Short, efficient routes towards the synthesis of fluorinated nitrogen heterocycles

Cogswell, Thomas (2015) Short, efficient routes towards the synthesis of fluorinated nitrogen heterocycles. PhD thesis, University of Glasgow.

Abstract

Fluorinated compounds make up a large proportion of the output from both the pharmaceutical and agrochemical industries. However, there are still a limited number of methodologies involving the synthesis of such molecules. Six-membered nitrogen containing heterocycles such as pyridines and lactams are key compounds for medicinal chemistry. Therefore, there is much interest into the synthesis of fluorinated nitrogen heterocycle libraries which can be utilised effectively for numerous substrate screens.

This thesis aims to produce a novel route for the generation of a host of fluorinated pyridines, lactams and piperidines. Work on non-fluorinated analogues has lead to a rapid two-pot process for the production of dihydropyridones, a potential intermediate for the above targets, starting from common aldehydes.

This methodology has been utilised in the synthesis of fluorinated lactams through an efficient ring-closing metathesis protocol of vinyl fluoride compounds. A variety of aldehydes, including aromatic, aliphatic and heterocyclic examples, could be converted in 6 efficient steps into novel fluorinated δ-lactams. The final hydrogenation occurred on the opposite face to the R groups giving a single diasteromer in all cases.

Taking inspiration from the δ-lactams series, a synthetic route was designed and implemented to grant access to an array of fluorinated polysubstituted pyrroles. The final step involved a novel addition-aromatisation reaction which allowed late-stage variation of the resulting fluorinated pyrroles. Installation of a hydride, n-butyl, phenyl and allyl moieties could be achieved, all in high yields of 75-93%.

Finally the synthesis of a number of interesting benzoxazole containing compounds was undertaken to produce a range of novel fluorinated poly(ADP-ribose) polymerase (PARP) inhibitors, yielding a group of potential anti-cancer agents.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic Chemistry, Organofluorine, Synthesis, fluorinated nitrogen heterocycles
• Subjects: Q Science > Q Science (General); Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Marquez, Dr. Rudi
• Date of Award: 2015
• Depositing User: Mr Thomas / TJ Cogswell
• Unique ID: glathesis:2015-6774
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Oct 2015 13:44
• Last Modified: 22 Dec 2015 15:46
• URI: https://theses.gla.ac.uk/id/eprint/6774