NHC-catalyzed Reaction Research Articles

Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study.

To elucidate the mechanism and origins of chemo- and enantioselectivities of the reaction between aliphatic aldehydes and hydrazones catalyzed by triazolium-derived NHC, density functional theory computations have been performed. According to our calculated results, the whole catalytic cycle for the formation of dihydropyridazinones proceeds via the initial nucleophilic addition of NHC to an aliphatic aldehyde, followed by the concerted intramolecular proton transfer and C-Cl bond cleavage. Subsequent deprotonation generates an enolate intermediate. The enolate intermediate then undergoes 1,4-addition to hydrazone to construct a new carbon-carbon bond. The following ring-closure would lead to a six-membered ring intermediate, which, upon the release of NHC, affords the final product dihydropyridazinone. The computation results reveal that intramolecular proton transfer is significantly promoted by the Brønsted acid DIPEA·H+. The carbon-carbon bond formation step could determine not only the chemoselectivity but also the stereoselectivity and lead to the S-isomer product. It was found that the stereoselectivity arises from a combination of weak interactions, including C-H···O, C-H···N, C-H···π, and LP···π. NHC could enhance the nucleophilicity of the aliphatic aldehyde and facilitate further reaction with hydrazone. This work could be beneficial for the development of new catalytic strategies in the future.

Construction of Highly Functionalized 2-Styrylfurans by N-Heterocyclic Carbene/Brønsted Acid Catalysis.

This research presents an original method for synthesizing styrylfurans using N-heterocyclic carbenes (NHCs) and Brønsted acid catalysis. By exploiting 2,4-dioxoesters as conjugated 1,3-dicarbonyls, we have developed a technique allowing the efficient formation of highly functionalized styrylfurans with interesting photochemical properties, through a NHC-catalyzed cross-benzoin reaction followed by a Brønsted acid-driven Paal-Knorr-like condensation. This approach permits the integration of various substituents on the furan ring, with preliminary biological studies indicating potential as fluorescent dyes.

NHC-Mediated Photochemical/Electrochemical Synthesis of Carbonyl Compounds

AbstractGreat progress has been made in the photochemical/electrochemical reactions of carbonyl compounds catalyzed by N-heterocyclic carbenes (NHCs), allowing for many incredible reactions. The form of active intermediates hugely varies in different reactions. Under light or electricity, different active intermediates can be generated during NHC-catalyzed reactions depending on their interaction with different substrates and the reaction conditions. Intermediates can be converted into α,β-unsaturated acylazoliums, Breslow intermediates, homoenolates, and acylazoliums and subsequently undergo single- or double-electron conversions. This study reviews the different active intermediates formed by NHC in photochemical/electrochemical catalysis.1 Introduction2 NHC-Mediated Photoreactions3 NHC-Mediated Electrochemical Reactions4 Conclusion and Prospects

NHC-Catalyzed Reaction of Aldehydes for C(sp2)–O Bond Formation

In the past few decades, N-heterocyclic carbenes (NHCs) have opened the new field of organocatalysis in synthetic organic chemistry. This review highlights the dramatic progress in the field of NHC-catalyzed C–O bond formation based on the activation of aldehyde C(sp2)–H bonds. The oxidative and redox transformations for the synthesis of various molecules with structural diversity and complexity are summarized. Furthermore, new methods and strategies for NHC catalysis are emerging continuously; thus, cooperative catalysis with Brønsted acid, hydrogen-bonding catalyst, transition-metal catalyst, and photocatalyst are also described.

FluoroFusion: NHC-Catalyzed Nucleophilic Aromatic Substitution Reaction Unveils Functional Perfluorinated Diarylmethanones.

A mild, facile, and metal-free approach via the N-heterocyclic carbene-catalyzed SNAr reaction between aryl aldehydes with perfluoroarenes to obtain the coveted functional perfluorinated diarylmethanones is disclosed. This method accommodates a diverse substrate range and exhibits notable tolerance toward various functional groups. Our success in modifying biologically relevant molecules, crafting a fully fluorinated bioisosteric analogue of drug candidate D1, and highlighting the potential of these ketones as valuable electrolyte additives for lithium-ion batteries (LIBs) underscores the versatility of our methodology.

NHC-Catalyzed Formal [4 + 2] Annulation of o-Formyl-Tethered Michael Acceptors and Ynones to Access Highly Functionalized Naphthalene Derivatives.

Herein we demonstrate a novel organocatalytic method to access multifunctionalized naphthalenes via an NHC-catalyzed reaction of ynones and o-formyl-tethered Michael acceptors. The presented method proceeds through an intermolecular Stetter reaction-cyclization-aromatization cascade and represents a rare example of organocatalytic benzannulation for the synthesis of substituted arenes by using ynone as a two-carbon synthon. The current method has broad substrate scope; postsynthetic transformations and gram-scale syntheses highlight the practicality of the displayed methodology.

