Radical Cascade Reaction of Heterocyclic Ketene Aminals with Thiocyanates Promoted by Visible Light: Synthesis of Functionalized Fused 2-Iminothiazolines.

Herein, a visible-light-promoted radical cascade cyclization of heterocyclic ketene aminals (HKAs) and thiocyanates was developed to access functionalized fused 2-iminothiazolines. This novel cascade reaction can be realized under only visible-light irradiation without the help of external photocatalysts, oxidants, and additives. These multicomponent cascade reactions demonstrate excellent selectivity for the Z-isomers and ensure the formation of the products only in their isomeric form. Preliminary mechanism investigations demonstrated that HKAs and thiocyanates can form electron donor-acceptor complexes for harvesting the energy of visible light to activate substrates and generate reactive radicals. This protocol can be used for synthesizing various natural-like products such as fused 2-iminothiazolines. This approach demonstrates multiple advantages such as commercially available substrates, convenient operation, environmentally friendly, mild conditions, and an efficient multicomponent reaction (2A + B).

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.

Divergent Synthesis of 2-Chromonyl-3-hydrazono-chromones and 2-Alkoxy-3-hydrazono-chromones through Switchable Annulation Reactions of o-Hydroxyphenylenaminones with Aryldiazonium Salts.

An unprecedented selective chromone annulation reaction controlled by solvent for the divergent synthesis of two types of 2,3-disubstituted chromone skeletons has been developed. A variety of 2-chromonyl-3-hydrazono-chromones and 2-alkoxy-3-hydrazono-chromones were constructed efficiently from readily available o-hydroxyphenylenaminones (o-HPEs) and aryldiazonium salts at room temperature. This strategy is highly chemoselective and features mild reaction conditions, broad substrate scope, broad functional group tolerance, easy gram-scale preparation, and simple filtration to obtain the pure products without tedious column chromatography.

Rh(III)-Catalyzed [3 + 2] Annulation/Pinacol Rearrangement Reaction of Enaminones with Iodonium Ylides: Direct Synthesis of 2-Spirocyclo-pyrrol-3-ones.

A novel Rh(III)-catalyzed cascade alkenyl C-H activation/[3 + 2] annulation/pinacol rearrangement reaction of enaminones with iodonium ylides has been developed. This methodology provides a new and straightforward synthetic strategy to afford highly functionalized 2-spirocyclo-pyrrol-3-ones in satisfactory yield from readily available starting materials under mild conditions. Moreover, gram-scale reactions and further derivatization experiments are implemented to demonstrate the potential utility of this developed approach.

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+.

Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1H-Pyrrolo[3,4-c]quinoline-1,3(2H)-diones.

A novel protocol for the construction of functionalized 1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diones (PQLs, 3) from N-phenylglycines and maleimides was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuBr as a catalyst in chlorobenzene. Consequently, a diverse series of PQLs 3 were synthesized in moderate-to-good yields (43-73%). The synthesis of the PQLs was enabled via a one-pot cascade reaction that proceeded through subsequent oxidative decarboxylation, 1,2-addition, intramolecular cyclization, tautomerization, and aromatization reactions. This protocol can be used for the synthesis of functionalized PQLs via a one-pot oxidative decarboxylation annulation reaction rather than through a series of multistep reactions, making it suitable for both combinatorial and parallel syntheses of PQLs.

Synthesis of benzo[b][1,5]diazocin-6(5H)-one derivatives via the Cu-catalysed oxidative cyclization of 2-aryl-1H-indoles with 1,1-enediamines.

A novel protocol for the synthesis of highly functionalized benzo[b][1,5]diazocin-6(5H)-one derivatives (BDCOs, 4 and 5) from 2-aryl-1H-indoles and 1,1-enediamines was developed via a complex cascade of reactions including regioselective free radical oxidation, the 1,2-addition of imine, imine-enamine tautomerization, intramolecular cyclization, and ring expansion. The cascade reaction was enabled by refluxing a mixture of two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuI as a catalyst in toluene under argon protection. Consequently, a series of BDCOs (4 and 5) were synthesized with high regioselectivity in good yield. This protocol can be used for the synthesis of functionalized BDCOs via a one-pot oxidative annulation reaction rather than a multi-step reaction, which is suitable for both combinatorial and parallel syntheses of BDCOs.

Cu-Catalyzed Oxidative [3 + 2] Annulation of 2-(Pyridine-2-yl)acetates with Maleimides: Synthesis of 1H-Pyrrolo[3,4-b]indolizine-1,3-diones.

A novel protocol for the construction of highly functionalized indolizine derivatives, that is, 1H-pyrrolo[3,4-b]indolizine-1,3-diones (PIZDOs, 3) from 2-(pyridine-2-yl)acetates and maleimides via a regioselective oxidative [3 + 2] annulation was developed. The cascade oxidative reaction was enabled by heating a mixture of the two substrates in the presence of Ag2CO3 as an oxidant and Cu(OAc)·H2O as a catalyst in chlorobenzene. Consequently, a series of PIZDOs 3 were synthesized with high regioselectivity in moderate yields. This protocol can be used in the synthesis of functionalized PIZDOs via the one-pot oxidative annulation reaction rather than through multistep reactions, which is suitable for both combinatorial and parallel syntheses of PIZDOs.

