Synthesis and bioassay of ethyl-2- (2-((Diethoxyphosphoryl) (Aryl) Methylamino)thiazol-4-Yl)-2-(Methoxyimino)acetates

Article abstract of DOI:10.1080/10426507.2013.769982

A simple, efficient, and environmentally benign methodology has been accomplished for the synthesis of α-aminophosphonates by one-pot three-component reaction of ethyl-2-amino-α-(methoxy-imino)-4- thiazoleacetate, aldehydes, and diethylphosphite by using Amberlyst-15 as catalyst at room temperature under solvent-free conditions. Their chemical structures were characterized by infrared (IR), NMR (¹H, ¹³C & ³¹P), mass spectral, and elemental analysis. All the title compounds were screened for radical-scavenging activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitic oxide (NO), and hydrogen peroxide (H₂O₂) methods. Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text and figures.

Full text of DOI:10.1080/10426507.2013.769982

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Synthesis and Bioassay of Ethyl-2-(2-
((diethoxyphosphoryl) (aryl)methylamino)thiazol-4-
yl)-2-(methoxyimino)acetates
S. Santhi Sudha a , Ch. Syama Sundar a , N. Bakthavatchala Reddy a , K. Uma Maheswara Rao
b , S. H. Jaya Prakash a & C. Suresh Reddy a
a Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
b Department of Chemistry, Yonsei University, Wonju, Gangwon-do, 220-710, South Korea
Accepted author version posted online: 25 Mar 2013.
To cite this article: S. Santhi Sudha , Ch. Syama Sundar , N. Bakthavatchala Reddy , K. Uma Maheswara Rao , S. H. Jaya
Prakash & C. Suresh Reddy (2013): Synthesis and Bioassay of Ethyl-2-(2-((diethoxyphosphoryl) (aryl)methylamino)thiazol-4-
yl)-2-(methoxyimino)acetates, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:10.1080/10426507.2013.769982
To link to this article: http://dx.doi.org/10.1080/10426507.2013.769982
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ACCEPTED MANUSCRIPT
Synthesis and Bioassay of Ethyl-2-(2-((diethoxyphosphoryl) (aryl)methylamino)thiazol-4-
yl)-2-(methoxyimino)acetates
S. Santhi Sudhaa, Ch. Syama Sundara, N. Bakthavatchala Reddya, K. Uma Maheswara
Raob, S. H. Jaya Prakasha and C. Suresh Reddya*
aDepartment of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India.
bDepartment of Chemistry, Yonsei University, Wonju, Gangwon-do 220-710, South Korea.
*Corresponding author: Tel: +91-9849694958; Fax: +91-877-2289555;
E-mail: csrsvu@gmail.com
OCH3
N
OCH3
EtO
N
O
O
P
EtO
Amberlyst-15
OEt
OEt
O
P
N
OEt
OEt
H
O
H
N
N
S
H
R
O
neat, 30-45 min
S
NH2
R
(1)
(2a-j)
(3)
(4a-j)
ABSTRACT
A simple, efficient and environmentally benign methodology has been accomplished for
the synthesis of α-aminophosphonates by one pot three-component reaction of ethyl-2- amino-α-
(methoxy-imino)-4-thiazoleacetate, aldehydes and diethylphosphite by using Amberlyst-15 as
catalyst at room temperature under solvent-free conditions. Their chemical structures were
characterized by IR, NMR (1H, 13C & 31P) and mass spectral and elemental analysis. All the title
compounds were screened for radical scavenging activity by DPPH, NO and H2O2 methods.
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Keywords: α-Aminophosphonates, Amberlyst-15, biological activity, ethyl-2-amino-α-(methoxy
-imino)-4-thiazoleacetate.
[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 and figures.]
