Direct synthesis of trisubstituted isoxazoles through gold-catalyzed domino reaction of alkynyl oxime ethers

Article abstract of DOI:10.1021/ol100803e

Alkynyl oxime ether underwent a gold-catalyzed domino reaction involving cyclization and subsequent Claisen-type rearrangement to afford trisubstituted isoxazoles in a direct, efficient, and regioselective manner. The products were successfully applied to the synthesis of unusual heterocycles as an illustration of the potential utility of the reaction.

Full text of DOI:10.1021/ol100803e

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2594-2597
Direct Synthesis of Trisubstituted
Isoxazoles through Gold-Catalyzed
Domino Reaction of Alkynyl Oxime
Ethers
Masafumi Ueda, Aoi Sato, Yuki Ikeda, Tetsuya Miyoshi, Takeaki Naito, and
Okiko Miyata*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
miyata@kobepharma-u.ac.jp
Received April 7, 2010
ABSTRACT
Alkynyl oxime ether underwent a gold-catalyzed domino reaction involving cyclization and subsequent Claisen-type rearrangement to afford
trisubstituted isoxazoles in a direct, efficient, and regioselective manner. The products were successfully applied to the synthesis of unusual
heterocycles as an illustration of the potential utility of the reaction.
Highly substituted isoxazoles are core components of many
natural products, biologically active compounds, and func-
tional materials.1-3 Thus, synthesis of these molecules with
high efficiency is highly desirable.4-11 Although a common
and typical strategy for the synthesis of isoxazoles is the
[3+2] cycloaddition reaction between alkynes and nitrile
oxides, a cycloaddition reaction with internal alkynes for the
direct construction of trisubstituted isoxazole has been less
frequently reported.12-14 Furthermore, these methods require
harsh conditions and provide poor chemo- and regioselec-
tivities. As an alternative strategy for efficient construction
of isoxazoles, Larock recently reported stepwise synthesis
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10.1021/ol100803e  2010 American Chemical Society
Published on Web 05/04/2010

of trisubstituted isoxazoles by electrophilic cyclization of
O-methyl alkynyl oxime ethers and a subsequent palladium-
catalyzed coupling reaction of the resulting 4-haloisoxazole.15
From the viewpoint of atom economy, the direct and waste-
free synthesis of trisubstituted isoxazoles with high chemo-
and regioselectivities in one sequence is highly desirable and
challenging. We anticipated that π-acidic transition metal-
catalyzed cyclization of alkynyl oxime ether would lead to
new generation of a vinyl metal intermediate, in which the
substituent R3 could rearrange to the C4 position providing
trisubstituted isoxazoles under suitable conditions (eq 1).
oxime ether moiety to alkyne has not yet been reported.25,26
Herein, we report the direct synthesis of trisubstituted
isoxazole through a domino process involving cyclization
and subsequent rearrangement in connection with our recent
explorations of the domino reaction of conjugated imines.27
The O-allyl alkynyl oxime ether 1a, which was prepared
by the condensation of 1,3-diphenylprop-2-yn-1-one with
O-allylhydroxylamine hydrochloride, was initially employed
in this study. We expected that the oxonium intermediate
would easily undergo Claisen-type [3,3]-sigmatropic rear-
rangement. Our studies commenced with a survey of catalysts
with the goal of identifying effective conditions. When 1a
was treated with 20 mol % of AgBF4 in 1,2-dichloroethane
at reflux for 5 h, the expected reaction proceeded successfully
to give trisubstituted isoxazole 2a in 85% yield (Table 1,
π-Acidic transition metal-catalyzed intramolecular addition
of a heteroatom to an alkyne and subsequent migration of
the substituent is one of the most powerful strategies for the
synthesis of heterocyclic compounds.16 Although these
transformations have provided useful access to benzofurans,17
indoles,18 benzothiophenes,19 furans,20 pyrans,21 and pyrro-
lidine,22 less is known about the synthesis of isoxazoles.23,24
Moreover, intramolecular addition of the oxygen atom in the
Table 1. Optimization of Cyclization-Rearrangement Reaction
entry
catalyst (mol %)
t (h)
yield (%)a
1
2
3
4
5
AgBF4 (20)
5
12
12
2
85
17
27
90
88
AuCl(PPh3) (20)
PdCl2(PPh3)2 (20)
AuCl3 (20)
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M. P.; Rider, J. T. Org. Lett. 2006, 8, 3679. (b) Denmark, S. E.; Kallemeyn,
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M.; Varasi, M. J. Chem. Soc., Perkin Trans. 1 1993, 2151.
AuCl3 (5)
2
a Isolated yields.
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Larock, R. C. J. Comb. Chem. 2008, 10, 658. (b) Waldo, J. P.; Larock,
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entry 1). Although Ag(I), Au(I), or Pd(II) catalysts all
afforded the desired product, AuCl3 was found to be the most
effective catalyst. Thus, the cyclization-rearrangement reac-
tion in the presence of only 5 mol % of AuCl3 proceeded
effectively with high yield (entry 5).28,29
To examine the scope of the reaction, we treated various
O-allyl alkynyl oxime ethers 1b-l with AuCl3 in refluxing
1,2-dichloroethane and obtained the trisubstituted isoxazole
2b-l in good to high yields (Table 2). Electron-rich or
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T.; Terada, M. J. Am. Chem. Soc. 2009, 131, 2804
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Org. Lett., Vol. 12, No. 11, 2010
2595

