Three-component Coupling Research Articles

Fixing CO2 under Atmospheric Conditions and Dual Functional Heterogeneous Catalysis Employing Cu MOFs: Polymorphism, Single-Crystal-to-Single-Crystal (SCSC) Transformation and Magnetic Studies.

New copper compounds, [Cu(C14H8O6)(C10H8N2)(H2O)] (1), [Cu(C14H8O6)(C10H8N2)(H2O)]·(C3H7ON)2 (2), [Cu(C14H8O6)(C10H8N2)(H2O)2]·(C3H7ON) (3), [Cu(C14H8O6)(C10H8N4)] (4), and [Cu(C14H8O6)(C10H8N4)]·(H2O) (5), were prepared employing 2,5-bis(prop-2-yn-1-yloxy)terephthalic acid (2,5-BPTA) as the primary ligand and 4,4'-bipyridine (1-3) and 4,4'-azopyridine (4-5) as the secondary ligands. Single-crystal studies indicated that compounds 1-4 have two-dimensional layer structures and compound 5 has a three-dimensional structure. Compounds 1-3 were isolated from the same reaction mixture but by varying the time of reaction. The framework structures of compounds 1-3 are similar and may be considered as polymorphic structures. Compounds 4 and 5 can also be considered polymorphic with a change in dimensionality of the structure. Compounds 1-3 can be formed through a single-crystal-to-single-crystal transformation under a suitable solvent mixture. The Cu center was explored for the Lewis acid-catalyzed cycloaddition reaction of epoxide and CO2 under ambient conditions in a solventless condition and also for the synthesis of propargylamine derivatives by three-component coupling reactions (A3 coupling) in a DCM medium. The Lewis basic functionality of the MOF (-N═N- group) has been explored for the Henry reaction (aldol condensation) in a solventless condition. In all of the catalytic reactions, good yields and recyclability were observed. The magnetic studies indicated that compounds 1 and 4 have antiferromagnetic interactions and compound 5 has ferromagnetic interactions. The present studies illustrated the rich diversity that the copper-containing compounds exhibit in extended framework structures.

Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones.

The incorporation of fluorine atoms in organics conduces to improvement of their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. However, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched. Herein, we report asymmetric 1,4-oxyamination of gem-difluorodiene via chiral rhodium-catalyzed three-component coupling with readily available carboxylic acid and dioxazolone to forge a gem-difluorinated and enantioenriched 1,4-amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4-regio- and enantioselectivity with utility in the late-stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π-allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.

Synthesis of Novel Phosphorus-Substituted Stable Isoindoles by a Three-Component Coupling Reaction of ortho-Phthalaldehyde, 9,10-Dihydro-9-oxa-10-phosphaphenanthrene 10-Oxide, and Primary Amines

AbstractA three-component coupling reaction of ortho-phthalaldehyde, 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide, and various primary amines readily afforded novel phosphorus-substituted stable isoindoles in good to excellent yields. The importance of the reversible ring-opening of 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide by methanolysis in the three-component coupling reaction became apparent.

Asymmetric Carbohydroxylation of Alkenes Using Photoenzymatic Catalysis.

Alkene difunctionalizations enable the synthesis of structurally elaborated products from simple and ubiquitous starting materials in a single chemical step. Carbohydroxylations of olefins represent a family of reactivity that furnish structurally complex alcohols. While examples of this type of three-component coupling have been reported, catalytic asymmetric examples remain elusive. Here, we report an enzyme-catalyzed asymmetric carbohydroxylation of alkenes catalyzed by flavin-dependent "ene"-reductases to produce enantioenriched tertiary alcohols. Seven rounds of protein engineering reshape the enzyme's active site to increase activity and enantioselectivity. Mechanistic studies suggest that C-O bond formation occurs via a 5-endo-trig cyclization with the pendant ketone to afford an α-oxy radical which is oxidized and hydrolyzed to form the product. This work demonstrates photoenzymatic reactions involving "ene"-reductases can terminate radicals via mechanisms other than hydrogen atom transfer, expanding their utility in chemical synthesis.

Three-component coupling of boronic acids, amines, and carbon disulfide by a heterogeneous catalyst of copper (II) embedded in a highly porous and magnetic Schiff base network of melamine

Three-component coupling of boronic acids, amines, and carbon disulfide by a heterogeneous catalyst of copper (II) embedded in a highly porous and magnetic Schiff base network of melamine

Multicomponent Oxidative Nitrile Thiazolidination Reaction for Selective Modification of N-terminal Dimethylation Posttranslational Modification.

