Acyl Azolium Research Articles

Mechanistic Studies on N-Heterocyclic Carbene-Catalyzed Umpolung of β,γ-Unsaturated α-Diketones.

The mechanism of N-heterocyclic carbene-catalyzed umpolung of β,γ-unsaturated α-diketone was studied using both density functional theory (DFT) calculations and experimental methods. In contrast to the originally proposed mechanism, the calculations revealed a more complicated process involving both nucleophilic O-acylated homoenolate and electrophilic α,β-unsaturated acyl azolium intermediates. The experimental studies confirmed the existence of the aforementioned two key intermediates. A revised mechanism has been proposed to demonstrate the detailed mechanistic insights into the product formation.

Carbene-Catalyzed Alkylation of Carboxylic Esters via Direct Photoexcitation of Acyl Azolium Intermediates

A carbene-catalyzed reductive coupling reaction of carboxylic esters and substituted Hantzsch esters is disclosed. Key steps of this reaction include one-electron reduction of a carbene catalyst-bound acyl azolium intermediate to generate the corresponding radical intermediate for subsequent alkylation reactions. The reaction is promoted by irradiation with visible light without the involvement of transition-metal photocatalysts. Mechanistic studies suggest that direct photoexcitation of the in situ formed acyl azolium intermediate is likely responsible for this light-induced one-electron-reduction process. Photoexcitation converts the acyl azolium intermediate to a single-electron oxidant, enabling single-electron oxidation of Hantzsch esters to generate radical intermediates. Our reactions work well for a broad range of aryl carboxylic ester and Hantzsch ester substrates. Sophisticated structures, including those present in medicines, can be incorporated into ketone molecules using our approach via very mild conditions that tolerate various functional groups.

Acyl Donor Intermediates in N‐Heterocyclic Carbene Catalysis: Acyl Azolium or Azolium Enolate?

AbstractAzolium enolates and acyl azolium cations have been proposed as intermediates in numerous N‐heterocyclic carbene (NHC) catalyzed transformations. Acetyl azolium enolates were generated from the reaction of 2‐propenyl acetate with both saturated (SIPr) and aromatic (IPr) NHCs, isolated, and characterized (NMR, XRD). Protonation with triflic acid gave the corresponding acetyl azolium triflates which were isolated and characterized (NMR, XRD). Acyl azolium cations have been proposed as immediate precursors of the ester product, for example, in the redox esterification of α,β‐enals. Studies with d3‐acetyl azolium triflate suggest that ester formation originates instead from an azolium enolate intermediate. Furthermore, the acetyl azolium enolate selectively reacted with alcohol nucleophiles in the presence of amines. While the acetyl azolium cation did not react with alcohols, an ester‐selective reaction was induced by addition of base, by intermediate formation of the acetyl azolium enolate.

Acyl Donor Intermediates in N-Heterocyclic Carbene Catalysis: Acyl Azolium or Azolium Enolate?

Azolium enolates and acyl azolium cations have been proposed as intermediates in numerous N‐heterocyclic carbene (NHC) catalyzed transformations. Acetyl azolium enolates were generated from the reaction of 2‐propenyl acetate with both saturated (SIPr) and aromatic (IPr) NHCs, isolated, and characterized (NMR, XRD). Protonation with triflic acid gave the corresponding acetyl azolium triflates which were isolated and characterized (NMR, XRD). Acyl azolium cations have been proposed as immediate precursors of the ester product, for example, in the redox esterification of α,β‐enals. Studies with d 3‐acetyl azolium triflate suggest that ester formation originates instead from an azolium enolate intermediate. Furthermore, the acetyl azolium enolate selectively reacted with alcohol nucleophiles in the presence of amines. While the acetyl azolium cation did not react with alcohols, an ester‐selective reaction was induced by addition of base, by intermediate formation of the acetyl azolium enolate.

NHC-catalyzed enantioselective C2-functionalization of 3-hydroxychromenones via α,β-unsaturated acyl azoliums.

A novel synthetic method for enantioselective C2-functionalization of 3-hydroxychromenones promoted by N-heterocyclic carbenes via the formation of α,β-unsaturated acyl azolium intermediates, which occurs with Coates-Claisen rearrangement is established. This synthetic strategy enabled the rapid assembly of enantiomerically enriched δ-hydroxychromenone-derived esters/amides under mild conditions with good to excellent yields and broad substrate scope.

Carbene-catalyzed enantioselective annulation of dinucleophilic hydrazones and bromoenals for access to aryl-dihydropyridazinones and related drugs.

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-derived α,β-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our protocol can be readily transformed into drugs and bioactive molecules.

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.

Enantioselective N-Heterocyclic Carbene Catalysis via Acyl Azolium without Exogenous Oxidants

An approach to the α,β-unsaturated acyl azolium has been developed that exploits N-heterocyclic carbenes (NHCs) and acyl fluorides, without additional oxidants, bases, or preactivated pro-nucleophi...

Advances in N‐Heterocyclic Carbene Catalysis for Natural Product Synthesis

N‐heterocyclic carbenes (NHCs) efficiently catalyze new bond formations with high regio‐ and stereoselectivity through umpolung and non‐umpolung processes. These processes typically involve four species: Breslow intermediates, homoenolates, enolates, and α,β‐unsaturated acyl azoliums. Organic syntheses are increasingly relying on NHC catalysis, and this minireview highlights developments in NHC‐catalyzed reactions that, over the past two decades, have been used as key steps in the total syntheses of natural products. Crucial intermediates and reaction mechanisms are presented in detail.

