Acid Derivatives 3a Research Articles

Synthesis, antimicrobial activity and molecular modeling study of substituted 5-aryl-pyrimido[5,4-c]quinoline-2,4-diones

A series of pyrimido[5,4-c]quinoline-2,4-dione derivatives 5a–k were synthesized in moderate yields via a thermolysis reaction of equimolar ratio of 5-arylidine-1,3-dimethylbarbituric acid derivatives 3a–d with aniline derivatives 4a–d at 150–180 °C for 1–2 h. Eight of the synthesized compounds were chosen for a primary in vitro one-dose anticancer assay performed using the full NCI 60 cell panel. Only compound 5b showed moderate GI% at the used dose (10 μM) against four of the tested cell lines corresponding to leukemia SR (GI%: 51), non small-cell lung cancer HOP-92 (GI%: 63), melanoma UACC-62 (GI%: 53) and renal cancer UO-31 (GI%: 69). On the other hand, antimicrobial screening of the whole set of the synthesized compounds was performed against three Gram +ve and two Gram −ve bacterial strains. Results of the antimicrobial screening showed that compounds 5d, 5e, 5f, 5h and 5k have broad-spectrum antibacterial efficacy being moderately active against all the tested Gram +ve and two Gram −ve bacteria. Also, compound 5a showed interesting results being only active against Streptococcus faecalis and both tested Gram −ve strains viz. E. coli and P. aeruginosa. In order to compare the binding mode of the most active compounds 5e and 5f along with the inactive compound 5c we docked these compounds into the empty binding site of topoisomerase II DNA gyrase (PDB ID: 1KZN), and results were compared with the bound inhibitor Clorobiocin.

Absolute configuration assignment of 3-oxindolylacetyl-4-phenyloxazolidinone derivatives

The straightforward determination of the absolute configuration of 2-oxo-3-indolylacetic acid derivatives 5a–e, based on analysis of the 1H NMR spectra of their oxindolylacetyl-phenyloxazolidinones 6a–e, is described. The conformational preferences for two diastereomeric amides were calculated by DFT, which matched well with the experimental results, while X-ray diffraction analysis allowed us to validate the methodology. Independent absolute configuration evidence was also obtained by vibrational circular dichroism.

Kinetic studies of the reaction of phenacyl bromide derivatives with sulfur nucleophiles

The reaction of the substituted phenacyl bromides 1a–e and 2a–e with thioglycolic acid 3 and thiophenol 6 in methanol underwent nucleophilic substitution SN2 mechanism to give the corresponding 2‐sulfanylacetic acid derivatives 4a–e, 5a–e and benzenethiol derivatives 9a–e, 10a–e. The reactants and products were identified by mass spectra, infrared and nuclear magnetic resonance. We measured the kinetics of these reactions conductometrically in methanol at a range of temperatures. The rates of the reactions were found to fit the Hammett equation and correlated with σ‐Hammett values. The ρ values for thioglycolic acid were 1.22–1.21 in the case of 4‐substituted phenacyl bromide 1a–e, while in the case of the nitro derivatives 2a–e they were 0.39–0.35. The ρ values for thiophenol were 0.97–0.83 in the case of 4‐substituted phenacyl bromide 1a–e, while in the case of the nitro derivatives 2a–e they were 0.79–0.74. The Brønsted‐type plot was linear with a α = −0.41 ± 0.03. The kinetic data and structure‐reactivity relationships indicate that the reaction of 1a–e and 2a–e with thiol nucleophiles proceeds by a concerted mechanism. The plot of log k45 versus log k30, the plot log(kx,3‐NO2/kH) versus log(kx/kH), and the Brønsted‐type correlation indicate that the reactions of the thiol nucleophiles with the substituted phenacyl bromides 1a–e and 2a–e are attributed to the electronic nature of the substituents. Copyright © 2011 John Wiley & Sons, Ltd.

First synthesis of 2-(benzofuran-2-yl)-6,7-methylene dioxyquinoline-3-carboxylic acid derivatives

A facile and inexpensive synthesis of a series of novel methylenedioxy-bearing 2-(benzofuran-2-yl)-quinoline-3-carboxylic acid derivatives 3a–h via the one-pot reaction of ethyl 2-chloromethyl-6,7-methylenedioxyquinoline-3-carboxylate (5) with various substituted salicylaldehydes 6a–g as well as 2-hydroxy-1-naphthaldehyde (6h) is described. Substrate 5 was synthesized by the Friedländer condensation reaction of 2-amino-4,5-methylenedioxybenzaldehyde (4) with ethyl 4-chloro-3-oxobutanoate using KHSO4 as catalyst under ultrasound irradiation conditions. The targeted compounds 3a–h were obtained in good yields of 52–82% and their structures were established based on spectral data and elemental analyses.

