Current Organic Synthesis - Volume 16, Issue 3, 2019

Background: The Wieland-Miescher ketone consists of a couple of enantiomers of 9-methyl- Δ5(10)-octalin-1,6-dione, in which the configuration at 9-position is S- or R-type. The Robinson annulation of 2-methyl-1,3-cyclohexanedione with methyl vinyl ketone is able to afford the Wieland-Miescher ketone. As widely used in the total synthesis, the Wieland-Miescher ketone is treated at the beginning of total synthesis, and protocols for treating the Wieland-Miescher ketone are worthy to be addressed. Objective: The presented review provides the progress of the usage of Wieland-Miescher ketone for the total synthesis, while treatments on C=C and C=O in the Wieland-Miescher ketone at the beginning of total synthesis are exemplified herein. Conclusion: Modifications of the Wieland-Miescher ketone are composed of oxidation, reduction, and electrophilic or nucleophilic addition. In addition, protection of non-conjugated C=O with glycol or protection of conjugated C=O with ethanedithiol, and the introduction of substituents into α-position of C=C can also be used to modify the structure of the Wieland-Miescher ketone. It is reasonably believed that many novel strategies will be found to treat the Wieland-Miescher ketone in the future total synthesis.

The furo [2,3-b] indoline ring system is one of the most important structural units in various natural products. It has been known to have inherent biological activities and is utilized as a synthetic target for a number of natural compounds; therefore, this has contributed to a great demand for the growth of synthetic methods for this ring system. Most important compounds with furoindoline ring system are physovenine, madindoline A and B and makomotindoline etc. These compounds are well known to exhibit biological activity against different diseases such as glaucoma, cancer, cachexia, Castleman’s disease, rheumatoid arthritis, etc. The current article focuses on various synthetic approaches for furoindoline containing compounds and essential furoindoline moiety, such as oxindole-5-O-tetrahydropyranyl ether route etc., and various other diastereoand enantio- controlled approach in a very concise way.

In the past two decades, a plethora of lysine (Lys) posttranslational modifications (PTMs) has been discovered on proteins, major groups are acylation, alkylation, and ubiquitination. Although considered biologically important, functional annotation of proteins with Lys PTMs has largely fallen behind the discovery. One grand challenge of characterizing proteins with PTMs is the procurement of homogenously modified proteins. To resolve this obstacle, sophisticated methods have been developed. These include total synthesis, semisynthesis that is based on native chemical ligation, expressed protein ligation, and enzyme-catalyzed peptide ligation, and the amber-suppression based noncanonical amino acid mutagenesis technique that may need to couple with follow-up bioorthogonal chemistry. This review summarizes currently identified significant PTMs and chemical biology methods for their installation in proteins. We hope that the current review will provide helpful insights and critical perspectives to this important research frontier.

Background: Pharmaceutical co-crystals are the homogeneous crystalline substances composed of two or more substances bound together in the same crystal lattice via noncovalent interactions like hydrogenbonding, electrostatic interaction and Vander Waals interactions. Currently, co-crystals provide excellent opportunities to the formulation scientists in developing new pharmaceutical products by improving the pharmaceutically significant properties like solubility, dissolution rate, bioavailability, stability, and some other derived properties. Due to their ability to improve pharmacokinetic performance and their important intellectual property status, co-crystals are likely to have a very significant role in future drug development. Thus, formulation scientists have their focus on the development aspects of a co-crystallization process that include a rational selection of co-former, the discovery of novel synthetic procedures and new characterization techniques, and large scale production of these novel materials. Objective: The objective of this article is to present an extensive review of solvent-free methods for co-crystal synthesis, mainly focusing on the principle mechanisms, advantages, and drawbacks of each method. Conclusion: From the review of the topic, it is clear that the solvent-free methods can offer numerous advantages over solvent-based methods in the design and the production of co-crystals of pharmaceutical use and these methodologies can also pave the path to advancing the field of co-crystal synthesis. Some of the advantages accompanied with solvent-free methods are the use of no or very less amount of solvent(s), exceptional purity and quality of produced co-crystal, large scale production and the short reaction times in few cases.

