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Harnessing Cyclic Alkynes for the Synthesis of Heterocyclic Compounds and Nickel- Catalyzed C–C Bond Forming Reactions From Amide Derivatives


This dissertation describes synthetic endeavors aimed at harnessing the reactivity of arynes and cyclic alkynes toward the synthesis of heterocycles. Arynes and cyclic alkynes are highly reactive intermediates that act as electrophilic arene and alkyne surrogates. Additionally, this dissertation outlines the strategic activation of the amide C–N bond using nickel catalysis. This recently discovered mode of reactivity is employed for the generation of molecular complexity.

Chapter One describes a systematic experimental and computational study of a particularly important class of arynes, 3-halobenzynes. Our efforts show that aryne distortion, rather than steric factors or charge distribution, are responsible for the regioselectivities observed in 3-halobenzyne trapping reactions. Experiments also validate the synthetic utility of 3-halobenzynes for the synthesis of heterocycles, using a tandem aryne trapping / cross-coupling sequence involving 3-chlorobenzyne.

Chapter Two outlines synthetic studies pertaining to two heterocyclic aryne intermediates: the 2,3-pyridyne and the 4,5-pyrimidyne. 2,3-pyridyne generation and trappings were used to access a variety of functionalized pyridines in a regioselective manner. Additionally, synthetic routes to two isomeric silyl triflates, which were intended to serve as precursors to the 4,5-pyrimidyne, are disclosed. Subsequent 4,5-pyrimidyne generation and trapping experiments were ultimately unfruitful.

Chapter Three reports on the synthesis of poly(benzonorbornadiene) polymers via a strategic blend of benzyne chemistry and ROMP. Through a comparative study, we demonstrate that substitution at the benzylic / allylic position prevents oxidative deformation and polymer decomposition, yet does not inhibit polymerization by common ruthenium catalysts with good control over molecular weight dispersity.

Chapter Four illustrates the strategic use of cyclohexyne and the more elusive intermediate, cyclopentyne, as efficient tools for the synthesis of new heterocyclic compounds with high sp3 character. Experimental and computational studies of the first 3-substituted cyclohexyne are also described. The observed regioselectivities are explained by the distortion / interaction model.

Chapter Five describes the generation of the first 3,4-piperidyne and its use as a building block for the synthesis of highly decorated piperidines. Experimental and computational studies of this intermediate are disclosed, along with comparisons to the well-known 3,4-pyridyne aromatic analogue. Additionally, the distortion / interaction model is used to explain the observed regioselectivities.

Chapter Six pertains to the generation of two stained oxacyclic intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds. Across all trapping reactions performed, product distributions are consistent with predictions made with the distortion / interaction model. Oxygen-containing strained intermediates were also found to react with higher selectivities when compared to their corresponding nitrogen-containing analogues.

Chapter Seven depicts the first non-decarbonylative Mizoroki–Heck reactions of amide derivatives. The transformation relies on the use of nickel catalysis and proceeds with sterically hindered tri- and tetrasubstituted olefins to yield products containing quaternary centers. Moreover, a diastereoselective variant of this reaction demonstrates its utility for accessing adducts bearing vicinal stereocenters. Our results demonstrate that amide derivatives can be used as building blocks for the assembly of complex scaffolds.

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