The functionalization of nitrous oxide for the synthesis of triazolopyridines and triazoloquinolines, which are useful building blocks for heterocycle synthesis, was reported by Severin et al. in 2021.[1] The reaction was performed in two steps: the first consisting of the lithiation of 2-alkylpyridine and 2-alkylquinoline derivatives, and the second one involving nitrous oxide for its functionalization to triazolopyridine and triazoloquinoline scaffolds. In the present study, the whole reaction mechanism of the functionalization of nitrous oxide for the synthesis of triazolopyridine and triazoloquinoline scaffolds has been unveiled by means of DFT calculations. The rate determining step of such transformation is found to be the hydrogen transfer from the former carbanion to the oxygen of the nitrous oxide species to yield the intermediate diazo species, being this able to cyclize to the final desired scaffold. Theoretical calculations also show the direct correlation between the product yield for the studied transformation and the energy barrier of the rate determining step. Moreover, the mechanism for the reaction of trans-1,2-di(pyridyl)ethylene with alkylithium reagents and the formation of ester-functionalized triazolopyridines were also unveiled showing a similar profile. We also predict the feasibility of the preparation of 2 and 3-nitrogen containing scaffolds by means of the reported methodology, as well as sulfur and oxygen-containing diazo species.

[1] Landman, I. R.; Faradei-Tirani, F.; Severin, K. Nitrous oxide as a diazo transfer reagent: the synthesis of triazolopyridines. Chem. Commun. 2021, 57, 11537–11540.