Letters in Organic Chemistry - Volume 15, Issue 4, 2018

Background: Biginelli reaction is one of the most important multiple-component chemical reactions which creates 3,4-dihydropyrimidin-2(1H)-ones. Even though Biginelli reaction was reported over a century using different substrates, literature lacks the example of the use of alcohols as a substrate. The substitution of aldehyde component with another functional group has not been explored so far. Method: In the present study, we have used Propylphosphonic anhydride (T3P®)-DMSO as an efficient and mild reagent for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones from aromatic alcohols. Results: Alcohols are oxidized in situ to aldehydes under mild conditions, which in turn undergo a three-component reaction with β-ketoester and urea/thiourea to afford 3,4-dihydropyrimidin-2(1H)- ones/thiones. Conclusion: The synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones directly from alcohols has been reported for the first time under mild reaction conditions in good yield. Easy work up procedure, low cost and less toxicity of the reagent are the main advantages of this protocol.

A simple, convenient and facile approach for the synthesis of a series of 2,3- dihydroquinazolin-4(1H)-ones in an environmentally benign method has been developed. This method involves a direct cyclocondensation of 2-aminobenzamide with aromatic aldehydes and ketones using aspartic acid as a catalyst in water.

Introduction: Phenol or carbolic acid is an aromatic compound and has mild acidic nature. In 1834, it was firstly achieved by Friedlieb Ferdinand by the destructive extraction of coal tar. It is used as a significant raw material in quite a lot of chemical manufacturing. Phenol derivatives have been found to possess Antimicrobial, Analgesic, Anti-inflammatory, Antioxidant, Anti-convulsant, Anti-cancer, Anesthetic, Antiseptic and Disinfecticides, Anti-tubercular and Anti-parkinson activity. Several more compounds have been discovered and many are still being focused. Conclusion: The main objective of this article is to show up the different derivatives and the pharmacological activities of Phenol and its derivatives. It can be concluded that Phenol and its derivatives posses significant therapeutic functions and many potent derivatives are still to be discovered.

Background: The 3-Substituted indoles are found to possess a wide range of biological and pharmacological activities. The efficient and impurity free scalable preparation of 2-(1H-Indol-5-yl)- ethanesulfonic acid methylamide has been successfully achieved for the synthesis of Naratriptan and its novel 3-substituted derivatives. Method: The preparation of 2-(1H-Indol-5-yl)-ethanesulfonic acid methylamide involves the condensation of (2,2-Dimethoxy-ethyl)-trimethylammonium bromide with thiophenol followed by Fischer indolisation with polyphosphoric acid. Finally, desulfurisation was achieved using catalytic amount of Raney nickel under hydrogen pressure to target the synthetic precursor in good yield. Results: The synthesis of Naratriptan has been explored from the 2-(1H-Indol-5-yl)-ethanesulfonic acid methylamide obtained under modified reaction condition. Some novel 3-substituted indole derivatives were also synthesized from the same synthetic precursor. Structures of all the new compounds were confirmed by the spectral data (IR, 1H-NMR, 13C-NMR and Mass). Conclusion: A significantly improved and commercially viable method has been developed for the preparation of the synthetic precursor for Naratriptan and its novel 3-substituted derivatives. This method furnished impurity free target products in good to excellent yield.

Background: Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that can occur in any age group but often seen in adults and contributing for about 20% of adult leukemias and it may contribute up to 15% of all types of leukemias threatening the globe. Therefore, treatment of CML remains as a major challenge in cancer therapeutics. Methods: We synthesized a library of novel 2-amino-4-(4-substituted phenyl) thiazole derivatives and evaluated their anti-leukemic activity by trypan blue and MTT assay. 4-(4'-phenoxybiphenyl-4-yl) thiazol- 2-amine (compound 3m) was identified as a lead anticancer agent and further, the effect of 3m on CML cells (K562) was investigated by flow cytometry, annexin V-FITC-propidium iodide staining, measuring the mitochondrial membrane potential (JC-1 staining) and DNA fragmentation assay. Results: MTT and trypan blue dye exclusion assay results presented 3m as the lead anticancer agent. Flow cytometric analysis revealed the accumulation of K562 cells in subG1phase in a time- and dosedependent manner. Annexin-V-FITC-PI staining demonstrated the increase in percentage of apoptotic cells on treatment with 3m. Furthermore, 3m also induced DNA fragmentation and disrupted mitochondrial membrane potential in K562 cells in dose-dependent manner. In addition, apoptosis inducing effect of 3m was reconfirmed by live-dead assay and confocal microscopic studies. Conclusion: The present study suggests that compound 3m has the potential to be a promising candidate for the treatment of CML.