Protein α-N-terminal dimethylation (Nme2) is an underexplored posttranslational modification (PTM) despite the increasing implications of α-N-terminal dimethylation in vital physiological and pathological processes across diverse species; thus, it is imperative to identify the sites of α-N-terminal dimethylation in the proteome. So far, only ∼300 α-N-terminal methylation sites have been discovered including mono-, di-, and tri-methylation, due to the lack of a pan-selective method for detecting α-N-terminal dimethylation. Herein, we introduce the three-component coupling reaction, oxidative nitrile thiazolidination (OxNiTha) for chemoselective modification of α-Nme2 to thiazolidine ring in the presence of selectfluor, sodium cyanide, and 1,2 aminothiols. One of the major challenges in developing a pan-specific method for the selective modification of α-Nme2 PTM is the competing reaction with dimethyl lysine (Kme2) PTM of a similar structure. We tackle this challenge by trapping nitrile-modified Nme2 with aminothiols, leading to the conversion of Nme2 to a five-membered thiazolidine ring. Surprisingly, the 1,2 aminothiol reaction with nitrile-modified Kme2 led to de-nitrilation along with the de-methylation to generate monomethyl lysine (Kme1). We demonstrated the application of OxNiTha reaction in pan-selective and robust modification of α-Nme2 in peptides and proteins to thiazolidine functionalized with varying fluorescent and affinity tags under physiological conditions. Further study with cell lysate enabled the enrichment of Nme2 PTM containing proteins.

Circular Design and Functionalized Upcycling of Waste Commodity Polystyrene via C-H Activation Using Microwave-Assisted Multicomponent Synthesis.

The inefficient reuse and recycling of plastics-and the current surge of medical and take-out food packaging use during the pandemic-have exacerbated the environmental burden. This impels the development of alternative recycling/upcycling methods to pivot toward circularity. We report the use of the Mannich three-component coupling reaction for the modification of polystyrene (PS) recovered with a 99.1% yield from waste food containers to form functionalized nitrogen and oxygen-rich PS derivatives. A series of functionalized PS with increasing moles of formaldehyde (F) and morpholine (M) (0.5 × 10-2, 1.0 × 10-2, and 2.0 × 10-2 mol) was achieved using a sol-gel-derived Fe-TiO2 catalyst in a solvent-free, microwave-assisted synthesis. Modified polymers were characterized with viscometry, 1H NMR, 13CNMR (DEPT) FTIR, XPS, UV, and TGA. Functionalization scaled with an increasing ratio, validating the 3CR approach. Further functionalization was constrained by a competing oxidative degradation; however, the varying hydrogen bond density due to nitrogen and oxygen-rich species at higher ratios was shown to compensate for molecular weight loss. The integration of the N-cyclic quaternary ammonium cations exhibited the potential of functionalized polymers for ion-exchange membrane applications.

C(sp3)–C(sp2) Reductive Elimination versus β-Hydride Elimination from Cobalt(III) Intermediates in Catalytic C–H Functionalization

The cationic bis(phosphine) cobalt(I) arene complex, [(depe)Co(η6-C7H8)][BAr4F] (depe = 1,2-bis(diethylphosphino)ethane; BAr4F = B[(3,5-(CF3)2)C6H3]4), was investigated as a precatalyst for three-component coupling of arenes, alkenes, and alkynes. Although a sterically attenuated catalyst was targeted with the goal of accelerating C–H functionalization, hydrovinylation derived from the alkene and alkyne was favored over three-component coupling. Remarkably, no catalytic hydrovinylation was observed in the absence of arene, demonstrating the role of C–H activation in the hydrovinylation process and ruling out a mechanism that involves β-H elimination from a cobalt(III) metallacycle. Deuterium labeling supported β-H elimination from a putative cobalt(III)–alkyl,aryl intermediate that forms after C–H activation by a cobalt(III) metallacycle. By varying the arene and alkene coupling partners, factors affecting the selectivity of C(sp3)–C(sp2) reductive elimination versus β-H elimination from the cobalt(III)–alkyl,aryl intermediate were determined.

Copper-Catalyzed Regio- and Stereoselective Three-Component Coupling of Allenyl Ethers with gem-Dichlorocyclobutenones and B2pin2.

The three-component coupling method for regio- and stereoselective difunctionalization of allenes with allenyl ethers, bis(pinacolato)diboron, and gem-dichlorocyclobutenones as electrophiles was reported, yielding a variety of highly functionalized cyclobutenone products tethering with an alkenylborate fragment. The polysubstituted cyclobutenone products also underwent diverse transformations.

