Domino Knoevenagel Condensation Research Articles

Meldrum's acid-induced and FeCl3-catalyzed one-pot domino reactions for construction of bis(indolyl)methanes

An eco-friendly and efficient Meldrum's acid-induced and FeCl3-catalyzed domino reactions of aromatic aldehydes and indoles for the formation of 3,3′-bis(indolyl)methanes has been developed. The present strategy features with inexpensive catalyst, green solvent, mild conditions, good functional group tolerance, and gram-scale synthesis. The transformation proceeded by a domino esterification, Knoevenagel condensation, 1,2-addition, elimination, and subsequent 1,4-conjugate addition process.

Pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles: A three-component synthesis and AChE inhibitory studies

The one-pot three-component reaction of 3-methyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one, aromatic aldehydes, and malononitrile in the presence of piperidine in ethanol has been carried out. The reaction proceeded through domino Knoevenagel condensation – Michael addition – O-cyclization sequence of reactions in a single transformation affording structurally intriguing novel pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles in excellent yields in short reaction time. The high-throughput AChE inhibition studies of these pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles disclosed one compound with maximum potency with an IC50 value of 2.6 µM/L. The structure–activity relationship revealed that the pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles bearing alkyl or alkoxy substituted phenyl ring at C-4 exhibited more potency than the compounds with halogen-substituted phenyl ring.

Correction to: 1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a nanostructured molten salt catalyst: application to the synthesis of pyrano[4,3‐b]pyrans

In this work, we have synthesized a novel nanostructured molten salt, 1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1), as an efficient and green protocol-compatible catalyst. This new molten salt has been fully characterized by different analytical techniques, such as FT-IR, 1HNMR, 13CNMR, thermal gravimetric analysis, derivative thermal gravimetric analysis, differential thermal analysis, X-ray diffraction, scanning electron microscopy, and high-resolution transmission electron microscopy. Additionally, the catalytic activity of {[HIMI]C(CN)3} (1, 2 mol%) has been tested in a three-component domino Knoevenagel condensation reaction. A range of structurally diverse aromatic aldehydes (2a–p), malononitrile (3), and 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one (4) are tolerated for the synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile derivatives (5a–p) under neat conditions at 50 °C. The obtained results have demonstrated that catalyst 1 shows interesting catalytic properties, such as clean reaction profile, cost-effectiveness, and green conditions. Importantly, the aforementioned catalyst is thermally stable with a 171 °C melting point not showing any significant loss in catalytic activity after 7 reaction cycles.

Nickel(II) chromite nanoparticles promoted efficient synthesis of novel [1]benzopyrano[4,3-b]pyridines in aqueous media

A library of new 9,11-dimethyl-7-aryl-6H-[1]benzopyrano[3′,4′:5,6]pyrido[2,3-d]pyrimidine-6,8,10(9H,11H)triones was successfully synthesized via one-pot three-component reaction of 4-aminocoumarin, aromatic aldehydes, and 1,3-dimethylbarbituric acid using nickel(II) chromite nanoparticles as an efficient novel heterogeneous catalyst in aqueous media at 70 °C. The presented reaction is presumed to proceed via a domino Knoevenagel condensation–Michael addition, followed by intramolecular cyclization, and subsequent aromatization. The structures of the title compounds which have been successfully synthesized for the first time in this work were characterized by IR, 1H NMR, and 13C NMR spectroscopic data and also by elemental analysis. Surprisingly, the new protocol described herein provides several advantages such as high yields of products, short reaction times, mild reaction conditions, easily operated and environmentally friendly procedure. Furthermore, the catalyst can be recovered conveniently and reused without obvious loss of activity.

Magnetic carbon nanotube as a highly stable and retrievable support for the heterogenization of sulfonic acid and its application in the synthesis of 2‐(1H‐tetrazole‐5‐yl) acrylonitrile derivatives

AbstractIn the present study, a novel magnetic carbon nanotube functionalized by chlorosulfonicacid (Fe3O4‐CNT‐SO3H) with nanotube morphology decorated by the spherical nanoparticles was prepared, characterized and introduced as a retrievable magnetic heterogeneous nanocatalyst for green synthesis a variety of 2‐(1H‐tetrazole‐5‐yl) acrylonitrile via multicomponent domino Knoevenagel condensation/ 1,3‐dipolar cycloaddition reaction between aromatic aldehydes, malononitrile, and sodium azide under solvent free conditions. The catalyst was magnetically separated from the reaction system by an outer magnetic force and recycled up to five runs without a remarkable loss in its efficiency. The as‐preparedacidic magnetic nanocomposite was characterized by different techniques inclusive Fourier transform infrared, thermogravimetric analysis, energy dispersive X‐ray, field emission scanning electron microscopy, X‐ray diffraction, vibrating sample magnetometry, CHNS elemental analysis, and acid‐base titration. Easy workup, affordability, elimination of volatile and toxic solvents, and high yield of products are some merits of this protocol.

Hydroxyl alkyl ammonium ionic liquid assisted green and one-pot regioselective access to functionalized pyrazolodihydropyridine core and their pharmacological evaluation

Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two CC and one CN bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.