Background: 3,3,7,7-tetrakis (difluoramino) octahydro-1,5-dinitro-1,5-diazocine (HNFX), as an important oxidizer in propellants, has received much attention due to its high density and energy. However, there are many difficulties that need to be solved, such as complex synthetic processes, low product yield, high cost of raw materials and complicated purification. In the synthesis of HNFX, the intermediate named 1,5-bis (p-toluenesulfonyl)-3,7-dihydroxyoctahydro-1, 5-diazocine (gem-diol), is difficult to synthesize. Methods: A simple method was used to synthesize the gem-diol. This prepared gem-diol was characterized by FT-IR, 1H NMR, melting point and mass spectrometry. In order to increase the yield of gem-diol, response surface methodology (RSM) was introduced to optimize experimental conditions. Results: After the establishment of the model, the optimal conditions of synthesis were found to be 9.33h for reaction time, 6.13wt. % for the concentration of NaOH and 1.38:1 for ratio of ECH (p-toluenesulfonamide): TCA (epichlorohydrin). Under the optimal conditions, the experimental value and the predicted value of yield were 22.18% and 22.92%, respectively. Conclusion: 1,5-bis (p-toluenesulfonyl)-3,7-dihydroxyoctahydro-1,5-diazocine (gem-diol) can be synthesized using the low cost of chemical materials, including p-toluenesulfonamide, epichlorohydrin, sodium hydroxide and ethanol. Response surface methodology (RSM) is an effective method to optimize the synthesis process, thereby improving the yield of gem-diol.

Aim and Objective: This work presents the synthetic capability and the exploitation of 1,3-diphenyl- 1H-pyrazole-4-carboxladehyde 1 and 5-diphenyl pyrazolyl-2-pyrazoline analogue 8 to serve as excellent precursors for the synthesis of substituted indol-2,3-dione, trizolo[3,4-a]benzazoles, thiazolo[2,3- a]benzimidazole-3-one, substituted 2-pyrazoline and pyrazole-substituted-pyrazolines using various reagents. Materials and Methods: Using chemicals from Aldrich, Fluka, or Merck, and pure solvents, we apply the synthetic procedures for the synthesis of novel heterocycles. The melting points of these compounds were determined using APP. Digital ST 15 melting point apparatus. SP3-100 spectrophotometer recorded FT-IR spectra (KBr) (cm-1). NMR spectra (δ, ppm) were recorded on 400 MHz AVANCE-III High-Performance FT-NMR Spectrometer BRUCKER (Switzerland) and some 1H NMR spectra were recorded on Varian EM-360L NMR Spectrophotometer (90 MHz) (USA) in CDCl3 or DMSO-d6 as a solvent. Elemental analyses were carried out at a Vario EL C, H, N, and S Analyzer. Bromine was determined using direct titration method after carius combustion. Results: The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analyses. Conclusion: 1,3-Diphenyl-1H-pyrazole-4-carboxladehyde 1 and 2-pyrazoline derivative 9 confirmed their importance in the synthetic organic chemistry. Depending on the formyl group of aldehyde 1 and active methylene of pyrazoline 8, we synthesized new series of heterocycles; indol-2,3-dione, trizolo[3,4-a]benzazole, thiazolo[2,3-a]benzimidazole-3-one and pyrazolyl-pyrazoline derivatives expecting their pharmacological applications. The targeted compounds were substantiated from its spectral data.

Aim and Objective: It is known that rhodanine drug has various biocidal activities. The aim of this work was to improve the structure of rhodanine drug via alkylation at N, S, and O- centers in addition to the introduction of fluorine atoms. The new fluorinated modified rhodanines 2-16 were evaluated as enzymatic probes for cellobiase activity produced by fungi and as CDK2 inhibitors of tumor cells. Materials and Methods: Novel fluorine substituted N-alkyl, S-alkyl and amino-rhodanines were obtained via Hydroxy methylation, Mannich reactions, chlorination and amination of 5-(4'-fluorophenylene)-2-thioxothiazolidin- 4-one, and the enzymatic effects of cellobiase produced by fungi and /or CDK2 inhibition of tumor cells were evaluated. Results: Most of the targets were obtained in high yield and in the form of very pure crystals with characteristic colors. Only compounds 5, 8, 10, 13, and 14 exhibited a higher activity as cellobiase while compounds 2 and 5 showed a highly enzymatic effect on tumor cells. In addition, compounds 2 and 10 can be used as Olomoucine (standard referees). Conclusion: Various N, S and O-alkyl derivatives of fluorine-substituted rhodanines were prepared via a simple method and used as enzymatic probes for cellobiase activity produced by fungi and CDK2 inhibitors for tumor cells. The more bioactive compounds had rich fluorine atoms as p-fluorophenyl and p-fluorobenzoyl bearing N, S, O-alkyl rhodanine. The highly active compounds may be used as enzymatic materials for various biological transformations in the future.

