Green Synthesis of Spiro Compounds with Potential Anticancer Activity through Knoevenagel/Michael/Cyclization Multicomponent Domino Reactions Organocatalyzed by Ionic Liquid and Microwave-Assisted.

In this work a microwave-assisted Knoevenagel/Michael/cyclization multicomponent domino methodology, using ethanol as solvent and the ionic liquid 1-methylimidazolium chloride as catalyst was developed for the synthesis of spiro compounds. The reaction conditions considered ideal were determined from a methodological study varying solvent, catalyst, amount of catalyst, temperature, and heating mode. Finally, the generality of the methodology was evaluated by exploring the scope of the reaction, varying the starting materials (isatin, malononitrile, and barbituric acid). Overall, the twelve spiro compounds were synthesized in good yields (43-98%) and the X-ray structure of compound 1b was obtained. In addition, the in vitro antiproliferative activities of the spirocycles against four types of human cancer cell lines including HCT116 (human colon carcinoma), PC3 (prostate carcinoma), HL60 (promyelocytic leukemia), and SNB19 (astrocytoma) were screened by MTT-based assay. It is noteworthy that spiro compound 1c inhibited the four cell lines tested with the lowest IC50 values: 52.81 µM for HCT116, 74.40 µM for PC3, 101 µM for SNB19, and 49.72 µM for HL60.

3,4-Dihydro-2(1H)-Pyridones as Building Blocks of Synthetic Relevance.

3,4-Dihydro-2(1H)-pyridones (3,4-DHPo) and their derivatives are privileged structures, which has increased their relevance due to their biological activity in front of a broad range of targets, but especially for their importance as synthetic precursors of a variety of compounds with marked biological activity. Taking into account the large number of contributions published over the years regarding this kind of heterocycle, here, we presented a current view of 3,4-dihydro-2(1H)-pyridones (3,4-DHPo). The review includes general aspects such as those related to nomenclature, synthesis, and biological activity, but also highlights the importance of DHPos as building blocks of other relevant structures. Additional to the conventional multicomponent synthesis of the mentioned heterocycle, nonconventional procedures are revised, demonstrating the increasing efficiency and allowing reactions to be carried out in the absence of the solvent, becoming an important contribution to green chemistry. Biological activities of 3,4-DHPo, such as vasorelaxant, anti-HIV, antitumor, antibacterial, and antifungal, have demonstrated this heterocycle's potential in medicinal chemistry.

Piperidine-Iodine as Efficient Dual Catalyst for the One-Pot, Three-Component Synthesis of Coumarin-3-Carboxamides.

A simple and efficient one-pot, three-component synthetic method for the preparation of coumarin-3-carboxamides was carried out by the reaction of salicylaldehyde, aliphatic primary/secondary amines, and diethylmalonate. The protocol employs piperidine-iodine as a dual system catalyst and ethanol, a green solvent. The main advantages of this approach are that it is a metal-free and clean reaction, has low catalyst loading, and requires no tedious workup.

Multicomponent Reactions (MCRs) with o-Quinone Methides.

This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho-quinone methide intermediates (o-QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron-rich dienophiles in inverse-electron demand hetero-Diels-Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.

2,5-Diketopiperazines via Intramolecular N-Alkylation of Ugi Adducts: A Contribution to the Synthesis, Density Functional Theory Study, X-ray Characterization, and Potential Herbicide Application.

To investigate the herbicidal potential of 2,5-diketopiperazines (2,5-DKPs), we applied a known protocol to produce a series of 2,5-DKPs through intramolecular N-alkylation of Ugi adducts. However, the method was not successful for the cyclization of adducts presenting aromatic rings with some substituents at the ortho position. Results from DFT calculations showed that the presence of voluminous groups at the ortho position of a benzene ring results in destabilization of the transition structure. Lower activation enthalpies for the SN2-type cyclization of Ugi adducts were obtained when bromine, instead of a chlorine anion, is the leaving group, indicating that the activation enthalpy for the cyclization step controls the formation of the 2,5-DKP. Some Ugi adducts and 2,5-DKPs formed crystals with suitable qualities for single-crystal X-ray diffraction data collection. Phytotoxic damage of some 2,5-DKPs on leaves of the weed Euphorbia heterophylla did not differ from those caused by the commercial herbicide diquat.

Antioxidant Activity of Bioactive Peptide Fractions from Germinated Soybeans Conjugated to Fe3O4 Nanoparticles by the Ugi Multicomponent Reaction.

The conjugation of biomolecules to magnetic nanoparticles has emerged as promising approach in biomedicine as the treatment of several diseases, such as cancer. In this study, conjugation of bioactive peptide fractions from germinated soybeans to magnetite nanoparticles was achieved. Different fractions of germinated soybean peptides (>10 kDa and 5-10 kDa) were for the first time conjugated to previously coated magnetite nanoparticles (with 3-aminopropyltriethoxysilane (APTES) and sodium citrate) by the Ugi four-component reaction. The crystallinity of the nanoparticles was corroborated by X-ray diffraction, while the particle size was determined by scanning transmission electron microscopy. The analyses were carried out using infrared and ultraviolet-visible spectroscopy, dynamic light scattering, and thermogravimetry, which confirmed the coating and functionalization of the magnetite nanoparticles and conjugation of different peptide fractions on their surfaces. The antioxidant activity of the conjugates was determined by the reducing power and hydroxyl radical scavenging activity. The nanoparticles synthesized represent promising materials, as they have found applications in bionanotechnology for enhanced treatment of diseases, such as cancer, due to a higher antioxidant capacity than that of fractions without conjugation. The highest antioxidant capacity was observed for a >10 kDa peptide fraction conjugated to the magnetite nanoparticles coated with APTES.

