Synthesis and study of some new 1,3-isoindoledione derivatives as potential antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2009.12.064

In an effort to establish new candidates with improved antibacterial activities, we reported here the synthesis and in vitro antibacterial evaluation of various series of 2-substituted-3a,4,9,9a-tetrahydro-4,9-benzeno-benz[f]isoindole-1,3-diones: 4-acetyl-phenyl 2, 2,2-dibromoacetylphenyl 3, benzimidazole 4, acetylbenzimidazole 5, aminophenyl 6, acetamide 7, naphthalene 8, disulfide 9, mercaptophenyl 10, hydroxyphenyl 11, phenyl ester 12, triazole 13, benzothiophene 14, benzothiazole 15 phenylazo 16a, b and aminomethane 17 derivatives. The newly synthesized compounds were characterized by (IR, ¹H NMR, ¹³C NMR and mass spectrum studies). Representative compounds of the synthesized products were established and evaluated as antibacterial agents.

Full text of DOI:10.1016/j.ejmech.2009.12.064

European Journal of Medicinal Chemistry 45 (2010) 1552–1559
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and study of some new 1,3-isoindoledione derivatives as potential
antibacterial agents
*
A.M. Khalil, M.A. Berghot, M.A. Gouda
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to establish new candidates with improved antibacterial activities, we reported here the
synthesis and in vitro antibacterial evaluation of various series of 2-substituted-3a,4,9,9a-tetrahydro-4,9-
benzeno-benz[f]isoindole-1,3-diones: 4-acetyl-phenyl 2, 2,2-dibromoacetylphenyl 3, benzimidazole 4,
acetylbenzimidazole 5, aminophenyl 6, acetamide 7, naphthalene 8, disulfide 9, mercaptophenyl 10,
hydroxyphenyl 11, phenyl ester 12, triazole 13, benzothiophene 14, benzothiazole 15 phenylazo 16a,
b and aminomethane 17 derivatives. The newly synthesized compounds were characterized by (IR, 1H
NMR, 13C NMR and mass spectrum studies). Representative compounds of the synthesized products were
established and evaluated as antibacterial agents.
Received 9 June 2009
Received in revised form
12 December 2009
Accepted 23 December 2009
Available online 13 January 2010
Keywords:
Dibenzobarallene
Isoindole
Ó 2010 Elsevier Masson SAS. All rights reserved.
Benzimidazole
Benzothiazole
Bacillus thuringiensis
Escherichia coli
1. Introduction
prepared according to the previous reported method [13]. The
reaction of 1 with 4-aminoacetophenone in DMF yielded 4-acetyl-
In the past decades, the synthesis of heterocyclic compounds has
been a subject of great interest due to their wide applicability.
Heterocyclic compounds occur very widely in natural and are
essential to life. Among a large variety of heterocyclic compounds,
heterocycles containing isoindole moiety are of interest because the
show some pharmacological and biological activities [1–4] (Fig. 1).
Isoindole derivatives were reported to possess anti-neoplastic
and antiviral drugs [5], antimalarial [6] and anti Mycobacterium
tuberculosis activity [7], antitumor [8] and antimicrobial activities
[9]. In view of the above mentioned findings and as continuation of
our effort [10–12], to identify new candidates that may be of value in
designing new, potent, selective and less toxic antimicrobial agent,
we report herein the synthesis of some new heterocycles incorpo-
rating isoindole moiety starting from dibenzobarallene [13] (Fig. 1).
phenyl derivatives 2. The structure of 2 was established on the basis
of both analytical and spectral data. The 1H NMR spectrum of 2
revealed the presence of singlet signal at
COCH3 protons. Moreover, the 13C NMR spectrum displayed signals
at 196.7 and 26.5 due to acetyl moiety. Bromination of 2 in acetic
d 2.5 characteristic for
d
acid afforded the geminal dibromo derivative 3 which was estab-
lished on the basis of analytical and spectral data. The 1H NMR
spectrum of compound 3 displayed singlet signal at
d 6.5 due to
CHBr2 proton. The 13C NMR spectrum was characterized by
downfield signals at
d 39.1 and 206.4 which were assigned to
O]CHBr2 moiety.
Cyclization of 3 by refluxing with o-phenylenediamine was
studied in the aim of formation of new benzoimidazole derivative
with potential biological activities [14,15]. Thus, it reacted with
o-phenylenediamine in DMF containing a catalytic amount of TEA to
give benzimidazole derivative 4 which was established on the basis of
analytical and spectral data. The 1H NMR spectrum displayed clearly
2. Results and discussion
the presence of singlet signal at
(Scheme 1).
d 9.4 due to one proton of NH group
2.1. Chemistry
The present work was also extended to include the reaction of 1
with o-phenylenediamine, o-aminothiophenol and o-aminophenol
by adapting the previously published procedure for the analogues
reaction [16]. Refluxing of equimolar amounts of 1 and o-phenyl-
enediamine in acetic acid afforded N-acetylbenzimidazole
The synthetic procedures adopted to obtain the target
compounds are depicted in Schemes 1–3. Dibenzobarallene was
* Corresponding author. Tel.: þ20 50 6432235; fax: þ20 50 2246781.
