Bulk synthesis of thermally unstable 5-amino-3-methylisoxazole using silica coated magnetite nanoparticles (Fe3O4@SiO2)

Article abstract of DOI:10.14233/ajchem.2017.20155

5-Amino-3-methylisoxazole is an important intermediate in medicinal chemistry. Bulk scale synthesis of it is reported and the reaction yields are typically around 40 %. The reaction of 3-aminocrotonitrile and hydroxylamine hydrochloride in aqueous environment in about 12 h at room temperature results in 5-amino-3-methylisoxazole. This simple one pot synthesis has an issue, which contributes to lower reaction yields. The melting point of 5-amino-3-methylisoxazole is 83-85 °C, but around 70 °C it can rapidly decompose causing an explosion. Hence, this molecule is synthesized by maintaining reaction temperature at 0-25 °C. Due to exothermic nature of the reaction, maintenance of lower temperature is mandatory. Due to lower reaction temperature, this reaction yields are usually low. Though these kind of lower yields are reported for synthesis of this class of compounds, attempts to improve the reaction yields are sparse. We report silica coated magnetic nanoparticle (Fe₃O₄@SiO₂) as an inert surface for preparation of 5-amino-3-methylisoxazole. The yield of reaction is around 80 %, almost double the reported yield and it is enabled by the 40 nm Fe₃O₄@SiO₂ particles. The 40 nm Fe₃O₄@SiO₂ are synthesized by modification to the famous "Stober" protocol. The obtained 40 nm particles contain intermittent particles with about 200 nm as reported in literature. Though isolation of 40 nm size magnetic nanoparticles in reactions is difficult, presence of about 200 nm size Fe₃O₄@SiO₂ is enabling for easy isolation. The work up of reaction is simple isolation of Fe₃O₄@SiO₂ by magnet, basification of reaction mixture to pH 10, dissolving the precipitated solid in diethyl ether, removal of ether to obtain crude 5-amino-3-methylisoxazole, which was recrystallized using distilled water. This protocol paves way for simple synthesis of related isoxazoles, which are increasingly forming base structure for many drugs and medicinal chemistry leads.

Full text of DOI:10.14233/ajchem.2017.20155

Asian Journal of Chemistry; Vol. 29, No. 1 (2017), 124-128
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2017.20155
Bulk Synthesis of Thermally Unstable 5-Amino-3-methylisoxazole
Using Silica Coated Magnetite Nanoparticles (Fe
3
O
4
@SiO )
2
1
2,3
1
1
1,2,3,*
G.V. SHIVA REDDY , M. CHANDRAPPA , FAZLUR RAHAMAN , B. NARASIMHA MURTHY and PHANI KUMAR PULLELA
1
2
3
CMR Institute of Technology, ITPL Main Road, Bangalore, Karnataka-560 037, India
CMR University, HRBR Layout, 2nd Block, Kaylan Nagar, Bangalore-560 043, India
Bigtec Pvt. Ltd., 59th “C” Cross, 4th “M” Block, Rajajinagar, Bangalore-560 010, India
*
Corresponding author: E-mail: phanikumar.p@cmrit.ac.in
Received: 23 June 2016; Accepted: 21 September 2016;
Published online: 29 October 2016;
AJC-18111
5
-Amino-3-methylisoxazole is an important intermediate in medicinal chemistry. Bulk scale synthesis of it is reported and the reaction
yields are typically around 40 %. The reaction of 3-aminocrotonitrile and hydroxylamine hydrochloride in aqueous environment in about
2 h at room temperature results in 5-amino-3-methylisoxazole. This simple one pot synthesis has an issue, which contributes to lower
1
reaction yields. The melting point of 5-amino-3-methylisoxazole is 83-85 °C, but around 70 °C it can rapidly decompose causing an
explosion. Hence, this molecule is synthesized by maintaining reaction temperature at 0-25 °C. Due to exothermic nature of the reaction,
maintenance of lower temperature is mandatory. Due to lower reaction temperature, this reaction yields are usually low. Though these
kind of lower yields are reported for synthesis of this class of compounds, attempts to improve the reaction yields are sparse. We report
silica coated magnetic nanoparticle (Fe
is around 80 %, almost double the reported yield and it is enabled by the 40 nm Fe
3
O
4
@SiO
2
) as an inert surface for preparation of 5-amino-3-methylisoxazole. The yield of reaction
@SiO particles. The 40 nm Fe @SiO are
3
O
4
2
3
O
4
2
synthesized by modification to the famous “Stober” protocol. The obtained 40 nm particles contain intermittent particles with about 200
nm as reported in literature. Though isolation of 40 nm size magnetic nanoparticles in reactions is difficult, presence of about 200 nm size
Fe
3
4
O @SiO
2
is enabling for easy isolation. The work up of reaction is simple isolation of Fe
3
O
4
@SiO by magnet, basification of reaction
2
mixture to pH 10, dissolving the precipitated solid in diethyl ether, removal of ether to obtain crude 5-amino-3-methylisoxazole, which
was recrystallized using distilled water. This protocol paves way for simple synthesis of related isoxazoles, which are increasingly
forming base structure for many drugs and medicinal chemistry leads.
