C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel-Crafts Reaction Catalyzed by Y(OTf)3.

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel-Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Synergistic Photoredox/Palladium Catalyzed Enantioconvergent Carboxylation of Racemic Heterobiaryl (Pseudo)Halides with CO2.

Herein, we report a synergistic photoredox/palladium catalytic system for the efficient enantioconvergent synthesis of axially chiral esters from racemic heterobiaryl (pseudo)halides (bromides/triflates) with CO2 and alkyl bromides under mild conditions. A wide range of axially chiral esters were obtained in good to high yields with excellent enantioselectivities. Detailed mechanistic studies unveiled that the ratio of photocatalyst and palladium catalyst exhibited significant impact on the chemo- and enantioselectivities of the reaction. Kinetic studies and control experiments supported the proposed mechanism involving cascade asymmetric carboxylation followed by SN2 substitution. The achievement of high enantioselectivity relies not only on the choice of synergistic metallaphotoredox catalysts but also on the utilization of alkyl bromides, which trap the generated chiral carboxylic anions in situ, thus preventing their immediate racemization.

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines.

Herein, we report a visible-light-mediated palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines, affording unsaturated γ- and ε-amino acid derivatives with diverse structures. In this methodology, the diazo compound readily transforms into a hybrid α-ester alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε-amino acid derivative. This approach proceeds under mild and simple reaction conditions and shows high functional group tolerance, especially in the incorporation of various bioactive molecules. The studies on scale-up reactions and diverse derivatizations highlight the practical utility of this multicomponent reaction protocol.

Nickel-Catalyzed Three-Component Unsymmetrical Bis-Allylation of Alkynes with Alkenes: A Density Functional Theory Study.

Density functional theory (DFT) characterizations were employed to resolve the structural and energetic aspects and product selectivities along the mechanistic reaction paths of the nickel-catalyzed three-component unsymmetrical bis-allylation of alkynes with alkenes. Our putative mechanism initiated with the in situ generation of the active catalytic species [Ni(0)L2] (L = NHC) from its precursors [Ni(COD)2, NHC·HCl] to activate the alkyne and alkene substrates to form the final skipped trienes. This proceeds via the following five sequential steps: oxidative addition (OA), ß-F elimination, ring-opening complexation, C-B cleavage and reductive elimination (RE). Both the OA and RE steps (with respective free energy barriers of 24.2 and 24.8 kcal·mol-1) contribute to the observed reaction rates, with the former being the selectivity-controlling step of the entire chemical transformation. Electrophilic/nucleophilic properties of selected substrates were accurately predicted through dual descriptors (based on Hirshfeld charges), with the chemo- and regio-selectivities being reasonably predicted and explained. Further distortion/interaction and interaction region indicator (IRI) analyses for key stationary points along reaction profiles indicate that the participation of the third component olefin (allylboronate) and tBuOK additive played a crucial role in facilitating the reaction and regenerating the active catalyst, ensuring smooth formation of the skipped triene product under a favorably low dosage of the Ni(COD)2 catalyst (5 mol%).

Elaborate Modulating Binding Strength of Intermediates via Three-component Covalent Organic Frameworks for CO2 Reduction Reaction.

The catalytic performance for electrocatalytic CO2 reduction reaction (CO2RR) depends on the binding strength of the reactants and intermediates. Covalent organic frameworks (COFs) have been adopted to catalyze CO2RR, and their binding abilities are tuned via constructing donor-acceptor (DA) systems. However, most DA COFs have single donor and acceptor units, which caused wide-range but lacking accuracy in modulating the binding strength of intermediates. More elaborate regulation of the interactions with intermediates are necessary and challenge to construct high-efficiency catalysts. Herein, the three-component COF with D-A-A units was first constructed by introducing electron-rich diarylamine unit, electron-deficient benzothiazole and Co-porphyrin units. Compared with two-component COFs, the designed COF exhibit elevated electronic conductivity, enhanced reducibility, high efficiency charge transfer, further improving the electrocatalytic CO2RR performance with the faradic efficiency of 97.2 % at -0.8 V and high activity with the partial current density of 27.85 mA cm-2 at -1.0 V which exceed other two-component COFs. Theoretical calculations demonstrate that catalytic sites in three-component COF have suitable binding ability of the intermediates, which are benefit for formation of *COOH and desorption of *CO. This work offers valuable insights for the advancement of multi-component COFs, enabling modulated charge transfer to improve the CO2RR activity.

