Reaction of phthalaldehydic acid with different substituted aniline as well as hydrazine derivatives

Article abstract of DOI:10.1002/jhet.5570440317

Phthalaldehydic acid 1 is often represented as having two tautomeric forms 1a and 1b. The reaction of phthalaldehydic acid with different aryl amine and heterocyclic aryl hydrazine derivatives afforded different products depending on the reaction conditio

Full text of DOI:10.1002/jhet.5570440317

May-Jun 2007
617
Reaction of Phthalaldehydic Acid with Different Substituted Aniline
as well as Hydrazine Derivatives
Sherine N. Khattab*, Seham Y. Hassan, Ayman El-Faham,
Abdel Moneim M. El Massry and Adel Amer
Department of Chemistry, Faculty of Science, University of Alexandria, Alexandria 21321, Egypt
*Corresponding author: Phone: +20-12-3140924, e-mail address: ShKh2@link.net
Received June 30, 2006
O
N
Benzene/
N
H
O
P
T
Me
S
HO
X
X
H
NH2
O
6
4
X
H
HO
CHO
OH
O
O
O
Ar-NH-NH2
1a
1b
Me
S
T
P
O
H
nzene/
e
NH
B
DMF
N
Ar
H
OH
N
N
O
O
N
O
Ar
N
N
N
14
15
17
Phthalaldehydic acid 1 is often represented as having two tautomeric forms 1a and 1b. The reaction of
phthalaldehydic acid with different aryl amine and heterocyclic aryl hydrazine derivatives afforded
different products depending on the reaction conditions such as solvent and temperature.
J. Heterocyclic Chem., 44, 617 (2007).
Our interest was focused on studying the reaction of
phthalaldehydic acid with different aryl amine and hetero-
cyclic aryl hydrazine derivatives in various solvents. The
change of solvent had a great effect on the type of
products obtained. The microbiological activity of the
obtained compounds was also evaluated.
INTRODUCTION
Phthalaldehydic acid 1 (namely, 2-formyl benzoic
acid) and its derivatives represent an important member
in aromatic hydrocarbon, chemistry for their wide
usages in the preparation of 3-substituted phthalides [1-
4], heterobicyclic, tricyclic and tetracyclic systems [5-7],
in addition to their broad spectrum of biological
activities [8,9]. Reported among these activities, were
anorexic, anti HIV, anti-inflammatory, analgesic or anti-
allergic effects [8, 10-12]. Some have been used in
therapy, in particular as nootropic agents [13].
RESULTS AND DISCUSSION
Chemistry. Phthalaldehydic acid 1 is often represented
as having an aldehyde and an acid group 1a. However, the
tautomeric structure 3-hydroxy phthalide form 1b was
suggested by Racine in 1886 [20]. On the basis of
spectroscopic evidence, 1 exists in both the open 1a and ring
form 1b depending upon the solvent and temperature [19].
At 500 MHz 1 is shown to exist in the two tautomeric
forms 1a and 1b in CDCl3 by exhibiting both the CH
hydrogen at ꢀ 6.65 ppm and CHO hydrogen at ꢀ 10.58
ppm. Examination of the influence of acid such as p-
toluenesulfonic acid on this equilibrium revealed a
complete shift to the cyclic form 1b by displaying the CH
at ꢀ 6.01 ppm and no aldehydic hydrogen was detected.
Derivatives of phthalaldehydic acid
1 also show
activities as hypnotics, sedatives, muscle relaxants [14],
and the non-nucleosidic HIV-reverse transcriptase
inhibitors [8,15]. Also related compounds are important
herbicides for bud growth inhibition [16,17] and plant
regulation [18].
The bi-functionality at ortho-position of this
molecule gives it the ability for introducing hetero-
cycle moieties. Several procedures have been applied
in that aspect [5-7, 19a].

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S. N. Khattab, S. Y. Hassan, A. El-Faham, A. M. M. El Massry and A. Amer
Vol 44
The reaction of phthalaldehydic acid 1 with aniline 2a
contains the two tautomeric forms (1a and 1b) as observed
from its spectral data. Thus, the ir spectrum of 5 showed an
absorption peak at 3072 cm-1 due to the NH group and a
broad absorption peak at 2921-2630 cm-1 due to the NH+
group, and two absorption peaks at 1776, 1708 cm-1 due to
the (C=O) group of the ring form, and the (C=O) group
corresponding to the (COO-) group respectively. The 1H nmr
spectrum of 5 showed two broad peaks at ꢀ 4.36 and 6.08
corresponding to the NH and NH+ group which are D2O
exchangeable, and a singlet corresponding to the –CH group
of the ring form at ꢀ 7.36. The 13C nmr spectrum of 5
showed twenty two resolved carbon signals. The carbon
signal of the -CH group of the ring part of 5 was observed at
ꢀ 84.32, the carbon signal of the imino group (CH=N) was
observed at ꢀ 154.67. The carbon signals of the two
carbonyl groups were observed at ꢀ 167.52 and 168.24. The
rest of the resolved signals were corresponding to the rest of
the carbon atoms. The HMQC confirmed that the carbon
signal at ꢀ 84.32 is correlated to the singlet CH signal at ꢀ
7.36, which confirmed the proposed structure.
was described previously [1-4]. The 3-anilino phthalide
3a was the only product obtained when methanol was
used as solvent, by allowing the reaction mixture to
undergo reflux for 3 hours. The ir, melting point and
elemental analysis were in accordance with the reported
data [1-4].
The same reaction was performed using o-substituted
aniline 2b-d under the same conditions. Reactive
equimolar amount of o-phenylene diamine 2b with 1 in
methanol as a solvent, led to formation of the Schiff’s
base 4b. The zwitter ion form of 4b (Scheme 1) was
observed in solid and in solution states. The ir spectrum of
4b in KBr showed one broad absorption peak at 3066-
+
2600 cm-1 due to the ammonium (NH3 ) group, and one
absorption peaks at 1638 cm-1 due to the carbonyl (COO-)
1
group of the carboxylate. The H nmr spectrum of 4b in
dimethyl sulfoxide-d6 showed a broad peak at ꢀ 3.58
corresponding to NH3+ group which is D2O exchangeable.
The 13C nmr spectrum of 4b showed eleven resolved
carbon signals. No signals in the sp3-carbon region were
observed; the carbon signal of the imino group (CH=N)
and the carbonyl (C=O) were observed at ꢀ 151.77 and
169.99, respectively, which rules out the existence of any
ring tautomer. The rest of the carbon signals correspond
to the remaining carbon atoms.
