Liquid-Accelerated Mechanochemical C-Cl Bond Activation And Cross-Coupling Reactions

Cross-coupling reaction,as an important organosynthetic tool,has received sufficient attention from the pharmaceutical industry.The technique has been applied to the key steps in the synthesis route of active pharmaceutical ingredients?API?,which has achieved remarkable results.Among them,aryl chloride has been considered as an ideal substrate for cross-coupling reaction due to its low cost and wide structure availability.However,the activation of inert C-Cl bonds in aryl chlorides remains problematic,and usually requires costly high-active ligands to promote its oxidative addition.Thus,the application of the aryl chloride in cross-coupling has been restrained in the field of APIs synthesis.Mechanochemistry,an emerging green chemical technique,has been used to facilitate the heterogeneous chemical transformations in solvent-free or solvent-less environments,and could enable the transformations that are difficult in conventional solution conditions.The recent introduction of liquid-assisted grinding?LAG?technique,by adding stoichiometric liquid during the grinding,could promote the reaction efficiency,enhance the selectivity control,which expands the scope of mechanosynthesis.Although the technique had been emerged as one of the prevailing tools for mechanochemical research,the fundamental understanding of the mechanism of LAG effect remains unclear.In the thesis presented,the work was commenced with the finding of a single drop of methanol enhanced mechanochemical Suzuki-Miyaura coupling.To understand the process,the work aimed to clarify the mechanism underlying this LAG effect.Through the research,the hypothesis was proposed and verified that in the mechanochemical LAG process,the liquid molecule added can interfere with the reaction by participating in the mechanism,thereby cause the LAG effect.Especially,in the transition-metal catalyzed reaction,the added liquid may enact as a ligand to regulate the activity of the catalytic species,thereby affects the reaction outcomes.The thesis was comprised with seven chapters,where Chapter 3 to 6 describe the main research works.The contents as arranged based on the discovery of LAG effect,mechanism elucidation,reaction scope expansion,and its application in APIs'synthesis.The main contents are as follows:1)The introduction part focuses on the research background,purpose and its significance,where a brief introduction of the research plan,research goals and basic framework of the thesis was presented.Then,the review chapter summarizes the history of mechanochemistry,the main research methods,and its application in the field of organic synthesis.The recent progress of LAG application in the filed mechanosynthesis was carefully analyzed,which was followed by the suggestion of the opinion of"In the transition-metal catalyzed reaction,the added liquid may enact as a ligand to regulate the activity of the catalytic species,thereby affecting the reaction outcomes.".2)The first chapter of the research section presented the discovery of the LAG enabled high-efficiency mechanochemical Suzuki-Miyaura couplings of aryl chlorides.The work employed an economy-friendly and readily-available PCy₃·HBF₄ as ligand source,whose performance was promoted from 38%to 95%by adding a single drop of MeOH during the grinding.3)By the mechanistic investigation of this MeOH enhanced Suzuki-Miyaura coupling,the liquid molecule was found to enact as a ligand during the catalytic cycling.During this part,the measurement of MeOH in this reaction was discussed.The results indicated the MeOH has a stoichiometric relationship with the reaction,rather than the widely accepted relationship with the total mass of grinding stock.Then,according to the chemokinetic and control experiments,a plausible mechanism was proposed for this MeOH accelerated C-Cl bond oxidative addition,which indicated a much higher active catalytic system Pd/PCy₃.4)After the mechanism elucidated,the MeOH accelerated C-Cl bond activation strategy was expanded to other cross-coupling of aryl chlorides.The work employed Buchwald-Hartwig amination,Mizoroki-Heck coupling,and?-arylation as a model reaction to investigate the influence of different coupling reagents to the strategy.Although the strategy could promote the C-Cl activation in most cases,the competitive coordination from strong ligands may disturb the process,and even deactivate the species during the reaction.Besides,the catalytic cycle of some cross-couplings tested stopped in some organometallic unit reaction,resulting in the failure of catalysis.5)The application of MeOH accelerated C-Cl bond activation strategy in the synthesis of APIs and their intermediates.In this part,the strategy was applied in the synthesis of APIs and their intermediates including sartanbiphenyl and fenbufen,whose potential of scaling up was also examined.Based on the previous results,the possibility of feedback from the mechanochemical LAG research results to the solution reaction was discussed.It was found that MeOH as a solvent can also form a highly active catalytic system in a solution environment,which indicated the LAG technology as a potential tool for solvent effect investigation.By the thesis presented,a mechanochemical C-Cl bond activation strategy promoted by LAG technique was developed,and corresponding high-efficiency mechanochemical Suzuki-Miyaura coupling and Buchwald-Hartwig amination were achieved by this strategy.The work proved the hypothesis that in the transition metal catalyzed reaction,the LAG additive could enact as a ligand participating in the catalytic species,thereby generating the LAG effect.In addition,the study also indicated that LAG technique could be used as a research tool for solvent effect investigation to further help the explanation of the relationship between solvent molecules and reaction activity in solution reaction,and even promote the efficiency of solution reaction.