AbstractThe use of cobalt catalysts for Suzuki-Miyaura cross-coupling reactions that form biaryl products are explored in this thesis. Following an introduction that describes the importance of this transformation and the desire to steer away from the use of precious-metal catalysts both in academia and industry, our developments of the reaction are discussed.
The limitations of the only few reported examples of cobalt-catalysed Suzuki cross-coupling reactions are highlighted, and in Chapter 2, an improved protocol which was previously developed in the Bedford group, is introduced. This reaction allowed for a wide range of aryl chlorides to couple with aryl boronates, formed using nBuLi to activate arylboronic acid pinacol esters. Basic mechanistic experiments revealed the boronate to be capable of reducing the Co(II)-NHC pre-catalyst to a Co(0)NHC species, and the stable Co(0) species, (SIPr)Co(nbe)2 (nbe = norbornene) to be a competent precatalyst. Whilst a much more detailed mechanistic investigation is required, the main drawback of the methodology, which is the use of nBuLi to form the boronate reagent, was more importantly addressed.
Chapter 3 describes the findings from our optimisation studies for an alkoxide-promoted cobaltcatalysed Suzuki cross-coupling reaction. KOtBu was found to be the most effective base – a much milder alternative to organolithium reagents. The optimal nucleophilic coupling partners are arylboronic acid neopentyl glycol esters, and slight changes in the backbone of the ester resulted in pronounced differences in catalytic activity, which could not be accounted for by its thermodynamic propensity to transfer the aryl group (assessed by DFT analysis). Under the optimised conditions, which uses a CoCl2/IPr·HCl catalyst system, a broad range of functionalised aryl chlorides and arylboronic acid neopentyl glycol esters were found to be good coupling partners. However, substrates containing nitro, ester and sulphur functionalities are examples of those that were poorly tolerated.
The following chapter investigates the mechanism of the KOtBu-promoted cross-coupling methodology described in the previous chapter. A long induction period was observed, accounting for catalyst activation, which we propose to be the formation of an (IPr)Co(I) species. Mechanistic studies, including kinetic analysis and DFT computational investigations allowed us to suggest a sensible catalytic cycle that features a Co(I)/Co(III) manifold, with a step relating to the coordination of the boronate to the Co prior to transmetalation likely to be rate-determining. The possible identity of a catalyst deactivation product was determined to be [Co(OtBu)2]n, and a plausible pathway for its accumulation, via (IPr)Co(OtBu)2 is suggested.
Finally, having understood some of the challenges in cobalt-catalysed Suzuki biaryl cross-coupling, our attention was drawn towards the work of another research group who reported that the coupling between aryl halides and phenylboronic acid is achievable using a variety of cobalt pre-catalysts (bearing Schiff base and PNP pincer ligands), with loadings as low as 0.5 mol %, and mild bases such as K2CO3. This led to an examination of the reproducibility of these reports, and others by the same authors which describe the iron-, nickel-, and copper-catalysed Suzuki coupling under similar conditions. Our findings, discussed in Chapter 5, conclusively show that not only are the cross-coupling reactions irreproducible, the synthesis of several of the pre-catalysts could not be achieved. Furthermore, indications of possible data fabrication are highlighted, and as a result of our investigation, three of the reports have now been retracted by journal editors, to date.1-3
Subsequently, the use of Schiff-base ligands as alternatives to NHC ligands in the coupling of 4bromooanisole with nBuLi-activated phenylboronic acid pinacol ester is explored in Chapter 5, and a yield of 49% was achieved. This shows potential for an attractive methodology to be developed that allows for the use of bench-stable Co-Schiff base pre-catalysts to be employed, upon further optimisation.
|Date of Award||21 Jan 2021|
|Supervisor||Robin B Bedford (Supervisor)|