Multicomponent Cascade Reaction Research Articles

Electrophotocatalytic Tellurosulfonylation of Alkynes for the Synthesis of β-(Telluro)vinyl Sulfones.

Difunctionalization of alkynes has gained a lot of interest in current organic chemistry. Herein, we developed an electrophotocatalytic multicomponent cascade reaction of alkynes and indoles with sulfinic acid sodium salts using elemental tellurium as the tellurium source. Using synergistic anodic oxidation and visible-light irradiation, various β-(telluro)vinyl sulfones have been prepared. This strategy features mild reaction conditions, excellent substrate scope, readily available starting materials, and great functional group tolerance.

Skeletal Formation of Carbocycles with CO2: Selective Synthesis of Indolo[3,2-b]carbazoles or Cyclophanes from Indoles, CO2, and Phenylsilane.

The catalytic reactions of indoles with CO2 and phenylsilane afforded indolo[3,2-b]carbazoles, where the fused benzene ring was constructed by forming two C-H bonds and four C-C bonds with two CO2 molecules via deoxygenative conversions. Nine-membered cyclophanes made up of three indoles and three CO2 molecules were also obtained, where the cyclophane framework was constructed by forming six C-H bonds and six C-C bonds. These multicomponent cascade reactions giving completely different carbocycles were switched simply by choosing the solvent, acetonitrile or ethyl acetate.

Access to Functionalized Cyclohex-2-enones from a Multicomponent Cascade Reaction of Readily Available Alkynes, Ketones, and Ethyl Acetoacetate.

The synthesis of cyclohex-2-enone derivatives is a topic of current interest in organic chemistry. A novel three-component cascade reaction of alkynes with ketones and ethyl acetoacetate has been uncovered. This process provides di- and trisubstituted cyclohex-2-enones in good yields with excellent functional group tolerance. A variety of terminal alkynes and a wide range of aryl, alkyl, and cyclic ketones are viable in this transformation. Successful scale-up preparation and synthetic transformations have demonstrated the potential of this simple operating protocol.

Electrochemical Multicomponent Cascade Radical Process Enabling Synthesis of Iodomethyl Spiropyrrolidinyl‐Oxindoles

Comprehensive SummaryA novel electrochemical multicomponent cascade reaction of indole‐tethered alkenes with CF3SO2Na and n‐Bu4NI has been developed, which enables the rapid assembly of spiropyrrolidinyl‐oxindoles in good yields. The experimental results and DFT calculations suggest that this reaction proceeds through the oxidation of CF3SO2Na, radical coupling with alkene, spirocyclization, oxidation of sulfinate, iodide substitution, and water coupling. This strategy features mild reaction conditions, easy‐to‐handle reactants, and good chemical yields. This finding not only enriches the research contents of indole‐tethered alkenes but also provides a green strategy for the construction of spiropyrrolidinyl‐oxindoles compared with the existing methodologies.

Synthesis of N-fused polycyclic indoles via a Pd-catalyzed multicomponent cascade reaction consisting of an amide-directed [3+1+1] annulation reaction of 3-diazo oxindole and isocyanides

A palladium-catalyzed and amide-assisted multicomponent reaction of 3-diazo oxindole, isocyanide, and water to generate biologically important oxazole-fused indole scaffolds has been reported.

Palladium-Catalyzed Multicomponent Assembly of (Z)-Alkenylborons via Carbopalladation/Boronation/Retro-Diels-Alder Cascade Reaction.

A palladium-catalyzed multicomponent cascade reaction of aryl iodides, oxanorbornadiene, and diborns to access (Z)-alkenylborons is reported. This transformation proceeds through the sequential carbopalladation/boronation/retro-Diels-Alder domino reaction. The oxanorbornadiene used in this reaction serves as an acetylene surrogate, which is generated via a retro-Diels-Alder reaction. Such a stereoselective and scalable approach has a wide range of functional group tolerance and good substrate universality.

Palladium-Catalyzed Multicomponent Cascade Reaction of 3-Hydroxypropionitrile: Synthesis of Substituted Dihydrochalcones.

