Reactions of palladium (II) chloride with 1,4 - diphenyl - 2,3 - dimethyl - 1,4 - diazabutadiene and 1,4-DI(p-methoxyphenyl)-2,3-dimethyl- 1,4 - diazabutadiene

The reactions of palladium(II) chloride with 1,4 - diphenyl - 2,3 - dimethyl - 1,4 - diazabutadiene and 1,4 - di(p - methoxyphenyl) - 2,3 - dimethyl - 1,4 - diazabutadiene are described. With 1,4 - diphenyl - 2,3 - dimethyl - 1,4 - diazabutadiene diimine fission is produced, giving rise to a product identified by elemental analysis, IR and Raman spectra, and X-ray diffraction, as trans-dichlorobis(aniline) palladium(II). The complex is soluble in dimethylformamide and crystallizes with two molecules of solvent. The substance crystallizes in the monoclinic space group P2₁/n. The X-ray data were refined to R = 0.047 and R_w = 0.046. Final distances are PdN = 2.060(5)Åand PdC1 = 2.299(2)Å. There are two bifurcated intermolecular NH ... C1 and CH... C1 hydrogen bonds which, together with one more intermolecular hydrogen bond NH... O, are responsible for the packing of the molecules. However, when 1,4 - di(p - methoxyphenyl) - 2,3 - dimethyl - 1,4 - diazabutadiene was treated with palladium chloride under the same conditions cis - dichloro - 1,4 - di(p - methoxyphenyl) - 2,3 - dimethyl - 1,4 - diazabutadiene was formed, as deduced from elemental analysis, and IR and Raman spectra.     

Tele-substitution reactions in the naphthalene series : The behaviour of 1,4 - dimethyl - 2 - nitro - 3 - phenylsulphonyl - and 2,3 - bisphenylsulphonyl - 1,4 - dimethyl - naphthalene towards sodium arenethiolates and secondary aliphatic amines

1,4 - Dimethyl - 2 - nitro - 3 - phenylsulphonylnaphthalene (2) reacts with sodium benzenethiolate in DMSO at 120° to give 1 - methyl - 2 - nitro - 4 - phenylthiomethylnaphthalene (4) [tele-substitution product (TSP) of the phenylsulphonyl group] and 1,4 - dimethyl - 3 - phenylsulphonyl - 2 - phenylthionaphthalene (5) [normal substitution product (NSP) of the nitro group]. The analogous reactions of 2 with sodium 2,4,6- trimethylbenzenethiolate and of 2,3 - bisphenylsulphonyl -1,4 - dimethylnaphthalene (3) with sodium benzenethiolate or aliphatic amines give only TSPs of the phenylsulphonyl group. In the case of the reaction of 2 with aliphatic amines both the possible TSPs (tele-substitution of the phenylsulphonyl or of the nitro group) were isolated in 9:1 relative yield. All the data show that the phenylsulphonyl is a leaving group far better than the nitro in such tele-substitution processes. The mechanism previously proposed to account for the formation of TSPs from 1,4-dimethyl - 2,3 - dinitronaphthalene is strongly supported by the obtained results.     

Novel (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles from (E)- and (Z)-3-styrylchromones: the unexpected case of (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles

An efficient synthetic method for the preparation of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles has been developed. The reaction of (E)- and (Z)-3-styrylchromones with hydrazine hydrate afforded the corresponding (E)- and (Z)-4-styrylpyrazoles, respectively, saved 4′-nitro-derivatives where both (E)- and (Z)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations was discussed and the stereochemistry of all products was assigned by NMR experiments.     

Biosynthesis of (+)-,(-)- and (±)-tetrahydropalmatines

Specific incorporation of didehydroreticuline and reticuline into (±)- (+)-, and (-)-tetrahydropalmatines in Cocculus laurifolius and of (R)- and (S)-reticulines into (R)- and (S)-tetrahydropalmatines respectively has been demonstrated. Feeding of[l-³H, 4'-methoxy-¹⁴C]reticuline suggested that reticuline was not converted in the plants into didehydroreticuline and racemisation of optically active forms of tetrahydropalmatine did not take place via dehydrotetrahydropalmatine     

Preparation,molecular structures,and characteristic properties of (E)-1-(2-furyl)- and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylenes and (E)-1-(3-furyl)- and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylenes

Wittig reactions of 2-furaldehyde (20) [and thiophene-2-carbaldehyde (21)] with (3-guaiazulenylmethyl)triphenylphosphonium bromide (19) in ethanol containing NaOEt at 25 °C for 24 h under argon give (E)-1-(2-furyl)-2-(3-guaiazulenyl)ethylene (22E) and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylene (23E) in 53 and 36% yields. Similarly, Wittig reactions of 3-furaldehyde (29) [and thiophene-3-carbaldehyde (30)] with 19 under the same reaction conditions as for 20 and 21 afford (E)-1-(3-furyl)-2-(3-guaiazulenyl)ethylene (31E) and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylene (32E) in 32 and 46% yields. Molecular structures and characteristic properties as well as preparation of the title E (i.e., one of the geometrical isomers) forms, with a view to comparative study, are reported. Moreover, reactions of those conjugated π-electron systems with TCNE (=tetracyanoethylene) in benzene [and in DMF (=N,N-dimethylformamide)] at 25 °C for 24 h under argon yield unique products, possessing interesting molecular structures, respectively, whose characteristic properties and crystal structures are documented, also.     

Synthesis of 6,8-substituted 4-(hydroxyphenylamino)- and 4-(aminophenylamino)-2-methylquinolines

A procedure has been developed for the synthesis of 4-(hydroxyphenylamino)- and 4-(aminophenylamino)-2-methylquinolines having a substituent in the 6(8)-position of the quinoline ring from the corresponding 4-chloro-2-methylquinolines and o-, m-, and p-aminophenols and o-, m-, and p-phenylenediamines.     

Effect of salts on the reaction direction of (2R*,3R*)-2-[(1R*)-1-iodoethyl)]-3-methyl(3,5-dimethyl)-1-(4-methylphenylsulfonyl)-2,3-dihydro-1H-indoles with dimethylformamide

Transformations of (2R*,3R*)-2-[(1R*)-1-iodoethyl)-3,5-dimethyl-1-(4-methylphenylsulfonyl-2,3-dihydro-1H-indole on heating in boiling dimethylformamide in the presence of various salts were studied.     

Synthesis and antimicrobial activity of some novel 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines

The synthesis of several 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines (2a-t) was carried out by base-catalyzed cyclization of corresponding 1-(fluorobenzoyl)-3-(fluorophenyl)thioureas (1a-t) with 2-bromoacetone in aqueous medium. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa). The minimum inhibitory concentration (MIC) was determined for the most active compounds. In vitro antifungal activity was also determined against the five fungal species (Rhizopus oryzae, Fusarium oxysporum, Aspergillus terreus, A. niger and A. fumigatus).     

Efficient synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-ω-iodoalkanoates

The efficient synthesis of four benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-ω-iodoalkanoates {benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3-iodopropanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-iodobutanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-5-iodopentanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-6-iodohexanoate} from natural or protected l-amino acids is described.     

Synthesis of enantiomeric (+)- and (-)-6-(1-methylethylidene)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-1-ones

Baeyer-Villiger oxidation of racemic [2 +2 ]-cycloadduct derived from dichloroketene and dimethylfulvene gave 3,3-dichloro-6-(1-methylidene)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one, and opening of the lactone ring in the latter with (+)-α-methylbenzylamine produced diastereoisomeric amides which can be readily separated by chromatography on silica gel. The subsequent lactonization and reductive dechlorination afforded enantiomeric (?)- and (+)-6-(propan-2-ylidene)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]-furan-1-ones.     

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.     

Stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one

A stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is reported. The strategy utilizes an olefin cross-metathesis, syn-benzylidene acetal formation and a preferential (Z)-Wittig olefination reaction and lactonization as the key steps.     

Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

An efficient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate (5), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1) and (+)-deoxypyridinoline (Dpd, 2) was described from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (6) in six steps. Also, an improved synthesis of iodide (2S)-(−)-4b was presented.     

Synthesis of σ-(o-carboran-9-yl)- and σ-(m-carboran-9-yl)-π-cyclopentadienyldicarbonyliron and their rearrangement in reactions with bromine to π-(o-carboran-9-yl)cyclopentadienyl- and π-(m-carboran-9-yl)cyclopentadienyl-dicarbonylironbromides,respectively

9-o- and 9-m-carboranylcarboxylic acids were used to synthesize σ-(o-carboran-9-yl)- and σ-(m-carboran-9-yl)-π-cyclopentadienyldicarbonyliron. The latter complexes, in reactions with bromine, undergo rearrangement with the cleavage of the BFe σ-bond, involving migration of the 9-o- and 9-m-carboranyl groups into the cyclopentadienyl ring, to give π-(o-carboran-9-yl)cyclopentadienyl- and π-(m-carboran-9-yl)cyclopentadienyl-dicarbonyliron bromides, respectively. A simple method to obtain these acids by the oxidation of 9-alkyl-o- and 9-alkyl-m-carboranes with CrO₃ in CH₃COOH has been found.     

