We have discovered that copper-free Sonogashira cross-coupling reaction proceeds through the so called bicyclic rather than the previously incorrectly proposed monocyclic mechanism. Experimentally, this has been supported by identification of reaction intermediates using state of the art nuclear magnetic resonance spectroscopy and mass spectrometry, as well as kinetic studies. Experimental results were additionally supported by theoretical DFT studies. This work will contribute to the knowledge of metal-catalyzed reactions in general, having favourable economic and environmental implications in relevant industrial chemical processes. The Editors of Nature Communications selected this work for the Organic Chemistry and Chemical Biology Editors’ Highlights.
COBISS.SI-ID: 1538034627
We discovered that the Pd-Py-tzNHC catalyst, where the palladium active center is stabilized by the mesoionic-carbene and pyridine moieties of the bidentate ligand, catalyzes the reaction between acetylenes and anilines without any added additive. The hemilabile bounded pyridine fragment is designed to allow intramolecular proton transfer in the catalytic process and thus mimicking enzyme-like catalysis. Unlike the previously described processes, the reaction with this catalyst takes place under extremely mild reaction conditions, at room temperature, with complete regioselectivity, excellent yields and in the absence of any additive. Such a role of pyridine ligand in proton transfer has not yet been described, and it has been confirmed by a number of experimental and theoretical methods. The described new type of catalytic reaction means the improvement of all known processes for the preparation of imines. The article was featured on the cover of Organic Letters.
COBISS.SI-ID: 1538522051
In cross-coupling the optimal use of both metals is crucial for the efficient performance of the reaction. Based on the previously accepted mechanism of the copper-free Sonogashira cross-coupling reaction, palladium played a role only in the process of oxidative addition. In contrast and following our mechanistic proposal, we designed conditions where two different palladium pre-catalysts were used simultaneously in the reaction mixture. The first, Pd-CataCXium, was optimal for oxidative adduct, and the second, Pd-Py-tzNHC, for palladium acetylide formation. The reaction conditions were successfully optimized in dioxane for the catalytic reaction between aryl bromides and terminal acetylenes, which took place successfully at an extremely low total (0.125 mol%) loading of palladium, already at room temperature. Optimal reaction conditions were demonstrated by improving the synthesis process of the anticancer agent LY231514.
COBISS.SI-ID: 14359811