Theoretical Study Of A~3 Coupling Cascade Reaction Catalyzed By Transition Metal Gold And Coppe

Propargylamine derivatives have multiple active reaction centers and are active as important reaction intermediates and building blocks in synthesis,pharmacology and medicinal chemistry.As a green and efficient method for the synthesis of propargylamine derivatives,the transition-metal-catalyzed A³-coupling（aldehyde-alkyne-amine）reaction has attracted widespread attention,and its development of tandem reaction has been widely used in the preparation of various nitrogen-containing heterocyclic compound,pharmaceuticals and biologically active molecules.In this paper,we use theoretical methods to systematically study the transition metal gold-catalyzed and copper-hydroacylation and intramolecular cyclization reactions based on A³-coupling tandem reactions,and the optimal reaction mechanism was clarified to explain the experimental consequence at the molecular level.The specific work is divided into the following two parts:（1）The DFT calculations have been conducted to study the distinctive mechanistic scenarios and substituent effects of gold（Ⅰ）-,copper（Ⅰ）-and copper（Ⅱ）-catalyzed hydroacylation of terminal alkynes with aldehydes,and we analyzed the role of bases and solvent.Although the three reactions are catalyzed by the same group of transition metals,they follow different reaction mechanisms.（1）The gold（Ⅰ）-catalyzed reaction follows A³-coupling forming propargylamine intermediate,then isomerization of propargylamine through stepwise 1,2-proton transfer,and hydrolysis.In contrast,copper（Ⅰ）/copper（Ⅱ）-catalyzed reaction follows the same mechanism in A³-coupling process,while it undergoes a different stepwise 1,3-proton transfer in the subsequent isomerization of propargylamine.They finally undergo hydrolysis to finish the catalytic cycle.The strength difference between Au-C and Cu-C is the main origin causing the mechanism difference between two metal catalysts.（2）To compared with Cu（Ⅰ）-catalyzed reaction,the deprotonation of alkyne in Cu（Ⅱ）-catalyzed reaction is more favorable due to the coordination of Cu（Ⅱ）with alkyne section renders the alkyne proton more acidic.In the isomerization stage of propargylamine（1,3-proton transfer）,the base in the Cu（Ⅰ）-catalyzed reaction acts as a proton shuttle to assist the proton transfer.However,the base abstracts the hydrogen and copper-carbon coordination undergoes deformation in Cu（Ⅱ）-catalyzed reaction.The hydrogen first transfers to the O atom of SO₄^2-,then transfers to base and finally transfers to target carbon atom.In hydrolysis stage,the Cu（Ⅰ）-catalyzed reaction carried out normally without the aid of ligand.However,the ligand-assisted hydrolysis is necessary in Cu（Ⅱ）-catalyzed reaction.The bases and solvent DMSO as ligands can stabilize the intermediates and transition states by enhancing the interaction between ligands and Cu（Ⅱ）.Piperidine as a ligand assisted hydrolysis is the most favorable pathway in Cu（Ⅱ）-catalyzed reaction duo to it has the strongest ability to stabilize Cu（Ⅱ）compounds.（3）Analyzing the substituent effects of aldehyde 2a and 2b on the rate-determining transition states of gold（Ⅰ）-and copper（Ⅰ）-catalyzed systems,it is found that Ph group increases the catalytic activity in gold（Ⅰ）-catalyzed system by strengthening the interaction between catalyst and alkene section.While in copper（Ⅰ）-catalyzed system,the more electron-donating OEt group promotes the reaction by dispersing the positive charge of the forming carbocation to stabilize the transition state.（4）In addition,bases show significant roles in the whole catalytic cycle:they assist to furnish the nucleophilic and electrophilic species as reactants;they act as shuttles to assist the proton transfer;they serve as the hydrogen bond partners to stabilize some intermediates and they act as ligands to stabilize intermediates and transition states of the reactions.（2）The detailed reaction mechanisms of Cu Br-catalyzed A³-coupling-based tandem reactions of terminal propargyl alcohols,aldehydes and amines to synthesize five-membered dihydrofuran P1,disubstituted furan P2 and six-membered pyrone P3have been developed by density functional theory（DFT）calculations,and we uncovered the origins of substituent effects on the transformation of P1 to P3.Computational results suggest that the catalytic cycle of P1 is divided into three main processes:A³-coupling,isomerization and intramolecular cyclization.Condensation and protodemetallation are the rate-determining steps of this catalytic cycle.The generation of P2 from P1 proceeds via N-methylation and deprotonation steps.P1 can also transfer to P3 by ring expansion,OEt group departure and deprotonation under the different condition.The transformation of P1 to P3 is affected by the substituents R on substrate aldehyde.When R=OEt,this transformation proceeds smoothly,undergoing the favorable OEt departure pathway.In contrast,the departure pathway is unworkable for Ph-and Me-substituted aldehydes due to the lack of hydrogen-bonding stabilization.They could only follow 1,2-R migration pathways.However,the high activation barriers in the migration pathways for the two aldehydes render the transformation infeasible.The results also reveal that silica gel acts as a significantly important hydrogen bond partner to stabilize the complexes in the transformation process.The theoretical research contributes to the deeper insights into the mechanisms and the origins of substituent effects on the transformation between different heterocycles of the title reaction,which would promote the further development and design of the five-and six-membered oxygen-containing heterocycles.