Energizing Listless Pyrimidines by Pre-Distortion for the General Synthesis of 7-Aza-Indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and usually only reactions under drastic conditions were historically reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines can be exceptionally activated by trifluoro acetylation. This allows a Diels-Alder cycloaddition under very mild conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general, scalable and has an excellent functional group tolerance. Quantum mechanical calculations show how the simple N-trifluoromethylation of 2-hydrazonylpyrimidines distorts the substrate into a transition state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.