Intermolecular Stetter Reaction Research Articles

Synthesis of Novel 1,4-Diketone Derivatives and Their Further Cyclization.

One of the important reactions to obtain a new carbon-carbon bond is the Stetter reaction, which is generally via a nucleophilic catalyst like cyanide or thiazolium-NHC catalysts. In particular, 1,4-diketones with very functional properties are obtained by the Stetter reaction with the intermolecular reaction of an aldehyde and an α,β-unsaturated ketone. In this study, we synthesized new derivatives (substituted arenoxy) of 1,4-diketone compounds (2a-2n) with useful features by a new version of the Stetter reaction method. In our work, arenoxy benzaldehyde derivatives with different structures as the Michael donor and methyl vinyl ketone as the Michael acceptor were used for the intermolecular Stetter reaction. The reaction was catalyzed by 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (3b), using triethylamine for the basic medium and dimethyl sulfoxide as the solvent. As a result, some novel arenoxy-substituted 1,4-diketones were gained with good yields at room temperature within 24 h through an intermolecular Stetter reaction. In addition, new furan and pyrrole derivatives were prepared by performing the cyclization reaction with one of the obtained new diketone compounds.

N,N-Dimethylbenzimidazolium iodide as an Efficient Catalyst for a Green Reaction of Intermolecular Stetter Reaction in Water

N,N-dimethylbenzimidazolium iodide in the presence of NaOH catalyst intermolecular Stetter reaction in water was developed to afford the desired 1,4-addition products in satisfactory to good yields, although aroin products occurred competitively. The benzimidazolium salt catalyst and NaOH mixture can be reused several times without significant loss of efficiency.

α-Trifluoromethyl Carbanion-catalyzed Intermolecular Stetter Reaction of Aromatic Aldehydes with 2-Bromo-3,3,3-trifluoropropene: Synthesis of β-Alkoxyl-β-trifluoromethylated Ketones.

The intermolecular Stetter reaction of aromatic aldehydes with 2-bromo-3,3,3-trifluoropropene is achieved by the in situ generated α-trifluoromethyl carbanion catalyst. It not only represents the first example for α-trifluoromethyl carbanion-catalyzed umpolung reaction but also reveals a new protocol for the umpolung of aldehydes. Various useful β-alkoxyl-β-trifluoromethylated ketones were obtained in high yields, which could further convert to attractive bioactive compounds. Mechanism studies indicated an intramolecular 1,4-shift of the hydrogen atom was involved in this reaction.

A Highly EfficientN‐Mesityl Thiazolylidene for the Aliphatic Stetter Reaction: Stereoelectronic Quantification for Comparison of N‐Heterocyclic Carbene Organocatalysts

AbstractThe NHC‐catalysed intermolecular Stetter reaction provides direct access to 1,4‐diketones, however current NHC catalysts for this specific transformation remain underdeveloped, significantly limiting the use of this reaction in target‐oriented synthesis. Here we report a novelN‐mesityl thiazolium NHC as a high‐performing catalyst for this reaction, enabling high yields and short reaction times for a range of sterically non‐trivial aliphatic aldehydes reacting with enone substrates. Quantification of the properties of novel and known NHC organocatalysts revealed that both steric and electronic properties play an important role in the success of the newN‐mesityl thiazolium NHC for this reaction. These developments will facilitate wider application of the Stetter reaction as a key carbon‐carbon bond forming reaction for coupling of complex fragments under mild conditions.

Intermolecular Stetter Reaction Catalyzed by Copper-Doped g-C3N4 in H2O under LED Irradiation

Intermolecular Stetter Reaction Catalyzed by Copper-Doped g-C3N4 in H2O under LED Irradiation

Enantioselective Stetter Reactions Catalyzed by Bis(amino)cyclopropenylidenes: Important Role for Water as an Additive.

The first highly enantioselective intermolecular Stetter reaction using simple enones is reported. A series of novel chiral BAC structures were designed and prepared. They were tested in the Stetter reaction with simple aldehydes and enones. The products were generated in excellent yields and enantioselectivities (up to 94% ee). Surprisingly, a substoichiometric amount of water was crucial to obtain high enantioselectivities. Chiral BACs were also shown to catalyze 1,6-conjugate addition reactions with paraquinone methides enantioselectively.

