Synthesis of 1,2-benzisoxazole 2-oxides

Article abstract of DOI:10.1080/00397911.2011.563451

(Chemical Equation Presented) A series of 2-hydroxyaryl ketoximes were converted to the corresponding 1,2- benzisoxazole 2-oxides by treatment with iodobenzene diacetate (in acetic acid or methanol) or N-chlorosuccinimide in water. Both methods gave moderate to excellent yields for a variety of substituted oximes under mild conditions within short reaction times. The latter method has the advantages of an aqueous solvent and lack of halogenated organic by-products. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.563451

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Synthesis of 1,2-Benzisoxazole 2-Oxides
Martin G. Kociolek a & Olivia Hoermann a
a Pennsyivania State Erie, Behrend College, School of Science, Erie,
Pennsylvania, USA
Accepted author version posted online: 09 Nov 2011.Published
online: 29 May 2012.
To cite this article: Martin G. Kociolek & Olivia Hoermann (2012) Synthesis of 1,2-Benzisoxazole 2-
Oxides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:17, 2632-2638, DOI: 10.1080/00397911.2011.563451
To link to this article: http://dx.doi.org/10.1080/00397911.2011.563451
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Synthetic Communications1, 42: 2632–2638, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.563451
SYNTHESIS OF 1,2-BENZISOXAZOLE 2-OXIDES
Martin G. Kociolek and Olivia Hoermann
Pennsyivania State Erie, Behrend College, School of Science,
Erie, Pennsylvania, USA
GRAPHICAL ABSTRACT
Abstract A series of 2-hydroxyaryl ketoximes were converted to the corresponding 1,2-
benzisoxazole 2-oxides by treatment with iodobenzene diacetate (in acetic acid or
methanol) or N-chlorosuccinimide in water. Both methods gave moderate to excellent
yields for a variety of substituted oximes under mild conditions within short reaction times.
The latter method has the advantages of an aqueous solvent and lack of halogenated organic
by-products.
Keywords Benzisoxazole; 1,2-benzisoxazole 2-oxide; iodobenzene diacetate; N-chloro-
succinimide
INTRODUCTION
In the course of our investigations into new methods for the synthesis of
benzo-fused heterocycles, a number of reagents employing electrophilic halogen
atoms were examined for their ability to facilitate N-O bond formation. While many
reagents proved unsatisfactory, two were found to be useful in this capacity, iodo-
benzene diacetate (IBDA) and N-chlorosuccinimide (NCS). It was observed that
2-hydroxyaryl ketoximes 1 were smoothly converted to the corresponding 1,2-
benzisoxazole 2-oxides 2a–k (Scheme 1). The synthesis of 1,2-benzisoxazole 2-oxides
using lead tetraacetate[1,2] and sodium perborate,[3] as well as the structure and
properties of these heterocycles,[4–9] have been previously reported. It was the goal
of this study to investigate the scope and limitations of these two reagents for this
transformation.
Received December 31, 2010.
Address correspondence to M. G. Kociolek, Penn State Erie, Behrend College, School of Science,
Erie, PA 16563, USA. E-mail: mgk5@psu.edu
2632

