Acyl Azolium Research Articles

Mechanisms and Stereoselectivities of NHC‐Catalyzed [3 + 4] Cycloaddition Reaction between Isatin‐Derived Enal and N‐(ortho‐Chloromethyl)aryl Amide

Possible mechanisms and origins of stereoselectivity of N‐heterocyclic carbene (NHC) promoted spirobenzazepinone formation from the annulation of an isatin‐derived enal and N‐(ortho‐chloromethyl)aryl amide have been investigated computationally. DFT results (M06–2X) suggest that the preferred mechanism consists of six steps: The nucleophilic coupling of the NHC catalyst and isatin‐derived enal was considered as the first reaction step (step I), followed by generation of the Breslow intermediate through a HCO3– assisted proton transfer event (step II). The next step is the addition of Breslow intermediate to N‐(ortho‐chloromethyl)aryl amide generating the acyl azolium intermediate (step III). Then the reaction proceeds through successive intramolecular cycloaddition (step IV), H2O‐mediated 1,3‐proton transfer (step V) and catalyst elimination (step VI) affording the [3+4] cycloaddition product. Step V plays a pivotal role in determining the stereoselectivity of the reaction and leads to the experimentally observed S‐configuration product. The DFT results account for the experimental observations. Global reactivity index analysis has also been conducted to identify the role of NHC catalyst.

Synthesis of chromans and kinetic resolution of 2-aryl-3-nitro-2H-chromenes via the NHC-bound azolium homoenolate pathway

Herein, an effective kinetic resolution (KR) of racemate 2-aryl-3-nitro-2H-chromenes to afford synthetically valuable chromans and 2H-chromenes through an NHC-bound acyl azolium homoenolate pathway has been demonstrated.

N‐Heterocyclic Carbene Catalyzed Quadruple Domino Reactions: Asymmetric Synthesis of Cyclopenta[c]chromenones

AbstractAn N‐heterocyclic carbene catalyzed domino sequence via α,β‐unsaturated acyl azolium intermediates has been developed. This strategy provides a convenient enantioselective route to functionalized tricyclic coumarin derivatives and cyclopentanes. DFT studies and control experiments were performed to gain better insight into the reaction mechanism.

N-Heterocyclic Carbene Catalyzed Quadruple Domino Reactions: Asymmetric Synthesis of Cyclopenta[c]chromenones.

An N-heterocyclic carbene catalyzed domino sequence via α,β-unsaturated acyl azolium intermediates has been developed. This strategy provides a convenient enantioselective route to functionalized tricyclic coumarin derivatives and cyclopentanes. DFT studies and control experiments were performed to gain better insight into the reaction mechanism.

Carbene-Catalyzed Enantioselective Addition of Benzylic Carbon to Unsaturated Acyl Azolium for Rapid Synthesis of Pyrrolo[3,2-c]quinolines

A carbene-catalyzed enantioselective addition of benzylic carbon to α,β-unsaturated acyl azolium intermediate generated via N-heterocyclic carbene catalysis is disclosed. This addition is followed by a stereoselective Mannich reaction and a chemo-selective lactam formation cascade to afford pyrrolo[3,2-c]quinolones as the products with excellent yields and optical purities. This work constitutes an effective asymmetric benzyl sp3-carbon functionalization and single-step rapid access to multicyclic heterocycles bearing four contiguous chiral centers.

Enantioselective N-Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium.

Herein we report the enantioselective N-heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio- and diastereo-enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6-addition/β-lactonization.

Enantioselective N‐Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium

AbstractHerein we report the enantioselective N‐heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio‐ and diastereo‐enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6‐addition/β‐lactonization.

N-Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations.

N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC-catalyzed transformations involving Breslow intermediates, acyl azoliums, α,β-unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC-catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates.