E-mail address: dr_mostafa_chem@yahoo.com (M.A. Gouda).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.12.064

A.M. Khalil et al. / European Journal of Medicinal Chemistry 45 (2010) 1552–1559
1553
at
d 8.1 and 8.4 due to NH and C3–H of quinonoid system protons.
O
A
Me
13C NMR spectrum of 8 exhibited signal at 181.0 due to C]O of 1,2-
quinonoid system (Scheme 3).
N
O
C
O
OH
D
O
F
MeO
The reaction of 1 with o-aminothiophenol in acetic acid, gave
the disulfide 9, whereas a mixture of 9 and 10 was obtained when
the reaction carried out in DMF or dioxane/pyridine instead of
acetic acid. The formation of 10 may be interpreted through the
auto-oxidation of 9. The structures of 9 and 10 were assigned on the
basis of their mass spectra. The mass spectrum of 9 exhibited the
molecular ion peak at m/z 764, which is in agreement with its
molecular formula C48H32N4O4S2. The base peak at m/z 178 corre-
sponding to anthracene and the other fragment ion peaks at m/z
732 and 383 due to [Mþ ꢁ S] and [(1/2 Mþ) þ 1], whereas, the mass
spectrum of 10 exhibited the molecular ion peak at m/z 383.
On the other hand, 2-hydroxyphenyl derivative 11 was obtained
by refluxing of 1 with o-aminophenol in acetic acid, DMF or dioxane/
pyridine. The structure 11 was established on the basis of IR, 1H and
13C NMR spectra. The 1H NMR spectrum displayed singlet signal at
O
O
E
B
OH
RO
OH
O
Me
O
Me
HO
1, R=
2, R=
;
OH
Fig. 1. Structures of lactonamycin (1) and Z-lactonamycin (2).
derivative 5, while the isoindole derivative 6 was formed when the
reaction was carried out in DMF or dioxane/pyridine instead of
acetic acid (Scheme 2).
d
9.9 due to OH proton, beside all signals in the expected regions.
The formation of both 5 and 6 was explained via the interme-
diate ½A!A0ꢀ. (Scheme 2) Acylation of compound 6 using acetyl
chloride afforded phenyl acetamide derivative 7. The structures 5–7
were confirmed on the basis of analytical and spectral data, which
are in good agreement with its formulations. The mass spectrum of
5 exhibited beside the molecular ion peak at m/z 408 which is
adopted with its molecular formula C26H20N2O3, two fragment ion
Moreover, its 13C NMR spectrum revealed signals at
d
142.1, 153.8 and
(162.7, 176.4) due to carbons of C–N, C–OH and 2C]O, respectively.
Treatment of compound 11 with p-toluenesulphonyl chloride in
DMF and in the presence of a catalytic amount of TEA gave the
corresponding ester derivative 12. (Scheme 4) The structure 12 was
confirmed on the basis of analytical and spectral data. The 1H NMR
spectrum clearly displayed singlet signal at d 2.4 due to CH3 proton.
peaks at m/z 348 and 178 (base peak) corresponding to [Mþ
ꢁ
Also, its 13C NMR spectrum revealed signals at 21.6 due to CH3
carbon (Scheme 4).
(CH2]C]O, H2O)] and anthracene, respectively. The mass spec-
trum of 7 exhibited beside the molecular ion peak at m/z 408 which
is in agreement with its molecular formula C26H20N2O3, three
fragment ion peaks at m/z 366, 349 and 178 (base peak) corre-
sponding to [Mþ ꢁ (CH2]C]O)], [Mþ ꢁ (CH2]C]O, NH3)] and
anthracene, respectively. It is note worthily that, the molecular ion
peaks of both 5 and 7 are the same at m/z 408, but the fragment ion
patterns were differ.
Moreover, compound 6 was reacted with 1,2-naphthoquinone-
4-sulphonic acid sodium salt in water/DMF to give the unexpected
product 8 according to the plausible mechanism in Scheme 3. The
structure of 8 was established on basis of elemental analysis and
spectral data. The mass spectrum exhibited peaks at m/z 870, 692
and 514 corresponding to [Mþ], [Mþ ꢁ anthracene] and [Mþ ꢁ 2
anthracene]. The 1H NMR spectrum displayed among other signals
Moreover, the present work was also extended to include the
reaction of 1 with some selective amino compounds, namely 3-
amino[1,2,4]-triazole, ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]
thiophene-3-carboxylate [17], 2-amino-6-methylbenzothiazole
[18], 4-aminoarylazobenzene [19] and tris-(hydroxymethyl)amino
methane. Thus, refluxing of 1 with 3-amino-[1,2,4]-triazole in
acetic acid/sodium acetate or in DMF afforded the corresponding
isoindole derivative 13. The structure 13 was established on the
basis of both analytical and spectral data. The 1H NMR spectrum
displayed a clearly singlet signal at
d
8.4 due to one proton of C5–H
7.9 due to NH proton.
of triazole moiety and a singlet signal at
d
Also, the 13C NMR spectrum showed signals at
characteristic for C-3 and C-5 of triazole ring.
d 150.3, 144.2
NH2
O
O
+
Cage
O
O
Cage
N
O
COCH3
COCH3
2
1
Br2 / AcOH
O
O
H
N
O
C
o-phenylenediamine
Cage
N
Cage
N
COCHBr2
DMF/Et3N
N
O
O
3
4
Cage =
Scheme 1.

