Letters in Organic Chemistry - Volume 15, Issue 10, 2018

Efforts towards the novel synthesis of second generation non-sedating antihistamine drug, Bilastine was described in this manuscript. This competitive synthetic approach involves the convergent synthesis of Bilastine via simple Friedel-Crafts acylation as an alternate for earlier reported Stille and Suzuki couplings. The selectivity in Friedel-Crafts acylation reaction with chloro acetyl chloride on different substituted arenes was studied and employed the best conditions for the synthesis of Bilastine. Further synthetic approach involves the deoxygenation of aryl ketone to corresponding alkane in single step and finally provides Bilastine with 39% of improved overall yields, utilizing simple and cost-effective reagents, suitable for kilogram scale synthesis.

An improved and operationally simple synthesis of 3-indoxyl-β-D-galactopyranoside (indoxyl- gal) is disclosed. Indoxyl-gal is a sensitive chromogenic histochemical used for the identification of β-galactosidase enzymatic activity (lacZ gene). Synthesis of indoxyl-gal is improved to 25% overall yield in 5 linear steps from affordable starting materials with minimal chromatography. Biological testing confirmed the detection of β-galactosidase activity in all (100%, 19 strains) coliform bacteria using membrane filtration and modified MI agar.

Organic solvents are required to carry out most organic transformations, which cause environmental pollution because of their low volatility. Glycerol, a side product obtained from biodiesel production, has emerged as a friendly solvent due to its advantageous properties. In this paper, an efficient procedure for the synthesis of flavones and chromones, using heteropolyacids as recyclable catalyst and glycerol as the solvent, is presented. The use of heteropolyacids as catalysts allows for excellent yields, easy separation and recovery, low environmental impact, and low cost. Glycerol can also be readily recovered and used over again. In addition, the presented method provides other advantages such as the low formation of waste and the replacement of corrosive mineral acids.

A simple, fast and efficient procedure for the cleavage of a wide of range ketoximes and aldoximes to the corresponding compounds using a safe and low-cost reagent, N,N′-dichlorophenobarbital, under mild reaction conditions at room temperature is described.

Background: Several transition-metal-catalyzed reactions have been used to synthesize biologically active α-amidoketones. These approaches involve inconvenient conditions or expensive catalysts. Alternative attempts based on transition-metal-free catalysts have also been reported including cross-coupling reaction of aldehydes with acylimines in the presence of thiazolium salt as an organic catalyst. We report herein the use of N,N-dimethylbenzimidazolium iodide which is a safe and recyclable organic pre-catalyst, along with N-(amidobenzyl)benzotriazoles as activated N-acylimines for this cross-coupling reaction. Method: N-(Amidobenzyl)benzotriazoles (9a-c) were prepared from benzamide, aromatic aldehydes and benzotriazole. N,N-Dimethylbenzimidazolium iodide (11) was easily prepared via the methylation reaction of benzimidazole. Cross-coupling reactions were carried out in refluxing THF in the presence of DBU and organo-catalyst 11 for 5 hours. Results: N,N-Dimethylbenzimidazolium-catalyzed cross-coupling reactions of various aromatic aldehydes (10a-f) with N-(amidobenzyl)benzotriazoles (9a-c) afforded α-amidoketones (12a-r) in good yields. Conclusion: An alternative approach for the synthesis of α-amidoketones based on organo-catalytic cross-coupling reaction of aromatic aldehydes with acylimines have been accomplished in high yields.

The Hendrickson reagent (triphenylphosphonium anhydride trifluoromethanesulfonate), prepared from the reaction of triphenylphosphine oxide (Ph3PO) and triflic anhydride (Tf2O) (2:1 stoichiometry), promotes dehydrations and various coupling reactions. The reagent has been used to transform oximes to nitriles and to prepare esters, amides and many other functional groups through the intermediacy of an alkoxyphosphonium salt. The reagent proved useful in heterocycle synthesis of thiazolines, imidazolines, quinoline precursors, isoquinolines, β-carbolines, phenanthridines, 11Hindolo[ 3,2-c]quinolines, quinoline-lactones, furoquinolinones, and indolizino[1,2-b]quinolin-9(11H)- ones. Moreover, the reagent has been key to the successful total synthesis of several natural products. Aryl propargyl alcohols with a terminal α-acetylenic group undergo rapid conversion to the corresponding α,β-unsaturated aldehydes at room temperature in dichloromethane in the presence of one equivalent of triphenylphosphonium anhydride trifluoromethanesulfonate. The reaction involved adding freshly distilled Tf2O (1.0 mmol) to a solution of Ph3PO (2.0 mmol) in CH2Cl2 (10 mL) at 0 oC under N2 atmosphere. After stirring for 10 min, the propargyl alcohol (1.0 mmol) was added as a CH2Cl2 solution (2 mL), followed by the addition of water and Et3N (2.0 mmol) and further stirring at room temperature for 1h. Subsequent workup with 5% NaHCO3 (20 mL) and purification afforded α,β- unsaturated aldehydes. Eighteen aryl propargyl alcohol substrates with a terminal α-acetylenic group were transformed in good to excellent yields (71-85%) to enals. The methodology proved successful with secondary and tertiary alcohols with stereoselectivity favouring exclusively the E isomer. All the synthesized compounds are known and were characterized (1H, 13C, and M.P) and compared to literature values. The method offers several advantages such as exclusive stereoselectivity, short reaction time, good yield, mild reaction conditions, and simple operational procedure.