Mechanism and Origin of Stereoselectivity for the NHC-Catalyzed Desymmetrization Reaction for the Synthesis of Axially Chiral Biaryl Aldehydes.

Organocatalytic desymmetrization reaction is a powerful tool for constructing axial chirality, but the theoretical study on the origin of stereoselectivity still lags behind even now. In this work, the N-heterocyclic carbene (NHC)-catalyzed desymmetrization reaction of biaryl frameworks for the synthesis of axially chiral aldehydes has been selected and theoretically investigated by using density functional theory (DFT). The fundamental pathway involves several steps, i.e., desymmetrization, formation of Breslow oxidation, esterification, and NHC regeneration. The desymmetrization and formation of Breslow processes have been identified as stereoselectivity-determining and rate-determining steps. Further weak interaction analyses proved that the C-H···O hydrogen bond and C-H···π interactions are responsible for the stability of the key stereoselective desymmetrization transition states. This research contributes to understanding the nature of NHC-catalyzed desymmetrization reactions for the synthesis of axially chiral compounds.

Mechanisms and origins of stereoselectivity in the NHC-catalyzed oxidative reaction of enals and pyrroles: a density functional theory study.

The mechanism, chemoselectivity and stereoselectivity in the NHC-catalyzed reaction between enals and pyrroles for the synthesis of 5,6-dihydroindolizine were studied using DFT calculations. The cycle for catalytic generation of 5,6-dihydroindolizine proceeds via seven steps: (1) addition of the NHC to enal, (2) formation of a Breslow intermediate through [1,2]-proton transfer, (3) oxidation, (4) Michael addition, (5) [2+2] cycloaddition, (6) liberation of NHCs and (7) decarboxylation. Our results show that the presence of DMAP·H+ lowers the barrier for [1,2]-proton transfer. In addition, NHC·H+ plays a key role in decarboxylation. Michael addition which involves the formation of a new C-C bond was identified to be the chemo- and stereoselectivity-determining step, leading to the experimentally observed 5S,6R-dihydroindolizine. Analysis of the noncovalent interactions revealed that the observed stereoselectivity is attributed to the differential weak interactions (CH⋯π, LP⋯π and CH⋯CH) involved in the transition states during the Michael addition step. The computational results not only rationalize experimental observations but also provide some useful information for the future design of new catalytic processes.

Isolation and characterization of an annelated N-heterocyclic carbene stabilized Breslow enolate

The highly reactive intermediate (Breslow enolate) of NHC-catalyzed radical reactions has been successfully synthesized and structurally characterized by X-ray diffraction for the first time.

Enantioselective synthesis of tricyclic oxoquinolines via NHC-catalyzed Michael-aldol-lactamization-dehydration cascade.

The enantioselective synthesis of tricyclic oxoquinolines via NHC-catalyzed cascade reaction of enals with malonates bearing a 2-aminophenyl group is reported. The chiral α,β-unsaturated acylazoliums underwent a smooth Michael-aldol-lactamization-dehydration quadruple cascade with the amino malonate derivative to afford the desired tricyclic products.

Disclosing the mechanism and origin of stereoselectivity of the NHC-catalyzed transformation reaction of enals with acyl azolium as a key intermediate

The reaction mechanism and origin of stereoselectivity of the NHC-catalyzed transformation of an acyl azolium intermediate have been theoretically investigated using the DFT method.

NHC-Catalyzed Reaction of Carboxylic Acids Using Allene Ketones as Substrates and Activating Reagents.

We present a new reaction between carboxylic acids and allene ketones mediated by N-heterocyclic carbene (NHC) catalysts, which exhibit, in principle, nearly perfect atom economy. In this new approach, allene ketones act as both an activating reagent and a reactant. All atoms in the substrates end up in the product without the need for coupling reagents. The present study aims to encourage further explorations of NHC catalytic reactions with alternative activation strategies and better atom economy.

Construction of Cyclopentanes Consisting of Five Stereocenters via NHC-Catalyzed Cascade Reactions of Enals with Oxindole-Dienones.

Despite the widespread presence of the chiral cyclopentane motif, the asymmetric synthesis of cyclopentanes containing five stereocenters remains a formidable challenge. Here, we present an N-heterocyclic carbene (NHC)-catalyzed cascade reaction of enal and oxindole-dienone, which allows access to spiroxindole cyclopentanes featuring a complete set of chiral centers on the five-membered carbocycle. This strategy, characterized by the formation of multiple bonds and chiral centers, demonstrates a broad substrate scope, exclusive diastereoselectivity, and up to 99:1 er.

NHC-Catalyzed Tandem Reaction: A Strategy for the Synthesis of 2-Pyrrolidinone-Functionalized Phenanthridines.

