On October 10, 2022, Beijing time, the team of Professor Xu Haichao of the School of Chemistry and Chemical Engineering of Xiamen University published a research result entitled “Photoelectrochemical asymmetric catalysis enables site- and enantioselective cyanation of benzylic C–H bonds” in the journal Nature Catalysis. The team developed the first photocatalytic asymmetric synthesis method to achieve an efficient asymmetric cyanide reaction of the benzyl C(sp3)–H bond.
Professor Xu Haichao is the corresponding author of the paper, and doctoral students Cai Chenyan and Lai Xiaoli are co-first authors.
Xu Haichao’s research group has long been committed to the research of organic electrosynthesis. The team combined electrochemistry and molecular photocatalysis in the early stages, and opened up a new field of molecular photocatalytic synthesis (Angew. Chem. Int. Ed. 2019, 58, 4592）。 Molecular photocatalysis combines the complementary advantages of electrochemistry and molecular photocatalysis, and it is expected to achieve synthesis methods that are not easy to achieve through a single strategy. A major challenge in this field is that there is no strategy to precisely control the absolute stereochemistry of chiral product formation. Given the importance of chirality in organic molecules, the development of photoelectric asymmetric catalysis methods will undoubtedly greatly enhance the utility of molecular photocatalysis and promote the further development of the field.
The team chose to develop a site and enantiomer-selective photocatalytic Bian(sp3)-H cyanide reaction as its first attempt at photosymmetric catalysis. It is worth noting that Stahl and Liu’s pioneering work in the early stages achieved this asymmetric transformation using equivalent NFSI reagents and copper catalysis (Science 2016, 353, 1014). This radical-mediated asymmetric hydrocarbon functional grouping is formed by the hydrogen atom transfer (HAT) by cutting off the C-H bond to form a carbon radical intermediate. Xu Haichao’s research group took a different approach to achieve high-region selective C-H fracture through step-by-step electron/proton transfer (Figure 1).
Figure 1: Reaction design and development
The experimental results show that benzyl radicals can be obtained smoothly by using AQDS as a photocatalyst, and by adding water, TFE and acidic additives, the rate of benzyl carbon radical formation can be adjusted to match the subsequent cyanocyanosis steps. Under optimal conditions, the authors then examined the substrate range. The results show that the photocatalytic method has the characteristics of wide substrate range, strong functional group compatibility, and high regional and stereoselectivity. For aromatic rings of different electrical properties, the reaction can get better results. When aromatic rings with different electrical properties are present in the substrate at the same time, the cyanide reaction can selectively occur at the benzyl position where the electron-rich benzene ring is located (Figure 2). The authors then demonstrate the practicality of this methodology through further transformation of cyanogen groups in the product (Figure 2).
Figure 2: Benzylation cyanolysis reaction substrate range and product transformation
The authors verified the proposed reaction mechanism through a series of mechanism experiments, including the determination of the oxidation potential of the substrate and the excited state reduction potential of the photocatalyst, the capture of benzyl radical intermediates, the analysis of the Hammett curve, the exploration of the bond breaking law of special substrates, and the determination of kinetic isotopic effects.
In short, Xu Haichao’s research group developed the first photoelectric asymmetric catalytic method, which realized the asymmetric benzyl C(sp3)-H cyanidation reaction without oxidation reagents. Future work will focus on the application of photosymmetric catalytic methods to the enantiomerically selective reaction of C(sp3)-H bonds with other nucleophiles. This work proves that molecular photocatalysis and asymmetric catalysis can be combined to achieve efficient enantiomselective C-H functional grouping, which is of great significance for the further development of stereoselective and sustainable synthesis. (Source: Science Network)
Related Paper Information:https://doi.org/10.1038/s41929-022-00855-7