Regioselectivity for the Rh(I)-catalyzed Annulation of 1,2,3-Thiadiazoles with Alkynes: Experimental and Computational Analysis Reveal the Surprising Role of the Alkyne Substituent

The Rh(I)-catalyzed denitrogenative annulation reactions of 1,2,3-thiadiazoles are a new direct approach to synthesizing densely functionalized heterocycles. The synthesis of multisubstituted thiophenes is possible using this methodology, however the difficulty to predict which regioisomer will form is a current limitation. In this current work, systematic computational and experimental studies were performed addressing how the terminal alkyne substituent effects regioselectivity. The data revealed that the electronic and steric properties of the alkyne substituent effects regioselectivity, including whether the group is aryl or alkyl. The insight gained from this study has allowed the development of a framework for predicting regioselectivity for the Rh(I)-catalyzed denitrogenative transannulation of 1,2,3-thiadiazoles with terminal alkynes. For the Rh(I)-catalyzed denitrogenative transannulation of 1,2,3-thiadiazoles with alkynes, the effect of the coupling partner (alkyne, alkene or nitrile), 1,2,3-thiadiazole substituent and ligand on regioselectivity has been previously reported. However, the role of the alkyne substituent has not been examined. This work reports systematic computational and experimental studies addressing how the terminal alkyne substituent effects regioselectivity, uncovering the role of both sterics and electronics.+image

Automated summary

The Rh(I)-catalyzed denitrogenative annulation reactions of 1,2,3-thiadiazoles provide a new approach for synthesizing densely functionalized heterocycles. This study investigates the effects of terminal alkyne substituents on regioselectivity, revealing the influence of electronic and steric properties. The findings contribute to the development of a predictive framework for the reaction's regioselectivity.