Reversible Radical Addition Guides Selective Photocatalytic Intermolecular Thiol-Yne-Ene Molecular Assembly.

In modern organic chemistry, harnessing the power of multicomponent radical reactions presents both significant challenges and extraordinary potential. This article delves into this scientific frontier by addressing the critical issue of controlling selectivity in such complex processes. We introduce a novel approach that revolves around the reversible addition of thiyl radicals to multiple bonds, reshaping the landscape of multicomponent radical reactions. The key to selectivity lies in the intricate interplay between reversibility and the energy landscapes governing C-C bond formation in thiol-yne-ene reactions. The developed approach not only allows to prioritize the thiol-yne-ene cascade, dominating over alternative reactions, but also extends the scope of coupling products obtained from alkenes and alkynes of various structures and electron density distributions, regardless of their relative polarity difference, opening doors to more versatile synthetic possibilities. In the present study, we provide a powerful tool for atom-economical C-S and C-C bond formation, paving the way for the efficient synthesis of complex molecules. Carrying out our experimental and computational studies, we elucidated the fundamental mechanisms underlying radical cascades, a knowledge that can be broadly applied in the field of organic chemistry.

An efficient synthesis of functionalized ß-amino- and ß-hydrazinoalkylphosphonates by three-component reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and aromatic amines or hydrazines.

Three-component reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and aromatic amines afforded ß-aminoalkylphosphonate derivatives. Similar reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and dinitrophenylhydrazine afforded ß-hydrazinooalkylphosphonate derivatives. This method includes both the C-N and C-P bond formation in a one pot and single synthetic step in neutral and simple reaction conditions. All reactions were conducted in CH2Cl2 as solvent at room temperature without using any catalyst, and the stable products were obtained in high yields. The structures of all products were proved by 1H, 13C and 31P NMR and IR spectral and elemental analysis data.

Microwave-induced one-pot synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole hybrids as antiproliferative agents and density functional theory study.

Herein, we outline a highly efficient PEG-4000-mediated one-pot three-component reaction for the synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole derivatives (5a-r) at up to 96% yield as antiproliferative agents. This three-component protocol offers the advantages of an environmentally benign reaction, excellent yield, quick response time, and operational simplicity triggered by the copper catalyst under microwave irradiation. All the synthesized compounds were tested for antiproliferative activity against six human solid tumor cell lines, that is, A549 and SW1573 (nonsmall cell lung), HBL100 and T-47D (breast), HeLa (cervix), and WiDr (colon). Among them, six compounds, 5g-j, 5m, and 5p, demonstrated effective antiproliferative action with GI50 values under 10 µM. Furthermore, density functional theory (DFT) calculations were performed for all the synthesized molecules through geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The theoretical DFT calculation was performed using the DFT/B3LYP/6-31+G (d,p) basis set. Moreover, the biological reactivity of all the representative synthesized molecules was compared with the theoretically calculated quantum chemical descriptors and MESP 3D plots. We also investigated the drug-likeness characteristic and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. In general, our approach enables environmentally friendly access to 3-imidazolyl indole clubbed 1,2,3-triazole derivatives as prospective antiproliferative agents.

Passerini three-component reaction for the synthesis of saccharide branched cellulose.