Aims and Objective: 1-Alkynes are the important precursors for the CuAAC click chemistry. The hybrid of 1,2,3-triazole ring to the chromene ring and sugar moiety could bring some remarkable biological properties. Propargyl derivatives are usually used in the click chemistry. This article reported the synthesis of 2-amino-4-aryl-7-propargyloxy-4-aryl-4H-chromene-3-carbonitriles using propargyl bromide as alkylation agent and the use of potassium carbonate and sodium hydride as bases in the conversion of 2-amino-4-aryl-7- hydroxy-4-aryl-4H-chromene-3-carbonitriles into corresponding propargyl ethers in Williamson’s ether synthesis. Materials and Methods: The use of CTAB for the synthesis of benzylidene malononitriles and anhydrous potassium carbonate as a catalyst in absolute ethanol in the synthesis of 2-amino-7-hydroxy-4H-chromene-3- carbonitriles is an efficient and simple synthetic method. Propargyl ether compounds of these 4H-chromene-3- carbonitriles were obtained from the alkylation reaction by propargyl bromide. Two procedures were applied: K2CO3 as a base in acetone solvent (Procedure A) and NaH as a base in DMF solvent (Procedure B). The single-crystal X-ray structure of propargyl ether 5e has been studied. Results: The use of K2CO3 and NaH as bases in the Williamson’s ether synthesis from 2-amino-7-hydroxy-4Hchromene- 3-carbonitriles showed that Procedure B was the better route and gave ethers in the higher yields. 2- Amino-4-aryl-7-propargyloxy-4-aryl-4H-chromene-3-carbonitriles were obtained from corresponding 7- hydroxy-4H-chromene-3-carbonitriles. Yields of ethers 5a-i were 70−89% and 80−96%, respectively depending on the used procedures. Conclusion: The described methods are simple, clean and environmentally friendly alternatives for the preparation of 2-amino-4-aryl-7-hydroxy-4H-chromene-3-carbonitriles. The conditions for the transformation of these compounds into propargyl ethers include dried DMF as a solvent, NaH as a base and reaction time of 2 h at the room temperature. A series of 2-amino-4-aryl-7-hydroxy-4-aryl-4H-chromene-3-carbonitriles were obtained based on investigated reaction condition.

Aims and Scope: The 2-hydroxy-1,4-naphthoquinone (lawsone) and 2,5-dihydroxy-1, 4-naphthoquninone (5-hydroxylawsone) are synthesized by one step process. The process involves an inexpensive catalyst urea hydrogen peroxide and a base (t-BuOK) in alcohol for the transformation of 1-naphthol or 2,5-dihydroxynaphthalene to lawsone or its derivatives in the presences of oxygen. The process is further directed to produce lawsone or its derivatives, with no extraneous heating to make it energetically efficient. The synthesized compounds are analyzed by FT-IR, 1H and 13C NMR spectral studies. Materials and Methods: All the raw materials were purchased from commercial suppliers and used as such without further purification. The infrared spectra were recorded on a Thermo Nicolet-Avatar-330 FT-IR spectrophotometer using KBr (pellets) and noteworthy absorption values (cm-1) are obtained. 1H and 13C NMR spectra are recorded at 293K on BRUKER AMX-400 Spectrometer operating with the frequencies of 300 MHz and 75, 125 MHz respectively using DMSO-d6 as solvent. Results: The 2-hydroxy-1,4-naphthoquinone (lawsone) and 2,5-dihydroxy-1,4-naphthoquninone (5- hydroxylawsone) are synthesised from 1-naphthol and 1,5-dihydorxynaphalene with urea-hydrogen peroxide as the catalyst in basic medium and oxygen as the oxidizing agent. After purification, the formed products are analysed by IR and NMR spectroscopy. The yield is 82% and the purity of the products is > 95%. Conclusion: The present study highlights the process for the manufacturing of lawsone and its derivatives which is efficient in terms of energy needed for the activation of products from reactants. The advantages include its cost-effective nature in terms of simple inexpensive catalyst required for the process and high yield. The mild reaction conditions employed and the harmless by product obtained further confirm the usefulness of this synthetic process.