<AQ> Editorial work on your manuscript has created a file of supplemental materials
that will be available on-line only.</AQ>
INTRODUCTION
Organophosphorus compounds have found a wide range of applications in the areas of
industrial, agricultural and medicinal chemistry owing to their biological and physical properties
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as well as their utility as synthetic intermediates.1-2 α-Aminophosphonates are important class of
biologically active compounds and their synthesis has received great attention due to their
structural similarity of natural aminoacids.3-4 Also, they act as peptide mimics, enzyme
inhibitors, antibiotics and pharmacological agents.5-6 Furthermore, α-aminophosphonates are
used in agricultural industry as fungicidal, herbicidal agents, and plant growth regulators.7-10
A
number of synthetic approaches for α-aminophosphonates have been developed. Among them,
nucleophilic addition of phosphites to imines is established as the most successful platform to
accomplish the α-aminophosphonates through Kabachnik-Field’s reaction.11-13 Generally, these
transformations were catalyzed by bases, Lewis acids, transition metals and lanthanide
triflates.14-17 However some of these procedures were associated with one or more shortcomings
such as long reaction time, low yield, lack of generality, requirement of excess of reagents, the
use of expensive or less easily available catalysts and vigorous reaction conditions. Owing to the
importance of α-aminophosphonates from pharmaceutical, industrial and synthetic points of
view, introduction of an efficient method for the preparation of these compounds is still in
demand.18-23
Multicomponent, one-pot synthesis has received considerable attention because of its wide
range of applications in pharmaceutical chemistry for the creation of structural diversity and
combinatorial libraries of drug discovery.24 Multicomponent reactions are extremely convergent
and producing remarkably high increase of molecular complexity in a single step operation.25
In recent years, solid phase catalysis has received considerable position in organic
synthesis.26 Amberlyst-1527-28 possesses unique property to be used as a catalyst for the
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preparation of α-aminophosphonates. Amberlyst-15 is a strong acidic sulfonic acid, macro
reticular polymeric resin based on cross-linked styrene divinylbenzene copolymers. Its
continuous open pore structure and excellent physical, thermal and chemical stability makes it
the resin of choice in many applications. Its physical and chemical stability, non-corrosive and
non toxic nature, selectivity in reactions, reusability and environmental compatibility make this
as a versatile catalyst for performing the various functional group transformations in the organic
synthesis.29 In continuation of our interest to develop synthetic routes for biologically active
compounds and the use of green chemical techniques in organic synthesis,30-31 herein we
successfully endeavor at yet another application of Amberlyst-15 as a catalyst for the synthesis
of α-aminophosphonates32-33 under solvent free and room temperature condition. All the
synthesized α-aminophosphonates (4a-j) were screened for radical scavenging activity by DPPH,
NO and H2O2 methods (Supplemental Materials).
RESULTS AND DISCUSSION
An efficient and environmentally benign one pot approach was developed for synthesis
of α-aminophosphonate derivatives (4a-j) by reaction of ethyl-2-amino-α-(methoxy-imino)-4-
thiazoleacetate (1), various aldehydes (2a-j) and diethylphosphite (3) in the presence of
Amberlyst-15 under solvent-free conditions at room temperature (Scheme 1).
[Insert Scheme 1]
In order to delineate the standard operating conditions the reaction among 3-nitro
benzaldehyde, ethyl-2-amino-α-(methoxy-imino)-4-thiazoleacetate, and diethylphosphite in the
presence of Amberlyst-15 was selected as a model. There is no formation of product was
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observed in the absence of catalyst, which indicated that catalyst should be necessary for this
transformation. Initially, the catalyst optimization was screened against various reported
catalysts. The interpretation of the reaction times and product yields ascertained Amberlyst-15 as
an efficient catalyst for the set of components designed under this study. The catalyst screening
results are summarized in Table 1.
[Insert Table 1]
The yield was greatly affected by the amount of catalyst loaded. When 0.01, 0.02, 0.04,
0.06, 0.08 and 0.1 mol% of the catalyst was used, the yields varied from 62, 81, 93, 93, 92 and
92% respectively (Table 2, entries 7–12). Therefore, 0.04 mol% of Amberlyst-15 was sufficient
and use of excessive catalyst had no impact either on the rate of the reaction or on the compound
yield. Meanwhile, we also tested the solvent effect on this reaction. Excellent results were
obtained, when the reaction was carried out with 0.04 mol % of Amberlyst-15 under solvent-free
condition. It shows that the use of solvent retards the rate of reaction which leads to decrease in
yield of product (Table 2).
[Insert Table 2]
After optimization of experimental conditions, we extended this three-component
coupling reaction of a series of aldehydes, ethyl-2-amino-α-(methoxy-imino)-4-thiazoleacetate
and diethyl phosphate under solvent-free conditions at room temperature in the presence of
Amberlyst-15. In all the cases, the reactions were completed within 30–45 min and gave the
corresponding α-aminophosphonates in 74-93 % yields (Table 3). The chemical structures of all
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1
31
the newly synthesized products were fully characterized by IR, H, 13C & P NMR and mass
spectral data.
