Letters in Organic Chemistry - Volume 13, Issue 10, 2016

Background: Despite the large number of publications in the synthesis of heterocyclic compounds based on unsaturated lactones, there are no systematic and modern data's on 3-arylmethylidene- 3H-furan-2-ones. These compounds are convenient starting materials for the synthesis of azaheterocycles and are of independent interest as biologically active compounds. This review examines the interaction of (3H) furan-2-ones with a variety of N-nucleophiles. Methods: A systematic search of published data on the interaction of (3H) furan-2-ones with a variety of N-nucleophiles was done. All the information collected was analyzed for quality and reliability. Results: 55 articles were analyzed, of which more than 50% of the articles over the past 15 years. Conclusion: It was shown, that 3-arylmethylidene-3H-furan-2-ones are available as substrates for construction of heterocyclic systems with large preparative capabilities. A wide range of heterocycles has been synthesized, which are promising for further studies as both synthons for fine organic synthesis and substrates for the design of new biologically active compounds.

Background: We have developed a one-pot, simple and efficient protocol for the direct synthesis of symmetrical organic disulfides in high yields via domino reaction between aryl/alkyl halides and Sodium thiosulfate as the sulfur source, in the presence of copper/imidazole and K2CO3. Methods: Owing to the importance seen in the synthesis disulfides, as is evident from the number of publications in the recent past, and our continuing interest in the synthesis of organosulfur compounds using direct synthesis and domino reaction. Herein we designed the synthesis of various disulfide using reaction of aryl/alkyl halides with sodium thiosulfate in presence CuI catalyst, K2CO3 and imidazol as ligand in solvent DMSO. The reaction of iodobenzene with sodium thiosulfate was studied under normal atmospheric conditions in order to optimize the reaction conditions in terms of temperature, amount of reagent and catalyst, and the type of ligand. Results: Effect of solvent and ligand was perceptible, The reaction proceeded not well in the absence of a ligand. The best ligand for these reaction was imidazole. The various solvents tested in this investigation. It was observed that excellent yield of the product was obtained when the reaction was carried out by using DMSO as solvent. The reaction no proceeded in the absence of a base. K2CO3 was a good choice. We examined various amount of the copper salt. It was found to be the best choice in presence 0.7 mmol from copper salt. Also it was significantly found that the reaction yield and rate increased with temperature. The reaction favoured at 130ºC temperature. The 3 mmol Na2S2O3•5H2O concentration was sufficient to give maximum yield of the required product in comparison with other amounts. Diaryl/alkyl disulfides were synthesized in terms of the connecting and type position of the substituents on the aryl/alkyl groups, so that products with different substituents, both electron withdrawing and electron-donating substituent, were synthesized in the ortho, meta and para positions. The results show that iodobenzene and bromobenzene were effective for the reaction. Although it was seen that the reaction cannot progress with compound of aryl chloride. Symmetrical diheteroaryl disulfides were well synthesized from the corresponding heteroaryl iodides, bromides and chlorides. Conclusion: In summary, we have developed a new and effective method for the direct synthesis of diaryl/ alkyl disulfides from various aryl/alkyl halides by domino reaction. In this work reports an effective and cheap metal catalyzed sulfur transfer reaction, which is more economic, and more environmentally friendly and more comprehensive than previous methods. As a novel sulfur source, Na2S2O3 shows notable advantage in this system. This reaction functions under mild conditions, and various functional groups are well tolerated.

