Synthesis of a series of diphenyl (arylamino)(pyridin-3-yl) methylphosphonates as potential antimicrobial agents

Article abstract of DOI:10.1080/10426507.2012.717141

Diphenyl 1-(arylamino)(pyridin-3-yl)methylphosphonates were obtained in high yields from the reactions of nicotinaldehyde with aromatic amines and triphenylphosphite in the presence of titanium tetrachloride (TiCl₄) as a catalyst. The structure

Full text of DOI:10.1080/10426507.2012.717141

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of a Series of
Diphenyl (Arylamino)(Pyridin-3-
yl)Methylphosphonates as Potential
Antimicrobial Agents
Mohamed F. Abdel-Megeed a , Gamal A. El-Hiti a b , Badr E. Badr c &
Mohamed M. Azaam a
a Department of Chemistry, Faculty of Science , Tanta University ,
Tanta , Egypt
b School of Chemistry , Cardiff University , Cardiff , UK
c Department of Botany, Faculty of Science , Tanta University ,
Tanta , Egypt
Accepted author version posted online: 09 Aug 2012.Published
online: 05 Jul 2013.
To cite this article: Mohamed F. Abdel-Megeed , Gamal A. El-Hiti , Badr E. Badr & Mohamed M. Azaam
(2013) Synthesis of a Series of Diphenyl (Arylamino)(Pyridin-3-yl)Methylphosphonates as Potential
Antimicrobial Agents, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:7, 879-885, DOI:
10.1080/10426507.2012.717141
To link to this article: http://dx.doi.org/10.1080/10426507.2012.717141
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Phosphorus, Sulfur, and Silicon, 188:879–885, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.717141
SYNTHESIS OF A SERIES OF DIPHENYL
(ARYLAMINO)(PYRIDIN-3-YL)METHYLPHOSPHONATES
AS POTENTIAL ANTIMICROBIAL AGENTS
Mohamed F. Abdel-Megeed,1 Gamal A. El-Hiti,1,2
Badr E. Badr,3 and Mohamed M. Azaam1
1Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
2School of Chemistry, Cardiff University, Cardiff, UK
3Department of Botany, Faculty of Science, Tanta University, Tanta, Egypt
GRAPHICAL ABSTRACT
NHAr
O
CHO
P(OPh)3, TiCl4
P
Ar NH2
+
OPh
PhO
DCM, RT, 24 32 h
N
N
2
6 (78 89%)
1
Ar = C6H5, 4-ClC6H4, 4-HOC6H4, 4-MeOC6H4, 4-MeC6H4
Abstract Diphenyl 1-(arylamino)(pyridin-3-yl)methylphosphonates were obtained in high
yields from the reactions of nicotinaldehyde with aromatic amines and triphenylphosphite in
the presence of titanium tetrachloride (TiCl4) as a catalyst. The structures of the synthesized
compounds were confirmed by IR, 1H NMR and mass spectral data and their purities were
confirmed by elemental analyses. The synthesized α-aminophosphonates showed moderate to
high antimicrobial activities against Escherichia coli (NCIM2065) as a Gram-negative bac-
terium, Bacillus subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram-positive
bacteria, and Candida albicans and Schccaromycies cerevisiae as fungi, at various concentra-
tions (10–100 μg/mL).The lethal dose of the synthesized compounds was also determined and
indicated that most compounds are safe to use.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the related elements to view the free supplemental file.
Keywords α-Aminophosphonate; nicotinaldehyde; minimum inhibitory concentrations; an-
timicrobial properties; lethal dose
INTRODUCTION
Heterocyclic compounds containing nitrogen play an important role in medicinal
chemistry and have been intensively used in drug development.1 The pyridine moiety
Received 3 June 2012; accepted 15 July 2012.
Address correspondence to Gamal A. El-Hiti, School of Chemistry, Cardiff University, Main Building, Park
Place, Cardiff CF10 3AT, UK. E-mail: el-hitiga@cardiff.ac.uk
879