The reaction of o-amino thiophenol 2c with phthalal-
dehydic acid 1 using methanol as solvent gave the
corresponding cyclized product 3c (Scheme 1) as observed
from its spectral data. The ir spectrum of 3c showed
absorption peak at 3409 cm-1 due to the NH group, and an
absorption peak at 1717 cm-1 due to the carbonyl group of the
Scheme 1
H
N
H
O
N
O
CHO
OH
X
NH3
O
O
3 a, X = H
3 c, X = SH
lux
f
4 b
e
x
u
/r
fl
re
H
OH/
e
O
O
M
e
M
1a
NH2
X
2b+1
+
(
1
: 2)
/
Me
OH/r
Dean
e
f
l
ux
Be
O
S
n
zen
t
ark
2 a, X = H
e
H
O
H
/
PT
OH
2 b, X = NH2 -H2O
2 c, X = SH
NH
S
O
2 d, X = OH
O
O
O
NH
O
N
1b
X
5
6 b, X = NH
6 c, X = S
6 d, X = O
ring form. The 1H nmr spectrum of 3c showed a singlet at ꢀ
1.60 and 7.25 corresponding to SH and NH groups which are
D2O exchangeable, a singlet at ꢀ 6.99 corresponding to the
CH group of the ring form. The 13C nmr spectrum of 3c
showed fourteen resolved carbon signals. The carbon signal
of the CH group of the ring form was resolved at ꢀ 64.54 and
When two equivalents of 2b are allowed to react with
phthalaldehydic acid 1 under the same conditions mentioned
above, only one product was obtained. Its structure was
assigned as 2-[(E)-({2-[(3-Oxo-1,3-dihydro-2-benzofuran-1-
yl)amino]phenyl}imino)methyl] benzoic acid 5 on the basis
of its spectroscopic data (Scheme 1). The formed product 5

May-Jun 2007
Reaction of Phthalaldehydic Acid with Different Substituted Aniline
619
the carbon signal of the carbonyl group was observed at ꢀ
163.86. The remaining signals were in accordance with the
remaining carbon atoms.
On the other hand, the reaction of o-amino phenol 2d
with phthalaldehydic acid 1 using methanol as solvent
gave more than one product on TLC which couldn’t be
isolated as a pure product.
We extended our work to use different solvent system
such as dry benzene in presence of p-toluenesulfonic acid
(PTS) using Dean Stark trap [6]. The reaction of o-
substituted anilines 2b-2d with phthalaldehydic acid 1 in dry
benzene in presence of p-toluenesulfonic acid using Dean
Stark trap afforded a tetracyclic product 6 (Scheme 1) as a
single product in nearly all cases as observed from spectral
analysis. The only exception is in the case of o-aminophenol
2d, where the product 6d was isolated as an isomeric mixture
in a ratio 2:3 (Scheme 1) as evident from its spectral data. On
the other hand the reaction of o-phenylene diamine 2b and o-
amino thiophenol 2c gave in excellent yield with high
stereoselectivity only one product 6b and 6c respectively.
The ir spectrum of compound 6d showed absorption peak at
Figure 1
from its spectral data. While using dimethyl formamide
(DMF) as solvent gave a tetracyclic product 9 in yield 82
% with high stereoselectivity, only one product was
obtained as observed from its spectral data. The ir
spectrum of 9 showed one absorption peak at 1784 cm-1
corresponding to the carbonyl group. The 1H nmr
spectrum of 9 showed a singlet at ꢀ 7.61 corresponding to
one proton for the CH group. As expected from the
proposed structure 9 the 13C nmr spectrum showed sixteen
resolved carbon signals with the CH of the ring form
resolved at ꢀ 84.51. The reaction of 7 and phthalaldehydic
acid 1 in dry benzene in presence of p-toluenesulfonic
acid using Dean Stark trap gave also the same tetracyclic
product 9 as in case of using DMF as a solvent but in
much better yield (94 %) (Scheme 2). The formation of 9
could be explained due to the attacking of the amino
group in 7 at the tautomeric carbon atom to generate the
transient intermediate, in which the sulphur atom attacks
the tautomeric carbon followed by elimination of one
equivalent of water to form the product 9 (Scheme 2).
1
1780 cm-1 due to the carbonyl group. Its H nmr spectrum
showed two singlet peaks at ꢀ 6.57 and ꢀ 6.90 in ratio 2:3
corresponding to the CH groups of the two isomeric products
13
of 6d. Its C nmr spectrum showed eleven resolved carbon
signals. The carbon signals of the CH groups were observed
at ꢀ 98.30 and 99.11 and the carbonyl carbon signals were
observed at ꢀ 167.95 and 168.26. The rest of the resolved
carbon signals are corresponding to the aromatic carbon
atoms of the two isomeric mixtures. The two isomers of
compound 6d were separated by a mass selective detector
(GC/MS) using an HP-5MS column. 1 micrometer split less
injection at inlet temperature 250°C and detector temperature
280°C. They showed 2 peaks at retention time (tR) 5.97 and
6.50 min, and in ratio 47.999 % and 52.001 % respectively.
The two isomers showed the same molecular ion peak at m/z
223. The ir spectrum of 6c showed one absorption peak at
Scheme 2
N
NH
NH
Cl
N
S
S
Cl
MeOH/reflux
+
1
1
1719 cm-1 due to the carbonyl group. The H nmr spectrum
N
N
N
NH2
of 6c showed only one singlet at ꢀ 7.29 corresponding to the
CH group. The 13C nmr spectrum of 6c showed two resolved
carbon signals corresponding to the CH and C=O groups at ꢀ
69.26 and 168.63 respectively. The rest of the resolved
carbon signals were consistent with the expected product.
The ir and nmr spectra of compound 6b were in agreement
with the proposed structure 6b.
7
DMF/Reflux or
Dean Stark/PTS/benzene
HO
8
O
N
N
N
N
Cl
Cl
SH
N
S
N
H
HN
HO
HN
O
The energy minimization of the tetracyclic products 6,
9 and 17 were processed utilizing PM3/MOPAC [21] and
the observed structure for 6b is represented as a prototype
(Figure 1).
O
O
-H2O
N
N
Cl
The bi-functional system 4-amino-5-(3-chlorophenyl)-
2,4-dihydro-[1,2,4]triazole-3-thione 7 reacted with phthal-
aldehydic acid 1 using methanol as solvent under the
same conditions used for the aniline derivatives to afford
the corresponding Schiff’s base 8 (Scheme 2) as observed
N
S
N
O
9

620
S. N. Khattab, S. Y. Hassan, A. El-Faham, A. M. M. El Massry and A. Amer
Vol 44
This mechanism is the same predicted for the formation of
the previously prepared compound 6.
The probable reaction mechanism for the formation of
compound 12 is through attack of the NH2 group in 10 at
the tautomeric carbon atom to generate the transient
intermediate, which rearranges to afford the trans-imine
intermediate, followed by elimination of one equivalent of
water to form the product 12 [7a].
The reaction of phthalaldehydic acid 1 with 1-
hydrazinophthalazine 13 using methanol as solvent gave
the Schiff’s base 14 in good yield and the spectral data
were identical to that reported in the literature [22]. On
the other hand, when the reaction was performed using
DMF as solvent the cyclized product 15 was obtained in
good yield and the spectral data were identical to the
reported data by R. N. Castle and et al. [23] (Scheme 4).
As extension to our work the reaction of phthalald-
ehydic acid 1 with hetero aryl hydrazine derivatives was
studied. The reaction of phthalaldehydic acid 1 with (3-
benzyl-quinoxalin-2-yl)-hydrazine 10a, 3-hydrazino-1H-
quinoxalin-2-one 10b or 6-benzyl-5-hydrazino-2H-[1,2,4]-
triazin-3-one 10c gave two different products (Scheme 3)
depending on the reaction conditions used. The Schiff’s
base 11 was obtained when using methanol as solvent,
where the cyclized product 12 was isolated when
dimethyl formamide (DMF) was used as solvent (Scheme
3). The structures of 11a-c and 12a-c were established by
ir, 1H nmr, 13C nmr and elemental analyses.
