3. On azirines. 2/2

In the last post I concluded on the fact that you could obtain 4-phenyloxazole by a Lewis acid-mediated rearrangement from a phenyl-substituted azirine-carbaldehyde. It seems at first like trying to establish a synthesis from an intermediate more convoluted than the final product is. When seeing the azirine structure for the first time, I figured how to call it referring to nomenclature rules, but I was only vaguely aware of their existence, I thought azirines would be reaction intermediates at best. I was surprised to discover that you could actually isolate some of these compounds, and even more surprised to find that their synthesis was not that dreadful. Actually, you can synthesise 3-phenyl-2H-azirine-2-carbaldehyde in two steps from easily accessible and dirt cheap starting materials. The first step is a Vilsmeier-Haack-type reaction on acetophenone that generally delivers the β,β-disubstitued acrolein in pleasingly high yields.1 Then, reaction of said acrolein with sodium azide affords the azirine in moderate-to-high yield (typically around 60-70%).2

3.a Azirine synth

I found this second reaction quite intriguing. Guessing that azide, as a good nucleophile, would add in a Michael fashion to the acrolein, leading eventually to the bromide being kicked out, an then something else would happen to the newly formed vinyl azide en route to the azirine. The only way out I could imagine was the elimination of a nitrogen molecule, leaving a highly unstable vinyl nitrene that would rearrange to the more stable azirine form, Curtius rearrangement-style.

 3.b vinyl azide rearr

It seems that I wasn’t too unrealistic here because, according to Wikipedia, the rearrangement of vinyl azides is the most popular way to synthesise azirines directly. This led me to discover that azirines are also reliable precursors for the in situ formation of nitrile ylides, which can be involved in dipolar cycloadditions, e.g. with an alkyne to form a 3,4-substituted pyrrole after tautomerisation.

 3.c nitrile ylide

Azirines apparently also play a role as an intermediate in the Neber rearrangement (to be honest I had never heard of it before) that converts oximes to α-aminoketones.

 3.d Neber rearr

1. J. Org. Chem. 2013, 78, 6223-6232 link
2. J. Heterocycl. Chem. 2008, 45, 311-317. link


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