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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.

A novel protocol was developed for the construction of highly functionalized 5H-chromeno[4,3-d]pyrimidines (CMPDs) from 3-formylchromones, heterocyclic ketene aminals (HKAs), and amidine hydrochlorides via a novel cascade reaction involving ring-opening and 1,3-H shift reactions. As a result, a series of CMPDs was produced by exploitation of the cascade reaction, which involved the formation of three bonds and the cleavage of one bond through multiple reactions in one pot. This protocol can be used in combinatorial and parallel syntheses of various CMPD derivatives with the potential to exhibit biological activities against clinically relevant pharmacological targets and will be widely used for designing and synthesizing various novel chromene-containing heterocycles in the future.

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.

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.

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.

A concise and efficient route for the synthesis of quinone methide substituted neonicotinoid derivatives (4–5) via the one-pot Cs2CO3-catalyzed 1,6-conjugate addition of N-benzyl nitro ketene amines (2) or 1,1-enediamines (3) with para-quinone methides (1) in acetone and an oxidation reaction using atmospheric oxygen has been developed. This protocol represents a route to obtain a novel class of quinone methide substituted neonicotinoid derivatives in a concise, rapid, and practical manner. This reaction is particularly attractive because of the following features: low-cost and biocompatible solvent, mild temperature, atomic economy, high yields, and potential biological activity of the product.

Two types of novel bicyclic compounds such as pyridinone 3 and 1,3-oxazinane derivatives 4 have been synthesised via the regioselective condensation reaction of heterocyclic ketene aminals (HKAs) with ethyl 2-cyano-3,3-bis(methylthio)-acrylate or 2-(bis(methyl-thio)methylene)-malononitrile in xylene at refluxing temperature. The bicyclic pyridinone compounds 3 can be efficiently obtained using catalyst-free conditions whereas 1,3-oxazinane derivatives 4 are obtained by adding Cs2CO3 under the same conditions. The reactions have the advantage of excellent yield, inexpensive raw materials and convenient final treatment.

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.

A concise and eco-friendly route for the synthesis of highly functionalized bicyclic pyridinium derivatives (3) via a one-pot reaction of chromone-3-carboxaldehydes (1) and N-benzyl nitro ketene aminals (NBNKAs) (2) under reflux in ethanol media has been developed. The targeted compound was efficiently obtained by filtration without further post-treatment. In the one-pot two step reaction, C—C and C═N bonds were constructed, while at the same time one C—O bond was cleaved. This protocol represents a valuable route to obtain highly functional bicyclic pyridinium derivatives in a concise, rapid, and practical manner. The reaction is particularly attractive due to features such as low cost, mild conditions, atom economy, high yield, using biocompatible solvent, and potential biological activity of the product.

A efficient and concise one-pot procedure has been developed for the synthesis of highly functional morphan derivatives 3 based on diastereoselective double Michael addition reactions of various quinone monoketals 1 with a variety of heterocyclic ketene aminals (HKAs) 2 in the green solvent water at 60 °C. This protocol is especially suitable for efficient and rapid parallel syntheses of N-containing bridged heterocycles possessing pharmacological activities. As a result, a library of highly functional morphan derivatives was easily synthesized using this reported environmentally benign, mild, and catalyst-free one-pot reaction.

A facile synthesis of highly functionized indanone fused multicyclic pyrrolines using the heterocyclic ketene aminal and ninhydrin is described. Derivative alkoxyl or amine substituted analogues were also directly achieved upon adding alcohols or amines as corresponding starting materials. The reaction conditions are environment friendly and have a good tolerance towards a variety of heterocyclic ketene aminals. A library including three series of molecularly diverse indanone fused pyrrolines with potential bioactivities was demonstrated to be rapidly constructed with good to excellent yields.

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.

