Direct functionalization of aromatic rings using temporary dearomatization

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


Numerous organic natural products and pharmaceuticals contain heavily functionalized aromatics, a motif which is difficult to create from simple aromatics without harsh or forcing conditions. Aromatics and heterocyclics are core to the development of new biologically active compounds. The development and expansion of synthetic methodology to create new more sustainable and effective routes to pharmaceutical building blocks is therefore essential for the future of drug discovery. Developing direct functionalization methods for aromatic rings, particularly heterocycles, will allow selective late-stage functionalization for aromatic moieties commonly used in pharmaceuticals. Using catalytic techniques to do so allows our transformations to be achieved sustainably. The project's aim is to expand upon some previous work from the Donohoe group on the direct functionalization of pyridines using Rhodium metal catalysed hydrogen-borrowing techniques. We wish to understand the mechanism of the reaction better, firstly by studying various methods of activating the heteroarene, using electron deficient arenes, easily removeable activating groups or new techniques for heteroarene activation. Such techniques include Lewis acids, metal chelation from neighbouring groups, protonation of the nitrogen or by using annulated analogues. We also wish to expand the scope of electrophiles used in our process. Currently the reaction is limited to using formaldehyde as both the electrophile and terminal reductant. Unpublished work suggests that methyl vinyl ketone could be a suitable electrophile and we will use various Michael acceptors and carbonyls to test the reaction scope. It may be possible to use this chemistry to generate one-pot annulation techniques where a side chain added via temporary dearomatization could then be used as a nucleophile to attack the heteroarene thereby generating a new adjacent ring in a single step. This reaction could become a very general annulation procedure for pyridines that create products with suitable potential for further derivatization. Our third route for reaction tuning involves investigating the reductant so that nucleophiles can compete to attack intermediates before the final reduction event, either by adjusting catalyst loading or using a different hydride source. Some exciting possibilities involve using an internal nucleophile to attack the partially dearomatized pyridine thereby inserting a chain and creating a new ring in a single step, or using aryl boronic acids or aryl halides that will transmetalate onto the Rhodium catalyst and allow aryl addition to the partially dearomatized pyridine intermediate. Another aspect that would be interesting to explore is using computation to better understand the mechanism by computing charge density and MO energies of the key intermediate species. Predictions of possible activating groups or potentially suitable heteroarenes will be possible with computational techniques. Our methodology builds on numerous years of hydrogen borrowing expertise in the group, more recently focused on applications to heteroarenes. Dearomatization of heteroarenes is a large field with many publications, but nearly all use dearomatization as a technique to access dihydro pyridines, not to rearomatize the resultant intermediate. A few papers using temporary dearomatization techniques have been published but all are very limited in their scope and are only useful for select circumstances. Our method aims to be more generally useful to many electrophiles and heteroarene compounds. This project falls within the Synthetic Organic Chemistry research area, within the EPSRC Physical sciences research theme. This project is conducted in collaboration with GSK.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/W522211/1 30/09/2021 29/09/2027
2605101 Studentship EP/W522211/1 30/09/2021 29/09/2025 Timothy Jenkins