Ultrasound-assisted synthesis of novel α-aminophosphonates and their biological activity

Article abstract of DOI:10.1002/ardp.201100256

The synthesis of a series of novel α-aminosubstituted phosphonates was accomplished by the reaction of various substituted aldehydes with an amine amlodipine (3-ethyl 5-methyl (±)2-((2-aminoethoxy)methyl)-4-(2- chlorophenyl)-6-methyl-1,4-dihydropyridene-3,5-dicarboxylate) followed by diethylphosphite/dibutylphosphite in ethanol using SnCl₂.2H ₂O as a Lewis acid catalyst, under conventional and ultrasonic irradiation. Their structures were established by analytical and spectral data. The title compounds showed good antibacterial, antifungal and antiviral activity depending on the nature of the bioactive groups at the α-carbon. A new class of α-aminosubstituted phosphonates was synthesized and evaluated for their antimicrobial and antiviral activity.

Full text of DOI:10.1002/ardp.201100256

294
Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
Full Paper
Ultrasound-Assisted Synthesis of Novel
a-Aminophosphonates and Their Biological Activity
Syed Rasheed1, Katla Venkataramana1, Kuruva Chandrasekhar1, Gemmalamadugu Fareeda2, and
Chamarthi Naga Raju1
1 Department of Chemistry, Sri Venkateswara University, Tirupati, India
2 Department of Plant Sciences, Hyderabad Central University, Hyderabad, India
The synthesis of a series of novel a-aminosubstituted phosphonates was accomplished by the
reaction of various substituted aldehydes with an amine amlodipine (3-ethyl 5-methyl (ꢀ)2-((2-
aminoethoxy)methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridene-3,5-dicarboxylate) followed by
diethylphosphite/dibutylphosphite in ethanol using SnCl2.2H2O as a Lewis acid catalyst, under
conventional and ultrasonic irradiation. Their structures were established by analytical and
spectral data. The title compounds showed good antibacterial, antifungal and antiviral activity
depending on the nature of the bioactive groups at the a-carbon.
Keywords: Aminophosphonates / Antimicrobial activity / Antiviral activity / Pudovik reaction / Ultrasound irradiation
Received: July 18, 2011; Revised: October 1, 2011; Accepted: October 11, 2011
DOI 10.1002/ardp.201100256
Introduction
acids [12, 13] are known to catalyze this reaction under mild
conditions.
Phosphonic acids and their phosphonate derivatives are of
immense interest in synthetic organic chemistry due to their
biological activities [1]. They are employed in synthetic
operations leading to carbon-carbon and carbon-phosphorus
bond formation [2]. In recent years, considerable interest has
been focused on the synthesis of a-aminophosphonates
because they are considered to be structural analogues of
a-amino acids. These compounds have several potential
applications in medicine as anticancer agents [3], potential
enzyme inhibitors [4], antiviral agents [5, 6], antibiotics
and pharmacological agents [7], antitumour agents [8] and
in agriculture as herbicides [9] and insecticides [10], as is well
documented.
Amlodipine (3-ethyl 5-methyl (ꢀ)2-((2-aminoethoxy)methyl)-
4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridene-3,5-dicarboxylate),
commercially available as Norvasc1 is a long acting calcium
channel blocker used as a hypertensive drug and the
mechanism involved in it is a dihydropyridine calcium
antagonist that inhibits the transmembrane influx of
calcium ions into vascular smooth muscle and cardiac
muscle. The contractile processes of cardiac muscle and
vascular smooth muscle are dependent upon the movement
of extracellular calcium ions into these cells through
specific ion channels. It selectively inhibits calcium ion influx
across cell membranes, with a greater effect on vascular
smooth muscle than on cardiac muscle to cause a reduction
in peripheral vascular resistance and reduction in blood
pressure.
Having several potential applications,
a variety of
synthetic approaches [11] have been developed for the
synthesis of a-aminophosphonates. Of these methods
the nucleophilic addition of phosphonate containing
labile hydrogen at the imine carbon catalysed by an acid
or a base is one of the most convenient methods. Lewis
The present paper describes the synthesis of a-aminosub-
stituted phosphonates by Pudovik reaction by conventional
and under ultrasonic irradiation by one-pot reaction of
amlodoipine with various substituted aromatic/heterocyclic
aldehydes followed by diethyl/dibutylphosphite in dry ethanol
with catalytic amount of SnCl2.2H2O. Nowadays ultrasonic
irradiation is becoming a powerful tool for a synthetic organic
chemist because of high yields and very short reaction times
[14–16]. The effects of ultrasound on organic reactions are
Correspondence: Chamarthi Naga Raju, Department of Chemistry, Sri
Venkateswara University, Tirupati–517502, India
E-mail: rajuchamarthi10@gmail.com
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Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
Ultrasound-assisted Synthesis of Novel a-aminophosphonates
295
attributed to cavitations, a physical process that creates, Biology
enlarges and implodes gaseous and vaporous cavities in an
irradiated liquid [17]. The cavitations induce very high
local temperatures and pressures inside the bubbles (cavities),
leading to a turbulent flow in the liquid and enhanced
mass transfer [18]. The increasing failure of chemotherapeu-
tics and antibiotic resistance exhibited by pathogenic
microbial infectious agents has led to the screening of several
organophosphorus compounds for their potential biological
activity.
Antibacterial, antifungal and antiviral activities
All the synthesized compounds exhibited prominent anti-
bacterial, antifungal and antiviral activities (Tables 2–4).
