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.

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

The applications of axially chiral benzonitriles and their derivatives remain mostly unexplored due to their synthetic difficulties. Here we disclose an unusual strategy for atroposelective access to benzonitriles via formation of the nitrile unit on biaryl scaffolds pre-installed with stereogenic axes in racemic forms. Our method starts with racemic 2-arylbenzaldehydes and sulfonamides as the substrates and N-heterocyclic carbenes as the organocatalysts to afford axially chiral benzonitriles in good to excellent yields and enantioselectivities. DFT calculations suggest that the loss of p-toluenesulfinate group is both the rate-determining and stereo-determining step. The axial chirality is controlled during the bond dissociation and CN group formation. The reaction features a dynamic kinetic resolution process modulated by both covalent and non-covalent catalytic interactions. The axially chiral benzonitriles from our method can be easily converted to a large set of functional molecules that show promising catalytic activities for chemical syntheses and anti-bacterial activities for plant protections. 

https://www.nature.com/articles/s41467-021-27813-4.pdf

Catalytic atroposelective synthesis of axially chiral benzonitriles via chirality control during bond dissociation and CN group formation

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A visible-light-mediated late-stage arylation of N–S bonds in sulfonamides has been developed with using readily available imines as sulfonyl radical source. Diverse complex sulfones could be synthesized by prefunctionalizaiton and subsequent N–S bond arylation, demonstrating the advantages of using sulfonamides as sulfonylation reagents. Additionally, the mechanism research revealed that probably both EDA complex chemistry and photoredox catalysis were responsible for the formation of sulfones. This methodology characterized by broad substrate scope and simple reaction conditions also has high atom economy, since the aldehyde for the synthesis of imines could be recovered after workup of the reactions. 

Visible-Light-Mediated Late-Stage Sulfonylation of Boronic Acids via N–S Bond Activation of Sulfonamides

By performing density functional theory (DFT) calculations, we investigated and identified the fundamental pathway for N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral benzothiophene-fused biaryls using enal and 2-benzyl-benzothiophene-3-carbaldehyde, which includes (1) nucleophilic attack on enal by the organocatalyst NHC, (2) [1,2]-proton transfer, (3) oxidation, (4) stereoselective formation of the C-C σ bond, (5) intramolecular [2 + 2] cycloaddition, (6) dissociation of NHC, (7) release of CO2, and (8) transformation to axial chirality. Moreover, the calculated results can reasonably explain the observed chemo- and stereoselectivities for the formation of both benzothiophene/benzofuran-fused biaryls in these kinds of reactions. Further non-covalent interaction (NCI) and atoms-in-molecules (AIM) analyses demonstrate that the hydrogen bond interactions are responsible for the stability of key stereoselective transition states. This work would be useful for understanding the origin of stereoselectivity of NHC-catalyzed intermolecular cyclization reactions for the synthesis of axially benzothiophene/benzofuran-fused biaryl compounds.

The mechanism and origin of selectivities for NHC-catalyzed synthesis of axially chiral benzothiophene/benzofuran-fused biaryls.

NHC-catalyzed desulfonylation of tosylated aldimines provides facile access to aryl nitriles in generally good to excellent yields with good functional group compatibilities under mild reaction conditions. DFT calculations demonstrate that the reaction undergoes multiple stepwise processes including nucleophilic addition of NHC to tosylated imine, formation of an aza-Breslow intermediate, deprotonation, and dissociation of the tosyl group.

A combined experimental and computational study of NHC-promoted desulfonylation of tosylated aldimines

N-Heterocyclic carbene (NHC) catalyzed regiospecific β-additions of nitrogen-containing nucleophiles including nitrogenous heterocycles and trifluoromethylated acylhydrazone to allenoates were accomplished under mild reaction conditions, harnessing NHC as a Lewis base to furnish branched N-alkyl compounds in moderate to good yields with high E/Z selectivity and broad substrate scope. DFT calculations on the possible reaction mechanisms show that the β-addition pathway is more energetically favourable than the γ-addition pathway, which is in agreement with the experimental observations.

NHC-catalyzed β-specific addition of N-based nucleophiles to allenoates

An NHC-catalyzed regiospecific allylation of α-substituted allenoates with MBH carbonates derived from aryl aldehyde furnished highly functionalized 1,5-enynes bearing a quaternary carbon successfully. Combining with DFT calculations, the reaction mechanism of this conversion was proposed. This method has the advantages of high regioselectivity, good yields and mild reaction conditions. This transformation not only provided a new access to 1,5-enyne, but also enriched the chemistry of allenoates and NHC catalysis.

A combined experimental and computational study of NHC-catalyzed allylation of allenoate with MBH esters: new regiospecific and stereoselective access to 1,5-enyne

Wenchao Wu

Papers

A combined experimental and computational study of NHC-promoted desulfonylation of tosylated aldimines

NHC-catalyzed β-specific addition of N-based nucleophiles to allenoates

A combined experimental and computational study of NHC-catalyzed allylation of allenoate with MBH esters: new regiospecific and stereoselective access to 1,5-enyne