Microwave-assisted synthesis, structural elucidation and biological assessment of 2-(2-acetamidophenyl)-2-oxo-N phenyl acetamide and N-(2-(2-oxo-2(phenylamino)acetyl)phenyl)propionamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2012.01.028

A facile solid-state synthesis of 2-(2-acetamidophenyl)-2-oxo-N phenyl acetamide and N-(2-(2-oxo-2(phenylamino)acetyl)phenyl)propionamide six derivatives has been achieved by microwave promoted condensation of N-acylisatin or N-propionylisatin with various aniline derivatives. The six products were characterized by IR and NMR (H¹ and C¹³). Only two of them, The N-[2-(4-Bromo-phenylaminooxalyl)-phenyl]-propionamide and 2-(2-Acetylamino-phenyl)-2-oxo-N-p-tolyl-acetamide molecular structures were verified by X-ray single-crystal diffraction. The Br?Br intermolecular interaction in the crystal structure of N-[2-(4-Bromo-phenylaminooxalyl)-phenyl] -propionamide was evaluated by DFT/B3LYP calculation. The antimicrobial activity was evaluated against eight bacterial strains and two fungal species. The N-[2-(4-Bromo-phenylaminooxalyl)-phenyl]-propionamide and 2-(2-Acetylamino- phenyl)-2-oxo-N-p-tolyl-acetamide exhibit selective high inhibitory effects against Aspergillus niger and Staphylococcus aureus, respectively.

Full text of DOI:10.1016/j.molstruc.2012.01.028

Journal of Molecular Structure 1013 (2012) 163–167
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Microwave-assisted synthesis, structural elucidation and biological assessment
of 2-(2-acetamidophenyl)-2-oxo-N phenyl acetamide and
N-(2-(2-oxo-2(phenylamino)acetyl)phenyl)propionamide derivatives
Mohamed Ghazzali a, , Ayman El-Faham a,b, Ahmed Abdel-Megeed c,d, Khalid Al-Farhan a,e
⇑
a Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
b Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, 12321 Alexandria, Egypt
c Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
d Faculty of Agriculture, Saba Basha, Alexandria University, Alexandria, Egypt
e Hydrogen Energy Research Group, SET, King Saud University, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile solid-state synthesis of 2-(2-acetamidophenyl)-2-oxo-N phenyl acetamide and N-(2-(2-oxo-
2(phenylamino)acetyl)phenyl)propionamide six derivatives has been achieved by microwave promoted
condensation of N-acylisatin or N-propionylisatin with various aniline derivatives. The six products were
characterized by IR and NMR (H1 and C13). Only two of them, The N-[2-(4-Bromo-phenylaminooxalyl)-
phenyl]-propionamide and 2-(2-Acetylamino-phenyl)-2-oxo-N-p-tolyl-acetamide molecular structures
were verified by X-ray single-crystal diffraction. The Brꢀ ꢀ ꢀBr intermolecular interaction in the crystal
structure of N-[2-(4-Bromo-phenylaminooxalyl)-phenyl]-propionamide was evaluated by DFT/B3LYP cal-
culation. The antimicrobial activity was evaluated against eight bacterial strains and two fungal species.
The N-[2-(4-Bromo-phenylaminooxalyl)-phenyl]-propionamide and 2-(2-Acetylamino-phenyl)-2-oxo-
N-p-tolyl-acetamide exhibit selective high inhibitory effects against Aspergillus niger and Staphylococcus
aureus, respectively.
Received 16 November 2011
Received in revised form 19 January 2012
Accepted 19 January 2012
Available online 31 January 2012
This work is dedicated to the memory of
Prof. Hassan Al-Hazemi, King Saud
University, who recently passed away
Keywords:
Isatins
Microwave assisted synthesis
X-ray crystallography
Halogenꢀ ꢀ ꢀhalogen intermolecular
interactions
Ó 2012 Elsevier B.V. All rights reserved.
Biological activity
1. Introduction
ucts formation [14,15], coupled with shorter reaction times, simple
reaction conditions and enhancements in chemical yields [16,17].
N-isatin derivatives are known to display a broad range of biolog-
ical activities as antibacterial [1–4], antifungal [5], anticonvulsant
[6], anti-HIV [7], anticancer [3,8], antiviral [4] and as enzymatic
inhibitor [3,10–12]. These wide applications of isatin derivatives
are referring to its structure-dependent function [2–11]. From syn-
thetic and biological viewpoints, the reaction of carbonyl group at
the b-position of N-isatin and N-acetylisatin is simulating a reason-
able interest to explore [11,12].
