Current Organic Synthesis - Volume 14, Issue 4, 2017

Chiral ionic liquids (CILs) have potential application in asymmetric organic synthesis, chiral drug synthesis, stationary phases in chiral chromatography, optical resolution of racemic mixtures and chiral shifting reagents in NMR spectroscopy. CILs may possess central, planar or axial chirality and can be synthesized from chiral pool or via asymmetric synthesis. Although, the synthesis of these species is difficult and costly yet in view of their prominent properties and wide range of applications, recently large number of CILs have been synthesized and employed in synthetic strategies. The present review enlightens various protocols for the synthesis of CILs. The use of these chiral ionic liquids as organocatalysts in synthetically important asymmetric reactions has also been discussed.

The diversity and chemoselectivity in rearrangements of N,N’-diarylhydrazines are reviewed and summarized. The symmetric N,N’-diarylhydrazines without any para-substituents generally favor para-benzidine rearrangement accompanying diphenyline rearrangement, even semidine rearrangement in some cases, while those with single or double N-naphthyl(s) or double para-substituent phenyls undergo ortho-benzidine rearrangement accompanying ortho-semidine rearrangements occasionally because double and single nitrogen atom(s) are/is protonated. Some symmetric N,N’-diarylhydrazines with electron-withdrawing para-substituents take place predominately disproportionation reaction, resulting in the formation of the corresponding diaryldiazenes (azoarene compounds) and aromatic amines. However, unsymmetric N,N’-diarylhydrazines predominate semidine rearrangement(s) accompanied by the diphenyline rearrangement since electron-rich nitrogen atom is protonated favorably and non-protonated electron-poor nitrogen atom undergoes N[1,3] sigmatropic shift with inversion of the N atom configuration. Occurrence of ortho- and para-semidine rearrangements depends upon the substituted pattern of the unsymmetric N,N’-diarylhydrazines. Some N,N’-diarylhydrazines with strong electronwithdrawing substituents, especially para-substituents, are sensitive to air, favoring oxidation to generate azo product N,N’-diaryldiazenes.

In recent decades, a large number of reports related to synthesis of N, O and S containing heterocycles have appeared owing to a wide variety of their biological activity. We need a catalyst system that not only shows high activity and selectivity but also possesses the ease of catalyst separation and recovery. Therefore, the different metals are used as a catalyst for the synthesis of oxygen containing heterocyclic compounds. This review focuses on the use of metal as a catalyst for the synthesis of O-heterocylces. It describes the formation of sixmembered heterocyclic rings.

The development of efficient routes to pyrazines and their ring fused analogues is an attractive area of research since these compounds are now widely recognized as important N-heterocycles for their potential use in medicinal and agricultural scientific fields. In this review, we describe the most representative and interesting methods for the synthesis of pyrazines from N-propargylamines. Mechanistic aspects of the reactions are considered and discussed in detail.

Michael addition reaction has been a very classical reaction in the field of organic synthesis. It is widely used to synthesize all kinds of natural products and drugs. Since the beginning of 21st century, people's environmental awareness has been enhanced and the research on green chemistry has been advanced. The Michael addition method with high efficiency, simplicity and greenness has been the goal pursued by organic chemists. Herein, the concepts and mechanisms of Michael addition reaction were discussed, and the applications of Michael addition reaction in the synthesis of natural products and complex compounds with biological activities were summed up.

Background: The chemistry of tetrazine has gained an increased attention in the last decades due to their applications materials science and coordination chemistry. 1,3-Dipolar cycloaddition of nitrile imines to C60 is the standard method for annelating the pyrazoline ring to the fullerene sphere. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions, which provide routes heterocyclic compounds. Results: A facile synthesis of polytetrazines based on bishydrazonoyl halides is described. Bis(pyrazolino[60] fullerenes) were synthesized from the reaction of bishydrazonoyl halides with [60]fullerene. Moreover, an efficient synthesis of new polypyrazoline-maleimide is reported. The synthetic methods involves 1,3-dipolar cycloaddition reactions of bisnitrilimines (generated in situ by the effect of the triethylamine on bishydrazonoyl halides) to give the final products. Structures of the newly synthesized products were elucidated via elemental analyses and spectral data (FT-IR, MS, 1H and 13C NMR). Conclusion: Novel heterocycles of polytetrazines, bis(pyrazolino[60]fullerenes) and Polypyrazoline-maleimide based on 1,3-dipolar cycloaddition reaction are reported.