Synthesis and cytotoxicity evaluation of 1-[3-(9 H-carbazol-4-yloxy)-2-hydroxypropyl]-3-aryl-1 H-pyrazole-5-carboxylic acid derivatives

Several novel molecules, 1-(3′-(9 H-carbazol-4-yloxy)-2′-hydroxypropyl)-3-aryl-1 H-pyrazole-5-carboxylic acid derivatives 3a–g were synthesized and screened to evaluate their cytotoxicity against cancer cells in vitro. The compounds 3a–g has been prepared by the reaction of ethyl 3-aryl-1 H-pyrazole-5-carboxylate with 4-oxiranylmethoxy-9 H-carbazole in moderate to excellent yields. The cytotoxicity of synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against cancer cell such as SK–N–SH human neuroblastoma (NB), human A549 lung carcinoma, human breast cancer MCF-7 cell lines. The results showed that seven compounds can suppress SK–N–SH tumor cancer cell growth. Among them, compound 3d was the most effective small molecule in inhibiting SK–N–SH cell growth.

Synthesis of ‘Reversed’ Pyrimidine and Pyrazolo[1,5-a]pyrimidine-C-Nucleoside Analogues from Push-Pull Functionalized α-d-xylo-Hept-5-ulofuranurononitrile

3- O-Benzyl-6-deoxy-1,2- O-isopropylidene-6-[bis(meth-ylsulfanyl)methylene]-α- D- XYLO-hept-5-ulofuranurononitrile ( 1) was reacted with acetamidinium chloride, S-methylisothiouronium sulfate, and guanidinium chloride, respectively, in the presence of triethylamine to furnish the 2-substituted 4-(3- O-benzyl-1,2- O-isopropylidene-α- D- XYLO-tetrofuranos-4-yl)-6-methylsulfanylpyrimidine-5-carbonitriles 2A- C. Treatment of 1 with different 5-aminopyrazole-4-carboxylic acid derivatives yielded the 8-(3- O-benzyl-1,2- O-isopropylidene-α- D- XYLO-tetrofuranos-4-yl)-6-methylsulfanylpyrazolo[1,5- A]pyrimidine-3,7-dicarboxylic acid derivatives 3A- C.

Metal‐Free Triazole Formation as a Tool for Bioconjugation

The development of selective and site-specific bio-orthogonal conjugation methods is an important topic in chemical biology. A wide range of methods, such as the Staudinger ligation, native chemical ligation, genetic incorporation, expressed-protein ligation, Huisgen azide–alkyne cycloaddition, and the Diels–Alder ligation are currently employed in the selective modification of proteins and other biomolecules. In recent years, the Cu-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition, also referred to as “click reaction”, has been increasingly applied in various fields of chemistry as a versatile and mild ligation method. This method allows for the synthesis of complex materials, which include bioconjugates, glycopeptides, functionalized polymers, virus particles, and therapeutics. However, due to the toxicity of the copper catalyst to both bacterial and mammalian cells applications that involve in vivo ligation are limited. In order to circumvent the use of copper ions, Bertozzi and co-workers have devised a strain-promoted [3+2] cycloaddition reaction that involves azides and a strained cyclooctyne derivative. Recent reports by Ju et al. have also shown successful applications of copper-free 1,3-dipolar cycloaddition by using either elevated temperatures or electron-deficient alkynes. We envisioned that the combination of ring strain and electron deficiency, as occurs in oxa-bridged bicyclic systems 2a and 2b, could also lead to an increased reactivity toward [3+2] cycloaddition reactions. Here, we report a spontaneous tandem [3+2] cycloaddition–retro-Diels–Alder ligation method that results in a stable 1,2,3-triazole linkage. This methodology can be applied to biomacromolecules that contain various functional groups under physiological conditions. The oxabridged bicyclic systems 2a and 2b were prepared by a Diels– Alder reaction of substituted propiolates with furan (Scheme 1). Subsequent hydrolysis provided the desired carboxylic acid derivatives 3a and 3b, in excellent yield. To compare the reactivity of Diels–Alder products 2a and b with the corresponding alkynes, [3+2] cycloaddition reactions were performed under ambient conditions by using benzyl azide, and monitored over time with H NMR spectroscopy (Figure 1). The oxanorbornadienes 2a and 2b and their respective alkynes provided identical 1,4,5-substituted triazoles to the products.

