5292 Li et al.
Asian J. Chem.
research workers identified the antimicrobial potential of
benzophenone nucleus and much research has been focused
on the synthesis of its various derivatives for antibacterial and
was poured onto ice water (100 mL) and extracted with EtOAc
(3 × 50 mL). The organic extracts were combined, washed
with ice water, dried over Na2SO4 and evaporated in vacuo to
dryness. Residue was recrystallised from EtOH to get products
(5a-f).
antifungal activities20,21
.
The combination of two pharmacophores in a single mole-
cule may enable synergistic interaction, where the efficacy of
a single agent is enhances by the addition of a second com-
pound. In view of these observations, it was decided to synthe-
size aminobenzophenone linked 1,4-dihydropyridines deriva-
tives by incorporating aminobenzophenone pharmacophore
on 1,4-dihydropyridines scaffold (Fig 3.) and screen them for
their level of antimicrobial activity in the hope to obtained
potent antibacterial agents.
Method B:A mixture of substituted 1,4-dihydropyridines
(2 mmol) and anhydrous potassium carbonate (0.7 g, 5 mmol)
in ethyl methyl ketone (50 mL) was refluxed for 2 h with
stirring. To this, 2-(chloroacetamido)-5-chlorobenzophenone
(1.23 g, 4 mmol) was added and the reaction mixture was
refluxed for another 6 h. The resulting slurry was filtered off
and the solvent was recovered under reduced pressure to obtain
oily residues which was recrystallized from ethanol to get
products (5a-f).
Dimethyl 4-[4-{2-((2-benzoyl-4-chlorophenyl)amino)-
2-oxoethoxy}-3-methoxyphenyl]-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (5a): Yield = method A: 71 %,
method B 65 %, m.p. 112-115 °C; Rf = 0.62 [chloroform:
methanol] [9:1], IR (KBr, νmax, cm-1): 3350 (Sec N-H str. of
DHP), 3088 (aromatic C-H str.), 2984 (C-H alkanes str.),
1681(> C=O str. ester), 1488 (C=C aromatic ring), 1214 (C-O
str.) and 750 (C-Cl). 1H NMR (CDCl3 ) δ (ppm): 2.33 (s, 6H,
2 × CH3), 3.64 (s, 2H, OCH2), 3.65 (s, 6H, 2 × COOCH3),
3.83 (s, 3H, -OCH3), 4.93 (s, 1H, -CH of DHP), 5.63 (s, 1H,
NH of DHP) and 6.71-7.74 (m, 11H, ArH), 8.61 (s, 1H, NH).
Anal. calcd. for C33H31N2O8Cl: C % 64.02, H % 5.05, N %
4.53; Found: C % 64.22, H % 5.18, N % 4.58
O
O
O
O
H
N
Cl
O
H
N
H
Cl
O
Cl
H3CO
O
O
2- Aminobenzophenone
derivative
O
O
H
H
RO
H3C
OR
RO
H3C
OR
N
H
CH3
N
H
CH3
1,4-DHP Derivatives
1,4-DHPs-aminobenzophenone
hybrid
Fig. 3. Design of aminobenzophenone linked 1,4-dihydropyridine
derivatives as possible antimicrobial agents
EXPERIMENTAL
Dimethyl 4-[3-{2-((2-benzoyl-4-chlorophenyl)amino)-
2-oxoethoxy}phenyl]-2,6-dimethyl-1, 4-dihydropyridine-
3,5-dicarboxylate (5b): Yield = method A 68 %, method B
62 %, m.p. 163-165 °C; Rf = 0.68 [chloroform:methanol] [9:1]
IR (KBr, νmax, cm-1): 3329 (N-H str.), 3091(ar C-H str.), 3000
(C-H str. alkanes), 1681 (> C=O str. amide), 1484 (C=C str.