Keywords: 5-Amino-3-methylisoxazole, Magnetite nanoparticles, Fe
3
O
4
@SiO , Silanization, Tetraethyl orthosilicate.
2
this molecule did not have much reported methods for
improvement of its yield. The mechanism as shown in Scheme-
II, requires the N-O bond formation and is a rate limiting step.
Use of solid supports for isoxazole ring cyclization are less
INTRODUCTION
Isoxazoles are an interesting functional group for medi-
cinal chemistry [1-4], bringing two hetero atoms to the drug
molecule. Though excess presence of heteroatoms in mole-
cule violates Lipinski rule of five [5-8], now most medicinal
chemistry leads are based on heteroatoms [9-12]. 5-Amino-3-
methylisoxazole [13-15] is a starting material mostly used for
introduction of isoxazole ring on a lead molecule. Fig. 1 shows
the isoxazole base ring with functional groups: acid (1a, 1b),
acid chloride (1c, 1d), bromo (1e), cyano (1f), etc.
Scheme-I shows the most favoured synthetic route for
-amino-3-methylisoxazole. The starting materials are hydroxyl-
amine hydrochloride [16-18] and 3-aminocrotonitrile [19-21]
and are used in a one pot synthesis in aqueous environment.
Reaction is typically performed for overnight, maintaining
known and silica coated magnetic nanomaterials (Fe
are not reported in literature. Fe @SiO is an inert material
and around 100 nm size are widely used in organic chemistry
as solid support [24-27]. Fe @SiO is especially useful for
3 4 2
O @SiO )
O
3 4
2
O
3 4
2
lowering reaction temperature [28], improving yields [29,30],
elimination of reaction steps [31] and reported to catalyze
formation of some key organic products [32,33]. In case of 5-
amino-3-methylisoxazole, the molecule melts at 82-84 °C, but
occasionally decomposes explosively at around 70 °C [34].
Hence, the reaction cannot be allowed to cross room temperature
due to exothermic nature of condensation of hydroxylamine
and 3-aminocrotonitrile. The maintenance of 0-25 °C reaction
temperature reduces the yield of the reaction and is thermody-
namically maintained at around 50 %. The aim of this study
5
0
-25 °C and the typical reaction yields are 40-50 %. Though
catalysts for similar cyclization reactions are reported [22,23],

Vol. 29, No. 1 (2017)
Bulk Synthesis of 5-Amino-3-methylisoxazole Using Silica Coated Magnetite Nanoparticles 125
HO
is to improve reaction yields to around 80 % using reusable
40 nm size Fe O @SiO particles in a one pot synthesis.
O
COOH
3
4
2
H C
3
EXPERIMENTAL
All the starting materials are laboratory reagent grade with
minimum of 98 % purity and purchased from Sigma-Aldrich.
Organic solvents are of analytical grade and THF used is a
dry grade solvent. The magnetite nanoparticle characteriz-
ation done with IR spectroscopy, SEM and TEM. Organic
molecules synthesized by using magnetite nanoparticles were
characterized by NMR, Mass spectrometry and elemental
analysis.
NH2
N
N
O
b
O
a
1
1
COCl
Cl
O
H C
3
N
NH2
O
Synthesis of silanized magnetite nanoparticles
N
1
c
O
Preparation of magnetite nanoparticles (MNPs): 17 g
of sodium nitrate and 10 g of sodium hydroxide were taken in
a clean, dry, three necked round bottom flask and to that 950
mL of distilled water was added. This was degassed using argon
gas and heated for 30 min on water bath at 90 °C. This mixture
was cooled to ≤ 60 °C. In a separate beaker, 1 mL of 2 M
sulfuric acid was added to 13.9 g of ferrous sulphate, dissolved,
made up to 100 mL. The iron sulfate solution was added to
the above mixture slowly with a constant flow rate. Black
magnetic nanoparticles formation was observed. Continued
the degassing for 5 min and heated for 4 h at 90 °C under
argon atmosphere. The hot reaction contents were transferred
into a beaker, left on a magnet for 15 min. After the magnetic
nanoparticles settled at the bottom of flask and the resultant
clear supernatant was decanted. To remove the unreacted
sodium hydroxide, distilled water was added, swirled, allowed
the contents to settle down and supernatant was discarded.
