Current Organic Synthesis - Volume 15, Issue 8, 2018

Background: 1,4-Dithiane-2,5-diol (1,4-DTD) is the stable dimer of α-mercapto acetaldehyde. This commercially available ambidentade compound is characterized as having in its chemical structure one group that acts as an electrophile and another that acts as a nucleophile, this permits its use as versatile and efficient synthon in synthetic heterocycle procedures. Objective: The aim of this review is to present synthetic applications of 1,4-DTD in heterocyclic chemistry and their applicability to the synthesis of bioactive compounds. Conclusion: Gewald reactions to obtain C-4 and C-5 unsubstituted 2-amino-thiophene derivatives; sulfa- Michael/Henry and sulfa-Michael/aldol sequences to obtain polysubstituted tetrahydrothiophenes, and other heterocyclic reactions that allow synthesizing several functionalized sulfur-containing heterocycles such as thiazolidines, oxathiazinoles and thiazoles are presented and discussed. The use of such heterocyclics in subsequent reactions allows obtaining various bioactive compounds including the antiretroviral lamivudine which is one of the examples presented in this review.

Background: The majority of naturally occurring compounds, pharmaceuticals, and drug-candidate molecules possess heterocyclic scaffolds. In this context, tetrahydobenzo[b]pyrans are of considerable importance. In the line with the synthesis of these valuable heterocyclic compounds, the researchers tried to synthesize these molecules using different organocatalysts. The development of new strategies for three-component condensation of dimedone, various aldehydes and malononitrile for construction of tetrahydrobenzo[b]pyrans is of particular interest to organic chemists and pharmacologists. Objective: In this review, three-component catalyzed synthesis of tetrahydrobenzo[b]pyran compounds is introduced, focusing on the developments in the use of organocatalysts. Organocatalytic approaches were investigated for the synthesis of tetrahydrobenzo[b]pyrans. This contribution covers the literature concerning the synthesis of heterocycles referred to, in recent times. Conclusion: This review article is associated with the study of the three-component synthesis of tetrahydrobenzo[b]pyrans using organocatalysts. This review also provides an insight into the importance of these heterocycles. In the vast majority of these reactions, water and water-ethanol system have been used as green solvent media for implementation of them. The use of green solvents, the development of less toxic and promising reagents/catalysts as well as the design of inexpensive and reliable approaches are some of the principles of green chemistry, and most of the methods are benefited from them. Tetrahydrobenzo[b]pyrans and organocatalysts open avenue ofnew horizons. The recyclability of the many of these organocatalysts offers an additional merit for the use of these catalysts in 3-CR of aldehydes, dimedone, and malononitrile reactions.

Background: The use of solid bases as heterogeneous catalysts allows the replacement of conventional bases in Organic Chemistry, being of outmost importance. Lamellar double hydroxides or hydrotalcites are materials having excellent basic properties and high surface areas. As their surface properties have been used as bifunctional catalysts allowing the incorporation of metals and depending on the calcination temperature, these materials may exhibit Lewis or Brönsted basic sites. Additionally, they are widely used in various organic synthesis reactions. Objective: This contribution has been aimed to provide a compilation of the application of hydrotalcites as basic materials in organic synthesis, with a particular emphasis on multicomponent reactions. Conclusion: Hydrotalcites act as heterogeneous catalysts that conduct highly efficient processes in short reaction times and with the advantage of their easy recovery and reuse without significant loss of their catalytic activity. In addition, due to the modification of their structural and chemical properties, they are catalysts with multiple applications in organic synthesis such as Michael addition reactions, dehydrogenation reactions of alcohols, Knoevenagel condensations, reduction reactions, oxidations, epoxidations, multicomponent reactions, among others. Multicomponent reactions are of major interest since they allow obtaining compounds that have high biological activity and are generated through processes in a single step by combining three or more starting reagents under solvent-free conditions.