Scheme 3
Ar
NH
N
x
lu
f
e
HO
ol/r
n
a
th
e
M
O
11a-c
NH2
Ar
1
+
N
H
DM
10a-c
F
/
or
r
e
Be
f
l
ux
n
z
Ar
ene/
P
H
T
S
O
N
O
OH NH
N
O
Ar
O
NH
N
N
Ph
Ar
10 a, Ar =
10 b, Ar =
10 c, Ar =
H
H
-H2O
N
N
H
N
O
12a-c
N
N
HN
Ph
O
N
The reaction of the hydrazines 10a and 10c with
phthalaldehydic acid 1 in dry benzene in presence of p-
toluenesulfonic acid using Dean Stark trap afforded the
cyclized products 12a and 12c respectively. While the
hydrazine 10b when reacting with phthalaldehydic acid 1
under the same previously mentioned conditions gave
only the Schiff’s base 11b. The Schiff’s base obtained is
highly insoluble and contains hydrogen bonding (Figure
2). This probably prevents further ring closure.
The reaction of 1-hydrazinophthalazine 13 with
phthalaldehydic acid 1 in dry benzene in presence of p-
toluenesulfonic acid using Dean Stark trap gave the
corresponding pentacyclic product 17 as an isomeric
mixture in ratio 1:2 (Scheme 4) as observed from its
spectral data. A possible explanation for the formation of
17 was based on the unique reactivity of compound 13
having the N-2 nitrogen atom [19a,24-28]. Hydralazine is
known to adopt the tautomeric form where the nitogen
ring is in the second nucleophilic reactivity. Using
hydralazine-HCl with phthaladehydic acid in aqueous
medium was reported to undergo the formation of the
intermediate 16 under such acidic condition [19a].
A plausible explanation for the formation of compound 17
could be through the dehydration of the intermediate 16
under acidic condition as shown in Scheme 4. The ir
spectrum of compound 17 showed absorption peak at 1778
cm-1 due to the carbonyl group. The 1H nmr spectrum of 17
showed two singlet peaks at ꢀ 7.04 and ꢀ 7.12 in ratio 1:2
H
N
O
N
H
N
N
COOH
11b
Figure 2

May-Jun 2007
Reaction of Phthalaldehydic Acid with Different Substituted Aniline
621
Scheme 4
N
NH
N
N
N
N H
N
NH2
O
x
HO
u
l
f
e
14
OH/r
e
M
O
DMF/refulx
N
+
1
N
N
N
N
N
HN
NH2
13
15
N
H
N
Benzen
N
Dean S
e/
P
T
N
t
S
ar
k
O
17
-H2O
N
NH
N
H
-H2O
N
NH
O
N
O
H
NH
N
O
H2O
16
corresponding to the CH group of the two isomeric products
of 17. The 13C nmr spectrum of 17 showed two resolved
carbon signals corresponding to the CH group at ꢀ 99.89 and
102.18 and also the two carbonyl carbon signals were
observed at ꢀ 168.30 and 168.46. The two isomers of
compound 17 were separated by a mass selective detector
(GC/MS) using an HP-5MS column. 1 micrometer split less
injection at inlet temperature 250°C and detector temperature
280°C. They showed 2 peaks at retention time (tR) 5.99 and
6.52 min, and in ratio 56.6 % and 43.4 % respectively. The
two isomers showed the same molecular ion peak at m/z 274.
Biology. Four test organisms representing different
groups of microorganisms were used to evaluate the
bioactivity of the designed products. The utilized test
organisms were: Escherichia coli (E. coli) ATCC 25922
and Pseudomonas aeruginosa (P. aeruginosa) as Gram-
negative bacteria, Staphylococcus aureus (S. aureus)
ATCC 19433 as an example of Gram-positive bacteria, and
Candida albicans (C. albicans) as yeast-like fungi. The
inhibition zone results are given in Table 1. It is apparent
from the data listed in Table 1 that some of the synthesized
compounds showed antibacterial activity comparable to
that of ampicillin, ciprofloxacin and clotrimazole.
However, concerning the activity against gram-positive
bacteria, compounds 3a, 6d, 11c, 12c and 17 showed
excellent activity higher and comparable to that of both
ampicillin and ciprofloxacin, where compounds 6c, 8, 9,
11a, 11b and 14, exhibit good activity which is higher and
comparable to that of ampicillin. On the other hand, the
activity against the gram-negative bacteria (Escherichia
coli) of a number of the designed compounds 3a, 5, 6b, 6d,
8, 11a, 11c, 12a, 12b, 15, showed higher and comparable
activity to that of ampicillin. Concerning the data of
antifungal activity, the synthesized compounds showed
moderate activity against Candida albicans, comparable to
that of clotrimazole. The microdilution susceptibility test in
Müller-Hinton Broth (Oxoid) and Sabouraud Liquid
Medium (Oxoid) were also used for the determination of
antibacterial and antifungal activity [31,32]. The minimal
inhibitory concentration (MIC) listed in (Table 1) showed
that the test compounds 4b and 12a have antifungal activity
about 25% of that of Clotrimazole (Canesten®, Bayer). The
test Compound 11a has antimicrobial activity against
S.aureus 25% of that of ampicillin, while its activity is
about 50% of that of ciprofloxacin. Compounds 3a, 8, 11b
and 12a have antimicrobial activity against E. coli 50% to
that of ampicillin, while the activity of these compounds is
about 25% of that of ciprofloxacin. From the data given in
Table 1 we also notice that compounds 3a, 4b, 6b, 8, 12a
and 12c have antibacterial activity against P. aeruginosa
about 50% of that of ciprofloxacin.
EXPERIMENTAL
Chemistry. Melting points were determined with a Mel-
Temp apparatus and are uncorrected. Magnetic resonance

622
S. N. Khattab, S. Y. Hassan, A. El-Faham, A. M. M. El Massry and A. Amer
Vol 44
ArH). 13C nmr (DMSO-d6): ꢀ 88.53, 114.39, 114.84,
119.84, 124.62, 125.43, 129.64, 131.04, 134.91, 145.67,
146.38, 169.70. Anal. Calcd for C14H11NO2: C, 74.65; H,
4.92; N, 6.22. Found: C, 74.78; H, 5.06; N, 6.03.
spectra (1H nmr and 13C nmr spectra) were recorded on a
JEOL 500 MHz spectrometer with chemical shift values
reported in ꢀ units (part per million) relative to an internal
standard. Infrared (ir) data were obtained on a Perkin-Elmer
1600 series Fourier transform instrument as KBr pellets.
Elemental analyses were performed on Perkin-Elmer 2400
elemental analyzer, and the found values were within
2-{(E)-[(2-Aminophenyl)imino]methyl}benzoic acid
(4b). Compound 4b was obtained as white crystal, 2.14 g
+
(89 %) yield, mp 264-265°C. ir (KBr): 3066-2600 (NH3 ),
Table 1
In Vitro antimicrobial activity of the test compounds, and evaluation of the antimicrobial activity of the test
compounds, and determination of the IZ (inhibition zone) and the MIC (minimal inhibitory concentration).
