Synthesis of some highly functionalized thiophene-3-carboxylates and alcohols

Highly functionalized thiophenes are prepared by two methods. The first uses a lithium-halogen exchange reaction on a trisubstituted 5-bromothiophene 25 to generate the corresponding 5-lithiothiophene 26 which is then reacted with either dimethylformamide or formaldehyde to give the 5-formyl 28 or 5-hydroxymethylthiophene derivative 31 in good yields. These are further transformed to other tetrasubstituted thiophenes. The second method assembles the thiophene ring from three components: a benzyl mercaptan, an aldehyde, and a vinylphosphonate 10 . Thus, the benzyl mercaptan is dilithiated then reacted with an appropriate aldehyde to afford a 2-mercapto-2-phenylethanol derivative 37 . Michael addition of 37 to 10 followed by oxidation of the hydroxyl group furnishes ketophosphonate 39 . An intramolecular Wittig-type reaction produces the thiophene skeleton.     

New liquid crystalline compounds based on 2-arylthiophenes and 2-(biphenyl-4-yl)thiophenes

A general and versatile route to the 2-alkyl-5-(4'-cyanophenyl)thiophenes was established, involving the condensation of an aryl vinyl ketone with an aldehyde in the presence of a thiazolium catalyst (Stetter procedure) to give a 1,4-diketone which with Lawesson's reagent undergoes ring-closure to give the corresponding arylthiophene. In the final step the exchange of a bromo substituent on the phenyl ring for a cyano group is accomplished by copper(I) cyanide in N,N-dimethylforamamide at reflux. The same sequence afforded 2-alkyl-5-(4'-cyanobiphenylyl)thiophenes. Several of the 1,4-diketones were obtained by conjugate addition of nitroalkanes to aryl vinyl ketones, and treatment of the γ-nitroketones with silica gel-supported potassium permanganate. Three alkyl 5-(4-cyanophenyl)thiophene-2-carboxylates were prepared by condensing β-chlorovinylaldehydes with thioglycolates. The cyanophenylthiophenes exhibited only monotropic phases, but incorporation of an additional phenyl ring provided cyanobiphenylylthiophenes of wide nematic ranges. Transition temperatures of binary mixtures of the cyanophenylthiophenes with 4-n-pentyl-4'-cyanobiphenyl were measured, and extrapolated virtual nematic-isotropic transition temperatures were determined.     

Synthesis of 2-carbethoxy-3-methyl-4-hydroxybenzofuran derivatives

A number of 2-.carbethoxy-3-methylbenzofuran derivatives were synthesized. A 5,5-gem-dibromo derivative was obtained in the bromination of 2-carbethoxy-3-methyl-4-oxo-4, 5,6,7,tetrahydrobenzofuran. Dehydrobromination of this, dibromo derivative gave 2-carbethoxy-3-methyl-4-hydroxy-5-bromobenzofuran. Depending on the structure of the starting compound and the brominating agent, the bromine in the bromination of 2-carbethoxy-3-methyl-4-hydroxy- and 4-acetoxybenzofurans with bromine and N-bromosuccinimide is incorporated either in the methyl group or in 5 and 7 positions of the benzofuran ring. The nitration of 2-carbethoxy-3-methyl-4-hydroxybenzofuran and its bromo derivative leads to 5-nitro- and 5,7-dinitrobenzofuran derivatives. The structures of the synthesized benzofuran derivatives were established by means of the PMR spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 27–29, January, 1980.     

Benzo[b]thiophene derivatives. XXVII. 5-methoxy-6-halo-3-β-acetamidoethylbenzo[b]thiophenes,blocked analogs of melatonin

The preparation of the 6-fluoro and 6-chloro analogs of the title compound is described, in a seven-step synthesis giving 30-40% overall yields. All intermediates have been isolated and characterized, including important by-products, such as the corresponding benzo[b]thienyl-3-acetic acids, and 3-methylbenzo[b]thiophenes. Cyclization of the 3-halo-4-methoxyphenylthioacetoacetic esters gave more ortho-cyclization in the chlorine case than was observed for the fluorine derivative. The title compounds were shown to have weak antiovulatory action, with the fluoro analog most active.     

