The recent advances in homogeneous nickel catalysis have showcased the ability of nickel to facilitate challenging transformations. Most reactions are performed using the temperature, air, and moisture unstable complex, Ni(COD)2 (COD = 1,5-cyclooctadiene). Do to the instability of this nickel catalyst, high-throughput experimentation (HTE) of nickel catalyzed reactions could not be performed. HTE is an important tool for rapid reaction optimization because many variables are screened and large quantities of data are collected for further understanding the reactivity. This proposal describes a strategy to perform HTE with Ni-catalysis to expedite the optimization of difficult chemical transformations necessary for drug development. Recently, a new class of Ni(II)-precatalysts have been developed by Jamison, Yang, Percec, Buchwald, and Hartwig. The precatalysts offer many advantages over traditional nickel catalysts, such as Ni(COD)2, and other available precatalysts because of their moisture- and air-stability, ease of activation, and reduced catalyst loadings. However, because the ligands are preinstalled, the precatalysts cannot directly participate in HTE. Continuous-flow chemistry has several notable advantages over traditional batch chemistry, including the ability to telescope syntheses and purifications. Due to the streamlining capabilities, developing a continuous- flow synthesis of the Ni(II)-precatalysts will enable their on-demand production. Furthermore, the flow synthesis could then be integrated into an HTE-system previously developed by the Jensen group. The current Ni(II)-precatalysts are phosphine-based. NHC-based precatalysts exist, however, these precatalysts are not easily activated. Before designing a flow synthesis for NHC-based precatalyst, a new class similar to the phosphine-based precatalysts will be investigated. Lastly, the value of the HTE system will be demonstrated through optimizing a novel reaction of high importance: Ni-photoredox catalyzed trifluoromethylation. Ni-catalyzed trifluoromethylations have not been realized due to the difficulty of nickel to form bonds between carbon and highly electronegative groups. However, Ni-photoredox utilizes a higher oxidation state, Ni(III), that has been shown to facilitate these difficult bond formations. Through leveraging Ni-photoredox catalysis and the developed HTE-system, new and efficient methods of trifluoromethylations will be developed.
High-throughput experimentation (HTE) is a valuable tool for reaction optimization. Currently, methods for HTE in nickel catalysis are limited due to the current availability of nickel sources. This proposal describes a strategy for performing HTE with Ni(II)-precatalysts and then applying this strategy towards discovering and optimizing novel Ni-catalyzed trifluoromethylations.
| Strieth-Kalthoff, Felix; Longstreet, Ashley R; Weber, Jessica M et al. (2018) Bench-Stable N-Heterocyclic Carbene Nickel Precatalysts for C-C and C-N Bond-Forming Reactions. ChemCatChem 10:2873-2877 |
