Solvent-free sonochemical kabachnic-fields reaction to synthesize some new α-aminophosphonates catalyzed by nano-BF3?SiO2

Article abstract of DOI:10.1080/10426507.2018.1424163

To obtain a rapid, efficient synthesis of some new α-aminophosphonates, ultrasonic irradiation has been applied to the reaction mixtures containing amine, aromatic or heteroaromatic aldehydes and triethyl phosphite. The Kabachnik-Fields reaction was performed by using nano-BF₃?SiO₂ as a recyclable catalyst under solvent free conditions. Key advantages of this procedure consist in the eco-friendly and highly efficient reaction conditions, high yields, an easy work-up procedure, short reaction times and solvent free conditions. All title compounds were characterized by spectral and elemental analysis. They were further screened for their in vitro antioxidant activity by the DPPH, O^2? and NO methods. The majority of the title compounds showed good antioxidant activity when compared with the standard antioxidants.

Full text of DOI:10.1080/10426507.2018.1424163

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Solvent-Free Sonochemical Kabachnic-
Fields Reaction To Synthesize Some New α-
Aminophosphonates Catalyzed By Nano-Bf •Sio
3
2
D. Ravikumar, S. Mohan, Ch. Subramanyam & K. Prasada Rao
To cite this article: D. Ravikumar, S. Mohan, Ch. Subramanyam & K. Prasada Rao (2018):
Solvent-Free Sonochemical Kabachnic-Fields Reaction To Synthesize Some New α-
Aminophosphonates Catalyzed By Nano-Bf •Sio , Phosphorus, Sulfur, and Silicon and the Related
3
2
Elements, DOI: 10.1080/10426507.2018.1424163
To link to this article: https://doi.org/10.1080/10426507.2018.1424163
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Date: 08 January 2018, At: 18:38

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SOLVENT-FREE SONOCHEMICAL KABACHNIC-FIELDS REACTION TO
SYNTHESIZE SOME NEW α-AMINOPHOSPHONATES CATALYZED BY
NANO-BF •SiO2
3
*
D. Ravikumar, S. Mohan, Ch. Subramanyam and K. Prasada Rao
Department of Chemistry, Bapatla Engineering College, Bapatla - 522101, India.
Running head: Nano-BF •SiO catalyzed synthesis of some novel α-aminophosphonates
3
2
Abstract: To obtain a rapid, efficient synthesis of some new α-aminophosphonates, ultrasonic
irradiation has been applied to the reaction mixtures containing amine, aromatic or
heteroaromatic aldehydes and triethyl phosphite. The Kabachnik-Fields reaction was performed
by using nano-BF •SiO as a recyclable catalyst under solvent free conditions. Key advantages of
3
2
this procedure consist in the eco-friendly and highly efficient reaction conditions, high yields, an
easy work-up procedure, short reaction times and solvent free conditions. All title compounds
were characterized by spectral and elemental analysis. They were further screened for their in
vitro antioxidant activity by the DPPH, O  and NO methods. The majority of the title
compounds showed good antioxidant activity when compared with the standard antioxidants.
2
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Keywords
α-aminophosphonates; ultrasonic irradiation; nano-BF •SiO ; antioxidant activity
3
2
*
Corresponding author Tel: +918008514677, E-mail address: prasad17467@gmail.com
Received 24 October 2017
Revised 14 December 2017
Accepted 18 December 2017
INTRODUCTION
The synthesis and applications of α-aminophosphonates has received the attention of
organic chemists since these compounds represent structural analogues of the important α-
2
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1
-3
2
aminoacids. Various applications of α-aminophosphonates as antimicrobial , antioxidant ,
4
-6
7
8
9-11
antitumor , antiviral , anti-inflammatory and enzyme inhibitors
have been reported.
These numerous applications have encouraged the development of a number of techniques for
1
2, 13
the synthesis of α-aminophosphonates.
