Angelw: Masahiro Miura group of Osaka University realized iridium catalyzed Alkynylation of indole at C4 and C7 sites

Indole heteroaromatic skeleton is one of the dominant heterocyclic compounds due to its wide presence in a variety of commercially available drugs, bioactive compounds and functional molecules Therefore, researchers are very interested in the site selective modification of indole derivatives In recent years, transition metal catalyzed direct conversion of C-H bonds has also become an important synthesis tool for later functionalization There are six unique reaction sites in the indole core However, the selective functionalization of indole in the benzene segment rather than in the highly reactive C2 and C3 sites is still challenging In order to solve the above problems, in recent years, researchers have developed a variety of catalytic methods (scheme 1a) including alkylation, alkenylation, arylation, amination and boric acid Although the researchers used bromoalkyne or ethynylbenzi odoxole s (tips-ebx) as Alkynylation reagents, and have developed a catalytic system (scheme1b) for C2 and C3 functionalization, there is no report of Alkynylation on the core of benzene ring Recently, the team of Professor Masahiro Miura of Osaka University, Japan, has realized iridium catalyzed direct Alkynylation of indole at C4 and C7 sites for the first time under the action of sulfur guiding group The related research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201904709) (source: angelw Chem Int ed.) at the beginning of the study, the author used 1-methyl-3 - (methylthio) - 1H - indole (1a) as the model substrate and tips-ebx (2) as Alkynylation reagent to optimize the conditions of C4 Alkynylation (Table 1) In the presence of [Cp * IRCL 2] 2 / agotf catalyst and naopiv · H 2O additive, the coupling product 3A was obtained by reaction of 1a and 2 in trifluoroethanol at 80 ℃, and the yield was 72% (entry 1) The results of control experiments show that both catalyst and additive are necessary for the reaction (source: angelw Chem Int ed.) under the optimal reaction conditions, the author investigated the application range of indoles (scheme 2) The reaction is sensitive to the steric hindrance near C4 site, so the C5 substituted indole reaction is rather slow The corresponding product 3B was obtained in 27% yield of 5-Chloroindole The substrate with substituents at C6 or C7 position can obtain the Alkynylation product 3C - 3H in good yield 1-methylbenzoindole or indole with phenyl and naphthyl at C2 position is also suitable for this method, and a single C4 alkynyl compound 3I - 3K is obtained In addition, indole with other protecting groups on nitrogen and sulfur atoms also had good tolerance, and the C4 Alkynylation product (3L - 3P) was obtained in medium yield It is worth noting that the reaction is also suitable for regioselective Alkynylation of other aromatic compounds (5 and 7) (source: angelw Chem Int ed.) in order to further prove the synthesis and application of sulfur guided Alkynylation strategy, the author proposes to realize C7 selective functionalization by installing SME guided group on indole nitrogen atom Interestingly, the target c7alkynylated indole 9A (scheme 4) was obtained from the reaction solution of 1 - (methylthio) indole (8a) and tips-ebx (2) under standard conditions in 65% yield (source: angel Chem Int ed.) as shown in scheme 5, the strategy can tolerate a variety of functional groups, such as chlorine, bromine, ester and cyano (9b - 9i) The presence of C3 competitive guiding group did not affect the regioselectivity of the reaction, and only c7alkynylated indole 9L was obtained 9 - (methylthio) - 9h carbazole can also take part in the reaction, and 9 m diacetylation product can be obtained in 77% yield (source: angelw Chem Int ed.) Summary: Masahiro Miura research group developed the first method of catalytic Alkynylation of indole benzene ring fragments with tips-ebx as Alkynylation reagent The sulfur functional group can guide the reaction process correctly, and the selective C4 and C7 functional group indole can be obtained, and the sulfur oriented group can be easily removed In addition, the reaction substrate has a wide range and can tolerate a variety of functional groups on indole.