Ag/SiO2 as a recyclable catalyst for the facile green synthesis of 3-methyl-4-(phenyl)methylene-isoxazole-5(4H)-ones

Article abstract of DOI:10.1007/s11164-015-2167-2

An efficient and facile green method for synthesis of 3-methyl-4-(phenyl)methylene-isoxazole-5(4H)-one (4a-m) via room temperature reaction of hydroxylamine, ethylacetoacetate and substituted aromatic aldehydes is designed, using Ag/SiO₂ as cat

Full text of DOI:10.1007/s11164-015-2167-2

Res Chem Intermed
DOI 10.1007/s11164-015-2167-2
Ag/SiO2 as a recyclable catalyst for the facile green
synthesis of 3-methyl-4-(phenyl)methylene-isoxazole-
5(4H)-ones
Surya Narayana Maddila1 Suresh Maddila1
•
•
Werner E. van Zyl1 Sreekantha B. Jonnalagadda
1
•
Received: 10 April 2015 / Accepted: 4 July 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract An efficient and facile green method for synthesis of 3-methyl-4-(phe-
nyl)methylene-isoxazole-5(4H)-one (4a-m) via room temperature reaction of hydroxy-
lamine, ethylacetoacetate and substituted aromatic aldehydes is designed, using Ag/SiO2
as catalyst with water as solvent. This protocol offers several advantages, such as it being
a benign, energy conserving and eco-friendly reaction with products obtained in
excellent yields (88–93 %). The reaction requires relatively short reaction times (\1 h),
a simple workup procedure with good atom efficiency and easily recoverable catalyst.
The heterogeneous catalyst, Ag/SiO2, was fully characterized and is reusable without
loss of activity for up to seven cycles with marginal activity loss.
Graphical Abstract
OEt
CH3
CHO
O
NH2OH.HCl
O
O
Ag/SiO2
O
H2O / R.T, 1h
N
R
R
4a-m
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2167-2)
contains supplementary material, which is available to authorized users.
&
Sreekantha B. Jonnalagadda
jonnalagaddas@ukzn.ac.za
1
School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus,
Chiltern Hills, Durban 4000, South Africa
123

S. N. Maddila et al.
Keywords Green synthesis Á Heterogeneous catalyst Á Isoxazoles Á Ag/SiO2 Á
One-pot reaction
Introduction
In recent years, multicomponent reactions (MCR) have captivated researchers due to a
number of green principles, including facile operation, and being environmental
friendly and economical. MCRs allow three or more compounds to react together,
providing products in high yields without having to isolate intermediates. This is an
attractive option [1–3], thus making MCRs an important tool in the synthesis of
heterocyclic molecules with combinatorial, medicinal and agricultural chemistry
applications [3–5]. The other advantages of these reactions include high bond-forming
efficiency, cost effectiveness, energy saving and simple workup procedures [6, 7].
Interest in the use of heterogeneous catalysts in organic syntheses has increased
due to improved selectivity, facile separation, reusability and low cost [8, 9]. Metal
oxides have emerged as candidates for such a role due to their proven record as
catalysts, supports, and as ion-exchangers. Mixed metallic oxides with both acidic
and basic sites can be generated by calcination at about 700 K. The calcined
composites have moderate surface areas and can accelerate various condensation
reactions. Relative to conventional linear syntheses, these eco-friendly protocols
also have benefits, such as long catalytic life, thermal stability, cost effectiveness,
atom economy and scope to modify the surface properties [10].
Silica (SiO2), which is an acidic functional material in pure form, is one of the
widely used inorganic supports in the catalytic systems [11, 12] used in the
activation and stabilization of several metals [13, 14]. The crystalline structure of
SiO2 has been documented as one of the key factors for the justification of the
structure–activity relationships of metal-based catalysts [15]. In organic synthesis,
silica as support for various metal oxide catalysts allows the design of a varied
distribution of its Lewis and Brønsted acidic and basic sites [16–19] on the surface,
facilitating its use as catalyst for specific applications.
Isoxazoles are an important class of heterocyclic compounds; they are predominant
in nature and display fascinating biological and pharmaceutical properties [20, 21].
Isoxazole is considered a major scaffold compound in the discovery of combinatorial
synthesis and protein kinase inhibitors, playing a crucial role in the development of
chemotherapeutic agents [22, 23]. Many isoxazole derivatives exhibit antibacterial
[24], antifungal [25], antitumor [26], antioxidant [27], antiprotozoal [28], antiviral
[29], anti-tubercular [30], anti-inflammatory [31] and anti-HIV [32] activities. Several
procedures have been reported in the literature for the synthesis of isoxazole
derivatives and their analogues. A Literature survey shows that many catalyzed
methods were reported for the synthesis of various isoxazole derivatives. To mention a
few, such protocols employed sodium saccharin [33], ultrasonic irradiation [34],
sodium silicate [35], sodium benzoate [36], pyridine [37, 38], DABCO [39],
CH3COONa/UV [40], sodium ascorbate [41], sodium tetraborate [42], sodium sulfide
[43], pyridine/UV [44], and boric acid [45] as catalysts. Many of these methods have
some limitations and drawbacks, such as use of toxic reagents, strong acidic or basic
123

