ORGANIC
LETTERS
2012
Vol. 14, No. 4
1164–1167
Intramolecular 1,3-Dipolar Cycloaddition
of Nitrile N-Oxide Accompanied by
Dearomatization
Morio Yonekawa,† Yasuhito Koyama,*,† Shigeki Kuwata,‡ and Toshikazu Takata*,†
Department of Organic and Polymeric Materials, Department of Applied Chemistry,
Tokyo Institute of Technology 2-12-1 (H-126), Ookayama, Meguro-ku, Tokyo 152-
8552, Japan
ttakata@polymer.titech.ac.jp; ykoyama@polymer.titech.ac.jp
Received January 18, 2012
ABSTRACT
Intramolecular 1,3-dipolar cycloaddition of 2-phenoxybenzonitrile N-oxides to benzene rings, accompanied by dearomatization, formed the
corresponding isoxazolines in high yields. The X-ray single-crystal structure analysis revealed that the reaction formed the cis-adduct as a single
isomer. The substituents on the benzene rings markedly affected the reaction rate, yield, and structure of the final product.
Nitrile N-oxide is an important class of 1,3-dipoles,
which facilitates catalyst-free [2 þ 3] cycloaddition to
various unsaturated bonds, such as alkenes, alkynes, and
nitriles.1ꢀ3 In particular, the cycloaddition of nitrile N-
oxide is regarded as an effective tool for the synthesis of
pharmaceuticals, natural products, polymeric materials,
and supramolecules because it is accompanied by CꢀC
bond formation; in addition, the resulting heterocycles
serve as versatile scaffolds for a variety of reactive deriv-
atives, such as aldol, diketone, β-aminoalcohol, and
β-aminoenone.4,5 Typically, nitrile N-oxide is labile and
dimerizes easily to form furoxan; however, it can be made
sufficiently stable by the introduction of bulky substituents,
which are capable of preventing dimerization, and thus
can be isolated.6
Recently, we developed a kinetically stabilized homo-
ditopic nitrile N-oxide as a new chemical ligation tool
between unsaturated bond-containing compounds, mainly
directed toward both catalyst-free cross-linking reactions
of common polymers, such as fibers, rubbers, and resins,
and catalyst-free polycycloaddition of bisdipolarophiles.7
In the elaborate process of developing the homoditopic
nitrile N-oxide, we encountered a very interesting fact:
bisphenol A-skeleton-linked homoditopic nitrileN-oxide 1
exhibited low stability, which rapidly decomposed at room
temperature, whereas the tetramethylated analogue 2 ex-
hibited sufficient stability to be isolated without loss in
the reactivity of the 1,3-dipole (Figure 1). The structural
analysis of the resultant mixture from 1 revealed that
† Department of Organic and Polymeric Materials.
‡ Department of Applied Chemistry.
(1) Quilico, A.; Fusco, R. Gazz. Chim. Ital. 1937, 67, 589–603.
(2) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565–598.
(3) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339–
5342.
(4) For selected reviews on 1,3-dipolar cycloaddition of nitrile N-
oxides in targeted syntheses, see: (a) Kozikowski, A. P. Acc. Chem. Res.
1984, 17, 410–416. (b) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–
12275.
(6) For selected reports of stable nitrile N-oxides, see: (a) Beltrame,
P; Veglio, C.; Simonetta, M. J. Chem. Soc. (B) 1967, 867–873. (b)
Grundmann, C; Richter, R. J. Org. Chem. 1968, 33, 476–478.
(7) (a) Koyama, Y.; Yonekawa, M.; Takta, T. Chem. Lett. 2008, 37,
918–919. (b) Lee, Y. G.; Koyama, Y.; Yonekawa, M.; Takata, T.
Macromolecules 2009, 42, 7709–7717. (c) Lee, Y. G.; Koyama, Y.;
Yonekawa, M.; Takata, T. Macromolecules 2010, 43, 4070–4080. (d)
Lee, Y. G.; Yonekawa, M.; Koyama, Y.; Takata, T. Chem. Lett. 2010,
39, 420–421. (e) Matsumura, T.; Ishiwari, F.; Koyama, Y.; Takata, T.
Org. Lett. 2010, 12, 3828–3831. (f) Koyama, Y.; Takata, T. Kobunshi
Ronbunshu 2011, 68, 147–159. (g) Koyama, Y.; Seo, A.; Takata, T.
Nippon Gomu Kyokaishi 2011, 84, 111–116.
€
(5) (a) Caramella, F.; Grunanger, P. 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Intersciences: New York, NY, 1984; p
€
291. (b) Jager, V.; Colinas, P. A. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons: New Jersey, NJ, 2003;
p 361.
r
10.1021/ol300125s
Published on Web 02/09/2012
2012 American Chemical Society