Kondrat’eva pyridine synthesis

What is Kondrat’eva pyridine synthesis?

In 1957, Kondrat’eva reported a reaction that has become a widely used method for synthesizing pyridine derivatives. This reaction involves an inverse demand Diels-Alder cycloaddition between an azadiene, particularly oxazoles, and a dienophile, followed by an extrusion of the resulting bridge of the bicyclic intermediate. It is known as the Kondrat’eva pyridine synthesis, Kondrat’eva reaction, Kondrat’eva cycloaddition, or Kondrat’eva approach.

Kondrat'eva pyridine synthesis - general reaction scheme - Kondrat'eva reaction - Kondrat'eva cycloaddition - Kondrat'eva approach
Kondrat’eva pyridine synthesis

When 2-butene-1,4-diols or derivatives of maleic acid and fumaric acid are used as dienophiles and substituted oxazole as diene, pyridine derivatives are produced. However, only specific isooxazoles with certain substituted patterns can undergo cycloaddition to give pyridine derivatives. For instance, 4-methyl-oxazole reacts with both electron-rich and electron-deficient alkenes and the resulting bicycles can decompose in different ways depending on the substituent R on alkenes. Additionally, an intramolecular version of the Kondrat’eva pyridine synthesis between the tethered oxazole and the alkene usually proceeds smoothly.

However, extremely activated oxazoles like 5-amino-oxazole can undergo different patterns of cycloaddition, including [2+4], [2+3], and even [2+2] cycloaddition, based on the reaction conditions.

References

Kondrat’eva, G. Ya., Khim. Nauk. Prom., 1957, 2, 666

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