Test compound Escherichia coli Staphylococcus aureus Candida albicans Pseudomanas aerogenisa
IZ
18
----
28
19
17
17
19
19
17
20
18
17
18
16
18
18
18
16
16
19
17
MIC
25
-----
12.5
50
100
100
100
100
100
200
50
100
100
50
IZ
22
-----
30
MIC
12.5
------
25
IZ
-----
29
-----
18
17
17
16
22
18
18
16
17
16
17
18
18
16
16
15
17
17
MIC
------
12.5
------
100
100
50
>200
100
200
200
>200
100
>200
>200
100
IZ
-----
-----
38
20
18
23
20
20
18
17
22
21
17
22
18
20
20
20
18
20
18
MIC
-----
------
25
50
>200
50
100
50
>200
>200
50
100
>200
100
>200
50
>200
50
>200
100
>200
Ampicillin
Clotrimazole
Ciprofloxacin
3a
3c
4b
5
6b
6c
6d
8
9
11a
11b
11c
12a
12b
12c
14
15
17
36
100
------
------
100
100
100
100
100
100
50
100
100
------
------
100
100
------
>200
-----
-----
16
20
27
30
26
29
27
28
33
------
------
36
26
------
36
100
50
50
>200
>200
>200
100
>200
>200
>200
>200
>200
>200
1
1638 (COO-) cm-1. H nmr (DMSO-d6): ꢀ. 3.58 (br.s, 3H,
±0.3% of the theoretical values. Agilet mass selective
detector using a HP-5MS column was used for separation
of some compounds. Reaction progress and product purity
was ascertained by TLC on silica gel-protected aluminium
sheets (Type 60 GF254, Merck) and the spots were
detected by exposure to UV-lamp at ꢁ 254 nm for few
seconds. The compounds were named using Chem. Draw
Ultra version 9.0, Cambridge soft Corporation.
+
NH3 , D2O exchangeable), 7.19 (m, 2H, ArH), 7.54-7.59
(m, 4H, ArH + CH), 7.65 (t, 1H, ArH, J = 6.9 Hz), 7.76,
7.81 (2d, 2H, ArH, J = 7.7 Hz). 13C nmr (DMSO-d6): ꢀ
115.62, 122.55, 130.08, 130.17, 130.57, 130.66, 131.46,
133.73, 139.41, 151.77, 169.29. Anal. Calcd for
C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.23;
H, 5.24; N, 11.43.
3-[(2-Mercaptophenyl)amino]-2-benzofuran-1(3H)-
one (3c). Compound 3c was obtained as colorless needles,
2.41 g (94 %) yield, mp 164-165°C. ir (KBr): 3409 (NH),
General procedure for the reaction of aniline and
aniline derivatives with phthalaldehydic acid 1 in
methanol. A Solution of (10 mmol) of the aniline or
aniline derivatives in 20 mL methanol was refluxed with
(1.50 g, 10 mmol) phthalaldehydic acid for 3 hours in
presence of 2 drops of acetic acid. The product which
separated out on concentration was collected by filtration,
dried and recrystallized from ethanol..
1
1717 (C=O) cm-1, H nmr (CDCl3): ꢀ 1.60 (s, 1H, SH,
D2O exchangeable), 6.99 (s, 1H, CH), 7.09 (t, 1H, ArH, J
= 7.7 Hz), 7.18-7.22 (m, 2H, ArH), 7.25 (s, 1H, NH, D2O
exchangeable), 7.54-7.60 (m, 2H, ArH), 7.64-7.68 (m,
2H, ArH), 7.94 (d, 1H, ArH, J = 7.6 Hz). 13C nmr
(CDCl3): ꢀ 64.54, 113.83, 118.40, 118.91, 120.49, 121.17,
121.27, 125.25, 127.99, 128.52, 131.15, 131.81, 138.39,
163.86. Anal. Calcd for C14H11NO2S: C, 65.35; H, 4.31;
N, 5.44. Found: C, 65.52; H, 4.13; N, 5.61.
3-Anilino-2-benzofuran-1(3H)-one (3a). Compound
3a was obtained as colorless needles, 2.05 g (91 %) yield,
mp 179-180°C (Lit 179-180°C) [1-4], ir (KBr): 3332
1
(NH), 1740 (C=O) cm-1; H nmr (DMSO-d6): ꢀ 6.54 (d,
1H, CH, J = 9.9 Hz), 6.79 (m, 1H, ArH), 6.84 (d, 1H,
ArH, J = 8.4 Hz), 6.94 (t, 1H, ArH, J = 7.7 Hz), 7.13 (d,
1H, NH, D2O exchangeable), 7.20 (t, 1H, ArH, J = 7.7
Hz), 7.27 (m, 1H, ArH), 7.69 (m, 2H, ArH), 7.83 (m, 2H,
2-[(E)-({2-[(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)-
amino]phenyl}imino)methyl]benzoic acid (5). A Solution
of (1.08 g, 10 mmol) of the o-phenylenediamine in 20 mL
methanol was refluxed with (3.0 g, 20 mmol) phthalaldehydic

May-Jun 2007
Reaction of Phthalaldehydic Acid with Different Substituted Aniline
623
GC/MS: isomer 6d1, tR 5.97 min (47.999 %), m/e 223 (M+, 7 %);
isomer 6d2, tR.6.50 min (52.001 %), m/e 223 (M+, 9 %).
acid 1 for 3 hours in presence of 2 drops of acetic acid. The
product which separated out on concentration was collected by
filtration, dried and recrystallized from ethanol. Compound 5
was obtained as white powder, 3.45 g (93 %) yield, mp 183-
184°C. ir (KBr): 3072 (NH), 2921-2630 (NH+), 1776 (C=O
cyclic), 1708 (C=O carboxylate) cm-1, 1H nmr (DMSO-d6): ꢀ
4.36, 6.08 (2 br.s, 2H, NH + NH+, D2O exchangeable), 7.00 (t,
1H, CH, J = 7.7 Hz), 7.19 (t, 1H, ArH, J = 7.7 Hz), 7.36 (s, 1H,
CH), 7.59 (d, 1H, ArH, J = 6.9 Hz), 7.63-7.67 (m, 3H, ArH),
7.69-7.80 (m, 5H, ArH), 7.99 (d, 1H, ArH, J = 6.9 Hz), 8.05 (d,
1H, ArH, J = 7.7 Hz). 13C nmr (DMSO-d6) (HMQC, HMBC): ꢀ
84.32, 111.05, 120.42, 120.46, 123.23, 123.31, 123.78, 124.61,
125.94, 126.98, 130.67, 130.96, 131.21, 131.93, 132.38, 132.75,
135.71, 143.68, 144.49, 154.67, 167.52, 168.24. Anal. Calcd for
C22H16N2O4: C, 70.96; H, 4.33; N, 7.52. Found: C, 71.17; H,
2-((Z)-{[3-(3-Chlorophenyl)-5-thioxo-1,5-dihydro-4H-1,2,4-
triazol-4-yl]imino})benzoic acid (8). A Solution of (2.27 g,
10 mmol) of 4-amino-5-(3-chlorophenyl)-2,4-dihydro[1,2,4]-
triazole-3-thione 7 in 20 mL methanol was refluxed with
(1.50 g, 10 mmol) phthalaldehydic acid 1 for 3 hours in
presence of 2 drops of acetic acid. The product which
separated out on concentration, collected by filtration, dried
and recrystallized from ethanol. Compound 8 was obtained as
yellow powder, 2.22 g (62 %) yield, mp 186-187°C. ir (KBr):
3300-2596 (OH), 3111 (NH), 1705 (C=O) cm-1. 1H nmr
(DMSO-d6): ꢀ 7.52, 7.58 (2 m, 2H, ArH), 7.70 (m, 3H, ArH),
7.81 (d, 1H, ArH, J = 7.6 Hz), 7.88 (s, 1H, CH), 7.98 (d, 1H,
ArH, J = 5.4 Hz), 8.03 (d, 1H, ArH, J = 6.1 Hz), 10.53 (s, 1H,
OH, D2O exchangeable), 14.31 (br.s, 1H, NH, D2O
exchangeable). Anal. Calcd for C16H11ClN4O2S: C, 53.56; H,
3.09; N, 15.61. Found: C, 53.33; H, 3.24; N, 15.43.
