Carbene Organocatalysis Research Articles

Assembly of versatile fluorine-containing structures via N-heterocyclic carbene organocatalysis

Assembly of versatile fluorine-containing structures via N-heterocyclic carbene organocatalysis

Desymmetrization of N-Cbz glutarimides through N-heterocyclic carbene organocatalysis

Over the past decade, the catalysis of N-heterocyclic carbenes has achieved significant advances. In this area, aldehydes, enals, and esters, are commonly employed as starting materials through various catalytic activation modes. However, NHC-activated strategy of amide and its derivatives remains elusive. Described herein is the realization of asymmetric desymmetrization of N-Cbz glutarimides with alcohols through an imide C-N bond cleavage under NHC organocatalysis. A structurally diverse set of enantioenriched 4-amido esters is generated with acceptable yields and high enantioselectivities. This method features mild reaction conditions, excellent substrate scope, and excellent atom economy. DFT calculations have been performed to explore the detailed reaction mechanism and the origin of the enantioselectivity, which indicate that the strength of the C-H···O hydrogen bond and C–H⋯π interactions should be responsible for the stereoselectivity. The current strategy could open a door for efficient construction of (R)-Rolipram with excellent stereoselectivity.

Electroredox carbene organocatalysis with iodide as promoter

Oxidative carbene organocatalysis, inspired from Vitamin B1 catalyzed oxidative activation from pyruvate to acetyl coenzyme A, have been developed as a versatile synthetic method. To date, the α-, β-, γ-, δ- and carbonyl carbons of (unsaturated)aldehydes have been successfully activated via oxidative N-heterocyclic carbene (NHC) organocatalysis. In comparison with chemical redox or photoredox methods, electroredox methods, although widely used in mechanistic study, were much less developed in NHC catalyzed organic synthesis. Herein, an iodide promoted electroredox NHC organocatalysis system was developed. This system provided general solutions for electrochemical single-electron-transfer (SET) oxidation of Breslow intermediate towards versatile transformations. Radical clock experiment and cyclic voltammetry results suggested an anodic radical coupling pathway.

Mesoionic carbene-catalyzed arylacylation of alkenes

Significant advancements in N-heterocyclic carbene (NHC) organocatalysis via so-called Breslow intermediates (BIs) have been achieved in the past few decades. However, the use of BIs via single electron transfer (SET) pathways is still in its infancy and the scope is limited by the moderate reduction potential of BIs derived from classical NHCs. We reported a radical-relay arylacylation of alkenes via the reduction of iodobenzene by BIs derived from mesoionic carbenes (BIMICs).

Progress in Organocatalytic Dearomatization Reactions Catalyzed by N‐Heterocyclic Carbenes

AbstractDearomative reactions allow for concise assembly of structurally complex, highly functionalized three‐dimensional molecules by breaking the plane of two‐dimensional aromatic starting materials. With the growing interest in N‐heterocyclic carbene (NHC) organocatalysis as a powerful strategy for synthesizing diversiform molecules, mainly by polarity‐reversal (umpolung) approaches, NHC‐catalyzed dearomatization reactions have recently been successfully used for the construction of the skeletons of natural products and drugs. By generating various key intermediates (i. e., Breslow intermediates, acyl azolium intermediates, homoenolate intermediates, enolate intermediates, and azolium dienolate intermediates), NHCs can readily destroy aromaticity by electrophilic or nucleophilic interactions with aromatic compounds. In this overview, progress in NHC‐catalyzed dearomative reactions is summarized; the reactions are grouped according to reaction modes and categories of intermediates, and representative mechanisms are provided. This review aims to serve as a comprehensive reference for work in the emerging field of organocatalytic dearomatization.

