Heterocyclic Ketene Aminals Research Articles

Cycloaddition and Skeleton Rearrangement of Heterocyclic Ketene Aminals (HKAs) with 1-Diazonaphthalen-2(1H)-ones for the Synthesis of Functionalized 1,2,3-Triazoles.

We developed a protocol for the synthesis of highly functionalized 5,6-dihydro-imidazo[1,2-c][1,2,3]triazole derivatives 4-5 (DHITs) from 1-diazonaphthalen-2(1H)-one derivatives with heterocyclic ketene aminals (HKAs). This strategy involved cycloaddition and skeletal rearrangement entailing the heating of a mixture of substrates 1 with HKAs 2-3 and THF without any catalyst. As a result, a series of DHITs 4-5 were produced by cleaving one bond (1 C═N bond) and forming three bonds (1 N-N and 2 C-N bonds) in a single step. This protocol achieved the dual functionalization of diazo building blocks involving both the aromatic nitrogen alkylation reaction to form an ArC-N bond without any metal catalyst and the intermolecular cycloaddition of the N═N bond. These strategies can be used to synthesize functionalized DHITs for combinatorial and parallel syntheses via one-pot reactions without any catalyst.

Substrate-Controlled Three-Component Synthesis of Diverse Fused Heterocycles.

A chemoselective strategy toward a variety of fused heterocyclic scaffolds relying on a three-component condensation of heterocyclic ketene aminals (HKAs) or corresponding thioaminals with aryl glyoxals and cyclic 1,3-dicarbonyl compounds has been developed and explored. Depending on the applied combination of substrates, the strategy can be tuned to provide straightforward access to imidazo[1,2-a]quinoline, pyrrolo[1,2-a]imidazole, and pyrrolo[2,1-b]thiazole frameworks.

Functionalized Diazabenzo[a]anthracenediones: Regioselective Multicomponent Synthesis and Biological and Computational Studies as Potential Cholinesterase Inhibitors

AbstractHeterocyclic ketene aminals (HKAs) have been used to synthesize diaza‐benzo[a]anthracenedione derivatives through highly efficient one pot three‐component cascade reaction from readily available precursors. 2‐Hydroxy‐1,4‐naphthoquinone (HNQ) and aromatic aldehydes are reacted with heterocyclic ketene aminals via Et3N‐catalyzed tandem [3+2+1] annulation under solvent‐free conditions. These reactions were very smooth, productive with high yield and highly regioselective for the synthesis of novel fused tetracyclic compounds (4 a–4 i). These synthesized compounds were discovered to be potent inhibitors of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, with Ki values for BChE ranging from 27.37±4.70 to 78.06±6.96 nM and AChE from 59.01±6.91 to 150.88±14.84 nM, respectively. Molecular docking studies was carried out to find the interactions of most potent inhibitors.

Hydroxyl-Directed Rh(III)-Catalyzed C-H Functionalization: Access to Benzo[de]chromenes.

A cascade oxidative annulation reaction of heterocyclic ketene aminals (HKAs) with internal alkynes catalyzed by [Cp*RhCl2]2 and oxidized by Cu(OAc)2·H2O was developed to efficiently synthesize highly functionalized benzo[de]chromene derivatives in good to excellent yields. The reaction proceeded by the sequential cleavage of C(sp2)-H/O-H and C(sp2)-H/C(sp2)-H bonds. These multicomponent cascade reactions were highly regioselective. In addition, all of the benzo[de]chromene products exhibited intense fluorescence emission in the solid state, and they demonstrated concentration-dependent quenching in the presence of Fe3+, indicating that these compounds could be used in the recognition of Fe3+.

