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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.

The Stetter reaction, a conjugate umpolung reaction, is well known for cyanide-catalyzed transformations of mostly aromatic aldehydes. Enzymatic Stetter reactions, however, have been largely unexplored, especially with respect to preparative transformations. We have investigated the kinetics of the MenD-catalyzed 1,4-addition of α-ketoglutaric acid to acrylonitrile which has shown that acrylonitrile, while an interesting candidate, is a poor substrate for MenD due to low affinity of the enzyme for this substrate. The kinetic model of the reaction was simplified to double substrate Michaelis–Menten kinetics where the reaction rate linearly depends on acrylonitrile concentration. Experiments at different initial concentrations of acrylonitrile under batch, repetitive batch, and fed-batch reactor conditions were carried out to validate the developed mathematical model. Thiamine diphosphate dependent MenD proved to be quite a robust enzyme; nevertheless, enzyme operational stability decay occurs in the reactor. The spontaneous reactivity of acrylonitrile towards polymerization was also taken into account during mathematical modeling. Almost quantitative conversion of acrylonitrile was achieved in all batch reactor experiments, while the yield of the desired product was dependent on initial acrylonitrile concentration (i.e., the concentration of the stabilizer additive). Using the optimized reactor parameters, it was possible to synthesize the product, 6-cyano-4-oxohexanoic acid, in a concentration of 250 mM. The highest concentration of product was achieved in a repetitive batch reactor experiment. A fed-batch reactor experiment also delivered promising results, especially regarding the short reaction time needed to achieve a 200 mM concentration of product. Hence, the enzymatic Stetter reaction with a highly reactive acceptor substrate can be performed on a preparative scale, which should enable similar transformations with acrylate, methacrylate, and methyl vinyl ketone.

A strategy toward tetrapetalones was explored including a site-selective ethylenation of the silyl enol ether A to afford a quaternary stereocenter that serves in a stereogenic capacity. Regio- and diastereoselective reactions were observed in conjunction with the oxidative formation of cation B, which included subsequent selective formation of either carbon-oxygen or carbon-carbon bonds at the δ or ζ position on the seven-membered ring. The fourth ring was formed using a Stetter reaction.

Recent developments of N-heterocyclic carbenes (NHCs)- catalyzed acyl-anion equivalent (Stetter reaction), homoenolate and enolate reactions with reactive nitroalkene as a Michael acceptor are described. Systematically, a unique strategy for NHC-catalyzed C-C bond formation reactions using nitroalkenes for the synthesis of synthons are presented, particularly in asymmetric approach. Advances in the single-electron-transfer (SET) reaction merging with NHC as an organocatalyst are also discussed with nitroalkenes as important coupling partners. This review attracts both the accomplishments and the future works needed in this important area.

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.

4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) serves as a trifluoromethyl-containing building block for the preparation of trifluoromethyl-substituted thiophenes, furans, pyrrols, and piperazines. Key steps are an addition–elimination reaction to ETFBO followed by the thiazolium-catalyzed Stetter reaction. The scope of this chemistry was demonstrated in a new synthetic approach towards the COX-2 selective, nonsteroidal anti-inflammatory drug Celebrex® (celecoxib).

Highly concise total syntheses of paullone and kenpaullone were developed. Cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines derived from methyl 2-aminocinnamate derivatives and 2-nitrobenzaldehyde provided 2-(2′-nitrophenyl)indole-3-acetic acid derivatives. Subsequent reduction of the nitro group with zinc under acidic conditions to an amino group followed by spontaneous lactam formation allowed for the total syntheses of paullone and kenpaullone to be completed in two steps starting from commercially available materials. The direct use of a nitro group as the precursor of an amino group present in the phenyl ring at the 2-position in the indole ring significantly streamlined the total syntheses of these target molecules.

We 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.

N-Heterocyclic carbene catalysis allows the rapid formation of functionalized carbon–carbon bonds. Our group has spent the previous decade focusing on broadening practical applications of this type of catalysis. The design and discovery of novel reactivities and catalysts in our group can best be divided into work focusing on the Stetter, ring-expansion, and cross-benzoin reactions. Along with our expansion of the reaction scope, our introduction of novel bis(amino)cyclopropenylidene catalysts for the Stetter reaction successfully suppresses formation of side products, increasing synthetic utility. Concurrent work on ring-expansion reactions allows access to functionalized lactones and lactams. In addition to expanding the scope of the cross-benzoin reaction through use of α-ketoesters and α-amino aldehydes, the introduction of a new triazolylidene catalyst has allowed access to general chemoselective cross-benzoin reactions between aliphatic and aromatic aldehydes. 1 Introduction 2 Stetter Reactions 2.1 Domino Stetter Reactions 3 Ring-Expansion Reactions 4 Cross-Benzoin Reactions 5 Summary and Outlook

The microwave-assisted coupling-isomerization reaction is a practical entry to 1-thienyl-substituted 3-(hetero)arylpropenones, which can be transformed, either stepwise or in a one-pot fashion, via Stetter reaction into thienyl-substituted 1,4-diketones. The terminal Paal–Knorr condensation with Lawesson's reagent gives rise to the formation of bi- or terthiophenes in good yield. The title compounds show substantial blue to blue-green fluorescence upon excitation with UV light.

