Syntheses of various 5-(bromoaryl)-substituted uracils

The Suzuki Pd(0)-catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium, previously further developed by us, has been used for regioselective preparation of 5-(2′-bromo-5′-furyl)-, 5-(2′-bromo-4′-furyl)-, 5-(2′-bromo-5′-thienyl)-, 5-(2′-bromo-4′-thienyl)-, 5-(4′-bromo-2′-thiazolyl)-, 5-(3′-bromophenyl)-, 5-(6′-bromo-2′-pyridyl)- and 5-(4′-bromo-2′-pyrimidyl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4-di-t-butoxy-5-pyrimidineboronic acid and the nine different aryl dibromides that were tried as coupling partners, only the 2,4- and 2,5-dibromothiazoles did not give satisfactory yields, 15% and 0%, respectively. The other seven aryl dibromides gave the desired 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 58-89% yield. Attempts to synthesise 2,4-di-t-butoxy-5-(2′-bromo-4′-thienyl)pyrimidine from 2-bromo-4-iodothiophene failed. Dealkylation of the 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 2.5 M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields.     

Synthesis of 6-(α-thienyl)azulene from 2-butoxy-4-(α-thienyl)-Δ5-dihydropyran

2,5-Dibutoxy-4-(α-thienyl)-Δ³-dihydropyran was obtained by bromoalkoxylation at the double bond and dehydrobromination of 2-butoxy-4-(α-thienyl)-Δ⁵-dihydropyran. Acid hydrolysis of the product in the presence of N-methylaniline hydrochloride gave a salt of 3-(α-thienyl)glutaconic dialdehyde dianil, treatment of which with cyclopentadienylsodium in alcohol gives the corresponding fulvene, which is thermally cleaved to N-methylaniline and 6-(α-thienyl)azulene.     

Cyclometalated Compounds of Platinum(II) with two different C,N-aromatic ligands

A synthetic route leading to bis-heteroleptic cyclometalated complexes is described. The complexes [2-(2′-thienyl)pyridinato-N, C-^3′]{2-[3′-(trimethylsilyl)2′-thienyl]pyridinato-N, C^3′}platinum(II) ([Pt(thpy) (TMS-thpy)]; I ) and (l-phenylpyrazolato-N², C^2′)[2-(2′-thienyl)pyridinato-N, C^3′]platinum ([Pt(Phpz)(thpy)]; II ) are characterized by UV/VIS, NMR, and mass spectroscopy. Thermal and photochemical oxidative addition reactions yield two out of the 10 possible pairs of enantiomers of octahedral Pt(IV) compounds.     

New approach to the formation of azepine ring: Synthesis of 2-methyl-6-(5-methyl-2-thienyl)-3H-azepine from 2-methyl-5-propargylthiophene and isothiocyanate

The first representative of thienyl-substituted 3H-azepines has been synthesized starting from dilithiated 2-methyl-5-propargylthiophene and isopropyl isothiocyanate. It was shown that N-(1-methylethylidene)-2-(5-methyl-2-thienyl)-1-(methylthio)-1,3-butadiene-1-amine (2-aza-1,3,5-triene) formed as a result of this reaction is readily converted into 2-methyl-6-(5-methyl-2-thienyl)-3H-azepine under the action of super bases. Dedicated to Academician B. A. Trofimov of the Russian Academy of Sciences on his 70^th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1380–1383, September, 2008.     

Synthetic Applications of Stereodefined 2-Substituted 1-Silyl-1-stannylethenes: A New Synthesis of 5-Ethenyl-5′-(1-propynyl)-2,2′-bithiophene,a Naturally-Occurring Phototoxin)

(E)-2-(5-Trimenthylstannyl-2-thienyl)ethenyldimethylphenylsilane. (E)-8, which can be stereospecifically prepared from (Z)-1-dimethylphenylsilyl-2-(2-thienyl)-1-trimethylstannyl-ethene, (Z)-6, or from (E)-2-(2-thienyl)ethenyldimethylphenylsilane, (E)-9, serves as an equivalent to the 2-ethenylthiophene d ¹', d ⁵-synthon, 20, in an efficient two-step synthesis of 5-ethenyl-5′-(1-propynyl)-2,2′-bithiophene, 10, a naturally-occurring phototoxin. In the first step of this synthesis compound (E)-8 undergoes a palladium-catalyzed cross-coupling reaction with 2-iodo-5-(1-propynyl)thiophene, 16, and in th second step the so obtained cross-coupling product, (E)-17, undergoes a protodesilylation reaction.     

