Synthesis

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Molbank (2015) M870

3-(3,4-Dihydroxyphenyl)-8-hydroxy-2H-chromen-2-one
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We report a novel protocol for the synthesis of 3-(3,4-dihydroxyphenyl)-8-hydroxy-2H-chromen-2-one via demethylation/delactonization/elimination/lactonization/ decarboxylation domino reaction sequence of diastereomeric mixture of cis- and trans-3-(2,3-dimethoxyphenyl)-6,7-dimethoxy-1-oxoisochroman-4-carboxylic acids in boiling HBr/AcOH. The structure of the target compound was established for the first time by means of spectral methods such as 1H-, 13C-, DEPT-135-NMR, IR and HRMS.
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Molecules 20 (2015) 2555–2575

Synthesis and antioxidant activity of polyhydroxylated trans-restricted 2-arylcinnamic acids
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A series of sixteen polyhydroxylated trans-restricted 2-arylcinnamic acid analogues 3a–p were synthesized through a one-pot reaction between homophthalic anhydrides and various aromatic aldehydes, followed by treatment with BBr3. The structure of the newly synthesized compounds was confirmed by spectroscopic methods and the configuration around the double bond was unequivocally estimated by means of gated decoupling 13C-NMR spectra. It was shown that the trans-cinnamic acid fragment incorporated into the target compounds’ structure ensures the cis-configuration of the stilbene backbone and prevents further isomerization along the carbon–carbon double bond. The antioxidant activity of compounds 3a–p was measured against 1,1-diphenyl-2-picrylhydrazyl (DPPH●), hydroxyl (OH●) and superoxide (O2●▬) radicals. The results obtained showed that the tested compounds possess higher activities than natural antioxidants such as protocatechuic acid, caffeic acid and gallic acid. Moreover, it was shown that a combination of two different and independently acting fragments of well-known pharmacological profiles into one covalently bonded hybrid molecule evoke a synergistic effect resulting in higher than expected activity. To rationalize the apparent antioxidant activity and to establish the mechanism of action, a SAR analysis and DFT quantum chemical computations were also performed.
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Eur. J. Med. Chem. 78 (2014) 198–206

One-Pot Synthesis and Radical Scavenging Activity of Novel Polyhydroxylated 3-Arylcoumarins
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An unexpected domino rearrangement brought about the development of a novel one-pot procedure for synthesis of coumarins. This protocol allowed the gram-scale synthesis of a variety of polyhydroxylated derivatives 3a–p, from readily available starting materials at a low cost. Based on two proven intermediates, a probable mechanism consisting of boron tribromide induced demethylation/lactone ring opening/elimination/isomerization/lactone ring closure reaction sequence of in situ formed 3-aryl-3,4-dihydroisocoumarin-4-carboxylic acids was deduced. Compared to the common methods, used for the synthesis of coumarins, the proposed herein possesses great advantages, such as mild conditions, good yields for short reaction time, simple work-up procedure and easy isolation of the final products. The structure of the newly synthesized compounds 3a–p was established by spectroscopic methods (1H NMR, 13C NMR, IR, MS and HRMS) and their radical scavenging activity was evaluated in vitro against 1,1-diphenyl-2-picrylhydrazyl free radical (DPPHradical dot). The results obtained show that compounds 3g–p posses higher radical scavenging activity (3.16 ≤ SC50 [μM] ≤ 6.82) than well-known antioxidants such as trolox, protocatechuic acid, caffeic acid and gallic acid (SC50 [μM] = 9.34, 8.83, 9.48, 5.33, respectively), which is a precondition for promising antioxidant activity of these compounds to be expected.
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Eur. J. Med. Chem. (2013) 185–192

A novel one-pot synthesis and preliminary biological activity evaluation of cis-restricted polyhydroxy stilbenes incorporating protocatechuic acid and cinnamic acid fragments
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A series of new stilbenes 4a–e, 5 were synthesized through a novel one-pot Perkin-like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods (1H NMR, 13C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling 13C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH• radical (IC50 ≤ 10 μM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 μmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 μM.
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Eur. J. Org. Chem. (2011) 377–384

