Palladium‐Catalyzed Enantioselective Domino Heck–Cyanation Sequence: Development and Application to the Total Synthesis of Esermethole and Physostigmine

Abstract An efficient synthesis of functionalized 3‐alkyl‐3‐cyanomethyl‐2‐oxindole 1 by a palladium‐catalyzed domino Heck–cyanation reaction has been developed. Reaction of ortho ‐iodoanilide 5 with potassium ferro( II )cyanide, K 4 [Fe(CN) 6 ], dissolved in DMF in the presence of palladium acetate and sodium carbonate afforded oxindole 1 in good to excellent yields. An enantioselective domino Heck–cyanation process has been developed for the first time using ( S )‐DIFLUORPHOS as a chiral supporting ligand, and an enantioselectivity of up to 79 % ee in the enantiomerically enriched oxindole was obtained under optimized conditions. A concise total synthesis of esermethole and physostigmine, powerful inhibitors of acetyl‐ and butyryl‐cholinesterase, is documented.