Synthesis of Selenium-Decorated N-Oxide Isoquinolines: Arylseleninic Acids in Selenocyclization Reactions.

Herein, we describe the use of benzeneseleninic acid derivatives (BSA) as a bench-stable and easy to handle selenium reagent to access 4-(selanyl)isoquinoline-N-oxides through the selenocyclization of o-alkynyl benzaldehyde oximes. The reaction is conducted in refluxing methanol, allowing the thermal generation of electrophilic selenium species in situ. By this new protocol, a library of 19 selenium-decorated N-oxide isoquinolines was accessed in up to 96% yield with an outstanding substrate tolerance and the feasibility to scale it up 10 times (from 0.25 to 2.5 mmol).

Bioactivity of selenium-containing pyridinium salts: Prospecting future pharmaceutical constituents to treat liver diseases involving oxidative stress.

Redox imbalance leads to oxidative stress that causes irreversible cellular damage. The incorporation of the antioxidant element selenium (Se) in the structure of pyridinium salts has been used as a strategy in chemical synthesis and can be useful in drug development. We investigated the antioxidant activity of Se-containing pyridinium salts (named Compounds 3A, 3B, and 3C) through in vitro tests. We focused our study on liver protein carbonylation, liver lipoperoxidation, free radical scavenging activity (1,1-diphenyl-2-picryl-hydrazil [DPPH]; 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid [ABTS]), and enzyme-mimetic activity assays (glutathione S-transferase [GST]-like; superoxide dismutase [SOD]-like). In addition, 2-(4-chlorophenyl)-2-oxoethyl)-2-((phenylselanyl)methyl)pyridin-1-ium bromide (3C) was selected to evaluate the acute oral toxicity in mice due to the best antioxidant profile. The three compounds were effective in reducing the levels of protein carbonylation and lipoperoxidation in the liver in a µM concentration range. All compounds demonstrated scavenger activity of DPPH and ABTS radicals, and GST-like action. No significant effects were detected in the SOD-like assay. Experimental data also showed that the acute oral treatment of mice with Compound 3C (50 and 300 mg/kg) did not cause mortality or change markers of liver and kidney functions. In summary, our findings reveal the antioxidant potential of Se-containing pyridinium salts in liver tissue, which could be related to their radical scavenging ability and mimetic action on the GST enzyme. They also demonstrate a low toxicity potential for Compound 3C. Together, the promising results open space for future studies on the therapeutic application of these molecules.

Visible Light and Triselenium Dicyanide (TSD): New Horizons in the Synthesis of Organic Selenocyanates.

Herein, we describe a new method for the synthesis of α-carbonyl selenocyanates by reacting triselenium dicyanide (TSD) and styrenes under blue light irradiation and O2 atmosphere. The reactions are triggered by the formation of Se-centered radical species, followed by the addition/oxidation of the styrene π-bond. α-Carbonyl selenocyanates and α-hydroxy selenocyanates were obtained in moderate to excellent yields from aryl- and alkyl-substituted alkenes, respectively. It was demonstrated that α-carbonyl selenocyanates could be used as a synthetic platform in a multicomponent reaction strategy to prepare 2-phenylimidazo[1,2-a]pyridine derivatives, which were evaluated for their photophysical properties. Overall, this new method provides a useful tool for synthesizing α-carbonyl selenocyanates, and demonstrates their potential for use in the synthesis of other compounds, thus giving new synthetic opportunities to construct organic selenocyanate compounds.

Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules.

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile.

A general methodology to access valuable 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines was developed by the reaction of 2-azidobenzaldehyde with phenylchalcogenylacetonitriles (sulfur and selenium) in the presence of potassium carbonate (20 mol%) as a catalyst. The reactions were conducted using a mixture of dimethylsulfoxide and water (7:3) as solvent at 80 °C for 4 h. This new methodology presents a good functional group tolerance to electron-deficient and electron-rich substituents, affording a total of twelve different 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines selectively in moderate to excellent yields. The structure of the synthesized 4-(phenylselanyl)tetrazolo[1,5-a]quinoline was confirmed by X-ray analysis.

Synthesis of Seleno-Dibenzocycloheptenones/Spiro[5.5]Trienones by Radical Cyclization of Biaryl Ynones.

We report herein an alternative method for the synthesis of seleno-dibenzocycloheptenones and seleno-spiro[5.5]trienones through the radical cyclization of biaryl ynones in the presence of diorganyl diselenides, using Oxone as a green oxidizing agent. The reactions were conducted using acetonitrile as the solvent in a sealed tube at 100 °C. The protocol is operationally simple and scalable, exhibits high regioselectivity, and allows the synthesis of 24 dibenzocycloheptenones/spiro[5.5]trienones in yields of up to 99%, 17 of which are unpublished compounds. Additionally, synthetic transformations of the prepared compounds, such as oxidation and reduction reactions, are demonstrated.

Radical cyclization of alkynyl aryl ketones for the synthesis of 3-seleno-substituted thiochromones and chromones.