Acidity Constants of the Thienyl- and Phenyl-Pyridines and Stability Constants of the Corresponding Copper (II) 1:1 Complexes

The acidity constants of the six thienyl- and the three phenyl-pyridines, and the stability constants of the corresponding Cu²⁺ 1:1 complexes were determined in aqueous solution (I = 0.1, NaCIO₄; 25°). The basicity of the pyridyl group is increased by a shift of a thienyl or phenyl group in the order 2 < 3 < 4 and the influence of the 2′-thienyl group is greater than that of the 3′-thienyl group. The stability of the Cu²⁺ 1:1 complexes formed with 3- and 4-substituted pyridines is only dependent on their basicity, as is commonly observed for structurally related ligands and their complexes. Due to steric hindrance the complexes of the 2-substituted derivatives are less stable by about 1.5 log units. There is no evidence that the aromatic bonded sulfur of 2-(2′-thienyl)-pyridine participates in complex formation with Cu²⁺, in opposition to an earlier claim [1].     

Heterocyclic fused tropylium ions VII. On the synthesis of 9H-dithieno[2,1 -b:4,5-c′]tropylium fluoborate and 4H-dithieno[1,2-b:4,5-c′]tropylium fluoborate

9H-Dithieno[2,1 -b:4,5-c′]tropylium ion (III) and 4ii-dithieno[1,2-b:4,5-c′]tropylium ion (IV) have been synthesized by ring-closure of 1-(4-carboxy-3-thienyl)-2-(3′-thienyl)ethane (IX) and 1-(4-carboxy-3-thienyl)-2-(2′-thienyl)ethane (XVI), respectively, followed by bromination-debrom-ination to 9H-cyclohepta[2,1-b:4,5-c′] dithiophen-9-one (XI) and 4H-cyclohepta[1,2-b:4,5-c′]-dithiophen-4-one (XVIII), and finally by reduction and hydride transfer. The tropylium ions III and IV were less stable than the [b,b′]-fused isomers previously studied.     

Synthesis,characterization, and biological activities of some novel thienylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines and related heterocycles

3-Cyano-5-ethoxycarbonyl-6-methyl-4-(2′-thienyl)-pyridine-2(1H)-thione ( 1 ) is synthesized and reacted with chloroacetamide or chloroacetonitrile to give 3-amino-5-ethoxycarbonyl-6-methyl-4(2′-thienyl)-thieno[2,3-b]pyridine-2-carboxamide 3a or its 2-carbonitrile analog 3b , respectively. Cyclocondensation of 3a with triethylorthoformate produced the corresponding pyridothienopyrimidineone 4 , which on heating with phosphorus oxychloride gave 4-chloropyrimidine derivative 5 . Compound 5 was used as key intermediate for synthesizing compounds 6 , 9 , 10 , 11 , and 12 upon treatment with some nucleophilic reagents such as thiourea, 5-phenyl-s-triazole-3(1H)-thione, piperidine, morpholine, or hydrazine hydrate, respectively. Reaction of pyridothienopyrimidinethione 6 with N-(4-tolyl)-2-chloroacetamide or ethyl bromoacetate afforded the corresponding S-substituted methylsulfanylpyrimidines 7 or 8 . The condensation of 3b with triethylorthoformate gave azomethine derivative 13 , which was reacted with hydrazine hydrate to give ethyl 3-amino-3,4-dihydro-4-imino-7-methyl-9-(2′-thienyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-8-carboxylate ( 14 ). Compounds 12 and 14 were used as precursors for synthesizing other new thienylpyridothienopyrimidines as well as isomeric thienyl-s-triazolopyridothieno- pyrimidines. All synthesized compounds were characterized by elemental and spectral analyses such as IR, ¹H NMR, and ¹³C NMR. In addition, majority of synthesized compounds were tested for their antifungal activity against five strains of fungi. Moreover, compounds 3a , 5 , 6 , 8 , and 22 were screened for their anticancer activity against HEPG-2 and MCF-7 cell lines.     

