N-Heterocyclic Carbene Catalyzed Research Articles

Microwave-Assisted Synthesis of Symmetrical 1,4-Disubstituted Bis-1H-1,2,3-triazoles Using Copper N-Heterocyclic Carbene Catalysts

Bis-triazoles separated by a symmetrical linking group are joined at C4 of each triazole or at N1 of each triazole. Preparation of a series of bis-1H-1,2,3-triazoles derived from o-bis(azidomethyl)benzene and an alkyne is reported with use of copper N-heterocyclic carbene catalysis with microwave-assisted heating in an aqueous solvent. The products were symmetrical N1–N1′-bis-1H-1,2,3-triazoles. Additional syntheses utilized dialkynes and organic azides to prepare symmetrical C4–C4′-bis-1H-1,2,3-triazoles. Pure products were often obtained directly when water was used as the solvent with microwave-assisted heating. Results are given for experiments using conventional heating or no heating. Sonication results are given for a reaction where microwave-assisted heating was unsatisfactory.

Light-Driven N-Heterocyclic Carbene-Catalyzed Multi-Component Reaction for the Synthesis of β-Amino Ketones.

A N-heterocyclic carbene-catalyzed (NHC) three-component reaction involving N-aminopyridinium salts, alkenes, and aldehydes for the synthesis of β-amino ketones is described. In this reaction, N-aminopyridinium salts and the Breslow intermediate, which is generated from NHC and aldehydes, are utilized to undergo a single-electron transfer process, forming a ketyl radical intermediate and amidyl radicals. Subsequent to the formation of the amidyl radical, it undergoes selective capture by alkenes, followed by radical cross-coupling to yield the desired β-amino ketones.

Asymmetric Synthesis of Benzofuranones with a C3 Quaternary Center via an Addition/Cyclization Cascade Using Noncovalent N-Heterocyclic Carbene Catalysis.

An asymmetric addition/cyclization cascade of amidoesters and iminoquinones is developed using noncovalent N-heterocyclic carbene (NHC) catalysis. The process enables access to various functionalized benzofuranones with an all-carbon quaternary stereocenter with high yields and ee values. The reaction displays a broad substrate scope. Via product modifications, enantioenriched synthesis of biologically relevant spirocyclic lactones and lactams is achieved. Substrate activation via noncovalent interaction with NHC is suggested for the process.

Facile construction of 2-pyrones under carbene catalysis.

2-Pyrones are valuable structural motifs in organic chemistry, found in numerous natural products and pharmaceuticals. The synthesis of these heterocycles has been significantly advanced by the application of N-Heterocyclic Carbene (NHC) catalysis. This review examines the recent advancements in NHC-catalyzed synthesis of 2-pyrones, highlighting key methodologies, mechanisms, and synthetic applications. NHC catalysis has revolutionized the synthesis of 2-pyrones, providing efficient, selective, and versatile methods for constructing these valuable heterocycles.

Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc‐mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N‐heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol‐derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring‐opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate‐determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species.

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc-mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N-heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol-derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring-opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate-determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

N-Heterocyclic Carbene Catalyzed Reassembly of Dibenzyl Ethers: Facile Access to α-Hydroxy Ketones

AbstractA novel one-pot cascade process of oxidation-initiated, N-heterocyclic carbene catalyzed, reintegration of dibenzyl ethers has been developed for the first time. This protocol allows straightforward access to α-hydroxy ketones from dibenzyl ethers. It is noteworthy that the present method is the first attempt to synthesize benzoin from dibenzyl ether.

N-Heterocyclic carbene catalytic 1,2-boron migrative acylation accelerated by photocatalysis.