An efficient strategy for the synthesis of substituted bicyclic 2-pyridones is developed. The proposed approach is based on the regioselective N-acylation of heterocyclic ketene aminals (HKAs) with methacrylic anhydride or crotonic anhydride. The tolerance of the developed methodology allows for the construction of fused 2-pyridone ring systems in excellent yields with a variety of functional groups HKAs as synthons under neutral conditions.

A three-component domino [3+2] cyclization for the synthesis of new multi-functional fused pyrroles has been developed via reaction of heterocyclic ketene aminals (HKAs) 1 with arylglyoxal monohydrates 2 and 1,3-diphenylpropane-1,3-dione 3 under catalyst-free conditions in ethanol. In the one-step domino reaction, one C–N bond and two C–C bonds were formed and one C–C bond was cleaved. The established protocol is advantageous in providing excellent regioselectivity and concise one-pot methodology with the use of environmentally friendly solvents and readily available starting materials.

A series of novel fused polyhalogeno-7a-hydroxy-[1,2-a]indol-5-one derivatives has been synthesized with good yields based on the Nenitzescu reaction of heterocyclic ketene aminals (HKAs) with halogenated quinones without catalyst in acetone under room temperature. The highly efficient, catalyst-free and one pot synthesis serves as a nice addition to group-assisted-purification (GAP) chemistry, and the pure products were obtained simply by washing the crude products with 95% ethanol.

A concise and efficient one-pot three-component synthesis of structurally diverse fluorine substituted bicyclic pyridines was constructed by simply refluxing a mixture of different types of heterocyclic ketene aminals, triethoxymethane, and fluorine-containing methylene compounds under solvent-free and catalyst-free conditions. These bicyclic pyridines are promising candidates for drug discovery; consequently, a library of fluorine substituted bicyclic pyridines was rapidly constructed in 79%–93% yields.

A novel C–N cleavage strategy for the regioselective synthesis of 2-nitroso heterocyclic ketene aminals (HKAs) has been established. In this procedure, the C–N bond of nitrobenzenyl nitroethene is cleaved by the oxidation reaction and selective nitroso reaction of the α-carbon in HKAs. The presented synthetic route features excellent selectivity, straightforward purification and simple starting materials.

A concise and efficient synthesis of pyrrolo[1,2-a]imidazoles and imidazo[1,2-a]-pyridines was developed by regioselective aza-ene additions and regioselective cyclic–condensation reactions of heterocyclic ketene aminals with ethyl 3-benzoylacrylate or methyl acetylacrylate derivatives under catalyst-free conditions. This method has some advantages including high regioselectivity, good yields and simple work-up procedures.

An efficient and convenient method was developed for the preparation of 2-benzenesulfonothiol-HKAs via a silver(I)-mediated direct sulfenylation of heterocyclic ketene aminals (HKAs). The method involves a variety of functionalized substrates, leading to α-arylthioyl HKAs in a mild, easy operation, and mild reaction conditions.

An efficient and straightforward synthesis of polycyclic 1,4-dihydropyridine derivatives has been developed by reacting heterocyclic ketene aminals (HKAs) with 1,3-cyclohexanedione derivatives and a number of substituted salicylaldehyde, respectively, via three-component cascade reactions in water. This strategy provides an efficient and environmentally friendly approach for easy access to various new fused polycyclic 1,4-dihydropyridine derivatives without the need of organic solvents in moderate to good yields.

A three-component strategy for the efficient and diastereoselective synthesis of unprecedented polycyclic pyrroles (4) bearing four consecutive quaternary stereocenters has been developed. The reaction was performed with three readily available starting materials: heterocyclic ketene aminals (HKAs) (1), acenaphthylene-1,2-dione (2), and ethyl trifluoroacetylacetate (3). In the one-step cascade reaction, two C–C bonds, two C–Hetero bonds, four consecutive quaternary stereocenters, and two heterocycles were constructed. The established protocol presented outstanding diastereoselectivity (up to 99:1) and provided a valuable route to access highly functionalized polycyclic pyrroles with conciseness, rapidness, and practicability. The reaction is particularly attractive due to the following advantages: atom economy, optimum convergence, high bond-forming efficiency, and operational simplicity.

