One-pot three-component synthesis of 3,5-disubstituted isoxazoles by a coupling-cyclocondensation sequence

Article abstract of DOI:10.3987/COM-14-12965

A convenient one-pot procedure for the synthesis of 3,5-disubstituted isoxazoles from acid chloride, terminal alkyne, and hydroxylamine hydrochloride catalyzed by Pd(PPh₃)₂Cl₂/CuI has been developed. The coupling of acid c

Full text of DOI:10.3987/COM-14-12965

HETEROCYCLES, Vol. 89, No. 5, 2014, pp. -. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 18th February, 2014, Accepted, 26th March, 2014, Published online, 2nd April, 2014
DOI: 10.3987/COM-14-12965
ONE-POT THREE-COMPONENT SYNTHESIS OF 3,5-DISUBSTITUTED
ISOXAZOLES BY A COUPLING–CYCLOCONDENSATION SEQUENCE
Hai-Ling Liu,* Zhu-Feng Geng, Si-Yu Zhang, and Jie Han
Analytical & Testing Center, Beijing Normal University, Beijing 100875, P. R.
China; E-mail: liuhailing@bnu.edu.cn
Abstract – A convenient one-pot procedure for the synthesis of 3,5-disubstituted
isoxazoles from acid chloride, terminal alkyne, and hydroxylamine hydrochloride
3 2 2
catalyzed by Pd(PPh ) Cl /CuI has been developed. The coupling of acid
chlorides to terminal alkynes afforded α,β-unsaturated ynones that underwent in
situ cyclocondensation with hydroxylamines to afford the desired isoxazoles in
4
4–76% isolated yields.
1
A tandem reaction refers to two consecutive reactions in the same reaction vessel. Tandem one-pot
2
3
4
reactions are powerful tools to construct important cyclic compounds such as pyrroles pyrimidines,
5
6
furans, and triazoles. Recently, we reported the tandem reactions for the synthesis of polysubstituted
7
8
tetrahydropyrimidines and pyrazoles. Encouraged by the results, we investigated similar tandem
reactions for other N-containing heterocycles.
Isoxazoles are important five-membered heterocyclic compounds bearing both nitrogen and oxygen
9
atoms and found in diverse natural products. They possess important biological and pharmaceutical
10
11
activities and useful building blocks in organic synthesis. Therefore, the development of new methods
1
2
for their synthesis is of great interest. In general, isoxazoles are prepared by (i) the reaction of
1
3
1
,3-dicarbonyl compounds with hydroxylamine, (ii) the 1,3-dipolar cycloaddition of alkenes and
1
4
15
alkynes with nitrile oxides, (iii) the reaction of hydroxylamines with α,β-unsaturated ketones, and
1
6
other methods. One-pot syntheses of isoxazoles from in situ generated intermediates such as nitrile
17
18
19
20
21
oxides, propargylic N-hydroxylamines, oximes, oxime ether and ynones have been reported.
Unfortunately, certain reagents used in these cases are toxic, air sensitive, difficult to obtain, and
hazardous.
The one-pot synthesis of isoxazoles from inexpensive, safe, and easily available starting materials would
be more facile and efficient. Several methods for the synthesis of ynones by the coupling of acid chlorides

