Activating 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 only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonyl­pyrimidines, easily obtained in two steps from commercially available 2-halo­pyrimidines, can be exceptionally activated by trifluoro­acetylation. This allows a Diels–Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general and scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer’s Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N-trifluoro­acetylation of 2-hydrazonyl­pyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intra­molecular Diels–Alder cycloaddition.