Isocyanide Component Research Articles

Divergent Synthesis of Pentacyclic Isoindolinones Enabled by Sequential Insertion of Two Different Isocyanides and Acid Promoted Cyclization of Ketenimines

A palladium-catalyzed multicomponent reaction involving o-bromobenzaldehydes and two different isocyanides was developed to assemble series of isoindolinones with spiroindolenine or azepinoindole skeletons. This sequential insertion reaction features mild conditions, a wide substrate scope, and high efficiency. Preliminary mechanistic study indicated that the difference in steric hindrance between isocyanide components is crucial when regulating the reaction sequence, whereas the ligand also played an important role during the whole process.

Enantiopure β-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure β-substituted β-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 β-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.Graphical abstract

Synthetic Study of 5‐Hydroxymethylfurfural in Groebke‐Blackburn‐Bienaymé Reaction

AbstractIn the present study, we explored the reactivity of 5‐hydroxymethylfurfural (5‐HMF), a renewable platform chemical, as the aldehyde component in the Groebke‐Blackburn‐Bienaymé (GBB) multicomponent reaction. Given the limited stability of 5‐HMF under conventional conditions used for this reaction, acidic milieu in combination with high temperature or long reaction times, we explored factors which influence the course of the reaction (solvent, catalyst, time, and temperature) within the guidelines of previously reported green reaction conditions. Mild conditions and short reaction times were achieved to obtain good conversion and selectivity values. The reaction scope was exemplified by preparing a small compound library based on the optimized conditions varying the amidine and the isocyanide component. The hydroxymethylfuran moiety present in the GBB products, imidazo[1,2‐a]heterocycles, provides useful functionalization for further transformations, which could expand the diversity of the chemical space.

Synthesis of imidazolocoumarins by the amide-directed oxidative cyclisation of enol-Ugi derivatives.

The oxidative C(sp3)-H intramolecular imination of hydroxycoumarin enol-Ugi adduct derivatives affords selectively diversely substituted imidazolocoumarins in one pot. The amide group derived from the enol-Ugi isocyanide component directs the functionalisation of the adjacent C(sp3)-H and then is lost as an isocyanate molecule in an unprecedented transformation. This strategy was applied for the synthesis of potential modulators of innate immune system receptor TLR7, which showed high binding affinities in the molecular docking studies.

One‐Pot Synthesis of Thiocarbamates

AbstractAn efficient isocyanide‐based synthesis of S‐thiocarbamates was discovered and thoroughly investigated. The new reaction protocol is a one‐pot procedure and allows the direct conversion of N‐formamides into thiocarbamates by initial dehydration with p‐toluene sulfonyl chloride to the respective isocyanide and subsequent addition of a sulfoxide component. Contrary to recent literature, which also uses isocyanides as starting material, but with other sulfur reagents than sulfoxides, in this protocol, no isolation and purification of the isocyanide component is necessary, thus significantly decreasing the environmental impact and increasing the efficiency of the synthesis. The new protocol was applied to synthesize a library of sixteen thiocarbamates, applying four N‐formamides and four commercially available sulfoxides. Furthermore, experiments were conducted to investigate the reaction mechanism. Finally, four norbornene‐based thiocarbamate monomers were prepared and applied in controlled ring‐opening metathesis polymerization (ROMP) reactions. The polymers were characterized by size‐exclusion chromatography (SEC) and their properties were investigated utilizing differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

Novel 2‐Pyrazolin‐5‐one Derivative through Unforeseen Orthoamide Intermediate: Mechanistic Insights on Isocyanide Based [4+1] Cycloaddition

AbstractThis work relates a unique one‐pot procedure to assembly novel 2‐pyrazolin‐5‐one derivative functionalized through an isocyanide based formal [4+1] cycloaddition. A new, unexpected multicomponent reaction occurred when a pyrazolone was condensed with an aldehyde, an isocyanide, and water or alcohol components. Nine novel molecules with an embedded alkyl carboxamide group were obtained in moderate yield. Surprisingly, an unforeseen orthoamide intermediate was isolated and characterized, proving the plausible mechanism for the opened imidate obtained by formal [4+1] cycloaddition. This one‐pot approach to pyrazolone derivatives functionalized with amides stands as a significant advance for preparing this class of molecules.

Polymers of lignin-sourced components as a facile chemical integrant for the Passerini three-component reaction

