Cross-dehydrogenative Coupling Reaction Of Phenol Catalyzed By Ethoxycarbonyl Copper Porphyrin

Cross-dehydrogenative coupling（CDC）reaction is an important tool for construction of C-Y（Y=C,O,N）bonds in organic synthesis.The reaction does not need the pre-functionalization of starting materials,which makes it become a convenient,atom economical and environmentally benign method.It is significant to construct C-O bonds through CDC reaction because C（sp³）-O and C（sp²）-O bonds are vital building blocks in various natural products and medical intermediates.The CDC reaction of phenolic hydroxyl with cyclic ether and phenolic hydroxyl with formamide could generate acetal and carbamate respectively,which can not only more efficiently synthesize pharmaceutical intermediates containing acetal or carbamate structural units,but also be used for the protection of phenolic hydroxyl groups in organic synthesis.However,the CDC reaction of phenolic hydroxyl with cyclic ether or formamide still has some challenges,such as the ortho-directing groups of phenols are required.In recent years,metalloporphyrins has exhibited good catalytic activity in CDC reaction,and CDC reaction catalyzed by metalloporphyrins has gradually become an important topic in contemporary porphyrins chemistry.Therefore,the CDC reactions of phenolic substrates with cyclic ethers and phenolic substrates with formamide catalyzed by metalloporphyrins have been studied.The main contents are as follows:1.Tetrakis（ethoxycarbonyl）porphyrin（TECP）,tetraphenylporphyrin（TPP）,tetrakis（perfluorophenyl）porphyrin(F₂₀TPP)and their metal complexes Cu TPP、F₂₀Cu TPP、Cu TECP、Ni TECP、Co TECP、Mn TECPCl、Fe TECPCl、Ag TECP、Pd TECP and Zn TECP were synthesized by“one-pot”reaction and characterized;2.Copper porphyrin-catalyzed formation of C（sp³）-O bond by cross-dehydrogenative coupling of cyclic ether with phenols was developed.The results showed that when methyl p-hydroxybenzoate（0.5 mmol）,1,4-dioxane（2 m L）,Cu TECP（5 mol%）and DTBP（3.5 equiv）mixture were reacted at 120℃ for 12 h,the highest yield（97%NMR yield,85%isolated yield）was obtained.A broad range of substrates（50 examples）afforded various acetals in moderate to excellent yields with good functional group tolerance.The developed methods overcame the limitation of ortho-directing group of phenols.Significantly,a high turnover number（TON）of7300 was achieved in gram-level test,demonstrating the industrial utility of the developed synthetic method.Preliminary mechanistic investigations revealed that the current reaction proceeded via a free-radical pathway and the cleavage of C（sp³）-H bond of 1,4-dioxane is the rate-determining step of current CDC reaction;3.Copper porphyrin-catalyzed cross-dehydrogenative coupling（CDC）of formamides with phenols to access carbamates was described.The optimal reaction conditions were obtained as follows:methyl p-hydroxybenzoate（0.5 mmol）,DMF（2 m L）,Cu TECP（3 mol%）and DTBP（3.5 equiv）mixture were reacted at 120℃ for 12 h to obtain the highest yield（NMR yield of 78%and isolated yield of 63%）.A broad range of substrates offered various carbamates in moderate yields with good functional group tolerance at low catalyst loading.It turned out current reaction was related to electronic structure of substrates and steric hindrance of formamides.It can proceed smoothly between the electron-deficient phenols and formamides with small steric hindrance and EDG_S.Intermolecular competing kinetic isotope effect（KIE）experiment suggested that the generation of formamide radical via cleavage of the carbamoyl C（sp²）-H bond is the rate-determining step of the CDC reaction.