Current Organic Synthesis - Volume 14, Issue 8, 2017

Background: The incorporation of selenium (Se) atom onto organic scaffolds is a very promising approach to obtain more active and selective compounds against several types of cancer. During the last decade, a plethora of organoselenium compounds have been reported with very potent anticancer activity through diverse mechanisms of action, some of the most interesting being autophagy, angiogenesis, affectation of cancer stem cells and lethal mitosis. Several studies have related Se status and different selenoproteins with the development of Leishmania. Furthermore, one of the most used approaches for seeking new antitrypanosomal drugs is the drug repositioning. Considering both facts, our research group is developing organoselenium derivatives with dual activity against cancer and Leishmaniasis. Objective: The objective of this review is to gather, for the first time, every organic selenocompound with this dual activity. Thereby, the synthetic procedures will be discussed, along with their most important biological effects in both pathologies. Conclusion: To conclude, the reported results show that the introduction of Se atom onto organic molecules is a valid rational approach to obtain dual anticancer/leishmanicidal agents. Furthermore, the synthetic procedures needed are quite straightforward and occur with good yields. Thus, bisacylimidoselenocarbamates and diselenides are very good candidates to further develop as dual agents.

Aim and Objective: Selenium (Se) compounds are often associated with good reactivity and selectivity due to specific modifications of thiol groups in peptides, proteins and enzymes. Among them, selenazolinium salts are of particular interest, as they react readily with their thiol targets. This study was undertaken to verify whether this reactivity translates into biological activity against a few selected organisms. Materials and Methods: To screen the activity of selenazolinium salts, we performed nematicidal activity assay using Steinernema feltiae. To determine their impact on microbial proliferation, viability of Escherichia coli and Saccharomyces cerevisiae cells was monitored. For a chemical genetic phenotyping focused on a redox link, 32 redox-related S. cerevisiae mutants were used. DNA double-strand breakage caused by selenazolinium salts was investigated using pulsed-field gel electrophoresis and their physico-chemical properties were assessed using nuclear magnetic resonance (NMR). Results: Some of selenazolinium salts are toxic against S. feltiae at a concentration of 100-500 μM. In E. coli, selenazolium salts display no toxicity at a concentration of 100 μM; however, at a concentration of 500 μM some of them show a statistically relevant toxicity. Similar findings were obtained in wild-type S. cerevisiae cells. Only a few redox-related mutants show higher sensitivity to selenazolinium salts compared to wild-type cells. Selenazolinium salts induce DNA double-strand breaks at moderate doses (10-100 μM). 77Se-NMR shifts reflect some of the trends observed in the biological assays. Conclusion: Our results confirmed that several of selenazolinium salts show a significant biological activity that is executed via an electrophilic attack.

Background: During the last decade, numerous research has indicated a promising perspective for selenophene and benzo[b]selenophene (BBS) as a promising scaffold for biologically active compounds. Selenophene is regarded as a bioisostere of benzene, hence numerous of selenophene derivatives have been synthesized to imitate the biological activities of benzene-containing analogues. Benzo[b]selenophene is regarded as a bioisostere of naphthalene, benzo[b]furan, benzo[b]thiophene, and indole. The main approach to the discovery of new biologically active BBS derivatives is based on the synthesis of selenium analogues of already known bioactive molecules. Objective: The recent interest of introducing selenium for biologically active compounds may arise from the fact that the selenium is a very useful element. In this review, we are presenting the biological activities described for functionalized selenophenes and benzoselenophenes. Conclusion: We could show in this review the biological future for selenophenes and benzo[b]selenophenes. Several selenophenes have been studied for different biological activities especially in the field of cancer treatment. For benzoselenophenes, the results of the most recent studies predict promising future in the field of medicinal chemistry. These activities are varying mainly between antioxidant and antitumor.

Background: As a chalcogen selenium has an interesting role in biology e.g. when it replaces sulfur in the amino acid cysteine, giving selenocysteine, which has an essential role in mammalian redox metabolism, being an essential part of the active site of mammalian glutathione peroxidase enzymes. Like other chalcogens selenium has several formal oxidation states and selenium compounds can interact with the cell's redox system, which must be tightly regulated for cell survival. Thus, selenium compounds can be physiologically active in cells and have potential as tools to investigate cell biochemistry and physiology and, depending on their mode of action, as therapeutic substances in medicine. Methods and Results: This article aims to show the potential that baker's yeast (Saccharomyces cerevisiae), a single-celled organism, offers as a model system for mode-of-action studies for novel and already known selenium compounds of potential therapeutic and biotechnological interest. For this purpose, sodium selenite (Na2SeO3) as an example test compound has been used in a selection of screening procedures to identify genes potentially involved in cellular responses. For example, the glutathione reductase gene seems to be important to protect cells against Na2SeO3. Conclusions: The article is aimed at chemists and hopes to introduce and demystify the biology behind the common tests used with yeast. It is not intended to be an exhaustive treatment of yeast biology and much is missing, which would be found in a comprehensive practical manual, but it is hoped that it will be an introduction for scientists reading outside their specialization and helps making them aware of useful techniques for their own research.

