K2CO3/Al2O3: An efficient and recyclable catalyst for one-pot, three components synthesis of α-aminophosphonates and bioactivity evaluation

Article abstract of DOI:10.14233/ajchem.2019.22194

A simple and efficient method has been employed for synthesis of a novel series of biologically active α-aminophosphonates (4a-j) by reacting 1H-benzo[d]imidazole-2-carbaldehyde (1) and various aromatic amines (2a-j) and diethyl/dimethyl phosphite (3) by

Full text of DOI:10.14233/ajchem.2019.22194

Asian Journal of Chemistry; Vol. 31, No. 10 (2019), 2383-2388
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22194
K2CO3/Al2O3: An Efficient and Recyclable Catalyst for One-Pot, Three
Components Synthesis of α-Aminophosphonates and Bioactivity Evaluation
1,
2
1,3
4,
1,*,
G. SRAVYA , G. SURESH , GRIGORY V. ZYRYANOV , A. BALAKRISHNA
and N. BAKTHAVATCHALA REDDY
1Ural Federal University, Chemical Engineering Institute, Yekaterinburg 620002, Russia
2Anhui Provincial Engineering Technology Research Centre of New Silicon-Based Materials, Bengbu University, Caoshan Road 1866, Bengbu
233030, Anhui
3I.Ya. Postovskiy Institute of Organic Synthesis, Ural Division of RussianAcademy of Sciences, 22 S. Kovalevskoy Street, 620219,Yekaterinburg,
Russia
4Rajeev Gandhi Memorial College of Engineering and Technology (Autonomous), Nandyal-518501, India
*Corresponding author: E-mail: drbvreddyn@gmail.com
Received: 30 May 2019;
Accepted: 10 July 2019;
Published online: 30 August 2019;
AJC-19556
A simple and efficient method has been employed for synthesis of a novel series of biologically active α-aminophosphonates (4a-j) by
reacting 1H-benzo[d]imidazole-2-carbaldehyde (1) and various aromatic amines (2a-j) and diethyl/dimethyl phosphite (3) by Kabachnik-
Field's reaction in the presence of efficient heterogeneous K2CO3/Al2O3 catalyst under solvent-free conditions at 140 ºC. Structures of all
the compounds were confirmed by 1H, 13C and 31P NMR and LC-MS. In addition to this antioxidant activity were also evaluated.
Keywords: K2CO3/Al2O3 catalyst, α-Aminophosphonates, Antioxidant activity, Kabachnik-Field′s reaction.
Al2O3 [19], Cu(OTf)2 [20], BiCl3 [21], In(OTf)3/MgSO4 [22],
GaI3 [23] and also in the presence of Lewis acid-surfactant-
combined catalyst [24-27]. Specific synthetic cases even in
solvent free and catalyst-free conditions are also reported [28].
However, these catalysts have few disadvantages, they require
long reaction times, moisture sensitive catalysts and stoichio-
metric amounts of toxic catalysts. They ofen yield poor products
and generate large amounts of waste which affects the quality
of the reaction. It is a challenging goal to overcome these
drawbacks. Due to these problems, development of an efficient
and versatile method using heterogeneous and reusable
catalysts is still in demand.
In recent years, heterogeneous catalysts have acquired
considerable importance in diverse areas of organic synthesis
due to their economic and environmental compatibility comb-
ined with the good yield and selectivity that can be accomp-
lished [29-34]. In addition, the activity and selectivity of a reagent
dispersed on the surface of a support are improved as the
effective surface area of the reagent is increased significantly,
and hence they are expected to perform more effectively than
the individual reagents [35-41]. Among the various supported
INTRODUCTION
α-Aminophosphonates being structural analogues of natural
amino acids constitute an important class of compounds are
receiving attention in organic and medicinal chemistry due to
their broad spectrum in biological activities such as antifungal
and antibacterial activities, inhibitors of synthase, HIV protease
[1], plant growth regulators [2,3], antithrombotic agents [4],
peptide mimetics [5], insecticides [6], herbicides [7] and viru-
cides [8], haptens of catalytic antibodies [9], inhibitors of serine
hydrolases [10], inhibitors of UDP-galactopyranose mutase
[11], pharmacogenic agents [12] and enzyme inhibitors [13].