Multicomponent Cascade Reaction of 3-Cyanochromones: Highly Site-Selective Synthesis of 2-(1H-Imidazol-1-yl)-4H-chromen-4-one Derivatives.

A method for the synthesis of 2-(1H-imidazol-1-yl)-4H-chromen-4-one derivatives (IMCMs) from 3-cyanochromones and α-isocyanoacetates via a one-pot cascade reaction involving a 1,2-addition, Michael reaction, ring-closing, tautomerization, ring-opening, and [3 + 2] cyclization was enabled by refluxing a mixture of the starting materials in THF in the presence of Ag2CO3 as a catalyst. The cascade reaction resulted in the formation of five bonds and the cleavage of two bonds, including a triple bond, in one pot. This protocol enabled not only the synthesis of functionalized imidazoles (i.e., IMCMs) but also the synthesis of functionally useful enamine building blocks. This strategy is suitable for combinatorial and parallel syntheses of IMCMs.

Cu-Catalyzed decarboxylative annulation of N-substituted glycines with 3-formylchromones: synthesis of functionalized chromeno[2,3-b]pyrrol-4(1H)-ones.

A novel protocol was developed for preparing functionalized chromeno[2,3-b]pyrrol-4(1H)-ones 3 (CMPOs) from 3-formylchromones with N-substituted glycine derivatives. The method entailed decarboxylative annulation of the acyl group of 3-formylchromones by simply heating a mixture of substrates 1-2 and toluene oxidized by 2-di-tert-butyl peroxide (DTBP) and catalyzed by CuBr. As a result, a series of CMPOs 3 were produced via a cascade reaction. This protocol can be used to synthesize functionalized CMPOs via combinatorial and parallel syntheses in a one-pot reaction rather than a tedious multi-step reaction.

An Environmentally Benign Multicomponent Cascade Reaction of 3-Formylchromones, 2-Naphthols, and Heterocyclic Ketal Aminals: Site-Selective Synthesis of Functionalized Morphan Derivatives.

A novel protocol has been developed for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives by the interesting three-component cascade reaction of 3-formylchromones, 2-naphthol, and heterocyclic ketal aminals (HKAs) in the ionic liquid [BMIM]PF6 promoted by the organic base Et3N. A complex cascade reaction is required, which includes a 1,2-addition, two Michael reactions, two tautomerizations, and an N-alkylation accompanied by a ring-opening reaction and involving the cleavage of one C-O bond and the formation of four bonds (one C-N bond, one C-O bond, and two C-C bonds). As a result, functionalized morphans (5 and 6) bearing naphthalene-structured skeletons were prepared by simple heating of a mixture of 3-formylchromones, 2-naphthols, and HKAs in the environmentally friendly ionic liquid [BMIM]PF6. This protocol can be used in the synthesis of various morphans and is suitable for combinatorial and parallel syntheses of natural-like morphan derivatives. This approach has several advantages such as the use of an environmentally friendly solvent, simple and practical operation (multicomponent one-pot reaction), and satisfactory yields (65-88%).

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.

Multi-component cascade reaction of 3-formylchromones: highly selective synthesis of 4,5-dihydro-[4,5'-bipyrimidin]-6(1H)-one derivatives.

A novel protocol for the construction of highly functionalized bipyrimidine derivatives 4 and 5 from 3-formyl-chromones, ethyl 2-(pyridine-2-yl)acetate derivatives, and amidine hydrochlorides via an interesting and considerably complex multi-component cascade reaction was developed. The cascade reaction was manifested by refluxing a mixture of the three substrates in acetonitrile or DMF along with Cs2CO3. A series of 4,5-dihydro-[4,5'-bipyrimidin]-6(1H)-ones (DBPMOs) 4 was constructed regioselectively in suitable to excellent yields. Moreover, intermediates 4 then underwent a novel, metal- and oxidant-free cascade reaction to produce a series of [4,5'-bipyrimidin]-6(1H)-ones (BPMOs) 5. The formation of the bipyrimidine derivatives 4-5 was enabled by the formation of five bonds and the cleavage of one bond in one pot. This protocol can be used in the synthesis of functionalized bipyrimidine derivatives via a multi-component one-pot cascade reaction rather than multi-step reactions, which is suitable for both combinatorial and parallel syntheses of bipyrimidine derivatives.

An Environmentally Benign Cascade Reaction of 1,1-Enediamines (EDAMs) for Site-Selective Synthesis of Highly Functionalized 2,10-Dihydro-1H-imidazo[1',2':1,6]pyrido[2,3-b]indoles and Pyrroles.

