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A new protocol to access benzo[a]carbazole derivatives was developed, via the cyanide-catalyzed imino-Stetter reaction/Friedel–Crafts reaction sequence. The cyanide-catalyzed imino-Stetter reaction of aldimines derived from 2-aminochalcones and aromatic aldehydes provided the corresponding 2-aryl-3-arenacylindole derivatives, which could be converted to benzo[a]carbazoles via intramolecular Friedel–Crafts ractions. Various 2-aminochalcones and aldehydes were applicable to this protocol, affording the desired benzo[a]carbazoles in good to high yields. Furthermore, we also developed a sequential protocol for the construction of benzo[a]carbazoles from 2-aminochalcones and aldehydes, without isolating any intermediates.

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.

Thiazolium carbene-catalyzed reaction of aromatic 1,2-diketones with enones in aprotic solvents gave double acylation products in good yields, whereas hydroacylation products formed by Stetter reaction were not detected at all. These results suggested the generation of aroyloxyenamine species from the 1,2-diketones instead of hydroxyenamines (Breslow intermediates).

A systematic theoretical study has been carried out on the NHC-catalyzed homoenolate reaction of enals and nitroalkenes. The detailed mechanism of these nitroalkenes participated homoenolate reactions, the chemoselectivity of the homoenolate (vs. Stetter) pathway and the intriguing syn- (vs. anti-) stereoselectivity have been investigated. Calculations show that the homoenolate and Stetter reaction (Path-homo and Path-set) first undergo the same formation process of the Breslow intermediate, which proceeds via a HOAc mediated stepwise mechanism. The subsequent process of Path-homo consists of five steps: nucleophilic attack of the Breslow intermediate (C3 atom) on the nitroalkene, intramolecular proton transfer, HOAc involved protonation of C2, concerted nucleophilic attack of OEt on the carbonyl, and final carbene dissociation. The subsequent process of Path-set consists of three steps: nucleophilic attack of the Breslow intermediate (C1 atom) on the nitroalkene, intramolecular proton transfer and carbene dissociation. Path-homo is more feasible than Path-set. The highly exoergonic nucleophilic attack, the facile intramolecular proton transfer and attack of OEt on the carbonyl in Path-homo result in its feasibility. The stereoselectivity determining step of Path-homo is the attack of the Breslow intermediate on the nitroalkene, in which the steric hindrance and hydrogen bonding determine the syn stereoselectivity.

A rapid assembly of the tetracyclic core of FD-838, featuring a catalytic asymmetric Stetter reaction, is described.

The total synthesis of 8-epi, 8,9-epi, and 9-epi-(−)-cephalimysin A is described. Our catalytic enantioselective synthesis takes advantage of a novel tandem photoisomerization/Stetter reaction. The approach provides rapid access to the desired spirofuranone lactam core in good yield and excellent enantioselectivity. A late stage oxidation strategy allows for flexible access to three of the four diastereomers of cephalimysin A. Access to the epimers provides further support for the correction of the initially proposed relative stereochemistry of cephalimysin A.

The changes in electron-density along the C–C bond-formation step in the N-heterocyclic carbene-catalyzed hydroacylation of unactivated double bonds has been studied by an electron localization function (ELF) analysis at the B3LYP/6-31G** level in order to characterize the reaction mechanism. Analysis of DFT reactivity indices and the natural bond orbital and ELF analysis at the most relevant points of the intrinsic reaction coordinate indicate that the reaction path takes place through a two-stage one-step mechanism with non-polar character. In the first stage a hydrogen atom is transferred from the hydroxyl group of Breslow intermediate 12 to the terminal olefinic carbon atom, to yield a pseudodiradical species. The barrierless C–C bond formation in this species constitutes the second stage of the reaction allowing the formation of the corresponding alcohoxy intermediate 13. The present theoretical study establishes that this mechanism is completely different to that involved in the intramolecular Stetter reaction, which is initialized by a polar Michael-type addition.

Enantioselective desymmetrization of cyclohexadienones via a d-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction was realized. With 10 mol% of camphor-derived triazolium salt E and 10 mol% of DIEA, various substituted cyclohexadienones proceeded through an intramolecular Stetter reaction, affording tricyclic products in moderate to good yields and excellent ee.

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.

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.

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.

The asymmetric intermolecular Stetter reaction is catalyzed by a novel triazolium salt derived N-heterocyclic carbene leading to 1,4-diketones in moderate to excellent yields (49-98%) and moderate to good enantioselectivities (56-78% ee), which could be enhanced by one recrystallization to excellent levels (90-99% ee).