New explorations in visible-light mediated energy and single electron transfer for nitrogen heterocycle synthesis

Oddy, Meghan Jessica

New explorations in visible-light mediated energy and single electron transfer for nitrogen heterocycle synthesis

Thesis / Dissertation

2024

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

With the recent push toward green chemistry, photocatalysis has emerged as a powerful alternative for reactions that might otherwise need high temperatures, poor atom economy or harsh reactants to proceed. This thesis explores the use of visible-light mediated photocatalysis for the synthesis of biologically important nitrogen containing heterocycles, investigating both single electron transfer and energy transfer methods. The results section of this thesis is presented in three chapters, each focusing on a different ring size, namely 4, 5 and 6 membered nitrogen heterocycles. Chapter two explores the use of photocatalysis to enable stereoselective access to 3,3-disubstitued oxindoles via newly developed N-acyl chiral auxiliaries, serving as chiral C1 radical synthons. These acyl radicals are generated under visible-light mediated single electron transfer to N-hydroxyphthalimido esters, which then undergo a radical addition–cyclisation sequence with N-phenyl acrylamides. A model 3,3-disubstitued oxindole is isolated as separable diastereomers in 81% yield with 2.2:1 dr. This advanced intermediate could be telescoped toward the formal synthesis of the natural cyclotryptamine alkaloid, physovenine. Chapter three describes an efficient thioxanthone-catalysed triplet energy transfer process for the synthesis of 3,4-dihydroquinolin-2-ones from N-acrylamides. This work features a rare example of a metal-free formal C(sp2)–H/C(sp3)–H arylation mediated by visible-light. Using 450 nm light with 2 chlorothioxanthone in 2,2,2-TFE:CHCl3, a selection of 23 substituted 3,4-dihydroquinolin-2-ones are isolated in moderate to excellent yields (16–97%). The reaction is amenable to gram-scale synthesis, and the 3,4-dihydroquinolin-2-ones obtained are easily oxidized to the corresponding quinolin-2-ones, ultimately producing facile access to two privileged bioactive scaffolds. The reaction mechanisms presented are supported by Stern-Volmer plots as well as deuterium labelling studies. Finally, chapter four explores the synthesis of 2-azetidinones (β-lactams) from simple acrylamide starting materials by visible-light-mediated energy transfer catalysis. The reaction features a C(sp3)−H functionalisation via a variation of the Norrish–Yang photocyclisation involving a rare carbon-to-carbon 1,5-hydrogen atom transfer. The proposed mechanism is supported by deuterium labelling and DFT calculations. The optimised reaction conditions use 2-chlorothioxanthone under irradiation with 405 nm light which enables the synthesis of 30 substrates in moderate to excellent yields (40–98%), mostly as 2 separable diastereomers (generally 1.5:1 dr).

Keywords

chemistry

Reference:

Collections

PhD / Doctoral

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