Improved Synthesis of Phosphoramidite-Protected N⁶-Methyladenosine via BOP-Mediated S_NAr Reaction

N⁶-methyladenosine(m⁶A) is the most abundant modification in mRNA. Studies on proteins that introduce and bind m⁶A require the efficient synthesis of oligonucleotides containing m⁶A. We report an improved five-step synthesis of the m⁶A phosphoramidite starting from inosine, utilising a 1-H-benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP)_-mediated S_NAr reaction in the key step. The route manifests a substantial increase in overall yield compared to reported routes, and is useful for the synthesis of phosphoramidites of other adenosine derivatives, such as ethanoadenosine, an RNA analogue of the DNA adduct formed by the important anticancer drug Carmustine.