Sequential Four-component Reaction Research Articles

Convenient Synthesis of Functionalized Tetracyclic Dihydrochromeno[2,3-b]pyrrolo[3,4-e]pyridine-triones via Four-Component Reactions

AbstractIn this research, a simple and efficient strategy for the straightforward synthesis of tetracyclic dihydrochromeno[2,3-b]pyrrolo[3,4-e]pyridine-trione derivatives is presented by a sequential four-component reaction of arylamines, dimethyl acetylenedicarboxylate, alkylamines, and 3-formylchromones as readily available starting materials in MeOH at room temperature. The merit of this sequential enamine formation/1,2-nucleophilic addition/intramolecular aza-Michael addition is highlighted by its high energy conserving (short reaction times at room temperature), excellent yields, metal-free catalyst, easy purification (the products can be purified by simple filtration and washing with EtOH), and green and mild conditions in a one-pot reaction. Presumably, there are no previous reports for the synthesis of these classes of heterocyclic dihydrochromeno[2,3-b]pyrrolo[3,4-e]pyridine-trione derivatives.

Formal [4 + 1] cycloadditions of ketiminoboranes and isonitriles

A formal [4 + 1] cycloaddition reaction of ketiminoboranes with isonitriles is described. This sequential four-component reaction could successfully incorporate HB(C6F5)2, 2,5-dimethylhexa-2,4-diene, nitriles, and isonitriles, into new BN-cycles.

Synthesis and in vitro anticancer activity evaluation of spiro[indolo[2,1-b]quinazoline-pyrano[2,3-c]pyrazole] via sequential four-component reaction

Cancer is still incurable and it is considered as a main health problem worldwide. The identification of novel compounds with high toxicity and low side effects is one of the biggest challenges among interested researchers. In this study, a rapid and simple strategy for synthesis of spiro[indolo[2,1-b]quinazoline-pyrano[2,3-c]pyrazole] derivatives via sequential four-component reaction of isatoic anhydride, isatin, malononitrile, and 3-methyl-pyrazolones in CH2Cl2 at room temperature is described. This procedure has short reaction time and mild reaction conditions. Simple purification and no chromatographic process, are the other notable advantages of this protocol which make it attractive. To evaluate the anticancer activity of our synthetic compounds, pancreatic cancer cell (Panc1), cancer cell of breast (MDA-MB-231), colon cancer cell (HT-29), and normal human adult dermal fibroblast (HDF) were firstly cultured and by using MTT assay, the possible toxicity of related compounds was analyzed. Our results suggested that no compounds have 50% growth inhibitory concentration (IC50) values lower than etoposide (as a reference drug) against all cancer cell lines and among nine synthetic compounds, only 4a compound was effective against Panc1 pancreatic cancer cells.

Sequential four-component protocol for the synthesis of pyrido[1,2-a]pyrimidin-6-one derivatives in water

A highly efficient and environmentally benign synthesis of N-fused heterocyclic compounds including pyrido[1,2-a]pyrimidine-6-one moiety is successfully achieved via a sequential four-component reaction. The process involves the formation of diversely substituted 9-nitro-1,2,3,4,7,8-hexahydro-6H-pyrido[1,2-a]pyrimidin-6-ones from the reaction of Meldrum’s acid, benzaldehydes, 1,1-bis(methylthio)-2-nitroethylene and various diamines in the presence of p-toluene sulfonic acid (PTSA) as an acidic catalyst in water as a green solvent. The salient features of the present methodology are easily available starting materials, the use of water as environmentally benign solvent, simple execution, applicable to a wide range of starting materials and good to excellent yields.

Mo@GAA-Fe3O4 MNPs: a highly efficient and environmentally friendly heterogeneous magnetic nanocatalyst for the synthesis of polyhydroquinoline derivatives.

Polyhydroquinolines were efficiently obtained from a sequential four-component reaction between dimedone or 1,3-cyclohexandione, ethyl acetoacetate, or methyl acetoacetate as a β-ketoester, aldehydes, and ammonium acetate, under the catalysis of Mo@GAA-Fe3O4 MNPs as a green, effective, recyclable, and environmentally friendly nanocatalyst. Due to its magnetic nature the prepared catalyst can be easily separated from the reaction mixture by an external magnet and reused several times without significant changes in catalytic activity and reaction efficiency. The catalyst was characterized using energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM).

Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds.

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,4′-pyrano[2,3-c]pyrazol], spiro[indoline-3,5′-pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3′-indoline] and spiro[benzo[g]chromene-4,3′-indoline] in moderate to good yields. The use of various active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with potential biological properties. The present strategy has many advantages, such as convenient one-pot operation, simple workup procedures and straightforward isolation without using tedious purification steps such as column chromatography, progress under catalyst-free condition and high molecular diversity.