1554
A.M. Khalil et al. / European Journal of Medicinal Chemistry 45 (2010) 1552–1559
COO
NH2
NH2
Cage
H
+
1
C
O
N
H
H2N
COOH
COOH
Cage
Cage
H
C
O
N
C
N
OH
H2N
H2N
A
A'
DMF or
dioxane/pyridine
AcOH
AcONa
O
COOH
Cage
N
O
Cage
N
N
H2N
6
H3COCO
Cage =
5
Scheme 2.
Ar
MeCOCl
Et3N
HN
H3C
O
O
6
O
7
O
Ar =
N
O
SO3Na
8
DMF/H2O
O
O
O
O
OH
O
+
6
NH
N
SO3Na
Ar
Ar
6, -H2O
O
O
H
N
N
Ar
Ar
8
NH
Ar
N
Ar
Scheme 3.

A.M. Khalil et al. / European Journal of Medicinal Chemistry 45 (2010) 1552–1559
1555
O
O
O
N
S
S
O
N
Cage
N
+
O
HS
e
O
g
C
NH2
SH
10
a
g
AcOH, DMF or
Ca
1
e
+
dioxane/ pyridine
9
O
Cage
N
HO
Cage =
O
11
p-toluenesulphonyl-
chloride
O
Cage
N
O
Ar
12
Ar= 4-CH3-C6H4-SO3
Scheme 4.
Ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
late was reacted with 1 in acetic acid/sodium acetate to yield the
corresponding derivative 14 which was established on the basis of
both elemental analysis and spectral data. The 1H NMR spectrum
It was found that, compounds containing arylazomethylene and
N-cyclic imide bearing arylazo moiety exerts antimicrobial prop-
erties [20,21]. Thus, p-aminoarylazobenzene derivatives were
reacted with 1 in DMF or in glacial acetic acid/anhydrous sodium
acetate to afford 2-arylazobenzene isoindole derivatives 16a, b. The
structures of 16a, b were ascertained through their analytical and
spectral data. IR spectra of 16a, b showed bands at 1503–1500 cmꢁ1
attributed to azo groups.
displayed signals of ethyl protons at
1.8–2.8 due to eight protons of 4CH2 groups. 13C NMR spectrum
showed signals at 14.0, 21.7, 22.2, 22.5, 25.0 and 26.1 characteristic
d 1.2, 4.2 and multiplet signals at
d
for CH3, 5CH2 carbons, respectively.
Isoindoldione derivatives 15 was obtained from the reaction of
the adduct 1 with 2-amino-6-methylbenzothiazole in DMF. The
spectral data of this compound supported the assigned structure 15
(Scheme 5).
The pharmacological importance [22,23], of tris-(hydrox-
ymethyl)-aminomethane prompted us to investigate the synthesis
of some new derivatives of expected biological activity. Thus, the
adduct 1 was reacted with tris-(hydroxy methyl)-aminomethane
N NH
N
O
N
NH
H2N
Cage
N
AcOH/ AcONa
or DMF
N
O
13
COOEt
O
EtOOC
NH2
S
1
Cage
N
AcOH/ AcONa
S
O
14
Cage =
N
O
NH2
N
S
H3C
Cage
N
DMF
S
CH3
O
15
Scheme 5.

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A.M. Khalil et al. / European Journal of Medicinal Chemistry 45 (2010) 1552–1559
O
H2N
N N
R
Cage
N
N
N
R
AcOH/ AcONa
O
16a, R= H
16b, R= CH3
1
O
H2N C(CH2OH)3
dioxane/ pyridine
Cage
N
CH2(CH2OH)3
O
Cage =
17
Scheme 6.
in dioxane/pyridine to yield the derivative 17 in good yield. The
structure of 17 was established on the basis of its elemental
analysis and spectral data. The 1H NMR spectrum of 17 displayed
standard. Mass spectrum recorded on Finnegan MAT 212 instru-
ment and elemental analyses (C, H, and N) were carried out in The
Microanalytical Center of Cairo Univ., Egypt.
signals at
d
3.6 and 3.9 due to 3CH2 and 3OH protons groups,
67.6,
respectively. Also, the 13C NMR spectrum revealed signals at
d
4.1.1. Synthesis of 2-[4-acetyl-phenyl]-3a,4,9,9a-tetrahydro-4,9-
benzeno-benz[f]isoindole-1,3-dione (2)
Amixtureof1(6.76 g; 0.05 mol) and p-aminoacetophenone (13.8 g;
0.05 mol) in DMF (30 mL) was heated under reflux for 3 h. The reaction
mixture was then poured into a beaker contain cooled water. The
separated product was crystallized from ethanol–benzene to give 2.
57.8 and 38.3 due to (CH2OH)3 and N–C carbons, respectively
(Scheme 6).
3. Pharmacology
Yield 70%, 13.7 g; mp 278 ꢂC; IR (KBr):
n
/cmꢁ1 ¼ 2846 (aliphatic C–H),
Seventeen compounds were screened in vitro for their antimi-
crobial activities against two strains of bacteria Bacillus thur-
ingiensis and Escherichia coli by the agar diffusion technique [24].
