Rhodium(?)-catalyzed Direct C-H Alkylation Of Ferrocenes With Diazo Compounds Under Weakly Coordinating Approach

Ferrocene and its derivatives have received extensive attention in various fields such as medicinal chemistry,materials science asymmetric catalysis due to their unique sandwich structure and stable chemical properties.The classical synthesis method of functionalized ferrocene derivatives were achieved via Friedel-Crafts acylation,the resulting acyl ferrocene was subsequently subjected to functional group conversion;and using alkyllithium reagent to afford ferrocenyl lithium,which would react with the corresponding electrophile to afford the functionalized ferrocene derivatives.These methods were harsh and incompatible with many functional groups.Transition-metal-catalyzed C–H activation has the advantages of mild conditions,which is of great value and significance in exploring the synthesis of new and efficient ferrocene derivatives.In this paper,rhodium???-catalyzed C–H alkylation of ferrocene was studied using amide as a directing group.Diazo compounds as a source of alkylating agent,a series of 1,2-disubstituted ferrocene alkylation products were obtained by a electrophilic metalation,generating rhodium carbene intermediate,which undergoes rapid migratory insertion and protonation.The effects of catalyst,base,silver salt,solvent and other conditions on the reaction were investigated,and the possible reaction mechanism was proposed.The main contents as shown in the following:The ferrocenecarbonxamide 1a and 1b were synthesized from ferrocene by Friedel-Crafts acylation;the ferroceneformyl chloride was obtained from ferrocene formic acid by an acyl chlorination,which followed by nucleophilic substitution to obtian the ferrocenecarbonxamide bearing different substitutents?1c-1h and 1j-1t?.In addition,N,N-diethyl-1-[?1'-isopropyl?ferrocenyl]amide 1i was prepared from 1a after the Friedel-Crafts acylation,Wittig reaction and reduction.Using N,N-diethylferrocene carbonxamide and dimethyl 2-diazomalonate as substrates,by exploring the effects of catalyst,bases,solvent,silver salts and reaction temperature,and the optimized reaction conditions were determined:[Cp*RhCl₂]₂?5 mol%?,KOAc?20 mol%?,AgNTf₂?20 mol%?,and anhydrous 1,2-dichloroethane?1 m L?,stirred at 100°C for 12h,a monosubstituted alkylated product 3a was obtained in 83%yield.With the optimal reaction conditions in hand,the scope of ferrocene derivatives with different substituents were examined.The corresponding alkylation products could be obtained in a moderate to good yield when R¹ and R² have the same substituents or different substituents.Affected by steric hindrance,the reaction yield of3c was lower than that of 3a and 3b when using isopropyl as a substitutent for R¹ and R².In addition,the corresponding products were obtained in moderate yield when the ferrocene substrates with different ring sizes,but the yield would decrease as the number of rings increases;and the alkylation products were also obtained in moderate yields when the ferrocene substrates containing azacycles.The substrate of N,N-diethyl-1-[?1'-isopropyl?ferrocenyl]amide was also compatible with the reaction conditions.The result of the reactivity of various diazo compounds shown that,diazo compounds with the same ester group for R¹ and R² were compatible with the reaction conditions.The ferrocene diol compound was obtained through the gram-scale experiment and the derivatization of the product.The structure of all new compounds was characterized by ¹H NMR,¹³C NMR,HRMS,IR and melting point,and the structure of the target compounds were further determined by the X-ray single crystal diffraction results of compounds 3n and 4c.The great importance of amide as a directing group was illustrated by the H/D exchange and two control experiments,and a possible reaction mechanism was proposed.In this paper,rhodium???-catalyzed C–H alkylation of ferrocenecarbonxamide and diazo compounds was studied,achieving C–H alkylation of ferrocene under the influence of amide as a weakly coordinating group.The reaction system has better functional group tolerance and substrate applicability,and the corresponding alkylation products were obtained in moderate to good yields.This method open up more possibilities for the further development of some novel structures and application of ferrocene,and has important application and theoretical significance.