One-pot regio- and chemo-selective synthesis of thiaazatricyclododecane

A highly regio- and chemo-selective heteroannulation protocol for the synthesis of unreported polysubstituted thiaazatricyclododecanes has been developed by a sequential four-component reaction of isoquinoline, 2-bromoacetophenones, aryl isothiocyanates, and methyl 4-chloro-3-oxobutanoate under mild conditions in CH3CN. To the best of our knowledge there are no previous reports for the synthesis of these classes of thiaazatricyclododecanes. The method features formation of various CN, CS, and CC bonds, low-cost and readily available substrates, as well as simple one-pot operation, which makes this process highly profitable. This synthesis serves as a nice addition to chemistry in which purification via chromatography and recrystallization can be avoided, and the pure products were obtained simply by washing the crude products with hexane–ethyl acetate (10:1).

Catalyst- and solvent-free synthesis of highly functionalized octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions

Abstract This is a report of an innovative, one-pot, catalyst-free, four-component synthesis of octahydro-imidazo[1,2- a ]quinolin-6-ones from aromatic aldehydes, cyclic 1,3-diones, diamines, and nitro ketene dithioacetal in stoichiometric melt conditions. The protocol avoids the use of expensive catalysts, toxic organic solvents and anhydrous conditions, and affords potentially bioactive compounds in excellent to high yields.

Nef-isocyanide adducts as useful synthons in a novel synthesis of functionalized 5-imino-2-thioxothiazolidines

An efficient synthesis of alkyl 3-alkyl-5-(alkylimino)-4-hydroxy-2-thioxothiazolidine-4-carboxylates via a novel sequential four-component reaction between alkyl amines, CS2, and Nef-isocyanide adducts, under basic conditions, is described.

Diastereoselective, multicomponent access to trans-2-aryl-4-arylamino-1,2,3,4-tetrahydroquinolines via an AA′BC sequential four-component reaction and their application to 2-arylquinoline synthesis

The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA'BC sequential multicomponent transformation related to the Povarov reaction that was also extended to the use of a second aniline as the C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed adapting the method to the synthesis of 4-unsubstituted 2-arylquinolines, by treatment of the crude product from the MCR with FeCl(3) in methanol.

Synthesis of Heterocyclic [3.3.3]Propellanes via a Sequential Four-Component Reaction

A highly chemoselective heteroannulation protocol for the synthesis of unreported polysubstituted heterocyclic [3.3.3]propellanes has been developed by sequential four-component reaction of ninhydrin, malononitrile, primary amines, and dialkyl acetylenedicarboxylates under mild conditions in water. To the best of our knowledge, there are no previous reports for the synthesis of these classes of heterocyclic [3.3.3]propellanes. The merit of this sequential Knoevenagel condensation/enamine formation/Michael addition/cyclization sequence is highlighted by its high atom-economy, excellent yields, the use of water as reaction media, and the efficiency of production without the use of any activator or metal promoters. This synthesis serves as a nice addition to group-assistant-purification (GAP) chemistry in which purification via chromatography and recrystallization can be avoided, and the pure products were obtained simply by washing the crude products with 95% ethanol.

Synthesis of a Library of 5,6-Unsubstituted 1,4-Dihydropyridines Based on a One-Pot 4CR/Elimination Process and Their Application to the Generation of Structurally Diverse Fused Nitrogen Heterocycles

Indium trichloride is an efficient catalyst for the sequential four-component reaction between aliphatic amines, β-ketoesters, α,β-unsaturated aldehydes, and ethanol to afford 6-ethoxy-1,4,5,6-tetrahydropyridines, which were converted in situ into 5,6-unsubstituted 1,4-dihydropyridines via ethanol elimination in the presence of neutral Al(2)O(3), in a very efficient, one-pot protocol from acyclic, readily available starting materials that involves the generation of two C-N σ and one C-C π bonds. The structural variety of the dihydropyridine library thus generated was extended by base-promoted γ-alkylation of their C-2 position. The application of these 1,4-dihydropyridines to the facile generation of molecular diversity and complexity was demonstrated by employing them as dienophiles for Yb(OTf)(3)-catalyzed imino Diels-Alder (Povarov) reactions leading diastereoselectively to hexahydrobenzo[h][1,6]-naphthyridine derivatives containing three adjacent stereocenters. The synthesis of fused dihydropyridines derived from the pyrido[2,1-a]azepine (homoquinolizine) frameworks was also achieved using a four-component tetrahydropyridine synthesis/ring-closing metathesis/elimination strategy.