Microwave irradiation (MW) is emerged as a powerful tech-
nique to initiate a variety of chemical reactions [13]. During the
last years, synthesis under microwave dielectric heating is expand-
ing rapidly [14–16]. Some advantages of MW irradiation are the
minimum needs for organic solvents, the low possibility of byprod-
Accordingly, we report here the MW-assisted synthesis, solution
and solid state characterization of six N-2-(2-acetamidophenyl)-2-
oxo-N-phenylacetamide and N-(2-(2-oxo-2(phenylamino)acetyl)
phenyl)propionamide derivatives, in a search for new antifungal
or antibacterial active compounds. The structures of two deriva-
tives, N-[2-(4-Bromo-phenylaminooxalyl)-phenyl]-propionamide
and 2-(2-Acetylamino-phenyl)-2-oxo-N-p-tolyl-acetamide (IIa and
IIb in Scheme 1) were verified by single crystal X-ray diffraction
and found to be in accordance with NMR solution characterizations.
The two derivatives biological assessment was performed against
Gram-negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella
pneumonia, Proteus spp., Salmonella spp. and Gram-positive Bacillus
cereus, Streptococcus pneumonia and Staphylococcus aureus as well
as Aspergillus niger and Aspergillus flavous fungal species. Only S.
aureus and A. niger are showing pronounced sensitivity against
N-[2-(4-Bromo-phenylaminooxalyl)-phenyl]-propionamide and 2-
(2-Acetylamino-phenyl)-2-oxo-N-p-tolyl-acetamide, respectively.
⇑
Corresponding author. Tel.: +966 14673734; fax: +966 14675992.
E-mail address: mghazzali@ksu.edu.sa (M. Ghazzali).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2012.01.028

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M. Ghazzali et al. / Journal of Molecular Structure 1013 (2012) 163–167
10), 162.13 and 169.47(CO–NH), 190.63(CO). Elemental Anal. Calcd.
for C17H16N2O3 (296.32): C, 68.91; H, 5.44; N, 9.45. Found: C, 69.07;
H, 5.56; N, 9.62.
2.1.5. 2-(2-Acetamidophenyl)-N-(4-bromophenyl)-2-oxoacetamide
(IIc)
M.p. 180 °C; Yield 90% (95% method B); IR (KBr, cmꢁ1): 3285,
3250(NH), 1698(CO), 1677, 1606(CO, amide); 1H NMR d: 199(3H, s),
7.27(1H, m), 7.56(2H, d, J = 8.8 Hz), 7.76(2H, d, J = 8.8 Hz), 7.61–
7.63(3H, m), 10.52, 10.82(each NH); 13C NMR d: 24.15, 122.39,
124.43, 125.20(s), 131.54, 134.20, 139.11(s), 117.05(C-40), 124.57(C-
20,60), 132.22(C-30,50), 137.96(C-10), 162.06 and 169.47(CO–NH),
189.63(CO). Elemental Anal. Calcd. for C16H13BrN2O3(361): C, 53.21;
H, 3.63; N, 7.76. Found: C, 53. 03; H, 3.71; N, 7.94.
Scheme 1. Reaction of N-acetylisatin and N-propionylisatin with substituted
aniline.
2.1.6. N-(2-(2-oxo-2-(p-tolylamino)acetyl)phenyl)propionamide (IId)
M.p. 147 °C; Yield 95% (97% method B); IR (KBr, cmꢁ1): 3302,
3262(NH), 1701(CO), 1674, 1606(CO, amide); 1H NMR d: 1.08(3H,
t, J = 7.2 Hz), 2.26(2H, q, J = 7.2 Hz), 3.71(3H, s), 7.21(1H, t,
J = 7.5 Hz), 7.48(1H, t, 7.5 Hz), 7.80–7.83(2H, m), 6.75(2H, d,
J = 8.8 Hz, H-3,5), 7.51(2H, d, J = 8.8 Hz), 10.50, 10.62(each NH);
13C NMR d: 10.20, 25.82, 55.88, 121.89, 124.60, 127.92(s), 129.80,
134.64, 142.86(s), 114.10(C-30,50), 121.25(C-20,60), 130.50(C-10),
159.35(C-40), 158.12 and 171.52(CO–NH), 187.68(CO). Elemental
Anal. Calcd. for C18H18N2O3 (310): C, 69.66; H, 5.85; N, 9.03. Found:
C, 69.43; H, 5.90; N, 9.22.
