Three-component Cyclization Research Articles

Lewis Acid Promotes Three-Component Cyclization to Construct Dithioxazole Derivatives.

A simple and effective strategy for the construction of disulfide-substituted oxazole derivatives from amides, ynals, and acetyl disulfides via a Lewis acid-promoted three-component reaction has been reported. In addition, this reaction possesses other unique advantages, such as transition-metal-free catalysis, the production of disulfides, good functional group tolerance, and good regioselectivity.

Cu-Catalyzed [3+1+1] Cascade Cyclization of O-Acyl Oximes with Sulfur and Silyl Enol Ethers: Rapid Access to Naphthothiazoles.

A three-component cyclization reaction of O-acyl oximes, silyl enol ethers and elemental sulfur has been developed, in which silyl enol ether acts as a C1 synthon to participate in cyclization reaction and build series of 2-aroylnaphthothiazoles and 2-aroylbenzothienothiazoles. The preliminary exploration of the reaction mechanism indicated that this transformation probably proceeded through a radical process, involving S3•- as a key intermediate, enabling subsequent nucleophilic substitution with O-acyl oximes to afford iminosulfur radical, which undergoes 1,3-H shift to yield sulfur-centered radical intermediate. And then this intermediate undergoes radical addition with silyl enol ether, leading to the formation of the titled products through intramolecular cyclization and oxidation. Moreover, the products obtained exhibit favorable fluorescence properties, which indicates their potential application as functional materials.

Palladium-Catalyzed Three-Component Cascade Carbonylation Reaction to Construct Benzofuran Derivatives.

A novel three-component cyclization carbonylation reaction of iodoarene-tethered propargyl ethers with amine and CO is reported. This palladium-catalyzed cascade reaction undergoes a sequence of oxidative addition, unsaturated bond migration, carbonyl insertion, and nucleophilic attack to deliver the benzofuran skeleton. Both aromatic amines and aliphatic amines could proceed smoothly in this transformation under one atm of CO.

Green and clean synthesis of 4-arylideneisoxazol-5-ones using NaCl aqueous solution

The one-pot, three-component cyclization reaction a wide variety of aryl/heteroaryl aldehydes, hydroxylamine hydrochloride, and β-keto ester compounds was performed in a simple manner. The reactions carried out in the presence of sodium chloride (NaCl) as a profitable, green, and efficient catalyst at room temperature. Optimization experiments indicate that the amount of 17 mol% of loaded NaCl is sufficient to catalyze the reaction. Among the advantages of this NaCl-catalyzed method are availability of catalyst, no need for catalyst synthesis in several steps, commercially available reactants, use of aqueous conditions, clean synthesis, non-inflammable reaction medium, no environmental pollution, safety, cost-effectiveness, pot-economy, optimum efficiency, carbon efficiency, and economy of reaction steps. Due to the absence of harmful solvents, the use of sodium chloride as an abundant, low-cost, and useful catalyst, and the use of water as a solvent, this method is considered a green synthesis.

Metal-free three-component tandem cyclization for modular synthesis of 2,3-dihydrobenzothiazin-4-ones

The first three-component cyclization reaction of benzo[c][1,2]dithiol-3-ones based on S–S bond cleavage is disclosed herein.

Combined C-H amination and intermolecular alkyne insertion for a three-component cyclization

Combined C-H amination and intermolecular alkyne insertion for a three-component cyclization

Radical-Polar Crossover Enabled Triple Cleavage of CF2Br2: A Multicomponent Tandem Cyclization to 3-Fluoropyrazoles.

The elaboration of step-economy and catalytic approaches for accessing diverse fluorinated heterocyclics is highly desirable. Described herein is a radical-polar crossover enabled three-component cyclization to polysubstituted fluoropyrazoles by using CF2Br2 as a novel C1F1 synthon. Mechanistic experiments revealed that the in situ generation of the reactive intermediate gem-difluorovinylimine ion is the key to this transformation. This protocol unlocks the novel reactivity of CF2Br2 and adds significant synthetic values to fluorine chemistry.

Macrocyclizing DNA-Linked Peptides via Three-Component Cyclization and Photoinduced Chemistry.

While DNA-encoded macrocyclic libraries have gained substantial attention and several hit compounds have been identified from DNA-encoded library technology, efficient on-DNA macrocyclic methods are also required to construct DNA-linked libraries with a high degree of cyclization and DNA integrity. In this paper, we reported a set of on-DNA methodologies, including the use of an OPA-mediated three-component cyclization with native handles of amino acids and photoredox chemistries. These chemistries proceed smoothly under mild conditions in good to excellent conversions, successfully generating novel isoindole, isoindoline, indazolone, and bicyclic scaffolds.

2-Butyne Biscarbonate as a "Bridge" in Rhodium(III)-Catalyzed [4 + 2] Cyclization and Diels-Alder Reaction.

Described herein is the development of an unprecedented approach to construct multiple heterocycles with high selectivity through Rh(III)-catalyzed two- or three-component cyclization reaction from simple and readily available starting materials: N-methoxybenzamides, 2-butyne biscarbonate, and maleimides. This methodology provides an efficient strategy for the synthesis of diverse and complicated heterocycles in a one-pot manner and displays excellent features of extremely mild reaction conditions, easy operation, excellent regioselectivity, and good functional group compatibility.

Construction of Functionalized Oxazole via Three-Component Cyclization Using a Lewis Acid

Key words cyclization - amides - axazoles - alkynaldehydes

Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles.

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using 1H, 19F, 13C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones.

KI-mediated three-component annelation for the regioselective synthesis of angular azolo[1,5-a]pyrimidine derivatives

A straightforward and regioselective avenue to angular azolo[1,5-a]pyrimidine derivatives via the three-component cyclization of aldehydes and α-aminoazoles with cycloketones.