Titelbild: Remote C(sp 3 )−H Acylation of Amides and Cascade Cyclization via N‐Heterocyclic Carbene Organocatalysis (Angew. Chem. 15/2022)

Eine organokatalytische C(sp3)-H-Acylierung von Amiden wurde auf der Grundlage einer 1,5-Wasserstoffatom-Transferstrategie entwickelt. Im Forschungsartikel von Jun-Long Li et al. (e202116629) wurden über 120 funktionalisierte δ-Aminoketone und Isochinolinone in bis zu 99 % Ausbeute unter milden Bedingungen synthetisiert. Mechanistische Untersuchungen, einschließlich Kontrollreaktionen, KIE-Experimente und theoretische Studien, geben Aufschluss über den Mechanismus der organokatalytischen Radikalreaktion.

Cover Picture: Remote C(sp3)−H Acylation of Amides and Cascade Cyclization via N‐Heterocyclic Carbene Organocatalysis (Angew. Chem. Int. Ed. 15/2022)

An NHC-organocatalyzed remote C(sp3)−H acylation of amides is developed based on a 1,5-hydrogen atom transfer strategy. As reported in the Research Article by Jun-Long Li et al. (e202116629), over 120 functionalized δ-amino ketones and isoquinolinones were synthesized in up to 99 % yield under mild conditions. Mechanistic investigations, including control reactions, KIE experiments, and computational studies, shed light on the organocatalytic radical reaction mechanism.

The Role of the Fused Ring in Bicyclic Triazolium Organocatalysts: Kinetic, X-ray, and DFT Insights.

Bicyclic triazolium scaffolds are widely employed in N-heterocyclic carbene (NHC) organocatalysis. While the incorporation of a fused ring was initially for synthetic utility in accessing chiral, modular triazolyl scaffolds, recent results highlight the potential for impact upon reaction outcome with the underpinning origins unclear. The common first step to all triazolium-catalyzed transformations is C(3)-H deprotonation to form the triazolylidene NHC. Herein, we report an analysis of the impact of size of the fused (5-, 6-, and 7-membered, n = 1, 2, and 3, respectively) ring on the C(3) proton transfer reactions of a series of bicyclic triazolium salts. Rate constants for the deuteroxide-catalyzed C(3)-H/D-exchange of triazolium salts, kDO, were significantly influenced by the size of the adjacent fused ring, with the kinetic acidity trend, or protofugalities, following the order kDO (n = 1) > kDO (n = 2) ≈ kDO (n = 3). Detailed analyses of X-ray diffraction (XRD) data for 20 triazolium salts (including 16 new structures) and of computational data for the corresponding triazolylidene NHCs provide insight on structural effects of alteration of fused ring size. In particular, changes in internal triazolyl NCN angle and positioning of the most proximal CH2 with variation in fused ring size are proposed to influence the experimental protofugality order.

Remote C(sp3)−H Acylation of Amides and Cascade Cyclization via N‐Heterocyclic Carbene Organocatalysis

AbstractThe direct functionalization of inert C(sp3)−H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote C(sp3)−H acylation of amides and cascade cyclization through a radical‐mediated 1,5‐hydrogen atom transfer mechanism using N‐heterocyclic carbene as the catalyst. Notably, a diversity of nitrogen‐containing substrates, including simple linear aliphatic carbamates and ortho‐alkyl benzamides, can be successfully applied to this organocatalytic system. With the established protocol, over 120 examples of functionalized δ‐amino ketones and isoquinolinones with diverse substituents were easily synthesized in up to 99 % yield under mild conditions. The robustness and generality of the organocatalytic strategy were further highlighted by the successful acylation of unactivated C(sp3)−H bonds and late‐stage modification of pharmaceutical molecules. Then, the asymmetric control of the radical reaction was attempted and proven feasible by using a newly designed chiral thiazolium catalyst, and moderate enantioselectivity was obtained at the current stage. Preliminary mechanistic investigations including several control reactions, KIE experiments, and computational studies shed light on the organocatalytic radical reaction mechanism.

Remote C(sp3 )-H Acylation of Amides and Cascade Cyclization via N-Heterocyclic Carbene Organocatalysis.

