Isocyanide Insertion Research Articles

Synthesis of Quinoxaline‐2,3‐diamines via Palladium‐Catalysed Double Isocyanide Insertion Cyclization

An approach for the synthesis of quinoxaline‐2,3‐diamines is reported using a palladium‐catalyzed cyclization reaction of o‐phenylenediamines and isocyanides. Various quinoxaline‐2,3‐diamines could be obtained in 25%‐95% yields at 100 °C for 3 h. The key to the success of this protocol involves the formation of two C‐N and one C‐C bonds via the double insertion of isocyanide.

Synthesis of β-Carbonyl α-Iminoamides by Double Insertion of Isocyanides into Aldehydes.

An unprecedented trimethylsilyl trifluoromethanesulfonate (TMSOTf)-promoted selective double insertion of isocyanides into aldehydes was developed, providing an efficient protocol for synthetically challenging β-carbonyl α-iminoamides. The given approach is applicable for a diverse selection of readily accessible aldehydes, along with isocyanides serving as essential precursors for "amide" and "imine" scaffolds. The versatile transformations of the given products were demonstrated, and the pivotal intermediates for the plausible mechanism were identified.

Palladium‐Catalyzed Isocyanide Insertion into the Remotely Activated N−H bond of 3‐(Phenylhydrazono)oxindoles: Facile Access to Indole‐N‐Carboxamide Derivatives

AbstractA convenient approach for synthesizing indole‐N‐carboxamide derivatives through palladium‐catalyzed isocyanide insertion into the N−H bond of 3‐(phenylhydrazono)oxindoles has been developed. The inclusion of the 3‐phenylhydrazone group proved essential in remotely activating the N−H bond of the oxindole. Also, it has been established that the reaction outcome is highly dependent on the electronic effects of the substituents.

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge. Herein, an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction for assembling ketoamides in aqueous DMSO from (hetero)aryl halides and pseudohalides under mild conditions is reported. The effectiveness and utility of this protocol are demonstrated by its diverse substrate scope (93 examples), the ability to late-stage modify pharmaceuticals, scalability to large-scale synthesis, and the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand that modulates the Pd-catalyzed double isocyanide insertion process, thereby selectively providing the desired α-ketoamides in a unique manner. In addition, the imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, confirming that they are probable intermediates in the catalytic pathway.

Dimensional Reduction of Metal-Organic Frameworks for Photocatalytic Synthesis of Fused Tetracyclic Heterocycles.

Heterogeneous palladium catalysts with high efficiency, high Pd atom utilization, simplified separation, and recycle have attracted considerable attention in the field of synthetic chemistry. Herein, we reported a zirconium-based two-dimensional metal-organic framework (2D-MOF)-based Pd(II) photocatalyst (Zr-Ir-Pd) by merging the Ir photosensitizers and Pd(II) species into the skeletons of the 2D-MOF for the Pd(II)-catalyzed oxidation reaction. Morphological and structural characterization identified that Zr-Ir-Pd with a specific nanoflower-like structure consists of ultrathin 2D-MOF nanosheets (3.85 nm). Due to its excellent visible-light response and absorption capability, faster transfer and separation of photogenerated carriers, more accessible Pd active sites, and low mass transfer resistance, Zr-Ir-Pd exhibited boosted photocatalytic activity in catalyzing sterically hindered isocyanide insertion of diarylalkynes for the construction of fused tetracyclic heterocycles, with up to 12 times the Pd catalyst turnover number than the existing catalytic systems. In addition, Zr-Ir-Pd inhibited the competitive agglomeration of Pd(0) species and could be reused at least five times, owing to the stabilization of 2D-MOF on the single-site Pd and Ir sites. Finally, a possible mechanism of the photocatalytic synthesis of fused tetracyclic heterocycles catalyzed by Zr-Ir-Pd was proposed.

Cyclic (Alkyl)(Amino)Carbene-Iminoboryl Compounds with Three Formal Oxidation States.