The syntheses and NMR spectra of the twelve isomeric thieno[b]fused naphthyridines

Through the use of Pd(0)-catalyzed couplings between 2-(2-trimethylstannyl-3-pyridyl)-1,3-dioxolane, 3-trimethylstannyl-2-pyridine carboxaldehyde, 3-trimethylstannyl-4-pyridine carboxaldehyde and 4-trimethyl-stannyl-3-pyridine carboxaldehyde with t-butyl-N-(3-bromo-2-thienyl)carbamate, t-butyl-N-(2-bromo-3-thienyl)carbamate and t-butyl-N-(4-bromo-3-thienyl)carbamate in N,N-dimethylformamide at 100°, using cupric oxide as a coreagent, all twelve isomeric thieno[b]naphthyridines have been synthesized in an one-pot procedure. A detailed study of the ¹H and ¹³C nmr spectra of these isomers has been undertaken.     

Electron impact mass spectra of 2-(2-pyridyl)methylene-1,3-dicarbonyl compounds: Unusual abundance of the [M + 1]+ ion and the effect of stereochemistry

Electron impact mass spectra of 2-(2-pyridyl)methylene-1,3-dicarbonyl compounds and related heteroaryl species have been investigated. In 3-(2-pyridyl)methylene-2,4-pentanedione, its 6′-methyl and 6′-methoxycarbonyl derivatives and in E- and Z-ethyl 3-oxo-2-(2-pyridyl)methylenebutanoates the base peak arises from the loss of methyl radical from the molecular ion to produce a 3-oxo-3H-indolizinium ion. A marked difference is observed in the behaviour of the geometric isomers of the keto esters. The diketones and E-keto ester carrying a 2-pyridyl substituent and ketone functionality on the same side of the carbon-carbon double bond exhibit an unusually high [M + 1]⁺/[M]^+˙ ratio (about 2.5) under normal ionization conditions (pressure 10–100 μPa). This abnormality is a function of pressure only and independent of temperature. In the case of the Z-keto ester, the corresponding malonate, 3- and 4-(2-pyridyl)methylene-2,4-pentanediones, and 2-furyl, 2-thienyl and phenyl diketone analogues, the ratio does not differ much from that due to the natural isotope abundance. Results for 1,1,1,5,5,5-hexadeuterio-2-(2-pyridyl)-methylene-2,4-pentanedione (strong M + 2 peak) suggest one mass unit transfer as an intermolecular proton shift from a methyl group to give a 3-hydroxy-3-methyl-3H-indolizinium ion. This real mass spectrometric phenomenon is a unique example of low pressure self-chemical ionization.     

Conformational analysis of some (E)-α-phenyl-β-(2-thienyl)- and -(2-furyl_acrylic acids

NMR spectral data of some (E)-α-phenyl-β-(2-thienyl) acrylic acids indicate that these compounds exist in the preferred s-trans conformation. In the case of (E)-α-phenyl-β-(2-furyl)acrylic acids and their methyl esters the presence of only s-cis rotamer has been established.     

Dehydration of 3- and 4-aryl- substituted 3-hydroxy acids in acetic anhydride in presence of zinc chloride

The reaction of several di- and triaryl-substituted 3-aryl-3-hydroxy acids and a 4-aryl-3-hydroxy acid in acetic anhydride in the presence of anhydrous zinc chloride has been investigated. It has been shown that the reaction discovered with 3-(2′-thienyl)-substituted 3-hydroxy acids, namely, their conversion under the above stated conditions into α, β-unsaturated methyl ketones,^1,2 occurs also with 3-aryl 3-hydroxy acids but to a smaller degree due to the concurrent cyclization reaction which leads to indene-1-ones. It has been established that the unsaturated methyl-ketones obtained, containing three aromatic substituents at the CC bond, exist in s-cis-(CC, CO)-conformation. It has been found that with the 4-aryl-substituted 3-hydroxy acid almost no unsaturated ketone is obtained, whereas instead the main product is a 2,3-disubstituted 1-naphthol which is acetylated under the conditions of the reaction. Its structure has been proved by its UV, IR and NMR spectra and confirmed by the mass spectrum of the compound.     