α-Aminophosphonates can be synthesized from the three
component reaction of carbonyl compound with amine and
dialkylphosphite through Kabachnik-Field reaction. It is very
important in drug discovery research for generating peptido-
mimetic compounds. Based on their utility a number of synthetic
methods for them have been carried out under neat conditions,
such as nano Fe3O4 [14], [Yb(PFO)3] [15], CoCl2·6H2O [16],
metal triflate [17] and Mg(ClO4)2 [18]. α-Aminophosphonates
have also been synthesized in organic solvents using SbCl3/
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2384 Sravya et al.
Asian J. Chem.
catalysts, particu-larly, alumina and silica supported reagents
have advantages of low cost, ease of preparation and catalyst
recycling [42-46].
Considering the above facts and due to our interest in the
solid catalysts for organic reactions [47], we report herein the
investigation of K2CO3/Al2O3 as an efficient, low cost and hetero-
geneous reusable catalyst for the synthesis of α-aminophos-
phonates by the reaction of 1H-benzo[d]imidazole-2-carbalde-
hyde (1) and various aromatic amines (2a-j) and diethyl/dimethyl-
phosphite (3) under solvent-free conditions (Scheme-I).
6′), 62.8 (C-11 & C-13), 16.4 (C-12 & C-14). 31P NMR (161.7
MHz, DMSO-d6) δppm: 22.0; EI-MS (m/z, %): 359 (M+•, 100);
Elemental anal. calcd. (found) for C18H22N3O3P: C, 60.16 (60.12);
H, 6.17 (6.14); N, 11.69 (11.59).
Diethyl (1H-benzo[d]imidazol-2-yl)(4-fluorophenylamino-
methyl)phosphonate (4b): White solid;Yield 89 %; m.p.: 122-
124 °C; IR (KBr, νmax, cm-1): 3292 (NH), 1246 (P=O), 752 (P-
Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.10 (s, 1H,
imad-azole NH), 7.65-7.05 (m, 8H, Ar-H), 6.21 (s, 1H, NH),
4.68 (d, J = 24.4 Hz, 1H, P-CH), 4.22-4.09 (m, 4H, 2 × P-
OCH2CH3), 1.30-1.28 (m, 6H, 2 × P-OCH2CH3); 13C NMR
(100.5 MHz, DMSO-d6) δ ppm: 124.4 (C-1 & C-2), 140.4 (C-
4 & C-5), 117.2 (C-3 & C-6), 140.8 (C-8), 72.4 (C-10), 117.9 (C-
1′ & C-5′), 116.2 (C-2′ & C-4′), 156.2 (C-3′), 144.0 (C-6′),
62.6 (C-11 & C-13), 16.2 (C-12 & C-14). 31P NMR (161.7
MHz, DMSO-d6) δ ppm: 22.2; EI-MS (m/z, %): 377 (M+•, 100);
Elemental anal. calcd. (found) for C18H21N3O3FP: C, 57.29
(57.24); H, 5.61 (5.58); N, 11.14 (11.09).
Diethyl (1H-benzo[d]imidazol-2-yl)(4-chlorophenylamino-
methyl)phosphonate (4c):Yellow solid;Yield 91 %; m.p. 194-
196 ºC; IR (KBr, νmax, cm-1): 3294 (NH),1252 (P=O), 750 (P-
Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1H,
imad-azole NH), 7.62-6.50 (m, 8H, Ar-H), 6.18 (s, 1H, NH),
4.64 (d, J = 24.2 Hz, 1H, P-CH), 4.21-4.07 (m, 4H, 2 × P-
OCH2CH3), 1.31-1.29 (m, 6H, 2 × P-OCH2CH3); 13C NMR
(100.5 MHz, DMSO-d6) δ ppm: 123.4 (C-1 & C-2), 140.2 (C-
4 & C-5), 116.4 (C-3 & C-6), 140.6 (C-8), 71.5 (C-10), 116.9
(C-1′ & C-5′), 128.8 (C-2′ & C-4′), 126.4 (C-3′), 144.5 (C-
6′), 62.2 (C-11 & C-13), 16.4 (C-12 & C-14). 31P NMR (161.7
MHz, DMSO-d6) δ ppm: 21.4; EI-MS (m/z, %): 393 (M+•,
100); Elemental anal. calcd. (found) for C18H21N3O3PCl: C,
54.90 (54.85); H, 5.38 (5.32); N, 10.67 (10.59).