Background: As evidence suggests a key role played by the low-activity pyruvate kinase M2 (PKM2) in tumor progression it emerges as an attractive target in cancer therapy. Objective: The aim of the present study was to design and develop a synthetic method for the preparation of a new sulfonamide compound as a potential PKM2 activator. Method: A seven-step synthesis procedure was carried out. It started with tert-butyl 3-oxoazetidine-1-carboxylate to produce amine compound (2) through nucleophilic addition reaction and deprotection of the Boc-group. By the ring closing reaction of 3-bromobenzene-1,2-diol followed by lithium-halogen exchanges, sulfides compound (4) was obtained which was subsequently oxidized and acylated to produce compound (6). Finally, the reaction of compound (6) with previously prepared amine compound (2) by dehydration resulted in the final sulfonamide product. Results: The aimed sulfonamide compound was synthesized, namely N-[4-[(3-benzyl-3-hydroxyazetidin-1- yl)carbonyl]phenyl]-2,3-dihydro-1,4-benzodioxine-6-sulfonamide, and the final product was confirmed by spectral analysis with 1H NMR and LC-MS. Conclusion: A pyruvate kinase M2 (PKM2) activator was successfully prepared through a seven-step synthesis procedure. This compound represents one of the few available small molecule activators of PKM2 which may be further investigated on its biological activities and capacity.

Background: 2-Substituted benzothiazoles are a class of heterocyclic compounds that have a wide range of applications in agriculture, pharmaceutical and chemical industry due to their wide spectrum of biological and biophysical properties. Benzothiazole is usually prepared by the condensation of 2-aminobenzenethiols or 2,2'-disulfanediyldianilines, the cyclization of thioformanilides, or the sulfurization of 2-haloanilides. Furthermore, in the reaction of 2,2'-disulfanediyldianilines with aldehydes to prepare benzothiazole, the S-S bond cleavage is the key to the construction of C-S bond. Method: 2-Arylbenzothiazoles could be successfully synthesized from the reaction of 2,2'-disulfanediyldianilines with aldehydes by using easily available Na2S·9H2O as a catalyst under microwave irradiation in low power. Results: A novel methodology for preparing 2-arylbenzothiazoles from disulfides and aromatic aldehydes under microwave irradiation in the presence of Na2S has been reported. The reaction mechanism was determined by 1HNMR in detail. It is found for the first time that the S-S bond of the Schiff base could be cleaved by Na2S·9H2O and subsquent could cyclize to form the corresponding 2-arylbenzothiazole. Conclusion: 2-Substituted benzothiazoles were synthesized efficiently via the condensation of 2,2'- disulfanediyldianiline with aromatic aldehydes catalyzed by Na2S·9H2O under microwave irradiation. This methodology provides a green and general synthetic route to prepare benzothiazole with short reaction time, low microwave irradiation power, and high-yield.

Background: β-Lactam antibiotics are plenty applied for the treatment of bacterial infections.Other biological activities and utilizing as a building block of 2-azetidinones is also well reported. The most useful method for the synthesis of 2-azetidinones is the Staudinger reaction. Generally ketenes were prepared from acyl halides which acyl halides shows unfavorable results such as low stability, low yield of products, and difficulties in handling and preparation. Objective: In the present study, efficient procedure for synthesis of 2-azetidinoes from imines and carboxylic acids via 1,4-dichlorophthalazine was investigated. Method: In the model reaction, a Schiff base reacts with phenoxyacetic acid in the presence of triethylamine and 1,4-dichlorophthalazine at room temperature in dry dichloromethane to form corresponding 2-azetidinone. Optimization of condition reaction was performed using this model reaction. According to optimization of condition, different Schiff bases were treated with different substituted acetic acids, 1,4-dichlorophthalazine and triethylamine, to prepare several 2-azetidinones which were purified by crystallization from EtOAc or column chromatography. Results: The optimized condition was found 1.3 mmol of 1,4-dichlorophthalazine and 1.3 mmol phenoxyacetic acid react with 1.0 mmol of Schiff base in dry dichloromethane at room temperature overnight. The 2- azetidinones were obtained in moderate to excellent yields and their structures were confirmed by spectral data and elemental analyses. Conclusion: A mild and efficient one-pot methodology to synthesize monocyclic, spirocyclic, polycyclic, N-alkyl and 3-electron-withdrawing group 2-azetidinones of from readily available Schiff bases and carboxylic acids using 1,4-dichlorophthalazine has been developed.

