Utilizing unactivated alkyl amine derivatives in reductive cross-electrophile coupling reactions
Date
2025
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Publisher
University of Delaware
Abstract
This dissertation focuses on the utilization of unactivated alkyl amines, a diverse and abundant substrate class, in cross-electrophile coupling reactions. Alkyl amines can be activated through a condensation reaction to form the corresponding Katritzky alkylpyridinium salts. Under reductive conditions, the alkylpyridinium salts fragment, resulting in the formation of an alkyl radical that can react with an aryl partner through a nickel-catalyzed mechanism. Compared to redox neutral cross-coupling techniques, reductive deamination has become an attractive approach to the formation of carbon–carbon (C–C) bonds for valuable, bioactive molecules and precursors. ☐ Chapter 1 details a systematic examination of the scope of aryl bromide (ArBr) reactivity in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated using high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr reactivity are similar for the primary and secondary alkylpyridinium salts investigated, although distinctions were observed in isolated cases. In addition, the effectiveness of electrochemical conditions compared favorably to that of chemical reductants, especially for the more complex, drug-like aryl halides. ☐ Chapter 2 focuses on the development of a nickel-catalyzed electrochemical method for the cross-electrophile coupling of primary alkylpyridinium salts and aryl chlorides (ArCls). A cobalt anode and stainless-steel cathode were utilized in an undivided cell to yield various arylated products. During the reaction optimization process it was observed that high concentrations of electrolyte and aryl chloride coupling partner promote reaction efficiency. When reactions were done on large scale (1.0 mmol), larger surface area of anodes and cathodes are required to maintain sufficient electrolysis. This work demonstrates that the challenging coupling of alkylpyridinium salts is possible, but that several key limitations remain. ☐ Chapter 3 describes a cascade cyclization of alkene-tethered alkylpyridinium salts. Alkyl amine starting materials can be functionalized with alkene tethers and activated as Katritzky pyridinium salts. When subjected to reductive nickel-catalyzed conditions, deamination of the alkene-tethered substrate occurred to give an alkyl radical, which then cyclized on the pendant alkene. Subsequent coupling with an aryl halide then allowed the formation of two new C–C bonds in one step. This chemistry provides an efficient method to access saturated (hetero)cyclic molecules.
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Keywords
Salts fragment, High-throughput experimentation, Katritzky alkylpyridinium, Secondary substrates, Alkyl radical