Ru(Ⅱ)-Catalyzed C-H Alkynylation Of Brominated Alkynes With Ferrocene Amides

Ferrocene derivatives have been widely used in various fields due to their unique electronic and structural properties.Alkyne compounds are important backbone supports in organic synthesis.The insertion of alkyne groups into the ferrocene structure is more favorable for its subsequent diversification of applications.The conventional synthesis of functionalized ferrocenes,including ferrocenyl acetals,relies on Friedel-Crafts acylation reactions,followed by functional group conversion of the resulting acyl ferrocene or cross-coupling of ferrocene with stoichiometric lithiation reagents to produce lithium ferrocene.However,these traditional methods usually require complex steps and involve environmental pollution in the synthesis process.Therefore,it is necessary to develop methods for the direct sy nthesis of functionalized ferrocene alkynes.Transition metal-catalyzed C-H bond activation reactions are of great importance in organic chemistry because of their simple operation and atomic/step economy advantages.So far,transition metal-catalyzed ferrocene C-H bond activation reactions have been reported successively(alkenylation,alkylation,arylation,acylation and amination),but the report of ferrocene C-H bond alkynylation is very limited.In the reported C-H bonded alkynylation reactions catalyzed by transition metals,the common source of alkynyl groups is a high-valent iodine reagent.However,high-valent iodine reagents produce by-products during the catalytic process and the synthesis steps are complicated.Compared with high-valent iodine reagents,the synthesis steps of brominated alkynes are simpler and more valuable in catalytic synthesis.The ferrocenamide structure is found in a variety of drug active molecules.Therefore,amides have a very important application as a guide group for the activation reaction of ferrocene C-H bond.Compared to strongly oriented groups(pyridine),monodentate oriented ferrocenamides have been less reported as weakly oriented groups,where ruthenium-catalyzed functionalization of weakly oriented groups of ferrocenamides have not been seen.Therefore,it is of great importance to investigate a method for the synthesis of a series of ferrocenyl amides with brominated alkynes catalyzed by ferrocene amides using cheaer metals.In this review,the study of C-H bonded alkynylation reactions of ferrocene amides with brominated alkynes catalyzed by divalent ruthenium is discussed.Our work extends the functionalization of ferrocene by using inexpensive and stable ruthenium catalysts to catalyze the C-H bond alkynylation reactions of ferrocene amides with simple and readily available brominated alkynes.The mild reaction conditions,wide range of alkyne substrates,good functional group compatibility,and only monodentate substitution products were obtained,which expanded the scope of derivatization studies of reaction products and achieved efficient synthesis of ferrocene alkynes and preliminary asymmetric C-H bond alkynylation studies also promoted wider application of ferrocene structures.The contents are shown as follows:The main synthesis steps of ferrocene derivatives 1a-1p: Firstly,ferrocene is used as the starting material,and ferrocene amide derivatives are obtained by Fucetylation reaction.Alternatively,ferrocenecarboxylic acid was used as the starting material,and ferrocenecarbonyl chloride was obtained after the chloroformylation reaction,and then the ferrocene amide derivatives with different substituents were obtained after the substitution reaction.Subsequently,N,N-dimethyl or diethyl ferrocene was used as the starting material and the bisubstituted ferrocene amides were obtained after acetylation reaction,Witting reaction and reduction reaction.Using terminal alkynes as starting materials,substitution reactions were carried out in the presence of silver nitrate and NBS to produce bromoalkyne derivatives 2a-2l,2n-2r.Alternatively,bromoalkyne compounds 2m,2s and 2t were synthesized by a two-step experimental procedure.Initially,we used N,N-diethylferrocenamide 1a and triisopropylsilylbromoacetylene 2a as starting compounds and obtained the desired alkynylation products when [Ru Cl2(p-cymene)]2 was used as catalyst.The effect of silver salt,solvent,and additives on the product yields was subsequently explored under the conditions of determining the catalyst.The optimal catalytic conditions were defined: 1a(0.05 mmol),2a(0.075 mmol),[Ru Cl2(p-cymene)]2(5 mol%),silver bis(trifluoromethanesulfonyl)imide(40 mol%),silver carbonate(20 mol%)dissolved in 1,4-dioxane(0.4 M)and reacted for 24 h at 60 °C.The final ferrocenyl amide alkyne3 a was obtained in 86% yield.After defining the optimal reaction conditions,we explored the range of substrates for ferrocene amide derivatives.It was found that a substituent with a large spatial site resistance would give a lower yield for the catalytic reaction.In addition,another ferrocene substrate with a substituent on the ferrocene ring is also well suited for the catalytic reaction.The catalytic reaction can also be applied to brominated alkynes with different substituents substitution.In this catalytic reaction,we expanded the range of substrates for brominated alkynes.Silyl,aryl and alkyl-substituted brominated alkynes were able to generate the corresponding alkynylated products with ferrocenamide.To demonstrate the synthetic utility of alkynes in catalytic reactions,we investigated the derivatization reactions of ferrocenyl acetylenes with high yields of the corresponding derivatized products.Subsequently,we carried out a preliminary investigation of the ruthenium-catalyzed asymmetric C-H bond alkynylation of ferrocenylamides with brominated alkynes to give asymmetric ferrocenylamides alkynes in 58.5:41.5 er.Finally,we explored the mechanism of the catalytic reaction.In conclusion,we have developed a transition metal ruthenium-catalyzed direct alkynylation of brominated alkynes on amide-directed ferrocene derivatives.The present reaction is a rare example of alkynylation of ferrocene C-H bond under the influence of a weakly directing group.This approach may offer the possibility to further develop some new ferrocene structures.