Activating Pyrimidines by Pre-distortion for the General Synthesis of 7‑Aza-indazoles from 2‑Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions Vincent Le Fouler Yu Chen Vincent Gandon Vincent Bizet Christophe Salomé Thomas Fessard Fang Liu K. N. Houk Nicolas Blanchard 10.1021/jacs.9b07037.s003 https://acs.figshare.com/articles/dataset/Activating_Pyrimidines_by_Pre-distortion_for_the_General_Synthesis_of_7_Aza-indazoles_from_2_Hydrazonylpyrimidines_via_Intramolecular_Diels_Alder_Reactions/9786221 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 <i>N</i>-trifluoro­acetylation of 2-hydrazonyl­pyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intra­molecular Diels–Alder cycloaddition. 2019-09-09 16:50:30 reaction conditions transition-state-like geometry cycloaddition strategy Activating Pyrimidines General Synthesis Diel hydrazonyl group tolerance 2- trifluoro calculations show unreactive partners