An ongoing problem of modern biochemistry is the search for ways of synthesizing new hybrid compounds based on available natural adducts with various pharmacophore groups with anticancer activity and, at the same time, with a small effect on normal cells of the organism as a whole. Methyl maleopimarate MMP, obtained from rosin was treated with different amines in DMSO to give maleopimarimides by thermal condensation during 60 min and condensation with ultrasonic (US) treatment during 30 min. All the synthesized compounds including parent compounds – maleopimaric acid and MMP) were subjected to in vitro cytotoxicity MTT assay in HEK293 (human embryonic kidney cells) and Jurkat cells (human T- cell lymphoblast-like cell line). By the developed method а series of new maleopimarimides were obtained. It was found that the use of two-fold excess of amines and ultrasonic influence increased yield of target products and reduced reaction time. The structures of the products were proved by two-dimensional correlation spectra of HSQC, HMBC, COSY, NOESY. A new efficient method for the synthesis of a large group of hybrid potentially biologically active compounds by condensation of methyl maleopimarate with various amines (glycine, β-alanine, γ- aminobutyric acid, aminocaproic acid, α-alanine, β-phenyl-α-alanine, hydrazine, phenylhydrazine, aminoguanidine, 9-aminonacridine, glycyl methionine) under ultrasonic influence in dimethylsulfoxide (DMSO) was developed. Screening of new methyl maleopimarate derivatives afforded to identify a compound with moderate cytotoxicity and establish a selective towards different cells mechanism of its cytotoxic action.

A novel series of ten substituted 4H-pyrimido [2,1-b] [1,3] benzothiazole curcumin derivatives have been synthesized and evaluated for their antimicrobial activity against Gram positive and Gram negative bacteria viz. Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus and against fungi viz. Alternaria solani, Aspergillus niger, Fusarium culmorum and Rhizopus stolonifer. The mechanism involves condensation of substituted benzaldehyde and curcumin via Knovenegal reaction which further reacts with substituted benzothiazole through Michael addition in the presence of pyridine catalyst using methanol as a solvent. The synthesized compounds were analyzed by elemental and spectral analysis.

Nine triazine derivatives were synthesized by reacting triazine with different aromatic amines. The synthesized derivatives were characterized by IR, NMR spectral studies and micro analytical data. The resulted compounds had also been evaluated for their in vitro antinemic studies against root knot nematode, Meloidogyne incognita. All compounds showed considerable nematicidal activity as compared to the control when screened for their hatching inhibition and mortality potential.

A mild and efficient protocol for the synthesis of phenols from arenes has been developed using aqueous hydrogen peroxide as an oxidizing agent and hexaphenyloxodiphosphonium triflate as a promoter. The reactions were carried out with the simple procedure in EtOH-H2O at room temperature in short reaction times.

Background: Indole motif is frequently present in biologically active compounds. Enantiomerically pure or enriched 2,2-dimethyl-5-(aryl(1H-indol-3-yl)methyl)-1,3-dioxane-4,6-diones can be considered as a convenient starting point for the synthesis of a indole ring fused with cyclic ketones with biological activity. Preparation of chiral 2,2-dimethyl-5-(aryl(1H-indol-3-yl)methyl)-1,3-dioxane- 4,6-diones requires the reaction of indole with 2,2-dimethyl-5-arylidene-1,3-dioxane-4,6-diones in the presence of chiral catalysts or other source of chiral induction. Methods: Enantioselective Friedel-Crafts alkylation of indole has been performed with 2,2-dimethyl-5- arylidene-1,3-dioxane-4,6-diones in the presence of organocatalysts to give 5-((1H-indol-3- yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones. Broad scope of organocatalysts as well as various temperatures and solvents used for the reaction were tested. Results: 2,2-Dimethyl-5-(aryl(1H-indol-3-yl)methyl)-1,3-dioxane-4,6-diones were obtained with quantitative yield and enantiomeric ratio 1:3 using thiourea organocatalyst. Also a new spectroscopic method for discrimination of 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones enantiomers was developed. Conclusion: Enantioselective Friedel-Crafts alkylation of indole has been developed. In the presence of thiourea catalysts, 2,2-dimethyl-5-arylidene-1,3-dioxane-4,6-diones react with indole to give 2,2- dimethyl-5-(aryl(1H-indol-3-yl)methyl)-1,3-dioxane-4,6-diones with good yields and reasonable ee.

An efficient and novel nitrating reagent has been developed for ipso-nitration of arylboronic acids. By using inexpensive and commercially available Cu(NO3)2/CF3COOH as nitrating reagent, various nitroarenes are produced in moderate to excellent yields (51-96%). Advantages of this procedure are the operational simplicity and no need of extra catalyst.

An efficient protocol is described for the oxidation of alcohols to the corresponding aldehydes or ketones with 1,3-dibromo-5,5-dimethylhydantoin in the presence of aqueous H2O2.