Three-component Tandem Reaction Research Articles

Synthesis of Unsymmetrical 1,6-Dicarbonyl Compounds through Photocatalytic One-Pot Tandem Three-Component Reaction.

Unsymmetrical 1,6-dicarbonyl compounds are useful building blocks in organic synthesis. However, the synthetic methods are limited. Herein we report a three-component one-pot reaction for the synthesis of unsymmetrical 1,6-diketones. This reaction utilizes sulfides as radical precursors and enol ethers as building blocks. It takes advantage of photocatalysis and Lewis acid catalysis. Its synthetic utility was demonstrated in the modification of biorelevant compounds.

In Situ Activation of Azaarenes and Terminal Alkynes to Construct Bridged Polycyclic Compounds Containing Isoquinolinones.

A copper-catalyzed [4+2] cyclization reaction of isoquinolines and alkynes is developed for the one-step construction of isoquinolinone derivatives with multisubstituted bridging rings. The unique feature of this three-component tandem cyclization reaction is the functionalization of the C1, N2, C3, and C4 positions of 3-haloisoquinolines via the construction of new C-N, C═O, and C-C bonds. This dearomatization strategy for the synthesis of structurally complex isoquinolinone-bridged cyclic compounds offers good chemoselectivity, broad functional group compatibility, greenness, and high step economy.

Copper-Catalyzed Three-Component Tandem Reaction of Alkynes, α-Diazo Esters, and TMSN3 to Access N-Substituted 1,2,3-Triazoles.

An efficient copper-catalyzed three-component tandem reaction of alkynes, α-diazo esters, and TMSN3 to construct triazoles has been developed. Through this strategy, a number of diverse N-substituted 1,2,3-triazoles were conveniently obtained in moderate to good yields from simple and readily available starting materials using K2CO3 as the base. The mechanism of the tandem Cu-catalyzed azide-alkyne cycloaddition (CuAAC) and Cu-carbenoid-participated C-N coupling reaction has been investigated.

Metal- and Solvent-Free Synthesis of Substituted Pyrimidines via an NH4I-Promoted Three-Component Tandem Reaction.

A facile and practical approach for the preparation of substituted pyrimidines from ketones, NH4OAc, and N,N-dimethylformamide dimethyl acetal has been described. This NH4I-promoted three-component tandem reaction affords a broad range of substituted pyrimidines in acceptable yields under metal- and solvent-free conditions. The present methodology features the advantages of simple and easily available starting materials, metal- and solvent-free conditions, a broad substrate scope with good functional group tolerance, and gram-scale synthesis.

Theoretical studies on the mechanisms and origins of substituent effects in CuBr-catalyzed three-component tandem reactions of terminal propargyl alcohols, aldehydes and amines

The CuBr-catalyzed A3-coupling-based tandem reactions of terminal propargyl alcohols, aldehydes and amines to synthesize five-membered dihydrofuran P1, disubstituted furan P2 and six-membered pyrone P3 have been developed. In this work, density functional theory (DFT) calculations have been performed to uncover the detailed reaction mechanisms and the substituent effects on the transformation of dihydrofuran P1 to pyrone P3. Computational results suggest that the catalytic cycle of dihydrofuran P1 is divided into three main processes: A3-coupling, isomerization and intramolecular cyclization. The generation of disubstituted furan P2 from dihydrofuran P1 proceeds via N-methylation and deprotonation steps. The transformation of five-membered dihydrofuran P1 to six-membered pyrone P3 is affected by the substituents R on substrate aldehyde 2. When R = OEt this transformation proceeds smoothly, undergoing the favorable OEt departure pathway. In contrast, the departure pathway is unworkable for Ph- and Me-substituted aldehydes due to the lack of hydrogen-bonding stabilization. They could only follow 1,2-R migration pathways. However, the high activation barriers in the migration pathways for the two aldehydes render the transformation infeasible. The results also reveal that silica gel acts as a significantly important hydrogen bond partner to stabilize the complexes in the transformation process. The theoretical research contributes to deeper insights into the mechanisms and the origins of substituent effects on the transformation between different heterocycles of the title reaction, which would promote the further development and design of the five- and six-membered oxygen-containing heterocycles.

A H4SiW12O40-catalyzed three-component tandem reaction for the synthesis of 3,3-disubstituted isoindolinones

A H4SiW12O40-catalyzed three-component tandem reaction of 2-acylbenzoic acids, primary amines and phosphine oxides to form 3,3-disubstituted isoindolinones was developed. By employing H4SiW12O40 as the catalyst and dimethyl carbonate (DMC) as the solvent, a diverse range of 2-acylbenzoic acid derivatives and primary amines worked well to give the C3-phosphinoyl-functionalized 3,3-disubstituted isoindolinones with the yield range of 61%-87%. Advantages of this transformation include green catalyst and solvent, available starting materials, broad substrate scope, high efficiency and operational simplicity with water as the sole by-product. The strategy achieved an efficient and green molecular fragment assembly to access isoindolinones, which would provide opportunities for the synthesis of potential biologically active molecules in a green manner.

