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The utility of bio-isosteres is broad in drug discovery and methodology herein enables the preparation of deuterium-labeled products is the most fundamental of known bio-isosteric replacements. As such we report the use of both [D1]-aldehydes and [D2]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a t 1/2 limiting metabolic soft-spot via use of [D1]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of t 1/2 of the new deuterated analogs. We also report the first preparation of [D2]-isonitriles from [D3]-formamides via a modified Leuckart-Wallach reaction and their use in an MCR to afford products with [D2]-benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.

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The Groebke-Blackburn-Bienaymé (GBB) three-component reaction, discovered in 1998, is a very efficient strategy to assemble imidazo[1,2-a]-heterocycles starting from amidines, aldehydes and isocyanides. This review aims to exhaustively describe innovative aspects of this reaction achieved during the last five years, and classifies them into five categories: synthetic methods, building blocks, scaffolds, biological activities and physical properties.

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By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing ß-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was prepared and characterized. Surprisingly, a well-documented approach to obtain peptide-containing carboxylic acids through acid hydrolysis of the convertible isocyanide moiety in the Ugi bisamides proceeded in an unexpected manner in our case, leading to the formation of derivatives of amides of heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the ß-chlorovinyl fragment into a vinyl one is provided.

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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.

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Isocyanides and isocyanates are some of the most reactive compounds in organic chemistry, making them perceived as compounds with high potential for use in both the laboratory and industry. With their high reactivity also comes several disadvantages, most notably their potentially high toxicity. The following article is a collection of information on the toxic effects of the isocyanide group on the human body and the environment. Information on the mechanism of how these harmful substances affect living tissues and the environment, worldwide information on how to protect against these chemicals, current regulations, and exposure limits for specific countries is compiled. The latest research on the application uses of isocyanates and isocyanides is also outlined, as well as the latest safer and greener methods and techniques to work with these compounds. Additionally, the presented article can serve as a brief guide to the organic toxicity of a group of isocyanates and isocyanates.

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In X-ray structures of the isomorphic mer-[IrX3(THT)(CNXyl)2] (X=Cl 1, Br 2; THT=tetrahydrothiophene; Xyl=2,6-Me2C6H3-) complexes, we revealed short intermolecular contacts between the C-atom of an isocyanide methyl group and halide ligands of another molecule. Geometrical consideration of the X-ray data and analysis of appropriate DFT studies allowed the attribution of these contacts to CMe⋅⋅⋅X-IrIII (X=Cl, Br) tetrel bond. Specifically, through the application of DFT calculations and various theoretical models, the presence of tetrel bonding interactions was validated, and the contribution of the CMe⋅⋅⋅X-IrIII interaction was assessed. The reinforcement of the tetrel bond upon the isocyanide coordination to iridium(III) is substantiated by molecular electrostatic potential (MEP) surface calculations. To distinguish the tetrel bonding characteristics of CMe⋅⋅⋅X-IrIII (X=Cl, Br) interactions from conventional hydrogen bonding, we employed multiple computational methodologies, including Natural Bond Orbital (NBO) analysis and Electron Localization Function (ELF) analysis. Additionally, Energy Decomposition Analysis (EDA) was applied to selected model systems to explore the underlying physical nature of these interactions.

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We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma-type monoterpene indole alkaloids. By variation of the isocyanide and carboxylic acid inputs we demonstrate the rapid generation of molecular diversity and the possibility to introduce handles for further modification. The key Ugi three-component reaction showed full diastereoselectivity towards the cis-fused ring system, which can be rationalized by DFT calculations that moreover indicate that the reaction proceeds via a Passerini-type hydrogen bonding mechanism. Several post-Ugi modifications were also performed, including Pictet-Spengler cyclization to highly complex nonacyclic natural product hybrid scaffolds.

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An ultrasonic-assisted isocyanide-based protocol to access a series of functionalized spirorhodanine-cyclopentadiene and spirorhodanine-iminobutenolide conjugates from alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 5-ylidene rhodanines in MeCN, is described. The reaction proceeds via interception of the reactive Winterfeldt's zwitterions by 5-ylidene rhodanine derivatives. The structures of the target compounds were confirmed by X-ray diffraction studies.

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Stefano Marcaccini was one of the pioneers in the use of isocyanide-based multicomponent reactions in organic synthesis. Throughout his career at the University of Florence he explored many different faces of isocyanide chemistry, especially those geared towards the synthesis of biologically relevant heterocycles. His work inspired many researchers who contributed to other important developments in the field of multicomponent reactions and created a school of synthetic chemists that continues today. In this manuscript we intend to review the articles on isocyanide multicomponent reactions published by Dr. Marcaccini and analyse their influence on the following works by other researchers. With this, we hope to highlight the immense contribution of Stefano Marcaccini to the development of isocyanide chemistry and modern organic synthesis as well as the influence of his research on future generations. We believe that this review will not only be a well-deserved tribute to the figure of Stefano Marcaccini, but will also serve as a useful inspiration for chemists working in this field.