The bacteria were maintained on nutrient agar. DMSO showed no
inhibition zones. The agar media were incubated with different
microorganism culture tested. After 24 h of incubation at 30 ꢂC, the
diameter of inhibition zone (mm) was measured (Table 1). Ampi-
cillin and chloramphenicol were purchased from Egyptian market
and used in a concentration 2 mg mLꢁ1 as references.
1770,1702,1654 (3CO); 1H NMR (CDCl3): dppm ¼ 2.5 (s, 3H, COCH3), 3.3
(s, 2H, C11–H, C12–H), 4.8 (s, 2H, C9–H, C10–H), 6.8 (d, 2H, Ar–H), 7.1–7.6
(m, 8H, Ar–H) and 7.9 (d, 2H, Ar–H); 13C NMR (CDCl3): dppm ¼ 196.7,
175.5, 167.4, 141.1, 138.6, 136.8, 135.4, 129.0, 128.2, 127.2, 126.9, 126.4,
125.1, 124.3, 111.7, 47.0, 45.8, and 26.5; EIMS (m/z) (%) ¼ 393 (Mþ, 0.6),
231 (0.2), 200 (12.2), 178 (100.0), 116 (3.0), and 90 (3.8). Anal. for
C26H19NO3 (393.43): calcd.: C 79.37, H 4.87, N 3.56%; found: C 79.49, H
4.96, N 3.69%.
The results depicted in Table 1 revealed that compounds 4 and
15 exhibited interesting high antibacterial activities against the
reference drugs. It is worth mentioning that incorporation of iso-
indole to the benzimidazole or benzotriazole produce a high anti-
bacterial activities.
In conclusion, we reported herein a simple and convenient route
for the synthesis of some new heterocycles based on isoindole
moiety for antibacterial evaluation.
Table 1
Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial
activities of the newly synthesized compounds.
Compound No.
Inhibition zone in mm
Gram-positive bacteria
‘‘Bacillus thuringiensis’’
Gram-negative bacteria
‘‘Escherichia coli’’
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16a
16b
17
15
17
20
17
17
18
17
17
18
17
15
17
15
26
13
11
15
12
14
23
13
12
16
17
17
16
16
18
15
14
29
14
14
14
4. Experimental
4.1. General
All melting points are in degree centigrade, are uncorrected and
were measured on Gallenkamp electric melting point apparatus.
TLC analysis was carried out on silica gel 60 F254 precoated
aluminum sheets. IR spectra were recorded on Waffer technique on
a MATSON 5000 FTIR spectrometer, Faculty of Science, Mansoura
University. 1H NMR spectra were determined on a Varian XL 200
MHz, Faculty of Science, Cairo University, a Brucker WP 300 Georg–
August University Goettingen, Germany and a Brucker AC 300
Eberhard–Karls University, Tuebingen, Germany, in CDCl3 or DMSO
solvent using TMS as internal standard. 13C NMR spectra were
determined on Brucker AC 300 Eberhard–Karls University, Tue-
bingen, Germany, in CDCl3 or DMSO solvent using TMS as internal
Reference drugs
Ampicillin
Chloramphenicol
18
23
19
20

A.M. Khalil et al. / European Journal of Medicinal Chemistry 45 (2010) 1552–1559
1557
4.1.2. Synthesis of 2-[4-(2,2-dibromo-acetyl)-phenyl]-3a,4,9,9a-
tetrahydro-4,9-benzeno-benz[f]isoindole-1,3-dione (3)
(0.5), 277 (0.1), 203 (1.8), 202 (2.6), 178 (100), 152 (3.5) and 89 (1.8).
Anal. for C26H20N2O3 (408.45): calcd.: C 76.45, H 4.94, N 6.86%;
found: C 76.57, H 4.50, N 6.94%.
A mixture of bromine (1.6 g; 0.01 mol) in glacial acetic acid (15
mL) was added drop wise over a period of 30 min to a hot solution
of 1 (3.9 g; 0.01 mol) in acetic acid (75 mL) and acetic anhydride (0.5
mL). The reaction mixture was heated on water bath at 80–90 ꢂC for
3 h. The separated product was then crystallized from ethanol–
benzene afforded dibromo derivative 3. Yield 45%, 2.5 g; mp 250 ꢂC;
4.1.7. Synthesis of 2-[2-{4-(2-[1,3-dioxo-1,3,3a,4,9,9a-hexahydro-
4,9-bezeno-benz[f]isoindol-2-yl]-phenylimino)-1-oxo-naphthalen-
2-yl-amino}-phenyl]-3a,4,9,9a-tetrahydro-4,9-benzeno-
benz[f]isoindole-1,3-dione (8)
A mixture of 6 (1.83 g; 0.005 mol) and 1,2-naphthoquinone-4-
sulphonic acid sodium salt (1.56 g; 0.006 mol) in water/DMF (20 mL;
1:1 V) was refluxed for 1 h. The separated product was crystallized
from benzene–ethanol to afford isoindole derivative 8. Red crystals;
IR (KBr):
n
/cmꢁ1 ¼ 2881 (aliphatic C–H) and 1774, 1707, 1681 cmꢁ1
(3CO); 1H NMR (CDCl3): dppm ¼ 3.4 (s, 2H, C11–H, C12–H), 4.8 (s, 2H,
C9–H, C10–H), 6.5 (s, 1H, CHBr3), 6.8 (d, 2H, Ar–H), 7.1–7.5 (m, 8H,
Ar–H) and 8.1 (d, 2H, Ar–H); 13C NMR (CDCl3): dppm ¼ 184.8, 175.4,
141.0, 138.6, 136.5, 130.5, 127.2, 126.9, 126.6, 125.1, 124.3, 47.1, 45.9
and 39.1; EIMS (m/z) (%) ¼ 552 (Mþ þ 2, 0.1), 551 (Mþ þ 1, 24), 550
(Mþ, 0.2), 378 (0.9), 344 (0.1), 264 (5.1), 178 (100.0), 176 (9.5) and 54
(3.3). Anal. for C26H17Br2NO3 (551.23): calcd.: C 56.65, H 3.11, N
2.54%; found: C 56.72, H 3.14, N 2.60%.