Facile Synthesis of γ‐Ketonitriles in Water via C(sp2)–H Activation of Aromatic Aldehydes over Cu@g‐C3N4 under Visible‐Light

A facile C(sp2)–H activation of aldehyde under visible‐light conditions using Cu@g‐C3N4 as photocatalyst and water as solvent is reported. The envisaged method involves photocatalytic intermolecular Stetter reaction using differently substituted aldehydes and acrylonitrile to produce various γ‐keto nitriles in good to excellent yield (80–95 %) and 4–10 h at r.t. Operational simplicity, ambient reaction conditions, visible‐light condition, and application of the Cu@g‐C3N4 as photocatalyst make the envisaged protocol an efficient and highly green alternative to the existing methods for synthesis of γ‐keto nitriles.

Isa‒NHC‒catalyzed intermolecular Stetter reaction of aromatic aldehydes with maleimides: An efficient access to 3‒aroylsuccinimides

An intermolecular Stetter reaction of aromatic aldehydes with maleimides has been developed using thiazolylidene salt derived Isa‒NHC as an efficient organocatalyst. The synthesized Stetter products “3‒aroylsuccinimides” are important building blocks for the synthesis of natural products and bioactive compounds. The reaction conditions are mild, and various substituents on aromatic aldehyde and maleimide nitrogen were tolerated.

Synthesis of Succinimide Derivatives by NHC-Catalyzed Stetter Reaction of Aromatic Aldehydes with N-Substituted Itaconimides.

An N-heterocyclic carbene-catalyzed intermolecular Stetter reaction of aromatic aldehydes with N-substituted itaconimides has been developed. A delicate balance between the Stetter reaction and the competing isomerization of the itaconimide double bond has been achieved in this operationally simple reaction to afford valuable new succinimide derivatives containing 1,4 and 1,5 dicarbonyl scaffolds in good to excellent yields. The reaction tolerates variable substituents on both aldehydes and N-substituted itaconimides.

Intermolecular Stetter Reactions on Morita‐Baylis‐Hillman Adducts: an Approach to Highly Functionalized 1,4‐Dicarbonyl Compounds

AbstractWe reported herein an N‐heterocyclic carbene (NHC)‐mediated intermolecular Stetter reaction between oxidized Morita‐Baylis‐Hillman (MBH) adducts and a variety of aldehydes. This protocol allows the synthesis of highly functionalized 1,4‐dicarbonyl compounds. The reaction is an alternative approach to these compounds using commercially available starting materials. This metal‐free process exhibits a wide substrate scope, excellent atom economy, compatibility with functionalized substrates and mild reaction conditions. The 1,4‐dicarbonyl compounds were prepared in two steps via MBH reactions with overall yields up to 99 %. This protocol is easily scalable. The synthetic usefulness of this method was demonstrated in a high yield synthesis of a tri‐substituted pyrrole used as an advanced intermediate in the total synthesis of kinase inhibitors as well as in the synthesis of another heterocycles.

ChemInform Abstract: Intermolecular Stetter Reaction of Aromatic Aldehydes with (E)‐(2‐Nitrovinyl)cyclohexane Induced by N‐Heterocyclic Carbene and Thiourea.

AbstractVarious β‐nitroketones are prepared in moderate to good yields using thiazolium perchlorate as catalyst and in the presence of thiourea.

Intermolecular Stetter reaction of aromatic aldehydes with (E)-(2-nitrovinyl)cyclohexane induced by N-heterocyclic carbene and thiourea

Abstract Intermolecular Stetter reaction of aromatic aldehydes with (E)-(2-nitrovinyl)cyclohexane catalyzed by thiazolium A has been developed. The reaction rate and efficiency are profoundly impacted by the presence of thiourea B. The reaction affords moderate to good yields of the Stetter product. Some factors influencing yield were discussed.

Recent Advances in the N-Heterocyclic Carbene (NHC)-Organocatalyzed Stetter Reaction and Related Chemistry

Recent developments in the N-heterocyclic carbene (NHC)-catalyzed umpolung of aldehydes followed by their interception with activated carbon–carbon double bonds, namely the Stetter reaction, are presented. Advances in the inter- and intramolecular versions of this reaction, enantioselective transformations as well as the use of unactivated olefins in this type of reaction are discussed. 1 Introduction 2 Proposed Mechanism of the Stetter Reaction 3 Intramolecular Stetter Reactions 4 Intermolecular Stetter Reactions 5 Hydroacylation Reactions 6 Applications in Total Synthesis 7 Conclusion

ChemInform Abstract: Facile Synthesis of γ‐Ketophosphonates by an Intermolecular Stetter Reaction onto Vinylphosphonates.