Ag/SiO2 as a recyclable catalyst for the facile green…
conditions, costly reagents and catalysts, strict reaction conditions, tedious steps, and
low product yields and/or long reaction times, which restrict their scope in practical
applications. Therefore, a novel protocol with good and inexpensive catalyst
demanding short reaction times is sought after.
In continuation of our interest in the environmental friendly protocols for the
various syntheses of heterocyclic derivatives with better yields [46–49], we herein
report the one-pot reaction of ethylacetoacetate, hydroxyl amine and substituted
aldehydes in the presence of a catalyst Ag/SiO2 for the synthesis of isoxazole
derivatives in excellent yields.
Experimental
Catalyst characterization
Micromeritics Tristar-II porosity and surface area analyzer was used to determine the
values of surface area, pore size and pore volume of the catalyst material. The catalyst
sample was degassed overnight using N2 flow at 200 °C. The BJH adsorption–
desorption curves were generated at -196 °C and were used to assess the catalyst’s
particulate properties. Employing a Bruker D8 Advance instrument (Cu K radiation
˚
source with a wave length of 1.5406 A), the X-ray diffraction data related to the
structural phases of the catalyst were acquired. Using a Jeol JEM-1010 electron
microscope and JEOL JSM-6100 microscope, transmission electron microscopy
(TEM) and scanning electron microscope (SEM) analysis data were recorded. iTEM
software was used analyze the TEM data and images. Employing the X-ray analyzer
(energy-dispersive), EDX-analysis on the SEM images was conducted. To confirm the
elemental composition catalyst materials, an inductively coupled plasma optical
emission spectrometer (ICP-OES) (Optima 5300 DV) was used.
Preparation of catalyst
The wet impregnation method was used for the synthesis of catalyst material, Ag/
SiO2. An appropriate amount of silver nitrate hydrate AgNO3Á9H2O, Aldrich
(99.9 %) was dissolved in double distilled water (50.0 ml), which was added to
silica (3.0 g) with continuous stirring with a magnetic stirrer at room temperature
for 12 h. Then the resulting slurry was dried in an oven at 110–130 °C for 12 h and
calcined in the presence of air at 450 °C for 3 h to acquire the 5 % w/w catalyst [50,
51].
General procedure for the synthesis of 3-methyl-4-(phenyl)methylene-
isoxazole-5(4H)-one derivatives
To equimolar ratios of hydroxylamine (1.1 mmol), ethylacetoacetate (1 mmol) and
aldehyde (1 mmol) dissolved in water (10 ml) at room temperature (RT) using Ag/
SiO2 (30 mg) as catalyst. The reaction mixture was stirred continuously for 1 h at
RT, (Scheme 1) using a magnetic stirrer. The progress of the reaction was
123

S. N. Maddila et al.
O
CHO
O
O
Ag/SiO2
NH2OH.HCl
O
OEt
H2O / R.T, 1h
H3C
N
R
1
2
R
4a-m
3a-m
Scheme 1 Synthesis of 3-methyl-4-(phenyl)methylene-isoxazole-5(4H)-one derivatives
monitored by thin-layer chromatography (TLC). The reaction mixture was then
filtered, and the filtrate was subsequently extracted with ethyl acetate and
evaporated under reduced pressure to obtain the crude product. Further, the crude
product was purified with a 4:6 ratio of EtOAc:Hexane mobile solvent to afford pure
products (4a-m). The recovered catalyst was subjected to washing with ethanol,
dried, and could be reused for up to seven cycles.
3-Methyl-4-(4-hydroxyphenyl)methylene-isoxazole-5(4H)-one (4a) Yellow solid:
1H NMR (400 MHz, DMSO-d6) d = 2.24 (s, 3H, CH3), 6.94 (d, J = 8.80 Hz, 2H,
ArH), 7.78 (s, 1H, =CH), 8.44 (d, J = 8.84 Hz, 2H, ArH), 10.85 (s, 1H, OH); 13C
NMR (100 MHz, CDCl3): d 11.24, 113.83, 116.12, 124.53, 137.44, 151.51, 162.24,
163.82, 168.78; IR (KBr, cm-1): 3232, 2363, 1734, 1559, 1358, 1297, 1179, 669;
HRMS of [C11H9NO3–H]? (m/z): 202.0503; Calcd.: 202.0504.
3-Methyl-4-(4-methoxyphenyl)methylene-isoxazole-5(4H)-one (4b) Yellow solid:
1H NMR (400 MHz, DMSO-d6) d = 2.25 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 7.14
(d, J = 8.96 Hz, 2H, ArH), 7.85 (s, 1H, =CH), 8.51 (d, J = 8.96 Hz, 2H, ArH); 13
C
NMR (100 MHz, CDCl3): d 11.24, 55.80, 114.63, 115.19, 125.76, 136.86, 151.19,
132.23, 164.21, 168.57; IR (KBr, cm-1): 3446, 2362, 1734, 1594, 1269, 1176, 668;
HRMS of [C12H11NO3 ? Na]? (m/z): 240.0641; Calcd.: 240.0637.
3-Methyl-4-phenyl-methylene-isoxazole-5(4H)-one (4c) Light yellow solid: 1H
NMR (400 MHz, DMSO-d6) d = 2.29 (s, 3H, CH3), 7.56–7.67 (m, 3H, ArH), 7.96
(s, 1H, =CH), 8.40 (d, J = 7.40 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3):
d 11.25, 118.32, 128.84, 132.40, 133.51, 133.86, 151.62, 162.18, 167.78; IR (KBr,
cm-1): 3446, 2362, 1739, 1561, 1341, 1284, 1140, 685; HRMS of [C11H10NO2 ?
Na]? (m/z): 211.0618; Calcd.: 211.0609.
3-Methyl-4-(4-dimethylaminophenyl)methylene-isoxazole-5(4H)-one
(4d) Red
solid: 1H NMR (400 MHz, DMSO-d6) d = 2.20 (s, 3H, CH3), 3.33 (s, 6H,
N(CH3)2), 6.85 (d, J = 9.16 Hz, 2H, ArH), 7.60 (s, 1H, =CH), 8.45 (d,
J = 8.80 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): d 11.27, 108.98, 111.59,
120.95, 137.52, 150.44, 154.32, 162.08, 169.79; IR (KBr, cm-1): 3432, 2362, 1709,
1582, 1380, 1202, 1161, 668; HRMS of [C13H14N2O2 ? Na]? (m/z): 253.0953;
Calcd.: 253.0953.
Anal. calcd. for C13H14N2O2: C 67.81, H 6.13, N 12.17; Found: C 67.83, H 6.10,
N 12.14.
123

