Each Interruption is an Opportunity: Novel Synthetic Strategies Explored Through Interrupted Click Reactions.

The particular and unique mechanism of the copper-catalyzed reaction between azides and alkynes (CuAAC) has not only allowed for the efficient synthesis of 1,2,3-trisubstituted 1,4-triazoles in excellent yields and under mild conditions, becoming the quintessential click reaction, but it has also enabled the straightforward formation of a metallocycle intermediate, the copper triazolyl. This, under suitable reaction conditions able to suppress its protonolysis, can be used either for the creation of new bicyclic triazolyl structures or for the generation of novel three or four-component reactions. The aim of this review is to rationalize and unify all these transformations, which are collectively referred to as "interrupted click reactions".

Visible light-promoted C(sp3)-H α-carbamoylation of cyclic ethers with isocyanides.

A protocol exploiting isocyanides as carbamoylating agents for the α-C(sp3)-H functionalization of cyclic ethers has been optimized via a combined visible light-driven hydrogen atom transfer/Lewis acid-catalyzed approach. The isocyanide substrate scope revealed an exquisite functional group compatibility (18 examples, with yields up to 99%). Both radical and polar trapping, kinetic isotopic effect and real-time NMR studies support the mechanistic hypothesis and provide insightful details for the design of new chemical processes involving the generation of oxocarbenium ions.

Exploiting the Different Nucleophilicity of the Isocyano Group: A Strategy for the Isocyanide Functionalization.

By exploiting the different nucleophilicity of aromatic and aliphatic isocyanides, we selectively react aliphatic isocyano groups while preserving aromatic ones in Passerini and Ugi multicomponent reactions. This simple approach allows the synthesis of α-acyloxy carboxamides or α-acylamino carboxamides possessing one or two isocyanide groups, which are challenging to achieve through traditional formylation and dehydration protocols. These analogues have the potential to serve as valuable building blocks with diverse applications.

Isocyanide-Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis.

Isocyanide-based multicomponent reactions claim a one century-old history of flourishing developments. On the other hand, the enormous impact of recent progresses in visible light photocatalysis has boosted the identification of new straightforward and green approaches to both new and known chemical entities. In this context, the application of visible light photocatalytic conditions to multicomponent processes has been promoting key stimulating advancements. Spanning from radical-polar crossover pathways, to photoinduced and self-catalyzed transformations, to reactions involving the generation of imidoyl radical species, the present literature analysis would provide a general and critical overview about the potentialities and challenges of exploiting isocyanides in visible light photocatalytic multicomponent reactions.

Isocyanides as Catalytic Electron Acceptors in the Visible Light Promoted Oxidative Formation of Benzyl and Acyl Radicals.

The recent disclosure of the ability of aromatic isocyanides to harvest visible light and act as single electron acceptors when reacting with tertiary aromatic amines has triggered a renewed interest in their application to the development of green photoredox catalytic methodologies. Accordingly, the present work explores their ability to promote the generation of both alkyl and acyl radicals starting from radical precursors such as Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. Mechanistic studies involving UV-visible absorption and fluorescence experiments, electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provide key insights to promote a rationale design of a new generation of isocyanide-based organic photoredox catalysts. Importantly, the green potential of the investigated chemistry is demonstrated by a direct and easy access to deuterium labeled compounds.

Visible-Light Photoredox Catalysis in Water.

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.

Medicinal Chemistry of Isocyanides.

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 isocyanide-containing 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.

Domino synthesis of 5-aminoimidazoles from Strecker multicomponent adducts via ytterbium-promoted isocyanide insertion/5-exo-dig cyclization.

A new Lewis acid promoted domino isocyanide insertion/5-exo-dig cyclization of readily available Strecker 3-component adducts to 4-substituted 5-aminoimidazole derivatives is herein reported. Despite their potential as relevant heterocyclic scaffolds in medicinal chemistry programs, this class of compounds is still underrepresented, with current synthetic strategies poorly efficient in terms of timing and yields. To this end, we show how the exploitation of unconventional reactivities of isocyanides, promoted by ytterbium-triflate, could represent a key resource to enable a fast and easy access to such an unexplored area of the chemical space.

eHydrogenation: Hydrogen-free Electrochemical Hydrogenation.

Hydrogenation reactions are staple transformations commonly used across scientific fields to synthesise pharmaceuticals, natural products, and various functional materials. However, the vast majority of these reactions require the use of a toxic and costly catalyst leading to unpractical, hazardous and often functionally limited conditions. Herein, we report a new, general, practical, efficient, mild and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro and azido groups. Finally, this method has been applied to deuterium labelling.

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds.

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.

The Dark Side of Isocyanides: Visible-Light Photocatalytic Activity in the Oxidative Functionalization of C(sp3)-H Bonds.

The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp3)-H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron-donor-acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N-phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.

The 115 Year Old Multicomponent Bargellini Reaction: Perspectives and New Applications.

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.

Enriching the Arsenal of Pharmacological Tools against MICAL2.

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.

Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals.

A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species.

Photocatalytic Isocyanide-Based Multicomponent Domino Cascade toward the Stereoselective Formation of Iminofurans.

A visible-light-promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labeled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.

Aryl Azides as Forgotten Electrophiles in the Van Leusen Reaction: A Multicomponent Transformation Affording 4-Tosyl-1-arylimidazoles.

Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism in two different ways, with the second molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the final product.

Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines.

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.

To each his own: isonitriles for all flavors. Functionalized isocyanides as valuable tools in organic synthesis.

The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed.

Pharmacological folding chaperones act as allosteric ligands of Frizzled4.

Upon binding, ligands can chaperone their protein targets by preventing them from misfolding and aggregating. Thus, an organic molecule that works as folding chaperone for a protein might be its specific ligand, and, similarly, the chaperone potential could represent an alternative readout in a molecular screening campaign toward the identification of new hits. Here we show that small molecules selected for acting as pharmacological chaperones on a misfolded mutant of the Frizzled4 (Fz4) receptor bind and modulate wild-type Fz4, representing what are to our knowledge the first organic ligands of this until-now-undruggable GPCR. The novelty and the advantages of the screening platform, the allosteric binding site addressed by these new ligands and the mechanism they use to modulate Fz4 suggest new avenues for development of inhibitors of the Wnt-ß-catenin pathway and for drug discovery.

A Successful Replacement of Phenols with Isocyanides in the Bargellini Reaction: Synthesis of 3-Carboxamido-Isobutyric Acids.

Old multicomponent reactions are still a source of inspiration for discovering novel combinations of three or more reactants. A simple idea is to replace one of the educts of a known multicomponent reaction with another functional group and still be able to mimic the same reactivity. Following this line of thought, we report a three-component reaction in which isocyanides are able to open the epoxide intermediate of the Bargellini reaction affording 3-carboxamido-isobutyric acids in yields of 47-95%.