Modified Skraup 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. 

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

This reaction was initially reported by Doebner and von Miller in 1881 as a modification of the original Skraup Reaction, and it was subsequently modified by Beyer in 1886 It is an acidic condensation between primary aromatic amines (e.g., anilines) and Q ,j8-unsaturated carbonyl compounds (mostly o ,y3-unsaturated aldehydes) to give 2,3-disubstituted quinolines. Therefore, this reaction is generally known as the Doebner-Miller reaction, or Doebner-Miller synthesis." In addition, this reaction is also referred to as the Doebner-von Miller quinoline synthesis, Skraup-Doebner-von Miller reaction, Skraup-Doebner-von Miller quinoline synthesis, Doebner-Miller condensation, and Doebner-Miller Quinaldine Synthesis. For comparison, the modification from Beyer, known as the Beyer method for quinoline, is an acidic condensation between anilines and Q ,j8-unsaturated carbonyl compounds generated in situ from aldehyde or aldehyde and methyl ketone to afford 2,4-disubstituted quinolines." The optimal condition of this reaction is to heat the mixture of aniline/aldehyde (1 2) at 100°C for 6 h with hydrochloric acid and zinc chloride in addition, an oxidizing reagent is also needed in this reaction, such as nitrobenzene. However, it has been reported that A -alkylanilines are also formed in this reaction. The nature and... 

Theoclitou ME, Robinson LA (2002) Novel facile synthesis of 2,2,4 substituted 1,2-dihydro-quinolines via a modified Skraup reaction. Tetrahedron Lett 43 3907-3910... 

Lown and Sim (5i) have prepared several streptonigrin analogues for a study of structure-activity relationships. The approach taken by these workers was quite closely related to that described above and in one series involved initial formation of quinoline (52) by a modified Skraup synthesis, shown in Scheme 5. This compound was transformed to dichloroquinone (53), which upon stepwise displacements of the chlorines by methoxide and by azide, followed-by catalytic reduction, gave (54). 

---