Current Organic Synthesis - Volume 15, Issue 3, 2018

Background: The chemists have been interested in light as an energy source to induce chemical reactions since the beginning of the scientific chemistry. This review summarizes the chemistry of photochemical reactions with emphasis of their synthetic applications. The organic photochemical reactions avoid the polluting or toxic reagents and therefore offer perspectives for sustainable processes and green chemistry. In summary, this review article describes the synthesis of a number of six-membered O-heterocycles. Objective: Photochemistry is indeed a great tool synthetic chemists have at their disposal. The formation of byproducts was diminished under photochemical substrate activation that usually occurred without additional reagents. Photochemical irradiation is becoming more interesting day by day because of easy purification of the products as well as green chemistry. Conclusion: This review article represents the high applicability of photochemical reactions for organic synthesis and research activities in organic photochemistry. The synthesis of heterocyclic molecules has been outlined in this review. Traditional approaches require expensive or highly specialized equipment or would be of limited use to the synthetic organic chemist due to their highly inconvenient approaches. Photochemistry can be used to prepare a number of heterocycles selectively, efficiently and in high yield.

Background: In recent years, the development and diversification of heterocyclic compounds has become central to the discovery of bioactive compounds with novel or improved pharmacological properties. In particular, N-containing heterocycles are proved to be promising leads and drug candidates, and received huge attention of the medicinal chemists. Objective: Many drugs especially antibiotics are becoming obsolete due to the development of multidrug resistance. Moreover, toxicity and other side effects of some drugs necessitated the quest for safer and more potent drug candidates. The current review article described biological potential of various monocyclic azoles. Recent developments in the synthesis of azole derivatives have been also reviewed. Conclusion: The presence of N-heterocyclic rings can influence the pharmacokinetics, pharmacodynamics, pKa and bioavailability profile of the drug molecules. Compounds containing monocyclic azole rings showed various biological activities and number of molecules are in clinical practice. A number of important leads and potential drug candidates containing azole nucleus are in advance stages of drug developments. Thus, simple, atom economic and more efficient synthetic strategies are desired for the synthesis of new libraries of the compounds.

Background: Xanthene is pharmacologically important oxygen containing heterocyclic moeity exhibiting an array of potent biological activities like antibacterial, antiviral, antiinflammatory, antitumor, antioxidant, antiplasmodial etc. Other useful applications of these heterocycles are as fluorescent materials for the visualization of biomolecules and in laser technology. Objective: This review gives an insight of the literature available on the methods for the construction of xanthene nucleus. This review article can be reasonably encouraging for those involved in the synthesis of molecules exhibiting a wide range of biological activities involving xanthene as central nucleus and would provide them assistance in developing new eco-friendly, efficient and economical viable methods. Conclusion: Owing to diverse applications of xanthenes, various synthetic methodologies have been developed, whether to construct this privileged scaffold. Many of the reported methods involve the use of various harsh catalysts/reagents that are not environmentally benign, produce a large amount of waste and need longer reaction times. The sustainable and diversity oriented synthesis of xanthene scaffold which incorporates Green Chemistry tools like multicomponent reaction approach, heterogeneous catalysts, alternate reaction media such as water, ionic liquids, polyethylene glycol etc. has also been developed.

Aim and Objective: Although many synthetic methods are known for seven-membered N,Oheterocycles, most of them focus on fused benzoxazepines. In fact, an exhaustive searching of the literature revealed that very few synthetic approaches for non-fused 1,4-oxazepanes have been reported. Thus, straightforward and efficient synthetic strategies for the construction of diversely substituted 1,4-oxazepanes would be a welcome access to a relatively underexplored chemical space. Two of these strategies were undertaken in this study. Materials and Methods: One of our reactions proceeded by the treatment of ethanolamines with polyformaldehyde and N-vinylpyrrolidin-2-one in ACN as solvent at room temperature in order to obtain the title 1,4- oxazepane derivatives. Alternatively, through a careful temperature control, analog structures were selectively obtained from a H2SO4 catalyzed intramolecular etherification reaction of diversely substituted N-tethered bisalcohols in p-dioxane as solvent. Results: Based on intramolecular etherifications, two strategies (i.e. a three-component Mannich-type approach and cyclization of N-tethered bis-alcohols), were implemented for the synthesis of novel and diversely 4,7- disubstituted 1,4-oxazepanes in moderate to good yields. Structures of the new obtained compounds were confirmed by 1- and 2D NMR techniques as well as MS spectra. Conclusion: According to the results, the above intramolecular etherification reactions proceeded with the formation of benzylic carbocations as the key intermediates for the generation of the title compounds. Temperature and the nature of the R1 substituent in the N-tethered bis-alcohols were critical variables for the selective formation of the desired products from this kind of precursors.

