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.Keywords: 1,6-Conjugate addition; Environmentally friendly; Neonicotinoids; Oxidation; para-Quinone methides;

Self-labeled inhibitors (SLIs) are promising for creating links, ranging from cancer therapy and metastatic pathways to mechanistic elucidation. In this study, a new category of “two-in-one” fluorescent xanthone inhibitors was developed for the systematic evaluation of anticancer activity and the selective imaging of cytoplasm in vitro. These xanthone inhibitors presented high fluorescent brightness, working over a wide pH range enabled by a “switchable reaction” of the heterocyclic backbone. The strength and nature of fluorescence were probed via spectroscopic methods and density functional theory calculations on the molecular level, respectively. Along with the potent anticancer activity, which was demonstrated using MTT and clonogenic assays with high fluorescent brightness in the cytoplasm, SLI 3fd could be established as a modeled self-monitoring drug in cancer therapy.

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.Keywords: Atom economy; Environment friendly; Imidazopyridine; Neonicotinoids; Pyridinium;

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.

The methods for the synthesis of two novel types of compounds, including pyridin-2-ones 3 and pyrimidin-4-ones 4 were developed. Pyridin-2-ones 3 were synthesised via the regioselective reaction of N,N′-disubstituted 1,1-ene diamines 1a–1w with mercaptals 2a–2c in acetonitrile promoted by Cs2CO3 under refluxing conditions. Fortunately, pyrimidin-4-ones 4 were obtained when the N-monosubstituted 1,1-ene diamines 1x–1b′, used as substrate, by accident, reacted with mercaptals 2 under similar conditions. As a result, two kinds of novel heterocycles were synthesised by this protocol. The reactions have some advantages, such as excellent yield, inexpensive raw materials and convenient final treatment. The antitumor bioactivity screening showed that certain compounds had potent antitumor activity. Especially, compounds 3r, which showed the most potent activity with IC50 values lower than 12.3 μmol L−1 against four human tumor cell lines, making it more active than cisplatin (DDP). In addition, a preliminary assessment of the structure–selectivity relationship of the compounds was also performed.

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 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.

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 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.

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.

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.Keywords: Cascade reaction; C−C bonds; C−Hetero bonds; Diastereoselective; Heterocyclic ketene aminals; Multicomponent reaction; Pyrrole; Quaternary stereocenters;

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. In conclusion, this novel synthetic strategy offers an alternative method using thermodynamic or kinetic control for regioselective construction of biologically meaningful fused pyrrole architectures from a concise, rapid, and environmentally friendly vision.Keywords: Catalyst-free; Fused pyrroles; Green and sustainable chemistry; Heterocyclic ketene aminals; Kinetic; Multicomponent reactions; Regioselective synthesis; Thermodynamic; Water−ethanol media

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.

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.

A method for regioselective synthesis of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives has been developed. The reaction was readily performed by reacting inexpensive materials, 4-chloro-3-formylcoumarin and HKAs, in EtOH catalyzed by Et3N. This protocol has many advantages including convenient operation, short reaction times, green solvent, and simple purification by washing the crude products with 95% EtOH, defined as GAP (Group-Assistant-Purification) chemistry. The library of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives has been constructed with excellent yields.

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 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 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.

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 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.