In this work, we investigate a multicomponent synthetic method for combining saccharides with cellulose to produce saccharide branched cellulose (b-Cel). First, cellulose is modified conventionally using carboxymethyl to create carboxyl functional groups for multicomponent reactions. The Passerini three-component reaction (Passerini-3CR) is then used to synthesize the saccharide b-Cel, with particular attention paid to the scope of the substrate and reaction process optimization. The structure of saccharide b-Cel is regulated by modifying the carboxyl group of cellulose molecules, the kind of saccharide molecules (including glucose, galactose, lactose, cellobiose, and cellulose), and the degree of branching. The branched structure of saccharide b-Cel greatly influenced its rheological characteristics and solubility. This work presents a practical method for the synthesis of artificial branching polysaccharides and is crucial for the development of innovative materials based on biomass.

A Facile Synthetic Approach to UV-Degradable Hydrogels.

Light-degradable hydrogels have a wide range of application prospects in the field of biomedicine. However, the provision of a facile synthetic approach to light-degradable hydrogels under mild conditions remains a challenge for researchers. To surmount this challenge, a facile synthetic approach to UV-degradable hydrogels is demonstrated in this manuscript. Initially, an UV-degradable crosslinker (UVDC) having o-nitrobenzyl ester groups was synthesized in a single step through the employment of the Passerini three-component reaction (P-3CR). Both 1H NMR and MS spectra indicated the successful synthesis of high-purity UVDC, and it was experimentally demonstrated that the synthesized UVDC was capable of degradation under 368 nm light. Furthermore, this UVDC was mixed with 8-arm PEG-thiol (sPEG20k-(SH)8) to promptly yield an UV-degradable hydrogel through a click reaction. The SEM image of the fabricated hydrogel exhibits the favorable crosslinking network of the hydrogel, proving the successful synthesis of the hydrogel. After continuous 368 nm irradiation, the hydrogel showed an obvious gel-sol transition, which demonstrates that the hydrogel possesses a desirable UV-degradable property. In summary, by utilizing solely a two-step reaction devoid of catalysts and hazardous raw materials, UV-degradable hydrogels can be obtained under ambient conditions, which greatly reduces the difficulty of synthesizing light-degradable hydrogels. This work extends the synthetic toolbox for light-degradable hydrogels, enabling their accelerated development.

Facile One-Pot Three Component Synthesis, Characterization, and Molecular Docking Simulations of Novel α-Aminophosphonate Derivatives Based Pyrazole Moiety as Potential Antimicrobial Agent.

An efficient method has been developed for the synthesis of novel α-aminophosphonates (AAP) (3 a-m) through a one-pot three-component reaction of 1,3-disubstituted-1H-pyrazol-5-amine, aromatic aldehydes, and phosphite using lithium perchlorate as catalyst. All newly synthesized compounds were characterized via different spectroscopic techniques. The synthesized compounds' mode of action was investigated using molecular docking against the outer membrane protein A (OMPA) and exo-1,3-ß-glucanase, with interpreting their pharmacokinetics aspects. The results of the antimicrobial effectiveness of these compounds revealed a broad spectrum of their biocidal activity and this in-vitro study was in line with the in- silico results. Additionally, it has been demonstrated that these compounds exhibited a minimum inhibitory concentration (MIC) with significant activity at low concentrations (7.5-30.0 mg/mL). Further, the radical scavenging (DPPH* ) activity of the synthesized compounds fluctuated, with compounds 3 h, 3 a, and 3 f showing the highest antioxidant activity. Overall, the formulated compounds can be employed as antimicrobial and antioxidant agents in medical applications.

Mannich-type addition of cyclic 1,3-diketones to N-acyliminium ions: Access to aza-sugars.

A novel three-component strategy has been developed for the synthesis of iminosugars in good to excellent yields. This is the first report on the Mannich type addition of cyclic 1,3-diketones to aza-acetal derived from hydroxy-γ-lactone and arylamine to produce a novel series of aza-sugars with high selectivity.

Efficient Synthesis of Diaryl Quaternary Centers by Rh(II)/Xantphos Catalyzed Relay C-H Functionalization and Allylic Alkylation.