Herein, an N-heterocyclic carbene (NHC)-catalyzed tandem cyclization/addition/cyclization reaction of 2-isocyanobiaryls and α-bromo-N-cinnamylamides for the synthesis of 2-pyrrolidinone-functionalized phenanthridines is developed. This protocol features a radical cascade process, broad substrate scope, and good functional group compatibility under metal- and oxidant-free reaction conditions.

Switchable Organocatalysis from N-heterocyclic Carbene-Carbodiimide Adducts with Tunable Release Temperature.

N-Heterocyclic carbenes (NHCs) are powerful organocatalysts, but practical applications often require in situ generation from stable precursors that "mask" the NHC reactivity via reversible binding. Previously established "masks" are often simple small molecules, such that the NHC structure is used to control both catalytic activity and activation temperature, leading to undesirable tradeoffs. Herein, we show that NHC-carbodiimide (CDI) adducts can be masked precursors for switchable organocatalysis and that the CDI substituents can control the reaction profile without changing the NHC structure. Large electronic variations on the CDI (e.g., alkyl versus aryl) drastically change the catalytically active temperature, whereas smaller perturbations (e.g., different para-substituted phenyls) tune the catalyst release within a narrower window. This control was demonstrated for three classic NHC-catalyzed reactions, each influencing the NHC-CDI equilibrium in different ways. Our results introduce a new paradigm for controlling NHC organocatalysis as well as present practical considerations for designing appropriate masks for various reactions.

Mechanisms and Stereoselectivities in the NHC-Catalyzed [4 + 2] Annulation of 2-Bromoenal and 6-Methyluracil-5-carbaldehyde.

To disclose the reaction mechanism and selectivity in the NHC-catalyzed reaction of 2-bromoenal and 6-methyluracil-5-carbaldehyde, a systematic computational study has been performed. According to DFT computations, the catalytic cycle is divided into eight elementary steps: nucleophilic attack of the NHC on 2-bromoenal, 1,2-proton transfer, C-Br bond dissociation, 1,3-proton transfer, addition to 6-methyluracil-5-carbaldehyde, [2 + 2] cycloaddition, NHC dissociation, and decarboxylation. The Bronsted acid DABCO·H+ plays a crucial role in proton transfer and decarboxylation steps. The addition to 6-methyluracil-5-carbaldehyde determines both chemoselectivity and stereoselectivity, leading to R-configured carbocycle-fused uracil, in agreement with experimental results. NCI analysis indicates that the CH···N, CH···π, and LP···π interactions should be the key factor for determining the stereoselectivity. ELF analysis shows the main role of the NHC in promoting C-Br bond dissociation. The mechanistic insights obtained in the present work may guide the rational design of potential NHC catalysts.

NHC-catalyzed regiodivergent transformations of Ynones with trifluoromethyl ketones: Aldol reaction or [3+2] annulation

A novel NHC-catalyzed regiodivergent reaction of ynones with trifluoromethyl ketones consisting of Aldol reactions and intermolecular [3 + 2] annulations has been developed. Employing two different NHC catalysts, various tertiary alcohols and dihyrofuranones containing trifluoromethyl can be obtained in moderate to good yields (35 examples, up to 91% yield). This protocol features mild reaction conditions, high efficiency and broad substrates scope, promoting the development of NHC catalysis and transformations of ynones.

N-Heterocyclic Carbene-Catalyzed Atroposelective Synthesis of N–N Axially Chiral 3-Amino Quinazolinones

Although the atroposelective synthesis of biaryls and related compounds bearing axially chiral C–C bonds is well-known, the synthesis of axially chiral C–N bond-containing compounds is relatively less explored, and the construction of axially chiral N–N bonds has received only scant attention. Demonstrated herein is the N-heterocyclic carbene (NHC)-catalyzed selective amidation reaction, leading to the atroposelective synthesis of N–N axially chiral 3-amino quinazolinones. The NHC-catalyzed reaction of quinazolinones containing a free N–H moiety with α,β-unsaturated aldehydes under oxidative conditions furnished the atropisomeric quinazolinone derivatives under mild conditions and broad scope. Preliminary studies on experimental and density functional theory-based N–N rotational barrier determination are also presented.

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.

Construction of C(CO)–C(CO) Bond via NHC-Catalyzed Radical Cross-Coupling Reaction

A C(sp2)-C(sp2) bond can be constructed via a photoredox/N-heterocyclic carbene (NHC)-cocatalyzed radical cross-coupling reaction, which provides a complementary strategy to classic electron pair processes. The present protocol represents the first example of an NHC-catalyzed two-component radical cross-coupling reaction involving C(sp2)-centered radical species. The decarboxylative acylation of oxamic acid with acyl fluoride was conducted under mild conditions and allowed the preparation of a variety of useful α-keto amides, including sterically congested ones.