Non-activated o-quinones derived from natural hydroxytyrosol and other catechols were electrogenerated under mild conditions. They provided polysubstituted 2-amino-2,3-dihydro-1,4-benzodioxane derivatives, through [4 + 2] cycloaddition with enamines.

Low-cost pyrogallol precatalyst undergoes an oxidative self-processing step for delivering the active organocatalystin situthrough a dual biomimetic process.

The goal of sustainable development has been accepted as a common policy in current society. In response to this challenge, the development of green processes which utilize environmentally benign oxidants, reduce chemical waste and handling costs, is highly desirable. Given the widespread importance of imines as pivotal synthetic intermediates and essential pharmacophores in numerous biologically active compounds, various catalytic methods allowing the aerobic oxidation of amines to imines have been developed. Recently, noticeable progress has arisen from the discovery of various quinone-based catalytic systems, inspired by copper amine oxidase enzymes (CuAOs), which are able to reproduce the selectivity of CuAOs for primary amines and even to expand the amine substrates scope. However, the need for synthesizing these catalysts prior use adversely affects the economics as well as the eco-friendly nature of the method. To surpass these drawbacks, the "second-order" biomimicry idea has been recently advanced to describe a system in which in situ modification of pre-catalyst components affords the active biomimetic catalyst. This minireview especially covers our recent contribution to the design of bioinspired quinone-based catalysts for the aerobic oxidation of amines to imines which has culminated in a dual bioinspired protocol as an example of "second-order" biomimicry.

Benzimidazole belongs to the top five most commonly used five-membered aromatic nitrogen heterocycles among U.S. FDA approved pharmaceuticals. Over the last few years, a large number of improved synthetic strategies have been developed to construct the benz­imidazole molecular framework under environmentally benign conditions. This review focuses on the use of primary amines as readily available substrates for the synthesis of benzimidazole derivatives through different types of oxidative cross-coupling reactions.1 Introduction2 Catalyst-Free Oxidative Coupling of Primary Amines3 Catalytic Oxidative Coupling of Primary Amines3.1 Metal-Catalyzed Reactions3.2 Metal-Free Catalyzed Reactions3.3 Bioinspired Catalyzed Reactions4 Conclusion

Recent efforts to design synthetic quinone-based catalysts for the efficient aerobic oxidation of amines to imines have been inspired by copper amine oxidases (CuAOs), a family of metalloenzymes which selectively converts primary amines into aldehydes, using molecular oxygen through the cooperation of a quinone-based cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ) and a copper ion. Two distinct classes of bioinspired quinone-based catalytic systems have been developed. The first class consists of catalytic systems, which mimic the activity of CuAOs by exhibiting exquisite selectivity for primary amines. The second class consists of catalytic systems, which allow the expansion of the substrate scope to the oxidation of α-branched primary amines and secondary amines including nitrogen heterocycles, two reaction types that natural CuAOs are not able to accomplish. These catalytic oxidative green processes can be applied to the C-H functionalization of primary amines and to the synthesis of several nitrogen-containing heterocycles.

A bioinspired organocatalytic cascade reaction for the selective aerobic oxidative cross-coupling of primary amines to imines is described. This approach takes advantages of commercially available pyrogallol monomeric precursor to deliver low loadings of natural purpurogallin in situ, under air. This is further engaged in a catalytic process with the amine substrate affording, under single turnover, the active biomimetic quinonoid organocatalyst and the homocoupled imine intermediate, which is then converted into cross-coupled imine after dynamic transimination. This organocatalytic cascade inspired by both purpurogallin biosynthesis and copper amine oxidases allows the aerobic oxidation of non-activated primary amines that non-enzymatic organocatalysts were not able to accomplish alone.

Benzimidazoles are of fundamental importance in chemistry and biology, and the development of efficient, environmentally benign methods for their preparation remains a key challenge for organic chemists. In a biomimetic approach inspired by copper amine oxidases, we disclose herein the scope and factors influencing the success of the cooperative action of CuBr2 as electron-transfer mediator and a topaquinone-like substrate-selective catalyst in the oxidative cyclocondensation of primary amines with o-aminoanilines. This one-pot atom-economic multistep process, which works under green conditions with ambient air as the terminal oxidant, low loadings of catalyst, and equimolar amounts of commercially available amine substrates, is particularly suitable for the preparation of 1,2-disubstituted benzimidazoles. Furthermore, it allows the functionalization of nonactivated primary aliphatic amines, which are known to be challenging substrates for non-enzymatic catalytic aerobic systems.

The direct oxidative cross-coupling of primary amines is a challenging transformation as homocoupling is usually preferred. We report herein the chemoselective preparation of cross-coupled imines through the synergistic combination of low loadings of Cu(II) metal-catalyst and o-iminoquinone organocatalyst under ambient conditions. This homogeneous cooperative catalytic system has been inspired by the reaction of copper amine oxidases, a family of metalloenzymes with quinone organic cofactors that mediate the selective oxidation of primary amines to aldehydes. After optimization, the desired cross-coupled imines are obtained in high yields with broad substrate scope through a transamination process that leads to the homocoupled imine intermediate, followed by dynamic transimination. The ability to carry out the reactions at room temperature and with ambient air, rather than molecular oxygen as the oxidant, and equimolar amounts of each coupling partner is particularly attractive from an environmentally viewpoint.