New Perkin/Michael/Addition Domino Reaction Between Homophthalic Anhydride and Aromatic Aldehydes: A Facile Approach to Blue Fluorescent 6-oxo-dibenzo[c,h]chromenes
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A series of new trans-11-aryl-6-oxo-6H-dibenzo[c,h]chromene-12-carboxylic acids has been synthesised through anew Perkin/Michael addition domino reaction between homophthalic anhydride and aromatic aldehydes. The synthesis is straightforward and gives good overall yields by taking into account the concomitant formation of four C–C, C–O and C=C bonds. The structures of the newly synthesised compounds were established by spectroscopic methods (1H NMR, 13C NMR and IR) and X-ray diffraction analysis, and the fluorescent properties were investigated. A probable reaction mechanism including three proven intermediates is proposed.
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Spectrochim. Acta A 77 (2010) 902–907

Synthesis, spectroscopic and structural study of trans- and cis- (±)-3-phenyl-4-(pyrrolidine-1-carbonyl)isochroman-1-ones
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Synthesis, spectroscopic and structural study of trans- and cis-(±)-3-phenyl-4-(pyrrolidine-1-carbonyl)-isochroman-1-ones is performed in order to obtain the correlation between the crystal structure and spectroscopic properties of both isomers in solid-state. The methods such as single crystal X-ray diffraction, conventional and linear-polarized IR-spectroscopy, UV-spectroscopy, mass spectrometry, 1H and 13C NMR are employed. Quantum chemical ab initio and DFT calculations are performed, to support the experimental data for the electronic structure and optical properties.
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Ann. Univ. Sofia, 102 (2010) 145–152

Synthesis and mass spectral study of trans- and cis- (±)-3-phenyl-3,4-dihydroisocoumarin-4-carboxamides
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A series of trans- and cis-(±)-3-phenyl-3,4-dihydroisocoumarin-4-carboxamides (4a-c) were synthesized and the electron impact (EI) ionization mass spectral fragmentation was described. For all studied compounds, both diastereomers follow the same fragmentation pattern, but differ on the abundance of the base peaks, which shows the opportunity to distinguish 3,4-dihydroisocoumarin diastereomers using mass spectrometry.
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Ann. Univ. Sofia, 101 (2009) 89–98

Synthesis of new 1,2,3,4-tetrahydroisoquinolin-1-one-4-Carboxamides as Conformationally Restricted GABA Analogs
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J. Liq. Chromatogr. & Rel. Technol. 30 (2007) 2155–2169

Automatic selection of mobile phases. VII. Thin-layer chromatography on silica and alumina of 11,12-disubstituted trans/cis-11,12-dihydro-6H- dibenzo[c,h]chromen-6-ones
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Fifteen title compounds with four fused rings and two varying substituentswere used to further specify the scope and limitation of a theoretical approach(the Snyder theory and LSChrom software) for selection of mobile phases avoidingany trial and error experiments. Based on the structure of the compounds, thetheoretical treatment predicted values of strength 1 of suitable mobile phases forTLC, namely 0.311 for silica and 0.446 for alumina. Sixteen specific mobilephases with such or close values of 1 were arbitrarily selected from listsprepared by complex calculations. They were used to perform TLC. The dataobtained showed that the retentions in all 256 measurements done were abovethe origin and below the solvent front. Thus, a good agreement between the theoreticaland experimental data was established, thus proving a successful applicationof the approach. The retentions of all compounds and separation of one cis/transpair depended on the stationary phase, 1, and the tuning parameters m and P0 ofthe mobile phases.
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Z. Naturforsch C 62 (2007) 477–482

Preliminary evaluation of antimicrobial activity of diastereomeric cis/trans-3-aryl(heteroaryl)-3,4-dihydroisocouamrin-4-carboxylic acids
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Preliminary differentiating screening of the antibacterial and antifungal activity of a seriesof diastereomeric cis/trans-3-aryl(heteroaryl)-3,4-dihydroisocoumarin-4-carboxylic acids (3aÐi) was performed by the agar diffusion method against twelve microorganism strains of differenttaxonomic groups. S. aureus and A. niger were the most sensitive strains to the antibioticeffect of the tested compounds, both inhibited by 10 of 12 compounds. The most potentantibacterial agent was cis-3-phenyl-3,4-dihydroisocoumarin-4-carboxylic acid (cis-3a), exhibitingactivity against all seven bacterial test strains.
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J. Heterocyclic Chem. 44 (2007) 673–677

