Comparative Screening of DalPhos/Ni Catalysts in C‐N Cross‐couplings of (Hetero)aryl Chlorides Enables Development of Aminopyrazole Cross‐couplings with Amine Base

Abstract

A systematic competitive evaluation of the DalPhos ligand family in nickel-catalyzed N-arylation chemistry is reported, involving primary (linear and branched) and secondary alkylamines, as well as a primary five-membered heteroarylamine (aminopyrazole), in combination with a diverse set of test electrophiles and bases (NaOtBu, K 2 CO 3 , DBU/NaTFA). In addition to providing optimal ligand/catalyst identification, and bringing to light methodology limitations (e. g., unwanted CÀ O cross-coupling with NaOtBu), our survey enabled the development of the first efficient catalyst system for heteroatom-dense CÀ N cross-coupling of aminopyrazoles and related nucleophiles with (hetero)aryl chlorides by use of an amine 'dual-base' system.

Ligand-Enabled Nickel Catalysis for the O-Arylation of Alcohols and Phenols with (Hetero)aryl Chlorides Using a Soluble Organic Base

“…We focused our attention on the use of air-stable ( L )­Ni­( o -tolyl)Cl precatalysts, where L = PAd2-DalPhos ( L1 ) or CyPAd-DalPhos ( L2 ). The L1 -precatalyst, while not previously examined in O -arylations of the type under investigation herein, has proven useful in combination with DBU/NaTFA for Ni-catalyzed C–N cross-couplings, ,, while ( L2 )­Ni­( o -tolyl)Cl is an effective precatalyst for the O -arylation of aliphatic alcohols and amino alcohols using an inorganic base.…”

Nickel‐Catalyzed Chemoselective Arylation of Amino Alcohols

“…For simplicity, and to focus specifically on ascertaining the impact of the bisphosphine ancillary ligand identity on reaction outcome, we employed a single set of conditions (5 mol % Ni, NaO t Bu, toluene, 110 °C, 18 h). Moreover, given the general favorability of C−N over C−O bond formation in competitive metal‐catalyzed cross‐couplings, [1g, 9] including as observed in selected examples involving (DalPhos)Ni( o ‐tol)Cl pre‐catalysts, [12c,g, 14] emphasis was placed on identifying the combination of ancillary ligand and amino alcohol component structural features that enable C−O cross‐coupling to be achieved in the presence of potentially contending NH reactive sites. In the competitions, the cross‐coupling of 6‐chloroquinoline with 4‐methyl‐1‐pentanol ( 1 a ) leading to 3 a was examined throughout, using structurally varied competing NH nucleophiles ( 2 a – 2 e , Figure 3A–E).…”

The development of cage phosphine ‘DalPhos’ ligands to enable nickel-catalyzed cross-couplings of (hetero)aryl electrophiles

“…Furthermore, strong inorganic bases exhibit poor substrate functional group tolerance, and in the case of NaO t Bu can react as a competitive nucleophile in cross-coupling chemistry. 42 In 2019, Simmons and co-workers reported a so-called ‘dual-base’ system using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and halide scavenger sodium trifluoroacetate (NaTFA) to circumvent the limitations of inorganic bases in palladium-catalyzed C–N cross-couplings of primary amides or anilines with (hetero)aryl chlorides. 43 Inspired by this strategy, in 2021 we targeted the nickel-catalyzed N -arylation of amides using a DBU/NaTFA through an initial ligand screen that included PAd-DalPhos, CyPAd-DalPhos, PhPAd-DalPhos ( vide infra ), PAd2-DalPhos ( vide infra ), XantPhos, DPPF, JosiPhos CyPF-Cy, IPr, and SIPr.…”

“…As such, in 2023 we conducted a systematic ‘head-to-head’ reactivity study employing representative reaction classes (known and new transformations) as a means of directly comparing the performance of these DalPhos ligands in nickel-catalyzed C–N cross-coupling. 42 In this study, 672 individual experiments were conducted under mild conditions (3 mol% Ni, 60 °C), with various reaction parameters examined in the C–N cross-coupling of NH nucleophiles with (hetero)aryl chlorides, including: base ( i.e. , NaO t Bu, K 2 CO 3 , or DBU/NaTFA); solvent ( i.e.…”