Abstract
The development of photoredox reactions of aryloxy-amides for the generation of amidyl radicals and their use in hydroamination-cyclization and N-arylation reactions is reported. Owing to the ease of single-electron-transfer reduction of the aryloxy-amides, the organic dye eosin Y was used as the photoredox catalyst, which results in fully transition-metal-free processes. These transformations exhibit a broad scope, are tolerant to several important functionalities, and have been used in the late-stage modification of complex and high-value N-containing molecules.
Highlights
N itrogen-containing compounds form the structural basis of almost all pharmaceuticals, agrochemicals, and materials.[1]
Amidyl radicals represent a very useful class of reactive intermediates with potentially broad applications in the preparation of amides and carbamates.[2]. Their implementation in synthesis is somewhat limited by (i) their available precursors, which are often difficult to make and highly reactive, and (ii) the reaction conditions required for their generation, which often preclude the presence of many functional groups.2a Pioneering studies from Ingold revealed that amidyl radicals display remarkably high electrophilic character, and this offers the advantage of an umpolung reactivity complementing the nucleophilic character of Nspecies in classical polar reaction modes.[3,4]
As detailed by Newcomb, the amidyl radical electrophilicity means that both inter- and intramolecular H-atom abstraction reactions are very favorable, and this frequently thwarts the development of C−N bond-forming processes.[5]
Summary
Having developed a photoredox transition-metal-free hydroamination process, we decided to evaluate whether our method could be used to achieve intermolecular N-arylation reactions (Scheme 5A).[17] Mechanistically, we envisaged that, upon photoredox amidyl radical generation (A → C) and in the presence of an electron-rich aromatic partner, an intermolecular reaction[18] would take place to forge the C−N bond in G This species would close the photoredox cycle and provide the product H. We were intrigued by the idea of modifying the core structure of lysergic acid, a molecule that has been a source of interest and imagination in both chemistry and popular culture.[19] We were delighted to see that, upon exposure of the therapeutically active ergot derivatives nicergoline and metergoline to our reaction conditions, the C-2 aminofunctionalized products 11u and 11v were obtained in good yields We believe that these examples showcase the power of our arylation manifold owing to the high structural complexity and the number of functional groups that are tolerated, which includes an unprotected carbamate.
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