A novel synthesis of dibenzo[c,f]chromenes, dibenzo[c,h]chromenes and benzo[7,8]chromeno[3,4-f]isoindoles as antimicrobial agents

Article abstract of DOI:10.1016/S0014-827X(00)00008-2

Naphtho[2,1-b]pyranone (3) was allowed to react with arylmethylenemalononitriles to yield 4-amino-5-oxo-2-aryl-5H-dibenzo[c,f]chromene-3-carbonitriles (4a,b); with ethyl 3,4-dichlorobenzylidene cyanoacetate to furnish dibenzo[c,f]chromene (5) and with ele

Full text of DOI:10.1016/S0014-827X(00)00008-2

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 227–232
A novel synthesis of dibenzo[c,f ]chromenes, dibenzo[c,h]chromenes
and benzo[7,8]chromeno[3,4-f ]isoindoles as antimicrobial agents
Mohamed S.A. El-Gaby a,*, Medhat A. Zahran b, Magda M.F. Ismail c,
Yousry A. Ammar b
a Chemistry Department, Faculty of Science, Al-Azhar Uni6ersity at Assiut, Assiut 71524, Egypt
b Chemistry Department, Faculty of Science, Al-Azhar Uni6ersity, Nasr City, Cairo, Egypt
c Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girl’s), Al-Azhar Uni6ersity, Nasr City, Cairo, Egypt
Received 30 July 1999; accepted 3 February 2000
Abstract
Naphtho[2,1-b]pyranone (3) was allowed to react with arylmethylenemalononitriles to yield 4-amino-5-oxo-2-aryl-5H-diben-
zo[c,f ]chromene-3-carbonitriles (4a,b); with ethyl 3,4-dichlorobenzylidene cyanoacetate to furnish dibenzo[c,f ]chromene (5) and
with elemental sulfur in dioxane containing piperidine to give thieno[3,4-d]naphtho[2,1-b]pyranone (6). Similarly, naphtho[1,2-
b]pyranone (7) was reacted with arylmethylenemalononitriles and elemental sulfur to furnish dibenzo[c,h]chromenes (8) and
thieno[3,4-d]naphtho[1,2-b]pyranone (10), respectively. Compound 10 underwent cycloaddition with N-arylmaleimides to yield
benzo[7,8]chromeno[3,4-f ]isoindoles (11a–c). Some of these compounds were screened in vitro for their antimicrobial activities.
© 2000 Elsevier Science S.A. All rights reserved.
Keywords: Chromenes; Isoindoles; Antimicrobial
1. Introduction
2. Chemistry
Naphthopyranones are biologically interesting com-
pounds with antimicrobial [1] and antihypertensive [2]
activities. Arylmethylenemalononitriles and ethyl a-
cyanocinnamates are versatile reagents for the construc-
tion of carbo- and heterocyclic systems [3–6]. They are
prone to react with a variety of compounds containing
acidic hydrogen atoms to provide Michael adducts as
intermediates, which undergo spontaneous cyclization
to o-aminonitriles or o-aminocarboxylic esters, respec-
tively [7,8]. The present study is part of our program
aimed at developing new approaches for the synthesis
of fused heterocyclic systems. We report here the syn-
thesis of naphtho[2,1-b]pyran derivatives and their util-
ity as building block in the synthesis of novel
heterocycles to evaluate the antimicrobial activity.
It has been found that 1-acetyl-2-naphthol (1) reacted
with ethyl cyanoacetate in the presence of catalytic
amount of ammonium acetate for which two products 2
and 3 seemed possible. Structure 2 was readily ruled
out on the basis of analytical and spectral data. Thus,
the IR spectrum of 3 exhibited absorption bands for
CꢀN (2196 cm−1) and CꢁO (1717 cm−1), while 1H
NMR revealed the presence of a signal at l 3.3 (3H, s,
CH3) and the absence of an OCH2CH3 fragment. The
mass spectrum of 3 also exhibited a molecular ion peak
m/z 235, which is the base peak in the spectrum whose
fragmentation pattern is illustrated in Scheme 2. Fur-
ther confirmation of the structure 3 was obtained by
studying the reactivity of the reaction product towards
various chemical reagents. Thus, compound 3 reacted
with arylmethylenemalononitriles in ethanol containing
a few drops of piperidine to afford 4-amino-2-aryl-5-
oxo-5H-dibenzo[c,f ]chromene-3-carbonitriles
(4a,b).
