A simple method for determining the absolute configuration of α-amino acids

Chiral α-amino acids react with 2-methoxy - 2,4 - diphenyl - 3 (2H) - furanone 1 to afford N-substituted 3,5 - diphenyl - 5 - hydroxy - 2 - pyrrolin - 4 - ones 2. The characteristic cotton effects given by these chromophoric derivatives provide a means for the determination of the absolute configuration of the parent amino acids. The longest wavelength(first) extremum in the chiroptical spectra (ORD and CD) of the l-amino acid derivatives is always positive, while it is negative for the d-amino acid derivatives.     

Enantioresolution by the chiral phthalic acid method: absolute configurations of (2-methylphenyl)phenylmethanol and related compounds

Racemic (2-hydroxymethylphenyl)phenylmethanol 5 was enantioresolved by the chiral phthalic acid method using acid-amide 2, and the absolute configurations of (−)-(2-methylphenyl)phenylmethanol 3 and related o-substituted diphenylmethanol derivatives were unambiguously determined by X-ray crystallography and chemical correlation.     

Synthesis,anti-inflammatory,analgesic and anticonvulsant activities of some new 4,6-dimethoxy-5-(heterocycles)benzofuran starting from naturally occurring visnagin

Novel 3-(4,6-dimethoxybenzofuran-5-yl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (3) and 3-chloro-3-(4,6-dimethoxybenzofuran-5-yl)propenal (4) were prepared via Vilsmeier–Haack reaction of 1-(4,6-dimethoxybenzofuran-5-yl)ethanone (1) and its hydrazone derivative 2. Reaction of compound 4 with some hydrazine derivatives, namely hydrazine hydrate, phenylhydrazine and benzylhydrazine hydrochloride led to the formation of pyrazole derivatives 5–8, respectively. On the other hand, reaction of compound 4 with thiourea, urea or guanidine gave the pyrimidine derivatives 9–11, respectively. Reaction of amino compound 11 with acetic anhydride, benzoyl chloride and benzenesulphonyl chloride yielded N-substituted pyrimidine derivatives 12–14, respectively. Reaction of diazonium salt of compound 11 with sodium azide afforded azidopyrimidine derivative 15, which upon reaction with ethyl acetoacetate gave 1,2,3-triazole derivative 16. Acid catalyzed reaction of 11 with p-nitrobenzaldehyde gave Schiff base 17, which cyclized upon reaction with thioglycolic acid or chloroacetyl chloride to give thiazolidin-4-one 18 and azetidin-2-one 19, respectively. The newly synthesized compounds were tested for their anti-inflammatory, analgesic and anticonvulsant activities. Depending on the obtained results, the newly synthesized compounds possess significant anti-inflammatory, analgesic and anticonvulsant activities.     

5'-Substituted 2,2'-anhydrouridines

3',5'-Di-O-acetyl-2'-halogenouridines (1a, 1c and 1d) can be partially deacetylated at C-5' by transesterification with methanol-HCl, providing the 3'-O-acetyl derivatives 2a–2c. These can be converted into the 5'-O-mesyl derivatives 3a–3c, and latter into the 5'-chloro compounds 3d-3f. All 5'-substituted 2'-halogeno compounds give the corresponding 2,2'-anhydrouridine derivatives 4a–4c on treatment with NaOMe. Structures were proved by IR and ¹H-NMR.     

Metal or ammonium alginates as Lewis base catalysts for the 1,2-addition of silyl nucleophiles to carbonyl compounds

Several metal (Na⁺, Ca²⁺) or ammonium (n-Bu₄N⁺) derivatives of alginic acid, an abundant bio-polymer obtained from the cell walls of brown algae, were synthesized. Their potential to act as organocatalysts to catalyze the 1,2-addition of various silyl derivatives to carbonyl compounds was evaluated for the first time. Ammonium alginate 1h is able to promote the reaction in modest to good isolated yields (up to 98%) affording access to a large range of substrates (β-cyano alcohols or ester, β-substituted methylacrylate or acrylonitrile, and cyanohydrin) by using only 5 mol % of catalyst.     

Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl₃ gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a–h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a–f furnished the 1-alkyl derivatives 17a–f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a–d and 16m,n, selectively.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.     

Diastereoselective elaboration of the carbon skeleton of β-hydroxyesters from yeast reductions Preparation of (2S)-2-Hydroxy-cyclohexane Carboxylic Acids with Three Contiguous Stereogenic Centers

The dioxanone-type acetal 2 from (1R, 2S)-2-hydroxy-cyclo-hexane carboxylic acid (1) and pivalaldehyde is dehydrogenated to a derivative 3 of 6-hydroxy-cyclohexene carboxylic acid. Highly selective Michael additions and trapping of the resulting enolates with electrophiles give single diastereomers 4 and 5 which can be hydrolized to 6-substituted 2-hydroxy-cyclohexane carboxylic acids of type C and D.     