Background: Sulfur-containing compounds are widespread among natural products and bioactive substances, and also useful ligands in asymmetric catalysis. Objectives: In this context, different methods for the preparation of oxazolidine- and oxazoline-2-thiones and their more recent applications are reviewed. Conclusions: In this survey, novel rearrangements and new reactions have also been summarized since 2007 until 2016.

Background: Since its discovery on the 1930 decade, phthalocyanines have occupied a prominent place in the textile and dye industries due to their thermal stability, low solubility and reactivity. However, over the last three decades, many different applications have been found for phthalocyanine derivatives including medicine, materials science, catalysis and energy fields. In this review, we discuss about the phthalocyanine chemistry, and the principal synthetic precursors as well. Strategies developed for obtaining soluble and nonaggregated phthalocyanine dyes are also covered, with insights on the reaction mechanisms. The main synthetic methods for the synthesis of symmetric and non-symmetric systems are presented and discussed. Objective: This review aims to present an overview on phthalocyanine chemistry and their principal synthetic precursors, covering strategies developed for obtaining soluble and non-aggregated phthalocyanine dyes with insights on the reaction mechanisms. Also, the main synthetic methods are presented, and different approaches to symmetric and non-symmetric phthalocyanine are discussed. Conclusion: Phthalocyanines are compounds with significant applications and growing interest in science. Their physical and chemical properties have been more and more elucidated. The major challenge is to make the synthetic protocols more suitable and cheaper, in order to allow studies and application on large scales.

Background: Tin-promoted allylation of carbonyl or imino groups is one of the most convenient and efficient methods for synthesis of homoallylic compounds, which are versatile building blocks in the preparation of many biologically active molecules and natural products. Objective: This review provides an insight into one-pot allylation reactions for the synthesis of different homoallylic compounds promoted by tin powder. Conclusion: In the last four decades, tin powder-promoted allylation process has been exploited in synthesis of homoallylic compounds. This multicomponent “one-pot” strategy avoids a lengthy separation process and purification of the intermediate chemical compounds, which saves time and resources while increasing the chemical yield. This tin-promoted process has the following features: operational simplicity, good tolerance to functional groups and improved yields. The protocol could be carried out under wet conditions or even in pure water.

Aim and Objective: Carbazoles and pyrrolidines derivatives exhibit a broad spectrum of biological and pharmacological properties, which exist in numerous drugs. Due to the high significance of these two classes of moieties in drug discovery, the synthesis of the compounds containing both of these two moieties are highly desirable. Method: A metal- and catalyst-free three-component decarboxylative coupling reaction of proline, aldehyde and 4-hydroxycarbazole has been developed. The synthesized compounds were examined for their antiproliferative and antioxidant activities. Molecular docking studies were performed on all synthesized compounds against tubulin structure using Schrodinger's Glide software. Results: This atom economic approach provides an access to pyrrolidinyl-carbazole derivatives in good yields. The antiproliferative activity of newly synthesized compounds was investigated on both normal cell line (CHO) and cancer cancer cell lines (MCF7, MDA-MB-231 and A549). The results indicated that, these compounds showed selective cytotoxicity against both normal and cancer cells. In addition, most of the compounds showed very good antioxidant activity. Molecular docking studies demonstrated that all the lead compounds selectively occupy the colchicine binding site of the tubulin polymer. Conclusion: In conclusion, we have developed a simple, metal- and catalyst-free three-component protocol to access synthetically as well as biologically important pyrrolidinyl-carbazole derivatives via decarboxylative coupling reaction involving proline, aldehydes and 4-hydroxycarbazole. The synthesized compounds were examined for their antiproliferative and antioxidant activities. The trend in the observed antiproliferative activity was further rationalized by molecular docking studies.

Aim and Objective: We explore the role of IBX as an electrophilic agent towards the synthesis of flavones. The main objective was to work within the framework of green chemistry by using eco-friendly, less toxic, iodine-hypervalent reagent to carry out a facile conversion to flavones. Material and Methods: The use of 1equivalent of IBX under refluxing condition in DMSO was the best employed method for the synthesis of flavones. All the synthesised compounds were characterised by spectroscopic methods such as IR, 1H NMR and 13C NMR spectroscopy. Results: In total, we successfully synthesized fifteen flavones derivatives in very good yields by using iodinehypervalent reagent. This method was proved to be the best method as it involved simple workup procedure i.e. by adding water to the reaction mixture followed by filtration of the solid product. The formation of the product was confirmed by IR, NMR and their characteristic melting points. Conclusion: A new and first approach towards the synthesis of flavones using non-toxic and eco-friendly hypervalent iodine (V) reagent, IBX has been demonstrated. Such a methodology has been well-extended towards the synthesis of hydroxy, and bromo flavones. The work signifies the electrophilic character of IBX, which is an oxidant.

