Acyl Azolium Research Articles

ChemInform Abstract: Synthesis of Functionalized Coumarins and Quinolinones by NHC‐Catalyzed Annulation of Modified Enals with Heterocyclic C—H Acids.

N-Heterocyclic carbene (NHC) catalyzed lactonization and lactamization of 2-bromoenals with heterocyclic C–H acids proceeding via the α,β-unsaturated acyl azolium intermediates is reported. The reaction furnished coumarin- or quinolinone-fused lactone/lactam derivatives. In addition, results of the enantioselective version of this reaction using chiral NHC are presented.

N-heterocyclic carbene catalyzed cyclocondensation of α,β-unsaturated carboxylic acids: enantioselective synthesis of pyrrolidinone and dihydropyridinone derivatives.

The catalytic cyclocondensation of in situ activated α,β-unsaturated carboxylic acids was developed. N-heterocyclic carbenes efficiently catalyzed the generation of α,β-unsaturated acyl azolium intermediates from α,β-unsaturated carboxylic acids via in situ generated mixed anhydrides for the enantioselective [3+2] and [3+3] cyclocondensation with α-amino ketones and alkyl(aryl)imines, respectively. The corresponding pyrrolidinones and dihydropyridinones were isolated in good yields with high to excellent enantioselectivities.

N‐Heterocyclic Carbene Catalyzed Cyclocondensation of α,β‐Unsaturated Carboxylic Acids: Enantioselective Synthesis of Pyrrolidinone and Dihydropyridinone Derivatives

AbstractThe catalytic cyclocondensation of in situ activated α,β‐unsaturated carboxylic acids was developed. N‐heterocyclic carbenes efficiently catalyzed the generation of α,β‐unsaturated acyl azolium intermediates from α,β‐unsaturated carboxylic acids via in situ generated mixed anhydrides for the enantioselective [3+2] and [3+3] cyclocondensation with α‐amino ketones and alkyl(aryl)imines, respectively. The corresponding pyrrolidinones and dihydropyridinones were isolated in good yields with high to excellent enantioselectivities.

Kinetic Resolution of 1,1′‐Biaryl‐2,2′‐Diols and Amino Alcohols through NHC‐Catalyzed Atroposelective Acylation

AbstractWe present here a highly efficient NHC‐catalyzed kinetic resolution of a wide range of 1,1′‐biaryl‐2,2′‐diols and amino alcohols to provide them in uniformly ≥99 % ee. This represents the first highly enantioselective catalytic acylation of axially chiral alcohols. The aldehyde backbone that is incorporated into the chiral acyl azolium intermediate was found to have a significant effect on the enantioselectivity of the process.

Kinetic resolution of 1,1'-biaryl-2,2'-diols and amino alcohols through NHC-catalyzed atroposelective acylation.

We present here a highly efficient NHC-catalyzed kinetic resolution of a wide range of 1,1'-biaryl-2,2'-diols and amino alcohols to provide them in uniformly ≥99% ee. This represents the first highly enantioselective catalytic acylation of axially chiral alcohols. The aldehyde backbone that is incorporated into the chiral acyl azolium intermediate was found to have a significant effect on the enantioselectivity of the process.

N-Mesityl-Substituted Triazolium Salts

Metal-free organocatalysis employing N-heterocyclic carbenes (NHCs) has attracted great interest because of its use in the construction of intricate molecular architectures from simple starting materials under mild reaction conditions.[1] The catalytic pathway of NHCs mimics that of thiamine-dependent enzymatic processes and passes through discrete reactive species, such as acyl anions and enolate or homoenolate equivalents.[2] This enables the selective generation of a set of versatile electrophilic (acyl azoliums) and nucleophilic (enolates, homoenolates) intermediates and makes NHCs efficient catalysts in such various reactions as acylation, cycloaddition, β-borylation, and elimination.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Activation of Esters: A New Option for Asymmetric Domino Reactions

AbstractReview: 26 refs.

Synthesis of Functionalized Coumarins and Quinolinones by NHC-Catalyzed Annulation of Modified Enals with Heterocyclic C–H Acids

N-Heterocyclic carbene (NHC) catalyzed lactonization and lactamization of 2-bromoenals with heterocyclic C-H acids proceeding via the α,β-unsaturated acyl azolium intermediates is reported. The reaction furnished coumarin- or quinolinone-fused lactone/lactam derivatives. In addition, results of the enantioselective version of this reaction using chiral NHC are presented.

N‐Heterocyclic Carbene Catalyzed Activation of Esters: A New Option for Asymmetric Domino Reactions

Esters-what else! A new strategy in NHC organocatalysis allows the α-, β- and γ-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities.