[Insert Table 3]
CONCLUSIONS
In conclusion, we have developed another application of Amberlyst-15 for the one-pot
reaction of aldehyde, diethylphosphite and amine to afford the corresponding α-
aminophosphonates in moderate to good yields. The main advantage of the present synthetic
protocol is mild, solvent-free condition, eco-friendly catalyst and easy work-up procedure. It is
expected that the present methodology will find application in organic synthesis. All the title
compounds were screened for radical scavenging activity by DPPH, NO and H2O2 methods and
some of the compounds were exhibit high activity compared to reference standard.
EXPERIMENTAL
General
All the chemicals were purchased from Aldrich and used without further purification.
TLC was performed on precoated plates with silica gel 60F254 (Merk). IR Spectra were
recorded on JASCO Japan FT/IR -5300 Spectrophotometer at University of Hyderabad,
Hyderabad using KBr optics. 1H, 13C and 31P NMR spectra were recorded on Bruker A VIII 400
MHz NMR spectrometer at IIT-Chennai operating at 400 MHz, 100 MHz and 161.6 MHz
13
respectevily. NMR data were recorded in CDCl3 and were referenced to TMS (1H and C) and
85% H3PO4 (31P). Mass spectra were recorded on LCMS-2010A Shimadzu, Japan, spectrometer
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at University of Hyderabad, Hyderabad. Elementary analyses were performed using EA 1112
Thermo Finnigan instrument, France at University of Hyderabad, Hyderabad, India.
Chemistry
General procedure for α-aminophosphonates (4a-j)
A mixture of aldehyde (1 mmol), amine (1 mmol) and diethylphosphite (1 mmol) was
stirred at 30 °C for the appropriate time in the presence of Amberlyst-15 as catalyst. After
completion of the reaction as indicated by TLC, the catalyst was separated by filtration. Then the
filtrate was quenched with water followed by extraction with ethyl acetate to give the crude
product. This was subsequently purified by column chromatography on 60-120 mesh silica gel
using ethyl acetate-hexane (1:4) as eluent. This procedure was applied successfully for the
preparation of 4a-j.
Spectral data for the representative title Compounds (4g & 4j):
Ethyl-2-(2-((diethoxyphosphoryl)(3,4-dimethoxyphenyl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4g):
Ethyl-2-(2-((diethoxyphosphoryl)(3-nitrophenyl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4a):
Solid, Yield: 78 %, mp: 123-125 °C. IR (KBr) (νmax cm-1): 3348 (NH), 1208 (P=O), 762 (P-C
aliphatic). 1H NMR (400 MHz, CDCl3) δ: 1.20 (3H, t, J = 8.0 Hz, P-OCH2CH3), 1.26 (3H, t, J =
8.2 Hz, P-OCH2CH3), 1.29 (3H, t, J = 8.4 Hz, O-CH2CH3), 3.67 (3H, s, C=N-OCH3), 3.72-3.94
(2H, m, P-OCH2CH3) 3.98-4.07 (2H, m, P-OCH2CH3), 4.21 (2H, q, J = 8.2Hz, O-CH2CH3), 4.05
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13
(1H, d, J = 23.6 Hz, P-CH), 5.68 (1H, s, NH), 7.20-8.50 (5H, m, Ar-H). C NMR (125.7 MHz,
CDCl3) δ: 13.8 (OCH2CH3), 16.1 (P-OCH2CH3), 16.8 (P-OCH2CH3), 62.1 (OCH2CH3), 62.3 (P-
OCH2CH3), 62.9 (P-OCH2CH3), 64.3 (-N=C-OCH3), 69.6 (CH-P), 113.5 (C-5), 123.7 (C-31 &
C-51), 127.8 (C-21 & C-61), 142.2 (C-11), 144.9 (C-4), 145.9 (C-4), 151.7 (C=N), 163.2 (C-2)
163.7 (C=O). 31P NMR (202.4 MHz, CDCl3) δ: 24.2. EI-MS (m/z, %): 501.12 (M+.+1, 21.1), 500
(M+.,100). Anal. Calcd for C19H25N4O8PS: C, 45.67; H, 5.04; N, 11.20. Found C, 45.31; H, 5.01;
N, 11.12.
