline-3-carbonitrile (3a)
with acetic anhydride upon reflux for 30 min, afforded the
2-acetylamino-4-(4-chlorophenyl)-5-hydroxy-8-methoxy-
4H-pyrano[3, 2-c]quinoline-3-carbonitrile (5), while heating
of (3a) with acetic anhydride upon reflux for 6 h afforded
the 7-(4-chlorophenyl)-6-hydroxy-3-methoxy-10-methyl-8,
9-dihydro-7H-pyrimido[5', 4':5, 6]pyrano[3, 2-c]quinolin-8-
one (6). The structure of (6) was confirmed by an independent
synthesis of the same product from (3b) and acetonitrile in
N
(ii)
(3a)
OH
Ar
12
(5)
2
H3CO
3
1
11
12b
12a
11a
O
N
CH3
4
10
(iii)
4a
(3b)
N
NH
9
5
7a
6a
6
14
8
7
presence of gaseous HCl at room temperature (Scheme 1).
OH
Ar
O
The structure of (5) and (6) were established by spectral data,
(6)
IR, MS, 1H NMR and 13C NMR.
Treatment of compound 3a with triethyl orthoformate in
acetic anhydride upon reflux gave the corresponding 7-(4-
chlorophenyl)-6-hydroxy-3-methoxy-10-methyl-8, 9-dihydro-
7H-pyrimido[5', 4':5, 6]pyrano[3, 2-c]quinolin-8-one (6)
(m.p. and mixed m.p.), while with triethyl orthoformate
without acetic anhydride afforded 4-(4-chlorophenyl)-2-
ethoxymethyleneamino-5-hydroxy-8-methoxy-4H-pyrano
[3, 2-c]quinoline-3-carbonitrile (7). The structure of compound
(7) was established by its IR, MS and 1H NMR.
Ammonolysis of compound (7) in methanol at room
temperature afforded 8-amino-7-(4-chlorophenyl)-6-hydroxy-
3-methoxy-7H-pyrimido[5', 4':5, 6]pyrano[3, 2-c]quinoline
(8), the structure of which was further supported by its
independent synthesis from (3a) and formamide (m.p. and
mixed m.p.)12,13 (Scheme 2).
Scheme 1 Reagents and conditions: (i) ethanol, piperidine,
reflux 0.5–1 h; (ii) Ac2O, reflux 0.5 h (for 5); 6 h (for 6);
(iii) HCl gas/MeCN, r.t, 4–6 h.
3-methoxy-8-imino-8, 9-dihydro-7H-pyrimido[5', 4' : 5,-6]
pyrano[3, 2-c]quinoline (9a), while the reaction of (7)
with methylamine yielded 7-(4-chlorophenyl)-6-hydroxy-
3-methoxy-8-imino-9-methyl-8, 9-dihydro-7H-pyrimido[5',
4':5, 6]pyrano[3, 2-c]quinoline (9b) (Scheme 2). The structure
of compounds (8, 9) were established by spectral data, IR, MS
and 1H NMR.
The interaction of compound (9a) with triethyl orthoformate
afforded 14-(4-chlorophenyl)-13-hydroxy-10-methoxy-14H-
[1, 2, 4]triazolo[2", 3":1', 6']pyrimido[5', 4':5, 6]pyrano[3,
2-c]quinoline (10a), while with acetyl chloride and benzoyl
chloride upon reflux gave the corresponding 14-(4-chloro-
phenyl)-13-hydroxy-10-methoxy-2-methyl-14H-[1,2,4]triazolo
[2", 3":1', 6']pyrimido[5', 4':5, 6]pyrano[3, 2-c]quinoline
(10b) and 14-(4-chlorophenyl)-13-hydroxy-10-methoxy-2-
The hydrazinoloysis of compound (7) in ethanol at room
temperature afforded 9-amino-7-(4-chlorophenyl)-6-hydroxy-
* Correspondent. E-mail: fatma_elmariah@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2009 589
(6)
(i)
H3CO
(3a)
(ii)
O
N=CHOEt
CN
(iii)
N
(iv)
H3CO
OH
Ar
(7)
O
N
H3CO
(V)
N
N
O
N
OH
Ar
NH2
N
N
(8)
R
OH
Ar
NH
(9)
(9a): R = NH2
(9b): R = Me
Scheme 2 Reagents and conditions: (i) CH(OEt)3, Ac2O, reflux 5 h; (ii) CH(OEt)3, reflux 5 h; (iii) HCONH2, reflux 6 h;
(iv) NH3 gas methanol, stirring 1 h; (v) NH2-NH2.H2O(for 9a) or MeNH2(for 9b), absolute ethanol, stirring, r.t, 1 h.
