Synthesis of Bioactive Nitrogen-Containing Heterocycles via Aryne Methodologies

The six chapters of this dissertation exemplify the application of aryne chemistry in medicinally-relevant, nitrogen-containing heterocycle synthesis. The arynes discussed in this dissertation are generated from Kobayashi\u27s aryne precursors that leads to novel synthetic methodology. Chapter 1 begins by detailing the overall organization of this dissertation and follows with a brief review of arynes, which provides the reader with a general understanding of this highly reactive intermediate and its application in various organic transformations. Chapter 2 describes the chemical reactivity of 2,3-pyridyne in the presence of amines. We have found that amines attack the 2-position of 2,3-pyridyne exclusively to afford the corresponding 2-aminopyridines. In addition, a series of benzonaphthyridinones have been synthesized by reacting 2,3-pyridyne with o-aminobenzoates. Chapter 3 describes a project involving the reaction of beta-lactams and arynes. In this process, the aryne inserts into carbon-nitrogen bond of the beta-lactam to form a 2,3-dihydroquinolin-4-one, which subsequently reacts with another molecule of aryne to form an acridone by extrusion of a molecule of ethylene. 2,3-Dihydroquinolin-4-ones react under the same reaction conditions to afford acridones. This is the first example of ethylene extrusion in aryne chemistry. Chapter 4 describes a rapid and efficient synthesis of 2H-indazoles using a [3 + 2] dipolar cycloaddition of sydnones and arynes. A series of 2H-indazoles have been prepared in good to excellent yields using this protocol, and subsequent Pd-catalyzed coupling reactions can be applied to the halogenated products to generate a structurally diverse library of indazoles. This methodology has been highlighted in Synfacts. Chapter 5 details a methodology for synthesizing 2H-isoindoles and 9,10-dihydro-9,10-epiminoanthracenes from arynes and münchnones. 2H-Isoindoles have been generated from arynes and münchnones by a [3 + 2] dipolar cycloaddition process under very mild reaction conditions. Due to the high reactivity of 2H-isoindoles with arynes, 9,10-dihydro-9,10-epiminoanthracenes are ultimately formed in the presence of arynes in good to excellent yields. Lastly, Chapter 6 makes some general conclusions about the previous chapters

Heterocycle Synthesis from Quinols

Three cascade reactions that provide access to various heterocyclic skeletons from quinols were developed. Various substituted 1-hydroxyacridones, 4-hydroxycarbazoles and 4-hydroxy-indolin-3-ones were readily synthesized in moderate to excellent yields. The common sequential transformation involves carbamation/Michael addition/mixed Claisen condensation/decarboxylative aromatization which were realized in one-pot reactions in the synthesis of acridones and indolin-3-ones, or two-step reactions in the synthesis of carbazoles. A side reaction from oxidative dearomatization of phenols, affording iodo diaryl ethers in one step from commercial phenols, albeit in low yields, revealed an intricate mechanistic pathway. The synthesis of jaboticabin was realized in nine linear steps from commercial phloroglucinol and 3,4-dihydroxybenzoic acid. In vivo experiments were undertaken and synthetic derivatives were made for future SAR studies

Asymmetric Oxidation of Enol Derivatives to α-Alkoxy Carbonyls Using Iminium Salt Catalysts: A Synthetic and Computational Study

We report herein the first examples of asymmetric oxidation of enol ether and ester substrates using iminium salt organocatalysis, affording moderate to excellent enantioselectivities of up to 98% ee for tetralone-derived substrates in the α-hydroxyketone products. A comprehensive density functional theory study was undertaken to interpret the competing diastereoisomeric transition states in this example in order to identify the origins of enantioselectivity. The calculations, performed at the B3LYP/6-31G(D) level of theory, gave good agreement with the experimental results, in terms of the magnitude of the effects under the specified reaction conditions, and in terms of the preferential formation of the (R)-enantiomer. Just one of the 30 characterized transition states dominates the enantioselectivity, which is attributed to the adoption of an orientation relative to stereochemical features of the chiral controlling element that combines a CH interaction between a CH 2 group in the substrate and one of the aromatic rings of the biaryl section of the chiral auxiliary with a good alignment of the acetoxy group with the other biaryl ring, and places the smallest substituent on the alkene (a hydrogen atom) in the most sterically hindered position

Formation of Acridones by Ethylene Extrusion in the Reaction of Arynes with β-Lactams and Dihydroquinolinones

<i>N</i>-Unsubstituted β-lactams react with a molecule of aryne by insertion into the amide bond to form a 2,3-dihydroquinolin-4-one, which subsequently reacts with another molecule of aryne to form an acridone by extrusion of a molecule of ethylene. 2,3-Dihydroquinolin-4-ones react under the same reaction conditions to afford identical results. This is the first example of ethylene extrusion in aryne chemistry