Synthesis of Duloxetine Intermediate (S)-3-Chloro-1-(2-thienyl)-1-propanol with Liquid-Core Immobilized Candida pseudotropicalis 104

(S) -3-Chloro-1-(2-thienyl)-1-propanol was synthesized by the asymmetric reduction of 3-chloro-1-(2-thienyl)propanone with liquid-core immobilized Candida pseudotropicalis 104. The optimum time was 28?h for the re-cultivation of immobilized cells. The optimum film solvent for the liquid-core capsule was 0.3?% chitosan (M _w 1.0?×?10⁵). Conversion decreased with the increase of the liquid-core capsule diameter and with the addition of more substrates at the same reduction time. The immobilized cells show good reduction ability in a potassium phosphate buffer (pH 6.6~7.2). The material outside the spread speed of immobilized cells was not restricted when the shaking speed was higher than 160?r/min. Liquid-core immobilized cells can be reused 11 times. Compared with the batch reduction, the continuous reduction of 3-chloro-1-(2-thienyl)propanone in the membrane reactor with liquid-core immobilized cells as catalyst can relieve the inhibition from a high-concentration substrate. Conversion and enantiometric excess of (S)-3-chloro-1-(2-thienyl)-1-propanol reached 100?% and >99?% in a continuous reduction of 12?g/L 3-chloro-1-(2-thienyl)propanone for 10?days.     

Tris(difluoro and trifluorobutane-2,4-dionato) gallium(III) and indium(III) complexes

Eight tris(β-diketonate)gallium(III) and seven tris(β-diketonate)-indium(III) complexes M(RCOCH-COR′)₃, with R′being difluoromethyl and trifluoromethyl substituents and R′ being methyl, phenyl, aryl, 2′-naphthyl and 2′-thienyl substituents have been studied by nuclear magnetic resonance spectroscopy. The complexes are all nonrigid (fluxional) and their ¹⁹F NMR spectra show four resonances in the nonexchanging regions due to cis and trans isomers. A variable low temperature study of these complexes was done for the gallium chelates and activation parameters are calculated. The indium complexes all have nonexchanging regions below ?100°C. The ¹³C NMR data on the complexes are also reported.     

Thin-Layer Chromatography of Some Monothio-β-Diketonate Complexes of Nickel,Zinc and Cobalt

Abstract

A silica gel adsorbent has been successfully used to separate three series of nickel, zinc and cobalt complexes of 1,1-difluoro-4-mercapto-4-(2′-thienyl)but-3-en-2-one, 1,1,1-trifluoro-4-mercapto-4-(2′-thienyl)but-3-en-2-one, 1,1,1-trifluoro-4-mercapto-2-(2′-naphthyl)but-3-en-2-one. For comparative purposes R_F data for the protonated ligands are also included. The ZnL₂ complexes gave R_F values in single and binary solvent systems which were similiar to the R_F values of the ligands; whereas, the NiL₂ and CoL₃ complexes gave R_F values which paralled each other in most solvents.     

Electrochemical Polymerization of Dithienylbenzene and Dithienylpyridine

1,4-Bis(2-thienyl)benzene (T14B), 2,5-bis(2-thienyl)pyridine (T25P), and 2,6-bis(2-thienyl)pyridine (T26P) were electrochemically polymerized. The conductivity of poly-T14B, poly-T25P, and poly-T26P was 1.7 × 10^?1, 2.6 × 10^?8, and 1.2 × 10^?7 S/cm, respectively. A poly-T26P film has a very even surface and is composed of fibrils growing on a thin, dense layer. Infrared spectra showed the monomer units to be linked through the 5,5′-positions of the thiophene rings. On electrochemical oxidation, poly-T26P became a quaternary ammonium salt. Visible/near-infrared spectra of poly-T14B showed that bipolaron states were formed. The conductivities of poly-T25P and poly-T26P rose to about 10^?2 S/cm by iodine doping, irrespective of the bonding sites of pyridine.     