Ethyl-2-(2-((diethoxyphosphoryl)(4-hydroxyphenyl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4b):
Solid, Yield: 82 %, mp: 132-135 °C. IR (KBr) (νmax cm-1): 3291 (NH), 1245 (P=O), 737 (P-
Caliphatic).1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, t, J = 8.4 Hz, P-OCH2CH3), 1.24 (3H, t, J =
8.6 Hz, P-OCH2CH3), 1.26 (3H, t, J = 8.4 Hz, OCH2CH3), 3.48 (3H, s, N=C-OCH3), 3.74-3.97
(2H, m, P-OCH2CH3), 3.89-4.04 (2H, m, P-OCH2CH3), 4.06 (1H, d, J = 23.9 Hz, P-CH), 4.24
(2H, q, J = 8.4 Hz, O-CH2CH3), 5.32 (1H, s, OH), 5.48 (1H, s, NH), 6.63-8.10 (5H, m, Ar-H).
13C NMR (125.7 MHz, CDCl3) δ: 13.6 (OCH2CH3), 16.3 (P-OCH2CH3), 16.7 (P-OCH2CH3),
62.4 (OCH2CH3), 62.9 (P-OCH2CH3), 63.1 (P-OCH2CH3), 64.6 (N=C-OCH3), 69.8 (CH-P),
113.7 (C-5), 115.7 (C-31 & C-51), 128.3 (C-21 & C-61), 128.7 (C-11), 144.9 (C-4), 156.5 (C-41),
152.3 (C=N), 162.8 (C-2), 163.5 (C=O). 31P NMR (202.4 MHz, CDCl3) δ: 19.3. EI-MS (m/z,
%): 471.13 (M+.+1, 21.1), 471.12 (M+.,100). Anal. Calcd for C19H26N3O7PS: C, 48.43; H, 5.57;
N, 8.20. Found C, 48.40; H, 5.50; N,8.14.
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Ethyl-2-(2-((diethoxyphosphoryl)(1H-indol-2-yl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4c):
Solid, Yield: 76 %, mp: 128-130 °C. IR (KBr) (νmax cm-1): 3358 (NH), 1208 (P=O), 756 (P-
1
Caliphatic). H NMR (400 MHz, CDCl3) δ: 1.14 (3H, t, J = 8.6 Hz, P-OCH2CH3), 1.26 (3H, t, J =
8.6 Hz, P-OCH2CH3), 1.23 (3H, t, J = 8.8 Hz, OCH2CH3), 3.51 (3H, s, J = 8.7 Hz, N=C-OCH3),
3.76-3.94 (2H, m, P-OCH2CH3), 3.92-4.06 (2H, m, P-OCH2CH3), 4.08 (1H, d, J = 24.1 Hz, P-
CH), 4.23 (2H, q, J = 8.5 Hz, OCH2CH3) 5.65 (1H, s, NH), 6.99-7.40 (6H, m, Ar-H), 12.45 (1H,
13
s, indoleNH). C NMR (125.7 MHz, CDCl3) δ: 14.1 (OCH2CH3), 16.6 (P-OCH2CH3), 16.9 (P-
OCH2CH3), 62.9 (OCH2CH3), 63.1 (P-OCH2CH3), 63.4 (P-OCH2CH3), 64.8 (N=C-OCH3), 69.6
(CH-P), 101.5 (C-31), 111.1 (C-21), 112.7 (C-51), 119.8 (C-51), 120.7 (C-41), 121.7 (C-61), 128.1
31
(C-91), 136.4 (C-81), 136.8 (C-21), 145.2 (C-41), 151.7 (C=N), 163.2 (C-21), 164.8 (C=O). P
NMR (202.4 MHz, CDCl3) δ: 23.5. EI-MS (m/z, %): 495.14 (M+.+1, 25.1), 494.14 (M+., 100).
Anal. Calcd for: C21H27N4O6PS: C, 51.01; H, 5.50; N, 11.33. Found C, 50.88; H, 5.41; N,
11.21.
