Doebner quinoline synthesis Mechanism

Doebner-von Miller reaction is a variant of the Skraup quinoline synthesis (page 545). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner-von Miller reaction. An alternative mechanism shown below is based on the fact that the preformed imine (Schiff base) also gives 2-methylquinoline ... 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehyde. The mechanism is probably similar to that given for the Doebner-Miller synthesis of quinaldine (Section V,2), involving the intermediate formation of a dihydroqulnoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

The Skraup-Doebner-Von Miller synthesis of quinolines - involving condensation of an aniline with an ,/i-unsalurated ketone - has been investigated using 13C-labelled ketones in cross-over experiments a complex fragmentation-recombination mechanism involving imine intermediates is indicated.17... 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

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