Synthesis of diverse spiro-imidazo pyridine-indene derivatives via acid-promoted annulation reaction of bindone and heterocyclic ketene aminals

A new multi-component reaction for the synthesis of novel and diverse spiro-imidazo pyridine-indene derivatives named spiro[imidazo[1,2-a]indeno[2,1-e]pyridine-5,1′-indene and indenylidene-1H-spiro[imidazo[1,2-a]pyridine-7,1′-indene was successfully developed by the reaction between heterocyclic ketene aminals (generated from 1,1-bis(methylthio)-2-nitro ethylene and diamine) and [1,2′-biindenylidene]-1′,3,3′-trione (bindone) (in situ generated from self-condensation of 1,3-indandion) by using malononitrile as a promoter or as one of the precursors respectively in the presence of p-TSA as the acid catalyst in EtOH as reaction medium under reflux conditions. Depending on whether the reaction is single-step or two-step, malononitrile can act as a promoter or reactant. The convenient one-pot operation, straightforward isolation without using additional purification methods, and the use of a variety of diamines and cysteamine hydrochloride causing a variety of structural products are attractive aspects of the present approach. The synthesized bindone and final product contains active methylene and this active site can be involved in further reactions to synthesize more complex heterocycles.

An environmentally benign multi-component reaction: Highly regioselective synthesis of functionalized 2-(diarylphosphoryl)-1,2-dihydro-pyridine derivatives

A novel protocol was developed for the construction of highly functionalized 2-(diarylphosphoryl)-1,2-dihydropyridine derivatives (DAPDHPs) from 3-formylchromones (1), heterocyclic ketene aminals (HKAs, 2), and phosphine oxides (R2P(O)H, 3) via a novel, one-pot cascade reaction. Optimization of the reaction conditions determined that refluxing the mixture of the 3-formylchromones, HKAs, and various R2P(O)H in propylene carbonate (PC) in the presence of triethylamine as a base facilitated the highest yields of the DAPDHP products. This cascade reaction, which involved the cleavage of one C–O bond in the 3-formylchromone substrates and the formation of three new bonds (one C–C, one C–N, and one C–P bond), enabled the synthesis of a small library of DAPDHP products. The dearomatized DAPDHP products were formed by the regioselective nucleophilic addition of the R2P(O)H reagents to the intermediate pyridinium salts 8. This approach has several advantages such as the use of an environmentally-friendly solvent, simple and practical operation (with filtration and washing without column chromatography separation), good yields, and a product with potential biological activity.

Multicomponent Cascade Reaction of 3-Formylchromones: Highly Selective Synthesis of Functionalized 9-Azabicyclo[3.3.1]nonane Derivatives.

A novel protocol for the preparation of functionalized 9-azabicyclo[3.3.1]nonane (ABCN) derivatives from 3-formylchromones, enaminones, and heterocyclic ketene aminals (HKAs) through an unprecedented cascade reaction has been developed by simply refluxing the mixture of the substrates 1-3. As a result, a series of ABCNs were produced through a very complex cascade reaction. This protocol can be used in the synthesis of ABCNs that are suitable for combinatorial and parallel syntheses of ABCN natural-like products in a one-pot reaction.

Base-promoted relay reaction of heterocyclic ketene aminals with o-difluorobenzene derivatives for the highly site-selective synthesis of functionalized indoles

A novel method was developed for the construction of highly functionalized indole derivatives (3), including fluorinated indoles, via a site-selective, one-pot, two-step nucleophilic aromatic substitution reaction of o-difluorobenzene derivatives (1) with heterocyclic ketene aminals (HKAs) (2) promoted by two different bases (K2CO3 and Cs2CO3). A diverse library of indoles 3 was generated in good to excellent yields using a conventional base-mediated approach rather than metal catalysts. As a result, the highly functionalized indoles were easily obtained in an environmentally friendly, rapid, and practical manner, and the products have potential biological activity.

Substrate-Tuned Domino Annulation for Selective Synthesis of Poly-substituted Benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-Azaheterocyclic Substituted 2-Arylquinolines

A domino annulation/oxidation of heterocyclic ketene aminals (HKAs) and 2-aminochalcones has been developed for the selective synthesis of poly-substituted benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-azaheterocyclic substituted 2-arylquinolines. These reactions proceed well under mild conditions without any additives. Plausible mechanisms for such a polycyclic ring system assembly were also proposed. Moreover, benzo[f]imidazo[2,1-a][2,7]naphthyridine 3g displayed a fluorescence effect, demonstrating the potential applications in organic optical materials.

Multicomponent cascade reactions of HKAs: synthesis of highly functionalized 5H-chromeno[4,3-d]pyrimidines

A novel protocol was developed for the construction of functionalized 5H-chromeno[4,3-d]pyrimidines from 3-formylchromones, heterocyclic ketene aminals, and amidine hydrochlorides via a novel cascade reaction involving ring-opening and 1,3-H shift reactions.

Cu(II)/Iodine(III) Oxide Dimerization of Heterocyclic Ketene Aminals: Tandem TEMPO Oxidation for the Highly Selective Synthesis of Functionalized 2H-Pyrrolo[1,2-a]imidazol-7(3H)-ones.

This study aimed to develop a novel protocol for the synthesis of 2H-pyrrolo[1,2-a]imidazol-7(3H)-ones (PIDOs) from heterocyclic ketene aminals (HKAs) through an unprecedented cascade reaction by refluxing. Consequently, a series of PIDOs was produced through an amazing oxidative dimerization, followed by sequential cleavage of the C-N and C-C bonds in dimeric HKAs. This formation of PIDOs was accompanied by the formation and cleavage of many bonds. This method is suitable for the parallel construction of bicyclic pyrrolidone-like products.

Synthesis of fused hydroxy dihydropyrroles and unexpected dihydropyrazine and dihydroquinoxaline derivatives based on heterocyclic ketene aminals

AbstractThe one‐pot four‐component synthesis of highly functionalized fused hydroxyl dihydropyrroles and dihydropyrazines from readily available diamines, 1,1‐bis (methylsulfanyl)‐2‐nitroethene, phenylglyoxal monohydrates, and C‐H acids have been developed. This strategy provides an efficient, catalyst‐free approach for easy access to various new hydroxyl‐dihydropyrrole and dihydropyrazine rings in good to high yields. The products were confirmed by 1H and 13C NMR, IR, mass, and X‐ray crystal structure analyses.

Tandem reaction of heterocyclic ketene aminals with diazoesters: Synthesis of pyrimidopyrrolidone derivatives

A tandem reaction of heterocyclic ketene aminals (HKAs) with diazoesters in the presence of a Cu catalyst is demonstrated for the efficient synthesis of pyrimidopyrrolidone derivatives. The reaction shows a broad substrate scope and excellent functional group tolerance. Our method provides rapid access to diverse pyrimidopyrrolidones in moderate to excellent yields under mild reaction conditions.

Multicomponent Tether Catalysis Synthesis of Highly Functionalized 4-(Pyridin-2-ylmethyl)-2-aminopyrroles via Cascade Reaction Is Accompanied by Decarboxylation.

A multicomponent tether catalysis protocol for the synthesis of 4-(pyridin-2-ylmethyl)-2-aminopyrroles (PMAPs) was constructed by simply refluxing a mixture of ethyl 2-(pyridin-2-yl)acetates 1 and various types of arylglyoxal monohydrates 2 and different heterocyclic ketene aminals 3 in EtOH solvent. Based on this reaction, a series of highly functionalized PMAPs were obtained through a novel cascade reaction accompanied by a decarboxylation mechanism. As a result, the pyridin-2-ylmethyl was successfully introduced in the target compounds, and a library of PMAPs were easily constructed using the cascade reaction described in this study. This protocol demonstrated that the most important feature was the decarboxylation reaction of the 2-(pyridin-2-yl)acetates 1, which can be used in the synthesis of pyridin-2-ylmethyl-substituted heterocycles, including pyrroles, pyridines, quinolones, and other heterocyclic compounds resembling those found in nature.

Cascade Reaction of Morita-Baylis-Hillman Acetates with 1,1-Enediamines or Heterocyclic Ketene Aminals: Synthesis of Highly Functionalized 2-Aminopyrroles.

