Letters in Organic Chemistry - Volume 14, Issue 10, 2017

Combination of urea hydrogen peroxide and p-toluenesulfonyl chloride in methanol was proved to be facile and highly efficient for the oxidative methyl esterification of various aldehydes to the corresponding carboxylic methyl esters.

Background: Heterocycles are the gold mines in medicinal chemistry. Most drugs used in today's medicinal period possess a heterocyclic nucleus. One of the interesting heterocycles, benzothiazole, a potent phamacophore, is highly important in the medicinal chemistry due to its association with diverse pharmacological properties. Development in biological evaluation of heterocyclic molecule has undergone manifold changes and the advancement in molecular biology has eased the design of new molecule based on their mechanism of action. Methods: A structured search of bibliographic databases for peer-reviewed research literature has been done using different database. The quality of retrieved papers was appraised using standard tools. The details of important papers were described to focus on the potency of derivatives of benzothiazole. Results: One hundred fourteen papers were included in the review indicating importance of benzothiazole derivatives. The review has been focussed on papers highlighting anticancer and antimicrobial activities. Several papers have been searched for anticonvulsant, anti-inflammatory, antitubercular and other miscellaneous activities. Conclusion: The findings of this review confirm the importance of a conceptual framework for widespread use of heterocyclic compounds containing nitrogen, sulfur and oxygen compounds. It is basically focused on the medicinal applications of benzothiazole derivatives in the recent years that are currently attributed to exploitation of drug design and discovery of biologically active compounds across a wide range of therapeutic areas on a reasonable time scale.

A series of lupane C19-(1,2,3-triazolyl)-triterpenoids were obtained by “click” reaction of 3,28-diacetoxy-29-norlup- 20(30)-yne with different aromatic and sugar azides after screening of several copper-based catalytic systems. DFT calculations were performed (B3LYP/6.311 level of theory) and showed that the alkyne moiety is hindered by the triterpenoid skeleton, thus explaining its low reactivity and the requirement of a very active catalytic system. Ultimately, it was found that the dinuclear copper complex [Cu(μ-OH)(TMEDA)]2Cl2 is the most efficient catalyst. Moreover, for the first time, a bis-(triazolyltriterpenoid)-derivative was obtained by the reaction of lupane C19-alkyne with 1,4-bis(azidomethyl)benzene using the same catalyst.

Background: The 4-benzyl biphenyl scaffold represents an important structural element widely used in optoelectronic materials and bioactive compounds, including a variety of antihypertensive drugs and prostate cancer agents. Therefore, the construction of 4-benzyl groups incorporating this structural feature with cheap and readily available starting materials is of great scientific interest. Methods: In this paper, the reductive coupling of biphenyl-4-carbonyl compounds derived from tosylhydrazones with phenols or benzyl alcohols under metal-free reaction conditions is described. Results: Various 4-benzyl biphenyl ether compounds, representing an important structural element in organic synthesis, could be obtained in moderate to good yields. Conclusion: The catalytic system presented here enables the use of easily accessible starting materials and may be employed on a wide variety of substrates with good functional group tolerance.

Thieno[3,2-b]thiophene represents a typical core structure in a large number of organic optoelectronic materials and molecular magnetism. One-pot efficient approach to modify the electronic structure of thieno[3,2-b]thiophene is to introduce suitable substituents into this π- conjugated skeleton. In this paper, we report on a facile route to precisely functionalize thieno[3,2- b]thiophene by the direct Pd-catalyzed arylation reaction with boronic acids. Based on this procedure, a number of 3,6-diarylthieno[3,2-b]thiophenes were prepared in good yields. NMR methods and XRay crystal structure analysis confirmed high regioselectivities at the C-3 and C-6 positions of thieno[3,2-b]thiophene skeleton.

Background: Amide bond is prevalent in peptides. Moreover, at least 25% pharmaceutical products also contain amide bond. A wide ranging strategy including Ugi reaction and related multicomponent reactions is available for the synthesis of amide. While HATU mediated direct one-pot diamide synthesis is scarcely investigated in the literature. Objective: The objective of this work is to achieve a one pot synthesis of diamide using various coupling reagents. Method: Straightforward one-pot coupling of dicarboxylic acid with corresponding amine was accomplished in the presence of HATU under ambient condition using 2-Me THF as an industrial green solvent. Results: A range of (hetero)aromatic and aliphatic dicarboxylic acids were coupled with aromatic and aliphatic amines to give 55-89% yield of the products at ambient temperature. Conclusion: Among various coupling reagents scrutinized, HATU was proven to be ‘gold standard’ to accomplish one-pot synthesis of diamides.

