Construction Of Axially Chiral Biaryl Compounds Via Arylation Strategy

Axially chiral biaryl skeletons are widely found in bioactive natural products and drug candidates.In asymmetric catalysis,ligands and catalysts built on chiral biaryl cores find wide applications across many mechanistically distinct transformations.Within this compound class,there are relatively few reports on non-C2-symmetric biaryldiols.Their restrictios arise mainly from the prevailing homo-coupling reactivity in aryl-aryl coupling reactions.On the other hand,the preparation of N-heterobiaryls mainly relies on transition metal-catalyzed crosscoupling reactions and photocatalytic addition of aryl radicals to pyridines.However,the efficiency of these schemes could be hampered by harsh reaction conditions required,deactivation of metal catalyst due to competing coordination of N-heterocycles,as well as regioselectivity issue in radical addition to pyridines.Therefore,the development of highly efficient and selective methods for the synthesis of non-C2-symmetric biaryldiols and N-heterobiaryls is of high research value and practical utility.Photoredox catalysis-enabled diverse arylation reactions with aryl radicals under mild reaction conditions.The research of this thesis realizes the construction of multiple classes of biaryls through arylation process promoted by organocatalysis or photoredox catalysis.The main contents include:Highly efficient and enantioselective synthesis of axially chiral aryl-p-quinones has been achieved through arylation of benzoquinones with 2-naphthols via chiral phosphoric acid(CPA)catalysis and “one-pot” oxidation(yield up to 75% and ee up to 96%).Notably,aryl-p-quinones represent one class of platform molecules:they were amenable to downstream functionalization by myriad nucleophiles including aryl thiophenols,diarylphosphine oxides,indoles and ?-keto esters with almost perfect preservation of enantioselectivities.This method allows rapid population of related chemical space with highly functionalized and str ucturally diverse axially chiral biaryldiols.The application of indole nucleophiles would regenerate the aryl-p-quinones after a re-oxidation event,thus enabling another follow-up synthetic elaboration.Overall,this method provides novel skeletons of axially chiral aryl-p-quinones and offers new pathway for the synthesis of nonC2-symmetric biaryldiols.With 1-bromo-2-naphthols as aryl radical precursors,the highly efficient synthesis of C1-symmetric 1,1’-bi-2-naphthol(BINOL)has been realized via arylation pathway enabled by photoredox catalysis with up to 80% yield.Compared to previous methods,this strategy c ould effectively improve the substrate scope and exhibited good tolerance of functional groups.The homocoupling side reactions were successfully circumvented in this photocatalytic system.The photocatalytic arylation process worked smoothly for both coupling partners that bear various functionalities.2-Naphthylamines are another class of compatible coupling partners under this photocatalytic system,hence establishing the protecting-or directing group-free synthesis of 2-amino-2’-hydroxy-1,1’-binaphthyls(NOBINs)in one step with up to 64% yield.Highly efficient synthesis of C1-symmetric BINOLs on gram-scale could be achieved with photocatalyst loading as low as 0.1 mol%(75% yield).A plausible mechanism was proposed on the basis of a series of mechanistic experiments,including radical trapping,luminescent quenching and cyclic voltammetry experiments,in which the product can be obtained through the aryl radical addition to 2-naphthols,followed by single electron transfer and rearomatization.This proposed mechanism served as basis for the preliminary studies conducted to develop photocatalytic asymmetric synthesis of C1-symmetric BINOLs by means of H-bonding catalysis,phase transfer catalysis and transition metal catalysis.The photocatalysis also underpinned the cross-coupling reactions of bromoazaarenes with phenols for the synthesis of N-heterobiaryls.In this protoncoupled electron transfer strategy,protonation of bromoazaarenes and the coupled single electron transfer process with photocatalyst would release the azaarene radicals that undergo cross-coupling with phenols in up to 83% yield.The phenol derivatives could be both substrates and proton donors in this transformation.A diverse range of functional groups,such as halogen,ester,cyano,trifluoromethyl,alkyl,alkoxy and so on were found compatible with the established conditions.The operational simplicity and commercial availability of all substrates greatly broaden the appeal of this reaction.For arenes without phenolic hydroxyl group,the construction of N-heterobiaryls could be accomplished by introducing other proton donors.To this end,hexafluoroisopropanol applied as solvent also fulfilled the protonation of bromoazaarenes,generating the corresponding N-heterobiaryls in up to 91% yield.