CeCl 3·7H 2O Catalyzed, microwave-assisted high-yield synthesis of α-aminophosphonates and their biological studies

Article abstract of DOI:10.1080/10426507.2013.798785

A new class of diethyl(3,5-dibromo-4-hydroxyphenylamino) (substituted phenyl/heterocyclic) methylphosphonates 4(a-j) has been synthesized by one-pot three component simultaneous reaction (Kabachnik-Fields) of 4-amino-2,6- dibromophenol 1, substituted heterocyclic/phenyl aldehydes 2(a-j), and diethylphosphite 3 using a Lewis acid catalyst, CeCl3·7H2O (5 mol%) under microwave irradiation as well as conventional conditions. It was observed that microwave irradiation method is more facile, efficient, and advantageous with respect to reaction time and yields. The structures of all the synthesized compounds were supported by analyzing IR, ¹H/¹³C/ ³¹P NMR, and mass spectral data. The synthesized compounds were screened for their in vitro antimicrobial and antioxidant activities.

Full text of DOI:10.1080/10426507.2013.798785

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Phosphorus, Sulfur, and Silicon and the
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CeCl3·7H2O Catalyzed, Microwave-
Assisted High-Yield Synthesis of α-
Aminophosphonates and their Biological
Studies
M. Varalakshmi a , D. Srinivasulu a , D. Rajasekhar a , C. Naga Raju a
& S. Sreevani b
a Department of Chemistry , Sri Venkateswara University , Tirupati ,
Andhra Pradesh , India
b Department of Microbiology , Sri Venkateswara University ,
Tirupati , Andhra Pradesh , India
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Accepted author version posted online: 02 Aug 2013.Published
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To cite this article: M. Varalakshmi , D. Srinivasulu , D. Rajasekhar , C. Naga Raju & S. Sreevani
(2014) CeCl3·7H2O Catalyzed, Microwave-Assisted High-Yield Synthesis of α-Aminophosphonates and
their Biological Studies, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:1, 106-112,
DOI: 10.1080/10426507.2013.798785
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Phosphorus, Sulfur, and Silicon, 189:106–112, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.798785
CeCl3·7H2O CATALYZED, MICROWAVE-ASSISTED
HIGH-YIELD SYNTHESIS OF α-AMINOPHOSPHONATES
AND THEIR BIOLOGICAL STUDIES
M. Varalakshmi,1 D. Srinivasulu,1 D. Rajasekhar,1
C. Naga Raju,1 and S. Sreevani2
1Department of Chemistry, Sri Venkateswara University, Tirupati,
Andhra Pradesh, India
2Department of Microbiology, Sri Venkateswara University, Tirupati,
Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract
A new class of diethyl(3,5-dibromo-4-hydroxyphenylamino) (substituted
phenyl/heterocyclic) methylphosphonates 4(a–j) has been synthesized by one-pot three
component simultaneous reaction (Kabachnik–Fields) of 4-amino-2,6-dibromophenol 1,
substituted heterocyclic/phenyl aldehydes 2(a–j), and diethylphosphite 3 using a Lewis
acid catalyst, CeCl3·7H2O (5 mol%) under microwave irradiation as well as conventional
conditions. It was observed that microwave irradiation method is more facile, efficient, and
advantageous with respect to reaction time and yields. The structures of all the synthesized
compounds were supported by analyzing IR, 1H/13C/31P NMR, and mass spectral data.
The synthesized compounds were screened for their in vitro antimicrobial and antioxidant
activities.
Keywords α-Aminophosphonates; Lewis acid catalyst (CeCl3·7H2O); microwave irradiation;
antimicrobial and antioxidant activities
Received 24 December 2012; accepted 20 April 2013.
The authors are grateful to acknowledge financial support from University Grants Commission [UGC F.No.
40-71/2011(SR)] under which this research was carried out, one of the authors M. Varalakshmi wishes to thank
University Grants Commission [RGNF, F1-17.1/2011-12] for providing the financial support through RGNF. The
authors are also thankful to B. Vijaya Lakshmi, Osmania University, Hyderabad for providing the spectral data
and would like to thank Jeanne Gilbert, USA and D. Subba Rao, S.V. University, India for providing technical
support to the final manuscript.
Address correspondence to D. Srinivasulu, Department of Chemistry, Sri Venkateswara University, Tirupati,
Andhra Pradesh, India. E-mail: doddaga s@yahoo.com
106