Ethyl-2-(2-(benzo[d][1,3]dioxol-5-yl(diethoxyphosphoryl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4d):
Solid, Yield: 82 %, mp: 107-110 °C. IR (KBr) (νmax cm-1): 3346 (NH), 1229 (P = O), 754 (P-
1
Caliphatic). H NMR (400 MHz, CDCl3) δ: 1.08 (3H, t, J = 8.5 Hz, P-OCH2CH3), 1.18 (3H, t, J =
8.7 Hz, P-OCH2CH3), 1.20 (3H, t, J = 8.8 Hz, O-CH2CH3), 3.52 (3H, s, J = 8.5 Hz, -N=C-
OCH3), 3.77- 3.96 (2H, m, P-OCH2CH3), 3.98-4.09 (2H, m, P-OCH2CH3), 4.14 (1H, d, J = 23.8
Hz, P-CH), 4.26 (2H, q, J = 8.4 Hz, O-CH2CH3), 5.76 (1H, s, NH), 6.07 (2H, OCH2O) 6.07-7.65
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(4H, m, Ar-H). 13C NMR (125.7 MHz, CDCl3) δ: 13.4 (OCH2CH3), 16.6 (P-OCH2CH3), 16.7 (P-
OCH2CH3), 62.5 (OCH2CH3), 63.4 (P-OCH2CH3), 64.4 (P-OCH2CH3), 64.9 (N=C-OCH3), 69.4
(CH-P), 101.2 (C-51), 113.7 (C-51), 112.2 (C-71), 114.8 (C-81), 120.2 (C-21), 130.2 (C-11), 144.2
(C-41), 145.5 (C-71), 146.2 (C-81), 154.3 (C=N), 161.1 (C-21), 164.9 (C=O). 31P NMR (202.4
MHz, CDCl3) δ: 22.4. EI-MS (m/z, %): 500.12 (M+.+1, 23.1), 499.12 (M+., 100). Anal. Calcd for
C20H26N3O8PS; C, 48.09; H, 5.25; N, 8.41. Found C, 48.01; H, 5.18; N, 8.34.
Ethyl-2-(2-((2-(benzyloxy)phenyl)(diethoxyphosphoryl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4e):
Solid, Yield: 84 %, mp: 114-116 °C. IR (KBr) (νmax cm-1): 3256 (NH), 1219 (P=O), 752 (P-
1
Caliphatic). H NMR (400 MHz, CDCl3) δ: 1.12 (3H, t, J = 8.7 Hz, P-OCH2CH3), 1.24 (3H, t, J =
8.6 Hz, P-OCH2CH3), 1.28 (3H, t, J = 8.7 Hz, OCH2CH3), 3.67 (3H, s, J = 8.5 Hz, -N=C-OCH3),
3.75-3.96 (2H, m, P-OCH2CH3) 3.86-4.05 (2H, m, P-OCH2CH3), 4.21 (1H, d, J = 24.5 Hz, P-
CH), 4.25 (2H, q, J = 8.6 Hz, OCH2CH3), 5.69 (1H, s, NH), 6.27 (2H, OCH2C6H5), 6.84-7.56
13
(10H, m, Ar-H). C NMR (125.7 MHz, CDCl3) δ: 13.9 (OCH2CH3), 16.8 (P-OCH2CH3), 17.1
(P-OCH2CH3), 62.9 (OCH2CH3), 63.6 (P-OCH2CH3), 63.8 (P-OCH2CH3), 65.1 (N=C-OCH3),
63.8 (CH-P), 71.4 (OCH2C6H5), 112.4 (C-31), 112.9 (C-5), 119.9 (C-11), 120.9 (C-51), 127.1 (C-
211 & C-611), 127.6 (C-411), 127.8 (C-41), 128.0 (C-61), 128.9 (C-311 & C-511), 136.9 (C-111),
145.2 (C-4), 154.8 (C=N), 156.5 (C-21), 162.7 (C-2), 165.4 (C=O). 31P NMR (202.4 MHz,
CDCl3) δ: 26.4; EI-MS (m/z, %): 562.17 (M+.+1, 30.7), 561.17 (M+., 100). Anal. Calcd for:
C26H32N3O7PS: C, 55.65; H, 5.76; N, 7.48. Found C, 55.58; H, 5.70; N, 7.40.