Aldehyde containing two halogens (4b, 4c, 4f, 4g, 4h, 4l)
exhibited excellent antibacterial, antifungal and antiviral
activity compared to the remaining compounds. Remaining
aldehydes exhibited promising activities. In spite of the
large number of antibiotics and chemotherapeutics currently
available for medical usage, the problem of increasing
bacterial resistance has made it necessary to continue the
search for new antimicrobial substances [24].
Results and discussion
Chemistry
First we synthesized a-aminophosphonates by adopting the Conclusion
conventional method. This method displayed a few drawbacks
such as longer reaction time and low yields. In order to
optimize the reaction conditions, the synthesis of 4a was
carried out under a variety of conditions. Then it was
determined that ultrasonic conditions should be used as the
reaction without ultrasonic activation was much slower and,
for example, the product was obtained in yield of 68% after 4 h
of conventional heating using SnCl2.2H2O as compared
with a yield of 78% obtained after 20 min under ultrasonic
irradiation (758C).
For an obvious examination of the influence of ultrasound
irradiation in this reaction, comparison of the reaction under
two methods, conventional method (method A) and ultra-
sonic irradiation (method B) were performed. As illustrated
in Table 1, method B is comparatively better than method A
in both yield and especially in the reaction times.
In conclusion, we have synthesized a novel series of a-amino-
substituted phosphonates by reacting amlodopine and
various substituted aldehydes with diethyl, dibutyl phosphites
by Pudovik reaction using stannous chloride as a catalyst in the
conventional method. In the other method, same phosphonates
with high yield in short reaction times under ultrasonic irradia-
tion were reported. We believe that sonochemical synthesies of
a-aminophosphonates may be considered as valuable contri-
bution in the field of phosphorus chemistry as compared to the
existing process. The compounds (4b, 4c, 4f, 4g, 4h, 4l) exhibited
excellent antibacterial, antifungal and antiviral activity due to
the presence of two halogens on the aldehyde moiety of
a-aminophosphonates.
A definite SAR could not be established due to lack
of structural diversity of the investigated compounds and
further research needs to be performed to identify lead
structures with better activity.
The chemical structures of all the title compounds (4a–l)
were characterized by IR, 1H, 13C, 31P NMR and mass spectral
studies and their data are presented in the experimental
section. Characteristic IR stretching absorptions were
observed in the regions 3250–3400 cmꢁ1, 1215–1230 cmꢁ1
Experimental
and 737–765 cmꢁ1 for N–H, P O, P–Caliphatic [19]. In 1H NMR
–
–
Chemistry
and 13C NMR spectra chemical shifts for amine were observed
in their expected regions [20]. The P–C–H protons resonated
as a doublet of doublet due to their coupling with phos-
phorus and neighbouring N–H proton. The N–H proton sig-
nal appeared as a triplet due to its coupling with neighboring
proton and phosphorus [21, 22]. 13C NMR spectra were
recorded for six compounds and their data are presented
in the experimental section. In 31P NMR, signals appeared as
singlets in the region 21.12–24.12 [23]. ESI mass spectra were
recorded for six compounds and they gave Mþ. ions.
The present method describes the preparation of a-amino-
phosphonates (4a–l) with increased yield and with short
reaction times compared to conventional methods. These
transformations were carried out without any significant
amounts of undesirable side products.
All chemicals were procured from Sigma-Aldrich, Merck and
were used as such. Solvents used for spectroscopic and physical
studies were reagent grade and were further purified by the
literature methods [25]. Melting points were deteremined in
open capillary tubes by Guna digitial melting point apparatus
expressed in (8C) and are uncorrected. Infrared spectra (ymax in
cmꢁ1) were recorded as KBr pellets on a Perkin-Elmer FT-IR 100
1
spectrophotometer. H, 13C and 31P NMR spectra were recorded
as solutions in DMSO-d6 on a Varian 400 MHz spectrometer
operating at 400 MHz for 1H, 125 MHz for 13C and 202 MHz
for 31P NMR. The 1H and 13C chemical shifts were expressed in
parts per million (ppm) with reference to tetramethylsilane
(TMS) and 31P chemical shifts to 85% H3PO4. ESI mass spectra
were recorded on an API-3000 mass spectrometer. Elemental
analysis was performed on a Thermo Finnigan instrument
at the University of Hyderabad, Hyderabad. Sonication
was performed using Bandelin Sonorex with a frequency of
35 kHz and a nominal power 200W ultrasonic bath for ultrasonic
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296
S. Rasheed et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
Table 1.
O
C
Cl
C
O
C
Cl
C
O
C
Cl
C
O
P
R"O
OR"
Reflux
Reflux
O
O
O
O
O
O
O
O
_____
H
___________
SnCl2.2H2O
O
+
R'-CHO
O
CH3
H3C
CH3
H3C
O
CH3
H3C
O
N
N
N
H
Sonication
H
Sonication
H
NH2
N
NH O
OR"
OR"
CH
C
P
R
R
H
Synthesis of a-aminosubstituted phosphonates (4a–l).
Compound
R
R1
Method A
Method B
Time (h)/Yield (%)
Time (min)/Yield (%)
4a
4b
Et
Et
4/68
4/78
20/78
N
Cl
F
21/87
22/82
4c
Et
Et
4.5/72
4.5/74
Br
F
4d
22/88
NO2
OH
S
4e
4f
Et
Et
5/69
6/70
20/78
24/82
Cl
Cl
N
4g
4h
Bu
Bu
4.5/65
4.5/80
21/76
22/88
Cl
F
4i
4j
Bu
Bu
4.5/70
5/66
21/83
19/84
Br
F
NO2
OH
S
4k
4l
Bu
Bu
5.2/64
6/68
22/76
23/84
Cl
Cl
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Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
Ultrasound-assisted Synthesis of Novel a-aminophosphonates
297
Table 2. Antibacterial activity of title compounds.
