CeCl3·7H2O-SiO2: Catalyst promoted microwave assisted neat synthesis, antifungal and antioxidant activities of α-diaminophosphonates

Article abstract of DOI:10.1016/j.cclet.2013.04.037

CeCl₃·7H₂O supported on silica (CeCl ₃·7H₂O-SiO₂) is used as a heterogeneous, efficient and recyclable catalyst for a three component one-pot reaction of an amine, aldehydes and diethyl phosphite to synthesize α-diaminophosphonate derivatives under microwave irradiation exploiting neat reaction conditions. Ten α-diaminophosphonates (6a-j) of 4,4′-sulfonyldianiline (Dapsone) (3) were synthesized and structural elucidation was confirmed by spectral data. Antifungal and antioxidant activities were evaluated include minimum inhibitory concentrations and IC₅₀ values, respectively of the titled compounds. Compounds 6h, 6i exhibited promising antioxidant activity at lower IC ₅₀ values 53.7 μg/mL, 53.2 μg/mL, respectively as compared with standard IC₅₀ value 51.6 μg/mL.

Full text of DOI:10.1016/j.cclet.2013.04.037

Chinese Chemical Letters 24 (2013) 759–763
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
CeCl3ꢀ7H2O-SiO2: Catalyst promoted microwave assisted neat synthesis,
antifungal and antioxidant activities of -diaminophosphonates
a
*
Subba Rao Devineni, Srinivasulu Doddaga , Rajasekhar Donka, Naga Raju Chamarthi
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
A R T I C L E I N F O
A B S T R A C T
Article history:
CeCl3ꢀ7H2O supported on silica (CeCl3ꢀ7H2O-SiO2) is used as a heterogeneous, efficient and recyclable
Received 5 March 2013
Received in revised form 9 April 2013
Accepted 16 April 2013
Available online 31 May 2013
catalyst for a three component one-pot reaction of an amine, aldehydes and diethyl phosphite to
synthesize
a
-diaminophosphonate derivatives under microwave irradiation exploiting neat reaction
-diaminophosphonates (6a–j) of 4,40-sulfonyldianiline (Dapsone) (3) were synthesized
conditions. Ten
a
and structural elucidation was confirmed by spectral data. Antifungal and antioxidant activities were
evaluated include minimum inhibitory concentrations and IC50 values, respectively of the titled
Keywords:
compounds. Compounds 6h, 6i exhibited promising antioxidant activity at lower IC50 values 53.7
53.2 g/mL, respectively as compared with standard IC50 value 51.6 g/mL.
mg/mL,
a-Diaminophosphonates
m
m
Green synthesis
ß 2013 Srinivasulu Doddaga. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
Kabachnik–Fields reaction
Antifungal activity
Antioxidant activity
reserved.
1. Introduction
reactions cannot proceed smoothly due to formation of water
during one-pot three component reactions. Recently, some new
a
-Aminophosphonates are important biologically active com-
Lewis acid catalysts were reported as effective catalysts for one-pot
reactions [12–23]. It is clear that some synthetic transformations
are more difficult using conventional conditions and may require
long reaction time and low yield. Moreover, it is necessary to
prevent waste generation by avoiding the use of auxiliary
substances such as solvents and additional reagents and minimiz-
ing the energy requirement in synthetic pathways/processes.
There has been increasing influence of green approaches in both
medicinal chemistry and research based chemistry organizations.
Recently, chemical transformations involving eco-friendly
reagents such as solid supported catalysts and those assisted by
microwaves under solvent-free conditions have gained popularity
because these methods are not only valuable for ecological and
economic reasons but also simplicity of procedure and high yield.
Further, lanthanide halides, particularly Ce(III) salts, are of great
research interest due to their low toxicity, ease of handling, low
cost, stability in air and water and recoverability. In silica
supported inorganic catalysts, SiO2 was originally introduced as
only a support in the beginning. Then, kinetic studies revealed that
it not only acts as a carrier to increase the surface area but also
enhances the rate of reaction.
pounds and structural analogs of natural amino acids [1], and have
received wide attention in medicinal, bioorganic, and agricultural
chemistry. Many of these derivatives have applications as
antibiotics [2], herbicides [3], fungicides, plant growth regulators
[4], anti-thrombotic agents [5], peptidases and proteinases [6], and
enzyme inhibitors [7]. They can also suppress the growth of
various tumors and viruses [8]. Moreover, some aminophosphonic
acids inhibit bone resorption, delay the progression of bone
metastases, exert direct cytostatic effects on a variety of human
tumor cells and have found clinical applications in the treatment of
bone disorders and cancer [9]. The inert nature of the C–P bond in
a
-aminophosphonates as well as physical and structural similarity
of phosphonic acid and phosphinic acid (see Fig. 1) to the
biologically important phosphate ester and carboxylic acid
functionalities attributed a great deal of these activities [10].
