Nucleophile-Directed Dichloromethane-Mediated Coupling of Carboxylic Acids for Access to Acyl Hydrazides and 3-Amino-1,2,4-Oxadiazoles

Abstract Carboxylic acids undergo direct coupling with hydrazine using CH2Cl2 as the coupling reagent and K3PO4 as the base to afford acyl hydrazides. Conversely, sequential one-pot coupling with guanidine in the presence of Cs2CO3, followed by PIDA-mediated oxidative cyclization, delivers 3-amino-1,2,4-oxadiazoles. Both protocols tolerate diverse functional groups, and the oxadiazole synthesis enables late-stage derivatization of probenecid, adapalene, and ataluren. Control experiments suggest that hydrazine reacts primarily through a bis(acyloxy)methane intermediate, whereas guanidine can engage both bis(acyloxy)methane and acyloxymethyl chloride intermediates. These results demonstrate that CH2Cl2-mediated carboxylic acid activation constitutes a programmable coupling platform wherein the identity of the nitrogen nucleophile governs the reaction pathway.