A novel method on Chem for aryne generation and direct insertion into the C–C σ-bond of unactivated ketones

Benzyne/aryne is a kind of highly reactive intermediate, which can be involved in many types of reactions and plays an important role in medicinal chemistry and drug synthesis. There are two major methods to produce benzyne: 1) The treatment of aryl halides with strong bases, which not only has poor functional group compatibility, but also easily leads to side reactions due to the rapid release of benzyne; 2) The famous Kobayashi’s protocol, that is,o-silylphenyl trifluoromethanesulfonate is used as the benzyne precursor, and benzyne can be generated in a controlled manner through the action of fluoride salts. Kobayashi’s reaction conditions are mild, and the substrate range and functional group compatibility are greatly improved (Fig. 1a). However, the synthetic route for Kobayashi’s precursors is tedious. Moreover, Kobayashi’s system is not omnipotent. For example, although aryne insertion into the C-C σ-bond of active methylene ketones is efficient for Kobayashi’s method, it fails to give any desired product for unactivated ketone substrates (Fig. 1c). For aryne chemistry, it’s an important goal to develop new aryne systems, which could make the synthesis of aryne precursors easier, and create new reaction activities for discovering a new type of reactions.

In recent years, Shilei Zhang/Yanwei Hu’s research group has been committed to the research on the new reactivity of sodium hydride, and the results could be applied to medicinal chemistry and drug synthesis. Recently, the research group has reported a series of reduction reactions based on the use of NaH/Pd as a reducing system. For example, removing benzyl and allyl protecting groups (ACS Catal.,2018,8, 3016-3020); Reducing electron-deficient olefins (Adv. Synth. Catal.2019,361, 1554-1558); Hydrodehalogenation (Org. Chem. Front.2021,8, 4685-4692); Removal of sulfonyl groups (Tetrahedron Lett.2020,61, 152442); Reducing aza-aromatic rings (Synthesis,2023,55, 1451-1459). On the basis of the above research, the team then cooperated with Professor Wei Wang of the University of Arizona and Professor Zhi-Xiang Yu of Peking University, publishing a research paper entitled Direct insertion into the C–C bond of unactivated ketones with NaH-mediated aryne Chemistry onChem, one TOP chemical journal of Cell Press. The College of Pharmaceutical Sciences of Soochow University is the first author of this paper. Professor Shilei Zhang, Professor Wei Wang, and Professor Zhi-Xiang Yu are the co-corresponding authors.

Figure1. The methods for aryne generation and the insertion reaction of aryne with various ketones

In this paper, the authors documented the reinvention of the aryne chemistry witho-diiodoarenes as aryne progenitors. A new NaH-mediated activation strategy has been established for the generation of highly reactive aryne species in a controlled manner. The resulting arynes can efficiently participate in a C-C σ-bond insertion reaction with unactivated ketones (Fig. 1d), which is difficult to achieve by existing methods. The process proceeds highly efficiently with an impressive broad functional group tolerance, as evidenced by more than 110 substrates (Fig. 2). Importantly, the operationally simple, mild protocol has been implemented for late-stage skeletal editing of structurally complex molecules. This is directly contrast to the classic methods using strong bases such as NaNH₂, alkyllithium, or Grignard reagents with drawbacks of narrow functional group scope and complicated side reactions.

Figure 2. Substrate scope

DFT calculations (Fig. 3) reveal the two adjacent iodines ino-diiodoarenes play critical roles in the formation of aryne. The nucleophilic attack of hydride to the electrophilic iodine requires the adjacent iodine acting as a directing group to accelerate this process (8.1 kcal/mol), while mono-substituted iodobenzene lacking the neighboring group participation makes it difficult (32.9 kcal/mol). The in situ formed enolates from ketones are proposed to adopt tetrameric aggregates to react with benzyne, which accounts for high regiochemistry for substrates with bulky substituents. The new activation mode for control formation of aryne active species holds significant potential for applications to a broad spectrum of novel organic reactions.

Figure 3. DFT calculation

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

References:

Fan Luo, Chen-Long Li, Peng Ji, Yuxin Zhou, Jingjing Gui, Lingyun Chen, Yuejia Yin, Xinyu Zhang, Yanwei Hu, Xiaobei Chen, Xuejun Liu, Xiaodong Chen, Zhi-Xiang Yu*, Wei Wang*, and Shi-Lei Zhang*.Direct Insertion into C-C Bond of Unactivated Ketones Enabled by NaH-mediated Aryne Chemistry.Chem, 2023,https://www.cell.com/chem/fulltext/S2451-9294(23)00264-4

Corresponding author

Shilei Zhang is a Professor of College of Pharmaceutical Sciences, Soochow University. Zhang's research group mainly focuses on the development of efficient methods for drug synthesis and process. In recent years, He has published more than 30 academic papers as corresponding author in relevant fields, such asNature Catal.,Chem,ACS Catal.,Org. Lett.,Org. Chem. Front.andAdv. Synth. Catal.. Moreover, he has been authorized near 20 Chinese patents.