Synthesis and antimicrobial activities of novel naphtho[2,1-b]pyran, pyrano[2,3-d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[2,3-c]-pyrimidine derivatives

Article abstract of DOI:10.1016/S0014-827X(01)01168-5

The synthesis of new naphtho[1′,2′:5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermediate 3-amino-8-bromo-1-(p-methoxyphenyl)-1H-naphtho[2,1-b] pyran-2-carbonitrile (3c) was obtained in one pot synthesis by treating α-cyanocinnamonitrile (1c) with 6-bromo-2-naphthol (2). Antimicrobial activity was shown for some of the synthesized compounds.

Full text of DOI:10.1016/S0014-827X(01)01168-5

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Il Farmaco 56 (2001) 965–973
Synthesis and antimicrobial activities of novel
naphtho[2,1-b]pyran, pyrano[2,3-d]pyrimidine and
pyrano[3,2-e][1,2,4]triazolo[2,3-c]-pyrimidine derivatives
Ahmed H. Bedair a, Hussien A. Emam a, Nagwa A. El-Hady b, Kamal A.R. Ahmed a,
Ahmed M. El-Agrody a,*
a Chemistry Department, Faculty of Science, Al-Azhar Uni6ersity, Nasr City, 11884 Cairo, Egypt
b Chemistry Department, Faculty of Science (Girl’s), Al-Azhar Uni6ersity, Nasr City, 11884 Cairo, Egypt
Received 16 November 2000; accepted 25 June 2001
Abstract
The synthesis of new naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermedi-
ate 3-amino-8-bromo-1-(p-methoxyphenyl)-1H-naphtho[2,1-b] pyran-2-carbonitrile (3c) was obtained in one pot synthesis by
treating a-cyanocinnamonitrile (1c) with 6-bromo-2-naphthol (2). Antimicrobial activity was shown for some of the synthesized
compounds. © 2001 Elsevier Science S.A. All rights reserved.
Keywords: Naphthopyrans; Pyranopyrimidines; Pyranotriazolopyrimidines; Antimicrobial activities
1. Introduction
synthesis of fused pyrans using enaminonitriles, we
report here the synthesis of a variety of new hetero-
cyclic compounds. Thus, condensation of various sub-
stituted a-cyanocinnamonitriles (1a–f) with 6-bromo-
2-naphthol (2) in ethanolic piperidine afford 1:1 ad-
ducts [12,14]. Structure 3 (Scheme 1) was established on
Pyrans and fused pyrans are biologically interesting
compounds with antibacterial activities [1,2], antifungal
activities [3], antitumor activity [4] and hypotensive
effect [5]. On the other hand, some pyran derivatives
also have various biological properties like antiprolifer-
ation effect [6], molluscicidal activities [7], local anes-
thetic and antiarrhythmic activities [8], antiallergic
effect [9,10] and hypolipidemic activity [11]. The present
study is part of our program aimed at developing new
approaches for the synthesis of fused heterocyclic sys-
tems. We reported here the synthesis of naphtho[2,1-
b]pyran derivatives and their utility as building blocks
in the synthesis of novel fused pyrans to evaluate the
antimicrobial activity.
1
the basis of the H NMR spectra, which showed 1-H at
l 5.27–5.51 ppm (3a–f). The increased chemical shift
for this signal, compared to the expected value (l
4.0–5.0 ppm) for such protons, can be attributed to the
deshielding effect of the diamagnetic current of the
naphthyl, aryl and allylic p-electrons [17–19]. The UV
spectrum of 3a–f revealed a weak shoulder [14,20],
characteristic for 4H-pyran, at umax (CH3COCH3) 275
nm (log m 2.80–2.86) (3a–f), respectively.
Interaction
of
3-amino-8-bromo-1-(p-methoxy-
phenyl)-1H-naphtho[2,1-b]pyran-2-carbonitrile
(3c)
with aromatic aldehydes in dioxane–piperidine under
reflux gave the corresponding 3-arylmethyleneamino
derivatives 4a–c (Scheme 1). When 8-bromo-1-(p-
methoxyphenyl)-3-phenylmethyleneamino-1H-naphtho-
[2,1-b]pyran-2-carbonitrile (4a) was treated with hydra-
zine hydrate or phenyl hydrazine in ethanol at room
temperature or reflux, an addition product formed (5),
from which elimination of benzaldehyde hydrazone and
2. Chemistry
In continuation of our previous work [12–16] on the
* Corresponding author.
E-mail address: elagrody am@yahoo.com (A.M. El-Agrody).
–
0014-827X/01/$ - see front matter © 2001 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(01)01168-5

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A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
benzaldehyde phenylhydrazone, respectively, gave the
enaminonitrile 3c [14,21] instead of the pyrimidine
derivative 6. Treatment of 3c with acetic anhydride for
30 min afforded the N-acetyl derivative 7, while heating
of 3c with acetic anhydride under reflux for 3 h af-
forded the naphthopyranopyrimidin-11-one 8. Struc-
ture 8 is supported by an independent synthesis of the
same product from 3f and acetonitrile in the presence
of HCl gas [22] (Scheme 1).
Reaction of 3c with formic acid gave the naphthopy-
ranopyrimidin-11-one derivative 9. The structure of 9
was supported by an independent synthesis from 3f and
formamide (Scheme 1). Structures 4, 7–9 were estab-
lished by spectral data and analogy with our previous
work [12,14–16]. Treatment of 3b,c with triethyl ortho-
formate in acetic anhydride at reflux gave the corre-
sponding ethoxymethyleneamino derivatives 10a,b
(Scheme 2). Hydrazinolysis of 10a,b in ethanol at room
temperature afforded the imino derivatives 11a,b
(Scheme 2). Ammonolysis of 10b in methanol at room
temperature afforded the pyrimidine derivative 12, the
structure of which was supported by its independent
synthesis from 3c and formamide (Scheme 2). Reaction
of 10b with methylamine yielded the pyrimidine deriva-
tive 13, while with dimethylamine the open-chain
product 14 was obtained (Scheme 2).
Interaction of 11b with triethyl orthoformate af-
forded 11-bromo-14-(p-methoxyphenyl)-14H-naphtho-
[1%,2%:5,6]pyrano[3,2 - e][1,2,4]triazolo[2,3 - c]pyrimidine
(15a) (Scheme 3), while with acetyl chloride and ethyl
cyanoacetate at reflux the corresponding 2-methyl (15b)
and 2-acetonitrile (15c) derivatives, respectively, were
formed. Reaction of 11b with diethyl oxalate and ben-
zoyl chloride at reflux afforded the corresponding 2-
carboxylate (15d) and 2-phenyl (15e) derivatives,
respectively (Scheme 3).
Instead of the anticipated formation of the tria-
zolopyrimidine derivative 16 [13,14], the reaction of 11b
Scheme 1.

A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
967
Scheme 2.
Scheme 3.

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A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
1
with methyl or ethyl chloroformate in dry benzene
afforded 18, through nucleophilic displacement followed
by spontaneous hydrolysis of the ester intermediate 17
into the corresponding carbamic acid derivative 18. The
formation of ion peak at 448 (13.6%) (M+−
CO2) for the mass spectrum of 18 (m/z M+, 0%)
supported the proposed structure due to the ready
elimination of CO2 molecule (Scheme 3).
Interaction of 11b with aromatic aldehydes in diox-
ane–piperidine for 16 h afforded 10-arylmethylene-
amino-3-bromo-11-imino-12-(p-methoxyphenyl)-10,11-
dihydro-12H-naphtho[1‘,2‘:5,6]pyrano[2,3-d]pyrimidine
(19a–c) (Scheme 3), while heating of 11b with benzalde-
hyde in dioxane–piperidine under reflux for 30 h af-
forded 15e (m.p. and mixed m.p.). The structure of 19
was supported by spectral data and TLC.
g (90%). IR: 3448, 3319 (NH2), 2200 (CN). H NMR
(DMSO-d6): 7.19–8.24 (m, 9H, Ar-H), 7.11 (br, 2H,
NH2), 5.37 (s, 1H, pyran CH). Anal. (C, H, N) for
C20H12BrClN2O.
3.1.4. 3-Amino-8-bromo-1-(p-methoxyphenyl)-
1H-naphtho[2,1-b]pyran-2-carbonitrile (3c)
Colorless crystals from benzene, m.p. 235 °C, yield
3.7 g (91%). IR: 3400, 3317 (NH2), 2966, 2927, 2833
(CH stretching), 2195 (CN). 1H NMR (DMSO-d6):
6.81–8.23 (m, 11H, Ar-H+NH2), 5.27 (s, 1H, pyran
CH), 3.68 (s, 3H, OCH3). Anal. (C, H, N) for
C21H15BrN2O2.
3.1.5. Ethyl 3-amino-8-bromo-1-phenyl-1H-
naphtho[2,1-b]-pyran-2-carboxylate (3d)
Colorless needles from benzene, m.p. 180 °C, yield 3.1
g (74%). IR: 3404, 3300 (NH2), 3024, 2987, 2901 (CH
stretching), 1666 (CO ester). 1H NMR (DMSO-d6):
7.07–8.21 (m, 12H, Ar-H+NH2), 5.49 (s, 1H, pyran
CH), 4.11 (q, 2H, CH2, J=6 Hz) and 1.26 (t, 3H, CH3,
J=6 Hz). Anal. (C, H, N) for C22H18BrNO3.
