Aerobic oxidative synthesis of 3,5-disubstituted isoxazoles directly from α,β-unsaturated ketones

Article abstract of DOI:10.3184/174751916X14744677622496

Using an efficient aerobic oxidative method, the synthesis of ten 3,5-disubstituted isoxazoles by treatment of α,β-unsaturated ketones with hydroxylamine and NaOH at room temperature has been achieved.

Full text of DOI:10.3184/174751916X14744677622496

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 OCTOBER, 643–644
RESEARCH PAPER 643
Aerobic oxidative synthesis of 3,5-disubstituted isoxazoles directly from
α,β-unsaturated ketones
Zheng Li*, Gong Wen, Rugang Fu and Jingya Yang
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, P.R. China
Using an efficient aerobic oxidative method, the synthesis of ten 3,5-disubstituted isoxazoles by treatment of α,β-unsaturated ketones
with hydroxylamine and NaOH at room temperature has been achieved.
Keywords: α,β-unsaturated ketone, hydroxylamine, aerobic oxidation, 3,5-disubstituted isoxazole
Isoxazoles have attracted much attention as a result of
their diverse biological activities, including antibacterial,1
antimalarial,2 antifungal,3 anticancer4 and antioxidant5
behaviours. In fact, the isoxazole framework is a frequent
structural motif in natural products. Due to the presence of
a comparatively weak N–O bond, isoxazoles can be readily
transformed into useful structures such as α-hydroxy-β-
diketones and other β-dicarbonyl compounds.6
Reported methods that have been employed for the synthesis
of isoxazoles, include (i) the oxidation of chalcone oximes,7
(ii) the reaction of N-hydroxy-4-toluenesulfonamide with α,β-
unsaturated aldehydes/ketones,8 (iii) cycloaddition of nitrile
oxides to terminal acetylenes,9,10 (iv) four-component coupling
of a terminal alkyne, hydroxylamine, carbon monoxide and
an aryl iodide,11 (v) intramolecular cyclisation of alkynone
O-methyloximes12,13 and (vi) the [3 + 2] cycloaddition of
aromatic imidoyl chlorides to terminal alkynes.14
However, the commonest methods usually involve the use
of expensive or commercially unavailable oxidants, such as
o-iodoxybenzoic acid (IBX),15 MnO2,16 Selectfluor17 and t-butyl
hypoiodite (t-BuOI),18 which largely limit the wide applications
of this method to the chemical industry.
Here, we report a convenient and simple method for the
synthesis of 3,5-disubstituted isoxazoles directly from α,β-
unsaturated ketones using air as the oxidant.
obtained by using DMSO as solvent (Table 1, entry 6). Moreover,
some transition metal compounds such as CuCl, CuI, AgI and
FeCl3 were also examined for catalytic activity, but no obvious
improvement to the yield was observed (data not tabulated).
In addition, it is important to mention that keeping the reaction
exposed to the air at 100 C was also an essential condition for
the reaction.
Using these optimised conditions, a series of α,β-unsaturated
ketones were investigated and the yields of the corresponding
3,5-disubstituted isoxazoles are shown in Table 2. It was found
that α,β-unsaturated ketones with either electron-donating
o
Table 1 The effect of reaction conditions (base, solvent, temperature) on
the yield of 3,5-diphenylisoxazole (2a, R1 = R2 =Ph) (Scheme 1)a
Entry Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
MeCN
EtOH
1,4-Dioxane
PhMe
Temp./oC
100
100
100
100
100
100
100
80
Yield/%b
1
–
0
86
82
65
85
88
80
63
0
2
3
4
5
t-BuONa
t-BuOK
NaHCO3
KOH
6
7
8
9
10
11
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
80
100
100
0
0
Results and discussion
aReaction conditions: 1a (0.5 mmol), HONH3Cl (1.0 mmol) and base (2.0 mmol) were
stirred at the appropriate temperature for 8 h in solvent (5 mL) under air.
bIsolated yields.
Our plan was to react an α,β-unsaturated ketone with HONH2 in
the presence of a base in a suitable solvent in which autoxidation
could occur (Scheme 1). We chose chalcone (1a, R1 = R2 = Ph)
as a model substrate and it was found that its reaction with
HONH3Cl in the presence of t-BuONa using DMSO under air
could produce 3,5-diphenylisoxazole (2a, R1 = R2 = Ph) by a
one-step procedure in 86% yield (Table 1, entry 2).
Other bases were investigated and of t-BuOK, NaHCO3, KOH
and NaOH (Table 1, entries 3−6), NaOH was the most suitable
base for the reaction (Table 1, entry 6). No reaction was observed
in the absence of base (Table 1, entry 1).
Table 2 Yields of 3,5-disubstituted isoxazoles 2a–j prepared by the
aerobic oxidative method (Scheme 1)a
Compound R1
R2
C6H5
4-FC6H4
3-BrC6H4
S
Yield/%b
88
81
2a
2b
2c
C6H5
C6H5
C6H5
83
2d
C6H5
80
The choice of solvent was found to be important. Reaction in
EtOH, 1,4-dioxane or PhMe gave no product (Table 1, entries
9−11), but DMSO, DMF and MeCN were effective solvents for
the reaction (Table 1, entries 6−8). However, the best yield was
2e
2f
2g
2h
2i
4-CH3OC6H4
4-FC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
O
C6H5
C6H5
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
74
78
83
82
77
O
N
O
HONH3Cl,NaOH
Solvent, heat, air
R2
2j
C6H5
76
R1
R2
R1
O
2a–j
aReaction conditions: 1 (0.5 mmol), HONH3Cl (1.0 mmol) and NaOH (2.0 mmol) were
stirred at 100 oC for 8 h in DMSO (5 mL) under air.
bIsolated yields.
1a–j
Scheme 1 Aerobic oxidative synthesis of 3,5-disubstituted isoxazoles.
* Correspondent. E-mail: lizheng@nwnu.edu.cn

644 JOURNAL OF CHEMICAL RESEARCH 2016
3,5-Bis(4-methoxyphenyl)isoxazole (2g): Grey solid; m.p.
134−136 oC (lit.15 142−143 oC); 1H NMR (400 MHz, CDCl3): δ
7.75−7.80 (m, 4H, ArH), 6.98 (d, J = 8.4 Hz, 4H, ArH), 6.65 (s, 1H,
CH), 3.86 (s, 6H, OCH3); 13C NMR (100 MHz, CDCl3): δ 170.1, 162.5,
161.1, 160.9, 128.1, 127.4, 121.8, 120.4, 114.4, 114.3, 95.9, 55.4, 55.3.
Anal. calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; found: C, 72.51;
H, 5.35; N, 5.00%.
(CH3, CH3O) or electron-withdrawing (F, Cl, Br) groups on
either of the aromatic rings could be converted successfully
into the corresponding products 2b, 2c, and 2e–j in good to
high yields. In addition, an α,β-unsaturated ketone bearing a
heterocyclic group (thiophen-2-yl) could also be converted into
the corresponding product 2d in a satisfactory yield.
The mechanism for the aerobic oxidative synthesis of
3,5-disubstituted isoxazoles is unknown.
5-(4-Methoxyphenyl)-3-(p-tolyl)isoxazole (2h): Grey solid; m.p.
o
1
142−144 C; H NMR (600 MHz, CDCl3): δ 7.80 (d, J = 8.6 Hz, 2H,
ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.27 (d, J = 8.0 Hz, 2H, ArH), 6.99
(d, J = 8.6 Hz, 2H, ArH), 6.71 (s, 1H, CH), 3.85 (s, 3H, OCH3), 2.40 (s,
3H, CH3); 13C NMR (150 MHz, CDCl3): δ 170.3, 162.5, 161.0, 140.4,
129.6, 128.2, 127.4, 126.7, 125.7, 114.3, 96.7, 55.3, 21.5. Anal. calcd
for C17H15NO2: C, 76.96; H, 5.70; N, 5.28; found: C, 76.88; H, 5.69; N,
5.30%.
Experimental
1H NMR and 13C NMR spectra were obtained with a Mercury-400BB
or Mercury-600BB spectrometer using CDCl3 as solvent and Me4Si as
the internal standard. Elemental analyses were performed on a Vario
El Elemental Analysis instrument. Melting points were observed using
an Electrothermal melting point apparatus. α,β-Unsaturated ketones
were prepared according to a literature procedure.19
3-(4-Chlorophenyl)-5-(4-methoxyphenyl)isoxazole (2i): Grey solid;
o
1
m.p. 130−132 C; H NMR (400 MHz, CDCl3): δ 7.75−7.80 (m, 4H,
ArH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 6.99 (d, J = 8.4 Hz, 2H, ArH), 6.67
(s, 1H, CH), 3.87 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): δ 170.7,
161.9, 161.2, 135.9, 129.1, 128.9, 128.0, 127.8, 127.4, 126.8, 120.1, 114.4,
95.9. 55.4. Anal. calcd for C16H12ClNO2: C, 67.26; H, 4.23; N, 4.90;
found: C, 67.37; H, 4.23; N, 4.88%.
Preparation of 3,5-disubstituted isoxazoles; general procedure
A
mixture of α,β-unsaturated ketone (0.5 mmol), HONH3Cl
(1.0 mmol) and NaOH (2.0 mmol) in DMSO (5 mL) was stirred
o
under air at 100 C for 8 h. After completion of the reaction, the
resulting mixture was cooled to room temperature, diluted with ethyl
acetate and washed with saturated sodium carbonate solution. The
resulting organic phase was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was isolated
by column chromatography using petroleum ether (boiling point:
60–90 °C)/ethyl acetate (10:1) as eluent to give the pure product.
