Resolving Oxygenation Pathways in Manganese-Catalyzed C(sp3)-H Functionalization via Radical and Cationic Intermediates

Abstract

The C(sp³)-H bond oxygenation of the cyclopropane-containing mechanistic probes 6-tert-butylspiro[2.5]octane and spiro[2.5]octane with hydrogen peroxide catalyzed by manganese complexes bearing aminopyridine tetradentate ligands has been studied. Mixtures of unrearranged and rearranged oxygenation products (alcohols, ketones, and esters) are obtained, suggesting the involvement of cationic intermediates and the contribution of different pathways following the initial hydrogen atom transfer-based C-H bond cleavage step. Despite such a complex mechanistic scenario, a judicious choice of the catalyst structure and reaction conditions (solvent, temperature, and carboxylic acid) could be employed to resolve these oxygenation pathways, leading, with the former substrate, to conditions where a single unrearranged or rearranged product is obtained in good isolated yield. Taken together, the work demonstrates an unprecedented ability to precisely direct the chemoselectivity of the C-H oxidation reaction, discriminating among multiple pathways. In addition, these results conclusively demonstrate that stereospecific C(sp³)-H oxidation can take place via a cationic intermediate and that this path can become exclusive in governing product formation, expanding the available toolbox of aliphatic C-H bond oxygenations. The implications of these findings are discussed in the framework of the development of synthetically useful C-H functionalization procedures and the associated mechanistic features.

Scheme 1. Mechanisms of Enzymatic C–H Oxidation by High-Valent Fe(V)=O Species

Figure 1

(a) Use of cyclopropane-containing hydrocarbons as mechanistic probes; (b) use of 6-tert-butylspiro[2.5]octane as a substrate to resolve the oxygenation pathways of Mn-catalyzed C–H oxygenation.

Scheme 2. Oxidation of S1

Reaction conditions: [Mn(OTf)₂(^TIPSmcp)] 1 mol %, H₂O₂ 3.5 equiv, AcOH 15 equiv, MeCN, 0 °C, 30 min. Catalyst enantiomers were used interchangeably.

Scheme 3. Oxidation of S1 Using Different Carboxylic Acids

Pie charts refer to product selectivities and adjacent small circles to normalized product ratios. Reaction conditions: (a) [Mn(OTf)₂(^TIPSmcp)] 1 mol %, H₂O₂ 3.5 equiv, RCO₂H 15 equiv, MeCN, 0 °C, 30 min. (b) [Mn(OTf)₂(^Me2Npdp)] 1 mol %, H₂O₂ 2.5 equiv, RCO₂H 15 equiv, MeCN, 0 °C, 30 min. ^aCatalyst enantiomers were used interchangeably. ^b[Mn(OTf)₂(^TIPSmcp)] 5 mol %, H₂O₂ 5 equiv, Phth-Tle-OH 1.0 equiv. Addition of [Mn(OTf)₂(^TIPSmcp)] 5 mol % and Phth-Tle-OH 1.0 equiv after 10 and 20 min. ^cPhth-Tle-OH 1.0 equiv, H₂O₂ 3.5 equiv. ^dIsolated yield.

Scheme 4. Oxidation of S1 at Different Temperatures and in Different Solvents

Pie charts refer to product selectivities and adjacent small circles to normalized product ratios. Reaction conditions: (a) [Mn(OTf)₂(^TIPSmcp)] 1 mol %, H₂O₂ 1.5 equiv, AcOH 15 equiv, HFIP, 0 or 25 °C, 30 min. (b) [Mn(OTf)₂(^TIPSmcp)] 1 mol %, H₂O₂ 1.5 equiv, HFIP, 0 or 25 °C, 30 min. (c) [Mn(OTf)₂(^Me2Npdp)] 1 mol %, H₂O₂ 1.0 equiv, HFIP or NFTBA, 0 °C, 30 min. ^aCatalyst enantiomers were used interchangeably. ^b8% yield of P1a-OH and 3% yield of P1-O. ^cAc-Gly-OH 3 mol %. ^dIsolated yield. ^e1.5 equiv of H₂O₂.

Scheme 5. Oxidation of S2

Pie charts refer to product selectivities and adjacent small circles to normalized product ratios. Reaction conditions: (a) [Mn(OTf)₂(^Me2Npdp)] 1 mol %, H₂O₂ 3.5 equiv, Phth-Tle-OH 1.0 equiv, MeCN, 0 °C, 30 min. (b) [Mn(OTf)₂(^TIPSpdp)] 1 mol %, H₂O₂ 1.5 equiv, AcOH 15 equiv, HFIP, 25 °C, 30 min. (c) [Mn(OTf)₂(^TIPSpdp)] 1 mol %, H₂O₂ 1.5 equiv, Ac-Gly-OH 3 mol %, HFIP, 25 °C, 30 min. (d) [Mn(OTf)₂(^Me2Npdp)] 1 mol %, H₂O₂ 1.5 equiv, NFTBA, 0 °C, 30 min. ^aFormation of P2-O as the exclusive oxidation product at C-4. ^bFormation of P2a-OH as the exclusive oxidation product at C-4.

Figure 2

Origin of the observed diastereoselectivity in the formation of the unrearranged products in the oxidation of S1.

Scheme 6. Proposed Mechanism for the Oxidation of S1

Scheme 7. Oxidation of S1 by Different Mn Catalysts

Reaction conditions: Mn cat 1 mol %, H₂O₂ 1.5 equiv, PivOH 15 equiv, HFIP, 25 °C, 30 min. ^aCatalyst structures are displayed in the Supporting Information (Figure S1). ^bH₂O₂ 0.5 equiv.

Scheme 8. Oxidation of S1 in the Presence of H₂¹⁸O₂ (80% Enriched in ¹⁸O) and Piv¹⁶OH

Reaction conditions: [Mn(OTf)₂(^TIPSmcp)] 1 mol %, H₂¹⁸O₂ 0.1 equiv, Piv¹⁶OH 15 equiv, HFIP, 0 °C, 30 min. The labeling experiment was analyzed using GC–MS analysis via chemical ionization with NH₃/NH₄. The reported ¹⁸O incorporations were obtained after correction for the isotopic purity of the labeled reactant.