N-Heterocyclic Carbene Catalyzed Research Articles

Enantioselective [3 + 3] Annulation-Deoxalation Strategy for Rapid Access to δ-Oxoesters via N-Heterocyclic Carbene Catalysis.

A new and unprecedented stereoselective synthetic approach to δ-oxoesters derivatives from readily available starting materials has been developed. This method, catalyzed by N-heterocyclic carbene, involves an annulation-deoxalation reaction of alkynyl aldehydes with 2,4-diketoesters and proceeds via the chiral α,β-unsaturated acylazolium intermediates. The annulation includes the in situ formation of dihydropyranones, which undergo ring-opening methanolysis with Lewis acid activation, followed by deoxalation to afford chiral 1,5-ketoesters in moderate to good yields.

Wingtip-Flexible N-Heterocyclic Carbenes: Unsymmetrical Connection between IMes and IPr.

IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed β-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.

Enantioselective synthesis of C3-functionalized 2,1-benzothiazine 2,2-dioxides by N-heterocyclic carbene catalysis.

We present herein an approach for the enantioselective C3-functionalization of 2,1-benzothiazine 2,2-dioxides using N-heterocyclic carbene (NHC) catalysis. Our method involves a sequence of [3+3] cycloaddition and ring-opening reactions with different N- and O-nucleophiles, followed by silylation. Overcoming the challenge of selectivity targeting the C3 position, this protocol demonstrates a broad substrate scope and high enantioselectivity. This marks a significant advancement in the field of NHC-catalyzed transformations.

Cooperative photoredox and N-heterocyclic carbene-catalyzed formal C-H acylation of cyclopropanes via a deconstruction-reconstruction strategy.

Cyclopropanes are ubiquitous and key structural motifs in commercially available drugs and bioactive molecules. Herein, we present regio-selective acylation of aryl cyclopropanes with cooperative photoredox and N-heterocyclic carbene catalysis. This approach involves a deconstruction-reconstruction strategy via γ-chloro-ketones as intermediates and fulfills the formal C(sp3)-H functionalization of cyclopropanes.

Pd/NHC sequentially catalyzed atroposelective synthesis of planar-chiral macrocycles.

Planar-chiral macrocycles play a pivotal role in host-guest chemistry and drug discovery. However, compared with the synthesis of other types of chiral compounds, the asymmetric construction of planar-chiral macrocycles still remains a forbidding challenge. Herein, we report a sequential palladium and N-heterocyclic carbene catalysis to build planar-chiral macrocycles. This protocol features broad scope and good functional group tolerance, and allows a rapid assembling of planar-chiral macrocycles with excellent enantioselectivities.

Recent advances in cooperative N-heterocyclic carbenes and photocatalysis

Combination of N-heterocyclic carbene catalysis and photocatalysis with radical process is a powerful strategy to access useful molecules. In this review, we summarized recent advances in this growing area from the perspective of reaction mechanism.

Synthesis of α-chiral amides via synergistic visible-light-induced Wolff rearrangement and asymmetric NHC catalysis

Herein, a visible-light-induced chiral N-heterocyclic carbene (NHC) catalyzed asymmetric amination of ketenes has been developed. This strategy provides a facile synthetic protocol for the efficient construction of α-chiral amides.

Synthesis of Pyrroloindolines via N-Heterocyclic Carbene Catalyzed Dearomative Amidoacylation of Indole Derivatives.

Pyrroloindoline is a privileged heterocyclic motif that is widely present in many natural products and pharmaceutical compounds. Herein, we report an amidyl radical-mediated dearomatization for synthesizing a series of pyrroloindolines via N-heterocyclic carbene catalysis. In this organocatalytic process, the Breslow enolate served as both a single electron donor and an acyl radical equivalent to assemble C3a-acyl pyrroloindolines with a broad substrate scope. Sequential reduction of the indole derivatives provided the analogues of (±)-desoxyeseroline, which exhibited potential anticancer activity.

Cooperative Photoredox and N-Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α-Trifluoromethyl-Substituted Ketones.