Dioxiranes are three-membered strained ring peroxides that are typical archetype examples of electrophilic entities. A dioxirane-based oxidant named 3-methyl(trifluoromethyl)dioxirane (TFDO) is a fluorinated analogue of the extremely valuable oxidant dimethyldioxirane (DMDO). Owing to the strained threemembered ring and presence of electron-withdrawing trifluoromethyl group, TFDO is several times more reactive than DMDO and acts as a significant chemical reagent. Moreover, TFDO exhibits high regio-, chemo- and stereo-selectivity even under unusual reaction conditions, i.e. at pH values close to neutrality and at subambient temperatures. The TFDO transfers an oxygen atom to “unactivated” carbon-hydrogen bonds of alkanes as well as to the double bonds of alkenes and also helps in oxidation of compounds containing heteroatoms having a lone pair of electrons, such as sulfides and amines. TFDO-mediated oxidation is considered to be one of the main procedures in the 21st century for the synthesis of oxygen-containing organic molecules. This review throws light on the applications of TFDO in organic syntheses to provide an insight into the future research and gives a comprehensive summary of the selective functionalization of activated and non-activated organic compounds.

Background: We present here the synthesis of 1,3-thiazolidin-4-one (1) and its functionalised analogues, such as the classical isosteres, glitazone (1,3-thiazolidine-2,4-dione) (2), rhodanine (2-thioxo-1,3- thiazolidin-4-one) (3) and pseudothiohydantoin (2-imino-1,3-thiazolidin-4-one) (4) started in the midnineteenth century to the present day (1865-2018). Objective: The review focuses on the differences in the representation of the molecular structures discussed here over time since the first discussions about the structural theory by Kekulé, Couper and Butlerov. Moreover, advanced synthesis methodologies have been developed for obtaining these functional group, including green chemistry. We discuss about its structure and stability and we show the great biological potential. Conclusion: The 1,3-thiazolidin-4-one nucleus and functionalised analogues such as glitazones (1,3- thiazolidine-2,4-diones), rhodanines (2-thioxo-1,3-thiazolidin-4-ones) and pseudothiohydantoins (2-imino-1,3- thiazolidine-2-4-ones) have great pharmacological importance, and they are already found in commercial pharmaceuticals. Studies indicate a promising future in the area of medicinal chemistry with potential activities against different diseases. The synthesis of these nuclei started in the mid-nineteenth century (1865), with the first discussions about the structural theory by Kekulé, Couper and Butlerov. The present study has demonstrated the differences in the representations of the molecular structures discussed here over time. Since then, various synthetic methodologies have been developed for obtaining these nuclei, and several studies on their structural and biological properties have been performed. Different studies with regards to the green synthesis of these compounds were also presented here. This is the result of the process of environmental awareness. Additionally, the planet Earth is already showing clear signs of depletion, which is currently decreasing the quality of life.

Background: The synthesis of N-polyheterocycles by environmentally benign method is highly attractive but challenging proposition. New strategies have been developed for the preparation of polycyclic heterocycles in the last decades. In this review article, the synthesis of nitrogen containing six-membered polycyclic heterocyclic compounds is presented with the application of ionic liquids. This contribution focuses on the literature related to the total synthesis of six-membered N-polyheterocycles. Objective: Ionic liquids not only acted as environmentally benign reaction media but also as catalysts which afforded the very promising replacements of traditional molecular solvents in organic chemistry due to their stability, non-flammability, non-volatility and ease of recyclability. Ionic liquids are utilized in metal catalyzed reactions in place of organic solvents in the last years. It has attracted considerable attention in recent years. Ionic liquids acted as alternatives of organic solvents and these ILs are environment friendly. Conclusion: In the area of green chemistry ionic liquid assisted synthesis is a very promising technique which afforded a flexible platform for the formation of heterocycles. The influence of ILs on the development of efficient and new synthetic protocols over the last decade for the construction of N-polyheterocycles is featured in this review article. These synthetic strategies will continue to attract more attention and will find a wide range of applications in organic synthesis. In conclusion, ionic liquids assisted syntheses have become an efficient and powerful tool in organic chemistry quickly.