EXPERIMENTAL
All reagents were purchased from Sigma-Aldrich, Hyderabad,
India, and used without further purification. Melting points
were determined on Guna Mel-Temp apparatus (Tempo Instru-
ments and Equip., Mumbai, India) and were uncorrected. The
IR spectra were recorded on Bruker Alpha ECO-ATR FTIR
(Attenuated total reflection-Fourier transform infrared) interfero-
meter with single reflection sampling module equipped with
ZnSe crystal. 1H, 13C NMR spectra were taken on Jeol JNM
ECP 400 NMR instrument (Tokyo) at room temperature in
DMSO-d6 or CDCl3 using tetramethylsilane (TMS) as internal
standard. EI-Mass spectra were obtained on JEOL GCMATE
II GC-MS spectrometer (Tokyo) at SAIF IIT-Madras, Chennai.
General procedure for the synthesis of α-aminopho-
sphonates (4a-j): To a mixture of 1H-benzo[d]imidazole-2-
carbaldehyde (1 mmol) (1) and aniline (1 mmol) (2a) and diethyl
phosphite (1.1 mmol) (3) in a round-bottom flask connected
to a reflux condenser was added K2CO3/Al2O3 (0.15 g) and the
resulting mixture was stirred in an oil-bath at 140 ºC for an
appropriate time (10-15 min). The progress of reaction was
monitored by thin-layer chromatography.After completion of
reaction, the reaction mixture was cooled to room temperature,
hot ethanol (20 mL) was added and filtered to remove the catalyst.
Again the catalyst was washed with 10 mL of absolute ethanol
(hot). The solvent of combined filtrate was evaporated under
reduced pressure, and the crude product was recrystallized from
ethyl acetate/n-hexane (1:3) or ethanol. The same procedure was
adopted for the synthesis of remaining compounds (4b-j).
Diethyl (1H-benzo[d]imidazol-2-yl)(phenylamino-
methyl)phosphonate (4a): White solid;Yield 85 %; m.p.: 172-
174 ºC; IR (KBr, νmax, cm-1): 3294 (NH), 1242 (P=O), 743 (P-
Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.20 (s, 1H,
imada-zole NH), 7.80-6.75 (m, 9H, Ar-H), 6.40 (s, 1H, NH),
4.71 (d, J = 24.4 Hz, 1H, P-CH), 4.24-4.10 (m, 4H, 2 × P-
OCH2CH3), 1.32-1.29 (m, 6H, 2 × P-OCH2CH3); 13C NMR
(100.5 MHz, DMSO-d6) δ ppm: 125.4 (C-1 & C-2), 140.2 (C-
4 & C-5), 117.4 (C-3 & C-6), 140.5 (C-8), 72.2 (C-10), 114.0
(C-1′ & C-5′), 130.2 (C-2′ & C-4′), 122.0 (C-3′), 148.0 (C-
Diethyl (1H-benzo[d]imidazol-2-yl)(4-bromophenyl-
aminomethyl)phosphonate (4d): White solid; Yield 90 %;
m.p.: 140-142 ºC; IR (KBr, νmax, cm-1): 3290 (NH), 1248 (P=O),
1
752 (P-Caliphatic); H NMR (400 MHz, DMSO-d6) δ ppm: 8.95
(s, 1H, imadazole NH), 7.64-6.65 (m, 8H, Ar-H), 6.16 (s, 1H,
NH), 4.66 (d, J = 24.2 Hz, 1H, P-CH), 4.19-4.08 (m, 4H, 2 ×
P-OCH2CH3), 1.32-1.29 (m, 6H, 2 × P-OCH2CH3); 13C-NMR
(100.5 MHz, DMSO-d6) δ ppm: 123.6 (C-1 & C-2), 139.0 (C-
4 & C-5), 116.2 (C-3 & C-6), 140.8 (C-8), 71.2 (C-10), 115.0
(C-1′ & C-5′), 131.8 (C-2′ & C-4′), 116.4 (C-3′), 145.5 (C-
6'), 62.3 (C-11 & C-13), 16.2 (C-12 & C-14). 31P NMR (161.7
MHz, DMSO-d6) δppm: 21.6; EI-MS (m/z, %): 438 (M+•, 100);
Elemental anal. calcd. (found) for C18H21N3O3PBr: C, 49.33
(49.30); H, 4.83 (4.79); N, 9.59 (9.56).
