CROATICA CHEMICA ACTA

CCACAA, ISSN 0011-1643, e-ISSN 1334-417X

Croat. Chem. Acta 85 (3) (2012) 255–268.
http://dx.doi.org/10.5562/cca1983

Original Scientific Article

Highly Efficient One-pot Synthesis, Antimicrobial and Docking Studies

of Newer β-amino Carbonyl Derivatives Catalyzed by Silica Sulfuric Acid

Kh. A. M. El-Bayouki,a,* W. M. Basyouni,a A. S. El-Sayed,b W. M. Tohamy,a and A. A. El-Henawyb

a
Organometallic and Organometalloid Chemistry Dept., National Research Centre, Dokki, Cairo, Egypt
b
Chemistry Dept. Faculty of Science, Al-Azhar University, Cairo, Egypt

RECEIVED OCTOBER 9, 2011; REVISED APRIL 12, 2012; ACCEPTED APRIL 24, 2012

Abstract. Mannich reaction was applied between 4-fluorobezaldehyde, selected acetophenone and several
anilines, catalyzed by silica sulfuric acid for the synthesis of β-amino carbonyl derivatives. Reaction time
and yield of the products depended on the nature of acetophenone and aniline subsituents. Using aliphatic
amines instead of aromatic amines under same reaction conditions, afforded aldol condensation products
without yielding the expected β-amino ketones. Replacing the acetophenone derivatives with rhodanine
yielded 5-(4-fluorobenzylidene)-thioxothiazolidin-4-one. Using 2-aminothiophenol instead of the aniline
derivatives, 2-(4-fluorophenyl)benzothiazole was obtained without isolation of the expected (mercapto-
phenylamino)-1-(4-substitutedphenyl)propan-1-ones. A proposed reaction mechanism was suggested.
Docking studies were designed to gain clear picture of the high active compound(s). A model of high ac-
tive molecules was mapped for the antimicrobial screening and compared with least active compound(s).
(doi: 10.5562/cca1983)
Keywords: multi-component reaction; Mannich reactions; β-aminoketones; silica sulfuric acid; docking
studies

INTRODUCTION pounds has attracted much attention. Due to the limited

applications of the classic Mannich reaction, numerous
Fluorine has been reported to exert many pronounced versions of this reaction were developed using per-
effects on the properties of organic compounds when formed electrophiles, such as imines and stable nucleo-
employed as a substituent. As a result, in many areas of philes, enolates, enol ethers, and enamines.6 Hence,
applied organic chemistry, including polymer chemistry there is high interest in developing convenient methods
and biological or medicinal chemistry, fluorinated com- for the synthesis of β-amino ketone nucleus. Some of
pounds are attractive synthetic targets and the effects of these achievements in the efficient construction of this
fluorination on structure-activity relationships received nucleus included the development of Lewis acid cata-
much scrutiny.1 Moreover, owing to the growing appli- lysts; however, few useful Lewis acid catalysts were
cations of fluorinated molecules in agro- and pharma- developed in the past years.7 Also, several one-pot pro-
ceutical chemistry, several groups have proposed new cedures on the use of unmodified aldehydes or ketones
multifunctional fluorinated synthons, which are very were reported with a variety of catalysts such as SDA–
useful as building blocks.2 For example, the initial bio- HCl,8−10 PS–SO3H,11 and chiral Brønsted acid.12,13
logical studies of a new 2'-deoxy-2'-fluoro-2'-C-methyl Silica sulfuric acid (SSA) was introduced as a solid
nucleoside analogue that was designed and synthesized inorganic acidic proton source catalyst14 by the reaction
indicated that this compound showed promising activity of silica-gel and chlorosulfonic acid for the various func-
against hepatitis C virus (HCV) replication.3 tional group transformations.15−22 In addition, many novel
Three-component coupling Mannich reactions are heterogenized catalysts were based on silica supports
among the most important carbon-carbon bond forming such as silica sulfuric acid (SSA) due to their high surface
reactions in organic synthesis.4 These reactions provided areas and porosities, excellent stabilities (chemical and
β-amino carbonyl compounds, which are important thermal), and facile functionalization with organic groups
synthetic intermediates for various pharmaceuticals and that can be robustly anchored to the surface.23−25
natural products.5 Therefore, the development of new Therefore, the present work is intended for apply-
synthetic methods leading to β-amino carbonyl com- ing a facile and efficient one-pot three-component reac-

* Author to whom correspondence should be addressed. (E-mail: [email protected])

256 Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis

tion between 4-fluorobenzaldehyde, selected aceto- 3-(4-Fluorophenyl)-3-(4-fluorophenylamino)-1-