The Kabachnik-Fields reaction is one of the most
direct and efficient routes for the synthesis of α-aminophosphonates. It consists in a one-pot-
1
4
15
three-component reaction of aldehyde, amine and dialkyl phosphite or trialkyl phosphite.
Recently several reports have been published which described the synthesis of α-
16a
aminophosphonates via Kabachnik-Fields reaction using Lewis acids like In(OTf)3,
1
6b
2-16c
16d
16e
16f
16g
Yb(P O) ,
Fe O @ZrO /SO ,
SmI2,
BF -Et O, CdI /benzene, CdI /microwave,
3 2 2 2
f
3
3
4
2
4
17a
17b
17c
17d
Brønsted acids like o-benzenedisulfonimide, acetic acid, formic acid, sulfamic acid and
17e
18a
18b
19a
oxalic acid, solid acids like H PMo O , silica sulfuric acid, bases such as NaOH, 1,8-
3
12 40
1
9b
20a
20b
diazabicyclo[5.4.0]undec-7-ene (DBU), nano-catalysts like nano-TiO2, CuO@Fe O , and
3
4
2
1a
21b
21c
other catalysts like quaternary ammonium salts, boric acid, Cu(I)/Cu(II), zirconocene-
2
1d
22a,b,c
bis(perfluorobutanesulfonate). Microwave irradiation
technique is also used for one-pot
syntheses of α-aminophosphonates. However, some of the reported procedures are associated
with disadvantages like the need to use solvents and additional reagents, long reaction times,
costly and moisture sensitive catalyst, etc. As a result, there is still need to develop a more
efficient, simple, milder and high yield protocol for the synthesis of α-aminophosphonates.
Ultrasonication has increasingly been used in organic synthesis in the last three decades.
For many organic reactions which are ordinarily accomplished by heating, ultrasonication has
been demonstrated as an alternative energy source. The use of ultrasound in organic
transformations, particularly for the synthesis of α-aminophosphonates is well known to enhance
3
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2
3a,b
reaction rates, yields and selectivity.
Ultrasound facilitates organic transformations at
ambient temperatures, which otherwise require drastic conditions of high temperature and/or
pressure.
BF ·Et O as a strong Lewis acid is corrosive, toxic, volatile and it also generates
3
2
2
4a,b
significant amounts of waste. Nano-BF •SiO2
is a bench-top catalyst that has many
3
advantages such as simple preparation, reusability, large surface area, strong Lewis acid
character, easy handling and being environmentally benign.
By considering the above facts and in continuation of our studies towards developing new
3
, 8
methods for the synthesis of α-aminophosphonates, we decided to explore the possibility of
implementing a one-pot three-component reaction for the preparation of α-aminophosphonates in
the presence of nano-BF •SiO , using ultrasonication under solvent-free conditions. Both
3
2
conventional and ultrasonicated conditions are used to optimize the method. The catalyst, nano-
BF •SiO has been described as an effective promoting catalyst in the preparation of α-
3
2
aminophosphonates by the reaction of amine, various aldehydes and triethyl phospite via the
Kabachnic-Fields reaction under two methods. High yield of the products in the range of 87-97%
are reported under ultrasonication conditions.
2

The antioxidant activity was screened for the title compounds by the DPPH, O and NO
methods. The majority of the title compounds showed good antioxidant activity.
RESULTS AND DISCUSSION
In this letter, we report an efficient and environmentally benign protocol for the synthesis
of α-aminophosphonates (5a-k) by condensation of 4-(2,4-dichlorophenyl)thiazol-2-amine (2)
4
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which was previously prepared from 2,4-dichloroacetophenone (1), various aldehydes (3a-k) and
triethyl phosphite (3) in the presence of 37% nano-BF •SiO under solvent-free conditions using
3
2
conventional and ultrasonic irradiation methods (Scheme 1).
