Ammonium Enolate Research Articles

A Diels-Alder reaction / oxa-Michael addition / acyloin rearrangement cascade on tropolonic substrates

We describe a novel pericyclic/anionic cascade reaction on tropolonic substrates that combines a Diels-Alder reaction, an oxa-Michael addition, and an acyloin rearrangement to afford tricyclic α-hydroxy-β-methoxyketones. Spectroscopic, crystallographic, and mechanistic studies indicate that the process requires stabilization of reaction intermediates through intramolecular H-bonding to take place, and suggest that the conjugate addition step involves a catalytic cycle with initial formation of an ammonium enolate and sustained by an alkoxide ion pair. Given the rich functionality and structural complexity generated in a single step, the process could be exploited in the preparation of natural product-like compound libraries.

Total Synthesis of (±)-Aspergilline A.

The total synthesis of (±)-aspergilline A (1) is described. Key features of the synthesis include pyrrolinone formation via reaction of an intermediate propargyl amine with a methyl malonyl chloride derived ammonium enolate and a formal [3+2] cycloaddition between an imidate and cyclopropenone.

Exploring the Mechanism and Stereoselectivity in Chiral Cinchona-Catalyzed Heterodimerization of Ketenes.

Catalytic heterodimerization of ketenes can lead to important four-membered β-lactones. A recent asymmetric organocatalytic [2 + 2] cycloaddition between methylketene (MK) and methylphenylketene (MPK) in the presence of pseudoenantiomeric cinchona catalysts (trimethylsilylquinine (TMSQ) or methylquinidine (MeQd)) provided β-lactones with high enantio- and diastereoselectivities. We employ DFT(M06-2X) computations to understand the mechanism and the origin of stereoselectivity in this ketene heterodimerization. The mechanism is found to involve the formation of an ammonium enolate first, by the action of the quinuclidine tertiary amine of the cinchona catalyst on MK. A stepwise pathway wherein the MK-cinchona enolate (enolate-A) adds to MPK in the selectivity-determining C-C bond formation step leading to the R-Z and S-Z product respectively with TMSQ and MeQd catalysts is predicted. The inclusion of LiClO4 is found to favor the C-C bond formation transition state to the S-E isomer in the case of MeQd and the R-E isomer with TMSQ catalysts. In the most preferred transition states, more effective C-H···π (between the phenyl ring of the EPK and the catalyst) and C-H···O interactions (between the catalyst and LiClO4) are noticed than that in the higher energy analogues, underscoring the importance of noncovalent interactions in enantio- and diastereocontrol.

Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable Immobilized Isothiourea.

Higher-order cycloaddition reactions constitute an efficient approach towards the construction of medium to large ring systems. However, enantioselective versions of these transformations remain scarce, which hampers their deployment in medicinal chemistry, or any other discipline in which homochirality is deemed crucial. Herein, we report a novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea-catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The resulting bicyclic compounds can be hydrogenated, but, most remarkably, they can also undergo completely regioselective [4+2] cycloaddition with active dienophiles to give architecturally complex polycyclic compounds in a straightforward manner.

Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable Immobilized Isothiourea

AbstractHigher‐order cycloaddition reactions constitute an efficient approach towards the construction of medium to large ring systems. However, enantioselective versions of these transformations remain scarce, which hampers their deployment in medicinal chemistry, or any other discipline in which homochirality is deemed crucial. Herein, we report a novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea‐catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The resulting bicyclic compounds can be hydrogenated, but, most remarkably, they can also undergo completely regioselective [4+2] cycloaddition with active dienophiles to give architecturally complex polycyclic compounds in a straightforward manner.

Asymmetric [4+2] Annulation of C1 Ammonium Enolates with Copper-Allenylidenes.

An asymmetric catalytic decarboxylative [4+2] annulation of 4-ethynyl dihydrobenzooxazinones and carboxylic acids has been established by cooperative copper and nucleophilic Lewis base catalysis. A C1 ammonium enolate and copper-allenylidene complex, each catalytically generated from different substrates, underwent a cascade asymmetric propargylation and lactamization process to yield optically active 3,4-dihydroquinolin-2-one derivatives with excellent levels of stereoselectivity (up to 99 % ee, 95:5 d.r.).

Asymmetric [4+2] Annulation of C1 Ammonium Enolates with Copper‐Allenylidenes

AbstractAn asymmetric catalytic decarboxylative [4+2] annulation of 4‐ethynyl dihydrobenzooxazinones and carboxylic acids has been established by cooperative copper and nucleophilic Lewis base catalysis. A C1 ammonium enolate and copper–allenylidene complex, each catalytically generated from different substrates, underwent a cascade asymmetric propargylation and lactamization process to yield optically active 3,4‐dihydroquinolin‐2‐one derivatives with excellent levels of stereoselectivity (up to 99 % ee, 95:5 d.r.).

Exploiting the Imidazolium Effect in Base‐free Ammonium Enolate Generation: Synthetic and Mechanistic Studies

AbstractN‐Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition–cyclization reactions using different α,β‐unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the “imidazolium” effect in ammonium enolate formation and have highlighted key differences with traditional base‐mediated processes.

Exploiting the Imidazolium Effect in Base-free Ammonium Enolate Generation: Synthetic and Mechanistic Studies.

N-Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition-cyclization reactions using different α,β-unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the "imidazolium" effect in ammonium enolate formation and have highlighted key differences with traditional base-mediated processes.