3. Experimental
M.p.s are uncorrected and were determined on a
Stuart Scientific Co. Ltd melting point apparatus. IR
spectra wmax/cm−1 (KBr) were measured on a FT IR/
5300 spectrometer. Ultraviolet spectra were recorded on
Perkin–Elmer Lambda-3B UV–Visible spectrophoto-
3.1.6. Ethyl 3-amino-8-bromo-1-(p-chlorophenyl)-1H-
naphtho[2,1-b]pyran-2-carboxylate (3e)
Colorless needles from benzene, m.p. 170°C, yield 3.5
g (77%). IR: 3468, 3302 (NH2), 2974, 2926, 2901, 2955
(CH stretching), 1682 (CO ester). 1H NMR (DMSO-d6):
7.24–8.27 (m, 9H, Ar-H), 7.62 (br, 2H, NH2, cancelled
by D2O), 5.51 (s, 1H, pyran CH), 4.12 (q, 2H, CH2,
J=7.2 Hz) and 1.28 (t, 3H, CH3, J=7.2 Hz). Anal. (C,
H, N) for C22H17BrClNO3.
1
meter; H NMR spectra l (ppm) on Varian Mercury
(300 MHz) spectrometer and mass spectra on a Shi-
madzu GC-MS-QP 1000 EX spectrometer. Elemental
analyses were carried out in the Microanalytical Labo-
ratories of the Faculty of Science, Cairo University, and
analytical results for (C, H, N) were within 90.2% of
the calculated values.
3.1.7. Ethyl 3-amino-8-bromo-1-(p-methoxyphenyl)-
1H-naphtho[2,1-b]pyran-2-carboxylate (3f)
3.1. Reaction of 1a–f with 6-bromo-2-naphthol (2)
Colorless needles from benzene, m.p. 200 °C, yield 3.6
g (79%). IR: 3431, 3315 (NH2), 3045, 2975, 2927 (CH
stretching), 1678 (CO ester). 1H NMR (DMSO-d6):
6.73–8.21 (m, 11H, Ar-H+NH2), 5.43 (s, 1H, pyran
CH), 4.10 (q, 2H, CH2, J=6.9 Hz), 3.63 (s, 3H, OCH3)
and 1.27 (t, 3H, CH3, J=6.9Hz). Anal. (C, H, N) for
C23H20BrNO4.
3.1.1. General procedure
A solution of 1a–f (0.01 mol) in ethanol (30 ml) was
treated with 6-bromo-2-naphthol 2 (2.23 g, 0.01 mol)
and piperidine (0.5 ml). The reaction mixture was
heated until complete precipitation (reaction times: 15
min for 1a–c; 120 min for 1d–f). The solid product
which formed was collected by filtration and recrystal-
lized from a suitable solvent to give 3a–f.
3.2. 3-Arylmethyleneamino-8-bromo-1-(p-methoxy-
phenyl)-1H-naphtho[2,1-b]pyran-2-carbonitrile (4a–c)
3.1.2. 3-Amino-8-bromo-1-phenyl-1H-naphtho[2,1-b]-
pyran-2-carbonitrile (3a)
3.2.1. General procedure
Colorless crystals from benzene, m.p. 240 °C, yield
4.4 g (89%). IR: 3477, 3321 (NH2), 3064, 2968, 2868
(CH stretching), 2205 (CN). 1H NMR (DMSO-d6):
7.15–8.21 (m, 10H, Ar-H), 7.05 (br, 2H, NH2, cancelled
by D2O), 5.32 (s, 1H, pyran CH). Anal. (C, H, N) for
C20H13BrN2O.
A mixture of 3c (4.06 g, 0.01 mol), benzaldehyde,
p-chlorobenzaldehyde and p-anisaldehyde (0.01 mol),
dioxane (20 ml) and piperidine (0.5 ml) was refluxed for
4 h to give 4a–c.
3.2.2. 8-Bromo-1-(p-methoxyphenyl)-
3-phenylmethyleneamino-1H-naphtho[2,1-b]-
3.1.3. 3-Amino-8-bromo-1-(p-chlorophenyl)-
1H-naphtho[2,1-b]pyran-2-carbonitrile (3b)
Yellow crystals from benzene, m.p. 265 °C, yield 3.7
pyran-2-carbonitrile (4a)
Yellow crystals from benzene, m.p. 280 °C, yield 4.1
g (82%). IR: 3074, 3013, 2922, 2843 (CH stretching),

A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
969
2210 (CN), 1641 (CꢀN). Anal. (C, H, N) for
C28H19BrN2O2.
