Manganese-Catalyzed Anti-Markovnikov Hydroarylation of Enamides: Modular Synthesis of Arylethylamines

Comprehensive Summary The arylethylamine framework is a prevalent motif in a great range of biologically important organic compounds. One intractable task for frontline drug discovery is to find structurally new medicine candidates instead of opioid, based on the construction of a rich chemical space of arylethylamine motif. In this report, a practical protocol for the synthesis of arylethylamine functionality common in pharmaceutical chemicals has been developed. It proceeds by Mn-catalyzed anti-Markovnikov hydroarylation of electron-rich enamides under mild conditions without the use of ligands. In spite of mismatched electronic effects during the manganese-mediated migratory insertion process, both terminal and internal enamides can be regioselectively hydroarylated with various aryl boronic acids in 15 min. Also, the successful hydroalkenylation of enamides with alkenyl boronic acids in air atmosphere affords an elegant route to synthetically useful beta-alkenylated amines in satisfactory yields. The synthetic robustness and practicality of the reaction reveal its simple operation, short reaction time, viability on a gram-scale and its value in late-stage modification of complex molecules.

Automated summary

In this report, a practical protocol for the synthesis of arylethylamine functionality common in pharmaceutical chemicals has been developed. The protocol proceeds by Mn-catalyzed anti-Markovnikov hydroarylation of electron-rich enamides under mild conditions without the use of ligands. Both terminal and internal enamides can be regioselectively hydroarylated with various aryl boronic acids in 15 min. The reaction also allows for the hydroalkenylation of enamides with alkenyl boronic acids in air atmosphere, providing an elegant route to synthetically useful beta-alkenylated amines in satisfactory yields.