Washes are given till the pH of the medium reached below 7.5
1
d
CN
Br
Ph
NR2
N
N
O
O
1
e
1
f
Fig. 1. Common medicinal chemistry precursors for introduction of
isoxazole ring in leads
H C
3
C
N
NH
2
NH OH·HCl
2
N
O
NH
-aminocrotononitile
Scheme-I: Reaction of 5-amino-3-methylisoxazole
3
5-amino-3-methyl isoxazole
Fe
3
O
4
@SiO
2
N
H
NH OH
C
N
C
N
2
H O
2
O
O
NH OH
O
2
NH
NH2
3-iminobutyronitrile
Fe
3
O
4
@SiO
2
H
N
H
NH2
N
H
-
H O
2
N
O
N
O
OH
N
O
5
-amino-3-
H
H
methylisoxazole
Scheme-II: Mechanism of formation of 5-amino-3-methylisoxazole and role of silica surface in enhancement of rate of ring cyclization. 3-
aminocrotonitrile undergoes hydrolysis where imine group converted to ketone group. Ammonium hydroxide attack on carbon of
CN group. Lone pair of nitrogen attack on carbonyl carbon. Elimination of water molecule and rearrangement of hydrogen takes
place. The silica surface due to its acidic nature polarizes the hetero atom and hence the nucleophilic attack on the parent carbon
atom

126 Reddy et al.
Asian J. Chem.
and it indicated complete removal of unreacted sodium hydro-
xide. The yield obtained is about 10 g.
Silanization of magnetite nanoparticles: In a beaker,
8
00 mL of ethanol and 200 mL of water were taken, pH is
maintained at 12 using sodium hydroxide and was added to
magnetite nanoparticles. The solution was sonicated for 60
min for removal of lumps. To the above solution, 10 mL of
tetraethyl orthosilicate (dissolved in 20 mL of ethanol) was
added. Further sonication was continued for 1 h. The sonicated
Fe
3
O
4
@SiO solution was allowed to settle on magnet for 30
2
min and supernatant was discarded. The particles are washed
with distilled water (3 × 200 mL) till the pH was reached below
7
.5. Fig. 2 shows the procedure of silanization magnetite
Fig. 3. SEM image of Fe
3
O
4
@SiO
2
magnetic nanoparticles. The magnetite
nanoparticles.
nanoparticle are not coated with any surfactant and the aggregation
observed is expected. A mere mechanical stirring or ultra-sonication
in a solvent is used to suspend these particles just before the reaction.
The arrow marked magnetite nanoparticle are about 180 nm particles
and rest of the particles are of 40 nm size. The role of 180 nm
particle is increase the magnetism to isolate particles during the
reaction
TEOS/EtOH
Ultrasonication
Fig. 2. Conventional silanization procedure for magnetite nanoparticles.
The procedure involved addition of TEOS during sonication and
the resultant magnetite nanoparticle are of uniform size. The
significant deviation from reported silanization procedures is that,
the magnetite nanoparticle did not require calcination and the SiO
obtained is uniform for all synthetic purposes. To use Fe @SiO
2
3
O
4
2
as catalyst for bulk synthesis, elimination of calcination step was
very crucial
2
+
3+
Removal of traces of Fe and Fe : The magnetite nano-
2+
3+
particle synthesized by this method has traces of Fe or Fe
2+
3+
ions. The traces of unreacted Fe and Fe were removed by
refluxing in 0.3 M citrate at pH 6 and 10 mM tris containing 1
Fig. 4. TEM image of synthesized 40 nm magnetic nanoparticles. The dark
structure is the magnetic core and the light coloured layer is the
silica coating. The ideal performance of 40 nm particle for bulk
scale synthesis was probably obtained because of the appropriate
magnetism and improved surface area
mM EDTA at pH 8. For citrate wash, Fe
3
O
4
@SiO were mixed
2
with 200 mL of 0.3 M citrate buffer (pH 6) in round bottom
flask and heated for 0.5 h at 90 °C. After the solution was
cooled, water wash is given three times and Fe
separated using magnet. For Tris-EDTA wash, Fe
were mixed with 200 mL of 10 mM tris, 1 mM EDTA (pH 8)
and heated for 0.5 h at 90 °C. The Fe @SiO were separated
3 4
O @SiO
2
were
O
3 4
@SiO
2
O
3 4
2
using magnet and washed three times with distilled water.