High-throughput photocapture approach for reaction discovery

Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids.

As a key element in the construction of complex organic scaffolds, the formation of C-C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C-C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical-radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids**

AbstractAs a key element in the construction of complex organic scaffolds, the formation of C−C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single‐electron chemistry have enabled new methods for the formation of various C−C bonds. Disclosed herein is the development of a novel single‐electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N‐heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late‐stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Bifunctional N-Heterocyclic Carbenes Derived from l-Pyroglutamic Acid and Their Applications in Enantioselective Organocatalysis.

In nature, enzymes are a powerful medium for the construction of enantiomerically pure chemicals, which always inspires synthetic chemists to explore new catalysts to imitate the enzyme machinery for asymmetric transformations. Vitamin B1, a bifunctional thiazolium N-heterocyclic carbene (NHC) precursor, is the coenzyme for transketolase. In the past two decades, a series of chiral NHCs, including monocyclic, bicyclic, tetracyclic, and even bridged ones, have been synthesized and successfully utilized as efficient organocatalysts for a wide variety of asymmetric organic reactions. The utility of bifunctional catalysts can enhance catalytic activity and improve stereochemical control through their synchronous activation of both reaction partners. However, the NHCs possessing multiple activation sites are far less developed.This Account gives an overview of our research on the design, development, and applications of bifunctional NHCs in organocatalysis. We synthesized a series of l-pyroglutamic acid-derived bifunctional NHCs bearing a free hydroxyl group which can interact with carbonyl or imino groups via hydrogen-bonding. Further studies revealed that these bifunctional catalysts worked well for a variety of reactions. We have developed bifunctional NHC-catalyzed aza-benzoin reactions, [2 + 2], [2 + 3], and [2 + 4] cycloadditions of ketenes, [3 + 2] and [3 + 4] annulations of enals, and aza-MBH and Rauhut-Currier reactions of Michael acceptors. In addition to these reactions via nucleophilic Breslow intermediates, enolates, homoenolates, and zwitterionic azolium intermediates, the bifunctional NHC-catalyzed [3 + 3] annulation via 1,3-biselectrophilic α,β-unsaturated acyl azolium intermediates was also developed.In these reactions, bifunctional NHCs showed amazing effects compared to normal nonbifunctional NHCs. In some cases, the bifunctional NHCs facilitated reactions which did not work under normal NHC catalysis, possibly due to additional activation via H-bonding. More interestingly, the bifunctional NHCs could not only improve but also switch the enantioselectivity to get products with opposite stereochemistry through H-bond controlled stereochemical directing. Furthermore, the reaction mode could be totally changed from [3 + 2] to [3 + 4] annulation to give kinetically favored products when bifunctional NHCs were employed. In future, the applications of bifunctional NHCs in other challenging reactions, such as asymmetric reactions with carbon-carbon unsaturated bonds, and the reactions involving alkyl or heteroatom radicals will be the major focus in our group.

Chiral Acyl Azolium Permits Dynamic Kinetic Resolution of Hydroxyphthalides

Key words N-heterocyclic carbenes - acyl azolium compounds - hydroxyphthalides - redox esterification - asymmetric catalysis - kinetic resolution

N‐Heterocyclic Carbene‐Catalyzed Activation of Ynals for the Construction of Functional Pyridines

AbstractN‐heterocyclic carbene‐catalyzed activation of ynals for rapid synthesis of pyridine derivatives with important utilities has been reported. This successful strategy using NHC‐bound alkynyl acyl azolium as the key intermediate further improved the application of N‐Ts 2‐aminoacrylate as a nucleophile. Importantly, this work introduces an ester substituent to pyridines that could be easily transformed to other functional groups.

Carbene‐Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products

AbstractA catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.

Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products.

A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.

Carbene-Catalyzed Enantioselective Addition of Thioamides to Bromoenals for Access to Thiazinone Heterocycles.

A carbene-catalyzed reaction between α-bromoenals and thioamides was developed. Key steps include enantioselective 1,4-addition of thioamide sulfur atoms to α,β-unsaturated acyl azolium intermediate. Subsequent intramolecular annulation eventually affords thiazinone heterocycles with high optical purities. The introduction of Lewis acid additives such as Cu(OTf)2 to this NHC catalytic reaction could provide small but consistent improvements to reaction enantioselectivities.

Intramolecular α-Oxygenation of Amines via N -Heterocyclic Carbene-Catalyzed Domino Reaction of Aryl Aldehyde: Experiment and DFT Calculation

We have developed an N-heterocyclic carbene (NHC)-catalyzed domino reaction with aryl aldehyde through a simple acyl azolium intermediate using phenyliodine(III) diacetate (PIDA) as an oxidant. Con...

Carbene-catalyzed asymmetric Friedel\u2013Crafts alkylation-annulation sequence and rapid synthesis of indole-fused polycyclic alkaloids

Organocatalyzed asymmetric Friedel–Craft reactions have enabled the rapid construction of chiral molecules with highly enantioselectivity enriching the toolbox of chemists for producing complex substances. Here, we report N-heterocyclic carbene-catalyzed asymmetric indole Friedel–Crafts alkylation-annulation with α,β-unsaturated acyl azolium as the key intermediate, affording a large variety of indole-fused polycyclic alkaloids with excellent diastereo- and enantioselectivities. The reaction mechanism is also investigated, and the reaction products can be easily converted to highly functionalized indole frameworks with different core structures.