10.1002/adsc.201700881
Advanced Synthesis & Catalysis
give the desired product 2b (0.209 g, 87%) as a white solid.
cyano-3-ethoxyacrylate and ethyl 3-oxobutanoate
using NaOAc as base, but in
Methyl
3-amino-5-(2,4-dichlorophenyl)isoxazole-4-
o
carboxylate (2b). Mp 149-151 C; Rf = 0.59 (hexanes:
EtOAc, 6:4, v/v); IR (KBr) νmax: 1725 (CO2Me), 3321
1
(NH2) cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 3.66 (s,
3H), 4.94 (brs, 2H), 7.30-7.32 (m, 2H), 7.46 (d, J = 1.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 51.9, 102.3,
125.9, 127.1, 129.9, 132.0, 134.7, 137.6, 162.4, 162.5,
169.6. MS (ESI+): m/z = 287.1. ESI-HR-MS calculated for
C11H8Cl2N2O3 (M++H): 286.9990, found: 286.9989.
General procedure for the synthesis of substituted 3-
methoxyisoxazoles (4b-4f) as exemplified for the
synthesis of 4b.
To a stirred solution of methyl 5-(2,4-dichlorophenyl)-3-
nitroisoxazole-4-carboxylate 1b (0.2 g, 0.63 mmol) in
MeOH (4 mL) was added saturated MeOH-NH3 (100 µL)
at room temperature and the reaction was allowed to
continue for 6 h. After completion of the reaction (as
monitored by TLC), the solvent was removed under
vacuum. The crude product thus obtained was purified by
chromatography over a column of silica gel using hexanes/
EtOAc (9.0:1.0, v/v) as eluent to afford the desired product
4b (0.141 g, 74%) as a white solid. Further elution with
hexanes/ EtOAc (7.0:3.0, v/v) gave (.016 g, 9%) of 2b as a
Scheme 8. Synthetic utility of substituted 3-
hydrazinylisoxazoles.
white
solid.
Methyl
5-(2,4-dichlorophenyl)-3-
methoxyisoxazole-4-carboxylate (4b). Mp 149-151 oC; Rf
= 0.66 (hexanes: EtOAc, 8:2, v/v); IR (KBr) νmax: 1731
1
(CO2Me) cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 3.68
(s, 3H), 4.05 (s, 3H), 7.29-7.32 (m, 1H), 7.35 (d, J = 8.3
Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 51.9, 57.8, 102.9, 125.6, 127.1, 130.0,
132.0, 134.7, 137.8, 160.7, 169.7, 171.5. MS (ESI+): m/z =
302.0. ESI-HR-MS calculated for C12H9Cl2NO4 (M++H):
301.9987, found: 301.9982.
both cases the formation of uncyclized products 20
and 21 in 78 % and 81 % yield, respectively was
observed. It is very likely that like 3-
hydrazinylpyrazole,[15] the 3-hydrazinylisoxazole in
solution exist in two tautomeric form which may
disfavour the intramolecular cyclization.
General procedure for the synthesis of substituted 3-
hydrazinylisoxazole as exemplified for the synthesis of
7b.
In summary, we developed a sustainable route to
the synthesis of substituted 3-aminoisoxazoles and 3-
hydrazinylisoxazoles from 3-nitroisoxazoles under
aqueous acetonitrile solution. The methodology that
relies on nucleophilic substitution reaction, does not
involve any work up as the solid product separated
during the reaction could be readily isolated via
filtration. Although the yields were generally
excellent, the strategy works only when the ester
group is present at the C-4 position of the isoxazole.
Nevertheless, the work presented herein updates the
spectrum of 3-amino-derivatives which can be
accessed from alkyl 3-nitro-5-(aryl/ alkyl)isoxazole-
4-carboxylates. Further work to explore the synthetic
applications and biological activity of these new
To a stirred solution of methyl 5-(2,4-dichlorophenyl)-3-
nitroisoxazole-4-carboxylate 1b (0.2 g, 0.63 mmol) in
MeCN/H2O (4 mL, 1:1) was added NH2NH2.H2O (50-
60%) (69 µL g, 1.26 mmol) at room temperature and the
reaction was allowed to continue for 30 min. As the
reaction proceeds the reaction turns to white suspension.
After completion (as determined by TLC), water (20 mL)
was added to the reaction mixture and the separated solid
was collected by filtration, washed with water (3 x 10 mL),
and dried under vacuum overnight to give the desired
product 7b (0.154 g, 81%) as a brown solid. Methyl 5-
(2,4-dichlorophenyl)-3-hydrazinylisoxazole-4-
o
carboxylate (7b). Mp 119-121 C; Rf = 0.45 (hexanes:
EtOAc, 4:6, v/v); IR (KBr) νmax: 1720 (CO2Me), 3305
1
(NH), 3314 (NH2) cm-1. H NMR (400 MHz, CDCl3): δ
(ppm) 3.65 (s, 3H), 3.81 (brs, 2H), 6.57 (brs, 1H), 7.30-
7.31 (m, 2H), 7.46 (d, J = 1.4 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ (ppm) = 51.9, 101.3, 125.5, 127.1, 129.9,
132.0, 134.7, 137.8, 162.0, 165.8, 170.2. MS (ESI+): m/z =
301.9. ESI-HR-MS calculated for C11H9Cl2N3O3 (M++H):
302.0099, found: 302.0095.
substituted
3-aminoisoxazoles
and
3-
hydrazinylisoxazoles is underway and shall be
reported in due course.
Experimental Section
Acknowledgements
General procedure for the synthesis of substituted 3-
aminoisoxazoles (2a-z) as exemplified for the synthesis
of 2b.
Two of the authors SM and DB acknowledge CSIR, New Delhi
whereas IA acknowledge MHRD, New Delhi for the financial
assistance in the form of fellowships. Authors acknowledge the
Sophisticated Analytical Instrumentation facility at this institute
for providing the spectroscopic data. Authors thank Prof.
Sandeep Verma, Indian Institute of Technology, Kanpur for his
help in acquiring the X-Ray analysis data for the crystals. This
work was supported by the funds from CSIR Network project
BSC0114 and SERB grant EMR/2016/0020162. Authors
acknowledge the comments of the reviewers which has improved
the quality of this work.
To a stirred solution of methyl 5-(2,4-dichlorophenyl)-3-
nitroisoxazole-4-carboxylate 1b (0.2 g, 0.63 mmol) in
MeCN/H2O (4 mL, 1:1) was added aq. NH3 (25%) solution
(107 µL, 6.3 mmol) at room temperature and the reaction
was allowed to continue for 16 h at room temperature. The
white solid slurry separated as reaction progressed. After
completion (as determined by TLC), water (20 mL) was
added and the separated solid was collected by filtration,
washed with water (3 x 10 mL), and dried under vacuum to
6
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