phenyl-14H-[1, 2, 4]triazolo[2", 3":1', 6']pyrimido[5', 4':5, 6]
pyrano[3, 2-c]quinoline (10c) respectively (Scheme 3). The
structures of (10a–c) were established by spectral data, IR,
sterilised filter paper disc impregnated with the compound
(0.3 mg/0.1 mL of dimethyl formamide) was placed on an
agar plate seeded with the test organism. The plates were
incubated for 24 h at 37°C for bacteria and 28°C for fungi. The
inhibition zone of bacterial and fungi growth around the disc
was determined. The screening results are given in (Table 1).
Six compounds showed moderate inhibition effect
against only one of the examined Gram negative bacteria
Escherichia coli (compound 7, 9b and 11) or Pseudomonas
aeruginosa (compound 3a, 3b and 9a). Whereas seven
compounds showed weak or moderate inhibition effect
against only one of the examined Gram positive bacteria
Staphylococcus aureus (compound 8, 9a, 10b and 12) or
Bacillus subtilis (compound 7, 10a and 10b). On the other
hand all compounds showed high or very high antimicrobial
activity against the examined pathogenic yeast Candida
albicans except compound 6 showed moderate activity and
compound 12 did not show any antimicrobial activity. Only
two compounds showed weak (compound 9b) or moderate
(compound 6) antimicrobial activity against the examined
fungi Aspergillus niger.
1
MS and H NMR. Condensation of (9a) with benzaldehyde
in ethanolic piperidine solution gave the open-chain product
(11), which was supported by its IR, MS and 1H NMR, while
with benzaldehyde in dioxane piperidine gave the compound
(10c). The structure of (10c) was further supported by heating
compound (11) in dioxane piperidine15 (m.p. and mixed m.p.)
(Scheme 3).
Treatment of compound 3a with ethanolic potassium
hydroxideuponrefluxafforded4-(4-chlorophenyl)-5-hydroxy-
8-methoxy-3, 4-dihydro-2H-pyrano[3, 2-c]quinoline-2-one
(12) (Scheme 4), which was supported by its IR, MS and
1H NMR.
Antimicrobial activities
Applying the agar plate diffusion technique16 the newly
synthesisedcompoundswerescreenedinvitroforantimicrobial
activity against Gram positive bacteria (Staphylococcus
aureus, Bacillus subtilis), Gram negative bacteria (Escherichia
coli, Pseudomonas aeruginosa), yeast (Candida albicans) and
fungi (Aspergillus niger). In this method, a standard 5 mm
Table 1 Antibacterial and antifungal activity
Sample no.
Staphylococcus
aureus
Bacillus
subtilis
Escherichia
coli
Pseudomonas
aeruginosa
Candida
albicans
Aspergillus
niger
3a
–
–
–
+ +
+ + +
+ + + +
+ +
–
3b
–
–
–
+ +
–
6
–
–
–
–
+ +
–
+ +
7
+
–
+ + + +
+ + +
+ + + +
+ + + +
+ + +
+ + + +
+ + +
+ + +
–
–
8
+ +
–
–
–
–
–
9a
+
–
+ +
–
9b
–
–
+ +
–
+
10a
–
+ +
–
–
–
10b
+
+
–
–
–
10c
–
–
–
–
–
11
–
–
+ +
–
–
12
+
–
–
–
–
Ciprofloxacin
Fungicide Nystin
+ + + +
–
+ + + +
–
+ + + +
–
+ + + +
–
–
–
+ + + +
+ + + +
Zone of inhibition: + = < 15 mm; + + = 15 – 24 mm; + + + = 25 – 34 mm; + + + + = 35 – 44 mm; – = no inhibition.

590 JOURNAL OF CHEMICAL RESEARCH 2009
(9a)
(i-iii)
(iv)
9
H3CO
H3CO
8
10
11
7
O
6
N
O
N
5
4
N
N
N
N
N
12
3
N
13
14
OH
Ar
(11)
NH
OH
Ar
(10)
N
1
Ph
2
R
(10a): R = H
Me
(10b): R =
(v)
H3CO
(10c): R = Ph
O
N
N
N
N
(vi)
- H2
(9a)
(10c)
NH
Ph
OH
Ar
H
Scheme 3 Reagents and conditions: (i) CH(OEt)3, dry benzene, reflux 6 h (for 10a); (ii) AcCl, dry benzene, reflux 6 h (for 10b);
(iii) PhCOCl, dry benzene, reflux 6 h (for 10c); (iv) PhCHO/ethanol/piperidine, reflux 2 h; (v) dioxane/piperidine/reflux 2 h;
(vi) PhCHO/dioxane/piperidine/reflux 16 h.