4.61; N, 7.26.
General procedure for the reaction of aniline derivatives
with phthalaldehydic acid 1 for the preparation of 6. The
aniline derivatives (10 mmol), phthalaldehydic acid 1 (1.50 g, 10
mmol) and p-toluene sulfonic acid (1.90 g, 10 mmol) were
dissolved in benzene (40 ml). The mixture was heated at reflux
under Dean-stark conditions for 12 hours. The resultant solution
was allowed to cool, and the product which separated out on
concentration was collected by filtration, dried and recrystallized
from ethanol.
3-(3-Chlorophenyl)[1,2,4]triazolo[4',3':4,5][1,3,4]thiadiazolo-
[2,3-a]isoindol-6(10bH)-one (9).
Method A: A Solution of (2.27 g, 10 mmol) of 7 in 10 mL
DMF was refluxed with (1.50 g, 10 mmol) phthalaldehydic acid
1 for 3 hours in presence of 2 drops of acetic acid. The product
which separated out on concentration, collected by filtration,
dried and recrystallized from ethanol. The product was poured
into water, collected by filtration, dried and recrystallized from
ethanol. Compound 9 was obtained as colorless crystals, 2.77 g
4b,5-Dihydro-isoindolo[2,1-a]benzimidazole-11(11H)-one
(6). Compound 6b was obtained as colorless crystals, 2.05 g (92
%) yield, mp 230-231°C. ir (KBr): 3435 (NH), 1765 (C=O)
1
(82 %) yield, mp 220-221°C. ir (KBr): 1784 (C=O) cm-1. H
nmr: ꢀ 7.61 (s, 1H, CH), 7.68 (t, 1H, ArH, J = 6.9 Hz), 7.78 (m,
1H, ArH), 7.92 (m, 2H, ArH), 7.98 (m, 1H, ArH), 8.12 (s, 1H,
ArH), 8.33 (d, 2H, ArH, J = 6.1 Hz). 13C nmr: ꢀ 84.51, 124.29,
125.43, 126.91, 127.17, 127.24, 127.99, 129.64, 131.01, 133.40,
135.24, 135.43, 140.53, 146.12, 159.80, 169.29. Anal. Calcd for
C16H9ClN4OS: C, 56.39; H, 2.66; N, 16.44. Found: C, 56.43; H,
2.89; N, 16.32.
Method B: Compound 7 (10 mmol), phthalaldehydic acid 1
(1.50 g, 10 mmol) and p-toluene sulfonic acid (1.90 g, 10 mmol)
were dissolved in benzene (40 ml). The mixture was heated at
reflux under Dean-stark conditions for 12 hours. The resultant
solution was allowed to cool, the product that separated out on
concentration was collected by filtration, dried and recrystallized
from ethanol. Compound 9 was obtained as colorless crystals,
3.19 g (94 %) yield, 220-221°C. The spectral data are identical
to the one given above.
1
cm-1. H nmr (DMSO): ꢀ. 5.55 (s, 1H, CH), 7.55-7.59 (m, 2H,
ArH + NH, D2O exchangeable), 7.71, 7,78 (2t, 2H, ArH, J = 7.7
Hz), 7.90-7.96 (m, 4H, ArH), 8.11 (d, 1H, ArH, J = 7.7 Hz). 13
C
nmr (DMSO): ꢀ 51.11, 113.50, 116.20, 123.56, 125.55, 126.20,
129.78, 130.33, 133.20, 136.33, 138.36, 145.93, 146.42, 154.71.
Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found:
C, 75.43; H, 4.33; N, 12.82.
Isoindolo[1,2-b]benzothiazol-11(4bH)-one (6c) [33].
Compound 6c was obtained as colorless needles, 2.18 g (91 %)
yield, mp 160-161°C. ir (KBr): 1719 (C=O) cm-1. 1H nmr
(DMSO-d6): ꢀ. 7.12, 7.19 (2t, 2H, ArH, J = 7.7 Hz), 7.29 (s, 1H,
CH), 7.36 (d, 1H, ArH, J = 7.7 Hz), 7.51 (d, 1H, ArH, J = 8.5
Hz), 7.64, 7.74 (2t, 2H, ArH, J = 7.7 Hz), 7.78, 7.85 (2d, 2H,
ArH, J = 7.7 Hz). 13C nmr (DMSO-d6): ꢀ 69.26, 118.66, 123.88,
124.99, 125.05, 126.24, 126.54, 130.70, 131.89, 134.28, 136.31,
136.56, 143.97, 168.63. Anal. Calcd for C14H9NOS: C, 70.27; H,
3.79; N, 5.85. Found: C, 70.43; H, 3.94; N, 5.61.
Isoindolo[1,2-b]benzoxazole-11(4bH)-one (6d). Compound
6d was obtained as colorless needles, 1.99 g (89 %) yield, mp
204-205°C. ir (KBr): 1780 (C=O) cm-1. 6d1 (isomer 1, 40%):
1H nmr (CDCl3): ꢀ 6.57 (s, 1H, CH), 7.61 (t, 2H, ArH, J = 7.7
Hz), 7.65 (m, 1H, ArH), 7.70-7.76 (m, 2H, ArH), 7.79 (t, 1H,
ArH, J = 7.7 Hz), 7.92 (dd, 2H, ArH, J = 7.7, 11.0 Hz). 13C nmr
(CDCl3): ꢀ 98.30, 124.01, 124.52, 125.70, 125.83, 126.61,
126.87, 131.56, 135.07, 144.14, 167.95. 6d2 (isomer 2, 60%):
1H nmr (CDCl3): ꢀ 6.90 (s, 1H, CH), 7.61 (t, 2H, ArH, J = 7.7
Hz), 7.65 (m, 1H, ArH), 7.70-7.76 (m, 2H, ArH), 7.79 (t, 1H,
ArH, J = 7.7 Hz), 7.92 (dd, 2H, ArH, J = 7.7, 11.0 Hz). 13C nmr
(CDCl3): ꢀ 99.11, 124.01, 124.52, 125.70, 125.83, 126.61,
126.87, 131.50, 135.01, 144.14, 168.26. Anal. Calcd for
C14H9NO2: C, 75.33; H, 4.06; N, 6.27. Found: C, 75.43; H, 4.24;
N, 6.03. The two isomers 6d1 and 6d2.were separated using
General procedure for the reaction of hydrazine derivatives
with phthalaldehydic acid 1 for the preparation of Schiff’s
base 11.
Method A: A Solution of (10 mmol) of the hydrazine
derivatives in 20 mL methanol was refluxed with (1.50 g, 10
mmol) phthalaldehydic acid 1 for 3 hours in presence of 2 drops
of acetic acid. The product that separated out on concentration
was collected by filtration, dried and recrystallized from ethanol.
Method B: The hydrazine derivative 10 (10 mmol) when
allowed to react with (1.50 g, 10 mmol) phthalaldehydic acid 1
in presence of p-toluene sulfonic acid (1.90 g, 10 mmol) in
benzene (40 ml), and the mixture was heated at reflux under
Dean-stark conditions for 12 hours. The resultant solution was
allowed to cool, and the product that separated out on
concentration was collected by filtration, dried and recrystallized
from ethanol.

