Kelvin S. L. Chan

Pd-Catalyzed Intermolecular C―H Amination with Alkylamines

C-H amination of N-aryl benzamides with O-benzoyl hydroxylamines has been achieved with either Pd(II) or Pd(0) catalysts. Furthermore, we demonstrate that secondary amines can be directly used with benzoyl peroxide in a one-pot procedure that proceeds via the in situ generation of the appropriate O-benzoyl hydroxylamines. This catalytic reaction provides a new disconnection for the convergent synthesis of tertiary and secondary arylalkyl amines starting from benzoic acids.

Palladium-Catalyzed Transformations of Alkyl C–H Bonds

This Review summarizes the advancements in Pd-catalyzed C(sp3)-H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C-H bonds, many C(sp3)-H activation/C-C and C-heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)-H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C-H functionalization reactions.

Ligand-enabled methylene C(sp3)-H bond activation with a Pd(II) catalyst.

Pd(II) insertion into β-methylene C(sp(3))-H bonds was enabled by a mutually repulsive and electron-rich quinoline ligand. Ligand tuning led to the development of a method that allows for installation of an aryl group on a range of acyclic and cyclic amides containing β-methylene C(sp(3))-H bonds.

Palladium(II)‐Catalyzed Selective Monofluorination of Benzoic Acids Using a Practical Auxiliary: A Weak‐Coordination Approach

Transition-metal-catalyzed carbon–fluorine bond-forming reactions have been extensively studied because of the significant demand for versatile, mild, and regioselective methods to prepare fluorinated organic compounds, especially fluorinated arenes, which are valuable in pharmaceutical and agrochemical industries. 2] In addition to conventional electrophilic aromatic substitution reactions, fluorination reactions of aryl silicon, aryl boron, and aryl tin reagents using electrophilic fluorine sources mediated or catalyzed by transition metals have emerged as useful methods to prepare fluorinated arenes. Notably, the Pd-catalyzed displacement of the leaving groups in aryl bromides and aryl triflates by the nucleophilic fluoride anion has also been demonstrated recently. However, the development of methods to directly fluorinate unactivated aryl C H bonds has met with limited success; only two examples of directed ortho C H fluorination have been reported to date. In both of these cases, the formation of a mixture of inseparable monoand difluorinated arenes is often problematic for practical applications. Herein, we report the ortho fluorination of an important class of broadly useful benzoic acid substrates using a readily removable acidic amide as the auxiliary [Eq. (1); OTf = trifluoromethanesulfonyl]. Either monoor

Palladium(0)-Catalyzed Alkynylation of C(sp3)–H Bonds

The alkynylation of β-C(sp(3))-H bonds in aliphatic amides with alkynyl halides has been enabled using Pd(0)/N-heterocyclic carbene (NHC) and Pd(0)/phosphine (PR3) catalysts. This is the first example of utilizing [AlkynylPd(II)L(n)] complexes to activate C(sp(3))-H bonds.

Ligand-enabled cross-coupling of C(sp3)-H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis.

There have been numerous developments in C–H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C–H bonds, chemists have discovered reaction conditions that enable reactions of C(sp2)–H and C(sp3)–H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp3)–H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp3)–H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids. Despite advances in C–H activation reactions in the past decade, the development of suitable ligands that enable catalytic C(sp3)–H bond functionalization remains a significant challenge. Here, the discovery of a mono-N-protected amino acid ligand enables Pd(II)-catalysed cross-coupling of C(sp3)–H bonds in triflyl-protected amines with arylboron reagents.

Palladium(II)-catalyzed Highly Enantioselective C–H Arylation of Cyclopropylmethylamines

C-H arylation via a Pd(II)/Pd(IV) catalytic cycle has been one of the most extensively studied C-H activation reactions since the 1990s. Despite the rapid development of this reaction in the past two decades, an enantioselective version has not been reported to date. Herein, we report a Pd(II)-catalyzed highly enantioselective (up to 99.5% ee) arylation of cyclopropyl C-H bonds with aryl iodides using mono-N-protected amino acid (MPAA) ligands, providing a new route for the preparation of chiral cis-aryl-cyclopropylmethylamines. The enantiocontrol is also shown to override the diastereoselectivity of chiral substrates.

Enantioselective ortho-C-H cross-coupling of diarylmethylamines with organoborons.

The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the CH activation of amines for the first time. An enantioselective ortho-CH cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono-N-protected amino acid (MPAA) ligands as a promoter.