Diethyl (1H-benzo[d]imidazol-2-yl)(4-methoxyphenyl-
aminomethyl)phosphonate (4e): White solid; Yield 94 %;
m.p.: 126-128 ºC; IR (KBr, νmax, cm-1): 3304 (NH), 1250 (P=O),
OR
O
H
O
N
P
N
K2CO3 / Al2O3
Solvent-free
OR
HN Ar
H P OR
Ar NH2
CHO
N
H
N
OR
3
°
2(a-j)
140 C
1
4(a-j)
Ar = Ph, F-Ph, Cl-Ph, Br-Ph, MeO-Ph
R = Et, Me
Scheme-I: K2CO3/Al2O3 catalyzed synthesis of α-aminophosphonates

Vol. 31, No. 10 (2019)
K2CO3/Al2O3: An Efficient and Recyclable Catalyst for Synthesis of α-Aminophosphonates 2385
756 (P-Caliphatic); 1H NMR (400 MHz, DMSO-d6) δppm: 8.90 (s,
1H, imadazole NH), 7.60- 6.75 (m, 8H, Ar-H), 6.14 (s, 1H,
NH), 4.60 (d, J = 24.2 Hz, 1H, P-CH), 4.18-4.06 (m, 4H, 2 ×
P-OCH2CH3), 3.80 (s, 3H, OCH3), 1.30-1.28 (m, 6H, 2 × P-
OCH2CH3); 13C NMR (100.5 MHz, DMSO-d6) δ ppm: 123.2
(C-1 & C-2), 139.4 (C-4 & C-5), 116.6 (C-3 & C-6), 140.6
(C-8), 71.0 (C-10), 115.4 (C-1′ & C-5′), 116.8 (C-2′ & C-4′),
156.4 (C-3′), 140.5 (C-6′), 62.2 (C-11 & C-13), 16.3 (C-12 &
C-14). 31P NMR (161.7 MHz, DMSO-d6) δ ppm: 22.4; EI-MS
(m/z, %): 389 (M+•, 100); Elemental anal. calcd. (found) for
C18H24N3O4P: C, 58.61 (58.57); H, 6.21 (6.19); N, 10.79 (10.56).
Dimethyl (1H-benzo[d]imidazol-2-yl)(phenylamino-
methyl)phosphonate (4f): Green solid;Yield 84 %; m.p.: 142-
146 ºC; IR (KBr, νmax, cm-1): 3312 (NH), 1252 (P=O), 762 (P-
Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (s, 1H,
imad-azole NH), 7.65-6.70 (m, 9H, Ar-H), 6.12 (s, 1H, NH),
4.58 (d, J = 24.2 Hz, 1H, P-CH), 3.60 (s, 6H, 2 × POCH3); 13C
NMR (100.5 MHz, DMSO-d6)δppm: 123.1 (C-1 & C-2), 138.4
(C-4 & C-5), 116.5 (C-3 & C-6), 140.4 (C-8), 70.2 (C-10),
114.4 (C-1′ & C-5′), 129.8 (C-2′ & C-4′), 120.4 (C-3′), 147.5
(C-6′), 54.2 (C-11 & C-12). 31P NMR (161.7 MHz, DMSO-
d6) δ ppm: 21.8; EI-MS (m/z, %): 331 (M+•, 100); Elemental
anal. calcd. (found) for C16H18N3O3P: C, 58.00 (57.96); H, 5.48
(5.40); N, 12.68 (12.58).
Dimethyl (1H-benzo[d]imidazol-2-yl)((4-fluorophenyl-
aminomethyl)phosphonate (4g): White solid; Yield 86 %;
m.p.: 125-127 ºC; IR (KBr, νmax, cm-1): 3304 (NH), 1260 (P=O),
764 (P-Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98
(s, 1H, imadazole NH), 7.64-7.06 (m, 8H, Ar-H), 6.10 (s, 1H,
NH), 4.56 (d, J = 24.2 Hz, 1H, P-CH), 3.62 (s, 6H, 2 × POCH3);
13C NMR (100.5 MHz, DMSO-d6) δ ppm: 123.2 (C-1 & C-2),
138.6 (C-4 & C-5), 116.4 (C-3 & C-6), 140.2 (C-8), 70.0 (C-
10), 118.4 (C-1′ & C-5′), 117.1 (C-2′ & C-4′), 156.2 (C-3′),
143.5 (C-6′), 53.8 (C-11 & C-12); 31P NMR (161.7 MHz,
DMSO-d6) δ ppm: 23.2; EI-MS (m/z, %): 349 (M+•, 100);
Elemental anal. calcd. (found) for C16H17N3O3PF: C, 55.02
(54.97); H, 4.91 (4.82); N, 12.03 (11.92).
