JACS: Cuixin group of Mississippi State University realized asymmetric synthesis of dihydroindole derivatives by ruthenium catalyzed enantioselective C-H functionalization

Recently, a new type of C-H functionalization catalyst system has been developed rapidly Among them, directed C-H bond activation has become an effective tool in common use In addition to the oxidation addition based on C-H bond, the high valence metals (including PD (II), Ru (II), Rh (III), etc.) show new reactivity and selectivity through metallization / deprotonation In recent years, the group has successfully realized the enantioselective C-H activation (scheme 1a) catalyzed by Pd (II) using single protected amino acid (MPAA) and related ligands, two tooth chiral transient guide group (ctdg) and chiral transient medium In addition, the Cramer group and rovis group realized the enantioselective conversion catalyzed by RH (III), IR (III) and CO (III), respectively, using Cp * ligands and engineering enzymes Ru (II) arene complex has become an efficient C-H activation catalyst because of its low cost, easy to obtain, unique reactivity and selectivity However, the enantioselective C-H bond activation catalyzed by Ru (II) has not been reported (scheme 1c) (source: J am Chem SOC.) optically active indoles are important skeletons in synthetic and pharmaceutical chemistry However, the enantioselective synthesis of dihydroindole has not been developed Recently, Professor Cui Xin's research group of Mississippi State University reported the first Ru catalyzed enantioselective C-H activation / hydrogen aromatization reaction and applied it to the synthesis of tricyclic skeleton in ergot alkaloids A variety of chiral 4-formylindolines (scheme 2) were synthesized by the simple and easily obtained Ru (II) complex and chiral α - methylamine with EE value up to 96% Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b07251) (source: J am Chem SOC.) at first, the author mainly studied the hydrogen aromatization of m-aminobenzaldehyde in 1,2-dichloroethane catalyzed by [Ru (p-cymene) Cl 2] 2 and agbf 4 (Table 1) At 70 ℃, the yield of chiral amine CA1 is 35% and the EE value is 17% to dihydroindole 2AA (entry 1) After a series of screening conditions such as chiral amines, additives and Ru catalysts, the author finally determined that the best reaction conditions were as follows: Ru (p-cymene) Cl 2 and agbf 4 as catalysts, ca8 as transient guiding group, L-Tert-Leucine and KH 2PO 4 as additives, substrate 1AA reacted in phcl / HFIP at 60 ℃, with 88% yield and 94% ee It is worth to cyclize product 2AA (source: J am Chem SOC.) under the optimal reaction conditions, the author investigated the universality of substrate 1 (Table 2) The corresponding indoline 2ba-2ja can be successfully obtained from the o -, m-and p-methoxy, fluorine and trifluoromethyl substituents of benzaldehyde in 34% - 86% yield and 69% - 94% ee value In addition, the substrate with NS protecting group on nitrogen is also tolerant, and the yield and EE value are up to 2kA (source: J am Chem SOC.) later, the author investigated the application scope of substrate 1 with different internal olefin units (Table 3) The (E) - styrene with electron acceptor or electron donor at different positions can reach the corresponding dihydroindole 2Ab - 2An with a yield of 85% and an EE value of more than 90% In addition, aliphatic alkenyls can also be compatible with such reaction conditions, and 2ao - 2AR can be obtained efficiently It is worth noting that (E) - 1As and (z) - 1As will produce the same product, but the yield of the former is higher, while the EE value of the two is not much different This shows that the configuration of the internal alkenes does not play a decisive role in the control of enantiomers (source: J am Chem SOC.) based on mechanism experiments and previous reports, the author speculated on a possible mechanism (scheme 4) At first, the transient imine intermediate II was activated by reversible Ru (II) - catalyzed C-H in acid medium to form ruthenium ring III In addition to assisting the metallization / deprotonization step, the Carboxylates with large steric hindrance may form ion pairs with the cation part of intermediate IV Based on the assumed asymmetric induction model, alkene units tend to approach the Ru center from the same side of the conformational rigid methyl on the chiral carbon, thus forming the R-configuration chiral center in 2AA, which is consistent with its single crystal structure (source: J am Chem SOC.) in order to understand the asymmetric induction, the author transformed chiral imine 5 into ruthenium ring 6 as a simplified scheme 5 model for key intermediate III The single crystal structure of 6B confirms that the α - hydrogen of the chiral amine is indeed facing the aromatics above The vertical distance from the chiral carbon to the aromatic plane is 3.143 μ m, while the distance from the chiral carbon to the α - methylhydrogen center is 2.065 μ M This indicates that methyl group may also limit the rotational degrees of freedom of C-N bond in space (source: J am Chem SOC.) in a word, we have developed a Ru catalyzed C-H activation / hydrogen aromatization reaction for the first time The enantioselective C-H activation can be efficiently applied to the synthesis of dihydroindole derivatives The commercial and cheap Ru (II) complexes and chiral amines also make the new system have good practicability.