phenone derivatives and several aniline, catalyzed by phenylpropan-1-one (4c): White solid, yield: 72 %,
silica sulfuric acid (SSA) via Mannich reaction in order m.p.: 116−118 °C. Rf = 0.45. IR (KBr) vmax/cm−1: 3385
to synthesize new β-amino carbonyl compounds (4) (NH), 1671 (C=O). 1H NMR (500 MHz, DMSO-d6)
with potential biological activity. δ/ppm: 3.31−3.50 (m, 2H, COCH2), 4.46 (s, 1H, NH),
4.90 (t, J = 6.1 Hz, 1H, NCH), 6.40−7.94 (m, 13H,
ArH). 13C NMR (125 MHz, DMSO-d6), δ/ppm: 197.74
CHEMISTRY
(CO), 162.56, 160.64, 155.77, 153.92, 144.88, 140.43,
137.26, 133.74, 129.23, 129.13, 129.07, 128.57, 115.57,
Experimental
115.47, 114.14 (ArC, ArCH), 53.40 (CHNH), 46.95
Melting points are uncorrected. Microanalyses were (CH2). MS (EI) m/z = 337 (M+, 24.83 %). Anal. Calcd.
carried out by the Micro-analytical Laboratory, National for C21H17F2NO; (MW = 337.36): C, 74.76; H, 5.08; F,
Research Center, Cairo, Egypt. Infrared spectra (KBr) 11.26; N, 4.15. Found: C, 74.96; H, 5.11; N, 4.31 %.
were recorded using a Jasco FT/IR-300E spectropho- 3-(4-Chlorophenylamino)-3-(4-fluorophenyl)-1-
tometer. Analytical TLC was performed with silica-gel phenylpropan-1-one (4d): Pale yellow solid, yield: 72
GF254 plates (petroleum ether / ethyl acetate (4:1 by %, m.p.: 118−120 °C. Rf = 0.50. IR (KBr) vmax/cm−1:
volume), and the products were visualized by UV detec- 3367 (NH), 1662 (C=O). 1H NMR (500 MHz, DMSO-
tion. Proton and 13C-NMR spectra (500, or 125 Hz; d6) δ/ppm: 3.30−3.52 (m, 2H, COCH2), 4.45 (b, 1H,
whenever reported) were recorded in DMSO-d6. Chemi- NH), 4.95 (t, J = 6.1 Hz, 1H, NCH), 6.42−7.96 (m, 13H,
cal shifts (δ) reported in ppm using TMS as internal ArH). 13C NMR (125 MHz, DMSO-d6), δ/ppm: 197.55
standard and spin-spin coupling constants (J) were giv- (CO), 162.63, 160.70, 147.16, 140.19, 137.22, 133.74,
en in Hz. EI-MS spectra were measured on an HP 129.22, 129.00, 128.57, 119.85, 115.69, 115.52, 114.77
5988A spectrometer by direct inlet at 70eV. (Arc, ArCH), 52.78 (CHNH), 46.86 (CH2) MS (EI) m/z
= 353 (M+, 31.80 %). Anal. Calcd. for C21H17ClFNO;
Synthesis of Compounds (4a–n) MW = 353.82: C, 71.29; H, 4.84; N, 3.96. Found: C,
General Procedure: A mixture of 4-flourobenzaldehyde 71.44; H, 4.99; N, 3.41 %.
(2.0 mmol), aniline (2.0 mmol), aromatic ketone (2.0 3-(4-Bromophenylamino)-3-(4-fluorophenyl)-1-
mmol), and SSA (0.11 g, 0.04 mol %) was stirred in phenylpropan-1-one (4e): White solid, yield: 70 %,
EtOH (5 ml) at room temperature for 6–13 h. The reac- m.p.: 131−133 °C. Rf = 0.55. IR (KBr) vmax/cm−1: 3365
tion was monitored on TLC. After completion of the (NH), 1662 (C=O). 1H NMR (500 MHz, DMSO-d6),
reaction, CH2Cl2 was added and the catalyst removed by δ/ppm: 3.26−3.58 (m, 2H, COCH2), 4.46 (b, 1H, NH),
filtration. The obtained filtrate washed with saturated 4.93 (m, 1H, NCH), 6.41−7.93 (m, 13H, ArH). MS (EI)
NaHCO3 (aqueous) and brine, dried over anhydrous m/z = 398(M+,15.60 %). Anal. Calcd. for C21H17BrFNO;
Na2SO4, filtered and evaporated to dryness under re- MW = 398.27: C, 63.33; H, 4.30; N, 3.52. Found C,
duced pressure. The obtained residue purified by silica- 63.56; H, 4.88; N, 3.86 %.
gel chromatography to obtain compounds (4a–n). 3-(4-Fluorophenyl)-3-(phenylamino)-1-4-tolylpropan-1-
3-(4-Fluorophenyl)-1-phenyl-3-(phenylamino)propan-1- one (4f): White solid, yield: 76 %, m.p.: 92−93 °C. Rf =
one (4a): White solid, yield: 70 %, m.p.: 110−112 °C.26 0.41. IR (KBr) vmax/cm−1: 3369(NH), 1660 (C=O). 1H
Rf = 0.36. IR (KBr) vmax/cm−1: 3383 (NH), 1667 (C=O). NMR (500 MHz, DMSO-d6), δ/ppm: 2.46 (s, 3H, CH3),
1
H NMR (500 MHz, DMSO-d6) δ/ppm: 3.33−3.55 (m, 3.30−3.55 (m, 2H, COCH2), 4.60 (b, 1H, NH), 5.00 (t, J
2H, COCH2), 4.60 (b, 1H, NH), 4.96 (t, J = 6.75 Hz, = 6.4 Hz, 1H, NCH), 6.46−8.00 (m, 13H, ArH). MS (EI)
1H, NCH), 6.40−8.00 (m, 14H, ArH). MS (EI) m/z (%) m/z = 333 (M+, 10.22 %). Anal. Calcd. for C22H20FNO;
= 319 (M+, 30.24 %). Anal. Calcd. for C21H18FNO; MW MW = 333.40: C, 79.26; H, 6.05; N, 4.20. Found: C,
= 319.37: C, 78.98; H, 5.68; N, 4.39. Found C, 78.75; 79.11; H, 6.54; N, 4.65 %.
H, 5.79; N, 4.66 %. 3-(4-Fluorophenyl)-1-p-tolyl-3-(4-tolylamino) propan-
3-(4-Fluorophenyl)-1-phenyl-3-(4-tolylamino)propan-1- 1-one (4g): White solid, yield: 66 %, m.p.: 150−152 °C.
one (4b): White solid, yield: 68 %, m.p.: 131−132 °C.27 Rf = 0.39. IR (KBr) vmax/cm−1: 3357 (NH), 1673 (C=O).
Rf = 0.36. IR (KBr) vmax/cm−1: 3377 (NH), 1672 (C=O). 1
H NMR (500 MHz, DMSO-d6), δ/ppm: 2.33 (s, 3H,
1
H NMR (500 MHz, DMSO-d6) δ/ppm: 2.45 (m, 3H, CH3), 2.55 (s, 3H, CH3), 3.20−3.56 (m, 2H, COCH2),
CH3), 3.28−3.36 (m, 2H, COCH2), 4.93 (t, J = 6.90 Hz, 4.91 (m, 1H, NCH), 5.94 (s, 1H, NH), 6.35−7.82 (m,
1H, NCH), 5.96 (b, 1H, NH), 6.36−7.91 (m, 13H, ArH). 12H, ArH). 13C NMR (125 MHz, DMSO-d6), δ/ppm:
MS (EI) m/z = 333 (M+, 24.15 %). Anal. calcd. for 197.44 (CO), 160.53, 145.86, 144.10, 140.74, 134.81,
C22H20FNO; MW = 333.40: C, 79.26; H, 6.05; F, 5.70; 129.72, 129.07, 128.71, 124.89, 121.08, 120.24, 115.52,
N, 4.20. Found: C, 79.35; H, 6.44; N, 4.70 %. 115.36, 113.63 (ArC, ArCH), 53.08 (CHNH), 46.79

Croat. Chem. Acta 85 (2012) 255.

Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis 257

(CH2), 21.67 (CH3), 20.53 (CH3). MS (EI) m/z = 347 1-(2-Bromophenyl)-3-(4-fluorophenyl)-3-(phenylamino)

(M+, 25.24 %). Anal. Calcd. for C23H22FNO; MW = propan-1-one (4m): Yellow solid, yield 77 %, m.p.:
347.43: C, 79.51; H, 6.38; N, 4.03. Found: C, 79.88; H, 133−135 °C, Rf = 0.33. IR (KBr) vmax/cm−1: 3397 (NH),
6.80; N, 4.35 %. 1687 (C=O). 1H NMR (500 MHz, DMSO-d6), δ/ppm:
3-(4-Fluorophenyl)-3-(4-fluorophenylamino)-1-p- 3.35−3.46 (m, 2H, COCH2), 4.37 (s, 1H, NH), 5.00 (t, J
tolylpropan-1-one (4h): White solid, yield: 66 %, = 6.50 Hz, 1H, NCH), 6.44−7.90 (m, 13H, ArH). MS
m.p.:128−130 °C. Rf = 0.53. IR (KBr) vmax/cm−1: 3362 (EI) m/z = 398 (M+, 17.10 %). Anal. Calcd. for
(NH), 1656 (C=O). 1H NMR (500 MHz, DMSO-d6), C21H17BrFNO; MW = 398.27: C, 63.33; H, 4.30; N,
δ/ppm: 2.34 (m, 3H, CH3), 3.30−3.46 (m, 2H, COCH2), 3.52. Found C, 63.44; H, 4.80; N, 3.88 %.
4.50 (b, 1H, NH), 4.95 (t, J = 6.90 Hz, 1H, NCH), 1-(2-Bromophenyl)-3-(4-fluorophenyl)-3-(4-fluoro-
6.40−7.89 (m, 12H, ArH). MS (EI) m/z = 351 (M+, phenylamino)propan-1-one (4n): Creamy solid, yield:
20.15). Anal. Calcd. for C22H19F2NO; MW = 351.39: C, 77 %, m.p. 220−223 °C. Rf = 0.28. IR (KBr) vmax/cm−1:
75.20; H, 5.45; N, 3.99. Found: C, 75.42; H, 5.84; N, 3359 (NH), 1686 (C=O). 1H NMR (500 MHz, DMSO-
3.72 %. d6), δ/ppm: 3.33−3.41 (m, 2H, COCH2), 4.37(s, 1H,
1-(4-Chlorophenyl)-3-(4-fluorophenyl)-3-(phenyl- NH), 4.98 (t, J = 6.52 Hz, 1H, NCH), 6.42−7.99 (m,
amino)propan-1-one(4i): White solid, yield: 87 %, m.p.: 12H, ArH). MS (EI) m/z = 419 (M+ 3H) (38.9 %). Anal.
109−111°C. Rf = 0.45. IR (KBr) vmax/cm−1: 3364(NH), Calcd. for C21H16BrF2NO; MW = 416.26: C, 60.59; H,
1673 (C=O). 1H NMR (500 MHz, DMSO-d6), δ/ppm: 3.87; N, 3.36. Found C, 60.88; H, 3.71; N, 3.23 %.
3.38−3.52 (m, 2H, COCH2), 4.53 (b, 1H, NH), 4.95 (t, The synthesis of the compounds (5a–e), yellow solids:
J=6.75 Hz, 1H, NCH), 6.50−8.00 (m, 13H, ArH). MS Ar1= a) C6H5, b) C6H4-CH3-p, c) C6H4-Cl-p, d) C6H4-
(EI) m/z = 353 (M+, 6.01). Anal. Calcd. for Br-p, e) C6H4-Br-o has been described previously.28−31
C21H17ClFNO; MW = 353.82: C, 71.29; H, 4.84; N,
3.96. Found: C, 71.50; H, 4.41; N, 3.80 %. General Method for Preparation of 5-(4-fluoro-
1-(4-Chlorophenyl)-3-(4-fluorophenyl)-3-(4-fluoro- benzylidene)-2-thioxothiazolidin-4-one (6)
phenylamino)propan-1-one (4j): White solid, yield: 90 A mixture of 4-fluorobenzaldehyde (2.0 mmol),
%, m.p.: 80−82 °C. Rf = 0.38. IR (KBr) vmax/cm−1: 3365 Rhodanine (2.0 mmol), and SSA (0.11 g, 0.04 mol %)
(NH), 1673 (C=O). 1H NMR (500 MHz, DMSO-d6), was stirred in EtOH (5 ml) at room temperature for 6 h.
δ/ppm: 3.35−3.47 (m, 2H, COCH2), 4.40 (s, 1H, NH), The reaction was monitored on TLC (.petroleum ether /
4.90 (t, J = 6.72 Hz, 1H, NCH), 6.40−7.91 (m, 12H, ethyl acetate (4:1), Rf = 0.33. When the reaction com-
ArH). MS (EI) m/z = 371 (M+, 15.19 %). Anal Calcd. pleted, CH2Cl2 (5 ml) was added and catalyst was re-
for C21H16ClF2NO; MW = 371.81: C, 67.84; H, 4.34; N, moved by filtration. The Filtrate washed with saturated
3.77. Found C, 67.44; H, 4.10; N, 3.89 %. NaHCO3 (aqueous), brine and dried over anhydrous
1-(4-Bromophenyl)-3-(4-fluorophenyl)-3-(phenyl- Na2SO4, filtered and the obtained clear filtrate evapo-
amino)propan-1-one (4k): White solid, yield: 82 %, rated under reduced pressure to dryness. The obtained
m.p.: 112−114 °C. Rf = 0.45. IR (KBr) vmax/cm−1: 3365 residue was purified by silica-gel chromatographic
(NH), 1673 (C=O). 1H NMR (500 MHz, DMSO-d6), methods to obtain product (6) (yield 80 %).
δ/ppm: 3.25−3.57 (m, 2H, COCH2), 4.44 (s, 1H, NH), 5-(4-Fluorobenzylidene)-2-thioxothiazolidin-4-one (6):
4.93 (t, J=6.52 Hz, 1H, NCH), 6.43−7.86 (m, 13H, Orange solid, yield 80 %, m.p.: 219−220°C.32 IR (KBr)
ArH). 13C NMR (125 MHz, DMSO-d6), δ/ppm: 197.05 vmax/cm−1: 3424 (NH), 1698(C=O), 1189(S=O). 1H
(CO), 163.97, 162.55, 148.15, 140.53, 136.26, 132.29, NMR (500 MHz, DMSO-d6), δ/ppm: 7.36−7.64 (m, 5H,
130.64, 129.27, 129.04, 127.82, 116.49, 115.62, 115.45, ArH+ = CH), 13.83 (b, 1H, NH). MS (EI) m/z = 239
113.40 (ArC, ArCH), 52.80 (CHNH), 46.91 (CH2) MS (M+, 3.55). Anal Calcd. for C10H6FNOS2; MW =
(EI) m/z = 398 (M+, 5.54 %). Anal. Calcd. for 239.29: C, 50.19; H, 2.53; F, 7.94; N, 5.85. Found C,
C21H17BrFNO; MW = 398.27: C, 63.33; H, 4.30; N, 50.66; H, 2.40; F, 7.80; N, 5.65 %.
3.52. Found C, 63.77; H, 4.46; N, 3.99 %.
1-(4-Bromophenyl)-3-(4-fluorophenyl)-3-(4-fluoro- General Method for Preparation of 2-(4-fluoro-
phenylamino)propan-1-one (4l): White solid, yield: 82 phenyl) benzothiazole (8)
%, m.p.: 94−96 °C. Rf = 0.50. IR (KBr) vmax/cm−1: 3362 A mixture of 4-fluorobenzaldehyde (2.0 mmol), 2-
(NH), 1675 (C=O). 1H NMR (500 MHz, DMSO-d6), aminothiophenol (2.0 mmol), and SSA (0.11 g, 0.04
δ/ppm: 3.33−3.47 (m, 2H, COCH2), 4.40 (b, 1H, NH), mol %) was stirred in EtOH (5 ml) at room temperature
4.90 (t, J = 6.1 Hz, 1H, NCH), 6.42−7.78 (m, 12H, for 7 h. The reaction was monitored on TLC (petroleum
ArH). MS (EI) m/z = 416 (M+, 15.20 %). Anal. Calcd. ether / ethyl acetate (4:1), Rf = 0.75. When the reaction
for C21H16BrF2NO; MW = 416.26: C, 60.59; H, 3.87; N, completed; CH2Cl2 (5 ml) was added and the catalyst
3.36. Found C, 60.33; H, 3.44; N, 3.13 %. was removed by filtration. The obtained filtrate washed

