10.1021/jacs.9b07037.s003
Vincent Le Fouler
Vincent
Le Fouler
Yu Chen
Yu
Chen
Vincent Gandon
Vincent
Gandon
Vincent Bizet
Vincent
Bizet
Christophe Salomé
Christophe
Salomé
Thomas Fessard
Thomas
Fessard
Fang Liu
Fang
Liu
K. N. Houk
K. N.
Houk
Nicolas Blanchard
Nicolas
Blanchard
Activating
Pyrimidines by Pre-distortion for the General
Synthesis of 7‑Aza-indazoles from 2‑Hydrazonylpyrimidines
via Intramolecular Diels–Alder Reactions
American Chemical Society
2019
reaction conditions
transition-state-like geometry
cycloaddition strategy
Activating Pyrimidines
General Synthesis
Diel
hydrazonyl
group tolerance
2-
trifluoro
calculations show
unreactive partners
2019-09-09 16:50:30
Dataset
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.