Facile synthesis of disubstituted isoxazoles from homopropargylic alcohol via C=N bond formation

Article abstract of DOI:10.1021/ol503228x

A novel iron-catalyzed aerobic oxidative reaction to synthesize disubstituted isoxazoles from homopropargylic alcohol, t-BuONO, and H₂O is developed. The method provides mild conditions to afford a variety of useful substituted heterocycles in an efficient and regioselective manner. The mechanism has been studied and proposed, which indicates that the transformation can be realized through construction of a C=N bond and C=O bond, C-H oxidation, and then cyclization. Moreover, this method can be enlarged to gram scale.

Full text of DOI:10.1021/ol503228x

Letter
pubs.acs.org/OrgLett
Facile Synthesis of Disubstituted Isoxazoles from Homopropargylic
Alcohol via CN Bond Formation
Pin Gao, Hong-Xia Li, Xin-Hua Hao, Dong-Po Jin, Dao-Qian Chen, Xiao-Biao Yan, Xin-Xing Wu,
Xian-Rong Song, Xue-Yuan Liu,* and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A novel iron-catalyzed aerobic oxidative reaction
to synthesize disubstituted isoxazoles from homopropargylic
alcohol, t-BuONO, and H2O is developed. The method provides
mild conditions to afford a variety of useful substituted
heterocycles in an efficient and regioselective manner. The
mechanism has been studied and proposed, which indicates that the transformation can be realized through construction of a
CN bond and CO bond, C−H oxidation, and then cyclization. Moreover, this method can be enlarged to gram scale.
soxazole derivatives occupy an important field in organic
Ichemistry because of their wide applications in organic
synthesis pharmacy chemistry, biologically active molecules, and
advanced organic materials.1 As a consequence, the development
of versatile and efficient methods for the preparation of such
compounds is an important task.2 Commonly used strategies for
the formation of isoxazoles include oximation and cyclization of
1,3-dicarbonyl compounds and α,β-unsaturated compounds
with hydroxylamine as the nitrogen source,3a,b condensation of
oxime dianions,3c−e 1,3-dipolar cycloaddition reaction between
alkynes and the primary nitro compounds or nitrile oxides.3f−i
However, most of the above reactions often required harsh
reaction conditions, showed modest regioselectivities and yield,
and were neither economic nor eco-friendly. The discovery and
development of new methods with easy preparation material,
mild reaction conditions, and high regioselectivities for the
synthesis of isoxazoles is highly desirable and challenging.4 In
2010, Miyata’s group reported a gold-catalyzed domino reaction
involving cyclization and Claisen-type rearrangement of alkynyl
oxime resulting isoxazoles in a regioselective and atom economic
manner.5a In 2011, Carreira reported an unexpected cascade and
rearrangement reaction to give 3,4-disubtituted isoxazoles with
commercially available material.5b 1.3-Dipolar cycloaddition of
benzoylnitromethane with phenylacetylene under green con-
ditions has been realized by Pal’s group.5c Although significant
progress in the area has been made, synthesis of isoxazoles via
constructing the CN bond is still less exploited4a,5d and
remains both challenging and of great value.
novel iron-catalyzed aerobic oxidative reaction to synthesize
disubstituted isoxazoles from homopropargylic alcohol, t-
BuONO, and H2O (Scheme 1). This method is realized via
construction of a CN bond and CO bond in a highly
regioselective difunctionalization of alkyne, C−H oxidation, and
then cyclization.
Scheme 1. Our Method for Synthesis of Disubstituted
Isoxazoles
Our investigation commenced with the reaction of 1,4-
diphenylbut-3-yn-1-ol (1a) with tert-butyl nitrite (2), 10 mol %
of Zn(OTf)2 ,and 1.5 equiv of H2O in acetonitrile (MeCN) at
room temperature under air atmosphere. The disubstituted
isoxazoles (3a) were isolated in 12% yield (Table 1, entry 1). By
screening different metal salts for this cyclic transformation,
including Cu(OTf)2, Sc(OTf)3, Bi(OTf)3, Fe(OTf)2, Fe(OTf)3,
FeCl3, and Fe(NO3)3·9H2O, we found that Fe(OTf)3 was the
most efficient and increased the yield to 81% (Table 1, entries 2−
10). Next, different solvents were tested with Fe(OTf)3 as the
catalyst (Table 1, entries 11−14). Results revealed that the
reaction was highly solvent-dependent with optimal isolated
yields in acetonitrile, and the use of DCM, toluene, 1,4-dioxane,
DMF proved to be ineffective to promote this transformation.