2. Experimental
Chemicals were used as supplied from Sigma–Aldrich without
further treatments. IR spectra were recorded from KBr discs using
Shimadzu FT-1000 spectrophotometer. 1H and 13C NMR spectra
were recorded by JEOL ECP-400 NMR spectrometer operating at
400 MHz in DMSO-d6 with TMS as internal standard. The reactions
and the purity of the products were monitored by TLC silica gel
plates and spots were visualized by UV lamp (UVItec.UK). Elemen-
tal analyses were measured on Perkin-Elmer 2400 Series II CHNS/O
analyzer.
2.1.7. 2-(2-Acetamidophenyl)-2-oxo-N-(3,4,5-
trimethoxyphenyl)acetamide (IIe)
2.1. General procedure for synthesis of (IIa–f)
M.p. 160 °C; Yield 86% (92% method B); IR (KBr, cmꢁ1): 3278,
3190(NH), 1702(CO), 1665, 1605(CO, amide); 1H NMR d: 2.02(3H,
s), 3.64(3H, s), 3.75(2ꢂ 3H, s), 7.27(1H, t, J = 8.08 Hz), 7.60–
7.68(3H, m), 7.11(2H, s), 10.54, 10.56(each NH); 13C NMR d: 24.26,
56.32(2C), 60.69(OCH3), 92.02, 98.39, 122.29, 124.31, 131.62,
134.19, 134.60, 134.71, 138.22, 153.29, 161.74 and 169.42(CO–
NH), 189.98(CO). Elemental Anal. Calcd. for C19H20N2O6 (372): C,
61.28; H, 5.41; N, 7.52. Found: C, 61.47; H, 5.66; N, 7.75.
2.1.1. Method A (conventional method)
A mixture of N-acetylisatin (10 mmol) and aniline derivatives
(10 mmol) in ethanol (20 ml) was refluxed for 5–6 h. The reaction
mixture was left to cool at room temperature and the solid product
was filtered and recrystallized from ethanol.
2.1.2. Method B (microwave irradiation)
Employing a multimode reactor (Synthos 3000, Aton Paar GmbH,
1400 W maximum magnetron), the initial step was conducted with
4-Teflon vessels rotor (MF 100). N-acetylisatin (10 mmol) and ani-
line derivatives (10 mmol) in ethanol (10 mL) were mixed and the
reactions were processed by heating the vessels for 5 min. at
100 °C and hold at the same temperature for 5 min (0.2/s bar pres-
sure, 800 W). Cooling was accomplished by a fan (5 min) and the de-
sired product with enhanced yield was filtered and recrystallized
from ethanol.
2.1.8. N-(2-(2-oxo-2-(3,4,5-
trimethoxyphenylamino)acetyl)phenyl)propionamide (IIf)
M.p. 135–136 °C; Yield 83% (94% method B); 3320, 3199(NH),
1689(CO), 1671, 1603(CO, amide); 1H NMR d: 1.09(3H, t, J = 7.3 Hz),
2.26(2H, q, J = 7.3 Hz), 3.68(3H, s), 3.73(2ꢂ 3H, s), 7.16(1H, t,
J = 8.07 Hz), 7.51(1H, t, J = 8.07 Hz), 7.78–7.81(2H, m), 6.85(2H, s),
10.54, 10.58(each NH); 13C NMR d: 10.12, 24.80, 56.10(2C),
57.23(OCH3), 99.10(2C), 98.39, 120.90, 124.62, 128.58, 129.90,
134.50, 142.02, 132.50, 141.00, 148.84(2C), 158.5 and 172.70(CO–
NH), 187.34(CO). Elemental Anal. Calcd. for C20H22N2O6 (386): C,
62.17; H, 5.74; N, 7.25. Found: C, 62.34; H, 5.90; N, 7.51.