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Ethyl-2-(2-((4-chlorophenyl)(diethoxyphosphoryl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4f):
Solid, Yield: 79 %, mp: 122-124 °C. IR (KBr) (νmax cm-1): 3406 (NH), 1218 (P=O), 745 (P-
1
Caliphatic). H NMR (400 MHz, CDCl3) δ: 1.14 (3H, t, J = 8.2 Hz, P-OCH2CH3) ,1.18 (3H, t, J =
8.8 Hz,P-OCH2CH3), 1.24 (3H, t, J = 8.4 Hz, O-CH2CH3), 3.54 (3H, s, N=C-OCH3), 3.62-3.82
(2H, m, P-OCH2CH3), 3.87-4.10 (2H, m, P-OCH2CH3), 4.12 (1H, d, J = 24.6 Hz, P-CH), 4.28
(2H, q, J = 8.2 Hz, O-CH2CH3), 5.75 (1H, s, NH), 7.17-8.06 (7H, m, Ar-H). 13C NMR 125.7
MHz, CDCl3) δ: 13.5 (OCH2CH3), 16.4 (P-OCH2CH3), 16.7 (P-OCH2CH3), 62.6 (OCH2CH3),
63.3 (P-OCH2CH3), 63.5 (P-OCH2CH3), 64.8 (N=C-OCH3), 69.9 (CH-P), 112.9 (C-5), 122.9 (C-
31 & C-51), 128.3 (C-21 & C-61), 132.3 (C-41), 134.2 (C-11), 143.9 (C-4), 152.7 (C=N), 163.7
(C-2), 165.9 C=0).31P NMR (202.4 MHz, CDCl3) δ: 22.2. EI-MS (m/z, %): 488.11 (M+.+1,
23.1), 487.11 (M+., 100). Anal. Calcd for: C20H27ClN3O5PS: C, 49.23; H, 5.58; N,8.56. Found C,
49.18; H, 5.51; N, 8.48.
Ethyl-2-(2-((diethoxyphosphoryl)(3,4-dimethoxyphenyl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4g):
Ethyl-2-(2-((diethoxyphosphoryl)(3,4-dimethoxyphenyl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4g):
Solid, Yield: 81 %, mp: 121-123 °C. IR (KBr) (νmax cm-1): 3395 (NH), 1247 (P=O), 752 (P-
Caliphatic).1H NMR (400 MHz, CDCl3) δ: 1.16 (3H, t, J = 8.6 Hz, P-OCH2CH3), 1.18 (3H, t, J =
8.5 Hz, P-OCH2CH3), 1.20 (3H, t, J = 8.6 Hz, OCH2CH3), 3.79 (3H, s, J = 8 .5Hz, N=C-CH3),
3.74-3.95 (2H, m, P-OCH2CH3), 3.97-4.09 (2H, m, P-OCH2CH3), 4.12 (3H, s, C6H5-OCH3), 4.19
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(1H, d, J = 24.2 Hz, CH-P), 4.29 (2H, q, J = 8.7 Hz, OCH2CH3), 5.68 (1H, s, NH), 6.50-7.67
(7H, m, Ar-H). 13C NMR (125.7 MHz, CDCl3) δ: 13.7 (OCH2CH3), 16.6 (P-OCH2CH3), 16.7 (P-
OCH2CH3), 56.1 (C6H5-OCH3), 57.9 (C6H5-OCH3) 62.2 (OCH2CH3), 62.8 (P-OCH2CH3), 62.9
(P-OCH2CH3), 64.9 (N=C-OCH3), 69.7 (CH-P), 112.4 (C-21), 112.8 (C-51), 113.7 (C-51), 120.6
(C-61), 129.8 (C-11), 144.1 (C-41), 147.9 (C-41) 149.7 (C-31), 152.9 (C=N), 162.9 (C-21), 165.4
31
(C=O). P NMR (202.4 MHz, CDCl3) δ: 19.6. EI-MS (m/z, %): 516.15 (M+.+1, 24.9), 515.15
(M+., 100). Anal. Calcd for C21H30N3O8PS: C, 48.96; H, 5.88; N, 8.16. Found C, 48.81; H, 5.78;
N, 8.08.
