Current Organic Synthesis - Volume 15, Issue 6, 2018

Background: 2,3-Benzodiazepines represent an important class of biologically active compounds, some members of this family have reached the human clinical stage. With formal bioisosteric replacement of the benzene ring to five-membered nitrogen heterocycles, several new diazepine and 1,2,5-triazepine derivatives have been synthesized in the past 30 years. Objective: Investigations in the field of heterocyclic chemistry is very important, because there could be several new medicines among the newly synthesized heterocyclic ring systems, which could be used against several diseases which have no remedy yet, for example some types of cancer. The research on antibacterial compounds is also an important field because of spreading of multiresistant pathogens. This review aims to summarize the literature of certain 2,3-benzodiazepine analogues. Conclusion: After a brief historical introduction, various ring systems containing a 2,3-diazepine or a 1,2,5- triazepine ring condensed with five-membered nitrogen heterocycles are disclosed. First, pyrrole-fused compounds are introduced, followed by indole and carbazole derivatives. After that, diverse ring systems containing an imidazole ring are presented. The review is closed with the chemistry of some interesting triazole and tetrazole derivatives. Many of these compounds bear significant biological efficacy.

The chemical modifications of proteins or protein complexes have been a challenging but fruitful task in the post-genomic era. Bioorthogonal reactions play an important role for the purpose of selective functionalization, localization, and labeling of proteins with natural or non-natural structures. Among these reactions, reductive amination stands out as one of the typical bioorthogonal reactions with high efficiency, good biocompatibility, and versatile applications. However, not many specific reviews exist to discuss the mechanism, kinetics, and their applications in a detailed manner. In this manuscript, we aim to summarize some current developments and mechanistic studies of reductive amination reaction and its applications. We hope reductive amination reaction can contribute to a wider scope of protein chemistry research en route in the chemical biology frontier as one of the well-known bioorthogonal reactions.

Background: Transition metal catalysts are becoming increasingly more important in organic synthesis and are being used to catalyze novel reactions that allow for more efficient synthesis of many pharmaceuticals. Transition metal-catalyzed reactions of 3-aza-2-oxabicyco[2.2.1]hept-5-enes provide efficient synthetic pathways to generate a diverse range of biologically and synthetically useful products. 3-Aza-2- oxabicyclic alkenes undergo three main types of reactions: reductive N-O bond cleavage, C-O bond cleavage, and modification of the alkene component. Objective: The purpose of this review is to summarize and discuss the transition metal-mediated reactions of 3- aza-2-oxabicyclo[2.2.1]hept-5-enes, including the mechanisms of reactions based on the transition metal used, the different stereo- and regiochemical outcomes of reactions with this asymmetrical substrate, and the biological importance of exploring these reactions. Conclusion: It is clear from the review of the topic that a vast amount of work has been done in this area, and transition metals have been used to control the regio- and stereoselective reactions of 3-aza-2-oxabicyclic alkenes to create biologically active and synthetically useful products. The transition metal-catalyzed reactions of 3-aza-2-oxabicyclic alkenes proceed through three general reactions: through cleavage of the N-O bond, cleavage of the C-O bond, and modification of the alkene component. Without the use of transition metals, the substrate would not be activated and these reactions would not be possible. The use of transition metals opens up an array of new reactions that have the ability to create different functional groups with different regio- and stereoselectivities based on the metal and conditions used. The products made through these transition metalcatalyzed reactions can be useful as antibiotics, siderophores, and carbocyclic nucleosides such as noraristeromycin and carbocyclic polyoxin C.

