Facile regioselective synthesis of 5-Hydroxy-4,5-dihydroisoxazoles from acetylenic ketones

Article abstract of DOI:10.1002/jhet.1033

5-Hydroxy-4,5-dihydroisoxazoles were synthesized conveniently in good yields by tandem conjugate addition-cyclization reaction of acetylenic ketones and hydroxylamine hydrochloride salt.

Full text of DOI:10.1002/jhet.1033

1462
Facile Regioselective Synthesis of 5-Hydroxy-4,5-
dihydroisoxazoles from Acetylenic Ketones
Vol 49
*
Meihua Xie, Ming Li, Changqing Liu, Jitan Zhang, and Chengyou Feng
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key Laboratory of
Molecular Based Materials, College of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, China
*
E-mail: xiemh@mail.ahnu.edu.cn
Received March 22, 2011
DOI 10.1002/jhet.1033
View this article online at wileyonlinelibrary.com.
5-Hydroxy-4,5-dihydroisoxazoles were synthesized conveniently in good yields by tandem conjugate
addition-cyclization reaction of acetylenic ketones and hydroxylamine hydrochloride salt.
J. Heterocyclic Chem., 49, 1462 (2012).
INTRODUCTION
4,5-dihydroisoxazoles by the cyclization of b,g-unsaturated
oximes under different reaction conditions [8].
In recent years, considerable efforts have been
prompted toward the synthesis of heterocycles because
many of them are biologically active and have found
applications as pharmaceuticals [1]. 4,5-Dihydroisoxazoles
are important heterocycles in medicinal chemistry.
They are important constituent of a variety of biologi-
cally active molecules such as the antitumor drug Acivi-
cin and the antithrombotic agent DMP802 [2]. In
organic chemistry, they are highly useful synthetic inter-
mediates due to the fact that the N–O bond can be
cleaved under mild reducing conditions. For example,
cleavage of 4,5-dihydroisoxazole can give rise to several
useful synthetic units such as b-hydroxyketones, b-
hydroxynitriles, g-amino alcohols, and a,b-unsaturated
oximes [3]. Therefore, many synthetic methods have
been developed to prepare 4,5-dihydroisoxazoles.
Among them, the 1,3-dipolar cycloaddition of nitrile
oxides to olefins [4] and the reaction of a,b-unsaturated-
ketones with hydroxylamine [5] are most common syn-
thetic methods. However, these transformations have
some disadvantages arising from the dimerization of
nitrile oxide and the poor cycloaddition regioselectivity.
Thus, the development of facile and regioselective meth-
ods for the synthesis of this kind of compounds is an
area of considerable ongoing interest and significant
effort continues to be directed toward the new methods
for their construction. Recently, She et al. prepared 4,5-
dihydroisoxazole regioselectively from the reaction of
a,b-unsaturated ketones with N-hydroxyl-4-toluenesulfona-
mide [6]. Knight et al. reported the synthesis of 4,5-
dihydroisoxazoles by silver nitrate-catalyzed intramolecular
cyclization of O-propargylic hydroxylamines [7]. Mosher
et al. reported the synthesis of differently substituted
Acetylenic ketones are useful compounds in organic syn-
thesis. Perumal et al. [9] recently reported stepwise synthesis
of isoxazoles by oximation of acetylenic ketones and a sub-
sequent gold-catalyzed cycloisomerization of the resulting
a,b-acetylenic oximes. Müller et al. [10] synthesized isoxa-
zoles from 1,3-dipolar cycloaddition of acetylenic ketones
and nitrile oxides. However, to the best of our knowledge,
one pot synthesis of 4,5-dihydroisoxazole directly from
the reaction of acetylenic ketones with hydroxylamine
has not been reported. Herein,we wish to report a facile
regioselective procefor the synthesis of 5-hydroxyl-4,5-
dihydroisoxazoles by one-pot tandem conjugate addition-
cyclization reaction of acetylenic ketones and hydroxylamine
hydrochloride salt.
