The Quest for the Ideal Base: Rational Design of a Nickel Precatalyst Enables Mild, Homogeneous C–N Cross-Coupling

Abstract

Palladium-catalyzed amination reactions using soluble organic bases have provided a solution to the many issues associated with heterogeneous reaction conditions. Still, homogeneous C–N cross-coupling approaches cannot yet employ bases as weak and economical as trialkyl­amines. Furthermore, organic base-mediated methods have not been developed for Ni­(0/II) catalysis, despite some advantages of such systems over those employing Pd-based catalysts. We designed a new air-stable and easily prepared Ni­(II) precatalyst bearing an electron-deficient bidentate phosphine ligand that enables the cross-coupling of aryl triflates with aryl amines using triethyl­amine (TEA) as base. The method is tolerant of sterically congested coupling partners, as well as those bearing base- and nucleophile-sensitive functional groups. With the aid of density functional theory (DFT) calculations, we determined that the electron-deficient auxiliary ligands decrease both the pK a of the Ni-bound amine and the barrier to reductive elimination from the resultant Ni­(II)–amido complex. Moreover, we determined that the preclusion of Lewis acid–base complexation between the Ni catalyst and the base, due to steric factors, is important for avoiding catalyst inhibition.

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

“…4) Methods that are more amenable to microchannel flow conditions (e.g., the substitution of insoluble reagents with soluble ones [56] ) are required.…”

“…3) Methods for catalyst immobilization and recycling are important. 4) Methods that are more amenablet om icrochannel flow conditions (e.g.,t he substitutiono fi nsoluble reagents with soluble ones [56] )a re required. 5) Innovativet echniques for purification of intermediates and changings olvents are necessary for general applications.…”

“…Flow setup of the microfluidic platform used to optimize Pd-catalyzed organic base-assisted CÀNc oupling reactions. Reproduced from ref [56]. with permission from American Chemical Society, 2019 Copyright.…”

Nickel‐Catalyzed N‐Arylation of Fluoroalkylamines

“…To circumvent such issues, we sought to identify a complementary protocol that makes use of a more mild organic amine base, as has been developed lately for use in Pd‐catalyzed C‐N cross‐coupling, including with (hetero)aryl chlorides [18a, 24] . While Buchwald and co‐workers recently disclosed the first Ni‐catalyzed C‐N cross‐couplings that make use of such a base (NEt 3 ) without recourse to microwave, photoredox, or electrochemical protocols and/or use of exogenous reductants, the reported transformations are restricted to reactions of (hetero)aryl triflates and anilines [25] . Given our interest in cross‐couplings of aryl chlorides (as well as less reactive phenol‐derived electrophiles), we selected the “dual‐base” DBU/NaOTf system [24a] (DBU=1,8‐diazabicyclo(5.4.0)undec‐7‐ene) to test in C‐N cross‐couplings of 2,2‐difluoroethylamine using ( PAd2‐DalPhos )Ni( o ‐tol)Cl as a pre‐catalyst (Figure 4 A).…”

Standardized Stirring for Small Scale Surveys

“…Catalytic reactions are sensitive to a wide range of experimental conditions, even in homogeneous systems. [1][2][3][4][5][6][7][8][9] These conditions include variables, such as concentration of reactants and catalyst, [10] stirring rate, [11] reaction time and temperature, [12] which contribute to the outcome of a catalytic system after optimization. This study focuses on the influence of stirring in a small-scale crosscoupling reaction.…”