Magnetite nanoparticles were stored in distilled water and prior
to use, separated using magnet, dried in oven at 250 °C for
2
4 h. The obtained Fe
3
O
4
@SiO at this stage are around 40 nm
2
in size and the SEM images were shown in Fig. 3 and TEM
images were shown in Fig. 4. Fig. 5 shows IR spectra before
and after silanization.
Synthesis of 5-amino-3-methylisoxazole: 186.9 g (2.69
mol) of hydroxylamine hydrochloride and 150 g (1.8 mol)
4000
3000
2000
1500
1000
500
Fig. 5. IR spectra of magnetite nanoparticles before and after silanization.
Infrared (IR) spectral characterization of silanized (Blue) and non-
3
-amino crotonitrile was mixed in 3 L of water and taken in
flask, stirred for overnight. After 12 h of reaction, the reaction
was basified to pH 10 with 25 g of sodium carbonate. The
insoluble material was filtered, stirred in 600 mL of ether and
filtered. The obtained ether filtrate was combined with aqueous
filtrate. The ether layer was separated and the aqueous layer
was extracted with ether (2 × 300 mL). The ether layer was
-1
silanized magnetite nanoparticle (Green). The 1100-1200 cm peak
is characteristic of silanization and as reported it is one of the easiest
ways to characterize
KOH under vacuum. The solid was recrystallized from water
to give cream (pale pink) fine crystalline solid which was
collected on porcelain and washed with chilled water and dried.
Melting point reported 83-85 °C, obtained 82-84 °C.Yield 50 %.
combined, dried over anhydrous MgSO
4
(125 g), filtered and
stripped under vacuum to leave a solid which was dried over

Vol. 29, No. 1 (2017)
Bulk Synthesis of 5-Amino-3-methylisoxazole Using Silica Coated Magnetite Nanoparticles 127
Synthesis of 5-amino-3-methylisoxazole using 40 nm
size Fe @SiO : 186.9 g (2.69 moles) of hydroxylamine
hydrochloride, 150 g (1.8 mol) 3-amino crotonitrile and 30 g
1 % w/v) Fe @SiO was mixed in 3 L of water stirred for
the saved mother liquor, organic layer is separated, dried over
MgSO and concentrated under vacuum around 30 °C. It is
observed that upto 10 % of product is remained in saved
aqueous layer and the final ether wash is critical in obtaining
3
O
4
2
4
(
3
O
4
2
overnight in flask. After 12 h of reaction, the magnetic nano-
particles were removed using an external barium ferrite
magnet. The reaction mixture was alkalized to pH 10 using 25
g of sodium carbonate. The mixture was filtered, the solids
are stirred with 600 mL of ether and filtered. The obtained
ether filtrate was combined with aqueous filtrate, ethereal layer
was separated. The aqueous layer was extracted with ether
final yield close to 80 %. The Fe
washed with boiler water and reused.
Reaction yield improvement of 5-amino-3-methyl-
isoxazole: We could obtain a 30 % yield improvement in reac-
3
O
4
@SiO particles can be
2
tions by using 40 nm size Fe
3 4
O @SiO nanomaterials without
2
altering the reported reaction conditions. We also could observe
that the 40nm particles seems to be important and our experi-
ments with 100-120 nm traditional
(
2 × 300 mL), the ether layer was dried over anhydrous MgSO
125 g), organic solvent stripped under vacuum to leave a solid
4
(
Fe
O
3 4
@SiO has resulted only in marginal improvement
2
which was dried over KOH under vacuum. The solid was
recrystallized from water to give cream (pale pink) fine crysta-
lline solid which was collected on porcelain, washed with cold
as shown in Table-1. The improvement in reaction yields with
decrease in size of nanoparticles is in line with other published
observations.