RESULTS AND DISCUSSION
Initially, the reaction of 1-(p-methylphenyl)-3-phenyl-
2-propyn-1-one (1a) with excess hydroxylamine hydro-
chloride salt (2) was investigated and the results are
summarized in Table 1. The results show that 3a was
obtained in 52% yield when 1a react with 2 equiv 2 in
methanol for 24 h in the presence of potassium hydr-
oxide (2 equiv). Gratifyingly, the desired product 3a
was obtained in 93% yield when 4 equiv hydroxylamine
hydrochloride salts and potassium hydroxide were used.
The yield of 3a was increased to 98%, and the reaction time
was dramatically decreased to 8 h when a small amount
of water was added to methanol (entry 4, Table 1). Using
sodium hydroxide or potassium carbonate as bases resulted
in lower yields (entries 5 and 6, Table 1). Further investiga-
tions show that the solvents have apparent effect on the
© 2012 HeteroCorporation

November 2012
Facile Regioselective Synthesis of 5-Hydroxy-4,5-dihydroisoxazoles
from Acetylenic Ketones
1463
Table 1
Table 2
Reaction of acetylenic ketone 1a with hydroxylamine
hydrochloride salt 2.
Synthesis of 5-hydroxy-4,5-dihydroisoxazoles.
Yielda
Entry
R1
R2
Product
Yield (%)a
Entry
Molar ratio of 2:1
Base
Solvent
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-CH3C6H4
Ph
p-BrC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
87
83
95
81
85
84
92
75
78
81
1
2
3
2
3
4
4
4
4
4
4
4
4
KOH
KOH
KOH
KOH
NaOH
K2CO3
KOH
KOH
KOH
KOH
MeOH
MeOH
MeOH
MeOH/H2O
MeOH/H2O
MeOH/H2O
EtOH
CH2Cl2
Toluene
THF
52
82
93
98
91
86
24
28
0
4b
5b
6b
7
p-ClC6H4
p-O2NC6H4
p-CH3OC6H4
2,4-(CH3O)2C6H3
2,4-Cl2C6H3
p-O2NC6H4
Ph
8
9c
10
9
10
11
n-C4H9
n-C4H9
n-C4H9
3j
3k
34
p-CH3C6H4
aIsolated yields based on 1a.
aIsolated yield based on 1.
bMeOH/H2O (v/v) = 9/1.
cNo reaction was happened and the starting material was recovered.
reported. The procedure involves tandem conjugate
addition, intramolecular cyclization and isomerization.
The method has the advantages such as readily available
starting materials, mild reaction conditions, high effi-
ciency and high regioselectivity.
reaction. Among various solvents tested, methanol/H2O
was the most suitable (entries 7–10, Table 1). Therefore,
the general reaction conditions were 1.0 equiv of acetylenic
ketone 1, 4.0 equiv of hydroxylamine hydrochloride salt
2, and 4.0 equiv of potassium hydroxide in methanol/
H2O (v/v 9:1) at room temperature.
EXPERIMENTAL
With the optimal reaction conditions in hand, we next
examined the scope and generality of the reaction. The
results are compiled in Table 2.
All reagents and solvents were purchased from commercial
sources and were used without further purification. All solid
products were recrystallized from ethyl acetate and hexane,
and the melting points were obtained with a XT4A micromelt-
ing point apparatus and uncorrected. Infrared spectra were
recorded as KBr plates on an FT IR-8400 spectrometer.1H-
NMR and 13C-NMR spectra were measured on a Bruker
Avance 300 MHz NMR spectrometer in CDCl3 or in DMSO-
d6. HRMS (EI, 70 eV) were determined on a CA 064 mass
spectrometer. X-ray crystallographic analysis was carried out on
a Bruker SMART 1000 CCD diffractometer. Acetylenic ketones
were prepared according to literature procedures [12].
