Condition-Controlled Divergent Reactivity of Nitroaldol Isatin Adducts with Phenols: Friedel–Crafts Alkylation, Skeletal Rearrangement, and Spirocyclic Oxime Formation

We describe the condition-controlled divergent reactivity of nitroaldol isatin adducts with phenols. Under methanesulfonic acid, nitroalcohols undergo Friedel–Crafts alkylation to afford 3-aryl-3-(nitromethyl)indolin-2-ones in yields of up to 99%. Prolonged acidic treatment of selected Friedel–Crafts adducts leads to an unusual C3-to-C2 skeletal rearrangement, providing tetracyclic chromenoindolones in moderate yields. In contrast, treatment of the alkylation products with KOH in aqueous ethanol promotes intramolecular cyclization to spirocyclic hydroxyimino derivatives. This transformation afforded 16 compounds in 80–96% yields, whereas five new chromenoindolones were obtained in 40–56% yields. In total, 51 new compounds were synthesized, comprising 30 Friedel–Crafts alkylation products, 16 spirocyclic oxime derivatives, and five new chromenoindolones. The structures of representative products 8aa and 13ab were established by X-ray crystallography. The Friedel–Crafts reaction tolerates a range of alkyl, halogen, hydroxy, alkoxy, and N-substituted substrates, although several strongly electron-withdrawing substituents and α-naphthol were not compatible with the reaction conditions. Scalability was demonstrated on a 10 mmol scale for the synthesis of 7ae and its subsequent conversion to 13ae. The results demonstrate that nitroaldol isatin adducts can undergo markedly different reaction pathways depending on the reaction conditions, providing access to structurally distinct indole-containing frameworks.