Background: Steroidal ribbons (or steroid containing ribbons) are being studied for several reasons, firstly, they may be included in the lipid bilayer, especially if they have suitable size (as “extended cholesterol”), and they are interesting in binding to steroidal receptors, gelators, and/or superassembly synthons. Bile acids seem to be very suitable as their components have natural tendency to form supramolecular assemblies. Methods: Synthesis of ester bonded tetramer of (3α,5β,20S)-3-hydroxy-20-methyl-pregnan-21-oic acid was achieved using 2,6-dichlorobenzoyl chloride and DMAP in toluene. To prepare shortened side chain steroid, the oxidative decarboxylation of protected lithocholic acid was used, followed by oxidation of thus formed terminal double bond. Aggregation properties of the prepared steroidal ribbon were studied alone and after binding with copper(II) ions. Results: There was synthesized 3α-{3α-{3α-[(3α,5β,20S)-3-hydroxy-pregnane-20-carbonyl)oxy]- [(5β,20S)-pregnane-20-carbonyl)oxy]}-[(5β,20S)-pregnane-20-carbonyl)oxy]}-(5β,20S)pregnane-20- carboxylate as a steroidal ribbon derived from bile acid, however, with the shortened side chain. The aggregation of the ribbon prepared in chloroform after binding of Cu(II) ions was monitored by absorption and circular dichroism spectroscopy at different ratios [tetramer]/[Cu(II)]. A positive bisignate band centered at 280 nm emerges; whose intensity increases with the [tetramer]/[Cu(II)] ratio. This result suggests that chiral aggregates are obtained as a consequence of Cu(II) complexation. Time dependent experiments did not show any variation in both UV-Vis and CD spectra. Conclusion: Prepared and documented new type of tetrasteroidal ribbon is unique one for the length of the connecting steroidal side chain. Its construction was done aiming to have more rigid ribbon than the one of lithocholic acid, and on the other hand, less rigid than the one derived from etienic acid. Contrary to the fact that no (chiral) aggregation was found by studying the ribbon itself, absorption and CD spectra showed defined aggregates formed after binding of Cu(II) on tetramer.

Background: In this work a few approaches for the synthesis of 4,4-difluoro-8-(4’- carboxyphenyl)-4-bora-3a,4a-diaza-s-indacene are considered. The process of obtaining this boron fluoride complex involves the following stages: introduction of the protective group (methoxy-, 1’- pyrrolidine-2,5-dion-, trichloroethoxy-) on the carboxy-group of 4-formylbenzoic acid, condensation with pyrrole, removal of protection, oxidation, and complexation proper. A method of direct condensation of pyrrole with the 4-formylbenzoic acid in the presence of a catalytic amount of 0.1 M HCl was proposed to achieve a high yield of the target product. All synthesized compounds were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry and elemental analysis. Values of fluorescence quantum yield and Stokes shift were calculated for boron fluoride complexes of dipyrrolylmethenes. Methods: IR spectra were recorded on a Bruker Vertex 80V device in the regions of 7500–350 cm–1 from pellets with KBr. The NMR spectral studies on the nuclei 1Ц#157; and 13С were performed on a Bruker Avance-500 instrument (500.13 MHz) in CDCl3, the internal standard was TMS. Elemental analyses of crystalline compounds were carried out on a FlashEA 1112 analyzer. Mass spectra were registered on a JMS-700 JEOL (FAB) and JMS-100GCV JEOL (EI) mass-spectrometers. UV/V is spectra and fluorescence spectra were recorded on a spectrofluorimeter СЦ#156; 2203 (SOLAR) in CH2Cl2, with square quartz cavity being 10 mm thick. The fluorescence quantum yield was determined by formula utilizing fluorescein in 0.1 M NaOH as a standard (S=0.85). Results: All the synthesized compounds have a smaller fluorescence quantum yield as compared to the standard and most BODIPY, in which the meso-position does not contain aryl and the other mobile substituents. The decrease in the quantum yield of meso-aryl-substituted BODIPY due to the rotation of the meso-substituent relative BODIPY core leads to non-radiative transitions. Fluorophores are stable upon illumination (no changes in the electronic absorption and fluorescence spectra are observed when they are affected by a continuous light). The Stokes shift is from 30 to 52 nm. Conclusion: A few approaches to synthesize 4,4-difluoro-8-(4’-carboxyphenyl)-4-bora-3a,4a-diaza-sindacene are considered. The process of obtaining this boron fluoride complex involves the following stages: introduction of the protective group (methoxy-, 1’-pyrrolidine-2,5-dion-, trichloroethoxy-) on the carboxy-group of 4-formylbenzoic acid, condensation with pyrrole, removal of protection, oxidation, and complexation proper. A method of direct condensation of pyrrole with the 4-formylbenzoic acid in the presence of a catalytic amount of 0.1 M HCl was proposed to achieve a high yield of the target product. Values of fluorescence quantum yield and Stokes shift were calculated for boron fluoride complexes of dipyrrolylmethenes.

