Secondary 3‐Chloropiperidines: Powerful Alkylating Agents

In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart. The synthesis of secondary 3‐chloropiperidines and highly strained bicyclic aziridines is reported, including a new method for the selective mono‐chlorination of unsaturated primary amines. The novel compounds, which closely resemble natural alkylating agents, proved to be more active than previously reported 3‐chloropiperidines in a DNA cleavage assay, highlighting their potential as powerful alkylating agents.