Aim and Objective: We studied the synthesis of new groups of functionalized isobenzofurans and isoindolines by selective gold catalyzed cycloisomerization of some new optically active furandialkynes derived from the natural furanolabdanoid lambertianic acid. Functionalized isobenzofurans and isoindolines are considered as privileged structures that are currently experiencing a renewed interest in medicinal chemistry. Materials and Methods: Using the AuCl3-catalyzed cycloisomerization of furanolabdanoid dialkynes we synthesized several new groups of biologically interested isobenzofurans and isoindolines with labdanoid substitution. The structure of all new compounds was proven by elemental and spectral analysis: IR, mass-, and NMR data. Results: The synthesis of 15,16-dialkynyl substituted furanolabdanoids was carried out. Au(III)-Catalyzed cycloisomerization of those compounds proceeded highly selectively with the formation of optically active 4- substituted 7-hydroxy-3(6)-propargylaminomethylisobenzofurans or 7-hydroxy-3(6)-propargyloxymethylisoindolines. The cycloisomerization of the 15-(prop-2-yn-1-yloxymethyl)-16-((N-p-toluenesulfonyl)-prop- 2-yn-1-ylaminomethyl)labdatriene proceeded in part on the 15 position and involved the previously unknown intramolecular transfer of N-(p-toluenesulfonyl)propargylaminomethyl substituent to the oxygen in the stage of formation of an aromatic ring. A feasible reaction mechanism for this transformation is presented. It was revealed that the conversion of labdanoid furan-15-ynes to 1,3-dihydroisobenzofurans depends on the nature of the substituent in the 16 position of the furanolabdanoid. Conclusions: The present study sheds light on the Au(III)-catalyzed cycloisomerization of new group of highly functionalized furandialkynes. Also, new groups of alkynyloxymethyl or alkynylaminomethyl substituted optically active isobenzofurans and isoindolines were obtained and fully characterized.

Aims and Objectives: The aim of the research is to obtain and to investigate the cytotoxicity of a novel class of non-toxic oximes – derivatives of N-(benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-ω- (hetarylsulfanyl)-alkanamidines. Materials and Methods: To assess the possible toxicity of the compounds, acute oral LD50 was calculated. The calculations were based on tested compounds IC50 values in relation to 3T3 (mouse fibroblast cell line) using NRU assay. Monolayer tumor cell lines HT-1080 (human fibrosarcoma, ATCC® CCL-121™), MH-22A (mouse hepatoma, ECACC code, 96121721) and NIH/3T3 (mouse Swiss Albino embryo fibroblasts, ATCC® CRL-1658™), were cultured in standard medium (Dulbecco`s modified Eagle`s medium) supplemented with 10% fetal bovine serum (“Sigma”). Results: E-Stereoselective synthesis of novel N-(benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-ω- (hetarylsulfanyl)alkanamidines as potential cytotoxic agents was carried out in three steps from corresponding thiones. N-(Benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-5-(benzothiazol-2-ylsulfanyl)-pentanamidine exhibits high activity in vitro on the monolayer tumour cell lines: MG-22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). Besides this, the above compound exhibits low toxicity on the 3T3 cell line and low estimated acute oral LD50 (LD50 2759 mg/kg). Conclusion: In conclusion, such dramatic decreasing of expected acute toxicity and high cytotoxicity by the introduction of benzo[4,5]imidazo[2,1-b]thiazolyl fragment into N-hydroxy-ω-(hetarylsulfanyl)alkanamidines were demonstrated for the first time (see, for example, toxicity and cytotoxicity of compound 8b and corresponding unsubstituted oxime).

