Highly Enantioselective Oxidation of Nonactivated Aliphatic C–H Bonds with Hydrogen Peroxide Catalyzed by Manganese Complexes

Abstract

Monosubstituted cycloalkanes undergo regio- and enantioselective aliphatic C–H oxidation with H2O2 catalyzed by biologically inspired manganese catalysts. The reaction furnishes the corresponding ketones resulting from oxidation at C3 and C4 methylenic sites (K3 and K4, respectively) leading to a chiral desymmetrization that proceeds with remarkable enantioselectivity (64% ee) but modest regioselectivity at C3 (K3/K4 ≈ 2) for tert-butylcyclohexane, and with up to 96% ee and exquisite regioselectity toward C3 (up to K3/K4 > 99) when N-cyclohexylalkanamides are employed as substrates. Efficient H2O2 activation, high yield, and highly enantioselective C–H oxidation rely on the synergistic cooperation of a sterically bulky manganese catalyst and an oxidatively robust alkanoic acid. This represents the first example of nonenzymatic highly enantioselective oxidation of nonactivated methylenic sites. Furthermore, the principles of catalyst design disclosed in this work constitute a unique platform for further development of stereoselective C–H oxidation reactions.

Supramolecular Recognition Allows Remote, Site‐Selective C−H Oxidation of Methylenic Sites in Linear Amines

“…2) The selectivity amplification does not derive from increased steric hindrance,s ince the bulky catalyst TIPS 2-Mn [18] affords the same selectivity pattern of 2-Mn (entry 8). 1) Addition of free BC does not modify the selectivity of the parent 2-Mn complex, indicating that substrate binding to BC does not affect its reactivity (entries 5-7).…”

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.…”

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes.…”

Chiral Manganese Aminopyridine Complexes: the Versatile Catalysts of Chemo‐ and Stereoselective Oxidations with H2O2

“…In the substrates they considered (monosubstituted cyclohexane derivatives, Scheme ), the prochiral center did not coincide with the reaction center, the latter being oxidized to the ketone without stopping at the first, hydroxylation, step. In effect, Mn aminopyridine complexes 19 and 20 (Figure ), showed 51–53 % yields and 43–44 % ee in t ‐butylcyclohexane ketonization at the 3 rd position . The best substrates for these catalysts were found to be amide‐substituted cyclohexanes (Scheme ), affording ketones with good yields (up to 85 %) and good to high ee ’s (62‐96 %) …”

“…The last decade has given birth to a new generation of manganese based catalysts, relying on aminopyridine ligands, that have exhibited excellent chemo‐ and stereoselectivity in the asymmetric epoxidation of olefins with “green” H 2 O 2 , and 10 1 ‐10 2 times higher efficiencies than Mn‐salen catalysts ,,. Moreover, it has been found that Mn aminopyridine complexes are capable of catalyzing the selective oxidation of non‐activated aliphatic and benzylic C‐H groups with H 2 O 2 ; very recently, the possibility to conduct these transformations in enantioselective fashion has been demonstrated ,. Reactions of this type hold a potential for the paradigm shift in the syntheses of complex organic molecules, taking into consideration the introduction of oxidized functionality at late steps of multistep syntheses …”