Petrenko-Kritschenko piperidone synthesis
Encyclopedia
The Petrenko-Kritschenko reaction is a classic multicomponent name reaction that is closely related to the Robinson-Schöpf tropinone
synthesis, but was published 12 years earlier.
, 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.
In contrast to the Robinson synthesis, it does not employ dialdehydes like succinaldehyde or glutaraldehyde
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.
salts . The use of anilin has also been reported in the original Publication. The product of this reaction shows transoid configuration of the phenyl groups at C-2 and C-6.
.
in the presence of hydrogen peroxide
.
Tropinone
Tropinone is an alkaloid, famously synthesised in 1917 by Robert Robinson as a synthetic precursor to atropine, a scarce commodity during World War I. Tropinone and the alkaloids cocaine and atropine all share the same tropane core structure.-Synthesis:...
synthesis, but was published 12 years earlier.
Classic reaction
In the original publication diethyl-α-ketoglurate, a derivative of acetonedicarboxylic acidAcetonedicarboxylic acid
Acetonedicarboxylic acid or 3-oxoglutaric acid is a simple carboxylic acid, which may be used as a building block in organic chemistry....
, 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.
In contrast to the Robinson synthesis, it does not employ dialdehydes like succinaldehyde or glutaraldehyde
Glutaraldehyde
Glutaraldehyde is an organic compound with the formula CH22. A pungent colorless oily liquid, glutaraldehyde is used to disinfect medical and dental equipment...
but simpler aldehydes like benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
. Therefore the product of the reaction is not a bicyclic structure (see tropinone
Tropinone
Tropinone is an alkaloid, famously synthesised in 1917 by Robert Robinson as a synthetic precursor to atropine, a scarce commodity during World War I. Tropinone and the alkaloids cocaine and atropine all share the same tropane core structure.-Synthesis:...
and pseudopelletierine
Pseudopelletierine
Pseudopelletierine is an alkaloid derived from the bark of the pomegranate tree. It is a homolog of tropinone, and can be synthesized in a manner analogous to the classical Robinson tropinone synthesis, using glutaraldehyde , acetonedicarboxylic acid, and methylammonium chloride....
) 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
Hantzsch pyridine synthesis
The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component organic reaction between an aldehyde such as formaldehyde, 2 equivalents of a β-keto ester such as ethyl acetoacetate and a nitrogen donor such as ammonium acetate or ammonia. The initial reaction product is...
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
Chromium trioxide
Chromium trioxide is the inorganic compound with the formula CrO3. It is the acidic anhydride of chromic acid, and is sometimes marketed under the same name.This compound is a dark-red/orange brown solid, which dissolves in water concomitant with hydrolysis...
in acetic acid leads to a symmetrically substituted 4-pyridone, decarboxylation yields the 3,5-unsubstituted derivative.
Modern variants
Acetoacetate can be used instead of diethyl-α-ketoglurate in the presence of indiumIndium
Indium is a chemical element with the symbol In and atomic number 49. This rare, very soft, malleable and easily fusible post-transition metal is chemically similar to gallium and thallium, and shows the intermediate properties between these two...
salts . The use of anilin has also been reported in the original Publication. The product of this reaction shows transoid configuration of the phenyl groups at C-2 and C-6.
Natural product synthesis
The reaction has been used to prepare precoccinellin, an alkaloid found in certain ladybugsCoccinellidae
Coccinellidae is a family of beetles, known variously as ladybirds , or ladybugs . Scientists increasingly prefer the names ladybird beetles or lady beetles as these insects are not true bugs...
.
Applications to coordination chemistry
When benzaldehyde is substituted with 2-pyridinecarboxaldehyde the reaction can be used to prepare precursors for bispidone-ligands. 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 cyclohexaneCyclohexane
Cyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which being intermediates used in the production of nylon...
in the presence of hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
.