yield 70%, 1.53 g; mp 256 ꢂC; IR (KBr):
n
/cmꢁ1 ¼ 3256 (NH) and 1766,
1715,1659 (3CO); 1H NMR (CDCl3): dppm ¼ 3.2–3.6 (m, 4H, C11–H, C12
–
H), 4.7–4.9 (m, 4H, C9–H, C10–H), 6.9–7.6 (m, 20H, Ar–H), 8.1 (d, 1H,
NH) and 8.4 (s,1H, C3 of quinonoid system); 13C NMR (CDCl3): dppm
¼
181, 175.9, 175.3, 156.2, 141.2, 141.0, 138.8, 134.7, 133.6, 130.8, 129.9,
129.4, 128.1, 127.1, 127.0, 126.8, 126.6, 126.4, 125.1, 124.3, 124.1, 122.9,
121.2, 98.0, 47.3, 47.0, 45.8, 45.7 and 45.5; EIMS (m/z) (%) ¼ 870 (Mþ,
8.8), 692 (Mþ ꢁ anthracene, 98.0), 514 (Mþ ꢁ 2 anthracene, 23.0), 418
(3.5), 178 (100) and 89 (6.2). Anal. for C58H38N4O5 (870.95): calcd.: C
79.98, H 4.40, N 6.43%; found: C 80.08, H 4.52, N 6.53%.
4.1.3. Synthesis of 2-[4-(1H-benzoimidazole-2-carbonyl)-phenyl]-
3a,4,9,9a-tetrahydro-4,9-benzeno-benz-[f]isoindole-1,3-dione (4)
A solution of 3 (0.55 g; 0.001 mol), o-phenylenediamine (0.11 g;
0.001 mol) and TEA (0.5 mL) in DMF (20 mL) was warmed on water
bath at 95 ꢂC for 5 h. The separated product was crystallized from
DMF-ethanol to give 4. Yield 90%, 0.45 g; mp 272 ꢂC; IR (KBr):
n
/
4.1.8. Synthesis of 2,20-bis[1,3-dioxo-1,3,3a-,4,9,9a-hexahydro-4,9-
benzeno-benz[f]isoindol-2-yl]diphenyl-disulphide (9) and 2-[2-
(mercapto-phenyl)]-3a,4,9,9a-tetrahydro-4,9-benzeno-benz[f]-
isoindole-1,3-dione (10)
cmꢁ1 ¼ 3315 (NH), 2928 (aliphatic C–H), and 1774, 1707, 1681 cmꢁ1
(3CO); 1H NMR (CDCl3): dppm ¼ 3.1 (s, 2H, C11–H, C12–H), 4.8 (s, 2H,
C9–H, C10–H), 6.8 (d, 2H, Ar–H), 7.1–7.5 (m, 12H, Ar–H), 8.0 (d, 2H,
Ar–H) and 9.4 (s, H, NH); Anal. for C32H21N3O3 (495.53): calcd.: C
77.56, H 4.27, N 8.48%; found: C 77.59, H 4.33, N 8.55%.
A mixture of 1 (1.38 g; 0.005 mol), o-aminothiophenol (0.63 g;
1.005 mol) and fused sodium acetate (0.5 g; 0.006 mol) in glacial
acetic acid (20 mL) was refluxed for 5 h. The separated solid washed
with water and crystallized from DMF to give 9, 91% yield. Also, the
previous reaction was carried out in dioxane/pyridine (20 mL; 3.1
V) or DMF (20 mL) instead of acetic acid/sodium acetate; in this
case the reaction mixture was refluxed for 3 h, left to cool. The
precipitated solid product filtered off, crystallized from DMF to give
9, 40% yield and 45%, respectively. The filtrate was poured into
a beaker contain ice and the separated solid product crystallized
from benzene–ethanol to give 10, 19%, 21% yield, respectively.
4.1.4. Synthesis of 12-[1-acetyl-1H-benzimidazol-2-yl]-9,10-
dihydro-9,10-ethanoanthracene-11-carboxylic acid (5)
A mixture of 1 (1.38 g; 0.005 mol), o-phenylenediamine (0.54 g;
0.005 mol) and fused sodium acetate (0.41 g; 0.005 mol) in glacial
acetic acid (20 mL) was refluxed for 4 h. The solvent was concen-
trated under reducing pressure. The separated product washed
with water and crystallized from methanol–benzene afforded
compound 5. Yield 65%, 1.32 g; mp 263 ꢂC; IR (KBr):
n
/cmꢁ1 ¼ 2934
(OH) and 1757, 1714 (2CO); EIMS (m/z) (%) ¼ 408 (Mþ, 0.5), 348
(1.0), 290 (0.5), 227 (0.7), 202 (1.0), 178 (100.0), 152 (7.1), 114 (1.5)
and 63 (1.0). Anal. for C26H20N2O4 (424.45): calcd.: C 73.57, H 4.75,
N 6.60%; found: C 73.60, H 4.79, N 6.64%.