CeCl3·7H2O CATALYZED, MICROWAVE-ASSISTED HIGH-YIELD
107
INTRODUCTION
Phosphorus functionalized organic molecules have found a wide range of applications
in the areas of industrial, agricultural, and medicinal chemistry owing to their biological
and physical properties1 and offer fascinating possibilities for structural, synthetic, and
mechanistic study.2 As mimics of natural amino acids and of low mammalian toxicity, the
α-aminophosphonates and derivatives are currently attracting a great deal of interest in
industrial as well as in medicinal chemistry.3 They are also found to be effective in inhibit-
ing test-tube growth of malarial parasite4 plasmodium falciparum, and it has same effect
as related types of single-celled parasites such as Toxoplasma that causes opportunistic
infections in AIDS patients.5 Also, these derivatives have shown various biological activi-
ties such as antifungal activity,6 antibacterial activity,7 antitumor effects,8 antiviral activity,9
enzymes inhibitors such as rennin, HIV protease, serine protease,10 PTP1B inhibitors,11 her-
bicides,12 and pharmacological agents.13 The marine red algae of the family Rhodomelaceae
are known to contain high concentration of bromophenols with a diversity of molecular
structures. Some of the bromophenols previously isolated from this family have shown
significant nitrite scavenging, glucosidase inhibition, and antioxidant activities.14
Several methodologies have reported in the literature to synthesize α-
aminophosphonate (–P-C-N bond) derivatives by Pudovik reaction as well as other
pathways such as Mannich-type reactions and Kabachnik–Fields. Among them,
Kabachnik–Fields reaction is a powerful one-pot three component (amine, aldehyde,
phosphite) reaction to synthesize α-aminophosphonate derivatives.15 Several Lewis
acid catalysts, such as InCl3,16 BiCl3,17 FeCl3,18 YbCl3,19 and SbCl3,20 have been used
to promote this reaction easily and efficiently. Recently, Jafari et al.21 reported three
component synthesis of α-aminophosphonates using Cerium (III) chloride heptahydrate
catalyst under solvent-free conditions. Although the described procedures worked nicely in
many cases, they are associated with one or more shortcomings, such as long reaction time,
low yield, lack of generality, require stoichiometric amount of toxic catalyst, moisture
sensitive catalyst, the use of an expensive or less easily available catalysts, generate large
amount of waste, and vigorous reaction conditions.
CeCl3·7H2O has emerged as a potential catalyst for effecting various organic
transformations due to its high catalytic ability, water tolerance, economic availability, and
being a “eco-friendly” reagent.22 Moreover, microwave chemistry can provide access to syn-
thetic transformations that may be prohibitively long or low yielding using conventional
heating. As part of our research program, we synthesized a series of new diethyl(3,5-
dibromo-4-hydroxyphenylamino) (substituted phenyl/heterocyclic) methylphosphonates
4(a–j) in tetrahydrofuran (THF) solvent under microwave irradiation conditions as well
as conventional conditions using CeCl3·7H2O. Optimum yields of α-aminophosphonate
derivatives were obtained under microwave irradiation. The antibacterial and antifungal
activities of titled compounds were investigated against corresponding pathogens and some
of the compounds showed significant activity against microorganisms. Also, the antioxidant
activity of the synthesized compounds was examined; 4c, 4d, 4g, and 4i exhibited potent
antioxidant activity.
RESULTS AND DISCUSSION
The synthesis of new α-aminophosphonate derivatives was carried out effectively in
the presence of CeCl3·7H2O under microwave irradiation and conventional conditions as
depicted in Scheme 1.

108
M. VARALAKSHMI ET AL.
Scheme 1 Synthesis of α-aminophosphonates 4(a–j) in the presence of CeCl3·7H2O.
4-Amino-2,6-dibromophenol (1), 4-chloro-3-nitrobenzaldehyde (2c), and di-
ethylphosphite (3) were selected as materials for optimization of the reaction conditions.
The three component Kabachnik–Fields reaction was examined with these models in
different solvents, such as ethanol (EtOH), THF, toluene, dimethylformamide (DMF), and
acetonitrile (ACN) using 5 mol% of CeCl3·7H2O at 50–65◦C to synthesize compound
4c and the yields are shown in Table 1. The reaction in THF solvent gave the highest
yield (88%) of 4c (Table 1, entry 2) as compared with other solvents. To establish the
generality of the reaction, various aldehydes were examined in the presence of 5 mol%
of CeCl3·7H2O in THF solvent to afford the corresponding α-aminophosphonates 4(a–f)
(Table 2). To reduce the reaction time and improve the yields, the model reaction was
tested under microwave irradiation [CATA-4R, Power (70%) Watts (490)] using 5 mol% of
CeCl3·7H2O catalyst in THF solvent. A high yield (Table 2, entry 3) (94%) was observed
in a short reaction time (8 min). This optimized procedure was applied for the synthesis of
all the title compounds that were already prepared under conventional conditions and the
results are summarized in Table 2. The reusability of the catalyst was also examined up to
Table 1 Solvent effect on the synthesis of α-aminophosphonates using CeCl3·7H2O (5 mol%)
Entry
Solvent
Temp (◦C)
Time (h)
Yield (%)
1
2
3
4
5
Ethanol
THF
Toluene
DMF
60
65
80
85
50
6
3
6
5
7
75
88
70
78
69
ACN