3.5. 3-Bromo-12-(p-methoxyphenyl)-10,11-
dihydro-12H-naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidin-
11-one (9)
3.2.3. 8-Bromo-3-(p-chlorophenylmethyleneamino)-1-
(p-methoxyphenyl)-1H-naphtho[2,1-b]pyran-2-
carbonitrile (4b)
3.5.1. Method (a)
A solution of 3c (4.06 g, 0.01 mol) in formic acid (20
ml) was heated under reflux for 6 h to give 9 as colorless
needles, m.p. 170 °C, yield 2.9 g (67%). IR: 3510 (NH),
3026, 2955, 2924, 2887, 2833 (CH stretching) and 1768
Yellow crystals from benzene, m.p. 310 °C, yield 4.1
g (88%). IR: 3078, 2939, 2885 (CH stretching), 2212
1
(CN), 1641 (CꢀN). H NMR (DMSO-d6): 9.17 (s, 1H,
1
(CO). H NMR (DMSO-d6): 8.30 (s, 1H, pyrimidine
NꢀCH), 6.87–8.25 (m, 13H, Ar-H), 5.72 (s, 1H, pyran
CH), 3.69 (s, 3H, OCH3). Anal. (C, H, N) for
C28H18BrClN2O2.
CH), 6.90–9.07 (m, 10, Ar-H+NH), 5.54 (s, 1H, pyran
CH) and 3.70 (s, 3H, OCH3). Anal. (C, H, N) for
C22H15BrN2O3.
3.2.4. 8-Bromo-1-(p-methoxyphenyl)-3-
(p-methoxyphenylmethyleneamino)-1H-naphtho[2,1-b]-
3.5.2. Method (b)
A solution of 3f (4.53 g, 0.01 mol) in formamide (20
ml) was heated under reflux for 6 h to give 9 (m.p. and
mixed m.p.) yield 3.1 g (73%).
pyran-2-carbonitrile (4c)
Yellow crystals from benzene, m.p. 272 °C, yield 4.7
g (90%). IR: 3050, 3000, 2900, 2805 (CH stretching),
1
2208 (CN), 1641 (CꢀN). H NMR (DMSO-d6): 9.06 (s,
3.6. 1-Aryl-8-bromo-3-ethoxymethyleneamino-1H-
naphtho[2,1-b]pyran-2-carbonitrile (10a,b)
1H, NꢀCH), 6.84–8.22 (m, 13H, Ar-H), 5.65 (s, 1H,
pyran CH), 3.86 (s, 3H, OCH3) and 3.67 (s, 3H,
OCH3). Anal. (C, H, N) for C29H21BrN2O3.
3.6.1. General procedure
A mixture of 3b,c (0.01 mol), triethyl orthoformate
(0.01 mol) and acetic anhydride (20 ml) was refluxed for
5 h to give 10a,b.
3.3. 3-Acetylamino-8-bromo-1-(p-methoxyphenyl)-
1H-naphtho[2,1-b]pyran-2-carbonitrile (7)
A solution of 3c (4.06 g, 0.01 mol) in acetic anhydride
(20 ml) was heated under reflux for 30 min. The solid
product formed was filtered, washed with cold ethanol,
dried and recrystallized from ethanol to give colorless
needles, m.p. 240 °C, yield 3.6 g (81%). IR: 3200 (NH),
3047, 2916 (CH stretching), 2206 (CN), 1705 (CO ace-
3.6.2. 8-Bromo-1-(p-chlorophenyl)-3-ethoxy-
methyleneamino-1H-naphtho[2,1-b]pyran-2-carbonitrile
(10a)
Colorless needles from benzene, m.p. 210 °C, yield 3.5
g (75%). IR: 3036, 2987, 2951, 2827 (CH stretching),
1
2208 (CN); 1654 (CꢀN). H NMR (DMSO-d6): 8.74 (s,
1
tyl). H NMR (DMSO-d6): 11.15 (br,1H, NH), 6.83–
1H, NꢀCH), 7.28–8.25 (m, 9H, Ar-H), 5.68 (s, 1H,
pyran CH), 4.34 (q, 2H, CH2, J=6.9 Hz), 1.32 (t, 3H,
CH3, J=6.9 Hz). Anal. (C, H, N) for C23H16-
BrClN2O2.
8.22 (m, 9H, Ar-H), 5.55 (s, 1H, pyran CH), 3.66 (s, 3H,
OCH3) and 3.28 (s, 3H, COCH3). Anal. (C, H, N) for
C23H17BrN2O3.
