Novel four-component route to the synthesis of spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives

An effective route to spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives is described. This involves reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, and benzylamine derivatives or aliphatic amines in the presence of alkyl acetoacetate (1,3-dicarbonyl compounds) in dry methanol under reflux conditions. The reactive 1:1 enaminone, which is obtained from the addition of the amine to 1,3-dicarbonyl compound, adds to the α,β-unsaturated ketone, which is formed from the reaction of isatin and 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, to produce the alkyl 1′-benzyl-2′-methyl-2-oxo-6′-phenyl-1′H-spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives in excellent yields.     

Pd-catalyzed cross-coupling reactions of halogenated 1-phenylpyrazol-3-ols and related triflates

1-Phenyl-1H-pyrazol-3-ol was used as a versatile synthon for the preparation of various 1-phenyl-1H-pyrazole derivatives substituted at C-3 and C-4 of the pyrazole nucleus and at the phenyl ring para-position. Treatment of 1-phenyl-1H-pyrazol-3-ol with triflic anhydride in the presence of base gave 3-trifloyloxy pyrazole, while bromination and iodination yielded the corresponding halogenated derivatives. The obtained scaffolds were used in carbon-carbon bond forming Pd-catalyzed cross-coupling reactions to yield (het)aryl- and carbo-functionally substituted 1-phenyl-1H-pyrazoles.     

Synthesis of hydrogenated indazole derivatives starting with α,β-unsaturated ketones and hydrazine derivatives

The reaction of hydrazine derivatives with α,β-unsaturated ketones, such as cyclohexenyl(phenyl)methanone and (E)-2-benzylidenecyclohexanone, were investigated.The reaction between methylhydrazine and e.g., cyclohexenyl(phenyl)methanone was particularly interesting as 3a,4,5,6,7,7a-hexahydro-1-methyl-3-phenyl-1H-indazole was obtained as the major product together with 4,5,6,7-tetrahydro-2-methyl-3-phenyl-2H-indazole as a minor product.     

Stereoselective synthesis of 3-mono- and 1,3-disubstituted 4-phenyl-1,2,3,4-tetrahydroisoquinolines

(1S,2S)-(+)-Thiomicamine was transformed in high yield and with high diastereoselectivity into (3R,4R)-4-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and enantiomerically pure (3R,4R)-3-hydroxymethyl-4-phenyl- and (1R,3R,4R)-3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline derivatives.     

Synthesis of new polydentate tweezers ligands of amido-amine type

A series of new tweezers amido-amine ligands containing pyrrole, bipyrrole, and dipyrrolylmethane fragments were synthesized by reaction of 2-thioxothiazolidin-3-yl derivatives of α-pyrrolecarboxylic acids {5-[1-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-1-methylethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-[(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)phenylmethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, and 3,4-dimethyl-pyrrole-2,5-dicarboxylic acid} with o-phenylenediamine. All compounds obtained were characterized by elemental analysis, NMR and mass spectra.     

Synthesis of new analgesics based on 4-isopropyl-1-phenyl-3-(trifluoromethyl)pyrazol-5-one

Methyl 4-trifluoro-2-isopropyl-4-oxobutanoate prepared by the improved procedure was cyclized with hydrazines to afford the title pyrazole derivatives. N- and O-alkylation of 4-isopropyl-1-phenyl-3-(trifluoromethyl)pyrazol-5-ol gave trifluoromethyl analogues of Propyphenazone and 5-alkoxy derivatives. 4-Isopropylpyrazoles containing O-butoxy moiety with a terminal trifluoromethyl or acyloxy group were found to demonstrate a promising analgesic activity.     

Reactions of 2H-azirines with carbenoids from diazo esters: transformations of novel azirinium ylides

Thermocatalytic decomposition of diazo esters in the presence of 3-aryl-2H-azirines gives rise to azirinium ylides. The latter preferentially transform via isomerization into 2-azabuta-1,3-diene derivatives or, with excess diazo compound, via reaction with the Rh-carbenoid to form 3,4-dihydro-2H-pyrrole derivatives. In contrast, ylides generated from 2-monosubstituted or 2,2-disubstituted 3-phenyl-2H-azirines transform exclusively via isomerization into the corresponding 2-azabuta-1,3-dienes in high yields.     

Regioselective solvent-sensitive reactions of 6-(trifluoromethyl)comanic acid and its derivatives with phenylhydrazine

6-(Trifluoromethyl)comanic acid reacts regioselectively with phenylhydrazine in water to give 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylic acid. Similar reaction in dioxane leads to 3-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-5-carboxylic acid. A strong solvent influence on the reaction route was also found for 6-(trifluoromethyl)comanic acid derivatives.     

