Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Chinonmethidâ Dimere wurden durch milde anodische Oxidation vermittelt durch eine preiswerte und leicht verfügbare Aminbase mit exzellenter Ausbeute und Regiokontrolle hergestellt. Diese Strategie ermöglicht raschen Zugang zu Zwischenprodukten für die katalytische Synthese von Phenylpropenoidâ Oligomeren und bietet ein neues Werkzeug für die Totalsynthese dieser komplexen Moleküle.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/1/ange201810870.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/2/ange201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/3/ange201810870-sup-0001-misc_information.pd

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Quinone methide dimers are prepared via mild anodic oxidation mediated by a cheap and readily available amine base with excellent yield and regiocontrol. This strategy provides rapid access to intermediates for the synthesis of phenylpropenoid oligomers in a catalytic fashion, providing a new tool for the total synthesis of these complex molecules.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/1/anie201810870-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/2/anie201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/3/anie201810870.pd

Rapid Ni, Zn, and Cu Ion-Promoted Alcoholysis of <i>N</i>,<i>N-</i>Bis(2-picolyl)- and <i>N</i>,<i>N-</i>Bis((1<i>H</i>‑benzimidazol-2-yl)methyl)‑<i>p</i>‑nitrobenzamides in Methanol and Ethanol

The methanolysis and ethanolysis of the Ni­(II), Zn­(II), and Cu­(II) complexes of <i>N</i>,<i>N</i>-bis­(2-picolyl)-<i>p</i>-nitrobenzamide (<b>1</b>) and <i>N</i>,<i>N</i>-bis­((1<i>H</i>-benzimidazol-2-yl)­methyl)-<i>p</i>-nitrobenzamide (<b>2</b>) were studied under pH-controlled conditions at 25 °C. Details of the mechanism were obtained from plots of the <i>k</i>_obs values for the reaction under pseudo-first-order conditions as a function of [M²⁺]. Such plots give saturation kinetics for the Cu­(II)-promoted reactions of <b>1</b> and <b>2</b> in both solvents, the Zn­(II)-promoted reaction of <b>1</b> in methanol, and the Zn­(II)- and Ni­(II)-promoted reactions of <b>2</b> in methanol and ethanol. Logs of the maximal observed rate constants obtained from the latter plots, (<i>k</i>_obs^max), when plotted versus _s^spH, are curved downward only for the Cu­(II) complexes of <b>1</b> and <b>2</b> in both solvents and the Zn­(II) complex of <b>1</b> in methanol. Despite differences in the metal-binding abilities and p<i>K</i>_a values for formation of the active form, there is a common reaction mechanism, with the active form being <b>1</b>:M­(II):(^<b>–</b>OR) and <b>2</b>:M­(II):(^<b>–</b>OR), where M­(II):(^<b>–</b>OR) is the metal-bound alkoxide. The acceleration provided by the metal ion is substantial, being 10¹⁴–10¹⁹ relative to the <i>k</i>₂^¯OMe value for the alkoxide-promoted alcoholysis of the uncomplexed amide

Trifunctional Metal Ion-Catalyzed Solvolysis: Cu(II)-Promoted Methanolysis of <i>N</i>,<i>N</i>‑bis(2-picolyl) Benzamides Involves Unusual Lewis Acid Activation of Substrate, Delivery of Coordinated Nucleophile, Powerful Assistance of the Leaving Group Departure

The methanolyses of Cu­(II) complexes of a series of <i>N</i>,<i>N</i>-bis­(2-picolyl) benzamides (<b>4a</b>–<b>g</b>) bearing substituents X on the aromatic ring were studied under _s^spH-controlled conditions at 25 °C. The active form of the complexes at neutral _s^spH has a stoichiometry of <b>4</b>:Cu­(II):(⁻OCH₃)­(HOCH₃) and decomposes unimolecularly with a rate constant <i>k</i>_<i>x</i>. A Hammett plot of log­(<i>k</i>_<i>x</i>) vs σ_<i>x</i> values has a ρ_<i>x</i> of 0.80 ± 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro and 4-methoxy derivatives, <b>4b</b>:Cu­(II):(⁻OCH₃)­(HOCH₃) and <b>4g</b>:Cu­(II):(⁻OCH₃)­(HOCH₃), in the plateau region of the _s^spH/log­(<i>k</i>_<i>x</i>) profiles in both CH₃OH and CH₃OD. Activation parameters for decomposition of these complexes are Δ<i>H</i>^⧧ = 19.1 and 21.3 kcal mol^–1 respectively and Δ<i>S</i>^⧧ = −5.1 and −2 cal K^–1 mol^–1. Density functional theory (DFT) calculations for the reactions of the Cu­(II):(⁻OCH₃)­(HOCH₃) complexes of <b>4a,b</b> and <b>g</b> (<b>4a</b>, X = 3,5-dinitro) were conducted to probe the relative transition state energies and geometries of the different states. The experimental and computational data support a mechanism where the metal ion is coordinated to the <i>N</i>,<i>N</i>-bis­(2-picolyl) amide unit and positioned so that it permits delivery of a coordinated Cu­(II):(⁻OCH₃) nucleophile to the CO in the rate-limiting transition state (TS) of the reaction. This proceeds to a tetrahedral intermediate <i><b>INT</b></i>, occupying a shallow minimum on the free energy surface with the Cu­(II) coordinated to both the methoxide and the amidic N. Breakdown of <i><b>INT</b></i> is a virtually barrierless process, involving a Cu­(II)-assisted departure of the bis­(2-picolyl)­amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism where it activates intramolecular nucleophilic attack on the CO group by coordination to an amidic N in the first step of the reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the second order rate constant for methoxide attack on <b>4b</b>, the computed reaction of CH₃O^– and <b>4b</b>:Cu­(II):(HOCH₃)₂ is accelerated by roughly 2.0 × 10¹⁶ times