Croat. Chem. Acta 85 (2012) 255.

258 Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis

Table 1. Optimization of reaction conditions for the formation of representative compound (4a)

Entry(a) Catalyst solvent Catalyst / mol % Time / h(b) Yield / %(c) Ratio (4a/5a)
1 SSA MeOH 0.04 14 55 57/43
2 SSA CH3CN 0.04 15 63 62/38
3 SSA CH2Cl2 0.04 16 60 55/45
4 SSA EtOH 0.04 13 80 70/30
5 SSA EtOH 0.1 13 50 20/80
6 SSA EtOH 0.02 14 65 60/40
7 FeCl3 EtOH 0.04 14 75 57/43
8 SiCl4 CH2Cl2 0.04 10 60 10/90
9 HClO4SiO2 EtOH 0.04 10 70 30/70
10 Me3ClSi EtOH 0.04 9 65 20/80
(a)
Reaction carried out in the appropriate solvent using 4-fluorobenzaldehyde (2 mmol), acetophenone (2 mmol) and aniline
(2 mmol) at room temperature.
(b)
Detected by TLC.
(c)
Isolated yields after silica-gel chromatography.

with saturated NaHCO3 (aqueous), brine and dried over 2 duo 3.00 GHz workstation). The molecules were built
anhydrous Na2SO4, evaporated under reduced pressure by the builder module of MOE. The geometry opti-
to dryness. The obtained residue purified by silica-gel mized using the MMFF94 force-field followed by a
chromatography to give (8) (yield 85 %). flexible alignment with systematic conformational
2-(4-Fluorophenyl)benzothiazole (8): White solid, yield: search. Lowest energy aligned conformation(s)
85 %, m.p.: 98−100 °C.33 1H NMR (500 MHz, DMSO- identified through the analysis module of DSV.
d6), δ/ppm: 7.17−8.13(m, 8H, ArH). MS (EI) m/z = 229
(M+, 17.02 %). Anal Calcd. for C13H8FNS; MW = RESULTS AND DISCUSSION
229.27: C, 68.10; H, 3.52; N, 6.11. Found: C, 68.22; H,
3.42; N, 6.30 %. In continuation of our studies on silica reagents,35−37 the
present work was directed towards using silica sulfuric
Anti-microbial Screening acid (SSA) catalyst for the synthesis of new β-amino
The anti-bacterial activity of the synthesized compounds carbonyls derivatives. Initial studies were performed
between 4-fluorobenzaldehyde (1), acetophenones (2),
was tested against two Gram- negative bacteria: Esche-
and anilines (3) in the presence of this catalyst at room
richia coli NCTC 10416, Pseudomonas aeruginosa
temperature (Scheme 1) and TLC plates monitored the
NCIB 9016, and two Gram-positive bacteria: Bacillus
reaction progress.
subtilis NCIB 3610, Staphylococcus aureus NCTC
For optimization, the reaction was carried out un-
7447, and one fungus namely: Candida albicans IMRU
der various conditions using different catalysts and
3669 using nutrient agar medium. solvents to probe the role played by SSA to find out the
Paper-disc Diffusion Technique best catalyst and solvent as shown in Table (1). From
A sterilized (autoclaved at 120 °C for 30 min) medium the obtained results, the best catalyst and solvent in
(40−50 °C) was incubated (1 ml/100 ml of medium) terms of yield and time was silica sulfuric acid (0.04
with the suspension (105 cfu ml−1) of the microorganism mol) and EtOH (Table 1, entry 4). Therefore, EtOH
(matched to McFarland barium sulphate standard) and (solvent) and SSA (catalyst) were used throughout the
poured into a petri-dish to give a depth of 3–4 mm. The present study.
paper impregnated with the test compounds (µg/ml−1 in Substrate scope investigations revealed that a vari-
methanol) was placed on the solidified medium. The ety of aromatic ketones 2 and amines 3 reacted smooth-
plates were pre-incubated for 1 h at room temperature, ly with 4-fluorobenzaldehyde 1 to afford the corre-
incubated at 37 °C for 24 and 48 hr for anti-bacterial sponding β-amino fluorinated ketones (4a–n) and the
and anti-fungal activities respectively. Ampicillin aldol products (5a–e) (Scheme 1 and Table 2).
(mg/disc) was used as a standard for antibacterial and From the obtained results, it was noticed that, both
anti-fungal activity respectively. The observed inhibi- yield and reaction time depended on the nature of sub-
stituent. Thus, the presence of the electron-withdrawing
tion zones are depicted in (Table 3).
group on the aromatic ketones (entry 10) increased the
Conformational Search and Flexible Alignment yield of β-amino ketones with reducing the reaction
Conformational analysis and flexible alignment of the time (Table 2). Noteworthy to observe that when using
tested compounds were carried out using the software aliphatic amines such as methylamine and n-butyl
(MOE34 of Chemical Computing Group Inc., on a Core amine instead of aromatic amines under the same reac-

Croat. Chem. Acta 85 (2012) 255.

Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis 259

Scheme 1. One-pot synthesis of β-amino fluorinated carbonyl compounds (4a–n).

affording the intermediate II with splitting of a water

molecule through intramolecular rearrangement to the
intermediate III. In the mean time the carbonyl oxygen
atom of acetophone is activated by SSA, forming (enol
form) intermediate IV. In the reaction medium, the
π-electrons of the activated (or non-stabilized) imine
delocalized towards the activated enol to form a new
carbon-carbon bond through the reface of the double
bond plane. The π-electrons of the activated enol re-
Scheme 2. Reaction of methylamine or n-butyl amine with
distribute to give keto form (accompanied by the trans-
4-fluorobenzaldehyde 1, aromatic ketones 2 in EtOH in pres-
fer of hydrogen atom to nitrogen atom). Finally, the
ence of SSA at room temperature.
Mannich adduct is formed and catalyst (SSA) renewed
again (Scheme 3).
The present work was continued to explore replac-
tion conditions, the corresponding aldol condensation ing of acetophenone derivatives with other reagents.
products (5a and c) were isolated as clean cut com- Thus, when the reaction was carried out using rhodanine
pounds (100 % yield) without isolating the expected under the same reaction conditions 5-(4-fluoro-
β-amino fluorinated ketones of type 4 (Scheme 2). benzylidene)-2-thioxothiazolidin-4-one (6)38 (yield 80 %)
A possible mechanism of the Mannich-type reac- was obtained as a sole product rather than the expected
tion that involves the use of SSA as catalyst in ethanol product 5-((4-fluoro-phenyl)(phenyl amino)methyl)-2-
is proposed (Scheme 3). When SSA was added to the thioxothiazolidin-4-one (7). Structure of product (6) was
reaction mixture, the carbonyl oxygen atom of the alde- elucidated chemically by reacting rhodanine with 4-
hyde becomes activated and this lead to formation of the fluorobenzaldehyde under the same reaction conditions,
intermediate I. Then, aniline (as a nucleophile) attacks which gave the same product (m.p and mixed m.p.). Also,
the activated carbonyl group of benzaldehyde forming a upon using 2-aminothiophenol instead of aniline deriva-
hydrogen bond (between H and O) with SiO2-SO3H, tives 2-(4-fluorophenyl)benzo-thiazole (8)39 (obtained as

Table 2. One-pot synthesis of β-amino fluorinated carbonyl compounds (4a–n)

Reaction (b)
Entry 2 3 4a–n 5a–e (a)
Time / h
Ar1 Ar2 Ar1 Ar2 Yield / % Ar1 Yield / %
1 C6H5 C6H5 a) C6H5 C6H5 70 5a 30 13
2 C6H5 C6H4-CH3-p b) C6H5 C6H4-CH3-p 68 5a 32 11
3 C6H5 C6H4-F-p c) C6H5 C6H4-F-p 72 5a 28 11
4 C6H5 C6H4-Cl-p d) C6H5 C6H4-Cl-p 72 5a 28 12
5 C6H5 C6H4-Br-p e) C6H5 C6H4-Br-p 70 5a 30 12
6 C6H4-CH3-p C6H5 f) C6H5 C6H4-CH3-p 76 5b 33 15
7 C6H4-CH3-p C6H4-CH3-p g) C6H4-CH3-p C6H4-CH3-p 66 5b 34 13
8 C6H4-CH3-p C6H4-F-p h) C6H4-CH3-p C6H4-F-p 66 5b 34 13
9 C6H4-Cl-p C6H5 i) C6H4-Cl-p C6H5 87 5c 13 7
10 C6H4-Cl-p C6H4-F-p j) C6H4-Cl-p C6H4-F-p 90 5c 10 6
11 C6H4-Br-p C6H5 k)C6H4-Br-p C6H5 82 5d 18 8
12 C6H4-Br-p C6H4-F-p l) C6H4-Br-p C6H4-F-p 82 5d 18 8
13 C6H4-Br-o C6H5 m)C6H4-Br-o C6H5 77 5e 23 10
14 C6H4-Br-o C6H4-F-p n)C6H4-Br-o) C6H4-F-p 77 5e 23 9
(a)
5a–e: Ar1= a) C6H5, b) C6H4-CH3-p, c) C6H4-Cl-p, d) C6H4-Br-p, e) C6H4-Br-o.
(b)
Stirring time at room temperature.

Croat. Chem. Acta 85 (2012) 255.

260 Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis

Scheme 3. Proposed mechanism of the direct Mannich reaction catalysed by silica sulfuric acid.

authentic sample from reaction of 2-aminothiophenol with Biological Activity

4-fluorobenzaldehyde) was afforded (85 % yield) without
Antibacterial Activity
isolation of the expected 3-(4-fluorophenyl)-3-(2-
mercaptophenylamino)-1-(4-sub-stitutedphenyl)-propan- The synthesized β-amino ketones (4a–n), 5-(4-
1-one (9) (Schemes 4 and 5). fluorobenzylidene)-2-thioxothia zolidin-4-one (6) and 2-
Unequivocal proofs for the role played by steric (4-Fluorophenyl) benzothiazole (8) were tested for their
hindrance could come from the reaction of rhodanine in vitro antibacterial activity by using paper disc diffu-
and 2-aminothiophenol, which gave products (6) and (8) sion technique.40−44 The tested microorganism strains
respectively as sole products. Structure of products (6) were  (Gram-negative bacteria: Escherichia coli NCTC
and (8) was confirmed by spectroscopic methods and 10416, Pseudomonas aeruginosa NCIB 9016 and
elemental analyses. Gram-positive bacteria: Bacillus subtilis NCIB 3610,

Scheme 4. Synthesis of 5-(4-fluorobenzylidene)-2-thioxothiazolidin-4-one (6).

Croat. Chem. Acta 85 (2012) 255.

Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis 261

Scheme 5. Synthesis of 2-(4-fluorophenyl)benzothiazole (8).

Staphylococcus aureus NCTC 7447), Ampicillin was Antifungal Activity

used as standard drug control. The results of antimicro- The in vitro antifungal studies of all the synthesized com-
bial activity values are furnished in (Table 3); and de- pounds (4a–n, 6 and 8) were tested against Candida
picted graphically in (Figure 1). The data presented in albicans IMRU 3669, Ampicillin was used as reference
(Table 3) cleared that, compound (4n) was the most drug and their inhibition zone diameter values were depict-
active compound against all the tested bacterial strains; ed in (Table 3) and graphically in (Figure 1). In general, all
but compound (4m) was more potent against E. coli and the synthesized compounds exerted weak to inactive in
S. aureus than the standard drug Ampicillin. Other syn- vitro antifungal activity against all the tested organisms.
thesized compounds showed weak activity and / or loss Moreover, compounds (4m and 4n) were more effective
activity against the tested bacterial strains. against the tested fungus than the standard drug Ampicillin.

Table 3. Anti-microbial activity of the synthesized compounds

In vitro activity-zone of inhibition / mm (a)

Comp No. E. coli B. subtilis S. aureus P. aeruginosa C. albicans
4a ─ ─ ─ ─ ─
4b ─ ─ ─ ─ ─
4c ─ ─ ─ ─ ─
4d 9 8 10 11 9
4e ─ ─ ─ ─ ─
4g ─ ─ ─ ─ ─
4h ─ ─ ─ ─ ─
4i ─ ─ ─ ─ ─
4j ─ ─ ─ ─ ─
4k 9 8 8 8 10
4l ─ ─ ─ ─ ─
4m 30 15 28 15 30
4n 27 35 30 38 32
6 ─ ─ ─ ─ ─
8 ─ ─ ─ ─ ─
Ampicillin 19 19 18 21 17
Chloroform ─ ─ ─ ─ ─
(a)
(-) Inactive (< 8 mm), weak activity (8-12 mm), moderate activity (12-15 mm), strong activity (> 15).

Croat. Chem. Acta 85 (2012) 255.

262 Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis

Figure 1. Antimicrobial activities of compounds (4a–n), (6) and (8) against bacterial strains (Gram negative and positive bacte-
ria), and fungal strain.

Structural Activity Relationship show any activity against any microorganisms. Fur-
To obtained clear picture about the structure activity thermore, the observed marked antibacterial and anti-
relationship (SAR) for the synthesized compounds, the fungal activities could be considered as key steps for
target compounds were numbered (Figure 2). The ac- the building of novel therapeutic compound with
tivity of the tested compounds must be correlated with comparable pharmacological features with that of the
structure modifications and variation. The obtained standard drugs after considering results from toxicol-
screening results showed that, compounds (4m and 4n) ogy studies.
are the most active members.
A close survey in vitro antibacterial and antifun- Docking Studies
gal activity profile of the new β-amino ketones against
Absorption, Distribution, Metabolism, Elimina-
the tested bacterial and fungal organisms, gave a clear
tion(ADME)
idea about the structure-activity correlations among
the studied compounds. The presence of a fluo- Toxic Factors Profiling
ropheny moiety (phenyl ring C) at N-11 with the Oral bioavailability considerably plays an important role
presence of bromo substitution attached to phenyl ring for the development of bioactive molecules as therapeu-
(A) at the C-6 position compound (4n) exerted a sig- tic agents. Several potential therapeutic agents fail to
nificant varied range of biological activities. In addi- reach the clinic, because of ADME toxic Factors. There-
tion, the presence of bromine moiety at C-6 position fore, a computational study for prediction of ADME
(ring A) without substitution (ring C) showed signifi- properties of the molecules was performed for anti-
cant activity of compound (4n) against E.coli and C. microbial compounds (4d, k, m and 4n), by the deter-
albicans, which revealed moderate potency against
other microorganisms. For comparison, compounds Table 4. Molecular parameters of the active compounds
(4d and 4k), showed weak activity against all micro-
Compound* 4d 4k 4m 4n
organisms and the other tested compounds do not
TPSA 29.1 29.1 29.1 29.1
Log P 5.199 5.638 5.844 5.842
nON 2 2 2 2
nOHNH 1 1 1 1
Lip-V 1 1 1 1
Log S −5.52037 −5.95968 −6.31578 −6.31578
MR 9.46642 9.97162 10.24062 10.24062
*
TPSA: Total Polar surface area, Log P: Calculated
lipophilicity; nON: Number of hydrogen bond acceptor;
nOHNH: Number of hydrogen bond donor; Lip-V: Number of
violation from Lipinski’s rule of five; Log S: Solubility pa-
Figure 2. A numbered target molecules (4a-4n). rameter; MR: Molar refractometry.

Croat. Chem. Acta 85 (2012) 255.

Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis 263

Figure 3. Lowest energy conformers of the most active compounds (4m) and (4n) as representative examples in CPK rendering.

mination of topological polar surface area (TPSA), C fluoropheny core (ring B). The optimal distance for the
log P and ‘‘rule of five’’ which have been formulated best biological activity was found in 3.12 Å and 3.13 Å
by Lipinski.45 The same author established that, a chem- for (4m and 4n) respectively, and the higher distance
ical compound could be an orally active drug in hu- values in rang (3.16−3.18) lead to decrease in activity,
mans, if no more than one violation of the following as indicated in Figure 4.
rule: i) C log P < 5, ii) number of hydrogen bond donors
Flexible Alignment
sites ≤ 5, iii) number of hydrogen bond acceptors sites ≤
To understand similarity between the three-
10, iv) and molecular weight <500. In addition, the total
dimensional structures of active compounds (4m and
polar surface area (TPSA) is another key property
4n) a flexible alignment was employed (Figure 5),
linked to drug bioavailability, the passively absorbed
using MOE/MMFF94,50 and 200 conformers of each
molecules with (TPSA>140) have low oral bioavailabil-
compound were generated and minimized with a dis-
ity.46 Calculations were performed using MOE pro-
tance-dependant dielectric model. A low energy set of
gram,47 the results were disclosed in (Table 4). The
100 was selected for further analysis. Conformations
present results revealed that, the C Log P is the partition
of compound (4m) were generated using distance
coefficient between water and octanol (factor of
geometry and optimized with MMFF94. Five low
lipophilicity).48 Lipophilicity of most compounds is
energy, maximally dissimilar structures were selected
more than 5.0; the molecular weight (MW< 500), hy-
for comparison to the other compounds. After assign-
drogen bond acceptors between (1 and 2) and hydrogen
ing MMFF94 charges to all molecules, flexible align-
bond donors (1) which fulfill Lipinski’s rule. These data
ment was ranked overlays of compounds (4m and 4n)
may suggest that, these compounds of good passive oral
based on electrostatic, steric filed, hydrophobic areas
absorption.
overlap, hydrogen bond acceptors and donors overlap.
Conformational Analysis From the highest scoring superposition, the limited set
In order to gain a better insight into the molecular struc- conformers was used in the analysis for molecules
tures of the active compounds (4m and 4n) and low with high flexibility capable for achieving complete
active compounds (4d and 4k). The conformational atom-to-atom superposition (Figure 5a). A common
analysis of the target compounds were performed using feature of the MOE-generated alignments showed,
MMFF94 force-field49,50 (calculations in vacuum, bond comply of the two structures (4m and n) with: i) three
dipole option for electrostatics, Polake Ribiere algo- phenyl rings (A, B and C), ii) COCH2NH spacer be-
rithm, RMS gradient of 0.01 kcal/A mol) implemented tween rings (Figure 5a). With the same way, antimi-
in MOE 2009.10.). The most stable conformer was fully crobial of compound (4n) and the lowest active com-
optimized by AM149 semi-empirical molecular orbital pounds (4d and 4k) were subjected to flexible align-
calculation (Figure 3). ments. Analysis of weak active molecules (Figure 5b)
The calculation results showed that, the lowest is an important way to gain clear vision of the essen-
minimization energy structures of the compounds under tial features for a given activity. It is clear that com-
investigation exhibited a common arrangement and pounds (4d and 4k) were flexibly aligned in a differ-
critical distance of the aryl moiety in (ring C) from the ent manner when compared with the active compound

Croat. Chem. Acta 85 (2012) 255.

264 Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis

Figure 4. 2D-pharmacophoric design of β-amino ketone (red colors represent the HB regions, green colors represent hydrophobic
regions and blue colors represent spacer moiety).

(4n). Common feature of the MOE-generated align- Electrostatic and Hydrophobic Mappings
ments showed, the superposition of the COCH2NH In an attempt to understand the lowest activity repre-
fragments in (4k) have a slight deviation (0.5 Å) sented by (4k) and the highest antimicrobial activity
compared with high active compound (4n), the three represented by (4n), electrostatic and hydrophobic map-
phenyl rings arrangement are in similar manner to all pings was preformed for the lowest energy conformers,
investigated compounds. These features explaining to examine the comply and incompliance in electronic,
why such compound was the least active as antimi- electrostatic binding characteristics of the surface of the
crobial agents and showing the importance of both molecules and conformational properties (Figure 6).
COCH2NH moiety and the aromatic ring attached to it First: comparison of the electrostatic mappings of low-
(Figure 5b). est active compounds, represented by compound (4k)

Figure 5. Flexible alignments of the most active compounds (Left panel): 4d (in green), 4k (in red) and 4n (in blue). Right panel
showed flexible alignment of the high active compound 4n (in green) and lowest active compounds 4d (in red) and 4k (in blue).

Croat. Chem. Acta 85 (2012) 255.

Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis 265

Figure 6. Electrostatic maps (left panels a) and hydrophobic panels (right panels b) of the lowest energy conformers for the most
active compounds (4n) and the least active compounds (4k); maps are color coded: red for the hydrogen bond and a hydrophilic
region, cyan for a medium polar region, and green for a hydrophobic region.

(Figure 6a) showed common features: i) negative charge potential protein-binding site.
located on the carbonyl (in red), ii) non-polar area locat-
ed on the aryl moiety (in green), these features explain Pharmacophore Prediction
biological similarity among the low active analogues The aim of this approach is generation and prediction a
compounds. On the contrary, the high activity of com- pharmacophore model (hypothesis) depending on the
pounds (4m and n), represented by (4n, Figure 6) most active compound. These steps are employed for
showed decrees distribution of negative charge (in red) 3D pharmacophore applications: i) Compound 4n (Fig-
on carbonyl group. From the above features, the low ure 4) used as reference to other conformations of each
activity may be due to increasing negative charge locat- compounds. ii) Assignment of the pharmacophoric
ed on the carbonyl group region representing hydrogen features. ii) Application method for undertaking con-
bond acceptor (in red) (Figure 6a). As the same analogy, formational searching of databases for new structures
hydrophobic mappings of the most active compound matching to generated pharmacophoric features. These
(4n) showed that, the hydrophobic region (in green) was steps will be explained (hypothetical) pharmacophoric
distributed on all sides of aromatic rings (A, B and C) building of antimicrobial compounds. Molecular Oper-
while the hydrophilic region (in red) was located mainly ating Environment (MOE) programme was used for
on carbonyl fragments (Figure 6b). On the other hand pharmacophore building.51 The calculated conforma-
the hydrophobic distributions of the inactive compounds tional models were preformed with 15 kcal energy cut
(4k) occupying aromatic ring, indicating dissimilarity off (minimization convergence criteria during confor-
hydrophobic distributions of such compound (Figure mational analysis: energy convergence = 0.01 kcal/mol,
6b). It is clear that the related charge distribution, elec- gradient convergence = 0.01 kcal/mol). The number of
trostatic and hydrophobic mappings suggest a similar conformers generated for each substrate was limited to a
interaction and orientations of the molecules with a maximum of 500. All molecules with their associated

Croat. Chem. Acta 85 (2012) 255.

