Current Organic Synthesis - Volume 14, Issue 5, 2017

Aim and Objective: In this review, we summarize the current state of varied multicomponent/onepot protocols for synthesis of vital pyrazole derivatives under varied conditions, including in absence and presence of catalysts, solvent and solvent-free conditions, and using other techniques such as microwave irradiation and ultrasonication. In broad sense, this review covers the publications up to 2015. Material and Method: All the pyrazole derivatives were synthesized by using various techniques such as ultrasonication, heterogeneous catalysts, microwave irradiation and homogeneous catalyst systems. Results: As convincingly demonstrated by the synthetic approaches reported in this review, MCRs have facilitated many new methodologies with significant advantages for efficient and well organized synthesis of varied pyrazole derivatives. The methodology involved variety of options for catalysts that can be chosen using different solvents or solvent-free conditions and/or using alternative energy-efficient options such as microwave irradiation and sonification. This review brings together ample material about synthesis of varied pyrazole derivatives that may have prodigious scope, in drug design and therapeutics. It is anticipated that research efforts in this direction will endure in the search for novel, atom efficient, small molecules with excellent drug-like properties. Conclusion: As convincingly demonstrated over a selection of studies reported in this review, the uses of MCRs have facilitated many new methodologies with significant advantages for efficient and well organized synthesis of varied pyrazole derivatives. The diversity in approach, variation in transformations and scope of modification of pyrazoles were holistically summarized in this review.

Background: Catalytic kinetic resolution continues to be one of the hottest research topics in the community of synthetic chemistry owing to the huge demand of optically pure substances. Besides enzyme and transition metal-catalyzed asymmetric transformations, last two decades have witnessed tremendous advances enabled by organocatalysis. In this context, N-heterocyclic carbene catalysis, which is featured by its unique umpolung strategy, wide substrate scope, and diversified activation modes, has been widely applied in a series of kinetic resolutions to access molecules with high diastereo- and enantioselectivities. Objective: The review focuses on recent progress in the area of N-heterocyclic carbene-catalyzed kinetic resolutions. Three types of resolution methods, i.e., classic kinetic resolution, dynamic kinetic resolution, and divergent reactions on racemic mixtures, will be the focus of discussion. Conclusion: It can be seen that the mostly studied resolution methods are still classical kinetic resolution and dynamic kinetic resolution, the method of divergent reactions on racemic mixtures remains underdeveloped. Nevertheless, we believe that there remains great potential in N-heterocyclic carbene-catalyzed divergent reactions and further investigation in this field will definitely prove its value. There is still huge space for this field to be further promoted, beacuse many intermediates, like conjugated acyl azoliums, allenoates, and radicals, have not been involved in kinetic resolutions. Further novel transformations through N-heterocyclic carbenecatalyzed resolution of racemates can be expected in the near future.

Background: In the past decades, the hydroboration reaction was serendipitously discovered which occurred by the facile addition of diborane to alkenes and alkynes. Hydroboration reactions produce organoboranes. The organoboranes have marked a new era in the field of organic chemistry because they are versatile chemical intermediates that are readily available to chemists. Objective: The review focuses on recent advancements in organoborane reagents in asymmetric synthesis. We searched the scientific database using relevant keywords such an asymmetric hydroboration, organoboranes etc. The quality research papers were included in the review which discusses the asymmetric synthesis via organoborane compounds. Conclusion: The development of organoborane compounds increased remarkably in few years after hydroboration reaction discovered. Later on, new selective hydroboration agents were developed (for example thexylborane, disiamylborane, dipinylborane, 9-borabicyclenonane, and diisopinocamphylborane which have proven valuable in syntheses of organic compounds with new carbon-carbon bonds. H.C Brown and his co-workers established various procedures to synthesize asymmetric compounds with high enantiomeric excess (ee). There are many different types of strategies in the asymmetric syntheses, but asymmetric syntheses via chiral organoborane reagents have proven to be truly general and have been used to achieve reactions resulting in excellent ee. This review focuses on the advancement.

Background: Simplification and cost reduction of the selenophene derivatives synthesis is of intense interest due to their increasing applications in functional materials and pharmacology. Since there has been significant progress in the chemistry of organoselenium compounds in the past 30 years, a large diversity of synthetic methods are available to perform selenophene ring formation. Objective: In this minireview, we emphasize on the methods utilizing simple inorganic compounds as selenium precursors. In particular, widely available and relatively cheap elemental selenium, selenium dioxide and sodium selenide are covered. The review covers the publications during the last 15 years. Conclusion: It is clear from the review of the topic that most of the methods starting from simple inorganic selenium precursors are based on the addition of selenium to multiple carbon-carbon bonds and/or substitution of halogen atoms. The described approaches enable selenophenes with a variety of substituents at different selenophene ring positions as well as conjugated systems.

