Novel phenylyne production method facilitates C-C σ-bond insertion of non-activated ketones

On June 14, 2023, Professor Shilei Zhang of the School of Pharmacy of Soochow University, together with the team of Professor Wang Wei of the University of Arizona and Professor Yu Zhixiang of Peking University, published a research result entitled “Direct insertion into the C–C bond of unactivated ketones with NaH-mediated aryne chemistry” in the journal Chem.

This achievement reports that the phenylyne is produced gently and controllably at room temperature by using o-diiodobenzene/sodium hydride as the phenylyne generation system, and the C-C σ-bond insertion reaction of phenylyne to non-activated ketones that is difficult to complete with the existing benzene system is realized. DFT calculations revealed that o-diiodobenzene and NaH undergo metal-halogen exchange through a synergistic complexation mode and initiate the production of benzyne, which then reacts with the enol salts of the tetramer to complete the subsequent C-C σ-bond insertion reaction. The corresponding authors of the paper are Zhang Shilei, Wang Wei, Yu Zhixiang; The first authors are Luo Fan and Li Chenlong.

Phenylyne/aryne is a highly reactive intermediate capable of many types of reactions. Classical phenylyne chemical production of benzyne mainly uses two types of methods: 1) the production of benzene from halogenated benzene + soluble strong base, which not only has poor functional group compatibility, but also easily leads to side reactions because of the rapid release of benzene; 2) Kobayashi method, with o-silylphenyl trifluoromethanesulfonate as the precursor of phenylyne, can controllably produce benzyne through the action of fluorine salt, the conditions are mild, and the substrate range and functional group compatibility are greatly improved. However, the preparation of Kobayashi precursors is cumbersome, and the Kobayashi system is not omnipotent, such as the C-C σ- bond insertion reaction of benzyne to active methylene ketone is a representative example of this system, but it is ineffective against non-activated ketone substrates. Therefore, the development of new phenylyne systems, reducing the difficulty of synthesis of precursors, generating new reactive activities, and discovering new reactions are important goals pursued in the field of phenylyne chemistry.

In this study, Shilei Zhang’s research team and Wang Wei’s team based on their previous research on the new activity of sodium hydride (ACS Catal., 2018, 8, 3016-3020; Org. Chem. Front. 2021, 8, 4685-4692), o-Diiodobenzene can produce phenylyne under the action of NaH. NaH has long been widely used as a hydrogen pulling reagent, where hydrogen anion is found to produce phenyl anion through metal-halogen exchange with o-diiodobenzene by “iodophilic” action and further removal of another iodine to produce phenylyne. Yu Zhixiang’s team at Peking University conducted in-depth theoretical computational research on the course of this reaction (Figure 4), in the transition stateTS1In , two iodine atoms and Na ions complex, while driving hydrogen anion and one of the iodine to form a complex network. The transition stateTS1, only 8.1 kcal/mol of activation barrier is required. Subsequently, NaI was removed and benzyne was produced, and the heat was exothermic at 3.5 kal/mol. Therefore, the formation of phenylyne can be carried out at room temperature. In contrast, NaH attacks isolated iodobenzene, which can be as high as 32.9 kcal/mol, which is difficult to achieve under ordinary conditions. The o-Diiodobenzene/NaH benzene system in this report uses commercially inexpensive reagents. Because NaH is insoluble in solvents, o-diiodobenzene can only interact with NaH at the solid-liquid interface, and phenylyne is produced slowly and persistently, which is conducive to subsequent reactions; The special alkaline environment caused by NaH and its weak nucleophilia make this phenylyne system different from previous classical methods, and it is easier to produce new reactivity and obtain new products.

Figure 1: Aryne production method, aromatic insertion reaction to various ketones.

Figure 2: Reaction substrate expansion-aryl alkyl ketone.

Figure 3: Changes in reaction substrate expansion-phenylyne precursors.

For the question of regional selectivity of phenylyne and ketone reactions, the experimental facts are:4gis a single product,4hand4iis a mixture of isomers (Figure 3). It has been calculated that the monoenol negative ion of ketones attacks benzene , and no matter how large the phenylyne ortho substituents are, this reaction is spontaneous and not selective. According to David B. Collum (Cornell University), the ketone’s enol negative ion is in tetrameric form. Then follow the tetramerETThe model attacks 3-position substituted phenylyne, which produces high selectivity due to steric hindrance of the tetramer and larger substituents on the benzene (Figure 4b). Produced in tetramer degradation or ligand exchangeInt3Later, the subsequent intramolecular negative ion attacks the ketone to become a four-membered ringInt4, and ring cleavage into the final product, both performed in a reasonable course similar to that of previous studies (active methylene ketone, etc.) (Figure 4c).

Figure 4: DFT calculation.

This work was supported by the Natural Science Foundation of China (22271206, 21738002, 22071053 and 21933003), and the PAPD, A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. Support from the High-Performance Computing Platform of Peking University. (Source: Science Network)

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