A predictive chemistry DFT study of N2O functionalization for the preparation of triazolopyridine and triazoloquinoline scaffolds

The functionalization of molecules by N2O, which can transfer oxygen or nitrogen, is a challenging but fundamental task to counteract the greenhouse effect. Here, we disclose mechanistic insights by means of DFT calculations into the synthesis of triazolopyridine and triazoloquinoline scaffolds by dinitrogen transfer from N2O. The calculations indicate that the rate-determining step of such a transformation is hydrogen transfer from the previously metalated 2-alkylpyridine unit to the oxygen of the attached nitrous oxide species to yield an intermediate diazo species. Theoretical calculations also show a direct correlation between the product yield for the studied transformation and the energy barrier of the rate-determining step. As a further step we used predictive chemistry to assess the feasibility of the preparation of triazolopyrazine, triazolopyridazine, triazolopyridimidine and triazolotriazine scaffolds by means of applying the reported methodology to the diazine and triazine family of heterocycles. Finally, we assessed the feasibility of the preparation of sulfur- and oxygen-containing diazo species, potential useful substrates to access (2-furyl)- and (2-thienyl)carbene derivatives.

Automated summary

This study provides mechanistic insights into the functionalization of molecules by N2O through DFT calculations. The rate-determining step of transferring nitrogen or oxygen from N2O to synthesize target structures is revealed. Theoretical calculations show a correlation between the product yield and the energy barrier of the rate-determining step, as well as the potential application of predictive chemistry in the preparation of related compounds.