624
S. N. Khattab, S. Y. Hassan, A. El-Faham, A. M. M. El Massry and A. Amer
Vol 44
2-{(E)-[(3-Benzylquinoxalin-2-yl)hydrazono]methyl}benzoic
ArH, J = 8.0 Hz), 8.26 (d, 2H, ArH, J = 7.4 Hz), 8.47 (s, 1H,
ArH). 13C nmr (DMSO-d6): ꢀ 40.81, 126.52, 127.00, 127.65,
128.02, 128.75, 129.05, 129.21, 130.08, 131.27, 132.08, 133.35,
135.13, 137.39, 140.13, 140.40, 142.06, 148.61, 154.32, 159.4.
Anal. Calcd for C23H16N4O: C, 75.81; H, 4.43; N, 15.38. Found:
C, 76.04; H, 4.64; N, 15.12.
acid (11a). Using Method A, compound 11a was obtained as
yellow powder, 3.74 g (98 %) yield, mp 195-196°C. ir (KBr):
3138-2816 (OH), 3217 (NH), 1709 (C=O) cm-1. 1H nmr
(DMSO-d6): ꢀ 4.17 (s, 2H, CH2), 7.17 (t, 2H, ArH, J = 6.9 Hz),
7.26 (t, 3H, ArH, J = 7.7 Hz), 7.35 (m, 3H, ArH), 7.49-7.61 (m,
4H, ArH), 7.85 (d, 1H, ArH, J = 6.9 Hz), 8.47 (br.s, 1H, NH,
D2O exchangeable), 9.15 (s, 1H, CH), 11.40 (br.s, 1H, OH, D2O
exchangeable). 13C nmr (DMSO-d6) (DEPT, HMQC): ꢀ 39.50
(CH2), 115.61 (CH), 122.78 (CH), 126.82 (CH), 128.57 (CH),
128.80 (CH), 129.52 (CH), 129.75 (C, quart.), 129.96, 130.73,
132.14 (C, quart.), 135.50 (C, quart.), 138.39 (C, quart.), 146.58
(C quart.), 155.44 (CH), 159.55 (C=N), 168.84 (C=O). Anal.
Calcd for C23H18N4O2: C, 72.24; H, 4.74; N, 14.65. Found: C,
72.43; H, 4.84; N, 14.43.
2-{(E)-[(3-Oxo-3,4-dihydroquinoxalin-2-yl)hydrazono]-
methyl}benzoic acid (11b). By Method A compound 11b was
obtained as yellow powder, yield 2.75 g (89 %), mp 273-274°C.
ir (KBr): 3300-2827 (OH), overimposed 3217 and 3094 (2NH),
1726 (C=O carboxyle), 1688 (C=O amide) cm-1. 1H nmr
(DMSO-d6): ꢀ 7.16 (m, 4H, ArH), 7.49 (m, 2H, ArH), 7.61 (t,
1H, ArH, J = 7.7 Hz), 7.85 (d, 1H, ArH, J = 7.7 Hz), 8.07 (br.s,
1H, NH, D2O exchangeable), 9.21 (s, 1H, CH), 11.40 (br.s, 1H,
OH, D2O exchangeable), 12.36 (br.s, 1H, NH, D2O
exchangeable). 13C nmr (DMSO-d6): ꢀ 115.56, 124.00, 125.30,
126.14, 127.41, 129.30, 129.75, 130.75, 131.08, 132.39, 133.33,
135.55, 146.55, 146.83, 151.37, 168.69. Anal. Calcd for
C16H12N4O3: C, 62.33; H, 3.92; N, 18.17. Found: C, 62.47; H,
4.09; N, 17.96.
Using Method B the same product was obtained in yield 3.36
g (92.2 %).
3-(1-Oxophthalazin-2(1H)-yl)quinoxalin-2(1H)-one (12b).
Using Method A, compound 12b was obtained as pale buff
powder, 2.15 g (74 %) yield, mp 200-201°C. ir (KBr): 3437
1
(NH), 1690 (C=O, NH-CO), 1674 (C=O, N-CO) cm-1. H nmr
(DMSO-d6): ꢀ 7.40 (m, 2H, ArH), 7.65 (br. s, 1H, ArH), 7.83
(m, 1H, ArH), 7.93 (m, 1H, ArH), 8.03 (m, 2H, ArH), 8.27 (m,
1H, ArH), 8.60 (m, 1H, ArH), 12.78 (br.s, 1H, NH, D2O
exchangeable). 13C nmr (DMSO-d6): ꢀ 116.35, 124.58, 126.39,
127.59, 128.07, 129.48, 130.14, 130.86, 132.47, 133.35, 133.68,
135.15, 140.19, 151.08, 152.02, 159.18. Anal. Calcd for
C16H10N4O2: C, 66.20; H, 3.47; N, 19.30. Found: C, 65.94; H,
3.24; N, 19.43.
2-(6-Benzyl-3-oxo-2,3-dihydro-1,2,4-triazin-5-yl)phthalazin-
1(2H)-one (12c). Using Method A, compound 12c was obtained
as pale yellow crystals, 2.68 g (81 %) yield, 204-205°C. ir (KBr):
1
3230 (NH), 1701 (C=O, NH-CO), 1645 (C=O, N-CO) cm-1. H
nmr (DMSO-d6): ꢀ 4.21 (s, 2H, CH2), 7.26-7.27 (m, 5H, ArH), 7.43
(m, 2H, ArH), 7.52 (m, 2H, ArH), 7.71 (m, 1H, ArH), 11.35 (s, 1H,
NH, D2O exchangeable). Anal. Calcd for C18H13N5O2: C, 65.25; H,
3.95; N, 21.14. Found: C, 65.44; H, 3.84; N, 21.25.
Using Method B the same product was obtained in yield 2.32
g (70.1%).
Using Method B, the same product was obtained in 2.87 g
(93.1%) yield.
2-[(E)-(Phthalazin-1-ylhydrazono)methyl] benzoic acid
(14). A Solution of (1.60 g, 10 mmol) of the hydralazine 13 in
20 mL methanol was refluxed with (1.50 g, 10 mmol) phthal-
aldehydic acid 1 for 3 hours in presence of 2 drops of acetic
acid. The product which separated out on concentration was
collected by filtration, dried and recrystallized from ethanol.
Compound 14 was obtained as yellow powder, 2.48 g (85 %)
yield, mp 199-200°C (Lit 198°C)[23b, 34]. ir (KBr): 3494-3266
(OH), 3051 (NH), 1692 (C=O) cm-1. 1H nmr (DMSO-d6): ꢀ 7.46
(t, 1H, ArH, J = 7.7 Hz), 7.57 (t, 1H, ArH, J = 7.7 Hz), 7.69-
7.78 (m, 4H, ArH + NH), 7.83 (d, 1H, ArH, J = 7.7 Hz), 8.12 (s,
1H, ArH), 8.31 (d, 1H, ArH, J = 7.7 Hz), 8.65 (d, 1H, ArH, J =
8.4 Hz), 9.10 (s, 1H, CH), 12.18 (br.s, 1H, NH, D2O
exchangeable). 13C nmr (DMSO-d6) (HMQC, HMBC): ꢀ 124.44,
126.43, 127.05, 127.62, 128.58, 129.75, 130.52, 131.32, 132.00,
132.41, 133.04, 135.76, 138.55, 149.38, 152.35, 169.08. Anal.
Calcd for C16H12N4O2: C, 65.75; H, 4.14; N, 19.17. Found: C,
65.54; H, 4.36; N, 19.02.