Aim and Objective: The carboxylation of organoboronic esters with CO2 is an attractive way of preparing the functionalized carboxylic acid derivatives. For the silver-catalyzed carboxylation of arylboronic esters with CO2, sensibility of catalytic system to CO2 pressure resulted in a high CO2 pressure required in the reaction. This work focuses on solving this problem and promoting this transformation under atmospheric CO2 pressure. Material and Method: Arylboronic esters were synthesized according to the published procedure. Arylorganic esters, silver compound, base, PPh3 and solvent were introduced into a 25 mL Schlenk flask. Then, the gasexchanging operation via a “freeze-pump-thaw” method was conducted. After being enclosed with a CO2 balloon, the resulting mixture was stirred at 70oC for 12 h. Then, the reaction was quenched by 1 M HCl and extracted with ethyl acetate. The yields of the corresponding carboxylic acids were determined by GC. The structures of products were confirmed by NMR and GC-MS. Results: The carboxylation of arylboronic esters with ambient CO2 was achieved on the basis of the silver chloride/triphenylphosphine system by using cesium carbonate as the base and dimethyl sulfoxide as the solvent. Through this protocol, various functionalized carboxylic acids were synthesized in 85-99% yields. Conclusion: The silver-catalyzed carboxylation of arylboronic esters with ambient CO2 was established. This approach represents an alternative way to prepare carboxylic acids derivatives from the organoboron compounds with CO2 under mild reaction conditions.

Aim and Objective: In the chemical literature, there is very little data about copper catalysed synthesis of diaryl sulfides in water. In this work we present a novel highly selective Cu-catalysed “on-water” method of the synthesis of symmetrical and unsymmetrical sulfides from aryl iodides and 2-mercaptobenzoxazole as a novel sulfur transfer agent. Material and Method: 2-Mercaptobenzoxazole was presented as a novel sulfur transfer agent. Novel Cucatalysed “on-water” method for the selective synthesis of diaryl sulfides from diaryl iodides in the phase transfer catalytic system 2-mercaptobenzoxazole / CuI / proline/ KOH/ Adogen 464 was developed. Results: We have elaborated the novel catalytic system 2-mercaptobenzoxazole / KOH / CuI / Adogen464 / proline for the synthesis of diaryl sulfides from corresponding aryl iodides in water. The products were isolated in 30-76% yields. Modification of the presented method was successfully applied in the preparation of unsymmetrical sulfides. For example, benzylphenylsulfide and benzyl(3-fluorophenyl)sulfide were selectively prepared in 68% and 57% yields, correspondingly, by three-component, one-pot coupling reaction in the system PhCH2Br (1 mmol) / ArI (1 mmol) / 2-meracaptobenzoxazole (1 mmol) / CuI (20 mol.%) / proline (20 mol.%)/ Adogen464 / H2O at 160°C. Conclusion: Thus, novel Cu-catalyzed “on-water” method for the synthesis of symmetrical and unsymmetrical sulfides in the system aryl iodides (and benzyl bromide) /2-mercaptobenzoxazole / KOH / CuI / Adogen464 / proline / H2O was presented. Interestingly, similar reaction of 2-mercaptobenzothiazole in the above system led only to 2-arylsulfanylbenzothiazoles. According to our point of view, the presented method is the best for the selective preparation of sulfides possessing NH2, Br and F functional groups.

AIM and Objective: The present work outlines the synthesis of pyrazoles and pyrazolo[1,5- a]pyrimidines from the reaction of 2-aryl-3-oxopropanenitrile with hydrazine monohydrate under different conditions. Reactions of 2-aryl-3-oxopropanenitrile with 2,4-pentanedione or ethyl acetoacetate furnished a mixture of highly functionalized pyridones and enamines through two different mechanistic pathways under various applied conditions. Material and Method: 2-Aryl-3-oxopropanenitriles were prepared according to literature procedures. Other reagents and solvents were purchased and used without further purification. Reactions were carried out either at 0oC, room temperature or under reflux and product was isolated by filtration or concentration of reaction mixture. Results: This article outlines the synthesis of 5-aminopyrazoles and/or pyrazolo[1,5-α]pyrimidines from the reaction of multi-functional 2-aryl-3-oxopropanenitrile with hydrazine monohydrate under various controlled reaction conditions. When 2-aryl-3-oxopropanenitrile reacted with 2,4-pentanedione or ethyl acetoacetate, highly functionalized enamines and pyridines were formed via two different mechanistic pathways. While, novel ethyl 6-amino-5-(4-chlorophenyl)-2-methylnicotinate was obtained from the reaction of (Z)-Ethyl-3-((Z)- 2-(4-chlorophenyl)-2-cyanovinylamino)but-2-enoate with hydrazine monohydrate in ethanol. Conclusion: 2-Aryl-3-oxopropanenitrile proves to be a promising molecule that can be explored further to synthesize new nitrogen compounds which can be used as building blocks in synthetic heterocyclic chemistry.