Hydrogen Atom Transfer-Based C(sp3)–H Bond Oxygenation of Lactams and Cycloalkenes: The Influence of Ring Size on Reactivity and Site Selectivity

Abstract

Kinetic and product studies on the reactions of the cumyloxyl (CumO^•) and tert-butoxyl (tBuO^•) radicals with secondary and tertiary N-methyl and N-benzyl lactams and with cycloalkenes, accompanied by BDE calculations of the substrate C–H bonds involved in these reactions, are reported. Within the lactams, the rate constants for HAT (k_H) from the C–H bonds to CumO^• decrease by a factor ∼4 going from the 5- and 6-membered derivatives to the 8-membered ones. Product distributions obtained through oxygenation initiated by tBuO^• show that HAT preferentially occurs from the most electron-rich α-C–H bonds, with site selectivity that, within the N-methyl and N-benzyl series, progressively shifts from the endocyclic to the exocyclic α-C–H bonds with increasing ring size, indicative of deactivation of the former bonds that, for the 8-membered derivatives, translates into competitive oxygenation at different sites. Similar trends have been observed for the corresponding reactions of the cycloalkenes, with k_H values that decrease by a factor of ∼4 together with site selectivity for HAT from the activated allylic C–H bonds, going from cyclopentene to cyclooctene. It is proposed that the greater flexibility of the medium-sized rings decreases the extent of hyperconjugative overlap between the α-C–H bonds and the amide or C═C π-systems, increasing the kinetic barrier for HAT from these sites, with decreases in reactivity that approach factors of 83 and 18, for the endocyclic α-C–H bonds of tertiary N-methyl lactams and the allylic C–H bonds of cycloalkenes, respectively.