Synthesis and Reactions of Some New Thiobarbituric Acid Derivatives

A series of novel thiobarbituric acid derivatives 3a–c , 5, and 12 were synthesized via the reaction of 4-benzoyl-1-cyanoacetylthiosemicarbazide ( 1 ) or its derivatives 2a–c , 9 with malonic acid and acetyl chloride. Coupling of thiobarbituric acid derivatives 3a-c and 5 with aromatic diazonium chlorides furnished a new series of the corresponding bisarylhydrazo-thiobarbituric dyes 4a–c . The reaction of 5 with cyclohexanone and sulfur under Gewald reaction condition afforded thieno[2,3-d]pyrimidine derivative 21 , that condensed with p-anisladehyde to give 5-arylidene thiobarbituric acid derivative 22 . The reaction of 1 with phenyl isothiocyanate afforded the non-isolable adduct 23 which was used as a key intermediate for the synthesis of polyfunctionally substituted thiazolidinone and thiobarbituric ring systems.

Synthesis of N‐Substituted 3‐Aminomethylidenetetramic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access the actual ChemInform Abstract, please click on HTML or PDF.

Solvent-free Photooxygenation of 5-methoxyoxazoles: Stereoselective Synthesis of α-amino-α-hydroxy Carboxylic Acid Derivatives

A solvent-free photooxygenation of 5-methoxyoxazoles 1a–j embedded in porphrin-loaded polystyrene beads as solid support is described and applied for the synthesis of 3H-1,2,4-dioxazole derivatives 2a–j. Acid catalysed hydrolysis of 3H-1,2,4-dioxazole derivatives gave α-amino-α-hydroxy carboxylic acid derivatives 3a–j. The structural elucidation of the new compounds were carried on the basis of spectral and X-ray analyses.

Asymmetric Synthesis of 3‐Substituted Unsaturated Prolines from Chiral Sulfoximine Substituted Allyl Titanium(IV) Complexes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids

(S)-3-(Dimethylamino)methylidene-5-benzyltetramic acid derivatives 4a and 4b were prepared in three steps from N-protected (S)-3-phenylalanines 1a and 1b, respectively. Similarly, N-[N-(benzyloxycarbonyl)glycyl]glycine (1c) was transformed into the enaminone 4c. Acid-catalysed coupling of enaminones 4a-c with aliphatic, aromatic, and heteroaromatic primary amines 5-34 afforded the corresponding N(3′)-substituted 3-aminomethylidenetetramic acid derivatives 35-64 in 29-96% yields.

Asymmetric synthesis of 3-substituted unsaturated prolines from chiral sulfoximine substituted allyl titanium(IV) complexes

An asymmetric synthesis of the 3-substituted Δ 3,4-unsaturated prolines 7a– e and 3-substituted 4-methylene prolines 14a– c starting from the corresponding γ,δ-unsaturated α-amino acids 4a– e and 11a– c , respectively, is described. Amino acid derivatives 4a– e and 11a– d were obtained through aminoalkylation of the corresponding sulfoximine substituted allyl titanium(IV) complexes 2a– e and 10a– d , respectively, with the N- tert-butylsulfonyl imino ester 3 . Activation of sulfoximines 4a– e and 11a– c through methylation of the sulfoximine group followed by a KF mediated isomerization of the vinyl aminosulfoxonium salts 5a– e and 12a– c , respectively, to the corresponding allyl aminosulfoxonium salt 6a– e and 13a– c , respectively, and a subsequent intramolecular nucleophilic substitution of the allylic aminosulfoxonium group afforded the enantio- and diastereomerically pure proline derivatives in medium to high yields.

Vicinal Dianion of Triethyl Ethanetricarboxylate: Syntheses of (±)-Lichesterinic Acid, (±)-Phaseolinic Acid, (±)-Nephromopsinic Acid, (±)-Rocellaric Acid, and (±)-Dihydroprotolichesterinic Acid

The vicinal dianion 2 derived from triethyl ethanetricarboxylate reacted regioselectively with aldehydes and ketones at C(β) to provide paraconic acid derivatives 5a–f in moderate to high yields as mixtures of diastereoisomers. The paraconic acid derivatives 5e and 5f were utilized as the starting materials for the syntheses of (±)-lichesterinic acid (12), (±)-phaseolinic acid (13), (±)-nephromopsinic acid (14), (±)-rocellaric acid (15), and (±)-dihydroprotolichesterinic acid (16).

Mechanistic aspects of hydrogen addition during enantioselective rhodium-catalysed reduction of CC double bonds with formic acid/triethylamine or molecular hydrogenBased on the presentation given at Dalton Discussion No. 4, 10–13th January 2002, Kloster Banz, Germany.

