Ni catalyzed single electron transfer (SET) reactions are central to many emerging catalytic methods in cross- coupling, photoredox catalysis, and reductive coupling. These catalytic methods are rapidly being adopted by the chemical industry and are vital to the synthesis of pharmaceutical agents relevant to human health. These seemingly disparate reactions are proposed to occur through radical chain mechanisms with common reaction intermediates, yet these key intermediates have not been isolated or characterized. An improved mechanistic understanding of these Ni catalyzed radical processes would directly impact multiple active avenues of organometallic research. Furthermore, Ni catalyzed radical processes have only recently been identified and their potential for overcoming additional catalytic challenges is underexplored. Ni catalysts have proven adept at converting carboxylic acids to reactive alkyl radicals that can be used to rapidly assemble complex natural products. The invention of additional carbon-carbon (C-C) and carbon-nitrogen (C-N) bond forming processes would provide new means of synthesizing lead compounds for drug discovery. The long-term goal of this proposal is to develop a fundamental mechanistic understanding of the Ni catalyzed radical chain processes integral to many emerging catalytic methods, and to expand upon these available methods by developing general, selective, and useful reactions that can impact the drug synthesis. In the proposed grant, a detailed study of the NiIII and NiI catalytic intermediates responsible for SET will be undertaken in parallel with the development of new methods that apply Ni SET catalysts to alkyl-alkyl bond formation and the conversion of carboxylic acids to amines. We hypothesize that the specific electronic nature of NiIII and NiI intermediates is essential to the radical chain mechanism proposed for multiple reaction classes?including cross-coupling, photoredox, and reductive coupling?and that understanding this mechanism will provide improved control over an array of processes that are being applied to the synthesis of bioactive compounds.
The specific aims of this proposal are to: 1) Spectroscopically observe and characterize catalytically active Ni intermediates in order to fill gaps in our mechanistic understanding of Ni SET processes; 2) Develop an alkyl-alkyl cross- coupling reaction that pairs two redox active esters derived from readily available carboxylic acids; and 3) Extend Ni catalyzed SET processes to the formation of C-N bonds by inventing a one-pot process for converting carboxylic acids directly to amines. The proposed research is significant because it will expand Ni SET reactions to form C-C and C-N bonds from common carboxylic acid starting materials. Such transformations will be applicable to the synthesis of pharmaceutical compounds. Additionally, the knowledge gained from the described mechanistic studies will provide insight into multiple reaction classes that proceed via radical chain mechanisms.
The proposed nickel catalyzed radical reactions will significantly expand the tools available for constructing bioactive molecules from readily available carboxylic acid starting materials, and the described mechanistic studies will provide fundamental insight into multiple related radical reactions (eg: cross-coupling, photoredox reactions, and reductive couplings) that are already being applied to the synthesis of bioactive compounds. This work will directly improve public health by providing efficient methods for the synthesis of pharmaceutical agents and increasing the number of available molecules that can serve as lead compounds for drug discovery. New bond forming reactions are an essential tool for synthesizing small molecule treatments that combat diseases and improve quality of life.
| Batesky, Donald C; Goldfogel, Matthew J; Weix, Daniel J (2017) Removal of Triphenylphosphine Oxide by Precipitation with Zinc Chloride in Polar Solvents. J Org Chem 82:9931-9936 |
