Yu Jinquan's group found that γ - C (SP3) - H functionalization of ketones can be realized by using appropriate ligands

The functionalization of β - C (SP 3) - h by transition metal catalyzed thermodynamically stable five membered metal rings has been widely developed in the past few decades However, due to the difficult formation of the six membered metal ring system, the research on the functionalization of γ - C (SP 3) - h has not made progress Up to now, γ - C (SP 3) - H aromatization has only been realized on methyl neopentyl ketone containing β - cyclodextrin (Science 2016, 351, 252) Recently, Yu Jinquan's research group published an article on "JACS" (DOI: 10.1021 / JACS 8b01359) on which γ - C (SP 3) - h of ketone was activated by ligands In this paper, Pd (II) mediated by 2,2-dimethylaminoxyacetic acid was used to catalyze the γ - C (SP 3) - H arylation of ketones Among them, it was first confirmed that the 2-pyridyl-ketone ligand can promote the activation of C (SP 3) - H (scheme 1), so as to carry out the (hetero) arylation and vinylation of γ - C (SP 3) - H; rare palladium intermediates with six membered rings were isolated and characterized, and the reaction mechanism was clarified Finally, a simple Mn (II) - catalyzed method for the removal of cofactors was developed, which further increased the practicability of the reaction Scheme 1 palladium catalyzed γ - C (SP 3) - H aromatization (source: J am Chem SOC.) the research group firstly screened the ligands widely (Table 1), and found that compound L11 had good effect After that, the structure of L18 was modified It was found that the reactivity of L18 with steric hindrance was poor and the yield of L18 with steric hindrance was low It was speculated that the reason was that L18 could not effectively combine with palladium catalyst and the protective ligand contained hydroxyl group (L19) ）The X-type ligands play an important role in the C-H activation In Table 1, the selection of γ - C (SP 3) - H arylated ligands (source: J am Chem SOC.) by using the established optimal ligands and reaction conditions, the author explored the scope of application of ketones (Table 2) Methylalkylketone and ketone with β - fourth carbon center can be functionalized in a good yield at the γ position; however, the yield of γ - methylene C-H activation by forming a six membered metal ring is very low Table 2 application scope of ketone substrate (source: J am Chem SOC.) next, the author screened the application scope of aryl and heteroaryl iodine (Table 3) Among them, the γ sites of various heterocycles are functionalized for the first time by γ - C (SP 3) - H activation The application scope of Table 3 (heteroaryl iodine) (source: J am Chem SOC.) further confirmed the ligand effect through the γ - C (SP 3) - H vinyl reaction (scheme 2) of 3-iodocyclopent-2-enone Scheme 2 γ - C (SP 3) - H ethylene reaction (source: J am Chem SOC.) finally, the author also uses the different reactivity between the catalyst without ligand and the catalyst with 2-pyridone as ligand, which provides a useful method for the later functionalization of multiple sites of active natural products In this paper, the effectiveness of this method is verified by taking the Muscone as an example (scheme 3) Later functionalization of scheme 3 Muscone (source: J am Chem SOC.) in order to further improve the practicability of the nitrogen-containing guiding group, the research team also started to develop more effective removal methods, screened various metal catalysts as single electron oxidants, and found that Mn (OAC) 2 was the best catalyst The reasonable reaction mechanism (scheme 4) is described in this paper, that is, CO 2 and acetone are released from Mn (OAC) 2 oxidation 2 A, ammonia free radical 9 is obtained, and the target product is obtained after Mn (I) reduction and nitrogen-containing guiding group removal Scheme 4 Mn (II) catalyzes the removal of guiding group (source: J am Chem SOC.) in order to understand the mechanism of the reaction and the action of 2-pyridone ligand (scheme 5), the author tried to separate and characterize the six membered palladium intermediate Based on the previous mechanism, the complex 14 was separated and its structure was determined by X-ray crystallography, which confirmed the expected reaction mechanism Possible reaction mechanism of scheme 5 (source: J am Chem SOC.) conclusion: Yu Jinquan research group first developed the method of γ - C (SP 3) - H (hetero) arylation suitable for a variety of ketones 5-nitro-2-pyridone was selected as the best ligand for the reaction, and its reaction mechanism was clarified through experiments The substrate ketone (hetero) aryl iodide involved in the reaction has a wide range of applications and is suitable for the late C (SP 3) - H functionalization of complex molecules Corresponding author: Professor Yu Jinquan