N-glycolylhydroxamic acids: an improved synthetic method and the in situ generation and intramolecular rearrangement of N-acetoxy-N-glycolyl-2-aminofluorene.

A new and improved method for the synthesis of glycolylhydroxamic acids is described. The two-step method involves acylation of arylhydroxylamines with acetoxyacetyl chloride, followed by saponification of the ester bond to give the desired products. The conversion of hydroxamic acids to their thallous salts followed by subsequent acetylation with acetyl chloride to give N-acyloxy esters is described. During the course of this investigation, it was observed that the N-acetoxy ester of an N-glycolylhydroxamic acid was highly unstable and underwent a novel O----O acyl migration. This facile rearrangement reaction was studied for the case of N-acetoxy-N-glycolyl-2-aminofluorene (N-OAc-GAF), which gave N-hydroxy-N-(acetoxyacetyl)-2-aminofluorene (N-OH-AcAAF) as the sole product of this rearrangement. HPLC was used to investigate this reaction and included the assignment of an HPLC peak to be due to N-OAc-GAF. A competition study employed the amide N-glycolyl-2-aminofluorene (GAF) and demonstrated the absence of intermolecular transfer of the N,O-acyl (acetyl) group of N-OAc-GAF. The mechanism for the probable intramolecular rearrangement reaction is presented, along with a consideration of the possible significance it might have for the toxicity of glycolylhydroxamic acids.