A novel method for the highly efficient synthesis of 1,2-benzisoxazoles under neutral conditions using the Ph3P/DDQ system

Article abstract of DOI:10.1016/j.tetlet.2006.09.120

The use of Ph₃P/DDQ offers a novel, neutral and highly efficient method for the efficient conversion of 2-hydroxyaryl aldoximes and ketoximes to 1,2-benzisoxazoles in excellent yields at room temperature.

Full text of DOI:10.1016/j.tetlet.2006.09.120

Tetrahedron Letters 47 (2006) 8247–8250
A novel method for the highly efficient synthesis
of 1,2-benzisoxazoles under neutral conditions using
the Ph3P/DDQ system
Nasser Iranpoor,* Habib Firouzabadi* and Najmeh Nowrouzi
Department of Chemistry, Shiraz University, Shiraz 71454, Iran
Received 25 July 2006; revised 13 September 2006; accepted 21 September 2006
Available online 10 October 2006
Abstract—The use of Ph3P/DDQ offers a novel, neutral and highly efficient method for the efficient conversion of 2-hydroxyaryl
aldoximes and ketoximes to 1,2-benzisoxazoles in excellent yields at room temperature.
Ó 2006 Published by Elsevier Ltd.
Isoxazoline ring systems are an important class of
nitrogen–oxygen heterocycles with many synthetic
applications as structural units of many molecules of
biological interest that has made them useful intermedi-
ates in medicinal chemistry.1 Due to their biological
activities, they have been the subject of extensive experi-
mental studies2 and many synthetic methods have been
employed in the synthesis of these compounds including
reactions of 2-hydroxy aryl aldoximes and ketoximes
with, (i) thionyl chloride in pyridine,3 (ii) trichloroacetyl
isocyanate,4 (iii) Ac2O and K2CO3,5 (iv) Ac2O in pyr-
idine6 or the reaction of hydroxylamine-O-sulfonic acid
with 2-hydroxyphenyl carbonyl compounds,7 etc.
atives. In continuation of our work on the use of Ph3P/
DDQ,10 we now report that this mixed reagent system
offers the possibility of preparing 1,2-benzisoxazoles
under mild and neutral reaction conditions at room tem-
perature without the formation of any side products.
We first optimized the reaction conditions for cycliza-
tion of salicylaldoxime to its corresponding 1,2-benz-
isoxazole. The reaction was carried out by mixing Ph3P
and DDQ in dichloromethane as solvent at room tem-
perature. The addition of the oxime immediately pro-
duced the corresponding benzisoxazole in an excellent
yield.
The methods developed so far have limitations and
drawbacks such as; they are usually two-step procedures
including the conversion of the hydroxyl group of the
oximes to leaving groups such as halides or acetates
followed by the base-catalyzed cyclization reaction to
the 1,2-benzisoxazoles3,5–7 and are usually temperature
dependent needed heating5,6 or cooling.3,7,8 Both elev-
ated temperatures and alkaline conditions may cause
unwanted secondary processes such as cyclization to
1,3-benzoxazoles4,7,9 which occurs through a Beckmann
rearrangement of the intermediate carbamoyl oxime and
subsequent ring closure or hydrolysis of the oxime deriv-
The optimized molar ratio of Ph3P/DDQ/oxime was
found to be 1.5/1.5/1.0. In this reaction, salicylaldoxime
on treatment with Ph3P/DDQ was cyclized without the
need to add any base.
The successful synthesis of 1,2-benzisoxazole derivatives
via the cyclization of different aldoximes prompted us to
investigate the applicability of this procedure for the
generation of other 1,2-benzisoxazoles. A similar behav-
iour was also observed in the cyclization of 2-hydroxy
aryl ketoximes to the corresponding 1,2-benzisoxazoles
(Scheme 1).
The results of this study are summarized in Table 1.
As shown in this table, the use of this method at room
temperature and under neutral conditions prevents the
formation of any 1,3-benzoxazoles, and 1,2-benzisoxazoles
are the only products obtained.
Keywords: Triphenylphosphine; DDQ; Oxime; 1,2-Benzisoxazole.
*
Corresponding authors. Tel.: +98 711 2287600; fax: +98 711
2280926; e-mail addresses: iranpoor@chem.susc.ac.ir; firouzabadi@
chem.susc.ac.ir
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.09.120