Investigation of the kinetics of the nitration of thiophene derivatives

The kinetics of the nitration of thiophene derivatives with nitric acid in acetic anhydride were investigated. The nitration of 2-substituted thiophenes is a second-order reaction. The rate constants and activation parameters of the reaction were calculated. The possibility of the use of the Hanmett and Yukawa-Tsuno equations for this reaction series is demonstrated. An isokinetic dependence is observed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 167–170, February, 1982.     

Synthesis and properties of isoviagra. A 2‐methyl‐2H‐pyrazolo[4,3‐d]pyrirnidin‐7‐one isomer of viagra®

The synthesis and spectral properties (ir, ms, nmr) of a substituted 2‐methyl‐2H‐pyrazolo[4,3‐d]‐pyrimidin‐7‐one ( 3 ), an isomer of Viagra^®, are described. The key synthon, 4‐amino‐1‐methyl‐5‐propyl‐3‐pyrazolecarboxamide ( 7 ), is prepared via the reaction of ethyl 2,4‐dioxoheptanoate with methylhydrazine, followed by cyclization, nitration, amidation, and nitro group reduction. Interaction of 7 with 2‐ethoxyben‐zoyl chloride yielded the respective bis‐amide ( 8 ) which was cyclized in polyphosphoric acid to the corresponding pyrazolo[4,3‐d]pyrimidin‐7‐one derivative 9 . Chlorosulfonylation of 9 , and subsequent treatment with 1‐methylpiperazine furnished iso Viagra ( 3 ).     

Nitration of Some 3-(2-Furyl)-2-propenones with Dinitrogen Tetraoxide

Nitration of 3-(2-furyl)-2-propenones with dinitrogen tetraoxide leads to the corresponding 3-(4-nitro-2-furyl)-2-propenones. If the furyl group contains a substituent in position 5, the nitration occurs at the side chain to afford 3-(5-R-2-furyl)-2-nitro-2-propenones.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 3, 2005, pp. 431–436.Original Russian Text Copyright © 2005 by Sitkin, Klimenko.     

2-Polyfluoroalkylchromones. 5. Nitration and chlorination of 2-trifluoromethylchromones

Electrophilic nitration of 2-trifluoromethylchromone and its 6- and 7-methoxy derivatives affords 6-, 5-, and 8-nitro derivatives, respectively, while 5,7-dimethyl-2-trifluoromethylchromone yields a 6,8-dinitro derivative. Radical chlorination results in 3-chloro derivatives.     

Synthesis and properties of 2-(2-furyl)benzothiazole

The electrophilic reactions (nitration, bromination, hydroxymethylation, formylation, acylation) and radical substitution reactions (nitration, arylation) of 2-(2-furyl)benzothiazole have been studied. It was found that all of the reactions occur at position 5 of the furan ring. Only nitration in PPA gave the 5',6-dinitro derivative. Quantum-chemical calculation data for the electron density distribution in the neutral and protonated 2-(2-furyl)benzothiazole molecules are given. Dedicated to Boris Aleksandrovich Trofimov on his 70^th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1331–1338, September, 2008.     

Reactivity of several deactivated 3-aminobenzo[b]thiophenes in the Buchwald–Hartwig C–N coupling. Scope and limitations

Di(hetero)arylamines were prepared in moderate to high yields by Buchwald–Hartwig C–N coupling of bromobenzenes bearing electron-withdrawing groups and of a bromobiphenyl with several methyl 3-aminobenzo[b]thiophene-2-carboxylates, using the coupling conditions for heteroaromatic amines [Pd(OAc)₂, Xantphos, Cs₂CO₃ in dioxane, 120 °C]. The use of these aminobenzo[b]thiophenes as coupling components avoids the step of changing the amino group into a bromine atom, like we have done before to perform C–N couplings using the corresponding 3-bromobenzo[b]thiophenes. Nevertheless, the couplings using the methyl 3-aminobenzo[b]thiophene-2-carboxylates were only successful with bromobenzenes bearing electron-withdrawing groups and a bromobiphenyl or with electron deficient rings such us as bromopyridines. Using the latter compounds, different substituted 6H-benzothieno[3,2-d]pyrido[1,2-a]pyrimid-6-ones were obtained by C–N coupling followed by an intramolecular cyclization. These tetracyclic compounds may have interesting biological activity like it was already demonstrated by us for the non substituted derivative.     