Direct access to substituted dihydrochalcones from the easily available starting materials 3-hydroxypropionitrile derivatives and arylboronic acids is described. The procedure involves a multicomponent aryl addition/hydroxyl elimination/reduction Heck approach in the presence of a Pd catalyst with excellent functional group tolerance and a wide range of substrates. In addition, mixed 1,3-diarylation of 3-hydroxypropanenitrile using two arylboronic acids with different electronic properties was also achieved.

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 α-amino carbonyl compounds: a brief review

α-Amino carbonyl compounds are an important class of nitrogen-containing substances. This review highlights their synthesis using various strategies and considers mechanisms of the processes. The strategies are classified into subcategories based on the type of starting materials, chemical reactions and synthetic methods in use. In the literature survey, different types of reactions are discussed like oxidation, reduction, addition, coupling, C–H amination, oxidative cleavage and rearrangement, amidation, multicomponent cascade reaction, <i>etc</i>., for the synthesis of these compounds.<br> The bibliography includes 100 references

Modular synthesis of unsaturated aza-heterocycles via copper catalyzed multicomponent cascade reaction

The unsaturated aza-heterocycles such as tetrahydropyridines pose significant applications in both drug discovery and development. However, the methods to construct polyfunctionalized tetrahydropyridines are still limited. Herein, we report a modular synthesis of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction. The reaction features mild conditions and broad substrate scope. In addition, the reaction could scale up to gram scale with similar yield. A variety of 1,2,5,6-tetrahydropyridines with C3 and C5 substituents could be assembled from simple starting materials. More importantly, the products could serve as versatile intermediate to access various functionalized aza-heterocycles which further demonstrates its utility.

Water as an oxygen source in I2-mediated construction of highly functionalized maleimide-fused phenols

A novel protocol for the construction of multi-substituted 4-hydroxyisoindoline-1,3-diones through an I2-mediated multicomponent cascade reaction has been described.

Highly selective synthesis of functionalized morphan derivatives through a multi-component cascade reaction of 3-formylchromones, 2-naphthols, and enaminones

A novel protocol for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives via a multicomponent cascade reaction, involving 3-formylchromones, 2-naphthols, and enaminones in the ionic liquid [BMIM]PF6 as the solvent and promoted by 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), was developed, which involved the cleavage of one C–O bond and formation of four bonds (1 ​C–O, 1 ​C–N, and 2 ​C–C bonds). As a result, a series of morphan derivatives were produced through a cascade reaction, including a sequence of 1,2-addition, enol-keto tautomerization, Michael addition, dehydration, another Michael addition, imine-enamine tautomerization, and N-alkylation reactions, which were accompanied by a ring-opening reaction. This protocol was suitable for combinatorial and parallel syntheses of natural product-like morphan compounds in a one-pot reaction rather than through tedious multi-step reactions.

Biomimetic Total Synthesis and Investigation of the Non-Enzymatic Chemistry of Oxazinin A.

We report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi‐component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non‐enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non‐enzymatic formation of oxazinin A using 1H‐15N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure–activity relationships (SAR).

Intermolecular direct catalytic cross-Michael/Michael reactions and tandem Michael/Michael/aldol reactions to linear compounds

Catalytic cross-Michael/Michael reactions of nitroalkenes and ethyl acrylate with pronucleophiles including thiols, dimethyl methylmalonate, and 2-nitropropane to linear three-component products were developed by using a catalytic amount of DBU in DMSO. Tandem sulfa-Michael/Michael/aldol reactions of a thiol, a nitroalkene, ethyl acrylate, and an aldehyde proceeded to give a linear four-component product. The high nucleophilicity of in situ-formed nitronate anions and ester enolates in DMSO was important for the present multi-component cascade reactions using pronucleophiles that had protons with relatively high acidity.

Copper-catalyzed cascade reaction of indole and benzimidazole radicals to synthesize 3-haloindole-benzimidazole compounds

A one-pot multi-component cascade reaction strategy between benzimidazole, indole, and N-halosuccinimides was developed through the combination of the Cu(II) catalyst and (bis(trifluoroacetoxy)iodo)benzene, mediated by initiating the formation of benzimidazole nitrogen-centered radicals. This strategy realizes the formation of nitrogen radicals centered on the aromatic nitrogen atoms in the ring. On this basis, the radical-level combined synthesis of substituted 3-haloindole-benzimidazole compounds was achieved. Furthermore, this study provides a reference direction for subsequent work utilizing nitrogen radicals.