Compounda
Zone of inhibition (mm)
S. aureus
E. faecalis
E. coli
P. aeruginosa
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
10.0 ꢀ 0.38
13.0 ꢀ 0.21
13.2 ꢀ 0.70
11.0 ꢀ 0.40
10.0 ꢀ 0.71
14.0 ꢀ 0.18
12.0 ꢀ 0.52
14.0 ꢀ 0.27
14.2 ꢀ 0.80
09.0 ꢀ 0.31
09.5 ꢀ 0.54
18.0 ꢀ 0.30
12.3 ꢀ 0.50
12.0 ꢀ 0.14
18.0 ꢀ 0.70
17.4 ꢀ 0.23
14.0 ꢀ 0.54
14.2 ꢀ 0.50
17.5 ꢀ 0.64
15.8 ꢀ 0.30
16.2 ꢀ 0.12
17.0 ꢀ 0.42
13.0 ꢀ 0.20
13.2 ꢀ 0.18
20.0 ꢀ 0.41
16.0 ꢀ 0.30
20.0 ꢀ 0.25
28.5 ꢀ 0.14
28.0 ꢀ 0.51
26.0 ꢀ 0.24
25.0 ꢀ 0.32
20.7 ꢀ 0.51
25.5 ꢀ 0.42
29.0 ꢀ 0.60
29.8 ꢀ 0.20
19.0 ꢀ 0.30
20.6 ꢀ 0.41
26.4 ꢀ 0.34
27.3 ꢀ 0.72
9.0 ꢀ 0.11
14.9 ꢀ 0.24
14.2 ꢀ 0.31
11.0 ꢀ 0.24
11.0 ꢀ 0.51
15.0 ꢀ 0.48
11.1 ꢀ 0.60
14.7 ꢀ 0.30
14.3 ꢀ 0.45
10.0 ꢀ 0.52
10.0 ꢀ 0.72
15.7 ꢀ 0.30
13.7 ꢀ 0.42
4l
Gatifloxacin b
Values are means ꢀ SD of three replicates (p <0.05)
a
100 mg/mL
100 mg/mL
b
irradiation with built in heating 30–80 (8C) thermostatically
adjustable. The reaction vessel was placed inside the ultrasonic
bath containing water.
mine and the reaction mixture was stirred at reflux temperature
for 2 h. Progress of the reaction was monitored by running TLC
(silica gel) using hexane and ethyl acetate (1:3) as a mobile phase
at different time intervals. After the completion of reaction, the
solvent was removed in a rota-evaporator at reduced pressure
and the crude product obtained was purified by column
chromatography on silica gel (60–120 mesh), using hexane
and ethyl acetate (3:1) as an eluent to afford the pure 3-ethyl
5-methyl 4-(2-chlorophenyl)-2-[(2-(diethoxyphosphoryl)(3-pyridyl)-
methyl)aminoethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridene
dicarboxylate (4a), yield, 68%.
General procedure
Method A: Conventional heating
A mixture of amlodopine (1) (0.5257 g, 0.005 mol) and pyridine-3-
carboxaldheyde (2) (0.5250 g, 0.005 mol) and few grams of
˚
molecular sieves of 4 A were taken in a round bottom flask,
refluxed in anhydrous ethanol for 2 h to form the corresponding
aldimine (Schiff’s base). The formation of Schiff’s base was
indicated by TLC using hexane and ethyl acetate (1:3) as a mobile
phase. Then catalytic amount of SnCl2.2H20 was added and
diethyl phosphite (0.49 mL, 0.005 mol) was added to the aldi-
Method B: Ultrasonication
In the first step of the reaction, amlodopine (amine), aldehyde
and molecular sieves were taken in a round bottom flask, soni-
cated for 10 min in anhydrous ethanol at reflux condition to
form aldimine. Then SnCl2.2H20 and phosphite were added to
the reaction mixture and again sonicated for 10 min for com-
pletion of the reaction as it was confirmed by running TLC. The
Table 3. Antifungal activity of the title compounds.
Compounda
Zone of inhibition (mm)
A. niger
A. flavus
F. oxysporum
Table 4. Antiviral activity of the title compounds.
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
11.3 ꢀ 0.21
20.4 ꢀ 0.40
21.1 ꢀ 0.21
12.1 ꢀ 0.20
11.3 ꢀ 0.32
19.3 ꢀ 0.43
15.3 ꢀ 0.56
18.3 ꢀ 0.25
20.4 ꢀ 0.34
16.5 ꢀ 0.56
14.3 ꢀ 0.70
19.3 ꢀ 0.54
17.3 ꢀ 0.60
14.2 ꢀ 0.26
21.2 ꢀ 0.54
17.8 ꢀ 0.80
09.3 ꢀ 0.23
14.5 ꢀ 0.14
17.8 ꢀ 0.25
13.2 ꢀ 0.52
17.9 ꢀ 0.31
20.4 ꢀ 0.19
16.0 ꢀ 0.80
12.0 ꢀ 0.21
18.5 ꢀ 0.25
16.7 ꢀ 0.43
11.2 ꢀ 0.52
23.2 ꢀ 0.28
24.2 ꢀ 0.39
15.4 ꢀ 0.26
13.2 ꢀ 0.42
20.3 ꢀ 0.73
17.2 ꢀ 0.53
19.3 ꢀ 0.60
21.2 ꢀ 0.40
13.2 ꢀ 0.51
15.2 ꢀ 0.24
19.2 ꢀ 0.53
18.2 ꢀ 0.26
Compound
Inhibition rate (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
40.8
56.8
55.4
42.0
38.0
55.6
41.8
54.6
55.0
41.0
39.0
54.9
53.8
4l
Clotrimazoleb
Values are means ꢀ SD of three replicates (p <0.05)
4l
Ningnanmycin
a
500 mg/mL
500 mg/mL
b
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Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
reaction mixture was worked up as described above and the yield
obtained was 78%.