1,2-BENZISOXAZOLE 2-OXIDES
2633
Scheme 1. Cyclization of 2-hydroxyaryl ketoximes.
The utility of iodobenzene diacetate in reactions with nitrogen-containing
carbonyl derivatives is well documented.[10] The treatment of aldoximes with hyper-
valent iodine reagents has been shown to give nitriles oxides.[11–13] While treatment
of ketoximes has been shown facilitate oxidative cleavage to give the corresponding
ketones,[14,15] the literature also contains sporadic references for hypervalent iodine
compounds used in the formation of heterocyclic N-oxides.[2,16–18]
With this in mind, a number of hypervalent iodine compounds were investi-
gated for the cyclization of 2-hydroxyaryl ketoximes. Initially, the cyclization
was attempted with Koser’s reagent (HTIB) and 1H-1-hydroxy-5-methyl-1,2,3-
benziodoxathiole 3,3-dioxide (HMBI) under a variety of conditions with neither
reagent giving any cyclized products. However, treatment of the oximes with iodo-
benzene diacetate yielded 1,2-benzisoxazole 2-oxides as the major products. It is
speculated that the increased basicity of the acetate ion (compared to tosylates in
HTIB and HMBI) is necessary for the cyclization. This is consistent with other meth-
ods reported in the literature for this cyclization, which involve either acetate or a
more basic counterion. Initially, acetic acid was used as the solvent (method A).
The reaction was usually complete within 15–20 with good yields obtained for most
substrates. However, a number of the lower-molecular-weight benzisoxazoles gave
poor yields (Entries 1 and 8), whereas higher-molecular-weight compounds gave bet-
ter results (entries 4, 5, 9, and 11). This may result from differing solubilities of the
final products in the acidic aqueous reaction mixture. Changing the solvent to meth-
anol (method B) improved the yields considerably (Table 1), with the only exception
being naphthisoxazole 2j (entry 10), which gave a dark reaction mixture and very lit-
tle product in either solvent. Reaction times in methanol were faster, with the reac-
tion for most substrates complete within 5 min.
In addition to hypervalent iodine reagents, a number of other electrophilic
halogen reagents were investigated. It has been previously demonstrated that sodium
hypochlorite can be used to facilitate formation of 1,2-benzisoxazole 2-oxides.[2]
Along theses lines, a number of other chlorinating reagents were attempted including
trichloroisocyanuric acid, cyanuric chloride, chloramine-T, and N,N-dichloro-p-
toluenesulfonamide. The only reagent that proved suitable was N-chlorosuccinimide
(NCS). NCS has been employed to convert aldoximes to hydroximinoyl chlorides[19,20]
or nitriles[21] and ketoximes to amides.[21] Treatment of a basic solution of 2-hydro-
xyaryl ketoximes with NCS (method C) yielded 1,2-benzisoxazoles 2-oxides in good
to excellent yields for most substrates (Table 1), with the reactions usual complete in
5–10 min. Interestingly naphthisoxazole 2j, which proved troublesome with IBDA,
gave reasonable yields with NCS. However, the related naphthisoxazole 2k gave a
dark reaction mixture and poorer yields with NCS.

2634
M. G. KOCIOLEK AND O. HOERMANN
Table 1. Synthesis of 1,2-benzisoxazole 2-oxides from 2-hydroxyaryl ketoximes
Yield (%)
(method A)
Yield (%)
(method B)
Yield (%)
(method C)
Entry
X
R
Product
1
2
3
4
5
6
7
8
9
H
5-CH3
6-CH3
5-Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Et
2a
2b
2c
2d
2e
2f
21
55
49
76
72
55
55
24
74
90
86
82
82
85
82
65
76
84
91
89
73
92
92
48
50
70
89
5-Br
6-OCH3
5-NO2
H
2g
2h
2i
H
Ph
10
CH3
CH3
2j
20
23
56
11
2k
72
81
24
In conclusion, we report the cyclization of 2-hydroxyaryl ketoximes with two
electrophilic halogen reagents, IBDA and NCS. Both methods give good to excellent
yields of most 1,2-benzisoxazole 2-oxides under mild conditions with fast reaction
times. The NCS method has the advantage of an aqueous solvent and lack of halo-
genated organic byproducts. These results demonstrate the ability of these two
reagents to facilitate N-O bond formation, a utility that could be exploited in the
synthesis of related heterocycles.
EXPERIMENTAL
1H and 13C NMR spectra were obtained on a Bruker 400-MHz spectrometer in
solvents specified using tetramethylsilane (TMS) as an internal standard. Elemental
analysis was performed by M=M, LLC. Solvents and reagents were obtained com-
mercially and used without further purification. All oximes were synthesized from
the commercially available ketones by standard methods (hydroxylamine hydro-
chloride, ethanol, aqueous sodium hydroxide).
Method A
The ketoxime (1 mmol) was dissolved in acetic acid (5–10 mL) at room tem-
perature. Iodobenzene diacetate (1 mmol) was added portionwise over a 5-min per-
iod, after which the reaction was stirred and monitored by thin-layer chromatographic
(TLC) analysis. Typically, the starting material disappeared within 15–20 min. The
reaction was poured into water (25 mL), and the resulting precipitate was vacuum
filtered and dried. When further purification was necessary, the 1,2-benzisoxazoles