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2,3,5,6-Tetramethyl-1,4-diisocyanobenzene (1), 1,4-diisocyanobenzene (2), and 1,4-dicyanobenzene (3) were co-crystallized with 1,3,5-triiodotrifluorobenzene (1,3,5-FIB) to give three cocrystals, 1·1,3,5-FIB, 2·2(1,3,5-FIB), and 3·2(1,3,5-FIB), which were studied by X-ray diffraction. A common feature of the three structures is the presence of I···Cisocyanide or I···Nnitrile halogen bonds (HaBs), which occurs between an iodine σ-hole and the isocyanide C-(or the nitrile N-) atom. The diisocyanide and dinitrile cocrystals 2·2(1,3,5-FIB) and 3·2(1,3,5-FIB) are isostructural, thus providing a basis for accurate comparison of the two types of noncovalent linkages of C≡N/N≡C groups in the composition of structurally similar entities and in one crystal environment. The bonding situation was studied by a set of theoretical methods. Diisocyanides are more nucleophilic than the dinitrile and they exhibit stronger binding to 1,3,5-FIB. In all structures, the HaBs are mostly determined by the electrostatic interactions, but the dispersion and induction components also provide a noticeable contribution and make the HaBs attractive. Charge transfer has a small contribution (<5%) to the HaB and it is higher for the diisocyanide than for the dinitrile systems. At the same time, diisocyanide and dinitrile structures exhibit typical electron-donor and π-acceptor properties in relation to the HaB donor.

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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.

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Charting the chemical reaction space around the combination of carbonyls, amines, and isocyanoacetates allows the description of new multicomponent processes leading to a variety of unsaturated imidazolone scaffolds. The resulting compounds display the chromophore of the green fluorescent protein and the core of the natural product coelenterazine. Despite the competitive nature of the pathways involved, general protocols provide selective access to the desired chemotypes. Moreover, we describe unprecedented reactivity at the C-2 position of the imidazolone core to directly afford C, S, and N-derivatives featuring natural products (e.g. leucettamines), potent kinase inhibitors, and fluorescent probes with suitable optical and biological profiles.

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The first consistent series of mononuclear 17-electron complexes of three Group 7 elements has been isolated in crystalline form and studied by X-ray diffraction and spectroscopic methods. The paramagnetic compounds have a composition of [M0 (CO)(CNp-F-ArDArF2 )4 ] (M=Mn, Tc, Re; ArDArF2 =2,6-(3,5-(CF3 )2 C6 H3 )2 C6 H2 F) and are stabilized by four sterically encumbering isocyanides, which prevent the metalloradicals from dimerization. They have a square pyramidal structure with the carbonyl ligands as apexes. The frozen-solution EPR spectra of the rhenium and technetium compounds are clearly anisotropic with large 99 Tc and 185,187 Re hyperfine interactions for one component. High-field EPR (Q band and W band) has been applied for the elucidation of the EPR parameters of the manganese(0) complex.

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Co-crystallization of 180°-orienting σ-hole-accepting tectons, namely, 1,4-diisocyanobenzene (1) and 1,4-diisocyanotetramethylbenzene (2), with such homoditopic halogen bond donors as 1,4-diiodotetrafluorobenzene (1,4-FIB) and 4,4'-diiodoperfluorobiphenyl (4,4'-FIBP) afforded co-crystals 1 ⋅ 1,4-FIB, 1 ⋅ 4,4'-FIBP, and 2 ⋅ 1,4-FIB. Their solid-state structures exhibit 1D-supramolecular arrangements, which are based on poorly explored I⋅⋅⋅C halogen bonding; this study is the first in which the supramolecular assembly utilizing halogen bonding with a terminal C atom was performed. The use of the potentially tetrafunctional σ-hole accepting tetraiodoethylene (TIE) leads to supramolecular architecture of a higher dimension, 3D-framework, observed in the structure of 1 ⋅ TIE. DFT calculations, used to characterize the halogen bonding situation, revealed that the I⋅⋅⋅C non-covalent interactions are moderately strong, ranging from -4.07 in 1 ⋅ TIE to -5.45 kcal/mol in 2 ⋅ 1,4-FIB. The NBO analysis disclosed that LP(C)→σ* charge transfer effects are relevant in all co-crystals.

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The cycloaddition reaction of o-diisocyanoarenes with interelement compounds under light is a very important reaction system to clarify whether this reaction proceeds by radical cyclization or by aza-Bergman cyclization. In this study, a series of diphosphines with phosphorus-phosphorus single bonds were selected as interelement compounds, and their cycloaddition reactions with o-diisocyanoarenes under light were investigated in detail to achieve a novel photoinduced synthesis of bisphosphinated quinoxalines via the radical cyclization pathway. In addition, the photoinduced reaction of diphosphines with isocyanides having o-functional groups such as cyano and ethenyl groups allowed us to elucidate the reaction pathway and product selectivity of this bisphosphination. Furthermore, the one-pot synthesis of PdII -quinoxaline complex was successfully achieved by applying the developed reaction.

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A novel, convenient and efficient protocol to access functionalized 5-amidoimidazoles is developed via one-pot synthesis from readily available materials of arylamines, carbon disulfide and isocyanides. The transformation was realized at room temperature and provided 5-amidoimidazoles in moderate to good yields in the presence of NaH. In addition, control experiments indicated that the process might be achieved via the base-induced cyclization of activated methylene isocyanides with N,N-disubstituted thioureas that produced from the reaction of amines and carbon disulfide.

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Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure ß-substituted ß-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the ß-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.

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Isocyanides are well-known as efficient CO surrogates and C1 synthons in modern organic synthesis. Although tremendous efforts have been devoted to fully exploiting the reactivity of isocyanides, these transformations are primarily limited by their utilization of stoichiometric toxic chemical oxidants. With the recent resurgence of organic electrochemistry, which has considerably laid dormant over the past several decades, electrolysis has been identified as a green and powerful tool to enrich structural diversity by solely utilizing electric current as clean and inherently safe redox equivalents of stoichiometric chemical oxidants. In this regard, the unique reactivity of isocyanides has been studied in numerous electrochemical transformations. This review comprehensively highlights the most relevant progress in electrochemical strategies towards the functionalization of isocyanides up until June of 2022, with a focus on reaction outcomes and mechanisms.

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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.

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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.

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