Angewandte
Communications
Chemie
Heterocycles
Synthesis of 2H-Azirines by Iridium-Catalyzed Decarboxylative Ring
Contraction of Isoxazol-5(4H)-ones
Kazuhiro Okamoto,* Takuya Shimbayashi, Masato Yoshida, Atsushi Nanya, and Kouichi Ohe*
Abstract: A phosphine-free iridium-catalyzed reaction of
isoxazol-5(4H)-ones (isoxazolones) has been developed, and
affords 2H-azirines through decarboxylation and ring con-
traction. This method provides an efficient and environmen-
tally benign protocol which could replace the conventional
approaches used to synthesize 2H-azirines.
alkenylnitrene equivalents in which a palladium catalyst
efficiently catalyzes either the intramolecular aziridination or
aza-Wittig-type condensation with aldehydes.[8,9] The key
intermediates in these reactions are considered to be vinyl-
imido complexes of palladium or azapalladacyclobutenes,
À
which are formed by the oxidative addition of N O bonds of
isoxazolones to palladium, followed by decarboxylation
(Scheme 2). The reductive elimination of these plausible
2H-Azirines, which are three-membered, nitrogen-con-
=
taining, unsaturated heterocyclic compounds bearing a C N
bond, are highly strained molecules. They are the structural
motifs seen in some antibiotic molecules.[1] The reactivity of
2H-azirines is characterized by their high ring-strain energy,
which can cause various ring-opening reactions, such as
hydrolytic formation of aminocarbonyl compounds,[2] transi-
tion-metal-catalyzed cycloaddition with unsaturated mole-
cules,[3] and various nucleophilic addition reactions leading to
aziridines.[4] Synthetic approaches to 2H-azirines are limited
to a few types of reactions: denitrogenative cyclization of
alkenyl azides (Scheme 1a) or base-mediated eliminative
Scheme 2. Palladium- and iridium-catalyzed reactions of isoxazol-5-
(4H)-ones.
Scheme 1. Conventional synthetic approaches to 2H-azirines.
Ts =4-toluenesulfonyl.
intermediates seems possible, and should afford 2H-azirines
as products. However, when we used palladium catalysts in
our investigations, the generation of 2H-azirines could not be
detected. We now report on an iridium-catalyzed decarbox-
ylative ring-contraction reaction of isoxazolones, a reaction
which affords 2H-azirines selectively.
cyclization reactions of oxime esters, N-haloimines, or hydra-
zonium salts (Scheme 1b; Neber reaction).[1e] Both reactions
require the generation of N-alkenylnitrene equivalents as
intermediates. In the former case, great care should be taken
when using explosive azide compounds as reagents. In the
latter case, undesired reactions of 2H-azirines with bases or
protic solvents should be carefully avoided.[5–7]
In a preliminary reaction, the isoxazolone 1a (bearing
a methallyl group) reacted with a catalyst precursor [{IrCl-
(coe)2}2] (5 mol%) and PPh3 (20 mol%) as a ligand in 1,4-
dioxane at 1008C for 3 hours. The corresponding 2H-azirine
2a was obtained in 56% yield at a 67% conversion of 1a
(Table 1, entry 1).[10] Then various polar and nonpolar sol-
vents were examined under these reaction conditions. The
yields, based on the consumed isoxazolone 1a, were low when
the following solvents were used: toluene, 1,2-dichloroethane,
and DMF (entries 2–4). Acetonitrile resulted in very low
conversion (entry 5). Examination of ether-type solvents
revealed the following: cyclopentyl methyl ether (CPME)
resulted in a high yield of 2a (85% yield) at full conversion of
1a, whereas 1,2-dimethoxyethane (DME) and 2-MeTHF
were as effective as 1,4-dioxane.
We have developed some reactions of isoxazol-5(4H)-
ones (isoxazolones) as new types of thermally stable N-
[*] Dr. K. Okamoto, T. Shimbayashi, M. Yoshida, A. Nanya,
Prof. Dr. K. Ohe
Department of Energy and Hydrocarbon Chemistry, Graduate School
of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: kokamoto@scl.kyoto-u.ac.jp
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Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 7199 –7202
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7199