Application of N,3-diaryl-3-oxo-propanethioamide in synthesis: an efficient and mild domino approach to highly substituted fused chromenones

A convenient and rapid synthesis of hitherto unknown 3-aroyl-4-aryl-2-phenylamino-4H-benzo[g]chromene-5,10-diones in high yield from β-aroyl-thioacetanilide, aromatic aldehyde, and 2-hydroxy-1,4-naphthoquinone via InCl₃ catalyzed one-pot three-component tandem Knoevenagel condensation–Michael addition–intramolecular cyclization–elimination reaction sequence is disclosed for the first time. This domino protocol has been used to obtain highly substituted pyrano[3,2-c]chromen-5(4H)-ones and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-ones from N,3-diaryl-3-oxo-propanethioamide, aromatic aldehyde, and 4-hydroxycoumarine or dimedone under mild reaction conditions. A plausible reaction mechanism is proposed. The 4H-pyrano[3,2-c]chromen-5-one and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-one derivatives possessing 3-(2-chlorobenzoyl)-2-phenylamino-substituents further cyclized under basic conditions to yield penta-cyclic 7,13-diaryl-5,14-dioxa-13-aza-benzo[a]naphthacen-6,8(7H,13H)-dione and tetra-cyclic 6,12-diaryl-3,3-dimethyl-3,4-dihydro-2H-chromeno[2,3-b]quinolin-1,11(6H,12H)-dione, respectively.     

Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction

Representatives of the 3H-imidazo[4,5-c]quinolin-4(5H)-ones have shown interesting biological activity. We have found 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-one as a potent dipeptidyl peptidase 4 inhibitor. However effective synthesis of this nucleus with various substituents at the 6-9-positions has not been reported. We report herein the development of a novel and efficient synthesis of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Our optimization of the reaction conditions revealed that the most important factors for this reaction are use of silver carbonate as a base and high reaction temperature.     

An efficient, greener, and solvent-free one-pot multicomponent synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones

Herein, we report an efficient, greener, and solvent-free novel method for the synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones in a one-pot sequence using methyl anthranilate or 2-aminothiophene-3-carboxylate with N,N′-dimethyl formamide dimethyl acetal and various anilines. The driving force for this reaction is the removal of N,N′-dimethylamine by various anilines resulting in 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones.     

Superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids: synthesis of quinolin-2(1H)-one derivatives

The superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids by Bronsted superacids (CF₃SO₃H, HSO₃F) or strong Lewis acids AlX₃ (X=Cl, Br) results in the formation of 4-aryl quinolin-2(1H)-ones in quantitative yields. The vinyl triflates or vinyl chlorides may be formed as additional reaction products. The investigated amides in reactions with benzene give 4,4-diaryl 3,4-dihydroquinolin-2-(1H)-ones under the superelectrophilic activation. 4-Aryl quinolin-2(1H)-ones in POCl₃ are converted into 4-aryl 2-chloroquinolines. 4-Fluorophenyl-4-phenyl 3,4-dihydroquinolin-2-(1H)-one give N-formylation products in a yield of 79% under the Vilsmeier–Haack reaction conditions.     

Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes

A combinatorial library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes was synthesized in high yield by C4-SMe substitution in N-alkyl/phenyl 4-(methylthio)-3-nitro-4H-chromen-2-amines with a variety of phenols. The reaction always provided C2 substitution in the phenol ring, dictated by hydrogen bond interactions between the phenolic hydroxyl group and the nitro group in 3-nitro-4H-chromenes. Reduction of the nitro group with concomitant hydrolysis of the enamine in 4-(2-hydroxyaryl)-3-nitro-4H-chromenes with Zn, Ac₂O in AcOH furnished hybrid amino-acid lactone incorporating ortho-tyrosine and phenyl alanine moieties.     

A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile derivatives

New 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitriles are synthesized in good yields, via cyclocondensation of 5-amino-1-(2-oxo-2-arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles, which are prepared by the reaction of 5-amino-3-arylamino-1H-pyrazole-4-carbonitriles and α-bromoacetophenone derivatives in the presence of K₂CO₃ using acetone as the solvent.     

Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

Antimony trichloride catalyzed three-component reaction of urea, aldehydes and cyclic enol ethers: a novel route to 4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones

Antimony trichloride efficiently catalyses diastereoselective three-component reaction of urea, aromatic aldehydes and 2,3-dihydrofuran or 3,4-dihydro-2H-pyran leading to 4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones and 4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-ones, respectively in good yield.     

