Novel and Efficient Copper‐Catalysed Synthesis of Nitrogen‐Linked Medium‐Ring Biaryls

Abstract

Herein, a new copper-catalysed strategy for the synthesis of rare nitrogen-linked seven-, eight- and nine-membered biaryl ring systems is described. It is proposed that the reaction proceeds through a highly activated intramolecularly co-ordinated copper catalyst. The process is technically simple, proceeds under relatively mild conditions, displays a broad substrate scope and forms biologically valuable products that are difficult to synthesise by other methods. We envisage that this methodology will prove useful in a wide synthetic context, with possible applications in both target-oriented and diversity-oriented synthesis.

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

“…Numerous compounds based around seven membered N-linked biaryl scaffolds have been found to demonstrate extraordinary biological properties [43]. Eight-membered-ring derivatives have also been reported, [45]; compound 19 has been reported to have anti-inflammatory effects and imipramine (20) and desipramine (21) are employed as anti-depressants [43,46]. B) Mechanistic blueprint for the copper(I)-catalysed N-linked biaryl cyclisation process.…”

“…Another class of scaffolds that are arguably underrepresented in current synthetic small molecule screening collections are nitrogen-linked medium ring biaryls [43]. Numerous compounds based around seven membered N-linked biaryl scaffolds have been found to demonstrate extraordinary biological properties [43].…”

“…The auxiliary nitrogen atom is expected to allow internal chelation to form the active intramolecular copper species and its geometry could possibly facilitate ring closure. Possible ancillary ligands omitted for clarity [43]. …”

Catalytic Asymmetric Synthesis of α‐Arylpyrrolidines and Benzo‐fused Nitrogen Heterocycles

“…[29] Our efforts next focused on exploring the asymmetric synthesis of nitrogen heterocycles with other ring sizes.I n comparison with a-arylpyrrolidines,the synthesis of four-and six-membered nitrogen heterocycles proceeded slowly. [33] Our approach to access the core structural scaffolds requires either af our-o rafive-step synthetic sequence,w hich culminated with the enantioselective Cu-catalyzed intramolecular hydroamination. [31] Va rying an umber of reaction parameters (ligand, solvent, temperature and concentration) did not further improve the results.A iming to facilitate the cyclization process,w ei ntroduced ag eometric constraint into the linear carbon chain of the starting material by introducing an aryl group between the olefin and the hydroxylamine-O-pivalate-containing side chain.…”

“…Successful construction of the enantioenriched tetraisohydroquinoline led us to examine dibenzo-fused nitrogen heterocycles with medium ring sizes, [32] since many compounds with these structural elements are found in pharmaceuticals and bioactive alkaloids (Scheme 2A). [33] Our approach to access the core structural scaffolds requires either af our-o rafive-step synthetic sequence,w hich culminated with the enantioselective Cu-catalyzed intramolecular hydroamination. Fori nstance,o xazonine 10 was prepared in five steps in excellent yield and enantioselectivity, starting from salicylaldehyde (Scheme 2B).…”