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Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on-and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible. 

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2’-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parame-terization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational lig-and library, correlation of observed reaction outcomes with features of the ligands, and in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a fivefold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt. 

Nickel‐catalyzed cross‐electrophile coupling (XEC) is an efficient method to form carbon‐carbon bonds and has become an important tool for building complex molecules. While XEC has most often used stoichiometric metal reductants, these transformations can also be driven electrochemically. Electrochemical XEC (eXEC) is attractive because it can increase the greenness of XEC and this potential has resulted in numerous advances in recent years. The focus of this review is on electrochemical, Ni‐catalyzed carbon‐carbon bond forming reactions reported since 2010 and is categorized by the type of anodic half reaction: sacrificial anode, sacrificial reductant, and convergent paired electrolysis. The key developments are highlighted and the need for more scalable options is discussed.

 

Strained rings are increasingly important for the design of pharmaceutical candidates, but cross‐coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all‐carbon quaternary centers is the coupling of abundant strained‐ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel‐catalyzed cross‐electrophile approach that couples a variety of strained ringN‐hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that^t‐BuBpyCam^CN, an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96‐well plates.

 

Strained rings are increasingly important for the design of pharmaceutical candidates, but cross‐coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all‐carbon quaternary centers is the coupling of abundant strained‐ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel‐catalyzed cross‐electrophile approach that couples a variety of strained ringN‐hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that^t‐BuBpyCam^CN, an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96‐well plates.

 

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

 

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.