2
M. Koufaki et al. / Ultrasonics Sonochemistry xxx (2013) xxx–xxx
When only copper turnings were used, copper was filtered off,
2. Experimental
the solvent was evaporated in vacuo and the crude product was
purified by column chromatography.
2.1. Material and methods
All starting materials and common laboratory chemicals were
purchased from commercial sources and used without further
purification. 1H NMR spectra were recorded on Varian spectrome-
ters operating at 300 MHz or 600 MHz and 13C spectra were re-
corded at 75 MHz using CDCl3 as solvent. Silica gel plates
Macherey–Nagel Sil G-25 UV254 were used for thin layer chroma-
tography. Chromatographic purification was performed with silica
gel (200–400 mesh). Mass spectra were obtained on HPLC–MSn
Fleet-Thermo, in the ESI mode. HRMS spectra were recorded, in
the ESI mode, on UPLC-MSn Orbitrap Velos-Thermo.The ultra-
sound-assisted reactions were carried out in a FALC INSTRUMENTS
s.r.l, bath cleaner LBS2, 4.5 Lt, (40 kHz, 59 kHz, 250 W) and a Sonics
& Material INC. Vibra-Cell VCX130 Titanium alloy Ti-6Al-4 V probe
(20 kHz, 130 W) with 2 mm tip diameter. The reaction tube was lo-
cated in the maximum energy area in the bath and the tempera-
ture was 60 °C. When combined ultrasound experiments were
performed, the probe was immerged in the tube, which was placed
in the ultrasonic bath (Fig. 1).
2.2.1. 3-(4-Methoxyphenyl)-5-phenyl-isoxazole [14]
White solid. TLC (pet. ether/ethyl acetate, 90:10) Rf = 0.5, 1H
NMR (600 MHz, CDCl3) d: 7.83–7.80 (m, 4H, ArH), 7.48–7.44 (m,
3H, ArH), 6.99 (d, J = 8.7 Hz, 2H, ArH), 6.77 (s, 1H, H-isoxazole),
3.86 (s, 1H, OCH3), 13C NMR (75 MHz, CDCl3) d: 170.1, 162.6,
161.0, 130.1,129.0, 128.2, 127.5, 125.8, 121.6, 114.3, 97.3, 55.4,
MS m/z: 524.60 (2 M + Na)+.
2.2.2. 3-(4-Methoxyphenyl)-5-propyl-isoxazole [15]
Yellowish oil, TLC (pet. ether/ethyl acetate, 90:10) Rf = 0.6, 1H
NMR (300 MHz, CDCl3) d: 7.73 (d, J = 8.8 Hz, 2H, ArH), 6.96 (d,
J = 8.8 Hz, 2H, ArH), 6.23 (s, 1H, H-isoxazole), 3.85 (s, 1H, OCH3),
2.75 (t, J = 7.5 Hz, 2H, CH3CH2CH2-), 1.83–1.71 (m, 2H, CH3CH2CH2-
), 1.02 (t, J = 7.4 Hz, 3H, CH3CH2CH2-), 13C NMR (75 MHz, CDCl3) d:
173.8, 161.9, 160.8, 128.1, 121.9, 114.2, 98.6, 55.3, 28.7, 21.0, 13.7,
MS m/z: 218.11 (M + H)+, 456.62 (2 M + Na)+.
2.2.3. 3-(4-Fluorophenyl)-5-phenylisoxazole [16]
White solid, TLC (pet. ether/ethyl acetate, 90:10) Rf = 0.5, 1H
NMR (600 MHz, CDCl3) d: 7.86–7.82 (m, 4H, ArH), 7.50–7.45 (m,
3H, ArH), 7.16 (t, J = 8.6 Hz, 2H, ArH), 6.78 (s, 1H, H-isoxazole),
13C NMR (75 MHz, CDCl3) d: 170.6, 165.5, 162.0, 130.3, 129.0,
128.7, 127.3, 125.8, 116.2, 115.9, 97.3, MS m/z: 240.08 (M + H)+.
