Microwave assisted synthesis of biologically active α- aminophosphonates catalyzed by nano-BF 3·SiO 2 under solvent-free conditions

Article abstract of DOI:10.1080/10426507.2012.723656

An efficient and high-yield synthesis of a class of new α-aminophosphonate derivatives as diethyl α-aryl/2-thienyl-α- [2-(phenylthio)phenylamino]methylphosphonates 6a-j in short reaction times from three component coupling reactions (Kabachnik-Fields reaction) of 2-aminodiphenylsulfide 3, substituted phenyl/heterocyclic aldehydes 4a-j, and diethyl phosphite 5 is reported. The reaction proceeds smoothly in the presence of the catalyst, nano-silica-supported boron trifluoride (BF₃· SiO₂) without using solvent under microwave irradiation. The title compounds were tested for in vitro antibacterial and antifungal activities at concentrations of 100 and 200 μg/disc. Minimum inhibitory concentrations (MICs) were also examined. Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures and tables.

Full text of DOI:10.1080/10426507.2012.723656

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Microwave Assisted Synthesis of
Biologically Active α-Aminophosphonates
Catalyzed by Nano-BF3·SiO2 under
Solvent-Free Conditions
D. Rajasekhar a , D. Subba Rao a , D. Srinivasulu a , C. Naga Raju a
M. Balaji b
&
a Department of Chemistry , Sri Venkateswara University , Tirupati ,
Andhra Pradesh , India
b Department of Biochemistry , Sri Venkateswara University ,
Tirupati , Andhra Pradesh , India
Accepted author version posted online: 27 Aug 2012.
To cite this article: D. Rajasekhar , D. Subba Rao , D. Srinivasulu , C. Naga Raju & M. Balaji (2013)
Microwave Assisted Synthesis of Biologically Active α-Aminophosphonates Catalyzed by Nano-BF3·SiO2
under Solvent-Free Conditions, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:8,
1017-1025, DOI: 10.1080/10426507.2012.723656
To link to this article: http://dx.doi.org/10.1080/10426507.2012.723656
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Phosphorus, Sulfur, and Silicon, 188:1017–1025, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.723656
MICROWAVE ASSISTED SYNTHESIS OF BIOLOGICALLY
ACTIVE α-AMINOPHOSPHONATES CATALYZED BY
NANO-BF3·SiO2 UNDER SOLVENT-FREE CONDITIONS
D. Rajasekhar,1 D. Subba Rao,1 D. Srinivasulu,1 C. Naga Raju,1
and M. Balaji2
1Department of Chemistry, Sri Venkateswara University, Tirupati,
Andhra Pradesh, India
2Department of Biochemistry, Sri Venkateswara University, Tirupati,
Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract An efficient and high-yield synthesis of a class of new α-aminophosphonate deriva-
tives as diethyl α-aryl/2-thienyl-α-[2-(phenylthio)phenylamino]methylphosphonates 6a–j in
short reaction times from three component coupling reactions (Kabachnik-Fields reaction) of
2-aminodiphenylsulfide 3, substituted phenyl/heterocyclic aldehydes 4a–j, and diethyl phos-
phite 5 is reported. The reaction proceeds smoothly in the presence of the catalyst, nano-silica-
supported boron trifluoride (BF3·SiO2) without using solvent under microwave irradiation. The
title compounds were tested for in vitro antibacterial and antifungal activities at concentrations
of 100 and 200 μg/disc. Minimum inhibitory concentrations (MICs) were also examined.
Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental
files: Additional text, figures and tables.
Keywords Nano-silica-supported boron trifluoride (BF3·SiO2); microwave irradiation;
solvent-free conditions; α-aminophosphonates; antimicrobial activity; minimum inhibitory
concentrations (MICs)
Received 26 July 2012; accepted 20 August 2012.
The authors gratefully acknowledge financial support from University Grants Commission [UGC F.No. 40-
71/2011 (SR)] under which this research was pursued, and for editing of the final manuscript by Jeanne Gilbert,
USA.
