Solvent‐ and Catalyst‐Free Aza‐Michael Addition of Imidazoles and Related Heterocycles

Abstract

This work demonstrates the scope and limitations of the aza‐Michael addition of imidazoles and related heterocycles with electron deficient olefins under solvent‐ and catalyst‐free conditions. The reaction proceeds at 80 °C within hours towards completion as long as the azole derivative is sufficiently soluble in the Michael acceptor, which has been used in small excess. Workup only comprises evaporation of surplus Michael‐acceptor, and no additional solvents are necessary for purifying the products.

Tetraphenylpyrazine-Based Manganese Metal–Organic Framework as a Multifunctional Sensor for Cu2+, Cr3+, MnO4–, and 2,4,6-Trinitrophenol and the Construction of a Molecular Logical Gate

“…All chemicals used for the synthesis were obtained commercially and used as received. 3-(1 H -Imidazol-1-yl)­propanenitrile and 2,3,5,6-tetrakis­[4-(methoxycarbonyl)­phenyl]­pyrazine ( 1 ) were prepared according to previous methods. , 1 H and 13 C NMR spectra were recorded on a Bruker 400 MHz Avance spectrometer using tetramethylsilane as the internal standard. Mass spectrometry (MS) spectra were obtained on a Bruker Daltonics APEX II 30e spectrometer.…”

Thermodynamic Understanding of an Aza-Michael Reaction Enables Five-Step Synthesis of the Potent Integrin Inhibitor MK-0429

“…Although aza-Michael reactions are commonly used to append certain electrophiles, including enones and unsaturated nitriles, onto nucleophilic heterocycles, the corresponding intermolecular transformation with β-substituted acrylates remains underutilized . Scattered reports describing successful reactivity exist; − however, we were interested in developing a general protocol for this transformation due to the presence of the product motif in biologically active molecules, particularly nonpeptidic α V -RGD (Arg-Gly-Asp) integrin inhibitors (Figure ). Compounds 1 – 3 are reported potent integrin inhibitors (subnanomolar to nanomolar IC 50 values) and have been proposed as potential therapeutics for treatment of myriad diseases, including cancer, fibrosis, and inflammatory disorders. − Of these, MK-0429 ( 1 ) has been taken into clinical studies for the treatment of osteoporosis and prostate cancer, and recent reports have shown it to be efficacious in animal models of renal and pulmonary fibrosis. , …”

Michael Acceptors Tuned by the Pivotal Aromaticity of Histidine to Block COVID-19 Activity

“…Actually, the facility of obtaining a proton by this ring is extremely helpful for the thiol group of Cys145 to deprotonate. This protonated imidazole together with any water molecule around then can create an oxyanion activating the keto group of 13b , , where the positive charge on the carbon aims for the negative charge on the deprotonated sulfur, facilitating C–S bond formation.…”