Aim and Objective: Pyrazolone sulfones have been reported to exhibit herbicidal and antibacterial activities. In spite of their good bioactivities, only a few methods have been developed to prepare pyrazolone sulfones. However, the substrate scope of these methods is limited. Moreover, the direct sulfonylation of pyrazolone by aryl sulfonyl chloride failed to give pyrazolone sulfones. Thus, developing a more efficient method to synthesize pyrazolone sulfones is very important. Materials and Method: Pyrazolone, aryl sulphonyl hydrazide, iodine, p-toluenesulphonic acid and water were mixed in a sealed tube, which was heated to 100°C for 12 hours. The mixture was cooled to 0°C and m-CPBA was added in batches. The mixture was allowed to stir for 30 min at room temperature. The crude product was purified by silica gel column chromatography to afford sulfuryl pyrazolone. Results: In all cases, the sulfenylation products were formed smoothly under the optimized reaction conditions, and were then oxidized to the corresponding sulfones in good yields by 3-chloroperoxybenzoic acid (m-CPBA) in water. Single crystal X-ray analysis of pyrazolone sulfone 4aa showed that the major tautomer of pyrazolone sulfones was the amide form instead of the enol form observed for pyrazolone thioethers. Moreover, the C=N double bond isomerized to form an α,β-unsaturated C=C double bond. Conclusion: An efficient method to synthesize pyrazolone thioethers by iodine-catalyzed sulfenylation of pyrazolones with aryl sulfonyl hydrazides in water was developed. Moreover, this method was employed to synthesize pyrazolone sulfones in one-pot by subsequent sulfenylation and oxidation reactions.

Background: Indolizine pharmacophore is known to exhibit various promising pharmacological properties such as analgesic, anticancer, antihistaminic, antidiabetic, anti-inflammatory, antileishmanic, antimicrobial, antimutagenic, antioxidant, antitubercular, antiviral, larvicidal and herbicidal activities. Objective: In the present investigation, it was envisaged to synthesize a series of novel ethyl-7-substituted-3-(4- substituted benzoyl)-2-substituted indolizine-1-carboxylates by employing chromium(IV)oxide as dehydrogenating agent with triethylamine combination. Method: Synthesis of a series of proposed polysubstituted indolizines by employing chromium(IV)oxide as dehydrogenating agent with triethylamine combination. Final compounds were characterized by spectroscopic techniques viz fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, liquid chromatography- mass spectrometry, elemental analysis and selected title compound diethyl-3-(4- cyanobenzoyl)indolizine-1,2-dicarboxylate by single crystal X-ray method. Results: Aromatic cycloimmoniumylides undergo smooth cyclization with electron-deficient alkenes in the presence of triethylamine and DMF at room temperature to afford intermediates ethyl 7-substituted-2- substituted-3-(4-substituted benzoyl)-1,2,3,8a-tetrahydroindolizine-1-carboxylates, which on dehydrogenation with chromium(IV)oxide to obtain the title compounds ethyl-7-substituted-3-(4-substituted benzoyl)-2- substituted indolizine-1-carboxylates. Conclusion: The research was focused on developing an efficient protocol for the synthesis of a novel series of ethyl 3-substituted benzoyl-7-substituted-2-substituted indolizine-1-carboxylates with suitable pharmacological properties in good to excellent yields.

Aim and Objective: Ceria loaded on solid zirconia was employed as heterogeneous catalyst for the synthesis of pyridine derivatives via a one-vessel, four-component reaction consisting of substituted aldehyde, malononitrile, dimethylacetylenedicarboxylate and dimethylaniline with good to excellent product yields (87 to 95%). The noteworthy advantages of the facile method with ethanol as solvent are excellent yields with short reaction times. Catalyst is reusable with little loss of activity up to six rounds. Materials and Method: All the catalyst materials were synthesized by using simple wet-impregnation method. The powder X-ray diffraction, TEM, SEM and N2 adsorption/desorption analysis techniques were employed for the structural interpretation of CeO2/ZrO2, the identity of target products were established and confirmed by diverse spectral (1H NMR, 13C NMR, 15N NMR, FT-IR and HRMS) techniques. Results: As convincingly demonstrated by the synthetic approaches reported in this review, MCRs have facilitated many new methodologies with significant advantages for efficient and well organized synthesis of varied pyrazole derivatives. The methodology involved variety of options for catalysts that can be chosen using different solvents or solvent-free conditions and/or using alternative energy-efficient options such as microwave irradiation and sonification. This review brings together ample material about synthesis of varied pyrazole derivatives that may have prodigious scope, in drug design and therapeutics. It is anticipated that research efforts in this direction will endure in the search for novel, atom efficient, small molecules with excellent drug-like properties. Conclusion: In this study, we report on a green and efficient one-pot protocol for the synthesis of functionalized 1,4-dihydropyridine-2,3-dicarboxylate derivatives through a four-component reaction between malononitrile, dimethylacetylenedicarboxylate, dimethylaniline and substituted aldehydes using 2.5% CeO2/ZrO2 as a catalyst in EtOH and at room temperature. This methodology has several advantages such as short reaction times (< 30 min), high product yields (87-95%), ease of handling, facile and green work-up. The easy recoverable and reusable catalyst meets the industrial and environmental requirements and is versatile and cost effective.