Direct covalent post-synthetic chemical modification of Cr-MIL-101 using nitrating acid

For the first time, functionality has been covalently introduced into the Cr-MIL-101 network by post-synthetic modification of the terephthalate linker molecule through nitration. The nitro group was reduced and the amino group was reacted with ethyl isocyanate to yield the corresponding urea derivative.     

Nitration products of substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones

Highly substituted, novel, 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones were obtained by direct nitration of the corresponding mono- or di-substituted 5-phenyl-1,4-benzodiazepines. Substituent effects and the orientation of aromatic substituents in the nitration products are discussed. The single-crystal X-ray structural data for one of these products, 18 , is given.     

Electrochemical Conversions of 2-Methyl-3-nitro-4-phenylquinoline, Its Quinolinium Salts, and Hydrogenated Derivatives

Classical polarography, cyclic voltammetry, and EPR spectroscopy was used to study electrochemical reduction and oxidation of 3-nitro derivatives of 2-methyl-4-phenylquinoline, the corresponding quinolinium perchlorates, and 1,2- and 1,4-dihydroquinolines. The nitro derivatives of quinoline and 1,2-dihydroquinoline are reduced in the first step at the nitro group; the quinolinium cations are reduced at the heterocycle followed by reduction of the nitro group; and in 1,4-dihydroquinolines, the nitro group is not reduced. Electrochemical reduction processes associated with electron transfer in the heterocycle mainly display the same behavior as established for pyridine derivatives. But important differences were observed in electrochemical oxidation: the N-methyl derivative of 1,4-dihydroquinoline is oxidized significantly more easily than the corresponding N-unsubstituted derivative of 1,4-dihydroquinoline (in the 1,4-dihydropyridine series, the difference in pot! enti als is fairly small), and even more easily than the corresponding N-methyl derivative of 1,2-dihydroquinoline.     

Synthesis and utility of 3-silylthiophenes having perfluoroalkyl groups

The synthesis of a novel class of 3-silyl substituted thiophenes possessing perfluoroalkyl groups on the silicon atom was investigated. The treatment of 3-bromothiophene with n-butyllithium followed by the reaction with halosilanes proceeded to afford the corresponding 3-silyl substituted thiophenes 1 in good yields. The chemical polymerization of the resulting 1 did not work well. However, the electropolymerization of 3-silylthiophenes 1a and 1b provided the corresponding polymers 5a and 5b with head-to-tail regioregularity. The cyclic voltammogram of the resulting polymers 5a and 5b indicated both n- and p-doping properties.     

Benzo[1,2-d:3,4-d′]diimidazole derivatives

A new path for the synthesis of 3-monoalkyl- and 3,6-dialkyl-substituted benzo[1,2-d:3,4-d']-diimidazole is described: 5-tosylamino-1-alkylbenzimidazole is converted to the 4-nitro derivative by nitration in glacial acetic acid, and the imidazole ring is closed after alkylation and cleavage of the tosyl group.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1406–1409, October, 1970.     