The reactions of 4-dicyanomethylene-2-phenyl-4H-1-benzopyran and some benzologs with nucleophiles

4-Dicyanomethylene-2-phenyl-4H-1-benzopyran (1) reacts with primary amines under mild conditions to give 4-imino-3-alkyl-5-alkylimino-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]-pyridine derivatives which, in turn, are hydrolyzed with acid to 4-imino-3-alkyl-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones. When more vigorous conditions are employed for the reactions of 1 with primary amines, Dimroth rearrangements take place and the products are derivatives of 4-alkyl- (or aryl)amino-5-alkyl- (or aryl)imino-2-phenyl-5H-[1]benzopyrano-[3,4-c]pyridine. The latter compounds are hydrolyzed by acid to the corresponding 5-pyridone derivatives. The reaction of 1 with piperidine gives 2-phenyl-4-piperidyl-5H-[1]benzopyrano-[3,4-c]pyridin-5-one. Sodium methoxide reacts with 1 to give 3-cyano-2-methoxy-4-(2-hydroxyphenyl)-6-phenylpyridine. Two benzologs of 1 have been allowed to react with primary and secondary amines and the products are analogous to those obtained from 1 .     

Synthesis of function-oriented 2-phenyl-2H-chromene derivatives using l-pipecolinic acid and substituted guanidine organocatalysts

Organocatalytic domino oxa-Michael/aldol reactions between salicylaldehyde with electron deficient olefins are presented. We screened guanidine, 1,1,3,3-tetramethylguanidine (TMG) and l-pipecolinic acid as organocatalysts for this transformation. 3-Substituted 2-phenyl-2H-chromene derivatives are synthesized with high yields and with poor enantioselectivity (5-17% ee) using l-pipecolinic acid while TMG works well with cinnamaldehyde without using co-catalyst. These 3-substituted-2-phenyl-2H-chromene derivatives are further derivatized to synthesize triazole and biotin-containing chromene derivatives, to facilitate purification of protein targets.     

Nitrone cycloadditions to 2,3-dihydro-1-phenyl-1H-phosphole 1-oxide. Double asymmetric induction and kinetic resolution by a chiral nitrone

The cycloadditions of nitrones with 2,3-dihydro-1-phenyl-1H-phosphole 1-oxide give a single cycloadduct deriving from a highly diastereoselective approach of the nitrone anti to the phenyl ring of phospholene oxide. When the chiral gliceraldehyde derived nitrone is used, only two diastereoisomers are produced in 1.7:1 ratio. The structural assignment based on NMR data and X-ray analysis of the major isomer established a trans C3–C4 stereochemistry (derived from endo TS with respect to nitrone) and a C3–C4′ relative stereochemistry of threo type in the major isomer and erythro in the minor one. Therefore, each enantiomer of phospholene oxide 6 gives exclusively one cycloadduct with five contiguous stereogenic centres in an established and predictable absolute configuration. The difference of reactivity of the two enantiomers allowed a partial kinetic resolution of the racemic phospholene oxide, affording (+)-(S) enantiomer with 90% enantiomeric excess.     

New cycloaddition reaction between 4-arylidene-2-phenyl-5(4H)-1,3-oxazolones and benzyne; facile synthesis of 1,4(H)-benzoxazepine-2-ones and their N-phenyl derivatives

Reaction of 4-arylidene-2-phenyl-5(4H)-1,3-oxazolones with benzyne afforded predominantly, 3-arylidene-7-hydroxy-7-phenyl-1,4(H)-benzoxazepine-2-ones in addition to their N-phenyl derivatives. However, the reaction of the target oxazolones with an excess of benzyne gave only the N-phenyl derivatives of 1,4(H)-benzoxazepine-2-ones in good yields. The reaction mechanism describing product formation is also explained. Arylation of 1,4(H)-benzoxazepine-2-ones with benzyne proceeded successfully to give the N-phenyl products.     

Azolyl-substituted 1,2,3-triazoles

Huisgen reaction of (E)-1,5-diarylpent-2-en-4-yn-1-ones and (E)-1,5-diarylpent-1-en-4-yn-3-ones afforded 1-aryl-3-(5-aryl-1H-1,2,3-triazol-4-yl)prop-2-en-1-ones and 3-aryl-1-(5-aryl-1H-1,2,3-triazol-4-yl)-prop-2-en-1-ones, respectively. (E)-1-Aryl-3-(5-phenyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-ones reacted with hydrazine hydrate and phenylhydrazine to give 72–93% of 4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-5-phenyl-1H-1,2,3-triazoles which underwent dehydrogenation on heating in boiling acetic acid with formation of the corresponding pyrazole derivatives. The molecular structures of (E)-3-phenyl-1-(5-phenyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-one and 4-[3-(4-methylphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-5-phenyl-1H-1,2,3-triazole were studied by X-ray analysis. 4-(3-Aryl-4,5-dihydro-1H-pyrazol-5-yl)-5-phenyl-1H-1,2,3-triazoles showed toxicity against Daphnia magna.     

