Synthesis of Novel 8‐ cyclo ‐1,5,3, 7‐Diazadiphosphocine Derivatives Via [4 + 2] Cycloaddition

As part of our research program into pharmacologically valuable compounds and chelating agents for transition metal ions, novel 8‐ cyclo ‐1,5,3,7‐diazadiphosphocines ( 5 – 16 ) were successfully synthesized in good yields via [4 + 2] cycloaddition reaction between 8‐ cyclo ‐1,5,3,7‐diazadiphosphocines ( 4a ‐ c ) with dienophiles (dimethyl acetylenedicarboxylate [DMAD], diethyl acetylenedicarboxylate [DEAD], diethyl diazene‐1,2‐dicarboxylate [DEDAD], and diisopropyl diazene‐1,2‐dicarboxylate [DIPDAD]). The core precursor scaffolds ( 4a ‐ c ) were prepared via a one‐pot reaction between heteroaromatic amine analogs ( 1a ‐ c ), paraformaldehyde and hypophosphorous acid in the presence of 6 M HCl. The biological activity of all synthesized 8‐ cyclo ‐1,5,3,7‐diazadiphosphocines ( 4a ‐ c , and 5 – 16 ) was evaluated against several cancer cell lines.