Stetter Reaction Research Articles

Insight into the Role of the Counteranion of an Imidazolium Salt in Organocatalysis: A Combined Experimental and Computational Study

N-Heterocyclic carbenes (NHCs) can serve as very reactive nucleophilic catalysts and exhibit strong basicity. Herein, we initiate a combined experimental and computational investigation of the NHC-catalyzed ring-closing reactions of 4-(2-formylphenoxy)but-2-enoate derivatives 1 to uncover the relationship between the counteranion of an azolium salt, the nucleophilicity and basicity of the carbene species, and the catalytic performance of the carbene species by taking imidazolium salts IPr⋅HX (X=counteranion, IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as the representative precatalysts. The plausible mechanisms of IPr-mediated ring-closing reactions have been investigated by using DFT calculations. The hydrogen-accepting ability, assigned as the basicity of the counteranion of IPr⋅HX and evaluated by DFT calculations, is correlated with the rate of deprotonation of C2 in IPr⋅HX, which could be monitored by the capture of the free carbene formed in situ with elemental sulfur. The deprotonation of C2 in IPr⋅HX with a more basic anion gives rise to a higher concentration of the free carbene and vice versa. At a relatively low concentration, IPr prefers to show a nucleophilic character to induce the intramolecular Stetter reaction. At a relatively high concentration, IPr primarily acts as a base to afford benzofuran derivatives. These data comprehensively disclose, for the first time, that the counteranions of azolium salts significantly influence not only the catalytic activity, but also possibly the reaction mechanism.

Synthesis of Kynurenine 3-Hydroxylase Inhibitor FCE28833

FCE28833 inhibits kynurenine 3-hydroxylase thereby elevating levels of kynurenic acid, an endogenous excitatory amino acid receptor antagonist. It may have therapeutic value in treating diseases linked to hyperfunction of excitatory amino acid receptors. A short and highly enantioselective synthesis of FCE28833 features an asymmetric intermolecular Stetter reaction catalyzed by the N-heterocyclic carbene E.

NHC-Catalyzed Intermolecular Stetter Reaction with Asymmetric Protonation

The Glorius group reports an ­intermolecular Stetter reaction between different aldehydes and N-acylamido acrylate catalyzed by the NHC derived from 1. The desired products, α-chiral amino acid derivatives, are obtained in high yields and high enantioselectivities for a broad scope of aldehydes. The observed enantio­selectivity arises from the stereoselective protonation of the Michael adduct rather than from the prior C-C bond-forming event. The authors propose that the chiral catalyst forces the Michael addition to proceed with a well-defined geometry, setting the stage for the construction of the desired stereocenter by the intramolecular protonation. An alternative concerted mechanism can also not be ruled out as mentioned by the authors.

Diastereoselective Synthesis of 3-Hydroxyindanones via N-Heterocyclic Carbene Catalyzed [4+1] Annulation of Phthalaldehyde and 1,2-Diactivated Michael Acceptors

The diastereoselective synthesis of 2,2-disubstituted-3-hydroxy-indanones was realized by the N-heterocyclic carbene catalyzed [4+1] annulation of phthalaldehyde and 1,2-diactivated Michael acceptors, which involves a tandem process of Stetter reaction, proton shift, and aldol reaction.

Mechanistic investigation of the enantioselective intramolecular stetter reaction: proton transfer is the first irreversible step.

A study on the mechanism of the asymmetric intramolecular Stetter reaction is reported. This investigation includes the determination of the rate law, kinetic isotope effects, and competition experiments. The reaction was found to be first order in aldehyde and azolium catalyst or free carbene. A primary kinetic isotope effect was found for the proton of the aldehyde. Taken together with a series of competition experiments, these results suggest that proton transfer from the tetrahedral intermediate formed upon nucleophilic attack of the carbene onto the aldehyde is the first irreversible step.

Dynamic Kinetic Asymmetric Synthesis of Five Contiguous Stereogenic Centers by Sequential Organocatalytic Stetter and Michael−Aldol Reaction: Enantioselective Synthesis of Fully Substituted Cyclopentanols Bearing a Quaternary Stereocenter

A synthesis of fully substituted cyclopentanes bearing a quaternary carbon center and five contiguous stereogenic centers has been achieved by sequential organocatalyzed Stetter and Michael-Aldol reactions of heteroaromatic aldehydes, nitroalkenes, and α,β-unsaturated aldehydes via the [1 + 2 + 2] annulation strategy with dynamic kinetic asymmetric transformation and excellent enantioselectivities (up to >99% ee).