H3CO
H3CO
O
NH2
CN
O
H
O
(i)
NH2
N
N
C=O
O
OH Ar
OH Ar
(3a)
(ii)
H3CO
O
O
N
(12)
OH Ar
Scheme 4 Reagents and conditions: (i) ethyl alcohol and potassium hydroxide reflux 30 min; (ii) dil. HCl.
(2a) (0.189 g, 0.001 mol) was heated for 30 min. The solid product
which formed was then collected by filtration and recrystallised from
Conclusion
It could be concluded from these results that the biologically
active synthesised compounds are nearly as active as fungicide
Nystin against the examined pathogenic yeast (Candida
albicans).
benzene to give (3a) (0.35 g, 79% yield) as a colourless solid, m.p.
294–295°C; IR (cm-1): 3452 (OH), 3319, 3264 (NH2), 3058, 2922,
2818 (CH stretching), 2198 (CN) cm-1; MS (m/z%) 379 (M+, 12),
381 (M+ + 2, 7.74), 278 (19), 251 (3), 225 (10), 197 (11), 169 (11),
149(25), 132 (20), 111(14), 105(22), 55 (100); 1H NMR (DMSO-d6)
d: 3.82 (s, 3H, OCH3), 4.47 (s, 4-H, 1H), 6.83 (s, 2H, NH2), 6.92–
7.82 (m, 7H, ArH), 11.67 (s, 1H, OH); 13C NMR (DMSO-d6) d 36.10
(C-4), 55.47(OCH3), 98.11 (C-4a), 105.71 (C-7), 106.22 (C-10a),
111.72 (C-9), 119.71 (CN), 123.36 (C-10), 128.26, 129.29, 131.15,
139.70 (aromatic-H), 143.57 (C-8), 151.46 (C-6a), 158.91 (C-10b),
160.81 (C-5), 161.70 (C-2); Anal. Calcd for C20H14ClN3O3; C, 63.25;
H, 3.72; N, 11.06. Found: C, 63.50; H, 3.60; N, 11.30%.
Ethyl 2-amino-4-(4-chlorophenyl)-5-hydroxy-8-methoxy-4H-pyrano
[3,2-c]quinoline-3-carboxylate (3b): A solution of 4-hydroxy-7-
methoxyquinolin-2(1H)-one (1) (0.191 g, 0.001 mol) in ethanol
(30 mL), piperidine (0.5 mL) and ethyl a-cyano-4-chloro- cinnamate
(2b) (0.236 g, 0.001 mol) was heated for 1 h. The solid product, which
was formed, was then collected by filtration and recrystallised from
ethanol to give (3b) (0.32 g, 74% yield) as a colourless solid, m.p.
238–239°C; IR (cm-1): 3401 (OH), 3293, 3201 (NH2), 3073, 2973,
2911 (CH stretching), 1687 (CO ester) cm-1; MS (m/z%) 426 (M+,
13.24), 428 (M+ + 2, 4.69), 335 (8.74), 337 (2.3), 315 (100), 298 (2),
278 (11), 269 (57), 242 (2), 213 (3), 151(2), 125(3), 111(2), 86(2),
Experimental
Melting points were determined in open glass capillaries and are
uncorrected. The IR spectra of the compounds were recorded on
a Perkin-Elmer spectrophotometer model 1430 using potassium
bromide pellets and the frequencies are reported in cm-1. The mass
spectra were recorded on a mass spectrometer HP model MS 5988
El 70ev. The 1H NMR and 13C NMR spectra were observed on a
Perkin-Elmer R12B spectrometer, and chemical shifts (d) are in ppm
relative to internal TMS. Elemental analyses were carried out in the
microanalytical laboratory of the Faculty of Science, Cairo University.
Reactions were routinely followed by thin layer chromatography
(TLC) on silica gel; F254 aluminum sheets (Merck). The spots were
detected by UV irradiation at 254–365 nm.
