Transformations of phenylhydrazones of dialkyl 2‐oxo‐propane‐1,3‐dicarboxylate and of ethyl acetoacetate in concentrated sulfuric acid

The hydrazones 3a,b , prepared from phenylhydrazine ( 1 ) and dialkyl 2‐oxopropane‐1,3‐dicarboxylate ( 2a,b ) were converted in concentrated sulfuric acid at ?5 °C into a mixture of alkyl (3‐carboxyindol‐2‐yl)acetates ( 5a,b ), and ethyl (5‐ethoxy‐1‐phenyl‐1H‐pyrazol‐3‐yl)acetate 6 . The hydrazone 8 , prepared from 1 and ethyl acetoacetate ( 7 ) was transformed under the same conditions into a mixture of five compounds: ethyl 2‐methylindol‐3‐carboxylate ( 9 ), 2‐methylindol‐3‐carboxylic acid ( 10 ), 2‐methylindol ( 11 ), 5‐ethoxy‐3‐methyl‐1‐phenyl‐1H‐pyrazole ( 12 ), and 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐one ( 13 ).     

Transformations of N-heteroarylformamidines and N-heteroarylformamidine oximes new syntheses and transformations of oxazolo[4,5—d]pyridazines

New syntheses of oxazolo[4,5—d]pyridazine derivatives7 and11 were achieved by the cyclization of substituted N-pyridazin-5-ylformamide oximes6 and10. Under mild reaction conditions the transformations of the substituted amino group at position 2 of the oxazolo[4,5—d]pyridazine system7 occured to produce the compounds11, 14, and15, while under more drastic reaction conditions the nucleophilic attack at carbon at position 2 followed by the ring opening of the oxazole part of the molecule was observed to give the compounds13, 16, 17 and18.

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Transformationen von N-Heteroarylformamidinen und N-Heteroarylformamidinoximen. Neue Synthesen und Transformationen von Oxazolo[4,5—d]pyridazinen

Zusammenfassung Mittels Cyclisierung substituierter N-Pyridazin-5-ylformamidoxime6 und10 wurden neue Synthesemöglichkeiten von Oxazolo[4,5—d]pyridazinderivaten erschlossen. Bei milden Reaktionsbedingungen trat Transformation der substituierten Aminogruppe an Position 2 des Oxazolo[4,5—d]pyridazin-Systems unter Bildung der Verbindungen11, 14 und15 ein, währenddessen unter drastischeren Reaktionsbedingungen ein nucleophiler Angriff am Kohlenstoff-2, gefolgt von einer Ringöffnung unter Bildung der Verbindungen13, 16, 17 und18 eintrat.

     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid and β-heteroarylamino-α-amino acid derivatives

From heteroarylaminomethyleneoxazolones 4 , obtained from N-heteroarylformamidines 2 and 2-phenyl-5-oxo-4,5-dihydro-1,3-oxazole ( 3 ), the following β-heteroarylamino-α,β-dehydro-α-amino acid derivatives were prepared: methyl 8 and ethyl esters 9 , amides 10 and 11 , hydrazides 12 , and azides 15 . By catalytic hydrogenation the compounds 4 were converted into β-heteroarylamino substituted amides 18 and β-heteroarylamino-α-amino acids 20 .     

Preparation of the stabilized glycoenzymes by cross-linking their carbohydrate chains

Each of the three high-mannose type glycoproteins studied, acid phosphatase, invertase, and glucose oxidase, could be specifically cross-linked through its carbohydrate chains. The procedure involves periodate oxidation of carbohydrate residues followed by reaction of the generated aldehyde groups with adipic acid dihydrazide as a cross-linker. The amount and size as well as solubility of the formed polymers could be efficiently controlled by varying the reaction conditions, i.e., the oxidation degree and the concentrations of glycoproteins, cross-linker, and hydrogen ions during the cross-linking reaction. It was found that the quantity and size of polymers increased with oxidation degree and protein concentration and by lowering the pH. When the protein concentration was above and pH below certain values, depending on the glycoenzyme, insoluble polymers formed. The soluble cross-linked polymers retained a high level of original activity, and the minor decrease in specific activity noticed was shown to occur during the periodate oxidation step. The cross-linked glycoenzymes are much more resistant to denaturation by high temperature and by changes in pH, demonstrating the usefulness of this method in preparation of the stabilized glycoprotein derivatives.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid derivatives via thiazolones

2-Alkoxy-4-heteroarylaminomethylene-5(4H)-thiazolones 4 were converted with various nucleophiles into β-heteroarylamino-α,β-dehydro-α-amino acid derivatives 11, 14, 15, 16, 17, 18 , and 19 . Reduction of 4 with sodium borohydride in ethanol saturated with gaseous ammonia afforded the corresponding β-heteroaryl-amino substituted alanyl amides 20 . Thiazoledione derivative 7a was transformed with sodium methoxide in methanol into 1-(4,6-dimethylpyrimidinyl-2)-4-mercaptocarbonylimidazol-2(3H)-one ( 8a ).     

