Abstract
Arylamines constitute the core structure of many therapeutic agents, agrochemicals, and organic materials. The development of methods for the efficient and selective construction of these structural motifs from simple building blocks is desirable but still challenging. We demonstrate that protonated electron‐poor O‐aryl hydroxylamines give aminium radicals in the presence of Ru(bpy)3Cl2. These highly electrophilic species undergo polarized radical addition to aromatic compounds in high yield and selectivity. We successfully applied this method to the late‐stage modification of chiral catalyst templates, therapeutic agents, and natural products.
Highlights
N,N-Dialkyl-aryl-amines are a privileged scaffold found in blockbuster drugs, agrochemicals and organic materials (Scheme 1A).[1]
While highly electrophilic amidyl[11] and sulfamidyl radicals[12] have been successfully coupled with highly electron rich aromatics, the use of di-alkyl-substituted nitrogen radicals – aminyl radicals – in related arylations has yet to be described
This lack of synthetic application can be explained by the intrinsic nucleophilic nature of aminyls that causes repulsive interactions between their lone pair and the aromatic.[13]
Summary
N Ar easy-to-make un-functionalized room temperature 15 min 52 examples late-stage amination. As E is expected to be the strongest electrophore in the system, any potential SET oxidation of the aromatic partner[20] will be minimised Overall, this approach would represent an umpolung alternative to the photoredox amination protocols developed by Nicewicz[20a] and Lei[20b] where nucleophilic pyrazoles react with aromatic radical cations. This approach would represent an umpolung alternative to the photoredox amination protocols developed by Nicewicz[20a] and Lei[20b] where nucleophilic pyrazoles react with aromatic radical cations This strategy was evaluated using piperidine 1a (Ered = –0.9 V vs SCE in CH3CN) prepared in one step from commercial materials on multi-gram scale,[21] t-Bu-benzene 2, Ru(bpy)3Cl2 as the photoredox catalyst in CH3CN under blue LEDs irradiation (450 nm) (Scheme 2B). A) Possible strategies for aminium radical generation and N-arylation Path a: SET first
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