Background: Pyrazole derivatives have remained a much studied class of heterocyclic compounds with application in several scientific areas such as agrochemicals, pharmaceuticals and building blocks for more elaborated structures. The cyclocondensation of enones with hydrazine derivatives is one of the most valuable ways of synthesizing pyrazole derivatives. This method produces a racemic mixture of 4,5-dihydro- 1H-pyrazoles also known as pyrazolines which can be converted into aromatic pyrazoles by oxidative aromatization. Objective: The aim of this review article is to cover the state of the art oxidative aromatization of pyrazolines to pyrazoles. Method: It was performed a comprehensive compilation from the literature concerning the reported methods for oxidative aromatization of pyrazolines from the last thirty years. The review of each method was presented along with a critical point of view. Results: Several oxidant systems were applied for converting pyrazolines into pyrazoles. Most of the reviewed protocols proved to be efficient for oxidize 1,3,5-trisubstituted pyrazolines when the group attached to the N1 was H, methyl and (substituted)-phenyl. On the other hand few methods were found to dehydrogenate pyrazolines containing other than the above groups on N1 such as (thio)carbamoyl and amidinyl. Conclusion: Conversion of pyrazolines into aromatic pyrazoles by oxidative aromatization attracted attention in the last decades. A range of reagents has been reported for this purpose, but there is still the need for developing general methods that fill the requirements of green chemistry and that are applicable for more elaborated substrates.

Background: Multimodal imaging is a tool that may allow visualization, by using a single multifunctional compound, of early stage tumors and pharmacokinetic processes, drug action mechanisms and tumor growth processes, taking advantage of the strengths of each modality. Closely related, the emergence of “noninvasive” in vivo imaging revealed several “tip of the spear” contrast agent based technologies, e.g. Positron Emission Tomography/ Single-Photon Emission Computed Tomography and Magnetic Resonance Imaging. Objective: This review aims to give an insight on the state of the art regarding the application of pyrrole-based macrocycles as contrast agents in multimodal imaging techniques, asserting on the synthesis, with careful selection of influential milestones over the last decade on this field. Conclusion: Of the possible contrast agents required, pyrrole-based macrocycles constitute an important family, many groups have been devoting a considerable effort over last years to develop suitable pyrrole-based molecules that can act as contrast agents for more than one modality at the same time. While nuclear medicine uses radiolabeled tracers that produce signals by means of radioactive decay only, other molecular imaging means may use imaging agents that function by means of magnetism, (magnetic resonance imaging), or light (optical techniques of fluorescence), to name a few. In other words, in order to exploit the potential synergic advantages of each molecular imaging technique, the development of multimodal probes is considered a crucial area to validate in vivo molecular imaging experiments and allow the detection of cancer at early stages, and should be the future focus of molecular imaging in further years.

Background: The reaction named for Pietro Biginelli was first reported in 1891. The method consists of the reaction of an aromatic aldehyde, urea and ethyl acetoacetate leading to dihydropyrimidinones. Currently, the scientific movement to develop economically viable green methods using compounds that are reusable, nonvolatile, easily obtained, etc., is growing. Objective: A synthetic method was developed for the preparation of dihydropyrimidinones and dihydropyrimidinthiones with a focus on green chemistry based on the Biginelli reaction, using propylene carbonate as solvent and molecular iodine as the catalyst. Method: A mixture of arylbenzaldehyde, ethyl acetoacetate, urea or thiourea, molecular iodine and propylene carbonate was stirred and heated at 70 °C for 4 hours. At the end of 4 hours, the mixture was treated with sodium thiosulfate and washed three times with hot water. The pure solid was obtained after filtration. Results: We developed a synthetic method for the preparation of dihydropyrimidinones and dihydropyrimidinthiones based on the Biginelli reaction using PC as the solvent with yields ranged from 22-76% with high purity. Conclusion: This methodology uses a green and inexpensive solvent and catalyst and has the advantage of being a non-complex purification method: only sodium thiosulfate is required for catalyst removal, hot water to remove the solvent. The yields obtained range from moderate to high.

