Arylation of Benzylic Ethers Using a Thiol Catalyst

Significance

MacMillan and co-workers report the arylation of benzylic ethers and alcohols using electron-poor arylnitriles as arylating agents and a combination of Ir(ppy)₃ and a thiol as photoredox and radical catalysts. The role of the iridium catalyst is to generate two radicals, A and B. Radical B, which is derived from the thiol catalyst, then abstracts a benzylic hydrogen atom from the substrate, which is further converted into the product by combination with A and subsequent elimination of cyanide. This byproduct was suggested to be detrimental for the reaction progress and to be scavenged by the octanal additive.

Comment

The broad substrate scope of this methodology, especially on the benzyl ether side, is noteworthy and increases the probability that it is implemented in the synthesis of pharmacologically relevant compounds. Especially in this context, it has to be pointed out that one important challenge remains to be met. As all compounds generated through this methodology are chiral but racemic, the development of an asymmetric variant would be highly desirable. However, the control of enantioselectivity in radical reactions is ­difficult, and only a few, more or less general approaches are available, such as the recent use of chiral phosphoric acids in asymmetric photoredox catalysis by the Knowles group (J. Am. Chem. Soc. 2013, 135, 17735).