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. The scope and mechanism of associated chiral N-heterocyclic methodologies are then outlined, including cascade processes that enable diverse alkene 1,2-carboaminations. The recent emergence of new N-O donors and the realization of highly enantioselective aza-Heck cyclizations are then discussed. Collectively, these studies suggest that the aza-Heck approach can underpin a broad family of redox-neutral and enantioselective C-N bond forming processes.
The scope and mechanism of aza-Heck methodologies that provide chiral heterocyclic systems are outlined.
Copper catalyzed Heck-like cyclizations of oxime esters are described. Mechanistic studies indicate a reaction pathway that proceeds via the generation and cyclization of an intermediate that ...possesses iminyl radical character. To the best of our knowledge, this work encompasses the first examples of Cu-catalyzed aza-Heck reactions that proceed via oxidative initiation at nitrogen to generate products containing a new alkene. This new protocol is also an effective alternative to Pd-based systems and highlights the value of replacing precious metal catalysts with cheaper and more sustainable variants.
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. Tuning the electronics of the indole, through judicious choice of N‐protecting group, is required to ensure selective β‐hydride elimination away from the indole core. Utility of this method is highlighted in a modular formal synthesis of an S1P1 agonist precursor developed by Merck.
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.
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.
Decisions that we make about email legitimacy can result in a pernicious threat to security of both individuals and organisations. Yet user response to phishing emails is far from uniform; some ...respond while others do not. What is the source of this diversity in decision-making? From a psychological perspective, we consider cognitive and situational influences that might explain why certain users are more susceptible than others. Alongside an email judgment task employed as a proxy for fraud susceptibility, 224 participants completed a range of cognitive tasks. In addition, we manipulated time pressure for email legitimacy judgments. We identify cognitive reflection and sensation seeking as significant, albeit modest, predictors of susceptibility. Further to this, participants asked to make quicker responses made more judgment errors. We conclude there are cognitive signatures that partially contribute to email fraud susceptibility, with implications for efforts to limit online security breaches and train secure behaviors.
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
)
...C
H
)
) 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. A series of mechanistic experiments differentiate the two pathways and the scope of the hybrid organometallic radical cyclization is outlined. This study represents a rare example in Pd-catalysis where selection between dichotomous mechanistic manifolds is facilitated solely by choice of phosphine ligand.
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. Computational analysis provides critical insight into the reaction mechanism, in particular the key selectivity-determining step.
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. A broad scope of phenols, various allylic alcohols, and an alkyl hydroperoxide are viable coupling partners in this process.
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. These processes are rare examples of reactions that proceed
enantioselective migratory insertion of alkenes into Pd-N bonds, and the first where trisubstituted alkenes are used to generate tetrasubstituted stereocenters with high enantioselectivity.
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.
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