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.

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

Catalytic asymmetric synthesis of spirooxindoles: recent developments

Catalytic, stereoselective N-heterocyclic carbene-catalyzed reactions facilitate efficient construction of many different heterocyclic compounds, such as the enantioenriched 5-membered (γ) lactones highlighted in this tutorial review. Herein, various strategies to enable formal [3+2] type annulations between electrophilic carbonyl equivalents and homoenolate nucleophiles for the synthesis of γ-lactones are summarized.

A continuing challenge: N-heterocyclic carbene-catalyzed syntheses of γ-butyrolactones

The 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.

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

Phenols are important starting materials, intermediates, and functional elements of a very broad range of chemicals and materials. They are large-volume products of benzene oxidation and are increasingly available from biomass. Investment in methodologies that improve the efficiency of their use can have both immediate and future impacts on chemical upgrading. This review summarizes recent phenol-directed C–H functionalization reactions, which provide efficient increases in molecular complexity. Catalytic methodologies play an increasingly important role in addressing long-standing challenges of chemo- and regioselectivity, setting the stage for increased use of phenols in fine-chemical synthesis. We discuss these advances while underscoring persistent challenges, with the goal of motivating increased interest in this versatile functional group.

Phenol-Directed C–H Functionalization

Contemporary literature offers a number of interesting examples for asymmetric multicatalytic reactions using chiral N-heterocyclic carbenes (NHCs) in conjunction with other catalysts. One of the very recent examples demonstrated a convenient strategy toward realizing chiral benzofuranones from salicylaldehyde and dimethyl acetylenedicarboxylate (DMAD). In this article, we report the mechanism and insights on the origin of asymmetric induction as obtained through a comprehensive density functional theory (M06-2X and mPW1K) investigation. Different likely catalyst–substrate combinations as well as the timing/sequence of activation of different substrates are carefully examined so as to identify the most preferred pathway. In the lowest energy path, the activation of DMAD by quinuclidine occurs first; the resulting zwitterionic intermediate then undergoes a Michael addition with a salicylate ion to yield a salicylate–DMAD adduct, which, in turn, is intercepted by the chiral NHC. In the next crucial step, an...

Asymmetric Dual-Catalytic Cascade by Chiral N-Heterocyclic Carbene and Quinuclidine: Mechanism and Origin of Enantioselectivity in Benzofuranone Formation

Origin of Stereoselectivity in a Chiral N-Heterocyclic Carbene-Catalyzed Desymmetrization of Substituted Cyclohexyl 1,3-Diketones

The functionalization of aliphatic and aromatic C–H bonds has remained a priority in transition-metal catalysis for the last few decades. N-heterocyclic carbenes (NHCs) have very recently been proven as an effective organocatalytic alternative toward site-selective sp3 β-C–H bond functionalization in aliphatic esters and related compounds. We have employed modern density functional theory computations to provide the first mechanistic insights into this entirely new form of reactivity of NHCs, leading to β-C–H bond activation. NHC-catalyzed coupling between hydrazone and β-phenyl propionate leading to a γ-lactam bearing two chiral centers is reported. An interesting two-step mechanistic cascade that helps surmount the high bond dissociation energy of an otherwise inert β-C–H bond is identified. An initial addition–elimination at the ester group installs the chiral triazolium NHC to the substrate. The deprotonation of the α-C–H by the departing phenoxide first furnishes an α-enolate intermediate. A concerte...

Mechanistic Studies on Stereoselective Organocatalytic Direct β-C–H Activation in an Aliphatic Chain by Chiral N-Heterocyclic Carbenes

Polyesters constitute around 10% of the global plastic market with aromatic polyesters, such as poly(ethylene terephthalate) (PET), being the most prevalent because of their attractive properties. ...

Readily Degradable Aromatic Polyesters from Salicylic Acid

The control of the tacticity of synthetic polymers enables the realization of emergent physical properties from readily available starting materials. While stereodefined polymers derived from nonpolar vinyl monomers can be efficiently prepared using early transition metal catalysts, general methods for the stereoselective polymerization of polar vinyl monomers remain underdeveloped. We recently demonstrated asymmetric ion pairing catalysis as an effective approach to achieve stereoselective cationic polymerization of vinyl ethers. Herein, we provide a deeper understanding of stereoselective ion-pairing polymerization through comprehensive experimental and computational studies. These findings demonstrate the importance of ligand deceleration effects for the identification of reaction conditions that enhance stereoselectivity, which was supported by computational studies that identified the solution-state catalyst structure. An evaluation of monomer substrates with systematic variations in steric parameters and functional group identities established key structure-reactivity relationships for stereoselective homo- and copolymerization. Expansion of the monomer scope to include enantioenriched vinyl ethers enabled the preparation of an isotactic poly(vinyl ether) with the highest stereoselectivity (95.1% ± 0.1 meso diads) reported to date, which occurred when monomer and catalyst stereochemistry were fully matched under a triple diastereocontrol model. The more complete understanding of stereoselective cationic polymerization reported herein offers a foundation for the design of improved catalytic systems and for the translation of isotactic poly(vinyl ether)s to applied areas.

Yernaidu Reddi

Papers

Asymmetric Dual-Catalytic Cascade by Chiral N-Heterocyclic Carbene and Quinuclidine: Mechanism and Origin of Enantioselectivity in Benzofuranone Formation

Origin of Stereoselectivity in a Chiral N-Heterocyclic Carbene-Catalyzed Desymmetrization of Substituted Cyclohexyl 1,3-Diketones

Mechanistic Studies on Stereoselective Organocatalytic Direct β-C–H Activation in an Aliphatic Chain by Chiral N-Heterocyclic Carbenes

Readily Degradable Aromatic Polyesters from Salicylic Acid

Mechanistic Insight into the Stereoselective Cationic Polymerization of Vinyl Ethers.