Ag/SiO2 as a recyclable catalyst for the facile green…
1
3-Methyl-4-(anthracen-9-yl)methylene-isoxazole-5(4H)-one (4e) Brown solid: H
NMR (400 MHz, DMSO-d6) d = 2.57 (s, 3H, CH3), 7.72–776 (m, 3H, ArH),
8.07–8.09 (m, 3H, ArH), 8.79 (d, J = 8.74 Hz, 3H, ArH), 8.86 (s, 1H, CH); 13C
NMR (100 MHz, CDCl3): d 11.46, 123.44, 125.05, 125.39, 125.73, 125.81, 127.05,
127.43, 128.72, 148.35, 158.68, 161.09, 166.22, 168.25, 168.78; IR (KBr, cm-1):
3431, 2360, 1752, 1352, 1292, 1182, 668; HRMS of [C19H13NO2 ? Na]? (m/z):
310.0848; Calcd.: 310.0844.
3-Methyl-4-(2,5-dihydroxyphenyl)methylene-isoxazole-5(4H)-one (4f) Yellow solid:
1H NMR (400 MHz, DMSO-d6) d = 2.23 (s, 3H, CH3), 6.85 (d, J = 8.88 Hz, 1H,
ArH), 6.97–7.00 (m, 1H, ArH), 8.02 (s, 1H, =CH), 8.23 (d, J = 8.78 Hz, 1H, ArH),
9.18 (s, 1H, OH), 10.38 (s, 1H, OH); 13C NMR (100 MHz, CDCl3): d 11.16, 115.67,
116.45, 116.78, 119.69, 125.56, 144.98, 149.32, 153.36, 162.17, 168.23; IR (KBr,
cm-1): 3308, 2361, 1751, 1602, 1368, 1273, 1170, 668; HRMS of [C11H9NO4–H]?
(m/z): 218.0453; Calcd.: 218.0453.
3-Methyl-4-(3,4-dihydroxyphenyl)methylene-isoxazole-5(4H)-one (4g) Yellow solid:
1H NMR (400 MHz, DMSO-d6) d = 2.19 (s, 3H, CH3), 6.42 (s, 2H, ArH), 7.96 (s,
1H, =CH), 8.97 (d, J = 8.81 Hz, 1H, ArH), 9.90 (s, 1H, OH), 11.06 (s, 1H, OH);
13C NMR (100 MHz, CDCl3): d 11.17, 101.69, 109.02, 110.57, 113.01, 135.14,
143.94, 162.22, 163.10, 166.63, 169.40; IR (KBr, cm-1): 3487, 2363, 1734, 1589,
1391, 1258, 1212, 761.
3-Methyl-4-(3-hydroxyphenyl)methylene-isoxazole-5(4H)-one (4h) Light yellow
solid: 1H NMR (400 MHz, DMSO-d6) d = 2.27 (s, 3H, CH3), 7.06 (d,
J = 7.46 Hz, 1H, ArH), 7.37 (t, J = 7.90 Hz, 1H, ArH), 7.78 (d, J = 7.88 Hz,
1H, ArH), 7.85 (s, 1H, =CH), 7.92 (s, 1H, ArH), 9.90 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3): d 11.25, 118.48, 119.38, 121.34, 125.25, 129.80, 133.57,
151.98, 157.35, 162.21, 167.71; IR (KBr, cm-1): 3432, 2356, 1739, 1575, 1347,
1288, 1113, 668; HRMS of [C11H9NO3–H]? (m/z): 202.0512; Calcd.: 202.0504.
3-Methyl-4-(2,3-dimethoxyphenyl)methylene-isoxazole-5(4H)-one (4i) Light yel-
1
low solid: H NMR (400 MHz, DMSO-d6) d = 2.29 (s, 3H, CH3), 3.86 (s, 6H,
2OMe), 7.06 (d, J = 7.82 Hz, 1H, ArH), 7.36 (d, J = 7.64 Hz, 1H, ArH),7.99 (s,
1H, =CH), 8.22 (d, J = 9.08 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 11.13,
56.00, 61.67, 118.83, 119.26, 123.34, 123.70, 125.63, 145.12, 149.85, 152.15,
162.02, 167.47; IR (KBr, cm-1): 3432, 2362, 1698, 1524, 1268, 1125, 668.
3-Methyl-4-(2,5-dimethoxyphenyl)methylene-isoxazole-5(4H)-one (4j) Orange solid:
1H NMR (400 MHz, DMSO-d6) d = 2.25 (s, 3H, CH3), 3.75 (s, 3H, OMe), 3.87 (s,
3H, OMe), 7.12–7.27 (m, 2H, ArH), 8.01 (s, 1H, =CH), 8.41 (d, J = 8.04 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): d 11.12, 55.50, 56.50, 112.84, 115.78, 117.79,
120.79, 123.23, 144.21, 152.26, 154.43, 162.02, 168.01; IR (KBr, cm-1): 3430, 2362,
1730, 1596, 1237, 1045, 668; HRMS of [C13H13NO4 ? Na]? (m/z): 270.0742; Calcd.:
270.0742.
3-Methyl-4-(2,4,6-trimethoxyphenyl)methylene-isoxazole-5(4H)-one (4k) Yellow
1
solid: H NMR (400 MHz, DMSO-d6) d = 2.22 (s, 3H, CH3), 3.76 (s, 3H, OMe),
123