Insert Scheme 1]
[
At the beginning of our investigation, the reaction was tested with 4-(2,4-
dichlorophenyl)thiazol-2-amine (2) (0.010 mol), benzaldehyde (3a) (0.010 mol) and triethyl
phosphite (4) (0.020 mol) as model components (Table 1) in tetrahydrofuran (THF) at reflux
temperature without using any catalyst. Under this condition, the model compounds were not
able to undergo an effective reaction to produce the desired product, diethyl [4-(2,4-
dichlorophenyl)thiazol-2-ylamino]phenylmethanephosphonate (5a) but gave a very poor product
yield (20%) (Table 1, entry 1). Thus, a new method was developed to attain higher product
yields by using a catalyst. In search for an efficient catalyst and the best operational conditions,
the model reaction was carried out with different Lewis acid catalysts (10 mol%) such as ZnCl2,
CuCl , AlCl and BF •Et O. The results are summarized in Table 1 (entries 2-5).
2
3
3
2
It was observed that, upon addition of Lewis acid catalysts, the yield of the product 5a was
improved from 20% to the range of 58-63%, indicating that the Lewis acid catalyst plays a
promising role in the process. BF •SiO was found to be an excellent proton source in terms of
3
2
convenience, ease of production, cheapness and insolubility in all organic solvents. Hence it was
2
5-28
used for the synthesis of many organic compounds.
On the other hand, nano-BF •SiO
3 2
exhibits a high surface to volume ratio in addition to the above mentioned properties that makes
24b, 29
use of this catalyst in many chemical reactions.
Hence 37% nano-BF •SiO (0.25g) was
3 2
used as catalyst in the model reaction to synthesize compound 5a. We obtained a good product
5
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yield (70%, Table 1, entry 6) when THF was used as solvent. Further, we studied the effect of
solvents on the model reaction. The concentration of catalyst (0.25g) was kept constant for the
model reaction, and the solvent like methanol, dichloromethane, toluene, ethanol and solvent-
free condition was varied. The scrutiny revealed that in all solvents the product yields were
found to be 71-76% (Table 1, entry 7-10) after 2h. But in case of solvent-free conditions, we
obtained a good product yield (80%) after 1h (Table 1, entry 11). The use of ultrasound in
organic transformations is well known to enhance reaction rates, yields and selectivity. Hence,
ultrasonic irradiation under solvent free condition was used to synthesize compound 5a. We got
an excellent yield of the product (90%) in a very short period of time (10min) at room
temperature (Table 1, entry 12). The obtained results are summarized in Table 1.
Keeping in mind the above results and to achieve better results, we carried out the model
reaction with the catalysts ZnCl , CuCl , AlCl and BF •Et O under solvent free condition with
2
2
3
3
2
and without ultrasonic irradiation (Table 1, entry 13-20). We got better results with ultrasonic
irradiation under solvent free condition (Table 1, entry 14, 16, 18, 20). However, the time and
yield of the product 5a obtained with 37% nano-BF •SiO (0.25g) as catalyst under solvent free
3
2
condition was found to be better than the other catalysts used in the model reaction. Hence, 37%
nano-BF •SiO was selected as catalyst for further optimization of the reaction conditions.
3
2
[Insert Table 1]
The effect of the amount of the catalyst (37% nano-BF •SiO ) was also scrutinized by
3
2
varying the amount of the catalyst with ultrasonic irradiation under solvent free condition (Table
2
, entry 1-7). We have varied the concentration of catalyst to 0.05, 0.1, 0.15, 0.2, 0.25, 0.30 and
.35g. The result revealed that, when the reaction was carried out in the presence of 0.05, 0.1,
0
6
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0
.15, 0.2g of catalyst, it gave lower yield of product (Table 2, entry 1-4). It was observed that
almost same yield (96%) of the product 5a was obtained with the catalyst amount in the range of
.30-0.40g (Table 2, entry 6-8) and a lower yield (90%) for 0.25g (Table 2, entry 5). Hence, the
0
optimum amount of the catalyst, 0.30g was confirmed under ultrasound irradiation. The obtained
results are summarized in Table 2.
