Umpolung Amide Synthesis Mechanistic Studies, Development of a New N-Aryl Amide Synthesis, and α-Oxy- and α-Thio-nitroalkanes in the BAM-Catalyzed aza-Henry Reaction

Abstract

Umpolung amide synthesis (UmAS) exploits the unique properties of an α-halo nitroalkane in its reaction with an amine to produce an amide. The “umpolung” moniker reflects its paradigm-breaking C–N bond formation on the basis of evidence that the nucleophilic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct observation of a HANA, its conversion thermally to an amide functionality, and quantitative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation. The structure and stability data has allowed us to develop an umpolung synthesis of N-aryl amides involving a HANA. Mechanistic studies in this case suggest the HANA collapses to amide in an entirely new way and showcase the predictive power of our newly-developed understanding of UmAS. The conditions are very operationally simple and allow for the preparation of amides with highly-epimerizable stereocenters with complete retention of enantiopurity. The method has also been successfully applied to the synthesis of an Eli-Lilly patented glucokinase activator. Also, previously unexplored nucleophiles were applied in the BAM catalyzed aza-Henry reaction leading to two new highly-enantioselective reactions, one of which displayed unusually high diastereoselectivity.