Ruppert–Prakash Reagent as a Source of Difluorocarbene: Mechanistic, Synthetic, and Practical Perspectives for Small-Ring Synthesis

The Ruppert–Prakash reagent (TMSCF3) has become one of the most practical and widely used sources of difluorocarbene, enabling the efficient construction of gem-difluorocyclopropane and gem-difluorocyclopropene frameworks. Over the past decade, significant progress has been made in understanding its initiation pathways, reactivity patterns, and the factors that control reaction efficiency and safety. This review summarizes these advances, covering both mechanistic insights and the broad synthetic scope of TMSCF3-mediated transformations of alkenes, alkynes, and functionalized complex substrates, mostly leading to three- and four-membered rings. Particular attention is given to strategies that enhance practicality, including “slow addition,” catalytic approaches, and flow chemistry to enable safe handling and scale-up. The emerging structural diversity now accessible through these protocols highlights the growing importance of difluorinated small rings in modern molecular design. Together, these developments establish TMSCF3 as a cornerstone reagent for difluorocarbene chemistry, pointing toward promising opportunities for future discovery.

• Ryabukhin S^1,2,3,4
• Nosik P^1,2,3
• Leha D^2,3
• Volochnyuk D^1,2,3,4

•   ¹Enamine Ltd. 78 Winston Churchill str. Kyiv 02094 Ukraine
• ²Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., Kyiv, 01033 Ukraine
• ³Enamine Scientific Research Institute, 78 Winston Churchill str., Kyiv, 02094 Ukraine
• ⁴Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Akademik Kukhar str., Kyiv, 02094 Ukraine

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