| Background:As the core moiety of active ingredients in many medicinal plants,hydrobenzofuran derivatives widely exist in nature,and possess biological activities such as antiviral,antitumor and anti-inflammatory.Furthermore,they are important synthons and key intermediates for the synthesis of many drugs.However,their traditional synthetic methods mainly rely on o,o-disubstitution cyclization on the phenyl ring,benzofuran hydrogenation,and monosubstitution cyclization.These methods often require the preactivation of substrates,multiple-step synthesis,poor substrate compatibility,harsh conditions and/or low atom economy.To this end,it is particularly important to develop novel synthetic strategies for the efficient,atom-economical and green synthesis of hydrobenzofurans.In recent years,transition-metal-catalyzed directing group-assisted C-H functionalization reactions have emerged to be a powerful synthetic method for the synthesis of complex drug molecules.Among them,N-phenoxyamides,as a new type of substrates with an oxidizing directing group,can be used for redox-neutral C-H functionalization without the requirement of any external chemical oxidant.Thus,the development of new strategies for C-H functionalization of multifunctional N-phenoxyamides has become one of the hot and frontier research areas of organic synthesis.Purpose:Taking advantage of transition-metal-catalyzed C-H activation strategy,N-phenoxyamides were successfully coupled with 1,6-enynes or 2-alkenylphenols through C-H activation initiated tandem cyclizations.These reactions were mediated by coordination for the chemo-and site-selective synthesis of diverse dihydrobenzofuran derivatives in an efficient,atom-ecomonical,and green manner.The established protocols not only offer the opportunities for two-fold C-H functionalization,but also provides a new method for the synthesis of complex lead compounds,thus facilitating the discovery of new drugs.Methods:（1）N-Phenoxyamides were coupled with 1,6-enynes in the presence of[Cp*Rh Cl2]2 precatalyst and Zn（OAc）2 as a base in TFE at 60℃for 24 h.Deuterium experiments,control experiments and kinetic isotope experiments were conducted to probe the reaction mechanism.（2）N-phenoxyacetamides were able to couple with 2-alkenylphenols with the same combination of[Cp*Rh Cl2]2 and Zn（OAc）2 at room temperature for 24 h.The control experiments,deuterium experiments together with DFT calculations were carried out to clarify the detailed pathway.Results:（1）Using N-phenoxyacetamide and 1,6-enyne as substrates,a Rh（III）-catalyzed C-H activation/intramolecular Michael addition tandem reaction was developed to access hydrobenzofuran derivatives.In this reaction,the versatile oxidizing directing group are preserved due to coordination-mediated selective control,which thus provides a molecular platform for a second C-H activation.The protocol has good substrate compabilityand functional group tolerance.Mechanistic experiments illustrated that the reaction involves a C-H activation,alkyne migration insertion,Michael addition and C-Rh/N-Rh bond protonlysis to promote the catalytic cycle.（2）Based on the above research study,we further explored the coupling of 2-alkenylphenols with N-phenoxyacetamides,and developed an efficient and practical Rh（III）-catalysed tandem reaction initiated by C-H activation synergistically mediated by dual DGs under redox-neutral conditions,thus leading to diverse dihydrobenzofuran frameworks.The combination of DFT calculations and experimental mechanism studies clarified the detailed reaction pathway.This transformation features mild reaction conditions and good substrate compatibility,as well as is suitable for late-stage C-H functionalization and asymmetric synthesis of chiral dihydrobenzofurans.Conclusions:In summary,two novel tandem reactions initiated by Rh（III）-catalyzed C-H activation of N-phenoxyamides with 1,6-enynes or 2-alkenylphenols were developed for the efficient synthesis of hydrobenzofuran derivatives.Combined mechanistic experiments and DFT calculations were conducted to clarify the reaction mechanism.Therefore,these research work would give a reference and guidance for subsequent development of novel reaction patterns and asymmetric catalytic versions.Also,they provides new synthetic methods to construct hydrobenzofuran derivatives in an efficient,atom-economical and mild manner. |