Aim and Objective: Benzodiazepines and indole fused heterocycles are pharmacologically significant scaffolds. Trivial work on indole fused benzodiazepine compounds is reported in the literature. Hence, it is imperative to explore the synthesis of indole-fused benzodiazepines that may act as a template for biological studies in the future. Hence, in the present work, the synthesis of indole fused benzodiazepine derivatives was undertaken using multi-phase nano-titania as catalyst under microwave irradiation. Materials and Methods: MAOS technique was used to carry out the synthesis of spiro-benzo [1,4]diazepine derivatives in the presence of multiphase nano-titania as a catalyst. Nano-titania was prepared by sol-gel method and characterized by XRD, FT-IR, FESEM, EDS and thermogravimetric techniques. The synthesized spiro-benzo [1,4] diazepine derivatives were identified by physical and spectral methods. Results: Synthesized compounds were obtained in excellent yields in a short span of time. The synthesis was also carried out in the presence of conventional catalysts in addition to nano-titania. Among all the catalysts, the best result was obtained with nano-titania. The amount of nano-titania was optimized to be 0.05g giving 93- 95% yield of products. The study of reusability of nano-titania revealed that it could be reused up to four times with a negligible change in efficiency. Conclusion: The paper reports an efficient, cost-effective and environmentally benign approach for the synthesis of spiro-benzo [1,4] diazepine derivatives in the presence of multiphase nano-titania catalyst under microwave irradiation.

Aim and Objective: The late transition metal complexes with five-membered heterocyclic mono-imine ligands have attracted much attention because of their potential application in olefin polymerization catalysis. In order to increase the coordination ability of heteroatom N and S to center metals, CH3 group was introduced into the side arm of pyrrole imine and thiophene imine respectively, to get two series of novel five-membered heterocyclic imine compounds, mono(imino)pyrroles and mono(imino)thiophenes. Materials and Methods: Two series of novel five-membered heterocyclic compounds with the mono-imine group were synthesized from the p-toluene sulfonic acid catalyzed Schiff base condensation of aromatic amines and 2-acetylpyrrole/ 2-acetylthiophene respectively, using CH3 group to substitute the common H atom on the side arm of pyrrole imine/ thiophene imine. Results: All the heterocyclic mono-imine compounds were characterized adequately by means of 1H NMR, 13C NMR, FT-IR, elementary analysis, as well as X-ray crystallographic diffraction. The reactivity differences between two precursor 2-acetylpyrrole and 2-acetylthiophene with aromatic amines were compared and discussed in detail. Conclusion: Compared to traditional heating methods, the solvent-free microwave irradiation seemed more efficient to prepare these series of five-membered heterocyclic mono-imine compounds, which resulted in a higher yield and cleaner product.

Aim and Objective: The direct β-functionalization of trans-β-nitroolefins by Michael reaction is regarded as an efficient way to provide precursors for β-functional amines. However, Michael additions by grinding means with solvent-free conditons are rarely reported. We have developed facile access to β-functional nitroalkanes by grinding means under solvent-free conditions. Materials and Methods: From commercially available materials including ethyl 2-nitroacetate, alkyl 2-cyanoacetates and malononitrile, the grinding reactions between these above-mentioned activated methylenecompounds and various trans-β-nitroolefins were performed at room temperature and solvent-free conditions. Results: A highly efficient direct Michael reaction of nitroolefins by simple grinding means has been developed. Various trans-nitrostyrenes were easily converted into corresponding β-functional nitroalkanes in excellent yields within 5~10 min (up to 36 examples). Conclusion: Herein, we have developed a simple and efficient way to β-functional nitroalkanes through Michael reactions by grinding means. The grinding Michael reaction is fast, clean and stable and these Michael adducts could be easily converted into the other amino compounds served as building blocks in organic synthesis.