Background: The production of 5-hydroxymethylfurfural (5-HMF) from biomass provides an alternative pathway for many commercial chemicals and polymers particularly for countries with high insolation such as sub-Saharan Africa. Objective: The goal is continuous or semi-continuous dehydration of glucose and fructose to 5-HMF over a reusable castalyst in a process which is commmercial viable. Method: We deploy a separable and resuable catalyst, a low volatility solvent and reactive vacuum distillation. Results: Using a sulfated zirconia (SZ) catalyst in 1-butyl-3-methylimidazolium chloride [BMIM]Cl ionic liquid as solvent, we are able to separate the product by reactive vacuum distillation and obtain yields for 5-HMF of 82% and 65% at a 5 g experimental scale using fructose and glucose as substrates in a 2 h reaction time at 180 oC. The ionic liquid and SZ exhibited high activity when recycled for five successive trials. Conclusion: The low volatility solvent and solid catalyst allow for reactive vacuum distillation taking the sequence of steps from biomass such as Cassava to 5-HMF closer to commercial viability.

Background: One-pot reactions have gained considerable and wide range of interests in the field of chemistry due to their simplicity and economy. Comparing to the step-by-step reactions that involve the formation of individual bonds for a given target product, the greatest attribute of one-pot reactions, is the formation of several bonds in one-pot operation without intermediate isolation, reaction condition changing and further reagents adding. Objective: We developed an one-pot, rapid, simple and eco-friendly synthetic strategy for benzothiazines, benzothiazoles and benzothiazpines through the interaction of o-aminothiophenol with ketones, nitriles and chalcones, respectively. Method: A mixture of o-aminothiophenol ketones, nitriles and chalcones was refluxed or stirred at room temperature in glacial acetic acid containing a catalytic amount of concentrated H2SO4 for 3h. Then, the resulting precipitate was collected by filtration, washed with water and crystallized from the appropriate solvent. Results: The interaction of o-aminothiophenol with aromatic and aliphatic ketones containing active α-hydrogens afforded the corresponding 2H-benzo[1,4]thiazines and 4H-benzo[1,4]thiazines, respectively. Similarly, the cyclic ketones afforded the corresponding tricyclic compounds. Treatment of o-aminothiophenol with nitriles under the same reaction condition gave benzo[1,3]thiazoles. Further, cyclocondensation with chalcones under the same reaction condition at room temperature yielded the corresponding benzo[1,5]thiazepines. The reaction mechanism was investigated and the structures of all new compounds were elucidated using spectral analysis. Conclusion: An efficient, simple and environmentally friendly synthesis of benzothiazines, benzothiazoles and benzothiazepines in one-pot synthesis has been developed. With this catalytic reaction, a very cheap sulfuric acid was used as a catalyst.

Background: In the recent years the 2-imino-1,3-thiazine and 2-iminothiazolidine ring systems can be found as moieties in biologically relevant compounds, including BACE1 inhibitors, or cannabinoid receptor agonists, while monoterpene-based 2-imino-1,3-thiazines, prepared from chiral 1,3-amino alcohols exhibiting pronounced antiproliferative activity. Methods: The antiproliferative activities of the prepared compounds were determined in vitro against a panel of human adherent cancer cell lines including HeLa, MCF7 and A431 by MTT assay. Results: Starting from pinane-, apopinane- and carane-based β-amino acid derivatives, 1,3-amino alcohols were prepared via two-step syntheses. The reactions of the product 1,3-amino alcohols and aryl isothiocyanates yielded -hydroxythioureas, which were transformed to monoterpene-fused 2-imino-1,3-oxazines via base-catalysed ring closure. The antiproliferative activities of these 2-imino-1,3-oxazines were examined and the structure–activity relationships were studied from the aspects of the type and stereochemistry of the monoterpene ring and the substituent effects on the 1,3-oxazine ring system. The N-unsubstituted monoterpene-based derivatives exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and A431). Conclusions: A mild and efficient method has been developed for the synthesis of 2-imino-1,3-oxazines by the ring closure of thiourea adducts of 1,3-amino alcohols. The resulting 1,3-oxazines exert marked antiproliferative action on a panel of human cancer cell lines.

Background: Thiazole ring is one of the most important heterocyclic ring systems due to their wide range of biological activities. Objective: we became interested in synthesizing a new series of thiazole derivatives to investigate their antitumor activity against liver and colon cancer cell lines. Method: A novel series of 5-arylazothiazoles was prepared from 2-(-1-morpholino-1-(2-arylhydrazono)propan-2- ylidene)-hydrazinecarbothioamide by different methods. Results: The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their synthesis by alternative methods. The newly synthesized products were evaluated for their anticancer activities and the results reveal that some derivatives show good to moderate activity against hepatocellular (HepG2) and colorectal (HCT-116) carcinoma cell lines. Moreover, the computational studies using MOE 2014.09 software are in full support of the results in biological activity. Conclusion: A new bioactive series of thiazole ring was synthesized and showed promising activities against hepatocellular (HepG2) and colorectal (HCT-116) carcinoma cell lines.