In the last few decades, research has been made for the
development of new methodologies for their synthesis due to
outstanding biological importance of
vatives. The traditional Lewis acid-catalyzed addition of diethyl
phosphite to aldimines has provided useful method for
preparation of -aminophosphonates [11]. However, these
a-aminophosphonate deri-
a
a
By considering all these advantages, we developed a simple
three component one-pot procedure under microwave assisted
neat reaction conditions for the synthesis of
a-diaminopho-
sphonates 6a–j of Dapsone using silica supported CeCl3ꢀ7H2O and
* Corresponding author.
screened for their antifungal and antioxidant activities.
E-mail address: doddaga_s@yahoo.com (S. Doddaga).
1001-8417/$ – see front matter ß 2013 Srinivasulu Doddaga. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.037

[
S.R. Devineni et al. / Chinese Chemical Letters 24 (2013) 759–763
O
O
OH
next reaction. This same procedure was adopted for preparing the
remaining title products.
H
OOC
H C
H
P
NH
2.1.3. Tetraethyl[4,40-sulfonylbis(4,1-phenylene)bis(azanediyl)]bis[
(3-nitrophenyl)methylene]diphosphonate (6c)
NH
3
3
2
H C
3
Alanine (2)
Alpha-aminophosphonic acid (1)
Pale orange solid, yield 96%, mp 140–142 8C; IR (KBr, cmꢂ1):
O
n
max 3282 (–N–H, str), 2983 (–C–H, str), 1595 (Ar–C–C–, str), 1352
(–NO2, str), 1300 (–SO2, str), 1284 (C–N, str), 1238 (–P55O, str),
1022 (P–C–O–, str); 1H NMR (400 MHz, CDCl3):
1.06 (t, 6H,
O
O
S
P
O
O
P
d
O
R
O
O
R
J = 5.6 Hz, –O–CH2–CH3), 1.13 (t, 6H, J = 5.6 Hz, –O–CH2–CH3),
3.79–3.84 (m, 2H, –O–CH2–CH3), 3.93–3.96 (m, 2H, –O–CH2–CH3),
4.02–4.07 (m, 4H, –O–CH2–CH3), 5.47 (dd, 2H, J = 7.6, 12.4 Hz, –P–
CH–NH), 6.88 (d, 2H, J = 8.0 Hz, –CH–NH), 7.44–7.46 (d, 4H,
N
N
H
H
Titled compounds 6(a-j)
Fig. 1. Biological active phosphorus compounds.
J = 8.0 Hz, Ar–H), 7.47–7.94 (m, 8H, Ar–H), 8.11 (d, 4H, J = 7.0 Hz,
Ar–H); 13C NMR (100 MHz, CDCl3):
d
151.1 (C8, C13), 148.1 (C3
,
,
1
1
2. Experimental
C311), 139.4 (C11, C111), 135.1 (C61, C611), 130.2 (C1, C3), 129.9 (C5
C511), 128.7 (C6, C10, C11, C15), 123.3 (C21, C211), 123.0 (C41, C411),
113.2 (C7, C9, C12, C14), 62.9 (C25, C28, C31, C34), 53.6 (C18, C19), 16.4
(C26, C29, C32, C35); 31P NMR (162 MHz, CDCl3):
d 20.9; MS (+ mode)
2.1. General procedure
2.1.1. Conventional method
(m/z): 791 (M+H+).
Dapsone (3) (1 mmol, 248 mg), 3-nitrobenzaldehyde (4c)
(1.1 mmol, 167 mg), diethylphosphite (5) and the catalyst,
2.2. Recycling of CeCl3ꢀ7H2O-SiO2 catalyst
CeCl3ꢀ7H2O-SiO2 (12 mol%), were placed into
a 50 mL flat-
bottomed flask. The reaction mixture was stirred vigorously at
80 8C. The progress of the reaction was monitored by TLC in 30 min
of intervals. After completion of the reaction, dichloromethane
(DCM, 15 mL) was added to the reaction mixture and filtered-off to
recover the catalyst and washed with DCM (2 ꢁ 10 mL) to remove
strains on the catalyst. The combined organic layer was
concentrated under reduced pressure and pure product 6c was
obtained using column chromatography eluting with ethylaceta-
te:hexane in a ratio of 4:6. The catalyst was dried and reused for
future reactions.
