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. 2023 Nov 8;145(44):24021-24034.
doi: 10.1021/jacs.3c07163. Epub 2023 Oct 24.

Radical and Cationic Pathways in C(sp3)-H Bond Oxygenation by Dioxiranes of Bicyclic and Spirocyclic Hydrocarbons Bearing Cyclopropane Moieties

Marco Galeotti  1   2 , Woojin Lee  3 , Sergio Sisti  1 , Martina Casciotti  1 , Michela Salamone  1 , K N Houk  3 , Massimo Bietti  1
Affiliations

Radical and Cationic Pathways in C(sp3)-H Bond Oxygenation by Dioxiranes of Bicyclic and Spirocyclic Hydrocarbons Bearing Cyclopropane Moieties

Marco Galeotti et al. J Am Chem Soc. .

Abstract

A product and DFT computational study on the reactions of 3-ethyl-3-(trifluoromethyl)dioxirane (ETFDO) with bicyclic and spirocyclic hydrocarbons bearing cyclopropyl groups was carried out. With bicyclo[n.1.0]alkanes (n = 3-6), diastereoselective formation of the alcohol product derived from C2-H bond hydroxylation was observed, accompanied by smaller amounts of products derived from oxygenation at other sites. With 1-methylbicyclo[4.1.0]heptane, rearranged products were also observed in addition to the unrearranged products deriving from oxygenation at the most activated C2-H and C5-H bonds. With spiro[2.5]octane and 6-tert-butylspiro[2.5]octane, reaction with ETFDO occurred predominantly or exclusively at the axial C4-H to give unrearranged oxygenation products, accompanied by smaller amounts of rearranged bicyclo[4.2.0]octan-1-ols. The good to outstanding site-selectivities and diastereoselectivities are paralleled by the calculated activation free energies for the corresponding reaction pathways. Computations show that the σ* orbitals of the bicyclo[n.1.0]alkane cis or trans C2-H bonds and spiro[2.5]octanes axial C4-H bond hyperconjugatively interact with the Walsh orbitals of the cyclopropane ring, activating these bonds toward HAT to ETFDO. The detection of rearranged oxygenation products in the oxidation of 1-methylbicyclo[4.1.0]heptane, spiro[2.5]octane, and 6-tert-butylspiro[2.5]octane provides unambiguous evidence for the involvement of cationic intermediates in these reactions, representing the first examples on the operation of ET pathways in dioxirane-mediated C(sp3)-H bond oxygenations. Computations support these findings, showing that formation of cationic intermediates is associated with specific stabilizing hyperconjugative interactions between the incipient carbon radical and the cyclopropane C-C bonding orbitals that trigger ET to the incipient dioxirane derived 1,1,1-trifluoro-2-hydroxy-2-butoxyl radical.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Use of cyclopropyl containing substrates (a) to induce selectivity in HAT-based C–H bond functionalization procedures and (b) as mechanistic probes.
Scheme 1
Scheme 1. Results Obtained in the Oxidation of Spiro[2.5]octanes with H2O2 Catalyzed by [(S,S)-Mn(TIPSmcp)] (HFIP = 1,1,1,3,3,3-Hexafluoro-2-propanol)
Scheme 2
Scheme 2. Mechanism of C(sp3)–H Bond Oxidation by Dioxiranes
Figure 2
Figure 2
Structures of the substrates investigated in this work.
Scheme 3
Scheme 3. Oxygenation of Bicyclo[n.1.0]alkanes (n = 3–6) (S1–S5) Promoted by ETFDO