The transformation of organoboron compounds plays an important role in synthetic chemistry, and recent advancements in boron-migration reactions have garnered considerable attention. Here, we report an unprecedented 1,2-boron migrative acylation upon photocatalysis-facilitated N-heterocyclic carbene catalysis. The design of a redox-active boronic ester substrate, serving as an excellent β-boron radical precursor, is the linchpin to the success of this chemistry. With the established protocol, a wide spectrum of β-boryl ketones has been rapidly synthesized, which could further undergo various C─B bond transformations to give multifunctionalized products. The robustness of this catalytic strategy is underscored by its successful application in late-stage modification of drug-derived molecules and natural products. Preliminary mechanistic investigations, including several control experiments, photochemistry measurements, and computational studies, shed light on the catalytic radical reaction mechanism.

Carbene-Catalyzed Enantioselective Addition of Sulfinate to Ketones.

A carbene-catalyzed enantioselective addition of sulfinate to ketones between 2-benzoylbenzaldehyde and sulfonyl chloride is disclosed. Up to now, the carbon and heteroatom nucleophiles have effectively undergone catalytic enantioselective addition to carbonyl molecules to introduce functionalities and chirality. Sulfone, as an important class of sulfur-containing functional groups, represents highly valuable motifs in medicines and natural products. It remains undeveloped for the catalytic asymmetric addition of sulfinate to carbonyls. Herein we disclosed the first catalytic enantioselective addition of sulfinate to ketones for the synthesis of sulfones via N-heterocyclic carbene (NHC) catalysis. The sulfonyl chloride behaves both as an oxidant and as a nucleophilic substrate in this carbene-catalyzed process. Experimental studies suggested that the Breslow intermediate can be SET oxidized by sulfonyl chloride to generate the sulfonyl radical. This novel synthetic approach for the asymmetric addition of sulfinate to carbonyls can also be used to modify the commercially available functional molecules.

Redox Active N-Heterocyclic Carbenes in Oxidative NHC Catalysis.

An N-heterocyclic carbene (NHC) covalently linked to a quinone introduces a novel avenue for internal oxidations within oxidative NHC catalysis. The deployment of this hybrid NHC class promotes intramolecular electronic flow in the oxidation of the Breslow intermediate to acyl azolium. The use of the redox active NHC as a catalyst is facilitated by employing aerobic regeneration, yielding carboxylic esters with efficiencies of ≤99%, while generating water as the sole byproduct.

NHC-Catalyzed Reaction of Aldehydes for C(sp2)–O Bond Formation

In the past few decades, N-heterocyclic carbenes (NHCs) have opened the new field of organocatalysis in synthetic organic chemistry. This review highlights the dramatic progress in the field of NHC-catalyzed C–O bond formation based on the activation of aldehyde C(sp2)–H bonds. The oxidative and redox transformations for the synthesis of various molecules with structural diversity and complexity are summarized. Furthermore, new methods and strategies for NHC catalysis are emerging continuously; thus, cooperative catalysis with Brønsted acid, hydrogen-bonding catalyst, transition-metal catalyst, and photocatalyst are also described.

Cross‐Coupling Reaction of Alkyl Halides with Aldehydes through NHC Catalysis

AbstractDuring the past decades, N‐heterocyclic carbene (NHC)‐catalyzed reactions have emerged as a versatile tool in synthetic chemistry. In particular, NHC‐catalyzed cross‐coupling reaction has been significantly developed in many respects, including new reaction development and mechanistic investigation. This concept article presents recent advances towards direct cross‐coupling reactions of aldehydes with alkyl halides enabled by NHC organocatalysis.

N-Heterocyclic Carbene-Catalyzed Facile Synthesis of Phthalidyl Sulfonohydrazones: Density Functional Theory Mechanistic Insights and Docking Interactions.

N-heterocyclic carbene catalysis reaction protocol is disclosed for the synthesis of phthalidyl sulfonohydrazones. A broad range of N-tosyl hydrazones react effectively with phthalaldehyde derivatives under open-air conditions, enabling the formation of a new C-N bond via an oxidative path. The reaction proceeds under mild reaction conditions with broad substrate scopes, wide functional group tolerance, and good to excellent yields. The mechanistic pathway is studied successfully using control experiments, competitive reactions, ESI-MS spectral analyses of the reaction mixture, and computational study by density functional theory. The potential use of one of the phthalidyl sulfonohydrazone derivatives as the inhibitor of β-ketoacyl acyl carrier protein synthase I of Escherichia coli is investigated using molecular docking.