BN/CC isosterism is an effective strategy to build hybrid functional molecules with unique properties. In contrast to the alkynyl iminium salts derived from cyclic (alkyl)(amino)carbenes (CAACs) that feature only one reversible reduction wave, the isoelectronic cationic CAAC-iminoboryl adducts could be singly and doubly reduced smoothly. Both the resultant neutral radical and anionic azaborataallenes bear NBC-mixed allenic structures. The former radical has a high spin-density of 0.55e at CCAAC carbon, yet exhibits formal boron-centered radical reactivity. The latter azaborataallenes feature the nucleophilic CCAAC center and polar N(δ-)═B(δ+)═C(δ-) unit, and readily undergo nucleophilic substitution, isocyanide insertion, dipolar addition and cycloaddition reactions etc. The N-substituents have been shown to have a significant influence on the solid-state structure, thermal stability, and reactivity of azaborataallenes. This work showcases the allenic BN-unsaturated species as versatile building blocks in organic synthesis.

Reductive Retrocyclization of a Mangana(II)cyclopentasilane to Form Manganese(0) Bis(η2-disilene) Complexes.

Ligand-exchange reactions on a mangana(II)cyclopentasilane complex that contains two THF ligands with aryl isocyanides led to the formation of manganese(0) bis(η2-disilene) complexes via a retrocyclization. In stark contrast, ligand-exchange reactions with CNtBu, an N-heterocyclic carbene, or pyridine-based ligands furnished manganese(II) complexes wherein the manganacyclopentasilane framework remained intact. The thermolysis of the obtained bis(η2-disilene) complex in the presence of mesityl isocyanide led to the formation of a cyclotetrasilane via the formal dimerization of the two η2-disilene moieties. The insertion of a mesityl isocyanide into the Mn-Siβ bond results in the formation of a manganese(II) complex supported by a [SiCSi]-type tridentate ligand scaffold.

Reductive Retrocyclization of a Mangana(II)cyclopentasilane to Form Manganese(0) Bis(η2‐disilene) Complexes

AbstractLigand‐exchange reactions on a mangana(II)cyclopentasilane complex that contains two THF ligands with aryl isocyanides led to the formation of manganese(0) bis(η2‐disilene) complexes via a retrocyclization. In stark contrast, ligand‐exchange reactions with CNtBu, an N‐heterocyclic carbene, or pyridine‐based ligands furnished manganese(II) complexes wherein the manganacyclopentasilane framework remained intact. The thermolysis of the obtained bis(η2‐disilene) complex in the presence of mesityl isocyanide led to the formation of a cyclotetrasilane via the formal dimerization of the two η2‐disilene moieties. The insertion of a mesityl isocyanide into the Mn−Siβ bond results in the formation of a manganese(II) complex supported by a [SiCSi]‐type tridentate ligand scaffold.

Direct access to thiomethyl/selenomethyl-substituted pyrazoles by combining isocyanide insertion into the inert C(sp)–S bond and intermolecular cyclization

A strategy for preparing a series of thiomethyl/selenomethyl substituted pyrazoles through palladium-catalyzed isocyanide insertion into the C(sp)–S bond, followed by TMSN3-involved CuI/Sc(OTf)3 catalyzed intermolecular cyclization was reported.

Hydrogen bond-promoted regio- and stereoselective synthesis of isoindoline derivatives through Pd-catalyzed isocyanide insertion reaction involving aziridines

We have successfully demonstrated an efficient and practical Pd-catalyzed reaction between aziridine and isocyanide, leading to the synthesis of isoindoline derivatives in moderate to good yields.

Synthesis of Polysubstituted Pyrimidines through Palladium-Catalyzed Isocyanide Insertion to 2H-Azirines.

The domino process of the palladium-catalyzed coupling reaction of isocyanides with 2H-azirine provides various tetrasubstituted pyrimidines via one C-C bond and two C-N bond formations with satisfactory yields. The title compounds are obtained with good functional group tolerance, high atom economy, and broad substrate scopes.

Cobalt-catalyzed C–H activation and isocyanide insertion of tryptamine derivatives

A cobalt-catalyzed C–H activation and isocyanide insertion of tryptamine derivatives has been developed for the construction of indole-2-carboxamide scaffolds. By using Co(OAc)2·4H2O as the non-noble catalyst, the reaction worked well to give various indole-2-carboxamides in moderate to high yields. Furthermore, the mechanistic experiments indicated that the Co(III) species was the active catalyst in a non-radical reaction pathway. Notably, silver salt as the oxidant could be recycled and reused.

