The overall goal of the proposed research is the development of general, efficient and cost-effective methods for the conversion of C-H bonds to C-C bonds. The products of the proposed transformations are structural motifs prevalent in biologically active molecules. The proposed methods have the potential to serve as cost-effective and environmentally friendly alternatives to the currently known methods for the strategic introduction of C-C bonds in the context of synthesis of medicinal drugs. Specifically this proposal seeks to develop palladium- and nickel-catalyzed methods for the construction of C-C bonds. The successful implementation of the research described herein will lead to novel intra- and intermolecular arylation of arene and alkyl C-H bonds.
Aim 1 seeks to develop palladium-catalyzed methods for the direct arylation of C-H bonds using phenolic electrophiles. The transformation will be a significant advance over the known methods for C-H arylations, the majority of which employ aryl halides as electrophiles. The use of inexpensive and readily accessible phenolic electrophiles render these transformations, more environmentally friendly than previously reported direct arylation methods.
Aims 2 and 3 are focused on the development of Ni-catalyzed direct arylation of C-H bonds. The use of earth abundant and inexpensive nickel catalysts will be significantly more cost effective than previously known methods, many of which utilize precious noble metal catalysts. The most significant challenge toward the accomplishment of the Ni-catalyzed arylations is the dearth of mechanistic understanding for C-H activation at a Ni center, a key step of the proposed transformations. As such the development of the Ni-catalyzed direct arylations is based on careful consideration of the mechanistic aspects of related well-studied Pd-catalyzed C-H arylations. Additionally, the research design includes fundamental-mechanistic investigations of the Ni-catalyzed arylations. These studies will aid in the accomplishment of the proposed work and will enable the discovery of other synthetically useful Ni-catalyzed C-H functionalizations. The PI's research group has enhanced the research environment at St. Olaf College, providing a unique opportunity to expose undergraduates to the cutting edge of organometallic research. The current proposal will provide the students with relevant experience and a foundation in the techniques used in both pharmaceutical and biomedical research at the next level.
The proposed research involves the formation of structural motifs that are prevalent in bioactive molecules. The successful implementation of the research has the potential to lower the costs associated with the production of pharmaceuticals. Furthermore, the proposal will enable undergraduate students to conduct research in organometallic chemistry, a field that is extensively used in the synthesis of medicinal drugs and in biomedical applications.
|Hanson, Mckenna G; Olson, Noelle M; Yi, Zubaoyi et al. (2017) Nickel-Catalyzed Coupling of Azoles with Aromatic Nitriles. Org Lett 19:4271-4274|
|Yi, Zubaoyi; Aschenaki, Yodit; Daley, Ryan et al. (2017) Palladium Catalyzed Arylation and Benzylation of Nitroarenes Using Aryl Sulfonates and Benzyl Acetates. J Org Chem 82:6946-6957|
|Steinberg, Deborah F; Turk, Morgan C; Kalyani, Dipannita (2017) Nickel-Catalyzed C-H Arylation of Benzoxazoles and Oxazoles: Benchmarking the Influence of Electronic, Steric and Leaving Group Variations in Phenolic Electrophiles. Tetrahedron 73:2196-2209|
|Sardzinski, Logan W; Wertjes, William C; Schnaith, Abigail M et al. (2015) Nickel-catalyzed decarboxylative cross-coupling of perfluorobenzoates with aryl halides and sulfonates. Org Lett 17:1256-9|
|Crawford, Jennifer M; Shelton, Kyle E; Reeves, Emily K et al. (2015) Nickel-Catalyzed Decarboxylative Arylation of Azoles with Perfluoro- and Nitrobenzoates. Org Chem Front 2:726-729|
|Wertjes, William C; Waller, Peter J; Shelton, Kyle E et al. (2014) Nickel-Mediated Synthesis of Isoindolinones at Room Temperature. Synthesis (Stuttg) 46:3033-3040|
|Wertjes, William C; Wolfe, Lydia C; Waller, Peter J et al. (2013) Nickel or phenanthroline mediated intramolecular arylation of sp3 C-H bonds using aryl halides. Org Lett 15:5986-9|