The IR spectra of 4a,b revealed the presence of amino,
cyano and carbonyl functions and the absence of a
methyl function in H NMR spectra. The formation of
* Corresponding author.
1
E-mail address: m elgaby@hotmail.com (M.S.A. El-Gaby)
–
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PII: S0014-827X(00)00008-2

228
M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 227–232
4 from the reaction of 3 with arylmethylenemalononi-
triles was assumed to proceed via Michael type addition
[8] of the methyl function of 3 to the activated double
bond to afford the acyclic Michael adduct that readily
cyclizes and loses hydrogen cyanide to yield 4, which
was observed with 3-cyano-4-methylcoumarin [9].
In addition, treatment of compound 3 with ethyl
3,4-dichlorobenzylidene cyanoacetate gave a product,
which was confirmed to be the ethyl 4-amino-5-oxo-2-
(3,4-dichlorophenyl)-5H-dibenzo[c,h]chromene-3-car-
boxylate (5) on the basis of its elemental analysis and
spectral data. Compound 3 also reacts with elemental
sulfur in dioxane–piperidine solution to yield 3-amino-
4H-thieno[3,4-d]naphtho[2,1-b]pyran-4-one (6). The IR
spectrum of 6 revealed the presence of amino and
carbonyl functions and the absence of a cyano group.
The formation of 6 is related to the Gewald synthesis of
alkylheterocyclic carbonitriles [10] (Scheme 1).
piperidine to yield 3-aminothieno[3,4-d]naphtho[1,2-
b]pyran-2-one (10) [11]. Treatment of compound 10
with N-arylmaleimides as electron-poor [11] olefins in
dioxane containing a few drops of glacial acetic acid to
yield 7-amino-9-(4-substitutedphenyl)-6,8,9,10-tetrahy-
drobenzo[7,8]chromeno[3,4 - f ]isoindole - 6,8,10 - trione
derivatives (11a–c). Analytical and spectral data were
consistent with the assigned structure. The formation of
these products is assumed to proceed via a [4+2]
cycloadduct, which is aromatized by hydrogen sulfide
liberation [11,12] to yield 11. Refluxing 10 with acetic
anhydride afforded 3-acetylamino-2H-thieno[3,4-d]-
naphtho[1,2-b]pyran-2-one (12) in high yield (Scheme
3).
3. Experimental
4-Methyl-2-oxo-3H-naphtho[1,2-b]pyran-3-carbo-
nitrile (7) was obtained by fusion of 2-acetyl-1-naphthol
with ethyl cyanoacetate in the presence of ammonium
acetate [11]. Reaction of 7 with arylmethylenemalonon-
itriles in ethanol in the presence of piperidine gave
7-amino-6-oxo-9-aryl-6H-dibenzo[c,h]chromene-8-car-
bonitriles (8) as established from their elemental analy-
ses and spectral data. Compound 7 also reacted with
ethyl 4-chlorobenzylidenecyanoacetate to afford diben-
zo[c,h]chromenes (9). In addition, compound 7 reacted
with sulfur in dioxane in the presence of few drops of
Melting points were measured by Griffen melting
point apparatus (England) and are uncorrected. IR
spectra wmax. (cm−1) were recorded on a Shimadzu 440
infrared spectrophotometer (Shimadzu, Japan) using
the KBr technique. 1H NMR spectra l (ppm) were
measured on a Varian Em 360 (90 MHz) spectrophoto-
meter (Varian, UK) using TMS as internal standard.
The mass spectra were performed by a Shimadzu GC–
MS-GP 100 EX using the direct inlet system. Analytical
data were obtained from the Microanalytical Data Cen-
ter at Cairo University.
Scheme 1.

M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 227–232
229
Scheme 2. Fragmentation pattern of compound 3.
