One-Pot Synthesis of Abietane-Type Hydroxamic Acids: Process Optimization and Mechanistic Insights.

The synthesis of hydroxamic acids from sterically hindered substrates, such as abietane-type resin acids, remains a synthetic challenge due to the congestion of the tricyclic skeleton. This study reports an efficient one-pot protocol for the direct conversion of abietic and dehydroabietic acids into their corresponding hydroxamic derivatives, achieving 65% and 74% isolated yields, respectively. Systematic screening of activating agents identified diethyl chlorophosphate (DCP) as the reagent for the hydroxyamidation. A critical finding of this work is that the optimization of the isolation process specifically minimizing the water amount during aqueous work-up was key to recovering these polar products and preventing important yield loss. The reaction proceeds through diethyl phosphate mixed anhydride intermediate, which was successfully isolated, providing direct experimental evidence of the activation pathway. The reaction mechanism was further elucidated using Density Functional Theory (DFT) calculations at the M062X/6-31G** level, identifying a concerted transition state for the simultaneous addition of hydroxylamine and expulsion of the phosphate group. Furthermore, the study rationalizes the observed chemoselectivity; although the ester is the more stable thermodynamic product, the formation of the N-hydroxy amide is kinetically favored through a substantially lower activation barrier. This combined experimental and theoretical approach establishes a practical and scalable methodology for the functionalization of abundant similar natural terpenoids.