S. N. Maddila et al.
3.83 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.25 (s, 1H, ArH), 6.35 (s, 1H, ArH), 7.72 (s,
1H, =CH), 8.11 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 11.16, 55.76, 55.99,
56.07, 90.68, 90.96, 104.25, 117.47, 141.08, 142.33, 159.16, 160.02, 160.98,
165.58; IR (KBr, cm-1): 3431, 2364, 1751, 1602, 1330, 1207, 1157, 668.
3-Methyl-4-(2,4-dimethylphenyl)methylene-isoxazole-5(4H)-one (4l) Cream solid:
1H NMR (400 MHz, DMSO-d6) d = 2.29 (s, 3H, CH3), 2.34 (s, 3H, ArCH3), 2.45
(s, 3H, ArCH3), 7.14 (d, J = 8.04 Hz, 1H, ArH), 7.19 (s, 1H, ArH), 8.00 (s, 1H,
=CH), 8.34 (d, J = 8.84 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 11.16,
19.45, 21.28, 117.86, 126.46, 127.91, 131.32, 131.52, 141.04, 144.23, 149.26,
162.03, 167.76; IR (KBr, cm-1): 3449, 2372, 1770, 1599, 1383, 1097, 658; HRMS
of [C13H14NO2 ? H]? (m/z): 216.1032; Calcd.: 216.1025.
3-Methyl-4-(4-ethylphenyl)methylene-isoxazole-5(4H)-one (4m) White solid: 1H
NMR (400 MHz, DMSO-d6) d = 1.20 (t, J = 8.12 Hz, 3H, CH2CH3), 2.27 (s, 3H,
CH3), 2.70 (q, J = 7.57 Hz, 2H, CH2CH3), 7.43 (d, J = 8.28, 2H, ArH), 7.91 (s,
1H, =CH), 8.36 (d, J = 8.20, 2H, ArH); 13C NMR (100 MHz, CDCl3): d 11.23,
14.84, 28.44, 117.62, 126.38, 128.38, 130.25, 131.79, 133.99, 151.09, 151.60,
162.20, 168.03; IR (KBr, cm-1): 3446, 2368, 1740, 1594, 1344, 1257, 1103, 668;
HRMS of [C13H14NO2 ? H]? (m/z): 216.1035; Calcd.: 216.1025.
Results and discussion
BET surface area (BET) and elemental (ICP) analysis
The texture of the prepared catalysts was determined by physisorption analysis. The
N2 adsorption–desorption isotherms showed a type-IV adsorption isotherm,
demonstrating the mesoporous nature of the catalysts (Fig. 1). The prepared
catalyst showed a surface area of 189 m2 g-1 with a pore volume of 0.994 cc g-1
.
The large surface area was obtained for the catalyst sample with high pore volumes
Fig. 1 N2 adsorption and
desorption spectra of Ag/SiO2
catalyst
Ag/SiO - Adsorption
600
2
Ag/SiO - Desorption
2
500
400
300
200
100
0.2
0.4
0.6
0.8
1.0
Relative Pressure (P/Po)
123