Three-Component Coupling Reactions Involving Arynes, Phosphites, and Aldehydes toward 3-Mono-Substituted Benzoxaphosphole 1-Oxides.

A mild, efficient, and transition-metal-free three-component coupling reaction involving arynes, phosphites, and aldehydes was established to afford 3-mono-substituted benzoxaphosphole 1-oxides. A range of 3-mono-substituted benzoxaphosphole 1-oxides was obtained from both aryl- and aliphatic-substituted aldehydes in moderate to good yields. Moreover, the synthetic utility of the reaction was demonstrated by a Gram-scale reaction and the transformation of the products into various P-containing bicycles.

A Green and Efficient Approach for Preparation of Diaryl Sulfones: Fe3O4@DABA-PA-CuBr2 Nanocomposite Catalyzed One-Pot Three-Component Aryl Iodides, Aryl Boronic Acids, and DABSO (as SO2 Source)

In this research work, Fe3O4@DABA-PA-CuBr2 nanocomposite was fabricated by a simple and inexpensive method by immobilizing copper(II) bromide on the surface of magnetic nanoparticles modified with 3,4-diaminobenzoic acid and picolinic acid. Deep eutectic solvents or DESs are green and environmentally friendly solvents that are used as catalyst or solvent in many reactions. The utilization of Fe3O4@DABA-PA-CuBr2 nanocatalyst in ChCl–Urea at 100 °C presented an attractive, environmentally benign and highly efficient catalytic system for the preparation of a broad range of diaryl sulfones through one-pot three-component coupling of aryl iodides, aryl boronic acids, and DABSO (as SO2 source). It should be noted that the Fe3O4@DABA-PA-CuBr2 catalyst was used several times without significant reduction of the catalytic activity. VSM, TEM, and ICP-OES analysis of the reused Fe3O4@DABA-PA-CuBr2 catalyst after eight cycles revealed that that the structure, magnetic property, shape, and size of the particles did not change significantly.

One-Pot Synthesis of Diverse 1,4-[60]Fullerephenols via Three-Component Umpolung Cascade Coupling of Phenols, C60 , and Nucleophiles.

A three-component umpolung cascade coupling reaction of phenols, C60 , and different nucleophiles which includes H2 O, alcohols, triphenylamines and carbazoles was developed. Furthermore, one-pot 1,4-bisphenol coupling on C60 has been realized by this method. This practical protocol features high chemo- and regioselectivity, wide substrate range, easy operation and low cost, thus providing a robust method for the one-pot synthesis of various unsymmetrical 1,4-[60]fullerephenols.

One-pot synthesis of heteroaryl diketoalkynyl C-glycoside and dialkynyl di-C-glycoside analogues by three-component successive coupling reaction

The synthesis of heteroaryl diketoalkynyl C-glycoside and dialkynyl di-C-glycoside analogues has been accomplished by successive coupling of heteroaromatics, oxalyl chloride and terminal sugar alkynes in one pot. The three-component coupling reaction catalyzed by CuI gives heteroaryl diketoalkynyl C-glycosides. The same three-component coupling in the presence of n-BuLi produces dialkynyl di-C-glycosides, and the 1:1 of molar ratio of heteroaromatics to terminal sugar alkynes affords the corresponding esters of dialkynyl di-C-glycosides. The desired products have been obtained in good to excellent yields. This sequential one-pot method is mild and efficient, suitable for different heteroaromatics and terminal sugar alkynes. The sugar alkynes include furanosides, pyranosides, and acyclic sugars. Twenty-seven examples have been given. The mechanism for the formation of the desired products has been elucidated.

Three-Component Approach to Densely Functionalized Trifluoromethyl Allenols by Asymmetric Organocatalysis.

We have developed a new three-component catalytic coupling reaction of alkynyl boronates, diazomethanes, and aliphatic/aromatic ketones in the presence of BINOL derivatives. The reaction proceeds with a remarkably high enantio- and diastereoselectivity (up to three contiguous stereocenters) affording tertiary CF3-allenols in a single operational step. The reaction proceeds under mild, neutral, metal-free conditions, which leads to a high level of functional group tolerance.

Regio and Stereoselective One-Pot Synthesis of 2-Deoxy-3-thio Pyranoses and Their O-Glycosides from Glycals.

