Direct construction of 5-methyl-2-phenylisoxazol-3(2H)-ones via hypervalent iodine mediated sequential tandem oxidative cyclization of 3-oxo-N- phenylbutanamides catalyzed by zinc oxide (ZnO)

Article abstract of DOI:10.1039/c2ob27145a

A sequential oxidative tandem cyclization reaction mediated by a combination of (diacetoxyiodo)benzene (DIB) with zinc oxide (ZnO) is presented for the synthesis of 5-methyl-2-phenylisoxazol-3(2H)-ones from β-ketobutylanilides. A variety of β-ketobutylanilide compounds were used in this approach, and a wide range of functionalized 5-methylisoxazol-3(2H) -ones were obtained in good to excellent yields.

Full text of DOI:10.1039/c2ob27145a

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Direct construction of 5-methyl-2-phenylisoxazol-
3(2H)-ones via hypervalent iodine mediated sequential
tandem oxidative cyclization of 3-oxo-N-
phenylbutanamides catalyzed by zinc oxide (ZnO)†
Cite this: DOI: 10.1039/c2ob27145a
Received 4th November 2012,
Accepted 22nd November 2012
DOI: 10.1039/c2ob27145a
www.rsc.org/obc
Weibing Liu,*a Peng Zhou,a Cui Chen,a Qing Zhanga and Zhibo Zhu*b
A sequential oxidative tandem cyclization reaction mediated by a
combination of (diacetoxyiodo)benzene (DIB) with zinc oxide
(ZnO) is presented for the synthesis of 5-methyl-2-phenylisoxazol-
3(2H)-ones from β-ketobutylanilides. A variety of β-ketobutylani-
lide compounds were used in this approach, and a wide range of
functionalized 5-methylisoxazol-3(2H)-ones were obtained in
good to excellent yields.
Scheme 1 Synthesis of 5-methyl-2-phenylisoxazol-3(2H)-ones.
structure and synthon, due to the occurrence of this unit in
many molecules that are of biological and pharmaceutical
interest.4
Introduction
Heterocycles feature prominently in pharmaceuticals, agro-
chemicals, organic intermediates and novel materials and this
has provided a driving force for synthetic organic and pharma-
ceutical chemists to develop increasingly efficient methods
toward their synthesis.1 The construction of many heterocyclic
molecules traditionally required several substrates or
reagents.2 Substrates with several reactive positions in the
same molecule, such as β-ketobutylanilides, have provided
advantageous alternatives for the synthesis of heterocycles. We
can regulate the different reactive positions to construct many
different five- and six-membered nitrogen- or oxygen-contain-
ing heterocyclic compounds. β-Ketobutylanilides are a typical
representative, and recently there have been several reports
about the synthesis of several heterocyclic compounds using
β-ketobutylanilides as the only substrate.3 In this communi-
cation, we report a novel method for the direct construction
of 5-methyl-2-phenylisoxazol-3(2H)-ones via (diacetoxyiodo)-
benzene (DIB)-mediated sequential oxidative tandem cycliza-
tion of β-ketobutylanilides catalyzed by zinc oxide (ZnO)
(Scheme 1). As is well known, isoxazole is an important
Results and discussion
Initially 3-oxo-N-phenylbutanamide 1a was selected as a model
substrate to optimize the reaction conditions (Table 1). The
results showed that this transformation did not occur in the
absence of zinc oxide (ZnO) (Table 1, entry 1). Notable efficacy
was achieved for this reaction when increasing the reaction
temperature from room temperature to 100 °C, and afforded
the desired product 5-methyl-2-phenylisoxazol-3(2H)-one in
61% GC yield (Table 1, entries 2–3). Results of the screening
study of the reaction time and the amount of ZnO (Table 1,
entries 2, 4–8) indicated that 0.2 equivalent of ZnO was
sufficient and 5 h was the optimal reaction time for the com-
pletion of the reaction. Among the various solvents examined,
dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfox-
ide (DMSO) were practical for this transformation (Table 1,
entries 4, 9–12).
With the optimized conditions in hand (Table 1, entry 4),
we then investigated the substrate scope of this protocol
(Scheme 2). A range of 3-oxo-N-phenylbutanamides 1a–1j were
all efficiently transformed to their corresponding products
2a–2j in high to excellent yields. Substrates bearing electron-
donating substituents, such as, methyl, methoxyl and ethoxyl,
at the ortho-, meta- or para-positions of benzene ring were also
smoothly converted to the expected 5-methyl-2-phenylisoxazol-
aSchool of Chemistry and Life Science, Guangdong University of Petrochemical
Technology, 139 of Guangdu Two Road, Maoming 525000, P. R. China.
E-mail: lwb409@yahoo.com.cn; Fax: +86-668-2923575; Tel: +86-668-2923956
bSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou
510515, China. E-mail: zzb24@yahoo.com.cn
†Electronic supplementary information (ESI) available: Full experimental details
and copies of NMR spectral data. See DOI: 10.1039/c2ob27145a
This journal is © The Royal Society of Chemistry 2012
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Table 1 Optimization of reaction conditionsa
Entry
Solvent
Reaction time (h)
ZnO (equiv.)
Yieldb (%)
1
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
3
3
3
5
7
5
5
5
5
5
5
5
None
0.2
0.2
0.2
0.2
0.2
0.5
1.0
0.2
0.2
0.2
0.2
None
61
None
88
88
57
88
88
85
82
2
3c
4
5
6
7
8
Scheme 3 Proposed mechanism.
smoothly provide the expected products 2b–2j in good to excel-
lent yield.
9
10
11
12
DMSO
DCE (reflux)
Toluene
72
33
Plausible reaction pathways have been proposed to account
for this transformation, exemplified by the formation of 2a
(Scheme 3). It is well known that Lewis acids can activate 1,3-
diketones to produce intermediate 3.5 Therefore, we speculate
that the O,O′-bound complex 3 is formed initially upon treat-
ment of 1a with Zn(II).6 Then, the nucleophilic nitrogen atom
or oxygen atom of 3 interacts with the electrophilic iodine(III)
of PhI(OAc)2,7 to form intermediate 4 or 5 by eliminating one
equivalent of acetic acid. Subsequent N–I or O–I σ-bond clea-
vage, along with nucleophilic attack of the carbonylic oxygen
atom or nitrogen atom, affords the final product 2a by elimi-
nating one molecule of iodobenzene and one molecule of
acetic acid.
a Reaction conditions: 1a (0.25 mmol), dioxane (2.0 mL). b GC yields.
c Reaction temperature: room temperature.
Conclusions
In summary, we have developed an efficient strategy for the
direct construction of 5-methyl-2-phenylisoxazol-3(2H)-ones
via a sequential tandem oxidative cyclization of 3-oxo-N-
phenylbutanamides using a combination of PhI(OAc)2–ZnO.
The reaction is tolerant of a range of functional groups and
thus effective for a broad scope of substrates. The current
direction for future research is aimed at extending the scope
and potential synthetic applications.
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