A3 Coupling Reaction Research Articles

N-Heterocyclic Silylene-Cu(I) Complexes as Efficient Catalysts for Three-Component Coupling Reactions.

We have explored NHSi-supported copper(I) complexes as active and highly efficient catalysts for A3 (aldehyde-alkyne-amine) and KA2 (ketone-alkyne-amine) three-component coupling reactions to synthesize propargyl amines in excellent yields with high TOF under solvent-and additive-free conditions.

High-throughput synthesis and optimization of ionizable lipids through A3 coupling for efficient mRNA delivery

BackgroundThe efficacy of mRNA-based vaccines and therapies relies on lipid nanoparticles (LNPs) as carriers to deliver mRNA into cells. The chemical structure of ionizable lipids (ILs) within LNPs is crucial in determining their delivery efficiency.ResultsIn this study, we synthesized 623 alkyne-bearing ionizable lipids using the A3 coupling reaction and assessed their effectiveness in mRNA delivery. ILs with specific structural features—18-carbon alkyl chains, a cis-double bond, and ethanolamine head groups—demonstrated superior mRNA delivery capabilities. Variations in saturation, double bond placement, and chain length correlated with decreased efficacy. Alkynes positioned adjacent to nitrogen atoms in ILs reduced the acid dissociation constant (pKa) of LNPs, thereby hindering mRNA delivery efficiency. Conversion of alkynes to alkanes significantly enhanced mRNA delivery of ILs both in vitro and in vivo. Moreover, combining optimized ILs with cKK-E12 yields synergistic LNPs that showed markedly augmented mRNA expression levels in vivo.ConclusionsOverall, our study provides insights into the structure–function relationships of ILs, providing a foundation for the rational design of ILs to enhance the efficacy of LNPs in mRNA delivery.Graphical

Designing Sustainable Copper‐Based Hybrid Framework Catalysts for One‐Pot Multicomponent Organic Reactions

AbstractThe recent breakthroughs in heterogeneous catalysis emphasize the need for novel materials capable of driving organic transformations. The present study explores two copper phosphonate hybrid framework materials, 2D Cu3[(Hhedp)2(C4H4N2)].2H2O (Cu(II)Pyz‐P) and 3D Cu3[(H3hedp)2(C4H4N2)4(SO4)].2H2O (Cu(I/II)Pyz‐P), as single crystals isolated via hydrothermal synthetic strategy using H4hedp (1‐hydroxyethane 1,1‐diphosphonic acid) and N‐donor secondary ligand (Pyrazine; C4H4N2). Cu(II)Pyz‐P contains exclusively +2 oxidation state of copper, while Cu(I/II)Pyz‐P is characterized by a mixed oxidation state, where copper +2 phosphonate is embedded within the network formed by copper +1 state. Moreover, magnetic study elucidates the distinct oxidation states of both compounds by showing deviations from each other. The aforementioned compounds are exceedingly effective for catalyzing multicomponent reactions, that is, A3 coupling reaction and click reaction. Cu(I/II)Pyz‐P ensures the regioselective synthesis of triazole with high purity, while A3 coupling reaction is facilitated by both the compounds. Solvent‐ and additive‐free efficient multicomponent reactions are explored for the first time in the copper phosphonate hybrid framework structures. The present study reveals the promise of copper‐based hybrid phosphonate frameworks as durable and efficient catalysts for organic synthesis, providing cost‐effective and sustainable ways for advanced catalytic transformations.

Synthesis of novel propargylated derivatives of noscapine using A3-coupling reaction and their anticancer properties

Synthesis of novel propargylated derivatives of noscapine using A3-coupling reaction and their anticancer properties

Glucoconjugated Dinuclear Copper(II) Complex: An Efficient Catalyst for Stereoselective Synthesis of Trisubstituted Propargylamines via Solvent-free A3 Coupling Reaction.

Development of catalytic systems using nontoxic natural precursors is the need of the era, and along this line, we have synthesized a new D-glucose derived ligand (4,6-O-ethylidene-N-(2-hydroxy-4-(octyloxy)benzylidene)-β-D-glucopyranosylamine) and its dinuclear copper(II) complex. The molecular structure of the complex has been established by single-crystal X-ray diffraction studies and detailed noncovalent intermolecular interactions present in it have been explored by Hirshfeld surface analysis. Further, the complex has been used as a catalyst in the enantioselective (87-99 % ee) synthesis of propargylamines in good to excellent yield (82-95 %) via aldehyde-amines-alkynes (A3) coupling reaction under solvent-free condition. The formation of aminal intermediate during the reaction has been confirmed by 1H-NMR and single-crystal X-ray diffraction studies. The catalytic system is reusable without any appreciable loss in the enantioselectivity or product yield.

