Synthesis of 4- and 6-Azaindoles via the Fischer Indole Reaction

Significance

Reported is an efficient application of the Fischer indole reaction for the synthesis of 4- and 6-azaindoles 3 by treatment of pyridyl­hydrazines 1, bearing electron-donating groups, with various carbonyl derivatives 2 (linear, cyclic alkyl and nonsymmetric ketones, and ketals) under acidic conditions (H₂SO₄). A tandem push-pull mechanism is used to rationalize the unusual reactivity and the para/ortho EDG (OMe, SMe) to the hydrazine is required to assist the C2 or C4 heterocyclization (H. Ishii Acc. Chem. Res. 1981, 14, 275). To provide additional analogy for this ­hypothesis, the synthesis of the 6-azaindole 8 was realized by the reaction of the 2-MeO hydrazine 6 with cyclohexanone. As an application of this methodology, the preparation of the aza analogue of the natural glycozoline 9 was achieved.