A new strategy applicable to the synthesis of indoloquinolizine natural products has been developed. A cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines, derived from 2-aminocinnamic acid derivatives and 2-pyridinecarboxaldehydes, provided indole-3-acetic acid derivatives bearing a pyridyl ring at the 2-position. Reduction of the carboxylic acid moiety to an alcohol followed by activation of the resulting alcohol with Tf2O or TsCl generated indoloquinolizinium salts, which were utilized as precursors for indoloquinolizine natural products. The advantage of this protocol was successfully demonstrated in the total syntheses of arborescidine A and nauclefidine.

A general and efficient method for the synthesis of tricyclic spirocarbocycles is described. Various cyclic enal-enones were reacted with an N-heterocyclic carbene, and an intramolecular Stetter reaction proceeded smoothly to give various tricyclic spiro-1,4-diketones in 31–72% yields. The ring size of the spiro compounds can be easily controlled using different cyclic enals and enones or by altering the length of the carbon tether.

Various benzaldehyde tethers with a cyclic enone were prepared from commercially available 2-hydroxybenzaldehydes via a three-step sequence involving triflate formation, Sonogashira cross-coupling, and regioselective hydrogenation. These substrates were then exposed to an N-heterocyclic carbene, whereupon intramolecular Stetter reaction proceeded smoothly to give various spirofused tricyclic 1,4-diketones in 30-87% yields. Furaldehyde and nicotinaldehyde derivatives also participated in the reaction under the Stetter conditions.

The α-regioselective asymmetric [3 + 2] annulation reaction of Morita–Baylis–Hillman carbonates from isatins and activated ortho-vinylbenzaldehyses was developed by the catalysis of a chiral tertiary amine. The sequential N-heterocyclic carbene-mediated intramolecular Stetter reaction was conducted to finally furnish the bridged 5,8-methanobenzo[7]annulen-9-one architectures incorporating a spirooxindole motif with excellent stereoselectivity.

Radical developments: Photochemical/secondary amine dual catalysis has proven to be an efficient strategy for radical umpolung reactions. Two new processes provide an elegant solution to a long-standing chemoselectivity problem for the synthesis of 1,4-dicarbonyl compounds.

Two novel chiral verbenone-derived triazolium salts have been synthesized from readily available (&minus, )-verbenone and found to be efficient for the enantioselective intramolecular Stetter reaction. The approach, based on the intramolecular annulation between acyl anion equivalents and Michael acceptors, benefits from broad substrate scope, high chemical and stereochemical efficiency, and operational simplicity. Mono-, and disubstituded chromanone derivatives have been obtained in excellent yields and in a highly stereochemical manner.

The intermolecular or intramolecular asymmetric benzoin reaction was catalyzed by a small amount of N-heterocyclic carbene (NHC) (0.2-1 mol %) under solvent-free conditions. The solvent-free intramolecular asymmetric Stetter reaction also proceeded efficiently with NHC (0.2-1 mol %). In some cases, even solid-to-solid or solid-to-liquid conversions took place with low catalyst loading (0.2-1 mol %).

A short and concise formal synthesis of enantiopure dihydroartemisinic acid from (R)-citronellal is described in this article. Intramolecular version of asymmetric Stetter reaction using Rovis aminoindane based NHC catalyst was explored to access the core substituted cyclohexanone framework which on functional group manipulation and late stage ring closing metathesis (RCM) reaction afforded an advanced intermediate for dihydroartemisinic acid.

A series of novel chiral triazolium salts derived from (−)-β-pinene were synthesized and found to be highly efficient precatalysts for the enantioselective intramolecular Stetter reaction. The triazolium salts prepared from a single precursor, (−)-β-pinene, react with antipodal enantiofacial selectivity in the Stetter reaction to afford mono-, di-, and trisubstituted chromanones in excellent yields with excellent stereoselectivity.

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.

A general method to generate umpolung of aldimines with cyanide was developed via the addition of cyanide to aldimines followed by a proton transfer from the carbon atom to the nitrogen atom in the resulting cyanide adducts. This novel method was successfully applied to the first imino-Stetter reaction of aldimines obtained from 2-aminocinnamic acid derivatives and aromatic aldehydes with cyanide, affording 2-aryl-substituted indole-3-acetic acid derivatives. Furthermore, the usefulness of this method was successfully demonstrated by the synthesis of an FPTase inhibitor, one of the biologically important 2-arylindole-3-acetic acid derivatives.

The regioselectivity of hydroacylation mediated by transition metal and organocatalyst has been and continues to be one of the most challenging questions in the synthesis field. To explore the possible mechanisms and origin of the regio-/enantioselectivity, the density functional theory (DFT) calculations were performed for studying intramolecular hydroacylation-Stetter reaction of alkynyl bisbenzaldehyde catalyzed by N-heterocyclic carbene (NHC). Computational results show that the hydroacylation process was the rate-determining step and irreversible. Four different stereoisomers (RR, RS, SR, and SS) were considered and the lowest energy mode agreed with the reported enantioselectivity in experiment. Global reaction index (GRI) analysis showed that NHC catalyst can convert alkynyl bisbenzaldehyde electrophilic carbonyl carbon into nucleophilicity to initiate the reaction. Moreover, electron localization function (ELF) and intrinsic reaction coordinate (IRC) analyses were performed to characterize the manner difference between the process of hydroacylation and Stetter reaction.

An N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction proceeding via the endo-fashion was the key step for the transition-metal-free and mild cross-dehydrogenative coupling of 2-cinnamoyl benzaldehydes allowing for the synthesis of 2-aryl naphthoquinones. In this transformation, the carbene generated from the triazolium salt using Na