Iron-catalyzed para-selective alkylation of aryl amides with tertiary Grignard reagents

The construction of quaternary carbon centers at the para-position of benzamide derivatives is of significant importance for the synthesis of pharmaceutical agents and their key precursors. Such structural motifs can serve directly as small-molecule targeted compounds or be further elaborated into complex ligand architectures to meet diverse pharmacological requirements. However, achieving high selectivity in the formation of these quaternary carbon centers remains a long-standing challenge. We herein report a method for the para-selective construction of quaternary carbon centers on benzamide derivatives via iron catalysis. This transformation proceeds at room temperature using benzamide derivatives and tertiary alkyl Grignard reagents. By employing a catalytic system comprising inexpensive iron(II) salt and tert-butylmagnesium chloride, this method enables the introduction of sterically demanding tertiary alkyl groups at the para-position with high regioselectivity, effectively suppressing common side reactions such as alkyl group isomerization or ortho-alkylation. This approach exhibits a diverse range of applicable aryl amides, though N-alkyl substrates are not tolerated.