Coupling is a reaction in which two reactants covalently combine to form a new compound. The palladium-catalyzed coupling of a terminal alkyne with an aryl halide to form a disubstituted alkyne, known as the copper-free Sonogashira reaction, is one of the most important synthetic methods for the industrial production of many materials indispensable in everyday life. We have recently found that this reaction proceeds via a bicyclic mechanism in which two different types of palladium are responsible for the activation of each reactant (Nature Communications 2018, 9, 4814). In this work, we have used a systematic analytical approach to define the two species of palladium that are simultaneously optimal for the activation of each reactant, do not interfere with each other, productively participate in the key step of product formation, and then return to the reactant activation step. One of the key palladium species was based on pyridine-functionalized 1,2,3-triazol-5-ylidene-N-heterocyclic carbene ligand (Py-tzNHC). Such a defined system enabled the coupling of a wide range of reactants, including those traditionally considered non-reactive, with enviably low palladium loadings. Optimal reaction conditions were demonstrated by improving the synthesis process of the anticancer agent LY231514. This work is a practical application of theoretical knowledge, conceptually a completely new way of carrying out the Sonogashira reaction, which now allows a much more ecologically and economically advantageous synthesis. The article was highlighted by the editors of Organic Letters with a cover illustration in the issue in which it was published (https://pubs.acs.org/toc/orlef7/22/13). It was among the 20 most-read articles in the journal in May, June, July, and August 2020, and among the 20 most-read articles in the journal in the preceding 12 months. The Editor of Organic Letters, Dr. Margaret Faul, who led the review process, nominated the article for the "Organic Letters Publication of the Year award.
COBISS.SI-ID: 14359811
Ligands that provide additional functions beyond their traditional spectator roles are becoming increasingly important in transition metal catalysis. Palladium complex with bidentate Py-tzNHC ligands exhibited exceptional catalytic activity in the carbon nitrogen bond formation, in the hydroamination of acetylenes. The reaction proceeded in the absence of an external base, at room temperature and with complete selectivity, reaching high yields of the products. The method thus developed afforded facile preparation of imines, an important group of building blocks and intermediates in organic synthesis. Additionally, the key intrinsic feature of the catalyst is the pyridine wingtip that is confined to the proximity of the alkynophilic metal active site and forms a catalytic pocket. It was demonstrated through a combined experimental and computational study that this pyridine wingtip actively participates in the reaction mechanism. It assists in the entropically favored proton transfers, which mimics the function of enzyme-like architectures and acts as an internal base. It is a proof of an unprecedented catalytic mode employing tzNHC ligands, demonstrating an active role of the pyridine dent that can also catalyze the crucial reaction steps in addition to stabilizing the metal center. A special recognition was given to the work of the magazine by presenting it with a cover graphic illustration (https://pubs.acs.org/toc/orlef7/22/6).
COBISS.SI-ID: 1538522051
Understanding reaction mechanisms is a cornerstone in the chemical sciences, enabling rational design and optimization of chemical processes. Palladium-catalyzed arylation of terminal acetylenes enables the efficient synthesis of many important natural products and compounds of pharmaceutical or agrochemical significance. Despite the enormous success of this cross-coupling reaction, which has lasted nearly half a century, critical mechanistic questions have remained unresolved. We have found that this reaction proceeds via the so-called bicyclic mechanism rather than the previously erroneously proposed monocyclic mechanism. This has been supported experimentally by the identification of reaction intermediates using state-of-the-art nuclear magnetic resonance spectroscopy and mass spectrometry, as well as kinetic studies. This work will contribute to the knowledge of metal-catalyzed reactions in general, with beneficial economic and environmental implications in relevant industrial chemical processes. The basis for this work was the understanding of the Sonogashira reaction catalyzed by a pyridine-functionalized 1,2,3-triazol-5-ylidene-N-heterocyclic carbene ligand (Py-tzNHC), which later led to the paper entitled "Designing Homogeneous Copper-Free Sonogashira Reaction through a Prism of Pd–Pd Transmetalation" published by B.A. Martek, M. Gazvoda, D. Urankar, J. Košmrlj in Org. Lett. 2020, 22, 4938-4943. The editors of Nature Communications selected this work for the Organic Chemistry and Chemical Biology Editors' Highlights. Award: Scientific Board of the Slovenian Research Agency (ARRS) for the field Natural Sciences selected the publication among the choices of Excellent in Science for 2018; http://www.arrs.si/en/gradivo/dokum/inc/19/ARRS-LP-18- ENG.pdf.
COBISS.SI-ID: 1538034627
A series of cationic chlorido arene-iridium(III) and arene-osmium(II) complexes with bidentate pyridyl functionalized mesoionic carbenes (MIC) of the 1,2,3-triazol-5-ylidene type have been prepared. The variations in the ligand structures include the position of the pyridyl substituent relative to the triazolylidene ring (N-wingtip vs C-wingtip), phenyl versus ethyl substituents, and incorporation of several functional groups at the phenyl substituents. Five complexes have been characterized by X-ray structural analysis. All complexes, including osmium(II) and ruthenium(II) analogues having a pyrimidyl in place of the pyridyl group, have been studied for their cytotoxic activity on a human cervical carcinoma HeLa cell line. Two of the compounds were the most cytotoxic with IC50 values of 7.33 µM and 2.01 µM. Examination of their cytotoxic effect on different cell lines revealed that they preferentially kill cancer over normal cells. The role of glutathione (GSH) in the protection of cells against the cytotoxicity was investigated. We were the first to show that complexes of some transition metals with pyridine-functionalized 1,2,3-triazol-5-ylidene-N-heterocyclic carbene ligands (Py-tzNHC) have the potential to develop new antitumor agents. A special recognition was given to the work of the magazine by presenting it with a cover graphic illustration (https://pubs.acs.org/toc/orgnd7/38/21). Listed among the journal's top "20 Most read articles in November and December 2019"
COBISS.SI-ID: 1538414787
We have developed a mild, simple, efficient and environmentally friendly method for the synthesis of stable aromatic and heteroaromatic diazonium salts. Aromatic diazonium salts serve as starting compounds in various synthetic methods, such as Sandmayer, Gomber-Bachman, Balz-Schiemann and Meerwein reaction. In addition, diazonium salts are becoming increasingly important as starting compounds for cross-coupling reactions. In the traditional method for the preparation of diazonium salts, the reaction between aniline, hydrochloric acid and sodium nitrite at a temperature of 0 °C, the diazonium salts formed cannot be isolated and must be used in situ for further reactions. One of the main problems with diazonium salts is their instability, since in isolated form they may even decompose explosively under normal conditions, as recently pointed out in Editorial in Org. Lett. 2020, 22, 7057-7059 (https://dx.doi.org/10.1021/acs.orglett.0c02685). We have developed an efficient method for the synthesis of diazonium p-toluenesulfonates that are stable for more than one year even in isolated form at room temperature. The reaction involves the use of tert-butyl nitrite as a cheap and simple nitrogen source and is carried out in a "green solvent", ethyl acetate, at room temperature. Diazonium p-toluenesulfonates will be tested in palladium complex coupling reactions with the pyridine-functionalized 1,2,3-triazol-5-ylidene-N-heterocyclic carbene ligands (Py-tzNHC) developed within this project.
COBISS.SI-ID: 26340867