In eons of evolution, isocyanides carved out a niche in the ecological systems probably thanks to their metal coordinating properties. In 1859 the first isocyanide was synthesized by humans and in 1950 the first natural isocyanide was discovered. Now, at the beginning of XXI century, hundreds of isocyanides have been isolated both in prokaryotes and eukaryotes and thousands have been synthesized in the laboratory. For some of them their ecological role is known, and their potent biological activity as antibacterial, antifungal, antimalarial, antifouling, and antitumoral compounds has been described. Notwithstanding, the isocyanides have not gained a good reputation among medicinal chemists who have erroneously considered them either too reactive or metabolically unstable, and this has restricted their main use to technical applications as ligands in coordination chemistry. The aim of this review is therefore to show the richness in biological activity of the isocyanidecontaining molecules, to support the idea of using the isocyanide functional group as an unconventional pharmacophore especially useful as a metal coordinating warhead. The unhidden hope is to convince the skeptical medicinal chemists of the isocyanide potential in many areas of drug discovery and considering them in the design of future drugs.

The use of water in organic synthesis draws attention to its green chemistry features and its unique ability to unveil unconventional reactivities. Herein, literature about the use of water as a reaction medium under visible-light photocatalytic conditions is summarized in order to highlight challenges and opportunities. Accordingly, this Synopsis has been divided into four different sections focused on (1) the unconventional role of water in photocatalytic reactions, (2) in-/on-water reactions, (3) water-soluble photocatalysts, and (4) photomicellar catalytic systems.

Scheme 3. Titanium dioxide promoted Ugi-like 3CR involving tertiary aromatic amines, isocyanides and water. Scheme 4. Metal-free photoredox catalyzed Ugi-like 3CR under continuous flow conditions. Scheme 5. Metal-free photoredox catalyzed Ugi-like 3CR using thin film vortex microfluidics.

With their three points of diversity, α-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the stability of the ester could be controlled, leading to the formation of hydrolytically stable α-acyloxy carboxamides. When the group directly attached to the ester moiety (R 3 ) is an ortho-substituted or ortho,ortho′-disubstituted aromatic ring, α-acyloxy carboxamides are stable. In human liver but not in rodents, due to the different expression of esterases, the ester function is also stable toward hydrolysis when the R 1 group is a bulky substituent regardless of the nature of the R 3 substituent.

A new visible light photocatalytic multicomponent reaction (MCR) involving N-alkyl-N-methylanilines, N-isocyanoiminotriphenyl phosphorane, and carboxylic acids leading to 1,3,4-oxadiazole derivatives is herein reported. The developed mild reaction conditions enable a broad substrate scope and a good functional group tolerance, as further highlighted in the late stage functionalization of amino acids and drugs. Additionally, a 2-step one-pot protocol for the obtention of non-symmetrical diacylhydrazines is also reported as an expeditious and green synthetic approach to such valuable scaffolds.