Mechanistic Investigation Of Copper-catalyzed Enantioseletive Cycloaddition Reactions Of Propargylic Acetate With Hydrazines

The transition metal-catalyzed C–H functionalization is an effective synthesis method for the selective formation of 2–pyrazoline compounds.Theses compounds are not only used in biology,agriculture,dyes and organic electroluminescence,but also are active components of some antiviral,anticancer,antibacterial and other medicines.In the past few decades,many precious metals Rh,Pt,Ru,Au and other catalysts for the catalytic C–H functionalization reaction have been greatly developed.The high cost and difficult recycle limit their application.At present,the combination of copper with excellent performance ligands to form new highily selective,cheap,environmental friendly catalysts has attracted extensive attention.Compared with the traditional method,the copper catalyzed reaction of propargyl acetate with hydrazine is simple and a wide range of substrate under mild conditions,the reaction shows good enantioselectivity?94% ee?towards monosubstituted hydrazine.The detailed reaction mechanism of Cu-catalyzed propargyl acetate with hydrazine has been investigated using B3 LYP density functional theory method.The purpose of this work is to clarify the formation of intermediates and transition states,as well as the energy change of possible pathways,so as to give the optimal path of the reaction.Moreover,it will provide theoretical basis for the experimental observation and the development of catalyst.The main contents and conclusions are as follows.Firstly,the propargyl acetate has been activated by Cu L to form the key speices copper acetylide complex.This process will undergo a series of hydrogen transfer intermediates and reductive elimination of acetic acid.Three possible pathways for the reductive elimination of acetic acid from propargyl acetate have been explored and analyzed.Path IA is the process without any solvent and additive molecule.Path IB is the process with N?CH₃?₃ participating in the reaction.Path IC is the MeOH solvent molecules involved in the reaction.The calculation results show that the MeOH involved in path IC may decrease the activation barrier 5.92 kcal/mol?18.81 vs 24.73 kcal/mol?,and N?CH₃?₃ may largely decrease the activation barrier to 13.33 kcal/mol?referenced to catalyst Cu L as zero point?.During the attack of the monosubstituted hydrazine on copper acetylide,the pushing effect of additive N?CH₃?₃ and MeOH on reaction is considered.Also,three pathways have been molded,that is,IIA?without any solvent?,IIB?the remove of alkyl hydrogen by N?CH₃?₃?,IID?the hydrogen transfer via solvent molecule MeOH?.Our calculations show that the MeOH molecule plays an important role in the activation of hydrazine.The hydrogen bond O···H-N1 in complex 2f is formed between hydrazine and MeOH,then the C-H reductive elimination takes place via the hydrogen transfer from MeOH to alkyl ?-C as well as the hydrogen shift from hydrazine to –OMe.Starting from 2g,path IID is more favorable than path IIB.After the 1,2–H migration among alkyl group inducted by MeOH,the –NH2 attacks the C1 atom to form a five-membered complex.Then,one molecule MeOH inducts the cleavage of N–H bond and hydrogen transfer.Finally,the N2–H bond occurs 1,3–H migration by inducement of two molecule MeOH.This is very in agreement with the experimental observations.It is found that the MeOH involved path is the most favorable by comparing the energetics of three paths.The rate-determing step is associated with 1,3–H migration.Our results provides not only a theoretical basis for the detailed understanding of Cu-catalyzed reaction path of propargtl acetate with hydrazine but also gives a good explanation for the effect of adding solvent experimentally.Moreover,it is supplementary and corrected information for the proposed path by experimental researchers.The N?CH₃?₃ molecules can promote the elimination of acetic in the formation of copper–allenylidene,while the participation of MeOH solvent molecules plays an important role in the activation and hydrogen transfer of N-H bond.