Dual-Catalytic Enantioselective Allylation of -(Heteroaromatic-methyl)imine Derivatives.

We report the dual-catalytic enantioselective allylic alkylation of 2-(pyridylmethyl)amine-derived ketimines with allylic carbonates. The reaction proceeds under mild reaction conditions to generate α-amino heteroaryl benzylamine stereocenters in good yield and enantioselectivity. Enantioselectivity is achieved through the use of a copper catalyst modified with chiral bisphosphine ligand (2,4)-bis(diphenylphosphino)pentane.

Aziridine Opening via a Phenonium Ion Enables Synthesis of Complex Phenethylamine Derivatives.

We report that the treatment of unsymmetrical 2,3-disubstituted aziridines with TiCl yields β-phenethylamine products via the intermediacy of a phenonium ion. Derivatization of the products obtained via this method is demonstrated. Computational analysis of the reaction pathway provides insight into the reaction mechanism, including the selectivity of the phenonium opening.

Homologation of Electron-Rich Benzyl Bromide Derivatives via Diazo C-C Bond Insertion.

The ability to manipulate C-C bonds for selective chemical transformations is challenging and represents a growing area of research. Here, we report a formal insertion of diazo compounds into the "unactivated" C-C bond of benzyl bromide derivatives catalyzed by a simple Lewis acid. The homologation reaction proceeds via the intermediacy of a phenonium ion, and the products contain benzylic quaternary centers and an alkyl bromide amenable to further derivatization.

Reagent Control Enables Selective and Regiodivergent Opening of Unsymmetrical Phenonium Ions.

We report the first examples of selective and regiodivergent opening of unsymmetrical phenonium ions with chloride ions. These reactions are enabled by the dual role of SnCl and TiCl as Lewis acids and chloride nucleophiles. Reagent control dictates addition of chloride at either the substituted internal position (SnCl) or unsubstituted terminal position (TiCl) of the phenonium ion.

Enantioselective C2-Alkylation of Indoles through a Redox-Relay Heck Reaction of 2-Indole Triflates.

A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand.

Recent developments in the use of aza-Heck cyclizations for the synthesis of chiral N-heterocycles.

Aza-Heck cyclizations are an emerging method for the construction of chiral N-heterocyclic systems. In these processes, an activated N-O bond replaces the C-X bond (X = halide, OTf) used in conventional Heck reactions, with the associated aza-Pd(ii)-intermediate engaging pendant alkenes in a Heck-like manner. This perspective article commences with an historical overview of the area, which stems from Narasaka's seminal studies using oxime esters as the initiating motif.

Enantioselective Narasaka-Heck cyclizations: synthesis of tetrasubstituted nitrogen-bearing stereocenters.

The first examples of highly enantioselective Narasaka-Heck cyclizations are described. A SPINOL-derived P,N-ligand system enables Pd-catalyzed 5- cyclization of a range of oxime esters with sterically diverse trisubstituted alkenes to generate dihydropyrroles containing tetrasubstituted nitrogen-bearing stereocenters in 56 to 86% yield and 90 : 10 to 95 : 5 e.r.

Palladium-Catalyzed Enantioselective Intermolecular Coupling of Phenols and Allylic Alcohols.

An enantioselective intermolecular coupling of oxygen nucleophiles and allylic alcohols to give β-aryloxycarbonyl compounds is disclosed using a chiral pyridine oxazoline-ligated palladium catalyst under mild conditions. As opposed to the formation of traditional Wacker-type products, enantioselective migratory insertion is followed by β-hydride elimination toward the adjacent alcohol. Deuterium labeling experiments suggest a syn-migratory insertion of the alkene into the Pd-O bond.

Dichotomous mechanistic behavior in Narasaka-Heck cyclizations: electron rich Pd-catalysts generate iminyl radicals.

Pd-catalyzed cyclizations of oxime esters with pendant alkenes are subject to an unusual ligand controlled mechanistic divergence. Pd-systems modified with electron deficient phosphines ( P(3,5-(CF)CH)) promote efficient aza-Heck cyclization, wherein C-N bond formation occurs alkene imino-palladation. Conversely, electron rich ligands, such as P(-Bu), cause deviation to a SET pathway and, in these cases, C-N bond formation occurs cyclization of an iminyl radical.

Palladium catalyzed cyclizations of oxime esters with 1,2-disubstituted alkenes: synthesis of dihydropyrroles.

Pd-catalyzed cyclizations of oxime esters with 1,2-dialkylated alkenes provide an entry to chiral dihydropyrroles. Substrate and catalyst controlled strategies for selective product formation (vs alternative pyrroles) are outlined.

Substituted pyrroles via olefin cross-metathesis.

Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-γ-aminoenones. When exposed to either acid or Heck arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this chemistry is demonstrated by its application to the tetrasubstituted pyrrole subunit of Atorvastatin.