Scott Grecian, V. Fokin
Oct 13, 2008
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Angewandte Chemie
Abstract
Isoxazoles, a major class of five-membered nitrogen heterocycles, are embedded in a number of pharmaceutically important compounds that have been the focus of numerous biological studies during the last several years. Although a variety of methods for their synthesis have been reported, few are general, regioselective, and high yielding. The cycloaddition of alkynes and nitrile oxides, which is probably the most direct route to access these heterocycles, is rarely used. The reasons for this are simple: in contrast to the reaction with olefins, the uncatalyzed, thermal cycloaddition reactions of nitrile oxides with alkynes are neither chemonor regioselective and, as a consequence, are plagued by low yields and the formation of multiple products. These shortcomings are not surprising considering the relatively high reactivity of nitrile oxides, their propensity to dimerize, and the general inert character of alkynes. Copper(I) acetylides have been shown to react regioselectively with nitrile oxides to generate 3,5-disubstituted isoxazoles. However, there are no reported methods for generating the regiocomplementary 3,4-disubstituted isomers. In fact, even when thermal cycloaddition reactions of nitrile oxides with alkynes are successful, they favor the formation of the 3,5-disubstituted isomer (Scheme 1). Furthermore, examples of reactions of nitrile oxides with internal alkynes are limited to a handful of highly activated alkynes (e.g. acetylene dicarboxylate and related electron-deficient acetylenes). Unactivated, electron-rich, or sterically hindered acetylenes usually fail to react altogether. The recent discovery of the ruthenium(II)-catalyzed azide– alkyne cycloaddition reaction, which produces 1,5-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles, prompted us to explore the catalytic activity of ruthenium complexes in nitrile oxide–alkyne cycloaddition reactions. Herein, we report that 3,5-diand 3,4,5-trisubstituted isoxazoles can be obtained with excellent regioselectivity at room temperature by a ruthenium(II)-catalyzed cycloaddition reaction of nitrile oxides (generated in situ from hydroximoyl chlorides by treatment with Et3N) and terminal or internal alkynes, respectively. Initially, we screened several ruthenium(II) complexes and common solvents for their catalytic activity (Table 1). When phenylacetylene and 4-chloro-N-hydroxybenzimidoyl chloride were combined with Et3N in the absence of a ruthenium catalyst at room temperature, the 3,5-disubstituted regioisomer 1b was formed exclusively, as determined by GC analysis of the crude reaction mixture (Table 1, entry 1). In contrast, when [Cp*RuCl(cod)] (cod = cycloocta-l,5-diene, Cp* = C5Me5) was used, 1a was formed preferentially, but incomplete conversion was observed in DMF, THF, and CHCl3 (Table 1, entries 2–4) With 5 mol% of [Cp*RuCl(cod)] in 1,2-dichloroethane (1,2-DCE), the starting materials were converted into the 3,4-disubstituted isoxazole 1a (95:3 1a/1b ; Table 1, entry 5). Other Ru complexes, lower Scheme 1. Cycloaddition reactions of nitrile oxides and alkynes. EWG = electron-withdrawing group.