Iron-Catalyzed
Synthesis of Conformationally Restricted
Bicyclic N‑Heterocycles via [2+2]-Cycloaddition: Exploring
Ring ExpansionMechanistic Insights and Challenges
posted on 2023-04-25, 13:03authored byLeif E. Hertwig, Thilo Bender, Felix J. Becker, Patrick Jäger, Serhiy Demeshko, Sophie Jana Gross, Joachim Ballmann, Dragoş-Adrian Roşca
We present an efficient iron-catalyzed method for synthesizing
conformationally restricted cyclobutane-fused N-heterocycles from
unactivated precursors. This method is orthogonal to the established
photocatalytic methods, extends the range of substrates, and provides
a single-step route to previously unattainable cyclobutane-fused piperidines
and azepanes. Ring stereochemistry depends on size, with five- and
six-membered rings adopting a cis configuration and seven-membered
rings preferring a trans configuration. A key aspect of this method
is the use of a catalyst design based on an electron-deficient, redox-active,
pyrimidinediimine scaffold. Mechanistic investigations suggest that
the π-acidic core significantly enhances catalyst stability
against deleterious intramolecular C–H activation pathways,
while the electron-rich flanking groups accelerate the reaction rate.
Mechanistic insights were obtained by extracting kinetic profiles
and establishing catalyst–activity relationships. Computational
studies established that the oxidative cyclization step proceeds with
the highest energy barrier, which is further confirmed by experimental
Hammett analysis.