2-Amino-4-(4-chlorophenyl)-5-hydroxy-8-methoxy-4H-pyrano-
[3,2-c]quinoline-3-carbonitrile (3a): A solution of 4-hydroxy-7-
methoxyquinolin-2(1H)-one (1) (0.191 g, 0.001 mol) in ethanol
(30 mL), piperidine (0.5 mL) and a-cyano-4-chloro- cinnamonitrile

JOURNAL OF CHEMICAL RESEARCH 2009 591
1
63(4); H NMR (DMSO-d6) d: 1.12 (t, 3H, CH2CH3, J = 3.1 Hz),
3339 (OH), 3273, 3215 (NH2), 3192 (NH), 2921, 2628, 2134 (CH
stretching), 1624 (C=N) cm-1; MS (m/z%) 421 (M+, 1), 423 (M+ + 2,
0.3), 327 (100), 310 (22), 294 (64), 248 (4), 173 (6), 164 (3), 111 (7),
94 (4), 84 (5); 1H NMR (DMSO-d6) d 3.78 (s, 3H, OCH3), 4.94 (s, 7-
H, 1H), 4.99 (br, 1H, NH), 6.62 (s, 2H, NH2), 7.15–7.82 (m, 8H, ArH),
10.73 (s, 1H, OH); Anal. Calcd for C21H16ClN5O3; C, 59.79; H, 3.82;
N, 16.60. Found: C, 59.50; H, 3.70; N, 16.30%.
3.82 (s, 3H, OCH3), 4.01 (q, 2H, CH2CH3, J = 3.1 Hz), 4.80 (s, 4-H,
1H), 6.85 (s, 2H, NH2), 7.26-8.39 (m, 7H, ArH), 11.62 (s, 1H, OH);
13C NMR (DMSO – d6) d 14.27(CH3), 34.10(C-4), 55.43(OCH3),
58.89(CH2), 77.02(C-3), 98.14(C-4a), 105.98(C-7), 109.23(C-10a),
110.94(C-9), 123.34(C-10), 127.72, 129.71, 130.43, 139.57(aromatic-
H), 145.23(C-8), 151.36(C-6a), 159.61(C-2), 161.16(C-10b),
161.53(C-5), 167.80(CO); Anal. Calcd forC22H19ClN2O5; C, 61.90;
H, 4.49; N, 6.56. Found: C, 61.60; H, 4.60; N, 6.40%.
2-Acetylamino-4-(4-chlorophenyl)-5-hydroxy-8-methoxy-4H-
pyrano[3,2-c]quinoline-3-carbonitrile (5): A solution of compound
(3a) (0.38 g, 0.001 mol) in acetic anhydride (20 mL) was heated under
reflux for 30 min, to give the N-acetyl derivative (5) (0.30 g, 79% yield)
and recrystallised from ethanol to give a colourless solid, m.p. 250–
251°C; IR (cm-1): 3405(OH), 3255 (NH), 2919, 2848 (CH stretching),
2204 (CN), 1675 (CO) cm-1; MS (m/z%) 421 (M+, 6.59), 423 (M+ + 2,
2.53), 312 (100), 314 (42), 273 (45), 250 (1), 190.5 (18), 156 (5), 108
(69), 77 (16); 1H NMR (DMSO- d6) d: 2.51 (s, 3H, COCH3), 3.84 (s,
3H, OCH3), 5.90 (s, 4-H, 1H), 6.64–8.32 (m, 7H, ArH), 11.52 (s, 1H,
NH), 11.95 (s, 1H, OH); Anal. Calcd for C22H16ClN3O4; C, 62.64; H,
3.82; N, 9.96. Found: C, 62.90; H, 3.70; N, 10.20%.
7-(4-Chlorophenyl)-6-hydroxy-3-methoxy-10-methyl-8,9-
dihydro-7H-pyrimido[5',4':5,6]pyrano[3,2-c]quinoline (6): (a)
