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Title: Metal-catalysed cross-coupling reactions of nitrogen heterocycles
Author: Siddle, James Spencer
ISNI:       0000 0004 2694 8246
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2010
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Described herein are copper-catalysed N-C heteroarylations of benzimidazole, 1-methylbenzimidazolone, imidazole and pyrrole. The products of these reactions then undergo palladium-catalysed C-C cross-couplings with aryl or heteroarylboronic acids under Suzuki-Miyaura conditions to provide a rapid entry to tris(hetero)aryl scaffolds comprising two or three N-heterocyclic rings. The sequential N-C and C-C couplings can be performed in a one-pot process. 1,5-Di(hetero)arylated-pyridin-2(1H)-one derivatives have been synthesised in good yields starting from (2-fluoro-5-pyridyl)boronic acid. The sequence comprises three steps: (i) palladium-catalysed Suzuki-Miyaura reaction; (ii) basic hydrolysis; (iii) copper-catalysed C-N coupling. X-ray crystal structures are reported for selected pyridin-2(1H)-one derivatives. These compounds are of interest as new scaffolds for drug discovery. A one-pot synthesis of 2-chloro-3,4-diiodopyridine from 2-chloropyridine is described via a Directed ortho Metallation (DoM)/Halogen Dance (HD) mechanism in 26-28% yields. By performing sequential iterative Suzuki-Miyaura cross-couplings using a variety of functionalised heteroaryl and arylboronic acids, a series of novel 2,3,4-triheteroarylpyridine scaffolds have been accessed in synthetically viable yields, including sterically hindered derivatives. An iterative two-fold Sonogashira/Suzuki-Miyaura reaction sequence gave access to 5-[3,4-bis(2-phenylethynyl)pyridine-2-yl]-2-fluoropyridine in 48% overall yield. Disclosed is a novel route towards benzimidazolo[1,2-f]phenanthridines starting from 4-tert-butyl-N-(2-iodophenyl)benzamide via a intermolecular palladium-catalysed N-C bond formation and dehydration to form 2-(4-tert-butylphenyl)-1-(2-bromophenyl)-1H-benzo[d]imidazole. Performing an intramolecular C-H activation reaction on this provided 6-tert-butylbenzimidazolo[1,2-f]phenanthridine. This compound could be of interest to materials science or as a new scaffold for drug discovery. Synthesis of novel soluble, shielding auxiliary ligand 4-(4-(2-ethylhexyloxy)-2,6-dimethylphenyl)pyridine-2-carboxylic acid (G1pic) has been achieved via a five step synthesis from commercially available starting materials utilising the Suzuki-Miyaura reaction on demanding substrates. A route towards a more shielded auxiliary ligand have been explored eventually providing 3-(4-pyridyl)-1,5-bis(4-(2-ethylhexyloxy)phenyl)-2,4-dimethylbenzene as an intermediate for future work. Ir(III) complexes have been synthesised with G1pic and picolinic acid.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available