880
M. F. ABDEL-MEGEED ET AL.
has been found in various biologically active compounds, natural products, and pharma-
ceuticals.2–4 On the other hand, various synthetic processes have been developed for the
production of α−aminophosphonates.5–7 However, the most efficient method involves a
one-pot Mannich-type8 process of carbonyl compounds, amines, and diphenyl phosphite in
the presence of a Lewis acid catalyst. Such process is high yielding, general, simple, and
accommodates various substituents into α-aminophosphonates.9–12
α-Aminophosphonates, and in particular the ones having heterocyclic moieties, show
very interesting biological activities13–15 and have been used as antibacterial,16,17 antifun-
gal,16,17 anticancer,18–20 anti-HIV enzyme inhibitors,16 antibiotics,5 and herbicidal agents.13
Therefore, the synthesis of α-aminophosphonates having a pyridine moiety in an attempt
to improve the biological activities of the synthesized compounds is always of interest.
We have developed simple and efficient synthetic procedures for the syntheses of a
range of biologically active heterocyclic compounds21–29 as part of our continuing work in
organic synthesis.30–37 Recently, we have shown that various novel α-aminophosphonates
can be produced efficiently, in high yields in a one-step reaction, and such compounds have
proven to be good antimicrobial and anticancer reagents.38–40 The present work was aimed
to synthesize a series of α-aminophosphonates containing pyridine moiety with the hope
that new antimicrobial agents could be developed. We now report the successful synthesis of
a range of diphenyl (arylamino)(pyridin-3-yl)methylphosphonates and their antimicrobial
properties.
RESULTS AND DISCUSSION
Chemistry
The reactions of nicotinaldehyde (1; 2 mol equiv.) with arylamines (aniline, 4-
chloroaniline, 4-hydroxyaniline, 4-anisidine, and 4-toluidine; 4 mol equiv.) and triph-
enylphosphite (3 mol equiv.) in the presence of titanium tetrachloride (TiCl4), as a Lewis
acid, were carried out in dichloromethane (DCM) at room temperature (r.t.) for 24–32 h un-
der identical conditions. The crude products obtained were purified by crystallization from
ethanol to give the corresponding α-aminophosphonates 2–6 (Scheme 1) in 78–89% yields.
The reaction represented in Scheme 1 is general, simple, high yielding, involves easy work-
up, and accommodates various substituents to produce substituted α-aminophosphonates
efficiently.
NHAr
O
CHO
P(OPh)3, TiCl4
P
Ar NH2
+
OPh
DCM, RT, 24 32 h
PhO
N
N
Ar = C6H5, 4-ClC6H4, 4-HOC6H4, 4-MeOC6H4, 4-MeC6H4
2 6
1
Scheme 1
1
The structures of α-aminophosphonates 2–6 were confirmed by IR, H NMR, and
mass spectroscopy and their purities were confirmed by elemental analyses. The IR spectra
of 2–6 are characterized by the presence of absorption bands within the 3424–3305 cm−1
region corresponding to the stretching vibrations of the NH groups. The bands within
the 1599−1582 cm−1 region are due to the stretching vibration of the C N groups of