Background: C-H activation has attracted great interests over the past two decades, which resulted in an explosive growth in both quality and quantity of published papers related to this topic. Objective: In this review, a bibliometric analysis was performed to evaluate the publications in this field from 1996 to 2015 based on the Science Citation Index (SCI) Expanded database. This work presented a detailed overview of C-H activation from aspects of types of articles, citations, h-indices, languages, years, journals, institutions, countries and author keywords. Conclusion: The results showed that the USA took the leading position in this research field, followed by P. R. China and German. Chinese Academy of Science had the most publications and the highest h-index, Scripps Research Institute won the first place as far as the highest average citation per paper is concerned. Organometallics, Angewandte Chemie International Edition and Journal of the American Chemical Society were the most productive journals in this field, and Chemistry was the most frequently used subject category. Keywords analysis indicated that most research focused on the Palladium, Rhodium and Copper catalyzed cross-coupling synthetic method development for the heterocycle synthesis. The research about exploring the asymmetric C-H functionalization, mechanism investigation and solving the regioselectivity issue is the development trend in this area.

Background: Quinazolines, the important group of benzodiazines, are widely known in medicinal chemistry due to their broad spectrum of biological activities. Notably, extensive research on the synthesis and application of quinazoline derivatives for electronic devices, luminescent elements, photoelectric conversion elements, and image sensors has been published recently. Objective: This review reports luminescent small molecules and chelate compounds including a quinazoline or pyrimidine ring in their scaffold highlighting their applications related to photo- and electroluminescence. Conclusion: It is clear from the review of the topic that the incorporation of quinazoline and pyrimidine fragments into π-extended conjugated systems is of great value for the creation of novel optoelectronic materials. Polyhalogen derivatives represent the major starting materials for polysubstituted fluorescent quinazolines. Electroluminescent properties of aryl(hetaryl)substituted quinazolines with π-extended conjugated systems proved to be the most important. Incorporation of benzimidazole, carbazole, triphenylene or triphenylamine fragments into quinazoline scaffold allows fabricating materials for organic light-emitting diodes, including white OLEDs and highly efficient red phosphorescent organic light-emitting diodes. Moreover, arylvinylsubstituted quinazolines are of great interest as potential structures for nonlinear optical materials and for colorimetric pH sensors. Iridium complexes based on 2-aryl(thienyl) quinazoline or pyrimidine derivatives represent high-efficiency phosphorescent materials for OLEDs. Pyrimidine push-pull systems are of considerable importance as potential photosensitizers for dye-sensitized solar cells. Pyrimidine derivatives bearing phenylacridine or phenylphenoxazine fragments at the positions 4 and 6 are capable to function as thermally activated delayed fluorescence emitters.

Background: I2/DMSO oxidative system catalyzed reactions have received considerable attention because they represent the advantages of being greener, efficient, atom-economical, low-cost, with mild conditions and ecofriendliness that meet with the requirements of sustainable chemistry. In recent times, the I2/DMSO oxidative system has been successfully applied in different types of organic reactions. Objective: The aim of this review is to highlight the synergistic effect of the combined use of iodine and DMSO in organic synthesis. Conclusion: It is clear from the review of the topic that a vast amount of work has been done in this area, employing an I2/DMSO system for diverse types of oxidative transformations as well as C-C and C-X bond formation reactions. In these reactions, iodine acts as a mild Lewis acid catalyst and DMSO servers as an oxidant, solvent and oxygen source. The role of iodine, DMSO as well as key intermediates involved in these reactions is discussed.

Background: N-phthalimide amino acid hydrazide is a class of compounds that have the potential therapeutic use. In general, hydrazinolysis of N-substituted amino acid(s) ester removes the ester group and yields the corresponding hydrazide. However, in case if N-substitution group is phthalimide, phthalimide group is cleaved and not the ester group. The resulted compound, therefore, is amino acid ester rather than Nphthalimide amino acid hydrazide. The above class of compounds, because of susceptibility of phthalimide group to hydrazinolysis, has previously been synthesized by a lengthy three-step procedure. Objective: N-phthaloylglycyl hydrazide was synthesized by using new efficient, simplified, one step process. Hydrazone derivatives from substituted benzaldehydes, and substituted furaldehyde were also synthesized. Method: N-phthaloylglycyl hydrazide was synthesized from the corresponding carboxylic acid using 1-Ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDC) as a coupling agent and hydroxybenzotriazole (HOBt) as an activator. Hydrazone derivatives were synthesized by condensation of N-phthaloylglycyl hydrazide with substituted benzaldehyde/substituted furaldehydes. All the compounds were characterized by IR, 1H-NMR, 13CNMR, mass spectroscopy and elemental analysis. Results: The presence of EDC/HOBt resulted in hydrazinolysis of the carboxylic acid group and not the phthalimide group. N-phthaloylglycyl hydrazide was synthesized in good yield. Conclusion: We report the improved process of the synthesis of N-phthaloylglycyl hydrazide. This is the first report where stability of phthaloyl amino acid compound to hydrazine is demonstrated. The reaction may be explored for the reaction schemes where stability of phthalimide group to hydrazinolysis is required.

