Development and mechanistic understanding of nickel-catalyzed cross-couplings via C-N and C-O bond activation
| Author(s) | Bercher, Olivia | |
| Date Accessioned | 2023-10-09T16:49:05Z | |
| Date Available | 2023-10-09T16:49:05Z | |
| Publication Date | 2023 | |
| SWORD Update | 2023-09-11T19:07:15Z | |
| Abstract | This dissertation is focused on developing methods through activation of C–N bonds to form new C(sp3)–C(sp3) bonds as well as understanding the mechanism behind these transformations. In addition to gaining understanding of the mechanism via C–N bond activation, it also focuses on gaining insight on the mechanism of a Suzuki arylation via C–O bond activation. ☐ In Chapter 1, a deaminative nickel-catalyzed reductive methylation of alkylpyridinium salts is described. Through activation of the C–N bond, a mild and efficient method for creating secondary C(sp3)–CH3 bonds was developed. Excitingly, this method can utilize alkylpyridinium salts derived from pharmaceutically relevant compounds, allowing this method to be suitable for structure-activity relationship studies. In addition to developing this method, with the help from a colleague Windsor Lundy, we are synthesizing amine precursors of bioactive compounds with isopropyl groups for installing 11CH3 groups for positron emission tomography (PET) studies in collaboration with Prof. Zibo Li at the University of North Carolina, Chapel Hill. ☐ Chapter 2 highlights my efforts toward developing a deaminative reductive alkylation utilizing alkylpyridinium salts. Originally performing this transformation using alkyl iodides and manganese as reductant proved to have scaling and reproducibility issues. Additionally, I have investigated the scope of a cross-electrophile coupling of secondary alkylpyridinium salts with secondary alkyl iodides. Unfortunately, the conditions and scope of this reaction was unsatisfactory. I hypothesized the irreproducibility of this reaction may be due to using manganese as a reductant, so I have switched to studying an alternative activation method, electrochemistry. Optimization using electrochemical conditions has been promising, and further investigations are currently ongoing. ☐ Chapter 3 describes the effect of ligand on the Negishi alkylation of alkylpyridinium salts. For the cross-coupling of secondary alkylpyridinium salts with primary alkyl zinc halides, bis-(N-pyrazolyl)-pyridine (1-bpp) was the optimal ligand, while cross-couplings involving primary alkylpyridinium salts required 4,4’,4”-tri-tert-butyl-2,2’:6’,2”-terpyridine (ttbtpy) as a ligand. With the help of my colleague Kristen Baker, we investigated utilizing 1-bpp as the ligand for primary-primary cross-couplings as well as incorporating benzylic pyridinium salts, which was a limitation in our original publication. Additionally, Kristen and I have studied the steric and electronic effects of the 1-bpp ligand in these cross-couplings. ☐ Chapter 4 describes mechanistic investigations of the stereospecific Suzuki arylation of benzylic carboxylates without naphthyl substituents. Utilizing naphthyl or other extended π-systems was a limitation in the field that our method overcame with the use of a novel stilbene additive. Kinetic experiments have been performed; however, a 90-minute induction period was observed. I hypothesize the induction period could be caused by slow Ni(II) to Ni(0) reduction. Elimination of this induction period has proven challenging, but I have been able to shorten the induction period to 10 minutes. Additionally, I studied the reduction step of Ni(II) to Ni(0) through UV/vis and NMR experiments. | |
| Advisor | Watson, Mary P. | |
| Degree | Ph.D. | |
| Department | University of Delaware, Department of Chemistry and Biochemistry | |
| DOI | https://doi.org/10.58088/qjtb-cn65 | |
| Unique Identifier | 1408654466 | |
| URL | https://udspace.udel.edu/handle/19716/33355 | |
| Language | en | |
| Publisher | University of Delaware | |
| URI | https://login.udel.idm.oclc.org/login?url=https://www.proquest.com/dissertations-theses/development-mechanistic-understanding-nickel/docview/2864438153/se-2?accountid=10457 | |
| Keywords | Nickel | |
| Keywords | Cross-couplings | |
| Keywords | Suzuki arylation | |
| Keywords | Alkylpyridinium salts | |
| Keywords | C-N bond activation | |
| Keywords | C-O bond activation | |
| Title | Development and mechanistic understanding of nickel-catalyzed cross-couplings via C-N and C-O bond activation | |
| Type | Thesis |