The direct functionalization of inert C(sp3 )-H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote C(sp3 )-H acylation of amides and cascade cyclization through a radical-mediated 1,5-hydrogen atom transfer mechanism using N-heterocyclic carbene as the catalyst. Notably, a diversity of nitrogen-containing substrates, including simple linear aliphatic carbamates and ortho-alkyl benzamides, can be successfully applied to this organocatalytic system. With the established protocol, over 120 examples of functionalized δ-amino ketones and isoquinolinones with diverse substituents were easily synthesized in up to 99 % yield under mild conditions. The robustness and generality of the organocatalytic strategy were further highlighted by the successful acylation of unactivated C(sp3 )-H bonds and late-stage modification of pharmaceutical molecules. Then, the asymmetric control of the radical reaction was attempted and proven feasible by using a newly designed chiral thiazolium catalyst, and moderate enantioselectivity was obtained at the current stage. Preliminary mechanistic investigations including several control reactions, KIE experiments, and computational studies shed light on the organocatalytic radical reaction mechanism.

Carbene catalyzed C(sp3)–Cl activation of chlorinated solvents for benzyne chlorination

A new mode of N-heterocyclic carbene (NHC) organocatalysis was discovered, in which the normally inert chlorinated solvents were activated by carbene to realize the chlorination of hexa-dehydro-Diels-Alder derived benzynes.

A General Method for α-Oxyacylation of Vinyl Ketones Using Koser's Reagent.

A direct general method for the preparation of α-oxyacylated vinyl ketones using Koser's hypervalent iodine reagent is reported. A variety of acyloxy groups from long-chain aliphatic, aromatic, α,β-unsaturated carboxylic acids have been installed efficiently for the first time. The oxyacylated adducts were used for the preparation of densely functionalized chiral δ-lactones and cyclopentenes using carbene organocatalysis.

Norrish type II reactions of acyl azolium salts

The photochemical reactivity of acyl azolium salts derived from aliphatic carboxylic acids has been investigated. These species, which serve as models for intermediates generated in N-heterocyclic carbene (NHC) organocatalysis, undergo Norrish type II elimination reactions under irradiation with UVA light in analogy to structurally related aromatic ketones. Moreover, efficient Norrish-Yang cyclization was observed from an adamantyl-substituted derivative. These results further demonstrate the ability of NHCs to influence the absorption properties and photochemical reactivity of carbonyl groups during a catalytic cycle.

NHC Organocatalysis in D2O for the Highly Diastereoselective Synthesis of Deuterated Spiropyran Analogues

AbstractMetal‐free N‐heterocyclic carbene (NHC) organocatalysis in D2O medium was elegantly utilised for the synthesis of highly diastereoselective deuterated spiropyran derivatives. Selective deuteration was exclusively achieved on the C5 carbon atom of the pyran ring. Quantum chemical calculations were performed to prove the preferential formation of a single diastereomer from the possible four diastereomers. The scope of NHC organocatalysis in D2O was also extended for the synthesis of deuterated spirooxindole derivative.

N-Heterocyclic carbene-catalyzed radical ring-opening acylation of oxime esters with aldehydes

We report a radical cross-coupling of cycloketone oxime esters with aldehydes by N-heterocyclic carbene (NHC) organocatalysis. This protocol features easy operation, with no need for external redox reagent, and a broad functional group compatibility.

Tale of the Breslow intermediate, a central player in N-heterocyclic carbene organocatalysis: then and now.

