Direct organocatalytic transfer hydrogenation and C–H oxidation: high-yielding synthesis of 3-hydroxy-3-alkyloxindoles

Abstract

Readily available 3-alkylideneoxindoles were effectively reduced to 3-alkyloxindoles through transfer hydrogenation using Hantzsch ester as a reducing agent at ambient temperature and the greenness/sustainability of this protocol was assessed by correlation with Pd/C-mediated hydrogenation with hydrogen gas. Furthermore, an organocatalytic method was developed to access drug-like 3-alkyl-3-hydroxyoxindoles by C–H oxidation of 3-alkyl-indolin-2-one, using a catalytic amount of 1,1,3,3-tetramethylguanidine (TMG) as an organic base and dissolved oxygen in THF as an oxidant at room temperature. Key reaction intermediates were observed by controlled on-line ESI-HRMS experiments and identified by their corresponding mass (m/z) analysis. This two-step high-yielding transfer hydrogenation/C–H oxidation protocol was used for the total synthesis of medicinally important 3-cyanomethyl-3-hydroxyoxindole and formal total synthesis of (±)-alline and (±)-CPC-I in very good overall yields compared to previous methods.