Search

The 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 novel N‐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 new N‐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. [ABSTRACT FROM AUTHOR]

The nucleophilic addition of a cyanide anion to a carbonyl group is the basis for several cyanide-catalyzed organic reactions, which are summarized in this review. Since cyanide is also a good leaving group, it is an excellent catalyst for transacylation reactions. As an electron-withdrawing group, it also stabilizes a negative charge in its α-position, thus allowing the umpolung of aldehydes to formyl anion equivalents. The two leading examples are the benzoin condensation and the Michael–Stetter reaction furnishing α-hydroxy ketones and 1,4-dicarbonyl compounds, which are both catalyzed by cyanides. The review also covers variants like the silyl-benzoin coupling, the aldimine coupling and the imino-Stetter reaction. Moreover, some cyanide-catalyzed heterocyclic syntheses are reviewed. 1 Introduction 2 Nucleophilic Additions 2.1 Cyanohydrin Formation 2.2 Corey–Gilman–Ganem and Related Oxidation Reactions 2.3 Conjugate Addition 2.4 Intramolecular Carbocyanation 3 Transacylation Reactions 3.1 Ester Hydrolysis and Transesterification 3.2 Formation of Amides 3.3 Ketones from Esters 3.4 Esters from Ketones 4 Transformations Involving an Umpolung 4.1 Benzoin Condensation 4.2 Aldimine Coupling 4.3 Michael–Stetter Reaction 4.4 Imino-Stetter Reaction 5 Formation of Heterocycles 5.1 Oxazolines from Isocyanoacetates 5.2 Imidazoles from TosMIC via Oxazolines 5.3 Bargellini Reaction 6 Conclusion [ABSTRACT FROM AUTHOR]

Mechanistic studies of the triazolium ion‐catalyzed intramolecular Stetter reaction using initial rates analysis in NEt3/NEt3 ⋅ HCl buffered methanol showed the reaction to be first‐order in catalyst and zero‐order in aldehyde over a broad range of aldehyde concentrations. The observed reaction rate is higher for catalysts bearing N‐aryl substituents with electron‐withdrawing groups. A concurrent, NHC‐independent substrate isomerization was also observed and found to demonstrate a first‐order dependence on aldehyde concentration. The reported data are consistent with deprotonation to form the Breslow intermediate being turnover‐limiting in this process. [ABSTRACT FROM AUTHOR]

The reliable design and prediction of enzyme promiscuity to access transformations not observed in nature remains a long‐standing challenge. Herein, we present the first example of an intramolecular stereoselective Stetter reaction catalyzed by benzaldehyde lyase, guided by the rational structure screening of various ThDP‐dependent enzymes using molecular dynamics (MD) simulations. After optimization, high productivity (up to 99 %) and stereoselectivity (up to 99:1 e.r.) for this novel enzyme function was achieved. [ABSTRACT FROM AUTHOR]

The Stetter reaction is actually a special C−C bond forming reaction through a 1,4‐addition reaction in the presence of nucleophilic catalyst. It involves a reaction between aldehydes and Michael acceptors catalyzed by N‐heterocyclic carbenes (NHC's) leading to preparation of 1,4‐dicarbonyl compounds via carbon‐carbon bond formation. It offers a powerful approach to access 1,4‐dicarbonyl compounds which are significant starting materials and intermediates in the synthesis of several heterocyclic systems, and bioactive heterocyclic framework which are present in natural products. In this review we try to underscore the recent advances in Stetter reaction and its applications from 2015 till date. Notably, we focused on the applications of Stetter reaction in the synthesis of various heterocyclic systems and total synthesis of natural products, which have largely been overlooked, previously. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A highly enantioselective intramolecular NHC‐catalyzed approach for the synthesis of benzo‐fused pyranones bearing quaternary stereocenter is described. The developed methodology is based on annulation reaction between acyl anion intermediates and β,β‐disubstituted Michael acceptors. The reaction offers streamlined and effective access to target products in a highly stereoselective manner. [ABSTRACT FROM AUTHOR]

Thiazolium carbene-catalyzed reactions of 1,2-diketones and 1,2,3-triketones with enones and ynones have been investigated. The diketones gave α,β-double acylation products via unique Breslow intermediates isolable as acid salts, whereas the triketones formed stable adducts with the NHC instead of the coupling products.

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine. Poles apart: Imine umpolung is an underdeveloped area of enantioselective catalysis. N‐Heterocyclic carbenes (NHCs) were used to catalyze an enantioselective aza‐Stetter reaction. In contrast to acyl umpolung with NHCs, this reaction requires highly nucleophilic catalysts. The reaction is highly enantioselective (all ≥96:4 er) and accepts various imines and 3‐methylenechroman‐2‐ones. [ABSTRACT FROM AUTHOR]

The valorization of vegetable oil‐derived methyl azelaaldehydate (methyl 9‐oxo‐nonanoate) to monomers was studied through NHC‐catalysed Stetter reaction. Among the Michael acceptors tested, dimethyl fumarate gave the highest selectivity (97 %) for the corresponding Stetter adduct, thus limiting the competing benzoin condensation. Vegetable oil derived methyl azelaaldehydate (methyl 9‐oxo‐nonanoate) was converted to monomers through a NHC‐catalysed Stetter reaction, with limitation of the competing Benzoin condensation. [ABSTRACT FROM AUTHOR]

