Aminoalkylation of Alkenes via Triple Radical Sorting

Keywords

N-heterocycles - (sp³)-hybridized carbon atoms - triple radical sorting - photoredox catalysis

Significance

Two prominent features of modern drug molecules and pharmaceutical scaffolds are nitrogen atoms and C(sp³)-hybridized carbon atoms. Nitrogen, in particular, is ubiquitous in drug molecules, as evidenced by its presence in 84 % of approved pharmaceutical scaffolds. Therefore, developing methods to access medicinally relevant scaffolds is a key focus in synthetic organic chemistry. Similarly, the incorporation of (sp³)-hybridized carbon atoms into drug candidates plays a crucial role in clinical success, as reflected in the increasing proportion of sp³-hybridized carbon atoms across different phases of drug discovery. The MacMillan lab has developed a method to forge both a C(sp³)−N and a C(sp³)−C(sp³) bond across commercial feedstock alkenes with perfect regioselectivity.

Comment

This work reports a three-component aminoalkylation reaction, which utilizes the principles of triple radical sorting, also developed by MacMillan, to regioselectively introduce N-centered and C-centered radicals onto alkenes. This process is based on photoredox catalysis to convert alkyl bromides and reductively activated N-centered radical precursors into high-energy radical species. A wide range of alkene and alkyl bromide cross-coupling partners are well tolerated, showcasing several synthetic applications. In a demonstration of the synthetic utility of this method, a series of pharmacophore-substituted saturated N-heterocycles was constructed through ‘couple-close’ sequences. N-Alkylated pyrrolidine and morpholine products were synthesized as well as an oxazolidinone.