Scheme 4
Scheme 4. Oxygenation of 1,1-Dimethylcyclohexane (S6) and of Spiro[2.5]octanes (S7 and S8) Promoted by ETFDO
Scheme 5
Scheme 5. Oxygenation of cis-Bicyclo[4.1.0]heptan-2-ol (P2a-OH) and trans-Bicyclo[4.1.0]heptan-2-ol (P2b-OH)
Conversion and product yields were determined by GC and averaged over two independent experiments. (a) Reaction conditions: P2a-OH or P2b-OH 1 equiv, oxone 1 equiv, NaHCO3 4 equiv, 1,1,1-trifluoro-2-butanone 0.2 equiv, HFIP/H2O (3:1), Bu4NHSO4 0.05 equiv, T = 0 °C, 3 h. (b) P2a-OH 1 equiv, P2b-OH 1 equiv, oxone 1 equiv, NaHCO3 4 equiv, 1,1,1-trifluoro-2-butanone 0.2 equiv, HFIP/H2O (3:1), Bu4NHSO4 0.05 equiv, T = 0 °C, 6 h. rsm: recovered starting material.
Scheme 6
Scheme 6. Oxygenation of trans-6-tert-Butylspiro[2.5]octan-2-ol (P8a-OH) and cis-6-tert-Butylspiro[2.5]octan-2-ol (P8c-OH)
Conversion and product yields were determined by GC and averaged over two independent experiments. (a) Reaction conditions: P8a-OH or P8c-OH 1 equiv, oxone 1 equiv, NaHCO3 4 equiv, 1,1,1-trifluoro-2-butanone 0.2 equiv, HFIP/H2O (3:1), Bu4NHSO4 0.05 equiv, T = 0 °C, 3 h. (b) P8a-OH 1 equiv, P8c-OH 1 equiv, oxone 1 equiv, NaHCO3 4 equiv, 1,1,1-trifluoro-2-butanone 0.2 equiv, HFIP/H2O (3.0:1.0), Bu4NHSO4 0.05 equiv, T = 0 °C, 6 h. rsm: recovered starting material.
Figure 3
Figure 3
Difference in activation free energies (ΔΔG‡, in kcal mol–1) for HAT from the C2–H and C3–H bonds in S1, S2, S4, and S5 to ETFDO: computational and experimental studies.
Figure 4
Figure 4
Computed difference in activation free energies (ΔΔG‡, in kcal mol–1) for HAT from the C2–H and C5–H bonds in S3 to ETFDO.
Figure 5
Figure 5
Energetics (in kcal mol–1) of C–H bond oxidation of S3 promoted by ETFDO.
Figure 6
Figure 6
Difference in activation free energies (ΔΔG‡, in kcal mol–1) for HAT from the C–H bonds of S7 and S8 to ETFDO: computational and experimental studies.
Figure 7
Figure 7
Energetics (in kcal mol–1) of C–H bond oxidation of S8 by ETFDO.
Figure 8
Figure 8
Normalized site-selectivities and diastereoselectivities observed in the hydroxylation of bicyclo[n.1.0]alkanes S1, S2, S4, and S5 by ETFDO.
Scheme 7
Scheme 7. Groves Mechanism for the Oxygenation of S2 Promoted by Cytochrome P450 Enzymes
Scheme 8
Scheme 8. Proposed Mechanistic Pathways for the Oxygenation of S3 Promoted by ETFDO
For the sake of simplicity, only the pathways initiated by HAT from the cis C2–H and C5–H bonds are displayed.
Figure 9
Figure 9
(a) Charge distribution of S8-Int1 by CM5 and the electrostatic potential on a constant electron density surface. The regions of positive and negative potential are indicated in blue and red. (b) Spin density of the hypothetical triplet radical pair S8-Int1a. (c) In silico redox potentials of 1,1,1-trifluoro-2-hydroxybutoxy and 6-(tert-butyl)spiro[2.5]octan-4-yl radicals.
Scheme 9
Scheme 9. Proposed Mechanism for the Oxygenation of S8 Promoted by ETFDO.
Figure 10
Figure 10
Normalized site-selectivities observed in the oxygenation of 1,1-dimethylcylohexane (S6), spiro[2.5]octane (S7) and 6-tert-butylspiro[2.5]octane (S8) promoted by ETFDO.
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