A novel protocol for the synthesis of pyrido[2,3-b]indoles (α-carbolines, 3) from (E)-3-(2-oxo-2-phenylethylidene) indolin-2-one derivatives 1 and 1,1-enediamine (EDAM) 2a via an unexpected cascade reaction in ethanol was developed. Pyrido[2,3-b]indole derivatives 4 were obtained by the same reaction, albeit by stirring the mixture for a longer period of time (about 48 h). As a result, two kinds of functionalized α-carbolines 3 and 4 were synthesized by the facile reaction of the (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one derivatives and 2-(nitromethylene)imidazolidine under basic conditions (Cs2CO3) in ethanol. In addition, a diverse array of EDAM substrates (2b-2k) were tested in this reaction to afford the expected target compounds 5. This protocol is suitable for the combinatorial and parallel syntheses of natural-like products, including highly functionalized α-carbolines and pyrroles, especially 2-oxoindolin-3-yl pyrroles. This approach features several advantages, such as being a simple and practical operation (requiring only filtration and washing without column chromatography), furnishing excellent yields (72-98%), and producing diverse libraries of target compounds with potential biological activities.

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.

Cascade reaction of isatins with nitro-substituted enamines: highly selective synthesis of functionalized (Z)-3-(1-(arylamino)-2-oxoarylidene)indolin-2-ones.

A novel protocol for the construction of functionalized (Z)-3-(1(-arylamino)-2-oxoarylidene)indolin-2-ones (AOIDOs) from isatins 1 with nitro-substituted enamines 2via an unprecedented cascade reaction catalyzed by sulfamic acid is developed. The AOIDOs are prepared by simply refluxing a mixture of isatins with a wide variety of nitro-substituted enamines. Interestingly, the AOIDOs 3 were formed through the novel cascade reaction involving a unique cleavage of two C-N bonds of the nitro-substituted enamines. Overall, the novel reaction is accomplished by the formation of three new bonds and the cleavage of two C-N bonds in a single step. This protocol can be used in the synthesis of a wide variety of AOIDOs and is suitable for combinatorial and parallel syntheses of natural-like AOIDO products.

Multicomponent Cascade Reaction by Metal-Free Aerobic Oxidation for Synthesis of Highly Functionalized 2-Amino-4-coumarinyl-5-arylpyrroles.

A novel approach has been constructed for the synthesis of two types of 2-amino-4-coumarinyl-5-arylpyrroles (ACAPs, 5 and 6) through a cascade reaction and a metal-free catalyzed aerobic oxidation reaction of arylglyoxal monohydrates 1, 1,1-enediamines (EDAMs) 2 and 3, and 4-hydroxy-2H-chromen-2-ones 4 via multicomponent reactions to produce the target compounds with good to excellent yields. Specifically, hydroxyl-substituted 2-amino-4-coumarinyl-5-arylpyrroles, that is, 2-amino-4-coumarinyl-5-aryl-6-hydroxylpyrroles (ACAHPs) 6, were obtained by metal-free aerobic oxidation in 1,4-dioxane at simple reflux for approximately 10 h. As a result, ACAHPs 6 have been produced without metal catalysts or traditional oxidizing agents. This method represents a route to obtain the novel ACAPs in an environmentally friendly, concise, rapid, and practical manner with potential biological activity of the product.

Three-Component Cascade Reaction of 1,1-Enediamines, N,N-Dimethylformamide Dimethyl Acetal, and 1,3-Dicarbonyl Compounds: Selective Synthesis of Diverse 2-Aminopyridine Derivatives.

A novel approach has been developed for the synthesis of three kinds of highly functionalized 2-aminopyridine derivatives (APDs) through a three-component reaction of 1,1-enediamines (EDAMs) 1, N,N-dimethylformamide dimethyl acetal (DMF-DMA) 2, and 1,3-dicarbonyl compounds 3-5 via a base-promoted cascade reaction, producing the desired products in good to excellent yields. This method represents a route to obtain a novel class of APDs in a concise, rapid, and practical manner. This approach is particularly attractive because of the following features: low cost, mild temperature, atom economy, high yields, and potential biological activity of the product.

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 1,1-Enediamines with 2-Benzylidene-1H-indene-1,3(2H)-diones: Selective Synthesis of Indenodihydropyridine and Indenopyridine Compounds.

A concise and environmentally friendly route for the synthesis of diverse indenodihydropyridines (3) via a cascade reaction of 1,1-eneamines (1) with benzylidene-1H-indene-1,3(2H)-diones (BIDs) (2) in ethanol media was developed. The targeted compounds were efficiently obtained by only filtration without any further post-treatment. In the one-step cascade reaction, C-C and C-N bonds were constructed. In addition, when 1,4-dioxane was used as a solvent and the mixture of 1,1-eneamines (1) was refluxed with benzylidene-1H-indene-1,3(2H)-diones (BIDs) (2) for about 12 h, indenopyridine compounds (4) were produced. Two kinds of indenopyridine derivatives 3-4 resulted from alternative solvents and temperatures. The reaction had the following features: mild temperature, atom economy, high yields, and potential biological activity of the product.