Address correspondence to D. Srinivasulu, Associate Professor, Department of Chemistry, Sri Venkateswara
University, Tirupati-517 502, Andhra Pradesh, India. E-mail: doddaga s@yahoo.com
1017

1018
D. RAJASEKHAR ET AL.
INTRODUCTION
Organophosphorus compounds are important substrates in drug design. Several pro-
drugs containing these constituents play a vital role in biochemical processes, in medicinal
chemistry and in agricultural chemistry because they are subject to cleavage by an en-
zyme digestive phosphatase.1–3 Both natural and synthetic phosphorus derivatives offer
fascinating possibilities for structural, synthetic, and mechanistic studies4,5 and play an
important role as metabolic intermediates as common regulatory switches for proteins and
as a backbone for the genetic information.6
Diphenyl sulfide is an important motif in drugs and drug intermediates. 2-[(2-dimeth-
ylaminomethyl)phenylthio]-5-iodo-benzylalcohol(IDAM) 1and2-[(2-dimethylaminomet-
hyl)phenylthio]-5-methoxyaniline (DAPP) 2 (Figure 1) have shown high in vitro and in vivo
affinities and selectivities for serotonin transporter (SERT) relative to the dopamine, which
plays a key-role in the regulation of serotoninergic function, numerous neurodegenerative,
psychiatric disorders, and the norepinephrine transporters (DAT, NET).7,8
α-Aminophosphonates are isosteric or bioisosteric analogues of the natural α-
aminocarboxylates9, which play a vital role in the chemistry of life and as structural units
in peptides, proteins, and enzymes. Hence, α-aminophosphonates have attracted much
attention owing to their biological activities such as in the development of inhibitors of
GABA receptors, enzyme inhibitors, antibiotics, peptide mimics, herbicides, pharmacolog-
ical agents, and many other applications that are well documented10 as well as for some
alkyl-substituted phosphonate compounds shown to have antifungal activity,11 antibacterial
activity,12 antitumor effects13, and antiviral activity.14
I
OMe
S
S
NH2
N
N
OH
1
2
IDAM
selective for serotonin transporter (SERT)
DAPP
1
10
6
5
2
9
11
27
29
26
12
13
3
8
S
25
21O
4
7
O
23
HN
P
H
14
C
22
O
28
24
19
15
20
R1
16
18
17
Title compounds 6(a-j)
Figure 1 Selected active diphenylsulfide derivatives.

BIOLOGICALLY ACTIVE α-AMINOPHOSPHONATES
1019
There are two main pathways such as the Pudovik reaction and the Kabachnik-Fields
reaction for synthesizing α-aminophosphonates. Of these methods, the Kabachnik–Fields
reaction15 is the most convenient method to synthesize 1-aminoalkylphosphonates, cat-
alyzed by an acid or a base. However, these reactions cannot proceed smoothly by a one-pot
method from aldehydes, amines, and diethyl phosphite due to water formation during the
course of reaction causing deactivation or decomposition of the catalysts. Several Lewis acid
catalysts such as InCl3,16 BiCl3,17 FeCl3,18 YbCl3,19 SbCl3/Al2O3, Zn(OAc)2.2H2O,21
20
Sn(II),22 and NbCl5 have been used to promote this reaction. Recently, trivalent cyclic
23
chlorophosphites played a key role to synthesize the α-aminophosphonates without us-
ing a catalyst under solvent-free conditions.24 Although these methodologies have worked
very well in many cases, some of these procedures were associated with one or more
shortcomings such as long reaction time, low-yield, lack of generality, requirement of sto-
ichiometric amounts of toxic catalyst, moisture sensitive catalyst, the use of expensive or
less easily available catalysts, generation of large amounts of waste, and rigorous reaction
conditions.