SYNTHESIS OF α-AMINOPHOSPHONATES AS ANTIMICROBIALS
881
the pyridine ring while the absorption bands at the 1361–1320 cm−1 region are due to
the symmetric stretching vibrations of the P O groups and absorption bands within the
869–801 cm−1 region are attributed to the P–O–C groups.
The 1H NMR spectra of α-aminophosphonates 2–6 showed a characteristic exchange-
able singlet within the 9.68–8.88 ppm region due to the NH protons while the CH protons
resonated as doublets (J = 13–16 Hz) within the 6.56–4.85 ppm region. The structures
of 2–6 were also confirmed by low-resolution mass spectra and the molecular or pseudo-
molecular ions were confirmed by the high-resolution mass spectra. Moreover, the elemental
analyses of compounds 2–6 were consistent with the suggested structures (see Experimental
section for details).
Antimicrobial Activities
α-Aminophosphonates 2–6 were screened for their in vitro antibacterial and antifun-
gal activities against Escherichia coli (NCIM2065) as a Gram-negative bacterium, Bacillus
subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram-positive bacteria, and
Schccaromycies cerevisiae and Candida albicans as fungi. The inhibition zones were mea-
sured in triplicates and the results are reported in Table S1 in the Supplemental Materials
(posted online only).
The results showed that compounds 2–6 showed moderate to high antimicrobial
activities against the tested organisms. It was found that compound 4 was the most effective
while compound 5 was the least active one.
Minimum Inhibitory Concentrations
The inhibition zone was measured in triplicates in four different concentrations
(10–1000 μg/mL) and the mean value standard deviation (SD) is recorded in Table S2
in the Supplemental Materials (posted online only). It is clear that compound 6 showed the
highest antimicrobial activities at low concentration (10 μg/mL). The compounds could be
arranged according to their minimum inhibitory concentration (MIC) as follows: 6 > 3, 4
> 2 > 5.
The Lethal Dose
Cytotoxic anticancer substances have unique problems that come primarily from
the lack of safety and side effects. Therefore, the cytotoxicity lethal dose (LD50) of α-
aminophosphonates 2–6 was determined to the larvae of Artemia salina using brine shrimp
lethality bioassay. The LD50 of compounds 2–6 are represented in Figures S1−S5 in the
Supplemental Materials (posted online only).
α-Aminophosphonates 2−6 showed low toxicity and they are safe to be used in vivo.
Moreover, α-aminophosphonates 2, 3, and 6 were found to be safe for use because they
exhibited high values of lethal dose. On the other hand, α-aminophosphonates 4 and 5
exhibited small values of lethal dose.
CONCLUSIONS
A convenient method for the synthesis of diphenyl 1-(arylamino)(pyridin-3-
yl)methylphosphonates was developed. The synthesized compounds exhibit a remarkable

882
M. F. ABDEL-MEGEED ET AL.
inhibition of the growth of Gram-positive, Gram-negative bacteria, and fungi at relatively
low concentrations. The lethal dose of the synthesized compounds indicated that most