[Insert Table 2]
The reusability of the nano-BF •SiO catalyst was also examined. After each run, the
3
2
product was filtered and the residue of catalyst was washed with CHCl to remove stains from
3
the catalyst surface and reuse it up to five cycles for the synthesis of compound 5a. (Table 3,
entry 1-5). It was found that 37% nano-BF •SiO could effectively catalyze this reaction under
3
2
solvent-free conditions to afford the desired products in high yields.
Insert Table 3]
[
After optimizing the conditions, the generality of this method for the synthesis of α-
aminophosphonates (5a-k) (Scheme 1) was examined by the reaction of several substituted
aldehydes (3b-k), amine (2) and triethyl phosphite (4) using 37% nano BF •SiO as a catalyst
3
2
under solvent free conditions by conventional and ultrasound irradiation methods. The results are
summarized in Table 4. A plausible reaction mechanism for the formation of α-
aminophosphonates in the presence of 37% nano-BF •SiO as a catalyst is shown in Fig. 1 [see
3
2
Supplementary Material files]. Initially the carbonyl group of the aldehyde reacts with the amine
to form an intermediate imine A. The activated intermediate imine then reacts with triethyl
phosphite to produce the corresponding α-aminophosphonates.
[Insert Table 4]
7
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3
1
The chemical structure of the title compounds 5a-k were supported by spectral data ( P,
1
13
H and C NMR, IR and LC-MS), elemental analysis. The results are presented in the
3
1
experimental section. P NMR signals were observed in the region 19.3-16.7 ppm for all the
1
compounds 5a-k. The H NMR spectra gave signals as multiplets due to Ar-H in the range of δ
8
.39-6.67 ppm. The proton signals in the range of 5.42-5.21 and 4.74-4.42 ppm are due to C-NH
and P-CH, respectively. The methylene protons of P-O-CH CH gave a multiplet and methyl
2
3
protons of P-O-CH CH resonated as a triplet in the region δ 4.09-3.88 and δ 1.30-1.19,
2
3
1
3
respectively for 5a-k. C NMR signals for P-CH, methylene and methyl carbons were observed
in the region 57.4-56.4, 64.3-63.7 and 16.9-16.7 ppm, respectively, for 5a-k. IR absorptions in

1
the regions 3399-3380, 1502-1485 and 1248-1225 cm were assigned to indazole-NH, NH and
+
P=O stretching vibrations respectively for 5a-k. The expected m/z values of M ions were
1
13
31
observed in the corresponding mass spectra. Representative H, C and P NMR spectra for the
new compounds 5a, 5d, 5g, 5i and 5k are presented in the Supplemental Materials (Figures S 2 -
S 15).
Antioxidant activity
3
0
2 31, 32
33
The antioxidant activity was examined using DPPH, O
and NO methods in the
concentration range 25-100μg/mL. The results are shown in Fig. 1, Fig. 2 and Fig. 3,
respectively.
[Insert Fig. 1], [Insert Fig. 2], [Insert Fig. 3]
All tested samples showed good to moderate antioxidant activity. Among 5a-k, compound
b bearing a 4-fluorophenyl moiety and 5i bearing a 3-chloro-4-fluorophenyl moiety exhibited a
5
slightly higher activity compared with the standard antioxidant ascorbic acid in superoxide and
8
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NO methods. The compounds 5k bearing a 6-methoxypyridin-2-yl moiety, 5c bearing a 4-
nitrophenyl moiety, 5f with an allylphenyl moiety, 5g bearing a 3-nitrophenyl moiety and 5h
with a 3-chlorophenyl moiety exhibited good activities compared with standard antioxidant in all
three methods. Their high antioxidant activity is due to the presence of the electronegative
heteroatom group which renders their N–H bond weaker. Consequently, the N–H bond easily
cleaves homolytically with the formation of the corresponding free radicals. The functionalities
like NH, NO , F, Cl and allyl in the title compounds might be the cause of the significantly
2
enhanced antioxidant activity. Overall, significant antioxidant activities were observed in α-
aminophosphonates 5a-k when compared with standard antioxidants.