Synthesis,anti-inflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

The title compounds 3a–l have been synthesized by the reaction of thiocarbohydrazide with substituted phenoxy acetic acid to obtained substituted 1,2,4-triazoles (1). Compound 1 was treated with various substituted aromatic aldehydes which results in 4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-2H-1,2,4-triazol-3(4H)-thiones (2a–g), further 2a–g is converted to 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3a–l) derivatives by the reaction with chloroacetic acid. All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 2-[4-(2,4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3d), 2-[4-(4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3e), 2-[4-(2,4-dichlorobenzylideneamino)-5-[(2,4-dichlorophenoxy)methyl]-4H-1,2,4-triazol-3-yl thio] acetic acid (3j) and 2-[5-[(2,4-dichlorophenoxy)methyl)]-4-(4-chlorobenzylideneamino)-4H-1,2,4-triazol-3-yl thio] acetic acid (3k) showed significant anti-inflammatory activity with P < 0.001 (63.4%, 62.0%, 64.1% and 62.5% edema inhibition, respectively), as compared to the standard drug diclofenac (67.0%) after third hour respectively and also compounds 3j, 3k exhibited significant analgesic activity with P < 0.001 (55.9% and 54.9% protection, respectively) and less ulcerogenic activity as compared with standard drug aspirin (57.8%).     

Synthesis of lithium,sodium, cesium,and calcium salts of (E)-4- or (E,S)-3-methyl-2-(5-arylisoxazol-3-yl)-methyleneaminobutanoic, (E,S)-4-methyl-2- or (E,2S,3S)-3-methyl-2-(5-arylisoxazol-3-yl)methyleneaminopentanoic,and (E)-6-(5-arylisoxazol-3-yl)methyleneaminohexanoic acids

Preparative method for the synthesis of lithium, sodium, cesium, and calcium salts of (E)-4-(5-arylisoxazol-3-yl)methyleneaminobutanoic, (E)-6-(5-arylisoxazol-3-yl)methyleneaminohexanoic, (E,S)-3-methyl-2-(5-arylisoxazol-3-yl)methyleneaminobutanoic, (E,S)-4-methyl-2-(5-arylisoxazol-3-yl)methyleneaminopentanoic and (E,2S,3S)-3-methyl-2-(5-arylisoxazol-3-yl)methyleneaminopentanoic acids was developed by reacting 5-phenyl(4-tolyl)isoxazole-3-carbaldehydes with amino acids like 4-aminobutyric and 6-aminocaproic acids, L-valine, L-leucine or L-isoleucine in the presence of lithium hydride, sodium methoxide, cesium carbonate or calcium hydride in boiling methanol.     

The autoxidation of 2-(2-aminophenyl)-3- methylindole

Fischer indolisation of 2-aminophenyl ethyl ketone phenylhydrazone using glacial acetic acid saturated with hydrogen chloride as catalyst affords 3-methylindolo(l′:2′-3:4)2-methylquinazoline and 2-(2-aminophenyl)-3-methylindole. The latter compound is autoxidised to 2-(2-amino-phenyl)-3-hydroxy-3-methyl-3H-indole, a reaction which is shown to be dependent upon the presence of the primary amino group at the 2-position of the 2-phenyl substituent and which is much slower than the corresponding autoxidation of 2-(2-hydroxyphenyl)-3-methylindole to 3-hydroxy-2-(2-hydroxyphenyl)-3-methyl-3H-indole previously reported.Nitration of isopropyl phenyl ketone occurs preferentially at the ortho- rather than the meta- positions of the benzene nucleus.     

An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.     

(R)- and (S)-N-(Benzyloxycarbonyl)-3,4-epoxybutylamine. New 4-amino-2-hydroxybutyl synthons for the synthesis of hypusine reagents and (R)-6- and (S)-7-hydroxyspermidine

The synthesis and application of the chiral reagents (R)- and (S)-N-(benzyloxycarbonyl)-3,4-epoxybutylamine is described for the first time. These 4-amino-2-hydroxybutyl synthons are successfully employed in the assembly of two hydroxylated triamines, (R)-6- and (S)-7-hydroxyspermidine, and a previously described hypusine reagent, (2S,9R)-11-[(benzyloxycarbonyl)amino]-7-(benzyloxycarbonyl)-2-[(9-fluorenylmethoxycarbonyl)amino]-9-(tetrahydropyran-2-yloxy)-7-azaundecanoic acid, useful for solution- and solid-phase peptide synthesis.     

Synthesis of (−)- and (+)-8-fluoro-galanthamine

The synthesis of racemic 8-fluorogalanthamine and its separation into (−)- and (+)-8-fluorogalanthamine (= (4aS,6R,8aS)- and (4aR,6S,8aR)-1-fluoro-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is described.