Amine Organocatalysis of Remote, Chemoselective C(sp³)–H Hydroxylation

Abstract

We introduce an organocatalytic approach for oxaziridinium-mediated C–H hydroxylation that employs secondary amines as catalysts. We also demonstrate the advantages of this operationally simple catalytic strategy for achieving high yielding and highly selective remote hydroxylation of compounds bearing oxidation-sensitive functional groups such as alcohols, ethers, carbamates, and amides. By employing hexafluoroisopropanol as the solvent in the absence of water, a proposed hydrogen-bonding effect leads to, among other advantages, as high as ≥99:1 chemoselectivity for remote aliphatic hydroxylation of 2° alcohols, an otherwise unsolved synthetic challenge normally complicated by substantial amounts of alcohol oxidation. Initial studies of the reaction mechanism indicate the formation of an oxaziridinium salt as the active oxidant and a C–H oxidation step that proceeds in a stereospecific manner via concerted insertion or hydrogen atom-transfer/radical rebound. Furthermore, preliminary results indicate that site selectivity can be affected by amine catalyst structure.

Hydrogen Bonding-Assisted and Nonheme Manganese-Catalyzed Remote Hydroxylation of C–H Bonds in Nitrogen-Containing Molecules

“…Inspired by the SCS hydrogen bonding in metallooxygenases (Figure C), , and encouraged by hydrogen bond donor solvents in oxidation catalysis, − we envisioned that SCS hydrogen bonding between the hydrogen bond donor solvent and the basic nitrogen atom would not only protect the nonheme manganese catalyst from arrest but also deactivate the basic nitrogen atom toward oxygen atom transfer (OAT) and the α-C­(sp 3 )–H bonds adjacent to nitrogen center toward H-atom abstraction (HAA) by electrophilic oxidant, thus addressing the challenges from catalyst deactivation and competitive nitrogen oxidation and C­(sp 3 )–H oxidation mediated by highly electrophilic high-valent metal–oxo intermediates (Figure D). We report herein an SCS solvent hydrogen bonding strategy to realize the remote and nonactivated C­(sp 3 )–H hydroxylation in the presence of basic N -heteroaromatics with low loadings of a simple nonheme manganese complex as catalyst and aqueous H 2 O 2 as a terminal oxidant (Figure D).…”

Selective Hydroxylation of C(sp3)−H Bonds in Steroids

“…The selectivity might be partly due to the hydrophobic effects of the activated iminium salt catalysts and their preference for aliphatic C−H oxidation over alcohol oxidation, an example of hydrophobically‐directed selectivity as described by Breslow [184] . Further explanation for the selectivity comes from Bronsted acidity of HFIP leading to polarity reversal of the C3β−OH, as has been observed in other oxaziridinium and high valent metal‐oxo mediated processes, leading to deactivation of this centre towards oxidation [185,186] …”

“…[184] Further explanation for the selectivity comes from Bronsted acidity of HFIP leading to polarity reversal of the C3βÀ OH, as has been observed in other oxaziridinium and high valent metal-oxo mediated processes, leading to deactivation of this centre towards oxidation. [185,186] Dioxiranes have a long history of use for steroid CÀ H hydroxylation. They still offer a good choice in terms of yield and can be an economical option.…”

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

“…The method for selective remote CH-hydroxylation involving unactivated C(sp 3 )-H bonds employing oxaziridinium organocatalysis was developed recently [138]. The advantage of this method is the compatibility with secondary alcohol groups, which are not oxidized and can be used as a directing moiety.…”