3.4. 3-Bromo-9-methyl-12-(p-methoxyphenyl)-
10,11-dihydro-12H-naphtho[1%,2%:5,6]pyrano[2,3-d]-
pyrimidin-11-one (8)
3.6.3. 8-Bromo-3-ethoxymethyleneamino-1-
(p-methoxyphenyl)-1H-naphtho[2,1-b]pyran-2-
carbonitrile (10b)
Colorless needles from benzene, m.p. 190 °C, yield 3.8
3.4.1. Method (a)
g (82%). IR: 2984, 2937, 2896 (CH stretching), 2212
1
A solution of 3c (4.06 g, 0.01 mol) in acetic anhydride
(20 ml) was heated under reflux for 3 h. The solid
product formed was filtered, washed with cold ethanol,
dried and recrystallized from benzene to give colorless
needles, m.p. 320 °C, yield 3.9 g (86%). IR: 3260 (NH),
3001, 2850 (CH stretching) and 1651 (CO). Anal. (C, H,
N) for C23H17BrN2O3.
(CN); 1651 (CꢀN). H NMR (DMSO-d6) 8.73 (s, 1H,
NꢀCH), 6.85–8.24 (m, 9H, Ar-H), 5.56 (s, 1H, pyran
CH), 4.34 (q, 2H, CH2, J=6.9 Hz), 3.70 (s, 3H, OCH3)
and 1.33 (t, 3H, CH3, J=6.9 Hz). Anal. (C, H, N) for
C24H19BrN2O3.
3.7. 10-Amino-12-aryl-3-bromo-11-imino-10,11-
dihydro-12H-naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidine
(11a,b)
3.4.2. Method (b)
A stream of dry HCl gas was passed through a
mixture of 3f (4.53 g, 0.01 mol) and acetonitrile (30 ml)
for 4–6 h. The reaction mixture was poured into ice-wa-
ter and basified with 10% ammonium hydroxide solu-
tion to give 8 (m.p. and mixed m.p.) yield 3.1 g (68%).
3.7.1. General procedure
A solution of 10a,b (0.01 mol) and hydrazine hydrate
(99%, 5 ml) in ethanol (50 ml) was stirred at room
temperature (r.t.) for 45 min to give 11a,b.

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A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
3.7.2. 10-Amino-3-bromo-12-(p-chlorophenyl)-11-
imino-10,11-dihydro-12H-naphtho[1%,2%:5,6]-
pyrano[2,3-d]pyrimidine (11a)
3.10. 8-Bromo-3-dimethylaminomethyleneamino-1-
(p-methoxyphenyl)-1H-naphtho[2,1-b]pyran-2-
carbonitrile (14)
Colorless needles from dioxan, m.p. 290 °C, yield 3.8
g (85%). IR: 3400, 3329 (NH2), 3200 (NH), 1614 (CꢀN).
Anal. (C, H, N) for C21H14BrClN4O.
Compound 14 was prepared from 10b (4.62 g, 0.01
mol) and dimethylamine (0.01 mol) according to the
procedure described for 11 to give 14 as colorless
crystals (benzene), m.p. 245 °C, yield 4.0 g (87%). IR:
2920, 2891, 2839 (CH stretching), 2199 (CN), 1647
(CꢀN). 1H NMR (DMSO-d6): 8.44 (s, 1H, NꢀCH),
6.79–8.16 (m, 9H, Ar-H), 5.23 (s, 1H, pyran CH), 3.65
(s, 3H, OCH3), 3.13 (s, 3H, NCH3) and 2.98 (s, 3H,
NCH3). Anal. (C, H, N) for C24H20BrN3O2.
3.7.3. 10-Amino-3-bromo-12-(p-methoxyphenyl)-11-
imino-10,11-dihydro-12H-naphtho[1%,2%:5,6]-
pyrano[2,3-d]pyrimidine (11b)
Colorless needles from dioxan, m.p. 240 °C, yield 3.9
g (87%). IR: 3341, 3292 (NH2), 3242 (NH), 3067, 2953,
2907, 2833 (CH stretching), 1649 (CꢀN). 1H NMR
(DMSO-d6): 8.22 (s, 1H, pyrimidine CH), 8.10 (br, 1H,
NH, cancelled by D2O), 6.75–7.93 (m, 9H, Ar-H), 6.00
(br, 2H, NH2, cancelled by D2O), 5.70 (s, 1H, pyran
CH) and 3.63 (s, 3H, OCH3). Anal. (C, H, N) for
C22H17BrN4O2.
3.11. 11-Bromo-14-(p-methoxyphenyl)-14H-
naphtho[1%,2%:5,6]pyrano[3,2-e][1,2,4]triazolo[2,3-c]-
pyrimidine (15a)
A solution of 11b (4.48 g, 0.01 mol) and triethyl
orthoformate (0.01 mol) in dry benzene was refluxed
for 6 h to give 15a as colorless crystals (benzene), m.p.
