Skraups quinoline synthesis

Quinolines 3 can be obtained from reaction of orr/zo-aminobenzaldehydes or o-aminoarylketones 1 with a-methylene carbonyl compounds.Various modified procedures are known a related reaction is the Skraup quinoline synthesis. 

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 ... 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

Scheme 7. The classical Skraup quinoline synthesis (a) and Fukuyama s modified approach (b) using /V-aryl-AZ-sulfonylaminopropionaldehydes (56).

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