Cooperative Photoredox and N-Heterocyclic Carbene Catalysis Suzuki-Miyaura-Type Reaction: Radical Coupling of Aroyl Fluorides and Alkyl Boronic Acids.

An intermolecular Suzuki-Miyaura-type reaction of benzoyl fluorides with alkyl boronic acids to synthetic ketone was revealed by cooperative N-heterocyclic carbene (NHC) and photoredox catalysis. Various alkyl boric acids can be converted into alkyl radicals without external oxidants or activators. Moreover, the catalytic system was feasible for the difunctionalization of styrenes via a radical relay process. Mechanistic experiments suggested that the benzoate anion intermediate might play a unique role in this reaction system.

Phosphonylacylation of Alkenes Enabled by Visible-Light-Induced N-Heterocyclic Carbene Catalysis.

Herein, we report the phosphonylacylation of alkenes via visible-light-induced N-heterocyclic carbene (NHC) catalysis to afford a series of γ-ketophosphonates in moderate to good yields. This protocol features mild conditions, free of photocatalyst, and good compatibility of functional groups. The excited Breslow enolate intermediate was proposed to undergo single-electron transfer with oxime phosphonate to generate the corresponding ketyl radical and phosphonyl radical.

N‐Heterocyclic Carbene Organocatalyzed [3+3] Annulation for the Enantioselective Synthesis of Benzopyranothiazinones

AbstractThe design, inspired by the core‐structure of oxicam has allowed the enantioselective synthesis of benzopyranothiazinone motifs employing N‐heterocyclic carbene (NHC) catalysis. The NHC‐mediated transformation involves the reaction of α,β‐unsaturated aldehydes with suitable substituted benzothiazinone derivatives. This process encompasses the initial formation of α,β‐unsaturated acylazoliums from ynals and concurrent generation of enolates from benzothiazinone. The culmination of these reactions results in an efficient annulation, yielding the desired products with reasonable yields and high stereoselectivities. This study underscores the potential of NHC catalysis in the streamlined synthesis of complex heterocyclic structures.

Enantioselective [3 + 3] Annulation-Deoxalation Strategy for Rapid Access to δ-Oxoesters via N-Heterocyclic Carbene Catalysis.

A new and unprecedented stereoselective synthetic approach to δ-oxoesters derivatives from readily available starting materials has been developed. This method, catalyzed by N-heterocyclic carbene, involves an annulation-deoxalation reaction of alkynyl aldehydes with 2,4-diketoesters and proceeds via the chiral α,β-unsaturated acylazolium intermediates. The annulation includes the in situ formation of dihydropyranones, which undergo ring-opening methanolysis with Lewis acid activation, followed by deoxalation to afford chiral 1,5-ketoesters in moderate to good yields.

Wingtip-Flexible N-Heterocyclic Carbenes: Unsymmetrical Connection between IMes and IPr.

IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed β-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.

Enantioselective synthesis of C3-functionalized 2,1-benzothiazine 2,2-dioxides by N-heterocyclic carbene catalysis.

We present herein an approach for the enantioselective C3-functionalization of 2,1-benzothiazine 2,2-dioxides using N-heterocyclic carbene (NHC) catalysis. Our method involves a sequence of [3+3] cycloaddition and ring-opening reactions with different N- and O-nucleophiles, followed by silylation. Overcoming the challenge of selectivity targeting the C3 position, this protocol demonstrates a broad substrate scope and high enantioselectivity. This marks a significant advancement in the field of NHC-catalyzed transformations.

Recent advances in cooperative N-heterocyclic carbenes and photocatalysis

Combination of N-heterocyclic carbene catalysis and photocatalysis with radical process is a powerful strategy to access useful molecules. In this review, we summarized recent advances in this growing area from the perspective of reaction mechanism.