Reactions Involving Multiple Isocyanide Insertions

AbstractIsocyanides (isonitriles or carbylamine) have been intensively used in organic synthesis to prepare a diverse variety of N‐heterocycles on the basis of the carbene‐like reactivity of their divalent carbon atom. Isocyanides participate in a variety of reactions involving one, two, or more isocyanides. Compared to the popularity of single isocyanide reactions, few examples of reactions involving two or more isocyanides have been reported. In this review, we categorized and classified the literatures of reactions involving two or more isocyanides especially double isocyanide insertions under metal‐catalyzed or metal‐free conditions from 2014 to 2022.magnified image

Construction of Tetrazole Derivatives via Sequential Ugi‐N3/Pd‐Catalyzed Isocyanide Insertion Reactions

AbstractHerein, a straightforward method for the construction of tetrazole derivatives has been achieved through Pd‐catalyzed isocyanide insertion reactions, which is a good extension for the response of multi‐molecule isocyanides. The Ugi‐N3 reaction was introduced to the transformation to enrich the diversity of skeleton structures. The commercially available starting materials and moderate to good yields make this method a valuable tool for generating N‐containing heterocyclic compounds.

Triple-Consecutive Isocyanide Insertions with Aldehydes: Synthesis of 4-Cyanooxazoles.

An efficient TMSOTf-promoted selective triple consecutive insertions of tert-butyl isocyanide into aldehydes has been developed, affording pharmacological interesting 4-cyanooxazoles in high yields in a one pot manner. The given method encompasses a wide range of substrates with tert-butyl isocyanide serving as sources of critical "CN" and "C-N═C" moieties. The versatile transformations of the resulting 4-cyanooxazoles were demonstrated. The key reaction intermediates for plausible mechanisms were determined.

Base-mediated ynone-isocyanide [3+2] cycloaddition: a general method to 2,3,4-tri-substituted 1-H-pyrroles and bis-pyrroles.

A transition-metal-free and base-promoted one-pot synthesis of 2,3,4-trisubstituted 1-H-pyrroles has been developed. The reaction occurs through the [3+2] cycloaddition of differently functionalized ynones and isocyanides. The reaction's advantageous features are operational simplicity, atom economy, and functional group tolerance with broad substrate scope. In addition, 1,3-bis-pyrrole formation and gram-scale synthesis were also achieved. Furthermore, the synthetic utility of the products was also investigated via isocyanide insertion and pyrrole-triazole hybrid formation in good yield.

Rh-catalysed divergent synthesis of polysubstituted pyrroles from α,β-unsaturated ketones via selective single or double insertion of isocyanides

A novel divergent synthetic method for polysubstituted pyrroles from isocyanides and α,β-unsaturated ketones in the presence of a rhodium catalyst and bis(pinacolato)diboron (B2pin2) is described here.

Boron Lewis acid-catalyzed formal insertion of isocyanides into a C–O bond of benzyl esters

A boron Lewis acid catalyzed cascade process consisting of a rare isocyanide insertion with benzyl esters and the Mumm rearrangement to afford valuable imides with 100% atom utilization.

Urea Synthesis from Isocyanides and O-Benzoyl Hydroxylamines Catalyzed by a Copper Salt

In the presence of CuOAc, a series of unsymmetric ureas can be generated in moderate to good yields under mild reaction conditions (10 mol% of CuOAc, 2 equiv t-BuONa or PhONa, 30 °C), using aryl isocyanides and O-benzoyl hydroxylamines as the readily accessible starting materials. The reactions might undergo a cascade process involving isocyanide insertion into the N-O bond and Mumm-type rearrangement. This work represents a rare example of isocyanide insertion into N-O bonds, which would extend isocyanide insertion chemistry.

Divergent Construction of Heterocycles by SOMOphilic Isocyanide Insertion under N-Heterocyclic Carbene Catalysis.

A variety of phenanthridines are rapidly constructed by an N-heterocyclic carbene (NHC)-catalyzed SOMOphilic isocyanide insertion-initiated homolytic aromatic substitution-type radical cyclization in the absence of any light, transition metals, and external oxidants. The aldehyde-free, scalable, and operationally simple protocol tolerates diverse functionalized biaryl isonitriles and activated α-halides. Moreover, it can be further applied to the divergent construction of other N-heterocycles. Preliminary mechanistic studies disclose that an NHC-derived radical cation intermediate is possibly involved.