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%).

Transition-metal-free synthesis of pyrimidines from lignin β-O-4 segments via a one-pot multi-component reaction

Heteroatom-participated lignin depolymerization for heterocyclic aromatic compounds production is of great importance to expanding the product portfolio and meeting value-added biorefinery demand, but it is also particularly challenging. In this work, the synthesis of pyrimidines from lignin β-O-4 model compounds, the most abundant segment in lignin, mediated by NaOH through a one-pot multi-component cascade reaction is reported. Mechanism study suggests that the transformation starts by NaOH-induced deprotonation of Cα-H bond in β-O-4 model compounds, and involves highly coupled sequential cleavage of C-O bonds, alcohol dehydrogenation, aldol condensation, and dehydrogenative aromatization. This strategy features transition-metal free catalysis, a sustainable universal approach, no need of external oxidant/reductant, and an efficient one-pot process, thus providing an unprecedented opportunity for N-containing aromatic heterocyclic compounds synthesis from biorenewable feedstock. With this protocol, an important marine alkaloid meridianin derivative can be synthesized, emphasizing the application feasibility in pharmaceutical synthesis.

Unexpected Formation of Pyrazoline-Fused Metallofullerenes from the Multicomponent Cascade Reaction of Sc3N@Ih-C80 with Tetrazines, Water, and Oxygen.

The multicomponent cascade reaction of Sc3N@Ih-C80 with 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazines, water, and oxygen unexpectedly affords the pyrazoline-fused Sc3N@Ih-C80 derivatives. The obtained endohedral metallofullerene derivatives have been characterized by various spectral means, and their structures have been unambiguously established by single-crystal X-ray crystallography. A possible reaction mechanism via a complicated sequence of Diels-Alder reaction, retro Diels-Alder reaction, hydration, rearrangement, and dehydrogenation processes is proposed for the formation of pyrazoline-fused metallofullerenes.

Site‐Selective Pyridylic C−H Functionalization by Photocatalytic Radical Cascades

AbstractAn efficient pyridylic C(sp3)−H functionalization has been developed through photocatalytic radical‐mediated fluoroalkylation or cascade reactions. This method is enabled by the reversible formation of alkylidene dihydropyridine intermediates via the facile enolate formation of C4‐alkylN‐amidopyridinium salts in the absence of an external base, thereby establishing the conditions necessary for subsequent intermolecular radical trapping. Rapid structural diversification of the pyridylic site can be achieved through photocatalytic multicomponent cascade reactions involving alkene trifluoromethylation, SO2‐reincorporation, and sulfonyl radical addition. This operationally simple method features a broad substrate scope and high chemoselectivity and offers a unique approach for the rational modification of the heterobenzylic C−H bonds of pyridines and quinolines with uniform site‐selective control. Furthermore, experimental and theoretical studies were performed to elucidate the reaction mechanism.

Site-Selective Pyridylic C-H Functionalization by Photocatalytic Radical Cascades.

An efficient pyridylic C(sp3 )-H functionalization has been developed through photocatalytic radical-mediated fluoroalkylation or cascade reactions. This method is enabled by the reversible formation of alkylidene dihydropyridine intermediates via the facile enolate formation of C4-alkyl N-amidopyridinium salts in the absence of an external base, thereby establishing the conditions necessary for subsequent intermolecular radical trapping. Rapid structural diversification of the pyridylic site can be achieved through photocatalytic multicomponent cascade reactions involving alkene trifluoromethylation, SO2 -reincorporation, and sulfonyl radical addition. This operationally simple method features a broad substrate scope and high chemoselectivity and offers a unique approach for the rational modification of the heterobenzylic C-H bonds of pyridines and quinolines with uniform site-selective control. Furthermore, experimental and theoretical studies were performed to elucidate the reaction mechanism.