Journal
ACS CATALYSIS
Volume 13, Issue 9, Pages 6416-6429Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.3c01305
Keywords
bioisosteres; cyclobutanes; [2+2]-cycloaddition; redox-active ligands; kinetics
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We present an efficient iron-catalyzed method for synthesizing conformationally restricted cyclobutane-fused N heterocycles. This method extends the range of substrates and provides a single-step route to previously unattainable cyclobutane-fused piperidines and azepanes. Mechanistic investigations suggest that the catalyst design based on an electron-deficient, redoxactive, pyrimidinediimine scaffold enhances catalyst stability and reaction rate.
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, redoxactive, pyrimidinediimine scaffold. Mechanistic investigations suggest that the pi-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.
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