Palladium-Catalyzed C(sp3)–H Bond Functionalization of Aliphatic Amines

Abstract

Methods that enable the practical and selective functionalization of traditionally unreactive aliphatic C-H bonds have synthetic applications in fields ranging from drug discovery to advanced materials. One of the major challenges is the development of strategically important reactions on aliphatic molecules containing synthetically useful functional groups. Aliphatic amines are central to the function of many biologically active molecules, as evidenced by their prevalence in a large number of pharmaceutical agents. Over the past decade, chemists have found ways to tailor the electronic and steric properties of directing functionalities and ligands to enable palladium-catalyzed C-H activation of aliphatic amine derivatives. Many of these methods have been successfully applied to the synthesis of pharmaceuticals and complex natural products. This review provides an overview of these methods and describes recent contributions, as well as the remaining challenges, in this emerging field.

Carboxylate‐Assisted Oxidative Addition to Aminoalkyl PdII Complexes: C(sp3)−H Arylation of Alkylamines by Distinct PdII/PdIV Pathway

“…The transformation of unactivated C(sp 3 )−H bonds into C–aryl bonds using transition‐metal catalysts has been the focus of intense academic research over the past decade . Within this field, Pd‐catalyzed C(sp 3 )−H arylation of alkylamines has stimulated significant interest as the products of such a transformation display structural features that are highly represented in pharmaceutical agents . As a general premise, amine‐directed C−H activation leads to the formation of a palladacycle intermediate, from which arylation can be promoted through a variety of pathways.…”

“…Over the last five years, our group has been engaged in a research program geared towards the use of free (NH) alkylamines in Pd II ‐catalyzed β and γ C(sp 3 )−H activation reactions . The success of these strategies has been dependent on either a) the use of hindered alkylamine substrates, which destabilize rapidly formed bis‐amine Pd II complexes and lead to a higher concentration of the mono‐amine Pd II species empirically required for C−H activation; or b) the presence of reagents (such as CO) that strongly impact on the mechanism of the process .…”

Exogenous Directing Group Free, Ligand-Enabled gamma-C(sp3)–H Arylation of Free Primary Aliphatic Amines and α-Amino Esters

“…It should be noted that aliphatic amines without α-substituents are usually more unreactive substrates in C−H activation of amines than those bearing α-substituents. [3,10] Furthermore, the sterically unhindered secondary amine such as N-methylpropylamine could also afford the desired product, albeit in a low yield (2ab). It is worth mentioning that the bromo group on the aryl iodide could be tolerated, rendering the opportunity of further elaborations for the corresponding products (2d, 2x).…”

“…much less hindered free secondary amines was also realized by the Gaunt group via using a sterically hindered carboxylate ligand. [19] Nevertheless, the use of free primary amino group as the DG for C(sp 3 )-H activation remains a formidable challenge. [20] To date, only a single report on C-H functionalization of C(sp 3 )-H bond of free primary aliphatic amine was disclosed by Shi and co-workers, who developed a C(sp 3 )-H acetoxylation of hindered free primary α-tertiary amines through the protonation strategy by running the reaction in HOAc to moderate the coordination ability of primary amines (Scheme 1d).…”

“…[19] Nevertheless, the use of free primary amino group as the DG for C(sp 3 )-H activation remains a formidable challenge. [20] To date, only a single report on C-H functionalization of C(sp 3 )-H bond of free primary aliphatic amine was disclosed by Shi and co-workers, who developed a C(sp 3 )-H acetoxylation of hindered free primary α-tertiary amines through the protonation strategy by running the reaction in HOAc to moderate the coordination ability of primary amines (Scheme 1d). [21] Inspired by these pioneering works, we envisioned two tactics to keep enough amount of reactive mono(amine)-Pd II species for developing a more general C-H functionalization of C(sp 3 )-H bond of free primary aliphatic amine: (1) introducing a suitable acid to moderate the binding ability of the amino group and prevent substrate oxidation as well;…”