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-[(diethoxyphosphoryl)(4-hydroxy-3-nitrophenyl)-
methyl]amino}ethoxy)methyl]-6-methyl-1,4-dihydro-3,5-
pyridinedicarboxylate 4d
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-{[(diethoxyphosphoryl)(3-pyridyl)methyl)amino}-
ethoxy)methyl)]-6-methyl-1,4-dihydro-3,5-pyridene
dicarboxylate 4a
Orange solid. Mol.Wt: 696. mp 201–2038C. IR (KBr) (vmax cmꢁ1): 741
1
–
(P–C), 1230 (P O), 3200 (NH); H-NMR (DMSO-d ) d ppm: 1.13 (t, 6H,
–
6
2CH3, J ¼ 7.3 Hz, H-200), 1.30 (t, 3H, CH3, H-12), 2.20 (s, 3H, CH3,
H-15), 2.90 (dd, 2H, CH2, J ¼ 4.0, 5.2 Hz, H-9), 3.40 (s, 3H, OCH3,
H-14), 3.71 (t, 2H, CH2, J ¼ 7.0 Hz, H-8), 4.06–4.24 (m, 8H, 4CH2,
H-11, H-7, H-100), 4.60 (s, 1H, CH, H-4), 5.27 (dd, 1H, P–C–H, J ¼ 3.0,
9.0 Hz, H-22), 6.90 (t, 1H, J ¼ 7.4 Hz, NH), 7.20–8.30 (m, 7H, Ar–H),
8.1 (s, 1H, Ar–OH), 8.40 (s, NH, H-1); 31P-NMR (DMSO-d6) d (ppm):
22.30; ESI mass m/z (%) 696 (100) [Mþ.], 698 (30) [Mþ.þ2] , 650 (14),
721 (14), 681 (10). Anal. cald. for C31H39ClN3O11P: C: 53.49, H: 5.65,
N: 6.04. Found C: 53.38, H: 5.64, N: 6.03.
Dark red solid. Mol.Wt: 636. mp 210–2128C. IR (KBr) (vmax cmꢁ1):
1
–
741 (P–C), 1230 (P O), 3210 (NH); H-NMR (DMSO-d ) d ppm: 1.16
–
6
(t, 6H, 2CH3, J ¼ 7.1 Hz, H-200), 1.22 (t, 3H, CH3, J ¼ 6.5 Hz, H-12),
2.10 (s, 3H, CH3, H-15), 3.18 (dd, 2H, CH2, J ¼ 4.1, 5.1Hz, H-9), 3.30
(s, 3H, OCH3, H-14), 3.60 (t, 2H, CH2, J ¼ 6.8 Hz, H-8), 4.04–4.20
(m, 8H, 3CH2, H-11, H-7, H-100), 4.40 (s, 1H, CH, H-4), 5.30 (dd, 1H,
P–C–H, J ¼ 2.0, 8.5 Hz, H-22), 5.90 (t, 1H, J ¼ 7.0 Hz, NH), 7.00–
7.50 (m, 8H, Ar-H), 8.20 (s, 1H, NH, H-1); 13C-NMR (DMSO-d6)
d (ppm): 15.2 (C-12), 16.6 (C-200), 18.7 (C-15), 37.2 (C-4), 39.0
(C-9), 50.2 (d, P–C–H, C-22), 54.0 (C-14), 60.2 (C-11), 63.1 (C-100),
67.8 (C-7), 68.0 (C-8), 103.1 (C-5), 103.7 (C-3), 123.2 (C-20 & 50), 126.1
(C-21), 126.8 (C-20), 127.4 (C-19), 128.0 (C-18), 131.0 (C-17), 142.7
(C-6), 144.3 (C-2), 145.5 (C-10), 144.6 (C-16), 146.8 (C-30 & 40), 166.4
(C-10), 166.5 (C-13); 31P-NMR (DMSO-d6) d (ppm): 22.14; ESI mass
m/z (%) 636 (100) [Mþ.], 638 (32) [Mþ.þ2], 599 (10), 589 (10). Anal.
cald. for C30H39ClN3O8P: C: 56.65, H: 6.18, N: 6.61. Found C: 56.50,
H: 6.14, N: 6.45.
