Studies Of Phosphine Ligands-Promoted Copper-catalyzed N-Alkenylation Reaction

The Chan-Evans-Lam coupling reaction is widely used to efficiently construct new C-heterobonds and C-C bonds because of its mild reaction conditions and easy operation.This reaction can not only synthesize compounds that are difficult to synthesize under mild conditions by traditional methods,but also provides a new idea for the synthesis of natural products and drug molecules.Among the skeletons of oxygen-containing heterocyclic rings,2,3-dihydrobenzofuran is a very common core skeleton in natural products.At present,the main methods for synthesizing 2,3-dihydrobenzofuran compounds are [3+2] cycloaddition reaction.This article mainly focuses on phosphine ligands to promote copper-catalyzed N-alkenylation reaction.Under the action of phosphine ligands,it promotes the catalysis of copper,which makes the coupling reaction of N-aryloxyamide and alkenyl boronic acid to form a new C-N bond.Through further [3,3] rearrangement,a series of 2,3-dihydrobenzofuran compounds were synthesized and a series of N-alkenylated products were directly synthesized by the reaction of secondary amines with alkenyl boronic acid.This paper consists of two parts:In the first part,phosphine ligands were used to promote copper(II)-catalyzed Nalkenylation of N-phenoxyamide and alkenyl boronic acid and [3,3] rearrangement to construct 2,3-dihydrobenzofuran compounds.The method has relatively mild reaction conditions,simple operation,good functional group compatibility,and can synthesize a variety of 2,3-dihydrobenzofuran compounds with moderate to good yields,and can be prepared in gram scales.The method was also applied to the modification of drug molecules.The deuteration experiment and the isotope effect experiment show that the cleavage of C-H bond in the reaction is not a rate-determining step.The Hammett equation shows that the electron-withdrawing group on the benzene ring of Naryloxyamide is more favourable to promote the reaction than that electron-donating group.The experiment of monitoring the reaction intermediates by LC-MS shows that in the reaction,the phosphine ligand first coordinated with copper acetate to form the real catalyst.At the same time,the formation of the trivalent copper intermediate can also be monitored so that the reaction mechanism of the Chan-Evans-Lam coupling reaction was further clarified.In the second part,the phosphine ligand promotes the copper(II)-catalyzed Nalkenylation reaction of secondary amines with alkenyl boronic acid was further explored.This reaction produces a series of N-alkenylation products,and tolerates the range of substrates Wider.It can be seen that the addition of phosphine ligands to most secondary amine substrates can indeed greatly improve the yield of coupling products.Experiments on the influence of the electronic effect of the ligand show that in the same time,the electron-donating group on the aromatic ring of the phosphine ligand is more favourable to accelerating the reaction than those with the electron-withdrawing group.The LC-MS monitoring intermediate tracking experiment shows that the reaction is a process of anion exchange,metal transfer,disproportionation reaction,and reduction and elimination.We discovered for the first time that a phosphine ligand can promote the ChanEvans-Lam coupling reaction,and the reaction mechanism of Chan-Evans-Lam reaction was confirmed by LC-MS experiments,so that the Chan-Evans-Lam coupling reaction can be further developed and applied.