A new strategy for the construction of two kinds of fully substituted pyrroles, including 2-aminopyrroles and bicyclic pyrroles from Morita-Baylis-Hillman (MBH) acetates with 1,1-enediamines (EDAMs), or heterocyclic ketene aminals (HKAs) via base-promoted tandem Michael addition, elimination, and aromatization sequence has been developed, affording the expected products in moderate to excellent yields. This methodology is a highly efficient, concise way to access 2-aminopyrroles or bicyclic pyrroles with diversity in molecular structures from accessible building blocks under moderate reaction conditions.

Synthesis of spiroimidazopyridineoxindole, spiropyridopyrimidineoxindole and spiropyridodiazepineoxindole derivatives based on heterocyclic ketene aminals via a four-component reaction.

Here, we have described the synthesis of novel spiropyridineoxindole derivatives containing a pyridone ring via a four-component reaction between various diamines, 1,1-bis(methylthio)-2-nitroethylene, isatin derivatives and Meldrum's acid in the presence of p-toluenesulfonic acid. This protocol has some advantages such as the availability of starting materials, good yields, facile separation of products, the use of ethanol as an environmentally benign solvent and easy formation of three new bonds in one operation.

An efficient synthesis of new imidazo[1,2-a]pyridine-6-carbohydrazide and pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives via a five-component cascade reaction.

A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including N′-(1-(4-nitrophenyl)ethylidene)imidazo[1,2-a]pyridine-6-carbohydrazide and N′-(1-(4-nitrophenyl)ethylidene)pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives is successfully achieved via a five-component cascade reaction utilizing cyanoacetohydrazide, 4-nitroacetophenone, 1,1-bis(methylthio)-2-nitroethylene and various diamines in a mixture of water and ethanol. The new efficient domino protocol involving a sequence of N,N-acetal formation, Knoevenagel condensation, Michael reaction, imine–enamine tautomerization and N-cyclization as key steps. The merit of this catalyst free approach is highlighted by its easily available starting materials, operational simplicity, clean reaction profile, the use of environmentally benign solvents and tolerance of a wide variety of functional groups.

Enantioselective Epoxypyrrolidines via a Tandem Cycloaddition/Autoxidation in Air and Mechanistic Studies.

A tandem cycloaddition/autoxidation reaction between heterocyclic ketene aminals and diazoester in air is described for the enantioselective preparation of epoxypyrrolidines. Notably, the results of mechanistic studies suggest that epoxide was oxidized from an sp3 C-C single bond, which is of mechanistic and practical interest as this protocol may be suitable for constructing other bioactive heterocyclic epoxides.

Synthesis of Pyrimidopyrrolopyridazines via a Tandem Reaction of Heterocyclic Ketene Aminals with 1,2-Diaza-1,3-dienes.

A tandem reaction of heterocyclic ketene aminals and 1,2-diaza-1,3-dienes was developed for the expedient synthesis of pyrimidopyrrolopyridazine derivatives. This process involved an intramolecular conjugate addition followed by CuCl2-catalyzed hydrazone formation.

Facile Route to the Synthesis of 1,3-Diazahetero-Cycle-Fused [1,2-a]Quinoline Derivatives via Cascade Reactions

A one-step protocol without transition-metal catalysts with simple post-treatment for the synthesis of 1,3-diazaheterocycle-fused [1,2-a]quinoline derivatives via the cascade reaction of 2-fluorobenzaldehyde (1) and heterocyclic ketene aminals (2) was developed. In the one-step cascade reaction, C=C and C–N bonds were constructed, and the targeted compound can be efficiently obtained by filtering without column chromatography. This protocol describes a valuable route to concisely and feasibly obtain 1,3-diazaheterocycle-fused [1,2-a]quinoline derivatives. The synthetic methodology is particularly attractive because of the following features: low-cost solvent, mild temperature, atom economy, high yield, and potential biological activity of the product.