Green Chemical Synthesis of Cube‐Shaped CuFe2O4 Nanoparticles for Use as Magnetically Retrievable Catalysts in A3 Coupling Reactions

ABSTRACTA3 coupling reaction is a multicomponent reaction (MCR) involving aryl aldehydes, phenyl acetylenes and amines to synthesize a variety of biologically active propargylamine derivatives. Herein, we report the preparation of cube‐shaped CuFe2O4 nanoparticles (NPs) via the hydrothermal method in the presence of Lantana camara flower (LCF) extract to use them as catalysts to synthesize propargylamine derivatives. X‐ray diffraction study confirms the formation of CuFe2O4 NPs with cubic spinel structures. In the presence of LCF extract, cube‐shaped CuFe2O4 NPs are formed predominantly irrespective of the type of alkali used as the hydrolyzing agent. However, a mixture of nearly spherical and cube‐shaped particles has been formed in the absence of additives. The synthesized CuFe2O4 NPs exhibit superparamagnetic behaviour and are magnetically ordered. The synthesized cube‐shaped CuFe2O4 NPs exhibit excellent catalytic activity in the A3 coupling reaction between benzaldehyde, piperidine and phenylacetylene to give propargylamine with a yield of 90% under the optimum conditions. The catalyst is highly stable and magnetically retrievable facilitating reusability for up to five cycles without considerable loss of catalytic activity. The protocol is suitable for the synthesis of a diverse range of propargylamine derivatives with moderate to excellent yield.

Synthesis of Au/Ce2S3@CeO2/CuS nanocomposites for promoted catalytic performance in propargylamine conversion

A newly developed nanocomposite catalyst, Au/Ce2S3@CeO2/CuS, has been engineered for effective propargylamine synthesis through the A3 coupling reaction. The catalyst’s synthesis involved the targeted addition of 15 wt% CeO2 to the CuS sulfur precursor, leading to the formation of a Ce2S3 layer due to its lower solubility product constant (Ksp). This layer, along with 0.5 wt% Au nanoparticles, significantly increased the Ce3+ concentration (16.9 % to 33 %∼52 %), which can accelerate the Cu+/Cu2+ valence state changes, thereby promoting the activation of the alkynyl hydrogen to enhance propargylamine formation. After 2 h reaction, the Au/Ce2S3@CeO2/CuS catalyst achieved over 99 % conversion, nearly 55 % more than pure CuS (45.5 %). The Au/Ce2S3@CeO2/CuS nanocomposite also showed excellent recyclability (80 % retention after 5 cycles) and a high conversion rate of 222.5 mmol·g−1·h−1.

Directly accessing the alkyne-aldehyde-amine (A3) coupling catalytic cycle using molecular gold(I) acetylide complexes for synthesizing propargylamines and amino indolizines

The gold(I) acetylide complexes of Acyclic Aminooxy Carbene (AAOC) ligands, [{(4-R1-2,6-t-Bu2-C6H2O)(NCy2)}methylidene]Au[CC(p-C6H4R2)] [where R1 = H; R2 = H (1), and R1 = t-Bu; R2 = H (4)] efficiently catalyzed the three-component Alkyne-Aldehyde-Amine (A3) coupling yielding propargylamine and amino indolizine compounds, thereby implicating its direct role in the catalytic cycle. The DFT studies performed on a simplified gold(I) precatalyst, [{(2,4,6-Me3-C6H2O)(NCy2)}methylidene]Au[CCPh] (4’), at B3LYP-D3/def2-TZVP of theory implicated the role of non-covalent Au•••H–C interactions in the A3 coupling reactions producing propargylamine and subsequently amino indolizine via intramolecular cyclization of propargylamine followed by an intramolecular 1,2-hydrogen transfer-step for the 2-formylpyridine substrate. The non-covalent Au•••H–C(alkyl) and Au•••H–C(aryl) interactions participate in tandem to influence the overall reaction kinetic barrier, and thereby illustrating the importance of such interactions in gold catalysis. The gold(I) acetylide complexes, [{(4-R1-2,6-t-Bu2-C6H2O)(NCy2)}methylidene]Au[CC(p-C6H4R2)] [where R1 = H; R2 = H (1), Me (2), OPh (3): R1 = t-Bu; R2 = H (4), Me (5), OPh (6)] were conveniently synthesized from the corresponding chloro analogues [{(4-R1-2,6-t-Bu2-C6H2O)(NCy2)}methylidene]AuCl (where R1 = H, t-Bu) by the treatment with terminal alkyne HCC(p-C6H4R2) (where R2 = H, Me, OPh) in the presence of K2CO3 as a base in ca. 88−95 % yield.

Rapid Access to Divergent Fused Polycycles Via One-Pot A3 Coupling and Intramolecular Diels-Alder Reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Gold catalysis in quinoline synthesis.