A reaction of glycals with two different types of nucleophiles in the presence of SnCl4 enabled one-pot rapid access to 2-deoxy-3-thio pyranoses and their O-glycosides. The process involves thioaryl substitution at C-3 with stereoretention and α-selective O-glycosylation at C-1 from d-glycals, thus combining two reactions with three interventions. The present methodology features an attractive three-component coupling (1:1.2:1.5 ratio) with operational simplicity at 0 °C in 10-20 min. This stereoselective one-pot 1,3-difunctionalization approach of glycals is compatible with wide range of primary and secondary alcohols affording products in good to excellent yields. This methodology was successfully extended toward disaccharide synthesis. Several control experiments suggested a plausible reaction mechanism and rationale behind regio and stereoselectivity. The reaction strategy possesses an intrinsic ability for the synthesis of various natural products and drug molecules.

Redox-Neutral Three-Component Coupling of Phenacyl Azides, Aldehydes, and 1,3-Dicarbonyls to Access β-Enaminodiones.

Heating an equimolar mixture of phenacyl azides, aldehydes, and cyclic 1,3-dicarbonyls to 100 °C without any solvent, catalyst, or additive led to efficient three-component redox-neutral coupling to yield β-enaminodiones in high yields (75-86%). The scope of the synthetic method that gives dinitrogen and water as the only byproducts was successfully demonstrated by synthesizing 34 structurally diverse β-enaminodiones by taking differentially substituted phenacyl azides, aldehydes and 4-hydroxycoumarins, and 4-hydroxy-1-methylquinolin-2(1H)-one and dimedone.

Regioselective C-H Active Carbonylation via 1,4-Palladium Migration.

We report a highly regioselective three-component coupling reaction of styrene, CO gas, and an amine compound to synthesize multisubstituted α,β-unsaturated amides, which involves a palladium-catalyzed sequential 1,4-palladium migration, C(sp2)-H activation, carbonylation, and amination. Salient features of this strategy include the use of 1 atm of CO, excellent stereochemistry, and good functional group tolerance. Further, a series of control experiments and density functional theory calculations were performed to afford some insights for the transfer mechanism.

A3 polycondensation: A multicomponent step-growth polymerization reaction for the synthesis of polymeric propargylamines

Multicomponent reactions lead to the straightforward synthesis of organic compounds in a one-pot manner. The three-component coupling of aldehydes or ketones with amines and alkynes, commonly known as A3 or KA2 coupling, respectively, is a convenient, highly efficient strategy for the synthesis of propargylamines, a family of compounds with multifaceted chemical behavior. Transferring this multicomponent strategy into the polymer synthesis field can lead to polymers bearing a variety of properties and possible applications. Herein, we report the efficient, straightforward, air tolerant, and sustainable synthesis of various new polymeric propargylamines, in very high to excellent yields. A highly-reactive, earth-abundant, inexpensive, well-defined copper catalyst is employed. An extensive thermal degradation study of the new polymers is also carried out.

Insights into the Three-Component Coupling Reactions of Aldehydes, Alkynes, and Amines Catalyzed by N-heterocyclic Carbene Silver: A DFT Study

Density functional theory (DFT) was used to investigate the three-component coupling reactions of aldehydes, alkynes, and amines (A3 coupling) using N-heterocyclic carbene silver as the catalyst. This study reveals that the addition reaction between the catalyst N-heterocyclic carbene silver and phenylacetylene (PAE) forms Ag_PAE. Subsequently, one hydrogen atom of the Ag_PAE migrates to the nitrogen atom of the Amine. Thereafter, the amine aldehyde condensation reaction generates a molecule of water and an imine ion with (Path one) or without (Path two) another amine catalyst. Path one has a lower reaction barrier than Path two. Subsequently, the imine ion reacts with silver phenylacetylide to generate the A3 coupling reaction product propargylamine (PPA). Furthermore, the triple bond and −N3 group in PPA undergo a cycloaddition reaction and generate the final product (PR). The entire reaction is strongly exothermic, and, therefore, the reaction is easy to conduct. Moreover, conceptual density functional theory calculations confirm the reaction mechanism. Investigating the mechanism of these reactions will be helpful for understanding and developing new synthesis strategies for similar functional compounds.

Manganese-Catalyzed Chemoselective Coupling of Secondary Alcohols, Primary Alcohols and Methanol.

Herein, we report a manganese-catalyzed three-component coupling of secondary alcohols, primary alcohols and methanol for the synthesis of β,β-methylated/alkylated secondary alcohols. Using our method, a series of 1-arylethanol, benzyl alcohol derivatives, and methanol undergo sequential coupling efficiently to construct assembled alcohols with high chemoselectivity in moderate to good yields. Mechanistic studies suggest that the reaction proceeds via methylation of a benzylated secondary alcohol intermediate to generate the final product.