Letters in Organic Chemistry - Volume 13, Issue 7, 2016

Background: Substituted-silyl thiophene carboxylates are important intermediates for the synthesis of substituted-silyl thiophene carboxamides which have been found to show high biological activities. Methods: Using α-mercapto ketones and 3-(substituted-silyl)propiolates as raw materials, 2-(substituted-silyl)thiophene-3-carboxylates could be synthesized smoothly via cycloaddition reaction catalyzed by potassium tert-butoxide. Results: A small library of target compounds was prepared under optimized reaction conditions in moderate to good yields. The reaction mechanism has been proposed. Conclusion: Potassium tert-butoxide is an environmentally friendly and efficient catalyst for the cycloaddition reaction of α -mercapto ketones and 3-(substituted-silyl)propiolates. This methodology provides ready access to 2-(substituted-silyl)thiophene-3-carboxylic acids which can be serve as the raw materials of 2-(substituted-silyl)thiophene-3-carboxamide and other pharmaceutically intriguing compounds.

Background: The development of efficient methodologies for the preparation of benzoxazole and its derivatives has gained a lot of importance in current research. There are many methods are reported for the synthesis of benzoxazoles includes condensation of 2-aminophenol with carboxylic acid. Traditional methods also have several side reactions, non renewable oxidative reagents and solvents which negatively affect the environmentally and eco-friendly nature of the reaction. We have developed PTA catalyzed synthesis of 2-arylbenzoxazole from 2-aminophenols with different aromatic aldehydes using a grinding strategy in excellent yield. Methods: The synthesis of benzoxazoles in high yields by using silica supported PTA/PTA as solid acid catalyst at room temperature using grinding method. Results: Aromatic aldehydes which have electron donating or electron withdrawing groups were also investigated and as expected it gives good to excellent yield of products, it can be seen that electron donating and electron withdrawing groups does not show any difference on their action yields. Conclusion: We have developed PTA catalyzed synthesis of 2-arylbenzoxazole from 2-aminophenols with different aromatic aldehydes using a grinding strategy in excellent yield. The use of this reusable catalyst under solvent-free conditions has made this protocol practical, environmentally friendly and economically attractive. The simple work-up procedure, the short reaction times the mild reaction conditions, the high yields of products and the non-toxicity of the catalyst are other advantages of the present method. This protocol approaches combines the advantages of both focused library synthesis and diversity oriented synthesis because of the simplification of reaction protocol that we have been developed.

Background: 4H-benzo[b]pyran derivatives have attracted great interest due to biological and pharmacological properties including antimicrobial, antiviral, antiproliferative, sex pheromone, antitumor, cancer therapy, central nervous system activity and other interesting biological activities. For these reasons several synthetic methods are reported. For our part we want to propose an efficient procedure which respects the environment. Method: To achieve our study we performed a one-pot three-component reaction of aromatic aldehydes, dimedone, malononitrile and pyridinium p-toluenesulfonate as catalyst under different conditions. Results: We found that the optimal conditions for the preparation of 2-amino-4H-benzo[b]pyrans catalyzed by p-toluenesulfonate pyridinium are in refluxed water and with 10 mol% of catalyst. Given these results and to show the generality of the procedure, we applied the optimized reaction conditions for the synthesis of various 2-amino-4H-benzo[b]pyrans from a range of substituted aromatic and heteroaromatic aldehydes. The desired products are obtained in good to excellent yields. Conclusion: We have synthesized a variety of 4H-benzo[b]pyran derivatives according to a three component reaction between aromatic aldehydes, dimedone and malononitrile using pyridinium p-toluenesulfonate as a catalyst. This method gives very good yields and has the merit of simplicity, respect for the environment by using water as solvent and an available and inexpensive catalyst.

Background: 3-[4-(Benzyloxy)phenyl]propanoic acid moiety is central to many advanced agonists of free fatty acid receptor 1 (FFA1 or GPR40) which are a new, promising class of antidiabetic drugs. An aldehydo carboxylic acid tert-butyl ester building block is required for speedy SAR exploration of analogs of Eli Lilly’s GPR40 agonist LY2881835 which was in phase I clinical trials. Methods: The aldehyde functionality of the target building block was masked as methyl carboxylate. The phenylpropionic acid tert-butyl ester portion was constructed using Horner-Wadsworth-Emmons chemistry followed by olefin hydrogenation. The aldehyde function was unmasked via methyl ester hydrolysis, mixed anhydride reduction to alcohol and back-oxidation with manganese (IV) dioxide. Results: The synthesis of the target building block was realized in 7 chemical steps (the final three of which were conducted in succession not requiring interim purifications) involving isolation and characterization of four hitherto undescribed intermediates. Conclusion: The method described is suitable for production of the target alehydo carboxylic acid tertbutyl ester building block on a multigram scale, which will facilitate the parallel synthesis of LY2881835 analogs and expedite the respective SAR exploration.

A new heterogenized silica-based organocatalyst was prepared via anion exchange of imidazolium ionic liquid with L– hydroxyproline material. This was evaluated as a heterogenous organocatalyst for the asymmetric aldol reaction of nitrobenzaldehydes, cyclohexanone and cyclopentanone by performing the reaction under different conditions by using several solvents and reaction temperatures. Excellent isolated yields of the aldol products of up to %90 were achieved. In addition, excellent selectivity (ee up to %98) was obtained. In one case, dr reached up to > 99:1.