A One-Pot Six-Component Reaction for the Synthesis of 1,5-Disubstituted Tetrazol-1,2,3-Triazole Hybrids and Their Cytotoxic Activity against the MCF-7 Cell Line.

A high-order multicomponent reaction involving a six-component reaction to obtain the novel linked 1,5-disubstituted tetrazole-1,2,3-triazole hybrids in low to moderate yield is described. This one-pot reaction is carried out under a cascade process consisting of three sequential reactions: Ugi-azide, bimolecular nucleophilic substitution (SN2), and copper-catalyzed alkyne-azide reaction (CuAAC), with high atom and step-economy due the formation of six new bonds (one C-C, four C-N, and one N-N). Thus, the protocol developed offers operational simplicity, mild reaction conditions, and structural diversity. Finally, to evaluate the antitumoral potential of the synthetized molecules, a proliferation study was performed in the breast cancer (BC) derived cell line MCF-7. The hybrid compounds showed several degrees of cell proliferation inhibition with a remarkable effect in those compounds with cyclohexane and halogens in their structures. These compounds represent potential drug candidates for breast cancer treatment. However, additionally assays are needed to elucidate their complete effect over the cellular hallmarks of cancer.

Greener organic synthetic methods: Sonochemistry and heterogeneous catalysis promoted multicomponent reactions.

Ultrasound is an essential technique to improve organic synthesis from the point of view of green chemistry, as it can promote better yields and selectivities, in addition to shorter reaction times when compared to the conventional methods. Heterogeneous catalysis is another pillar of sustainable chemistry being the recycling and reuse of the catalysts one of its great advantage. In the other hand, multicomponent reactions provide the synthesis of structurally diverse compounds, in a one-pot fashion, without isolation and purification of intermediates. Thus, the combination of these protocols has proved to be a powerful tool to obtain biologically active organic compounds with lower costs, time and energy consumption. Herein, we provide a comprehensive overview of advances on methods of organic synthesis that have been reported over the past ten years with focus on ultrasound-assisted multicomponent reactions under heterogeneous catalysis. In particular, we present pharmacologically important N- and O-heterocyclic compounds, considering their synthetic methods using green solvents, and catalyst recycling.

How and Why to Investigate Multicomponent Reactions Mechanisms? A Critical Review.

We review the most innovative efforts and greatest challenges faced when elucidating multicomponent reactions (MCRs) mechanisms. When compared to traditional reactions, the often two or more concurrent reactions pathways and the greater number of possible intermediates in MCRs turn their mechanistic investigation both a harder and trickier task. The common approaches used to investigate reaction mechanisms are often unable to clarify MCRs mechanisms; hence few but clever approaches are currently used to determine these mechanisms and to depict their key transformations. Their complexity has required most innovative approaches and the use of a number of unique techniques that have shed light over the favored pathway selected from the myriad of alternatives theoretically available for MCRs. This review focuses on the most successful efforts applied by a few leading groups to perform these puzzlingly investigations.

Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles.

A one-pot iodine-catalyzed multicomponent reaction has been developed for the selective preparation of 5-amino-4-(arylselanyl)-1H-pyrazoles from a diverse array of benzoylacetonitriles, arylhydrazines and diaryl diselenides. The reactions were conducted in MeCN as solvent at reflux temperature under air. The methodology presents a large functional group tolerance to electron-deficient, electron-rich, and bulky substituents and gave the expected products in good to excellent yields. The synthesized 1,3-diphenyl-4-(phenylselanyl)-1H-pyrazol-5-amine was submitted to an oxidative dehydrogenative coupling to produce a diazo compound confirmed by X-ray analysis.

Synthesis of α-amino-1,3-dicarbonyl compounds via Ugi flow chemistry reaction: access to functionalized 1,2,3-triazoles.

The Ugi multicomponent reaction has been used as an important synthetic route to obtain compounds with potential biological activity. We present the rapid and efficient synthesis of [Formula: see text]-amino-1,3-dicarbonyl compounds in moderate to good yields via Ugi flow chemistry reactions performed with a continuous flow reactor. Such [Formula: see text]-amino-1,3-dicarbonyl compounds can act as precursors for the production of [Formula: see text]-amino acids via hydrolysis of the ethyl ester group as well as building blocks for the synthesis of novel compounds with the 1,2,3-triazole ring. The [Formula: see text]-amino acid derivatives of the Ugi flow chemistry reaction products were then used for dipeptide synthesis.

Inhibition of tyrosinase by 4H-chromene analogs: Synthesis, kinetic studies, and computational analysis.

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent tyrosinase inhibitory activity with a Ki value of 4 µm, comparable to the reference standard inhibitor kojic acid. A kinetic study suggested that these synthetic heterocyclic compounds behave as competitive inhibitors for the L-DOPA binding site of the enzyme. Furthermore, molecular modeling provided important insight into the mechanism of binding interactions with the tyrosinase copper active site.