Background: The regioselective synthesis of spiro-heterocyclic compounds is intriguing since those compounds have unique non-planar structures and great potential for binding to biomolecules because of their inherent rigid chiral structure. A novel class of furanone and spiro-heterocyclic derivatives were synthesized and evaluated for antifungal activities to establish structure-activity relationship (SAR). Results: The synthesis was carried out through one-pot multicomponent reaction (MCR) of 4-aryl-4-oxo-2- butenoic acids, camphor, urea, and hydrogen peroxide in the presence of sodium ethoxide as a catalyst using a microwave irradiation method and / or a traditional thermal method. They are used as key starting materials to synthesize some heterocyclic compounds. Structures of all synthesized compounds were elucidated by elemental analyses and spectroscopic data. Conclusion: A facile and efficient method for the preparation of a new furanone, chalcone and spiropyrimidone derivatives via the one-pot MCR with the microwave-assisted irradiation was established.

Aims and Objective: A series of novel phthalazine derivatives was synthesized with versatile, readily accessible electrophilic and nucleophilic reagents. The newly synthesized compounds were confirmed by the results of spectroscopic measurements. Hence, their potential clinical application investigated in particular for cancer treatment. Materials and Methods: The newly synthesized compounds were characterized by spectroscopic measurements and were tested for their in vitro anticancer activity by MTT assay against human liver cancer cell line. Docking study of all the synthesized compounds was performed within the active site of the enzyme VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2). Results: The quinazoline derivative 12 emerged as the most potent compound in this study with an IC50 value of 5.4 μM. Docking study showed that the synthesized compounds were fit in the VEGFR-2 active site almost at the same position of sorafenib and vatalanib with comparable docking scores (-15.20 to -8.92 was kcal/mol). Conclusion: we have synthesized a novel series of phthalazine derivatives and evaluated their potential anticancer activity against HEPG2 cell line. The quinazoline derivative 12 emerged as the most potent compound in this study with an IC50 value of 5.4 μM. The SAR and docking studies pointed out that rigidification of the structure resulted in better activity and better binding within the active site of VEGFR-2 as in compounds 3, 5, 6 and 12. These results introduced new phthalazine derivatives having promising activity which could lead to the development of more potent anticancer agents.

Background: The Cruciferous family of vegetables which includes Brassica Turnips showed antioxidant and hepatoprotective effects. The phytochemical investigations of the aerial parts of the traditional Japanese turnip vegetable (B. rapa L. 'hidabeni') revealed the presence of three chalcone glycosides, along with other glycoside components. As many natural products inhibited Ag-stimulated degranulation in cellular system, those chalcone glycosides have biological significance of suppressing antigen-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells. Aim and Objective: Further investigation on the biological importance of those chalcone glycosides demands ample quantities of well-defined compounds. Therefore, we report herein a convenient and concise synthetic approach for the preparation of those chalcone glycosides. Materials and Methods: 4'-O-β-D-Glucopyransoyl-4-hydroxy-3'-methoxychalcone and 4'-O-(β-D-Glucopyransoyl)- 3',4-dimethoxychalcone were synthesized using a three-step strategy includes: i) O-glucosylation of 4-OH of 4'-hydroxy-3'-methoxy acetophenone (Acetovanillone); ii) introduction of the cinnamoyl residue by aldol condensation with p-benzyloxy benzaldehyde and p-methoxy benzaldehyde respectively; iii) full debenzylation of all the sugar hydroxyl groups. Meanwhile, 4,4'-Di-O-β-D-glucopyransoyl-3-methoxychalcone was synthesized by an alternative way where a double armed aglycon acceptor was utilized in a one pot double glycosylation reaction. Results: Constructing the target chalcone glycosides: 4'-O-β-D-Glucopyransoyl-4-hydroxy-3'-methoxychalcone, 4'-O-(β-D-Glucopyransoyl)-3',4-dimethoxychalcone and 4,4'-Di-O-β-D-glucopyransoyl-3-methoxychalcone were achieved in 13%, 14%, and 90% yields. Conclusion: A simple and practical synthetic procedure by which the target chalcone glycosides were synthesized could be a promising and viable method. Furthermore, this strategy could be utilized in the synthesis of various O-diglycosyl chalcones having more complicated structures.

Aim and Objective: The use of glycosyloxymethylfurfural (GMF), the dehydration product of isomaltulose, in the one-step multicomponent aza-Morita-Baylis-Hillman (aza-MBH) reaction, was studied. Materials and Methods: The reaction conditions and scope were investigated with respect to solvent, combinations of catalysts (Lewis acids and nucleophilic base), and the nature of the amine and the acrylic partners. Results: The three-components one step aza-MBH reaction using GMF, sulfonamides and a Michael acceptor provides carbohydrate-based a-methylene-b-amino carbonyl derivatives in moderate to good yields. Optimized conditions are the use of La(OTf)3 and 3-HQD in methanol. The use of diphenylphosphinamide, though requiring the use of a protected GMF and a two-step protocol, offers alternatives in the type of activated imine involved the classical sulfonyl substitution. Conclusion: A wide structural range of adducts were obtained in fair to good yields, showing the synthetic efficiency of the strategy able to provide highly functionalized carbohydrate-containing new molecules in an unique step from very available starting materials. These explorations show that GMF can be transformed in very short sequences to rather elaborated new compounds using the MBH and aza-MBH strategy.