ar. ring), 1348 (C-N), 1227 (C-O str. ester) and 759 (C-Cl).1H
NMR (DMSO-d6) δ (ppm): 2.27 (s, 6H, 2 × CH3), 3.58 (s, 6H,
2 × COOCH3), 3.94 (s, 2H, OCH2), 4.63 (s, 1H, -CH of DHP),
4.9 (s, 1H, NH of DHP), 6.89-8.06 (m, 12H, ArH), 10.6 (s,
1H, NH). Anal. calcd. for C32H29N2O7Cl: C % 65.25, H % 4.96,
N % 4.76; Found: C % 65.58, H % 5.12, N % 4.62
The melting points were determined on Veego-progra-
mmable melting point apparatus (microprocessor based) and
are uncorrected. Infrared (IR) spectra were obtained with on a
Perkin Elmer 882 Spectrum and RXI, FT-IR model using a
potassium bromide pellets (KBr) in cm-1. 1H NMR spectra were
obtained using BruckerAC-400 F, 400 MHz spectrometer and
are reported in parts per million (ppm), downfield from
tetramethylsilane (TMS) as internal standard. To monitor the
reactions, as well as to established the identity and purity
of reactants and products, thin layer chromatography was
performed on microscopic slides (2 × 7.5 cm), which were
coated with silica gel G and activated at 110 °C for 0.5 h. The
plates were developed by exposure to iodine vapours. All
the chemicals used in the synthesis are of analytical grade.
Anhydrous sodium sulphate was utilized as drying agents.
All the solvents were dried and freshly distilled prior to use
according to standard procedure. The starting compound
2-(chloroacetamido)-5-chlorobenzophenone and substi-
tuted 1,4-dihydroyridines were earlier synthesized in our
lab by conventional as well as microwave irradiation tech-
Diethyl 4-[4-{2-((2-benzoyl-4-chlorophenyl)amino)-2-
oxoethoxy}-3-methoxyphenyl]-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (5c): Yield = method A 67 %,
method B 60 %, m.p. 128-130 °C; Rf = 0.85 [chloroform:
methanol] [9:1] IR (KBr, νmax, cm-1): 3332 (N-H str. of DHP),
3061(ar. C-H str.), 2976 (C-H str. alkanes), 1691 (> C=O str.
ester), 1596 (C=CAr), 1505 (N-H bend), 1212 (C-O str. ester)
and 748 (C-Cl). 1H NMR (CDCl3) δ (ppm): 1.22-1.25 (m, 6H,
2 × OCH2CH3), 2.32 (s, 6H, 2 × CH3), 3.83 (s, 5H, -OCH3 +
OCH2), 4.07-4.10 (q, 4H, 2 × OCH2CH3), 4.94 (s, 1H, CH of
DHP), 5.54 (s, 1H, NH of DHP), 6.84-7.82 (m, 11H, ArH),
8.60 (s, 1H, NH). Anal. calcd. for C35H35N2O8Cl: C % 64.96,
H % 5.45, N % 4.33; Found: C % 65.24, H % 5.70, N % 4.45
Diethyl 4-[4-{2-((2-benzoyl-4-chlorophenyl)amino)-2-
oxoethoxy}phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (5d): Yield = method A 74 %, method B 64
%, m.p. 158-161 °C; Rf = 0.82 [chloroform:methanol] [9:1]
IR (KBr, νmax, cm-1): 3347 (N-H str.), 2984 (C-H str. alkanes),
1659 (> C=O str. amide), 1486 (C=C str. ar. ring), 1333 (C-N),
nique19,22,23
.
General method for the synthesis of dimethyl/diethyl-
4/3(substituted)-2-oxoethoxy)-4-methoxyphenyl)-2,6-
dimethyl-1, 4-dihydropyridine-3,5-dicarboxylate (5a-5f)
Method A: A mixture of 2-(chloroacetamido)-5-chloro-
benzophenone (1.23 g, 4 mmol), potassium fluoride (0.116 g,
2 mmol) and dry powdered potassium carbonate (0.7 g, 5
mmol) in dry DMF (15 mL) was stirred at room temperature
for 1 h.A solution of substituted 1,4-dihydropyridines (1 mmol)
in dry DMF (5 mL) was added into the above mixture and it
was stirred at room temperature for 24 h. The reaction mixture
1
1228 (C-O str. ester) and 745 (C-Cl). H NMR (DMSO-d6)