Lowering the catalyst loading reduced the yield of 3a to 67%
(Table 1, entry 15). Considering that the catalyst might be
hydrolyzed to produce trifluoromethanesulfonic acid, different
amounts of trifluoromethanesulfonic acid were investigated and
gave the product in moderate yield (Table 1, entries 16 and 17).
Other NO2 sources were tested but did not afford better yields
Difunctionalization of unactivated alkynes has gained more
and more attention in organic synthesis. To continue our interest
in functionalization of homopropargylic alcohol,6 we anticipated
that the alcohol would react with additional nitrogen source to
produce the nitrogen-containing heterocycles. tert-Butyl nitrite is
a safe and extensively used reagent in organic synthesis as a
nitrating reagent7a−g or a diazo reagent to undertake Sandmeyer-
type reaction;8 however, it has rarely been reported as the
nitrogen source to construct heterocycles.7g,h Herein, we report a
Received: October 12, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503228x | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
ab
,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope of the Synthesis of Isoxazoles
b
entry
cat
solvent
yield (%)
1
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
Fe(OTf)2
AgOTf
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
12
2
trace
64
3
4
58
5
trace
67
6
Bi(OTf)3
Yb(OTf)3
Fe(OTf)3
FeCl3
7
63
8
81
9
56
10
11
12
13
14
Fe(NO3)3·9H2O
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
HOTf
trace
17
toluene
dioxane
DMF
trace
trace
trace
67
c
15
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
d
16
65
e
17
HOTf
42
f
18
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
18
g
19
trace
0
h
20
21
0
a
Reaction conditions: 1a (0.2 mmol), tert-butyl nitrite (2) (0.24
mmol), catalyst (0.02 mmol), H2O (0.3 mmol) in solvent (2.0 mL)
a
Reaction conditions: 1a (0.2 mmol), tert-butyl nitrite (2) (0.24
b
c
mmol), Fe(OTf)3 (0.02 mmol), and H2O (0.3 mmol) in solvent (2.0
mL) were stirred at rt for 6.0 h under air. Isolated yield.
were stirred at rt for 6.0 h under air. Isolated yield. Catalyst (0.01
b
d
e
mmol) was used. Catalyst (0.10 mmol) was used. Catalyst (0.05
f
mmol) was used. Fe(NO3)3·9H2O (0.24 mmol) was added instead of
t-BuONO. AgNO2 (0.24 mmol) was added instead of t-BuONO. 4
g
h
tested. Substrates bearing methyl substituents in the ortho, meta,
or para position of the aryl groups provided the corresponding
disubstituted isoxazoles 3m−o in moderate yield. When the
substrate bearing a methoxyl substituent in para position of the
aryl group was examined (1p), the reaction system was complex
and trace product was observed. Halo-substituted alcohols 1q−s
were tolerated in the cyclization reaction, producing the products
3q−s in good yields. The structure of 3s was determined by X-ray
crystallographic analysis (see the Supporting Information).9 This
cyclization transformation protocol could be applicable to
substrates 1t and 1u with a 4-trifluoromethyl group or 2,6-
difluoro groups on the aromatic ring, giving 3t and 3u in
moderate yield. Notably, the naphthalene group of isoxazoles 3v
was also tolerated in this transformation. Unfortunately,
substrates containing the furyl or cinnamyl groups (1w and
1x) were not compatible with the reaction conditions.
To expand the synthetic efficiency of this method, a gram-scale
reaction of 1a was performed under the standard conditions. The
desired isoxazole 3a was isolated in 68% yield, which means there
is a potential industrial application (Scheme 3).
Next, some additional experiments were performed in order to
give a better understanding of the cyclization reaction. When the
reaction was stirred under the standard conditions for 10 min, we
Å MS (40 mg) were added instead of H2O.
(Table 1, entries 18 and 19). The control experiment revealed
that the iron catalyst and H2O were essential for the reaction
(Table 1, entries 20 and 21). Consequently, the reaction
proceeded efficiently in the presence of 10 mol % of Fe(OTf)3
and 1.5 equiv of H2O in acetonitrile at room temperature.