A concise and efficient synthesis of novel bicyclic pyrroles has been achieved by PdCl2-catalyzed cyclic condensation of six-membered heterocyclic ketene aminals (HKAs) or seven-membered HKAs with ethyl 2,3-diiodoacrylate and diethyl 2,3-diiodofumarate in the presence of Cs2CO3, respectively. A series of novel bicyclic pyridones have also been obtained via five-membered HKAs with diethyl 2,3-diiodofumarate under the optimized conditions in moderate yields. These reactions are the first application of a transition metal to catalyze the building blocks HKAs to form the bicyclic pyrrole library via condensation reaction.

The title compounds (IV), (VI), (VIII), (X) are efficiently and regioselectively obtained by cascade reaction of ketene aminals with triethoxymethane (II), and 4-hydroxy coumarin derivatives (III) without any catalyst and solvent.

A three-component catalyst-free protocol for the regioselective synthesis of dual highly functionalized fused pyrroles has been developed from a cascade [3 + 2] cyclization of heterocyclic ketene aminals (HKAs) 1 with arylglyoxal monohydrates 2 and cyclohexane-1,3-diones 3 in water–ethanol media. The kinetically controlled products 4 could be synthesized within 1 h but would irreversibly transform to thermodynamically controlled products 5 over an additional 5 h. At the same time, the transformative synthesis of 5a from 4a by controlling the oxygen or nitrogen proved the proposed mechanism. Furthermore, the DFT calculation also corroborated that the stability of products 5 are a 100,000 times more thermodynamically stable than products 4. Finally, the origin of the greater stability of 5 could be explained by the reduced density gradient (RDG) analysis, which hinted that the crucial factors are the formation of a new intramolecular hydrogen bond and the release of the steric effect of the crowded rings. I...

An efficient one-pot synthesis of highly functionalized bicyclic pyrrole derivatives by a three-component domino reaction of heterocyclic ketene aminals (HKAs), arylglyoxal monohydrate, and indoles in ethanol medium catalyzed by acetic acid is described. In this procedure, three sigma bonds were formed simultaneously. The present synthesis features excellent regio-selectivity, easy purification as well as simple starting materials.

A novel silver(I)-mediated direct coupling reaction using heterocyclic ketene aminals (HKAs) and diaryl dichalcogenides for the construction of C(sp2)–S and C(sp2)–Se bonds was reported. The transformation involves a variety of functionalized substrates, leading to α-arylthio and α-phenylselanyl HKAs in a mild, facile and efficient way with high regioselectivity and excellent yields. The broad scope of the starting materials enhanced the chemo-diversity of the target materials, thus affording a number of potential applications in the synthesis of heterocycles and its relevant medicinal chemistry.

As a classical and well-established named reaction, the Nenitzescu reaction is of special value for the construction of biologically meaningful 5-hydroxyindole derivatives. However, to date, its sister, the anti-Nenitzescu reaction and the corresponding synthetic methodology for 3a-hydroxy-indol-6-one derivatives, has remained an unexplored area. We discovered herein an environmentally benign, mild, and catalyst-free reaction in ethanol for the site-selective construction of rarely fused [1,2-a]indolone derivatives (3) from quinones (1) and heterocyclic ketene aminals (HKAs) (2) via an unexpected anti-Nenitzescu strategy. This unconventional methodology suggests that it will be suitable for the site-selective synthesis of 3a-hydroxy-indol-6-one derivatives from a green perspective. On the other hand, the developed target compounds 3 have a promising future for the further synthesis of aromatic 6-hydroxyindoles or dehydroxylated indol-6-ones in situ. In order to systematically elucidate the mechanistic details and controlling factors of the two Nenitzescu reactions, density functional theory (DFT) calculations were also performed. According to the computational results, the origin of site-selectivity can be explained by the following reasons: all energy barriers for the anti-Nenitzescu reaction can be overcome at room temperature, yet the extremely high energy barrier of imine–enamine tautomerization for the Nenitzescu reaction indicates its failure under the same conditions. The reduced density gradient (RDG) analysis hinted that the greater thermodynamic stability of the Nenitzescu product 3h′ mainly depends on the release of the strong steric effect.