We report a strategy for the direct synthesis of 3-organylselanylthiochromones and 3-organylselanylchromones via the radical cyclization reaction between alkynyl aryl ketones containing an ortho-thiopropyl/methoxy group and diorganyl diselenides promoted by Oxone®. This method allows the construction and seleno-functionalization of thiochromones and chromones using Oxone® as a stable and non-hazardous oxidizing agent in the presence of CH3CN at 82 °C. These reactions tolerate a variety of substituents, and allowed the synthesis of twenty-one new 3-organylselanylthiochromones and selanylchromones in good to excellent yields (55-95%). Additionally, the developed method proved to be suitable for scale up (3.0 mmol, 80%), and the synthetic usefulness of the prepared compounds was demonstrated in the oxidation of 2-phenyl-3-(phenylselanyl)-4H-thiochromen-4-one.

Transition-Metal-Free C-S, C-Se, and C-Te Bond Formation from Organoboron Compounds.

The present review describes the successful application of organoboron compounds in transition-metal-free C-S, C-Se, and C-Te bond formations. We presented studies regarding these C-Chalcogen bond formations using organoboron reagents, such as boronic acids, boronic esters, borate anions, and several sources of chalcogen atoms/moieties. Moreover, a broad range of transition-metal-free approaches to synthesize sulfides, selenides, and tellurides were described using conventional heating methods, which are sometimes green since they use green solvents, safe reagents, among others. Furthermore, protocols using alternative energy sources, including ultrasound, microwave irradiation, photocatalysis, and electrolytic processes, were also shown to be suitable. These protocols were applied to prepare a broad scope of functionalized chalcogenides with high molecular diversity. These studies and their proposed mechanisms were also reported herein in addition to the reuse of reaction promoters.

Oxone-Promoted Synthesis of 4-(Chalcogenyl)isoquinoline-N-oxides from Alkynylbenzaldoximes and Diorganyl Dichalcogenides.

We report a protocol for the synthesis of 3-organyl-4-(organylchalcogenyl)isoquinoline-2-oxides via electrophilic cyclization between alkynylbenzaldoximes and diorganyl dichalcogenides promoted by Oxone. A total of 21 3-organyl-4-(organylchalcogenyl)isoquinoline-2-oxides were selectively obtained in yields of up 93% under an ultrasound irradiation condition in short reaction times (10-70 min). Additionally, the synthetic usefulness of the 3-phenyl-4-(phenylselanyl)isoquinoline-2-oxide was demonstrated in the annulation reaction with 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and in the deoxygenation reaction with phenylboronic acid.

Synthesis of 4-Selanyl- and 4-Tellanyl-1H-isochromen-1-ones Promoted by Diorganyl Dichalcogenides and Oxone.

A new method was developed for the synthesis of 4-chalcogenyl-1H-isochromen-1-ones through the 6-endo-dig electrophilic cyclization of 2-alkynylaryl esters and diorganyl dichalcogenides under ultrasound irradiation. The reactions were performed under mild conditions, using Oxone as a green oxidant to promote the cleavage of the chalcogen-chalcogen bond in diorganyl diselenides and ditellurides to generate electrophilic species in situ. A total of 25 compounds were selectively obtained after 30-70 min, in good to excellent yields (74-95%). This procedure was extended to prepare 5H-selenopheno[3,2-c]isochromen-5-ones. Additionally, for the first time, the 4-chalcogenyl-1H-isochromen-1-ones were used as substrates in the thionation reaction, using Lawesson's reagent and microwave irradiation under solvent-free conditions, obtaining the thio derivatives in yields of up to 99% in only 15 min.

Synthesis of benzo[b]chalcogenophenes fused to selenophenes via intramolecular electrophilic cyclization of 1,3-diynes.

We describe herein an alternative and transition-metal-free procedure for the access of benzo[b]chalcogenophenes fused to selenophenes via intramolecular cyclization of 1,3-diynes. This efficient protocol involves a double cyclization of 1,3-diynyl chalcogen derivatives promoted by the electrophilic species of organoselenium generated in situ by the oxidative cleavage of the Se-Se bond of dibutyl diselenide using Oxone® in acetonitrile as solvent in an open-flask at 80 °C. In this study, 15 selenophenes with broad substrate scope were prepared in moderate to excellent yields (55-98%) with short reaction times (0.5-3.0 h).

α-Keto Acids: Acylating Agents in Organic Synthesis.

A significant number of important acyl-transfer reactions, such as direct acylation, ortho acylation, heteroatom acylation, and a diversity of cyclization reactions using the title compound as a key starting material, have been described in recent years. Just like a sleeping beauty, α-oxocarboxylic acids were awakened from a 17-year sleep to become important reagents in classical and new acylation reactions. The greener characteristic of the coproduct formed in reactions using α-keto acid (only CO2), together with its versatility as a building block in catalytic organic synthesis, accredit it as a candidate to green acylating agent, an alternative to acyl chloride, and other acyl-transfer reagents. This review presents the impressive breakthroughs achieved mainly in the past decade in the development of new catalytic reactions for the formation of C-C, C-N, and C-S bonds using α-keto acids.