CONCLUSION
In conclusion, we demonstrated here an efficient, inexpensive, environmentally benign
protocol for the formation of α-aminophosphonates through an intermediate imine by the
Kabachnik-Fields reaction under solvent free condition in the presence of an efficient solid acid,
nano-BF •SiO at room temperature by conventional and ultrasonication methods. The
3
2
advantages of this attractive method are good yield of the products, less reaction time, easy
workup procedure and reusability of the heterogeneous catalyst, nano-BF •SiO . Promisingly,
3
2
high product yields (69-83%) were obtained under conventional conditions, and 87-97% under
ultrasonication. Moreover, the reaction time in ultrasonication method (10 min) is much shorter
as compared with conventional (1h) conditions. The antioxidant activity α-aminophosphonates
2

was evaluated by the DPPH, O and NO methods. Compound 5b bearing a 4-fluorophenyl motif
and 5i bearing a 3-chloro-4-fluorophenyl ring exhibited potent antioxidant activity when
9
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compared with the standard antioxidants. The remaining compounds showed moderate to good
antioxidant activity. These remarkable results of this study can provide a foundation for the
design and development of some more structurally diversified α-aminophosphonates as potential
antioxidants.
EXPERIMENTAL DETAILS
Chemicals and analytical-grade reagents used for the synthesis are commercially available
and were procured from Sigma-Aldrich/Merck, and Sd Fine-Chem Limited. Glassware was dried
in an oven at 150 °C prior to use. All solvents are reagent grade and were further purified and
stored under a nitrogen atmosphere. IR spectra were recorded on Bruker Alpha FT-IR
spectrophotometer. NMR spectra were recorded on a Bruker 400-MHz spectrometer operating at
1
13
31
4
00MHz for H NMR, 100.25MHz for C NMR, and 161.9MHz for P NMR in DMSO-d .
6
1
13
Tetramethylsilane and 85% H PO were used as internal standards for H and C NMR spectra
3
4
3
1
and external standard for P NMR spectra, respectively. L.C. mass spectra were recorded on a
SHIMADZU 2010A mass spectrometer. Elemental analyses were performed on a Thermo
Finnigan Flash 1112 instrument at the University of Hyderabad, Hyderabad. Chemical shift
values  and coupling constants J are reported in ppm and Hz, respectively. The reaction
progress was monitored by pre-coated thin-layer chromatography (TLC) plates (Merck) and
spots were visualized with ultraviolet (UV) light. Sonication was performed using BANDELIN
SONOREXR (Germany) with a frequency of 35 kHz and a nominal power of 200 W ultrasonic
bath for ultrasonic irradiation with inbuilt heating 30-80 °C, which is thermostatically
changeable. The reaction vessel was placed inside the ultrasonic bath containing water.
1
0
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2
4a, 29
Preparation of the catalyst
0
.37g of BF (0.7 mL of BF •Et O) was added drop-wise to a mixture of 0.63g of silica gel
3
3
2
or nano-silica gel and 5 mL of CHCl . The mixture was stirred for 1 h at room temperature. The
3
resulting suspension was filtered. The obtained solid was washed with CHCl and dried at room
3
temperature.
Synthesis of 4-(2,4-dichlorophenyl)thiazol-2-amine (2)
Bromine (0.010 mol) was added drop wise to a mixture of 2,4-dichloroacetophenone (1.4
mL, 0.010 mol) and thiourea (1.52g, 0.020 mol). After the complete addition of bromine, the
reaction mixture was heated on a water bath overnight. Then, water was added and again heated
until most of the solid had dissolved. The hot reaction mixture was filtered and the filtrate was
cooled, made alkaline with ammonium hydroxide to obtain compound 2. It was filtered, washed
with alcohol and dried over P O . It was finally crystallized from ethanol to obtain pure
2
5
compound 4-(2,4-dichlorophenyl)thiazol-2-amine (2). M.p. 156-158 °C.