1,2-BENZISOXAZOLE 2-OXIDES
2635
2-oxides were either recrystallized in ethanol=water mixtures or purified by column
chromatography using hexanes=ethyl acetate as the eluting solvent.
Method B
The ketoxime (1 mmol) was dissolved in methanol (5–10 mL) at room tempera-
ture. Iodobenzene diacetate (1 mmol) was added portion wise over a 5-min period
after which the reaction was stirred and monitored by TLC analysis. Typically, start-
ing material disappeared within 5 min. The reaction was concentrated under reduced
pressure. The crude product was triturated with hexanes, during which the products
typically precipitated. The solid was vacuum filtered and washed with additional
hexanes. When further purification was necessary, the 1,2-benzisoxazoles 2-oxides
were recrystallized in ethanol=water mixtures or purified by column chromatography
using hexanes=ethyl acetate as the eluting solvent.
Method C
The oxime (1 mmol) was suspended in water (5–10 mL) at room temperature,
and 1 M NaOH (1 mL) was added. The solution was stirred until all solids dissolved
completely. N-Chlorosuccinimide (1 mmol) was added portionwise over a 5-min per-
iod during which a precipitate formed. The solid was vacuum filtered and dried.
When further purification was necessary, the 1,2-benzisoxazoles-2-oxides were
recrystallized in ethanol=water mixture or purified by column chromatography using
hexanes=ethyl acetate as the eluting solvent.
1,2-Benisoxazole 2-oxides 2a, 2b, and 2d–i have been previously reported and
were characterized by the physical and spectral properties, which were consistent
with those in the literature. 1,2-Benisoxazole 2-oxides 2c, 2j, and 2k were character-
1
ized by H NMR, 13C NMR, and elemental analysis, all of which were consistent
with the proposed structures.
Entry 1
3-Methyl-1,2-benzisoxazole 2-oxide (2a): mp 94–95 ꢀC, lit. mp 96 ꢀC;[2] 1H
NMR (400 MHz, acetone-d6): 7.61 (d, J ¼ 7.2 Hz, 1H), 7.53 (m, 1H), 7.32 (m, 1H),
7.24 (d, J ¼ 8.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6): 151.6, 130.08, 125.5,
123.0, 121.3, 116.6, 108.1, 10.0.
Entry 2
3,5-Dimethyl-1,2-benzisoxazole 2-oxide (2b): mp 75–77 ꢀC, lit. mp 74 ꢀC;[2] 1H
NMR (400 MHz, acetone-d6): 7.36 (s, 1H), 7.32 (d, J ¼ 8.4 Hz, 1H), 7.09 (d,
J ¼ 8.4 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, acetone-d6):
149.8, 135.0, 130.9, 122.9, 120.8, 116.6, 107.7, 21.8. 9.9.
Entry 3
3,6-Dimethyl-1,2-benzisoxazole 2-oxide (2c): mp 104–105 ꢀC; 1H NMR
(400 MHz, acetone-d6): 7.45 (d, J ¼ 8.0 Hz, 1H), 7.14 (d, J ¼ 8.0 Hz, 1H), 7.05 (s,