Dimethyl (1H-benzo[d]imidazol-2-yl)(4-chlorophenyl-
aminomethyl)phosphonate (4h): White solid; Yield 85 %;
m.p.: 138-140 ºC; IR (KBr, νmax, cm-1): 3312 (NH), 1258 (P=O),
762 (P-Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.92
(s, 1H, imadazole NH), 7.69-6.58 (m, 8H, Ar-H), 6.14 (s, 1H,
NH), 4.58 (d, J = 24.2 Hz, 1H, P-CH), 3.64 (s, 6H, 2 × POCH3).
13C NMR (100.5 MHz, DMSO-d6) δ ppm: 123.4 (C-1 & C-2),
138.8 (C-4 & C-5), 116.6 (C-3 & C-6), 140.0 (C-8), 70.4 (C-
10), 114.4 (C-1′ & C-5′), 130.1 (C-2′ & C-4′), 126.4 (C-3′),
144.9 (C-6′), 53.4 (C-11 & C-12). 31P NMR (161.7 MHz,
DMSO-d6) δ ppm: 22.6; EI-MS (m/z, %): 365 (M+•, 100);
Elemental anal. calcd. (found) for C16H17N3O3PCl: C, 52.54
(52.42); H, 4.69 (4.54); N, 11.49 (11.39).
Dimethyl (1H-benzo[d]imidazol-2-yl)(4-bromophenyl-
aminomethyl)phosphonate (4i): White solid; Yield 89 %;
m.p.: 130-132 ºC; IR (KBr, νmax, cm-1): 3310 (NH), 1256 (P=O),
764 (P-Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90
(s, 1H, imad-azole NH), 7.60-6.65 (m, 8H, Ar-H), 6.16 (s, 1H,
NH), 4.56 (d, J = 24.2 Hz, 1H, P-CH), 3.68 (s, 6H, 2 × POCH3).
13C NMR (100.5 MHz, DMSO-d6) δ ppm: 123.2 (C-1 & C-2),
138.6 (C-4 & C-5), 116.4 (C-3 & C-6), 140.1 (C-8), 70.2 (C-
10), 114.8 (C-1′ & C-5′), 132.1 (C-2′ & C-4′), 116.4 (C-3′),
144.9 (C-6′), 53.2 (C-11 & C-12). 31P NMR (161.7 MHz,
DMSO-d6) δ ppm: 21.2; EI-MS (m/z, %): 410 (M+•, 100);
Elemental anal. calcd. (found) for C16H17N3O3PBr: C, 46.85
(46.70); H, 4.18 (4.08); N, 10.24 (10.04).
Dimethyl (1H-benzo[d]imidazol-2-yl)(4-methoxyphenyl-
aminomethyl)phosphonate (4j): White solid; Yield 90 %;
m.p.: 132-134 ºC; IR IR (KBr, νmax, cm-1): 3306 (NH), 1254
(P=O), 762 (P-Caliphatic); 1H NMR (400 MHz, DMSO-d6) δ ppm:
8.94 (s, 1H, imadazole NH), 7.62-6.75 (m, 8H, Ar-H), 6.12 (s,
1H, NH), 4.54 (d, J = 24.2 Hz, 1H, P-CH), 3.82 (s, 3H, OCH3),
3.64 (s, 6H, 2 × POCH3). 13C NMR (100.5 MHz, DMSO-d6) δ
ppm: 123.6 (C-1 & C-2), 138.2 (C-4 & C-5), 116.2 (C-3 & C-
6), 140.2 (C-8), 69.8 (C-10), 116.1 (C-1′ & C-5′), 115.6 (C-2′
& C-4′), 152.4 (C-3′), 144.9 (C-6'), 53.3 (C-11 & C-12). 31P
NMR (161.7 MHz, DMSO-d6) δ ppm: 22.3; EI-MS (m/z, %):
361 (M+•, 100); Elemental anal. calcd. (found) for C17H20N3O4P:
C, 56.51 (56.46); H, 5.58 (5.51); N, 11.63 (11.49).
