Hydrodeuteroalkylation of Unactivated Olefins Using Thianthrenium Salts

• Published in: Angewandte Chemie 2024-09, Vol.136 (36), p.n/a
• Main Authors: Zhang, Jie, Jiao, Mengjie, Lu, Zheng, Lu, Hongjian, Wang, Minyan, Shi, Zhuangzhi
• Format: Article
• Language: eng ; ger
• Subjects: Alkanes; Alkenes; Chemical synthesis; Deuteration; Deuterium; hydrodeuteroalkylation; Hydrogen isotopes; Hydrogen-deuterium exchange; Nickel; nickel catalysis; Pharmaceuticals; Reagents; Salts; thianthrenium salts
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202409862

Isotopically labeled alkanes play a crucial role in organic and pharmaceutical chemistry. While some deuterated methylating agents are readily available, the limited accessibility of other deuteroalkyl reagents has hindered the synthesis of corresponding products. In this study, we introduce a nickel‐catalyzed system that facilitates the synthesis of various deuterium‐labeled alkanes through the hydrodeuteroalkylation of d2‐labeled alkyl TT salts with unactivated alkenes. Diverging from traditional deuterated alkyl reagents, alkyl thianthrenium (TT) salts can effectively and selectively introduce deuterium at α position of alkyl chains using D2O as the deuterium source via a single‐step pH‐dependent hydrogen isotope exchange (HIE). Our method allows for high deuterium incorporation, and offers precise control over the site of deuterium insertion within an alkyl chain. This technique proves to be invaluable for the synthesis of various deuterium‐labeled compounds, especially those of pharmaceutical relevance. A range of d2‐labeled alkanes can be synthesized via nickel‐catalyzed hydrodeuterioalkylation of deuterated alkyl thianthrenium (TT) salts with unactivated alkenes. The deuterated alkyl reagents effectively integrate deuterium from D2O via pH‐dependent hydrogen isotope exchange (HIE). Our method enables high deuterium incorporation and precise control over insertion site, essential for drug synthesis.