A three-component reaction of N, N-disubstituted aniline, α-diazo ester, and an allylic electrophile has been realized by [Rh(II)]2 /Xantphos catalysis, providing a direct access to various aniline derivatives bearing diaryl allylic quaternary centers in good yields. The synthetic utility of this protocol was demonstrated by facile derivatization of the products for preparation of biologically relevant molecules and structural scaffolds, which offers a high potential for increasing the molecular diversity. Mechanistic studies identified α, α-diarylacetate species as an active intermediate, thereby revealing the presence of a C(sp2 )-H functionalization of aniline derivatives/allylic alkylation cascade in this attractive catalytic transformation.

Efficient and green synthesis of novel hexahydro-5H-thiazolo[2',3':2,3]pyrimido[4,5-b]quinoline derivatives.

Herein, we report a catalyst-free, one-pot three-component reaction of 5-amino-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one, aromatic aldehyde, and dimedone in ethylene glycol as a green solvent at 100 °C for the easy access of hexahydro-5H-thiazolo[2',3':2,3]pyrimido[4,5-b]quinoline. Catalyst-free, green solvent, simple procedure, mild reaction conditions, easy work-up procedure, and good to excellent yields are the significant advantages of this protocol.

A diastereoselective three-component reaction for the assembly of succinimide and isatin hybrid molecules with potent anticancer activities.

A Rh2(OAc)4 catalyzed three-component reaction of vinyl diazosuccinimides with alcohols and isatins has been reported, which provides a practical assess to the direct assembly of succinimide and isatin hybrid molecules in good-to-high yields with excellent stereoselectivity. The antiproliferation activity of these synthesized succinimide and isatin hybrid products has been tested via the CCK8 assay in different cancer cell lines, and compounds 4g (SJSA-1, IC50 = 3.82 µM) and 4r (HCT-116, IC50 = 9.02 µM) exhibit higher anticancer potency than other tested compounds.

Facile synthesis of 6-organyl-4-(trifluoromethyl)pyridin-2(1H)-ones and their polyfluoroalkyl-containing analogs.

The three-component cyclization of 3-polyfluoroalkyl-3-oxopropanoates and methyl ketones with ammonium acetate affords 6-organyl-4-(polyfluoroalkyl)pyridin-2(1H)-ones (organyl is alkyl, aryl, or hetaryl). The synthesized pyridones were evaluated for antifungal, antibacterial, and analgesic activity.

Catalyst-Controlled Selectivity Switch in Three-Component Reaction: An NHC-Catalyzed Strategy for the Synthesis of δ-Lactone-Fused Spirobenzofuran-3-ones.

An efficient, three-component reaction of aldehydes and benzofuran-3-ones was developed. This process provides a new approach for the preparation of synthetically and biologically important spirobenzofuran-3-one derivatives with moderate-to-good yields under mild conditions. A switch of intramolecular to intermolecular domino Michael-aldol-lactonization leading to differential product formation was achieved by different NHCs catalysis.

Microwave-Assisted Three-Component Synthesis of Novel N-Arylated-Dihydrobenzo[g]quinoline-5,10-Diones and Their Potential Cytotoxic Activity.

A convenient three-component synthetic approach was developed en route to new and significative N-arylated-dihydrobenzo[g]quinoline-5,10-diones using 2-hydroxy-1,4-naphthoquinone, a variety of aromatic aldehydes, and 4-(arylamino)furan-2(5H)-ones. A sequence of steps including Knoevenagel condensation, Michael addition, [1,3]-hydrogen shift, intramolecular cyclization and dehydration led to the formation of products. All the products were structurally characterized by spectroscopic techniques and assessed in terms of their cytotoxicity profile against four cancer cell lines (KB, HepG2, A549, and MCF7), and human embryonic kidney (Hek-293) cell lines.

IBX-Mediated Organic Transformations in Heterocyclic Chemistry-A Decade Update.

O-Iodoxybenzoic acid (IBX) is a very mild and efficient hypervalent iodine synthetic reagent useful to carry out several selective oxidations. The present review highlights research reports on IBX-assisted transformations in heterocyclic derivatives, particularly from 2010 onward.