2-{(E)-[(6-Benzyl-3-oxo-2,3-dihydro-[1,2,4]triazin-5-yl)-
hydrazono]methyl}benzoic acid (11c). Using Method A
compound 11c was obtained as yellow powder, 2.97 g (85 %)
yield, mp 219-220°C. ir (KBr): 3380 (NH), 3340-2800 (OH) and
overimposed 3216 (NH), 1708 (C=O carboxyl), 1698 (C=O
amide) cm-1. 1H nmr (DMSO-d6): ꢀ 3.86 (s, 2H, CH2), 7.16-7.29
(m, 6H, ArH), 7.51, 7.56 (2t, 2H, ArH, J = 7.7 Hz), 7.83 (d, 1H,
ArH, J = 7.7 Hz), 8.63 (br.s, 1H, NH, D2O exchangeable), 9.10
(s, 1H, CH), 11.02 (br.s, 1H, OH, D2O exchangeable), 11.58 (s,
1H, NH, D2O exchangeable). Anal. Calcd for C18H15N5O3: C,
61.89; H, 4.33; N, 20.05. Found: C, 62.11; H, 4.54; N, 19.88.
General procedure for the preparation of compound 12.
Method A: A Solution of the hydrazines derivatives 10 (10
mmol) in 10 mL dimethylformamide was refluxed with (1.50 g,
10 mmol) phthalaldehydic acid 1 for 3 hours in presence of 2
drops of acetic acid. The product was poured into water,
collected by filtration, dried and recrystallized from ethanol.
Method B: The hydrazine derivative 10 (10 mmol) was also
allowed to react with (1.50 g, 10 mmol) phthalaldehydic acid 1
in presence of p-toluene sulfonic acid (1.90 g, 10 mmol) in
benzene (40 ml). The mixture was heated at reflux under Dean-
stark conditions for 12 hours. The resultant solution was allowed
to cool, and the product that separated out on concentration was
collected by filtration, dried and recrystallized from ethanol.
2-(3-Benzylquinoxalin-2-yl)phthalazin-1(2H)-one (12a).
Using Method A, compound 12a was obtained as pale brown
crystals, 2.84 g (78 %) yield, mp 145-146°C. ir (KBr): 1672
1'H-1,2'-Biphthalazinyl-1'-one (15).
A Solution of the
hydralazine 13 (1.60 g, 10 mmol) in 10 mL dimethylformamide
was refluxed with (1.50 g, 10 mmol) phthalaldehydic acid 1 for
3 hours in presence of 2 drops of acetic acid. The product was
poured into water and the solid collected by filtration, dried and
recrystallized from ethanol. Compound 15 was obtained as white
crystals, 2.30 g (84 %) yield, mp 279-280°C (Lit 279-281°C)
1
[19,23]. ir (KBr): 1661 (C=O) cm-1. H nmr (DMSO-d6): ꢀ 7.87
(d, 1H, ArH, J = 8.4 Hz), 7.95-8.02 (m, 2H, ArH), 8.05-8.10 (m,
3H, ArH), 8.34 (t, 2H, ArH, J = 7.7 Hz), 8.69 (s, 1H, ArH), 9.87
(s, 1H, ArH). 13C nmr: ꢀ 124.07, 126.61, 127.69, 127.88, 128.18,
128.77, 130.35, 133.43, 134.33, 134.74, 135.16, 140.36, 153.49,
155.77, 159.77. Anal. Calcd for C16H10N4O: C, 70.06; H, 3.67;
N, 20.43. Found: C, 69.93; H, 3.44; N, 20.67.
1
(C=O) cm-1. H nmr (DMSO-d6): ꢀ 4.26 (s, 2H, CH2), 6.86 (d,
2H, ArH, J = 6.9 Hz), 6.99 (m, 3H, ArH), 7.90 (m, 2H, ArH),
8.00 (m, 2H, ArH), 8.07 (d, 1H, ArH, J = 8.0 Hz), 8.16 (d, 1H,

May-Jun 2007
Reaction of Phthalaldehydic Acid with Different Substituted Aniline
625
Isoindolo[2',1':1,5][1,2,4]triazolo[3,4-a]phthalazin-7(11bH)-
one (17). The hydralazine 13 (10 mmol), phthalaldehydic
acid 1 (1.50 g, 10 mmol) and p-toluene sulfonic acid (1.90
g, 10 mmol) were dissolved in benzene (40 ml). The mixture
was heated at reflux under Dean-stark conditions for 12
hours. The resultant solution was allowed to cool and the
product that separated out on concentration was collected by
filtration, dried and recrystallized from ethanol. Compound
17 was obtained as colorless needles, 2.52 g (92 %) yield,
mp 198-199°C. ir (KBr): 1778 (C=O) cm-1. 171 (isomer 1,
REFERENCES
[1] Wheeler, D. D.; Young, D. C.; Erley, D. S. J. Chem. Soc.
1957, 22, 547.
[2] Kubota, Y., Tatsuno, T. Chem. Pharm. Bull. 1971, 19,
1226.
[3] Shevchuk, M. I.; Shpak, S. T.; Tolochko, A. F. Zhurnal
Obshchei Khimii 1987, 57, 799.
[4] Mindl, J.; Norek, J.; Klicnar, J.; Vecera, M. Collection of
Czechoslovak Chemical Communications 1976, 41, 251.
[5] Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Z. J. Chem. Soc., Perkin Trans. I 2000, 1715.
1
67%): H nmr: ꢀ 7.04 (s, 1H, CH), 7.69-7.32 (m, 4H, ArH),
7.81-7.84 (m, 1H, ArH), 7.86-7.91 (m, 4H, ArH). 13C nmr: ꢀ
99.89, 124.69, 125.08, 125.45, 125.72, 126.44, 132.10,
135.81, 144.80, 168.30. 172 (isomer 2, 33%): 1H nmr: ꢀ
7.12 (s, 1H, CH), 7.69-7.32 (m, 4H, ArH), 7.81-7.84 (m, 1H,
ArH), 7.86-7.91 (m, 4H, ArH). 13C nmr: ꢀ 102.18, 124.69,
125.08, 125.45, 125.72, 126.40, 132.02, 135.63, 145.19,
168.46. Anal. Calcd for C16H10N4O: C, 70.06; H, 3.67; N,
20.43. Found: C, 69.83; H, 3.59; N, 20.62. The two isomers
171 and 172.were separated using GC/MS: isomer 171,
tR.5.99 min (56.554) %, m/e 274 (M+, 11 %); isomer 172,
tR.6.52 min (43.446 %), m/e 274 (M+, 8 %).
Biology. Inhibition Zone Measurement (IZ): Compounds 3a,
3c, 4b, 5, 6b-d, 8, 9, 11a-c, 12a-c, 14, 15 and 17 were in vitro
evaluated for antimicrobial activity against the following four
test organisms: Escherichia coli (E. coli) ATCC 25922 and
Pseudomonas aeruginosa (P. aeruginosa) as Gram-negative
bacteria, Staphylococcus aureus (S. aureus) ATCC 19433 as
Gram-positive bacteria, and Candida albicans (C. albicans) as
yeast-like fungi. Agar-diffusion method was used for the
determination of antibacterial and antifungal activity [30].
Standard sterilized filter paper discs (5 mm diameter)
impregnated with a solution of test compound in DMF
(1mg/mL) was placed on an agar plate seeded with the
appropriate test organisms in triplicate. The test organisms
Ampicillin trihydrate, ciprofloxacin and clotrimazole were used
as standard antibacterial and antifungal agents, respectively.
Dimethylformamide (DMF) alone showed no inhibition zone.