Compound 9: mp >320 ꢂC; IR (KBr):
n
/cmꢁ1 ¼ 1775, 1710 (2CO)
and 560 (–S–S–); EIMS (m/z) (%) ¼ 764 (Mþ, 48.6), 732 (0.1), 586
(2.6), 502 (0.1), 408 (0.5), 383 (6.2), 381 (0.8), 231 (0.4), 204 (9.7),
178 (100), 89 (0.4) and 44 (1.7). Anal. for C48H32N2O4S2 (764.91):
calcd.: C 75.37, H 4.22, N 3.66%; found: C 75.32, H 4.19, N 3.61%.
4.1.5. Synthesis of 2-[2-amino-phenyl]-3a,4,9,9a-tetrahydro-4,9-
benzeno-benz[f]isoindole-1,3-dione (6)
Compound 10: White powder; mp 315 ꢂC; IR (KBr):
n
/cmꢁ1
¼
2552, (SH) and 1770, 1712 (2CO); EIMS (m/z) (%) ¼ 383 (Mþ, 16.0),
351 (0.8), 276 (0.1), 231 (0.6), 202 (7.0), 178 (100),176 (5.3),152 (3.5)
and 96 (0.9). Anal. for C24H17NO2S (383.46): calcd.: C 75.17, H 4.47, N
3.65%; found: C 75.23, H 4.53, N 3.75%.
A mixture of 1 (1.38 g; 0.005 mol), o-phenylenediamine (0.54 g;
0.005 mol) in dioxane/pyridine (20 mL; 3.1 V) or DMF (20 mL) was
heated under reflux for 5 h. The reaction mixture poured in ice
water. The separated product was crystallized from ethanol–
benzene to give isoindole-1,3-dione 6. Yield 92.8%, 1.7 g; mp 277 ꢂC;
4.1.9. Synthesis of 2-[2-hydroxy-phenyl]-3a,4,9,9a-tetrahydro-4,9-
benzeno-benz[f]isoindole-1,3-dione (11)
IR (KBr):
n
/cmꢁ1 ¼ 3458, 3369 (NH2) and 1775, 1707 cmꢁ1 (2CO); 1H
NMR (DMSO): dppm ¼ 3.3 (s, 2H, C11–H, C12–H), 4.7 (s, 2H, C9–H, C10–H),
5.2 (s, 2H, NH2) and 7.1–7.6 (m, 12H, Ar–H); EIMS (m/z) (%) ¼ 366
(Mþ, 30.0), 266 (2.6), 203 (3.6), 188 (8.8), 178 (100), 119 (8.8) and 79
(3.5). Anal. for C24H18N2O2 (366.41): calcd.: C 78.67, H 4.95, N 7.65%;
found: C 78.72, H 5.01, N 7.71%.
A mixture of 1 (1.38 g; 0.005 mol), o-aminophenol (0.55 g; 0.005
mol) and fused sodium acetate (0.7 g; 0.007 mol) in glacial acetic
acid (20 mL) was heated under reflux for 4 h. The separated product
washed with water and crystallized from methanol–benzene to
give 11, 95% yield. Compound 11 was also obtained in 98% yield if
the reaction was carried out in dioxane/pyridine (20 mL; 3.1 V) or
4.1.6. Synthesis of N-[2-(1,3-dioxo-1,3,3a,4,9,9a-hexahydro-4,9-
benzeno-benz[f]isoindol-2-yl)-phenyl]-acetamide (7)
DMF (20 mL) instead of acetic acid/sodium acetate. Yield 95%, 98%,
ꢂ
1.75 g; mp 266 C; IR (KBr):
n
/cmꢁ1 ¼ 3282–3034 (OH) and 1775,
A mixture of 6 (0.5 g; 0.0013 mol), acetyl chloride (5 mL) and
TEA (0.5 mL) was heated on water bath at 70 ꢂC for 15 min. The
reaction mixture was allowed to cool. The separated product was
crystallized from benzene–ethanol to afford acetamide derivative 7.
1707 (2CO); 1H NMR (DMSO): dppm ¼ 3.3 (s, 2H, C11–H, C12–H), 4.9
(s, 2H, C9–H, C10–H), 7–7.9 (m, 12H, Ar–H) and 9.9 (s, 1H, OH); 13C
NMR (DMSO): dppm ¼ 176.4, 162.7, 153.8, 142.1, 139.9, 130.7, 128.8,
127.0, 126.8, 125.3, 124.8, 119.3, 117.0, 47.1 and 45.3; Anal. for
C24H17NO3 (367.40): calcd.: C 78.46, H 4.66, N 3.81%; found: C 78.50,
H 4.76, N 3.98%.
Yield 94%, 0.5 g; mp 264 ꢂC; IR (KBr):
n
/cmꢁ1 ¼3372, (NH) and 1775,
1706, 1629 (3CO); EIMS (m/z) (%) ¼ 408 (Mþ, 6.2), 366 (2.2), 349

1558
A.M. Khalil et al. / European Journal of Medicinal Chemistry 45 (2010) 1552–1559
4.1.10. Synthesis of toluene-4-sulphonic acid-2-[1,3-dioxo-
1,3,3a,4,9,9a-hexahydro-4,9-benzeno-benz[f]isoindol-2-yl]-
phenyl ester (12)
A solution of 11 (0.725 g; 0.002 mol), p-toluene sulphonyl chlo-
ride (0.38 g; 0.002 mol) and few drops of TEA in DMF (10 mL) was
heated on water bath at 90 ꢂC for 5 h. The separated product was
crystallized from ethanol–benzene to afford phenyl ester derivative
4.1.14. Synthesis of 2-[4-(phenylazo/tolylazo)-phenyl]-3a,4,9,9a-
tetrahydro-4,9-benzeno-benz[f]isoindole-1,3-dione (16a, b)
General procedure: A mixture of 1 (2.76 g; 0.01 mol), 4-amino-
phenylazobenzene or 4-aminotolylazobenzene (0. 01 mol) and
fused sodium acetate (1 g; 0.012 mol) in glacial acetic acid (75 mL)
was heated under reflux for 3–4 h. The separated product was
washed with water and crystallized from methanol–benzene to
12. Yield 67%, 0.7 g; mp 234 ꢂC; IR (KBr):
n
/cmꢁ1 ¼2958 (aliphatic C–
give 16a and 16b, respectively.
ꢂ
H), 1769, 1713 (2CO) and 1410 (SO3); 1H NMR (CDCl3): dppm ¼ 2.4 (s,
3H, CH3), 3.2 (s, 2H, C11–H, C12–H), 4.8 (d, 2H, C9–H, C10–H) and 7.1–
7.8 (m,16H, Ar–H); 13C NMR (CDCl3): dppm ¼ 174.7,145.6,145.0,141.2,
138.9,132.3,130.2,129.8,129.0,128.2,127.4,126.9,126.8,125.1,124.3,
123.1, 47.1, 45.6 and 21.6; Anal. for C31H23NO5S (521.58): calcd.: C
71.38, H 4.44, N 2.69%; found: C 71.46, H 4.53, N 2.79%.
Compound 16a: Red crystals; yield 80%, 3.64 g; mp 260 C; IR
(KBr):
n
/cmꢁ1 ¼ 2952 (aliphatic C–H), 1770, 1703 (2CO) and 1503
(N]N); 1H NMR (DMSO): dppm ¼ 3.5 (s, 2H, C11–H, C12–H), 4.8 (s,
2H, C9–H, C10–H) and 7.1–7.9 (m, 17H, Ar–H); EIMS (m/z) (%) ¼ 455
(Mþ, 18.7), 352 (0.3), 350 (10.6), 332 (0.6), 277 (2.8), 203 (2.5), 202
(4.6), 178 (100), 152 (5.5), 105 (5.5) and 77 (20.0). Anal. for
C30H21N3O2 (455.51): calcd.: C 79.10, H 4.65, N 9.22%; found: C
79.19, H 4.73, N 9.30%.
4.1.11. Synthesis of 2-(1H-[1,2,4]triazol-3-yl)-3a,4,9,9a-tetrahydro-
4,9-benzeno-benz[f]isoindole-1,3-dione (13)
Compound 16b: Red crystals; yield 77%, 3.61 g; mp 244 ꢂC; IR
A mixture of 1 (1.38 g; 0.005 mol), 3-amino-1,2,4-triazole (0.5 g;
0.006 mol) and fused sodium acetate (0.6 g; 0.007 mol) in glacial
acetic acid (15 mL) was heated under reflux for 3 h. The separated
product was washed with water and crystallized from ethanol–
benzene to give 13, 88% yield. Also, the reaction afforded compound
13, 65% yield when carried out in DMF instead of acetic acid. Yield
(KBr):
n
/cmꢁ1 ¼ 2968, 2922 (aliphatic C–H), 1773, 1705 (2CO) and
1500 (N]N); EIMS (m/z) (%) ¼ 469 (Mþ, 4.8), 455 (2.4), 350 (3.1),
291 (1.4), 204 (2.2), 202 (5.7), 178 (100), 152 (10.9) and 91 (24.5).
Anal. for C31H23N3O2 (469.53): calcd.: C 79.30, H 4.94, N 8.95%;
found: C 79.38, H 5.01, N 9.02%.
