Fundamental Studies of Ni-Catalyzed Organic Reactions

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Project Summary/Abstract Precious metal catalysts are typically used for the synthesis of active pharmaceutical ingredients (APIs) even though first-row transition metals such as Ni are more sustainable and can facilitate unique reactivity. For exam- ple, Ni-catalyzed reactions can readily form sp2-sp3 C–C bonds, which provides methods to synthesize the types of non-planar APIs that are challenging to prepare using precious metal-catalyzed reactions. However, in general, the relative lack of mechanistic understanding about Ni-catalyzed reactions has hindered their use in the syn- thesis of APIs because it inhibits the development of improved systems and the rational design of new reactions. One difficulty in elucidating the pathway of Ni-catalyzed transformations is that NiI complexes are often invoked as intermediates but information about their reactivity is limited. In this project, novel NiI halide, alkyl, and aryl species supported by bidentate nitrogen ligands, which are proposed as intermediates in reactions including cross-coupling, cross-electrophile coupling (XEC), and metallaphotoredox based processes, will be synthesized. The ability of these NiI complexes to undergo the proposed elementary steps in catalysis will be investigated as a function of the ancillary ligand and reaction conditions using experimental and computational techniques. These studies will be complemented by experiments to probe how NiI species are formed via comproportionation between Ni0 and NiII complexes and in situ studies to elucidate the speciation of Ni catalysts during catalysis. It is expected that our fundamental investigations will lead to the design of the next generation of Ni-catalyzed reactions by providing guidelines about the reactivity of NiI complexes. Another problem with the development of Ni-catalyzed reactions is that they often involve heterogeneous reductants, which complicate mechanistic studies, create difficulties for scale up, and cannot readily be tuned to vary the reduction potential. The PI’s group has developed a series of commercially available tunable homogeneous reductants, with reduction potentials similar to Zn0. Apart from leading to improvements in practicality, the tunability of these reductants was crucial for developing novel strategies for controlling the rate of alkyl radical generation from Katritzky salts and 1° alkyl halides in Ni-catalyzed C(sp2)–C(sp3) XEC, which led to new reactivity. Here, tunable homogeneous reductants, with reduction potentials similar to Mn0, a commonly used heterogeneous reductant, will be prepared. Kinetic studies will be performed to understand the ability of the reductants to control the rates of alkyl radical formation from N-hydroxyphthalimide (NHP) esters and 1°, 2°, and 3° alkyl halides. This will be accompanied by experi- ments to identify ancillary ligands on NiII complexes that enable facile trapping of alkyl radicals, which is currently unknown. The studies on alkyl radical generation and trapping will aid in solving significant problems in C(sp2)– C(sp3) XEC, such as the use of aryl and alkyl chlorides and 3° alkyl halides as substrates. Finally, through a collaboration with Merck, the new methods will be evaluated against medicinal chemistry targets and applied to nanomole scale chemistry, which is an emerging strategy to prepare diverse libraries of bioactive compounds.