AbstractHerein are reported the mechanistic investigation of novel catalytic methodologies for the iron- and cobalt-catalysed Suzuki-type cross-coupling reactions, as well as the development of an iron-catalysed ortho-C-H arylation of the synthesis of a small library of derivatives of edaravone, a promising MAO-B inhibitor.
A mechanistic investigation of the first reported protocol for iron catalysed, substrate-directed biaryl cross-coupling of aryl chlorides using organolithium-activated arylboronic esters was conducted. The role of the pyrrolamide directing group was investigated by means of DFT calculations and KIE experiments, revealing its involvement in the π-coordination of the active catalyst and the possibility of C-Cl bond activation through the formation of a ketyl radical intermediate. Analysis of the reaction kinetics at different loadings of MgBr2 additive suggest that it might be involved in multiple steps of the catalytic cycle as a source of bromide ions. Determination of the reaction orders in all the components suggests a rather intricate mechanism, in which most steps are in equilibrium with each other. On the basis of all the information acquired, a mechanistic cycle was proposed.
A protocol for cobalt-catalysed Suzuki biaryl cross-coupling of simple aryl chlorides with ample scope using mild alkoxide base was investigated. A rationale for the inherent preference of the reaction for a narrow set of NHC ligand precursors and boronic esters was proposed on the basis of stereoelectronic and structural reasons. A thorough analysis of the reaction kinetics was performed, which revealed the presence of two distinct phases: an early phase, in which the active catalytic species is formed by controlled reduction of the pre-catalytic mixture to a Co(I) species; and a second, faster catalytic phase in which the majority of the cross-coupling product is formed. Paramagnetic 1H NMR spectroscopy was employed to acquire further spectroscopic characterisation of the species involved in the early phase of the reaction. In the attempt to isolate catalytically relevant species, a potential deactivation product was isolated which could represent a “thermodynamic sink” of the reaction. DFT calculations were performed on all the steps of the proposed catalytic cycle, suggesting that the intermediate-spin pathway is the energetically favoured. Preliminary results on the expansion of our cobalt-catalysed Suzuki protocol to sp3-sp2 coupling are reported. A clear competition between cross-coupling and alpha-C-H arylation of the reaction solvent was observed. Conducting the reaction in deuterated solvent showed a significant increase in yield of cross-coupling product, corroborating our hypothesis.
Finally, the optimisation of a protocol for the iron-catalysed ortho-C-H arylation of edaravone is reported. The optimisation led to the synthesis of a small library of 2-aryledaravone derivatives, whose activity towards the inhibition of MAO-B has been assessed by means of in silico docking studies and in vitro biological essays.
|Date of Award||21 Jan 2021|
|Supervisor||Robin B Bedford (Supervisor)|
- ORGANOMETALLIC CHEMISTRY