Background: Clobazam (CLB) has been used as an anxiolytic, anticonvulsant and antiepileptic drug under the trade names, Frisium, Urbanol, Onfi and Tapclob. Impurity profiling in the pharmaceutical industries is a central task in the manufacturing of drug product. The quantification of impurities in active pharmaceutical ingredients (APIs) is also receiving considerable importance from the regulatory authorities in the point of stringent quality requirement. Thus, the provision of substantial quantity of impurities as standards, which are accomplished either by isolation from crude reaction mass or the synthesis of material with proposed structure using new synthetic route, to analytical method development and validation is a good demand. Therefore, easily accessible synthetic routes to the preparation of impurities with the lowest cost are sought after. To date, no synthetic specifics were found on the synthesis and characterization of CLB Imp-B, -C, -D and -F, and the synthesis of CLB Imp-E. Therefore, the comprehensive study was undertaken on the synthesis and characterization of CLB related impurities and this study might be useful to prepare CLB impurities in the required quantity with purity to use as a reference standard of analytical method development in pharmaceutical industry. Methods: The synthetic routes were developed for the synthesis of CLB impurities such CLB Imp-B to Imp-F and isolated them using purification techniques with purity in the required quantity. The commercially available key starting materials, reagents and solvents were used in the course of synthesis of impurities. The analytical techniques such as NMR, IR and mass were used to characterize the structure of synthesized CLB related impurities. Results: The easy accessible synthetic methods were developed for the synthesis of clobazam related impurities, CLB Imp-B to F in good to excellent yields with purity as well as described the cause to formation of these impurities. The KSM related impurity, 2-chloro-1-nitrobenzene and the active methylene hydrogens in clobazam are caused to the formation of CLB Imp-B and CLB Imp-C&-D, respectively. CLB Imp-E and -F are formed due to the degradation of drug molecule, CLB in the presence of base (NaOH). CLB Imp-B was prepared from 2-chloro-1-nitrobenzene by following similar process of CLB reported in the synthetic specific. CLB Imp-F was prepared from 5-chloro-N1 -phenylbenzene-1,2-diamine by coupling with mono-methyl malonate followed by N-methylation using dimethyl sulfate. The rest of all impurities were planned to prepare by taking CLB as starting material. CLB Imp-C and -D were synthesized by treating CLB with methyl iodide in the presence of inorganic base. The mixture of aqueous NaOH and CLB was agitated vigorously at 75-80°C to obtain CLB Imp-E. All the synthesized compounds were purified using purification techniques such as crystallization and column chromatography, and well characterized by IR, ESI-mass, 1H NMR, 13C NMR and DEPT analyses. Conclusion: The immaculate discussion about synthetic approaches and structural elucidation using analytical applications such as IR, NMR (1H, 13C and DEPT) of CLB Imp-B to F, which are listed in the European pharmacopoeia monograph of clobazam, has been described. All the impurities were obtained with stringent purity (>98%) in the described synthetic routes and the same impurities have been used in analytical method development in our pharmaceutical industry. Also, the plausible mechanistic path ways to the formation of impurities, keeping in view the regulatory importance of clobazam, were discussed in detail.

Background: Proline and its derivatives are versatile organocatalysts for many reactions. Especially prolinamide derivatives have been prepared and investigated in aldol reaction successfully. Generally, derivatizations have been made on side chain of proline to develop new effective catalysts. But, there are only few examples of different cyclic systems other than pyrrolidine ring used as chiral organocatalysts. Method: The methodology for this study was the synthesis of new thiazolidine-4-carboxylic acid based organocatalysts and investigation of their catalytic activities in asymmetric direct aldol reactions. Results: New thiazolidine based organocatalysts 6a-g [substituted (4R)-N-[(2S)-1-amino-1-oxo-3- phenyl-2-propyl]-4-thiazolidinecarboxamides] were synthesized and characterized. Their catalytic activity studies in asymmetric direct aldol reactions of aliphatic ketones with arylaldehydes were performed. Among the catalysts investigated in this study, especially methyl (2S)-3-phenyl-2-[(2S)-3- phenyl-2-[(4R)-thiazolidine-4-carboxamido]propanamido]propanoate (6a) and (4R)-N-[(2S)-1-(benzhydrylamino)- 1-oxo-3-phenyl-2-propyl]-4-thiazolidinecarboxamide (6b) gave the best diastereoselectivities (up to 91%), enantioselectivities (up to 88%) and yields (up to 94%) when different aliphatic ketones and aromatic aldehydes with electron withdrawing groups were used. Conclusion: Some new organocatalysts derived from thiazolidine-4-carboxylic acid were designed, synthesized, and successfully used in the direct asymmetric aldol reaction of aliphatic ketones and aromatic aldehydes under solvent free conditions. The results showed that these new products were promising organocatalysts for aldol reaction.

Background: Polyhydroquinoline derivatives are known as one of the most significant class of biologically active heterocycles. Herein, in this paper, magnetite polycitric acid (Fe3O4@PCA) nanoparticles as novel, efficient and reusable catalysts were used for the preparation of polyhydroquinoline derivatives. Method: Using aromatic and heteroaryl aldehydes with dimedone, ammonium acetate and ethyl acetoacetate, polyhydroquinoline derivatives could be synthesized under solvent-free microwave irradiation condition by Hantzsch multi-component reactions. Results: Polyhydroquinoline derivatives were prepared under optimized reaction conditions in excellent yield (97%). The reaction mechanism has been investigated. Conclusion: This method has the advantages of short reaction times, use of an economically convenient catalyst, and excellent product yields. Furthermore, the catalyst could be recycled and average chemical yield for seven consecutive runs was 92%, without any significant reduction of activity.