Conventional procedure for the synthesis of α-aminophosphonates (5a-k)
The mixture of benzaldehyde (3a) (1 mL, 0.010 mol), 4-(2,4-dichlorophenyl)thiazol-2-
amine (2) (2.45g, 0.010 mol) and triethyl phosphite (4) (3.4 mL, 0.020 mol) was placed in a
round bottomed flask. To this mixture, 37% nano-BF •SiO (0.30g) was added and the mixture
3
2
was heated to 70 °C and agitated for 1h. The progress of the reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was cooled to room temperature. CH Cl
2
2
2
(
15 mL) was added to the reaction mixture and stirred for 10 min. The catalyst, nano-BF •SiO
3
was separated by filtration, washed with CH Cl (2×10 mL) and the residue was dried under
2
2
vacuum at 100 °C to be utilized in further studies. The organic layer was washed with water
1
1
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(
15mL), dried over anhydrous Na SO and concentrated under vacuum at 50 °C to obtain crude
2 4
products. The pure diethyl [4-(2,4-dichlorophenyl)thiazol-2-ylamino]phenylmethanephosphonate
5a) was obtained by column chromatography using EtOAc/n-hexane 7:3 as eluent. The same
(
procedure was used for the preparation of the remaining compounds 5b-k.
Ultrasonication procedure for the synthesis of α-aminophosphonates (5a-k):
The mixture of benzaldehyde (3a) (1 mL, 0.010 mol), 2 (2.45g, 0.010 mol) and triethyl
phosphite (4) (3.4 mL, 0.020 mol) was placed in a round bottomed flask. To this mixture, 37%
nano-BF •SiO (0.30g) was added and the mixture was irradiated in the ultrasonicator at ambient
3
2
temperature for about 10 minutes. The progress of the reaction was monitored by TLC
EtOAc/n-hexane 7:3). After completion of the reaction as checked by TLC, the reaction mixture
was cooled to room temperature. CH Cl (15 mL) was added to the reaction content and stirred
(
2
2
for 10 min. The catalyst nano-BF •SiO was separated by filtration as residue, washed with
3
2
CH Cl (2×10 mL) and the residue was dried under vacuum at 100 °C to be utilized in further
2
2
studies. The combined organic layer was washed with water (15 mL), dried over anhydrous
Na SO and concentrated under vacuum at 50 °C to obtain crude 5a. Pure 5a was obtained by
2
4
column chromatography (EtOAc/n-hexane 7:3). The same procedure was used for the
preparation of the remaining compounds 5b-k.
Diethyl [4-(2,4-dichlorophenyl)thiazol-2-ylamino]phenylmethanephosphonate (5a). Yield: 96%;
3
1
1
semi-solid. P NMR: δ 17.4 ppm; H NMR: δ 8.16-6.90 (m, 9H, Ar-H), 5.28 (s, 1H, C-NH),
1
3
4
.48 (d, J = 9.2 Hz, 1H, PCH), 4.02 (m, 4H, OCH CH ), 1.21 (t, J = 7.2 Hz, 6H, OCH CH ); C
2 3 2 3
NMR: δ 166.3 (C-12), 149.2 (C-9), 138.3 (C-17), 136.9 (C-2), 132.4 (C-4), 129.8 (C-3), 128.5
C-6), 127.6 (C-26, C-28), 126.8 (C-25, C-29), 125.5 (C-5), 123.6 (C-1), 123.1 (C-27), 108.4 (C-
(
1
2
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
1
1
0), 63.4 (C-21, C-23), 57.0 (C-15), 16.7 (C-22, C-24); IR (KBr) (νmax/cm ): 3380 (NH), 1485
+
(
C=N), 1228 (P=O); LCMS (m/z, %): 471 (M+H , 100), 473 (M+2, 64); Anal. Calcd. for
C H Cl N O PS: C, 50.96; H, 4.49; N, 5.94%; found: C, 50.88; H, 4.55; N, 5.90%.
