Dr Jon Wilden

Research Overview

Currently, research in the Wilden group is focused on new radical methodology and transition metal free reactions and has been supported by EPSRC, Wellcome Trust, Leverhulme Trust and GSK. The group also has interests in the development of new reactions and the application of these reactions to the preparation of biologically relevant molecules.

Our early work in radical chemistry led to the development of a novel synthesis of indoles via addition to an arene followed by sulfonyl elimination (Scheme 1).

Scheme 1 GIF

Gray, V. J.; Wilden, J. D. Tetrahedron Lett. 2012, 53, 41-44

We have also demonstrated that the useful synthetic building blocks, ynol ethers could be prepared from acetylinic sulfonyl compounds. Isotopic labelling established an addition-elimination mechanistic pathway was in operation. We have also shown that these species are capable of generating ketenes via thermal elimination of isobutene. The newly generated ketene can then react with a molecule of ynol ether to give cyclobutenones in excellent yields (Scheme 2).

Scheme 2

Gray, V. J.; Slater, B.; Wilden, J. D. Chem. Eur. J. 2012, 18, 15582-15585

Detailed examination of the reaction of KOtBu with sulfonylacetylenes led us to refine the reaction mechanism from a simple addition-elimination process to one that involves radical intermediates. We also established that thioynol ethers could be prepared via the same protocol (Scheme 3).

Scheme 3

Gray, V. J.; Cuthbertson, J.; Wilden, J. D. J. Org. Chem. 2014, 79, 5869-5874

An understanding of the mechanistic process led us to an improved synthesis of thioynol ethers that employed the more user-friendly alkynyl chlorides as starting materials (Scheme 4).

Scheme 4 v3

Chowdhury, R. M.; Wilden, J. D. Org. Biomol. Chem. 2015, 5859-5861

These early mechanistic and synthetic studies led us to an interest in the chemistry of potassium tert-butoxide given the recent literature precedent of it being employed in a remarkable number of reactions where a transition metal (TM) was previously assumed to be essential. Earlier in 2014 we were the first to demonstrate that this reagent alone can promote carbon-carbon bond formation between aryl iodides and benzene to furnish biaryls. Previously a diamine ‘ligand’ or 1,10-phenanthroline was thought to be required to promote this reaction (Scheme 5).

Scheme 5Scheme 6

Cuthbertson, J.; Gray, V. J.; Wilden, J. D. Chem. Commun. 2014, 50, 2575-2578

Our work demonstrated that although these additives facilitate the reaction, they are not essential and a new model for the fundamental behaviour of group 1 alkoxides is required. Our hypothesis to explain this behaviour is that potassium tert-butoxide exists in equilibrium between covalent, ionic and a species, bearing a loosely bound (or even free) electron (Scheme 6). Transfer of this electron to an organic substrate can initiate the observed radical reactions (Scheme 7) with concomitant collapse of the t-butoxy radical.

Scheme 7

Having observed that a phenanthroline or diamine ligand was beneficial (though not essential) in TM free coupling protocols with KOtBu we have been studying in detail the effects of these additives on potassium alkoxides. We recently established that 1,10-phenanthroline is capable of abstracting an electron (presumably loosely bound) from KOtBu with the immediate collapse of the remaining alkoxy radical. The phenanthroline radical anion then shuttles the electrons between the starting aryl halide and the penultimate dienyl radical as outlined in Scheme 8.

Scheme 8

Our most recent work has exploited the mechanistic insight we have uncovered and allowed us to develop an anti-Markovnikov addition of potassium alkoxides to alkynes (Scheme 9)

Scheme 9

Cuthbertson, J.; Wilden, J. D. Tetrahedron, 2015, 71, 4385-4392

We have also investigated the mechanism of this reaction. The results have led us to suggest a radical mechanism since the diyne outlined in Scheme 10 undergoes what appears to be an initial 5-exo cyclisation to give the polyaromatic compound outlined. No transition metals or other additives are required.

Scheme 10

Cuthbertson, J.; Wilden, J. D. Tetrahedron, 2015, 71, 4385-4392