As shown in Table 2, various 3,5-disubstituted 5-
hydroxyl-4,5-dihydroisoxazoles can be readily synthe-
sized in good to excellent yields from acetylenic ketones
and hydroxylamine hydrochloride salt. R1 can be phenyl
or n-butyl. R2 can be phenyl, electron-rich phenyl or
electron-poor phenyl. All products were characterized
by spectral data and the molecular structure of com-
pound 3a was further confirmed by X-ray diffraction
analysis (Fig. 1) [11]. However, no reaction occurred
under the same reaction conditions when hydroxylamine
was replaced by N-methylhydroxylamine and a complex
mixture was obtained when R2 is an alkyl group.
The plausible mechanism was suggested as following
(Scheme 1): first, conjugate addition adduct I was
formed through the reaction of hydroxylamine and ace-
tylenic ketone; then intramolecular cyclization of I gen-
erated intermediate II; finally, product 3 was obtained
by the isomerization of the enamine II to the more
stable imine. The reaction is highly regioselective and no
regioisomers were formed in all cases.
General procedure for the synthesis of 5-hydroxy-4,5-
dihydroisoxazoles 3. To a solution of acetylenic ketone
(0.5 mmol) and hydroxylamine hydrochloride salt (2.0 mmol) in
4.0 mL methanol/water (v:v = 9:1) was added potassium
hydroxide (2.0 mmol) at room temperature. The reaction mixture
was stirred at room temperature and the progress was
monitored by TLC. When the reaction was completed, the reaction
In summary, a regioselective synthesis of 5-hydroxy-
4,5-dihydroisoxazoles from direct reaction of acetylenic
ketones with hydroxylamine hydrochloride salt was
Figure 1. The molecular structure of compound 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1464
M. Xie, M. Li, C. Liu, J. Zhang, and C. Feng
Vol 49
Scheme 1. Plausible mechanism.
2H), 3.83 (s, 3H), 3.66 (d, J = 17.4 Hz, 1H), 3.46 (d, J = 17.4 Hz,
1H), 3.20 (s, 1H); 13C-NMR (75 MHz, CDCl3): d 159.8, 157.4,
132.7, 130.3, 129.2, 128.7, 126.9, 126.7, 113.7, 107.6, 55.2, 48.8;
HRMS (EI): calcd for C16H15NO3 [M+]: 269.1052, found: 269.1057.
5-(3,4-Dimethoxyphenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (3g).
White solid, mp 134À135 ꢀC; IR (KBr): v (cmÀ1) 3506, 1591,
1
1456, 1022; H-NMR (300 MHz, CDCl3): d 7.72À7.68 (m, 2H),
7.44À7.41 (m, 3H), 7.23-7.15 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H),
3.91 (s, 6H), 3.66 (d, J = 17.4 Hz, 1H), 3.47 (d, J = 17.4 Hz, 1H),
3.24 (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 157.1, 149.0,
148.6, 134.5, 130.4, 130.1, 129.2, 126.9, 118.6, 111.5, 110.0, 107.9,
55.9, 55.8, 48.6; HRMS (EI) calcd for C17H17NO4 [M+]: 299.1158,
found: 299.1152.
mixture was added 5 mL saturated ammonium chloride and
extracted with ethyl acetate (3 Â 10 mL). The organic extract
was combined and dried over anhydrous sodium sulfate. The
crude product was purified by flash chromatography on silica
gel (10/1 hexane/ethyl acetate) to afford products 3.
3-Phenyl-5-p-tolyl-4,5-dihydroisoxazol-5-ol (3a). White solid,
mp 176À177 oC; IR (KBr): v (cmÀ1) 3300, 1595, 1446, 1045;
1H-NMR (300 MHz, CDCl3): d 7.77À7.66 (m, 2H), 7.53 (d, J = 7.7
Hz, 2H), 7.45À7.28 (m, 3H), 7.23À7.20 (m, 2H), 3.66 (d, J = 17.4
Hz, 1H), 3.46 (d, J = 17.4 Hz, 1H), 3.17 (s, 1H), 2.37 (s, 3H);
13C-NMR (75 MHz, CDCl3): d 157.4, 138.7, 137.7, 130.3, 129.2,
129.1, 128.7, 126.7, 125.4, 107.5, 48.8, 21.1; HRMS (EI) calcd for
C16H15NO2 [M+]: 253.1103, found: 253.1111.