Ethyl-2-(2-((diethoxyphosphoryl)(4-(dimethylamino)phenyl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4h):
Solid, Yield 81%, mp: 132-134 °C. IR (KBr) (νmax cm-1): 3384 (NH), 1212 (P=O), 772 (P-
1
Caliphatic). H NMR (400 MHz, CDCl3) δ: 1.15 (3H, t, J = 8.9 Hz, P-OCH2CH3), 1.20 (3H, t, J =
8.7 Hz, P-OCH2CH3), 1.24 (3H, t, J = 8.5 Hz, OCH2CH3), 3.08 (6H, s, N-CH3), 3.85 (3H, s, J =
8.8 Hz, N=C-OCH3), 3.71-3.98 (2H, m, P-OCH2CH3), 3.97-4.07 (2H, m, P-OCH2CH3), 4.20
(1H, d, J = 23.8 Hz, P-CH), 4.24 (2H, q, J = 8.6 Hz, OCH2CH3), 5.72 (1H, s, NH), 6.50-7.50
(5H, m, Ar-H). 13C NMR (125.7 MHz, CDCl3) δ: 14.1 (OCH2CH3), 16.2 (P-OCH2CH3), 16.5 (P-
OCH2CH3), 41.5 (N-CH3), 62.5 (d, J = 8.7, OCH2CH3), 62.6 (P-OCH2CH3), 62.9 (P-OCH2CH3),
65.4 (N=C-OCH3), 68.8 (CH-P), 112.7 (C-31 & C-51), 113.9 (C-5), 125.1 (C-11), 127.8 (C-21 &
C-61), 143.8 (C-4), 149.4 (C-41), 153.2 (C=N), 163.4 (C-2), 65.8 (C=O). 31P-NMR (202.4 MHz,
CDCl3) δ: 25.6. EI-MS (m/z, %): 499.17 (M+.+1, 25.4), 498.16 (M+., 100). Anal. Calcd for
C21H31N4O6PS: C, 50.59; H, 6.28; N, 11.35. Found C, 51.51; H, 6.18; N, 11.28.
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Ethyl-2-(2-((4-chloro-3-nitrophenyl)(diethoxyphosphoryl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4i):
Solid, Yield: 76 %, mp: 118-120 °C. IR (KBr) (νmax cm-1): 3278 (NH), 1265 (P=O), 769 (P-
1
Caliphatic). H NMR (400 MHz, CDCl3) δ: 1.02 (3H, t, J = 8.8 Hz, P-OCH2CH3), 1.14 (3H, t, J =
8.4 Hz, P-OCH2CH3), 1.18 (3H, t, J = 8.7 Hz, OCH2CH3), 3.89 (3H, s, J = 8.3 Hz, N=C-OCH3),
3.74-3.92 (2H, m, P-OCH2CH3), 3.90-4.10 (2H, m, P-OCH2CH3), 4.16 (1H, d, J = 23.9 Hz, P-
CH), 4.27 (2H, q, J = 8.8 Hz, -OCH2CH3), 5.72 (1H, s, NH), 7.50-8.06 (4H, m, Ar-H). 13C NMR
(125.7 MHz, CDCl3) δ: 13.8 (OCH2CH3), 16.8 (P-OCH2CH3), 16.9 (P-OCH2CH3), 62.8
(OCH2CH3), 62.9 (P-OCH2CH3), 63.3 (P-OCH2CH3), 65.9 (N=C-OCH3), 68.6 (CH-P), 112.9
(C-5), 124.9 (C-21), 125.8 (C-41), 132.8 (C-51), 134.8 (C-61), 135.6 (C-11), 143.8 (C-4), 147.4
31
(C-31), 153.8 (C=N), 162.8 (C-2), 164.8 (C=O). P NMR (202.4 MHz, CDCl3) δ: 19.6. EI-MS
(m/z, %): 534.14 (M+.+1, 36.8), 534.07 (M+., 100). Anal. Calcd for C19H24ClN4O8PS: C, 42.65;
H, 4.50; N, 10.47. Found C, 42.58; H, 4.45; N, 10.35.
Ethyl-2-(2-((2,4-dichlorophenyl)(diethoxyphosphoryl)methylamino)thiazol-4-yl)-2-
(methoxyimino)acetate (4j):
Solid, Yield: 74 %, mp: 112-114 °C. IR (KBr) (νmax cm-1): 3468 (NH), 1214 (P=O), 747 (P-
Caliphatic). 1H NMR (400 MHz, CDCl3) δ: 1.12 (3H, t, J = 8.3 Hz, P-OCH2CH3), 1.16 (3H, t, J =
8.1 Hz, P-OCH2CH3), 1.18 (3H, t, J = 8.8 Hz, OCH2CH3), 3.48 (3H, s, J = 8.7 Hz, N=C-OCH3),
3.56-3.79 (2H, m, P-OCH2CH3), 3.84-4.06 (2H, m, P-OCH2CH3), 4.14 (1H, d, J = 24.4 Hz, P-
CH), 4.29 (2H, q, J = 8.8 Hz, OCH2CH3), 5.54 (1H, s, NH), 7.02-7.98 (4H, m, Ar-H). 13C NMR
(125.7 MHz, CDCl3) δ: 13.6 (OCH2CH3), 16.4 (P-OCH2CH3), 16.6 (P-OCH2CH3), 63.2
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(OCH2CH3), 63.4 (P-OCH2CH3), 63.7 (P-OCH2CH3), 65.6 (N=C-OCH3), 68.9 (CH-P), 113.6 (C-
5), 128.1 (C-21), 126.8 (C-61), 131.8 (C-51), 132.2 (C-41), 132.8 (C-31), 136.1 (C-11), 142.8 (C-
4), 152.9 (C=N), 163.2 (C-2), 165.4 (C=O). 31P NMR (202.4 MHz, CDCl3) δ: 24.6. EI-MS (m/z,
%): 34.14 (M+.+1, 36.8), 534.07 (M+., 100). Anal. Calcd for C19H24Cl2N3O6PS: C, 43.56; H,
4.64; N, 8.42. Found C, 43.51; H, 4.58; N, 8.37.
