Cobalt(Ⅲ)-Catalyzed C-H Alkynylation Of C7-Indolines With Bromoalkynes

Indoles/indolines and their derivatives are abundantly present in the framework of numerous chiral drug molecules and biologically active compounds,and they can be used in the main backbone or substructure of many organic molecular materials,promising applications in new materials and drug molecules.With the development of catalytic C-H functionalisation techniques,a large number of indole and indoline analogues have been developed and a great deal of research has been carried out on transition metal-mediated selective C-H functionalisation of indoles/indolines.As an important class of pharmaceutical and chemical intermediates,alkynes are widely used in modern organic synthesis,medicinal chemistry and materials science,and their synthesis and functionalisation have attracted the attention of synthetic chemists.Also the alkyne group is considered to be a versatile functional group that can be conveniently converted into a variety of functional or various useful molecules.Therefore,direct C-H alkynylation of indoles/indolines at the C7 position is synthetically attractive.So far,indoline C7-position C-H alkynylation reactions have utilised noble transition metal catalysts such as rhodium and iridium and the synthesis of complex high-valent iodinated alkynes TIPS-EBX as alkynylation reagents;however,these noble transition metals are costly and toxic and alkynyl sources are not easily available.Therefore,the development of a simple and effective method for the study of C-H alkynylation at the C7 position of indoline derivatives would be of great significance.Given the abundance of cobalt metal on the planet and its low price,an efficient,cheap,simple and effective Co（Ⅲ）-catalyzed direct C7 alkynylation reaction of indoleines with halogenated alkynylation reagents was developed.The reaction showed high yield and excellent substrate applicability.This method allows the synthesis of a variety of 7-alkynyl substituted indoleines in good to excellent yields.Furthermore,the reaction can be extended to the coupling of n-aryl-7-aza-indole,highlighting the synthetic utility of the method.In the reaction,the conditions affecting the reaction yield were screened,the most suitable reaction conditions were determined,the substrate range of the reaction was explored,the practicability of the method was explored,and the gram-level reaction experiment was carried out.The main contents are as follows:We first reacted indoleines,carbazole,phenol and N-methylaniline with various substituents with 2-chloropyrimidine and dimethylcarbamoyl chloride to obtain a series of substrates 1a-1u;A series of halogenated alkynylation reagents 2a-2j were obtained by the reaction of NBS with terminal alkyne.The substrate 5a-5c was obtained from 7-aza-indole by reaction with bromobenzene with a substituent.Next,N-pyrimidinylindoline 1a and bromotriisopropylsilylacetylene 2a were used as raw materials and Cp*Co（CO）I₂ was used as catalyst,and the remaining conditions that may affect the yield such as silver salts,additives,solvents,temperature and time were screened.After determining the optimal reaction conditions,we explored the range of substrates for the reaction.Through the study of different substituents and different guiding groups of indoline derivative substrates,the results showed that the alkynylation reaction is good,the electronic properties of the substituents on the indoline ring did not play a key role,and good yields were obtained at different positions.In view of the unique structural characteristics and biological activity of carbazole,we also tried the alkynylation reaction of carbazole.In order to further expand the scope of substrates,we explored the reactivity of different alkynes with indoleine derivatives.The system is compatible and has a wide range of substrates.Bromoalkynes with TES and TBS substituents can also catalyze the reaction to obtain the corresponding alkynylation products,but when phenyl bromoalkyne is used as alkynylation reagent,The N,N-dimethylformyl group is required as a guide group and the yield is reduced.N-aryl-7-aza-indole is an important class of indole derivatives,which has been found in many natural products and marketed drugs.To investigate the applicability of this method,we tried to extend the method to the coupling of N-aryl-7-aza-indole,and also achieved good yields.The reaction amplification study was next carried out,and under the optimal reaction conditions,the catalyst was 5 mol%,and the final reaction yielded the corresponding alkynylation product in moderate yield,thus demonstrating the practicality of the study method.The catalyst Cp*Co（CO）I₂ generates active the Cp*Co（NTf₂）₂ in the presence of Ag NTf₂,which is then cleaved through the C-H bond at C7 to form the six-membered ring metallization Co complex A.Subsequently,the bromoalkyne 2a is inserted to form intermediate B.Then alkyne insertion into B generates the alkenyl-Co intermediate C of the seven-membered ring.Finally,Na HCO₃ promotes the reductive elimination of complex C,which leads to the formation of the alkynylation product 3,and the catalyst regeneration to complete the catalytic cycle.In summary,we have developed Co（Ⅲ）-catalyzed alkynylation of the direct C-H bond at the C7 position of indole,which can yield a wide range of C7 alkynyl indole in excellent yields.The synthetic utility of the current approach is demonstrated by successfully obtaining activation of a variety of different alkynyl groups at the C7position.In addition,we also extended this method to N-aryl-7-aza-indole in addition to indoleines.Considering the valuable structure of the products,we expect that this selective alkynylation reaction will be applied to a wider range of synthetic applications.