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Since the first reports, the Ugi four-component reaction (U-4CR) has been recognized as a keystone transformation enabling the synthesis of peptide mimetics in a single step and with high atom economy. In recent decades, the U-4CR has been a source of inspiration for many chemists fascinated by the possibility of identifying new efficient organic reactions by simply changing one of the components or by coupling in tandem the multicomponent process with a huge variety of organic transformations. Herein we review the synthetic potentialities, the boundaries, and the applications of the U-4CR involving α-amino acids, where the presence of two functional groups—the amino and the carboxylic acids—allowed a 5-center 4-component Ugi-like reaction, a powerful tool to gain access to drug-like multi-functionalized scaffolds.

Isocyanides are valuable compounds for organic synthesis. However, the poor stability and distressing odour have often limited their widespread applications in common laboratory practice and industrial setting. Herein, a continuous flow approach to enable the synthesis, purification and in-line multicomponent reaction of isocyanides, is presented.

Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929–1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it.

Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure–activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.

A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.