Heterocyclic compounds from 2-(alkoxycarbonylcyanomethylene)-1,3-dioxolanes

2-(Alkoxycarbonylcyanomethylene)-1,3-dioxolanes reacted with hydrazines and hydroxylamine to yield 1-substituted 4-alkoxycarbonyl-5-amino-3-(2′-hydroxyethoxy)pyrazoles and 4-alkoxycarbonyl-5-amino-3-(2′-hydroxyethoxy)isoxazoles respectively. With guanidine and benzamidine 2-substituted (R = NH₂, C₆H₅) 5-cyano-6-(2′-hydroxyethoxy)pyrimidin-4-ones were obtained. Reaction of 2-(cyanomethoxycarbonylmethylene)-1,3-dioxolane with 1,3-diaminopropane afforded 2-(cyanomethoxycarbonylmethylene)-1,3-hexahydro-pyrimidine whereas treatment of the same compound with 4,5-dimethyl-1,2-phenylenediamine gave 2-(cyanomethoxycarbonylmethylene)-5,6-benzimidazoline. The structures of pyrazoles and pyrimidones were assigned on the basis of ¹H-{¹H} and ¹³C-{¹H}-nOe experiments.     

A Convenient One-Pot Synthesis of Some New 3-(2-Phenyl-6-(2-thienyl)-4-pyridyl)hydroquinolin-2-ones Under Microwave Irradiation and Their Antimicrobial Activities

A series of 3-(2-phenyl-6-(2-thienyl)-4-pyridyl)hydroquinolin-2-ones 4a–o were synthesized in high yields by a one–pot cyclocondensation reaction under Kröhnke's reaction conditions using 2-chloro-3-formyl quinoline 1a–c, 2-acetyl thiophene 2, and various N-phenacylpyridinium bromides 3a–e in a mixture of ammonium acetate and acetic acid by microwave irradiation. All the compounds have been characterized by elemental analysis, FT-IR, ¹H NMR, and ¹³C NMR spectral analysis. These compounds have been screened for their antimicrobial activities.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Preparation and Structure of (E)-1-(3′-Hydroxy-2-Furanyl)-3-(3″-Hydroxy-4″-Methoxyphenyl)-2-Propen-1-One

Abstract

A facile procedure is presented for the synthesis of (E)-1-(3′-hydroxy-2′-furanyl)-3-(3″-hydroxy-4″-methoxyphenyl)-2- propen-1-one (6). Galactosylisomaltol (1) was condensed with isovanillin (2) under strong alkaline conditions at 25 [ddot]C to form (E)-1-(3′-O-β-D-galactopyranosyloxy-2′-furanyl)-3-(3″- hydroxy-4″-methoxyphenyl)-2-propen-1-one (4). (E)-1-(3′-hydroxy-2′-furanyl)-3-(3″-hydroxy-4″-methoxyphenyl)-2-propen-1-one (6) was obtained by acid hydrolysis of 4 in a 53.9% yield. This hetero-cyclic 2-propen-1-one was characterized on the basis of spectral data (IR and ¹H NMR), physicochemical properties, and conversion to a mono-O-acetyl derivative.     

1-AMINO-1-ARYL- AND 1-AMINO-1-HETEROARYL-METHANEPHOSPHONIC ACIDS AND THEIR N-BENZHYDRYL–PROTECTED DIETHYL ESTERS: PREPARATION AND CHARACTERIZATION

n-Benzhydryl-protected diethyl[3.3pc] esters of 1-amino-1-aryl- (phenyl, cumyl, p-dimethylaminophenyl, piperonyl, 1′-naphthyl, 9′-anthryl, 1′-pyrenyl) and 1-amino-1-heteroaryl- (furyl, 2′-thienyl, 3′-thienyl, 2′-pyrrolyl)-methanephosphonic acids, prepared by the addition of diethyl phosphite to the corresponding benzhydryl imines, have been isolated, purified, and characterized. The presence of chiral α -carbon and prochiral phosphorus in these esters gives rise to complicated features in their NMR spectra, which are discussed. Hydrolysis of the crude 1-aryl compounds in situ gave modest yields of the corresponding aminophosphonic acids (except for 1′-pyrenyl). Of the 1-heteroaryl derivatives, only the 2′-thienyl compound gave the expected aminophosphonic acid; in other cases, alternative[-18pc] modes of decomposition may occur under hydrolytic conditions. NMR and mass spectral data are given for all products.