3.1. Synthesis of 1-methyl-3-oxo-3H-naphtho-
[2,1-b]pyran-2-carbonitrile (3)
71.70; H, 4.50; N, 6.20. C27H20N2O5 requires: C, 71.68;
H, 4.42; N, 6.19%. IR: 3420, 3380 (NH2), 2935 (CH–
aliph), 2207 (CN), 1724 (CO). H NMR (DMSO-d6):
1
A mixture of equimolar amounts of 1 (1.86 g, 0.01
mol), ethyl cyanoacetate (1.13 g, 0.01 mol) and anhy-
drous ammonium acetate (1 g) was fused at 120°C for
15 min. The resulting product was then triturated with
ethanol and the solid product formed was collected by
filtration and recrystallized from dioxane to form green
crystals. Yield 1.65 g (70%); m.p. 260°C. Found: C,
76.50; H, 3.80; N, 5.90. C15H9NO2 requires: C, 76.59;
4.0 (3H, s, OCH3), 4.1 (6H, s, 2OCH3), 4.8 (2H, broad,
NH2; exchangeable), 7.2–8.4 (9H, m, Ar–H).
3.3. Ethyl 4-amino-5-oxo-2-(3,4-dichlorophenyl)-5H-
dibenzo[c,f ]chromene-3-carboxylate (5)
To a solution of 3 (2.35 g, 0.01 mol) in 20 ml of
dioxane, ethyl 3,4-dichlorobenzylidene cyanoacetate
(2.71 g, 0.01 mol) and a catalytic amount of piperidine
were added. The reaction mixture was refluxed for 4 h,
then poured into ice–HCl. The solid product was col-
lected by filtration to give 5 as yellow crystals from
benzene–petroleum ether. Yield: 2.87 g (60%); m.p.
70°C. Found: C, 65.30; H, 3.40; N, 2.70%.
C26H17Cl2NO4 requires: C, 65.28; H, 3.58; N, 2.93%.
IR: 3350, 3210 (NH2), 1720, 1690 (CO). 1H NMR
(DMSO-d6): 0.8(3H, t, CH3), 3.2 (2H, s, NH2; ex-
changeable), 4.1 (2H, q, OCH2), 7.25–7.89 (10H, m,
Ar–H). MS: m/z 478 [M+].
1
H, 3.86; N, 5.96%. IR: 2196 (CN), 1717(CO). H NMR
(DMSO-d6): 3.35 (3H, s, CH3), 7.54–8.63 (m, 6H,
Ar-H); MS: m/z 235 [M+].
3.2. General procedure for the preparation of 4a,b
To a solution of 3 (2.35 g, 0.01 mol) in 20 ml of
absolute ethanol, arylmethylenemalononitriles (0.01
mol) and a catalytic amount of piperidine were added.
The reaction mixture was heated under reflux for 3 h,
then poured into ice–HCl to give 4a,b.
3.2.1. 4-Amino-5-oxo-2-phenyl-5H-
dibenzo[c,f ]chromene-3-carbonitrile (4a)
3.4. Synthesis of 3-amino-4H-thieno[3,4-d]naphtho-
[2,1-b]pyran-4-one (6)
Compound 4a was obtained as yellow crystals from
ethanol. Yield 2.17 g (60%); m.p. 110°C. Found: C,
79.40; H, 3.70; N, 7.70. C24H14N2O2 requires: C, 79.54;
H, 3.84; N, 7.73%. IR: 3335, 3184 (NH2), 2058 (Ar–H),
To a solution of 3 (2.35 g, 0.01 mol) in 30 ml
dioxane, elemental sulfur (0.32 g, 0.01 mol) and
a catalytic amount of piperidine were added. The
reaction mixture was heated under reflux for 3 h. The
solid product formed on dilution with water was
collected by filtration and crystallized from ethanol.
Yield: 2.14 g, (80%); m.p. 240°C. Found: C, 67.30; H,
3.40; N, 5.30. C15H9NO2S requires: C, 67.40; H, 3.39;
N, 5.24%. IR: 3410, 3330 (NH2), 1677 (CO); MS: m/z
267 [M+].
1
2205 (CN), 1706 (CO). H NMR (DMSO-d6): 3.4 (2H,
s, NH2; exchangeable), 7.1–7.9 (12H, m, Ar–H); MS:
m/z 362 [M+].
3.2.2. 4-Amino-5-oxo-2-(3,4,5-trimethoxyphenyl)-
5H-dibenzo[c,f ]chromene-3-carbonitrile (4b)
Compound 4b was obtained as yellow crystals from
ethanol. Yield: 2.94 g (65%); m.p. 125°C. Found: C,

230
M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 227–232
3.5. General procedure for the preparation of (8a–c)
4.2(6H, s, 2OCH3); 5.0 (2H, broad, NH2; exchange-
able), 7.1–8.4 (9H, m, Ar–H).