Ag/SiO2 as a recyclable catalyst for the facile green…
due to the narrow pore size distribution of catalyst. The ICP analysis results showed
the presence of a nominal amount of Ag in the catalyst (4.94 wt%).
TEM analysis
The TEM micrograph reveals more structural information of the catalyst. Figure 2
shows a distinctive TEM image of Ag loaded on silica catalyst, from which it can be
seen that the Ag nanoparticles showed a sphere-shape with an average size of
13 nm, and are highly dispersed and homogeneously distributed on the silica
support with strong interaction between the AgNPs and silica supports.
SEM analysis
Figure 3 shows an illustrative SEM morphologies micrograph of the sample Ag on
silica. A lot of large white elliptical irregular shapes are perceived from the low
magnification SEM image of Ag/SiO2. This micrograph reveals that the aggregative
state of the silica important particles is with silver. While a homogeneous
distribution of Ag and silica on the catalyst is specified by the EDS analysis,
elemental analysis by ICP-OES confirmed the elemental composition in the catalyst
material (Fig. 4). Furthermore, the morphology of the catalyst, as per the SEM
images, noticeably points to the crystallinity and homogeneity of the sample.
Powder X-ray diffractogram (XRD) analysis
XRD patterns of the calcined Ag/SiO2 catalyst are shown in Fig. 5. All of the PXRD
diffraction patterns can be indexed to fcc silver. The calcined 2 % Ag on SiO2
sample showed diffraction peaks at 38.1°, 44.3°, 64.4° and 77.4°, corresponding to
Fig. 2 TEM micrograph of Ag/
SiO2 catalyst
123

S. N. Maddila et al.
Fig. 3 SEM micrograph of Ag/SiO2 catalyst
Fig. 4 SEM-EDX spectra of Ag/SiO2 catalyst
the (1 1 1), (2 0 0), (2 2 0) and (3 1 1) lattice planes of hexagonal Ag2O (JCPDS #
72-2108) and cubic Ag2O3 (JCPDS # 72-0607), respectively. Important peaks in the
silver XRD spectra agree with the JCPDS-PDF # 00-004-0783 files, and the two
broad peaks centered at 12.1° and 22.1° were due to the amorphous silica support.
Optimization procedure
At the start of the investigations, the impact of availability of catalyst material and
solvents was examined. With ethyl acetoacetate, aromatic aldehyde, hydroxyl amine
hydrochloride and water as solvent and with no catalyst, there was no reaction at
RT, even after 24 h under reflux conditions, (Table 1, entries 1, 2). The same
reaction was tried in ethanol in the absence of any catalyst at RT for 12 h, and failed
123

Ag/SiO2 as a recyclable catalyst for the facile green…
Fig. 5 XRD spectrum of Ag/
SiO2 catalyst
(200)
(111)
(220)
(311)
10
20
30
40
50
60
70
80
90
Degrees/2θ
to achieve any desired product (Table 1, entries 3, 4). The scope of the various types
of catalysts and use of NaOH and K2CO3 as a basic catalyst in aqueous media
provided no yield at RT (Table 1, entry 5, 6). The reaction was performed under
reflux conditions in ethanol, using pyridine and Na2S as basic catalysts, which gave
improved yields (Table 1, entry 7, 8). The use of ionic liquid (Bmim)BF4 on the
product yield was investigated, but yields were very low under reflux conditions
(Table 1, entry 9). Use of pure heterogeneous acidic catalysts such as SiO2, Al2O3,
Fe2O3, and CeO2 at RT in aqueous media showed no reaction progress or yield
(Table 1, entries 10–13). The reaction performed with AgNO3 as catalyst gave 18 %
yield (Table 1, entry 14). When Ag loaded on SiO2 was used as catalyst, a reaction
occurred with an impressive 93 % yield of isoxazole derivative at RT after 1 h
reaction time (Table 1, entry 15). The efficacy of this catalytic system was further
tested by comparing it with two other silica-supported catalysts under otherwise
similar conditions. Use of HClO4–SiO2 and FeCl3/SiO2 gave lower product yields
and took 4–6 h for completion of the reaction (Table 1, entry 16, 17). Furthermore,
the reaction using Ag/SiO2 as catalyst under solvent free conditions gave a small
yield, even after prolonged reaction time (Table 1, entry 18).
Accepting that Ag/SiO2 as catalyst and water as solvent are ideal means for the
reaction, the effect of amount of catalyst on the yield and reaction time was further
investigated. Performing the reaction with [ 30 mg of catalyst had no significant
improvement on the yield or reaction time. However, the decrease in the amount of
the catalyst used to 20 and 10 mg affected the product yield by reducing it to 70 and
63 %, respectively (Table 1, entries 19–23). Therefore, 30 mg of Ag/SiO2 at RT
with water as solvent is assumed as the optimal condition for the model reaction,
giving a conversion of 93 % in 1 h.
A perusal of the experimental results and the effect of various polar and non-
polar solvents on the three-component reaction clearly indicate that water as solvent
plays a vital role in facilitating the reaction (Table 1). Noticeably, under otherwise
similar conditions, the Ag/SiO2 catalyzed reaction in the presence of comparatively
123

