Deaminative couplings of alkylpyridinium salts
Date
2021
Authors
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Publisher
University of Delaware
Abstract
This dissertation focuses on investigations of deaminative couplings of alkyl amine electrophiles via C–N bond activation. ☐ Chapter 1 describes a nickel-catalyzed Suzuki-Miyaura arylation of α-amino acid-derived alkylpyridinium salts and aryl boroxines. Amino acids are abundant feedstock chemicals for organic synthesis and functionalization via cleavage of their C–N bond remains limited. By activating this C–N bond via an alkylpyridinium salt, we have demonstrated an efficient way to provide α-arylated products via deamination of amino acids. Notably, these alkylpyridinium salts can be synthesized in a single step from commercially available α-amino esters. Initial mechanistic studies support a radical mechanism, consistent with a NiI/III catalytic cycle. ☐ Chapter 2 describes a nickel-catalyzed Suzuki-Miyaura alkylation of alkylpyridinium salts with both alkenes and alkynes. By using High-Throughput experimentation interfaced with traditional reaction optimization, I have developed the coupling of alkylpyridinium salts with an alkyl boron species formed in situ from a simple alkene. Optimization relied on the realization of the importance of the identity and solubility of the base in the reaction. Notably, primary, secondary and benzylic alkylpyridinium salts can be utilized, including pyridinium salts derived from drug-intermediates. Additionally, when an alkyne is used instead of the alkene starting material, I observe the vinylation of alkylpyridinium salts under the same conditions as the alkylation. ☐ Chapter 3 describes a reductive cross-electrophile coupling of secondary alkylpyridinium salts with secondary alkyl iodides. This is the first coupling of unactivated secondary alkylpyridinium salts with an unactivated secondary alkyl coupling partner. Through traditional reaction optimization, I discovered the activation of the manganese reductant proved to be crucial for this reaction. Preliminary scope investigations are promising, and further investigations are currently ongoing. ☐ Chapter 4 describes investigations into the ligand effects on the Negishi cross-coupling of alkylpyridinium salts with primary zinc halides. Bis(N-pyrazolyl)pyridine (1-bpp) has proved to be the optimal ligand in a variety of alkylations of sterically bulky coupling partners, including alkylpyridinium salts. We investigated both the steric and electronic effect of different substituents on this 1-bpp ligand and correlated these observations to the rate of product formation in these reactions. Additionally, we have now demonstrated 1-bpp can be used as the ligand for the Negishi coupling of primary alkylpyridinium salts instead of the more expensive ttbtpy ligand used previously. ☐ Chapter 5 describes a thermally promoted deaminative addition of alkylpyridinium salts to sulfinimines to form enantiopure α-chiral amines. This reaction demonstrates a new mode of activation of alkylpyridinium salts via the unique ability of potassium carbonate to form an electron donor-acceptor complex with the alkylpyridinium salt, allowing for mild, transition metal-free conditions to be utilized for this transformation. I observed wide functional group tolerance, including a variety of heteroaryl examples. UV/Vis experiments were conducted to confirm the presence of our proposed EDA complex.
Description
Keywords
Deaminative coupling, Alkylpyridinium salt