2
2
to terminal alkynes are known. Herein, we report the one-pot synthesis of 3,5-disubstituted isoxazoles
by the cyclocondensation of hydroxylamines with ynones generated in situ from acid chlorides and
terminal alkynes.
First, the reaction of benzoyl chloride 1a with phenylacetylene 2a and hydroxylamine hydrochloride
(
2 3
Table 1) was investigated. When Na CO as the base and acetonitrile (MeCN) as the cosolvent at the
second step, the desired isoxazole 3aa was obtained in only 27% GC yield. The yield of 3aa could be
improved by refluxing the reaction mixture (Table 1, entry 2, 68% yield). Different solvents were
screened to improve the yield of the reaction with hydroxylamine hydrochloride. When water was used as
the cosolvent, 3aa was obtained in 73% yield (Table 1, entry 3). When 1,4-dioxane was used as the
cosolvent, 3aa was obtained in 80% yield (Table 1, entry 4). When no cosolvent was used, 3aa was
obtained in 81% yield (Table 1, entry 5). Next, the effect of different bases was examined in the absence
of a cosolvent. When triethylamine (Et
entry 6). When sodium acetate (NaOAc) was used as the base, 3aa was obtained in the highest yield
Table 1, entry 7, 87% yield). Thus, the reaction of 1a (1.5 mmol) with 2a (1.0 mmol) in the presence of 1
mol% Pd (PPh ) Cl , 3 mol% CuI, and 2 mmol Et N for 2 h in THF (5 mL) under nitrogen atmosphere
3
N) was used as the base, 3aa was obtained in 27% yield (Table 1,
(
3
2
2
3
followed by the addition of hydroxylamine (2.0 mmol) and NaOAc (3.0 mmol) and reflux for 12 h
afforded isoxazole 3aa in 87% yield.
a
Table 1. Optimization of the reaction conditions for the synthesis of isoxazole 3aa
b
Entry
Base
T
Cosolvent
Yield (％)
1
2
3
4
5
6
7
Na
Na
Na
Na
Na
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
r.t
MeCN
MeCN
27
reflux
reflux
reflux
reflux
reflux
reflux
68
H
2
O
73
1,4-dioxane
――
80
81
Et
3
N
――
27
NaOAc
――
87
a
Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), PdCl
2
(PPh
3
)
2
(0.01 mmol), CuI (0.03 mmol), and
Et
3
N (2.0 mmol) in THF (5 mL) at room temperature for 2 h. Then, hydroxylamine (2.0 mmol), cosolvent
(
5 mL), and base (3.0 mmol) were added and reacted for 12 h.
GC yields.
b

The one-pot tandem reactions of different terminal alkynes 2 (2a and 2b) with benzoyl chloride 1a and
hydroxylamine under the optimized reaction conditions were investigated (Table 2). The corresponding
isoxazoles 3aa and 3ab were obtained in 66% and 70% isolated yields, respectively. Next, the reactions
of diverse acid chlorides 1 with 2 and hydroxylamine were investigated. The corresponding isoxazoles
3ba to 3bb were obtained in 44–76% isolated yields.
Table 2. One-pot synthesis of isoxazoles 3
a
Entry
1
1
1
2
3
Yield(%)
66
1a (R =Ph)
2a
2
(
R =Ph)
2
2
3
1a
2b (R =4-MeC
6
H
4
)
70
62
1
1b (R =4-MeC
6
H
4
)
2a
1
4
5
6
1c (R =2-furan)
2a
2a
2a
58
65
44
1
1d (R =2-thiophene)
1
1e (R =cyclohexyl)
7
1b
2b
76
a
Isolated yields.

2
2,23
The ynones were obtained via Sonogashira coupling of acid chloride and terminal alkyne.
Subsequently, the ynones maybe take place 1,4-addition with hydroxylamine and then undergo
dehydration-cyclization process to afford isoxazole. The possible reaction mechanism was listed in
Scheme 1.
R2
+ CuX (X=I or Cl)
Et N
3
O
O
R1
O L
O
R2
Cu
L
R1
1
R2
R C Pd
R1
Cl
Pd0L2
Pd
R2
NH OH
Cl
L
L
2
HO
OH
HO
O
N
O
N
NH
R2
R2
-H O
2
R1
R1
R2
R1
product
Scheme 1. Proposed reaction mechanism
In summary, we developed a simple and efficient one-pot three-component protocol for the synthesis of
,5-disubstituted isoxazoles directly from acid chlorides, terminal alkynes, and hydroxylamine
hydrochloride catalyzed by Pd(PPh Cl /CuI system in moderate to good yields. Furthermore, the
3
3
)
2
2
protocol compatible to various substrates and has easy work-up procedures, facilitating heterocycle
synthesis.
EXPERIMENTAL
The NMR spectra were recorded using a Bruker Avance 400 MHz spectrometer. The infrared (IR) spectra
were recorded using a Bruker Vector 22 spectrometer. The GC–MS analyses were performed using a
Finnigan Trace DSQ spectrometer. All regents were commercially available.
A typical procedure for the preparation of compound 3. To a 25 mL round bottom flask, PdCl
0.01 mmol), CuI (0.03 mmol), Et N (2.0 mmol), 1 (1.5 mmol) and 2 (1.0 mmol) were added in THF (5
mL) at room temperature for 2 h under N . Then hydroxylamine hydrochloride (2.0 mmol) and NaOAc
3.0 mmol) were added and refluxed for 12 h. Then the reaction mixture was diluted with water (10 mL)
and extracted with CH Cl (220 mL). The combined organic layers were dried with sodium sulfate,
concentrated to dryness and isolated by preparative TLC to obtain pure products 3.
2 3 2
(PPh )
(
3
2
(
2
2
2
4 1
3
,5-Diphenylisoxazole (3aa).
3
H NMR (CDCl , 400 MHz) δ: 6.80 (s, 1H), 7.42–7.51 (m, 6H),
-1
.+
7
.80–7.86 (m, 4H). IR (KBr) ν: 2917, 1641, 1447, 1359, 1096 cm . MS (70 eV) m/z (%): 221 (M ), 218,

1
93, 165, 144, 105, 89, 77, 51.
3
-Phenyl-3-p-tolylisoxazole (3ab). H NMR (CDCl , 400 MHz) δ: 2.45 (s, 3H), 6.81 (s, 1H), 7.28–7.33
2
4 1
5
(
m, 2H), 7.49-7.52 (m, 3H), 7.76 (d, J=8 Hz 2H), 7.88-7.91 (m, 2H). IR (KBr) ν: 2918, 2850, 1658, 1446,
-
1
.+
1
3
104 cm . MS (70 eV) m/z (%): (235, M ), 207, 165, 144, 119, 105, 91, 77.
2
4 1
3
-Phenyl-5-p-tolylisoxazole (3ba). H NMR (CDCl , 400 MHz) δ: 2.45 (s, 3H), 6.81 (s, 1H), 7.28–7.33
(
m, 2H), 7.49-7.52 (m, 3H), 7.76 (d, J=8 Hz 2H), 7.88-7.91 (m, 2H). IR (KBr) ν: 3109, 2922, 1650, 1500,
-
1
.+
1
5
1
1
3
116 cm . MS (70 eV) m/z (%): 235 (M ), 207, 165, 144, 119, 91, 65, 28.
1
1
-(Furan-2-yl)-3-phenylisoxazole (3ca). H NMR (CDCl
3 1 2
, 400 MHz) δ: 6.54 (dd, J =3.2 Hz, J =1.6 Hz,
H), 6.67 (d, J=3.2 Hz 1H), 6.78 (s, 1H), 7.41–7.48 (m, 4H), 7.82–7.85 (m, 2H). IR (KBr) ν: 2923, 1653,
-
1
.+
501, 1356, 1112 cm . MS (70 eV) m/z (%): 211 (M ), 183, 154, 144, 116, 95, 77, 51.
2
5 1
-Phenyl-5-(thiophen-2-yl)isoxazole (3da). H NMR (CDCl
3
, 400 MHz) δ: 6.68 (s, 1H), 7.13 (dd,
J
1
=5.2 Hz, J =4.0 Hz, 1H), 7.45–7.47 (m, 4H), 7.55 (dd, J =3.6 Hz, J
2
1
2
=1.2 Hz, 1H), 7.82–7.84 (m, 2H).
-1
.+
IR (KBr) ν: 3106, 2926, 2854, 1659, 1595, 1516, 1446, 1361, 1237 cm . MS (70 eV) m/z (%): 227 (M ),
1
99, 186, 111 (100), 77, 51.
3
-Cyclohexyl-3-phenylisoxazole (3ea). H NMR (CDCl , 400 MHz) δ: 1.28–1.55 (m, 6H), 1.84–1.88
1
9 1
5
(
m, 2H), 2.11–2.15 (m, 2H), 2.82–2.85 (m, 1H), 6.27 (s, 1H), 7.44–7.48 (m, 3H), 7.81–7.83 (m, 2H). IR
-1
(
KBr) ν: 3008, 2928, 1664, 1567, 1497, 1102 cm . MS (ESI) m/z: 228 (M+1).
2
6 1
3
4
2
3
,5-Dip-tolylisoxazole (3bb). H NMR (CDCl , 400 MHz) δ: 2.44 (s, 6H), 6.78 (s, 1H), 7.29–7.32 (m,
-1
.+
H), 7.74–7.79 (m, 8H). IR (KBr) ν: 3033, 2919, 1665, 1568, 1116 cm . MS (70 eV) m/z (%): 249 (M ),
21, 208, 179, 158, 119, 103, 91, 65, 63.
ACKNOWLEDGEMENTS
The authors thank the Fundamental Research Funds for the Central Universities (No. 2013YB11) for
financial support of this work.
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