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-{(diethoxyphosphoryl)(2-thienyl)methyl]amino}-
ethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridene
dicarboxylate 4e
Black solid. Mol.Wt: 641. mp 188–1908C. IR (KBr) (vmax cmꢁ1): 765
(P–C), 1227 (P O), 3380 (NH); 1H-NMR (DMSO-d6) d ppm: 1.19
–
–
(t, 6H, 2CH3, J ¼ 6.7 Hz, H-200), 1.29 (t, 3H, CH3, H-12), 2.40
(s, 3H, CH3, H-15), 3.12 (dd, 2H, CH2, J ¼ 4.0, 5.2 Hz, H-9), 3.45
(s, 3H, OCH3, H-14), 3.80 (t, 2H, CH2, J ¼ 7.5 Hz, H-8), 4.10–4.26
(m, 8H, 4CH2, H-11, H-7, H-100), 5.00 (s, 1H, CH, H-4), 5.31
(dd, 1H, P–C–H, J ¼ 2.0, 8.4 Hz, H-22), 5.80 (t, 1H, J ¼ 7.6 Hz,
NH), 7.20–8.00 (m, 7H, Ar-H), 8.20 (s, NH, H-1); 13C-NMR (DMSO-
d6) d (ppm): 15.6 (C-12), 18.2 (C-200), 18.9 (C-15), 37.1 (C-4), 39.0 (C-9),
50.3 (d, P–C–H, C-22), 54.0 (C-14), 60.1 (C-11), 61.5 (C-100), 67.8 (C-7),
68.1 (C-8), 103.2 (C-5), 103.7 (C-3), 125.9 (C-21), 123.2 (C-20), 126.0
(C-30), 126.2 (C-20), 126.5 (C-40), 127.2 (C-19), 128.0 (C-18), 131.0
(C-17), 137.4 (C-10), 142.3 (C-16), 142.7 (C-6), 144.3 (C-2), 166.4
(C-10), 166.5 (C-13); 31P-NMR (DMSO-d6) d (ppm): 23.44; ESI mass
m/z (%) 641 (100) [Mþ.], 643 (30) [Mþ.þ3], 419 (10), 369 (10).
3-Ethyl-5-methyl 2-[(2-{[(2-chloro-6-
fluorophenyl)(diethoxyphosphoryl)methyl]amino}-
ethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-
dihydro-3,5 pyridene dicarboxylate 4b
Brown solid. Mol.Wt: 687. mp 222–2238C. IR (KBr) (vmax cmꢁ1):
1
–
749 (P–C), 1225 (P O), 3365 (NH); H-NMR (DMSO-d ) d ppm: 1.15
–
6
(t, 6H, 2CH3, J ¼ 6.8 Hz, H-200), 1.29 (t, 3H, CH3, H-12), 2.10 (s, 3H,
CH3, H-15), 3.00 (dd, 2H, CH2, J ¼ 4.0, 5.2 Hz, H-9), 3.30 (s, 3H, OCH3,
H-14), 3.74 (t, 2H, CH2, J ¼ 7.0 Hz, H-8), 4.03–4.21 (m, 8H, 4CH2,
H-11, H-7, H-100), 4.80 (s, 1H, CH, H-4), 5.28 (dd, 1H, P–C–H, J ¼ 2.2,
9.0 Hz, H-22), 6.70 (t, 1H, J ¼ 7.0 Hz, NH), 7.00–8.40 (m, 7H, Ar-H),
8.50 (s, NH, H-1); 13C-NMR (DMSO-d6) d(ppm): 15.4 (C-12), 18.2 (C-200),
18.8 (C-15), 37.4 (C-4), 39.1 (C-9), 48.3 (d, P–C–H, C-22), 54.0 (C-14),
60.2 (C-11), 63.1 (C-100), 67.6 (C-7), 68.2 (C-8), 103.2 (C-5), 103.5 (C-3),
114.2 (C-30), 123.4 (C-10), 126.2 (C-50), 126.4 (C-20), 127.4 (C-19), 128.2
(C-18), 130.1 (C-21), 131.1 (C-17), 131.8 (C-40), 133.8 (C-60), 142.3 (C-16),
142.7 (C-6), 144.4 (C-2), 158.2 (C-20), 166.8 (C-13), 167.0 (C-10); 31P-NMR
(DMSO-d6) d (ppm): 21.12. Anal. cald. for C31H38Cl2FN2O8P: C: 54.16,
H: 5.57, N: 4.07. Found C: 54.09, H: 5.49, N: 3.99.
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-{[(2,4-dichlorophenyl)-(diethoxyphosphoryl)methyl]-
amino}ethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridene
dicarboxylate 4f
Green solid. Mol.Wt: 703. mp 211–2138C. IR (KBr) (vmax cmꢁ1):
1
–
750 (P–C), 1224 (P O), 3350 (NH); H-NMR (DMSO-d ) d ppm: 1.18
–
6
(t, 6H, 2CH3, J ¼ 7.0 Hz, H-200), 1.30 (t, 3H, CH3 , H-12), 2.21
(s, 3H, CH3, H-15), 3.00 (dd, 2H, CH2, J ¼ 3.9, 4.4 Hz, H-9), 3.14
(s, 3H, OCH3, H-14), 3.83 (t, 2H, CH2, J ¼ 7.5 Hz, H-8), 4.20–4.29
(m, 8H, 4CH2, H-11, H-7, H-100), 5.10 (s, 1H, CH, H-4), 5.29 (dd, 1H,
P–C–H, J ¼ 1.9, 8.2 Hz, H-22), 6.20 (t, 1H, J ¼ 7.3 Hz, NH), 7.20–
8.00 (m, 7H, Ar–H), 8.20 (s, NH, H-1); 31P-NMR (DMSO-d6) d (ppm):
22.33; ESI mass m/z (%) 703.6 (100) [Mþ.], 705.6 (97) [Mþ.þ2],
707 (30), 709 (5), 698 (10), 684.2 (10), 665 (10).
