A novel and facile synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones via a one-pot multi-component reaction

A simple and efficient synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones was achieved via a one-pot multi-component reaction of cyclohexyl isocyanide, an aldehyde, a 1,3-dicarbonyl compound, and ammonium acetate in the presence of a catalytic amount of KHSO₄ in acetonitrile.     

Regioselective synthesis of cytotoxic 4-(1-alkynyl)-substituted 2-(5H)-furanones

4-(1-Alkynyl)-3-bromo- and 4-(1-alkynyl)-3-chloro-2(5H)-furanones have been regioselectively synthesized in moderate to good yields by a new version of the Pd/Cu-catalyzed Sonogashira reaction involving treatment of 1-alkynes with 3,4-dibromo- and 3,4-dichloro-2(5H)-furanone, respectively, in the presence of KF as a base. 4-(1-Alkynyl)-3-bromo-2(5H)-furanones have been found to be able to undergo Stille-type and Suzuki-type reactions with aryl(tributyl)tins and arylboronic acids, respectively, to give 4-(1-alkynyl)-3-aryl-2(5H)-furanones in modest to satisfactory yields. Some 4-(1-alkynyl)-substituted 2(5H)-furanones so prepared have been found to exhibit significant cytotoxic activities, especially against human leukemia cell lines.     

Regioselective synthesis of 2-unsubstituted 1-aryl-4- and 1-aryl-5-acylimidazoles

An efficient and simple method for the synthesis of 2-unsubstituted 1-aryl-4- and 1-aryl-5-acylimidazoles has been developed. It consists in the condensation of α-diketone monooximes with aromatic amines and formaldehyde on the presence of boron trifluoride etherate, leading to the formation of stable boron trifluoride complexes of N-oxides. Further reduction of these complexes led to the corresponding imidazoles. This method permits broad variations of substituents in the aryl part of these compounds.     

Regioselective synthesis of 4-(2-alkyl-5-methyl-2H-pyrazol-3-yl)-piperidines

The regioselective, scaleable synthesis of three 4-(2-alkyl-5-methyl-2H-pyrazol-3-yl)-piperidines is discussed.     

Regioselective synthesis of 1-aryl-3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-aryl-3-(methylthio)-4,5-substituted/annulated pyrazoles

[reaction: see text] Highly efficient and regioselective synthesis of 1-aryl-3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-aryl-3-(methylthio)-4,5-substituted/annulated pyrazoles has been reported via cyclocondensation of arylhydrazines with either alpha-oxoketene dithioacetals or beta-oxodithioesters.     

Synthesis of 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-aryl-4,5-dihydro-1H-pyrrole-3-carboxylates, a new triazafulvalene system

(2E,3Z)-2-(1-Methyl-2,5-dioxoimidazolidin-4-ylidene)-3-[(arylamino- or heteroarylamino)methylene]succinate 5 obtained by [2+2] cycloaddition of (5Z)-5-[(dimethylamino)methylene]-3-methylimidazolidine-2,4-dione (1) and dimethyl acetylenedicarboxylate (2) followed by substitution of the dimethylamino group with aromatic or heteroaromatic amines, afforded by heating in ethanol in the presence of potassium hydroxide, potassium salts 6. Acidification of 6 with hydrochloric acid afforded mixtures of (E)- and (Z)-isomers of methyl 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates. On the other hand, alkylation of compounds 6 with methyl iodide or benzyl bromide produced the corresponding methyl (E)-4-(2-methoxy- or 2-benzyloxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates 9, derivatives of a new triazafulvalene system.     

Regioselective synthesis of 1-aryl-4-bromo-5-trifluoromethylpyrazoles

A novel regioselective route to 1-aryl-4-bromo-5-trifluoromethylpyrazoles involves reactions of arylhydrazines with 3-bromo-4-ethoxy-1,1,1-trifluorobut-3-en-2-one. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 167–168, January, 2006.     

Studies on the reduction of the nitro group in 3-aryl-2-methylene-4-nitro-alkanoates afforded by the Baylis-Hillman adducts: synthesis of 4-aryl-3-methylene-2-pyrrolidinones and 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylates

The formation of substituted 2-pyrrolidinones and indoles by the reduction of the secondary nitro group in appropriate 3-aryl-2-methylene-4-nitroalkanoates afforded by Baylis-Hillman chemistry via different reducing agents is described. The 3-aryl-2-methylene-4-nitroalkanoate obtained from S_N2 nucleophilic reaction between the acetate of Baylis-Hillman adducts and ethyl nitroacetate upon reduction with indium-HCl furnishes a mixture of cis and trans substituted phenyl-3-methylene-2-pyrrolidinones. In contrast, similar reductions of analogous substrates derived from nitroethane stereoselectively furnished only the trans substituted phenyl-3-methylene-2-pyrrolidinones. On the other hand the SnCl₂·2H₂O-promoted reductions of substrates derived from nitro ethylacetate give oxime derivatives while the ones obtained from nitroethane yield a mixture of cis and trans 4-aryl-3-methylene-2-pyrrolidinones. Alternatively, the SnCl₂·2H₂O-promoted reduction of substituted 2-nitrophenyl-2-methylene-alkanoate furnished from ethyl nitroacetate yield 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylate while indium-promoted reaction of this substrate leads to a complex mixture. Analogous reactions with SnCl₂·2H₂O of substituted 2-nitrophenyl-2-methylene-alkanoate obtained from nitroethane yield 4-alkyl-3-methylene-2-quinolones in moderate yields.     