To a solution of 7 [11] (2.35 g, 0.01 mol) in 20 ml
ethanol, arylmethylenemalononitriles (0.01 mol) and a
catalytic amount of piperidine were added. The reac-
tion mixture was heated for 4 h, then poured into
ice–HCl. The solid product was collected by filtration
and crystallized from dioxane to give 8a–c.
3.5.3. 7-Amino-6-oxo-9-(1-naphthyl)-6H-
dibenzo[c,h]chromene-8-carbonitrile (8c)
Compound 8c was obtained as yellow crystals from
ethanol. Yield: 2.07 g (55%); m.p. 130°C. Found: C,
81.60; H, 3.60; N, 6.90. C28H16N2O2 requires: C, 81.54;
H, 3.88; N, 6.80%. IR: 3328, 3300 (NH2), 2199 (CN);
3.5.1. 7-Amino-6-oxo-9-phenyl-6H-
dibenzo[c,h]chromene-8-carbonitrile (8a)
1
1702 (CO). H NMR: 4.0 (2H, broad, NH2; exchange-
able), 7.2–8.3 (14H, m, Ar–H).
Compound 8a was obtained as green crystals from
dioxane. Yield: 2.17 g, (60%); m.p. 270°C. Found: C,
79.50; H, 3.70; N, 7.60. C24H14N2O2 requires: C, 79.54;
H, 3.89; N, 7.73%. IR: 3405, 3330 (NH2), 3035 (CH–
3.6. Synthesis of ethyl 7-amino-6-oxo-9-(4-chloro-
phenyl)-6H-dibenzo[c,h]chromene-8-carboxylate (9)
1
Ar); 2185 (CN), 1687 (CO). H NMR (DMSO-d6): 3.57
(2H, s, NH2; exchangeable), 7.43–8.11 (12H, m, Ar–
To a solution of 7 (2.35 g, 0.01 mol) in 20 ml of
dioxane, ethyl 4-chlorobenzylidene cyanoacetate (2.35
g, 0.01 mol) and a catalytic amount of piperidine were
added. The reaction mixture was refluxed for 4 h, then
poured into ice–HCl. The solid product was collected
by filtration and crystallized from benzene–petroleum
ether to give 9 as yellow crystals. Yield: 2 g, (45%); m.p.
275°C. Found: C, 70.40; H, 4.10; N, 3.00. C26H18ClNO4
requires: C, 70.35; H, 4.20; N, 3.16%. IR: 3438, 3317
(NH2), 3057 (CH–Ar), 2931 (CH–aliph), 1709, 1680
H); MS: m/z 362 [M+].
3.5.2. 7-Amino-6-oxo-9-(3,4,5-trimethoxyphenyl)-
6H-dibenzo[c,h]chromene-8-carbonitrile (8b)
Compound 8b was obtained as yellow crystals from
ethanol. Yield: 2.26 g (50%); m.p. 120°C. Found: C,
71.60; H, 4.50; N, 6.20. C27H20N2O5 requires: C, 71.68;
H, 4.42; N, 6.19%. IR: 3334, 3310 (NH2), 2204(CN);
1
1705(CO). H NMR (DMSO-d6): 4.1 (3H, s, OCH3),
Scheme 3.

M.S.A. El-Gaby et al. / Il Farmaco 55 (2000) 227–232
231
Table 1
61.70; H, 2.70; N, 5.60. C25H13BrN2O4 requires: C,
61.87; H, 2.70; N, 5.77%). IR: 3406, 3277 (NH2), 1708,
1695, 1650 (CO). 1H NMR (DMSO-d6): 4.4 (2H, broad,
NH2; exchangeable), 7.3–8.5 (11H, m, Ar–H).
Diameter of inhibition zones (mm) as a criterion of antibacterial and
antifungal activity of the tested compounds
Comp.