We report a visible‐light‐mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4‐dicarbonyl compounds. The process capitalizes upon the excited‐state reactivity of 4‐acyl‐1,4‐dihydropyridines that, upon visible‐light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst‐controlled bond‐forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3‐substituted 1,4‐dicarbonyl products. A 1,4 relation problem: Chiral 1,4‐dicarbonyls are important motifs, but their stereocontrolled synthesis is difficult. A photochemical asymmetric acyl radical addition to enals 2 is presented as one solution to this problem. This enantioselective catalytic strategy is triggered by iminium ion activation. It exploits the visible‐light excitation of 4‐acyl‐1,4‐dihydropyridines 1 to generate acyl radicals under mild conditions. [ABSTRACT FROM AUTHOR]

A bioinspired, intermolecular radical Stetter reaction of α‐keto acids and aldehydes is disclosed that is contingent on a formal "radical umpolung" concept. Enabled by secondary amine activation, electrostatic recognition ensures that the α‐ketocarboxylic acids, which function as latent acyl radicals, are proximal to the in situ generated iminium salts. This photoactive contact ion pair is an electron donor–acceptor (EDA) complex, and undergoes facile single electron transfer (SET) and rapid decarboxylation prior to radical–radical recombination. Importantly, decarbonylation is mitigated by this strategy. The initial computational validation on which the process is predicated matches closely with experiment. Synergising organo‐ and photocatalysis activation principles finally expands the mechanistic and synthetic scope of the classic Stetter reaction to include α,β‐unsaturated aldehydes as acceptors. A bioinspired radical Stetter reaction of α‐keto acids and aldehydes is contingent on a formal "radical umpolung". Electrostatic recognition ensures that the α‐keto carboxylates, which function as latent acyl radicals, are proximal to the iminium ions generated in situ. Synergising organo‐ and photocatalysis activation principles finally expand the mechanistic and synthetic scope of the classic Stetter reaction to include α,β‐unsaturated aldehyde acceptors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

This research is focused on the rational approach to design and synthesis of a novel series of triazole linked pyrrole derivatives through a sequential Paal-Knorr reaction and Click chemistry. These new molecules were screened against Mycobacterium tuberculosis H37Rv and found to display promising anti-mycobacterial activity. Among various compounds, 7g and 7l were identified as leads with minimum inhibitory concentration value 0.78 (μg/mL), which are more effective than standard drugs such as pyrazinamide, ethambutol, and ciprofloxacin and less active than isoniazid and rifampicin. These molecules (minimum inhibitory concentration values <12.5 μg/mL) were also screened against HEK-293T cancer cell lines. Most of these molecules are less toxic but possess higher selectivity index, which indicates the suitability of these compounds for further evaluation. [ABSTRACT FROM AUTHOR]

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, ringexpansion, 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. [ABSTRACT FROM AUTHOR]

We synthesized 2-[2-methyl-5-phenyl-1-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl]-2-oxo-N-(pyridin-4-yl) acetamide 4 as a novel compound derived from the indibulin and combretastatin scaffolds, which are known anti-mitotic agents, using a multistep reaction. We tested its cytotoxic activity against three breast cancer cell lines, namely, MCF-7, T47-D, and MDA-MB 231 as well as normal cell line NIH-3T3, by 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The biological activity results showed good cytotoxicity on cancerous cell lines (IC50 value 27.7–39.2 µM) and low toxicity on normal cell line (NIH-3T3, IC50 value > 100 µM).

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 [ABSTRACT FROM AUTHOR]

This review summarizes developments in N-heterocyclic carbene-mediated transformation of silicon reagents over the past decade. Several reactions of silicon reagents, including the sila-Stetter reaction, 1,2-addition, carbon–carbon and carbon–oxygen double bond reduction, polymerization, and other miscellaneous reactions, are discussed. The mechanisms of these reactions are also presented. [ABSTRACT FROM AUTHOR]

Methyl 10-undecenoate (2b) has been oxidized with tert-butyl hydroperoxide/selenium dioxide and potassium dichromate to 53% of methyl 9-oxo-10-undecenoate (4). Based on the conversion of 2b, the yield of 4 is 81%. Residual selenium in ester 5 was determined to be less than 1 ppm. The electrophilic double bond in enone 4 reacts in good to excellent yield with a variety of nucleophiles. With dimethyl malonate, acetylacetone, and methyl acetoacetate Michael-adducts at C-11 of enone 4 were obtained in 88-99% yield. Corresponding additions were achieved with nitroethane, 1- and 2-nitropropane in 78- 89% yield. In a Nef-reaction some nitroalkyl adducts were converted to methyl esters of 9,12-dioxofatty acids in 99% yield. In methanol/sodium methoxide the ester methyl 11-methoxy-9-oxoundecanoate was obtained in 86% yield from enone 4. In a three step reaction with ammonium chloride/sodium cyanide, hydrochloric acid/acetic acid, and methanol/2,2-dimethoxypropane the ester 4 yielded 63% of dimethyl 4-oxo-dodecanedioate. With the cyanide ion the electrophilic carbon atom in aldehydes can be converted into a nucleophile (Stetter-reaction). Catalysed by sodium cyanide in DMF aromatic and heteroaromatic aldehydes RCHO with R¼phenyl, 2-thienyl, 2-furyl and 3-pyridyl were added to enone 4 to afford methyl 12-aryl- and methyl 12-heteroaryl-9,12-dioxododecanoates in 54-73% yield. [ABSTRACT FROM AUTHOR]

A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q &5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 µM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line. [ABSTRACT FROM AUTHOR]