In this work, poly(methacrylated vanillin) (PMV) was investigated for its reactivity in multicomponent reactions as a reactive polymer that can be sourced from lignin-based components. To achieve sustainable polymer chemistry, the PMV reactivity in a Passerini three-component reaction (Passerini-3CR) was investigated because the reactants in the Passerini-3CR can be abundantly sourced from biobased compounds. First, the Passerini-3CR of the PMV in solution phases revealed that the PMV pendant aldehydes can be converted into the corresponding α-acyloxy amides with >90% conversions under the optimized conditions. Taking advantage of this high reactivity of PMV, its immobilized cellulose fabric (Cell-g-PMV), a wood biomass-sourced organic hybrid, was subjected to the Passerini-3CR. Although the aldehydes were not completely converted, the PMV segments surrounding the fabric surfaces successfully reacted via the Passerini-3CR to engraft carboxylic acid and isocyanide components on the cellulose-based fabrics. Poly(methacrylated vanillin) (PMV) was investigated for its reactivity in multicomponent reactions as a reactive polymer that can be sourced from lignin-based components. The Passerini three-component reaction (Passerini-3CR) of the PMV in solution phases revealed that the PMV pendant aldehydes can be converted into the corresponding α-acyloxy amides with >90% conversions under the optimized conditions. Taking advantage of this high reactivity of PMV in solution phase, its immobilized cellulose fabric (Cell-g-PMV), a wood biomass-sourced organic hybrid, was subjected to the Passerini-3CR, enabling an engraftment of carboxylic acid and isocyanide components on the cellulose-based fabrics.

Synthesis of bis(1,5‐disubstituted tetrazoles) via double four component Azido‐Ugi reaction

AbstractA double four component Azido‐Ugi reaction of isocyanide, TMSN3, aldehyde, and 4,4′‐sulfonyldianiline with two amine functional groups in MeOH at 65°C has been described. The synthesis of pharmacologically and structurally interesting compounds with two 1,5‐disubstituted tetrazole rings via a reaction from available and inexpensive reagents under a convenient process and mild reaction conditions has been reported. Modifications in the structure of the reaction product could be followed by varying the aldehyde or isocyanide component. The products are new and were well described by Mass, 1H NMR, and 13C NMR spectral studies.

Multicomponent Approach to Homo- and Hetero-Multivalent Glycomimetics Bearing Rare Monosaccharides

We applied a multicomponent approach to access a library of densely functionalized homo- and hetero-multivalent glycomimetics comprising aldehyde, amine, and isocyanide components related to isopropylidene-protected d-fructose, l-sorbose, d-galactose, and d-allose. Passerini products were obtained in very good yields (up to 78%) and high diastereoselectivities (up to 98:2). Three types of products were obtained by the Ugi reaction; along with the "classical" four-component product, α-acylaminoamides, a three-component α-aminoamides, and a four- component α-aminoacylamides were isolated. The presence of multiple pathways is rationalized by the structure of the imidate intermediate, mainly influenced by the amine component.

Sequential Multicomponent Synthesis of 2‐(Imidazo[1,5‐α]pyridin‐1‐yl)‐1,3,4‐Oxadiazoles

A 21 membered library of 2‐(imidazo[1,5‐α]pyridine‐1‐yl)‐1,3,4‐oxadiazoles is synthesized in an unprecedented short sequence starting from an Ugi tetrazole reaction with a cleavable isocyanide component. The intermediate tetrazole is subjected to an acetic anhydride‐mediated cyclization, followed by a Huisgen‐type rearrangement with acyl chlorides to afford the imidazopyridine‐oxadiazole bis‐heterocycles. The scope and limitations of the methodology were investigated with substitutions on both the oxadiazole and the imidazopyridine rings. The introduced enabling technology for imidazopyridine oxadiazole synthesis combines a short reaction sequence with high scaffold diversity, based on commercially available starting materials and high functional groups tolerance.

A Multicomponent Stapling Approach to Exocyclic Functionalized Helical Peptides: Adding Lipids, Sugars, PEGs, Labels, and Handles to the Lactam Bridge.

Peptide stapling is traditionally used to lock peptide conformations into α-helical structures using a variety of macrocyclization chemistries. In an endeavor to add a diversity-generating tool to this repertoire, we introduce a multicomponent stapling approach enabling the simultaneous stabilization of helical secondary structures and the exocyclic N-functionalization of the side chain-tethering lactam bridge. This is accomplished by means of a novel solid-phase methodology comprising, for the first time, the on-resin Ugi reaction-based macrocyclization of peptide side chains bearing amino and carboxylic acid groups. The exocyclic diversity elements arise from the isocyanide component used in the Ugi multicomponent stapling protocol, which allows for the incorporation of relevant fragments such as lipids, sugars, polyethylene glycol, fluorescent labels, and reactive handles. We prove the utility of such exocyclic reactive groups in the bioconjugation of a maleimide-armed lactam-bridged peptide to a carrier protein. The on-resin multicomponent stapling proved efficient for the installation of not only one, but also two consecutive lactam bridges having either identical or dissimilar N-functionalities. The easy access to helical peptides with a diverse set of exocyclic functionalities shows prospect for applications in peptide drug discovery and chemical biology.

Multicomponent Approach to a Library of N-Substituted γ-Lactams.

The γ-lactam motif is often found in naturally occurring compounds with diverse biological activities. We prepared a 28-member library of N-substituted γ-lactams following a single-pot, three-component Ugi reaction comprising bifunctional building block, l-glutamic acid methyl ester. The reaction tolerates structurally diverse carbonyl and isocyanide components providing a robust access to functionalized γ-lactams. Antimicrobial susceptibility testing, including agar well diffusion assay, serial microdilution broth assay, and antibiofilm activity testing, identified a potent compound with antibiofilm activity against Staphylococcus aureus ATCC 6538.

