Development of photoredox-catalysed transformation of enamides and allenamides
thesisposted on 2019-02-18, 16:47 authored by Kayode Koleoso
Enamides and allenamides are two versatile functional groups that offer a wide variety of alternatives for the inclusion of nitrogen-based moiety into an organic system. Nitrogen-containing structures are prevalent among medicinally interesting natural and unnatural products and, thus, are useful in developing new therapeutics. Their chemical utilities have been exploited by a number of research groups. They represent interesting functional groups and useful in organic synthesis. Photoredox catalytic approach was develop to synthetically transform enamides into useful products, N-acyl-N -aryl-N,N -aminals. A novel approach using iridium polypyridyl complex photoredox catalyst to initiate a three-component domino transformation of enamides to N-acyl-N -aryl-N,N -aminals via photoredox catalysed β-alkylation of enamide intermediates and their subsequent trapping with an arylamine was successfully developed. The N-acyl-N′-aryl-N,N′-aminal structural motif is prevalent within a wide range of biologically important compounds and have attracted considerable attention as building blocks for the synthesis of drug candidates. This method uses the addition of a radical precursor to an enamide, with subsequent interception of the cationic iminium intermediate with an arylamine. The reaction was found to be compatible with both electron-rich and electron-deficient arylamines, and moderate to good levels of diastereoselectivity were attained using a chiral enamide. The N-acyl-N -aryl-N,N -aminals formed were used as precursors to synthesis of valuable γ-lactams building blocks under a mild condition by cyclization. The γ-lactams were obtained by intramolecular cyclization of the N,N -aminals with the lone pair of the nitrogen atom of the arylamine as the nucleophilic centre attacking the electrophilic carbon of the carbonyl carbon of the ester in the molecule. This is a novel synthetic route to these valuable γ-lactams. The photoredox reaction procedure developed was also applied on allenamides. There are limited reports of radical reactions on allenamides, the major and seemingly single intermolecular radical cyclization involving allenamides was the one reported by Hsung. There are no reports of radical photoredox reactions on allenamides in the literature. The addition reaction was initiated by the electrophilic malonate radical generated by irradiation with blue light in the presence of iridium photoredox catalyst. The malonate radical attacked the central carbon of the allenic group which led to the formation of β-alkyl allenamide radical that was oxidized to an iminium ion intermediate. The iminium intermediate was subsequently trapped with an arylamine giving rise to α,β-addition product (N-acyl-N -aryl-N,N -aminals) with exo-methylene or β,γ-addition product leading to the formation of double bond substituted enamides. It was found that the α,β-adduct product is more favourable, however, the alternative product was formed when the α-position is sterically hindered by the substituents on the allenamide or the arylamine nucleophile.
Nigeria, Tertiary Education Trust Fund (TETFund).
Rights holder© Kayode Koleoso
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NotesA Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.
Supervisor(s)Marc C. Kimber; Gareth Pritchard
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