Exploring New Parameter Spaces for the Oxidative Homocoupling of Aniline Derivatives: Sustainable Synthesis of Azobenzenes in a Flow System

Aromatic azo compounds have countless applications, not merely in the chemical industry, but also in medicinal chemistry, biotechnology, and the field of renewable resources. However, in the synthetic batch routine, the synthesis of azobenzenes often constitutes a significant challenge, mainly because of the ease of overreaction leading to nonoptimal selectivity, and also because of reactivity issues necessitating long reaction times and special reaction conditions. We therefore exploited the benefits of continuous-flow processing for the copper-mediated oxidative homocoupling of arylamines to facilitate the time-, cost-, and atom-effective synthesis of azobenzenes. The novel process window of increased temperature and pressure ranges in combination with the application of overheated solvents afforded a remarkable chemical intensification. Precise control of the residence time restricted the possibility of undesired reaction pathways, such as overreaction to azoxy products, but at the same time ensured sufficient reactivity to furnish valuable aromatic azo compounds, even in the cases of deactivated halogen-substituted anilines and multisubstituted derivatives. As compared with earlier batchwise syntheses, the designed process displays significant advances in terms of sustainability and productivity

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein‑1 (VAP-1): Old Target–New Inhibition Mode

Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific, and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity, and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor–VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Although they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors, and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors

Copper(II)-Binding Ability of Stereoisomeric <i>cis-</i> and <i>trans</i>-2-Aminocyclohexanecarboxylic Acid–l-Phenylalanine Dipeptides. A Combined CW/Pulsed EPR and DFT Study

With the aim of an improved understanding of the metal-complexation properties of alicyclic β-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper­(II) of l-phenylalanine (F) derivatives of <i>cis</i>/<i>trans</i>-2-aminocyclohexanecarboxylic acid (<i>c</i>/<i>t</i>ACHC), <i>i.e</i>. the dipeptides F-<i>c</i>/<i>t</i>ACHC and <i>c/t</i>ACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu­(aqua)]²⁺, [CuL]⁺, [CuLH_–1], [CuLH_–2]⁻, and [CuL₂H_–1]⁻), and an EPR-inactive species ([Cu₂L₂H_–3]⁻) in aqueous solutions for all studied cases. [CuLH]²⁺ was included in the equilibrium model for the <i>c</i>/<i>t</i>ACHC-F–copper­(II) systems, and [CuL₂], together with two coordination isomers of [CuL₂H_–1]⁻, were also identified in the F-<i>t</i>ACHC–copper­(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1<i>S</i>,2<i>R</i>)-ACHC and F-(1<i>R</i>,2<i>S</i>)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the <i>trans</i> than for the <i>cis</i> isomers for both the F-<i>c</i>/<i>t</i>ACHC and the <i>c</i>/<i>t</i>ACHC-F pairs in the case of [CuLH_–1] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the <i>trans</i> isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial–equatorial ring positions can bind to copper­(II), whereas both equatorial-axial conformers of the <i>cis</i> isomers are capable of binding. From a consideration of the proton couplings obtained with X-band ¹H HYSCORE, ²H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH_–1] complexes. For the F-<i>cAC</i>HC case, the conformer did not match the most stable conformer of the free ligand