Mechanistic Study Of Transition Metals-Catalyzed Synthesis Of Benzofuran Derivatives

Benzofuran is often used to treat cancer,cardiovascular disease,diabetes,migraine,dementia,and depression due to its diverse biological activities.Therefore,benzofuran compounds have a very broad application prospect in the field of medicine.In this paper,In this paper,we have carried out the density functional method M06 to unravel the reaction mechanism of transition metal-catalyzed synthesis of benzofuran derivatives studied in detail.The main contents are as follows:First,we briefly describe the various experimental methods and research significance of the preparation of benzofuran compounds.Second,the ab initio self consistent method,density functional theory,transition state theory and the application of computational software involved in the study of reaction mechanism are introduced.Third,the reaction mechanism of palladium-catalyzed C-H activation and cyclization to 5-hydroxybenzofuran derivatives has been studied in detail.According to the sequence of reaction between Pd（OAc）₂and reactant molecules,three possible reaction mechanisms are proposed,namely,mechanism A,mechanism B,and mechanism C.It is found that mechanism A is the most feasible,involving the sequence of the reaction in which Pd（OAc）₂reacts with one molecule of phenylacetylene first,then with benzoquinone,and finally with another molecule of phenylacetylene.In the mechanism A,Pd（OAc）₂activates the C1-H1 bond of phenylacetylene through the concerted metalation deprotonation（CMD）mechanism.Then phenylhydrazone（BQ）coordinates with Pd center to generate Pd（II）-hydride 6,followed by a stepwise H migration from Pd atom to the O atom of BQ to generate intermediate 11.Starting from intermediate 11,there are two possible paths a and b.In path b,compound 11 reacts with another molecule of phenylacetylene to obtain final product,involving the sequence of the cyclization reaction,phenylalkynyl migration,and catalyst regeneration.This reaction needs to overcome the energy of 34.29kcal/mol,it is more advantageous than path a（46.46 kcal/mol）which occurs aromatization reaction by constructing Pd-O bond first.The rate-determining step of the catalytic cycle is phenalkynyl migration with the energy barrier of 34.29 kcal/mol.Fourth,the detailed reaction mechanism of rhodium-catalyzed C-C bond cleavage and C-H activation to synthesize polysubstituted cyclopenta[b]benzofuran compounds was systematically studied.Based on the experimental reaction conditions,we proposed the[Cp*Rh OAc]⁺ion reaction mechanism.According to the different activation positions of the substrate chalcone reacting with the catalyst[Cp*Rh OAc]⁺,mechanism I（the O-H bond is activated first）and mechanism II（the C-H bond is activated first）are proposed.In the mechanism II,[Cp*Rh OAc]⁺activates the C-H bond of the substrate chalcone to form intermediate B2,and then alkyne insertion occurs.Starting from intermediate B4,two different catalytic cycle paths are proposed.In path A,carbonyl insertion is proceeded to generate compound B5.Then O-H bond cleavage,β-C elimination,olefin insertion,reduction elimination,and catalyst regeneration occur in sequence to finally obtain the target product product.In path B,the intermediate B4’is formed by intramolecular[2+2]and retro-[2+2]cycloaddition from compound B4.Although the newly formed compound B4’has the same structure as the formed B4 after the alkyne insertion reaction,the position of the carbon atom changes.Finally,the target product product’is obtained through the carbonyl insertion,O-H bond cleavage,β-C elimination,olefin insertion,reduction elimination and catalyst regeneration.The rate-determining step of path A and path B are bothβ-C elimination with the energy barrier of 23.25 kcal/mol.The calculation results show that the catalytic path A and B in mechanism II are more favorable than those proposed by the experiment（36.09 kcal/mol and 43.26 kcal/mol）in mechanism I.In addition,the use of difluoroacetylene as the substrate is also investigated in order to test the reliability of results.The results showed that the reaction was universal for substrates containing different substituents,which was consistent with the experimental conclusion.