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Petrenko-Kritschenko piperidone synthesis

The Petrenko-Kritschenko reaction is a classic multicomponent-name reaction^[1] that is closely related to the Robinson–Schöpf tropinone synthesis, but was published 12 years earlier.

In the original publication^[2] diethyl-α-ketoglurate, a derivative of acetonedicarboxylic acid, is used in combination with ammonia and benzaldehyde. The relative stereochemistry was not elucidated in the original publication, structural analysis using X-rays or NMR was not available in these days. In the absence of ammonia or ammonium salts a 4-oxotetrahydropyran is formed.^[3]

In contrast to the Robinson synthesis, it does not employ dialdehydes like succinaldehydeorglutaraldehyde but simpler aldehydes like benzaldehyde. Therefore, the product of the reaction is not a bicyclic structure (see tropinone and pseudopelletierine) but a 4-piperidone. The synthesis of tropinone can be seen as a variation of the Petrenko-Kritschenko reaction in which the two aldehyde functions are covalently linked in a single molecule. Apart from the Hantzsch synthesis the Petrenko-Kritschenko reaction is one of the few examples in which a symmetric pyridine precursor can be obtained in a multicomponent ring-condensation reaction followed by an oxidation. The oxidation by chromium trioxide in acetic acid leads to a symmetrically substituted 4-pyridone, decarboxylation yields the 3,5-unsubstituted derivative.^[2]

Acetoacetate can be used instead of diethyl-α-ketoglurate in the presence of indium salts.^[4] The use of aniline has also been reported in the original Publication.^[2] The product of this reaction shows transoid configuration of the phenyl groups at C-2 and C-6.

The reaction has been used to prepare precoccinellin, an alkaloid found in certain ladybugs.^[1]

When benzaldehyde is substituted with 2-pyridinecarboxaldehyde the reaction can be used to prepare precursors for bispidone-ligands.^[5] Essentially this method is based on two subsequent Petrenko-Kritschenko reactions. These ligands can be used to prepare compounds containing high-valent iron, that are able to oxidize cyclohexane in the presence of hydrogen peroxide.

• A picture of Paul Petrenko-Kritschenko taken at the Kazan School of Chemistry in 1928 (1st row, first on the left): http://www.ksu.ru/chmku/images/30b.jpg