Deuterium labelling experiments reveal a remarkably different hydrogen addition mode during homogeneously catalysed CC bond reduction of itaconic acid derivatives 1a–d using molecular hydrogen (hydrogenation) or formic acid/triethylamine (transfer hydrogenation). The expected vicinal addition of two hydrogen atoms across the double bond prevails for all substrates in conventional hydrogenation, whereas the deuterium pattern depends largely on the nature of the carboxyl group in the β (or allylic) position during transfer hydrogenation. Vicinal addition is observed only in case of itaconic acid 1a and α-methylitaconate 1c, while 1,3-addition is preferred with dimethylitaconate 1b and β-methylitaconate 1d. Significant amounts of polydeuterated products are formed also during hydrogenation and transfer hydrogenation. Monitoring the deuterium pattern as a function of time reveals that deuterium scrambling is responsible for polydeuteration, but not for the change of the addition mode. The use of monodeuterated formic acid isotopomers shows that the incorporation from the hydridic formyl position occurs preferentially at the terminal end of the double bond (C-3) whereas the protic hydrogen is directed either in the higher substituted olefinic (C-2) or the methylene (C-1) position. Control experiments using mesaconic (2) and citraconic (3) acids demonstrate that double bond migration in 1a–d is negligible under the reaction conditions. These results are best rationalised on the basis of a common mechanism for hydrogenation and transfer hydrogenation that involves (i) the generation of Rh–H intermediates, (ii) reversible hydride transfer to coordinated substrate to form two isomeric σ-alkyl intermediates, and (iii) irreversible product liberation through protolytic Rh–C cleavage. The key intermediates are similar if not identical for hydrogenation and transfer hydrogenation. The change of the hydrogen transfer pattern can be explained on the basis of the relative rates of the individual steps within the catalytic cycle as compared to the rate of isomerisation of the σ-alkyl intermediates.

Highly selective and facile synthesis of dihydro- and tetrahydropyridine dicarboxylic acid derivatives using electroreduction as a key step

Electroreduction of pyridinedicarboxylic acid derivatives 1a–g in methanol containing ammonium chloride using a divided cell brought about highly selective hydrogenation to give the corresponding dihydropyridines in good yields. From the electrolysis of dimethyl 2,3- and 2,5-pyridinedicarboxylates 1a,c, only the corresponding 1,2-dihydropyridine derivatives 2a,c were obtained in a regioselective manner while that of 2,4-, 2,6-, and 3,4- disubstituted pyridines 1b,d,e afforded the corresponding 1,4-dihydropyridines 2b,d,e selectively in good yields. Further hydrogenation of the resultant dihydropyridines by several methods led to the selective and facile formation of the corresponding tetrahydropyridines 6. Furthermore, Mg-promoted hydrosilylation of the N-acetylated product 5a gave C-silylated tetrahydropyridines in a stereoselective manner.

ChemInform Abstract: Diastereoselective Conjugate Addition of Thiols to Camphor Pyrazolidinone Derived Chiral α,β-Unsaturated Carbonyls: Synthesis of β-Mercaptocarboxylic Acid Derivatives.

Abstract Reaction of chiral α,β-unsaturated carboxylic acid derivatives 2a – e derived from camphor pyrazolidinone 1 with thiols affords β-mercaptocarboxylic acid derivatives 3a – e with a wide range of stereoselectivities (up to >90% de). The stereoselectivity as a function of Lewis acid is described. The auxiliary can be easily recovered from the Michael adducts under mild conditions.

Synthesis of 3C,4R,5T-1,2-Dimethyl-3,5-Diaryl Pyrazolidine-4-Carboxylic Acid via Intermolecular [3++2] Cycloaddition

1,2-Dimethyl-3,5-diarylpyrazolidine-4-carboxylic acid derivatives 4a–d were synthesised stereo-selectively via intermolecular [3++2] cycloaddition of aldehydes 1a–d and 1,2-dimethylhydrazine dihydrochloride (2) with ethyl trans-cinnamate (3), stereochemistries of which were assigned by 1H-NOESY spectroscopy, and relative configurations confirmed by X-ray diffraction of one of them (4a).

Diastereoselective conjugate addition of thiols to camphor pyrazolidinone derived chiral α,β-unsaturated carbonyls: synthesis of β-mercaptocarboxylic acid derivatives

Reaction of chiral α,β-unsaturated carboxylic acid derivatives 2a– e derived from camphor pyrazolidinone 1 with thiols affords β-mercaptocarboxylic acid derivatives 3a– e with a wide range of stereoselectivities (up to >90% de). The stereoselectivity as a function of Lewis acid is described. The auxiliary can be easily recovered from the Michael adducts under mild conditions.

Synthesis of 3c,4r,5t-1,2-dimethyl-3,5-diaryl pyrazolidine-4-carboxylic acid via intermolecular [3++2] cycloaddition

1,2-Dimethyl-3,5-diarylpyrazolidine-4-carboxylic acid derivatives 4a–d were synthesised stereo-selectively via intermolecular [3++2] cycloaddition of aldehydes 1a–d and 1,2-dimethylhydrazine dihydrochloride (2) with ethyl trans-cinnamate (3), stereochemistries of which were assigned by 1H-NOESY spectroscopy, and relative configurations confirmed by X-ray diffraction of one of them (4a).