Quinolines are biologically and pharmaceutically important N-heterocyclic aromatic compounds, which have broad applications in medicinal chemistry. Thus, their efficient synthesis has attracted extensive attention, and a broad range of synthetic strategies have been established. Of note, gold-catalyzed methodologies for the synthesis of quinolines have greatly advanced this field. Various gold-catalyzed intermolecular annulation reactions, such as annulations of aniline derivatives with carbonyl compounds or alkynes, annulations of anthranils with alkynes, and annulations based on A3-coupling reactions, as well as intramolecular cyclization reactions of azide-tethered alkynes, 1,2-diphenylethynes, and 2-ethynyl N-aryl indoles, have been developed. This review provides an overview of this exciting research area. Typical achievements in reaction methodologies and plausible reaction mechanisms are summarized.

Propargyl amines by aldehyde-amine-acetylene coupling mediated by Ag(I) and Cu(I) complexes of super bulky N-heterocyclic carbenes: Unveiling the role of the super bulky ligands in the coupling reaction

The copper (1–2)a and the silver (1–2)b complexes of the super bulky N-heterocyclic carbene (NHC) variants namely, [1,3-{2,4,6-(Ph2CH)3C6H2}2-imidazol-2-ylidene]MX [where, M = Cu; X = Cl (1a), Br (2a): M = Ag; X = Cl (1b), Br (2b)] effectively facilitated the A3 coupling reaction of diverse amine, aldehyde, and acetylene substrates yielding a wide array of propargylamines in moderate to good (ca. 24−89 %) yields. A metal bound acetylide species, [1,3-{2,4,6-(Ph2CH)3C6H2}2-imidazol-2-ylidene]M(CCPh) [where, M = Cu (A), Ag (B)] has been identified as a key catalytic species by mass spectrometric studies. The Density functional theory (DFT) studies further revealed the rate-limiting step as the formation of the C-C coupling transition state (TS2) from the silver-acetylide species (Int2). The super bulky ligand framework plays a pivotal role in this step by anchoring the protonated Schiff's base imine in the vicinity of the alkyne through several non-covalent-interactions, including a strong C–H•••O interaction, thereby reducing the corresponding kinetic barrier leading to an efficient catalytic transformation as reflected in the high propargylamine yields. Furthermore, the catalytic utility of the coupling reaction was further extended by synthesising pargyline, which is a monoamine oxidase B (MAO-B) inhibitor drug molecule, in a one-pot manner and that to in a gram-scale synthesis.

Differences in mechanisms between divalent and univalent copper complexes-catalyzed hydroacylation of terminal alkyne with aldehyde and amine

DFT calculations are carried out to investigate the hydroacylation mechanism based on copper-catalyzed A3-coupling tandem reaction of terminal alkynes, aldehydes and amines. The study reveals significant mechanistic differences between copper(I) and copper(II) catalysts. In the Cu(II)-catalyzed system, incorporation of a ligand is deemed necessary for facilitating reactivity, whereas no ancillary ligand is required in Cu(I) system. The ligand, through coordination with the Cu(II) center, stabilizes the key transition states and intermediates, resulting in a substantial reduction in the activation barrier. The ligand exhibits varying effect, with the order of activity being piperidine > pyridine > DMSO, correlating positively with the interaction energy between ligand and Cu complex. Additionally, the study sheds light on the pivotal roles played by the catalyst, ligand, base, and solvent DMSO in the reaction.

Copper-Catalyzed Multicomponent Coupling Reaction of Primary Aromatic Amines, Rongalite, and Alkynes: Access to N-Aryl Propargylamines.

In this work, a practical copper-catalyzed multicomponent coupling reaction of primary aromatic amines, rongalite, and alkynes for the direct synthesis of N-aryl propargylamines has been developed. This method could overcome the substrate limitation in A3 coupling reactions of primary aromatic amines, formaldehyde, and alkynes. Mechanistic studies revealed that rongalite acts as not only the active C1 unit but also the accelerator to activate the in situ-generated N-arylmethanimines for the coupling reaction with alkynes. This coupling reaction is highly efficient and features a broad substrate scope, as well as utility with scale-up synthesis and converting the corresponding product N-aryl propargylamines into useful heterocyclic skeletons.

Design of a Copper(II) Complex with Tetradentate Bis‐Benzotriazole‐Appended Bipyridine Ligand and its Catalytic Application in A3 Coupling Reaction

AbstractIn this report, a Cu(II) complex Cu‐L4 containing a new tetradentate benzotriazole‐appended bipyridine ligand was synthesized and characterized fully via spectroscopic and crystallographic techniques. The crystal structure of the complex revealed that the ligand is bound to copper in a tetradentate fashion in a plane and the axial positions are occupied by an anion and a solvent molecule, resulting in a distorted octahedral geometry of the complex in solid‐state. This air‐stable complex was utilized as homogeneous precatalyst for the synthesis of several propargylamine derivatives by 3‐component A3 coupling reactions of aldehydes, amines, and alkynes under aerial atmosphere.