N-Heterocyclic carbenes (NHCs) belong to the popular family of organocatalysts used in a wide range of reactions, including that for the synthesis of complex natural products and biologically active compounds. In their organocatalytic manifestation, NHCs are known to impart umpolung reactivity to aldehydes and ketones, which are then exploited in the generation of homoenolate, acyl anion, and enolate equivalents suitable for a plethora of reactions such as annulation, benzoin, Stetter, Claisen rearrangement, cycloaddition, and C–C and C–H bond functionalization reactions and so on. A common thread that runs through these NHC catalyzed reactions is the proposed involvement of an enaminol, also known as the Breslow intermediate, formed by the nucleophilic addition of an NHC to a carbonyl group of a suitable electrophile. In the emerging years of NHC catalysis, enaminol remained elusive and was largely considered a putative intermediate owing to the difficulties encountered in its isolation and characterization. However, in the last decade, synergistic efforts utilizing an array of computational and experimental techniques have helped in gaining important insights into the formation and characterization of Breslow intermediates. Computational studies have suggested that a direct 1,2-proton transfer within the initial zwitterionic intermediate, generated by the action of an NHC on the carbonyl carbon, is energetically prohibitive and hence the participation of other species capable of promoting an assisted proton transfer is more likely. The proton transfer assisted by additives (such as acids, bases, other species, or even a solvent) was found to ease the kinetics of formation of Breslow intermediates. These important details on the formation, in situ detection, isolation, and characterization of the Breslow intermediate are scattered over a series of reports spanning well over a decade, and we intend to consolidate them in this review and provide a critical assessment of these developments. Given the central role of the Breslow intermediate in organocatalytic reactions, this treatise is expected to serve as a valuable source of knowledge on the same.

Desymmetrization of Cyclic 1,3-Diketones under N-Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers.

Symmetric 1,3-diketones with fluorine or fluorinated substituents on the prochiral carbon remain to be established. Herein, we have developed a novel prochiral fluorinated oxindanyl 1,3-diketone and successfully applied these substrates in carbene-catalyzed asymmetric desymmetrization. Accordingly, a versatile strategy for asymmetric generation of organofluorines with fluorine or fluorinated methyl groups has been developed. Multiple stereogenic centers were selectively constructed with satisfactory outcomes. Structurally diverse enantioenriched organofluorines were generated with excellent results in terms of yields, diastereoselectivities, and enantioselectivities. Notably, exchanging fluorinated methyl groups to fluorine for this prochiral 1,3-diketones leads to switchable stereoselectivity. Mechanistic aspects and origin of stereoselectivity were studied by DFT calculations. Notably, some of the prepared organofluorines demonstrated competitive antibacterial activities.

Organocatalytic Three-Component 1,2-Cyanoalkylacylation of Alkenes via Radical Relay.

Here, we report an unprecedented regioselective, intermolecular 1,2-cyanoalkylacylation of feedstock alkenes with readily available oxime esters and aldehydes by N-heterocyclic carbene (NHC) organocatalysis. The crux of this success is the exquisite control over the radical relay process by an NHC organocatalyst. This protocol offers a general platform for diversity-oriented synthesis of valuable ketonitriles under mild, transition-metal-free, and redox-neutral conditions and highlights its potential in the late-stage functionalization of pharmaceutical architectures and natural products.

Single-Electron Transfer Reactions Enabled by N-Heterocyclic Carbene Organocatalysis.

Over the past decades, N-heterocyclic carbene (NHC) organocatalysis has undergone a flourish of development on the basis of closed-shell reaction paths. By contrast, the emerging area of single-electron transfer (SET) reactions enabled by NHC catalysis still remain underdeveloped, but offer plenty of opportunities to develop new catalytic modes and useful synthetic methods. A number of interesting transformations were triggered by the SET process from the electron-rich Breslow intermediates to various single-electron acceptors. In additions, recent studies revealed that the Breslow radical cations could also be generated by single-electron reduction of the electron-deficient acyl azolium intermediates. These discoveries open a new avenue for NHC organocatalysis to harness radical reactions. The present review will focus on the exciting advancements in the dynamic area of radical NHC organocatalysis.

Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed [3 + 2] Annulation of Vinyl Enolates with 1-Tosyl-2-vinylaziridine.

The synergistic combination of N-heterocyclic carbene organocatalysis and transition-metal catalysis for a formal [3 + 2] annulation between 3-substituted but-2-enoates and 1-tosyl-2-vinylaziridine was developed. This cooperative strategy provides a facile and efficient access to various functionalized (E)-3-ethylidene-4-vinylpyrrolidin-2-ones in a regioselective and stereoselective manner. The preliminary asymmetric studies were also performed, which indicated a potential for enantioselective annulation of vinyl enolate intermediates with transition-metal-π-allyl species.