Synthesis of biaryls by reductive extrusion from N,N’-dimethyl-N,N’-diaryl ureas

Abstract

Biaryls are a valuable synthetic target present in pharmaceuticals, agrochemicals, ligands and catalysts, and natural products. Their synthesis most commonly utilises transition metal catalysed approaches such as the Suzuki-Miyaura reaction. Despite the broad utility of these reactions, limitations include the use of toxic metals which can limit their use in late-stage functionalisation. Therefore, it is of high importance to explore transition metal free biaryl coupling reactions.
Intermolecular transition metal free coupling reactions have been reported, however limitations include a need for a high excess of coupling partner, issues with regioselectivity and need for specific substrates. An alternative approach utilises an intramolecular coupling, facilitated by a heteroatom linker. Examples of these linkers include phosphorus, boron, sulfur, sulfonamides, phosphates and ureas.
Work by Stevenson showed that upon reduction of N,N-dimethyl-N,N-diphenyl urea with sodium metal in HMPA, biphenyl radical anions were detected by EPR spectroscopy. Although this work was purely analytical, this highlighted the potential to be able to utilise these dimethyl urea linkers in a more practical application. The conformation of N,N-dimethyl-N,N-diaryl ureas is well understood— the two aromatic rings lie trans to the urea carbonyl, resulting in the two aromatic rings being held in close proximity. It is proposed that the unusual and interesting reactivity of these ureas can be attributed to this conformational preference.
In this project biaryl coupling by reduction of N,N-dimethyl-N,N-diaryl ureas was explored, with the aim of utilising less hazardous and more practical conditions than previously reported, and fully exploring the synthetic scope. Chemical reduction methods using lithium metal and DBB were successful (Figure 1). Variables such as temperature, reagent equivalents and additives were screened and a yields of up to 88% were achieved over a small substrate scope. During additive screening it was determined that Li cation coordinating additives, TPPA and DMPU, gave increased urea cleavage products, whereas the addition of LiCl gave improved biaryl yields.
Electrochemical reduction conditions were also optimised, screening electrode materials, solvent, concentration, current and charge passed (F), and good yields were achieved for a range of biaryl substrates (Figure 1). The reaction conditions allowed access to sterically hindered biaryls, with the presence of ortho substitution having a beneficial effect on yield in some cases.
A slight change to reaction conditions, changing the electrode material and removing LiCl, also allowed access to more electron-rich substrates. Mechanistic aspects were also explored, through linker variation, NMR, and cyclic voltammetry. Altering the linker, and hence altering the conformation of the system, further highlighted the importance of the conformation of the dimethyl urea linker. CV studies provided reduction potentials, from which a guideline on which reaction conditions were more suitable could be made. Additionally CV titration studies provided insight into the role of LiCl, suggesting a surface bound electron transfer step takes place with a urea-LiCl adduct.

Date of Award	21 Mar 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Alastair J J Lennox (Supervisor), Jonathan Clayden (Supervisor) & Christopher Parsons (Supervisor)