Stephen G. Newman

Palladium-Catalyzed Suzuki–Miyaura Coupling of Aryl Esters

The Suzuki-Miyaura coupling is among the most important C-C bond-forming reactions available due to its reliability, chemoselectivity, and diversity. Aryl halides and pseudohalides such as iodides, bromides, and triflates are traditionally used as the electrophilic coupling partner. The expansion of the reaction scope to nontraditional electrophiles is an ongoing challenge to enable an even greater number of useful products to be made from simple starting materials. Herein, we present how an NHC-based Pd catalyst can enable Suzuki-Miyaura coupling where the C(acyl)-O bond of aryl esters takes on the role of electrophile, allowing the synthesis of various ketone-containing products. This contrasts known reactions of similar esters that provide biaryls via nickel catalysis. The underlying cause of this mechanistic divergence is investigated by DFT calculations, and the robustness of esters compared to more electrophilic acylative coupling partners is analyzed.

Inherent vs Apparent Chemoselectivity in the Kumada-Corriu Cross-Coupling Reaction.

The Kumada-Corriu reaction is a powerful tool for C-C bond formation, but is seldom utilized due to perceived chemoselectivity issues. Herein, we demonstrate that high-yielding couplings can occur in the presence of many electrophilic and heterocyclic functional groups. Our strategy is mechanically based, matching oxidative addition rates with the rate of syringe pump addition of the Grignard reagent. The mechanistic reason for the effectiveness of this strategy is uncovered by continuous-infusion ESI-MS studies.

Switchable Selectivity in the Pd-Catalyzed Alkylative Cross-Coupling of Esters

The Pd-catalyzed cross-coupling of phenyl esters and alkyl boranes is disclosed. Two reaction modes are rendered accessible in a selective fashion by interchange of the catalyst. With a Pd-NHC system, alkyl ketones can be prepared in good yields via a Suzuki-Miyaura reaction proceeding by activation of the C(acyl)-O bond. Use of a Pd-dcype catalyst enables alkylated arenes to be synthesized by a modified pathway with extrusion of CO. Applications of this divergent coupling strategy and the origin of the switchable selectivity are discussed.

A Nickel‐Catalyzed Carbonyl‐Heck Reaction

The use of transition-metal catalysis to enable the coupling of readily available organic molecules has greatly enhanced the ability of chemists to access complex chemical structures. In this work, an intermolecular coupling reaction that unites organotriflates and aldehydes is presented. A unique catalyst system is identified to enable this reaction, featuring a Ni0 precatalyst, a tridentate Triphos ligand, and a bulky amine base. This transformation provides access to a variety of ketone-containing products without the selectivity- and reactivity-related challenges associated with more traditional Friedel-Crafts reactions. A Heck-type mechanism is postulated, wherein the πu2005bond of the aldehyde takes the role of the olefin in the insertion/elimination steps.

Flow-Assisted Synthesis of Heterocycles at High Temperatures

Performing selective and high-yielding transformations on complex organic molecules at temperatures in the range of 200–450°C may at first seem counterintuitive or even impossible. However, using continuous flow systems, conditions of this sort are indeed accessible and viable for useful chemistry. This review highlights recent endeavors in heterocycle synthesis and modification enabled by high-temperature (>200°C) flow chemistry, with emphasis placed on showcasing the variety and synthetic utility of different high-temperature enabled transformations. The reviewed content naturally falls into three categories: pericyclic transformations, condensation reactions, and modification/functionalization of heterocycles. Different shortcomings and considerations necessary when planning high-temperature flow reactions have also been highlighted where applicable.

Overcoming solid handling issues in continuous flow substitution reactions through ionic liquid formation

Substitutions such as acylations, arylations, and alkylations are some of the most commonly run reactions for building complex molecules. However, the requirement of a stoichiometric base to scavange acid by-products creates significant challenges when operating in continuous flow due to solid handling issues associated with precipitating base·HX salts. We present a general and simple strategy to overcome these solid handling issues through the use of acid scavenging organic bases that generate low- to moderate-melting ionic liquids upon protonation. The application of these bases towards the most commonly run substitutions are demonstrated, enabling reactions to be run in flow without requiring additional equipment, specific solvents, or dilute reaction conditions to prevent clogging.