On the Mechanism of N-Heterocyclic Carbene-Catalyzed Reactions Involving Acyl Azoliums

Catalytic reactions promoted by N-heterocyclic carbenes (NHCs) have exploded in popularity since 2004 when several reports described new fundamental reactions that extended beyond the long-studied generation of acyl anion equivalents. These new NHC-catalyzed reactions allow chemists to generate unique reactive species from otherwise inert starting materials, all under simple, mild reaction conditions and with exceptional selectivities. In analogy to transition metal catalysis, the use of NHCs has introduced a new set of elementary steps that operate via discrete reactive species, including acyl anion, homoenolate, and enolate equivalents, usually generated by oxidation state reorganization ("redox neutral" reactions). Nearly all NHC-catalyzed reactions offer operationally simple reactions, proceed at room temperature without the need for stringent exclusion of air, and do not generate reaction byproducts. Variation of the catalyst or reaction conditions can profoundly influence reaction outcomes, and researchers can tune the desired selectivities through careful choice of NHC precursor and base. The catalytically generated homoenolate and enolate equivalents are nucleophilic species. In contrast, the catalytically generated acyl azolium and α,β-unsaturated acyl azoliums are electrophilic cationic species with unique and unprecedented chemistry. For example, when generated catalytically, these species transformed an α-functionalized aldehyde to an ester under redox neutral conditions without coupling reagents or waste. In addition to providing new approaches to catalytic esterifications, acyl azoliums offer unique reactivities that chemists can exploit for selective reactions. This Account focuses on the discovery and mechanistic investigation of the catalytic generation of acyl azoliums and α,β-unsaturated acyl azoliums. These chemical species are fascinating, and their catalytic generation is an important development. Studies of their unusual chemistry, however, date back to the intense investigation of thiamine-dependent enzymatic processes in the 1960s. Acyl azoliums are remarkably reactive in acylation chemistry and are unusually chemoselective. These two properties have led to a new wave of reactions such as redox esterification reaction (1) and the catalytic kinetic resolution of challenging substrates (i.e., 3). Our group and others have also developed methods to generate and exploit α,β-unsaturated acyl azoliums, which have facilitated new C-C bond-forming annulations, including a catalytic, enantioselective variant of the Claisen rearrangement (2). From essentially one class of catalysts, the N-mesityl derived triazolium salts, researchers can easily prepare highly enantioenriched dihydropyranones and dihydropyridinones. Although this field is now one of the most explored areas of enantioselective C-C bond forming reactions, many mechanistic details remained unsolved and in dispute. In this Account, we address the mechanistic inquiries about the characterization of the unsaturated acyl triazolium species and its kinetic profile under catalytically relevant conditions. We also provide explanations for the requirement and effect of the N-mesityl group in NHC catalysis based on detailed experimental data within given specific reactions or conditions. We hope that our studies provide a roadmap for catalyst design/selection and new reaction discovery based on a fundamental understanding of the mechanistic course of NHC reactions.

N-Heterocyclic carbene-catalyzed enantioselective synthesis of functionalized cyclopentenes via α,β-unsaturated acyl azoliums.

Highly enantioselective NHC-organocatalyzed synthesis of functionalized cyclopentenes proceeding via α,β-unsaturated acyl azolium intermediates is reported. The organocascade reaction of modified enals with malonic ester derivatives having a γ-benzoyl group involves the Michael-intramolecular aldol-β-lactonization-decarboxylation sequence to deliver cyclopentenes in good yields and excellent ee values.

ChemInform Abstract: Divergent NHC‐Catalyzed Oxidative Transformations of 3‐Bromoenal: Selective Synthesis of 2H‐Pyran‐2‐ones and Chiral Dihydropyranones.

A selective synthesis of either 2H-pyran-2-ones (4) or chiral dihydropyranones (6) from the same substrates of 3-bromoenals and 1,3-dicarbonyl compounds upon oxidative N-heterocyclic carbene catalysis is presented. It is shown that the oxidative transformation of 3-bromoenals under NHC catalyst can be well controlled to proceed through two pathways, i.e., elimination of reducible β-bromide or by an external oxidant 3, allowing the selective generation two sorts of unsaturated acyl azoliums, respectively.

