Palladium-Catalyzed Aerobic Oxidative Spirocyclization of Alkyl Amides with Maleimides via β-C(sp³)–H Activation

Abstract

An efficient method for the synthesis of bicyclic spirodiamine molecules via β-C(sp 3 )−H bond activation of aliphatic amides, followed by cyclization with maleimides, has been developed. The reaction proceeds through an amide-directed β-C(sp 3 )−H bond activation of alkyl amides and subsequent cyclization with maleimides. The methodology is highly compatible with a wide variety of maleimides. Amides derived from biologically active aliphatic and fatty acids were also found to be highly compatible with the protocol. A palladacycle was synthesized and found to be the active intermediate in this reaction. A plausible reaction mechanism was also proposed to account for this spirocyclization.

C–H activation-initiated spiroannulation reactions and their applications in the synthesis of spirocyclic compounds

“…36 Meanwhile, Jeganmohan et al disclosed an efficient spirocyclization of alkyl amides with maleimides by using a Pd( ii ) catalyst and an external ligand, affording spirodiamine derivatives with good efficiency. 37…”

Recent advances in spirocyclization of maleimides via transition-metal catalyzed C–H activation

“…Very recently in 2023, Dutta et al 20 reported a Pd-catalyzed C(sp 3 )–H functionalization (Scheme 17). N -Tosyl or nosyl substituted aliphatic secondary amides 83 reacted with various N -substituted maleimides 16 in the presence of 10 mol% of Pd(OAc) 2 and 30 mol% of quinoline as ligand and 0.5 equivalents of Cu(OAc) 2 ·H 2 O in DCE medium at 110 °C resulting in the corresponding spirodiamines 84 in 20 hours.…”