Acyl Azolium Research Articles

Mechanisms and Origins of Regio- and Stereoselectivities in NHC-Catalyzed [3 + 3] Annulation of α-Bromoenals and 5-Aminoisoxazoles: A DFT Study.

Density functional theory (DFT) calculations were conducted to explore the mechanisms and origins of regio- and stereoselectivities underlying the [3 + 3] annulation reaction between α-bromoenals and 5-aminoisoxazoles with N-heterocyclic carbene (NHC) as the catalyst. The reaction occurs in nine steps: (1) nucleophilic addition of NHC to α-bromoenal, (2) Breslow intermediate formation through 1,2-proton transfer, (3) debromination, (4) α,β-unsaturated acyl azolium intermediate formation via 1,3-proton transfer, (5) addition of α,β-unsaturated acyl azolium intermediate to 5-aminoisoxazole, (6) deprotonation, (7) protonation, (8) ring closure, and (9) elimination of NHC. For the fifth step, 1,2-addition suggested in the experiment was not supported by our results. Instead, we found that Michael addition is energetically the most feasible pathway and the stereo-controlling step that preferentially provides the S-configuration product. DFT-computed results and experimental findings agree well. Analysis of distortion/interaction reveals that lower distortion energy leads to stability of the transition state corresponding to the S-configuration product. Global reactivity index analysis indicates that the behavior of the NHC catalyst differs significantly before and after the Breslow intermediate debromination. Before debromination, the nucleophilicity of α-bromoenal is enhanced by addition to NHC. However, after debromination, the α,β-unsaturated acyl azole generates and acts as an electrophilic reagent.

N-Heterocyclic Carbene Enabled Functionalization of Inert C(Sp3)-H Bonds via Hydrogen Atom Transfer (HAT) Processes.

Developing methods to directly transform C(sp3) -H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp3) -H bonds for cross C-C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp3) -H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp3)-H substrates, such as ethers, amines, and alkanes. This mini-review summarizes the progress in carbene organocatalytic functionalization of inert C(sp3)-H bonds enabled by HAT processes, categorizing them into two sections: 1) C-H functionalization involving acyl azolium intermediates; and 2) functionalization of C-H bonds via reductive Breslow intermediates.

Ionic Hydrogen Bond-Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols.

The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S-, P-, Si- and B-stereocenters over the past decades, the catalyst-controlled strategies to govern the formation of N-stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen-stereogenic compounds through a desymmetrization approach. Intriguingly, the pro-chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene-bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N-oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N-oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Ionic Hydrogen Bond‐Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols

AbstractThe control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S‐, P‐, Si‐ and B‐stereocenters over the past decades, the catalyst‐controlled strategies to govern the formation of N‐stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen‐stereogenic compounds through a desymmetrization approach. Intriguingly, the pro‐chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene‐bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N‐oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N‐oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Radical Reactions with N-Heterocyclic Carbene (NHC)-Derived Acyl Azoliums for Access to Multifunctionalized Ketones

Radical Reactions with N-Heterocyclic Carbene (NHC)-Derived Acyl Azoliums for Access to Multifunctionalized Ketones

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.

Acylation of Unactivated C(sp3)–H Bonds with Acyl Azolium Reagents under Photoinduced Cerium Catalysis

Acylation of Unactivated C(sp3)–H Bonds with Acyl Azolium Reagents under Photoinduced Cerium Catalysis

N-Heterocyclic Carbene-Catalyzed Highly Enantioselective Macrolactonization to Access Planar-Chiral Macrocycles.

An N-heterocyclic carbene (NHC)-catalyzed atroposelective macrolactonization has been disclosed. This approach affords planar-chiral macrocycles in high yields with excellent enantioselectivities over a broad substrate scope. Controlled experiments suggest that the enantioselectivity might arise from the cation-n interaction between the acyl azolium and the electron-rich moiety in the substrate. This mechanism is supported by density functional theory calculations, which also suggest an important π-π interaction in stabilizing the transition state.

Photo-Catalyzed Acyl Azolium Promoted Selective α-C(sp3 )-H Acylation of Acetone via HAT: Access to Thermodynamically Less Favoured (Z)-α,β-Unsaturated Ketones.