Enantioselective Synthesis of 3,5,6-Substituted Dihydropyranones and Dihydropyridinones using Isothiourea-Mediated Catalysis.

The scope of dihydropyranone and dihydropyridinone products accessible by isothiourea‐catalyzed processes has been expanded and explored through the use of 2‐N‐tosyliminoacrylates and 2‐aroylacrylates in a Michael addition‐lactonization/lactamization cascade reaction. Notably, to ensure reproducibility it is essential to use homoanhydrides as ammonium enolate precursors with 2‐aroyl acrylates, while carboxylic acids can be used with 2‐N‐tosyliminoacrylates, delivering a range of 3,5,6‐substituted dihydropyranones and dihydropyridinones with high enantioselectivity (typically >90 % ee). The derivatization of the heterocyclic core of a 3,5,6‐substituted dihydropyranone through hydrogenation is also reported.

ChemInform Abstract: Asymmetric Isothiourea‐Catalyzed Formal [3 + 2] Cycloadditions of Ammonium Enolates with Oxaziridines.

AbstractThe title process is investigated with racemic oxaziridine (II) under conditions A).

Asymmetric Isothiourea-Catalysed Formal [3+2] Cycloadditions of Ammonium Enolates with Oxaziridines.

A highly enantioselective Lewis base-catalysed formal [3+2] cycloaddition of ammonium enolates and oxaziridines to give stereodefined oxazolidin-4-ones in high yield is described. Employing an enantioenriched oxaziridine in this process leads to a matched/mis-matched effect with the isothiourea catalyst and allowed the synthesis of either syn- or anti-stereodefined oxazolidin-4-ones in high d.r., yield and ee. Additionally, the oxazolidin-4-one products have been derivatised to afford functionalised enantioenriched building blocks.

ChemInform Abstract: Amino Alcohol‐Mediated Enantioselective Syntheses of α‐Substituted Indanones and Tetralones, Ammonium Enolates as Key Intermediates

AbstractReview: [40 refs.

ChemInform Abstract: 2‐Arylacetic Anhydrides as Ammonium Enolate Precursors.

AbstractReadily prepared 2‐arylacetic anhydrides (I) act as convenient ammonium enolate precursors in isothiourea‐mediated catalytic asymmetric intermolecular Michael addition‐lactonization processes.

A base-free neutral phase-transfer reaction system.

Although phase-transfer reactions catalyzed by using quaternary ammonium salts are generally believed to require base additives, we discovered that, even without any base additives, conjugate additions of 3-substituted oxindoles to nitroolefins proceeded smoothly in the presence of lipophilic quaternary ammonium bromide under water-organic biphasic conditions. The mechanism of this novel base-free neutral phase-transfer reaction system is investigated and the assumed catalytic cycle is presented together with interesting effects of water and lipophilicity of the phase-transfer catalyst. The base-free neutral phase-transfer reaction system can be applied to highly enantioselective conjugate addition and aldol reactions under the influence of chiral bifunctional ammonium bromides as key catalysts. The structure of the chiral ammonium enolate intermediate is discussed based on the single-crystal X-ray structures of relevant ammonium salts and the importance of bifunctional design of catalyst is clearly explained in the model of intermediate.

2-Arylacetic anhydrides as ammonium enolate precursors

Readily prepared 2-arylacetic anhydrides act as convenient ammonium enolate precursors in isothiourea (HBTM-2.1)-mediated catalytic asymmetric intermolecular Michael addition-lactonisation processes, giving diverse synthetic building blocks in good yield with high diastereo- and enantiocontrol (up to 98 : 2 dr and >99% ee).

ChemInform Abstract: Asymmetric α‐2‐Tosylethenylation of N,N‐Dialkyl‐L‐amino Acid Esters via the Formation of Non‐Racemic Ammonium Enolates.

AbstractTitle tosylethenylation of pyrrolidinyl‐protected L‐amino acid esters (I) and (IV) proceeds with moderate to high enantioselectivity (up to 96% e.e.).

Asymmetric α-2-tosylethenylation of N,N-dialkyl-l-amino acid estersvia the formation of non-racemic ammonium enolates

Asymmetric α-2-tosylethenylation of (S)-2-(pyrrolidin-1-yl)propanoic acid esters was shown to produce good yields with high enantioselectivities. The reaction proceeds via the formation of a non-racemic ammonium enolate without an external source of chirality.

ChemInform Abstract: Synthesis of Fluorine-Containing Alkyl 2-Cyano-3-oxocarboxylates. Reactions with Nucleophiles.

Fluorine-containing alkyl 2-cyano-3-oxocarboxylates were synthesized for the first time by the reaction of ethyl cyanoacetate with fluorine-substituted carboxylic acid halides or alkyl carboxylates. The reactions with hydrazine hydrate, phenylhydrazine, ando-phenylenediamine give hydrazinium (ammonium) enolates or products of acid decomposition.

擬似分子内反応による高効率な合成手法の開発

A highly effective reaction is described, which involves the pseudo intramolecular process. The acyl groups of β-keto esters are activated by α-arylation or α-nitration, and are easily transferred to amines without forming any by-product. This reaction is initiated by forming ammonium enolate. When the amine is liberated under equilibrium, the nucleophilic amine and the electrophilic keto ester are close together, which undergoes the effective substitution like the intramolecular reaction despite the intermolecular reaction; it is called pseudo intramolecular process. This concept is applicable to other substrates having both acidic hydrogen and functionality to furnish polyfunctionalized compounds those are not easily prepared by alternative procedure.