Selective C–H bond electro-oxidation of benzylic acetates and alcohols to benzaldehydes

Barone, Mateus R.; Jones, Alan M.

doi:10.1039/c7ob02300f

Cited by 19 publications

(21 citation statements)

References 41 publications

(10 reference statements)

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“…Placement of a strong electron donating group in the ortho , meta or para positions (entry 8), led to the recovery of starting material in all cases. A reason for this may be due to the formation of a methoxy radical (in preference to tertiary amide oxidation) which may redox shuttle unproductively at the working and counter electrodes . To test this hypothesis, 1 i ( m ‐OMe) was subjected to analogous reaction conditions in a sintered glass frit divided H‐cell…”

Section: Resultsmentioning

confidence: 99%

“…The ubiquitous nature of the amide bond found both in nature; agrochemicals and drug molecules (Figure ) necessitated the development of a late‐stage electrosynthetic N ‐dealkylation method described herein. The Shono‐type oxidation manifold of amides coupled with the reported in situ collapse of ɑ‐oxidised intermediaries in the oxa‐Shono reaction prompted us to consider the generality of this reaction manifold for tertiary amide N ‐dealkylation.…”

Section: Introductionmentioning

confidence: 99%

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Metabolism Mimicry: An Electrosynthetic Method for the Selective Deethylation of Tertiary Benzamides

2019

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The electrosynthetic deethylation of tertiary amides, commonly encountered moieties in pharmaceuticals and agrochemicals, is an analogue of the function of cytochrome P450 enzymes, a major oxidant metabolic pathway for xenobiotics. The ability to tractably synthesise, in a late‐stage manner, drug metabolites from the parent drug is currently unsolved. We report the first study, mechanistic rationale, and synthetic scope of an undivided controlled current electrosynthetic method that selectively mono deethylates tertiary amides without over‐reaction. An optimisation survey found that changing the electron input from controlled voltage to controlled current conditions led to deethylation rather than the expected dehydrogenative coupling. The scope and limitations of the method were interrogated with 14 examples with the parent benzamide reaction optimised (86 % yield) and the scalable production of the major human metabolite of the insect repellent DEET was achieved from the parent molecule in one step.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolism Mimicry: An Electrosynthetic Method for the Selective Deethylation of Tertiary Benzamides

2019

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“…The deuterated solvents used for NMR analysis were: chloroform (CDCl 3 : δH 7.26, δC 77.2), dimethyl sulfoxide (d 6 -DMSO: δH 2.50, δC 39.5), and deuterium oxide (D2O: δH 4.79). Coupling constants are given in Hertz (Hz) 27 . All individual signals were assigned using 2D NMR spectroscopy ( 1 H-1 H-COSY, 1 H-13 C-HSQC, and 1 H-13 C-HMBC).…”

Section: Methodsmentioning

confidence: 99%

A novel exchange method to access sulfated molecules

Alshehri

Benedetti

Jones

2020

Sci Rep

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Organosulfates and sulfamates are important classes of bioactive molecules but due to their polar nature, they are both difficult to prepare and purify. We report an operationally simple, double ion-exchange method to access organosulfates and sulfamates. Inspired by the novel sulfating reagent, TriButylSulfoAmmonium Betaine (TBSAB), we developed a 3-step procedure using tributylamine as the novel solubilising partner coupled to commercially available sulfating agents. Hence, in response to an increasing demand for complementary methods to synthesise organosulfates, we developed an alternative sulfation route based on an inexpensive, molecularly efficient and solubilising cation exchanging method using off-the-shelf reagents. The disclosed method is amenable to a range of differentially substituted benzyl alcohols, benzylamines and aniline and can also be performed at low temperature for sensitive substrates in good to excellent isolated yield.

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“…1 H and 13 C-NMR spectra were recorded on a JEOL ECS 400 MHz NMR spectrometer. 1 H and 13 C NMR chemical shifts (δ) are reported in parts per million relative to tetramethylsilane (TMS), with the solvent resonance employed as the internal standard (CDCl 3 at 7.26 ppm, CDCl 3 at 77.2 ppm).…”

Section: General Pointsmentioning

confidence: 99%

“…Our interest in connecting the voltammetric behaviour of drug molecules to their biological properties is derived from our research into the electrochemistry of small molecules [12][13][14] and adverse drug reactions [15,16]. Recent disparate research has found connections between the redox behaviour of a drug and its biological potency [17][18][19] and the oxidation potential and toxicity of MDMA (Ecstasy) derivatives [20,21] and thiobenzamides [22], and voltammetric studies for assessing electrogenerated drug metabolisms [23] as well as a study of xeniobiotics in the environment [24].…”

Section: Introductionmentioning

confidence: 99%

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

et al. 2020

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Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t½), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short- (<10 min) and longer-circulation (>2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability.

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Selective C–H bond electro-oxidation of benzylic acetates and alcohols to benzaldehydes

Cited by 19 publications

References 41 publications

Metabolism Mimicry: An Electrosynthetic Method for the Selective Deethylation of Tertiary Benzamides

Metabolism Mimicry: An Electrosynthetic Method for the Selective Deethylation of Tertiary Benzamides

A novel exchange method to access sulfated molecules

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

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