Highly Enantioselective Synthesis of α‐Amino Acid Derivatives by an NHC‐Catalyzed Intermolecular Stetter Reaction

PROTONtype: An NHC-catalyzed (NHC=N-heterocyclic carbene), highly asymmetric intermolecular Stetter reaction allows the atom-economic and efficient formation of valuable α-amino acid derivatives (see scheme); the key step is an intramolecular stereoselective protonation. For the first time, a β-unsubstituted Michael acceptor was employed successfully in this kind of reaction, most importantly, with a broad range of different aldehydes.

N-Heterocyclic carbene-catalysed intermolecular Stetter reactions of acetaldehyde

A facile method for the intermolecular Stetter reaction of various Michael acceptors with acetaldehyde as a biomimetic acylanion source was realized using N-heterocyclic carbene catalysis. This catalytic system has also been applied to the enantioselective Stetter reaction and resulted in moderate to good enantioselectivities for the corresponding Stetter products.

Thiazolium-catalyzed intermolecular Stetter reaction of linear and cyclic alkyl α-diketones

An efficient method for the N-heterocyclic carbene (NHC)-catalyzed conjugate addition of acetyl anions to various α,β-unsaturated acceptors (Stetter reaction) has been optimized by using 2,3-butandione (biacetyl) as an alternative surrogate of acetaldehyde. The disclosed procedure proved to be compatible with microwave dielectric heating for reaction time reduction and with the use of different linear α-diketones as acyl anion donors (e.g. 3,4-hexanedione for propionyl anion additions). Moreover, the unprecedented umpolung reactivity of cyclic α-diketones in the atom economic nucleophilic acylation of chalcones is herein presented. Mechanistic aspects of the thiazolium-based catalysis involving linear and cyclic α-diketone substrates are also discussed.

Synthesis of (1R,2R)-DPEN-derived triazolium salts and their application in asymmetric intramolecular Stetter reactions

A series of novel chiral triazolium salts has been synthesized from readily available (1R,2R)-DPEN and found to be efficient for the enantioselective intramolecular Stetter reaction. With 10 mol% of the catalyst, the intramolecular Stetter reaction was realized in excellent yields with up to 97% ee.

Biotransformations

This report reviews significant developments in applications of biological catalysis in synthetic organic chemistry for the year 2010. Hydrolases have been applied in kinetic resolution and quantitative DKR processes and have been evolved in vitro to give enzymes displaying improved enantioselectivity and solvent stability. Applications of reductases have included an unusual instance of the generation of optically active atropisomers and also the identification of stereoselective imine reductases in Streptomyces spp. Other biotransformations leading to optically active amines have focused on transaminases, and a wide-ranging genomics analysis has revealed nineteen new and previously rare (R)-selective transaminases. A further (R)-selective transaminase was extensively engineered for process suitability for application in the industrial synthesis of sitagliptin. Improved carbon–carbon bond formation by aldolases is being addressed through the identification and improvement of enzymes accepting non-phosphorylated dihydroxyacetone as a substrate donor for the synthesis of sugars. In addition, new enzymatic activities, including natural enzymes that catalyse the Stetter reaction, and also the Michael-type addition of water to cyclohexenone have been reported. Finally, advances in the in silico design of enzymes are proceeding rapidly, with the report of the design of the first enzyme known to catalyse an bimolecular Diels-Alder reaction.

ChemInform Abstract: Polyether‐Substituted Thiazolium Ionic Liquid Catalysts — A Thermoregulated Phase‐Separable Catalysis System for the Stetter Reaction.

AbstractA new type of thermoregulated thiazolium ionic liquid catalyst for the Stetter reaction is synthesized by introducing a polyether chain to the thiazole.

Sequential Organocatalytic Stetter and Michael-Aldol Condensation Reaction: Asymmetric Synthesis of Fully Substituted Cyclopentenes via a [1 + 2 + 2] Annulation Strategy

A stereoselective synthesis of fully substituted cyclopentenes has been achieved by a sequential organocatalyzed Stetter and Michael-aldol condensation of aromatic aldehydes, nitroalkenes, and α,β-unsaturated aldehydes via the [1 + 2 + 2] annulation strategy with excellent diastereoselectivities and enantioselectivities (up to >99% ee).