Background: During the last years, condensed pyrimidine compounds have received much attention because of their immense biological properties. These compounds have gained too much interest as proven by large number of reviews and research articles published in the current years. The aim of this manuscript is to develop a one pot reaction for the synthesis of benzothiazole coupled pyrimidine compounds using alkynoic acids and substituted 2-aminobenzothiazoles under normal reaction conditions. Methods: Different 2-aminobenzothiazoles and substituted alkynoic acids have been used to synthesize 2H-Pyrimido[2,1-b]benzothiazol-2-ones via conjugate addition of the imino nitrogen of 2-aminobenzothiazoles to alkyne β-carbon atom of acetylenic acids followed by ring closure. The structural assignments of the synthesized compounds were made on the basis of elemental analysis and spectroscopic data (IR, 1H NMR, 13C NMR and Mass). The synthesized compounds were evaluated for their antioxidant (DPPH and ABTS assays) and antimicrobial activities (using broth microdilution method). Results: The synthesized compounds with different substituent’s were obtained in moderate to good yields (56-75%). Most of the compounds (6a, 7a, 8a) were found to be more active in DPPH and ABTS assays and have also showed significant antibacterial and antifungal activity. Conclusion: A series of novel compounds with high activity and low toxicity synthesized, showed excellent antioxidant activity due to presence of electron donating groups on the ring. Some of the synthesized compounds showed better antimicrobial activity as the electron withdrawing groups on the aromatic ring increases the activity. Thus, the synthesized compounds shall prove as future antioxidant and antimicrobial drugs with further research.

Background: An expeditious approach has been developed for the synthesis of two distinct classes of benzopyrones viz. flavones and coumarins under solvent-free conditions. L-Ascorbic acid was found to be an effective promoter under microwave irradiation and conventional heating. Various benzo-α-pyrones and benzo-γ-pyrones were synthesized with overall good yields. The present protocol is highly facile and needs no column chromatography for purification and therefore it would serve as an effective and compatible method under both microwave irradiation and conventional heating. Results: The catalytic ability of L-ascorbic acid was investigated for the synthesis of flavones and coumarins. For this purpose, cyclodehydration of 1-(2-hydroxyphenyl)-3-aryl-1,3-propanedione and Pechmann coumarin synthesis, reactions were selected. And accordingly, it was observed that one mole of L-ascorbic acid was necessary for the completion of reaction. In all the cases, the desired flavones were smoothly generated with good to excellent yields; indicating its excellent tolerance for various functional groups. However, electron donating groups favors coumarin synthesis under these conditions. All the reaction mixtures were carefully analyzed and NMR indicates high conversions and lack of side products. Conclusion: We have developed L-ascorbic acid-promoted, solvent-free and simple method for the synthesis of benzo-α-pyrones and benzo-γ-pyrone under microwave irradiation as well as conventional heating in good to excellent yields. The notable advantages of this method are solvent-free conditions, inexpensive and efficient eco-friendly promoter, and shorter reaction time and can be carried out under air. This methodology is highly facile and requires no column chromatography for purification. The resulting flavones and coumarins are versatile building blocks in the construction of heterocyclic architectures, dominant in natural products. Further studies of exploiting the efficiency of L-ascorbic acid as a promoter in synthesis of various heterocyclic compounds are in progress.

