Ir（Ⅲ）/Chiralacid System Catalyzed Ferrocene Carboxamides With Diazomalonates Asymmetric Alkylation Reaction Apporach

Ferrocene derivatives have unique planar chiral properties and are often involved in asymmetric catalytic reactions as chiral catalysts or ligands.The synthesis of planar chiral ferrocene compounds by transition metal-catalyzed asymmetric C–H bond functionalization is the most concise and effective method.A variety of transition metal catalysts have been used to construct planar chiral ferrocenes.For trivalent group 9 transition metals（Co,Rh,Ir）are less frequently used for the catalytic synthesis of planar chiral ferrocenes,but they have received much attention in the field of asymmetric catalysis due to their catalytic properties and stability.Trivalent group 9transition metals with chiral cyclopentadienyl ligands are the most widely studied in the field of asymmetric catalysis and can be used to catalyze a variety of typical reactions and to construct chiral compounds with optical purity,but chiral cyclopentadienyl ligands are synthesized in tedious steps and pre-mounted with metals.In recent years,achiral Cp*M（Ⅲ）（M=Co,Rh,Ir）plus chiral acid system-catalyzed asymmetric reactions have been developed.In this strategy,metal catalysts are commercially available and chiral acids are synthesized in simple steps and high yields,avoiding the cumbersome synthesis steps of chiral cyclopentadienyl ligands.The asymmetric reactions catalyzed by this strategy all yielded the target chiral products with satisfactory enantioselectivity.Therefore,it is of great research value and significance to explore the construction of planar chiral ferrocenes catalyzed by non-chiral Cp*M（Ⅲ）（M=Co,Rh,Ir）plus chiral acid systems.In this paper,the asymmetric C-H bonded alkylation reaction of ferrocenamide with diazomalonic acid esters catalyzed by an achiral Cp*Ir（Ⅲ）/chiral acid system was investigated.The chiral carboxylic acid of the binaphthyl skeleton was used as the chiral source,and the asymmetric alkylation reaction was achieved by selective breaking of the C–H bond assisted by the carboxylic acid,followed by insertion of an alkyl reagent.The conditions affecting the reaction yield as well as the enantioselectivity were screened in the reaction to determine the optimum reaction conditions.The practicality of the method was explored,and the steps for determining the enantioselectivity were determined based on H/D exchange experiments,mainly as follows.Ferrocene and ferrocenecarboxylic acid were used as raw materials to obtain ferrocene amide derivatives 1a-1m by Friedel-Crafts acylation,Friedel-Crafts alkylation,amidation,Witting and reduction reactions.p-Toluenesulfonyl azide and malonate were used as raw materials to obtain diazomalonic acid esters 2a-2i by diazotization reactions.chiral binaphthols were used as raw materials,and after monosulfonylation and trifluoromethanesulfonylation in intermediates were obtained after palladium-catalyzed carbonylation.Chiral carboxylic acids 4c-4h of the binaphthyl skeleton were obtained after nickel-catalyzed Suzuki-Miyaura coupling reactions and hydrolytic acidification.We first screened Boc-amino acids,amide-protected amino acids and chiral carboxylic acids of the binaphthyl backbone using N,N-dimethylferrocene amide 1a and dimethyl diazomalonate 2a as raw materials,and determined that the chiral carboxylic acids of the binaphthyl backbone were more advantageous compared to the chiral acids of the other two backbones,and then explored trivalent group 9 transition metal catalysts（Co,Rh,Ir）and ruthenium catalysts with similar properties to determine the most suitable catalyst as[Cp*Ir Cl₂]₂.The most suitable catalyst was determined to be[Cp*Ir Cl₂]₂.The most suitable chiral carboxylic acid 4h was optimized based on the binaphthyl skeleton,and the remaining conditions that may affect the yield and selectivity were screened to determine the optimum reaction conditions:1a（0.1 mmol）,2a（0.13 mmol）,5 mol%[Cp*Ir Cl₂]₂,30 mol%Ag NTf₂,30mol%4h,10 mol%Ag₂CO₃,in 2-Me-THF（0.2 M）and reacted at 5°C for 24 h.Asymmetric alkylated ferrocenamide 3aa could be obtained in 84%yield,92:8 er.After determining the optimum reaction conditions,we first explored the ferrocenamide substrate.It was found that in the ferrocene amide substrate,the large site blocking substituent on the N atom was unfavorable for the selectivity of the reaction,and when the ferrocene lower ring carried the substituent,it was favorable for the selectivity of the reaction,both of which could be obtained as planar chiral alkylated ferrocene amides with excellent results.The reaction is also applicable to different substituted diazomalonic acid ester derivatives,and most of the diazomalonic acid esters show good selectivity.To further extend the utility of the method,scale-up as well as conversion experiments were carried out,which all ended up with excellent yields and selectivity of the final products.Through H/D exchange experiments,the determining step of the enantioselectivity was determined,in which the highly active diazomalonic acid ester derivatives make the C–H bond breaking irreversible,which explains the reduced selectivity of the asymmetric alkylated products obtained from diazomalonic acid esters 2f and 2h due to their low activity.And finally,the reaction mechanism is proposed and the decisive step for the enantioselectivity is identified.In this paper,the asymmetric alkylation reaction of ferrocenamide with diazomalonic acid ester catalyzed by an achiral Cp*Ir（Ⅲ）/chiral acid system was investigated,and the asymmetric alkylation products were obtained with excellent yields and selectivity.Moreover,this method,with a wide range of substrates,has excellent selectivity.It is of great research significance to propose a more effective synthetic route for the construction of planar chiral ferrocenes.