Enantioselective Organocatalyzed aza‐Michael Addition Reaction of 2‐Hydroxybenzophenone Imines to Nitroolefins under Batch and Flow Conditions

Abstract

Herein, an asymmetric organocatalytic aza‐Michael addition reaction of ketimines to nitroolefins is presented. The use of 2‐hydroxybenzophenone imine improves the enantioselective addition of N‐centered nucleophiles to nitroalkenes by means of intramolecular hydrogen bond formation at the imine moiety. Moreover, the versatility of the process is demonstrated under both batch and flow conditions, showing the synthesis of a large variety of nitroamine derivatives with excellent yields and enantioselectivities. In addition, we applied this methodology to the formal synthesis of VNI, a drug‐like scaffold for the treatment of Chagas disease.

Intramolecular Hydrogen-Bond Activation: Strategies, Benefits, and Influence in Catalysis

“…Finally, the N-functionalization of nitroalkenes was envisioned in the event of an expansion of this chemical approach ( Scheme 13 ). 41 Given the importance of diamine derivatives in many scientific areas, the aza-Michael addition between ketimines and nitro-olefins was developed under both batch and flow conditions using a bifunctional thiourea as the catalyst. This reaction, which resulted in a limitation in the literature because moderate asymmetric induction values were obtained in the previous reported works with benzophenone imines as nucleophilic sources, 42 succeeded as excellent yields and enantioselectivities were achieved in 20 examples.…”

“…Our research group has also made a special effort in the activation of C- and N-centered nucleophiles under organocatalytic conditions. − The aforementioned acidity issues with respect to the use of monoactivated azomethine ylides in organocatalysis were resolved due to the glycine imine activation through an intramolecular hydrogen bond (Scheme ). , The presence of a hydroxyl group at the ortho position of the aromatic ring allowed for a H-bond with the iminic nitrogen, resulting in an acidity increase of the methylene hydrogens.…”