Background: A green path for the synthesis of 3-aryl-1-phenyl-4-(4,5-diphenyl-1H-imidazol-2-yl)-1Hpyrazole derivatives using [BMIM][BF4] as a catalyst and green methods such as ultrasound and microwave irradiation is discussed in this paper. The titled compounds were obtained by the multi-component condensation of various 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehydes, benzil and ammonium acetate. One pot synthesis, simple reaction conditions and quantitative yields illustrate the utility of this green approach. Methods: Conventional Reflux Condition: A mixture of 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM][BF4] (15 mmol %) was placed in a round bottom flask containing 10 mL of ethanol. The reaction mixture was refluxed for completion. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was poured over crushed ice. Solid imidazole thus obtained was separated by filtration, dried well, and recrystallized by ethanol. Ultrasound Irradiation Method: A mixture of 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM][BF4] (15 mmol %) was placed in a round bottom flask containing 10 mL of ethanol. The round bottom flask was placed in an US bath at 50ºC for 80-90 min. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was poured into crushed ice, solid imidazoles thus obtained were separated by filtration, dried well, and recrystallized by ethanol. Microwave Irradiation Method: A 10 mL round bottom flask was charged with 3-aryl-1-phenyl- 1H-pyrazole-4-carboxaldehyde 1 (1 mmol), benzil 2 (1 mmol), ammonium acetate 3 (2 mmol) and catalytic amount of [BMIM] [BF4] (15 mmol %), and placed under MW irradiation at 240 watts for 7-9 min. The course of the reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was poured over crushed ice, the solid imidazole thus obtained was separated by filtration, dried well, and recrystallized by ethanol. Results: The 3-aryl-1-phenyl-4-(4,5-diphenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives 4a-i (Scheme 1, Table 2) were synthesized by using [BMIM] [BF4] as a catalyst with good yields under reflux in ethanol (68-70%), US irradiation in ethanol (76-80%) and MW irradiation (80-86%) without solvent. All these methods provided good results with IL [BMIM][BF4]. However, the MW and US irradiation methods give good yield in a short period of time with 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehyde 1 containing a variety of substituents, whereas the conventional reflux condition gives lower yields and takes longer time as compared with MW and US irradiation. The structures of the synthesized compounds have been confirmed on the basis of spectroscopic techniques such as FTIR, HRMS, LCMS, 1H and 13C NMR. Conclusion: In conclusion, we have synthesized differently substituted imidazoles using [BMIM][BF4] as a catalyst under MW and US irradiation via MC condensation strategy. Under the conventional reflux conditions, we get a lower yield in a longer time, while US and MW assisted synthesis gave better results. Comparatively IL [BMIM][BF4] with US and MW irradiation protocol provides several advantages such as improved reaction speed, shorter reaction times, superior yields and a significant contribution towards sustainability.

Background: Sulfoxides and sulfones have been in the center of attention due to their wide range of promises in various approaches. The functional groups presented in these compounds serve as important building blocks in numerous natural, pharmeceutical and agricultural compounds. These deriatives have been prepared through a multitude of routes which were accompanied by several drawbacks. Therefore, there has been an ever-increasing interest to find a new methodology that leads to the production of these compounds via an environmentally benign path bringing about high yields. Recently, gem-dihydroperoxides have attracted much attention due to their oxidizing power and they have been utilized in several oxidation processes. Methods: We carried out a chemoselective oxidation of sulfides to sulfoxides and sulfones on treatment with urea-2,2-dihydroperoxypropane, a solid oxidant composed of equal amounts of 2,2- dihydroperoxypropane and urea, using THF as the solvent under catalyst-free conditions at room temperature. Results: Sulfides possessing a variety of substitutions namely dialkyl, diaryl, ally l and alkyl-aryl were subjected to the optimized reaction conditions and they could successfully afford different amounts of sulfoxides and sulfones depending on the amount of the oxidant utilized. Based on the results, electrondonating groups accelerated the reaction while electron-withdrawing substituents lowered the reactivity. Conclusion: Urea-2,2-dihydroperoxypropane as a solid oxidant which can be stored for several months without any loss in its activity has proved its capability to oxidize sulfides to sulfoxides and sulfones under catalyst-free and mild conditions. This approach is a cost-effective and environmentally benign methodology via which the products have been synthesized in high yields and short reaction times.

Background: Nitrosocarbonyl intermediates are fleeting compounds obtainable from the periodate oxidation of hydroxamic acids and easily trapped with dienes and alkenes to give the products of hetero Diels-Alder and ene reactions in high yields. Methods: A fleeting heterocyclic nitrosocarbonyl derived from the corresponding nitrile oxide is at work in a short-cut synthesis of 4-bromo-N-[(1R*,4S*)-4-hydroxy-2-cyclohexen-1-yl]-2-thiazolecarboxamide. The synthetic strategy is based on hetero Diels-Alder cycloaddition followed by mild reductive cleavage of the N-O bond. Results: A new 2-thiazolecarboxamide derivative is obtained in good yields and the results of the invitro antiviral tests are briefly discussed. The product was found active against HPV virus and some structural evidences allow shining some light on future perspectives on the application of pericyclic reactions to the synthesis of biological active molecules. Conclusion: The findings demonstrated that the synthetic methodology works well for the preparation of heterocyclic substituted novel compounds that displayed interesting and promising activity against viruses and in particular against the HPV.

