Regioselective reactions of arynes and heteroarynes
Lead Research Organisation:
University of Liverpool
Department Name: Chemistry
Abstract
Arynes and heteroarynes such as pyridynes are reactive chemical intermediates. Controlling the site of reactions of these molecules remains challenging. We have previously developed a rapid access to relevant precursors of heteroarynes. We will now develop new reactions of pyridynes and arynes: regioselective nucleophilic funtionalisation, C-H functionalisation, and bis-functionalisation with novel reagents. The fundamental knowledge gained through this research project should enable the development of improved synthetic methodologies that will benefit the fine chemical industry at large. The proposed research constitutes an important step towards the central goals of the EPSRC-Dial-a-Molecule grand challenge.
People |
ORCID iD |
| Christophe Aissa (Primary Supervisor) | |
| Daniel Clare (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509267/1 | 01/10/2015 | 30/03/2021 | |||
| 1635941 | Studentship | EP/N509267/1 | 01/10/2015 | 30/09/2019 | Daniel Clare |
| Description | We have been developing sulfoxonium ylides as alternatives to diazocarbonyl compounds in C-H functionalisation reactions. We were attracted to sulfoxonium ylides as they appear to be more stable (they can be kept for months at a time without decomposition), and safer than diazocarbonyl compounds as they release a liquid (harmless DMSO) rather than nitrogen gas when they react. Diazocarbonyl compounds are often considered to be explosive, although data is difficult to come by in the literature. During my placement at AstraZeneca, I have carried out DSC tests on a sulfoxonium ylide and the equivalent diazocarbonyl compound. The results were encouraging: the sulfoxonium ylide releases 640 J/g (not explosive), whereas the diazo (at 80% purity) releases 860 J/g, which is considered to be explosive. We have developed 2 different reaction conditions, which allow us to selectively functionalise an aromatic or heteroaromatic C-H bond of a sulfoxonium ylide. The first set of conditions is metal-free, and makes use of the unique properties of the solvent hexafluoroisopropanol (HFIP). We have expanded the scope of the reaction to include a variety of sulfoxonium ylides. Although the mechanism of the reaction remains unclear, based on a number of ylides that did not react as expected, we believe that protonation of the ylide carbon followed by loss of DMSO leads to either an oxyallyl- or a hydroxyallyl- cation, which can be attacked by the aromatic ring to form the observed products. This mechanism can also explain the side products that we observe, and we have also demonstrated an ability to intercept the cation with a nucleophile to form new products. The second set of conditions are catalysed by an iridium catalyst, and work exclusively on heteroaromatic sulfoxonium ylides. We have also expanded the substrate scope to a variety of heterocycles and 5 and 6 membered rings. We believe the mechanism of this reaction involves the formation of an iridium carbene, which can then undergo C-H insertion. To the best of our knowledge, this kind of orthogonality in reaction conditions has not been demonstrated before, either on sulfoxonium ylides or diazoketones. |
| Exploitation Route | Enantioselective variants of both conditions may be developed, and the interception of the oxyallylcation by other C, O, N and S based nucleophiles could be further developed. These reactions could be put to use in the synthesis of pharmaceuticals and fine chemicals, as the synthesis of sulfoxonium ylides does not involve any hazardous reagents, and the only by-product of their reaction is DMSO, which is harmless. They are also very stable compounds, and as the DSC data described above shows, they are not explosive like their equivalent diazoketones. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |