Carbene Organocatalysis Research Articles

Asymmetric construction of axial and planar chirality with N-heterocyclic carbene (NHC) organocatalysis

Asymmetric construction of axial and planar chirality with N-heterocyclic carbene (NHC) organocatalysis

Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis

Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis

Design and Enantioselective Synthesis of Chiral Pyranone Fused Indole Derivatives with Antibacterial Activities against Xanthomonas oryzae pv oryzae for Protection of Rice.

A new class of chiral pyranone fused indole derivatives were prepared by means of N-heterocyclic carbene (NHC) organocatalysis and demonstrated notable antibacterial activity against Xanthomonas oryzae pv oryzae (Xoo). Bioassays showed that compounds (3S,4R)-5b, (3S,4R)-5d, and (3S,4R)-5l exhibited promising in vitro efficacy against Xoo, with EC50 values of 9.05, 9.71, and 5.84 mg/L, respectively, which were superior to that of the positive controls with commercial antibacterial agents, bismerthiazol (BT, EC50 = 27.8 mg/L) and thiodiazole copper (TC, EC50 = 70.1 mg/L). Furthermore, single enantiomer (3S,4R)-5l was identified as an optimal structure displaying 55.3% and 52.0% curative and protective activities against Xoo in vivo tests at a concentration of 200 mg/L, which slightly surpassed the positive control with TC (curative and protective activities of 47.2% and 48.8%, respectively). Mechanistic studies through molecular docking analysis revealed preliminary insights into the distinct anti-Xoo activity of the two single enantiomers (3S,4R)-5l and (3R,4S)-5l, wherein the (3S,4R)-configured stereoisomer could form a more stable interaction with XooDHPS (dihydropteroate synthase). These findings underscore the significant anti-Xoo potential of these chiral pyranone fused indole derivatives, and shall inspire further exploration as promising lead structures for a novel class of bactericides to combat bacterial infections and other plant diseases.

Elucidating the mechanism and origin of stereoselectivity in the activation/transformation of an acetic ester catalyzed by an N-heterocyclic carbene.

The activation of an ester by N-heterocyclic carbene (NHC) organocatalysis is an efficient and important approach for generating an NHC-bound enolate intermediate, an important active intermediate in the transformation of carbonyl compounds. Herein, we perform a theoretical study on the NHC-catalyzed activation and transformation reaction of an acetic ester in which the NHC-bound enolate intermediate is a key intermediate. Multiple activation and transformation pathways are proposed and analyzed to identify an energetically favorable pathway. The use of different substrates for the reaction is considered. When a chalcone substrate is used, [4+2] cycloaddition between the enolate intermediate and the chalcone is identified to be both the rate- and stereoselectivity-determining step for the reaction, with the R-configured product being generated as the major isomer. Noncovalent interaction (NCI) and atoms-in-molecules (AIM) analyses are performed to identify the origin of the stereoselectivity of the reaction, and a local reactivity analysis is conducted to explore substrate and catalyst effects on the reaction.

Direct Acylation of Unactivated Alkyl Halides with Aldehydes through N‐Heterocyclic Carbene Organocatalysis

AbstractCatalytic acylation of organohalides with aldehydes is an ideal strategy for the direct synthesis of ketones. However, the utilization of unactivated alkyl halides in such a transformation remains a formidable challenge. In this study, we developed a cross‐coupling reaction of aldehydes with unactivated alkyl halides through N‐heterocyclic carbene catalysis. With this protocol, various ketones could be rapidly synthesized from readily available starting materials under mild conditions. This organocatalytic system was successfully applied in the late‐stage functionalization of pharmaceutical derivatives. Mechanistic investigations suggest a closed‐shell nucleophilic substitution mechanism for this reaction.

Direct Acylation of Unactivated Alkyl Halides with Aldehydes through N-Heterocyclic Carbene Organocatalysis.

Catalytic acylation of organohalides with aldehydes is an ideal strategy for the direct synthesis of ketones. However, the utilization of unactivated alkyl halides in such a transformation remains a formidable challenge. In this study, we developed a cross-coupling reaction of aldehydes with unactivated alkyl halides through N-heterocyclic carbene catalysis. With this protocol, various ketones could be rapidly synthesized from readily available starting materials under mild conditions. This organocatalytic system was successfully applied in the late-stage functionalization of pharmaceutical derivatives. Mechanistic investigations suggest a closed-shell nucleophilic substitution mechanism for this reaction.

Access to Spiropyrazolone-butenolides through NHC-Catalyzed [3 + 2]-Asymmetric Annulation of 3-Bromoenals and 1H-Pyrazol-4,5-diones

The stereoselective synthesis of spirocyclic pyrazolin-5-ones by N-heterocyclic carbene (NHC) organocatalysis has been less studied so far. For this reason and considering the interest of this class of compounds, here, we present the NHC-catalyzed [3 + 2]-asymmetric annulation of β-bromoenals and 1H-pyrazol-4,5-diones that achieves to produce chiral spiropyrazolone-butenolides. The synthesis is general for aryl and heteroaryl β-bromo-α,β-unsaturated aldehydes and 1,3-disubstituted pyrazolones. The spirobutenolides have been obtained in good yields (up to 88%) and enantioselectivities (up to 97:3 er). This constitutes the first described example using pyrazoldiones as the starting materials for this class of spiro compounds.

Alkynyl Acylazolium: A Versatile 1,3-Bielectrophilic 3C-Synthon in NHC-Organocatalysis.

N-Heterocyclic carbene (NHC) organocatalysis has emerged as a powerful tool in the field of modern organic synthesis especially in the asymmetric construction of various cyclic skeletons. As an emerging NHC-bound 1,3-bielectrophilic intermediate, alkynyl acylazolium has drawn substantial attention in recent years, and has been used as a versatile 3C-synthon in synthesizing valuable organic molecules since its discovery. In this review, focused on the different pathways for the formation of alkynyl acylazoliums from different precursors like alkynoic esters, alkynoic acids and ynals, the recent advances in the transformations and applications of alkynyl acylazoliums pioneered or developed over the last decade under NHC-catalysis were summarized comprehensively. At the same time, the outlook for further investigation and exploration of novel reaction modes for alkynyl acylazoliums in the future was also discussed.

How To Enhance the Efficiency of Breslow Intermediates for SET Catalysis

Oxidative carbene organocatalysis, which proceeds via single electron transfer (SET) pathways, has been limited by the moderately reducing properties of deprotonated Breslow intermediates BI-s derived from thiazol-2-ylidene 1 and 1,2,4-triazolylidene 2. Using computational methods, we assess the redox potentials of BI-s based on ten different types of known stable carbenes and report our findings concerning the key parameters influencing the steps of the catalytic cycle. From the calculated values of the first oxidation potential of BI-s derived from carbenes 1 to 10, it appears that, apart from the diamidocarbene 7, all the others are more reducing than thiazol-2-ylidene 1 and the 1,2,4-triazolylidene 2. We observed that while the reducing power of BI-s significantly decreases with increasing solvent polarity, the redox potential of the oxidant can increase at a greater rate, thus facilitating the reaction. The cation, associated with the base, also plays an important role when a nonpolar solvent is used; large and weakly coordinating cations such as Cs+ are beneficial. The radical-radical coupling step is probably the most challenging step due to both electronic and steric constraints. Based on our results, we predict that mesoionic carbene 3 and abnormal NHC 4 are the most promising candidates for oxidative carbene organocatalysis.

Updating the Benzoin Condensation of Benzaldehyde Using Microwave-Assisted Organic Synthesis and N-Heterocyclic Carbene Catalysis

The benzoin condensation of benzaldehyde is a staple of the undergraduate organic chemistry laboratory, introducing the current topic of nucleophilic carbene organocatalysis. Our procedure makes notable improvements to current practice, including the elimination of solvent waste and an 18-fold reduction of reaction time. We have demonstrated that microwave heating provides yields comparable to current practice in 5 min, using significantly less power (70 W) than traditional heating methods. The highest yields were obtained with N,N′-(2,4,6-trimethylphenyl)imidazolium chloride (IMes·HCl) as the catalyst and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base. Our procedure has been successfully executed by multiple cohorts of organic chemistry undergraduates, both with and without pandemic social distancing constraints.

Catalyst-controlled stereoselective carbon–heteroatom bond formations by N-heterocyclic carbene (NHC) organocatalysis

This review highlights recent advances in stereoselective carbon–heteroatom bond forming reactions, including C–N, C–O, C–S, C–F, C–P, etc., that were enabled by NHC organocatalysis with a focus on new activation modes and reactive intermediates.

Merging N‐Heterocyclic Carbene Organocatalysis with Hydrogen Atom Transfer Strategy

AbstractRadical N‐heterocyclic carbene (NHC) organocatalysis has progressed significantly in recent years, enabling various incredible transformations. However, prefunctionalized substrates bearing a redox functionality were always required. As a result, the direct functionalization of aliphatic C−H bonds in simple substrates remains a challenge. This situation was changed once the hydrogen transfer atom (HAT) strategy was successfully applied in radical NHC catalysis very recently. This concept paper focused on the discussion of merging NHC catalysis with a classical intramolecular 1,5‐HAT process. Moreover, the unprecedented application of intermolecular HAT in radical NHC catalysis is highlighted as a novel catalysis model showing great synthetic promise.

Atroposelective Synthesis of Triaryl α‐Pyranones with 1,2‐Diaxes by N‐Heterocyclic Carbene Organocatalysis

AbstractAtropisomers bearing multiple stereogenic axes are of increasing importance to the field of material science, pharmaceuticals, and catalysis. However, the atroposelective construction of multi‐axis atropisomers remains rare and challenging, due to the intrinsical difficulties in the stereo‐control of the multiple stereogenic axes. Herein, we demonstrate a single‐step construction of a new class of 1,2‐diaxially chiral triaryl α‐pyranones by an N‐heterocyclic carbene organocatalytic asymmetric [3+3] annulation of well‐designed alkynyl acylazolium precursors and enolizable sterically hindered 2‐aryl ketones. The protocol features broad substrate scope (>50 examples), excellent stereo‐control (most cases >20 : 1 dr, up to 99.5 : 0.5 er), and potentially useful synthetic applications. The success of this reaction relies on the rational design of structurally matched reaction partners and the careful selection of the asymmetric catalytic system. DFT calculations have also been performed to discover and rationalize the origin of the high stereoselectivity of this reaction.

Atroposelective Synthesis of Triaryl α-Pyranones with 1,2-Diaxes by N-Heterocyclic Carbene Organocatalysis.

Atropisomers bearing multiple stereogenic axes are of increasing importance to the field of material science, pharmaceuticals, and catalysis. However, the atroposelective construction of multi-axis atropisomers remains rare and challenging, due to the intrinsical difficulties in the stereo-control of the multiple stereogenic axes. Herein, we demonstrate a single-step construction of a new class of 1,2-diaxially chiral triaryl α-pyranones by an N-heterocyclic carbene organocatalytic asymmetric [3+3] annulation of well-designed alkynyl acylazolium precursors and enolizable sterically hindered 2-aryl ketones. The protocol features broad substrate scope (>50 examples), excellent stereo-control (most cases >20 : 1 dr, up to 99.5 : 0.5 er), and potentially useful synthetic applications. The success of this reaction relies on the rational design of structurally matched reaction partners and the careful selection of the asymmetric catalytic system. DFT calculations have also been performed to discover and rationalize the origin of the high stereoselectivity of this reaction.

Exploring Molecular Complexity by N-Heterocyclic Carbene Organocatalysis: New Activation and Reaction Diversity.

The development of catalytic synthetic approaches towards molecular complexity from simple materials continues to be an ultimate goal in synthetic chemistry. Over the past decades, N-heterocyclic carbene (NHC) organocatalysis has been extensively investigated to provide opportunities for a vast number of novel chemical transformations. Various activation modes and reactive intermediates enabled by NHC small-molecule catalysts, such as Breslow intermediates, (homo)enolates, acyl azoliums and their derived unsaturated azoliums exhibit great potential in the construction of complicated skeletons. This personal account will summarize our group's recent work in the exploration of new activation modes of NHC catalysis towards molecular complexity with a focus on the development and applications of NHC to achieve diversity and enantioselectivity in the preparation of functional molecules.

Atroposelective Access to 1,3‐Oxazepine‐Containing Bridged Biaryls via Carbene‐Catalyzed Desymmetrization of Imines

AbstractWe disclose herein an atroposelective synthesis of novel bridged biaryls containing medium‐sized rings via N‐heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol‐derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3‐oxazepine‐containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product.

Atroposelective Access to 1,3-Oxazepine-Containing Bridged Biaryls via Carbene-Catalyzed Desymmetrization of Imines.

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium-sized rings via N-heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol-derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3-oxazepine-containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product.

Oxidative Radical NHC Catalysis: Divergent Difunctionalization of Olefins through Intermolecular Hydrogen Atom Transfer

AbstractOxidative N‐heterocyclic carbene (NHC) organocatalysis, typically leading to the formation of acyl azolium reactive intermediates, constitutes one of the most important activation strategies for the NHC‐catalyzed chemical transformations. Here, we report an unprecedented oxidative radical NHC catalysis by using peroxyester as the external single‐electron oxidant to realize divergent difunctionalization of olefins. The key to success of this chemistry is the catalytic generation of oxygen radicals that could trigger an intermolecular hydrogen atom transfer to activate the inert C−H bonds, thereby enabling the productive radical relay process. With this protocol, commonly used general chemicals could serve as radical precursors to allow efficient synthesis of value‐added products in a straightforward and cost‐effective manner. Preliminary mechanistic investigations, including control experiments and DFT calculations, shed light on the NHC organocatalytic radical reaction mechanism.

Oxidative Radical NHC Catalysis: Divergent Difunctionalization of Olefins through Intermolecular Hydrogen Atom Transfer.

Oxidative N-heterocyclic carbene (NHC) organocatalysis, typically leading to the formation of acyl azolium reactive intermediates, constitutes one of the most important activation strategies for the NHC-catalyzed chemical transformations. Here, we report an unprecedented oxidative radical NHC catalysis by using peroxyester as the external single-electron oxidant to realize divergent difunctionalization of olefins. The key to success of this chemistry is the catalytic generation of oxygen radicals that could trigger an intermolecular hydrogen atom transfer to activate the inert C-H bonds, thereby enabling the productive radical relay process. With this protocol, commonly used general chemicals could serve as radical precursors to allow efficient synthesis of value-added products in a straightforward and cost-effective manner. Preliminary mechanistic investigations, including control experiments and DFT calculations, shed light on the NHC organocatalytic radical reaction mechanism.

Ir and NHC Dual Chiral Synergetic Catalysis: Mechanism and Stereoselectivity in γ-Butyrolactone Formation.

Cooperative dual catalysis is a powerful strategy for achieving unique reactivity by combining catalysts with orthogonal modes of action. This approach allows for independent control of the absolute and relative stereochemistry of the product. Despite its potential utility, the combination of N-heterocyclic carbene (NHC) organocatalysis and transition metal catalysis has remained a formidable challenge as NHCs readily coordinate metal centers. This characteristic also makes it difficult to rationalize or predict the stereochemical outcomes of these reactions. Herein, we use quantum mechanical calculations to investigate formation of γ-butyrolactones from aldehydes and allyl cyclic carbonates by means of an NHC organocatalyst and an iridium catalyst. Stereoconvergent activation of the racemic allyl cyclic carbonate forms an Ir-π-allyl intermediate and activation of an unsaturated aldehyde forms an NHC enolate, the latter of which is rate-limiting. Union of the two fragments leads to stereodetermining C-C bond formation and ultimately ring closure to generate the product lactone. Notably, CO2 loss occurs after formation of the C-C bond and Et3NH+ plays a key role in stabilizing carboxylate intermediates and in facilitating proton transfer to form the NHC enolate. The computed pathways agree with the experimental findings in terms of the absolute configuration, the enantiomer excess, and the different diastereomers seen with the (R)- and (S)-spiro-phosphoramidite combined with the NHC catalyst. Calculations reveal the lowest energy pathway includes both an NHC ligand and a phosphoramidite ligand on the iridium center. However, the stereochemical features of this Ir-bound NHC were found to not contribute to the selectivity of the process.