Doctor of Philosophy
School of Chemistry and Molecular Bioscience
Transition metal-catalysed reactions represent a valuable tool for the construction of sp3-rich, stereodefined molecular scaffolds in a single synthetic step. Though these reactions have garnered considerable attention over the last few decades, recent literature indicates that the fractional sp3 character of drug-like molecules has gradually decreased over the last twenty years. This is in part, due to the increased use of transition metal-catalysed cross-coupling reactions such as the Heck and Suzuki–Miyaura reactions, which allow for the preparation of flat, aromatic molecules in a single synthetic step. It was therefore the aim of this dissertation to synthesise novel sp3-rich molecular scaffolds in a single synthetic step via transition metal-catalysed reactions. This has been achieved in two sections: Part I which details the use of vinyl benzoxazinanones as 1,4-dipole precursors in (4 + 2) dipolar cycloaddition reactions, and Part II which proposes a synthetic route towards novel allenyl benzoxazinanones and investigates the reactivity of these systems under nickel catalysis.
The synthesis of sp3-rich tetrahydro-5H-indolo[2,3-b]quinolines was achieved in Part I of this dissertation via the palladium-catalysed decarboxylative, dearomative (4 + 2) cycloaddition of vinyl benzoxazinanones with 3-nitroindoles. While initial attempts to react N-tosyl protected vinyl benzoxazinanones with 3-nitroindole in the presence of a palladium(0) catalyst were unsuccessful, replacing this substrate with the unprotected vinyl benzoxazinanone led to the formation of tetrahydro-5H-indolo[2,3-b]quinolines in moderate to excellent yields (42–94%), with excellent diastereoselectivity (up to >98:2). The relative stereochemistry of these tetrahydro-5H-indolo[2,3-b]quinolines was determined as trans through a combination of nuclear magnetic resonance (1-D NOE and 2-D NOESY) analysis and X-ray crystallographic analysis. The scope of this reaction was shown to accommodate a wide range of electron-donating and electron-withdrawing substituents on the benzene portion of the indole ring. This was in contrast to indoles which contained electron-donating groups at N-1 or groups that were less electron-withdrawing than tosyl (such as Bz, Ac, Me), and indoles containing C-3 substituents such as acetyl, cyano and methyl ester which resulted in no reaction. These findings highlight the significance of the C-3 electron-withdrawing nitro-substituent and the strong electron-withdrawing N-substituents in rendering the indole sufficiently electrophilic to participate in the cycloaddition reaction with vinyl benzoxazinanones. A brief asymmetric protocol of this reaction was also demonstrated in the presence of a chiral phosphinooxazoline ligand, generating the corresponding tetrahydro-5H-indolo[2,3-b]quinoline in high NMR yield (90%), moderate dr (46:54 trans:cis) and high enantioselectivity for the trans diastereomer (>98% ee).
Bird, Melissa Jane, Synthesis and Transition Metal-Catalysed Reactivity of Vinyl and Allenyl Benzoxazinanones, Doctor of Philosophy thesis, School of Chemistry and Molecular Bioscience, University of Wollongong, 2022. https://ro.uow.edu.au/theses1/1446
FoR codes (2008)
030503 Organic Chemical Synthesis, 039904 Organometallic Chemistry, 030207 Transition Metal Chemistry
Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.