2.1.3. N-(2-(2-(4-bromophenylamino)-2-
oxoacetyl)phenyl)propionamide (IIa)
M.p. 128–130 °C; Yield 91% (96% method B); IR (KBr, cmꢁ1): 3310,
3274(NH), 1701(CO), 1662(CO, amide); 1H NMR d: 0.99(3H, t,
J = 7.3 Hz), 2.26(2H, q, J = 7.3 Hz), 7.28(1H, t, J = 7.4 Hz), 7.55(2H, d,
J = 8.8 Hz), 7.76(2H, d, J = 8.8 Hz), 7.56–7.68(3H, m), 10.52, 10.83(each
NH); 13C NMR d: 10.12, 27.40, 121.08, 124.60, 128.61(s), 129.68,
134.50, 143.50(s), 118.80(C-40), 121.61(C-20,60), 132.22(C-30,50),
138.40(C-10), 159.10 and 171.95(CO–NH), 186.88(CO). Elemental Anal.
Calcd. for C17H15BrN2O3 (375): C, 54.42; H, 4.03; N, 7.47. Found: C,
54.26; H, 4.13; N, 7.64.
2.2. Crystal structure determinations
Suitable single crystal colorless plate of compound IIa and yel-
low prism of compound IIb (Scheme 1) were selected under an
optical microscope, glued and mounted onto thin glass capillary.
Diffraction data were collected on Rigaku R-axis RAPID diffrac-
tometer utilizing an imaging plate area detector by MoK
tion (k = 0.71075 Å) with graphite monochromator. Three swaps
of oscillation images were collected using -scans at a tempera-
a radia-
x
2.1.4. 2-(2-Acetamidophenyl)-2-oxo-N-p-tolylacetamide (IIb)
ture of 294 2 K to a maximum 2h of 55.0°. In both IIa and IIb,
preliminary orientation matrices, unit cell determinations and
data reductions were performed using CrystalClear package
[18]. The intensity data were corrected for absorption and extinc-
tion, for Lorentz and polarization effects. Both structures were
solved by direct methods and refined by full-matrix least squares
on all |F2| data using SHELX package [19]. Aromatic hydrogen
M.p. 163 °C; Yield 96% (97% method B); IR (KBr, cmꢁ1):
3276(NH), 1688(CO), 1662, 1602(CO, amide); 1H NMR d: 2.01 and
2.28(each 3H, s), 7.16(2H, d, J = 8.8 Hz), 7.27(2H, d, J = 8.08 Hz),
7.58–7.69(4H, m), 7.73(1H, d, J = 8.0 Hz), 10.56, 10.63(each NH);
13C NMR d: 24.32, 122.34, 124.34, 127.00(s), 131.85, 134.45,
139.62(s), 120.59(C-20,60), 129.77(C-30,50), 133.75(C-40), 135.96(C-

M. Ghazzali et al. / Journal of Molecular Structure 1013 (2012) 163–167
165
atoms were isotropically refined and constrained to ideal geome-
try using their appropriate riding model approximation and all
non-hydrogen atoms were anisotropically refined. The two amide
hydrogen atoms (H1A and H2A in IIa and IIb) involved in hydro-
gen bonding were located from difference map and refined
isotropically without geometrical restraints. Figs. 1 and 2 were
created using the Diamond package [20]. Crystal data and refine-
ment details of IIa: Empirical formula: C17H15BrN2O3, Formula
weight: 375.22, Crystal system: Monoclinic, space group: P21/a,
Unit cell dimensions: a = 10.0798(12) Å, b = 10.2097(14) Å,
c = 15.694(2) Å, b = 100.602(4)°, V = 1587.5(4) Å3, Z = 4, Calcu-
lated density: 1.570 mg/m3, Crystal size: 0.40 ꢂ 0.20 ꢂ 0.20 mm,
h-range for data collection: 3.3–27.50°, Reflections collected
/unique: 24,478/3624, Rint: 0.095, Completeness to h = 25.00°:
99.9%, Dataset: ꢁ13:12; ꢁ13:13; ꢁ20:20, Data/restraints/
parameters: 3624/0/217, Goodness-of-fit on F2: 1.101,
R[F2 > 2 (F2)] = 0.052, wR(F2) = 0.092, Largest diff. hole/peak:
r
ꢁ0.49, 0.44 e Aꢁ3
. Crystal data and refinement details IIb:
Empirical formula: C17H16N2O3, Formula weight: 296.32, Crystal
system: Monoclinic, space group: P21/a, Unit cell dimensions:
a = 9.9281(6) Å, b = 9.6769(5) Å, c = 15.9745(10) Å, b = 100.8
51(2)°, V: 1507.28(15) Å3, Z: 4, Calculated density: 1.306 mg/
m3, Crystal size: 0.4 ꢂ 0.1 ꢂ 0.1 mm, h-range for data collection:
Fig. 2. Presentation of the structure in IIa and IIb in the b-direction, showing the
one-dimensional ladder-like hydrogen bonding network generated by the inter-
molecular N–Hꢀ ꢀ ꢀO interactions. The N–Hꢀ ꢀ ꢀO hydrogen bonds are represented as
dashed lines and only hydrogen atoms involved in the bonding are shown.