The atom-economic and practical N-heterocyclic carbene (NHC) catalyzed Stetter reaction for the synthesis of γ-ketophosphonates by the reaction of aromatic aldehydes with vinylphosphonates is reported. The NHC derived from N-mesitylimidazolium salt (IMes) was an effective catalyst for this transformation, and the products were formed in moderate to good yields.

Facile synthesis of γ-ketophosphonates by an intermolecular Stetter reaction onto vinylphosphonates.

The atom-economic and practical N-heterocyclic carbene (NHC) catalyzed Stetter reaction for the synthesis of γ-ketophosphonates by the reaction of aromatic aldehydes with vinylphosphonates is reported. The NHC derived from N-mesitylimidazolium salt (IMes) was an effective catalyst for this transformation, and the products were formed in moderate to good yields.

Asymmetric Stetter reactions catalyzed by thiamine diphosphate-dependent enzymes.

The intermolecular asymmetric Stetter reaction is an almost unexplored transformation for biocatalysts. Previously reported thiamine diphosphate (ThDP)-dependent PigD from Serratia marcescens is the first enzyme identified to catalyze the Stetter reaction of α,β-unsaturated ketones (Michael acceptor substrates) and α-keto acids. PigD is involved in the biosynthesis of the potent cytotoxic agent prodigiosin. Here, we describe the investigation of two new ThDP-dependent enzymes, SeAAS from Saccharopolyspora erythraea and HapD from Hahella chejuensis. Both show a high degree of homology to the amino acid sequence of PigD (39 and 51 %, respectively). The new enzymes were heterologously overproduced in Escherichia coli, and the yield of soluble protein was enhanced by co-expression of the chaperone genes groEL/ES. SeAAS and HapD catalyze intermolecular Stetter reactions in vitro with high enantioselectivity. The enzymes possess a characteristic substrate range with respect to Michael acceptor substrates. This provides support for a new type of ThDP-dependent enzymatic activity, which is abundant in various species and not restricted to prodigiosin biosynthesis in different strains. Moreover, PigD, SeAAS, and HapD are also able to catalyze asymmetric carbon-carbon bond formation reactions of aldehydes and α-keto acids, resulting in 2-hydroxy ketones.

ChemInform Abstract: Diaminocyclopropenylidene Organocatalysts: Beyond N‐Heterocyclic Carbenes

AbstractReview: 20 refs.

Diaminocyclopropenylidene Organocatalysts: Beyond N‐Heterocyclic Carbenes

Cyclopropenylidene carbenes have been found to be efficient catalysts for the intermolecular Stetter reaction between aromatic aldehydes and α,β-unsaturated ketones. In this transformation, the cyclopropenylidene proved superior to more traditional thiazolium- and triazolium-derived carbenes. Preparation and evaluation of a chiral analogue have also been reported.

Role of base assisted proton transfer in N-heterocyclic carbene-catalyzed intermolecular Stetter reaction

The mechanism of the NHC-catalyzed intermolecular Stetter reaction between benzaldehyde and cyclopropene has been investigated using the PCM-M062X/6-311++G(3df,2p)//M062X/6-31+G(d,p) level of DFT. Compared to the direct reaction, a substantial reduction in the activation free energy by 10.6–14.4kcal/mol is observed when the reaction is performed in the presence of water, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The bases promote the proton transfer step of the reaction to yield the Breslow intermediate. An early concerted transition state has been located for the stereocontrolling C–C bond formation step (ΔG#=26.6kcal/mol) which is used to explain the diastereomeric ratio observed in the experiment.

N-Heterocyclic Carbene Catalyzed Asymmetric Intermolecular Stetter Reaction: Origin of Enantioselectivity and Role of Counterions

The mechanism and the role of KOtBu in an enantioselective NHC-catalyzed Stetter reaction between p-chlorobenzaldehyde and N-acylamido acrylate is established using DFT(M06-2X) methods. The Gibbs free energies are found to be significantly lower for transition states with explicit bound KOtBu as compared to the conventional pathways without the counterions. An intermolecular proton transfer from HOtBu to the prochiral carbon is identified as the stereocontrolling step. The computed enantioselectivities are in excellent agreement with the experimental results.