A solution of compound (3a) (0.38 g, 0.001 mol) in acetic anhydride
(20 mL) was heated under reflux for 6 h to give (6) (0.29 g, 76%
yield), which recrystallised from benzene to give a colourless solid,
m.p.312–314°C; IR (cm-1): 3558 (OH), 3072 (NH), 2935, 2853 (CH
stretching), 1681 (CO), 1618 (C=N) cm-1; MS (m/z%) 421 (M+, 1),
423(M+ + 2, 0.1), 355 (99) 357 (36), 327 (100), 329 (35), 313 (9),
315 (3), 173 (5), 111 (5), 89(5), 63 (11); 1H NMR (DMSO-d6) d: 1.92
(s, 3-H, 3H, CH3), 3.84 (s, 3H, OCH3), 4.5 (s, 7-H, 1H), 6.89–7.76
(m, 7H, ArH), 11.87 (s, 1H, OH), 11.98 (s, 1H, NH); 13C NMR
(DMSO-d6) d 21.06 (CH3), 36.13 (C-7), 55.50 (OCH3), 98.23 (C-6a),
106.09 (C-7a), 108.12 (C-4), 111.25 (C-12b), 121.14 (C-2), 123.29
(C-1), 128.57 (C-3), 128.84, 131.77, 140, 195 (aromatic-H), 143.84
(C-4a), 154.88 (C-12a), 161.24 (C-11a), 161.81 (C-10), 166.16 CO),
172.04 (C-6) Anal. Calcd for C22H16ClN3O4; C, 62.64; H, 3.82; N,
9.96. Found: C, 62.40; H, 3.70; N, 9.70%.
7-(4-Chlorophenyl)-6-hydroxy-3-methoxy-8-imino-9-methyl-
8,9-dihydro-7H- pyrimido[5',4':5,6]pyrano[3,2-c]quinoline (9b):
Prepared from substance (7) (0.436 g, 0.001 mol) and methyl
amine (0.001 mol) according to the procedure described above.
The compound (9b) (0.38 g, 81% yield), which recrystallised from
benzene to give a colourless solid, m.p.289–290°C; IR (cm-1): 3257
(OH), 3076 (NH), 2965, 2155 (CH stretching), 1629 (C=N)) cm-1;
MS (m/z%) 420 (M+, 0.82), 422 (M+ + 2, 0.55) 309 (4), 311 (1), 292
1
(3), 247 (2), 173 (2), 111 (24), 83 (38), 60 (100), 56 (52); H NMR
(DMSO-d6) d 3.01 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.89 (s, 7-H,
1H), 5.50 (s, br, 1H, NH), 6.51–8.04(m, 8H, ArH), 10.31(s, 1H, OH);
Anal. Calcd for C22H17ClN4O3; C, 62.78; H, 4.07; N, 13.31. Found:
C, 62.50; H, 3.90; N, 13.00%.
14-(4-Chlorophenyl)-13-hydroxy-10-methoxy-14H-[1,2,4]
triazolo[2",3" : 1',6']pyrimido[5',4' :5,6]pyrano[3,2-c]quinoline
(10a): A solution of compound (9a) (0.422 g, 0.001 mol) and triethyl
orthoformate (0.001 mol) in dry benzene (20 mL) was refluxed for
6 h to give (10a) (0.46 g, 81% yield), which was recrystallised from
dioxane to give a colourless solid, m.p.318–319°C; IR (cm-1): 3548
(OH), 3064, 2919, 2850 (CH stretching), 1654 (C=N) cm-1; MS (m/z%)
431 (M+, 1), 433 (M+ + 2, 0.56), 417 (1), 320 (1), 258 (0.5), 173 (0.5),
111 (24), 94 (13), 67 (14), 57 (100), 55 (59); 1H NMR (DMSO-d6) d:
3.84 (s, 3H, OCH3), 4.50 (s, 14-H, 1H), 6.89-7.76 (m, 9H, ArH, 2-H,
5-H), 11.86 (s, 1H, OH); Anal. Calcd for C22H14ClN5O3; C, 61.19; H,
3.27; N, 16.22. Found: C, 60.90; H, 3.40; N, 16.50%.
14-(4-Chlorophenyl)-13-hydroxy-10-methoxy-2-methyl-14H-[1,2,4]
triazolo[2",3":1',6']pyrimido[5',4':5,6]pyrano[3,2-c]quinoline (10b):
Preparedfrom(9a)(0.422g,0.001mol)andacetylchloride(0.001mol)
according to the procedure described above to give (10b) (0.43 g,
86% yield), which recrystallised from dioxane to give a colourless
solid, m.p.280–281°C; IR (cm-1): 3168 (OH), 2978 (CH stretching),
1644 (C=N), cm-1; MS (m/z%) 445 (M+, 1.7), 447(M+ + 2, 0.6), 334
(1), 327 (100), 272 (1), 173 (6), 118 (4), 111 (7), 108 (3), 69 (6), 66
(b) A stream of dry gaseous HCl was passed through a mixture of
(3b) (0.427 g, 0.001 mol) and acetonitrile (30 mL) for 6 h at room
temperature. The reaction mixture was poured into ice-water and
basified with 10% ammonium hydroxide solution to give compound
(6) (0.28 g, 65% yield).