α-Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α-CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem-difluoroalkenes through cooperative photoredox and N-heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre-functionalization, thus enabling an efficient and general synthetic method to access α-CF3 -substituted ketones. A wide variety of gem-difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono- or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

Cooperative Photoredox and N‐Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α‐Trifluoromethyl‐Substituted Ketones

Abstractα‐Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α‐CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem‐difluoroalkenes through cooperative photoredox and N‐heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre‐functionalization, thus enabling an efficient and general synthetic method to access α‐CF3‐substituted ketones. A wide variety of gem‐difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono‐ or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the 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.

An NHC-Catalyzed Desulfonylative Smiles Rearrangement of Pyrrole and Indole Carboxaldehydes.

The use of catalysis methods to enable Smiles rearrangement opens up new substrate classes for arylation under mild conditions. Here, we describe an N-heterocyclic carbene (NHC) catalysis system that accesses indole and pyrrole aldehyde substrates in a desulfonylative Smiles process. The reaction proceeds under mild, transition-metal-free conditions and captures acyl anion reactivity for the synthesis of a diverse array of 2-aroyl indoles and pyrroles from readily available sulfonamide starting materials.

Enantioselective SN 2 Alkylation of Homoenolates by N-Heterocyclic Carbene Catalysis.

The functionalization of the β-carbon of enals with electrophiles is a signature umpolung reactivity of N-heterocyclic carbene (NHC)derived homoenolates. However, only a limited number of electrophiles are shown to be compatible, with most of them being π-electrophiles. In this study, the successful enantioselective β-alkylation of homoenolates is reported using Csp3 electrophiles through an SN 2 strategy. The protocol shows a broad scope regarding alkyl electrophiles, delivering good yields, and excellent enantioselectivities (up to 99% ee). It enables the installation of drug-like structural motifs in either enals or alkylating agents, demonstrating its potential as a valuable tool for late-stage modification. Furthermore, a concise synthetic route is presented to chiral pyrroloindoline-type skeletons. Preliminary mechanistic studies support a direct SN 2 mechanism.

Non-Classical Molecular Activation by Phosphines and N-Heterocyclic Carbenes and Its Application to Catalytic Reactions

Abstract This Award Account reports our recent studies concerning the catalytic transformations that involve a non-classical mode of molecular activation by tertiary phosphines and N-heterocyclic carbenes (NHCs). Regarding organophosphine catalysis, we successfully designed reactions based on a P(III)/P(V) redox couple. A catalytic protocol for generating pentacoordinate P(V) species was devised by the reaction of tertiary phosphines, acyl fluorides and alkynoates. The ability of the thus generated fluorophosphoranes to participate in ligand coupling and ligand metathesis with organosilicon nucleophiles enables synthetic transformations that are otherwise unattainable, including the intermolecular carbofluorination of alkynes and the hydroalkenylation of enol ethers. Regarding nucleophilic NHC catalysis, the use of imidazolium-based NHCs can generate deoxy-Breslow intermediates that are sufficiently nucleophilic to promote the aromatic substitution of aryl halides, aryl ethers and anilides. The protocol can also be used for the nucleophilic activation of styrene derivatives, allowing for the generation of a series of ylide intermediates that can serve as non-stabilized vinyl anion equivalents. These results demonstrate that synthetic transformations involving non-stabilized carbanions can be conducted under catalytic conditions without the use of strong organometallic nucleophiles.

Silylacylation of Alkenes through N-Heterocyclic Carbene Catalysis.

The construction of silicon-containing molecules has received increasing attention in recent years. Herein, we report the generation of silyl radicals through NHC catalysis under mild reaction conditions. This methodology offers a novel and convenient route to a diverse range of β-silyl ketones with a broad substrate scope and good functional group compatibility. Both the radical clock and electrochemical studies are consistent with the hypothesis of ground-state SET, and a plausible mechanism for the organocatalytic transformation is proposed.

Oxidative NHC Catalysis: An Unconventional Tool for Macrocyclic Oligoesters Synthesis.