Background: In spite of significant progress made toward the synthesis of triazole amino acids as structural scaffolds of peptides and leading structures of new drugs, a need still exists for effective methods of trisubstituted triazole amino acid synthesis. Methods: A protocol based on ruthenium(II)-catalyzed alkyne-azide cycloaddition (RuAAC) was developed to synthesize 5-bromo-1,4,5-trisubstituted 1,2,3-triazole-based amino acid – tert-butyl 5-bromo-1-(2-(1,3-dioxo-2,3dihydro-1H-isoindol-2-yl)ethyl]-1H-1,2,3-triazole-4-carboxylate (5Br- TzlAA). Two other disubstituted regioisomers, 1,4- and 1,5-TzlAA, were also synthesized to evaluate the influence of the 5-bromo substituent for triazole ring bioactivity. Results: Under optimal conditions, 5Br-TzlAA was synthesized within 1 h with 93% yield. NMR confirmed the structure of 5Br-TzlAA and showed regioselectivity of the RuAAC reaction. None of the TzlAAs were cytotoxic for the human cell lines investigated and showed a small pro-proliferatory effect at the highest concentrations (50-100 μg/mL) studied. A small anti-proliferative effect was visible for 1,4-TzlAA. Conclusion: A simple and effective protocol for the synthesis of 5-bromo-1,4,5-trisubstituted TzlAA (5Br-TzlAA) was developed. Bioassay results show that N-phthalimido modifying the TzlAAs are well tolerated by human cells and may be used as leading or scaffold structures to design new biologically active molecules.

Background: Benzimidazole and benzothiazole subunits exist in many biologically active molecules, natural products, and synthetic compounds. These compounds have recently gained widespread interest due to their key role in medically important compounds, such as those exhibiting anticancer activity, antimicrobial activity, inhibition of hepatitis C virus NS5B polymerase, p38 kinase inhibitory activity, and anti-inflammatory activity. Methods: 2-Substituted benzimidazole and benzothiazole derivatives have been synthesized by the condensation of 1,2-phenylenediamine or 2-aminobenzothiophenol with 5-arylidenepyrimidine-2,4,6-(1H,3H, 5H)-trione derivatives via cleavage of C-C double bond without using a catalyst in EtOH under reflux conditions. Results: We report here a very simple, novel, efficient, and catalyst-free method for the synthesis of benzimidazole and benzothiazole in good to excellent yields from the treatment of 1,2-phenylenediamine and 2-aminothiophenol with various 5-arylidenepyrimidine-2,4,6(1H,3H,5H)-trione, respectively. This reaction proceeds via cleavage of a C=C double bond and elimination of barbituric acid. Conclusion: This method appears to be general for the synthesis of benzimidazoles and benzothiazoles using 5-arylidenepyrimidine-2,4,6-(1H,3H,5H)-trione derivatives containing various aromatic and heteroaromatic aldehydes such as furfural and thiophene-2-carbaldehyde with electron-withdrawing and electron-releasing groups.

Background: Bis(indolyl)methane derivatives exhibit varied biological and pharmacological properties like antibacterial and antiangiogenic activities, acting as cytotoxic agents and tumor growth inhibitors. Several approaches of bis(indolyl)methane synthesis have been reported, most of them involving condensation of indoles with aldehydes or ketones in the presence of protic or Lewis acids. Also other catalysts like enzymes were used in this reaction that did not result in high yields. Still, there is a long way to modify this reaction by better ways. Methods: Due to massive applications of magnetic sulfated zirconia as a catalyst, we decided to study its abilities to synthesize bis(indolyl)methane derivatives. In this work, to increase the yield and lower the time of the reaction, we synthesized Fe3O4@ZrO2/SO42- as a heterogeneous nanocatalyst and used it in one pot reaction of aldehyde and indole to obtain bis(indolyl)methane derivatives. Results: An effective method for the synthesis of bis(indolyl)methane derivatives in high yields was developed by the use of Fe3O4@ZrO2/SO42- as a catalyst. The synthesis of bis(indolyl)methane by this catalysts resulted in short reaction times and high yields. Easy separation from the reaction mixture and capability of reusing heterogeneous nanocatalysts are the advantages of these type of catalysts. Fe3O4@ZrO2/SO42- as a magnetic recyclable heterogeneous nanocatalyst can be used 5 times with no significant loss of activity. Conclusion: According to the importance of bis(indolyl)methane derivatives in industrial applications and biological properties, we synthesized the sulfated zirconia nanoparticles as acidic heterogeneous magnetic catalyst by sol-gel method and used it in the synthesis of bis(indolyl)methane derivatives. It was found that products with high efficiency can be achieved in a relatively short period of time. This catalyst is more capable than many other heterogeneous magnetic catalysts and due to its advantages like thermal stability and also its chemical bonding of functions with surface that do not extract with changing solvent; it can be used widely in a variety of multi-component reactions.