The catalyst is inserted residue obtained (CeCl3ꢀ7H2O-SiO2) by
filtration of reaction mixture was washed with 10 mL of DCM two
or three times to remove the strains and tars, then dried in an oven
at 90 8C for 2 h. The catalyst was reused up to five cycles with slight
decrease of catalytic activity.
3. Results and discussion
Herein, we report a three component reaction of diamine
(Dapsone) (3) substituted aryl/heteroaryl aldehydes (4a–j) and
diethylphosphite (5), which led to the formation of tetraethyl[4,40-
2.1.2. Microwave conditions
sulfonylbis(4,1-phenylene)bis(azanediyl)]bis[(substituted
aryl/
The mixture of Dapsone (3) (1 mmol, 248 mg), 3-nitrobenzal-
dehyde (4c) (1.1 mmol, 167 mg), diethylphosphite (5) and the
catalyst, CeCl3ꢀ7H2O-SiO2 (12 mol%) was placed into a 50 mL flat-
bottomed flask. The reaction mixture was irradiated under
microwave radiations using catalyst systems (CATA-4R), % power
is 65% and 465 W. After completion of the reaction (monitored by
TLC), DCM (15 mL) was added to the reaction mixture. The catalyst
was filtered and washed with DCM (5 mL) to recover it. The
combined filtrates and washings were concentrated under reduced
pressure, followed by purification on column chromatography
using ethylacetate:n-hexane in the ratio of 4:6 as an eluent to
afford pure tetraethyl[4,40-sulfonylbis(4,1-phenylene)bis(azane-
diyl)]bis[(3-nitrophenyl)methylene]diphosphonate (6c). The fil-
tered residue catalyst was dried under vacuum and reused for the
heteroaryl)methylene]diphosphonates (6a–j) using heteroge-
neous solid support catalyst, CeCl3ꢀ7H2O-SiO2 under solvent-free
conditions in conventional and microwave irradiation methods as
depicted in Scheme 1.
To optimize the experimental conditions, the reaction of 4,40-
sulfonyldianiline (3), 3-nitrobenzaldehyde (4c) and diethyl phos-
phite (5) was considered as a model reaction. The progress of the
reactions was investigated without catalyst and with different
catalysts in EtOH under conventional conditions (Table 1, entries
1–8). Overall, CeCl3ꢀ7H2O-SiO2 (10 mol%) achieved the best results
(Table 1, entry 8) to synthesize 6c when compared to other
catalysts. Further, CeCl3ꢀ7H2O-SiO2 was investigated in different
solvents like THF, Toluene, CH3CN (Table 1, entries 9–11) besides
solvent-free conditions by keeping the temperature at 80 8C
[(Scheme_1)TD$FIG]
Conventional condition
reflux 7-8 h
R
O
P
OEt
EtO
O
S
O
S
OEt
OEt
CH
OEt
OEt
H
N
.
P
H2N
CeCl3 7H2O-SiO2
P
NH2
R
CHO
H
+
+
N
H
O
CH
R
O
O
O
Microwave irradition
3-5 min
5
3
4a-j
6a-j
6d
6a
6c
Compd.
6b
6e
6f
6g
6h
6i
6j
Br
OMe
NO2
Cl
H
N
S
N
R
Cl
OH
OMe
OH
OMe
Cl
Scheme 1. Synthesis of
a
-diaminophosphonates (6a-j) in the presence of CeCl3ꢀ7H2O-SiO2.

S.R. Devineni et al. / Chinese Chemical Letters 24 (2013) 759–763
761
Table 1
Effect of the different catalysts on Kabachnik–Fields reaction for the synthesis of compound 6c.
