New progress in C-H bond activation: aromatization of ketones by β - C (SP3) - H activation

It is a hard and creative work to activate the inert C-H bond and then functionalize it directly Since 1970s, transition metal catalyzed functionalization of ketone β - C (SP 3) - H bond has been developed However, in the past, such reactions have serious substrate limitations, including: (a) the functionalization of methylene (SP 3) - H bond is very limited; (b) a variety of functional groups are incompatible (such as esters, amines, ethers, acetals, etc.); and (c) aromatic heterocyclization cannot be achieved Recently, Professor Yu Jinquan's team from Scripps Institute in the United States published a paper in J am Chem SOC., reporting the successful solution of the substrate limitation of β - C (SP 3) - H arylation of ketones by using the auxiliary structure of aminoacetic acid It is worth mentioning that most of the reported substrates are previously incompatible On the basis of previous studies, the β - methylene C-H arylation of 2-pentanone was studied The reaction conditions were PD (OAC) 2 (10 mol%), methyl 4-iodobenzoate (2.0 equivalent), AgTFA (2.0 equivalent), and HFIP at 120 ℃ The experimental results show that the compound (DG2) with the auxiliary structure of 2,2-dimethylaminoacetic acid has obvious reaction advantage Figure 1 Auxiliary structure research source: J am Chem SOC Next, the author expanded the substrate ketone, iodobenzene and heterocyclic aryl iodide Fig 2 is the results of the extended experiments of ketones It can be seen that a series of methylalkylketones (2a-f), the methylene C-H bonds (2k-p) of other chain ketones (2g-j) and cyclic ketones, and the primary carbon C-H bonds (2q-2ab) of chain and cyclic ketones can be compatible with this reaction, and the yield can reach medium to good In particular, the substrate containing sensitive groups such as α - ester, benzyl alcohol and ketal can also be used in this reaction condition Fig 2 Expanding source of ketone substrate: the expanding result of J am Chem SOC Iodobenzene is shown in Fig 3 The reaction effect of para (3a - L) and meta (3m - s) substituted iodobenzene is very good, and the corresponding product can be obtained in good to excellent yield The iodobenzene (3T - x) with ortho substituents can also react smoothly, but the yield is relatively low due to the steric effect Figure 3 Extended source of iodobenzene substrate: J am Chem SOC Considering the importance of aromatic heterocycles in medicine, the author further explored the aromatic heterocyclization of β - methylene C-H bond, as shown in Figure 5 Heteroaromatic rings have strong coordination ability, which often preferentially combine with palladium or directly inactivate the catalyst Therefore, there has been no successful case of heteroaromatization of ketone methyl or methylene C-H bond in the past In this study, 2-substituted pyridine (4a-h), which has relatively weak coordination ability, participated in the reaction, and the heteroaromatic products can be obtained in medium to good yields Strong coordination of pyridine (4I - J) and quinoline (4K - L) can also be successfully reacted, but the yield is moderate In addition, weakly coordinated indole, thiophene and furan can react to form biaryl heterocyclic products (4m - P) All of the above are heteroaromatization of cyclic methylene C-H bond, and heteroaromatization of acyclic substrate can also be achieved (4q - R) Fig 4 Source of heterocyclic iodide substrate expansion: J am Chem SOC Substrate expansion results show that the new method has a wide range of applications and can be used for the later functional modification of natural products or drug molecules In addition, the reaction can be carried out smoothly by reducing catalyst loading and increasing substrate scale Finally, it should be mentioned that the auxiliary structure of 2,2-dimethylaminoxyacetic acid can be removed in HCl to obtain β - arylketone Conclusion: Yu Jinquan team has developed a simple and efficient method of β - C-H bond arylation of ketones The new method breaks the limitation of the past and can be applied to a wide range of substrates, which is expected to be an effective strategy for the direct functionalization of C-H bonds Paper link: http://pubs.acs.org/doi/10.1021/jacs.7b09761 subject group link: http:// Yu Jinquan