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N. Iranpoor et al. / Tetrahedron Letters 47 (2006) 8247–8250
crude mixture on silica gel using n-hexane and ethyl ace-
R
C
R
O
tate (3:1) as eluent gave the desired 1,2-benzisoxazole in
NOH
a 95% yield. Bp 91–92 °C/15 mmHg. Lit.7 bp 35–38 °C/
Ph3P/DDQ
N
1
CH2Cl2, rt
immediately
2 mmHg; H NMR (250 MHz, CDCl3): d (ppm) = 8.71
OH
(1H, s), 7.28–7.87 (4H, m); 13C NMR (250 MHz,
CDCl3): d (ppm) = 109.70, 121.27, 121.99, 123.72,
130.02, 146.18, 162.20.
X
X
90-95%
R = H, alkyl, aryl
X = H, CH3, C2H5, OH, OCH3, Br
In order to show the advantages of the present work in
comparison with other recently reported protocols, we
compared the reaction conditions of this method with
those reported previously (Table 2).
Scheme 1.
A mixture of Ph3P (1.5 mmol, 0.392 g) and DDQ
(1.5 mmol, 0.34 g) in dry CH2Cl2 (5 mL) was stirred at
room temperature for 1 min. Salicylaldoxime (1 mmol,
0.137 g) was then added. The green color of the reaction
mixture changed to brown after 1 min. GC or TLC
monitoring showed completion of the reaction. The
solvent was evaporated. Column chromatography of the
As shown in Table 2, the highest yield, shortest reaction
time, and the most neutral reaction conditions are
achieved using the present methodology.
We suggest a mechanism for the reaction which occurs
through the formation of the adduct (I) from the reac-
Table 1. The conversion of 2-hydroxyaryl aldoximes and ketoximes to 1,2-benzisoxazoles using Ph3P/DDQ in dichloromethane at room
temperaturea
Entry
Compound
Product
Isolated
yield (%)
H
C
NOH
1
95
N
O
OH
H
C
Br
Br
NOH
2
93
N
O
OH
H
C
NOH
N
3
4
93
92
O
OH
OCH3
OCH3
H
C
NOH
N
O
HO
HO
OH
CH3
CH3
C
NOH
5
6
95
95
N
O
OH
CH3
CH3
C
NOH
N
O
HO
HO
OH
CH3
NOH
CH3
C
7
93
N
O
H3C
H3C
OH

N. Iranpoor et al. / Tetrahedron Letters 47 (2006) 8247–8250
8249
Table 1 (continued)
Entry
Compound
Product
Isolated
yield (%)
CH3
C
CH3
NOH
NOH
8
9
92
90
N
O
Et
Et
OH
Ph
C
Ph
N
O
H3C
OH
H C
3
(CH2)4CH3
(CH2)4CH3
C
NOH
10
11
12
13
94
93
95
91
N
O
H3C
H3C
OH
OH NOH OH
OH
N
N
O
NOH OH
O
OH
N
OH
OH NOH
O
CH3
CH3
a Quantitative conversion was obtained after 1 min.
Table 2. Comparison of the reaction conditions of the present method
with those reported in the literature
O PPh3
Cl
NC
NC
HON
OH
Entry
Reagent
Conditions
Time
Yield (%)
Ph3P + DDQ
1
2
3
4
Ph3P/DDQ
CH2Cl2/rt
THF/rt
Et2O/0 °C
H2O/0 °C
1 min
30 min
2 h
90–95
33–90
—
Cl
O
Cl3CCONCO
SOCl2/pyridine
Hydroxylamine-
O-sulfonic acid
Ac2O/K2CO3
(I)
1 h
88–95
OH
NC
NC
Cl
Cl
5
C6H6/reflux
5 h
43–61
+
+
Ph3P=O
N
O
OH
tion between Ph3P and DDQ.11 The reaction of the
hydroxyl group of the oxime with the positively charged
phosphorus atom in this intermediate is followed by
cyclization and the formation of the corresponding
1,2-benzisoxazole and triphenylphosphine oxide
(Scheme 2).
Scheme 2.
hydroxyaryl aldoximes and ketoximes under mild and
neutral conditions using a mixture of Ph3P and DDQ
as commercially available, cheap, chemicals. Excellent
yields, fast reactions and the absence of any rearranged
products are worthy of mention for the presented
method.
In conclusion, we have introduced a highly efficient pro-
tocol for the preparation of 1,2-benziosxazoles from 2-

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N. Iranpoor et al. / Tetrahedron Letters 47 (2006) 8247–8250
5. Roman, G.; Comanita, E.; Comanita, B. Tetrahedron
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We are thankful to the Organization of Management
and Planning of Iran and the Shiraz University
Research Council for the support of this work.
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395–398.
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