260 °C, yield 3.6 g (79%). IR: 3032, 3007, 2835 (CH
stretching), 1634 (CꢀN). 1H NMR (DMSO-d6): 9.63
(s,1H, pyrimidine CH), 8.62 (s, 1H, triazole CH),
6.72–8.23 (m, 9H, Ar-H), 6.26 (s, 1H, pyran CH) and
3.60 (s, 3H, OCH3). Anal. (C, H, N) for C23H15BrN4O2.
3.8. 11-Amino-3-bromo-12-(p-methoxyphenyl)-
12H-naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidine (12)
3.8.1. Method (a)
A stream of NH3 gas was passed through 10b (4.62 g,
0.01 mol) in methanol at r.t. for 1 h. The solid product
formed in cooling was collected to give 12 as colorless
needles (benzene), m.p. 275 °C, yield 4.2 g (88%). IR:
3.12. 11-Bromo-2-methyl-14-(p-methoxyphenyl)-
14H-naphtho[1%,2%:5,6]pyrano[3,2-e]-[1,2,4]-
triazolo[2,3-c]pyrimidine (15b)
1
3479, 3350 (NH2) and 1679 (CꢀN). H NMR (DMSO-
d6): 8.23 (s, 1H, pyrimidine CH), 6.76–8.15 (m, 9H,
Ar-H), 7.18 (br, 2H, NH2, cancelled by D2O), 5.60 (s,
1H, pyran CH) and 3.63 (s, 3H, OCH3). Anal. (C, H,
N) for C23H19BrN4O3.
Compound 15b was prepared from 11b (4.48 g, 0.01
mol) and acetyl chloride (0.01 mol) according to the
procedure described for 15a to give 15b as colorless
crystals (benzene), m.p. 255 °C, yield 4.0 g (84%). IR:
3080, 2980, 2831 (CH stretching), 1667 (CꢀN). 1H
NMR (DMSO-d6): 8.83 (s, 1H, pyrimidine CH),
6.80–8.26 (m, 9H, Ar-H), 6.64 (s, 1H, pyran CH), 3.63
(s, 3H, OCH3) and 2.14 (s, 3H, triazole CH3). Anal.(C,
H, N) for C24H17BrN4O2.
3.8.2. Method (b)
Compound 12 was prepared from 3c (4.06 g, 0.01
mol) and formamide (0.01 mol) according to the proce-
dure described for 9 (method b) to give 12 (m.p. and
mixed m.p.) yield 3.1 g (65%).
3.9. 3-Bromo-10-methyl-11-imino-12(p-methoxy-
phenyl)-10,11-dihydro-12H-naphtho[1%,2%:5,6]-
pyrano[2,3-d]pyrimidine (13)
3.13. 11-Bromo-14-(p-methoxyphenyl)-14H-
naphtho[1%,2%:5,6]pyrano[3,2-e][1,2,4]triazolo[2,3-c]-
pyrimidin-2-acetonitrile (15c)
Compound 13 was prepared from 10b (4.62 g, 0.01
mol) and methylamine (0.01 mol) according to the
procedure described for 11 to give 13 as colorless
crystals (benzene), m.p. 280 °C, yield 3.7 g (83%). IR:
3352 (NH), 3020, 2924, 2837 (CH stretching), 1645
A mixture of 11b (4.48 g, 0.01 mol), ethyl
cyanoacetate (0.01 mol) and absolute ethanol (20 ml)
was refluxed for 6 h to give 15c as colorless crystals
(ethanol), m.p. 270 °C, yield 3.2 g (65%). IR: 3059,
3030, 2933 (CH stretching) and 2200 (CN), 1636 (CꢀN).
1H NMR (DMSO-d6): 9.62 (s, 1H, pyrimidine CH),
6.73–8.24 (m, 9H, Ar-H), 6.25 (s, 1H, pyran CH), 4.47
(s, 2H, CH2) and 3.59 (s, 3H, OCH3). Anal. (C, H, N)
for C25H16BrN5O2.
1
(CꢀN). H NMR (DMSO-d6): 8.23 (s, 1H, pyrimidine
CH), 6.73–8.20 (m, 10H, Ar-H+NH), 5.83 (s, 1H,
pyran CH), 3.61 (s, 3H, OCH3) and 3.28 (s, 3H,
NꢁCH3). Anal. (C, H, N) for C23H18BrN3O2.