CeCl3·7H2O CATALYZED, MICROWAVE-ASSISTED HIGH-YIELD
109
Table 2 Synthesis of α-aminophosphonates using CeCl3·7H2O (5 mol%) under conventional and microwave
irradiation conditions
Conventional conditions
Microwave irradiation
Time (min) Yield (%)
10 90
Entry
Compd
Time (h)
Yield (%)
mp (◦C)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
3.5
4
3
4
4
3.5
3.5
3.5
3
84
81
88
83
84
84
85
82
85
83
118–120
183–185
145–147
178–180
129–131
135–137
137–139
178–180
131–133
112–114
11
8
89
94
89
90
91
90
90
92
91
10
11
9
9
9
9
10
8
10
4j
3.5
two cycles to synthesize compound 4c and gave the corresponding yields 80% and 76% in
conventional conditions and 90% and 87% in microwave conditions.
A reasonable pathway for the reaction of an amine and an aldehyde with diethylphos-
phite using CeCl3·7H2O catalyst in THF is presented in Figure 1, in which CeCl3·7H2O
exhibits dual activity: one action is in situ generation of imine and the second action is to
Figure 1 The plausible mechanism for synthesis of α-aminophosphonates in the presence of CeCl3·7H2O
catalyst.

110
M. VARALAKSHMI ET AL.
enhance the activity of imine, and to bring the diethylphosphite substrate close to the imine
by the template effect.21,23
The structures of the title compounds 4(a–j) were confirmed by analytical and spec-
tral data (see Experimental section). The IR absorption bands appeared in the region of
3400–3520, 3200–3380, and 1210–1260 cm−1 of the –O-H, -N-H, and -P=O stretches,
respectively. In 1H NMR spectra, the chemical shifts appeared in the region of 1.00–1.30,
3.50–4.20, 4.50–5.40, 6.00–6.93, and 6.50–8.50 of the –CH3, -OCH2, -CHP-N-, -NH-CH,
and aromatic protons, respectively. Further, the structural confirmation of the designed
compounds 4(a–j) was confirmed by the corresponding 13C NMR chemical shift values
and molecular ions, fragmentation ion peaks in the mass spectra.
The synthesized compounds in the present paper were screened for their antibacterial
activity (Table S1, Supplemental Materials) against the growth of Staphylococcus auerus,
Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa by employing cup-plate
agar diffusion method,24 and streptomycin was used as standard drug. The antifungal ac-
tivity was tested (Table S2, Supplemental Materials) against fungi such as Trichoderma
harzanium, Aspergillus flavus, and Aspergillus niger by using agar disc-diffusion method,25
and bovastin was used as reference drug. Minimum inhibitory concentrations of the syn-
thesized compounds against tested strains were also investigated by using micro-broth
dilution method.26 Antioxidant activity of the titled compounds was also tested using 1,1-
diphenylpicrylhydrazyl (DPPH)27 (Table S3) and nitric oxide (NO) (Table S4) method.28
CONCLUSION
We have prepared biologically active α-aminophosphonate derivatives in excellent
yields in short reaction times by a one-pot, three component reaction using CeCl3·7H2O as
a catalyst under microwave irradiation as well as conventional conditions in THF solvent. In
vitro antimicrobial activity includes minimum inhibition concentrations (MICs) against the
growth of selected microorganisms and antioxidant activity was examined. Most of the com-
pounds exhibited potent to moderate activity against the tested pathogens. It is concluded
that the present method might be useful for the synthesis of α-aminophosphonate derivatives
in short reaction time with high yields in small scale and the title compounds may be act
as reference compounds or intermediates for further synthesis of potent chemotherapeutic
agents in future.
EXPERIMENTAL
All chemicals were purchased from Merck, Aldrich and S. D. Fine-chem. (India) for
use without further purification. Solvents were distilled from the appropriate drying agents
and degassed before use. Melting points were determined in open capillaries on Guna
melting point apparatus and are uncorrected. IR spectra were recorded on JASCO FT-IR
5300 using KBr discs. 1H NMR, 31P NMR, and 13C NMR spectra were recorded on Bruker
AV-400 spectrometer. Mass spectra were recorded on an API 3000 mass spectrometer
(Positive mode). The progress of the reactions was monitored by thin layer chromatography
(TLC) on Merck silica plates. Results are presented as chemical shift δ in ppm, multiplicity,
J values in Hertz (Hz), number of protons, and proton’s position. Multiplicities are shown as
the abbreviations: s (singlet), brs (broad singlet), d (doublet), t (triplet), and m (multiplet).