Table 2. Au-Catalyzed Cyclization-Rearrangement Reaction
Table 3. Substitution Effect on the Allyl Group
entry substrate
R1
R2
product yield (%)a
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
1g
1h
1i
4-MeOC6H4 Ph
4-CF3C6H4 Ph
2b
2c
2d
2e
2f
2g
2h
2i
88
85
80
83
53
81
90
72
83
99
78
furyl
cyclohexyl
CO2Me
Ph
Ph
Ph
Ph
cyclohexyl
nBu
Ph
8b
9b
10
11
Ph
Ph
2-BrC6H4
allyl
1j
1k
1l
2j
2k
2l
Ph
Ph
CH2OTBS
CH2OH
a Isolated yields. b Reactions were carried out with AuCl3 (20 mol %).
electron-poor aryl groups, and alkyl groups for R1, were
readily accommodated, producing the expected trisubstituted
isoxazoles 2b-e (entries 1-4). Imino ester 1f was also
employed in this reaction, thus affording isoxazole carboxy-
late 2f (entry 5). Variation of the substituent on the triple
bond terminus was also tolerable (entries 6-11). Remark-
ably, a 2-bromophenyl group and an allyl group for R2 were
tolerated under the reaction condition; these groups are
advantageous for further transformation (entries 8 and 9). It
is noteworthy that the unprotected hydroxyl group did not
affect the course of the reaction (entry 11).
We next studied the substituent effect on the allyl moiety
(Table 3). The additional substituents caused an increase in
catalyst loading and prolonged reaction time for complete
consumption of the substrate, probably because of steric
repulsion. The linear (E)-crotylated isoxazole 4a was regio-
and stereoselectively obtained in 42% yield when O-1-
methylallyl oxime ether 3a was used as a substrate in the
presence of 20 mol % of AuCl3, while the formation of a
small amount of branched product was observed by 1H NMR
of the reaction mixture (entry 1). It is noteworthy that the
new carbon-carbon bond was generated predominantly at
the γ-position in an SN2′ fashion. This result indicated that
the migration of the allyl moiety would proceed not through
a shift of the allyl cation intermediate,20c,22,30 but rather
through a Claisen-type [3,3]-sigmatropic rearrangement.
The reaction of methallyl derivative 3b proceeded ef-
fectively to afford trisubstituted isoxazole 4b in 78% yield
(entry 2). On the other hand, the methyl group at the terminal
position of the allyl moiety led to a decrease in the chemical
yield of branched product 4c, and a significant amount of
linear product 4a was also formed via a 1,3-shift of the crotyl
group (entry 3). The gold-catalyzed reaction of 3d, which
a Isolated yields. b Reactions were carried out with AuCl3 (20 mol %)
in DCE at reflux. c Reaction was carried out with AuCl3 (5 mol %) in DCE
at reflux. d Reactions were carried out with AuCl3 (5 mol %) followed by
treatment with Et3N (3 equiv).
bears an additional allyl group, provided unconjugated diene
(E)-4d in 64% yield (entry 4). Interestingly, substrate 3e
bearing a silyloxymethyl group efficiently underwent the
domino reaction with use of 5 mol % of AuCl3 to yield the
corresponding isoxazole 4e (entry 5). Possibly, the chelation
of the oxygen atom in 3e enhanced the reactivity of the
catalyst. The cyclization/rearrangement reaction can be
applied to the electron-deficient allyl moiety. The reaction
of crotonate 3f with 5 mol % of AuCl3 followed by
stereoselective isomerization by Et3N afforded the function-
alized isoxazole 4f in 70% yield (entry 6).
On the basis of the above results, a possible reaction
pathway is shown in Scheme 1. It commences with the
addition of an oxygen atom to an Au(III)-activated C-C
triple bond, generating an oxonium intermediate A, which
would undergo Claisen-type rearrangement to form inter-
mediate B. The subsequent aromatization of B would afford
isoxazole and liberate the catalytic gold species. In the case
(30) (a) Bae, H. J.; Baskar, B.; An, S. E.; Cheong, J. Y.; Thangadurai,
D. T.; Hwang, I. C.; Rhee, Y. H. Angew. Chem., Int. Ed. 2008, 47, 2263.
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2596
Org. Lett., Vol. 12, No. 11, 2010

