Selective mono N-alkylations of cyclen in one step syntheses

In this Letter, we describe selective one step mono N-alkylations of cyclen (1,4,7,10-tetraazacyclododecane) using a range of functionalized alkyl halides. This 'easy to use' synthesis gives rise to mono-derivatives of cyclen from various alkyl halides or, when using alkyl dihalides, bis-cyclen derivatives, where the alkyl group links two cyclen macrocycles together. While the reaction conditions require the use of 1:4 stoichiometry (alkyl halide:cyclen), any unreacted cyclen can be recovered with an aqueous extraction and successfully reused. This procedure was found to be quite versatile, being particularly well-suited for cyclen targets bearing protected thiol groups, as well as α-chloroamide-derived chromophores; such cyclen pendant chromophores are employed as antennae for lanthanide luminescence probes and sensors.