Staphylococcus Escherichia coli Candida
aureus
albicans
3.8. Formation of 1-acetylamino-11H-
thieno[3,4-d]naphtho[1,2-b]pyran-11-one (12)
3
4b
5
16
18
17
15
19
12
6
7
8a
9
15
17
18
18
15
16
24
21
17
16
14
19
11
24
A solution of 10 (2.67 g, 0.01 mol) in 8 ml acetic
anhydride was heated under reflux for 0.5 h. The solid
product was collected by filtration and crystallized from
ethanol to give 12 as brown crystals. Yield: 1.85 g
(90%); m.p. 260°C. IR: 3273 (NH), 2935 (CH–aliph),
11
14
18
10
22
10
11b
1
Reference a
1697, 1670 (CO). H NMR: (DMSO-d6), 3.25 (3H, s,
COCH3), 7.39–7.9 (6H, m, Ar–H), 8.6 (1H, d, thio-
phene proton), 10.9 (1H, s, NH; exchangeable).
a For bacteria: streptomycin (25 mg) For fungi: mycostatin (30 mg).
(2CꢁO). 1H NMR (DMSO-d6): 0.8(3H, t, CH3), 1.5
(2H, broad, NH2; exchangeable); 4.0 (2H, q, OCH2),
7.38–8.00 (11H, m, Ar–H); MS: m/z 444 [M+].
4. Antimicrobial activity
The antimicrobial activity of the nine naphthopyra-
none derivatives 3, 4b, 5, 6, 7, 8a, 9, 10 and 11b was
determined by the agar diffusion technique [13,14]. The
organisms tested were Staphylococcus aureus (gram pos-
itive), Escherichia coli (gram negative) and Candida
albicans (pathogenic fungus). The agar media were
inoculated with the test organisms and a solution of the
tested compound in DMSO (3 mg/ml) was placed sepa-
rately in cups (8 mm diameter) in the agar medium.
Streptomycin (25 mg) and mycostatin (30 mg) were used
as a reference for antibacterial and antifungal activities,
respectively. The inhibition zones were measured after
24 h incubation. The results are represented in Table 1.
The antimicrobial activity of the naphthopyranone
derivative 3 was assumed as the base level of activity.
Enhanced activity was obtained with dibenzochromene
4b. The thienonaphthopyranone 6 offered an improve-
ment over the parent 3 against C. albicans. While, on
the contrary, the ester derivative 5 showed a marked
decrease in activity. It is interesting to note that the
naphtho[1,2-b]pyran derivative (7) showed higher activ-
ity than the parent naphtho[2,1-b]pyran (3). However,
none of the tested compounds showed superior activity
than the reference.
3.7. General procedure for the preparation of 11a–c
To a solution of 10 [11] (2.67 g, 0.01 mol) in 20 ml
dioxane, N-arylmaleimides (0.01 mol) and 2 ml glacial
acetic acid were added. The reaction mixture was
heated under reflux for 3 h. The solid obtained was
filtered to give 11a–c.
3.7.1. 7-Amino-9-(4-methylphenyl)-6,8,9,10-
tetrahydrobenzo[7,8]chromeno[3,4-f ]isoindole-
6,8,10-trione (11a)
Compound 11a was obtained as brown crystals from
ethanol. Yield: 2.1 g (50%); m.p. 130°C. Found: C,
74.30; H, 3.8; N, 6.70. C26H16N2O4 requires: C, 74.28;
H, 3.8; N, 6.67%. IR: 3403, 3302 (NH2), 1710, 1660,
1
1650 (CO). H NMR (DMSO-d6): 2.2 (3H, s, CH3), 4.2
(2H, broad, NH2; exchangeable); 7.4–8.6 (11H, m,
Ar–H); MS: m/z 420 [M+].
3.7.2. 7-Amino-9-(4-chlorophenyl)-6,8,9,10-
tetrahydrobenzo[7,8]chromeno[3,4-f ]isoindole-
6,8,10-trione (11b)
Compound 11b was obtained as brown crystals from
ethanol. Yield: 2.42 g (55%); m.p. 120°C. Found: C,
68.00; H, 2.80; N, 6.20. C25H13ClN2O4 requires: C,
68.11; H, 2.97; N, 6.36%. IR: 3410, 3279 (NH2), 1730,
1665, 1650 (CO). 1H NMR (DMSO-d6): 4.0 (2H, broad,
NH2; exchangeable), 7.2–8.3 (11H, m, Ar–H).
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