An efficient synthesis of highly substituted bicyclic pyrrolidinone derivatives via a cascade reaction of heterocyclic ketene aminals (HKAs) and N-substituted maleimide in an environmentally friendly medium under catalyst-free conditions is described. This protocol uses group-assisted 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. The library of bicyclic pyrrolidinone derivatives has been constructed with moderate to excellent yields.

Heterocyclic ketene aminals (HKAs) have proven to be a class of fascinating and versatile synthetic building blocks for use in the construction of heterocyclic or fused heterocyclic compounds. The bicyclic, tricyclic, and tetracyclic nitrogen-containing analogues with HKA skeleton widely exist in natural and synthetic drugs. To understand and to master the reaction properties of HKAs and to construct other new fused heterocycles in the future, it is very important and necessary to investigate HKAs. This review covers the relevant contributions of the last twenty years with respect to the developments and applications of HKAs, categorized by reaction type.

An efficient synthesis of novel bicyclic pyridone derivatives via cascade reaction of heterocyclic ketene aminals (HKAs) and 4-arylmethylene-2-phenyloxazol-5(4H)-ones in the presence of acetic acid has been established. Significantly, the protocol affords a straightforward approach to the construction of multisubstituted bicyclic pyridones in which one C–O bond was cleaved and new C–C and C–N bonds were formed in one pot under mild conditions.

A simple, straightforward and versatile multicomponent protocol for the synthesis of indanone-fused spirooxindole derivatives has been developed. The strategy involves the one-pot three-component reaction of heterocyclic ketene aminals, 1H-indene-1,3(2H)-dione and the dicarbonyl compounds isatins or acenaphthenequinone in an ethanol/water medium catalysed by p-TSA at reflux. Mild reaction conditions, operational simplicity, wide substrate scope and overall excellent yields make this method highly efficient for the library synthesis of indanone-fused spirooxindole.

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.

A facile synthesis of highly functionized indanone fused multicyclic pyrrolines using the heterocyclic ketene aminal and ninhydrin is described. Derivative alkoxyl or amine substituted analogues were also directly achieved upon adding alcohols or amines as corresponding starting materials. The reaction conditions are environment friendly and have a good tolerance towards a variety of heterocyclic ketene aminals. A library including three series of molecularly diverse indanone fused pyrrolines with potential bioactivities was demonstrated to be rapidly constructed with good to excellent yields.

We here described an efficient method for the synthesis of a series of highly functionalized pyrimidines via the addition and condensation reaction of ketene dithioacetals with guanidine carbonate or amidine hydrochlorides by microwave irradiation under solvent-free conditions in the absence of a catalyst, giving the products with good yields (79–98%).

A series of heterocycle-fused 1,2,3-triazoles were easily prepared by the 1,3-dipolar cycloaddition of heterocyclic ketene aminals or N,O-acetals with sodium azide and polyhalo isophthalonitriles in a one-pot reaction at room temperature without a catalyst and evaluated in vitro against a panel of human tumour cell lines. 1,3-Oxazoheterocycle fused 1,2,3-triazoles were more potent against the tumour cell lines Skov-3, HL-60, A431, A549 and HepG-2 than 1,3-diazoheterocycle fused 1,2,3-triazoles. 4-Methoxyphenyl substituted 1,3-oxazoheterocycle fused 1,2,3-triazole 6j was found to be the most potent derivative with IC(50) values lower than 1.9 microg/mL against A431 and K562 human tumour cell lines.