Background: As the phenols and its derivatives are considered as versatile precursors, herbicides, drugs and antioxidants, the synthesis of phenols has been gaining much attention during the last decades. Despite the numerous methods for phenol synthesis there is a serious need for “green” protocols with greater environmental benign and economic viability. Method: We used a highly abundant and inexpensive natural feedstock WEBPA (Water Extract of Banana Peel Ashes) with 30% aqueous H2O2 as an oxidant for the synthesis of phenol and its derivatives. Results: Ipso-hydroxylation of twelve different types aryl and hetero aryl boronic acids with both electron donating and electron withdrawing groups such as OMe, Me, Cl, NO2, COMe etc. has been carried out by the newly developed protocol with excellent yields in a short period of time. The catalytic system has also been found effective up to 5th cycle without significant loss of activity. Conclusion: In conclusion, we have developed a reusable, mild, and efficient protocol for the ipsohydroxylation of aryl/heteroarylboronic acids. This protocol seems to be one of the greenest and economic alternatives to the existing protocol.

Background: We synthesized two new organic chelating agents, such as 2-thiophene carboxaldehyde-4- phenylthiosemicarbazone (TCPTSC) and 4-methylbenzaldehyde-4-phenylthiosemicarbazone (MBP TSC) and applied to chelation with Cd(II). Both the ligands (TCPTSC and MBPTSC) their Cd(II) complexes [(Cd-(TCPTSC-H)2) and (Cd-(MBPTSC-H)2)] are characterized by molar conductivity measurements, elemental analysis, FT-IR, 1H NMR spectroscopy, X-ray powder diffraction (XRD), and field emission scanning electron microscopy (FESEM). Initially the formation of TCPTSC and MBPTSC and their Cd(II) complexes is confirmed by FTIR. Thermogravimetric studies reveal the thermal stability of Cd(II) complexes over their ligands. The XRD and SEM studies reveal the change in crystal structure and morphology of both the TCPTSC and MBPTSC due to chelation with Cd(II). Methods: Molar conductivity measurements were carried out with conductivity portable meter Profiline Cond 3110 (WTW, a xylem brand, Germany). The FTIR spectra of TCPTSC and MBPTSC and their complexes were recorded on a Nicolet FT-IR 560 Magna spectrometer. Elemental analysis (N, C, H, and S) for TCPTSC and MBPTSC and their complexes was performed on Thermo Scientific elemental analyzer (Thermo Eager 300 Flash EA1112, Waltham, MA, USA). Powder XRD (PAN analytical X’pert PRO, Boulder, CO, USA) was carried out using CuKα (0.154056 nm) radiation at 40 kV and 30 mA. The data was collected between 10º and 60º 2 with a step size of 0.02º. The morphology of the crystals and powder was examined by FESEM (S-4200, Hitachi, and Tokyo, Japan). An ultra-thin layer of platinum was sputter-coated (E-1030 Ion Sputter, Hitachi, Japan) on the powder sample surface to improve the conductivity during the FESEM measurements. The 1H NMR spectra for both TCPTSC and MBPTSC and their complexes were obtained from NMR-vnmrs 600 instrument (Agilent, Santa Clara, CA, USA). Thermogravimetric analysis (DSC-TGA) was carried out in the temperature range of 25-800 ºC in nitrogen atmosphere and a heating rate of 10 ºC/min using SDT Q600 V20.9 Build 20 (TA instruments, Waters, USA). Results: The present study confirms the synthesis of new organic chelating agents, such as 2-thiophenecarboxaldehyde- 4-phenylthiosemicarbazone, 4-methylbenzaldehyde-4-phenylthiosemicarbazone. The chelation of these organic chelating agents with Cd(II) was also confirmed by various analytical techniques, such as elemental analysis, FT-IR, 1H NMR, XRD, and SEM. The thermogravimetric studies were performed to evaluate the thermal stability of free TCPTSC and MBPTSC and their Cd(II) complexes. The thermogravimetric studies reveal that the TCPTSC and MBPTSC lost over 97% weight at 800ºC whereas; the complexes still have a weight of 14-25%. Molar conductivity studies reveal that the complexes are neutral. The molar conductivity and elemental analysis studies predicted the tetrahedral geometry of both Cd(II) complexes. Conclusion: To evaluate more crystal studies of TCPTSC and MBPTSC and their complexes, single crystal studies are in progress. From the literature it was revealed that thiosemicarbazones and their metal complexes have biological activities, such as anti-bacterial, anti-fungal and anti-oxidants.