1
(4); H NMR (DMSO-d6) d: 2.34 (s, 3H, CH3), 3.80 (s, 3H, OCH3),
4.49 (s, 14-H, 1H), 6.78–7.91 (m, 7H, ArH), 9.71 (s, 5-H, 1H), 11.83
(s, 1H, OH); Anal. Calcd for C23H16ClN5O3; C, 61.96; H, 3.62; N,
15.71. Found: C, 61.70; H, 3.50; N, 16.00.
4-(4-Chlorophenyl)-2-ethoxymethyleneamino-5-hydroxy-8-
methoxy-4H-pyrano[3,2-c]quinoline-3-carbonitrile (7): A mixture
of compound (3a) (0.38 g, 0.001 mol), triethyl orthoformate (0.001
mol) and acetic anhydride (20 mL) was refluxed for 5 h to give (6)
(0.27 g, 74% yield, m.p. and mixed m.p.), while repeating the reaction
without acetic anhydride for 5 h give (7) (0.27 g, 71% yield) which
recrystallised from benzene to give a colourless solid, m.p.240–
241°C; IR (cm-1): 3555(OH), 3070, 2927, 2852(CH stretching),
2052 (CN), 1620 (C=N) cm-1; MS (m/z%) 435 (M+, 0.3), 437 (M+
+ 2, 0.1), 363 (0.3), 337 (0.3), 226 (1), 111 (6), 72 (19), 60 (100);
1H NMR (DMSO-d6) d: 1.34 (t, 3H, CH2CH3, J = 1.2 Hz), 4.37 (q,
2H, CH2CH3, J = 1.2 Hz), 3.84 (s, 3H, OCH3), 4.5 (s, 4-H, 1H),
6.89–8.16 (m, 7H, ArH), 8.87 (s, 1H, CH=N), 11.70 (s, 1H, OH);
Anal. Calcd for C23H18ClN3O4; C, 63.38; H, 4.16; N, 9.64. Found: C,
63.60; H, 4.30; N, 9.90%.
14-(4-Chlorophenyl)-13-hydroxy-10-methoxy-2-phenyl-14H-
[1,2,4]triazolo[2",3" : 1',6']pyrimido[5',4' : 5,6]pyrano[3,2-c]
quinoline (10c): (a) Prepared from (9a) (0.422 g, 0.001 mol) and
benzoyl chloride (0.001 mol) according to the procedure described
above to give (10c) (0.34 g, 61% yield), which recrystallised from
dioxane to give a colourless solid, m.p.285–286°C; IR (cm-1): 3267
(OH), 3054, 2998, 2850 (CH stretching), 1638 (C=N) cm-1; MS
(m/z%) 507 (M+, 1), 509 (M+ + 2, 0.3), 406 (1), 390 (3), 243 (1), 170
1
(1), 149 (100), 143(1), 111(7), 77 (5); H NMR (DMSO-d6) d: 3.84
(s, 3H, OCH3), 4.50 (s, 14-H, 1H), 6.90–7.96 (m, 12H, ArH), 10.52
(s, 5-H, 1H), 11.86 (s, 1H, OH); Anal. Calcd for C28H18ClN5O3; C,
66.21; H, 3.57; N, 13.79. Found: C, 66.50; H, 3.40; N, 13.50.
(b)Amixture of compound (9a) (0.422 g, 0.001 mol), benzaldehyde
(0.001 mol), dioxane (20 mL) and piperidine (0.5 mL) was refluxed
for 16 h to give (10c) (0.45 g, 85% yield) which recrystallised from
dioxane as colourless solid.
8-Amino-7-(4-chlorophenyl)-6-hydroxy-3-methoxy-7H-pyrimido
[5',4':5,6]pyrano[3,2-c]quinoline (8): (a) A solution of compound
(3a) (0.38 g, 0.001 mol) in formamide (20 mL) was heated under
reflux for 6 h to give (8) (0.28 g, 74% yield), which recrystallised
(c) A mixture of compound (11) (0.510 g, 0.001 mol), dioxane
(20 mL) and piperidine (0.5 mL) was refluxed for 2 h to give (10c)
(0.44 g, 86% yield) which recrystallised from dioxane as colourless
solid.
from benzene to give
a colourless solid, m.p.216–217°C;
IR (cm-1): 3482 (OH), 3394, 3153(NH2), 1627 (C=N) cm-1; MS
(m/z%) 406 (M+, 9.42), 408 (M+ + 2, 3.45), 391 (3), 339 (4), 315
(100), 311 (6), 295.5 (19), 279 (52); 1H NMR (DMSO-d6) d 3.35
(s, 3H, OCH3), 3.78 (s, 7-H, 1H) 6.23 (s, 2H, NH2), 6.69–7.87
(m, 7H, ArH), 8.40 (s, 10-H, 1H), 10.79 (s, 1H, OH); Anal. Calcd for
C21H15ClN4O3; C, 62.00; H, 3.72; N, 13.77. Found: C, 61.70; H, 3.80;
N, 13.50%.