The plates were incubated at 37°C for 24 h. The results were
recorded for each tested compound as the average diameter of
inhibition zone of bacterial growth around the discs in mm
(Table 1).
[6] Kim, H. S.; Chung, Y. M.; Park, Y. J.; Kim, J. N. Bull.
Korean Chem. Soc. 2000, 21, 371.
[7] (a) Katritzky,A. R.; Xu, Y.-J.; He, H.-Y.; Steel, P. J. J.
Chem. Soc., Perkin Trans. I 2001, 1767. (b) Katritzky, A. R., Xu, Y.-
J.; He, H.-Y.; Mehta, S. J. Org.Chem. 2001 , 66, 5590.
[8] Mertens, A.; Zilch, H.; König, B.; Schäfer, W.; Poll, T.;
Kampe, W.; Seidel, H.; Leser, U.; Leinert, H. J. Med. Chem. 1993,
36, 2526.
[9] (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A.
M. Z. Tetrahedron Lett. 1997, 38, 3627. (b) Allin, S. M.; Northfield,
C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1999, 40, 141.
(c) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1999, 40, 143. (d) Allin, S. M.; Hodkinson, C. C.;
Taj, N. Synlett 1996, 781.
[10] Orzalesi, H.; Chevallet, P.; Berge, G.; Bouchard, H.;
Serrano, J. J.; Privat, G.; Andrary, C. Eur. J. Med. Chem.-Chim.
Ther. 1978, 13, 259.
[11] Pestellini, V.; Ghelardoni, M.; Volterra, G.; Del Soldato,
P. Eur. J. Med. Chem.-Chim. Ther. 1978, 13, 296.
[12] Schwender, C.F.; Sunday, B. R.; Kerbleski, J. J.; Herzig,
D. J. J. Med. Chem. 1980, 23, 964.
[13] Pinza, M.; Riccaboni, A. M. T.; Cerri, A.; Farina, C. EP
335, 483, 1989; Chem. Abstr. 1990, 112, 158246a.
[14] Rang, H. P.; Dale, M. M.; Ritter, J. M. in Pharmacology,
3rd edn., Churchill-Livingstone, London, 1995.
[15] Schäfer, W.; Friebe, W.-G.; Leinert, H.; Mertens, A.; Poll,
T.; von der Saal, W.; Zilch, H.; Nuber, B.; Ziegler, N. L. J. Med.
Chem. 1993, 36, 726.
[16] (a) Los, M. Ger. Offen. 2, 700, 269, 1977; Chem Abstr.
1978, 89, 146905h. (b) Los, M. USP 4, 041, 045, 1977; Chem Abstr.
1977, 87, 168034j.
[17] (a) Ashkar, S. A. USP 4, 090, 860, 1978; Chem Abstr.
1978, 89, 192503y. (b) Ashkar, S. A. USP 4, 067, 718, 1978; Chem
Abstr. 1978, 88, 165485s.
[18] Ashkar, S. A. USP 4, 093, 441, 1978; Chem Abstr. 1979,
90, 49647p.
Minimal Inhibitory Concentration (MIC) measurements: The
MIC measurement was carried out for compounds that showed
significant growth inhibition zones using the twofold serial
dilution technique. The compounds were prepared in
concentration range (400, 200, 100, .12.5 μg/ml). The micro-
dilution susceptibility test in Müller-Hinton Broth (Oxoid) and
Sabouraud Liquid Medium (Oxoid) were used for the
determination of antibacterial and antifungal activity [31,32].
The same test organisms were utilized. Ampicillin, ciprofloxacin
and clotrimazole were used as standard antibacterial and
antifungal agents, respectively. Solutions of the test compounds,
ampicillin trihydrate and clotrimazole were prepared in DMSO
at concentration of 1600 μg/ml. The microorganism suspensions
at 106 CFU/ml (Colony Forming Unit/ml) concentrations were
inoculated to the corresponding wells. Plates were incubated at
37°C for 24 h to 48 h. The incubation chamber was kept
sufficiently humid. At the end of the incubation period, the
minimal inhibitory concentrations (MIC) were determined
(Table 1).
[19] (a) Amer, A.; Zimmer, H. J. Heterocyclic Chem. 1981, 18,
1625. (b) Buu-Hoï, Ng-Ph.; Lin, Che-Kin Compt. Rend. 1939, 209,
221. (c) Shemyakin, M. M. Zhur. Obshchei Khim. 1943, 13, 290.
[20] Racine, S. Ber. 1886, 19, 778.
[21] Young, D. C. Computational Chemistry, John Wiley &
Sons, New York, NY, 2001, pp 37, pp 342.
[22] (a) Rodda, H. J.; Rogasch, P. E. Aus. J. Chem. 1966, 19,
1291. (b) Zimmer, H.; Kokosa, J. M.; Shah, K. J. J. Org. Chem. 1975,
40, 2901.
[23] (a) Castle, R. N.; Takano, S. J. Heterocyclic Chem. 1966,
3, 381. (b) Rodda, H. J.; Rogasch, P. E. Australian J. Chem. 1966,
19, 1291. (c) Morrison, D. C. J. Am. Chem. Soc. 1954, 76, 4483. (d)
Badger, G. M.; McCarthy, I. J.; Rodda, H. J. Chemistry & Industry
(London, United Kingdom) 1954, 964.
[24] Okabe, N.; Fukunda, H.; Nakamura, T. Acta Cryst. 1993,
C49, 1844.
[25] Reece, P. A. Medicinal Research Reviews 1981, 1, 73.
[26] (a) Zimmer, H.; Amer, A.; Baldwin, L.; Pharrmazie
1982, 37, H6. (b) Amer, A.; Zimmer, H. J. Heterocyclic Chem.
1983, 20, 1231. (c) Zimmer, H.; Amer, A. Heterocycles 1987,

626
S. N. Khattab, S. Y. Hassan, A. El-Faham, A. M. M. El Massry and A. Amer
Vol 44
26, 1177. (d) Amer, A.; Weisz, K.; Zimmer, H. Heterocycles
1987, 26, 1853.
[27] Amer, A.; El Massry, A. M.; El Sadany, S.; Zimmer, H. J.
Chem. Research (S) 1988, 298.
[28] Khattab, Sh. N.; El Massry, A. M.; El-Faham, A.; Bekhit, A.
A.; Amer, A. J. Heterocyclic Chem. 2004, 41, 387.
[29] Abdul-Ghani, M.; Khattab, Sh. N.; El Massry, A. M.; El-
Faham, A.; Amer, A. Org. Prep. And Proc. Int. 2004, 36, 121.
[30] Conte, J. E.; Barriere, S. L. Manual of Antibiotics and
Infectious Disease, 1st Ed., Lea and Febiger, USA, 1988, pp 135.
[31] Henderson, B. In; Dale M. M.; Foreman J. C.; Fan T-P. D.
(eds): Textbook of immunopharmacology, 3rd ed. pp 16, 193, Blackwell
Scientific Publications, London 1994.
[32] Murray, P. R.; Baron, E. J.; Pfaller, M. A.; F. C. Tenover;
Yolken, R. H.; Manual of clinical microbiology, in: Woods, G. L.; J. A.
Washington (Eds.), Antimicrobial Agents and Susceptibility Testing,
Am. Soc. Microbiol.,Washington, DC, 1995.
[33] Hucher, N.; Decroix, B.; Daiech, A. J. Org. Chem. 2001, 66, 4695.
[34] Zimmer, H.; Kokosa, J. M.; Shah, K. J. J. Org. Chem. 1975,
40, 2901.