3-Ethyl-5-methyl 2-[(2-[(3-bromo-4-
fluorophenyl)(diethoxyphosphoryl)methyl]-
aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-
dihydro-3,5-pyridinedicarboxylate 4c
Light yellow solid. Mol.Wt: 732. mp 198–2008C; IR (KBr)
(vmax cmꢁ1): 737 (P–C), 1215 (P O), 3365 (NH); 1H-NMR
–
–
(DMSO-d6) d ppm: 1.15 (t, 6H, 2CH3, J ¼ 7.3 Hz, H-200), 1.28
(t, 3H, CH3, H-12), 2.12 (s, 3H, CH3, H-15), 2.90 (dd, 2H, CH2,
J ¼ 4.0, 5.2 Hz, H-9), 3.50 (s, 3H, OCH3, H-14), 3.64 (t, 2H, CH2,
J ¼ 7.2 Hz, H-8), 4.08–4.24 (m, 8H, 4CH2, H-11, H-7, H-100), 4.90
(s, 1H, CH, H-4), 5.34 (dd, 1H, P–C–H, J ¼ 2.3, 8.7 Hz, H-22), 6.48
(t, 1H, J ¼ 7.4 Hz, NH), 7.41–8.20 (m, 7H, Ar–H), 8.30 (s, NH, H-1);
31P-NMR (DMSO-d6) d (ppm): 22.00. Anal. cald. for C31H38BrClFN2O8P:
C: 50.87, H: 5.23, N: 3.83. Found C: 50.78, H: 5.18, N: 3.72.
3- Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[2-{[(dibutoxyphosphoryl)(3-pyridyl)methyl]amino}-
ethoxy)methyl]-6-methyl-1,4-dihydro-3,5 pyridene
dicarboxylate 4g
Dark reddish solid. Mol.Wt: 692. mp 200–2028C. IR (KBr)
(vmax cmꢁ1): 745 (P–C), 1235 (P O), 3345 (NH); 1H-NMR (DMSO-
–
–
d6) d ppm: 0.85–1.80 (m, 17H, 4CH2, 3CH3, H-200, H-300, H-400, H-12),
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Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
Ultrasound-assisted Synthesis of Novel a-aminophosphonates
299
2.10 (s, 3H, CH3, H-15), 3.16 (dd, 2H, CH2, J ¼ 4.0, 3.0 Hz, H-9), 3.30
(s, 3H, OCH3, H-14), 3.62 (t, 2H, CH2, J ¼ 7.3 Hz, H-8), 4.04–4.20
(m, 8H, 4CH2, H-11, H-7, H-100), 4.40 (s, 1H, CH, H-4), 5.28 (dd, 1H,
P–C–H, J ¼ 1.9, 8.2 Hz, H-22), 6.80 (t, 1H, J ¼ 7.5 Hz, NH), 7.00–
7.50 (m, 8H, Ar–H), 8.30 (brs, 1NH, H-1); 13C-NMR (DMSO-d6)
d (ppm): 13.6 (C-400), 15.4 (C-12), 18.6 (C-300), 18.9 (C-15), 30.2
(C-200), 37.4 (C-4), 39.1 (C-9), 50.2 (d, P–C–H, H-22), 54.2 (C-14),
60.4 (C-11), 61.0 (C-100), 67.8 (C-7), 68.2 (C-8), 103.2 (C-5), 103.5
(C-3), 123.2 (C-20 & 50), 126.1 (C-21), 127.2 (C-19), 126.4 (C-20), 128.0
(C-18), 131.0 (C-17), 142.3 (C-16), 142.6 (C-6), 144.2 (C-2), 145.5
(C-10), 146.8 (C-30 & 40), 166.2 (C-10), 166.5 (C-13); 31P-NMR
(DMSO-d6) d (ppm): 23.50; ESI mass m/z (%) 692 (100) [Mþ.], 694
(32) [Mþ.þ2]. Anal. cald. for C34H47ClN3O8P: C: 59.00, H: 6.84,
N: 6.07. Found C: 58.94, H: 6.72, N: 5.96.
H-15), 3.16 (dd, 2H, CH2, J ¼ 4.8, 5.5 Hz, H-9), 3.40 (s, 3H, OCH3,
H-14), 3.72 (t, 2H, CH2, J ¼ 6.9 Hz, H-8), 4.06–4.24 (m, 8H, 4CH2,
H-11, H-7, H-100), 4.60 (s, 1H, CH, H-4), 5.28 (dd, 1H, P–C–H, J ¼ 2.0,
8.2 Hz, H-22), 6.40 (t, 1H, J ¼ 7.8 Hz, NH), 7.20–8.10 (m, 7H, Ar–H),
8.1 (s, 1H, Ar–OH), 8.40 (brs, NH, H-1); 31P-NMR (DMSO-d6) d (ppm):
23.12; Anal. cald. for C35H47ClN3O11P: C: 55.89, H: 6.30, N: 5.59.
Found C: 55.80, H: 6.22, N: 5.50.