New isochromans. 1. Synthesis and antimicrobial activity of 4-substituted (±)-1H-Spiro[benzo(c)pyran-3(4H),1’-cyclohexane]-1-ones
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The reaction between homophthalic anhydride and cyclohexanone was examined both in the presence of DMAP or BF3•Et2O complex as a catalyst. The latter yielded (±)-1-oxo-1H-spiro[benzo[c]pyran-3(4H), 1′-cyclohexane]-4-carboxylic acid (3) in a higher yield (82 %). A series of new (±)-4-(N,N-disubstituted-1-carbamoyl)-1H-spiro[benzo[c]pyran-3(4H),1′-cyclohexane]-1-ones (5a-h) were synthesized from the parent acid 3 by a two-step reaction. Differentiating microbial screening was performed for most of the synthesized compounds against twelve microorganisms belonging to different taxonomic groups. The spiro acid 3 was active against all bacterial strains with MIC ≥ 20 μg/ml against B. subtillis and P. vulgaris. E. coli was the most sensitive strain to the antibacterial effect of the tested compounds.
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Molecules 11 (2006) 403–414

Synthesis of new trans-2-benzyl-3-(furan-2-yl)-4-substituted-1,2,3,4-tetrahydroisoquinolinones
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The reaction of homophthalic anhydride and N-(furan-2-yl-methylidene)- benzylamine in different solvents and varying temperatures was studied in detail. Mixtures of the expected trans- and cis-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids trans-5 and cis-5, alongwith by-products 6 and 7 were obtained in dichloroethane or benzene. In pyridine, used for the first time, the reaction became completely diastereoselective, giving only the trans isomer. The carboxylic acid group of trans-5 was transformed in four steps into cyclic aminomethyl groups which yielded various new tetrahydroisoquinolinones trans- 11a-g, incorporating both a known fragment of pharmacological interest and various pharmacophoric substituents.
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Tethrahedron 60 (2004) 2525–2530

cis/trans-Isochromanones. DMAP induced cycloaddition of homophthalic anhydride and aldehydes
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Homophthalic anhydride (1) reacts with wide variety of aromatic aldehydes, in the presence of chloroform and DMAP (N,N-dimethyl-4-amino-pyridine) at room temperature, to give in high yields cis- and trans-1-oxo-isochroman-4-carboxylic acids. Under these conditions, the trans-isomer is predominant and formation of Perkin-type products was not observed in contrast to the reaction carried out in the presence of pyridine. The unexpected trans-6-oxo-11-thiophen-2-yl-11,12-dihydro-6H-dibenzo[c,h]chromene-12-carboxylic acid methyl ester (8) was isolated when the reaction between 1 and thiophene-2-carbaldehyde was carried out in pyridine.
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J. Liq. Chrom. & Rel. Technol. 27 (2004) 2003–2018

Automatic selection of mobile phases. IV. Thin-layer chromatography on silica of simple and complex organic compounds
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The LSChrom software incorporating the Snyder theory was applied to organic compounds with simple and complex structure being cis or trans olefinic derivatives and substituted tetrahydroisoquinolines, respectively. Lists of recommended mobile phases for thin‐layer chromatography (TLC) on silica of the compounds studied were obtained, avoiding any preliminary trial and error experiments. The procedure is based on the structure of any compound, literature data for the adsorption properties of the relevant groups available in the structure, and numerous calculations. The experiments with 12 arbitrarily selected mobile phases from the recommended lists showed, for about 150 measurements, the proper retention of any compound and good separation of the cis–trans isomers. Thus, a new successful application of the both theory and software was achieved.
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Tetrahedron Lett. 45 (2004) 8383–8386

Configuration and conformational equilibrium of (±)-trans-1-oxo-3-thiophen-2-yl-isochroman-4-carboxylic acid methyl ester
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The X-ray analysis of 1-oxo-3-thiophen-2-yl-isochroman-4-carboxylic acid methyl ester 1 confirmed its trans-configuration and a conformation with diaxial H-3 and H-4 atoms in solid state. NMR experiments indicated that trans-1 exists in solution in both expected conformers. In CDCl3 and especially in CD3OD or DMSO, the conformational equilibrium is shifted towards the conformer with diequatorial H-3 and H-4, which was also determined by 2D NOESY experiments. The shift is due to the greater polarity of that conformer deduced by ab initio calculations.