J IRAN CHEM SOC
OH
Cl
General procedure for synthesis of 3,5-disubstituted
R2
O
N
CDSCS, NaHCO3
N
isoxazoles using CDSCS
R2
H
R1
i-PrOH/H2O (1:1), r.t.
R1
To a round bottom flask (50 mL), was added a mixture of
alkyne (0.012 mol), CDSCS (0.3 g, 0.05 mol %), the
appropriate imidoyl chloride [53] (0.01 mol), and NaHCO3
(0.012 mol) in a mixture of i-PrOH/H2O (1:1 V/V,
20 mL). The reaction mixture was stirred at room tem-
perature until TLC monitoring indicated no further pro-
gress in the conversion (Table 4). The catalyst was filtered
off, washed with i-PrOH/H2O (1:1 V/V, 3 9 10 mL) and
the filtrate was evaporated under vacuum to remove the
solvent. The remaining foam was dissolved in CHCl3
(100 mL) and subsequently washed with water
(2 9 100 mL). The organic layer was dried (Na2SO4) and
evaporated. The crude product was purified by short col-
umn chromatography on silica gel eluting with n-hex-
SiO2
CDSCS:
OSO3Cu
R1, R2= aryl, alkyl, CH2OH, CH2OAr, ...
Scheme 1 1,3-Dipolar cycloaddition of alkynes and in situ generated
nitrile oxides using CDSCS at room temperature
organic reactions. However, to the best of our knowledge,
there have been no reports yet on the application of het-
erogeneous copper catalyst for cycloaddition reaction
between alkynes and nitrile oxides. Hence, a practical
method for the preparation of 3,5-disubstituted isoxazoles
is still of great interest in organic synthesis. Recently, we
have reported the synthesis, characterization, and appli-
cation of copper-doped silica cuprous sulfate (CDSCS) as
a novel and efficient heterogeneous nano catalyst for the
Cu(I)-catalyzed ‘click’ cycloaddition of organic azides
with terminal alkynes [52]. In continuation of our interest
in discovering the new applications for CDSCS in organic
synthesis hereby, we report that 1,3-dipolar cycloaddition
of structurally diverse alkynes and in situ generated nitrile
oxides can be efficiently achieved using CDSCS in
i-PrOH/H2O (1:1, V/V) at room temperature to afford 3,5-
disubstituted isoxazoles in good to excellent yields
(Scheme 1).
1
ane:EtOAc (10:1). All products were characterized by H
NMR, 13C NMR, IR, CHN and MS analysis. Selected
spectral data for entries 10, 11, 16 and 17 are given below:
5-Pentyl-3-phenylisoxazole (Table 4, entry 10)
Column chromatography on silica gel (EtOAc:n-hexane,
1:10) afforded the product as a colorless foam; yield:
1.87 g (87 %); Rf (EtOAc:n-hexane, 1:10) = 0.48; 1H
NMR (250 MHz, CDCl3): d = 1.09 (t, J = 7.2 Hz, 3H,
CH3), 1.24–1.27 (m, 2H, CH2CH3), 1.35–1.39 (m, 2H,
CH2CH2CH3), 1.71–1.75 (m, 2H, CH2(CH2)2CH3), 2.63 (t,
J = 7.4 Hz, 2H, CH2(CH2)3CH3), 6.38 (s, 1H, C(4)-H,
isoxazole), 7.54–7.61 (m, 5H, aryl); 13C NMR (62.5 MHz,
CDCl3): d = 16.23, 24.67, 32.85, 34.79, 37.15, 101.63,
126.50, 129.46, 130.17, 134.76, 159.28, 170.81; IR (liquid
film): 3087, 2961, 1695, 1542, 1431 cm-1; MS (EI) m/z
(%): 215 (7.3) [M?]; Anal. Calcd for C14H17NO: C, 78.10;
H, 7.96; N, 6.51; Found: C, 78.25; H, 7.89; N, 6.63.
Experimental
General information
All chemicals were prepared from Fluka or Merck
chemical companies. Solvents were purified and dried by
standard procedures, and stored over molecular sieves
0.3 nm. The progress of reaction was followed with TLC
using silica gel SILG/UV 254 plates. Silica gel 60,
0.063–0.200 mm (70–230 mesh ASTM) was used for
column chromatography. IR spectra were run on a Shi-
madzu FTIR-8300 spectrophotometer. The 1H NMR
(250 MHz) and 13C NMR (62.5 MHz) were run on a
Bru¨ker Advanced DPX-250, FT-NMR spectrometer;
Chemical shifts (d) are reported in ppm and coupling
constants (J) in Hz. Mass spectra were recorded on a
Shimadzu GC MS-QP 1000 EX apparatus. Microanaly-
ses were performed on a Perkin–Elmer 240-B microan-
alyzer. Melting points (m.p.) were recorded on a Bu¨chi
510 apparatus in open capillary tubes and are
uncorrected.
3-(4-Methoxyphenyl)-5-pentylisoxazole
(Table 4, entry 11)
Column chromatography on silica gel (EtOAc:n-hexane,
1:10) afforded the product as a colorless foam; yield:
2.08 g (85 %); Rf (EtOAc:n-hexane, 1:10) = 0.35; 1H
NMR (250 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 3H,
CH3), 1.28–1.31 (m, 2H, CH2CH3), 1.37–1.40 (m, 2H,
CH2CH2CH3), 1.73–1.78 (m, 2H, CH2(CH2)2CH3), 2.71 (t,
J = 7.5 Hz, 2H, CH2(CH2)3CH3), 3.79 (s, 3H, OCH3),
6.34 (s, 1H, C(4)-H, isoxazole), 6.92 (d, J = 8.6 Hz, 2H,
aryl), 7.38 (d, J = 8.6 Hz, 2H, aryl); 13C NMR (62.5 MHz,
CDCl3): d = 16.45, 25.13, 33.80, 34.92, 38.31, 56.37,
101.27, 127.64, 130.76, 134.31, 158.49, 162.09, 170.24; IR
(liquid film): 3050, 2975, 1698, 1552, 1446 cm-1; MS (EI)
123