Iron-Catalyzed Synthesis of Conformationally Restricted Bicyclic N‑Heterocycles via [2+2]-Cycloaddition: Exploring Ring ExpansionMechanistic Insights and Challenges

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.