I guess you can see through again at the fascination with aromatic heterocycles, and the isoxazole ring system is one of them. Got to dabble in their construction early in my medicinal career as a replacement for a a pyridine ring in nicotinic analogs — so long ago (abbott). Most of my interest came from one of the chemists in our group at the time was constructing these with 1,3-dipolar cycloaddition through the nitrile oxide — man, that was cool. In the end somewhat limiting on the substitutions but very cool — so you need a nitrile oxide and a C-C double or triple bond dipolarophile. Here’s an example of the kind of thing I am talking about:

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1,3-cycloaddtion to from isoxazoles

As the story goes however we had a nice chiral proline advanced intermediate that we could use — either as an ester to react with the dianion of an alkyl oxime or and advanced b-ketoester which would react and cyclize with acetone oxime. Well the nitrile oxide chemist said we should be cautious of the hydrogen alpha to the nitrogen protected proline ester — we could racemize the center with a strong base — hahaha, we did. But eventually with enough good chemists around we tackled and made some improvements to generate libraries of these compounds. See the approach:

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Dianion approach to isoxazoles

Ok so that’s a couple of strategies in place. With the first, it makes sense that it could be conceived that this would be set-up to take advantage of microwave irradiation. I have included a few approaches that have been used:

Synthesis 2008

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Sonogashira coupling followed by cycloaddtion

Indian Journal of Chemistry 2011

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Oxime formation followed by ring closure

Synthesis 2002

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Enaminoketone formation followed by cyclization

Athough the formation of the heterocycle is set-up for dipolar cycloadditions, there are a number of opportunities b-diketones and b-ketoesters to react and regioselectively form the desired isoxazole in good yield without relying on dianions to form the advanced intermediate — in careful combination, oxime formation followed by ring closure can be easily achieved.

Happy reading — can anyone think of a good microwave example of vinyl nitrenes used as a substrate or generated in situ as a reactive component? It’s kind of a quiz — there are not many examples.

 

 

 

 

 

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