Straightforward Ball‐Milling Access to Dinucleoside 5′,5′‐Polyphosphates via Phosphorimidazolide Intermediates

A solvent-assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5'-polyphosphates is reported. Under ball-milling conditions, nucleoside 5'-monophosphates are quantitatively activated using N,N'-carbonyldiimidazole into their phosphorimidazolide derivatives. The addition of a nucleoside 5'-mono, di or triphosphate directly leads to the formation of the corresponding dinucleotides. Benefits of the reported one-pot method include the use of unprotected nucleotides in their sodium or acid form, activation by the eco-friendly N,N'-carbonyldiimidazole, non-dry conditions, short reaction time, high conversion rates and easy setup and purification. This work offers new perspectives for the synthesis of nucleotide conjugates and analogues, combining the phosphorimidazolide approach and milling conditions.