Arch. Pharm. Pharm. Med. Chem. 2004, 337, 556−562
Antimicrobial Activity of Substituted Benzamides 561
4,5-Dichloro-N-isopropylbenzene-1,2-diamine (3)
agents. From this point of view, there is an urgent
need to discover novel antibacterial agents in different
classes from existing agents. In addition, it has been
observed that 2-ethylaminoethyl substitution on the N-
carboxamide should be the optimum group in this
series of compounds.
1 (1.25 g, 5 mmol) dissolved in EtOH (50 mL) was added to
10 % Pd/C (50 mg), and the solution was hydrogenated at
room temperature at 35 psi. The reaction was stopped after
cessation of H2 uptake. The catalyst was filtered through a
bed of Celite, washed with EtOH and concentrated to provide
a brown-colored semi-solid oily product that was used im-
mediately for the further steps without crystallization. 1H-NMR
(CDCl3) δ: 1.22 (d, 6H, J = 6.4 Hz), 3.28 (br.s, 3H), 3.51 (m,
1H, J = 6.1 Hz), 6.64 (s, 1H), 6.74 (s, 1H); MS (ESI) m/z (rel.
intensity): 219 (M+H, 100), C9H12Cl2N2.
In conclusion, we have discovered a novel series of
benzimidazole antibacterial agents. These compounds
are active against a variety of susceptible, as well as
resistant, gram-positive organisms. Some modifi-
cations to improve the potency of this series by diversi-
fication of the position and type of amides are currently
under investigation and will be reported in the future.
4,5-Dichloro-N-(p-chlorobenzyl)benzene-1,2-diamine (4)
The mixture of 2 (1 g, 3 mmol) in 15 mL HCl (25 %) and 10
mL EtOH was stirred vigorously, and to this mixture, zinc dust
(3.5 g) was added in several portions at room temperature.
After the addition of zinc dust was completed, the mixture
was heated in a water bath for 1 h. The reaction mixture was
cooled and made alkaline with 10% NaOH solution and was
then extracted with EtOAc. The extract was washed with
water, dried over anhydrous Na2SO4 and evaporated. The
residue was purified by column chromatography by using
(EtOAc/n-hexane 1:3). mp 100Ϫ103°C, light green in color,
yield 69%, 0.63 g; 1H-NMR (CDCl3) δ: 3.35 (br.s, 2H), 3.71
(br.s, 1H), 4.24 (s, 2H), 6.62 (s, 1H), 6.79 (s, 1H), 7.30 (m,
4H); MS (ESI) m/z (rel. intensity): 301 (M+H, 100),
Acknowledgment
This work was supported by Ankara University Re-
search Fund (Project No: 0000018-2003). The Central
Laboratory of Pharmacy Faculty of Ankara University
provided support for the acquisition of the NMR and
Mass spectrometer used in this work.
C13H11Cl3N2.
Experimental
Synthesis of 5Ϫ7
Melting points were measured with a capillary melting point
apparatus (Buchi SMP 20 and Electrothermal 9100) and are
uncorrected. The IR spectra were recorded on a Jasco FT/
IR-420 spectrometer as KBr pellets. 8Ϫ20: 1610Ϫ1638 cmϪ1
(C=O amide). The 1H-NMR spectra were recorded with
VARIAN Mercury 400 FT-NMR spectrophotometers, δ scale
(ppm) from TMS. LC/MS analyses were performed with
Waters Alliance and Micromass ZQ (ESI +) by using MeOH
and a C-18 column (15 cm) with a flow rate of 0.5Ϫ0.6 mL/
min. The LC apparatus was equipped with a diode array UV
detection system monitoring at 254 nm. Elemental analyses
were taken on a Leco 932 CHNS-O analyzer (TUBITAK In-
strumental Analyze Lab., Ankara, Turkey). For the HCl salt of
compound 9, the oily free base was dissolved in isopropanol,
and dry HCl gas was passed through the solution.
4-Carboxybenzaldehyde (15 mmol) was dissolved in 50 mL
EtOH. Sodium bisulfite (1.6 g) in water (10 mL) was added
to a cooled solution in portions, stirred vigorously and, after
addition of EtOH, cooled. The precipitate was filtered off and
dried. Yield 90%. The mixture of this salt (2 mmol) and the
appropriate 1,2-phenylenediamines (4,5-dichloro-1,2-phen-
ylenediamine and compounds 3 and 4, 2 mmol) in DMF (2Ϫ3
mL) were heated at 120°C for 4 h. The reaction mixture was
cooled, poured into the water, and solid was crystallized from
EtOH. The purification procedure and some spectral findings
of 5Ϫ7 are given in Table 3.
Synthesis of 8Ϫ20
Related benzoic acids 5؊7 (0.25 g) were refluxed in benzene
(5 ml) with SOCl2 (5 mL) for 2 h at 80°C. Then, solvent and
excess of SOCl2 were evaporated completely, and the resi-
due was dissolved in chloroform (15 mL). An excess of corre-
sponding amine derivatives (1 mL) was added, and the mix-
ture was stirred and heated for 30 min at 50°C and, after
chloroform was added, washed with Na2CO3 (5 %), then
water, and purified by column chromatography. Some
physicochemical properties, spectral findings, purification
procedure and elemental analysis results of compounds
8؊20 are given in Table 1 and Table 2.
(4,5-Dichloro-2-nitrophenyl)isopropylamine (1) [10]
To a solution of 1,2,4-trichloro-5-nitrobenzene (12.22 mmol,
2.75 g) in EtOH (3 mL), isopropylamine (8 mL) was added
and heated for 8 h at 80°C. The hot reaction mixture was
allowed to crystallize from EtOH: yield 56 %, 1.7 g, mp
100°C, orange in color; 1H-NMR (CDCl3) δ: 1.34 (d, 6H, J =
6 Hz), 3.77 (m, 1H, J = 6.1 Hz), 6.96 (s, 1H), 7.9 (br.s, 1H),
8.25 (s, 1H), C9H10Cl2N2O2.
(4-Chlorobenzyl)-(4,5-dichloro-2-nitrophenyl)amine (2)
References
To a solution of 1,2,4-trichloro-5-nitrobenzene (22.2 mmol, 5
g) in DMF (3 mL), p-chlorobenzyl-amine (8 mL) was added
and heated for 1 h at 80°C. The hot reaction mixture was
allowed to crystallize from EtOH. Second-time crystallization
of the crude product from n-hexane gave pure 2: yield 77%,
[1] S. J. Projan, P. J. Youngman, Curr. Opin. Microbiol.
2002, 5, 463Ϫ465.
[2] H. Göker, E. Tebrizli, U. Abbasoglu, Farmaco, 1996,
51, 53Ϫ58.
1
5.63 g, mp 115Ϫ116 °C, yellow in color; H-NMR (DMSO-d6)
δ: 4.66 (d, 2H, J = 5.6 Hz), 7.15 (s, 1H), 7.40 (4H), 8.27 (s,
[3] H. Göker, M. Tuncbilek, S. Süzen, C. Kus, N. Altanlar,
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 148Ϫ152.
1H), 8.8 (t, 1H), C13H9Cl3N2O2.
2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Oezden, Seckin