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2.

The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 µM and 8 µM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.

Recent Advances in the Oxone-Mediated Synthesis of Heterocyclic Compounds.

Oxone is a commercially available oxidant, composed of a mixture of three inorganic species, being the potassium peroxymonosulfate (KHSO5) the reactive one. Over the past few decades, this cheap and environmentally friendly oxidant has become a powerful tool in organic synthesis, being extensively employed to mediate the construction of a plethora of important compounds. This review summarizes the recent advances in the Oxone-mediated synthesis of N-, O- and chalcogen-containing heterocyclic compounds, through a wide diversity of reactions, starting from several kinds of substrate, highlighting the main synthetic differences, advantages, the scope and limitations.

Synthesis of 3,4-Bis(Butylselanyl)Selenophenes and 4-Alkoxyselenophenes Promoted by Oxone®.

We describe herein an alternative transition-metal-free procedure to access 3,4-bis(butylselanyl)selenophenes and the so far unprecedented 3-(butylselanyl)-4-alkoxyselenophenes. The protocol involves the 5-endo-dig electrophilic cyclization of 1,3-diynes promoted by electrophilic organoselenium species, generated in situ through the oxidative cleavage of the Se-Se bond of dibutyl diselenide using Oxone® as a green oxidant. The selective formation of the title products was achieved by controlling the solvent identity and the amount of dibutyl diselenide. By using 4.0 equiv of dibutyl diselenide and acetonitrile as solvent at 80 °C, four examples of 3,4-bis(butylselanyl)selenophenes were obtained in moderate to good yields (40-78%). When 3.0 equiv of dibutyl diselenide were used, in the presence of aliphatic alcohols as solvent/nucleophiles under reflux, 10 3-(butylselanyl)-4-alkoxyselenophenes were selectively obtained in low to good yields (15-80%).

Arylseleninic acid as a green, bench-stable selenylating agent: synthesis of selanylanilines and 3-selanylindoles.

Arylseleninic acids were used as an electrophilic selenium source in aromatic substitution reactions, using N,N-substituted anilines and indoles as nucleophiles at 70 °C for 6-15 h. A total of fourteen 4-selanylanilines and five 3-selanylindoles were selectively obtained in good to excellent yields. The starting benzeneseleninic acids are easily prepared from the respective diselenides, are bench stable and easy to handle, affording water as the only waste at the end of the reaction.

Recent Advances in the Synthesis of Selenophenes and Their Derivatives.

The selenophene derivatives are an important class of selenium-based heterocyclics. These compounds play an important role in prospecting new drugs, as well as in the development of new light-emitting materials. During the last years, several methods have been emerging to access the selenophene scaffold, employing a diversity of cyclization-based synthetic strategies, involving specific reaction partners and particularities. This review presents a comprehensive discussion on the recent advances in the synthesis of selenophene-based compounds, starting from different precursors, highlighting the main differences, the advantages, and limitations among them.

Regioselective Synthesis of 1-Sulfanyl- and 1-Selanylindolizines.

We describe herein a new approach to prepare unprecedented bioactive indolizine motifs decorated with organosulfur and organoselenium groups. A total of 12 1-sulfanylindolizines and 2 1-selanylindolizines were prepared in excellent yields by an intramolecular annulation of easily prepared chalcogen-containing pyridinium salts. The reaction is fast (1 h at 70 °C or 5 min under sonication) and transition-metal-free, using glycerol as a green solvent.

Synthesis of Isoxazolines by the Electrophilic Chalcogenation of ß,γ-Unsaturated Oximes: Fishing Novel Anti-Inflammatory Agents.

Herein, we describe a new strategy to prepare chalcogen-functionalized isoxazolines. The strategy involves the reaction of ß,γ-unsaturated oximes with electrophilic selenium and tellurium species, affording 19 new selenium- and tellurium-containing isoxazolines in good yields after 1 h at room temperature. The method was efficiently extended to the synthesis of 5 new (bis)isoxazoline ditellurides. One of the prepared compounds, 3-phenyl-5-((phenylselanyl)methyl)-isoxazoline, demonstrated better anti-inflammatory and antiedematogenic effects than the reference drug Celecoxib.

NMR chiral discrimination of chalcogen containing secondary alcohols.

Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatizing agents. The BINOL/DMAP ternary complex demonstrated a simple and fast protocol for determining enantiopurity. The drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral derivatizing agent (CDA) for NMR chiral discrimination of chalcogen containing secondary alcohols. The chiral recognition by CDA and chiral solvating agent (CSA) was assessed using 1 H, 77 Se-{1H}, and 125 Te-{1H} NMR spectroscopy. A simple model for the assignment of the absolute configuration from NMR data is presented.