Quinolines Vilsmeier-Haack reaction

Preparation of Quinoline (Vilsmeier-Haack Reaction) and Substituted... 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

Subjecting acetanilides to the conditions of the Vilsmeier-Haack reactions is an effective method for the preparation of quinolines <8iJCS(Pi)i537>. On the other hand, if the phenacetanilide of anthranilic acid is subjected to the identical reaction conditions, 4-dimethylamino-3-phenyl-5H-benz[()]azepine-2,5-dione (189) is formed in high yield <84S349>. The phenyl group of anthranilic acid may be replaced by thienyl and pyridyl without loss in the efficiency of cyclization. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

The reaction of orf/to-nitroarylacetonitriles with the Vilsmeier-Haack reagent, prepared from Ai-methylpyrrolidone, followed by intramolecular cyclization, induced by diazabicycloimdecene (DBU) in the presence of h -trimethylsilylacetamide (BSA), leads directly to pyrrolo[3,2-h]quinoline derivatives (Scheme 90) [213]. 

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