Diversity Driven Decoration and Ligation of Fullerene by Ugi and Passerini Multicomponent Reactions.

Aiming at providing an efficient and versatile method for the diversity-oriented decoration and ligation of fullerenes, we report the first C60 derivatization strategy based on isocyanide-multicomponent reactions (I-MCRs). The approach comprises the use of Passerini and Ugi reactions for assembling pseudo-peptidic scaffolds (i.e., N-alkylated and depsipeptides, peptoids) on carboxylic acid-functionalized fullerenes. The method showed wide substrate scope for the oxo and isocyanide components, albeit the Ugi reaction proved efficient only for aromatic amines. The approach was successfully employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C60 , as well as for the construction of bis-antennary as well as PEG-tethered dimeric fullerenes. The quantum yields for the formation of 1 O2 was remarkable for the selected compounds analyzed.

Library-to-Library Synthesis of Highly Substituted α-Aminomethyl Tetrazoles via Ugi Reaction.

α-Aminomethyl tetrazoles, recently made accessible by an Ugi multicomponent reaction (MCR), were shown to be excellent starting materials for a further Ugi MCR, yielding substituted N-methyl-2-(((1-methyl-1H-tetrazol-5-yl)methyl)amino)acetamides having four points of diversity in a library-to-library approach. The scope and limitations of the two-step sequence was explored by conducting more than 50 reactions. Irrespective of electron-rich and electron-deficient oxo-components and the nature of the isocyanide component, the reactions give excellent yields. Sterically less hindered α-aminomethyl tetrazoles give better yields of in further Ugi MCR. The target scaffold has four points of diversity and is finding applications to fill screening decks for high-throughput screening (HTS) in the European Lead Factory and in structure-based drug design.

One step access to oxindole-based β-lactams through Ugi four-center three-component reaction.

A multicomponent Ugi reaction involving isatin, isocyanide and β-amino acid components has been developed. The reactions proceeded smoothly to give β-lactam-containing 3,3-disubstituted oxindoles in only one step and generally high yields. When chiral, non racemic, β-amino acids were used, products were obtained as enantiomerically pure β-lactams diastereoisomers, whose relative stereochemistry was determined by X-ray analysis. For one compound, a weak antibacterial activity has been preliminarily highlighted.

Ugi Four-Component Assembly Process: An Efficient Approach for One-Pot Multifunctionalization of Nanographene Oxide in Water and Its Application in Lipase Immobilization

Graphene-based materials are revealing the leading edge of advanced technology for their exceptional physical and chemical properties. Chemical manipulation on graphene surface to tailor its unique properties and modify atomic structures is being actively pursued. Therefore, the discovery of robust and general protocols to anchor active functionality on graphene basal plane is still of great interest. Multicomponent reactions promise an enormous level of interest due to addressing both diversity and complexity in combinatorial synthesis, in which more than two starting compounds react to form a product derived from entire inputs. In this article, we present the first covalent functionalization route beginning with carboxylated-graphene oxide through Ugi four-component assembly process (Ugi 4-CAP), in which amine, aldehyde, isocyanide, and acid components come together in a one-pot reaction to generate hydrophobic-, hydrophilic-, or amiphiphilic multifunctionalized graphene composites. Investigation on the...

Aminocatalysis-Mediated on-Resin Ugi Reactions: Application in the Solid-Phase Synthesis of N-Substituted and Tetrazolo Lipopeptides and Peptidosteroids.

A new solid-phase protocol for the synthesis of N-substituted and tetrazolo peptides is described. The strategy relies on the combination of aminocatalysis-mediated on-resin Ugi reactions and peptide couplings for the N-alkylation of peptides at selected sites, including the N-terminal double lipidation, the simultaneous lipidation/biotinylation, and the steroid/lipid conjugation via tetrazole ring formation. The solid-phase Ugi four-component reactions were enabled by on-resin transimination steps prior to addition of the acid and isocyanide components. The strategy proved to be suitable for the feasible incorporation of complex N-substituents at both termini and at internal positions, which is not easily achievable by other solid-phase methods.

A straightforward approach towards cyclic photoactivatable tubulysin derivatives.

The development of a new photolabile protecting group containing an additional allyl functionality allows the synthesis of cyclic photoactivatable natural products. Cyclization occurs between the allyl moiety in the protecting group and a second double bond in the target molecule by means of ring-closing metathesis. Cyclization should increase the metabolic stability towards proteases. On the other hand, the conformational change should cause diminished biological activity. As illustrated for tubulysin derivatives, cyclic and photoactivatable drug candidates can easily be obtained in only two steps from simple building blocks through Ugi reaction and ring-closing metathesis. The photolabile protecting group is introduced by means of the isocyanide component during the Ugi reaction.

Photocaging of carboxylic acids: a modular approach.

Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.

Photocaging of Carboxylic Acids: A Modular Approach

AbstractPhotocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.