3.10–27.50°, Reflections collected/unique: 35,087/3449, Rint
:
0.088, Completeness to h = 25.00°: 99.9%, Dataset: ꢁ12:12;
ꢁ12:12; ꢁ20:20, Data/restraints/parameters: 3449/0/208, Good-
ness-of-fit on F2: 1.00, R[F2 > 2 (F2)] = 0.076, wR(F2) = 0.205, larg-
r
purified. The used solutions of IIa and IIb compounds were pre-
pared in DMSO (0.1 mg/0.5 ml).
est diff. hole/peak: ꢁ0.38/0.25 e Aꢁ3
.
The CIF files were deposited at the Cambridge Crystallographic
Data Centre, CCDC and deposition numbers are 826008 and
826009; these are freely available upon request from the following
web site: www.ccdc.cam.ac.uk/data_request/cif.
2.5. Antibacterial activity
The inhibitory effect of IIa and IIb compounds (Scheme 1) was
tested by the disc diffusion method [22]. S. aureus, E. coli and
P. aeruginosa were pre-cultured in a nutrient broth overnight using
rotary shaker at 37 °C before being centrifuged at 10,000 rpm for
5 min. The tested microorganisms were seeded into respective
medium by the spread plate method. A 5 mm diameter disc was
saturated with IIa or IIb solutions before being placed on organ-
ism-seeded plates. Plates were incubated at 37 °C for 4 h. The
diameters of the inhibition zones were measured in mm.
2.3. Theoretical calculations
Single-point quantum calculations for IIa was made with the ab
initio DFT module in Spartan 08-version 1.2.0 [21], using the B3LYP
exchange and correlation functional as a perturbation on self con-
sistent density with the 6-31G⁄ basis set. The calculation has been
carried out with a high accuracy large integration grid, so that sen-
sitivity is minimized. The starting z-matrix was imported from the
single crystal structure coordinates and used without geometrical
constraints.
2.6. Antifungal activity
The fungal species A. niger-ATCC 9763 and A. flavous-ATCC 7096
were maintained and subcultured on Czapek’s Dox agar medium
and incubated at 25 °C for 4 days. The agar medium was prepared
using 30.0 g of sucrose, 3.0 g of NaNO3, 0.5 g of MgSO4, 0.1 g of KCl,
0.01 g of FeSO4, 1.0 g of K2HPO4 and 13.0 g agar in 1.0 L of distilled
water using a shaker for 30 min. The medium pH was adjusted to
2.4. Biological assessment
Gram negative E. coli, P. aeruginosa, K. pneumonia, Proteus spp.,
Salmonella spp. and Gram positive B. cereus, S. pneumonia, S. aureus
as well as A. niger and A. flavous fungal species were isolated and
Fig. 1. Perspective drawing of IIa (left) and IIb (right) showing the atom-numbering scheme. The atomic displacement ellipsoids are shown at the 50% probability level.
Hydrogen atoms are drawn as spheres of arbitrary radius.

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M. Ghazzali et al. / Journal of Molecular Structure 1013 (2012) 163–167
7.3. The medium was autoclaved at 121 °C for 15 min. The fungal
growth was harvested, washed with normal saline, suspended in
100 mL of normal saline and the suspension was stored in refriger-
ator till used, then was poured in Petri dishes. The plates were
incubated at room temperature for 7 days. The results are ex-
pressed in mm of colony diameter. Two discs of filter paper
(0.5 mm) were saturated with IIa and IIb DMSO solutions, and then
placed on the inoculated agar with fungal suspension. Control
plates without IIa or IIb compounds were assessed. The antifungal
assay plates were incubated at 37 °C for 240 min.
bond distances and angles are within normal ranges, See Table 1.
A presentation of hydrogen bonding intermolecular interactions
in IIa and IIb is shown in Fig. 2.
In the crystal structure of IIa and IIb, the overall conformation
of the molecule is twisted, where in IIb the dihedral angle between
the least-squares plane of phenyl ring (C1 to C6) and the least-
squares plane of the six atoms group (C9 to C14) is 69.506(8)°. In
IIa, the same previously defined dihedral angle is 45.349(9)°. This
molecular twisting is exemplified in the O1–C7–C8–O2 torsion an-
gle to be of ꢁ158.465(3)° in IIa and of 154.443(3)° in IIb.