The scope of the substrates was investigated under the
optimized conditions (Scheme 2). A variety of substituted
homopropargylic alcohols were found to be compatible with this
tandem cyclization transformation, giving various 3,5-disubsti-
tuted isoxazoles derivatives. First, the influences of substituents
on the aryl groups attached to the alkyne were tested. When
homopropargyl alcohols bearing electron-donating substituents
(Me, OMe) and electron-drawing substituents (F, Cl, Br,
COOMe) were placed on the para or meta position, the
substrates performed well and afforded the desired products in
good yield (3a−d,f−i). The steric hindrance effect was obvious
on the transformation reactivity. The corresponding product 3e
was obtained in a low yield when the ortho position was
substituted with a methyl group (1e). Substrate 1j containing a
strong electron-withdrawing CF3 group afforded the disubsti-
tuted isoxazoles 3j in moderate yield. It is noteworthy that
substrates with thiophene 1k and naphthalene (1l) attached to
the triple bond could also undergo tandem cyclization
successfully, affording the desired products in 76% and 74%
yield, respectively. However, when the methyl attached to the
alkyne was tested, no desired product was observed. Then, a
number of alcohols derived from substituted benzaldehydes were
Scheme 3. Synthetic Application: Gram-Scale Reaction
B
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Letter
not only obtained the product 3a in 24% yield but also isolated
the oxime intermediate 4 in 34% yield (Scheme 4, eq 1). X-ray
Scheme 6. Proposed Mechanism
Scheme 4. Mechanistic Studies and Control Experiments
BuONO7g,11a and H2O, to the triple bond of homopropargylic
alcohol 1a led to the formation of a vinyl nitrite A11b with HOTf
as the catalyst, which was generated from Fe(OTf)3. The
intermediates A can easily isomerize to the acyloxime
intermediates 4.11b Subsequently, aerobic oxidation of the
intermediates 4 produces the intermediates B,12,13 which
would convert to the desired isoxazole 3a by treatment with
acid.3a
In conclusion, we have developed a novel iron-catalyzed
aerobic oxidative reaction to synthesize disubstituted isoxazoles
from homopropargylic alcohol, t-BuONO, and H2O under mild
conditions. The reaction proceeds efficiently in a highly
regioselective manner to give various disubstituted isoxazoles
in moderate to excellent yields. Preliminary mechanistic studies
revealed that the transformation is realized via construction of a
CN bond and CO bond in a highly regioselective
difunctionalization of alkyne, C−H oxidation, and then
cyclization. To our knowledge, this is the first example employing
t-BuONO as the nitrogen source to construct isoxazoles, thus
making it an attractive reagent for synthetic purposes.
crystallographic analysis revealed that the intermediate 4 is the
absolute E-stereoisomer, which is the favored style for the
cyclization.10 However, when the system was stirred under argon
atmosphere for 6.0 h, 3a could only be obtained in 17% yield; the
intermediate 4 was also observed and isolated in 22% (Scheme 4,
eq 2). When the intermediate 4 was stirred under argon
atmosphere for 6 h, only trace 3a was isolated (Scheme 4, eq 3).
These observations indicated that O2 is necessary for the
conversion of the key intermediate 4 to the product. This
intermediate 4 can be directly transformed into isoxazole product
3a with Fe(OTf)3 or tert-butyl nitrite as the catalyst in 91% and
70% yield, respectively (Scheme 4, eqs 4 and 5). However, the
intermediate 4 was fully recovery without the catalyst or with
trifluoromethanesulfonic acid, which can be produced by the
Fe(OTf)3 and H2O, as the catalyst (Scheme 4, eq 6). It can thus
be concluded that ferric catalyst or tert-butyl nitrite play an
important role in the further transformation of intermediate 4.
The 18O-Labeled Experiment in the presence of H218O has
been performed to understand the cyclization reaction
mechanism (Scheme 5). The results showed that a mixture of
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures and spectroscopic data (1H
NMR and 13C NMR) for the corresponding products. This
material is available free of charge via the Internet at http://pubs.
acs.org.
Scheme 5. 18O-Labeled Experiment
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liuxuey@lzu.edu.cn
*E-mail: liangym@lzu.edu.cn
Notes
The authors declare no competing financial interest.
mono-oxygen-atom-containing products 3a, O118, and 3a were
observed with a 1:1.2 ratio. This suggests that the oxygen atom of
the product 3a can be from t-BuONO and H2O (for details, see
the Supporting Information).
On the basis of these preliminary results and previous
reports,3a,7g,11,12 a possible mechanism is proposed (Scheme
6). Initially, addition of HNO2, in situ generated from t-
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (NSF21272101,
21302076, 21472074) for financial support. We also acknowl-
edge support from the “111” Project and Program for Changjiang
Scholars and innovative Research Team in University
(IRT1138).
C
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Organic Letters
Letter
(9) The structure of 3s was confirmed by X-ray crystallography. For
details of the crystal analysis data, see the Supporting Information.
(10) The structure of 4 was confirmed by X-ray crystallography. For
details of the crystal analysis data, see the Supporting Information.
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