of the synthesized compounds are safe and are promising for their uses as in vivo
antimicrobial reagents.
EXPERIMENTAL
General Experimental. Melting point determinations were performed by the open
capillary method using an electrothermal MEL–TEMP II apparatus, at Tanta, Egypt, and are
reported uncorrected. IR spectra were recorded on a Perkin-Elmer 1430 spectrophotometer,
1
at Tanta, Egypt, using the KBr disc technique. The H NMR spectra were recorded on a
Bruker AC400 spectrometer operating at 400 MHz at Tanta, Egypt. The 31P NMR spectra
were recorded on a Bruker AC500 spectrometer operating at 202.48 MHz at Cardiff, UK.
The spectra were recorded in DMSO-d6. Chemical shifts δ are reported in parts per million
(ppm) relative to tetramethylsilane (TMS). Assignments of signals are based on integra-
tion values and expected chemical shift values and have not been rigorously confirmed.
Low-resolution mass spectra were recorded on a Waters GCT Premier spectrometer, at
Cardiff, UK, and high-resolution mass spectra were recorded on a Waters LCT Premier XE
instrument at Cardiff, UK. Microanalysis was performed by analytical service at both the
Universities of Tanta and Cairo, Egypt. Analytical thin layer chromatography (TLC) was
performed on EM silica gel F254 sheet (0.2 mm) with petroleum ether (40–60 ◦C)/acetone
(5:2 by volume) as a developing eluent. The spots were detected with UV Lamp Model UV
GL-58. Reagents and solvents were obtained from commercial sources and used without
purification.
Chemistry
General Procedure for the Synthesis of Diphenyl (arylamino)(pyridin-3-
yl)methylphosphonates (2–6). A mixture of 1 (1.07 g, 10.0 mmol), aromatic amine
(20.0 mmol), triphenylphosphite (4.65 g, 15.0 mmol), and titanium tetrachloride (TiCl4;
0.19 g; 1.0 mmol) in DCM (10 mL) was stirred at r.t. for 24–32 h during which the progress
of the reaction was monitored by TLC. The solvent was removed under reduced pressure
and the residue obtained was treated with methanol (20 mL), and then filtered to remove
the solid materials. A mixture of water (10 mL) and DCM (20 mL) was added to the filtrate,
and the organic phase was separated and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give the crude product, which recrystallized from
1
ethanol to give the pure products 2–6 as white solids. The H and 31P NMR spectra for
compound 2 are presented as Figures S6 and S7 in the Supplemental Materials (posted
online only).
Diphenyl (phenylamino)(pyridin-3-yl)methylphosphonate (2). Reaction time:
◦
24 h; Yield: 81%; mp: 112−114 C. Selected IR data (KBr): 3390 (NH), 1596 (C N),
1320 (P O), and 823 (P–O–C) cm−1. H NMR (MeCOMe/DMSO-d6): δ 8.44–6.18 (m,
1
20 H, Ar–H, and NH) and 5.25 (2 d, J = 11 Hz, 1 H, CH) ppm. 31P NMR (DMSO-d6):
δ 16.0 ppm. AP+–MS: m/z (%) 418 ([M + 2 H]+, 28), 417 ([M + H]+, 100), 368 (4),
327 (12), 269 (18), 229 (51), and 199 (15). HRMS (AP+): m/z [M + H]+ calcd for
C24H22N2O3P: 417.1368; found: 417.1351. Anal calcd for C24H21N2O3P (416.41): C,
69.22; H, 5.08; N, 6.73; P, 7.44. Found: C, 69.25; H, 5.10; N, 6.74; P, 7.35.