Stereoselective Synthesis of Substituted (Z)-N-Allyl Sulfonamides via a Palladium-Catalyzed Three-Component Tandem Reaction.

This paper reports the efficient synthesis of substituted (Z)-N-allyl sulfonamides via a palladium-catalyzed three-component tandem reaction of N-buta-2,3-dienyl sulfonamides with iodides and sulfonyl hydrazide or sulfinic acid sodium salt as nucleophiles. Pd(PPh3)4 (2.5 mol %), K2CO3, and THF were used as the optimal catalyst, base, and solvent, respectively. The substituted (Z)-N-allyl sulfonamides were obtained in a 30-83% overall yield. Mechanistic investigations revealed that the formation of the single (Z)-isomer was controlled by the formation of a six-membered palladacycle intermediate.

Hydrogen Bond Assisted Three-Component Tandem Reactions to Access N-Alkyl-4-Quinolones

Hydrogen-bonding catalytic reactions have gained great interest. Herein, a hydrogen-bond-assisted three-component tandem reaction for the efficient synthesis of N-alkyl-4-quinolones is described. This novel strategy features the first proof of polyphosphate ester (PPE) as a dual hydrogen-bonding catalyst and the use of readily available starting materials for the preparation of N-alkyl-4-quinolones. The method provides a diversity of N-alkyl-4-quinolones in moderate to good yields. The compound 4h demonstrated good neuroprotective activity against N-methyl-ᴅ-aspartate (NMDA)-induced excitotoxicity in PC12 cells.

Nickel-Catalyzed Three-Component Tandem Radical Cyclization 1,5-Difunctionalization of 1,3-Enynes and Alkyl Bromide.

A nickel-catalyzed three-component tandem radical cyclization reaction of aryl bromides with 1,3-enynes and aryl boric acids to construct γ-lactam-substituted allene derivatives has been described. This protocol provides lactam alkyl radicals through the free radical cyclization process, which can be effectively used to participate in the subsequent multicomponent coupling reaction so that 1,3-enynes could directly convert into corresponding poly-substituted allene compounds. In addition, this efficient method enjoys a broad substrate scope and provides a series of 1,5-difunctionalized allenes in a one-pot reaction.

Diastereoselective construction of carbo-bridged polyheterocycles by a three-component tandem annulation reaction.

By a hydroamination-induced tandem annulation process, we herein report a new three-component reaction for room temperature construction of carbo-bridged polyheterocycles with exclusive diastereoselectivity, which features readily available feedstocks, catalyst-free conditions, good substrate and functionality compatibility, no need for transition metal catalysts, and high step and atom efficiency. The products are formed via initial formation of 1,2-dihydro-3H-pyrazol-3-one nucleophiles from but-2-ynedioates and hydrazine followed by 2,4-difunctionalization of N-heteroarenium salts. Given that the obtained products possess structurally important tetrahydroquinoline and pyranopyrazole motifs, the developed chemistry is anticipated to be further applied to the discovery of functional molecules including biomedical ones.

An Efficient One-Pot Green Protocol for the Synthesis of Dihydrochromeno[4,3-b]Pyrazolo[4,3-e]Pyridin-6(7H)-Ones Mediated by Diisopropyl Ethyl Ammonium Acetate at Room Temperature

Development of a green protocol to access pharmaceutically relevant functionalized coumarin-pyrazole molecular hybrids, dihydrochromeno[4,3-b]Pyrazolo[4,3-e]pyridin-6(7H)-ones, has been accomplished based on a three-component tandem reaction between aromatic aldehydes, 4-hydroxycoumarin and 3-aminopyrazoles in presence of Diisopropyl Ethyl Ammonium Acetate (DIPEAc) as catalyst and solvent at room temperature is reported. The remarkable features of this new procedure are high yields, short reaction times, simple experimental and work-up procedures, mild and environmentally friendly reaction conditions, and the economic availability of the catalyst.

Ultrasound-promoted convenient and ionic liquid [BMIM]BF4 assisted green synthesis of diversely functionalized pyrazolo quinoline core via one-pot multicomponent reaction, DFT study and pharmacological evaluation.

