Alkylamines and their N-heterocyclic derivatives are key structural features in molecules central to the medical, agroscience, and materials science industries, rendering general methods for their synthesis integral to the broader chemistry community. However, traditional synthetic strategies for these motifs, such as substitution reactions between nitrogen nucleophiles and alkyl halides, feature well-established, substrate-dependent limitations and competing reaction pathways under thermally-induced conditions. We now report that a metallaphotoredox approach, utilizing a halogen abstraction-radical capture (HARC) mechanism, provides a mild and valuable alternative to conventional N-alkylation. This visible-light-induced, copper-catalyzed protocol allows for room temperature coupling of aliphatic bromides using simple Cu(II) salts, exploiting open-shell reactivity governed by silyl radical halogen abstraction to bypass the prohibitively high barriers associated with SN2 or SN1 N-alkylation. This regio- and chemoselective protocol is compatible with &gt;10 classes of medicinally-relevant N-nucleophiles, including established pharmaceutical agents, in addition to structurally diverse primary, secondary, and tertiary alkyl bromides. Additionally, this HARC methodology readily engages conventionally inert coupling partners and substrates incompatible with nucleophilic substitution pathways, demonstrated via the union of N-nucleophiles with cyclopropyl bromides and unactivated secondary alkyl chlorides. This metallaphotoredox strategy for N-alkylation can ideally provide medicinal chemists with single-step access to valuable sp3-rich chemical diversity in drug discovery, including alkylamine motifs unattainable via typical methods.

New applications of halogen abstraction-radical capture (HARC) mechanisms: Silyl radical activation of alkyl halides enables a copper metallaphotoredox platform for N-alkylation

ACS Spring 2022

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