3,5-Diphenyl-4,5-dihydroisoxazol-5-ol (3b). White solid, mp
172À173ꢀC; IR (KBr): v (cm-1) 3309, 1597, 1448, 1043;
1H-NMR (300 MHz, CDCl3): d 7.67À7.64 (m, 4H), 7.50À7.31
(m, 6H), 3.68 (d, J = 17.4 Hz, 1H), 3.48 (d, J = 17.4 Hz, 1H), 3.26
(s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 157.0, 142.2, 130.4,
130.0, 129.1, 128.5, 128.4, 126.9, 126.1, 107.9, 48.8; HRMS (EI)
calcd for C15H13NO2 [M+]: 239.0946, found: 239.0939.
5-(4-Bromophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (3c).
White solid, mp 204À205ꢀC; IR (KBr): v (cm-1) 3269, 1595,
1446, 1039; 1H-NMR (300 MHz, CDCl3): d 7.71À7.67 (m,
2H), 7.54 (s, 4H), 7.44À7.42 (m, 3H), 3.68 (d, J = 17.4 Hz,
1H), 3.45 (d, J = 17.4 Hz, 1H), 3.15 (s, 1H); 13C-NMR (75
MHz, DMSO-d6): d 157.2, 141.7, 131.5, 130.6, 129.9, 129.3,
128.6, 127.0, 122.0, 107.6, 48.8; HRMS (EI) calcd for
C15H12BrNO2 [M+] (79Br): 317.0051, found: 317.0056.
5-(4-Chlorophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (3d).
White solid, mp 204À206ꢀC; IR (KBr): v (cmÀ1) 3273, 1598, 1446,
1045; 1H-NMR (300 MHz, CDCl3): d 7.69 (s, 2H), 7.60 (d, J = 8.2
Hz, 2H), 7.45À7.27 (m, 3H), 7.26 (s, 2H), 3.68 (d, J = 17.4 Hz, 1H),
3.46 (d, J = 17.4 Hz, 1H), 3.25 (s, 1H); 13C-NMR (75 MHz,
DMSO-d6): d 157.1, 141.2, 133.3, 130.5, 129.9, 129.2, 128.4,
128.2, 126.9, 107.5, 48.8; HRMS (EI) calcd for C15H12ClNO2
[M+] (35Cl): 273.0557, found: 273.0553.
5-(2,4-Dichlorophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol
(3h). White solid, mp 158À160 ꢀC; IR (KBr): v (cmÀ1) 3190, 1587,
1
1465, 1020; H-NMR (300 MHz, CDCl3): d 7.87 (d, J = 8.4 Hz,
1H), 7.71 (d, J = 4.3 Hz, 2H), 7.47À7.44(m, 4H), 7.31À7.28
(m, 1H), 3.83 (d, J = 17.7 Hz, 1H), 3.70 (d, J = 17.7 Hz, 1H),
3.45 (s, 1H); 13C-NMR (75 MHz, DMSO-d6): d 157.0, 138.0,
134.3, 133.12, 130.6, 130.5, 123.0, 129.6, 129.2, 127.2, 126.9,
106.1, 47.1; HRMS (EI) calcd for C15H11Cl2NO2 [M+](35Cl):
307.0167, found: 307.0162.
3-Butyl-5-(4-nitrophenyl)-4,5-dihydroisoxazol-5-ol (3i). Yellow
solid, mp: 68À70 ꢀC; IR (KBr): v (cmÀ1) 3167, 1600, 1454,
1
1028; H-NMR (300 MHz, CDCl3): d 8.23 (d, J = 8.3 Hz, 2H),
7.77 (d, J = 8.3 Hz, 2H), 3.36 (s, 1H), 3.27 (d, J = 17.7 Hz, 1H),
3.06 (d, J = 17.7 Hz, 1H), 2.43 (t, J = 6.9 Hz, 2H), 1.63–1.59
(m, 2H), 1.44–1.39 (m, 2H), 0.94 (t, J = 6.9 Hz, 3H); 13C-NMR
(75 MHz, CDCl3): d 160.3, 147.9, 147.7, 126.8, 123.5, 105.7,
51.4, 28.2, 27.3, 22.2, 13.6; HRMS (EI) calcd for: C13H16N2O4
[M+]: 264.1110, found: 264.1104.