A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
971
3.14. Ethyl 11-bromo-14-(p-methoxyphenyl)-14H-
naphtho[1%,2%:5,6]pyrano[3,2-e][1,2,4]triazolo[2,3-c]-
pyrimidine-2-carboxylate (15d)
3.17.2. 3-Bromo-11-imino-12-(p-methoxyphenyl)-10-
phenylmethyleneamino-10,11-dihydro-12H-
naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidine (19a)
Pale yellow needles from benzene, m.p. 280 °C, yield
Compound 15d was prepared from 11b (4.48 g, 0.01
mol) and ethyl oxalate (0.01 mol) according to the
procedure described for 15c to give 15d as colorless
crystals (ethanol), m.p. 213 °C, yield 4.2 g (80%). IR:
3041, 2995, 2961 (CH stretching), 1720 (CO), 1618
4.3 g (82%). IR: 3184 (NH), 3000, 2926, 2833 (CH
stretching), 1628 (CꢀN). H NMR (DMSO-d6): 11.12
(br, 1H, NH; cancelled by D2O), 8.35 (s, 1H, pyrim-
idine CH), 6.73–8.26 (m, 14H, Ar-H), 6.65 (s, 1H,
pyran CH), 3.58 (s, 1H, OCH3). Anal. (C, H, N) for
C29H21BrN4O2.
1
1
(CꢀN). H NMR (DMSO-d6): 8.66 (s, 1H, pyrimidine
CH), 6.78–8.27 (m, 9H, Ar-H), 6.25 (s, 1H, pyran CH),
3.93 (q, 2H, CH2, J=6.9 Hz), 3.61 (s, 3H, OCH3), 1.13
(t, 3H, CH3, J=6.9 Hz). Anal. (C, H, N) for
C26H19BrN4O4.
3.17.3. 3-Bromo-10-(p-chlorophenylmethyleneamino)-
11-imino-12-(p-methoxyphenyl)-10,11-dihydro-12H-
naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidine (19b)
Yellow needles from benzene, m.p. 285 °C, yield 4.8
g (84%). IR: 3198 (NH), 3034, 3003, 2907, 2833 (CH
stretching), 1628 (CꢀN). Anal. (C, H, N) for
C29H20BrClN4O2.
3.15. 11-Bromo-2-phenyl-14-(p-methoxyphenyl)-
14H-naphtho[1%,2%:5,6]pyrano[3,2-e][1,2,4]triazolo-
[2,3-c]pyrimidine (15e)
Compound 15e was prepared from 11b (4.48 g, 0.01
mol) and benzoyl chloride (0.01 mol) according to the
procedure described for 15a to give 15e as colorless
crystals (dioxan), m.p. 310 °C, yield 3.3 g (62%). IR:
3.17.4. 3-Bromo-11-imino-10-(p-methoxyphenyl-
methyleneamino)-12-(p-methoxyphenyl)-10,11-
dihydro-12H-naphtho[1%,2%:5,6]pyrano[2,3-d]pyrimidine
(19c)
1
3005 (CH stretching), 1634 (CꢀN). H NMR (DMSO-
Yellow needles from benzene, m.p. 260 °C, yield 4.9
d6): 9.60 (s, 1H, pyrimidine CH), 6.78–8.31 (m, 14H,
Ar-H), 6.34 (s, 1H, pyran CH) and 3.61 (s, 3H, OCH3).
Anal. (C, H, N) for C29H19BrN4O2.
g (86%). IR: 3196 (NH), 2959, 2928, 2905, 2833 (CH
1
stretching), 1628 (CꢀN). H NMR (DMSO-d6): 10.96
(br, 1H, NH; cancelled by D2O), 8.32 (s, 1H, pyrim-
idine CH), 6.73–8.25 (m, 13H, Ar-H), 6.63 (s, 1H,
pyran CH), 3.82 (s, 3H, OCH3), 3.56 (s, 3H, OCH3).
Anal. (C, H, N) for C30H23BrN4O3.
3.16. N-[3-Bromo-12-(p-methoxyphenyl)-
11-imino-12H-naphtho[1%,2%:5,6]pyrano[2,3-d]-
pyrimidyl-10]carbamic acid (18)
3.18. Preparation of 15e
Compound 18 was prepared from 11b (4.48 g, 0.01
mol) and methyl chloroformate or ethyl chloroformate
(0.01 mol) according to the procedure described for 15a
to give 18 as colorless crystals (benzene), m.p. 275 °C,
yield 3.3 g (74%). IR: 3753–2835 centered at 3049 (NH,
COOH, CH stretching) and 1649 (CO). 1H NMR
(DMSO-d6): 12.21 (br, 1H, OH), 8.70 (s, 1H, pyrim-
idine CH), 6.78–8.28 (m, 9H, Ar-H), 6.65 (br, 1H,
NH), 6.43 (s, 1H, pyran CH), 3.63 (s, 3H, OCH3). MS:
m/z 450/448 (M+−CO2, 16/14%), 434/432 (99/100),
328/326 (90/88), 301/299 (29/30), 220 (13), 193 (16), 164
(15), 63(13). Anal. (C, H, N) for C23H17BrN4O4.
A mixture of 11b (4.48 g, 0.01 mol), benzaldehyde
(0.01 mol), dioxan (20 ml) and piperidine (0.5 ml) was
refluxed for 30 h to give 15e (m.p. and mixed m.p.)
yield 4.3 g (81%).