Entry
Catalyst (mol%)
Solvent
Time
Yield (%)
Entry
Catalyst (mol%)
Solvent
Time
Yield (%)
1
2
No catalyst
EtOHa
EtOHa
EtOHa
EtOHa
EtOHa
EtOHa
EtOHa
EtOHa
THFa
24 h
24 h
18 h
18 h
16 h
18 h
14 h
15 h
15 h
15 h
15 h
Trace
30
12
13
14
15
16
17
18
19
20
21
FeCl3 (10)
Neata (80 8C)
Neatb
8 h
73
81
70
80
72
80
76
87
82
91
Et3N
FeCl3 (10)
7 min
8 h
3
FeCl3 (10)
67
AlCl3 (10)
Neata (80 8C)
Neatb
4
AlCl3 (10)
65
AlCl3 (10)
7 min
8 h
5
CuCl2 (10)
68
CuCl2 (10)
Neata (80 8C)
Neatb
6
ZnCl2 (10)
68
CuCl2 (10)
7 min
8 h
7
CeCl3ꢀ7H2O (10)
CeCl3ꢀ7H2O-SiO2 (10)
CeCl3ꢀ7H2O-SiO2 (10)
CeCl3ꢀ7H2O-SiO2 (10)
CeCl3ꢀ7H2O-SiO2 (10)
70
ZnCl2 (10)
Neata (80 8C)
Neatb
8
73
ZnCl2 (10)
6 min
7 h
9
78
CeCl3ꢀ7H2O-SiO2 (10)
CeCl3ꢀ7H2O-SiO2 (10)
Neata (80 8C)
Neatb
10
11
Toluenea
CH3CNa
63
5 min
69
a
Reactions were carried out under conventional conditions.
b
Reactions were carried out under microwave irradiation conditions.
Table 2
12 mol% (Table 2, entry 6) and excess addition of the catalyst does
not affect the reaction.
Effect of CeCl3ꢀ7H2O-SiO2 catalyst loading for synthesis compound 6c.
The reusability of this heterogeneous catalyst was also
inspected in both the methods. After each run, the reaction
mixture was filtered and the residual catalyst was washed with
CH2Cl2 to remove tars from the catalyst surface and re-used up to
four cycles to synthesize compound 6c (Table 3, entry 1–5), with
slight decrease of catalytic activity. To establish the generality,
Entry
Amount of
catalyst (%)
Conventional
Microwave
Time (h)
Yield (%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
7
8
9
9
8
7
7
7
7
75
78
80
82
86
90
90
9
8
7
5
5
4
4
87
90
91
91
94
96
96
9
10
11
12
13
various active aldehydes were used to synthesize titled
a-
aminophosphonates (6a–j) using 12 mol% of the catalyst under
assigned conditions (Table 3). Based on the experimental results,
new analogs were prepared in excellent yields with electron
deficient aldehydes as compared with electron rich aldehydes, and
the catalyst is very tolerant toward various substituents including
halides, alkoxy and nitro groups (Table 4).
Table 3
The effect of the reusability of the catalyst CeCl3ꢀ7H2O-SiO2 to synthesize
compound 6c.
The structures of the designed compounds were confirmed by
spectral data (see Supporting information). IR spectra showed
intensive bands in the region of 3240–3390 cmꢂ1 of the –NH str,
1310–1355 cmꢂ1 of the –SO2 asym. str and 1220–1246 cmꢂ1 of the –
P55O str confirmed the functionalities in the desired compounds
(6a–j). 1H NMR spectra showed chemical shift values in the region of
Entry
Reusability
Conventional
Time (h)
Microwave
Time (min)
Yield (%)
Yield (%)
1
2
3
4
5
1
2
3
4
5
7
7
7
7
7
90
90
85
84
82
4
4
4
4
4
96
95
91
91
89
d
1.02–1.17astriplet,
phosphate functionality. Doublet of doublet was observed at
5.54 due to –CH–P–, 5.20–5.68 as singlet/doublet due to –NH–CH–
and 6.40–8.20 corresponding to aromatic protons confirmed the
designed compounds. In 31P NMR spectra, the chemical shifts in the
region of 20.5–27.3 corresponding to phosphorus confirmed the
d
3.56–4.30asmultipletdueto–O–CH2–CH3 of
d
4.58–
d
d
(Table 1, entry 20). It was observed that high yield was obtained in
solvent-free condition (Table 1, entry 20). The model reaction was
also tested with different catalysts FeCl3, AlCl3, CuCl2 and ZnCl2
under neat reaction conditions (Table 1, entries 12, 14, 16, 18). In
comparison of catalytic activity, CeCl3ꢀ7H2O-SiO2 progressed the
reaction most effectively with high yields (Table 1, entry 20).
Again, the same reaction was run for microwave irradiation (CATA-
4R, % power is 70% and 490 W), which led to the excellent yield 91%
in the presence of CeCl3ꢀ7H2O-SiO2 in very short reaction time
(5 min) (Table 1, entry 21) as compared with other catalysts
(Table 1, entries 13, 15, 17, 19). Also, the effect of a catalytic
amount of CeCl3ꢀ7H2O-SiO2 (Table 2, entries 1–7) was examined in
conventional as well as in microwave conditions. The reaction was
stimulated effectively in the catalytic amount of CeCl3ꢀ7H2O-SiO2,
d
functional group phosphonategroup inthe synthesized compounds.
