Development of Rh(I)-catalyzed denitrogenative transformations of 1,2,3-thiadiazoles

Presented herein are a series of studies designed to increase the fundamental understanding, and expand the application in heterocyclic synthesis, of the Rh(I)-catalyzed denitrogenative transformations of 1,2,3-thiadiazoles − a new class of reactions within the metal-catalyzed denitrogenative annulation approach. There is a particular focus on the use of experimental and theoretical mechanistic studies to reveal the main reaction trends.

Firstly, a range of new structurally diverse 4-vinyl-1,2,3 thiadiazoles was synthesized via Knoevenagel condensation and fully characterized. The ability of new vinylic derivatives to undergo dimerization was observed, allowing the first 1,2,3-thiadiazole substituted cyclobutane to be isolated. Along with that, simple and convenient methods for the synthesis of new 1,2,3-thiadiazole derivatives, including ethyl esters, alcohols, and aldehydes, were developed.

Secondly, the synthesized 4-vinyl-1,2,3-thiadiazoles were utilized to develop new ligandcontrolled Rh(I)-catalyzed denitrogenative transformations. It was demonstrated that in the presence of [Rh(COD)2]BF4, 1,2,3-thiadiazoles possessing electron-donating substituents at the C5-position of the heterocycle undergo an intramolecular transannulation reaction to afford substituted furans. In contrast, the [Rh(COD)DPPF]BF4 catalytic system inhibits the intramolecular reaction but promotes intermolecular transannulation with both electron-deficient and electron-rich terminal alkynes, providing access to densely functionalized thiophenes with unexpected regioselectivity.

Experimental and computational mechanistic studies were performed to gain insights into the origin of ligand-controlled reactivity of vinylic 1,2,3-thiadiazoles, with a focus on understanding the influence of the substrate structure and the role of the DPPF ligand on the reaction outcome. Additionally, our crystallographic data uncovered that the true structure of the organorhodium intermediate involved in Rh(I)-catalyzed denitrogenative reactions of 1,2,3-thiadiazoles is likely to be a four-membered cyclometalated Rh(III) complex. The catalytic activity of the isolated complex was supported experimentally.

Lastly, systematic studies on the reactivity and regioselectivity in the Rh(I)-catalyzed intermolecular transannulation between a range of substituted 1,2,3-thiadiazoles and phenylacetylene have been conducted. Our experimental data revealed that the electronic nature of the C5-substituent on the 1,2,3-thiadiazole ring influenced reactivity significantly. Moreover, the substituent was shown to have a remarkable effect on the regioselectivity of the reaction, with electron-donating and small groups leading to 2,3,4-substituted thiophenes and strong electron-withdrawing or sterically demanding substituents favouring the 2,3,5-substituted products. Identified experimental trends have been supported and rationalized using density functional theory calculations. In addition, the influence of the C5-substituent on the 1,2,3-thiadiazole ring was also examined for the transannulation with benzonitrile and styrene.

The presented findings have contributed significantly to the fundamental understanding of the transition-metal-catalyzed denitrogenative reactions of 1,2,3-thiadiazoles and will allow for the rational design and application of new, synthetically powerful denitrogenative reactions of compounds that feature a 1,2,3-thiadiazole core. In addition, the wide range of new thiadiazole derivatives synthesized in this current work is anticipated to be of interest for biological screening and further development of new synthetic methods using the diverse reactivity of the 1,2,3-thiadiazole structural motif.