Reactions of bis-hydrazonoyl chloride 1 with each of KSCN and KSeCN yielded the corresponding bis-thiadiazoline 2A and bis-selenadiazoline 2B. Bispyrazole derivatives 7a-e and 8a-b were also obtained by reactions of 1 with the appropriate active methylene compounds. Reactions of 1 with each of 1, 2- dicyanoethylene, acenaphthylene and phenyl-5-arylidene-2-thioxo-thiazol-4-one as dipolarophiles led to the formation of the corresponding cycloadducts 9, 12 and 14, respectively. Also, reaction of bis-hydrazonoyl chloride 1 with triazinethione 16a-e afforded 1,4-Bis-(1,2,4-triazolotriazin)benzene 17a-e. The structures of the compounds prepared were established on the basis of elemental and spectral analyses as well as their chemical reactions.

An improved method with high yield and simple steps for the synthesis of 3-hydroxy-1-acetyladamantane was reported. 3-Hydroxy-1-acetyladamantane is an important intermediate of Saxagliptin for type 2 diabetes mellitus (T2DM). Its synthetic method started from 1-adamantanecarboxylic acid via oxidation by sulfuric acid/nitric acid, then VHA reagent (SOCl2/DMF) and sodium diethyl malonate were used in one-pot through acylation, substitution, decarboxylation and alkalization to give the target compound. It is an improved method that VHA reagent (SOCl2/DMF) was used in the step of acylation which effectively enhanced the total yield up to 74%, and the operations were effectually simplified by the one-pot method. The synthesized target compound has been characterized by single-crystal X-ray diffraction. The single-crystal X-ray diffraction analysis demonstrates that the target compound has extensive intermolecular hydrogen bondings involving the hydroxyl and acetyl groups in the solid state and the structure of the target compound was proved as 3-hydroxy-1-acetyladamantane.

Background: The imidazo[1,2-a]pyridine ring has been widely studied by medicinal chemists and displays great pharmaceutical potential. Methods: In a view to prepare a library of new molecules including an imidazo[1,2-a]pyridine scaffold, as original fragments for the conception of novel anti-protozoal compounds, the Sonogashira crosscoupling reaction between 3-halogenoimidazo [1,2-a]pyridines and phenylacetylene was studied. Results: From 3-iodoimidazo[1,2-a]pyridine, chosen as an optimal substrate for conducting the reaction at room temperature in 2 hours, a variety of terminal alkynes was involved into the reaction, leading to a series of 16 new 3-phenyethynylimidazo [1,2-a]pyridines in satisfying to good yields (50-82%) and 4 additional derivatives in moderate yields (30-40%). Conclusion: Such synthetic approach appears efficient for the rapid synthesis of imidazopyridine chemical libraries. The corresponding derivatives will next be evaluated for their anti-infective properties.

Multi-component reactions (MCRs) utilizing unconventional solvents like ionic liquids have become a new research direction that has emerged as an important facet of green chemistry. The present work deals constructively with the MC one pot synthesis of 4-aryl-5-ethoxycarbonyl-3,4-dihydro-6- methylpyrimidin-2(1H)-ones using L-valine sulfate 1:1 [H-Val][HSO4], a cheap, non-corrosive, and eco-friendly ionic liquid as a dual solvent-catalyst.

Background: Triazolobenzodiazepinones, i.e. 2,3-benzodiazepines condensed with a triazolone ring, exhibited significant anticonvulsant activity in vivo. In this paper, their new pyrrole bioisosteres, 2,11-dihydro-3H-pyrrolo[1,2-e][1,2,4] triazolo[4,3-b][1,2,5]triazepin-3-ones were synthesized. Methods: Starting from the corresponding bicyclic hydrazino intermediates, final ring closure of the triazolone ring has been attempted with several reagents under various conditions. Among these, only triphosgene provided the tricyclic title compounds. Results: Six representatives of the title new ring system were synthesized. The structure of the new scaffold was determined by single crystal X-ray measurement as well as 1H and 13C NMR spectra. Conclusions: Starting from 1-aryl-4-hydrazino-5H-pyrrolo[2,1-d][1,2,5]triazepines (15), representatives of a new tricyclic compound family, 6-aryl-2,11-dihydro-3H-pyrrolo[1,2-e][1,2,4]triazolo[4,3-b][1,2,5] triazepin-3-ones (17) have been synthesised. These compounds are pyrrole bioisosteres of 6-aryl-2,11- dihydro-3H-[1,2,4]triazolo[4,3-c][2,3] benzodiazepine-3-ones (8), a family exhibiting an outstanding in vivo anticonvulsant activity in mice.

Background: Hymenocallis littoralis is the unique genus in China and famous for its high content of alkaloids with anti-tumor activity. However, about twenty alkaloids were isolated and identified in this plant. Methods: The dichloromethane extract of H. littoralis (alkalization with 1% NaOH for 24h) was further subjected to normal-phase silica, ODS silica gel column chromatography, and semi-preparative HPLC chromatography, respectively. Chemical structures of these compounds were identified and elucidated by spectroscopic methods including 1D-NMR, 2D-NMR, and HR-MS. The cytotoxic activities of the new component were determined with the cell lines of HepG-2, LoVo, Hela and A549 using the MTT method after incubation for 48 h. Results: One new alkaloid, named Hymenolitatine (1), with two known compounds was obtained from the bulb of H. littoralis. The chemical structure of the new natural product was elucidated by spectroscopic analysis and comparison with literature data. The two known compounds were identified as trispheridine (2), tazettine (3), on the basis of comparison of their spectral data with the reported data, respectively. The IC50 values of the compound 1 on HepG-2, LoVo, Hela and A549 cell lines were 75.19, 69.81, 96.37 and 102.53 μM, respectively. Conclusion: This is the first report on the isolation and identification of Hymenolitatine (1), and this novel compound exhibited moderate cytotoxic activities against HepG-2, LoVo, Hela and A549 cell lines in vitro. Compound 2 was isolated from the title plant for the first time.