ACS catalyst: research group of Li Xingwei, Dalian Institute of chemistry, Chinese Academy of Sciences realizes divergent C-C cyclization coupling of indole derivatives

At present, manganese catalysts with unique activity and selectivity have been widely used in C-H activation Researchers have reported the alkylation, alkenylation, Alkynylation, amidation, cyanation and simple aromatics cyclization of manganese catalysts, but there are few examples of using manganese catalysts to construct complex fused rings It is worth noting that the Ackermann group has developed the manganese catalyzed bicyclization of ketimine and methylene cyclopropane (scheme1a) Wang Honggen's research group used Mn (I) and Ag (I) to catalyze the activation of C-H to synthesize scheme 1b Wang Honggen's group and rueping's group also developed manganese catalyzed C-H olefinization / smiles rearrangement series reaction to obtain pyrrolidindolone derivatives (scheme 1c) (source: ACS catalyst.) recently, on the basis of previous work, Li Xingwei research group of Dalian Institute of Chemical Physics realized the divergent synthesis of two ring products (scheme 2) by Mn catalyzed C-H activation of indole and coupling of indole with alkynyl substituted cyclohexanone Relevant articles were published on ACS catalyst (DOI: 10.1021 / acscalal 8b02560) (source: ACS catalyst.) at first, the author investigated the feasibility of alkyne insertion Michael addition series reaction in n-pyrimidine indole (1a) and 3,3-dimethylsubstituted 1,6-enyne (2a) coupling (Table 1) Using Mn 2 (CO) 10 (5 mol%) as catalyst and TFE as solvent, the target product 3AA of a single enantiomer can be separated from 1a and 2A at 130 ℃, with a yield of 49% (entry 1) Increasing the ratio of 2A: 1A increased the yield to 69% In order to promote Michael addition, we use Lewis acid to activate the ketene group and introduce bph3 (0.5 equivalent) into the reaction to further increase the yield to 76% (entry 9) Finally, the author found that with 1,4-dioxane as solvent, reducing the amount of bph3 to 0.25 equivalent, and prolonging the reaction time to 17 h, the reaction effect was the best, and the yield was 92% (condition a) (source: ACS catalyst.) under the optimal reaction conditions, the author investigated the scope of application of indole derivatives (scheme 3) 4 The indole substrates with electron donor and electron acceptor at 5 and 6 sites can be successfully coupled with 2a to obtain the intermediate to excellent product 3AA - 3PA 7-position and 3-methyl-substituted indoles are also feasible substrates, but their reactivity is slightly lower, which indicates that the reaction is greatly affected by steric hindrance The target coupling product 3sa - 3wa can also be obtained in good yield by changing the guide group into pyridyl, methyl or methoxy substituted pyrimidine group When n-pyridyl isoquinolone and n-phenylpyridine-2-amine were used as substrates, the reaction efficiency was poor Next, the scope of application of 1,6-enyne substrate was discussed The activity of ketene with β - methyl was weakened In the process of alkyne insertion, due to the steric hindrance effect, the introduction of methyl into alkyne will inhibit the reaction, but with TFE as the solvent, the product can be obtained in 35% yield for 3 days under slightly changed conditions The removal of 1,6-alkyne from 1,6-alkyne resulted in the reduction of the yield of the target coupling product, which may be due to the lack of Thorpe ingold effect Fortunately, under the condition of condition B, the corresponding product 3aE can be separated and the yield is 62% Under the same conditions, 5-aryl substituted 1,6-enynes were successfully coupled to obtain 3af in moderate yield (source: ACS catalyst.) during the synthesis of the product 3aE, the author also separated the secondary product, bridgering 5ae, with a yield of 24% On the contrary, when Zn (OAC) 2 and pivoh were introduced as additives, the main reaction was to obtain the fused phenol 4ae (condition C, scheme 4) The phenolic product may be formed by C-H insertion of alkynes, intramolecular Diels alder reaction and subsequent alcohol elimination aromatization (source: ACS catalyst.) next, the author investigated the synthesis range of fused phenol (scheme 5) Many substituted indoles can react with alkyne 2E smoothly, and the series cyclization products (4ae-4ce, 4he-4re) are usually obtained in medium to good yields Indole 6de-6fe was obtained by coupling the substrate with methyl, chlorine and benzyloxy groups at the position of indole 4, without further aromatization, which may be due to the fact that the torsional tension is not conducive to the subsequent elimination and the formation of phenol products Similarly, when methyl substituents are attached to the ketene in the alkyne substrate, the intramolecular Diels alder (IMDA) addition products 6aj and 6AK are mainly obtained without subsequent alcohol elimination or aromatization In order to further prove the practicability of the reaction, the author coupled the 1,6-enyne derivative derived from estrone with 1a to obtain a single enantiomeric adduct of IMDA, 6Al, which may be due to the fact that the rigid configuration of the product inhibits the interaction between Lewis acid and oxygen atom (source: ACS catalyst.) after a lot of mechanism experiments, the author proposed a possible reaction pathway (scheme 8) The C (2) - H activation of indole substrate produces metal ring a, and the Mn-C bond region of a selectively migrates to the alkyne part of 1,6-alkyne 2E to obtain alkenyl intermediate B, which can be protonated to produce alkenyl intermediate C The addition product 6ae was produced by IMDA and the aromatization product 4ae was produced by Zn (OAC) 2 mediated intramolecular elimination of 6ae On the contrary, when BPH 3 is used, Mn-C bond undergoes non enantioselective Michael addition to obtain intermediate D, which is further protonated to form product 3AA (source: ACS catalyst.) Summary: Professor Li Xingwei's research group realized Mn (I) catalytic C-H activation of indole and divergent series reaction of C-C coupling of alkyne, and obtained two kinds of C (2) functionalized indole On the one hand, when bph3 is used as additive, the reaction is coupled by C-H olefinization Michael addition route to obtain the outer ring olefins connected to the tetrahydrofuran ring On the other hand, in the presence of Zn (OAC) 2 / pivoh, the product of condensed phenol was mainly formed by continuous C-H alkenylation, IMDA and elimination aromatization.