SYNTHESIS OF α-AMINOPHOSPHONATES AS ANTIMICROBIALS
883
Diphenyl (4-chlorophenylamino)(pyridin-3-yl)methylphosphonate (3). Reaction
time: 28 h; Yield: 78%; mp: 135−137 ◦C. Selected IR data (KBr): 3305 (NH), 1588 (C N),
1361 (P O), and 820 (P–O–C) cm−1. 1H NMR (DMSO-d6): δ 8.88–6.97 (m, 19 H, Ar–H,
and NH) and 5.75 (2 d, J = 13 Hz, 1 H, CH) ppm. 31P NMR (DMSO-d6): δ 16.1 pm.
AP+–MS: m/z (%) 453 ([M37Cl + H]+, 33), 451 ([M35Cl + H]+, 100), 417 (12), 385 (27),
368 (30), 327 (32), and 249 (11). HRMS (AP+): m/z [M + H]+ calcd for C24H2135ClN2O3P:
451.0978; found: 451.0963. Anal calcd for C24H20ClN2O3P (450.85): C, 63.94; H, 4.47;
N, 6.21; P, 6.87. Found: C, 64.20; H, 4.21; N, 6.16; P, 6.85.
Diphenyl (4-hydroxyphenylamino)(pyridin-3-yl)methylphosphonate (4). Reac-
◦
tion time: 24 h; Yield: 81%; mp: 205−207 C. Selected IR data (KBr): 3424 (NH/OH),
1585 (C N), 1334 (P O), and 869 (P–O–C) cm−1. 1H NMR (DMSO-d6): δ 8.90–6.93 (m,
20 H, Ar–H, OH, and NH) and 5.73 (2 d, J = 15 Hz, 1 H, CH) ppm. 31P NMR (DMSO-d6):
δ 15.1 ppm. EI–MS: m/z (%) 433 ([M + H]+, 4), 432 (M+, 16), 339 (26), 246 (66), and 199
(100). HRMS (EI): m/z [M]+ calcd for C24H21N2O4P: 432.1239; found: 432.1241. Anal
calcd for C24H21N2O4P (432.41): C, 66.66; H, 4.90; N, 6.48; P, 7.16. Found: C, 66.70; H,
4.92; N, 6.45; P, 7.15.
Diphenyl (4-methoxyphenylamino)(pyridin-3-yl)methylphosphonate (5). Reac-
tion time: 30 h; Yield: 88%; mp: 160−162 ◦C. Selected IR data (KBr): 3422 (NH), 1582
(C N), 1325 (P O), and 801 (P–O–C) cm−1. 1H NMR (DMSO-d6): δ 8.93–6.71 (m, 19
H, Ar–H, and NH); 5.69 (2 d, J = 16 Hz, 1 H, CH); and 4.17 (s, 3 H, OCH3) ppm. 31P NMR
(DMSO-d6): δ 15.1 ppm. AP+–MS: m/z (%) 447 ([M + H]+, 3), 415 (2), 294 (5), 193 (6),
140 (8), 117 (22), 100 (100), 97 (57), and 77 (47). HRMS (AP+): m/z [M + H]+ calcd
for C25H24N2O4P: 447.1474; found: 447.1478. Anal calcd for C25H23N2O4P (446.43): C,
67.26; H, 5.19; N, 6.27; P, 6.94. Found: C, 67.22; H, 5.02; N, 6.57; P, 6.90.
Diphenyl (4-methylphenylamino)(pyridin-3-yl)methylphosphonate (6). Reaction
time: 32 h; Yield: 89%; mp: 194−196 ◦C. Selected IR data (KBr): 3391 (NH), 1599 (C N),
1343 (P O), and 836 (P–O–C) cm−1. 1H NMR (DMSO-d6): δ 8.73–6.66 (m, 19 H, Ar–H,
and NH); 4.85 (2 d, J = 14 Hz, 1 H, CH); and 2.29 (s, 3 H, CH3) ppm. 31P NMR (DMSO-
d6): δ 16.1 ppm. AP+–MS: m/z (%) 472 ([M + MeCNH]+, 9), 432 ([M + 2 H]+, 25), 431
([M + H]+, 100), 368 (12), 327 (17), and 294 (6). HRMS (AP+): m/z [M + H]+ calcd
for C25H24N2O3P: 431.1525; found: 431.1506. Anal calcd for C25H23N2O3P (430.43): C,
69.76; H, 5.39; N, 6.51; P, 7.20. Found: C, 69.72; H, 5.34; N, 6.48; P, 7.15.
Biological Assay
Gram-Negative Bacteria. After Gram-staining procedure, Gram-negative cells ap-
pear pink. The Gram-negative bacterium used in this study was E. coli, which is known
as the backbone for Gram-negative bacteria and causes urinary infection, wound infection,
and gastroenteritis.
Gram-Positive Bacteria. The thick cell wall of a Gram-positive organism retains the
crystal violet dye used in the Gram-staining procedure, so the stained cells appear purple
under magnification. Gram-positive bacteria used in this study were B. subtilis (PC1219)
and S. aureus (ATCC25292). B. subtilis are mostly involved in urinary infection, wound,
ulceration, and septicemia. S. aureus is the milestone of Gram-positive bacteria and is a
causative agent of pneumonia, meningitis, and food poisoning.
Fungi. Pathogenic fungi, especially yeasts, are responsible for a number of diseases
in humans, animals. A number of pathogenic strains of fungi are represented in C. albi-
cans and S. cerevisiae. The tested organisms were obtained from the culture collection

884
M. F. ABDEL-MEGEED ET AL.
of Bacteriology Unit, Department of Botany, Faculty of Science, Tanta University, Tanta,
Egypt.
Determination of Minimum Inhibitory Concentrations. The antimicrobial activi-
ties of the tested samples were determined by measuring the diameter of zone of inhibition
expressed in millimeters. The inhibition zones were measured in triplicates and expressed
as mean SD.42
The Lethal Dose. Brine shrimps lethality bioassay is very simple bench-top assay
used to measure cytotoxicity of plant extracts as well as the synthesized compounds. Three
replicates were used for each concentration and living larvae were counted after 72 h. All
data were expressed as mean SD.43
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