Biology
Antioxidant activity
The antioxidant activity of 4a-j was performed by to three methods. All the synthesized
compounds show good activity against DPPH, NO and Hydrogen peroxide scavenging. Among
the synthesized compounds, 4h exhibited high activity when compared with other compounds.
DPPH Radical Scavenging Activity
The scavenging activity of α-aminophosphonates against DPPH radical was performed
in accordance with Choi et al.34 and results are summarized in Figure S 1 (Supplemental
Materials).
Nitric Oxide (NO) Scavenging Activity
The scavenging activity of α-aminophosphonates against Nitric Oxide radical was
performed in accordance with A Shirwaiker et al.35 and results are summarized in Figure S 2
(Supplemental Materials).
Determination of Hydrogen Peroxide (H2O2) Scavenging Activity
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It was determined using a modified method of Gow-Chin Yen et al.36 and results are
summarized in Figure S 3 (Supplemental Materials).
ACKNOWLEDGEMENTS:
The authors express their grateful thanks to Prof. C.D. Reddy, Department of Chemistry,
Sri Venkateswara University, Tirupati, for his helpful discussions and also thank DRDO, New
Delhi, for providing financial assistance (ERIP/ER/1103894M/01/1346)
Supplemental Materials:
1
Figures S 1 – S 3 present the results of the biological activities. H, 13C and 31P NMR spectra for
4g and 4i (as examples) are presented in Figures S 4 – S 9
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Legends:
Table 1: Screening of catalyst for the synthesis of 4a
Entry Catalyst/ Mol (%)
Time (min)
Yield (%)a,b
1
2
3
4
5
6
7
8
TiO2/10
60
60
60
60
60
60
60
60
58
24
29
37
52
64
60
93
H3PW12O40/0.5
KHSO4/10
BiCl3/5
InCl3/0.1
Mg(ClO4)/5
FeCl3/5
Amberlyst-15/0.04
aIsolated yield
bAll the reactions were carried at 30 °C
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Table 2: Screening of solvents and the amount of catalyst for the synthesis of 4a
Entry Solvents
Amberlyst-15 Time (min)
(mol %)
Yield (%)a,b
1
2
3
4
5
6
7
8
9
EtOH
0.04
0.04
0.04
0.04
0.04
0
60
60
60
60
60
60
30
30
30
45
45
45
30
27
36
42
35
--
MeOH
THF
Toluene
CH2Cl2
Solvent-free
Solvent-free
Solvent-free
Solvent-free
0.01
0.02
0.04
0.06
0.08
0.1
62
81
93
93
92
92
10 Solvent-free
11 Solvent-free
12 Solvent-free
aIsolated yield
bAll the reactions were carried at 30 °C
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Table 3: Synthesis of α-aminophosphonates (4a-j)
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Yield (%)a
Entry
R
Time (min)
Product (4)
2a
4a
30
93
NO2
2b
4b
30
85
OH
2c
2d
2e
4c
4d
4e
35
30
40
79
91
84
N
H
O
O
OCH2C6H5
2f
4f
35
40
79
81
Cl
2g
4g
OMe
OMe
N
2h
4h
35
81
Me
Me
2i
2j
4i
4j
40
45
76
74
NO2
Cl
Cl
Cl
aIsolated yields
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Scheme 1: Synthesis of α-aminophosphonates (4a-j)
OCH3
N
OCH3
N
EtO
O
O
P
EtO
Amberlyst-15
OEt
OEt
O
P
N
S
OEt
OEt
H
O
H
N
H
R
N
O
neat, 30-45 min
NH2
S
R
(1)
(2a-j)
(3)
(4a-j)
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