Biological activity: The compounds 4(a-j) were evaluated
for antioxidant property by DPPH [48,49], H2O2 [50] and NO
[51,52] methods.
1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scaven-
ging activity: The hydrogen atom or electron donation ability
of the compounds was measured from the bleaching of purple
coloured methanol solution of 1,1-diphenyl-2-picrylhydrazyl
radical (DPPH). The spectrophotometric assay uses the stable
radical DPPH as a reagent. To 4 mL of 0.004 % w/v methanol
solution of DPPH, 1 mL of various concentrations of the test
compounds (50, 75 and 100 µg/mL) in methanol were added.
After 30 min incubation period at room temperature, the absor-
bance was read against blank at 517 nm. Ascorbic acid was
used as the standard. The percent of inhibition (I %) of free
radical production from DPPH was calculated by the following
equation:
Acontrol − Asample
Inhibition (%) =
×100
Acontrol
where Acontrol is the absorbance of control reaction (containing
all reagents except the test compounds),Asample is the absorbance
of the test compound (containing methanolic DPPH and test
compound). Tests were carried out in triplicate.
Hydrogen peroxide scavenging activity:The H2O2 scaven-
ging ability of the test compound was determined by a solution
of H2O2 (40 mm) was prepared in phosphate buffer (pH 7.4).
50, 75 and 100 µg/mL concentrations of the test compounds
in 3.4 mL phosphate buffer were added to H2O2 solution (0.6
mL, 40 mm). The absorbance value of reaction mixture was
recorded at 230 nm. Ascorbic acid was used as the standard.
The percent scavenging of H2O2 was calculated by the following
equation:
Acontrol − Asample
Scavenging (%) =
×100
Acontrol
whereAcontrol is the absorbance of the control reaction (containing
all reagents except the test compounds), Asample is the absor-
bance of the test compound (containing all reagents and test
compound). Tests were carried out in triplicate.
Nitric oxide scavenging activity: Sodium nitroprusside
(5 µM) in phosphate buffer pH 7.4 was incubated with different
concentrations (50, 75 and 100 µg/mL) of test compounds

2386 Sravya et al.
Asian J. Chem.
dissolved in a suitable solvent (methanol) and tubes were
incubated at 25 ºC for 2 h. Control experiment was conducted
with equal amount of solvent in an identical manner.At intervals,
0.5 mL of incubation solution was taken and diluted with 0.5
mL of Griess reagent (1 % sulfanilamide, 0.1 % N-naphthyl
ethylenediamine dihydrochloride and 2 % o-phosphoric acid
dissolved in distilled water). The absorbance of chromophore
formed during diazotization of nitrite with sulfanilamide and
subsequent N-naphthylethylenediaminedihydrochloride was
read at 546 nm. The experiment was run in triplicate. Nitric oxide
scavenging activity was calculated by the following equation:
model reaction. Initially, we carried out the model reaction at
room temperature, but there is minimal formation of the corres-
ponding α-aminophosphonates in the presence of K2CO3/Al2O3
catalyst under solvent-free conditions. By Increasing of the
reaction temperature from 30 to 140 ºC the formation of α-amino-
phosphonates took place in 94 % yield. Further by increase in
the temperature up to 170 ºC, there is no improvement in product
yield. The key step in the one pot synthesis of α-aminophos-
phonates is the nucleophillic addition of phosphite to the
resulting imine. Another important feature of this reaction is
survival of different functional groups such as fluoro, chloro,
bromo, methoxy groups under these reaction conditions which
made possible for the synthesis of α-aminophosphonates
(Table-1) with these functional groups and screen them for
bioactivity studies in order to establish the relevant structural
requirements for more potent bio activity. All the synthesized
compounds were characterized by FT-IR, 1H, 13C and 31P NMR
and all the spectral data were in good agreement with the pro-
posed structures.
Acontrol − Asample
Scavenging (%) =
×100
Acontrol
whereAcontrol is the absorbance of the control reaction (containing
all reagents except the test compounds), Asample is the absor-
bance of the test compound (containing all reagents and test
compound). Tests were carried out in triplicate.