20
21
2
2
3
Spectroscopic data of 5b-5k are given in the Supplemental Material files.
Antioxidant activity
The evaluation of antioxidant activity of newly synthesized compounds was performed by
the DPPH radical scavenging activity assay, following the method of Cotelle et.al., the
Superoxide radical scavenging activity following the method of Robak and Gryglewski and the
Nitric oxide scavenging activity using the modified protocol of Green et al. and Marcocci et al
[
see Supplemental Materials].
The experiment was carried out in triplicate. The results are presented in Fig. 1, Fig. 2 and
Fig. 3, respectively, for the three methods. The results revealed that the majority of the title
compounds showed good antioxidant activity when compared with standard antioxidants.
ACKNOWLEDGMENTS
The authors acknowledge Dr. Sk. Adam, Department of Biochemistry, Sri Venkateswara
University, Tirupathi, India, for providing the measurements of the biological activities. The
authors express their thanks to Hyderabad Central University for providing instrumentation
facilities for recording the spectra.
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Scheme 1. Synthesis of some novel α-aminophosphonates (5a-k)
Conventional method
NH2
R
14
15
18
N
22
O
HN
O
19
O
S
1
3
9
12 16
P
P(OC H )
Nano BF .SiO ,
Solvent free
R C H
2
5 3
3
2
N
21
24
6
3
O
S
1
11
2
0
Cl
Cl
5
23
10
3
a-k
2
4
5a-k
8
EtOH
2
4
Cl
Cl
7
Ultrasonication method
1
7
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Fig. 1: Antioxidant activity of novel α-aminophosphonates 5a-k by DPPH radical Scavenging
method.
90
80
70
60
50
40
30
20
10
0
2
5
7
1
5 μg/mL
0 μg/mL
5 μg/mL
00 μg/mL
1
8
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Fig. 2: Antioxidant activity of novel α-aminophosphonates 5a-k by Superoxide radical
scavenging method.
90
80
70
60
50
40
30
20
10
0
2
5
7
1
5 μg/mL
0 μg/mL
5 μg/mL
00 μg/mL
1
9
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Fig. 3: Antioxidant activity of novel α-aminophosphonates 5a-k by Nitric Oxide method.
1
1
20
00
80
60
40
20
0
2
5
7
1
5 μg/mL
0 μg/mL
5 μg/mL
00 μg/mL
a
Table 1. Synthesis of compound 5a under various conditions
2
0
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NH2
H
O
O
O
N
HN
model reaction
S
P
O
N
P(OC H )
2
5 3
S
Cl
Cl
2
3a
4
5a
Cl
Cl
EtOH
Temp.
Time
(h)
8
b
Entry
Catalyst
Solvent
Yield (%)
(°C)
1
2
3
-----
THF
THF
THF
r.t
20
58
56
ZnCl
CuCl
(10mol%)
r.t
r.t
4.5
5.0
2
(10mol%)
(10mol%)
2
4
AlCl
BF .Et
3
2
THF
r.t
3.0
60
5
6
7
8
9
3
O (10mol%)
THF
THF
r.t
r.t
r.t
r.t
r.t
r.t
2.5h
2.0
2.0
2.0
2.0
2.0
1h
63
70
73
71
74
76
82
37% nano BF
37% nano BF
37% nano BF
37% nano BF
37% nano BF
37% nano BF
.Et
.Et
.Et
.Et
.Et
.Et
O (0.25g)
O (0.25g)
O (0.25g)
O (0.25g)
O (0.25g)
O (0.25g)
3
3
3
3
3
3
2
2
2
2
2
2
Methanol
DCM
Toluene
Ethanol
1
1
0
1
Solvent-free
Solvent-free
ꢀ0 ꢁ ꢂ
1
1
2
3
37% nano BF
3
.Et
2
O (0.25g)
room temp. 10min
90
66
(
Ultrasonication)
ZnCl
(10mol%)
Solvent-free
ꢀ0
ꢁ
ꢂ
3h
2
2
1
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Solvent-free
Ultrasonication)
Solvent-free
1
1
1
1
1
1
2
4
5
6
7
8
9
0
ZnCl
2
(10mol%)
(10mol%)
(10mol%)
(10mol%)
(10mol%)
O (10mol%)
O (10mol%)
room temp. 1.5h
70
62
69
67
73
71
77
(
(
(
(
CuCl
CuCl
ꢀ0
ꢁ
ꢂ
3.5h
1h
2
2
Solvent-free
room temp.
