Anodic Oxidation and Organocatalysis: Direct Regio‐ and Stereoselective Access to meta‐Substituted Anilines by α‐Arylation of Aldehydes

Abstract

During the last decades chemists have witnessed the development of thousands of new catalytic reactions driven by need and interest from both industrial and academic settings. Asymmetric catalysis has been one of the focus areas as a result of the increased need for optically active compounds in life science. Many catalytic asymmetric processes are based on metal complexes and rely on activation modes such as Lewis acid catalysis, atom-transfer catalysis, as well as s-and p-bond insertions. Recently, organocatalysis [1] has emerged as a powerful source of enantioselective transformations and has led to the development of a-,[2] b-, [3] g-, [4] and SOMOactivations, [5] as well as cascade, domino, and tandem reactions. [6] Aromatic compounds are ubiquitous as medicines and functionalized materials, and are often formed by electrophilic substitution reactions. [7] Friedel-Crafts alkylations, in particular of highly nucleophilic aromatic compounds such as phenols and anilines, are difficult owing to the regioselectivity and the competitive nucleophilic heteroatoms, which lead to undesired alkylation products. The application of copper catalysis to direct the substitution meta to an amido group through dearomatizing oxy-cupration [8] provides a recent example of where selectivity has been circumvented. Additionally, it has been shown by Gaunt and co-workers that para-substituted phenols can be converted into highly functionalized chiral molecules through oxidative dearomatization and intramolecular enamine catalysis.[9] Breaking aromaticity changes the reactivity from nucleophilic to electrophilic, [10] and thus makes it susceptible to addition of systems such as enamines.Electrochemical reactions often follow environmentally friendly protocols because electrons, as reagents, are inherently pollution free. The ability of electrochemistry to reverse the polarity of a functional group-by selective removal or addition of electrons-makes it thus possible to induce reactions of otherwise nonreactive molecules.[11] Successful combinations of electrochemistry and metal catalysis or mediated electron-transfer processes have been reported in numerous cases, [11] although the risk of having electrode fouling is always present. For example, palladium metal deposition on the cathode has been observed from the reduction of palladium(II), which is generated at the anode, in an undivided cell. [12] Organocatalysts are stable organic molecules and many stereoselective organocatalytic reactions are performed under conditions not possible for metalcatalyzed reactions. We thus anticipated that it might be possible to combine organocatalysis with anodic molecular transformations. [11b, 13] Herein, the combination of electrochemistry and asymmetric organocatalysis is presented. This new concept is demonstrated by a direct intermolecular a-arylation [14] of aldehydes using electron-rich aromatic compounds providing meta-alkylated anilines-a transformation not possible by Friedel-Crafts reactions of anilines (Scheme 1). We show the poten...

Contributions of organic electrosynthesis to green chemistry

“…From five different aldehydes the products are obtained in 69-87% yield and 81-96% enantioselectivity. Similar yields can also be obtained with iodosobenzene diacetate as oxidant (Scheme 35) [64].…”

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

“…Excellent enantioselectivities were obtained for this process. 381 Electro-oxidation of 2- or 4-aminoaniline produces quinone di -imines which were found to exhibit similar reactivities as Michael acceptors, compared to 1,2-benzoquinones or its monoimino congener. 382–389 …”

Asymmetric Electrochemical Catalysis

“…In 2010, Jørgensen and co-workersr eportedt he asymmetric a-arylation of aldehydes with phenols 12 a under anodic oxidation conditions by chiral secondary aminocatalysis (Scheme 12). [30] Phenol 12 a was electrochemically oxidized to paraquinone 12 c,w hich then coupled with the enamine intermediate pictured in Scheme 12 to give the arylated adduct with good enantioselectivity.…”