water and dried. Melting point reported 83-85 °C, observed
1
8
3
4
2-84 °C. Yield 80 %, H NMR (CDCl
3
, 400 MHz): 2.25 (s,
TABLE-1
13
REACTION YIELDS OF 5-AMINO-3-METHYLISOXAZOLE
USING CONVENTIONAL ORGANIC SYNTHESIS AND
BY OUR NANOMATERIAL CATALYST
H, CH
00 MHz): 168.4, 164, 96.5 and 14.2, Mass 97.1 (M+1),
O (%): C-48.97, H-6.16, N-28.56 and
3
2
), 4.9 (s, 2H, NH ), 5.0 (s, 1H, CH). C NMR (CDCl
3
,
Elemental anal: C
H N
4 6 2
Conventional
synthesis
40 nm Size
MNPs@SiO2
100 nm Size
MNPs@SiO2
Scale
O-16.31. Found: C-48.4, H-5.98, N-28.2 and O-16.28.
1
g
43 ± 2 (n = 2)
47 ± 3 (n = 2)
44 ± 2 (n = 2)
72 ± 4 (n = 2)
74 ± 3 (n = 3)
80 ± 5 (n = 2)
54 ± 2 (n = 2)
52 ± 2 (n = 2)
48 ± 1 (n = 2)
RESULTS AND DISCUSSION
10 g
100 g
Synthesis and characterization of Fe
netite (Fe ) nanoparticles are synthesized by a modification
of Stober’s method [35]. Silanization of Fe was performed
3
O
4
@SiO
2
: Mag-
O
3 4
Mechanism of action of Fe
3
O
4
@SiO
2
particles: Silica
O
3 4
surface is a partially acidic surface and rarely reported to aid
in isoxazole formation. The main mechanism could be offer
of solid support for reaction at the temperature of 0-25 °C and
plays a major role in yield improvement. Use of montromalite
clay [37], silica [38] and alumina [39] are reported to perform
similar role in synthesis of other organic compounds [40,41],
especially for nitro compounds [42]. For isoxazole synthesis
also similar inert solid support catalysts are supported [43,44]
and the reaction mechanism shown in Scheme-II suggests that
acidic nature of silica surface might have a role in reaction
yield improvement.
using TEOS/EtOH system using ultra sonication. The SEM
image (Fig. 3) shows that the typical size of nanoparticles is
around 40 nm. There are about 180 nm big particles occa-
sionally present as shown in Fig. 3 and it reported that during
nucleation, this does happen with magnetic particles [36]. We
also use mild mixing during nucleation step for obtaining
majority of 40 nm particles. In this process, we provide a fine
stream of nitrogen/argon gas and this could have resulted in
non-uniform nucleation at the walls of the round bottom flask
causing the formation of 180 nm particles.
The Fe
in TEM image shown in Fig. 4. This is one of the few instances
where the uniform silica coating is obtained on a Fe core
O
3 4
core and the uniform silica coating are visible
Conclusion
O
3 4
We report almost a 30 % yield improvement for synthesis
particles without calcination. The reason for the same is (a)
Use of ultra-sonication instead of mechanical stirring for
mixing of particles. (b) Controlling the rate of TEOS hydrolysis
by using mild conditions for hydrolysis. It was reported in
literature that this kind of slow hydrolysis often results in non-
of 5-amino-3-methylisoxazole using 40 nm Fe
3
O
4
@SiO
2
nanoparticles. The inert catalysts could play significant role
in reaction yield improvement for pharmaceutically important
molecules and the uniqueness of this reported protocol will
have significant impact on bulk drug synthesis.
Fe
effects.
Synthesis of 5-amino-3-methylisoxazole by using
@SiO : Hydroxylamine hydrochloride, 3-amino croto-
nitrile and Fe @SiO particles are taken in water and the
3
4
O , only silica nanoparticles, but we didn’t notice any such
ACKNOWLEDGEMENTS
This study is supported by a grant for Dr. Pullela from
Vision Group on Science & Technology (VGST), Government
of Karnataka, India under the ‘Seed Money toYoung Scientists
for research (SMYSR)’scheme vide grant No:VGST/SMYSR/
GRD-444/2014-2015.
Fe
3
O
4
2
O
3 4
2
reaction temperature is maintained at 0-25 °C. A mechanical
stirrer is used for uniform mixing and the reaction was
continued for 6 h and the Fe
3
O
4
@SiO particles were separated
2
by a magnet. The reaction mixture was basified and filtered.
The caution need to be taken to maintain pH around 10 and
the filtrate is saved for second crop. The precipitated solid
contains most of the product and is suspended in diethyl ether
and organic solution is filtered. The ether layer is mixed with
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