Background: Acridine and quinoline derivatives have a wide range of biological activities such as antioxidant and antitumor where quinoline derivatives intercalate between base pairs of double-stranded DNA through π-π interactions. Therefore, the development of new compounds with antitumor activity could be an important therapeutic strategy against this metabolic syndrome. Objective: This study was undertaken to synthesize different series of new anilinoacridines and anlinoquinoline with different substituents having biological activity. Materials and Methods: A series of new anilinoacridines and anlinoquinoline with different substituents was prepared by condensation of methyl 3-amino-4-methoxybenzoate hydrochloride with 9- chloroacridine and 4- chloroquinoline to give the target derivatives. Results: New anilinoacridines and anlinoquinoline with different substituents have been synthesized as antioxidant and anti-cancer agents. The structure of the synthesized compounds was confirmed by using spectral methods (FT-IR, 1H-NMR). The antioxidant activity of the synthesized compounds was evaluated by using DPPH radical scavenging ability. Also, the anti-cancer activity was evaluated using lung carcinoma, breast adenocarcinoma and liver carcinoma. The developed compounds 4a, b, 5a,b, 7a,b and 8a,b have shown a potent antioxidant activity. On the other hand, 4a, b, 5a and 7a exhibited the best antitumor activity against both A-549 and MCF7 cancer cells. Conclusion: For the active developed compounds, the most active antioxidant and antitumor one was 4a which registered the highest radical scavenging as well as antitumor activity.

Aim and Objective: The efficient synthesis of disaccharide containing iminosugar moiety has a considerable interest in the field of glycoscience. In the present work, we describe a novel and applicable method for synthesis of five and six-membered N-substituted iminosugars attached with sugar moiety (pseudodisaccharides). Materials and Methods: The method of the glycosylation was based on the coupling of iminosugar thioglycoside (glycosyl donors) with partially protected sugars (glycosyl acceptors) in the presence of DMTST as a promoter. 2D COSY, HMQC, HMBC experiments were carried out to assist in NMR signal assignments. The pseudoanomeric configuration was established through NOE experiments and molecular modeling calculations. Results: Two classes of pseudodisaccharides were successfully obtained, five and six-membered N-substituted iminosugars glycosides. The six-membered pseudodisaccharides compounds were produced selectively with only β anomer. The corresponding five-membered pseudodisaccharides were achieved with moderate stereoselectivity. The yields obtained were good. These derivatives of iminocyclitols are thought to be precedents to develop various pseudodisaccharides, novel biologically active compounds, and new functional molecules. Conclusion: According to the results, utilizing iminosugar thioglycosides (1 and 2) as a glycosyl donor in glycosylation reactions is an efficient and highly stereoselective method to prepare (five- and six-membered) iminocyclitols (iminosugars) that bear a sugar moiety. The results will add to the synthesis of the iminosugars derivatives and contribute to make our approach among the few methods able to synthesize iminosugar glycosides.