CeCl3·7H2O CATALYZED, MICROWAVE-ASSISTED HIGH-YIELD
111
Synthesis of α-Aminophosphonates Under Conventional Conditions
4-Amino-2,6-dibromophenol (1) (264.87 mg, 1 mmol), 4-chloro-3-nitrobenz
aldehyde (2c) (144.99 mg, 1 mmol), and diethylphosphite (3) (0.162 mL, 1.2 mmol) were
dissolved in THF (10 mL) and stirred for 5 min to obtain a homogeneous solution. To
this reaction mixture, the catalyst CeCl3·7H2O (5 mol%) was added and the mixture was
refluxed at 60◦C for 3 h. After completion of the reaction (checked by TLC), the reaction
mixture was filtered to remove the catalyst. The filtrate was evaporated under vacuum and
the resulting crude material was purified by chromatography on small silica gel column
using 30% ethyl acetate and n-hexane as an eluent to afford diethyl(4-chloro-3-nitrophenyl)
(3,5-dibromo-4-hydroxyphenylamino)methylphosphonate 4c (88%).
Pale yellow solid, yield: 94%, mp: 145–147◦C. FT-IR (KBr) (νmax cm−1): 3423 (-OH,
1
str), 3029 (-NH, str), 1503 (-N=O, str), 1235 (-P=O, str), 1018 (-P-O-C, str); H NMR
(DMSO-d6, 400 MHz): δ 1.08 (t, J = 7.2 Hz, 3H, -CH3), 1.18 (t, J = 6.8 Hz, 3H, -CH3),
3.85–4.10 (m, 4H, -OCH2), 5.35 (dd, J = 13.2 Hz, J = 10.8 Hz, 1H, -P-CH-N), 6.52 (d,
J = 8.4 Hz, 1H, -NH-CH), 7.08 (s, 2H, Ar-H), 7.79–7.85 (m, 2H, Ar-H), 8.21 (s, 1H, Ar-H),
8.90 (s, 1H, Ar-OH); 13C NMR (DMSO-d6, 100.6 MHz): δ 16.3 (C15, C17), 62.5 (C14, C16),
62.04 (C7), 113.1 (C3, C5), 116.8 (C2, C6), 124.7 (C9), 125.8 (C11), 132.3 (C12), 134.0
(C13), 135.1 (C8), 142.6 (C4), 142.8 (C1), 147.0 (C10); 31P NMR (DMSO-d6, 200 MHz): δ
22.7. MS (positive mode) (m/z): 571 (M + H+), 573 (M + 2+H+), 575 (M + 4+H+), 577
(M + 6 + H+).
Reusability of the Active Catalyst
After completion of the reaction, the reaction mixture was cooled and filtered-off to
remove the catalyst. The residue, CeCl3·7H2O was washed with dichloromethane (DCM;
3 × 10 mL) to remove the tars and then dried in an oven at 60◦C for 2 h. The catalyst was
reused up to two cycles without loss of catalytic activity.
Synthesis of α-Aminophosphonates Under Microwave
Irradiation Conditions
A mixture of 4-amino-2,6-dibromophenol (1) (264.87 mg, 1 mmol), 4-chloro-
3-nitrobenzaldehyde (2c) (144.99 mg, 1 mmol), and diethylphosphite (3) (0.162 mL,
1.2 mmol) was dissolved in a 50 mL beaker containing THF (5 mL). The reaction mixture
was irradiated with microwave radiation using 4R Catalyst micro oven at Power cycling
70%, Watts 490. The progress of the reaction was monitored by TLC analysis. After com-
pletion of the reaction, the reaction mixture was filtered to remove the catalyst. The filtrate
was evaporated under vacuum and the resulting crude material was purified by column
chromatography using 30% ethyl acetate and n-hexane as an eluent to afford diethyl(4-
chloro-3-nitrophenyl)(3,5-dibromo-4-hydroxyphenylamino)methylphosphonate 4c (94%).
The characterization data for the other synthesized compounds can be found in the
Supplemental Materials.
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