One-pot synthesis of (3-phenylisoxazol-5-yl) methanol derivatives under ultrasound

Article abstract of DOI:10.2174/157017811795371467

An ultrasonic-assisted, one-pot, efficient, convenient procedure for the synthesis of (3-phenylisoxazol-5-yl)methanol derivatives has been developed. (3-Phenylisoxazol-5-yl)-methanol derivatives with biological and pharmaceutical property have been synthe

Full text of DOI:10.2174/157017811795371467

278
Letters in Organic Chemistry, 2011, 8, 278-281
One-Pot Synthesis of (3-Phenylisoxazol-5-yl)methanol Derivatives Under
Ultrasound
Chuansheng Shen,Yumin Zhang, Yuanming Gan, Tianqi Zhao and Qiang Gu*
College of Chemistry, Jilin University, 2699 Qianjin Avenue, Changchun 130012, P. R., China
Received January 26, 2010: Revised August 30, 2010: Accepted October 14, 2010
Abstract: An ultrasonic-assisted, one-pot, efficient, convenient procedure for the synthesis of (3-phenylisoxazol-5-
yl)methanol derivatives has been developed. (3-Phenylisoxazol-5-yl)-methanol derivatives with biological and
pharmaceutical property have been synthesized in moderate to excellent yields. The synthetic methods possess the
advantages of high yield, facile operation process and shorter reaction time, and so on.
Keywords: Ultrasound, aldoximes, 1,3-dipolar cycloaddition, nitrile oxide, isoxazole, one-pot synthesis.
INTRODUCTION
whereby the aldoximes are subjected to successive chemical
reactions in just one reactor, which can avoid a lengthy
separation process and purification of oxime halides, save
time and resources while increasing chemical yield. Overall,
compared with the traditional methods [18], as a results, the
synthesis of (3-phenylisoxazol-5-yl)methanol derivatives
from aldoximes can surely shorten reaction time and enhance
product yield in one-pot synthesis under ultrasound.
Isoxazole derivatives are widely used intermediates for
the synthesis of a variety of complex natural products [1, 2]
and important pharmacophores in medicinal chemistry [3, 4],
such as treating diseases of Alzheimer [5] and cardiovascular
[6], sterilization [7], herbicide [8] and so on. Therefore, an
effective method for preparation of isoxazole derivatives is
of great interest in organic synthesis. Isoxazole derivatives
were usually synthesized by reaction of 1,3-dicarbonyl
compounds with hydroxylamine, followed by dehydration
and cyclization of the intermediate monoxime [9]. The
synthetic and mechanistic aspects of 1,3-dipolar
cycloadditions using nitrile oxides to give all kinds of
heterocyclic compounds have been investigated in 1963 and
1984 [10, 11]. The synthesis of isoxazole derivatives via the
cycloaddition of nitrile oxide to unsaturated dipolarophiles is
one of successful examples [12]. In the previous reports, the
aldoximes have been used as starting materials [13]. The
widespread procedure to form the nitrile oxides is
halogenated by an active halogen compound and
subsequently dehydrohalogenation in a basic condition.
Then, the formation of isoxazoles by 1,3-dipolar
cycloadditions between nitrile oxides and alkynes. The
synthetic mothods possess the disadvantages of lower yield,
complex operation process, long reaction time and so on.
RESULTS AND DISCUSSION
The reaction for synthesizing (3-phenylisoxazol-5-
yl)methanol derivatives by one-pot method under ultrasound
and traditional method were illustrated by Scheme 1 and
Scheme 2, respectively. The traditional method was operated
by two process, which lead to the lower yields of products
and ineffective. To investigate the effect to synthesizing (3-
phenylisoxazol-5-yl)methanol derivatives in one pot under
ultrasound, compared the experiment results of in one pot
method to that of traditional method were summarized in
Table 1. As shown Table 1, various (3-phenylisoxazol-5-
yl)methanol derivatives were synthesized under irradiation
of ultrasound in one-pot synthesis to give the corresponding
(3-phenylisoxazol-5-yl)methanol derivatives by 45-87%
yield in 1.5-4.5h, however, the yields of products were only
5-73% in 3-6h in traditional method. Therefore, the entire
process was dramatically accelerated by ultrasound
irradiation in one pot, the reaction times were shorten over
an hour while the yields of the products were enhanced 14 -
40% comparable to those obtained previously.
It is known that ultrasound technology has recently
attracted more and more attention from synthetic organic
chemists due to the many advantages ultrasound irradiation
affords
over
conventional
heating
in
chemical
transformations, particularly the enormous acceleration of
the reaction rate, significant energy savings, as well as high
chemical yields and cleaner reactions [14-17]. In the report,
our group has been interested in projecting new
methodologies for the synthesis of isoxazole derivatives (3-
phenylisoxazol-5-yl)methanols from aldoximes in one-pot
synthesis under ultrasound. One-pot synthesis is a strategy to
improve the efficiency of 1,3-dipolar cycloadditions
It is noteworthy that the electron-rich substituting groups
on the aromatic ring have a higher yield than the electron–
poor ones. This can be observed in the following syntheses.
When the substituent is a nitro group (entry 8, 9), the yield is
very low between the traditional method and the ultrasonic
method. While the substituents are electron-donating groups,
the yields of compounds are above 70% under ultrasonic
conditions, because hydroxy group possess high electron-
donating characteristic, the yield of the product is the highest
in the reactions (87%). However, when it is the same
substituted with electron-donating groups on ortho position
*Address correspondence to this author at the College of Chemistry, Jilin
University, 2699 Qianjin Avenue, Changchun 130012, P. R., China; Tel:
+86-431-85168470(3): Fax: +86-431-85168420:
E-mail: guqiang@jlu.edu.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