In addition, the corresponding carbon chemical shift values in 13C
NMR spectra and the molecular ion peaks, fragmented ion peaks in
mass spectra have given further evidence to elucidate the structures
of the synthesized compounds (6a–j).
The titled
a-diaminophosphonates (6a–j) were screened for
their antibacterial activity against strains such as Staphylococcus
aureus (ATCC-19433), Bacillus cereus (ATCC-11778) and Escherichia
coli (ATCC-25922) using disk diffusion method at 200
mg/mL. All
the tested compounds did not exhibit good activity. Antifungal
activity of the synthesized compounds was also examined against
fungi such as Aspergillus niger (MTCC 1881), Fusarium oxysporum
Table 4
Physical data of the synthesized
a-diaminophosphonates (6a–j) under neat reaction conditions.
Entry
Conventional
Time (h)
Microwave
Time (min)
Mp (8C)
Entry
Conventional
Time (h)
Microwave
Time (min)
Mp (8C)
Yield (%)
Yield (%)
Yield (%)
Yield (%)
6a
6b
6c
6d
6e
7.5
8.0
7.0
7.5
7.0
89
88
90
86
89
4
4
4
5
5
92
91
96
90
91
169–171
189–191
140–142
170–172
108–110
6f
6g
6h
6i
7.5
7.5
8.0
8.0
8.0
86
86
87
86
84
4
4
5
5
4
90
91
90
91
91
106–108
128–130
140–142
114–116
118–120
6j

762
S.R. Devineni et al. / Chinese Chemical Letters 24 (2013) 759–763
Table 5
Antifungal zone of inhibition of the synthesized compounds (6a-j).
Compd.
Zone of inhibition (mm)a
A. niger (MTCC-1881)
MIC
F. oxysporum (MTCC-1755)
MIC
A. foetidus (NCIM-505)
MIC
6a
24.50
22.25
13.0
12
14
45
30
35
25
25
37
20
30
04
22.50
20.0
14
16
50
30
18
20
27
30
35
20
05
21.5
16
18
45
34
16
30
36
34
30
24
05
6b
21.25
14.75
16.25
18.50
21.0
6c
15.75
17.0
6d
19.50
17.0
6e
22.50
19.50
18.0
6f
20.50
20.50
18.25
21.75
19.0
6g
15.75
18.0
6h
19.0
6i
16.0
17.25
20.5
6j
21.50
26.0
Ketocon-azole
28.0
27.0
a
Antifungal activity of the titled compounds was tested at conc. 200 mg/mL.
[(Fig._2)TD$FIG]
IC50 values of title compounds (6a-j) by DPPH method
is environmentally benign and the new compounds are more
efficacious against fungi and as antioxidants.
122.3
114.9
Acknowledgments
106.4
104.5
94.2
89.8
The authors are grateful to acknowledge financial support from
University Grants Commission [UGC-BSR, UGC F.No. 40-71/2011
(SR)] under which this research was pursued. The authors also
thankful to Hyderabad Central University (Hyderabad), IICT
(Hyderabad) and Department of Biochemistry, S. V. University
for providing spectral data and evaluating the antimicrobial and
antioxidant activities, respectively.
80.9
79.8
53.7
53.2
51.6
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
Standard
Appendix A. Supplementary data
Fig. 2. Antioxidant IC50 values of a-diaminophosphonates (6a-j) by DPPH method.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.04.037.
(MTCC 1755) and Aspergillus foetidus (NCIM-505) using agar disk-
diffusion method [24]. Ketoconazole was used as the standard and
results were presented in Table 5. All the compounds showed
moderate to excellent antifungal activity. Among the compounds
6a, 6b and 6f exhibited excellent activity against all the tested
fungi. Compounds 6e, 6i and 6j are shown good inhibition against
F. oxysporum, A. niger and F. oxysporum and A. foetidus. Further, the
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derivatives of Dapsone in the presence of heterogeneous catalyst,
CeCl3ꢀ7H2O-SiO2 under solvent-free microwave assisted irradiation
conditions in short reaction time with good to excellent yields. The
presented procedure has many advantageous: (i) heterogeneous
catalyst is reusable, cheap, readily available, eco-friendly, versatile
and does not need any special precautions for preparation and
simple handling and storage, (ii) short reaction times, (iii) avoidance
of harmful organic solvents, (iv) simple work-up procedure, (v)
tolerance toward various functional groups including halides,
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