Diels-Alder reactions of 3-(1H-tetrazol-5-yl)-nitrosoalkenes: synthesis of functionalized 5-(substituted)-1H-tetrazoles

A general route to 1,2-oxazines and open chain oximes bearing a 1H-tetrazolyl substituent via Diels-Alder reaction of 3-(tetrazol-5-yl)-nitrosoalkenes is reported. It was also demonstrated that reduction of these adducts followed by deprotection of the tetrazolyl group give 5-(1-aminoalkyl)-1H-tetrazoles, α-amino acid analogues.     

Microwave synthesis of 1-aryl-1H-pyrazole-5-amines

A microwave-mediated synthesis of 1H-pyrazole-5-amines utilizing 1?M HCl at 150?°C was developed in order to provide products in a matter of minutes with minimal purification. Most reactions are complete in only 10?min and can be isolated via a simple filtration without the need for further purification by column chromatography or recrystallization. This method tolerates a range of functional groups and can be performed on milligram to gram scales.     

Synthesis of substituted 4-(1H-indol-6-yl)-1H-indazoles as potential PDK1 inhibitors

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki cross-coupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and S_NAr/reductive cyclisation sequences, respectively.     

Regioselective synthesis of 3(or 5)-styryl-/(4-aryl-1,3-butadienyl)-/(6-aryl-1,3,5-hexatrienyl)-5(or 3)-(methylthio)isoxazoles and pyrazoles via α-oxoketene dithioacetals

The regioselective synthesis of the title isoxazoles and pyrazoles through cyclocondensation of oxoketene dithioacetals with either hydroxylamine or hydrazine hydrate under controlled conditions is reported.     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

An unexpected multi-component reaction to synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acids in ionic liquid

A new, one-pot, four-component condensation of 3-methyl-1H-pyrazol-5(4H)-one, ammonium acetate, aromatic aldehydes, and meldrum’s acid in [bmim]BF₄ as solvent is described for the synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives. This methodology resulting in excellent isolated yields in short reaction time is characterized by simple work up procedure and little environmental impact.     

Facile synthesis of 3-aryl-1-((4-aryl-1,2,3-selenadiazol-5-yl)sulfanyl)isoquinolines

A new series of 1,2,3-selenadiazoles containing an aryl or a 3-arylisoquinoline sulfanyl moiety at carbons 4 and 5, respectively, was prepared by cyclization of the respective semicarbazones in the presence of selenium(II) oxide and tetrahydrofuran at 70–75°C. Semicarbazones required for the reaction were obtained from 2-((3-arylisoquinolin-1-yl)sulfanyl)-1-phenylethanones, I, by a reaction with semicarbazide hydrochloride in ethanol/water mixture and potassium acetate base.     

Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.     

A new methodology for the synthesis of 3-amino-1H-indole-2-carboxylates

A new methodology has been developed for the synthesis of 3-amino-1H-indole-2-carboxylates. 2-Aminobenzonitriles were protected as benzyl (2-cyanophenyl)carbamates and converted into corresponding glycinate esters using sodium hydride and bromoacetate esters. Sodium hydride efficiently promotes the addition of the glycinate α-carbon to the cyano group at low temperatures, resulting in the formation of the desired indole core with 3-amino and 2-carboxylate groups. This new methodology uses Pd–C mediated hydrogenolysis with molecular hydrogen, providing neutral conditions for removal of the N-carbamate protecting group. This methodology demonstrates good functional group tolerance towards a variety of substituents in the aromatic ring and ester groups. The overall yield of 3-amino-1H-indole-2-carboxylates obtained by this four-step methodology is at least 30% or higher with yields as high as 50% realised for three of the indoles investigated in this study.     

Efficient and simple synthesis of 3-aryl-1H-pyrazoles

Efficient preparation of 3-aryl-1H-pyrazoles by reaction of 1-protected-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoles with (het)aryl halides is described. The choice of THP protecting group is discussed.     

Fluorescence properties of 2-aryl-3-hydroxyquinolin-4(1H)-one-carboxamides

The fluorescence properties of 2-aryl-3-hydroxyquinolin-4(1H)-one-carboxamides (3HQCs) with carboxylic alkylamide groups at positions 6, 7 or 8 (3HQ6Cs, 3HQ7Cs, and 3HQ8Cs) have been studied to evaluate their potential as molecular probes.