Background: 2-Amino-4H-chromenes are an important class of heterocyclic compounds having important biological activities. Many of the methods reported for the synthesis of these compounds are associated with the use of hazardous organic solvents, long reaction time, use of toxic amine-based catalysts, and lack of general applicability. Thus, the development of an inexpensive, mild, general, environmentally and commercially available catalyst for MCRs remains an issue of interest. In continuation of our work on one-pot multicomponent reactions catalyzed by organocatalysts for the synthesis of various heterocyclic compounds, here we report a general and highly efficient onepot multicomponent reactions using an inexpensive, clean, safe, environmentally and commercially available imidazole/cyanuric acid as a mixture of organic and inorganic catalyst in aqueous media. Methods: 15 mol % of catalyst imidazole/cyanuric acid (3:1 mol %), dissolved in water (2 mL) at room temperature by magnetic stirring. The mixture of aromatic aldehyde (1 mmol), malononitrile (1 mmol, 0.066 mg) and resorcinol (1 mmol, 0.110 mg) or dimedone (1 mmol, 0.140 mg) was added, after completion of the reaction which was monitored by TLC, the precipitate was washed with distilled water and dried, then was crystallized in ethanol 96%. Results: The preparation of 2-amino-4-(4-chlorophenyl)-7-hydroxy-4H-chromene-3-carbonitrile was studied at different amounts of imidazole and cyanuric acid as catalyst. A longer reaction time would be necessary and lower yield was obtained when used Cyanuric acid or Imidazole alone and the best result was obtained by using 15 mol% of imidazole and cyanuric acid (3: 1) in aqueous media at room temperature under the optimized reaction conditions, a series of substituted 2-amino-4H-chromene derivatives were synthesized. The reactions worked well with a variety of aryl aldehydes including those bearing electron-withdrawing and electron-donating groups and the desired compounds were obtained in high to excellent yields. In all of the reactions, yields were dependent on substituents of aldehyde and their positions and enolizable C-H acid. Reaction for benzaldehyde with electron-withdrawing groups such as chloro- or nitro-, proceeded at faster rates than those with electron-donating groups such as methoxy-, methyl-, etc. Conclusion: We have demonstrated a simple and efficient protocol for the synthesis of 2-amino-4Hchromenes by the reaction between various benzaldehydes, malononitrile and enolizable C-H acidic compounds (resorcinol and dimedon), using imidazole/cyanuric acid as an efficient catalyst in aqueous media at room temperature. Compared with some other reported methods, the main advantages of this procedure are shorter reaction times, high to excellent yields, inexpensive operation, simple work-up and environment friendliness.

In this work, two new prolinamides with isosteviol skeleton were synthesized and used as chiral catalysts for the asymmetric aldol reaction. Solvent effects, catalyst loading, substrate scope and the influence of water on the reaction were investigated. With only 5 mol % loading, the synthesized catalysts showed excellent activity (up to 98% yield) and good stereoselectivity (up to 87:13 dr, 90% ee) for the direct aldol reaction of cyclohexanone and substituted benzaldehydes at room temperature.

Background: Dibenzo-oxazepine and Benzothiazole derivatives are used as antipsychotics, anticancer, antibacterial and anti-inflammatory agents. Methods: Arylidene derivatives of 1,2,3,4-Tetrahydro-Dibenzo[b,f][1,4]Oxazepine and 2-[2-Chloro- Cyclohex-1-enyl]- Benzothiazoles were synthesized by reacting benzylidene derivative of chloroaldehyde with 2-aminophenol and 2-aminothiophenol respectively. Benzylidene derivative of chloroaldehyde was prepared by Vilsmeier reaction of 2-benzylidenecyclohexanone derivatives, which were obtained from the condensation of various aromatic aldehydes with cyclohexanone. Results: Benzylidene derivatives of 1,2,3,4-Tetrahydro-Dibenzo[b,f][1,4]Oxazepine 6a-g exhibited promising antiproliferative activity with GI50 values in the micromolar range. The compounds containing halo, alkyl and alkoxyl groups as substituents on the benzylidine ring have been found to be very effective cytotoxic agents. Conclusion: This study identified dibenzo-oxapine as a prospective pharmacophore which set the stage for thorough exploration of this compound class as cytotoxic agents.

Background: Brain cancer (neuroblastoma) and liver cancer (hepatocellular carcinoma) are common cancer types among others worldwide which do not have a radical treatment and cure. Objective: In the current study, five novel pyridazinone derivates bearing benzelhydrazone moiety at second position were synthesized and evaluated for their cytotoxic activity against neuroblastoma and hepatocellular carcinoma (SHSY5Y and HEP3B) and human fibroblast (HF) cell lines. The aim of the current study is to identify antiproliferative activity of five novel pyridazinone derivates against neuroblastoma and hepatocellular carcinoma (SHSY5Y and HEP3B) and human fibroblast (HF) cell lines. Method: The compounds were synthesized by the reacting 6-[4-(phenyl/4-chlorophenyl)piperazine-1- yl]-3(2H)-pyridazinone-2-yl acetohydrazide with benzaldehyde in ethanol. The in vitro antiproliferative activities were determined with MTT assay. Bax, Bcl-2 and Casp3 gene expression levels were detected with RT-PCR analyses. Results: The lowest IC50 was observed for compound 4 in SHSY5Y and HEP3B cells. Apoptosis increased in cancer cells which was shown by changes inBax, Bcl-2 and Casp3 gene expression levels with 1-5 compound therapy. Conclusion: Novel pyridazinone derivates might be promising agents as new chemotherapeutic candidates in brain and liver cancer.