HFIP-assisted reductive C-S, C-N, and C-X coupling of carbonyl compounds: a combined computational and experimental mechanistic study

Owing to the importance of carbon-heteroatom bonds in synthetic organic chemistry and pharmaceuticals, developing reliable and catalyst-free methods for their construction sets a significant goal of high practical value for modern chemistry. The currently known approaches typically rely on pre-functionalized substrates or on combining catalysts with reducing agents incurring substantial cost and time. Herein, we report an expeditious HFIP-assisted direct reductive C-S, C-N, and C-X (X = Cl, I) coupling of carbonyl compounds with different nucleophiles using Me2SiClH as a mild reducing reagent. In this protocol, the solvent HFIP is essential for the activation of the carbonyl group. This approach is effective, operationally simple, and scalable. The methodology features a broad substrate scope and high functional group compatibility, demonstrating the synthetic potential in the late-stage modification of bioactive molecules. By combining control experiments with ab initio computational simulations we have also proposed a mechanism for this coupling reaction.

Automated summary

Due to the significance of carbon-heteroatom bonds in synthetic organic chemistry and pharmaceuticals, developing catalyst-free methods for their construction is an important goal in modern chemistry. This study presents an efficient HFIP-assisted direct reductive coupling of carbonyl compounds with nucleophiles, using Me2SiClH as a mild reducing agent. The protocol is practical, straightforward, and scalable, with broad substrate scope and high functional group compatibility. Additionally, a mechanism for this coupling reaction has been proposed based on control experiments and computational simulations.