A concise and efficient route for the synthesis of 1,3-diazaheterocycle-fused [1,2-a]indoles by simply refluxing a reaction mixture of different types of heterocyclic ketene aminals and 1,4-benzoquinones catalyzed by acetic acid was developed. This protocol provides an alternative method for application in combinatorial and parallel synthesis in drug discovery.

The substitution-cyclization reaction of heterocyclic ketene aminals with polyhalo isophthalonitrile in the presence of t-BuOK to form 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-imines, followed by hydrolysis with 1 N HCl, provides a concise and efficient route for the synthesis of highly functional polyhalo 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-ones.

Starting from heterocyclic ketene aminals, arylglyoxal monohydrates and 1,3-diphenylpropane-1,3-dione an efficient domino [3 + 2]-cyclization is developed which provides fused pyrrole derivatives in high yields and with excellent regioselectivity.

A series of novel fused polyhalogeno-7a-hydroxy-[1,2-a]indol-5-one derivatives has been synthesized with good yields based on the Nenitzescu reaction of heterocyclic ketene aminals (HKAs) with halogenated quinones without catalyst in acetone under room temperature. The highly efficient, catalyst-free and one pot synthesis serves as a nice addition to group-assisted-purification (GAP) chemistry, and the pure products were obtained simply by washing the crude products with 95% ethanol.

Regioselective aza-ene reactions and cyclocondensation reactions of heterocyclic ketene aminals with benzoyl- or acetylacrylate lead to pyrrolopyrimidines, erroneously named as pyrroloimidazoles, and imidazopyridines efficiently under catalyst-free conditions.

The reaction proceeds with 2-aryloylmethylidene-1,3-diazacycloalkanes with high regioselectivity forming the corresponding α-nitroso compounds.

Starting from heterocyclic ketene aminals, methylene-containing diones, and triethoxymethane a one-pot preparation of trifluoromethyl-substituted fused bicyclic pyridine systems is developed.

An efficient and convenient method was developed for the preparation of 2-benzenesulfonothiol-HKAs via a silver(I)-mediated direct sulfenylation of heterocyclic ketene aminals (HKAs). The method involves a variety of functionalized substrates, leading to α-arylthioyl HKAs in a mild, easy operation, and mild reaction conditions.

The title reaction provides a facile access to a wide variety of bicyclic pyrrolidine derivatives.

A novel silver(I)-mediated direct coupling reaction using heterocyclic ketene aminals (HKAs) and diaryl dichalcogenides for the construction of C(sp2)–S and C(sp2)–Se bonds was reported. The transformation involves a variety of functionalized substrates, leading to α-arylthio and α-phenylselanyl HKAs in a mild, facile and efficient way with high regioselectivity and excellent yields. The broad scope of the starting materials enhanced the chemo-diversity of the target materials, thus affording a number of potential applications in the synthesis of heterocycles and its relevant medicinal chemistry.

The title compounds (IV), (VI), (VIII), (X) are efficiently and regioselectively obtained by cascade reaction of ketene aminals with triethoxymethane (II), and 4-hydroxy coumarin derivatives (III) without any catalyst and solvent.

An environmentally benign method for the selective preparation of fused indolone derivatives via anti-Nenitzescu strategy is developed.

An eco-benign and highly efficient aza–ene reaction for preparing imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives from heterocyclic ketene aminals (HKAs) and 2,3-dioxopyrrolidines has been developed in environmentally benign solvent systems, as well as in the absence of any catalyst. The procedures feature excellent yields, short reaction times, a convenient one-pot method, and simple purification that not only minimise the generation of waste but also simplify the work-up procedure.

A one-step synthesis of the title compounds is developed via a base catalyzed cyclocondensation of heterocyclic ketene aminals (I) and (IV) with 4-chloro-3-carbaldehyde derivatives (II).

Review: [relevant contributions of the last twenty years with respect to the developments and applications of heterocyclic ketene aminals; 81 refs.