Antioxidant activity: The compounds 4a-j were tested
for antioxidant activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH),
hydrogen peroxide and nitric oxide (Table-2) methods. In all
the three methods, compounds 4e and 4j showed good radical
scavenging activity when compared with the standard drug
ascorbic acid. Further, the analysis of data presented in Table-
2 indicates that radical scavenging activity in DPPH, hydrogen
peroxide and nitric oxide methods increases with increase in
concentration. The free radical scavenging activity ofcompounds
4e and 4j was measured at different concentrations and monitored
RESULTS AND DISCUSSION
An efficient and environmentally benign one-pot three
components method for the synthesis of α-aminophosphonates
(4a-j) by reaction of 1H-benzo[d]imidazole-2-carbaldehyde
(1), various aromatic amines (2a-j) and diethyl/dimethyl phosphite
(3) in the presence of K2CO3/Al2O3 as catalyst under neat condi-
tions at 140 ºC (Scheme-I) is reported. In order to optimize the
reaction conditions, the reaction among 1H-benzo[d]imidazole-
2-carbaldehyde, aniline and diethyl phosphite was taken as a
TABLE-1
K2CO3/Al2O3 CATALYZED SYNTHESIS OF α-AMINOPHOSPHONATES
Entry
Ar
R
Product
Time (min)
Yield (%)
85
Et
15
2a
4a
Et
Et
14
13
14
12
14
13
14
13
14
89
91
90
94
84
86
85
89
90
2b
2c
2d
2e
2f
4b
4c
4d
4e
4f
F
Cl
Et
Br
Et
MeO
Me
Me
Me
Me
Me
2g
2h
2i
4g
4h
4i
F
Cl
Br
2j
4j
MeO

Vol. 31, No. 10 (2019)
K2CO3/Al2O3: An Efficient and Recyclable Catalyst for Synthesis of α-Aminophosphonates 2387
TABLE-2
in vitro ANTIOXIDANT ACTIVITY OF 4(a-j) BY DIFFERENT METHODS
DPPH method
75 µg/mL 100 µg/mL
H2O2 method
75 µg/mL
NO method
75 µg/mL
Compd.
IC50
(µg/mL)
50 µg/mL
50 µg/mL
100 µg/mL
50 µg/mL
100 µg/mL
59.02 0.12 61.59 0.32 63.84 0.38 42.35 0.029 65.42 0.18 66.54 0.22 68.62 0.40 66.20 0.14 68.92 0.24 70.40 0.32
62.32 0.09 65.74 0.14 67.70 0.66 40.11 0.031 66.92 0.24 67.53 0.34 69.84 0.43 67.72 0.26 69.80 0.35 71.80 0.16
64.74 0.14 66.52 0.24 68.38 0.32 38.61 0.029 67.34 0.22 68.20 0.30 70.58 0.37 68.62 0.18 70.10 0.20 72.12 0.34
67.32 0.12 69.24 0.20 71.20 0.30 37.13 0.030 69.98 0.16 70.84 0.22 73.96 0.34 70.96 0.16 72.89 0.22 74.90 0.30
72.04 0.11 74.69 0.34 75.94 0.29 34.70 0.030 74.22 0.32 76.25 0.18 78.34 0.42 76.62 0.22 78.86 0.18 80.92 0.24
50.98 0.10 52.84 0.32 54.92 0.24 49.03 0.028 58.86 0.18 60.90 0.24 62.24 0.36 60.84 0.14 63.76 0.22 66.60 0.28
51.86 0.12 53.80 0.22 55.98 0.20 48.20 0.031 60.92 0.16 62.86 0.22 64.96 0.32 61.86 0.12 63.90 0.24 67.97 0.26
52.35 0.15 54.32 0.32 57.54 0.38 47.75 0.029 62.62 0.19 64.64 0.30 66.52 0.34 62.33 0.20 64.62 0.16 68.75 0.16
58.64 0.14 60.54 0.24 62.90 0.14 42.63 0.030 64.74 0.30 66.32 0.62 68.46 0.42 64.42 0.18 66.86 0.24 69.24 0.20
70.33 0.11 71.34 0.18 73.54 0.20 35.54 0.032 72.85 0.45 74.32 0.64 76.24 0.37 74.92 0.36 76.66 0.12 79.70 0.28
73.23 0.10 75.22 0.13 77.34 0.35 34.04 0.008 75.28 0.19 77.29 0.09 79.20 0.12 77.11 0.31 79.86 0.43 81.36 0.34
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
AA
AA = Ascorbic acid; Values were the means of three replicates SD
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The authors declare that there is no conflict of interests
regarding the publication of this article.
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