Aim and Objective: We reported in this manuscript, synthesis of novel pyrazolopyrazinothienopyrimidines. The o-amino-thienopyrazolopyrazine-carbonitrile 4 was used as a versatile precursor for synthesis of new heterocyclic compounds. Due to development of resistance to the current antimicrobial therapy and non-steroidal anti-inflammatory drugs (NSAIDs), continues research for more effective agents is interesting. Hence, the suspected promising biological activities of pyrazolopyrazine compounds persuaded us to study the anti-microbial and anti-inflammatory activities in comparison with standard drugs. Materials and Methods: The chemical structures of the newly synthesized compounds were confirmed by elemental and spectral analyses. Activities of the synthesized compounds against a number of Gram-negative and Gram-positive bacterial strains were investigated. The fungal strains were obtained from some cases of human dermatophytosis. The antimicrobial activities were determined according to the Kwon-Chung and Bennett method. Anti-inflammatory activity was evaluated using carrageenan induced paw edema method. Results: The antibacterial screening of the synthesized compounds represented that the o-amino-carbonitrile 4 and triazepinone 11 have the highest activity towards E. coli & S. aureus and S. pneumonia. The amino-imino 6 was very effective against E. coli. Ring closure of 6 to triazolopyrimidine 7 increases the antibacterial activity against E. coli & K. pneumonia, their inhibition zones were higher than ciprofloxacin. Also, the triazolopyrimidines 7 and 10 exhibited high antifungal activity against all tested strains. Compounds 6 and 11 revealed high antifungal activity against S. racemosum and T. rubrum. The anti-inflammatory activity data indicated that all the tested compounds 4, 6, 7, 10 & 11 revealed the highest anti-inflammatory effect after 4 hrs. of carrageenan injection. Conclusion: we found that most of the examined novel thieno- pyrazolopyrazine compounds exhibited promising antibacterial, antifungal and anti-inflammatory activities which can be used as potential antibacterial, antifungal and anti-inflammatory drugs.

Aim and Objective: Chromene scaffold is one of the most famous oxygen heterocycles that have widely found in plants playing pivotal roles in medicinal and synthetic chemistry. This study was undertaken to provide a green protocol for the synthesis of novel functionalized chromen-pyrrole hybrids by a regioselective three-component reaction via both conventional and sonochemical methods. Because of fascinating features of these individual cores, a hybride molecular structure comprising of pyrrole and chromene moieties could result in a novel single molecule with increased efficacy. Materials and Methods: The synthesis of novel functionalized chromen-pyrrole hybrids was accomplished by regioselective three-component reaction of β-naphthol, 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanenitrile and diverse aromatic aldehydes catalyzed by triethylamine in H2O-EtOH via both conventional and sonochemical methods. The impact of some variants such as solvents, catalysts and temperature was also probed under both conventional heating and sonochemical methods to accomplish the optimized reaction condition. The synthesized products were screened for antibacterial activity against Gram positive (Ml, Bs, Sa) and Gram negative bacteria (Ps, Ec). Results: In initial attempt, the reaction of equimolar amounts of 2-fluorobenzaldehyde, 3-(1-methyl-1H-pyrrol- 2-yl)-3-oxopropanenitrile and β-naphthol was selected as a model reaction. The role of various solvents, temperature and different acidic and basic catalysts on the model reaction was examined. The optimized condition was the use of 20 mol% triethylamine in H2O-EtOH (1:1) under ultrasound irradiation at 65°C. The scope of this reaction was screened with respect to various substituted aromatic aldehydes. Considering the results, the electronic features of substituents affected the performance of this condensation. The reaction with aromatic aldehydes containing electron-withdrawing groups proceeded in lower reaction time, affording the productds in high to excellent yields while aldehydes with electron-donating groups reacted more slowly. This three-component reaction also provided a suitable procedure for the synthesis of bis-(chromen-pyrrole) in excellent yield. All of the synthesized products had significant antibacterial activity against the screened bacteria (Ml, Bs, Sa, Ps, Ec). Conclusion: A streamlined, regioselective and ecofriendly ultrasonic-promoted procedure for the synthesis of novel substituted benzo[f]chromenes from one-pot condensation of β-naphthol, 3-(1-methyl-1H-pyrrol-2-yl)-3- oxopropanenitrile and structurally diverse aldehydes catalyzed by triethylamine was developed. This green protocol furnishes all the products in reduced reaction times and high yields. In addition, the synthesized novel compounds showed narrow to wide spectral activity against the tested strains.