An ultrasound-assisted green protocol for one-pot synthesis of a new series of pharmaceutically relevant pyrazolo quinoline derivatives (4a-t) were synthesized, characterized, and evaluated using DFT and biological activities. Pyrazolo quinoline derivatives (4a-t) were synthesized via a three-component tandem reaction of 1,3-dicarbonyl compound (1a-b), substituted aromatic aldehyde (2a-o), and 5-amino indazole (3a) in the presence of 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM]BF4 ionic liquid in ethanol at ambient conditions. The main purpose of the present work is selective functionalization of pyrazolo quinoline (4a-t) core excluding another potential parallel reaction under environmentally benign reaction conditions. The present protocol shows features such as amphiphilic behavior of ionic liquid during reaction transformation, and reusability of the [BMIM]BF4 ionic liquid under mild reaction condition. All newly derived compounds were evaluated for their in vitro anti-inflammatory and antioxidant activity. Among them, compound 4c showed encouraging antioxidant activity compared with standard antioxidant ascorbic acid, and compounds 4n and 4r displayed very good anti-inflammatory activity compared with a standard drug. In this study, a theoretical computational density functional study was also executed to perform the geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The DFT study was carried out with the basis set DFT/B3LYP/6-31+G (d, p) level of theory. The quantum chemical descriptors (QCDS) and MESP diagrams were plotted to examine the biological reactivities of representative pyrazolo quinolines (4a-t).

Palladium(ii)-catalyzed three-component tandem reactions: synthesis of multiply substituted quinolines

The three-component tandem reaction of 2-aminobenzonitriles, arylboronic acids and ketones as available reagents allowing the synthesis of polysubstitution quinolines is reported.

B(C6F5)3-catalyzed three-component tandem reaction to construct novel polycyclic quinone derivatives: synthesis of a carbonate salt chromogenic chemosensor

A series novel polycyclic quinone derivatives were constructed providing a carbonate salt chromogenic chemosensor.

Palladium(II)-Catalyzed Three-Component Tandem Cyclization Reaction for the One-Pot Assembly of 4-Arylquinazolines

AbstractA one-pot method for joining three separate components leading to an assortment of 4-arylquinazolines (27 examples) in good to excellent yields is described. The method consists of a palladium(II)-catalyzed­ cascade reaction involving C(sp)–C(sp2) coupling followed by intramolecular C–N bond formation. The reaction was readily scaled up to gram quantity and successfully applied to the synthesis of a translocator­ protein (TSPO) ligand.

Pd-Catalyzed one-pot synthesis of vinylsilanesviaa three-component tandem reaction

A palladium-catalyzed three-component tandem reaction for stereoselective assembly of various tri- or tetrasubstituted vinylsilanes is established.

Visible-light promoted three-component tandem reaction to synthesize difluoromethylated oxazolidin-2-imine.

An effective synthetic method to achieve difluoromethylated oxazolidin-2-imine has been developed via visible-light promoted three-component tandem reaction of aryl allylamines, 2-BTSO2CF2H (BT = Benzothiazole) and isocyanates. This method features mild reaction conditions and good functional group tolerance, and the reaction mechanism was confirmed by experiments and interpreted by quantum chemical calculations.

Electrochemical diselenylation of indolizines via intermolecular C-Se formation with 2-methylpyridines, α-bromoketones and diselenides.

An efficient electrochemical system for the construction of diselenytlated indolizines from available pyridines, ketones and diselenides under undivided electrolytic conditions was developed. No external oxidants and transition-metal catalysts are needed for achieving this three-component tandem reaction realizing C-C, C-N and C-Se bond formations.

A Copper(I)-Mediated Tandem Three-Component Synthesis of 5-Allyl-1,2,3-triazoles

A copper(I)-mediated tandem three-component reaction using alkynes, azides, allyl iodides, CuI and NaNH2 is developed. The reactions proceed smoothly at room temperature to afford 5-allyl-1,2,3-triazoles, which can be further converted into 1,2,3-triazole-fused tricyclic scaffolds. This method features an efficient one-pot cascade route using commercial alkynes and affords the corresponding 5-allyl-1,2,3-triazoles with high yields and good selectivity under mild reaction conditions.

New library of pyrazole-imidazo[1,2-α]pyridine molecular conjugates: Synthesis, antibacterial activity and molecular docking studies.

A library of novel pyrazole-imidazo[1,2-α]pyridine scaffolds was designed and synthesized through a one-pot three-component tandem reaction. The structures of synthesized conjugates were confirmed by spectroscopic techniques (NMR, IR and HRMS). In vitro antibacterial evaluation of the twelve synthesized molecules (7a, 8a-k) against methicillin-resistant Staphylococcus aureus and normal strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa established 8b, 8d, 8e, 8h and 8i as potent antibacterial agents with superior minimum bactericidal concentration, compared with standard drug ciprofloxacin. Molecular docking studies of all active compounds into the binding site of glucosamine-6-phosphate synthase were further performed in order to have a comprehensive understanding of putative binding modes within the active sites of the receptor.