Mono α-acylation of acetone has been achieved for the first time by reacting with bench-stable acyl azolium salts under violet-LED light at room temperature. The intermolecular hydrogen atom transfer (HAT) from acetone to triplet state of azolium salts under violet LED irradiation resulted in thermodynamically less favourable (Z)-α,β-unsaturated ketones with up to 99 : 1 selectivity via C-C bond formation. This compelling protocol access the desired α-C(sp3 )-H acylation product under metal-, ligand- and oxidant-free conditions on a wide range of substrates.

α-Phenylthioaldehydes for the effective generation of acyl azolium and azolium enolate intermediates.

α-Phenylthioaldehydes are readily prepared using a simple multi-step procedure and herein are introduced as a new precursor for the NHC-catalysed generation of acyl azolium and azolium enolate intermediates that are of widespread synthetic interest and utility. Treatment of α-phenylthioaldehydes with an NHC precatalyst and base produces an efficient redox rearrangement via a Breslow intermediate, elimination of thiophenolate, and subsequent rebound addition to the generated acyl azolium to give the corresponding thiol ester. In the presence of an external alcohol, competition between redox rearrangement and redox esterification can be controlled through judicious choice of the N-aryl substituent within the NHC precatalyst and the base used in the reaction. With NEt3 as base, NHCs bearing electron-withdrawing (N-C6F5 or N-C6H2Cl3) substituents favour redox rearrangement, while triazolium precatalysts with electron-rich N-aryl substituents (N-Ph, N-Mes) result in preferential redox esterification. Using DBU, redox esterification is preferred due to transesterification of the initially formed thiol ester product. Additionally, α-phenylthioaldehyde-derived azolium enolates have been used in enantioselective formal [4 + 2]-cycloaddition reactions to access dihydropyridinone heterocycles with high enantioselectivity (up to >95 : 5 dr, 98 : 2 er).

Disclosing the mechanism and origin of stereoselectivity of the NHC-catalyzed transformation reaction of enals with acyl azolium as a key intermediate

The reaction mechanism and origin of stereoselectivity of the NHC-catalyzed transformation of an acyl azolium intermediate have been theoretically investigated using the DFT method.

Photoinduced cerium-catalyzed C-H acylation of unactivated alkanes.

Ketones are ubiquitous motifs in the realm of pharmaceuticals and natural products. Traditional approaches to accessing these species involve the addition of metal reagents to carboxyl compounds under harsh conditions. Herein, we report a cerium-catalyzed acylation of unactivated C(sp3)-H bonds using bench-stable acyl azolium reagents under mild and operationally-friendly conditions. This reaction exhibits excellent generality, accommodating a wide range of feedstock chemicals such as cycloalkanes and acyclic compounds as well as facilitating the late-stage functionalization of pharmaceuticals. We demonstrate further applications of our strategy with a three-component radical relay reaction and an enantioselective N-heterocyclic carbene (NHC) and cerium dual-catalyzed reaction.

Cooperative NHC/Photoredox Catalysis: Three‐Component Reaction of Aroyl Fluorides, Styrenes and Oxalates

Comprehensive SummaryCooperative NHC/photoredox catalysis has emerged as an important research field in recent years. Herein, this article describes the use of cesium salt derivatives of tert‐alcohols as alkyl radical precursors in a three‐component reaction with styrene and aromatic acyl fluorides to synthesize α‐arylalkyl aryl ketones. The aroyl fluoride reacts with the NHC catalyst, leading to the formation of an acyl azolium ion. This acyl azolium ion can then be reduced by the photoredox catalyst, generating the corresponding ketyl radical anion. The C‐radical generated from oxalate oxidation undergoes an addition reaction with the styrene derivative, followed by cross‐coupling of the addition radical with the ketone radical, which is fragmented by NHC to give the target ketone.

