Synthesis of Indoles from N-Aryl Amides and Ethyl Diazoacetate

Significance

The synthesis of indole 3-carboxylic acid derivatives 3 via the domino reaction of N-aryl amides 1 with ethyl diazoacetate 2 (EDA) is reported. The combination of 2-chloropyridine, 2,6-dichloropyridine and triflic anhydride proved to be the most efficient reagent system leading to indole products in moderate to excellent yield. A variety of functional groups is tolerated on the aromatic ring, including methyl, halo and ester substituents. A number of starting N-aryl amides were also examined, leading to C-2 alkyl-, branched alkyl- and aryl-substituted indoles. The mechanism for the reaction is discussed in analogy to previous work and likely includes formation of highly electrophilic species 5, which undergoes attack by EDA and intramolecular electrophilic substitution to give 7. Aromatization and tautomerization then leads to the indole 3.