Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

Tertiary alkylamines as effective directing groups for palladium-catalysed C(sp3)–H activation strategies

C–H activation has emerged as a powerful strategy to streamline organic synthesis by exploiting the ubiquitous nature of C–H bonds in any synthetic precursor. Within the last decade, primary and secondary alkylamines have been reported to direct C–H cleavage on a series of palladium-catalysed reactions. The work reported in this dissertation describes the development of a new palladium-catalysed strategy towards the functionalisation of aliphatic tertiary amines. Methyl, methylene, and methine C–H cleavage have been disclosed by exploiting direct coordination of the amine substrate to the palladium metal centre. Subsequent cross-coupling with aryl boron reagents delivered a series of C(sp3)-C(sp2) bond forming transformations. In an attempt to shape a greener, cheaper, and more atom economical reaction, studies towards the replacement of silver additives as terminal oxidants by a combination of oxygen and alkene derivates, and the reduction of palladium catalyst loadings were explored. Pivotal to the success of these discoveries was the use of mono-protected amino acid ligands. Combined experimental and computational analysis revealed that these readily available ligands can prevent amine decomposition by avoiding the geometrical coplanarity needed for β–H elimination processes. The inherent chirality of amino acids enabled the development of asymmetric C–H activation reactions, targeting both methyl and methylene C–H bonds to construct diastereo- and enantioselective aryl-amine motifs.La Caixa Foundation Cambridge Trus

Native amides as Enabling Vehicles for Forging sp3–sp3 Architectures via Interrupted Deaminative Ni-catalyzed Chain-Walking

Herein, we disclose an interrupted deaminative Ni-catalyzed chain-walking strategy that forges sp3–sp3 architectures at remote, yet previously unfunctionalized, methylene sp3 C–H sites enabled by the presence of native amides. This protocol is characterized by its mild conditions and wide scope, including challenging substrate combinations. Site-selectivity can be dictated by a judicious choice of the ligand, thus offering an opportunity to enable sp3–sp3 bond-formations that are otherwise inaccessible in conventional chain-walking events

Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

Pd(II)-catalyzed enantioselective C(sp3)–H arylation of cy-clopropanes and cyclobutanes guided by tertiary alkyla-mines.

ABSTRACT: Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp3)–H arylation of aminome-thyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C–H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers and with excellent enantiomeric ratios. Cen-tral to the success of this strategy is the use of a simple N-acetyl amino acid ligand, which not only controls the enantioselectivity but also promotes -C–H activation of over other pathways. Computational analysis of the cyclopalladation step provides an understanding of how enantioselective C–H cleavage occurs and revealed distinct transition structures to our previous work on enantioselective desymme-trization of N-iso-butyl tertiary alkylamines. This straightforward and operationally simple method simplifies the construction of func-tionalized aminomethyl-strained cycloalkanes, which we believe will find widespread use in academic and industrial settings relating to the synthesis of biologically active small molecules