Tertiary Amides as Directing Groups for Enantioselective C-H Amination using Ion-Paired Rhodium Complexes.

Enantioselective C-H amination at a benzylic methylene is a vital disconnection towards chiral benzylamines. Here we disclose that butyric and valeric acid-derived tertiary amides can undergo highly enantioselective benzylic amination using an achiral anionic Rh complex that is ion-paired with a Cinchona alkaloid-derived chiral cation. A broad scope of compounds can be aminated encompassing numerous arene substitutions, amides, and two different chain lengths. Excellent tolerance of ortho substituents was observed, which has not been achieved before in asymmetric intermolecular C-H amination with Rh. We speculate that the tertiary amide group of the substrate engages in hydrogen bonding interactions directly with the chiral cation, enabling a high level of organisation at the transition state for C-H amination. This is in contrast with our previous work where a substrate bearing a hydrogen bond donor was required. Control experiments led to the discovery that methyl ethers also function as proficient directing groups under the optimised conditions, potentially also acting as hydrogen bond acceptors. This finding has the promise to dramatically expand the applicability of our ion-paired chiral catalysts.

Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation.

The enantioselective amination of C(sp3)-H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C-H amination, Rh2(esp)2, with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C-H amination of substrates bearing pendant hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex, providing improved yields of product versus Rh2(esp)2 and highlighting the dual role that the cation is playing. These results underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.

A hydrogen borrowing annulation strategy for the stereocontrolled synthesis of saturated aza-heterocycles.

An iridium catalyzed method for the synthesis of saturated aza-heterocycles from amines and diols is reported. A wide range of substituted heterocycles can be obtained using this approach including products bearing substituents at the C2, C3 and C4 positions. Employing water as the solvent, enantiopure diols could undergo annulation with minimal racemization, enabling the synthesis of valuable enantioenriched C3 and C4-substituted saturated aza-heterocycles.