4. Biological screening
4.1. Antibacterial acti6ity
Some of the newly synthesized compounds 3b,c,f,
4b,c, 7–9, 10b, 11b, 12–14, 15a–e and 19b,c were
screened for their antibacterial activity against four
species of bacteria, Gram positive bacteria namely
Staphylococcus aureus (NCTC-7447), Bacillus cereus
(ATCC-14579) and Gram negative bacteria Serratia
marcescens (IMRU-70) and Proteus mirabilis (NTCC-
289) using Ampicillin (25 mg) as reference compound
[23].
3.17. 10-Arylmethyleneamino-3-bromo-11-imino-12-
(p-methoxyphenyl)-10,11-dihydro-12H-naphtho-
[1%,2%:5,6]pyrano[2,3-d]pyrimidine (19a–c)
3.17.1. General procedure
A mixture of 11b (4.48 g, 0.01 mol), benzaldehyde,
p-chlorobenzaldehyde, p-anisaldehyde (0.01 mol), diox-
ane (20 ml) and piperidine (0.5 ml) was refluxed for 16
h to give 19a–c.
The tested compounds were dissolved in N,N-
dimethylformamide (DMF) to get a solution of 1%
concentration. Filter paper discs (Whatman No. 3 filter
paper, 5 mm diameter) were saturated with former

972
A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
solution. The saturated filter paper discs were placed on
the nutrient agar (Difco) dishes seeded by test bacte-
ria.The inhibition zone was measured in millimeters at
the end of an incubation period of 48 h at 28 °C. DMF
showed no inhibition zone. The results are illustrated in
Table 1.
Table 2
Antifungal activity of some compounds
Comp.
A. ochraceus Wilhelm
(AUCC-230)
P. chrysogenum Thom
(AUCC-530)
3b
3c
3f
4b
4c
7
8
9
10b
11b
12
13
14
15a
15b
15c
10
13
15
19
18
18
22
17
14
18
19
19
17
20
19
18
20
19
20
20
22
9
10
15
20
17
19
20
16
13
20
13
20
17
19
20
21
22
18
20
17
24
4.2. Antifungal acti6ity
Some of the newly synthesized compounds 3b,c,f,
4b,c, 7–9, 10b, 11b, 12–14, 15a–e and 19b,c were
screened for their antifungal activity against two species
of fungi, Aspergillus ochraceus Wilhelm (AUCC-230)
and Penicillium chrysogenum Thom (AUCC-530) using
the Mycostatine (30 mg) as reference compound [24].
The tested compounds were dissolved in DMF to get
a solution of 1% concentration. Filter paper discs
(Whatman No. 3 filter paper, 5 mm diameter) were
saturated with former solution. The saturated filter
paper discs were placed on the Glucose–Czapek’s agar
medium (Difco) dishes seeded by test fungi. The inhibi-
tion zone was measured in millimeters at the end of an
incubation period of 48 h at 28 °C. DMF showed no
inhibition zone. The results are illustrated in Table 2.
15d
15e
19b
19c
Mycostatine a
(30 mg)
a Paper discs manufactured by Bristol–Myers Squibb, Giza, Egypt.
5. Conclusion
thopyran 3c. Enhanced activity was obtained with
naphthopyranopyrimidine derivatives 8, 9, 10b, 11b, 12,
13, 19c and naphthopyran derivatives 7 and 14. The
naphthopyranotriazolopyrimidine derivatives 15a–e
show more improvement in antibacterial activity over
The antibacterial activity of the naphthopyran
derivative 3c was assumed as the base level of activity.
The naphthopyran derivatives 3b,f and 4b,c offered an
improvement in antibacterial activity over the naph-
Table 1
Antibacterial activity of some compounds
Comp.
S. aureus (NCTC-7447) B. cereus (ATCC-14579)
S. marcescens (IMRU-70)
P. mirabilis (NTCC-289)
3b
3c
3f
4b
4c
7
8
9
10b
11b
12
13
14
15a
15b
15c
15d
15e
19b
19c
14
13
15
19
18
19
22
21
18
21
19
22
20
22
23
25
24
21
23
21
13
14
17
21
19
20
22
20
14
23
18
21
22
21
22
22
23
20
22
20
25
15
13
16
20
18
19
22
22
18
21
20
22
20
22
23
25
25
22
23
20
26
16
14
18
22
20
20
22
20
15
22
18
21
22
22
23
23
24
22
23
19
25
Ampicillin a (25 mg) 26
a Paper discs manufactured by Bristol–Myers Squibb, Giza, Egypt.

A.H. Bedair et al. / Il Farmaco 56 (2001) 965–973
973
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