Ultrasonication)
Solvent-free
AlCl
AlCl
ꢀ0
ꢁ
ꢂ
2.5h
3
3
2
2
Solvent-free
room temp. 50min
Ultrasonication)
Solvent-free
BF
.Et
.Et
ꢀ0
ꢁ
ꢂ
1.5h
3
3
Solvent-free
BF
room temp. 40min
Ultrasonication)
a
Reaction of benzaldehyde, 4-(2,4-dichlorophenyl)thiazol-2-amine and triethyl phosphite were
selected as models for the optimization of reaction conditions
b
Isolated yield.
2
2
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Table 2. The effect of the amount of the catalyst, 37% nano-BF -SiO to promote the
3
2
a
Kabachnik-Fields reaction
Entry Amount of Catalyst (gm) Time (min) Yield (%)
b
1
2
3
4
5
6
7
8
0.05
0.1
10
10
10
10
10
10
10
10
60
64
69
75
90
96
96
96
0.15
0.2
0.25
0.3
0.35
0.40
a
Reaction of benzaldehyde, 4-(2,4-dichlorophenyl)thiazol-2-amine and triethyl phosphite in
presence of 37% nano-BF -SiO under ultrasonic waves in solvent-free condition for 10 min. at
3
2
room temperature.
b
Isolated yield.
2
3
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a
Table 3. Reusability of the catalyst, 37% nano-BF -SiO for the synthesis of compound 5a
3
2
b
Entry 37% nano BF .SiO (0.30g) Time (min.) Yield (%)
3
2
st
1
2
3
4
5
1 run
10
10
10
10
10
96
93
91
89
81
nd
2 run
rd
3 run
th
4 run
th
5 run
a
Reaction of benzaldehyde, 4-(2,4-dichlorophenyl)thiazol-2-amine and triethyl phosphite in
presence of 37% nano-BF .SiO under ultrasonic waves in solvent-free condition for 10 min. at
3
2
room temperature.
b
Isolated yield.
Table 4. Sonochemical effect on the synthesis of α-aminophosphonates (5a-k)
2
4
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a
b
Without Ultrasonication
With Ultrasonication
Entry Aldehyde (R-CHO)
c
c
Time (min) Yield (%) Time (min) Yield (%)
CHO
5
a
60
60
82
81
10
13
96
92
CHO
5
b
F
CHO
5
c
60
60
60
83
77
79
12
15
11
97
91
93
O N
2
CHO
5
d
H CO
3
CHO
5
e
Cl
CHO
CHO
CHO
CHO
5
f
60
60
60
60
69
70
72
71
17
20
15
14
87
89
90
92
O N
2
5
g
Cl
5
h
Cl
F
5
i
Cl
CHO
5
j
60
60
68
70
18
19
90
94
Cl
CHO
5
k
N
OCH3
a
Reaction of 4-(2,4-dichlorophenyl)thiazol-2-amine, aldehyde and triethyl phosphite in presence
of 37% nano-BF -SiO (0.30g) under solvent-free condition at 70 °C by conventional method.
3
2
2
5
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b
Reaction of 4-(2,4-dichlorophenyl)thiazol-2-amine, aldehyde and triethyl phosphite in presence
of 37% nano-BF -SiO (0.30g) under solvent-free condition at room temperature by ultrasonic
3
2
b
irradiation method .
c
Isolated yield.
2
6
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