Tandem Synthesis Of Benzofuran-2-carboxylic Acids And Their Derivatives Via C-O Coupling And Carbonylation Reactions

Benzofuran-2-carboxylic acids and their derivatives are important intermediates for organic synthesis and have extensive application value in the fields of medicine,pesticides,materials and so on.As an important means in organic synthesis,carbonyl-ation reaction is often used to prepare carbonyl compounds?aldehydes,ketones,car-boxylic acids,esters,amides,etc.?.The carbonylation reaction generally uses CO gas as the carbonyl source and is catalyzed by a precious metal catalyst.However,CO gas is toxic,the reaction requires special pressure devices,precious metal catalysts are expensive and require complex ligands.Benzofuran-2-carboxylic acid derivatives are generally prepared by the Rap-Stoermer method.This method requires a large amount of alkali,the reaction temperature is high,and the raw materials are prone to side re-actions,resulting in a decrease in yield.And this method can not prepare three kinds of compounds of carboxylic acids,esters and amides at the same time.We have developed a divalent copper salt as an intramolecular C-O coupling cat-alyst,a solid metal carbonyl compound Mo?CO?₆ as a carbonylation reagent,reaction system for synthesizing benzofuran-2-carboxylic acids and their derivatives by using2-?2,2-dibromovinyl?phenols as raw materials for C-O coupling/carbonylation tandem reaction.The reaction system uses a relatively cheap and readily available divalent copper salt as a catalyst.The solid metal carbonyl compound Mo?CO?₆ is used as a carbonylation reagent,avoiding the use of precious metal catalysts and CO gas.The reaction system uses an alcoholic solvent,green environmental protection.Using2-?2,2-dibromovinyl?phenols as the raw material for tandem reaction to synthesizing benzofuran-2-carboxylic acids and their derivatives.Under the same reaction system,carboxylic acids,carboxylic acid esters and amides,no cumbersome experimental op-eration.The reaction was studied,and the type of catalyst,the type and amount of ligand,the type of base,the solvent,the reaction time and the reaction temperature were investigated,and the optimal conditions for the reaction were determined.The reaction was studied,using 5 mol%Cu Br₂ as the catalyst,5 mol%2,2'-Bpy as the ligand,0.6 equiv.of Mo?CO?₆ as the carbonylation reagent,and 3.0 equiv.of Et₃N as the base and alcohol reaction medium,2-?2,2-dibromovinyl?phenols C-O cou-pling/alkoxycarbonylation series reaction at 90 ^oC,the yield of the products are be-tween 48-88%.Using water as the nucleophile and tert-butanol as the solvent,the C-O coupling/hydroxycarbonylation tandem reaction was carried out,and the yield of the product was between 51-84%.When the types of copper salts and ligands are changed and for dosage,use 10 mol%Cu Cl₂·2H₂O as catalyst,10 mol%1,10-Phen as the lig-and,0.6 equiv.of Mo?CO?₆ as the carbonylation reagent,and 4.0 equiv.of amine as the nucleophile with acid binding agent,n-propanol as the reaction medium,the reac-tion temperature is increased to 100 ^oC,2-?2,2-dibromovinyl?phenols C-O cou-pling/aminecarbonylation series reaction can be carried out to improve the yield of the corresponding products.The yield of the products are between 50-93%.A total of 58benzofuran-2-carboxylic acids and their derivatives were obtained.Subsequently,gram-scale experiments were carried out on the substituted benzofuran-2-carboxylic acid/ester/amide on the basis of the above research,and the separation yields were77%,80%and 91%respectively.We explored the mechanism of the reaction,and the experimental results showed that the release of CO gas was not involved during the reaction,and no CO pressure was detected.The intramolecular C-O coupling is catalyzed by copper salt,and the subsequent carbonylation process is promoted by Mo?CO?₆.At the same time,pre-liminary explorations of other heterocycles have also been carried out.In conclusion,we have reported copper-catalyzed intramolecular C-O cou-pling/Mo?CO?₆ mediated intermolecular carbonylation series reaction to synthesize benzofuran-2-carboxylic acids and their derivatives with high efficiency,no precious metal catalyst,no CO gas,and substrate suitability extensive and therefore has good prospects.At the same time,we also found that the system can be applied to the prep-aration of benzothiophene-2-amides.