7-(4-Chlorophenyl)-6-hydroxy-3-methoxy-8-imino-9-phenyl-
methyleneamino-8,9-dihydro-7H-pyrimido[5',4':5,6]pyrano[3,2-c]
quinoline (11): A mixture of compound (9a) (0.422 g, 0.001 mol),
benzaldehyde (0.001 mol), ethanol (20 mL) and piperidine (0.5 mL)
was refluxed for 2 h to give (11) (0.42 g, 79% yield), which
recrystallised from ethanol to give a yellow solid, m.p.260–261°C;
IR (cm-1): 3434 (OH), 3213 (NH), 3026, 2998, 2944 (CH stretching),
1618 (C=N) cm-1; MS (m/z%) 509 (M+, 0.5), 511 (M+ + 2, 0.1), 447
(1), 428 (1), 384 (2), 358 (2), 291 (2), 185 (3), 149 (100), 173 (1),
(b) A solution of compound (7) (0.436 g, 0.001 mol) and gaseous
NH3 in methanol (50 mL) was stirred for 1 h at room temperature to
give (7) (0.34 g, 89% yield).
9-Amino-7-(4-chlorophenyl)-6-hydroxy-3-methoxy-8-imino-
8,9-dihydro-7H- pyrimido[5',4':5,6]pyrano[3,2-c]quinoline (9a):
A solution of compound (7) (0.436 g, 0.001 mol) and hydrazine
hydrate (99%, 5 mL) in absolute ethanol (50 mL) was stirred at room
temperature for 1 h to give (9a) (0.40 g, 85% yield) which recrystallised
from benzene to give a colourless solid, m.p.270–271°C; IR (cm-1):
1
111(9), 97 (10); H NMR (DMSO-d6) d: 3.37 (s, 3H, OCH3), 4.57
(s, 7-H, 1H), 8.73 (s, 1H, = HN), 7.52–7.91 (m, 12H, ArH), 8.37 (s,
10-H, 1H), 8.73 (s, 1H, HC=N), 9.14 (b, 1H, NH), 10.03 (s, 1H, OH);
Anal. Calcd for C28H20ClN5O3; C, 65.95; H, 3.95; N, 13.74. Found:
C, 65.70; H, 3.80; N, 14.00.

592ꢀ JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009
3
T. Ganesh, J. Min, P. Thepchatri, Y. Du, L. Li, I. Lewis, L. Wilson, H. Fu,
G.ꢀChiosis,ꢀR.ꢀDingledine,ꢀD.ꢀLiottaꢀandꢀJ.P.ꢀSnyder,ꢀA.ꢀSun,ꢀBioorg. Med.
Chem.,ꢀ2008,ꢀ16,ꢀ6903.
4-(4-Chlorophenyl)-5-hydroxy-8-methoxy-3,4-dihydro-2H-
pyrano [3,2-c]quinoline-2-one (12):ꢀAꢀsuspensionꢀofꢀcompoundꢀ(3a)ꢀ
(0.380ꢀ g,ꢀ 0.001ꢀ mol)ꢀ inꢀ ethanolicꢀ potassiumꢀ hydroxideꢀ (20%)ꢀ (25ꢀ
mL) was heated under reflux for 30 min. The reaction mixture was
cooledꢀandꢀneutralisedꢀwithꢀdilutedꢀHClꢀtoꢀgiveꢀ(12)ꢀ(0.25ꢀg,ꢀ66%ꢀ
yield),ꢀwhichꢀrecrystallisedꢀfromꢀethanolꢀtoꢀgiveꢀaꢀcolourlessꢀsolid,ꢀ
m.p.210–211ꢀ°C;ꢀIRꢀ(cm‑1):ꢀ3072ꢀ(OH),ꢀ2923,ꢀ2854ꢀ(CHꢀstretching),ꢀ
1679ꢀ(CO,ꢀd‑lactones)ꢀcm‑1;ꢀMSꢀ(m/z%)ꢀ355ꢀ(M+,ꢀ16.27),ꢀ357ꢀ(M+ꢀ+ꢀ
2,ꢀ5.93),ꢀ254ꢀ(3),ꢀ202ꢀ(6),ꢀ189ꢀ(100),ꢀ182ꢀ(7),ꢀ173ꢀ(5),ꢀ166ꢀ(7),ꢀ138ꢀ
(10),ꢀ124ꢀ(14),ꢀ111ꢀ(18);ꢀ1HꢀNMRꢀ(DMSO‑d6)ꢀd:ꢀ2.51,ꢀ3.93ꢀ(d,ꢀ2H,ꢀ
CH2),ꢀ3.80ꢀ(s,ꢀ3H,ꢀOCH3),ꢀ5.59ꢀ(s,ꢀ4‑H,ꢀ1H),ꢀ6.73–7.70(m,ꢀ7H,ꢀArH),ꢀ
11.06ꢀ(s,ꢀ1H,ꢀOH);ꢀAnal.ꢀCalcdꢀforꢀC19H14ClNO4;ꢀC,ꢀ64.14;ꢀH,ꢀ3.97;ꢀ
N,ꢀ3.94.ꢀFound:ꢀC,ꢀ63.90;ꢀH,ꢀ3.80;ꢀN,ꢀ3.80.
