Bio-inspired iron-catalyzed oxidation of alkylarenes enables late-stage oxidation of complex methylarenes to arylaldehydes

Abstract

It is a long-standing challenge to achieve efficient and highly selective aerobic oxidation of methylarenes to benzaldehydes, owing to overoxidation problem stemming from the oxidizability of benzaldehyde far higher than the toluene under usual aerobic conditions. Herein we report a bio-inspired iron-catalyzed polymethylhydrosiloxane-promoted aerobic oxidation of methylarenes to benzaldehydes with high yields and selectivities. Notably, this method can tolerate oxidation-labile and reactive boronic acid group, which is normally required to be transformed immediately after its introduction, and represents a significant advance in the area of the chemistry of organoboronic acids, including the ability to incorporate both aldehyde and ketone functionalities into unprotected arylboronic acids, a class that can be difficult to access by current means. The robustness of this protocol is demonstrated on the late-stage oxidation of complex bioactive molecules, including dehydroabietic acid, Gemfibrozil, Tocopherol nicotinate, a complex polyol structure, and structurally complex arylboronic acids.

Fig. 1

Biocatalysis and biomimetic oxidation of hydrocarbons. a Biocatalysis: cytochrome P-450 cycle driven by a reductase or bioreductant. b This work: biomimetic iron catalysis

Fig. 2

Iron-catalyzed oxidations of methyl aromatics and other alkyl aromatics. The substrate scope of methyl aromatics and other alkyl aromatics. Reaction conditions: substrate 1 or 3 (0.25 mmol), ferrocene (10 mol%), Fe(II) phthalocyanine (1 mol%), K₂S₂O₈ (0.25 mmol), PMHS (0.75 mmol), CH₃CN/H₂O (1:1, 2.0 mL), 80 °C, and air; Yields of the isolated products are given. ^aBased on ¹H NMR analysis on the crude reaction mixture with chlorobenzene as the internal standard. ^bK₂S₂O₈ (0.75 mmol)

Fig. 3

Substrate scope. The substrate scope of alkyl arylboronic acids and potassium methyl aryltrifluoroborates. Reaction conditions: substrate 5 (0.25 mmol), FeCl₂ (10 mol%), TBAB (50 mol%), K₂S₂O₈ (0.25 mmol), PMHS (0.75 mmol), CH₃CN/H₂O (1:1, 2.0 mL), 80 °C, and air; yields of the isolated products are given. ^aBased on ¹H NMR analysis

Fig. 4

Late-stage oxidation of complex molecules. a Oxidation of 7a and 7b; b Oxidation of 7c; c Oxidation of 7d; d Oxidation of 7e; e Oxidation of 7f; f Oxidation of 7g; g Oxidation of 7h; h Oxidation of 7i; i Oxidation of 7j. Reported yields are for the isolated products. Reaction conditions: substrate 7 (0.25 mmol), ferrocene (10 mol%), Fe(II) phthalocyanine (1 mol%), K₂S₂O₈ (0.25 mmol), PMHS (0.75 mmol), CH₃CN/H₂O (1:1, 2.0 mL), 80 °C, and air; RSM recovered starting material. ^aK₂S₂O₈ (0.75 mmol). ^bSubstrate (0.25 mmol), FeCl₂ (10 mol%), TBAB (0.5 equiv), K₂S₂O₈ (0.25 mmol), PMHS (3.0 equiv), CH₃CN/H₂O (1:1), 90 °C, O₂ (1 atm)

Fig. 5

Proposed mechanistic cycle. This reaction begins with the oxidation of Fe(II) by persulfate to generate the Fe(III) species and the sulfate radical anion I that reacts with alkylarene by single electron transfer (SET) to produce the alkylaromatic radical cation II

Fig. 6

Mechanistic experiments. a Probation for the presence of aromantic radical cation in the catalytic system. b Comparison of the reactivity between methyl and isopropyl groups in the catalytic system. c Intermolecular kinetic isotope effect. d Radical capture experiment. e Control experiments proving the reducing property of PMHS in the catalytic system

Fig. 7

Control experiments for probing the unique chemoselectivity for aldehydes. a ¹H NMR monitoring the potential intermediates of the model reaction. b The reaction using benzoic acid as a substrate. c The effect of PMHS on the oxidation of 2n; RSM recovered starting material. d Competition experiments between toluene (1a) and benzaldehyde (2a) in the presence of K₂S₂O₈ and the iron catalyst with and without PMHS