Efficient Et₃N-Catalyzed three-Component Synthesis of 4,5,6,7-Tetrahydro-3-Cyanoindoles and its Conversion to 3-Cyanoindoles

We report a highly efficient and scalable one-pot Et₃N-catalyzed cascade reaction for synthesizing 4,5,6,7-tetrahydro-3-cyanoindoles from hydroxycyclohexanone dimers, oxoacetonitriles, and primary amines in up to 91 % yield. This reaction proceeds through aldol condensation, cyclization via Paal-Knorr synthesis, and subsequent aromatization under mild, cyanide-free and metal-free conditions. The reaction uses readily available starting materials and accommodates a broad substrate scope, including diverse oxoacetonitriles and aliphatic or aromatic amines, without significant variations in yield. Gram-scale synthesis demonstrates its practical applicability, producing the target compounds with consistent efficiency. Additionally, the 4,5,6,7-tetrahydro-3-cyanoindoles were successfully converted to their corresponding 3-cyanoindoles, emphasizing the synthetic versatility of this approach and offering a practical and more environmentally friendly alternative for generating these compounds.