Heterocyclic synthesis via catalysis of N-heterocyclic carbenes: very classical and very modern chemical species

Abstract After a long history of medical and biochemical investigations of vitamin B1, N-heterocyclic carbenes (NHCs) have recently been used as organocatalysts for a variety of synthetic reactions. This review article highlights the application of NHC-catalyzed reactions including enantioselective reactions to the heterocyclic synthesis. NHC-catalyzed benzoin condensation and Stetter reaction of ether- and amine-linked aldehydes give four- to six-membered oxygen and nitrogen heterocycles. NHC-catalyzed conjugate additions of enals to ketones and imines afford γ-lactones and γ-lactams. When the NHC-catalyzed reaction intermediates of enals are protonated, the reaction of the resulting enols with enones and ene-imines furnish formal hetero-Diels-Alder products. Acyl fluoride and esters can be activated by NHCs, and subsequent aldol and Michael reactions give β-lactones. Oxidation of intermediates derived from enals or the intermediates from ynals provide unsaturated acyl azolium which are transformed into cyclic products via subsequent nucleophilic reactions. NHCs also catalyze [2+2] cycloadditions of ketenes and other heterocumulenes and ring expansion of cyclic aldehydes.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Addition of Aldehydes to Diazo Compounds: Stereoselective Synthesis of N‐Acylhydrazones.

An innovative stereoselective synthesis of N-acylhydrazones via an unprecedented N-heterocyclic carbene catalyzed addition of aldehydes to diazo compounds is presented. Enals exclusively afforded N-acylhydrazones, in yields up to 91%. The observed regioselectivity was traced back to the reaction of the vinylogous Breslow intermediate via the acyl anion pathway over competing homoenolate, enol, and acyl azolium pathways. This unusual reaction profile was studied based on DFT calculations, which revealed that the reaction is under orbital control, rather than being ruled by charge.

Divergent NHC-Catalyzed Oxidative Transformations of 3-Bromoenal: Selective Synthesis of 2H-Pyran-2-ones and Chiral Dihydropyranones

A selective synthesis of either 2H-pyran-2-ones (4) or chiral dihydropyranones (6) from the same substrates of 3-bromoenals and 1,3-dicarbonyl compounds upon oxidative N-heterocyclic carbene catalysis is presented. It is shown that the oxidative transformation of 3-bromoenals under NHC catalyst can be well controlled to proceed through two pathways, i.e., elimination of reducible β-bromide or by an external oxidant 3, allowing the selective generation two sorts of unsaturated acyl azoliums, respectively.

N-Heterocyclic Carbene Catalyzed Addition of Aldehydes to Diazo Compounds: Stereoselective Synthesis of N-Acylhydrazones

An innovative stereoselective synthesis of N-acylhydrazones via an unprecedented N-heterocyclic carbene catalyzed addition of aldehydes to diazo compounds is presented. Enals exclusively afforded N-acylhydrazones, in yields up to 91%. The observed regioselectivity was traced back to the reaction of the vinylogous Breslow intermediate via the acyl anion pathway over competing homoenolate, enol, and acyl azolium pathways. This unusual reaction profile was studied based on DFT calculations, which revealed that the reaction is under orbital control, rather than being ruled by charge.

ChemInform Abstract: Enantioselective, NHC‐Catalyzed Annulations of Trisubstituted Enals and Cyclic N‐Sulfonylimines via α,β‐Unsaturated Acyl Azoliums.

AbstractThe presented studies extend the scope of highly enantioselective NHC‐catalyzed reactions and offer, for the first time, the opportunity for highly enantio‐ and diastereoselective annulations of α‐ and β,β′‐substituted enals.

ChemInform Abstract: Exploiting Acyl and Enol Azolium Intermediates via N‐Heterocyclic Carbene‐Catalyzed Reactions of α‐Reducible Aldehydes.

AbstractReview: 103 refs.

ChemInform Abstract: Enantioselective Cyclopropanation of Enals by Oxidative N‐Heterocyclic Carbene Catalysis.

Abstractα,β‐Unsaturated aldehydes are activated by a carbene‐catalyzed redox pathway to generate the corresponding acyl azolium intermediates, which react with sulfur ylides and an alcohol to give cyclopropanecarboxylic acid esters.

Enantioselective, NHC‐Catalyzed Annulations of Trisubstituted Enals and Cyclic N‐Sulfonylimines via α,β‐Unsaturated Acyl Azoliums

All aboard please! A new reaction of enals and cyclic sulfonylimines, as the nucleophiles(!), is the first highly enantioselective NHC-catalyzed annulation of trisubstituted enals. The catalytically generated α,β-unsaturated acyl azolium undergoes a reaction with the enamine tautomer of the imine via an aza-Claisen rearrangement as the key CC bond-forming step. High yields and enantioselectivities were achieved using β-, α,β-, and β,β′-substituted enals.