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.