3-Butyl-5-phenyl-4,5-dihydroisoxazol-5-ol (3j). White solid,
mp: 122–124ꢀC; IR (KBr): v (cmÀ1) 3238, 2953, 1469, 1444,
1049; 1H-NMR (300 MHz, CDCl3): d 7.67À7.64 (m, 2H),
7.42À7.36 (m, 3H), 3.49 (d, J = 17.5 Hz, 1H), 3.21 (d, J = 17.5
Hz, 1H), 1.84 (m, 2H), 1.46-1.35 (m, 4H), 0.91 (t, J = 6.9 Hz,
3H); 13C-NMR (75 MHz, CDCl3): d 157.0, 130.1, 129.5,
128.5, 126.5, 102.6, 39.4, 35.0, 25.9, 22.8, 13.9; HRMS (EI)
calcd for C13H17NO2 [M+]: 219.1259, found: 219.1276.
3-Butyl-5-p-tolyl-4,5-dihydroisoxazol-5-ol (3k). White solid, m.
p. 82–83ꢀC; IR (KBr): v (cmÀ1) 3460, 3242, 2953, 1597, 1419,
1
1047; H-NMR (300 MHz, CDCl3): d 7.54 (d, J = 8.2 Hz, 2H),
7.2 (m, 2H), 3.45 (d, J = 17.5 Hz, 1H), 3.19 (d, J = 17.5 Hz, 1H),
2.37 (s, 3H), 1.86–1.82 (m, 2H), 1.46–1.28 (m, 4H), 0.91 (t, J =
6.9 Hz, 3H); 13C-NMR (75 MHz, CDCl3): d 157.0, 140.3, 129.2,
126.7, 126.5, 102.4, 39.6, 34.9, 25.9, 22.8, 21.4, 13.9; HRMS
(EI) calcd for C14H19NO2 [M+]: 233.1416, found: 233.1421.
5-(4-Nitrophenyl)-3-phenyl-4,5-dihydroisoxazol-5-ol (3e).
Acknowledgments. We are grateful to the National Natural Science
Foundation of China (Nos. 20672001 and 20772001) for financial
support of this work. We are also grateful to Prof. Jiping Hu and
Yun Wei for their helpful assistances.
>Yellow solid, mp: 155À157ꢀC; IR (KBr): v (cmÀ1) 3228,
1
1660, 1517, 1450, 1346, 1037; H-NMR (300 MHz, CDCl3):
d 8.26 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H),
7.75À7.67 (m, 2H), 7.50À7.32 (m, 3H), 3.74 (d, J = 17.5
Hz, 1H), 3.51-3.46 (m, 2H); 13C-NMR (75 MHz, DMSO-
d6): d 157.3, 148.8, 147.7, 130.8, 129.3, 129.2, 127.7 126.9,
123.7, 107.1, 48.7; HRMS (EI). calcd for C15H12N2O4 [M+]:
284.0797, found: 284.0802.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012
Facile Regioselective Synthesis of 5-Hydroxy-4,5-dihydroisoxazoles
from Acetylenic Ketones
1465
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a = 10.1203(9), b = 9.4778(8), c = 14.0262(13) Å; a = 90, b = 99.8160
(10), g = 90ꢀ. V = 1325.7(2) Å3, T = 293 K, Z = 4, Dc = 1.269 g cm–1
,
m = 0.087 mm–1, l = 0.71073 Å; F(000) 536, 3063 independent re-
flections (Rint = 0.0280), 11145 reflections collected; refinement method,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet