An unexpected hydrazine-mediated ring opening pathway of 3-substituted indole acetonitriles was identified during efforts to synthesize 3-pyrazolo-substituted indoles inspired by the meridianin scaffold. Treatment of DMF–DMA-activated indole acetonitriles with hydrazine under acidic conditions afforded together with the expected pyrazolo-substituted compounds a rarely reported class of pyridazino4,5- c quinoline derivatives arising from skeletal cleavage of the indole core. Systematic evaluation of reaction parameters revealed that temperature, solvent, and acid loading strongly influence the synthetic pathway. High-temperature conditions favor pyrazole formation, whereas acetic acid promoted competitive C2–N1 bond scission leading to pyridazine-fused products. Spectroscopic analysis, supported by mechanistic considerations, indicated that a highly activated intermediate may underwent nucleophilic cleavage of the indole framework, diverting the reaction from pyrazoloindole formation. • Unexpected indole ring opening observed during pyrazoloindole synthesis. • Isolation and characterization of a novel scaffold. • Competes with the classical DMF–DMA/hydrazine cyclocondensation. • Mechanistic proposal rationalizes divergent reactivity. • Provides new insight into activated indole acetonitrile behavior
Kalampaliki et al. (Thu,) studied this question.