Investigations into the N-dealkylation reaction of protected chelating agents

To comply with the specific requirements for the coordination of a certain metal ion, it is often necessary to decrease the substitution degree on the nitrogen atoms of well-known poly(aminocarboxylate) ligands used as chelators for the preparation of diagnostic or therapeutic probes. The procedures used so far to prepare such partially-alkylated compounds involve steps that suffer from product loss or the need to introduce protection/deprotection reactions, consequently lowering the final yield. The application of an N-dealkylation reaction to an exhaustively-substituted precursor could in principle allow to achieve the same result in fewer steps and therefore with higher yields. Dealkylation reactions have been known since the early 1900s, but they have never been exploited for such a purpose. We investigated the applicability of the simple iron-Polonovski N-dealkylation reaction to obtain a library of useful ligands starting from the tert-butyl-protected derivatives of chelators widely used in the biomedical fields such as CDTA, EDTA, NOTA, AAZTA and PCTA. The preparation of partially-alkylated ligands has already been reported in the literature but with several drawbacks and possible improvements. In most of the examples reported, it was found that the reaction occurred in an easy and straightforward way by only using an excess of oxidizing agent that was sufficient to convert the N-oxide into the N-dealkylated product without the need for a reducing agent.