Lewis Acid-Promoted Three-Component Cyclization for the Construction of Functionalized Oxazoles.

A simple and efficient synthetic strategy from amides, ynals, and sodium sulfinates via a Lewis acid-promoted three-component reaction has been reported. Thus, a broad range of various aryl (not alkyl)-substituted oxazoles could be synthesized via the formation of C-N, C-O, and C-S bonds in a one-pot process. In addition, this reaction possesses other unique advantages, such as transition metal-free catalysis, high step economy, good functional group tolerance, and good regioselectivity.

Copper-Catalyzed Nitrogen Atom Transfer to Isoquinolines via C-N Triple Bond Cleavage and Three-Component Cyclization.

A copper(I)-catalyzed tandem reaction of 2-bromoaryl ketones, terminal alkynes, and CH3CN is developed, which combines N atom transfer and three-component [3 + 2 + 1] cyclization, and efficiently produces densely functionalized isoquinolines in a facile, highly selective, and general manner. In the reaction, the formation of aromatic C-N bonds along with the complete C-N triple bond cleavage is first realized; Cu(III)-acetylide species might serve as the intermediates, which allow highly selective 6-endo-dig cyclization.

Facile synthesis of 6-organyl-4-(trifluoromethyl)pyridin-2(1H)-ones and their polyfluoroalkyl-containing analogs.

The three-component cyclization of 3-polyfluoroalkyl-3-oxopropanoates and methyl ketones with ammonium acetate affords 6-organyl-4-(polyfluoroalkyl)pyridin-2(1H)-ones (organyl is alkyl, aryl, or hetaryl). The synthesized pyridones were evaluated for antifungal, antibacterial, and analgesic activity.

An Expeditious Synthesis of Ethyl-2-(4-(arylmethylene)-5-oxo-4,5-dihydroisoxazol-3- yl)acetate Derivatives

Abstract:In this contribution, an operationally simple and efficient synthetic procedure for synthesizing derivatives of 4-(arylmethylene)-5-oxo-4,5-dihydroisoxazol-3-yl)acetate has been developed. This interesting synthetic protocol involves the one-pot cyclocondensation of diethyl 3-oxopentanedioate, aryl or heteroaryl aldehydes, and hydroxylamine hydrochloride catalyzed in an aqueous medium using an azolium salt as a robust organo-catalyst. In this work, for the first time, 1,3-dibenzyl-1H-benzo[d]imidazol-3-ium chloride was used as the catalyst for the synthesis of ethyl-2-(4-(arylmethylene)-5-oxo-4,5-dihydroisoxazol-3-yl)acetate derivatives from the commercially available starting materials. Notably, no by-products were observed during the multicomponent reaction. Optimization studies revealed that 5 mol% of 1,3-dibenzyl-1H-benzo[d]imidazol-3-ium chloride is sufficient to perform the experiment. Furthermore, examining the results of the temperature conditions showed that 70 ºC is the best temperature to carry out the reaction. In an optimization study, H2O was the most effective solvent to perform the three-component cyclization reaction. In this method, using H2O as the environmentally benign and inexpensive reaction medium, so from the point of view of the reaction medium, it can be said that this three-component heterocyclization obeys the principles of green chemistry. This procedure has several advantages, such as good to excellent yields, reasonable reaction times, isolation of heterocyclic products without column chromatography or other chromatographic methods, atom-economy, step-economy, and clean reaction profiles.

Steglich’s Base Catalyzed Three-Component Synthesis of Isoxazol-5-Ones

4-(Dimethylamino)pyridine (DMAP) has been used as an efficient Brønsted organo-base catalyst for the one-pot, three-component cyclization of various aldehydes, β-keto esters, and hydroxylamine hydrochloride. In this organocatalyzed reaction, 3,4-disubstituted isoxazole-5(4H)-ones were efficiently formed in high yields and relatively shorter reaction times. Using 8 mol% of DMAP, a mixture of water–ethanol solvent system, and 80 °C gave the best results. The three-component heterocyclization using arylaldehydes containing electron releasing groups is well performed and heterocyclic products were obtained in good to high isolated yields. Aldehydes with electron withdrawing groups did not lead to the formation of products. This method has many advantages such as broad substituent scope, mild and eco‐friendly conditions, step and atom economy, commercially available, and inexpensive organo-basic catalyst.

Electrochemical oxidative cyclization of alkenes, boronic acids, and dichalcogenides to access chalcogenated boronic esters and 1,3-diols

A sustainable, environmentally benign electrochemical oxidative three-component cyclization of allylic alcohols, boronic acids, and dichalcogenides under metal-free and oxidant-free conditions has been developed.

Visible-Light-Driven Multicomponent Cyclization by Trapping a 1,3-Vinylimine Ion Intermediate: A Direct Approach to Pyrimido[1,2-b]indazole Derivatives.

Here we develop a novel visible-light-driven three-component cyclization by trapping an 1,3-vinylimine ion intermediate for the direct synthesis of pyrimido[1,2-b]indazole derivatives from bromodifluoroacetic acid derivatives, enaminones, and 3-aminoindazoles under mild conditions. Notably, the robust methodology provides a valuable opportunity for the introduction of aliphatic substituents and enables good compatibility of complex bioactive molecules. Furthermore, this is the first example of photoinduced multicomponent reaction by employing bromodifluoroacetic acid derivatives as a C1-synthon.

Rh(iii)-Catalyzed one-pot three-component cyclization reaction: rapid selective synthesis of monohydroxy polycyclic BINOL derivatives

A Rh(iii)-catalyzed three-component C–H bond functionalization protocol has been successfully applied to access complex polycyclic BINOL derivatives in which the formation of intermediate amides occurred in situ from aldehydes and amines.