Expeditious highly C6-regioselective acylation of purines and purine nucleosides via a traceless proton aided approach at room temperature without metal catalysts is reported for the first time.

A metal‐, light‐free radical alkylation reaction of purines and nucleosides has been achieved with readily available alcohols (1°, 2°, 3°) as the alkyl radical sources enabled by oxalates, which does not need any catalysts, N2 protection, and protecting groups. Although there are three potential active C(sp2)H bonds and four interferential nitrogen atoms in the purine motif, the reaction still shows excellent regioselectivity at C6H position and does not face multialkylation problem. Besides, this approach shows broad functional groups tolerance and is scalable to the gram level, which can be applied to late‐stage CH alkylation of purine to synthesize 6‐cyclopentyl nebularine with anti‐CEM activity, thus demonstrating its utility.

Herein, we report the development of a radical deoxyfunctionalization strategy for the direct CÀ H alkylation of purines and purine nucleosides with alcohols (1°, 2°, 3°) intervened by oxalates under 12 W blue LED irradiation. The reaction shows high regioselectivity at C6À H position of purine and is suitable for N9-, N7-substitued purines. The process accommodates purines and alcohols to deliver a wide range of products (31 examples) in 41-91 % yields, which avoids transition metal catalysts and organometallic reagents, and is not sensitive to moisture and air. Besides, the mild protocol displays broad functional groups tolerance and is easily up scalable to gram scale and can be used for late-stage CÀ H alkylation of purine to synthesize pharmaceutical 6-cyclopentyl nebularine with anti-CEM activity or natural d-menthol modification.

The Cover Feature shows a radical deoxyfunctionalization strategy for C6−H alkylation of purines with alcohols. The cover image was inspired by a tenth ring in archery, which represents the high C6‐regioselectivity of the reaction with the help of oxalates under light irradiation. Cover design by Mingwu Yu and Miao Tian. More information can be found in the Research Article by M. Yu et al.