In both IIa and IIb, the molecular packing is supported with N–
H–O hydrogen bonding extended in the a-crystallographic direc-
tion with C(3) first-level chain motif and R22ð14Þ second-level ring
motif as earlier defined [28], featuring a one-dimensional ladder-
like network along a-crystallographic axis. See Fig. 2, for hydrogen
bonding geometries and symmetry operators, see Table 1. Graph-
Set analyses and hydrogen bonding network assignments were
performed with the aid of RPluto software [29].
In IIa, halogens C–Brꢀ ꢀ ꢀBr–C Type-I intermolecular interaction is
observed, with distance of 3.5532(8) Å, that is less than sum of bro-
mine atom van der Waals radii (2rvdW = 3.70 Å) [30] and with the
two angles (C–Brꢀ ꢀ ꢀBr and Brꢀ ꢀ ꢀBr–C) are the same and equal to
159.32(9)°. It is known that the different interaction modes be-
tween two bromines have been shown to arise either from the
anisotropy of the electrostatic potential around the Br atom or
from geometrical constraints [31–33].
In order to verify the type of interaction presents in IIa, we car-
ried out single-point DFT calculations. The resulting electrostatic
potential is shown in Fig. 3 and is relevant to recent results [34].
The highest positive electronic density or the highest delocaliza-
tion parameter is defined around the slightly acidic-nature amide
hydrogen atoms, which are pointing away from the electrostatic
density potentials space volume. Also, the highest negative elec-
tronic density is localized at the oxygen atoms, with indication
for their roles as hydrogen bond acceptors. In addition, the electro-
static density potentials space volume around the bromine atom is
adopting a donut-like pattern with two peripheral regions of posi-
tive polarization. Since the localized potential energy value for the
bromine atoms is comparable to that of oxygen, It should be noted
that this electrostatic model not only verify the type-I intermolec-
ular halogens interactions, but also indicates its part in the total
packing energy.
3. Results and discussion
Isatins derivatives can undergo nucleophilic attack at positions
C2 and/or C3. The chemical selectivity of these reactions depends
on the nature of the nucleophiles and the substituents attached
to the isatin molecule, especially those bounded to the nitrogen
atom [23]. Previous work demonstrated that N-acylisatins can
undergo reactions with primary amines and alcohols giving
heterocyclic ring-opened molecules [24,25].
The 2- and 3-sited carbonyl groups in N-isatin have different char-
acteristics, in which the carbonyl at C3 has a strong ketonic nature,
while that at C2 is typically an amide. In this work we reacted the com-
pounds N-acetylisatin and N-propionylisatin with substituted anilines
to afford several N-2-(2-acetamidophenyl)-2-oxo-N-phenyl acetamide
and N-(2-(2-oxo-2(phenylamino)acetyl)phenyl)propionamide deriva-
tives, using both conventional method and microwave irradiation.
The starting material, N-isatin is refluxed or microwave irradi-
ated with acetic anhydride or propionic anhydride to afford the
N-acetylisatin or N-propionylisatin respectively, following a known
procedure [26]. The reflux of N-acetylisatin or N-propionylisatin (Ia
and Ib, Scheme 1) with appropriate aniline in ethanol for 6 h yields
the corresponding amide (IIa–f, Scheme 1). These amides are
obtained through the reaction of basic nitrogen on the C2 amidic
carbonyl, not on the ketonic carbonyl C3 position [27] (Scheme
1) as observed from the NMR spectra and X-ray crystallography.
Both conventional and microwave irradiation preparations exhibit
excellent yields, but MW show higher purity for shorter time reac-
tion. The NMR and elemental analysis for the prepared compounds
(IIa–f) were consistent with the ring-opened hypothesis. The
structures of IIa and IIb were also studied by single crystal X-ray
crystallography.
The biological assessment explored by the disc method in the
present work reveals that compounds IIa and IIb exhibit potential
antibacterial activity against S. aureus, and antifungal activity
against A. niger, respectively and among all tested organisms (Figs.
4 and 5). Compound IIb exhibited an activity against S. aureus after
Selected bond distances and bond angles are given in Table 1.