<em>N</em>-Substituted 5-Chloro-6-phenylpyridazin-3(2<em>H</em>)-ones: Synthesis, Insecticidal Activity Against <em>Plutella xylostella </em>(L.) and SAR Study

A series of N-substituted 5-chloro-6-phenylpyridazin-3(2H)-one derivatives were synthesized based on our previous work; all compounds were characterized by spectral data and tested for in vitro insecticidal activity against Plutella xylostella. The results showed that the synthesized pyridazin-3(2H)-one compounds possessed good insecticidal activities, especially the compounds 4b, 4d, and 4h which showed > 90% activity at 100 mg/L. The structure-activity relationships (SAR) for these compounds were also discussed.     

Synthesis and structure of the unsymmetrical β-diimine precursor: The β-iminoamine

The reaction of benzoylacetone with ortho-substituted aniline derivatives gives the unsymmetrical β-iminoamine ligands (5–8) with high yields. A convenient synthesis is described. These compounds have been characterized by NMR and IR spectroscopies. The structure of the β-iminoamine 5, 3-N-(2,6-diisopropylphenylamino)-1-phenyl-1N-(2,6-diisopropylphenylimino)but-2-ene, was solved by X-ray diffraction methods.     

Metabolites of fusidium coccineum

Nine cometabolites of the antibiotic fusidic acid (1a) have been identified. These include the fusidane derivatives (5a, 6a, 7a, 8a, 9a, 10a, and 12a), 7,8-dehydropseudofusidic acid (11a), and fusilactidic acid (13a).     

Synthesis of New Pyrano[2,3-<Emphasis Type="Italic">d</Emphasis>]Pyrazoles and Furochromones Derivatives Utilizing Amino Acids Derivatives

Hydrolysis of oxazolone derivatives (2b) yielded α-khellinoyl(amino)-cinnamic acid (3) as a good precursor to react with ethyl esters of glycine, L-methionine, and glycylglycine affording 4, 5, and 4, 5 respectively with minor product 7. Hydrolysis of oxazolone derivatives (2b) afforded α,β-dehydroamino acid derivatives (DDAA) (8). Interaction of oxazolone derivatives (2a,b) with active methylene compounds as ethyl acetoacetate, malononitrile, ethylcyanoacetate, and cyanoacetamide afforded 9–16 respectively     

Electrochemical synthesis of polyhydroxylated aromatic derivatives substituted with mono- and dipyrimidinyl thioethers in aqueous medium

Polyhydroxylated aromatic pyrimidinyl thioethers are important compounds due to their potential anti-HIV integrase activity. The present work describes an electrochemical synthetic strategy and environmentally benign approach for the synthesis of these compounds, superior to conventional chemical reactions. Thus, the electrochemical oxidation of 4-substituted catechols and caffeic acid, in the presence of 2-mercaptopyrimidine derivatives 2, generates monopyrimidinylthio-substituted polyhydroxylated aromatics 3a–f in moderate yields. In the case of catechol itself and 3-substituted catechols, both mono- (3g–l) and dipyrimidinylthio-substituted derivatives (4g–l) were produced. Apparently, the anodic oxidation of catechol derivatives leads to nucleophilic addition products of types 3 and 4, which are different from the traditional nucleophilic substitution reaction of aryl halides and thiols. The electrochemically induced reaction mechanism is also discussed.     

Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives

Novel 46-membered chiral rhombamine macrocycles (R,R,R,R)-8a and 8b were synthesized by [2+2] cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and subsequent reduction with NaBH₄. The X-ray crystal structure of 1:4 dioxane complex with (R,R,R,R)-8a indicated a rhombus conformation of the chiral macrocycle. Compounds (R,R,R,R)-8a and 8b were tested as chiral shift reagents for a wide range of α-substituted carboxylic acids and amino acid derivatives. Enantiodiscrimination of ¹H NMR signals was observed with ΔΔδ values of up to 0.214 ppm.     

Flash vacuum pyrolysis of azolylacroleins and azolylbutadienes

2-Aryl-5-acroleinyl-1,2,3,4-tetrazoles (1a–d) and 2-aryl-5-butadienyl-1,2,3,4-tetrazoles (1e–g) were subjected to flash vacuum pyrolysis. Acroleinyl derivatives resulted in nitrogen extrusion to give nitrilimines followed by ring closure to give the corresponding indazoles 3a–d in good yields. On the other hand, butadiene derivatives underwent ring fragmentation to give p-substituted anilines without formation of the expected indazoles. Differences between thermal behaviour of 2-(4-chlorophenyl)-5-acroleinyl-1,2,3,4-tetrazole (1c) and 1-(4-chlorophenyl)-4-acroleinyl-1,2,3-triazole (2) were studied in details. DFT calculations have been used to examine the nitrilimine and carbene nature of the intermediates involved in the thermal reactions of azolyl derivatives.     