S. N. Maddila et al.
Table 1 Optimization condition for the synthesis of isoxazole by Ag/SiO2 catalysta
Entry
Catalyst
Solvent
Condition
Time (h)
Yield (%)b
1
No catalyst
No catalyst
No catalyst
No catalyst
NaOH
H2O
RT
24
24
12
12
12
12
2.5
5
–
2
H2O
Reflux
RT
–
3
EtOH
EtOH
H2O
–
4
Reflux
RT
–
5
–
6
K2CO3
H2O
RT
–
7
Na2S
EtOH
EtOH
EtOH
H2O
Reflux
Reflux
Reflux
RT
61
42
23
–
8
Pyridine
9
(Bmim)BF4
SiO2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
12
12
12
12
12
1
Al2O3
H2O
RT
–
Fe2O3
H2O
RT
–
CeO2
H2O
RT
–
AgNO3
H2O
RT
18
93
58
37
43
85
89
93
93
91
29
32
13
24
78
72
Ag/SiO2
H2O
RT
HClO4/SiO2
FeCl3/SiO2
Ag/SiO2
H2O
RT
3
H2O
RT
3.5
12
3
–
RT
Ag/SiO2 (10 mg)
Ag/SiO2 (20 mg)
Ag/SiO2 (30 mg)
Ag/SiO2 (40 mg)
Ag/SiO2 (50 mg)
Ag/SiO2
H2O
RT
H2O
RT
2
H2O
RT
1
H2O
RT
1
H2O
RT
1.5
3
CH3CN
DMF
n-Hexane
1,4-Dioxane
EtOH
MeOH
RT
Ag/SiO2
RT
2.5
8
Ag/SiO2
RT
Ag/SiO2
RT
6
Ag/SiO2
RT
1.5
2
Ag/SiO2
RT
–, No reaction
a
All products were characterized by IR, 1HNMR, 13C NMR and HRMS spectral analysis
b
Isolated yields
less polar solvents like CH3CN, DMF, n-hexane and 1,4-dioxane gave insignificant
yields (Table 1 entries 24–27). The efficiency of methanol and ethanol relative to
water was also investigated. Although comparable yields were observed (Table 1,
entries 28, 29), water had a marginal advantage, thus proving to be the best medium
for the reaction. A highly polar solvent that dissipates heat faster may provide
optimum conditions for formation of intermediates, and their conversion to final
products on the catalyst surface.
123

Ag/SiO2 as a recyclable catalyst for the facile green…
Employing the optimized reaction conditions, the strength of the protocol was
evaluated for the synthesis of 3-methyl-4-(phenyl)methylene-isoxazole-5(4H)-one
derivatives from various aromatic aldehydes. The Ag/SiO2 heterogeneous catalyst
proved to catalyze the facile one-pot synthesis of 3-methyl-4-(phenyl)methylene-
isoxazole-5(4H)-one derivatives with good to excellent yields. All the reaction
products with other details are depicted in Table 2. Interestingly, the substrates used
and reaction yields obtained show that the reaction using several electron-
withdrawing and electron donating substrates in ortho, meta and para positions of
the aromatic ring have also contributed positively to obtaining the desired isoxazole
derivatives in good to excellent yields (Table 2). A reaction scheme is proposed
based on the chemistry of the reacting substrates and observed selectivity towards
the product (Fig. 6). At first, the nucleophilic attack of hydroxylamine hydrochlo-
ride at the carbonyl carbon of the compound 1 afforded the intermediate compound
oxime. When the intermediate lost one hydrogen atom, the methylene group would
convert to be the active carbon anion. Then, the aldehyde carbonyl group was
attacked by carbon anion and a subsequent Knoevenagel reaction occurred. After
losing one ethanol molecule, ring-closing was brought to the corresponding
products. All the resultant products were characterized and structures were
1
confirmed by FTIR, H NMR, 13C NMR and HRMS spectral analysis (Electronic
Supplementary Information).
Table 2 Synthesis of isoxazole derivatives catalyzed by Ag/SiO2 catalyst
Entry
R
Product
Yield (%)
Mp °C
Lit Mp °C
1
4-OH
4a
4b
4c
4d
4e
4f
92
90
93
92
90
89
90
92
90
89
88
92
91
214–215
173–174
141–142
227–228
219–221
187–188
212–213
164–166
210–211
178–179
232–233
193–195
201–203
214–216 [32]
2
4-OMe
174–175 [32]
3
H
141–143 [35]
4
4-N(Me)2
Anthracenyl
2,5-(OH)2
3,4-(OH)2
3-OH
226–228 [35]
5
–
–
–
–
–
–
–
–
–
6
7
4g
4h
4i
8
9
2,3-(OMe)2
2,5-(OMe)2
2,4,6-(OMe)3
2,4-(Me)2
4-Et
10
11
12
13
4j
4k
4l
4m
–, New compounds/no literature available
a
Reaction conditions: hydroxylamine (1.1 mmol), ethylacetoacetate (1.0 mmol), aromatic aldehyde
(1.0 mmol) and water (10 ml), RT
b
All synthesized compounds are identified and their structures were confirmed with IR, 1H NMR, 13C
NMR and HRMS spectral data and melting points, as compared with literature values
123

