Chemoselective Aliphatic C–H Bond Oxidation Enabled by Polarity Reversal

Abstract

Methods for selective oxidation of aliphatic C–H bonds are called on to revolutionize organic synthesis by providing novel and more efficient paths. Realization of this goal requires the discovery of mechanisms that can alter in a predictable manner the innate reactivity of these bonds. Ideally, these mechanisms need to make oxidation of aliphatic C–H bonds, which are recognized as relatively inert, compatible with the presence of electron rich functional groups that are highly susceptible to oxidation. Furthermore, predictable modification of the relative reactivity of different C–H bonds within a molecule would enable rapid diversification of the resulting oxidation products. Herein we show that by engaging in hydrogen bonding, fluorinated alcohols exert a polarity reversal on electron rich functional groups, directing iron and manganese catalyzed oxidation toward a priori stronger and unactivated C–H bonds. As a result, selective hydroxylation of methylenic sites in hydrocarbons and remote aliphatic C–H oxidation of otherwise sensitive alcohol, ether, amide, and amine substrates is achieved employing aqueous hydrogen peroxide as oxidant. Oxidations occur in a predictable manner, with outstanding levels of product chemoselectivity, preserving the first-formed hydroxylation product, thus representing an extremely valuable tool for synthetic planning and development.

Activation and Deactivation Strategies Promoted by Medium Effects for Selective Aliphatic C−H Bond Functionalization

“…[5,15,49,63] As described in Scheme 32, nitrogen protonation deactivates the proximal secondary C À H bonds toward oxidation by electrophilic HATreagents.T he decylammonium ion was selected as the model substrate and the effect of different catalysts on oxidation was investigated. [5,15,49,63] As described in Scheme 32, nitrogen protonation deactivates the proximal secondary C À H bonds toward oxidation by electrophilic HATreagents.T he decylammonium ion was selected as the model substrate and the effect of different catalysts on oxidation was investigated.…”

“…[49] By employing hydrogen peroxide as the oxidant and 0.5-1.0 mol %o fa n iron or manganese catalyst (Scheme 17), good product yields and excellent selectivity for the alcohol products over the corresponding ketones were achieved when the reaction was carried out in fluorinated alcohols such as TFE and HFIP. [49] By employing hydrogen peroxide as the oxidant and 0.5-1.0 mol %o fa n iron or manganese catalyst (Scheme 17), good product yields and excellent selectivity for the alcohol products over the corresponding ketones were achieved when the reaction was carried out in fluorinated alcohols such as TFE and HFIP.…”

“…[49] Along this line,t he best results for the oxidation of propylbenzene were obtained in TFE by employing 2-ethylhexanoic acid (2-eha) in combination with the Mn( dMM pdp) or Mn( Me2N pdp) catalyst and H 2 O 2 at T = À35 8 8C. [49] Along this line,t he best results for the oxidation of propylbenzene were obtained in TFE by employing 2-ethylhexanoic acid (2-eha) in combination with the Mn( dMM pdp) or Mn( Me2N pdp) catalyst and H 2 O 2 at T = À35 8 8C.…”

“…[49] Illustrative examples on the oxidation of alcohols and ethers bearing remote secondary,t ertiary,a nd benzylic CÀHb onds with H 2 O 2 catalyzed by Mn( TIPS mcp) are displayed in Scheme 21, where the product distributions observed in MeCN (blue) and HFIP (red) are compared. This study showed that hydrogen bonding of the solvent to the HBAfunctional group strongly deactivates the a-C À Hbonds and promotes selective functionalization of remote unactivated C À Hb onds.…”

“…[49] In MeCN,the product derived from the hydrox-ylation of the most activated a-C À Hb ond was isolated in 65 %y ield and with excellent selectivity (65:1) over the product derived from hydroxylation of aremote tertiary CÀH bond (Scheme 22). [49] In MeCN,the product derived from the hydrox-ylation of the most activated a-C À Hb ond was isolated in 65 %y ield and with excellent selectivity (65:1) over the product derived from hydroxylation of aremote tertiary CÀH bond (Scheme 22).…”