Background: Construction of biaryls containing polyoxygenated groups via the palladiumcatalyzed Suzuki-Miyaura cross-coupling reaction of aryl halides with organoboronic acids is a very interesting area of research. A number of functionalized polyoxygenated biphenyls have received considerable attention during the past decades, due to their presence as the structural motifs in natural products with diversified biological activities. Due to the particular pharmaceutical interest concerning the specific substitution pattern of a biphenyl scaffold, several synthetic methods have been developed. On the basis of investigation, we developed a novel Suzuki-Miyaura cross-coupling route for preparing polyoxygenated biphenyls. Objective: In the work, we have successfully presented a synthetic route for the synthesis of polyoxygenated biphenyls via Suzuki-Miyaura cross-coupling reaction. Methods: Polyoxygenated biphenyls are prepared in six synthetic steps, included: (1) olefinic migration; (2) Baeyer-Villiger deformation; (3) O-benzylation; (4) olefin oxidative cleavage; (5) regioselective bromination; and (6) Suzuki-Miyaura cross-coupling reaction. Results: A series of novel polyoxygenated biphenyls have been synthesized through a facile strategy. These structures of polyoxygenated biphenyls are determined by 1H and 13C NMR. Three structures of the key products were confirmed by X-ray crystallography. Conclusion: We have successfully presented a synthetic route for the synthesis of polyoxygenated biphenyls via Suzuki-Miyaura cross-coupling reaction of polyoxygenated bromoarenes with different arylboronic acids. This synthesis begins with the starting material, isovanillin, and provides facile routes for preparing two skeletons of chromanones and tetraoxygenated benzenes. Many explorations are anticipated in the near future.

Aim and Objective: A new approach to synthesis of isoindoles condensed with other heterocycles and revelation of their spatial structure for biochemistry purposes was the main objective of this research. Material and Method: Starting materials for the proposed method, 1-furyl substituted pyrrolo[1,2-a]pyrazines, pyrrolo[1,2-a][1,4]diazepines and their benzoannulated analogues - 4-furyl substituted pyrrolo[1,2-a]quinoxalines and pyrrolo[1,2-a][1,4]benzodiazepines, were synthesized by known procedures. These compounds, all containing a furfurylamine moiety, were introduced into the tandem acylation/ intramolecular furan Diels-Alder (IMDAF) reaction with α,β-unsaturated acid anhydrides (maleic and itraconic anhydrides). In most cases, the key step - the IMDAF reaction - proceeds diastereospecifically with simultaneous formation of five new stereogenic centers and affording the title compounds in mild conditions with satisfactory overall yields. Results: Consequently a broad series of 10,12a-epoxypyrrolo[2',1':3,4]pyrazino[2,1-a]isoindoles, 11,13a-epoxypyrrolo[ 2',1':3,4][1,4]diazepino[2,1-a]isoindoles, tetrahydro-14bH-12,14a-epoxyisoindolo[2,1-a]pyrrolo[2,1-c]quinoxalines, and tetrahydro-9H,15bH-13,15a-epoxyisoindolo[1,2-c]pyrrolo[1,2-a][1,4]benzodiazepines was synthesized and their space structure was elucidated by X-ray analysis. Conclusion: New effective method for synthesis of isoindoles condensed with various heterocycles was proposed. The method is based on the IMDAF reaction and provided a broad diversity of target molecules with controlled stereochemistry.

Aim and Objective: The enzymatic method are used for the direct resolution of racemic atenolol. The catalytic activities of nine commercially available lipases were firstly compared, then all enzymes were tested for the kinetic resolution of (R,S)-atenolol by enantioselective acetylation in different reaction mediums. Additionally, the effects of the acetylating agent and its concentration were also investigated. The most effective conversion and the best enantioselectivity were achieved using lipase from Candida rugosa (OF). Material and Method: Kinetic resolution of racemic atenolol was performed in various organic solvents with the use of nine commercially available lipases. Additionally, the influence of different acetylating agents on efficiency of studied kinetic resolution was tested. The enantioselective acetylation was begun by the addition of native lipase to reaction mixture. Finally the samples were withdrawn at established time points and then evaporated and redissolved in pure acetonitrile, filtered, and injected into the UPLC-MS/MS system. Results: Among all tested catalytic systems the best results were obtained with the use of Candida rugosa OF lipase, toluene as the reaction medium and isopropenyl acetate as the acetylating agent. The aforementioned catalytic system made it possible to obtain enantiomerically pure (S)-atenolol acetate with eep = 92.9 %, with conversion c = 46.3 % and enantioselectivity E = 66.9. Conclusion: The reported results confirmed that nine commercially available lipases have different effects on the kinetic resolution of (R,S)-atenolol. The type of lipase, the concentration and type of the acetylating agent and the reaction medium have significant impacts on the efficiency of the catalyst system. However, it is necessary to optimize the methods for the kinetic resolution of chiral drugs to obtain enantiomerically pure products, and thus it is not possible to find a universal catalytic system for all syntheses, as each enzymatic process requires an individual approach.