S. N. Maddila et al.
HO
HO
O
O
O
N
O
N
H
NH2OH.HCl (2)
OEt
H3C
OEt
H3C
OEt
H3C
1
O
OH
OH
HO
O
O
N
N
O
N
OEt
OEt
H3C
H3C
OEt
H3C
Ag/SiO2
H2O
OH
Ar
Ar
O
Ar
O
H
O
O
N
O
N
EtOH
OEt
H3C
Ar
4c
CH3
Ar
Fig. 6 Proposed reaction mechanism
Reusability of catalyst
In one of the photochemical methods, using CH3COONa catalyst, visible light and
aqueous ethanol solvent conditions [40], the obtained yield was only 56–68 % in
20 min; furthermore, in this method the catalyst was not recyclable. The main
attraction of the use of heterogeneous catalysts is reusability. Experiments were
performed to investigate the recyclable phenomenon of the heterogeneous catalyst
in the title reaction. The catalyst was recovered after filtration, washed with EtOH
and dried under reduced pressure after the completion of reaction. The recovered
catalyst was reused for seven consecutive runs following a similar recovery
procedure, and observed loss of activity was minimal (Fig. 7). No significant loss
was observed in the first four cycles. The marginal loss in catalytic activity noticed
after the 4th run can be attributed to the probable organic contaminations, trivial
alterations and loss of catalyst material in the recovery process under the examined
conditions.
123

Ag/SiO2 as a recyclable catalyst for the facile green…
Fig. 7 Recyclability of Ag/SiO2 catalyst
Conclusion
We have described a green, simple, efficient and environmentally benign one-pot
multicomponent protocol for the synthesis of 3-methyl-4-(phenyl)methylene-
isoxazole-5(4H)-one derivatives with good to excellent yields. The new heteroge-
neous catalyst, Ag/SiO2 is simple, highly efficient and recyclable for the MCR
protocol at RT. The main advantages of this approach are green solvent, cheap
materials, easy workup, non-hazardous and environment friendly reaction condi-
tions, recyclable catalyst, excellent yields, and short reaction times.
Acknowledgments The authors are thankful to the National Research Foundation (NRF) of South
Africa, and University of KwaZulu-Natal, Durban, for financial support and research facilities.
References
1. M.M. Gawande, V.D.B. Bonifacio, R. Luque, P.S. Branco, R.S. Varma, Chem. Soc. Rev. 42(12),
5522 (2013)
2. A.P. Abbott, D. Boothby, G. Capper, D.L. Davies, R.K. Rasheed, J. Am. Chem. Soc. 126, 9142
(2004)
3. A. Domling, Chem. Rev. 106, 17 (2006)
4. A. Domling, W. Wang, K. Wang, Chem. Rev. 112(6), 3038 (2012)
5. S. Maddila, S. Rana, R. Pagadala, S. Kankala, S.N. Maddila, S.B. Jonnalagadda, Catal. Commun. 61,
26 (2015)
6. Y. Gu, Green Chem. 14, 2091 (2012)
7. K. Alfonsi, J. Colberg, P.J. Dunn, T. Fevig, S. Jennings, T.A. Johnson, H.P. Kleine, C. Knight, M.A.
Nagy, D.A. Perry, M. Stefaniak, Green Chem. 10, 31 (2008)
123