The application of N-heterocyclic carbene (NHC) catalysis under highly diluted oxidative condition to the polycondensation of dialdehydes and diols is herein presented as an alternative, atomeconomical synthetic route to macrocyclic oligoesters (MCOs). The disclosed protocol paves the way to the straightforward access to MCOs, starting from commercial dialdehydes, avoiding the use of toxic diacyl chlorides, commonly employed in traditional MCOs synthetic processes. The method is totally metal-free, takes place in the green Me-THF solvent and requires the use of a fully recyclable quinone oxidant. The protocol versatility is confirmed by the employment of fossil-based and bio-based monomers such as 2,5diformylfuran (DFF), 2,5-bis(hydroxymethyl)furan (BHMF), and isomannide, synthesizing a series of novel and known synthetically relevant macrocyclic oligoesters, fully characterized by NMR and MALDI-TOF MS analysis, with product yields (51-86%) comparable to those obtained by traditional synthetic routes. Finally, to emphasize the synthetic relevance of the target macrocycles, an entropicallydriven ring opening polymerization (ED-ROP) key study has been performed, optimizing the organocatalyzed synthesis of poly(2,5furan-dimethylene 2,5 furandicarboxylate) (PBHMF) with numberaverage molecular weight up to 8200 g mol-1 and 66% isolated yield.

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.

Aerobic oxidative N-heterocyclic carbene catalysis.

The ease with which simple starting materials can be transformed into highly functionalized products has made oxidative N-heterocyclic carbene (NHC) catalysis an area of significant interest. However, the use of stoichiometric amounts of high molecular weight oxidants in most reactions generates an undesired equivalent amount of waste. To address this issue, the use of oxygen as the terminal oxidant in NHC catalysis has been developed. Oxygen is attractive due to its low cost, low molecular weight, and ability to generate water as the sole by-product. However, molecular oxygen is challenging to use as a reagent in organic synthesis due to its unreactive ground state, which often requires reactions to be run at high temperatures and results in the formation of kinetic side-products. This review covers the development of aerobic oxidative carbene catalysis, including NHC-catalyzed reactions with oxygen, strategies for oxygen activation, and selectivity issues under aerobic conditions.

Carbene-Catalyzed Intermolecular Dehydrogenative Coupling of Aldehydes with C(sp3)-H Bonds.

The development of catalyst-controlled methods for direct functionalization of two distinct C-H bonds represents an appealing approach for C-C formations in synthetic chemistry. Herein, we describe an organocatalytic approach for straightforward acylation of C(sp3)-H bonds employing readily available aldehyde as "acyl source" involving dehydrogenative coupling of aldehydes with ether, amine, or benzylic C(sp3)-H bonds. The developed method affords a broad range of ketones under mild conditions. Mechanistically, simple ortho-cyanoiodobenzene is essential in the oxidative radical N-heterocyclic carbene catalysis to give a ketyl radical and C(sp3) radical through a rarely explored intermolecular hydrogen atom transfer pathway, rendering the acylative C-C formations in high efficiency under a metal- and light-free catalytic conditions. Moreover, the prepared products show promising anti-bacterial activities that shall encourage further investigations on novel agrochemical development.

Asymmetric redox benzylation of enals enabled by NHC/Ru cooperative catalysis

The development of general methods for asymmetric benzylation of prochiral carbon nucleophiles remains a challenge in organic synthesis. The merging of ruthenium catalysis and N-heterocyclic carbene (NHC) catalysis for asymmetric redox benzylation of enals has been achieved, which opens up strategic opportunities for the asymmetric benzylation reactions. A wide range of 3,3'-disubstituted oxindoles with a stereogenic quaternary carbon center widely existing in natural products and biologically interesting molecules is successfully obtained with excellent enantioselectivities [up to 99% enantiomeric excess (ee)]. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of oxindole skeletons. Furthermore, the linear correlation between ee values of NHC precatalyst and the product elucidated the independent catalytic cycle of either the NHC catalyst or the ruthenium complex.