Enantioselective [3+3] atroposelective annulation catalyzed by N-heterocyclic carbenes

Axially chiral molecules are among the most valuable substrates in organic synthesis. They are typically used as chiral ligands or catalysts in asymmetric reactions. Recent progress for the construction of these chiral molecules is mainly focused on the transition-metal-catalyzed transformations. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) atroposelective annulation of cyclic 1,3-diones with ynals. In the presence of NHC precatalyst, base, Lewis acid and oxidant, a catalytic C–C bond formation occurs, providing axially chiral α-pyrone−aryls in moderate to good yields and with high enantioselectivities. Control experiments indicated that alkynyl acyl azoliums, acting as active intermediates, are employed to atroposelectively assemble chiral biaryls and such a methodology may be creatively applied to other useful NHC-catalyzed asymmetric transformations.

A C1-symmetric N-heterocyclic carbene catalysed oxidative spiroannulation of isatin-derived enals: highly enantioselective synthesis of spirooxindole δ-lactones.

A C1-symmetric N-heterocyclic carbene (NHC)-catalysed activation of isatin-derived enals under oxidative conditions was achieved. The in situ generated α,β-unsaturated acyl azolium species was efficiently trapped by 1,3-dicarbonyl compounds via a Michael addition/spiroannualtion cascade, delivering a series of synthetically important spirooxindole δ-lactones with up to 96% enantioselectivity.

Potassium 2‐oxo‐3‐enoates as Effective and Versatile Surrogates for α, β‐Unsaturated Aldehydes in NHC‐Catalyzed Asymmetric Reactions

AbstractPotassium 2‐oxo‐3‐enoates, which are readily prepared at scale and easily stored, have been found to be effective and versatile surrogates for α,β‐unsaturated aldehydes in NHC‐catalyzed asymmetric reactions. Promoted by chiral N‐heterocyclic carbenes combined with LiCl, these easy‐to‐handle solid salts could release of CO2 and then undergo asymmetric reactions via homoenolate and α, β‐unsaturated acyl azolium intermediate. The reactions have broad substrate scopes with high enantioselectivities.magnified image

Esters as Alkynyl Acyl Ammonium and Azolium Precursors: A Formal [2 + 3] Annulation with Amidomalonates via Lewis Base/Lewis Acid Cooperative Catalysis.

Esters are for the first time used as α,β-unsaturated alkynyl acyl ammonium and azolium precursors to undergo a formal [2 + 3] annulation with amidomalonates through DMAP/LiCl or carbene/LiCl cooperative catalysis. A wide range of (Z)-5-amino-3-furanones were obtained in moderate to high yields with high regioselectivity and stereoselectivity. In addition, a plausible mechanism based on the calculated charge distribution of the intermediates is proposed to explain the regioselectivity.

N-Heterocyclic Carbene-Catalyzed Atom-Economical and Enantioselective Construction of the C–S Bond: Asymmetric Synthesis of Functionalized Thiochromans

An N-heterocyclic carbene-catalyzed cleavage and recombination of the C–S bond was developed. This is an efficient example of NHC reacting with an unsaturated thioester to generate an α,β-unsaturated acyl azolium with high atom economy. This protocol affords an alternative route for the construction of highly functionalized thiochroman derivatives with three consecutive stereogenic centers with good to high yields, as well as excellent diastereoselectivity and enantioselectivity.

Aryloxide-Promoted Catalyst Turnover in Lewis Base Organo­catalysis

This short review highlights select examples of enantioselective Lewis base promoted reactions that use tertiary amine (cinchona alkaloids, isothioureas, and DMAP/PPY derivatives) or NHC catalysts and employ aryloxide-promoted catalyst turnover from an acyl ammonium or azolium intermediate. This review focuses on the range of strategies that have been developed within this area, and discusses their evolution and context.1 Introduction2 Phenols as Additives To Promote Catalyst Turnover2.1 NHC Catalysis with α-Functionalised Aldehydes and Phenols2.2 Enantioselective Fluorination with Aryloxide-Promoted Catalyst Turnover3 In Situ Catalytic Generation Of Aryloxide3.1 Aryloxide-Promoted Turnover Generated from an Electrophilic Polyhalogenated Quinone: Overview3.2 Aryloxide-Promoted Catalyst Turnover Generated from an α-Aryl­oxyaldehyde or Aryl Ester Starting Material: Overview4 Summary and Outlook

Formal [3 + 4] Annulation of α,β-Unsaturated Acyl Azoliums: Accessto Enantioenriched N-H-Free 1,5-Benzothiazepines.