Dual visible-light and NHC-catalyzed radical relay trifunctionalization of unactivated alkenes

Radical trifunctionalization of unactivated alkenes remains rare and challenging, although they can provide a robust tool for the construction of molecules with high added value from simple materials. This work presents the relay dual N-heterocyclic carbene organocatalytic and visible-light photocatalytic multi-component trifunctionalization of alkyl alkenes via the merger of remote 1,4-cyano migration and alkylacylation. The method features a broad substrate scope and good compatibility of diverse functional groups. Density functional theory calculations were also carried out to rationalize the origin of this reaction. The cooperative N-heterocyclic carbene and photoredox catalysis enabled reductive single-electron transfer reaction of acyl azolium species and subsequent radical-radical cross-coupling, allowing for the facile construction of three new C−C bonds in one-pot reactions with high regioselectivity.

Carbene-Catalyzed Direct O-Functionalization of Ketone: Atroposelective Access to Non-C2-Symmetric Binaphthyls.

Disclosed here is NHC-catalyzed direct intermolecular trapping of the ketone oxygen atom with the acyl azolium intermediate. The overall reaction is a dynamic kinetic resolution process that converts ketone to the corresponding enol ester with well-controlled axial chirality. Our reaction eventually affords non-C2-symmetric binaphthyl derivatives with important applications, such as in the area of asymmetric catalysis.

Photoredox-Catalyzed Radical-Radical Coupling of Potassium Trifluoroborates with Acyl Azoliums.

Potassium trifluoroborates have gained significant utility as coupling partners in organic synthesis, particularly in the Suzuki-Miyaura coupling reaction. Recently, they have also been used as radical precursors under oxidative conditions to generate carbon-centered radicals. These versatile reagents have found new applications in photoredox catalysis, including radical substitution, conjugate addition reactions, and transition metal dual catalysis. In addition, this photomediated redox neutral process has enabled radical-radical coupling with persistent radicals in the absence of a metal, and this process remains to be fully explored. In this study, we report the radical-radical coupling of benzylic potassium trifluoroborate salts with isolated acyl azolium triflates, which are persistent radical precursors. The reaction is catalyzed by an organic photocatalyst and forms isolable tertiary alcohol species. These compounds can be transformed into a range of substituted ketone products by simple treatment with a mild base.

N‐Heterocyclic Carbene‐Catalyzed [3+3] Annulation of Alkynyl Acyl Azolium with β‐Keto Ester for the Synthesis of Tri‐Substituted α‐Pyranones

AbstractThe reactivity of N‐Heterocyclic carbene (NHC)‐bound alkynyl acyl azoliums is underexplored in chemistry. We herein reported an NHC‐catalyzed [3+3] annulation of alkynyl acyl azoliums with β‐keto esters. The strategy features mild reaction conditions and exhibits broad substrates scope, delivering a wide range of tri‐substituted α‐pyrones in moderate to excellent yields (up to 95%). This approach extends the reactivity of alkynyl acyl azoliums to β‐keto esters binucleophiles.

Enantioselective synthesis of 6-(Indole-2-yl)-3,4-dihydropyran-2-one skeletons by N-Heterocyclic carbene-catalyzed asymmetric [3 + 3] cycloaddition of α-bromocinnamaldehyde

The enantioselective construction of chiral 6-(indole-2-yl)-3,4-dihydropyran-2-one skeleton was demonstrated by the formal [3 + 3] cycloaddition reaction of α-bromocinnamaldehyde with β-ketoester indole catalyzed by chiral N -heterocyclic carbene (NHC). The reaction proceeds smoothly via a vinyl acyl azolium intermediate (electron-poor enone) generated from NHC-aldehyde adducts, providing 6-(indole-2-yl)-3,4-dihydropyran-2-one derivatives in good yields with excellent enantioselectivities (up to 98% ee ).

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals. These open-shell intermediates subsequently undergo the radical-radical cross-coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three-component reactions involving alkenes and enynes, resulting in structurally diverse cross-coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N‐Heterocyclic Carbene Catalysis

AbstractConsidering the prevalence of alcohols and carboxylic acids, their fragment cross‐coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N‐heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst‐free conditions, generating NHC‐derived ketyl radicals and alkyl radicals. These open‐shell intermediates subsequently undergo the radical‐radical cross‐coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three‐component reactions involving alkenes and enynes, resulting in structurally diverse cross‐coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.