Scheme 1
.
Possible Reaction Pathway
Scheme 3. Synthetic Application
of 3c, steric repulsion between the methyl group and the gold
moiety might decrease the chemical yield of 4c.
The proposed reaction pathway was partially supported
by the results of a crossover experiment (Scheme 2).
to afford pyrano[4,3-d]isoxazole 6, which could be used for
further functionalization of the carbon-iodine bond.32 Pal-
ladium-mediated intramolecular Heck reaction of 2i provided
4H-benzo[3,4]cyclohept[1,2-d]isoxazole 7 with a 76% yield
and high regioselectivity.33
Scheme 2. Crossover Reaction of 1b and 3e
In summary, we have developed a novel method for the
synthesis of trisubstituted isoxazoles from alkynyl oxime
ether. The trisubstituted isoxazoles were produced via gold-
catalyzed cyclization followed by an allyl oxonium Claisen-
type rearrangement. The present method was successfully
applied to the synthesis of unusual heterocycles. The domino
reaction is characterized by mild conditions, is straightfor-
ward, and allows for the efficient construction of function-
alized isoxazoles.
Acknowledgment. This work was supported in part by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology of Japan, and the Science
Research Promotion Fund of the Japan Private School
Promotion Foundation. M.U. is grateful for the Research
Foundation for Pharmaceutical Science.
Treatment of an equimolar mixture of 1b and 3e with 5 mol
% of AuCl3 gave 2b and 4e in 99% and 80% yields,
respectively, without any crossover products. This result
indicates that the transfer of the allyl moiety proceeds in an
intramolecular manner.
To demonstrate the synthetic utility of the trisubstituted
isoxazoles as highly versatile building blocks, we investigated
further transformations into a variety of different heterocycles
(Scheme 3). The 3,4-diallylisoxazole 2j was transformed into
dihydrobenzisoxazole 5 by ring closing metathesis with an
excellent yield.31 Iodoetherification of 2l with bis(2,4,6-
collidine)iodonium hexafluorophosphate proceeded smoothly
Supporting Information Available: Experimental pro-
cedure, characterization data, and 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100803E
(32) Tony, K. A.; Li, X.; Dabideen, D.; Li, J.; Mootoo, D. R. Org.
Biomol. Chem. 2008, 6, 1165.
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