ꢀ 4ꢀ P.ꢀ Narender,ꢀ U.ꢀ Srinivas,ꢀ M.ꢀ Ravinder,ꢀ B.ꢀ Anandaꢀ Rao,ꢀ Ch.ꢀ Ramesh,ꢀ
K Harakishore, B. Gangadasu, U.S.N. Murthy and V. Jayathirtha Rao,
Bioorg. Med. Chem.,ꢀ2006, 14,ꢀ4600.
5
K. Kaur, M. Jain, T. Kaur and R. Jain, Bioorg. Med. Chem.,ꢀ2009,ꢀ17,ꢀ
3229.
M. Behforouz, W. Cai, F. Mohammadi, M.G. Stocksdale, Z. Gu,ꢀ
M. Ahmadian, D.E. Baty, M.R. Etling, C.H. Al-Anzi, T.M. Swiftney,ꢀ
L.R. Tanzer, R.L. Merriman and N.C. Behforouz, Bioorg. Med. Chem.,ꢀ
2007, 15,ꢀ495.
6
7
F. Abas, N.H. Lajis, D.A. Israf, S. Khozirah and Y. Umi Kalsom, Food
Chem.,ꢀ2006, 95,ꢀ566.
ꢀ 8ꢀ L.G.ꢀ Rocha,ꢀ J.R.G.S.ꢀAlmeida,ꢀ R.O.ꢀ Macêdoꢀ andꢀ J.M.ꢀ Barbosa‑Filho,ꢀ
The author acknowledges the help of Quality Control and
Propagationꢀ ofꢀ Plants,ꢀ Departmentꢀ ofꢀ Botany,ꢀ Facultyꢀ ofꢀ
Girls,ꢀAinꢀShamsꢀUniversityꢀforꢀcarryingꢀoutꢀtheꢀantimicrobialꢀ
activity.
Phytomedicine,ꢀ2005, 12,ꢀ514.
9
Reen-Yen Kuo, Fang-Rong Chang, Chung-Yi Chen, Che-Ming Teng,
Hsin-Fu Yen and Yang-Chang Wu, Phytochemistry,ꢀ2001,ꢀ57,ꢀ421.
ꢀ10ꢀ F.ꢀEl‑Mariah,ꢀBulg.ꢀChem. Commun.,ꢀ2007,ꢀ39,ꢀ295.
11 F.A.A. El-Mariah and T. Kappe, Croat. Chem. Acta.,ꢀ1986,ꢀ59,ꢀ171.
12 M. El-Agrody, M.S. Abd El-Latif, N.A. El-Hady, A.H. Fakery andꢀ
A.H.ꢀBedair,ꢀMolecules,ꢀ2001,ꢀ519.
13 A.M. El-Agrody, M.H. El-Hakim, M.S. Abd El-Latif, A.H. Fakery,ꢀ
E.S.M. El-Sayed and K.A. El-Ghareab, Acta Pharm.,ꢀ2000,ꢀ50,ꢀ111.
14 K.G. Dave, C.J. Shishoo, M.B. Devani, R. Kalyanuraman, S. Ananthan,
G.V. Ullas and V.S. Bhadit, J. Heterocycl. Chem.,ꢀ1980,ꢀ17,ꢀ1497.
ꢀ15ꢀ A.S.ꢀAly,ꢀ N.H.ꢀ Fathy,ꢀ S.A.ꢀ Swelamꢀ andꢀ F.M.E.ꢀAbdel‑Megeid,ꢀ Egypt.ꢀ
J. Pharm. Sci.,ꢀ1995,ꢀ36,ꢀ177.
Received 18 June 2009; accepted 29 July 2009
Paper 09/0646 doi: 10.3184/030823409X12509546260155
Published online: 8 September 2009
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