The thermal ellipsoidal drawings for IIa and IIb with their atomic
numbering schemes are shown in Fig. 1. IIa and IIb are both crys-
tallized in the monoclinic P21/a space groups with interatomic
Table 1
Selected bond distances (Å) and angles (°) as well as hydrogen bonding geometries for IIa (left) and IIb (right).
O1–C7
O2–C8
O3–C15
N2–C14
N2–C15
N1–C6
N1–C7
Br1–C3
C6–N1–C7
C14–N2–C15
O1–C7–N1
O2–C8–C7
1.224(4) Å
1.215(4) Å
1.232(4) Å
1.411(4) Å
1.355(4) Å
1.415(4) Å
1.340(4) Å
1.898(3) Å
126.8(3)°
127.3(3)°
125.2(3)°
119.6(3)°
O1–C7
O2–C8
O3–C15
N2–C14
N2–C15
N1–C6
N1–C7
C17–C3
C6–N1–C7
C14–N1–C15
O1–C7–N2
O2–C8–C7
1.224(4) Å
1.212(4) Å
1.230(4) Å
1.422(4) Å
1.350(4) Å
1.422(4) Å
1.335(4) Å
1.513(5) Å
126.9(2)°
126.4(2)°
119.0(3)°
120.3(3)°
D–Hꢀ ꢀ ꢀA
d(Hꢀ ꢀ ꢀA)
2.05
2.11
d(Dꢀ ꢀ ꢀA)
2.891(3)
2.968(3)
<(DHA)
D–Hꢀ ꢀ ꢀA
d(Hꢀ ꢀ ꢀA)
2.14
2.20
d(Dꢀ ꢀ ꢀA)
2.903(4)
3.003(4)
<(DHA)
N1–H1Aꢀ ꢀ ꢀO1i
157
174
N1–H1Aꢀ ꢀ ꢀO1i
164
167
N2–H2Aꢀ ꢀ ꢀO3ii
N2–H2Aꢀ ꢀ ꢀO3ii
(i) ꢁ1/2 + x, 3/2 ꢁ y, z (ii) 1/2 + x, 3/2 ꢁ y, z
(i) 1/2 + x, 1/2 ꢁ y, z (ii) ꢁ1/2 + x, 3/2 ꢁ y, z

M. Ghazzali et al. / Journal of Molecular Structure 1013 (2012) 163–167
167
observations, the tested S. aureus and A. niger are totally deformed
and the surfaces of the bacterial cells are ruptured.
4. Concluding remarks
Microwave assisted organic synthesis is an evergreen technique
for chemical synthesis. The biological investigation indicates that
the antibacterial and antifungal activities of the synthesized com-
pounds are varying against the pathogen used.
Acknowledgements
Fig. 3. Isosurfaces of electronic density (solid in green–blue) and isoelectrostatic
potentials (mesh in gray) for IIa calculated by DFT. The bromine atom is pointing
downwards. Mesh isosurfaces are in the range +10 eV to ꢁ10 eV. Scales for
electronic density are given in kJ/mol. (For interpretation of the references to color
in this figure legend, the reader is referred to the web version of this article.)
The authors are indebted to the Deanship of Scientific research,
College of Science Research center at KSU. Mohamed Ghazzali is
gratefully acknowledging the National Plan for Science and Tech-
nology (NPST Grant 09-ENE909-02) for funding his research.
References
[1] C. Giselle, A. Ferreira, J. Braz. Chem. Soc. 17 (2006) 1.
[2] P.N. Solis, C.W. Wright, M.M. Anderson, M.P. Gupta, J.D. Phillipson, Planta Med.
59 (2007) 250.
[3] S.N. Pandeya, S. Smitha, M. Jyoti, S.K. Sridhar, Acta Pharmaceut. 55 (2005) 27.
[4] V.K. Sharma, S. Srivastava, A. Srivastava, Polish J. Chem. 80 (2006) 387.
[5] R.M. Abdel Rahman, Z. El Gendy, M.B. Mahmoud, Ind. J. Chem. B. 29 (1990) 352.
[6] S.N. Pandeya, A.S. Raja, J.P. Stables, J. Pharm. Pharmaceut. Sci 5 (2002) 266.
[7] T.R. Bal, B. Anand, P. Yogeeswari, D. Sriram, Bioorg. Med. Chem. Lett. 15 (2005)
4451.
[8] G. Pelosi, C. Pelizzi, M.B. Ferrari, M.C. Rodrıguez-Arguelles, C. Vieito, J.