3,5-Diphenylisoxazole (2a): White solid, m.p. 138−139 oC (lit.15
140−142 oC); 1H NMR (600 MHz, CDCl3): δ 7.87 (d, J = 6.5 Hz, 2H,
ArH), 7.83 (d, J = 7.1 Hz, 2H, ArH), 7.44−7.49 (m, 6H, ArH), 6.82 (s,
1H, CH); 13C NMR (150 MHz, CDCl3): δ 170.4, 163.0, 130.2, 130.0,
129.1, 129.0, 128.9, 127.5, 126.8, 125.8, 97.4. Anal. calcd for C15H11NO:
C, 81.43; H, 5.01; N, 6.33; found: C, 81.34; H, 4.99; N, 6.35%.
5-(Benzo[d][1,3]dioxol-5-yl)-3-phenylisoxazole (2j): Grey solid;
m.p. 128−130 oC; 1H NMR (600 MHz, CDCl3): δ 7.85 (d, J = 7.9 Hz,
2H, ArH), 7.46 (d, 3H, ArH), 7.37 (d, J = 8.0 Hz, 1H, ArH), 7.29 (s,
1H, ArH), 6.90 (d, J = 8.0 Hz, 1H, ArH), 6.69 (s, 1H, CH), 6.04 (s, 2H,
CH2); 13C NMR (150 MHz, CDCl3): δ 170.1, 162.9, 149.3, 148.2, 130.0,
129.2, 128.9, 126.8, 121.6, 120.5, 108.6, 106.2, 101.6. 96.5. Anal. calcd
for C16H11NO3: C, 72.45; H, 4.18; N, 5.28; found: C, 72.56; H, 4.19; N,
5.30%.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21462038, 21362034) and the Key Laboratory of Eco-
Environment-Related Polymer Materials, Ministry of Education
for the financial support of this work.
3-(4-Fluorophenyl)-5-phenylisoxazole (2b): Grey solid; m.p.
o
1
112−114 C; H NMR (600 MHz, CDCl3): δ 7.83−7.87 (m, 4H, ArH),
7.46−7.51 (m, 3H, ArH), 7.17 (t, J = 8.6 Hz, 2H, ArH), 6.79 (s, 1H, CH);
13C NMR (150 MHz, CDCl3): δ 165.4, 159.5, 157.8, 156.8, 125.1, 123.8,
123.6, 123.5, 120.6, 110.9, 110.8, 92.1. Anal. calcd for C15H10FNO: C,
75.30; H, 4.21; N, 5.85; found: C, 75.39; H, 4.20; N, 5.87%.
Received 18 June 2016; accepted 5 August 2016
Paper 1604154 doi: 10.3184/174751916X14744677622496
Published online: 27 September 2016
3-(3-Bromophenyl)-5-phenylisoxazole (2c): Grey solid; m.p.
128−130 oC; 1H NMR (600 MHz, CDCl3): δ 8.02 (s, 1H, ArH),
7.80−7.84 (m, 3H, ArH), 7.59 (d, J = 7.8 Hz, 1H, ArH), 7.47−7.51 (m,
3H, ArH), 7.35 (t, J = 7.9 Hz, 1H, ArH), 6.81 (s, 1H, CH); 13C NMR
(150 MHz, CDCl3): δ 170.8, 161.7, 132.9, 131.1, 130.5, 130.4, 129.8,
127.2, 125.8, 125.3, 123.0, 97.3. Anal. calcd for C15H10BrNO: C, 60.02;
H, 3.36; N, 4.67; found: C, 59.88; H, 3.35; N, 4.65%.
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1
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5-(4-Methoxyphenyl)-3-phenylisoxazole (2e): Grey solid; m.p.
o
o
1
132−134 C (lit.7 120−121 C); H NMR (600 MHz, CDCl3): δ 7.83
(d, J = 6.5 Hz, 2H, ArH), 7.81 (d, J = 8.6 Hz, 2H, ArH), 7.45−7.50 (m,
3H, ArH), 7.02 (d, J = 8.6 Hz, 2H, ArH), 6.78 (s, 1H, CH), 3.86 (s, 3H,
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5-(4-Fluorophenyl)-3-phenylisoxazole (2f): Grey solid; m.p.
o
1
116−118 C; H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 7.7 Hz, 1H,
ArH), 7.86 (d, J = 7.7 Hz, 2H, ArH), 7.62−7.66 (m, 2H, ArH), 7.51 (d,
J = 7.7 Hz, 2H, ArH), 7.18 (t, J = 8.1 Hz, 2H, ArH), 6.78 (s, 1H, CH);
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128.6, 128.5, 127.9, 126.8, 116.3, 97.3. Anal. calcd for C15H10FNO: C,
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