Synthesis of Halomethyl Derivatives of 3- and 4-(Dialkoxyphosphorylmethyl)-5-tert-butylfuran-2-carboxylic Acid and Their Reactions with Nucleophilic Agents

5-tert-Butyl-4-chloromethyl-, 5-tert-butyl-4-(diethoxyphosphorylmethyl)-3-methylfuran-2-carboxylates are effectively brominated with N-bromosuccinimide by the 3-methyl group. The bis(halomethyl)derivative is phosphorylated under conditions of the Arbuzov reaction to give the corresponding chloromethylphosphonate. The obtained organophosphorus derivatives of bromomethyl- and chloromethylfuran-2-carboxylic acid react with secondary amines and sodium butanethiolate to form the corresponding substitution products. Alkyl 5-tert-butyl-4-chloromethyl-3-(diethoxyphosphorylmethyl)-furan-2-carboxylate reacts with sodium acetate in acetic acid to give a 4-acetoxymethyl derivative. It is the first example of a facile reaction with O-nucleophiles of halomethyl derivatives of phosphonomethylated furans.     

Reaction of nitrogen tetroxide with 2-vinylthiophene and substituted 2-vinylthiophenes

1-(2-Thienyl)-2-nitroethylene was obtained by the reaction of nitrogen tetroxide with 2-vinylthiophene and 3-(2-thienyl)acrylic acid. The nitration of thenylideneacetone leads to 1-(2-thienyl)-2-nitro-3-methylpropen-3-one, whereas the products of the reaction of nitrogen tetroxide with thenylideneacetothienone and-acetophenone are mixtures of isomers with a nitro group attached to the ethylene bond or in the thiophene ring. 5-Nitro-2-thienyl analogs of chalcone were isolated as products of the nitration of benzene-ring-substituted thenylidene-acetophenones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 41–43, January, 1979.     

Condensed pyridine bases. A new approach to the synthesis of 3-phenacylbenzo[b]thiophenes and 3-phenacyl-5-ethylthieno[2,3-b]thiophene. Synthesis of new derivatives of benzothieno[2,3-c]pyrylium and thieno[2′,3′:5,4]thieno-[2,3-c]pyrylium and pyridine bases

A new method is proposed for the production of substituted 3-phenacylbenzo[b]thiophenes by the intramolecular cyclization of 1-phenyl-4-phenylthio-1,3-butanediones in polyphosphoric acid. The analogous cyclization of 1-phenyl-4-(5-ethyl-2-thienylthio)-1,3-butanedione leads to 3-phenacyl-5-ethylthieno[2,3-b]thiophene. The acylation of substituted 3-phenacylbenzo[b]thiophenes and 3-phenacyl-5-ethylthieno[2,3-b]thiophene by the anhydrides of aliphatic acids in the presence of perchloric acid leads to 1-alkyl-3-phenylbenzothieno[2,3-c]pyrylium perchlorates and 2-ethyl-5-phenyl-7-methylthieno[2′,3′:5,4]thieno[2,3-c]pyrylium perchlorate. The action of ammonium acetate on the obtained salts gives the corresponding pyridine bases. L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National Academy of Sciences of Ukraine, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1335–1339, October, 1998.     

Photochemistry of Tetraalkyl-2H-thietes

The 3-alkyl-2,2-dimethyl-4-(tert-butyl)-2H-thietes 9a–c were obtained in several steps from the corresponding, newly synthesized, 3-alkyl-2-(tert-butyl)thiophenes 5a–c. Irradiation (254nm) of these tetraalkylated four membered S-heterocycles leads to a photostationary equilibrium with enethiones 10a–c (thiete/enethione 3:1).     

Some Specific Features of Acid Nitration of 2-Substituted 4,6-Dihydroxypyrimidines. Nucleophilic Cleavage of the Nitration Products

The nitration of 2-substituted 4,6-dihydroxypyrimidines in concentrated sulfuric acid yields the corresponding 5,5-dinitro derivatives. When the substituent in position 2 is an alkyl group, the nitration occurs both at position 5 and at the -carbon atom of the side chain. Hydrolysis of 2-substituted 4,6-dihydroxy-5,5-dinitropyrimidines leads to formation of 1,1-diamino-2-R-2-nitroethylene derivatives. 1,1-Diamino-2,2-dinitro-ethylene was obtained by nitration of 4,6-dihydroxy-2-methylpyrimidine and subsequent hydrolysis of 4,6-dihydroxy-5,5-dinitro-2-(dinitromethylene)-2,5-dihydropyrimidine.