Sanmartin, Acta Crystallogr. C 61 (2005) 589.
[9] D. Sriram, T.R. Bal, P. Yogeeswari, J. Pharm. Pharmaceut. Sci. 8 (2005) 565.
[10] K.C. Joshi, P. Chand, A. Dandia, Ind. J. Chem. B23 (23) (1984) 743.
[11] M.M. Hossain, R.M. Islam, S.K. Saha, M.K. Islam, Tetrahedron Lett. 51 (2010)
1155.
[12] B.S. Joshi, M.A. Likhate, N. Viswanathan, Ind. J. Chem. B23 (1984) 114.
[13] P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57 (2001) 9225.
[14] M.M. Hossain, Y. Kawamura, K. Yamashita, M. Tsukayama, Tetrahedron 62
(2006) 8625.
Fig. 4. Inhibition zones of the compound IIa (left) and IIb (right) against
Staphylococcus aureus.
[15] M. Kidwai, Pure Appl. Chem. 73 (1) (2001) 147.
[16] P.T. Anastas, J.C. Warner, Green Chemistry: Theory and Practice, Oxford
Science Publications, New York, 1998.
[17] P.T. Anastas, T. Williamson, Green Chemistry: Frontiers in Benign Chemical
Synthesis and Processes, Oxford Science Publications, New York, 1998.
[18] Rigaku and Rigaku Americas, 9009 New Trails Dr. The Woodlands TX 77381
USA, 2000–2007.
[19] G.M. Sheldrick, Acta Crystallogr. A 64 (2008) 112.
[20] Diamond, Version 3.1e, Crystal Impact GbR. Bonn, Germany, 2007.
[21] Spartan, Wavefunction, Ver. 1.2.0, 18401 Von Karman Avenue, Suite Irvine, CA
92612, USA, 2009.
[22] P.R. Murray, E.J. Baron, J.H. Jorgensen, M.L. Landry, M.A. Pfaller, Manual of
Clinical Microbiology, ninth ed., ASM Press, Washington, DC, 2007.
[23] J.F.M. Silva, S.J. Garden, A.C. Pinto, J. Braz. Chem. Soc. 12 (2001) 273.
[24] J.H. Clark, Chem. Rev. 80 (1980) 429.
[25] N. Boechat, A.C. Pinto, US Pat. 6034266 (2000) CA132:194195.
[26] I. Fryšová, J. Slouka, T. Gucky´, ARKIVOC, xv (2005) 30.
[27] N. Boechat, W.B. Kover, M.M. Bastos, A.C. Pinto, L.C. Maciel, L.M.U. Mayer, F.S.Q.
Silva, P.M. Sá, J.S. Mendonça, S.M.S.V. Wardell, M.S.L. Arruda, J. Braz. Chem. Soc.
19 (2008) 445.
Fig. 5. Inhibition ZONES of the compounds IIa (up) and IIb (down) against
Aspergillus niger.
[28] J. Bernstein, R.E. Davis, L. Shimoni, N.L. Chang, Angew. Chem. Int. Ed. Engl. 34
(1995) 1555.
[29] W.D.S. Motherwell, G.P. Shields, F.H. Allen, Acta Crystallogr. B 55 (1999) 1044.
[30] A. Bondi, J. Phys. Chem. 68 (1964) 441.
[31] F. Zordan, L. Brammer, P. Sherwood, J. Am. Chem. Soc. 127 (2005) 5979.
[32] C.M. Reddy, M.T. Kirchner, R.C. Gundakaram, K.A. Padmanabhan, G.R. Desiraju,
Chem. Eur. J. 12 (2006) 2222.
[33] M. Ghazzali, V. Langer, C. Lopes, A. Eriksson, L. Ohrstrom, New J. Chem. 31
(2007) 1777.
12 h (10 mm). As antifungal active compounds, IIa and IIb showed
clear inhibition zone estimated by 8.5 mm after 12 h. The control
samples exhibit no activity. There were no pronounced activity
against gram negative E. coli, P. aeruginosa, K. pneumonia, Proteus
spp., Salmonella spp., and gram positive B. cereus and S. pneumonia
and A. flavous. For compound IIb, the results obtained from the disc
method revealed high potential antibacterial activity against
S. aureus and antifungal activity against A. niger. In general SEM
[34] G.A. van Albada, M. Ghazzali, K. Al-Farhan, J. Reedijk, Chem. Comm. 14 (2011)
1149.