Direct access to O-alkyl oximes under transition-metal-free conditions

Oxime ethers have increasingly emerged as versatile scaffolds in synthetic organic chemistry owing to their widespread prevalence in biologically relevant motifs and utility in diverse transformations. However, the design of a unified strategy to facilitate the O-alkylation of oximes using alkylating agents of varying substitution (primary, secondary, and tertiary) remains underexplored. Herein, we present the synthesis of a series of primary, secondary and tertiary alkyl-substituted oxime ethers by treating various aldoximes and ketoximes with aryl-substituted alkyl chlorides. Instead of relying on multiple reagents, our methodology leverages the ability of CH₃CN to trigger halogen bonding and achieve the targeted oxime ether under simple and straightforward metal-free reaction conditions. Interestingly, the addition of a base was found to be beneficial for the formation of primary O-alkyl oximes presumably by aiding nucleophilic substitution (S_N2), whereas tertiary and secondary alkyl-substituted oxime ethers could be accomplished without any reliance on a base. The existence of halogen bonding interactions to achieve tertiary and secondary O-alkyl oximes is reinforced via UV-Vis and FT-IR analyses together with DFT calculations. Furthermore, the protocol featured a broad substrate scope and afforded the target product in good to excellent yields (71-97%) along with successful gram-scale synthesis.