88%, 1.5 g; 65%, 1.1 g; mp 330 ꢂC; IR (KBr):
n
/cmꢁ1 ¼ 3110 (NH), 2922
4.1.15. Synthesis of 2-[2-hydroxy-1,1-bis-hydroxymethyl-ethyl]-
3a,4,9,9a-tetrahydro-4,9-benzeno-benz[f]isoindole-1,3-dione (17)
A mixture of 1 (2.76 g; 0.01 mol) and 2-amino-2-hydroxy-
methyl-1,3-propandiol (0.73 g; 0.01 mol) in DMF (20 mL) and was
heated under reflux for 3 h. The reaction mixture was poured into
a beaker contain ice water. The separated product was crystallized
from ethanol–benzene to give 17. Yield 94%, 3.1 g; mp 220 ꢂC; IR
(aliphatic C–H) and 1770, 1678 (2CO); 1H NMR (CDCl3): dppm ¼ 3.4
(s, 2H, C11–H, C12–H), 4.8 (s, 2H, C9–H, C10–H), 7.2–7.4 (m, 8H, Ar–H),
7.9 (s, 1H, NH) and 8.4 (s, 1H, C5–H (triazole)); 13C NMR (CDCl3):
dppm ¼ 167.2, 150.3, 144.2, 139.8, 138.2, 125.3, 125.0, 123.3, 122.7,
45.5 and 43.6; EIMS (m/z) (%) ¼ 342 (Mþ, 2.6), 260 (0.3), 204 (1.3),
202 (3.5), 178 (100), 152 (2.1), 84 (1.1) and 66 (3.5). Anal. for
C20H14N4O2 (342.35): calcd.: C 70.17, H 4.12, N 16.37%; found:
C 70.28, H 4.27, N 16.43%.
(KBr):
n
/cmꢁ1 ¼ 3410 (OH), 2910 (aliphatic C–H) and 1732, 1703
(2CO); 1H NMR (CDCl3/DMSO): dppm ¼ 3.1 (s, 2H, C11–H and C12–H),
3.6 (s, 6H, 3CH2), 3.9 (s, 3H, 3OH), 4.8 (s, 2H, C9–H and C10–H) and
7.1–7.6 (m, 8H, Ar–H); 13C NMR (CDCl3/DMSO): dppm ¼ 177.5, 139.9,
137.4, 124.8, 124.7, 123.1, 122.4, 67.6, 57.8, 44.5, 43.7 and 38.3; EIMS
(m/z) (%) ¼ 379 (Mþ, 0.9), 343 (1.1), 332 (2.4), 331 (10.0), 276 (57.0),
202 (10.6), 178 (100), 152 (11.3), 140 (4.1), 104 (19.4), 82 (2.6) and 68
(2.6). Anal. for C22H23NO5 (381.42): calcd.: C 69.28, H 6.08, N 3.67%;
found: C 69.37, H 6.14, N 3.74%.
4.1.12. Synthesis of 2-[1,3-dioxo-1,3,3a,4,9,9a-hexahydro-4,9-
benzeno-benz-[f]isoindol-2-yl]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylic acid ethyl ester (14)
A mixture of 1 (1.38 g; 0.005 mol), 2-amino-3-ethoxycarbonyl-
4,5,6,7-tetrahydrobenzo[b]thiophene (1.13 g; 0.005 mol) and fused
sodium acetate (0.41 g; 0.005 mol) in glacial acetic acid (20 mL) was
heated under reflux for 3 h. The reaction mixture was poured in to
a beaker contain cooled water. The separated product was crys-
tallized from ethanol to give 14, 80% yield and 92% yield if the
reaction was carried out in DMF instead of acetic acid. Yield 80%,
4.2. In vitro antimicrobial activity
The tested compounds were evaluated by the agar diffusion
technique [24], using a 2 mg mLꢁ1 solution in DMSO. The test
organisms were B. thuringiensis as gram-positive bacteria and E. coli
as gram-negative bacteria. A control using DMSO without the test
compound was included for each organism. Ampicillin and chlor-
amphenicol in DMSO were used as reference drugs.
1.93 g; 92%, 2.2 g; mp 203 ꢂC; IR (KBr):
n
/cmꢁ1 ¼ 2955 (aliphatic C–H)
and 1772, 1724, 1713 (3CO); 1H NMR (CDCl3): dppm ¼ 1.2 (t, 3H, CH3),
0
1.8 (m, 4H, H–C5 –H, C6–H), 2.6 (m, 2H, H–C7–H), 2.8 (m, 2H, H–C4–
H), 3.4 (s, 2H, C11–H, C12–H), 4.2 (t, 2H, O–CH2), 4.8 (s, 2H, C9–H,
C10–H) and 7.1–7.4 (m, 8H, Ar–H); 13C NMR (CDCl3): dppm ¼ 175.1,
161.5, 141.1, 138.5, 136.4, 135.4, 128.0, 127.2, 126.8, 125.0, 124.2, 60.2,
47.2, 45.8, 26.1, 25.0, 22.5, 22.2, 21.7 and 14.0; EIMS (m/z) (%) ¼ 383
(Mþ, 1.3), 437 (0.9), 409 (0.2), 305 (0.5), 259 (8.8), 231 (2.6), 178
(100), 138 (1.7), 110 (4.4), 84 (15.0) and 54 (7.0). Anal. for
C29H25NO4S (483.58): calcd.: C 72.03, H 5.21, N 2.90%; found:
C 72.14, H 5.27, N 2.96%.
Acknowledgements
To Dr. S. Bondock and Dr. E. Abd El-Latif, Chemistry Department,
Faculty of Science, Mansoura University, for carrying out spectral
measurements, also, to Dr. A. Mohamadin and Dr. A. El-Morsey,
Botany Department, Faculty of Science, Mansoura University, for
microbiological screening, they are greatly acknowledged.
4.1.13. Synthesis of 2-[benzothiazol-2-yl]-3a,4,9,9a-tetrahydro-4,9-
benzeno-benz[f]isoindole-1,3-dione (15)
A
solution of 1 (2.76 g; 0.001 mol), 2-amino-6-methyl-
References
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