One-Pot Synthesis of (3-Phenylisoxazol-5-yl)methanol Derivatives
Letters in Organic Chemistry, 2011, Vol. 8, No. 4
279
R
N
OH
1.NCS, DMF
N
R
O
2.Propargyl alcohol, Et3N
3.Ultrasound irradiation or
Conventional heating
HO
Scheme 1.
Cl
N
OH
R
N
OH
N
O
NCS, DMF
Propargyl alcohol, Et3N
OH
R
R
Scheme 2.
Table 1. Comparison Between Ultrasound and Conventional Method
entry
ArCH=NOH
Total time
Isolated yield a (%)
Mp (oC)
Classical(h)
U.S.(h)
Classical
U.S.
1
2
3
4
5
6
7
8
9
benzaldehyde oxime
3.0
5.0
5.0
4.0
4.0
5.0
3.2
4.0
6.0
1.5
4.0
4.0
2.5
2.5
3.0
2.0
2.2
4.5
27
10
45
73
58
20
67
5
70
79
74
83
75
87
74
59
45
49–50
66-67
2-chlorobenzaldehyde oxime
4-chlorobenzaldehyde oxime
2-methoxybenzaldehyde oxime
4-methoxybenzaldehyde oxime
4-hydroxybenzaldehyde oxime
4-tert-butylbenzaldehyde oxime
3-nitrobenzaldehyde oxime
4-nitrobenzaldehyde oxime
93-94
liquid
82-83
136-138
48-50
90-92
7
117-119
aYield refers to be purified by recrystallization after column chromatography.
of aromatic ring (such as -OCH3, -Cl), the yield is higher
than on para position, which may be because electron-
donating groups at ortho position of aromatic ring would
better benefit activity. Moreover, when the substituted is
tert-butyl group, the yield is lower than other electron-
donating groups, because tert-butyl group has larger steric
restriction.
in the cleaner and the temperature of the water bath was
controlled by automatic temperature control system.
General Procedure
Ultrasonic method: To a solution of aldoximes (10
mmol) in DMF (10 ml), NCS (10 mmol) was added at room
temperature. After ultrasonic irradiation for about 30 min,
the reaction mixture was cooled with ice. When the
temperature was about 0 oC, the Et3N (2.73 ml) was dropped
into the reaction solution followed by propargyl alcohol (2
ml). The reaction process was monitored by TLC. After
complete reaction, the reaction mixture was washed with
water and extracted with a mixture of ethyl acetate and
petrolrum ether through multiple extraction. The combined
organic layers were washed with deionized water (10 ml),
brine(10 ml), dried (Na2SO4) and evaporated under a vacuum
EXPERIMENTAL SECTION
Materials and Analysis
Et3N, DMF, propargyl alcohol and NCS (N-chloro
succinimide) were all reagent grade and used without further
purification. Aldoximes were generated from oximation of
aldehydes according to the reported procedure [19]. All
melting points were determined on a XT-4 melting point
1
apparatus and were uncorrected. H and 13C NMR spectra
to give
a
crude product which was purified by
were measured with Bruker AM-300 or a Bruker AVANCE-
500 NMR spectrometer using DMSO or CDCl3 as solvent
and with TMS as an internal standard. MS spectra were
recrystallization after column chromatography (silica gel,
200-300 mesh) to furnish the product.
Traditional method: compared the synthetic methods of
one-pot method under ultrasond to that of traditional method,
there existed employing ultrasound technology with the
measured with
a Q-trapspectrometer. Sonication was
performed in a Shanghai Branson–CQX ultrasonic cleaner
with a frequency of 25 kHz and a nominal power 250 W.
The reaction flask was located at the maximum energy area