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-{[(dibutoxyphosphoryl)(2-thienyl)methyl]amino}ethoxy)-
methyl]-6-methyl-1,4-dihydro-3,5-pyridene dicarboxylate 4k
Black solid. Mol.Wt: 697. mp 211–2138C. IR (KBr) (vmax cmꢁ1): 751
(P–C), 1231 (P O), 3340 (NH); 1H-NMR (DMSO-d6): 0.54–1.64
–
–
(m, 17H, 4CH2, 3CH3, H-200, H-300, H-400, H-12), 2.10 (s, 3H, CH3,
H-15), 3.60 (s, 3H, OCH3, H-14), 3.16 (dd, 2H, CH2, J ¼ 4.8, 5.5 Hz,
H-9), 3.25 (s, 1H, CH, H-4), 3.82 (t, 2H, CH2, J ¼ 6.8 Hz, H-8), 4.20–
4.29 (m, 8H, 4CH2, H-11, H-7, H-100), 5.30 (dd, 1H, P–C–H, J ¼ 1.9,
8.2 Hz, H-22), 6.80 (t, 1H, J ¼ 7.3 Hz, NH), 7.20–7.90 (m, 7H, Ar-H),
3-Ethyl-5-methyl 2-[(2-{[(2-chloro-6-fluorophenyl)-
(dibutoxyphosphoryl)methyl]amino}ethoxy)methyl]-4-
(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridene
dicarboxylate 4h
13
8.50 (bs, 1NH, H-1); C-NMR (DMSO-d6) d (ppm): 13.6 (C-400), 15.6
(C-12), 18.2 (C-200), 18.4 (C-300), 18.7 (C-15), 28.8 (C-200), 37.2 (C-4),
39.0 (C-9), 52.9 (d, P–C–H, C-22) 54.2 (C-14), 60.2 (C-11) 61.5 (C-100),
64.2 (C-100), 67.9 (C-7), 68.2 (C-8), 103.1 (C-5), 103.8 (C-3), 123.2 (C-20),
126.0 (C-30), 126.1 (C-21), 126.4 (C-20), 126.5 (C-40), 127.4 (C-19),
129.0 (C-18), 130.1 (C-17), 137.4 (C-1‘), 141.6 (C-6), 142.3 (C-16),
144.3 (C-2), 166.4 (C-10), 166.5 (C-13); 31P-NMR (DMSO-d6) d (ppm):
24.12.
Brown solid. Mol.Wt 743. mp 152–1538C. IR (KBr) (vmax cmꢁ1): 750
1
–
(P–C), 1227 (P O), 3390 (NH); H-NMR (DMSO-d ) d ppm: 0.90–1.90
–
6
(m, 17H, 4CH2, 3CH3, H-200, H-300, H-400, H-12), 2.10 (s, 3H, CH3,
H-15), 3.10 (dd, 2H, CH2, J ¼ 4.0, 3.0 Hz, H-9), 3.40 (s, 3H, OCH3,
H-14), 3.80 (t, 2H, CH2, J ¼ 7.0 Hz, H-8), 4.08–4.21 (m, 8H, 4CH2,
H-11, H-7, H-100), 4.80 (s, 1H, CH, H-4), 5.23 (dd, 1H, P–C–H, J ¼ 2.0,
8.2 Hz, H-22), 6.60 (t, 1H, J ¼ 7.2 Hz, NH), 7.00–8.10 (m, 7H, Ar–H),
13
8.30 (brs, NH, H-1); C-NMR (DMSO-d6) d (ppm): 13.0 (C-400), 15.5
(C-12), 16.5 (C-300), 18.8 (C-15), 28.9 (C-200), 37.2 (C-4), 39.1 (C-9), 48.3
(d, P–C–H, C-22), 54.0 (C-14), 60.2 (C-11), 64.2 (C-100), 67.6 (C-7), 68.0
(C-8), 103.2 (C-5), 103.5 (C-3), 114.2 (C-30), 123.4 (C-10), 126.2 (C-50),
127.2 (C-19), 128.1 (C-18), 131.1 (C-17), 142.3 (C-16), 142.7 (C-6),
144.2 (C-2), 166.0 (C-10), 166.1 (C-13), 126.0 (C-21), 126.4 (C-20),
131.8 (C-40), 133.8 (C-60), 158.2 (C-20); 31P-NMR (DMSO-d6) d (ppm):
21.12; ESI mass m/z (%) 743 (100) [Mþ.], 745 (66) [Mþ.þ2], 748 (11),
725 (14), 697 (17), 610 (21). Anal. cald. for C35H46Cl2FN2O8P: C:
56.53, H: 6.24, N: 3.77. Found C: 56.49, H: 6.18, N: 3.67.
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-[(dibutoxyphosphoryl)(2,3-dichlorophenyl)methyl]-
aminoethoxy)methyl]-6-methyl-1,4-dihydro-3,5-
pyridinedicarboxylate 4l
Green solid. Mol.Wt: 760. mp 214–2168C. IR (KBr) (vmax cmꢁ1):
742 (P–C), 1232 (P O), 3210 (NH); 1H-NMR (DMSO-d6): 0.52–1.80
–
–
(m, 17H, 4CH2, 3CH3, H-200, H-300, H-400, H-12), 2.10 (s, 3H, CH3,
H-15), 3.20 (dd, 2H, CH2, J ¼ 4.8, 5.5 Hz, H-9), 3.60 (s, 3H, OCH3,
H-14), 3.82 (t, 2H, CH2 , J ¼ 7.3 Hz, H-8), 4.20–4.29 (m, 8H, 4CH2,
H-11, H-7, H-100), 5.10 (s, 1H, CH, H-4), 5.30 (dd, 1H, P–C–H, J ¼ 1.9,
8.2 Hz, H-22), 6.50 (t, 1H, J ¼ 6.0 Hz, NH), 7.20–7.80 (m, 7H, Ar–H),
8.50 (bs, 1NH, H-1); 31P-NMR (DMSO-d6) d (ppm): 22.19; ESI mass
m/z (%), 760 (100) [Mþ.], 762 (96) [Mþ.þ2], 764 (30) [Mþ.þ4], 766 (10)
[Mþ.þ6].