A highly efficient N-rich Cu-MOF heterogeneous catalyst based on N,N-bis(1H-tetrazole- 5-yl)amine for the A3 coupling reaction

The preparation of propargylamines using metal-organic frameworks (MOFs) with high yields in short reaction times is a new method in organic chemistry. A N-rich Cu-MOF catalyst, [Cu(BTA)2]n, with N,N-bis(1(2)H-tetrazol-5-yl)amine (BTA) ligand has been prepared and characterized using FT-IR, XRD, SEM, EDX, and ICP-AES techniques to investigate its performance as a recyclable catalyst in aldehyde-alkyne-amine (A3) coupling reaction for the synthesis of propargylamine derivatives. This catalytic system offers various advantages such as simplicity, high efficiency, short reaction time, and environmental friendliness.

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

Catalytic Insights of Copper(I) Complexes with phosphole Ligands in three-component reactions to produce propargylamines and 1,4-substituted 1,2,3-triazoles.

The catalytic activity of two complexes, 2a ([CuCl{k1(P)-1a}{k2(P,N)-1a}]; 1a = 2,5-bis(2-pyridyl)-1-phenylphosphole) and 2b ([CuCl{k1(P)-1b}2]; 1b = 2,5-bis(2-thienyl)-1-phenylphosphole), was investigated in three-component reactions for the synthesis of propargylamines and 1,4-substituted 1,2,3-triazoles. This article introduces the first-time synthesis and characterization of complex 2a, while complex 2b has been previously reported by us. An X-ray crystallographic analysis revealed that the copper(I) complex 2a exhibits a pseudo-tetrahedral geometry with two phosphole ligands demonstrating k1(P)- and k2(P,N)-coordination, in contrast to complex 2b, which adopts a trigonal planar geometry. In a solution environment, 1a exhibits hemilability, leading to a dynamic equilibrium between the tetra-coordinated complex (2a) and its tri-coordinated counterpart (2a’). This behavior is substantiated by theoretical calculations, which confirm a preference for the tetra-coordinated geometry. Regarding catalytic activity, 2a and 2b exhibited effective catalytic activity in A3-coupling reactions and the direct synthesis of 1,4-disubstituted 1,2,3-triazoles. However, 2b demonstrated superior catalytic performance in both reactions compared to 2a. Theoretical calculations suggest that the stronger N–Cu σ-bond in 2a hinders the interaction of the alkyne with the copper center, whereas the trigonal planar geometry of 2b facilitates better copper-alkyne π-interactions.

Immobilized nickel nanoparticles on modified magnetic titanium dioxide: A proficient and eco-friendly nanocatalyst for the green A3-coupling synthesis of propargylamines

In this research, a novel and highly efficient magnetic catalyst was synthesized by surface modification of Fe3O4/TiO2 with epibromohydrine and N-(2-aminoethyl)piperazine linkers and then by immobilization of Ni nanoparticles onto the surface of magnetic titanium dioxide. The synthesized Fe3O4/TiO2-EP-NAEP/Ni nanocomposite was identified by FT-IR, PXRD, TEM, FE-SEM, ICP, EDX, TGA, and VSM techniques, and its catalytic performance was investigated in an A3 coupling reaction of amines, various aldehyde, and terminal alkynes in solvent-free conditions and propargylamine derivatives was gained with excellent yields. Also, the catalyst has high recyclability and can be reused at least six times in the synthesis of propargylamine derivatives with good yields.

Cinchona-Based Hydrogen-Bond Donor Organocatalyst Metal Complexes: Asymmetric Catalysis and Structure Determination.

In this study, we describe the synthesis of cinchona (thio)squaramide and a novel cinchona thiourea organocatalyst. These catalysts were employed in pharmaceutically relevant catalytic asymmetric reactions, such as Michael, Friedel-Crafts, and A3 coupling reactions, in combination with Ag(I), Cu(II), and Ni(II) salts. We identified several organocatalyst-metal salt combinations that led to a significant increase in both yield and enantioselectivity. To gain insight into the active catalyst species, we prepared organocatalyst-metal complexes and characterized them using HRMS, NMR spectroscopy, and quantum chemical calculations (B3LYP-D4/def2-TZVP), which allowed us to establish a structure-activity relationship.

Internal 2D networking of silver bromide with a bidentate N-heterocyclic carbene ligand enables the formation of an inherently heterogeneous reusable catalyst for multicomponent A3 coupling

We report the synthesis of an internal 2D networking heterogeneous silver catalyst stabilized by bidentate N-heterocyclic carbene ligands. The Ag–NHC catalyst is employed in A3 coupling reactions and demonstrated reusability for six cycles.