Synthesis of novel spiro[benzo[4,5]thiazolo[3,2-a]chromeno[2,3-d]pyrimidine-14,3′-indoline]-1,2′,13(2H)-triones via three component reaction

A new and efficient method for the synthesis of hitherto unreported spiro[benzo[4,5]thiazolo[3,2-a]chromeno[2,3-d]pyrimidine-14,3′-indoline]-1,2′,13(2H)-triones was developed via the Domino Knoevenagel condensation–Michael addition–intermolecular cyclization sequences of isatin derivatives, cyclohexane-1,3-diones, and 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones, employing 12-tungstophosphoric acid (H3PW12O40) as an effective and inexpensive catalyst.

1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a nanostructured molten salt catalyst: application to the synthesis of pyrano[4,3‐b]pyrans

In this work, we have synthesized a novel nanostructured molten salt, 1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1), as an efficient and green protocol-compatible catalyst. This new molten salt has been fully characterized by different analytical techniques, such as FT-IR, 1HNMR, 13CNMR, thermal gravimetric analysis, derivative thermal gravimetric analysis, differential thermal analysis, X-ray diffraction, scanning electron microscopy, and high-resolution transmission electron microscopy. Additionally, the catalytic activity of {[HIMI]C(CN)3} (1, 2 mol%) has been tested in a three-component domino Knoevenagel condensation reaction. A range of structurally diverse aromatic aldehydes (2a–p), malononitrile (3), and 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one (4) are tolerated for the synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile derivatives (5a–p) under neat conditions at 50 °C. The obtained results have demonstrated that catalyst 1 shows interesting catalytic properties, such as clean reaction profile, cost-effectiveness, and green conditions. Importantly, the aforementioned catalyst is thermally stable with a 171 °C melting point not showing any significant loss in catalytic activity after 7 reaction cycles.

One-pot synthesis of highly functionalized pyrano[2,3-c]pyrazole-4,4′-diacetate and 6-oxo-pyrano[2,3-c]pyrazole derivatives catalyzed by urea

A facile one-pot, multicomponent protocol for the synthesis of 1,4-dihydro-pyrano[2,3-c]pyrazole derivatives using a urea catalyst is reported. This transformation proceeds via a four-component reaction of ethyl acetoacetate, a hydrazine, 3-oxo-pentanedioic acid dimethyl ester, and malononitrile. The bifunctional nature of urea means that it catalyzes many steps in this transformation, including domino Knoevenagel condensation, Michael addition, and ring opening and closing reactions. This synthetic method has several advantages, including good yield, simple work-up, harmless by-products, and simple purification.

Chemodivergent, One-Pot, Multi-Component Synthesis of Pyrroles and Tetrahydropyridines under Solvent- and Catalyst-Free Conditions Using the Grinding Method.

A highly efficient, chemoselective synthesis of a library of polysubstituted pyrroles and tetrahydropyridines has been achieved through the one-pot, multicomponent reactions of ethyl (E)-3-(aryl/alkyl amino) acrylates, 2,2-dihydroxy-1-arylethan-1-ones, and malononitrile under solvent- and catalyst-free grinding conditions. The selective formation of pyrrole or tetrahydropyridines relied on substitution of the N-aryl of ethyl (E)-3-(4-arylamino) acrylates. These reactions presumably occurred via a domino Knoevenagel condensation and Michael addition followed by an intramolecular cyclization sequence of reactions in a single transformation.

ChemInform Abstract: 1‐Butyl‐3‐methyl Imidazolium Acetate Catalyzed Synthesis of N‐Substituted‐5‐arylidene‐rhodanines

Abstractby one‐pot four‐component domino Knoevenagel condensation of primary amine, carbon disulfide, ethyl acetoacetate, and aromatic aldehyde without any solvent

Domino four-component synthesis of novel cycloocta[b]pyridines

The four-component reactions of cyclooctanone, malononitrile, aromatic aldehydes, and MeOH or EtOH occurred via a domino Knoevenagel condensation–Michael addition–nucleophilic addition–cyclization–oxidative aromatization sequence affording novel 4-arylcycloocta[b]pyridines in good yields.

ChemInform Abstract: Domino Knoevenagel Condensation—Michael Addition—Cyclization for the Diastereoselective Synthesis of Dihydrofuropyrido[2,3‐d]pyrimidines via Pyridinium Ylides in Water.

A green method for the diastereoselective synthesis of dihydrofuropyrido[2,3-d]pyrimidines via the reaction of 6-amino-1,3-dimethyl pyrimidine-2,4(1H,3H)-dione, aldehydes and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides as a pyridinium ylide base on an organocatalyst assisted domino Knoevenagel condensation–Michael addition–cyclization is investigated. To the best our knowledge, employing 6-amino-1,3-dimethyl pyrimidine-2,4(1H,3H)-dione for the synthesis of dihydrofuropyrido[2,3-d]pyrimidines has not been report yet. 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 ethanol.