2636
M. G. KOCIOLEK AND O. HOERMANN
1H), 2.44 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, acetone-d6): 151.9, 140.9, 126.6,
120.8, 120.3, 116.5, 108.2, 22.5, 10.0; Anal. calcd. for C9H9NO2: C, 66.25; H, 5.56;
8.58. Found: C, 66.11; H, 5.59; N, 8.32.
Entry 4
5-Chloro-3-methyl-1,2-benzisoxazole 2-oxide (2d): mp 131–133 ꢀC, lit. mp
133 ꢀC;[2] 1H NMR (400 MHz, acetone-d6): 7.67 (d, J ¼ 2.0 Hz, 1H), 7.52 (dd,
J ¼ 8.4, 2 Hz, 1H), 7.26 (d, J ¼ 8.4 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz,
acetone-d6): 149.2, 129.6, 129.1, 124.0, 120.1, 115.7, 108.9, 9.3.
Entry 5
5-Bromo-3-methyl-1,2-benzisoxazole 2-oxide (2e): mp 122–123 ꢀC, lit. mp
117 ꢀC;[2] 1H NMR (400 MHz, acetone-d6): 7.80 (d, J ¼ 2.0 Hz, 1H), 7.65 (dd,
J ¼ 8.4, 2 Hz, 1H), 7.20 (d, J ¼ 8.4 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz,
acetone-d6): 149.6, 131.9, 124.8, 123.1, 116.8, 115.4, 109.2, 9.3.
Entry 6
6-Methoxy-3-methyl-1,2-benzisoxazole 2-oxide (2f): mp 128–131 ꢀC, lit. mp
132–135 ꢀC;[2] 1H NMR (400 MHz, acetone-d6): 7.48 (d, J ¼ 8.8 Hz, 1H), 6.92 (dd,
J ¼ 8.8, 2 Hz, 1H), 6.87 (d, J ¼ 2.0 Hz, 1H), 3.89 (s, 3H), 2.35 (s, 3H); 13C NMR
(100 MHz, acetone-d6): 163.1, 152.9, 121.7, 116.2, 115.2, 113.9, 93.3, 56.9, 9.9.
Entry 7
5-Nitro-3-methyl-1,2-benzisoxazole 2-oxide (2g): mp 172–174 ꢀC (dec.), lit. mp
176 ꢀC;[2] 1H NMR (400 MHz, acetone-d6): 8.19 (d, J ¼ 2.4 Hz, 1H), 8.44 (dd, J ¼ 8.8,
2.4 Hz, 1H), 7.49 (d, J ¼ 8.8 Hz, 1H), 2.53 (s, 3H); 13C NMR (100 MHz, acetone-d6):
153.6, 145.1, 124.7, 123.1, 117.0, 115.4, 107.8, 9.2.
Entry 8
3-Ethyl-1,2-benzisoxazole 2-oxide (2h): clear oil; 1H NMR (400 MHz, acetone-
d6): 7.62 (m, 1H), 7.51 (m, 1H), 7.32 (m, 1H), 7.22 (m, 1H), 2.85 (q, J ¼ 7.6 Hz), 1.31
(t, J ¼ 7.6 Hz); 13C NMR (100 MHz, acetone-d6): 150.9, 129.2, 124.7, 121.5, 120.5,
119.9, 107.4, 18.3, 10.2.
Entry 9
3-Phenyl-1,2-benzisoxazole 2-oxide (2i): mp 91–92 ꢀC, lit. mp 90 ꢀC;[2] 1H
NMR (400 MHz, acetone-d6): 8.11 (m, 2H), 7.86 (m, 1H), 7.66-7.56 (m, 4H),
7.41-7.33 (m, 2H); 13C NMR (100 MHz, acetone-d6): 151.2, 130.9, 129.9, 129.5,
128.5, 126.6, 125.3, 121.4, 120.5, 117.5, 107.7.

1,2-BENZISOXAZOLE 2-OXIDES
2637
Entry 10
3-Methyl-naphth[1,2-d]isoxazole 2-oxide (2j): mp 165 ꢀC (dec.); 1H NMR
(400 MHz, CDCl3): 8.59 (d, J ¼ 8.8 Hz, 1H), 7.88 (d, J ¼ 8.8, 1H), 7.60 (d, J ¼ 8.8 Hz,
1H), 7.68 (m,1H), 7.57 (m, 1H), 7.39 (d, J ¼ 8.8 Hz, 1H), 2.83 (s, 3H); 13C NMR
(100 MHz, CDCl3): 148.3, 130.7, 129.9, 129.6, 127.9, 126.3, 125.5, 122.1, 118.4,
114.1, 108.0, 12.1; Anal. Calcd. for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found:
C, 71.98; H, 4.32; N, 6.85.
Entry 11
3-Methyl-naphth[2,1-d]isoxazole-2-oxide (2k): mp 115 ꢀC (dec.); 1H NMR
(400 MHz, CDCl3): d 8.09 (d, J ¼ 7.6 Hz, 1H), 7.91 (d, J ¼ 7.6, 1H), 7.70 (d,
J ¼ 8.4 Hz, 1H), 7.60 (m, 2H), 7.43 (d, J ¼ 8.4 Hz, 1H), 2.51 (s, 3H); 13C NMR
(100 MHz, CDCl3): 146.7, 133.1, 128.6, 127.4, 127.2, 124.9, 120.8, 117.8, 117.1,
116.0, 115.9. 9.6. Anal. calcd. for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found:
C, 72.65; H, 4.52; N, 7.18.
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