280 Letters in Organic Chemistry, 2011, Vol. 8, No. 4
Shen et al.
function of heating, stirring and accelerating the reaction
rate, While magnetic stirring was used in traditional method.
153.87, 126.98, 126.33, 100.43, 56.77, 35.23, 31.59. MS
m/z: Calc. for C14H17NO2 231.1. Found: 232.0 [M+1]+, 233.0
[M+2]+, 254.0 [M+Na]+.
(3-(3-nitrophenyl)isoxazol-5-yl)methanol
Characterization of Products
Entry 8 (1.30g, yield 59%) mp: 90-92oC; 1H NMR (300
MHz, CDCl3) ꢀ ppm 8.62 (s, 1H), 8.46 – 8.22 (m, 1H), 8.22
– 8.05 (m, 1H), 7.66 (s, 1H), 6.67 (s, 1H), 4.87 (d, J = 0.8
Hz, 2H). 13C NMR (125.5 MHz, DMSO) ꢀ ppm 173.97,
159.59, 147.73, 132.27, 130.16, 129.68, 124.01, 120.31,
99.53, 54.27. MS m/z: Calc. for C10H8N2O4 220.0. Found:
221.0 [M+1]+, 222.0 [M+2]+.
(3-phenylisoxazol-5-yl)methanol
Entry 1 (1.22g, yield 70%) mp: 49–50 C; 1H NMR (300
o
MHz, CDCl3) ꢀ ppm, 7.78 (d, J = 3.7 Hz, 2H), 7.44 (d, J =
2.5 Hz, 3H), 6.56 (s, 1H), 4.81 (s, 2H). 13C NMR (125.5
MHz, CDCl3) ꢀ ppm 171.94, 162.50, 130.12, 128.96, 128.78,
126.81, 100.06, 56.57. MS m/z: Calc. for C10H9NO2 175.1.
Found: 175.1 [M]+, 176.1 [M+H]+.
(3-(4-nitrophenyl)isoxazol-5-yl)methanol
(3-(2-chlorophenyl)isoxazol-5-yl)methanol
1
Entry 9 (0.99g, yield 45%) mp: 117-119oC; H NMR
Entry 2 (1.65g, yield 79%) mp: 66-67 oC; H NMR (300
1
(300 MHz, CDCl3) ꢀ ppm 8.37 (dd, J = 28.8, 12.2 Hz, 4H),
6.65 (s, 1H), 4.87 (s, 2H). 13C NMR (125.5 MHz, DMSO) ꢀ
ppm 175.19, 160.75, 135.22, 128.35, 124.77, 100.83, 55.33.
MS m/z: Calc. for C10H8N2O4 220.0. Found: 220.9 [M+1]+,
221.8 [M+2]+.
MHz, CDCl3) ꢀ ppm 7.73 (dd, J = 7.1, 2.2 Hz, 1H), 7.48 (s,
1H), 7.41 – 7.34 (m, 2H), 6.73 (s, 1H), 4.86 (s, 2H). 13C
NMR (125.5 MHz, CDCl3) ꢀ ppm 171.09, 161.13, 132.95,
130.97, 130.45, 128.18, 127.15, 103.37, 56.59. MS m/z: Calc.
for C10H8ClNO2 209.0. Found: 209.9[M]+, 210.9 [M+1]+,
211.9 [M+2]+.
CONCLUSION
(3-(4-chlorophenyl)isoxazol-5-yl)methanol
1
Entry 3 (1.54g, yield 74%) mp: 93-94 oC; H NMR (300
In conclusion, an efficient, ultrasonic-assisted, one-pot
procedure for the direct conversion of aldoxime to (3-
phenylisoxazol-5-yl) methanol derivatives has been
developed. The desired isoxazole derivatives have been
obtained in moderate to excellent overall yields. This
approach provides an ideal synthetic approach for the similar
synthesis of an isoxazole derivatives library. However, we
believe that the operational facility of this method makes it
attractive for preparative applications as well as for the
synthesis of other interesting heterocycles which were
applied in biology and material field, etc, is currently in
progressing in our laboratory.
MHz, CDCl3) ꢀ ppm 7.74 (d, J = 8.7 Hz, 2H), 7.43 (d, J =
8.7 Hz, 2H), 6.54 (s, 1H), 4.83 (s, 2H). 13C NMR (125.5
MHz, CDCl3) ꢀ ppm 172.30, 161.56, 136.21, 129.27, 128.10,
127.29, 99.96, 56.53. MS m/z: Calc. for C10H8ClNO2 209.0.
Found: 209.9 [M] +, 210.9 [M+1]+, 211.9 [M+2]+.
(3-(2-methoxyphenyl)isoxazol-5-yl)methanol
Entry 4 (1.70g, yield 83%) liquid. 1H NMR (300 MHz,
CDCl3) ꢀ ppm 7.80 (dd, J = 7.7, 1.8 Hz, 1H), 7.38 (dd, J =
4.6, 3.7 Hz, 1H), 7.06 – 6.91 (m, 2H), 6.71 (s, 1H), 4.76 (d, J
= 0.6 Hz, 2H), 3.84 (s, 3H). 13C NMR (125.5 MHz, CDCl3) ꢀ
ppm 170.12, 159.10, 156.17, 130.29, 128.31, 119.81, 116.56,
110.47, 102.35, 55.13, 54.41. MS m/z: Calc. for C11H11NO3
205.0. Found: 205.9 [M+1]+, 206.9 [M+2]+, 227.9 [M+Na]+.
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