Both nano-BF3·SiO2 and BF3·SiO2 are bench-top catalysts that are reusable, cheap,
readily available, eco-friendly, versatile, and do not need any special precautions for prepa-
ration, handling, or storage. The nano-BF3·SiO2 enables better accessibility of reactants to
active sites and are efficient for promotion of many acid catalyzed organic reactions25,26 due
to more effective surface areas. Moreover, it is now recognized that many chemical reactions
proceed more rapidly with clean and high yield transformations under microwave irradia-
tion. Hence, it is clear that organic synthesis has greatly benefited from the development
of microwave methodology.27 In the present paper, we report an efficient and convenient
one-pot three component procedure for the synthesis of α-aminophosphonates in the pres-
ence of nano-BF3·SiO2 under microwave assisted neat reaction conditions. All synthesized
novel α-aminophosphonates 6a–j were screened for their antimicrobial activity.
RESULTS AND DISCUSSION
An efficient and environmentally benign one-pot approach was developed for the
synthesis of α-aminophosphonates 6a–j by condensation of 2-(phenylthio)aniline 3 with
various aromatic aldehydes 4a–j and simultaneous addition of diethyl phosphite 5 in the
presence of the catalyst (0.35 g, 37% nano-BF3·SiO2) under microwave assisted neat
reaction conditions and are represented in Scheme 1.
To optimize the experimental conditions, we carried out one-pot Kabachnik-Fields
reactions with 2-(phenylthio)aniline 3, 3-nitrobenzaldehyde 4c and diethyl phosphite 5 that
were selected as models. The progress of the reaction was investigated in the presence of
different catalysts under solvent-free conditions using both microwave assisted as well as
conventional methods to afford compound 6c (Table 1). It was observed that nano-BF3·SiO2
is a more effective heterogeneous catalyst for the synthesis of α-aminophosphonates under
microwave assisted neat reaction conditions with respect to reaction times and yields as
compared to the conventional method (Table 1, entry 11 and Figure 2). Also, there is no
significant difference between nano-BF3·SiO2 and BF3·SiO2 in reaction times and yields
(>2%, nano-BF3·SiO2). In addition, we examined the effect of amount of nano-BF3·SiO2
catalyst on the Kabachnik-Fields reaction (Table 1, entries 8–11 and Table 2). The reaction
is effective to afford the maximum yield of 93% at 0.35 g of nano-BF3·SiO2 catalyst. The
reusability of the nano-BF3·SiO2 catalyst was also examined. After each run, the product

1020
D. RAJASEKHAR ET AL.
O
Nano. BF3. SiO2
+ OHC R
H
P OEt
OEt
+
H
C
R
S
S
O
P
Solvent free
OEt
OEt
NH2
HN
MWI, 6-10 min
3
4
5
6(a-j)
R
Cl
O2N
HO
Cl
OH
Cl
a
6
6c
6b
6e
6d
S
MeO
MeO
MeO
OMe
O2N
OMe
OH
6g
OH
6i
Cl
6f
6h
6j
Scheme 1 Synthesis of α-aminophosphonates 6a–j in presence of nano-BF3·SiO2 catalyst.
was filtered and the residual catalyst was washed with CHCl3 to remove tars more efficiently
from the catalyst surface26 and reused up to five cycles to synthesize compound 6c and gave
corresponding yields (93%, 92%, 90%, 87%, and 87%). We have re-examined this reaction
and found that nano-BF3·SiO2 catalyst could effectively catalyze this reaction under solvent-
free microwave irradiation conditions to afford the desired products in high yields relatively
Table 1 Optimization of reaction conditions for the synthesis of α-aminophosphonate derivatives of 2-
aminodiphenylsulfide 6a–ja
Time
Yieldb (%)
Conventional
condition (h)
Microwave
irradiation (min)
Conventional
condition
Microwave
irradiation
Entry
Catalysts
1
2
3
4
5
6
7
8
9
Et3N
FeCl3 (10 mol%)
AlCl3 (10 mol%)
CuCl2 (10 mol%)
ZnCl2 (10 mol%)
ZnSO4 (10 mol%)
p-TSA (10 mol%)
37% BF3·SiO2 (0.3 g)
Nano-BF3·SiO2 (0.3 g)
37% BF3·SiO2 (0.35 g)
Nano-BF3·SiO2 (0.35 g)
10
5
5.5
6
17
13
15
16
12
15
10
6
55
67
64
60
70
65
69
82
85
82
86
75
81
75
73
86
78
82
91
93
93
93
4
4.5
3.5
2
2
2
6
6
6
10
11
2
aOne-pot Kabachnik-Fields reactions with 2-(phenylthio)aniline 3, 3-nitrobenzaldehyde 4c, and diethyl phos-
phite 5 in solvent free conditions using nano-BF3·SiO2 as heterogeneous catalyst under microwave irradiation.
bIsolated yield.

BIOLOGICALLY ACTIVE α-AMINOPHOSPHONATES
1021
Figure 2 Influence of the catalysts on the synthesis of α-aminophosphonates in conventional and microwave
irradiation methods. (Color figure available online).
in short times. After optimization of the reaction conditions, the generality of this method
progressed with several substituted aryl aldehydes 4a–j, 2-(phenylthio)aniline 3, and diethyl
phosphite 5 under assigned conditions (Table 3). The results reveal that aromatic aldehydes
bearing electron withdrawing groups afforded high yields when compared to aromatic
aldehyde bearing electron donating groups of the corresponding α-aminophosphonates
(Table 3).
Structures of the title compounds 6a–j were confirmed by analytical and spectral data.
IR stretching absorption bands were observed in the regions of 3500–3400, 3450–3300,
1260–1210, and 1060–1010 cm−1 for O–H, N–H, P O, and C–P–O, respectively. 1H NMR
chemical shift values observed in the region of δH = 1.00–1.30 as triplets, 3.50–4.20 as
multiplets, 4.50–5.40 as doublets of doublets, 6.00–6.93 as doublets, and 6.50–8.50 for
CH3, OCH2, CHP-NH, NH-CHP, and aromatic protons, respectively. 31P NMR signals
appeared at δP = 19.01–23.00 ppm. In addition, 13C NMR and MS are regarded as positive
evidence for structures of the title compounds.
All title compounds were screened for potential biological activities on bacteria
Escherichia coli, Bacillus subtilis, and Streptococcus bovis and fungi Fusarium oxyspo-
rum, Aspergillus flavus, and Aspergillus niger at two different concentrations of 100 and
200 μg/disc, along with minimum inhibitory concentrations (MICs) (Table S1 and Table
S2 are available online in Supplemental Materials). Most of the compounds were found
Table 2 Effect of catalyst loading on the synthesis of α-aminophosphonates 6a–ja
Entry
Amount of nano-BF3·SiO2 (g)
Time (min)
Yieldb
1
2
3
4
5
6
0.1
6
6
6
6
6
6
77
81
85
88
91
93
0.15
0.20
0.25
0.30
0.35
aOne-pot Kabachnik-Fields reactions with 2-(phenylthio)aniline 3, 3-nitrobenzaldehyde 4c, and diethyl phos-
phite 5 in solvent free conditions using nano-BF3·SiO2 as heterogeneous catalyst under microwave irradiation.
bIsolated yield (%).

1022
D. RAJASEKHAR ET AL.
Table 3 Physical characteristics of the α-aminophosphonates 6a–j
Compd.
Time (min)
Yields (%)
MPa/BPb (◦C)
6a
6b
6c
6d
6e
6f
6g
6h
6i
9
9
8
6
7
6
8
9
9
7
89
88
91
93
93
93
90
90
89
90
92–94a
136–139a
148–151a
108–109a
110–113a
94–95a
162–163a
134–136b
154–155a
105–108 b
6j
aMelting point.
bBoiling point.
to possess moderate to good antimicrobial activity. The compounds 6c, 6d (good activity
on E. coli), 6g, 6h, and 6i exhibited potential antibacterial and antifungal activity toward
all tested strains. The potential activity may be attributed to the presence of the functional
groups like OH in 6c, NO2 in 6d, and OCH3/OH in 6g, 6h, and 6i.
MICROBIOLOGY
Antibacterial Activity
The antibacterial activity of the newly synthesized α-aminophosphonate derivatives
6a–j was screened at 100 and 200 μg/mL against the growth of two Gram-positive (Bacil-
lus subtilis and Streptococcus bovis) and one Gram-negative (Escherichia coli) bacterial
strains using disc diffusion method.28,29 Streptomycin was used as standard drug, and the
inhibition zones of the test compounds were compared with controls (Table S1). Mini-
mum inhibitory concentrations (MIC) were determined by the broth dilution technique.30
Different concentrations (10, 20, 30, 40, 50, and 60 μg/mL) of test solutions were evaluated.
Antifungal Activity
The antifungal potency of the α-aminophosphonates 6a–j was performed at concen-
trations of 100 and 200 μg/mL against the fungal strains Fusarium oxysporum, Aspergillus
flavus, and Aspergillus niger by using the agar disc-diffusion method.31 Bovastin was used
as standard drug, and the inhibition zones of the test compounds were compared with
controls (Table S2). The Minimum Inhibitory Concentration (MIC) was determined by the
micro-broth-dilution method.30 To examine the MICs of the test solutions, concentrations
of 10, 20, 30, 40, 50, and 60 μg/mL of the test solutions were evaluated.
The results of antibacterial and antifungal activities have been summarized in Table
S1 and Table S2, respectively. Most of the compounds were found to possess moderate to
good antimicrobial activity; the compounds 6c, 6d (good activity on E. coli), 6g, 6h, and
6i exhibited potential antibacterial and antifungal activities toward all the tested strains.

BIOLOGICALLY ACTIVE α-AMINOPHOSPHONATES
1023
CONCLUSIONS
In summary, 37% nano-BF3·SiO2 was found to be an efficient catalyst in a one-
pot three component reaction of aldehydes, amines, and diethyl phosphite to afford α-
aminophosphonates in good to excellent yields under microwave assisted neat reaction
conditions. The procedure has several advantages such as short reaction time, small amount
of catalyst used that is easily recycled. It is especially the avoidance of harmful organic
solvents and toxicity in the reaction process that provides a green and efficient method
for synthesizing α-aminophosphonates. The developed methodology is a simple and good
contribution to the field of the α-aminophosphonate chemistry. Further, antimicrobial ac-
tivity was evaluated against different bacterial and fungal strains. Among the compounds,
6c, 6d, 6g, 6h, and 6i exhibited potential antibacterial and antifungal activities toward all
the tested strains.
EXPERIMENTAL
All chemicals were purchased from Merck, Aldrich, and S. D. Fine-Chem (India)
and used without further purification. Solvents were distilled over with appropriate drying
agents and degassed before use. Melting points were determined in open capillaries on a
Guna mp apparatus and are uncorrected. IR (KBr, νmax/cm−1) spectra were recorded on a
JASCO FT-IR 5300 spectrometer. 1H NMR (500 MHz), 31P NMR (125.01 MHz), and 13
C
NMR (100.6 MHz) spectra were recorded on a Bruker AV-500 spectrometer. Mass spectra
were recorded on an ESQUIRE 3000 mass spectrometer (negative mode). The progress
of the reactions was monitored by TLC on Merck silica plates. Results are presented
as chemical shift δ, multiplicity, coupling constants J, number of protons, and protons’
position. Multiplicities are shown as the abbreviations: s (singlet), bs (broad singlet), d
(doublet), t (triplet), and m (multiplet). Numbering was given to the title compound for
assigning the proper spectral characterization (Figure 1).
Preparation of the Catalyst26
5 mL of methanol containing 0.37 g of BF3 (0.7 ml of BF3·Et2O) and 0.63 g of silica
gel or nano-silica gel mixture was stirred for 1 h at r.t. The slurry was dried slowly on a
rotary evaporator at 40 ◦C. The obtained solid was washed with chloroform and dried at r.t.
for 2 h and stored in a dry container.
Synthetic Procedure for α-Aminophosphonates 6a–j
A mixture of m-nitrobenzaldehyde 4c (1 mmol, 1.0 equiv.), 2-(phenylthio)aniline
3 (1 mmol, 1.0 equiv.), diethyl phosphite 5 (1.2 mmol, 1.2 equiv.), and 37% nano-
BF3.SiO2·(0.35 g) was irradiated with microwaves (CATA-4R,% power is 65% and 465 W)
under solvent-free conditions. The progress of the reaction was monitored by TLC using
30% ethyl acetate/n-hexane as eluent. After completion of the reaction, CH2Cl2 (5 mL)
was added to the reaction mixture. To recover the catalyst, it was filtered and washed with
CH2Cl2 (5 mL). The combined filtrates and washings were concentrated under reduced pres-
sure, followed by purification with column chromatography (30% ethyl acetate/n-hexane) to
afford pure diethyl α-(3-nitrophenyl)-α-[(2-phenylthio)phenylamino]methylphosphonate
6d. The filter residue, the catalyst, was dried in vacuum and reused for the next reaction.

1024
D. RAJASEKHAR ET AL.
This same procedure was adopted for the preparation of remaining title products (Table 3).
All the title compounds 6a–j were characterized by spectroscopic methods. Complete char-
acterization data is presented in the Supplemental Materials available online, together with
selected NMR spectra for 6a and 6d (Figures S1–S6).
Diethyl α-(3-hydroxyphenyl)-α-[2-(phenyl◦thio)phenylamino]methyl phosphon-
ate (6c). White solid, yield: 91%, mp: 148–151 C. IR: 3476 (OH), 3373 (NH), 3070
(aromatic CH), 2982 (CH3), 1587 (C C), 1255 (P O), 1163 ( C O), 1022 (P–O C); 1H
NMR (DMSO-d6): 11.1 (t, J = 7 Hz, 3H, CH3), 1.13 (t, J = 7.5 Hz, 3H, CH3), 3.70–3.75
(m, 2H, OCH2), 4.88–4.94 (m, 2H, OCH2), 4.82 (dd, J = 17.7 Hz, 1H, CHP), 6.09
(t, J = 7.5 Hz, 1H, NH), 6.58 (d, J = 5 Hz, 1H, ArH), 6.71–6.75 (m, 4H, ArH),
7.06–7.10 (m, 2H, ArH), 7.12–7.20 (m, 3H, ArH), 7.23–7.28 (m, 2H, J = 3 Hz, ArH), 7.54
(t, J = 6.5 Hz, 1H, ArH), 8.46 (br, 1H, OH); 13C NMR (DMSO-d6): 6.16 (C29), 16.31 (C27),
54.77 (C21), 63.78 (C26), 63.85 (C28), 114.26 (C8), 118.49 (C10), 125.25 (C6, 17, 18), 127.38
(C9), 129.57 (C11), 129.59 (C12), 131.31 (C15, 19), 131.31 (C1), 131.68 (C2), 136.20 (C4, 5),
137.65 (C3, 20), 147. (C13), 157.41 (C16); 31P NMR (DMSO-d6): 21.58; MS (-) (m/z,%):
(M-H+, 29.4%) 442.50.
REFERENCES
1. Engel, R. Chem. Rev. 1977, 77, 349-367.
2. Hiratake, J.; Oda, J. Biosci. Biotechnol. Biochem. 1997, 61, 211-218.
3. Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 67-114.
4. Hartly, R. The Chemistry of Organophosphorus Compounds; John Wiley and Sons: New York,
USA, 1996.
5. Corbridge, D. Phosphorus; 4th ed., Elsevier: New York, USA, 1990.
6. Westheimer, F. H. Science 1987, 235, 1173-1178.
7. Oya, S.; Kung, M. P.; Acton, P. D.; Mu, M.; Hou, C.; Kung, H. F. J. Med. Chem. 1999, 42,
333-335.
8. Oya, S.; Choi, S. R.; Hou, C.; Mu, M.; Kung, M. P.; Acton, P. D.; Siciliano, M.; Kung, H. F.
Nucl. Med. Biol. 2000, 27, 249-254.
9. Kukhar, V. P.; Hudson, H. R. (Eds.), Aminophosphonic and Aminophosphinic Acids: Chemistry
and Biological Activity; Wiley: Chichester, 2000.
10. (a) Allenberger, F.; Klare, I. J. J. Antimicrob. Chemother. 1999, 43, 211-217; (b) Kafarski, P.;
LeJczak, B. Phosphorus Sulfur Silicon Relat. Elem. 1991, 53, 193-215; (c) Natchev, I. A. Liebigs
Ann. Chem. 1988, 861-867; (d) Atheron, F. R.; Hassal, C. H.; Lambert, R. W. J. Med. Chem.
1986, 29, 29-40.
11. (a) Ouimette, D.; Coffey, M. Phytopathology 1989, 79, 761-767; (b) Yang, S.; Gao, X. W.; Diao,
C. L. Chinese J. Chem. 2006, 24, 1581-1588.
12. Sonar, S. S.; Sadaphal, S. A.; Labade, V. B.; Shingate, B. B.; Shingare, M. S. Phosphorus Sulfur
Silicon Relat. Elem. 2010, 185, 65-73.
13. (a) Jin, L.; Song, B.; Zhang, G. Bioorg. Med. Chem. Lett. 2006, 16, 1537-1543; (b) Rao, X.;
Song, Z.; He, L. Heteroat. Chem. 2008, 19, 512-516.
14. Xu, Y.; Yan, K.; Song, B. Molecules 2006, 11, 666-676.
15. (a) Kabachnik, M. J.; Medved, T. Izv. Akad. Nauk SSSR 1953, 1126-1128; (b) Kabachnik, M. J.;
Medved, T. Izv. Akad. Nauk SSSR. 1954, 1024-1026.
16. Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141-1143.
17. Zhan, Z. P.; Li, J. P. Synth. Commun. 2005, 35, 2501-2508.
18. Wu, J.; Sun, W.; Wang, W.-Z; Xia, H-G. Chinese J. Chem. 2006, 24, 1054-1057.
19. Xu, F.; Luo, Y. Q.; Wu, J. T.; Shen, Q.; Chen, H. Heteroat. Chem. 2006, 17, 389-392.
20. Kumar, A. S.; Taneja, S. C.; Hundal, M. S.; Kapoor, K. K. Tetrahedron Lett. 2008, 49, 2208-2212.

BIOLOGICALLY ACTIVE α-AMINOPHOSPHONATES
1025
21. Arigala, U. R. S.; Matcha, C.; Yoon, K. R. Heteroat. Chem. 2012, 23, 160-165.
22. Gallardo-Macias, R.; Nakayama, K. Synthesis 2010, 57-62.
23. Hou, J.-T.; Gao, J.-W.; Zhang, Z.-H. Appl. Organomet. Chem. 2011, 25, 47-53.
24. Kumara Swamy, K. C.; Kumaraswamy, S.; Senthil Kumar, K.; Muthiah, C. Tetrahedron Lett.
2005, 46, 3347-3351.
25. Fatemeh, B. B.; Abdolhamid, M.; Ali Akbari, B. Tetrahedron Lett. 2008, 49, 6454-6456.
26. Fatemeh, B. B.; Abdolhamid, M. B.; Akbari, A. Iran. J. Catal. 2011, 1(2), 87-92.
27. Stephen, C.; Richard, F. Tetrahedron 2009, 65, 3325-3355.
28. Cruickshank, R.; Duguid, J. P.; Marion, B. P.; Swain, R. H. A. Medicinal Microbiology; 12th ed.;
Churchill Livingstone: London 1975, 2, 196-202.
29. Collins, A. H. Microbiological Methods, 2nd ed.; Butterworth: London, 1976.
30. Bonjar Shahidi, G. H. Asian J. Plant Sci. 2004, 3(1), 82-86.
31. (a) Bauer, A. W.; Kirby, M. M.; Sherris, J. C.; Truck, M. Am. J. Clin Pathol. 1966, 45, 493-496.
(b) National Committee for Clinical Laboratory Standards, Methods for Dilution, Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically. 5th ed., Approved Standards (M7A5);
Wayne, PA, 2000.