266 Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis

Table 5. Pharmacophoric and structure features of the most NH fragments (as hydrophilic) element and the aryl
active compounds moieties (as hydrophobic) were well superimposed
within the set distance tolerance, which confirms the
Pharmacophoric features Structure features
F1: Aro/Hydro Pheny and o-bromophenyl important role of the hydrophilic and hydrophobic
F2: Aro/Hydro p-florophenyl moieties for antimicrobial activity. The initial
F3: Aro/Hydro Pheny and p-florophenyl pharmacophore query was carried out, and introducing
F4: Acc C=O of 5 features, as summarized in (Table 5) and illustrated
F5: Don NH graphically in (Figure 7).
From (Figure 7a), Models for (4n) and its analogs
(4m) possess pharmacophore elements in the aromatic
conformations were regrouped depending biological (ring C) attached to NH group (as a hydrogen bond
data. Hypothesis generation carried out with low energy donor) which is out of plane with aromatic ring (B),
conformers of the molecules. The calculation and analy- which parallel with aromatic ring (A). In contrast, mod-
sis were preformed. After assignment of possible el for (4d) and its analogs (4k) (Figure 7b) showed
pharmacophore elements for each analogue using MOE common elements, the aromatic ring (B) coplanar with
program, then superposition of the molecules including aromatic ring (A), and aryl amino part out of plane with
the assigned elements, was attempted (Figure 7), to aromatic ring (A) (Figure 7b). Since the arylamino- part
generate Pharmacophore maps, many runs of calcula- of compound (4n) plays an important role in activity.
tion were repeated. For each run, a distinct number of According to the pharmacophore generated by MOE51
specified pharmacophore elements were generated. All the minimal structural requirements for antimicrobial
appropriate models showed that, the donor atoms of the activity consist of an aromatic ring (hydrophobic re-

Figure 7. a) Showed the best predicted pharmacophore features and geometries which are required for antimicrobial activity. b)
Showed the most active compounds 4m and 4n mapped to the pharmacophore model for antibicrobial activity. c) Showed the
lowest active compounds (4d and 4k) mapped to the pharmacophore model for antimicrobial activity. Pharmacophore features are
color coded: yellow for hydrophobic aromatics, cyane for a hydrogen bond donor, and blue for a hydrogen bond acceptor feature.

Croat. Chem. Acta 85 (2012) 255.

Kh. A. M. El-Bayouki et al., Highly Efficient One-pot Synthesis 267

gion) attached to NH fragment (H-bonding donor re- 6. (a) B. M. Trost and L. R. Terrell, J. Am. Chem. Soc. 125 (2003)
gion), and carbonyl fragment (H-bonding acceptor re- 338−339; (b) S. Matsunaga, N. Kumagai, S. Harada, and M.
Shibasaki, J. Am. Chem. Soc. 125 (2003) 4712−4713; (c) K. Juhl,
gion) (Figures 4 and 7). This pharmacophoric assump- N. Gathergood, and K. Jørgensen, Angew.Chem. 113 (2001)
tion was in consistence with biological data. 3083−3085; (d) B. List, J. Am Chem. Soc. 122 (2000)
9336−9337; (e) B. List, P. Pojarliev, W. T. Biller, and H. J. Mar-
tin, J. Am. Chem. Soc. 124 (2002) 827−833; (f) A. Cordova, W.
CONCLUSIONS Notz, G. Zhong and J. M. Betancort, J. Am. Chem. Soc. 124
(2002) 1842−1843; (g) S. Kobayashi, T. Hamada a nd K.
A facile and efficient one-pot three-component reaction Manabe, J. Am. Chem. Soc. 124 (2002) 5640−5641; (h) Y.
Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, and K.
between p-fluorobezaldehyde, selected acetophenone
Sakai, Angew. Chem. Int. Ed. 43 (2003) 3677−3680; (i) A. G.
and several aniline derivatives, catalyzed by silica sulfu- Wenzel and E. N. Jacobsen, J. Am. Chem. Soc. 124 (2002)
ric acid (SSA) for the synthesis of new β-amino carbon- 12964−12965.
yl compounds (4) was investigated via Mannich reac- 7. (a) M. M. Salter, J. Kobayashi, and S. Kobayashi, Org. Lett. 8
tion to yield products (4) in good to excellent yields and (2006) 3533−3536; (b) S. Kikuchi, T. Kobayashi, and Y. Hash-
imoto, Tetrahedron Lett. 47 (2006) 1973−1975; (c) J. Kobayashi,
in short time. Flexible alignment was conducted and
Y. Yamashita, and S. Kobayashi, Chem. Lett. 34 (2005)
justified the importance of the main molecular groups 268−269; (d) W. G. Shou, Y. Y. Yang and Y. G. Wang, Tetra-
(particularly, the carbonyl fragment and the aryl rings hedron Lett. 47 (2006) 1845−1847; (e) R. Wang, B -g. Li, T-k.
(A and C) as well as of their relative distance. In fact, Huang, L. Shi and X-x. Lu, Tetrahedron Lett. 48 (2007)
the substitution patterns on the phenyl ring (A or C) 2071−2073.
8. T. Akiyama, K. Matsuda, and K. Fuchibe, Synlett 2 (2005)
considerably affect the activity. The overall outcome of
322−324.
this model revealed that: i) the phenyl rings (A, B and 9. K. Matsuda, Y. Mori, and S. Kobayashi, Tetrahedron 57 (2001)
C) are a satisfactory backbone for antimicrobial activity, 2537−2544.
(ii) the aryl (ring A) should be about less than 3.16 Å 10. T. Akiyama, J. Takaya, and H. Kagoshima, Synlett 7 (1999)
apart from the (ring C) (Figure 2). iii) Absence of bro- 1045−1048.
11. S. Iimura, D. Nobutou, K. Manabe, and S. Kobayashi, Chem.
mine as hydrophobic moiety at position 6 decreased the
Commun. (2003) 1644−1645.
activity, such as 4-(fluoro, chloro and methyl) phenyl 12. T. Akiyama, J. Itoh, K. Yokota, and K. Fuchibe, Angew. Chem.
moiety, this indicted the importance of position 6 in the Int. Ed. 43 (2004) 1566−1568.
activity. These modeling studies could be very useful 13. A. Hasegawa, Y. Naganawa, M. Fushimi, K. Ishihara, and H.
for the virtual screening in the development of the pres- Yamamoto, Org. Lett. 8 (2006) 3175−3178.
14. M. A. Zolfigol, Tetrahedron 57 (2001) 9509−9511.
ently studied β-amino carbonyl compounds as antimi-
15. P. Salehi, M. A. Zolfigol, F. Shirini, and M. Baghbanzadeh,
crobial agents. Therefore, the present work led to the Curr. Org. Chem. 10 (2006) 2171−2189.
development of novel antimicrobial agents especially in 16. B. F. Mirjalili, M. A. Zolfigol, A. Bamoniri, and A. Hazar, Bull
case of the two novel molecules (4m and 4n) for their Korean Chem. Soc. 25 (2004) 865−868.
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Kitayama, Tetrahedron Lett. 45 (2004) 5135−5138.
pounds.
18. A. Shaabani and A. Rahmati, J. Mol. Catal. A. Chem. 249 (2006)
246−248.
19. P. Salehi, M. Dabiri, M. A. Zolfigol, and M. A. Badaghifard,
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