Nitroxydes—LXIII : Oxydation de nitroxydes isoquinuclidiniques par l'oxyde d'argent humide. Preparation de nitroxydes aza-6 bicyclo[3.2.1]octeniques

Moist silver oxide oxidation of three isoquinuclidinic nitroxide ketones is described. 1,3,3-Trimethyl-2-azabicyclo[2.2.2]octane-5-one-2-oxyl 3, and 1,3,3,7-anti-tetramethyl-2-azabicyclo[2.2.2]octane-5-one-2-oxyl 4 lead to 6-aza-bicyclo[3.2.1]oct-3-ene-2-one-7-oxyl derivatives 6, 7, and 1,3,3,7-syn-tetramethyl-2-aza-bicyclo[2,2.2]octane-5-one-2-oxyl 5 to 8-substituted p-menthenones.     

Nucleophilic substitution approach towards 1,3-dimethylbarbituric acid derivatives—new synthetic routes and crystal structures

We describe simple, convenient and high-yielding nucleophilic substitution reactions to synthesize new derivatives of 1,3-dimethylbarbituric acid (1a). Based on its active C5 position, condensing 1a with sulfuryl chloride gives the corresponding 5,5-dichloro-1,3-dimethylbarbituric acid (13). The latter was reacted with silver nitrite and potassium cyanide to afford 5-chloro-5-nitro-1,3-dimethylbarbituric acid (14) and 5-cyano-1,3-dimethylbarbiturate (17), respectively. Furthermore, by employing the nucleophilic character of 2,3-dihydro-1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene (8) the obtained compounds 13 and 14 have been converted to 2-chloro-1,3-diisopropyl-4,5-dimethyl-1H-imidazol-3-ium-1,3-dimethyl-5-nitro-1,3-dimethylbarbiturate (18) and 1,3-dimethylbarbituric acid trimer (21), respectively. X-ray structures for compounds 13, 14, 17, 18 and 21 were determined.     

Synthesis of a new series of pyridine and fused pyridine derivatives

The reaction of 4-methyl-2-phenyl-1,2-dihydro-6-oxo-5-pyridine- carbonitrile (1) with arylidene malononitrile afforded isoquinoline derivatives 2a,b. 6-Chloro-4-methyl-2-phenyl-5-pyridinecarbonitile (3) obtained by chlorination of compound 1 with phosphoryl chloride was converted into 6-amino-4-methyl-2-phenyl-5-pyridinecarbonitrile (4) and 6-hydrazido-4-methyl-2-phenyl-5-pyridinecarbonitrile (5) in good yield, through reactions with ammonium acetate and hydrazine hydrate, respectively. Treatment of 4 with ethyl acetoacetate, acetic anhydride, formic acid, urea and thiourea gave the corresponding pyrido [2,3-d] pyrimidine derivatives 7-10a,b. A new series of 6-substituted-4-methyl-2-phenyl-5-pyridine carbonitriles 11-13 has been synthesized via reaction of 4 with phenyl isothiocyanate, benzenesulphonyl chloride and acetic anhydride. Treatment of 4 with malononitrile gave 1,8-naphthyridine derivative 14. The reactivity of hydrazide 5 towards acetic acid, phenylisothiocyanate and methylacrylate to give pyrazolo-[3,4-b]-pyridine derivatives 15-17 was studied. Treatment of 5 with acetic anhydride, phthalic anhydride and carbon disulphide gave pyridine derivatives 18,19 and 1,2,4-triazolo-[3,4-a]-pyridine derivative 20.     

Chair-boat equilibria in bicyclo[3.3.1]nonane and some 3- and 3,7-substituted derivatives: Thermodynamic parameters and geometry of the conformers as obtained by molecular mechanics

ΔG-Values for conformational equilibria in 3,7-substituted bicyclo[3.3.1]nonanes have been obtained by means of epimerisation experiments (cc α bc) and by variable temperature ¹³C NMR (bc α bb). The results of these experiments fit well with those of molecular mechanics using the Schleyer force field. In bicyclo[3.3.1]nonane and 3β-substituted derivatives the cc conformation predominates; however, the bulky 3β-substituent t-butyl, is found to have a destabilizing effect. A 3α-substituent forces the substituted wing into the boat conformation. For the 3α,7α-substituted derivatives the conformational preferences depend on the size of the substituents: for 3α-methyl-7α-t-butylbicyclo[3.3.1]nonane the cb and t-bb conformers are of approximately equal enthalpy. The geometries, obtained by the calculations, show that the conformers of bicyclo[3.3.1]nonane (cc, bc and t-bb) are all distinctly flattened. The boat wings of bc conformers are not twisted to any extent. The t-bb is the most stable bb conformation. The influence of substitution at positions 3 or 7 is discussed in detail; in general, a bulky substituent such as t-butyl, affects the geometry of both wings of the ring system. The calculated geometries are in good agreement with the conclusions of previous ¹H NMR investigations.     

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3 gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with complete diastereoselectivity to give products (2S,6S)-11–13 whose hydrolysis under relatively mild conditions (2N CF₃CO₂H, CH₃OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16, with intact double bonds in the olefinic substituents.