Transformations of methyl L-(—)-thiazolidine-4-carboxylate, 2-amino-2-thiazoline and 2-aminothiazole into thiazoloazines and azolothiazoles

In the search for potential immunomodulators methyl L-(—)-thiazolidine-4-carboxylate (2), 2-amino-2-thiazoline (12), and 2-aminothiazole (19) were transformed into derivatives of various bicyclic systems. Thus, from compound 2 derivatives of perhydrothiazolo[3,4-a]pyrazine 4 and 5, perhydrothiazolo[4,3-c]-[1,4]oxazine 7, and perhydroimidazo[1,5-c]thiazole 9a,b, from compound 12 derivatives of 2,3-dihydro-thiazolo[2,3-b]pyrimidine 13a,b , and from compound 19 derivatives of imidazo[2,1-b]thiazole 21, 22, 24, and 25 were prepared. 6-(p-Sulfamoylphenyl)-7-oxoperhydroimidazo[1,5-c]thiazole-5-thione (9a) was found to exhibit immunorestoration activity.     

Semiempirical and ab initio transition state calculations for the transformation of N-acetyltetrazoles into corresponding 1,3,4-oxadiazoles

The transformation of 2-acetyl-5-substituted-tetrazoles into the corresponding 1,3,4-oxadiazoles was studied with the semiempirical and ab initio methods. Two mechanisms, one with two transition states and the other with three, were elucidated by . The first mechanism supported by PM3 and MNDO has a two-step, almost concerted, mechanism for the elimination of a nitrogen molecule from the tetrazole ring and formation of the oxadiazole product from an open-chain intermediate through carbon C₅ and acetyl oxygen bond formation. The second mechanism supported by AM1 and MINDO/3 breaks the elimination of the nitrogen molecule into two steps: first breaking the N₄-C₅ and then the N₂-N₃ bonds. Even when the AM1 and MINDO/3 transition state structures were optimized by PM3 and MNDO, the obtained transition states present only one bond breaking. The HF/STO-3G and HF/3-21G ab initio methods agree with the first mechanism where two bonds are breaking almost simultaneously. Despite the disagreement in the mechanism of the nitrogen elimination, the transition state that presents the product formation from open-chain intermediates is quite similar for all methods studied. The semiempirical calculation of this transition state is possible only if it is assumed that it has biradical character. The activation energies calculated by PM3 seem to be insensitive to the nature of the substituents.     

Die Oxydation von Blei in Wasser bei Gegenwart von atmosphärischem Sauerstoff, 2. Mitt.

Zusammenfassung Der zeitliche Verlauf der Oxydation von granuliertem Blei ist unregelmäßig, weil sich dessen Oberfläche während der Reaktion nicht konstant vermindert. Die Reaktion verläuft an der Luft mit und ohne CO₂ mit gleicher Geschwindigkeit, weil auch an der Luft nur eine Mischung von Bleioxyd und Hydroxydcarbonat entsteht. Auf die geometrische Oberfläche bezogen, hat die Oxydationsgeschwindigkeit unter den beschriebenen Bedingungen eine Größenordnung von 0,6 g/dm²h. Auch die Abhängigkeit der oxydierten Bleimenge vom Partialdruck des Sauerstoffes (0,00–0,21) wurde bestimmt. Die Bleikonzentration hat in breitem Intervall praktisch keinen Einfluß. Der Lichteinfluß ist positiv, auf die Reaktion in der Dunkelheit bezogen, ist die oxydierte Bleimenge 1,2mal höher. Die Bedingungen für die Herstellung von tetragonalem Bleioxyd, dessen Bildung über das rhombische Bleioxyd verläuft, werden wiedergegeben.Mit 3 Abbildungen     

Transformation of 4-(1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone into methyl 2-benzoylamino-3-oxobutanoate. The synthesis of 1-substituted 4-benzoylamino-3-methyl-5(2H)-pyrazolones

Methyl 2-benzoylamino-3-oxobutanoate ( 3 ) was prepared from hippuric acid (1) which was converted with N,N-dimethylacetamide and phosphorus oxychloride into 4-(1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone ( 2 ) followed by hydrolysis with hydrochloric acid in methanol. Compound 3 was treated with hydrazines 4 to give 4-benzoylamino-3-methyl-1H-pyrazol-5(2H)-one ( 6a ) and its 1-substituted derivatives 6b-j . The corresponding hydrazones 5f, i, j were isolated as intermediates.     

Transformations of Methyl 2‐[(E)‐2‐(Dimethylamino)‐1‐(methoxycarbonyl)ethenyl]‐1‐methyl‐1H‐indole‐3‐carboxylate

A simple and efficient synthesis of novel 2‐heteroaryl‐substituted 1H‐indole‐2‐carboxylates and γ‐carbolines, compounds 1 – 3 , from methyl 2‐(2‐methoxy‐2‐oxoethyl)‐1‐methyl‐1H‐indole‐3‐carboxylate ( 4 ) by the enaminone methodology is presented.