3-Ethyl-5-methyl 2-[(2-[(3-bromo-4-fluorophenyl)-
(dibutoxyphosphoryl)methyl]aminoethoxy)methyl]-4-
(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-
pyridinedicarboxylate 4i
Light yellow solid. Mol.Wt. 788. mp 198–2008C, IR (KBr)
(vmax cmꢁ1): 748 (P–C), 1229 (P O), 3400 (NH); 1H-NMR (DMSO-
–
–
Biological assays
d6) d ppm: 0.70–1.80 (m, 17H, 4CH2, 3CH3, H-200, H-300, H-400, H-12),
2.12 (s, 3H, CH3, H-15), 3.10 (dd, 2H, CH2, J ¼ 4.0, 3.0 Hz, H-9), 3.50
(s, 3H, OCH3, H-14), 3.64 (t, 2H, CH2, J ¼ 6.6 Hz, H-8), 4.08–4.24
(m, 8H, 4CH2, H-11, H-7, H-100), 4.80 (s, 1H, CH, H-4), 5.30 (dd, 1H,
P–C–H, J ¼ 1.9, 8.2 Hz, H-22), 6.10 (t, 1H, J ¼ 7.2 Hz, NH), 7.40–
8.10 (m, 7H, Ar–H), 8.50 (brs, NH, H-1); 31P-NMR (DMSO-d6) d (ppm)
22.12; Anal. cald. for C35H46BrClFN2O8P: C: 53.34, H: 5.88, N: 3.55
Found C: 53.22, H: 5.73, N: 3.40.
Antibacterial bioassay
All the synthesized compounds were screened for their anti-
bacterial activity against gram positive bacteria such as
Staphylococcus aureus and Enterococcus faecalis and gram negative
bacteria such as Escherichia coli and Pseudomonas aeruginosa
using the cup plate agar diffusion method [26]. The cultures
were diluted with sterilized saline to bring the final inocu-
lum size to approximately 105–106 CFU/mL. These solutions
containing 106 cells/ mL were added to each Whatmann No.1
filter paper disc (5 mm diameter) and acetone and diethyl
ether were used as the control. The results were compared
with the activity of the standard antibiotic gatifloxacin
(100 mg/mL).
3-Ethyl-5-methyl 4-(2-chlorophenyl)-2-
[(2-[(dibutoxyphosphoryl)(4-hydroxy-3-nitrophenyl)-
methyl]amino}ethoxy)methyl]-6-methyl-1,4-dihydro-3,5-
pyridinedicarboxylate 4j
Orange solid. Mol.Wt: 752. mp 204–2068C. IR (KBr) (vmax cmꢁ1):
1
747 (P–C), 1216 (P O), 3200 (NH); H-NMR (DMSO-d ) d ppm: 0.30–
–
–
6
1.30 (m, 17H, 4CH2, 3CH3, H-200, H-300, H-400, H-12), 2.20 (s, 3H, CH3,
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300
S. Rasheed et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 294–301
Antifungal bioassay
260 nm using an ultraviolet spectrophotometer.
The antifungal activity of the synthesized compounds was
tested against three pathogenic fungi, namely Fusarium oxy-
sporium, Aspergillus niger and Aspergilus flavus by the poison
plate technique [27]. Test compounds were dissolved in
acetone (10 mL) before mixing with potato dextrose agar
(PDA, 90 mL). The final concentration of the compounds in
the medium was fixed at 500 mg/ mL. Three kinds of fungi
were incubated in PDA at 25 ꢀ 18C for 5 days to get new
mycelium for antifungal assay, then a mycelia disk of
approximately 0.45 cm diameter cut from the culture
medium was picked up with a sterilized inoculation needle
and inoculated in the center of the PDA plate. The inoculated
plates were incubated at 25 ꢀ 18C for 5 days. Acetone in
sterilized distilled water served as control, while clotrima-
0:1%; 260 nm:
Virus concn ¼ ðA260 ꢂ dilution ratioÞ=E1 cm
Curative effect of compounds against TMV in vivo
Growing leaves on Nicotiana tabacum L. of the same ages were
selected. TMV (concentration of 6 ꢂ 10ꢁ3 mg/mL) was dipped
to inoculate the whole leaves. Then the leaves were
washed with water and dried. The compound solution was
smeared on the left side and the solvent was smeared on the
right side for control. The local lesion numbers were then
recorded 3–4 days after inoculation [29]. For each compound,
three repetitions were conducted. The inhibition rate of the
compound was then calculated according to the following
formula (‘av’ means average).
av local lesion numbers of control ðnot treated with compoundÞ ꢁ ðav local lesion numbers smeared with drugsÞ
av local lesion numbers of control ðnot treated with compoundÞ
Inhibition rate ð%Þ ¼
ꢂ 100
The authors express their grateful thanks to UGC, New Delhi, for giving
financial assistance through BSR fellowship.
zole was used as positive control. For each treatment, three
replicates were carried out. The radial growth of the fungal
colonies was measured on the sixth day. The in vitro inhibit-
ing effects of the test compounds on the fungi were calcu-
lated by the formula CV ¼ A–B/A, where A represents the
diameter of fungal growth on untreated PDA, B represents
the diameter of fungi on treated PDA, and CV represents the
rate of inhibition.
The authors have declared no conflict of interest.
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