New synthetic methods for 2,3-diarylacridin-9(10H)-one and (E)-2-aryl-4-styrylfuro[3,2-c]quinoline derivatives

Two new synthetic methodologies for 2,3-diarylacridin-9(10H)-ones were developed. The first one involves the Heck reaction of (E)-3-iodo-2-styrylquinolin-4(1H)-ones with styrenes, leading to (E,E)-2,3-distyrylquinolin-4(1H)-ones, which when heated at high temperatures cyclize in two different ways. Electrocyclization and further in situ oxidation leads to 2,3-diarylacridin-9(10H)-ones, while tautomerization, cyclization by nucleophilic addition and further in situ oxidation produces (E)-2-aryl-4-styrylfuro[3,2-c]quinolines as the main compound. The second method gives only 2,3-diaryl-10-methylacridin-9(10H)-ones and involves the Heck reaction of (E)-3-iodo-1-methyl-2-styrylquinolin-4(1H)-ones and styrenes, leading to (E,E)-1-methyl-2,3-distyrylquinolin-4(1H)-ones, which when heated at high temperatures cyclize through electrocyclization and oxidation processes affording the expected compounds. The structures of all new compounds were established by extensive NMR studies.     

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.     

Synthesis of new pyrazole-1,2,3-triazole dyads

An efficient two step synthetic methodology of new 5(4)-aryl-4(5)-[3(5)-(2-hydroxyphenyl)-1H-pyrazol-5(3)-yl]-1H-1,2,3-triazole dyads was established. The reaction of (E)-2-styryl-4H-chromen-4-ones, used as building blocks, with sodium azide, gave 4(5)-aryl-5(4)-(chromon-2-yl)-1H-1,2,3-triazoles bearing either electron-donating or electron-withdrawing substituents in their styryl moiety which upon reaction with hydrazine hydrate afforded the expected pyrazoles in moderate to very good yields.     

The reaction of 2-(1-hydropolyfluoro-1-alkenyl)-4H-3,1-benzoxin-4-ones with dinucleophilic reagents: a convenient route to fluoroalkylated nitrogen-containing tricyclic compounds

The reactions of 2-(1-hydropolyfluoro-1-alkenyl)-4H-3,1-benzoxin-4-ones (2) with hydrazine hydrate and phenyl hydrazine were investigated. The reaction of 2 with hydrazine hydrate in ethanol under reflux condition readily gave 2-fluoroalkyl-4H-pyrazolo[5,1-b]quinazolin-9-ones (3) in high yields. The reaction of 2 with phenyl hydrazine, however, resulted in the formation of 2-(2-phenyl-5-fluoroalkyl-2H-pyrazol-3-yl) benzoic acids (7). Further treatment of 7 with PPA gave 1-phenyl-4,9-dihydro-3-fluoroalkyl-1H-pyrozolo[3,4-b]quinolin-4-ones (4) in 65-80% overall yields.     

Various coordination architectures constructed from N-[(carboxyphenyl)-sulfonyl]glycine: Structural variation via ligand isomerism effects and metal-directed assembly

Using Cu(II), Mn(II) or Co(II) salt and the flexible ligands, N-[(4-carboxyphenyl)-sulfonyl]glycine (H₃L₁) and N-[(3-carboxyphenyl)-sulfonyl]glycine (H₃L₂), a series of new coordination polymers, [Mn(phen)(H₂O)₄][HL₁] (1), [Co₃(L₁)₂(bipy)₃(H₂O)₆]_n·8nH₂O (2), [Cu₄(L₁)₂(OH)₂(bipy)₄]_n·12nH₂O (3), [Na(H₂L₁)(H₂O)]_n (4), [Mn₂(HL₂)₂(dpe)₃(H₂O)₂]_n·ndpe (5), (phen = 1,10-phenanthroline, bipy = 4,4′-bipyridine, dpe = 1,2-di(4-pyridyl)ethylene), varying from 0D to 3D, have been synthesized and structurally characterized. Compound 1 has a [Mn(phen)(H₂O)₄]²⁺ cation and a HL₁²⁻ anion. Compound 2 features a new 1D triple chain, based on octahedral cobalt atoms bridged by bipy molecules and terminally coordinated by two H₃L₁ ligands. Compound 3 has a 2D layered structure, constructed from new alternating chains where H₃L₁, hydroxyl and water molecules simultaneously act as bridging ligands. Compound 4 possesses a bilayer structure in which two adjacent layers are pillared by H₃L₁ ligands into a 2D bilayer network. Compound 5 is a unique 3D coordination polymer in which each Mn center binds two trans-located dpe molecules. The thermal stability as well as magnetic properties of 5 was also studied. This work and our previous work indicate that the positional isomer of the anionic N-[(carboxyphenyl)-sulfonyl]glycine is important in the construction of these network structures, which are also significantly regulated by the metal centers.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

An efficient synthesis of highly substituted pyrroles from β-oxodithiocarboxylates

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinate hydrochlorides with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in presence of chloromethyleneiminium salt derived from POCl₃/DMF to afford alkyl-3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates in excellent yields. Alkyl-3-aryl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates were formed in moderate yields when the same N,S-acetals were treated with DBU.     

