Heterocyclic Ketene Aminals Research Articles

ChemInform Abstract: A New Rapid Multicomponent Domino Heteroannulation of Heterocyclic Ketene Aminals: Solvent‐Free Regioselective Synthesis of Functionalized Benzo[g]imidazo[1,2‐a]quinolinediones.

A highly efficient and straightforward three-component cascade reaction was developed to synthesize benzo[g]imidazo[1,2-a]quinolinedione derivatives from heterocyclic ketene aminals (HKAs), aldehydes, and 2-hydroxy-1,4-naphthoquinone (HNQ) via Et3N-catalyzed tandem [3 + 2 + 1] annulation under solvent-free conditions. The reactions were very mild, convenient and highly regioselective to form new fused tetracyclic target molecules.

One-pot synthesis and crystal structure of an unusual amidine derived from heterocyclic ketene aminal derivative

Abstract One-pot reaction of Meldrum’s acid (1) and heterocyclic ketene aminal (HKA, 2) in acetone affords an unusual amidine HKA derivative 4. The reaction catalysts were optimized and it was found that l-proline is the best catalyst for the one-pot reaction. The mechanism is discussed. The structure of compound 4 was determined by single crystal X-ray analysis.

ChemInform Abstract: Three‐Component Stereoselective Synthesis of Spirooxindole Derivatives

Abstractby refluxing mixtures of heterocyclic ketene aminals with isatins (I) and trifluoroacetate (III)

An Efficient One‐Pot Four‐Component Synthesis of Functionalized Imidazo[1,2‐a]pyridines

AbstractAn efficient one‐pot four‐component protocol for the synthesis of imidazo[1,2‐a]pyridines was developed by condensing ethane‐1,2‐diamine (2), 1,1‐bis(methylthio)‐2‐nitroethene (1), aldehydes 3, and activated methylene compounds in EtOH under reflux conditions (Tables 1–3). The features of this procedure are operational simplicity, good yields of products, in situ preparation of heterocyclic ketene aminals (HKA), and catalyst‐free conditions.

Regioselective construction of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives via cascade reaction of quinolines with heterocyclic ketene aminals: a joint experimental–computational approach

A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental-computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure-reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.

Three component solvent-free synthesis of 1H-pyrazol-5(4H)-one-based heterocyclic ketene aminal derivatives

An efficient one-pot three-component synthesis of novel 1H-pyrazol-5(4H)-one-based heterocyclic ketene aminal libraries was performed by simply refluxing a mixture of heterocyclic ketene aminals (HKAs), 1-phenyl-1H-pyrazol-5(4H)-ones and triethoxymethane under solvent-free and catalyst-free conditions. The protocol has the advantages of being highly efficient and environmentally benign, with excellent yields and easy work-up, making it suitable for large-scale and parallel combination synthesis. These compounds are promising candidates for drug discovery. Consequently, a library of diverse 1H-pyrazol-5(4H)-one-based HKAs was rapidly constructed using this method.

A new rapid multicomponent domino heteroannulation of heterocyclic keteneaminals: solvent-free regioselective synthesis of functionalized benzo[g]imidazo[1,2-a]quinolinediones

A highly efficient and straightforward three-component cascade reaction was developed to synthesize benzo[g]imidazo[1,2-a]quinolinedione derivatives from heterocyclic ketene aminals (HKAs), aldehydes, and 2-hydroxy-1,4-naphthoquinone (HNQ) via Et(3)N-catalyzed tandem [3 + 2 + 1] annulation under solvent-free conditions. The reactions were very mild, convenient and highly regioselective to form new fused tetracyclic target molecules.

Three-component stereoselective synthesis of spirooxindole derivatives

A concise and efficient one-pot regio- and stereoselective synthesis of structurally diverse spirooxindoles was constructed by simply refluxing a mixture of different types of heterocyclic ketene aminals, isatins and ethyl trifluoroacetate using catalytic piperidine. The advantages of this method include high efficiency, mild reaction conditions and environmentally benign reagents. These spirooxindoles are promising candidates for drug discovery; consequently, a library of diverse spirooxindoles was rapidly constructed using the present protocol.

ChemInform Abstract: Regioselective, Catalyst‐Free, One‐Step Synthesis of ABCD‐Fused Heterocyclic Ring System, Closely Related to Circumdatin Alkaloids.

AbstractA simple protocol is developed for the reaction of heterocyclic ketene aminals with 3‐formylchromones to give tetracyclic heterocycles.

Four-Component Cascade Heteroannulation of Heterocyclic Ketene Aminals: Synthesis of Functionalized Tetrahydroimidazo[1,2-a]pyridine Derivatives

An efficient and straightforward four-component synthetic protocol has been developed to synthesize imidazo[1,2-a]pyridines and imidazo[1,2,3-ij][1,8]naphthyridine derivatives incorporating medicinally privileged heterosystems from heterocyclic ketene aminals, aldehydes, diketene, and amines via cascade reactions, including diketene ring-opening, Knoevenagel condensation, aza-ene reaction, imine-enamine tautomerization, cyclocondensation, and intramolecular S(N)Ar. This strategy can provide an alternative approach for easy access to the highly substituted imidazo[1,2-a]pyridine derivatives in moderate to good yields using four simple and readily available building blocks under mild conditions. Importantly, the unusual splitting peaks in the (1)H NMR spectra of the products derived from heterocyclic ketene aminals with an o-halogen atom on the aryl ring were explained reasonably by varying the temperature in NMR analysis.