Background: 1, 3, 4-thiadiazoles, 1, 3, 4-thiadiazines and thienopyrimidines have newly attracted attention due to their forceful pharmacological activities. They showed antimicrobial, antiviral, analgesic and anti-inflammatory properties. Objective: The aim of this research is to synthesize new thiadiazolothienopyrimidines (2-10), thienopyrimidothiadiazines (11-15), quinoxaline-thienopyrimidinones (16) and thienopyrimido- thiadiazinoquinoxalinones (17) via effectual high yield procedure for assessing their antimicrobial activity. Method: A series of new 1, 3, 4-thiadiazolothienopyrimidines, thienopyrimidothiadiazines and thienopyrimidothiadiazinoquinoxalinones was prepared from 6-acetyl-3-amino-5-methyl-2-thioxo-2, 3-dihydrothieno [2, 3-d] pyrimidin-4(1H)-one (1) as the beginning material. Results: The 1, 3, 4-thiadiazoles, 1, 3, 4-thiadiazines derivatives (1-17) were synthesized in adequate to good yields (60-85%) in a stepwise effectual procedure under condition. The chemical structures of these new compounds were confirmed via many spectroscopic techniques as UV, IR, NMR, mass spectra and elemental analysis. In vitro, antimicrobial was evaluated for the synthesized compounds using minimal inhibitory concentration of these compounds against bacteria and fungi. Conclusion: The 1, 3, 4-thiadiazole and 1, 3, 4-thiadiazine derivatives (15-17) exhibited higher antimicrobial activity (Gram-positive, Gram-negative bacteria and fungi) compared with the standard antibiotic drugs; Levofloxacin (Tavanic) and Nystatin.

Aim and Objective: In this study, a new series of iminopyrimidine derivatives were synthesized from the reaction of the key intermediate 2-imino-6-phenyl-2,3-dihydropyrimidin-4(5H)-one 4 with a variety of electrophilic and nucleophilic reagents under a variety of mild conditions. The structures of the newly synthesized compounds were characterized on the basis of their elemental analysis and spectroscopic data. The antimicrobial activity of this series was evaluated in vitro and they showed either weak or moderate activities. Materials and Methods: All melting points were measured using Akofler Block instrument and are uncorrected. IR spectra (KBr) were recorded on FTIR 5300 spectrometer (υ, cm-1). The 1H NMR spectra were recorded on a Varian Gemini spectrometer. The 1H NMR spectra were run at 400 MHz and 13C NMR spectra were run at 100 MHz in DMSO-d6 as a solvent. The chemical shifts are expressed in parts per million (ppm) by using tetramethylsilane (TMS) as an internal reference. 1000 EX mass spectrometer at 70 eV. The purity of synthesized compounds was checked by Thin Layer Chromatography (TLC) (aluminum sheets) using n-hexane, ethyl acetate (7:3, V/V) eluent. Elemental analysis was carried out by the Microanalytical Research Center, Faculty of Science, and Microanalytical Unit, Faculty of Pharmacy, Cairo University, Egypt. Conclusion: In conclusion, compounds 4, 5 and 12 were used as efficient precursors for the synthesis of new heterocycles including 2-imino-2,3-dihydropyrimidine moiety with expected biological activities.

Aim and Objective: A simple catalytic method has been developed to achieve the reduction of nitroarenes with NaBH4 using diphenyl diselenide catalyst in order to obtain the azoxyarene, azoarene products under mild conditions. Materials and Methods: The reduction of different substituted nitroarenes was realized in alkaline ethanolic solution using mild sodium borohydride in the presence of diphenyl diselenide as an electron-transfer catalyst. The reactions were performed sometimes at room temperature and sometimes at refluxing conditions. Results: Diphenyl diselenide which is reduced to sodium phenylselenolate, presenting an electron transfer agent successfully permitted to reduce several nitroarenes, bearing different substituent groups whose electronic effects promote the formation of the azoxy or azo compounds. Conclusion: Treatment of nitroarenes with sodium borohydride in alkaline ethanol in the presence of catalytic amounts of diphenyl diselenide at room temperature leads to obtain the corresponding azoxy compounds in good yields by reaction with sodium phenylselenolate generated in situ. At higher temperature, further reduction to azo compounds occurs. Therefore, the results have indicated that the electronic effects of substituent groups rigorously take part in determination of their reduction efficiencies.