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