2.2. General procedure for preparation of 3,5-disubstituted isoxazoles
To a solution of aldehyde (1 eq) and hydroxylamine hydrochlo-
ride (1.05 eq) in a mixture of t-BuOH and H2O (1:1) was added 1 M
aqueous NaOH (1.05 eq). The reaction mixture was stirred at ambi-
ent temperature until thin-layer chromatography indicated con-
sumption of the aldehyde. After oxime formation was complete,
1.05 eq of chloramine-T [N-chloro-4-methylbenzenesulfonamide
sodium salt, TsN(Cl)NaÁ3H2O], was added, followed by CuSO4Á5H2O
(0.3 eq)/sodium ascorbate (0.6 eq) or CuSO4Á5H2O (0.3 eq)/Cu turn-
ings (0.6 eq) or Cu turnings (0.6 eq). Terminal alkyne (1.05 eq) was
then added, the pH of the reaction medium was adjusted to 6 by
addition of few drops of 1 M aqueous NaOH and the mixture was
stirred/heated or irradiated with US as indicated in the Table 1.
The reaction mixture was poured into ice/water and after addition
of 1 M aqueous NH4OH (1 ml), (to remove all copper salts), it was
extracted with AcOEt. The organic layer was washed with brine,
dried over Na2SO4 and concentrated in vacuo. The crude residue
was purified by column chromatography (pet. ether/ethyl acetate,
90:10).
2.2.4. 5-{[(3,4-Dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-
benzopyran-2-yl)methoxy] methyl-3-(4-methoxyphenyl)-isoxazole
[9]
Yellowish oil, TLC (pet. ether/ethyl acetate, 90:10) Rf = 0.3, 1H
NMR (600 MHz, CDCl3) d: d: 7.72 (d, J = 8.7 Hz, 2H, ArH), 6.96 (d,
J = 8.7 Hz, 2H, ArH), 6.47 (s, 1H, H-isoxazole), 4.76–4.70 (m, 2H),
3.84 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.63–3.55 (m, 2H), 2.60 (t,
J = 6.8 Hz, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.04–1.98
(m, 1H), 1.79–1.75 (m, 1H), 1.30 (s, 3H), 13C NMR (75 MHz, CDCl3)
d: 169.7, 161.9, 161.0, 149.7, 147.3, 128.2, 128.0, 125.9, 122.8,
121.4, 117.5, 114.3,114.2, 100.7, 74.9, 64.6, 60.4, 55.3, 28.3, 22.1,
20.2, 12.6, 11.9, 11.7 MS m/z: 438.10 (M + H)+, 460.25 (M + Na)+,
896.67 (2 M + Na)+.
2.2.5. 5-{[(3,4-Dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-
benzopyran-2-yl)methoxy] methyl-3-(3,4-dimethoxyphenyl)-
isoxazole
Colorless oil, TLC (pet. ether/ethyl acetate, 90:10) Rf = 0.2, 1H
NMR (600 MHz, CDCl3) d: 7.40 (s, 1H, ArH), 7.72 (dd, 1H, ArH),
6.91 (d, J = 8.3 Hz, 1H, ArH), 6.48 (s, 1H, H-isoxazole), 4.76–4.68
(m, 2H), 3.94 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.61 (s, 3H, OCH3),
3.62–3.55 (dd, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.17 (s, 3H), 2.12 (s,
3H), 2.08 (s, 3H), 2.01–1.97 (m, 1H), 1.78–1.76 (m, 1H), 1.29 (s,
3H), 13C NMR (75 MHz, CDCl3) d: 169.8, 162.1, 150.6, 149.7,
149.3, 147.3, 128.0, 125.9, 122.8, 121.6, 119.9, 117.4, 111.0,
109.2, 100.7, 74.9, 64.6, 60.4, 56.0, 55.9, 28.3, 22.0, 20.2, 12.6,
11.9, 11.7, MS m/z: 468.08 (M + H)+, 490.25 (M + Na)+, 956.6
(2 M + Na)+ HRMS: calcd for C27H34NO6 (M + H+) 468.2381; found:
468.2375.
3. Results and discussion
Initially, we investigated the 1,3-dipolar cycloaddition of highly
energetic nitrile oxide to alkyne using in situ generation of Cu(I)
moiety from CuSO4Á5H2O and sodium ascorbate in a mixture of
tert-butanol/water in a ratio of 1:1. Thus, commercially available
4-methoxy-benzaldehyde reacted with hydroxylamine hydrochlo-
Fig. 1. Experimental system (bath + probe).
Please cite this article in press as: M. Koufaki et al., Synergistic effect of dual-frequency ultrasound irradiation in the one-pot synthesis of 3,5-disubstituted