Mechanistic Study of SmI2/H2O and SmI2/Amine/H2O‑Promoted Chemoselective Reduction of Aromatic Amides (Primary, Secondary, Tertiary) to Alcohols via Aminoketyl Radicals

• Published in: Journal of organic chemistry 2017-07, Vol.82 (13), p.6528-6540
• Main Authors: Huq, Syed R, Shi, Shicheng, Diao, Ray, Szostak, Michal
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.7b00372

Samarium­(II) iodide–water and samarium­(II) iodide–water–amine complexes have been recognized as valuable reagents for the selective generation of aminoketyl radicals from amides and derivatives. The resulting aminoketyl radicals can undergo reduction or reductive cyclization pathways, providing a powerful method for (i) direct synthesis of alcohols from amides by the challenging N–C bond scission and (ii) synthesis of nitrogen-containing heterocycles via polarity reversal of the amide bond. This report describes mechanistic investigation into samarium­(II) iodide–water and samarium­(II) iodide–water–amine-mediated generation of benzylic aminoketyl radicals from aromatic primary, secondary, and tertiary amides (benzamides). The mechanistic experiments suggest that the rate and selectivity of the reduction is closely dependent on the water concentration and the type of amide undergoing the reduction. The data also suggest that benzylic aminoketyl radicals generated in the reduction of benzamides are significantly more dependent on the electronic effects of α-substitution than the corresponding aminoketyl radicals generated by single-electron transfer to unactivated aliphatic amides; however, little variation in terms of steric influence of N-substituents is observed. These observations will have implications for the design of reductive processes involving Sm­(II)-mediated reduction of amides and reductive umpolung cyclizations via aminoketyl radicals as a key step.