Highly glycosylated flavonoids from the pods of Bobgunnia madagascariensis

Methanolic extracts of the pods of Bobgunnia madagascariensis (Leguminosae) yielded four pentaglycosylated flavonoids, including the 3-O-α-l-rhamnopyranosyl(1→3)-α-l-rhamnopyranosyl(1→2)[α-l-rhamnopyranosyl(1→6)]-β-d-glucopyranoside-7-O-α-l-rhamnopyranosides of 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-benzopyran-4-one (kaempferol) and 3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-4H-benzopyran-4-one (quercetin), which were characterized by a novel O-linked branched tetrasaccharide. Spectroscopic and chemical methods were used to determine the structures of the latter, which co-occurred with the corresponding β-d-galactopyranosyl isomers, and two saponins. Conformational isomerism of quercetin 3-O-α-l-rhamnopyranosyl(1→3)-α-l-rhamnopyranosyl(1→2)[α-l-rhamnopyranosyl(1→6)]-β-d-glucopyranoside-7-O-α-l-rhamnopyranoside was detected in solution by NMR, a phenomenon previously associated only with C-glycosylflavonoids.     

Synthesis of 1H-pyrrolo[3,2-c]quinoline derivatives via palladium-catalyzed heteroannulation of 2-aryl-3-iodo-4-(phenylamino)quinolines and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines

Palladium(0)/copper iodide catalyzed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinolines with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single-step operation. Conversely, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo PdCl₂(PPh₃)₂/CuI catalyzed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines.     

Preparation, spectroscopic properties of 1,4-di (N,N-diisopropylacetamido)-2,3(1H,4H)-quinoxalinedione (L) lanthanide complexes and the supramolecular structure of [Nd2L2(NO3)6(H2O)2]·H2O

The reaction of lanthanide nitrate with 1,4-di (N,N-diisopropylacetamido)-2,3(1H,4H)-quinoxalinedione (L) yields six novel Ln(III) complexes ([Ln₂L₂(NO₃)₆(H₂O)₂]·H₂O) which are characterized by elemental analysis, thermogravimetric analysis (TGA), conductivity measurements, IR, electronic and ¹H NMR spectroscopies. A new quinoxalinedione-based ligand is used as antenna ligand to sensitize the emission of lanthanide cations. The lowest triplet state energy level of the ligand in the nitrate complex matches better to the resonance level of Eu(III) and Sm(III) than Tb(III) and Dy(III) ion. The f-f fluorescence is induced in the Eu³⁺ and Sm³⁺ complexes by exciting into the π-π* absorptions of the ligand in the UV. Furthermore, the crystal structures of a novel binuclear complex [Nd₂L₂(NO₃)₆(H₂O)₂]·H₂O has been determined by single-crystal X-ray diffraction. The binuclear [Nd₂L₂(NO₃)₆(H₂O)₂]·H₂O complex units are linked by the intermolecular hydrogen bonds and π-π interactions to form a two-dimensional (2-D) layer supramolecule.     

The synthesis of functional derivatives of the [1-CB9H10] anion by Brellochs reaction

Reactions of decaborane with various aldehydes in alkaline media were studied. The reactions with HCOH and 2-MeOC₆H₄CHO give the corresponding arachno-carboranes [6-R-arachno-CB₉H₁₃]⁻ (R = H, C₆H₄-2-OMe), whereas the reactions with C₆H₅CHO, 4-BrC₆H₄CHO, 4-MeCONHC₆H₄CHO, and 2-SC₄H₃CHO result in the nido-carboranes [6-R-nido-CB₉H₁₁]⁻ (R = C₆H₅, C₆H₄-4-Br, C₆H₄-4-NHCOMe, 2-SC₄H₃). Both the arachno- and nido-carboranes can be easily oxidized with elemental iodine in an alkaline aqueous solution giving the corresponding closo-derivatives [2-R-closo-2-CB₉H₉]⁻. These closo-2-isomers, under heating in solution, undergo rearrangement to more thermodynamically favorable closo-1-isomers [1-R-closo-1-CB₉H₉]⁻. The structure of (Bu₄N)[1-(4-BrC₆H₄)-1-CB₉H₉] was determined using single crystal X-ray diffraction.