3-Phenylpyrazolo(4,3-c)pyridine and derivatives: structure determination

The structures of 3-phenylpyrazolo(4,3-c)pyridine (1) and 5-methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo(4,3-c)pyridine (2) are determined by detailed ¹H and ¹³C NMR analysis and theoretical calculations in comparison with their N-methyl derivatives as fixed models. CNDO/2 and PPP calculations are performed on the three prototropic forms admissible for the tautomeric system 1. By comparison of the ¹³C NMR and UV spectra of 1 with those of its three fixed N-methyl derivatives and of the UV spectra calculated for the tautomers of 1 with that experimentally obtained in the range 200–450 nm, 3-phenylpyrazolo(4,3-c)pyridine (1) is established to exist entirely in the 1H tautomeric form 1A.By ¹³C NMR investigations of 5-methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo(4,3-c)-pyridine (2), in comparison with its fixed 1-methyl-1H derivative 9 and other substituted pyrazoles, 2 is determined to be a mixture of the 1H- (2A) and 2H- (2B) tautomers with 2A largely predominating. The compounds investigated are described here for the first time.     

AlCl3-mediated tandem Friedel-Crafts reactions of vinylidenecyclopropanes with acyl chlorides: a facile synthetic method for the construction of 1-[2-(2,2-diarylvinyl)-1-phenyl-3H-inden-5-yl]ethanone derivatives

AlCl₃-mediated tandem Friedel-Crafts reaction of vinylidenecyclopropanes with acyl chlorides produced the corresponding 1-[2-(2,2-diarylvinyl)-1-phenyl-3H-inden-5-yl]ethanone derivatives in moderate to good yields under mild conditions within short reaction time.     

Sc(OTf)<Subscript>3</Subscript> catalyzed synthesis of novel 6-phenyl-6<Emphasis Type="Italic">H</Emphasis>-chromeno[4,3-b]quinolines and evaluation of their cytotoxicity

Novel 6-phenyl-6H-chromeno[4,3-b]quinoline derivatives have been prepared by reaction of 4-chloro-2-phenyl-2H-chromene-3-carbaldehyde with various aromatic amines using 5 mol % of Sc(OTf)3 in acetonitile. This is the first example of one-pot synthesis of 6-phenyl-6H-chromeno[4,3-b]quinoline from 4-chloro-2-phenyl-2H-chromene-3-carbaldehyde at ambient temperature. Preliminary evaluation of cytotoxic activity of these chromeno[4,3-b]quinoline derivatives has been carried out. Some products exhibited anti cancer activity against two carcinoma cell lines A549 and B-16.     

Anti-inflammatory activity of heterocyclic systems using abietic acid as starting material

A series of pyridines, pyrimidinone, oxazinones, and their derivatives were synthesized as anti-inflammatory agents using abietic acid (7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylic acid) as the starting material. The arylidiene derivative was treated with cyanothioacetamide to give cyano pyridine-thione, which was reacted with ethyl chloroacetate to yield the corresponding cyano ester. The ester was hydrolysed to the sodium salt, which was reacted with acetic anhydride to afford 2-methyloxazinone, which was treated with ammonium acetate to afford 2-methylpyrimidinone followed by methylation with methyl iodide to yield 2,3-dimethyl- pyrimidinone. In addition, the oxazinone derivative was reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinones. The latter reacted with thiophene-2-carboxaldehyde or phenylisothiocyanate to afford Schiff’s bases or thiosemicarbazide derivatives. The pharmacological screening showed that many of these compounds have good anti-inflammatory activity comparable to Prednisolone^® as reference drug.     

Porphins and their derivatives: XXIV. meso-Tetraphenylporphyrins with β-pyrazole rings

A series of 5-substituted 2-(2-phenyl-3,4-dihydro-2H-pyrazol-3-yl)porphyrins was prepared by treating with phenylhydrazine tetraphenylporphyrin derivatives containing in the β-position fragments of β-unsaturated ketones or aldehydes. The compounds obtained were oxidized with o-chloranil into the corresponding pyrazolylporphyrins.     

Synthesis of isocoumarin, 1-isoquinolone and 4(1H)-quinolone derivatives via seleno-intermediates

The reaction of 2-styrylbenzoic acids 2 with N-phenylselenosuccinimide (N-PSS) affords 3-phenyl-iso-coumarin derivatives 3 and 3,4-dihydro-3-phenyl-4-(phenylseleno)isocoumarins 4 via selenolactonization. The reaction of 2-styrylbenzamides 5 and 1-(2-aminophenyl)-3-phenyl-2-peropen-1-one derivatives 11 with N-PSS also resulted in the formation of 1-isoquinolone 6 and 4(1H)-quinolone derivatives 12 , respectively.     

Modification of biologically active amides and amines with fluorine-containing heterocycles 6. Methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)propionate in cyclocondensation with 1,3-binucleophiles

A reaction of methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)propionate with 1,3-binucleophiles (N-benzylurea, N-substituted 3-aminocrotonates, N-substituted 3-aminocyclohexenones, and 6-aminouracyls), leading to the formation of fluorine-containing heterocyclic 3-methyl-1-phenylpyrazol-5-one derivatives, was studied.