Chemoselective Oxygenation at C(sp³)-H over C═C Bonds Guided by Polarity Enhancement

The selective oxidation of nonactivated C(sp³)-H bonds in the presence of olefinic sites is a nonsolved problem. Herein, the chemoselective oxygenation of α,β-unsaturated esters and diesters bearing remote C(sp³)-H bonds was studied through their reactions with H₂O₂ catalyzed by Mn complexes and with ethyl(trifluoromethyl)dioxirane (ETFDO), both in MeCN and in the strong hydrogen bond donor (HBD) fluorinated alcohols (R^FOHs) 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and nonafluoro-tert-butyl alcohol (NFTBA). In MeCN, reaction of linear and branched esters with the H₂O₂/Mn(^TIPSmcp) system delivered products deriving from remote oxygenation at tertiary or secondary C-H bonds, allylic ketonization, and C═C bond epoxidation. In NFTBA, selectivity for oxygenation at remote over proximal sites significantly increased, accompanied by a sharp decrease in the relative importance of the epoxidation pathway. Similar trends were observed with ETFDO where, however, epoxidation remained in most cases the predominant pathway and allylic oxygenation was never competing. These changes in chemoselectivity are rationalized in terms of a polarity enhancement effect via the electronic deactivation of the proximal sites imparted by the ester group coupled to solvent hydrogen bonding. Introduction of a dialkyl 2-methylenemalonate unit strongly impacted chemoselectivity, leading in R^FOHs to exclusive formation of oxygenation products at the most remote site, completely suppressing epoxidation and allylic ketonization. The use of this group, in combination with NFTBA and a benzimidazole-based catalyst Mn(^o,o-CF3bpebpdp), enabled, moreover, the exclusive hydroxylation at remote primary C-H bonds. Because 2-methylenemalonate units can be easily introduced on aldehyde functionalities and then transformed into α,β-unsaturated carboxylic acids, careful control over chemoselectivity obtained through their use in combination with R^FOHs provides a powerful strategy to be exploited in synthetically useful procedures.