An unprecedented formal [3 + 4] annulation of α,β-unsaturated acyl azoliums with 2-aminobenzenethiols has been utilized to synthesize enantioenriched N-H-free 1,5-benzothiazepines, which are recognized as privileged structures in numerous biologically active scaffolds. This protocol offers a rapid and direct pathway to access the target compounds with high enantioselectivities and has been applied in the concise synthesis of chiral drug (R)-thiazesim.

Oxidative N-Heterocyclic Carbene Catalyzed Dearomatization of Indoles to Spirocyclic Indolenines with a Quaternary Carbon Stereocenter.

An efficient method for the asymmetric intramolecular dearomatization of indoles by using oxidative N-heterocyclic carbene catalysis is demonstrated. Valuable optically active spirocyclic indolenines bearing an all-carbon quaternary stereocenter are obtained in excellent yields and with excellent enantioselectivity. The starting indoles are readily prepared and the reactions proceed through an intramolecular indole 3-acylation with an in situ generated acyl azolium intermediate to form a spirocyclic ketone moiety.

N-heterocyclic carbene-mediated formal [3+3] annulation of isatin-derived α, β-unsaturated acids: Access to functionalized 3,4′-spirooxindole δ-lactones

An in situ activation of isatin-derived α,β-unsaturated acids 2 for the generation of isatin-derived α,β-unsaturated acyl azoliums II was described. The acyl azoliums II were successfully applied to undergo a formal [3 + 3] annulation with 1,3-dicarbonyl compounds to access functionalized 3,4′-spirooxindole δ-lactones 4. A scale-up synthesis and an enantioselective variant of this protocol were also investigated. The stable and easily prepared acids 2 may be further utilized as promising versatile electrophilic 1,3-synthons for divergent synthesis of spirooxindoles.

N-Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl Azolium

First reported less than a decade ago, the α,β-unsaturated acyl azolium has emerged as a central reactive intermediate for reaction discovery using N-heterocyclic carbene catalysis. In this Perspective, an introduction to the four main reactivity patterns accessible from this intermediate is provided. The Perspective is handled in a largely chronological fashion, with an emphasis on alternate approaches to the key intermediate and first-in-class reaction cascades. Finally, a brief discussion of emerging trends in this field of catalysis is presented. Although not exhaustive, the Perspective provides an overview of this active area of research and serves as a guide for future investigations.

Catalytic Intermolecular Cross-Couplings of Azides and LUMO-Activated Unsaturated Acyl Azoliums

An example for the catalytic synthesis of densely functionalized 1,2,3-triazoles through a LUMO activation mode has been developed. The protocol is enabled by intermolecular cross-coupling reactions of azides with in situ-generated α,β-unsaturated acyl azoliums. High yields and broad scope as well as the investigation of reaction mechanism are reported.

Enantioselective intermolecular all-carbon [4+2] annulation via N-heterocyclic carbene organocatalysis.

The highly stereoselective intermolecular all-carbon [4+2] annulation between in situ generated acyclic dienolates and α,β-unsaturated acyl azoliums is disclosed. The identification of 2-acyloxy-3-butenones as suitable diene precursors is the key to the success of this transformation. The corresponding highly functionalized cyclohexene products, which are inaccessible from Diels-Alder reactions, were delivered with high levels of diastereo- and enantioselectivities. A series of further transformations based on the product showed the potential of this reaction.