Synthesis of thermoregulated phase-separable triazolium ionic liquids catalysts and application for Stetter reaction

A series of polyether-substituted triazolium ionic liquids catalysts have been first synthesized for resolving the problem of separation and reuse of Stetter catalysts. The catalysts possess the properties of critical solution temperature (CST) and inverse temperature-dependent solubility in toluene/heptane solvents. Based on these properties, the catalysts can achieve the catalytic process named as thermoregulated phase-separable catalysis (TPSC) with the characteristic of homogeneous reaction at higher temperature and phase-separation at lower temperature. The novel TPSC system has been successfully applied for Stetter reaction of furfural or butanal with ethyl acrylate. The experimental results have showed that the novel catalysts exhibit excellent TPSC with high recycling efficiency.

ChemInform Abstract: N‐Heterocyclic Carbene‐Catalyzed Cascade Reaction Involving the Hydroacylation of Unactivated Alkynes.

The N-heterocyclic carbene (NHC)-catalyzed hydroacylation of unactivated alkynes to provide α,β-unsaturated ketones is reported. In addition, a rare case of an efficient and selective dually NHC-catalyzed cascade reaction involving the hydroacylation of alkynes and a subsequent intermolecular Stetter reaction allows the formation of chromanones containing a 1,4-diketone moiety.

Multicatalytic, asymmetric Michael/Stetter reaction of salicylaldehydes and activated alkynes

We report the development of a multicatalytic, one-pot, asymmetric Michael/Stetter reaction between salicylaldehydes and electron-deficient alkynes. The cascade proceeds via amine-mediated Michael addition followed by an N-heterocyclic carbene-promoted intramolecular Stetter reaction. A variety of salicylaldehydes, doubly activated alkynes, and terminal, electrophilic allenes participate in a one-step or two-step protocol to give a variety of benzofuranone products in moderate to good yields and good to excellent enantioselectivities. The origin of enantioselectivity in the reaction is also explored; E/Z geometry of the reaction intermediate as well as the presence of catalytic amounts of catechol additive are found to influence reaction enantioselectivity.

NHC-Catalyzed Hydroacylation of Unreactive Alkynes

An intramolecular N-heterocyclic carbene (NHC) catalyzed hydroacylation of unactivated alkynes is described. In this paper, electron-rich alkynes are less reactive than electron-poor analogues, and less reactive alkynes are applied well to the cascade Stetter reaction. This work is the first example of a NHC-catalyzed cascade reaction involving the hydroacylation of unreactive alkynes without metal catalysts.

N-Heterocyclic Carbene-Catalyzed Cascade Reaction Involving the Hydroacylation of Unactivated Alkynes

The N-heterocyclic carbene (NHC)-catalyzed hydroacylation of unactivated alkynes to provide alpha,beta-unsaturated ketones is reported. In addition, a rare case of an efficient and selective dually NHC-catalyzed cascade reaction involving the hydroacylation of alkynes and a subsequent intermolecular Stetter reaction allows the formation of chromanones containing a 1,4-diketone moiety.

Polarity reversal induced by electrochemically generated thiazol-2-ylidenes: The Stetter reaction

The inversion of the normal reactivity (umpolung) of aldehydes has been induced via N-heterocyclic carbenes (NHCs) thiazol-2-ylidenes 2a or 3a, generated by simple electrolyses of solutions containing thiazolium salt 2 or 3. Accordingly, 1,4-dicarbonyl compounds have been obtained, in mild conditions and in moderate to very high yields, via 1,4-addition of the Breslow intermediates to the suitable Michael acceptor. The procedure has been performed in classical organic solvents (VOCs) as well as in room temperature ionic liquids (RTILs). The different reactivity of aliphatic aldehydes vs the one of aromatic and heteroaromatic aldehydes has been emphasized.

Polyether-substituted thiazolium ionic liquid catalysts – a thermoregulated phase-separable catalysis system for the Stetter reaction

A series of polyether-substituted thiazolium ionic liquids have been synthesized and used as catalysts in the Stetter reaction. The ionic liquids are a thermoregulated phase-separable catalysis (TPSC) system, because they possess the properties of critical solution temperature (CST) and inverse temperature-dependent solubility in toluene–heptane. The results showed that the novel TPSC system exhibits high recycling efficiency, and provides a potential route for a environmentally benign Stetter reaction.