S. N. Maddila et al.
8. J.P. Wan, S.F. Gan, G.L. Sun, Y.J.J. Pan, Org. Chem. 74, 2862 (2009)
9. A. Das, A. Kulkarni, B. Torok, Green Chem. 14, 17 (2012)
10. J. Virkutyte, R.S. Varma, Green synthesis of nanomaterials: environmental aspects, sustainable
nanotechnology and the environment: advances and achievements, Chapter 2, ACS Symposium
Series. vol. 1142, p. 11 (2013)
11. M. Choi, F. Kleitz, D. Liu, E.Y. Lee, A. Wha-Seung, R. Ryoo, J. Am. Chem. Soc. 127, 1924 (2005)
12. P. Bhaumik, T. Kane, P.L. Dhepe, Catal. Sci. Technol. 4, 2904 (2014)
13. A. Walcarius, Chem. Mater. 13, 3351 (2001)
14. J. Han, P. Fang, W. Jiang, L. Li, R. Guo, Langmuir 28, 4768 (2012)
15. W. Zhou, I.E. Wachs, C.J. Kiely, Curr. Opin. Solid State Mater. Sci. 16, 10 (2012)
16. S. Minakata, M. Komatsu, Chem. Rev. 109, 711 (2009)
17. J.H. Clark, Acc. Chem. Res. 35, 791 (2002)
18. G. Neri, G. Rizzo, A.S. Arico, C. Crisafulli, L. De Luca, A. Donato, M.G. Musolino, R. Pietropaolo,
Appl. Catal. A Gene. 325, 15 (2007)
19. A. Khalafi-Nezhad, E.S. Shahidzadeh, S. Sarikhani, F. Panahi, J. Mol. Catal. A: Chem. 379, 1 (2013)
20. A.P. Kozikowski, S. Tapadar, D.N. Luchini, K.H. Kim, D.D. Billadeau, J. Med. Chem. 51, 4370 (2008)
21. B.H. Norman, P.A. Lander, J.M. Gruber, J.S. Kroin, J.D. Cohen, L.N. Jungheim, J.S. Starling, K.L. Law,
T.D. Self, L.B. Tabas, D.C. Williams, D.C. Paul, A.H. Dantzig, Bioorg. Med. Chem. Lett. 15, 1526 (2005)
22. S. Batra, S.K. Rastogi, B. Kundu, A. Patra, A.P. Bhaduri, Tetrahed Lett. 41(31), 5971 (2000)
23. A. Barria, V. Derkach, T. Soderling, J. Biol. Chem. 272, 32727 (1997)
24. Y.K. Kang, K.J. Shin, K.H. Yoo, K.J. Seo, C.Y. Hong, C.S. Lee, S.Y. Park, D.J. Kim, S.W. Park,
Bioorg. Med. Chem. Lett. 10, 95 (2000)
25. C.V. Vicentini, C. Romagnoli, S. Manfredini, D. Rossi, D. Mares, Pharm. Biol. 49(5), 545 (2011)
26. R.K. Reddy, S.P. Rao, J.G. Dev, Y. Poornachandra, G.C. Kumar, S.P. Rao, B.B. Narsaiah, Bioorg.
Med. Chem. Lett. 24(7), 1661 (2014)
27. A. Padmaja, C. Rajasekhar, A. Muralikrishna, V. Padmavathi, Eur. J. Med. Chem. 46, 5034 (2011)
28. D.A. Patrick, S.A. Bakunov, S.M. Bakunova, E.V. Kumar, R.J. Lombardy, S.K. Jones, A.S. Bridges,
O. Zhirnov, J.E. Hall, T. Wenzler, R. Brun, R.R. Tidwell, J. Med. Chem. 50(10), 2468 (2007)
29. B. Loh, L. Vozzolo, B.J. Mok, C.C. Lee, R.J. Fitzmaurice, S. Caddick, A. Fassati, Chem. Biol. Drug
Des. 75(5), 461 (2010)
30. J. Mao, H. Yuan, Y. Wang, B. Wan, M. Pieroni, Q. Huang, R.B. van Breemen, A.P. Kozikowski,
S.G. Franzblau, J. Med. Chem. 52(22), 6966 (2009)
31. Y. Karabasanagouda, A.V. Adhikari, M. Girisha, Indian J. Chem. 48B, 430 (2009)
32. B.L. Deng, M.D. Cullen, Z. Zhou, T.L. Hartman, R.W. Buckheit Jr, C. Pannecouque, E. Declescq,
P.E. Fanwick, M. Cushman, Bioorg. Med. Chem. 14, 2366 (2006)
33. H. Kiyani, F. Ghorbani, Heterocyc. Lett. 3(3), 359 (2013)
34. K. Ablajan, H. Xiamuxi, Synth. Commun. 42, 1128 (2012)
35. Q. Liu, R-T. Wu, J. Chem. Res. 598 (2011)
36. Q. Liu, Y.-N. Zhang, Bull. Korean Chem. Soc. 32(10), 3559 (2011)
37. Z. Ying-Qun, M.A. Jing-Jun, W.L.I. Chun, Z. Jing-Ci, Z. Dong-Nuan, L. Xiao-Huan, L. Jie, Chin.
J. Org. Chem. 28, 141 (2008)
38. K. Ablajan, H. Xiamuxi, Chin. Chem. Lett. 22, 151 (2011)
39. M. Mirzazadeh, G.H. Mahdavinia, Eur. J. Chem. 9(1), 425 (2012)
40. F. Saikh, J. Das, S. Ghosh, Tetrahedr. Lett. 54, 4679 (2013)
41. H. Kiyani, F. Ghorbani, Org. Chem. Indian J. 9(9), 97 (2013)
42. H. Kiyani, F. Ghorbani, Open. J. Org. Chem. 1(1), 5 (2013)
43. Q. Liu, X. Hou, Phosph. Sulf. Silicon. 187, 448 (2012)
44. C. Qingfang, X. Xingyou, W. Qifa, L. Lisha, L. Wangjun, L. Qiao, Y. Xujie, Chin. J. Org. Chem. 8,
1267 (2009)
45. H. Kiyani, F. Ghorbani, Res. Chem. Intermed. 8, 45 (2013)
46. S. Maddila, R. Pagadala, S.B. Jonnalagadda, Lett. Org. Chem. 10(10), 693 (2013)
47. S. Maddila, S. Rana, R. Pagadala, S.B. Jonnalagadda, Res. Chem. Intermed. (2014). doi:10.1007/
s11164-014-1890-4
48. R. Pagadala, S. Maddila, S.B. Jonnalagadda, Catal. Commun. 45, 148 (2014)
49. R. Pagadala, S. Maddila, V. Moodley, W.E. van Zyl, S.B. Jonnalagadda, Tetrahed. Lett. 55, 4006 (2014)
50. S. Maddila, V.D.B.C. Dasireddy, S.B. Jonnalagadda, Appl. Catal. B Environ. 138–139, 149 (2013)
51. E.C. Chetty, S. Maddila, C. Southway, S.B. Jonnalagadda, Ind. Eng. Chem. Res. 51, 2864 (2012)
123