Study of the Mechanism of 7‐exo‐trig Cyclizations of Aryl, Vinyl, and Alkyl Radicals on Oxime Ethers

• Published in: European journal of organic chemistry 2024-02, Vol.27 (7), p.n/a
• Main Authors: Bejarano, Carlos A., Díaz, John E., Camacho, Jairo, Flores‐Bernal, Gustavo G., Miranda, Luis D., Mejía, Sol M., Loaiza, Alix E.
• Format: Article
• Language: English
• Subjects: 7-exo-trig radical cyclizations; Aromatic compounds; Bromination; Chemical reactions; Competition experiments; DFT; Ethers; Exothermic reactions; Mathematical analysis; Oxime ether; Rate constants; Reduction
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202301148

In this work, we conducted a study of 7‐exo‐trig cyclizations mechanism involving aryl, vinyl, and alkyl radicals on oxime ethers. Initially, the reaction of brominated oxime ether 9 a with (TMS)3SiH and AIBN gave rise to aryl radicals that underwent a 7‐exo‐trig cyclization on the oxime ether, yielding dibenzoxepine 10 a, and the ipso reaction and reduction products were obtained as well. Approximate rate constants at 80 °C for the 7‐exo‐trig (1.0×108 s−1) and the ipso cyclization (4.3×107 s−1) were determined by competition experiments. DFT calculations showed good agreement with the experimental results. The reduction rate constant of the N‐alkoxyaminyl radical with (TMS)3SiH was calculated to be 4.1×10−1 M−1 s−1; while the rate constants for the 7‐exo‐trig cyclizations of vinyl and alkyl radicals on the oxime ether were estimated in the ranges of 106 s−1–108 s−1 and 103 s−1–108 s−1, respectively. The 7‐exo‐trig cyclization reactions involving aryl, vinyl, and alkyl radicals with oxime ethers were found to be an exothermic and irreversible process, with the oximic carbon showing a preference for nucleophilic alkyl radicals. This kinetic study contributes to the deeper understanding of radical‐mediated cyclizations, enabling the efficient design of complex synthetic routes. Our research combines experimental techniques and DFT calculations to investigate the mechanism of 7‐exo‐trig cyclization of aryl, vinyl, and alkyl radicals on oxime ethers. These cyclization processes are exothermic and irreversible, showing a preference for nucleophilic alkyl radicals. The high cyclization rate constants (103–108 s−1) highlight the synthetic potential of these reactions for constructing seven‐membered carbocyclic and heterocyclic systems.