Amine-FUNC · Amine-Directed Diverse C(sp3)-H Functionalization

Amine-Directed Diverse C(sp3)-H Functionalization

The development of new catalytic methods that enable the functionalization of aliphatic C–H bonds is an important challenge to the continued advance of chemical synthesis. Meanwhile, the synthesis of architecturally complex aliphatic amines remains an important challenge to synthetic and medicinal chemists because their structural and functional properties are often fundamental to biological activity in many nitrogen containing molecules. Recently, palladium-catalyzed C–H functionalization of aliphatic amine derivatives has emerged as a potentially powerful tactic for the synthesis of complex variants of these important molecules. Central to the continued evolution of these synthetic strategies is the development of new activation modes and transformations on a range of aliphatic amine substrates. In fact, the direct use of the amine functionality as a directing group for cyclopalladation is less common, and most successful cases require protecting groups or auxiliaries to modulate the metal-binding properties of the nucleophilic nitrogen motif. As a result, catalytic strategies for the direct C-H activation of aliphatic amines remain underdeveloped. In 2014, our group has been engaged in the development of C(sp3)–H activation reactions guided by the free (NH)-amine. Key to the success of this strategy has been the steric-induced destabilization of rapidly formed bisamine Pd(II) complexes, which leads to higher concentrations of the putative mono-amine Pd(II) complexes empirically required for C–H bond cleavage. As part of the evolution of this distinct C–H activation mode, this project aims to: (I) develop unprecedented diverse C(sp3)-H functionalization of amine technology, access diverse functionalized amine compounds, (II) develop novel Pd-catalyzed enantioselective C-H functionalization methods to make enantioenriched chiral molecules. Conclusions of the action: over the last two years, we have developed a number of distinct transformations of aliphatic amine based on discrete 4- and 5-membered cyclopalladation pathways, such as C–H arylation and C–H alkenylation, which allows access to highly functionalized phenethyl amines and aliphatic N-heterocycles. By using chiral amino-acid-derived ligand, we have demonstrated the basis of a catalytic enantioselective arylation reaction. In addition, our studies also indicated that an amino-acid-derived ligand renders the C–H bond activation step reversible and promotes the traditionally difficult alkenylation process.

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