The tandem oxidation-inverse electron demand Diels-Alder reaction of o-aminophenol derivatives and enamines has been accomplished at room temperature using a stoichiometric amount of manganese dioxide as the oxidant to furnish highly substituted 1,4-benzoxazine cycloadducts with complete regiochemical control. Because of its efficiency in introducing diverse elements in both cycloaddition partners, this one-pot process should allow the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives. In this respect, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3n was found to be a potent neuroprotective agent in an animal model of excitotoxic lesions in newborn mice.

Aerobic oxidative CH functionalization of primary aliphatic amines has been accomplished with a biomimetic cooperative catalytic system to furnish 1,2-disubstituted benzimidazoles that play an important role as drug discovery targets. This one-pot atom-economical multistep process, which proceeds under mild conditions, with ambient air and equimolar amounts of each coupling partner, constitutes a convenient environmentally friendly strategy to functionalize non-activated aliphatic amines that remain challenging substrates for non-enzymatic catalytic aerobic systems.

Two regioisomeric polycyclic xanthones, 3,16-oxyguttiferone A (2) and 1,16-oxyguttiferone A (3), which are polyprenylated acylphloroglucinol-derived analogues, were isolated from the seeds of Symphonia globulifera, together with their presumed o-dihydroxybenzoyl precursor, guttiferone A (1). Anodic oxidation of 1 into the corresponding o-quinone species proved to be an efficient biomimetic method to generate xanthones 2 and 3 in high overall yield and to confirm their structures. Both compounds displayed cytotoxicity against the HCT 116 colon carcinoma cell line with IC₅₀ values of 8 and 3 μM, respectively.

Metalloenzyme-like catalytic systems oxidize amines to imines under environmentally friendly conditions.

AbstractReview: major achievements during the last five years; 86 refs.

The catalytic oxidation of amines to imines is of intense current interest, owing to the importance of imines as pivotal intermediates in the synthesis of fine chemicals and numerous biologically active compounds. Whereas considerable efforts had been made to develop efficient methods for the oxidation of secondary amines to imines, little attention had until recently been given to the oxidation of primary amines, probably because the generated imines are intermediate products that are easily dehydrogenated to nitriles. A surge of activity in this area originated with the discovery of new catalytic systems that allow the oxidation of primary amines to imines under green conditions. This microreview focuses on the major achievements during the last five years.

(±)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates. As yet, chirality of MDMA was not considered in previously reported in vivo studies because HHMA was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the total synthesis of enantiomerically pure precursors, R-(-)-HHMA and S-(+)-HHMA, was envisioned with the ultimate goal to prepare substantial amounts of optically active thioether conjugates. Recently, we reported the first total synthesis of the R-enantiomer. In this paper, a novel synthesis of the S-enantiomer is described, in 45% overall yield (six steps) and 99% ee, using commercially available l-Boc-alanine (99% ee) as the chiral source. Having at our disposal suitable amounts of R-(-)-HHMA and S-(+)-HHMA precursors, a straightforward one-pot electrochemical procedure has been further developed for the synthesis of several catechol-thioether conjugates in acceptable yields (40-53%) and high degree of purity (99%), with complete diastereoselectivity. The availability of these newly synthesized optically active catechol-thioether conjugates is crucial for ongoing future in vivo studies about their role in MDMA neurotoxicity.

AbstractThe process tolerates the presence of various reactive functional groups and allows selective cross‐coupling of two amines.

The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating that persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in the brains of these animals was not related to the unstable nature of the THMA molecule because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA or oxidized cyclic forms (e.g., the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo.

Primary aliphatic biogenic amines have been successfully oxidized using a quinonoid species that mimics the metabolic activity of copper-containing amine oxidase (CuAO) enzymes. Especially, high catalytic performances were observed with aminoacetone, a threonine catabolite, and methylamine, a metabolite of adrenaline, and with the primary amino groups of putrescine and spermidine which are both decarboxylation products of ornithine and S-adenosyl-methionine. Furthermore, contrary to flavine adenine dinucleotide (FAD)-dependent amine oxidase enzymes, no activity was found toward secondary and tertiary amines.

Chemoselective oxidation of primary aliphatic biogenic mono-and polyamines into imines has been successfully achieved, under metal-free conditions, by using an electrocatalytic system that mimics the activity of semicarbazide-sensitive amine oxidase (SSAO) enzymes. Accordingly, high catalytic performance was observed with unbranched primary amines such as methylamine and aminoacetone, and with the primary amino groups of diamines and polyamines like putrescine and spermidine, all of them being reference substrates for SSAO enzymes. Furthermore, contrary to flavin-adenine dinucleotide (FAD)-dependent amine oxidase enzymes, no activity was found with secondary and tertiary amines. Finally, when compared with the direct electrochemical oxidation of primary aliphatic amines, which occurs at high anodic potential (E-an > + 1.5 V vs SCE) and led to unstable cation radicals that rapidly deprotonate and attach to the electrode surface (Pt, carbon), 1.0 V was gained using this electrocatalytic process (E-an = + 0.5 V vs SCE).