1‐Butyl‐3‐methyl Imidazolium Acetate Catalyzed Synthesis of N‐substituted‐5‐arylidene‐rhodanines

A direct method for the synthesis of N‐substituted‐5‐arylidene‐rhodanines has been reported in high yield via [bmim]OAc‐catalyzed one‐pot four‐component domino Knoevenagel condensation of primary amine, carbon disulfide, ethyl chloroacetate, and aromatic aldehyde under neat condition. The catalytic role of [bmim]OAc is due to the acidic nature of C‐2 hydrogen of bmim cation and the basic nature of acetate anion in the noncovalent interactions. The synthetic methodology is simple and offers a wide scope for the synthesis of N‐substituted‐5‐arylidene‐rhodanines.

Indium Trichloride Catalysed Domino Reactions of Isatin: A Facile Access to the Synthesis of Spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one Derivatives

A versatile high-yielding indium trichloride mediated one-pot regioselective synthesis of spiroxindoles via domino one-pot, three-component reaction of isatins, pyrazoles, and (<i>E</i>-)-<i>N</i>-methyl-1-(methylthio)-2-nitroethenamine is described. This reaction presumably occurs via domino Knoevenagel condensation–­Michael addition–intramolecular O-cyclization sequence. The salient features of the methodology are its clean reaction conditions, the eco-friendly medium, low cost, easy isolation, and excellent yields without column chromatographic purification.

Domino Knoevenagel condensation–Michael addition–cyclization for the diastereoselective synthesis of dihydrofuropyrido[2,3-d]pyrimidines via pyridinium ylides in water

A green method for the diastereoselective synthesis of dihydrofuropyrido[2,3-d]pyrimidines via the reaction of 6-amino-1,3-dimethyl pyrimidine-2,4(1H,3H)-dione, aldehydes and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides as a pyridinium ylide base on an organocatalyst assisted domino Knoevenagel condensation–Michael addition–cyclization is investigated. To the best our knowledge, employing 6-amino-1,3-dimethyl pyrimidine-2,4(1H,3H)-dione for the synthesis of dihydrofuropyrido[2,3-d]pyrimidines has not been report yet. 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 ethanol.

‘On-water’ one-pot pseudo four-component domino protocol for the synthesis of novel benzo[a]cyclooctenes

Abstract An environmentally benign ‘on-water’ pseudo four-component, domino protocol for the synthesis of novel benzo[a]cyclooctenes is reported. The reaction presumably occurs via a domino Knoevenagel condensation–Michael addition–Thorpe–Ziegler cyclization–tautomerization–elimination sequence of reactions.

Novel magnetic nanoparticles Fe3O4-immobilized domino Knoevenagel condensation, Michael addition, and cyclization catalyst

Abstract The synthesis, characterization and applications of guanidine supported on magnetic nanoparticles Fe 3 O 4 (MNPs–Guanidine) as a novel magnetically separable base nanocatalyst are described. We have studied the application of this new catalyst for the Knoevenagel condensation reaction of aromatic aldehydes with malononitrile or cyanoacetate in PEG/water = 1:1 at room temperature. Also, the three-component and one-pot synthesis of 2-amino-4 H -chromenes and 2-amino-4 H -benzo[ h ]chromenes by condensing aldehydes, malononitrile and cyclic 1,3-dicarbonyl/α-naphthol, in the presence of catalytic amount of MNPs–Guanidine under same conditions is investigated. The supported catalyst could simply be separated and recovered from the reaction mixture with the assistance of an external magnet and reused several times.

ChemInform Abstract: An Efficient Synthesis of 3‐(1H‐Tetrazol‐5‐yl)coumarins (= 3‐(1H‐Tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) via Domino Knoevenagel Condensation, Pinner Reaction, and 1,3‐Dipolar Cycloaddition in Water.

A novel straightforward synthesis of 3-(1H-tetrazol-5-yl)coumarins (=3-(1H-tetrazol-5-yl)-2H-1-benzopyran-2-ones) 6 via domino Knoevenagel condensation, Pinner reaction, and 1,3-dipolar cycloaddition of substituted salicylaldehydes (=2-hydroxybenzaldehydes), malononitrile (propanedinitrile), and sodium azide in H2O is reported (Scheme 1 and Table 2). This general protocol provides a wide variety of 3-(1H-tetrazol-5-yl)coumarins in good yields under mild reaction conditions.

A one-pot three-component domino protocol for the synthesis of penta-substituted 4H-pyrans

A library of novel 2-(1H-indol-3-yl)-6-(methylamino)-5-nitro-4-aryl-4H-pyran-3-carbonitriles and 6-(methylamino)-4-(aryl)-5-nitro-2-phenyl-4H-pyran-3-carbonitriles were synthesized in excellent yields via domino one-pot three-component reactions of 3-(1H-indol-3-yl)-3-oxopropanenitrile or benzoylacetonitrile, aromatic aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine respectively. This reaction presumably occurs via domino Knoevenagel condensation–Michael addition–intramolecular O-cyclization sequence of reactions. The significant advantages of this reaction include one-pot process, simple work-up procedure, excellent yields and no column chromatographic purification.