Regioselective, Catalyst-Free, One-Step Synthesis of ABCD-Fused Hetero­cyclic Ring System, Closely Related to Circumdatin Alkaloids

A novel method for the synthesis of tetracyclic fused-ring heterocycles, closely related to circumdatin alkaloids, is developed via regioselective reaction of heterocyclic ketene aminals (HKA) with 3-formylchromones.

The synthesis of new pyrrolo[1,2-a]perimidin-10-one dyes via two convenient routes and its characterizations

Efficient synthesis of pyrrolo[1,2-a]perimidin-10-ones (4, 8) are accomplished via two new convenient methods in moderate yields. The first method is the reaction of oxalyl chloride with heterocyclic ketene aminals (HKAs) containing perimidine moiety (3), and the second is the reaction of 1,8-naphthalenediamine (1) with 2-alkoxycarbonylmethylene substituted furan-3-ones (7). The visible absorption spectrums of 4 and 8 were dominated by the characteristic perimidines bands in the region 381–439 nm. While compounds 4b-d show thermal stability up to 250 °C, compounds 8 are stable up to 216–235 °C. The structures of all products were confirmed by IR, 1H and 13C NMR spectroscopic methods, in case of 8b also by XRD analysis.

Solvent-free and efficient synthesis of imidazo[1,2-a]pyridine derivatives via a one-pot three-component reaction

A green and highly efficient method for the regioselective synthesis of imidazo[1,2-a]pyridine derivatives has been developed by annulation of heterocyclic ketene aminals (HKAs) and β-oxodithioesters (ODEs) as building blocks with aldehydes under solvent-free conditions using Et3N as the catalyst. The present green synthesis shows fascinating properties such as high regioselectivity, concise one-pot methodology, short reaction times, easy purification and avoids the use of transition metals. This methodology provides an alternative approach for easy access to highly substituted imidazo[1,2-a]pyridines in good yields.

Synthesis of the novel pyrimido[1,6-a]pyrimidine and imidazo[1,2-c]pyrimidine derivatives based on heterocyclic ketene aminals

A concise and efficient route for the synthesis of pyrimido[1,6-a]pyrimidines and imidazo[1,2-c]pyrimidines by simply refluxing a reaction mixture of different heterocyclic ketene aminals and N,N′-bis(arylmethylidene)arylmethane was developed. This protocol provides an alternative method for application in combinatorial and parallel synthesis in drug discovery.

Cascade Reaction of Isatins with Heterocyclic Ketene Aminals: Synthesis of Imidazopyrroloquinoline Derivatives

A concise and efficient route for the synthesis of highly substituted imidazopyrroloquinoline derivatives by simply refluxing a reaction mixture of different types of isatins and heterocyclic ketene aminals (HKAs) by acetic acid was developed. This method is suitable for combinatorial and parallel syntheses in drug discovery; consequently, a library of highly substituted imidazopyrroloquinoline derivatives was rapidly constructed using the present protocol.

Preparation of perinones via a novel multicomponent synthesis of isoindole scaffold

A convenient procedure for the preparation of isoindole derivatives is described. The method is based on the multicomponent reaction of heterocyclic ketene aminals with dialkyl acetylenedicarboxylates in presence of DMAP. The reaction is very simple from an experimental point of view and allows the creation of a fused isoindole moiety with concomitant formation of benzene and pyrrole ring in a single operation.

Facile and Quantitative Synthesis of 1,3-Diazaheterocycle-Fused 1,2,3-Triazole Derivatives Using Fluoroalkanesulfonyl Azide as a Diazo Transfer Reagent

A series of 1,3-diazaheterocycle-fused 1,2,3-triazoles were conveniently and quantitatively prepared by 1,3-dipolar cycloaddition of heterocyclic ketene aminals with fluoroalkanesulfonyl azide, followed by elimination of fluoroalkanesulfonyl amide at room temperature without any catalyst.

ChemInform Abstract: Application of 2‐(2‐Chloroaroyl)methyleneimidazolidines in Domino and Multicomponent Reaction: New Entries to Imidazo[1,2‐a]pyridines and Benzo[b]imidazo[1,2,3‐ij][1,8]naphthyridines.

Abstract A new strategy for the synthesis of tetrahydroimidazo[1,2-a]pyridines and unusual tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridines has been successfully developed by cascade reactions including Knoevenagel condensation, aza–ene reaction, imine–enamine tautomerization, cyclocondensation/oxidation, and intramolecular SNAr of precursors 2-(2-chloroaroyl)methyleneimidazolidines as new heterocyclic ketene aminals (HKA), which represent a class of polyfunctional scaffolds with four active reaction sites with aromatic aldehydes and malononitrile or ethyl 2-cyanoacetate under mild conditions. In this domino reaction, nine different active sites are involved, and two C–C bonds, two C–N bonds, and two new rings are constructed with all reactants efficiently utilized in the chemical transformation.

ChemInform Abstract: Reactions of Heterocyclic Ketene Aminals with Acrylonitrile: An Efficient Synthesis of Dihydropyridine‐Fused 1,3‐Diazaheterocycles.

AbstractA simple method for the synthesis of dihydropyridine‐fused 1,3‐diazaheterocycles based on the reaction of heterocyclic ketene aminals with acrylonitrile and subsequent intramolecular cyclization of the addition products (III) is developed.

ChemInform Abstract: Synthesis of Novel Tetracyclo‐Isocoumarins via AcOH‐Catalyzed Cascade Reaction of Heterocyclic Ketene Aminals with 2,2‐Dihydroxy‐2H‐indene‐1,3‐dione.

AbstractA cyclocondensation/rearrangement cascade of ninhydrin with cyclic ketene aminals (II) results in a convenient synthesis of tetracycloisocoumarins of potential biological interest.