Cobalt(Ⅲ)-catalyzed C-h Bond Hydroarylation Of Alkynes

Transition metal-catalyzed C–H bond activation is increasingly used in organic synthesis.Compared with traditional coupling reactions,transition metal-catalyzed C–H bond activation does not require the pre-activation step of the substrate,avoiding the use of expensive ligands and reducing the discharge of inorganic metal waste,the experimental steps are simplified,and the atom economy of the reaction is improved.By activating the inert C–H bond,the construction of C–C bond,C–N bond,C–O bond,and C–S bond chemical bond can be realized.In this way,it can be achieved in an atomic-economy and step-economy method to construct more complex compounds,so as to realize the construction of more complex molecules through high atom economy and high efficiency with simple and easily available raw materials.The hydroarylation of alkyne is one of the most in-depth researches on the functionalization of aryl C–H bonds,and the Heck coupling reaction is the main way to construct unsaturated olefins.However,this reaction has higher requirements for the structure of the substrate,and the activity of the olefins involved in the reaction is not high,it is difficult to achieve satisfactory results in this reaction.The transition metal-catalyzed C–H bond activation reaction can solve these problems,and has important research value for exploring new and efficient alkynes hydroarylation reactions.In this paper,the transition metal cobalt-catalyzed C–H bond hydroarylation of terminal alkynes is studied.Using N-pyridine indole as hydroarylation reagent to react with terminal alkynes containing carbonate five-membered ring.Coordination of the pyridine directing group is followed by a concerted metalation-deprotonation process to generate the five-member ring metal intermediate.The pyridine group and the transition metal cobalt complex form an indolyl cobalt metal intermediate.Then the terminal alkyne inserts the cobalt-carbon bond to form a vinyl cobalt intermediate.In this process,the steric hindrance on the Cp ring affects the binding site of alkyne and indole.When there is a larger sterically hindered group attached to the Cp ring.The terminal alkyne is coupled with indole by means of 1,2insertion to obtain a seven-membered ring vinyl cobalt intermediate.Finally,protonation obtains a series of hydroarylation products containing carbonate five-membered ring,and the rare ring-opening reaction did not occur.The experiment investigated the effects of catalyst,additive,solvent,concentration,temperature,reaction time and other conditions on the reaction,and proposed possible reaction mechanisms.Mainly include the following aspects:（1）Using indole as raw material,react with 2-bromopyridine or 5-methyl-2-bromopyridine and 2-chloropyrimidine to obtain a series of indole derivatives 1a-1t;starting from hydroxyacetone,it undergoes a nucleophilic addition reaction with ethynylmagnesium bromide,and then reacts with triphosgene or N,N-carbonyldiimidazole to form a ring reaction to produce terminal alkynes with five-membered carbonate ring 2a;N-pyridine indole 1a and a carbonate 5-membered terminal alkyne 2a as typical reaction substrates.In the selection of the catalyst,we choose the catalyst with a larger sterically hindered group（phenyl）attached to the Cp ring[Cp*^PhCo（CH₃CN）₃][Sb F₆]₂.The reaction has good selectivity,and the yield of the target product is high.The terminal alkyne was coupled with indole by way of 1,2insertion,and the ratio of the product is 3aa/4aa>20/1.By explores the influence of catalyst usage,additive,solvent,concentration,temperature,reaction time and other conditions on the reaction,get the optimal reaction conditions,under the argon protection environment,10 mol%[Cp*^PhCo（CH₃CN）₃][Sb F₆]₂as the catalyst,50 mol%2,4,6-trimethylbenzoic acid as additive,and O-xylene/dichloromethane=1/2（0.2 M）as the solvent,and reacted for 16 hours at 60℃.The hydroarylation product 3aa was obtained with a reaction yield of 86%,the ratio of the product is 3aa/4aa>20/1.（2）The applicability of indole derivatives with different substituents was explored.Studies have found that N-pyridine indole with different substituents can obtain the corresponding hydroarylated products in a moderate to good yields.Affected by the electronic effect,when electron-withdrawing substituents such as fluorine,chlorine and bromine are attached to positions 5 and 6,the yield of the reaction product is generally higher.When electron-withdrawing groups are attached to position 4,the reaction is obtained Lower yield and poor selectivity.The yield of the target product is slightly lower.When the electron-donating groups such as methyl,methoxy,and benzyloxy are attached,the yield obtained is above the middle.When the cyano group is attached alkyne and indole.The reaction effect is poor,the yield of the reaction is low,and the reaction selectivity is not good;when the guiding group attached to indole is 5-methyl-2-pyridine or pyrimidine,the reaction conditions are still compatible,the reaction obtains the corresponding hydroarylation product with a higher yield and better selectivity.（3）Under the best reaction conditions,the applicability of another terminal alkyne containing carbonate five-membered ring 2b for the reaction was investigated,and it was found that the alkyne and N-pyridine indole can be well compatible with the reaction system under the same reaction conditions.The corresponding hydroarylation product can also be obtained in a moderate yield and a good reaction selectivity.（4）Next,a scale-up reaction study was carried out.Under the optimized reaction conditions,catalyst loading is 5 mol%.In the end,the hydroarylation product was obtained with a moderate reaction yield.In addition,the further derivatization of the hydroarylation products resulted in diol and amino alcohol compounds with potential application value,thus shows the practicality of the research method.The structure of all new compounds was characterized by ¹H NMR,¹³C NMR and other methods for characterization.Then a competitive reaction experiment was carried out to explore the reaction mechanism,The reaction is more inclined to electron-rich indole substrates,and a possible reaction mechanism is proposed.In this paper,by studying the hydroarylation reaction of terminal alkynes catalyzed by trivalent cobalt,the hydroarylation reaction of N-pyridine indole and terminal alkynes containing carbonate five-membered ring catalyzed by a new type of cobalt catalyst was realized,selectively obtains terminal alkynes combined with indole in a rare 1,2-insertion manner to generate hydroarylation products.The functional group tolerance of the catalytic system is good,the universality of the substrate is high,and the corresponding hydroarylation product can be obtained at a moderate to good yield.This method opens up more possibilities for the further development of some novel structures and applications of vinyl indole,and has important applications and theoretical significance.