Studies on dehydro- -ascorbic acid 2-arylhydrazone 3-oximes: Conversion into substituted triazoles and isoxazolines

-threo-2,3-Hexodiulosono-1,4-lactone 2-(arylhydrazones) (2) were prepared by condensation of dehydro- -ascorbic acid with various arylhydrazines. Reaction of 2 with hydroxylamine gave the 2-(arylhydrazone) 3-oximes (3). On boiling with acetic anhydride, 3 gave 2-aryl-4-(2,3-di-O-acetyl- -threo-glycerol-l-yl)-1,2,3-triazole-5-carboxylic acid 5,4¹-lactones (4). On treatment of 4 with liquid ammonia, 2-aryl-4-( -threo-glycerol-l-yl)-1,2,3-triazole-5-carboxamides (5) were obtained. Acetylation of 5 with acetic anhydride-pyridine gave the triacetates, and vigorous acetylation with boiling acetic anhydride gave the tetraacetyl derivatives. Periodate oxidation of 5 gave the 2-aryl-4-formyl-1,2,3-triazole-5-carboxamides (8), and, on reduction, 8 gave the 2-aryl-4-(hydroxymethyl)-1,2,3-triazole-5-carboxamides, characterized as the monoacetates and diacetates. Controlled reaction of 2 with sodium hydroxide, followed by neutralization, gave 3-( -threo-glycerol-l-yl)-4,5-isoxazolinedione 4-(arylhydrazones), characterized by their triacetates. Reaction of 2 with HBr-HOAc gave 5-O-acetyl-6-bromo-6-deoxy- -threo-2,3-hexodiulosono-1,4-lactone 2-(arylhydrazones); these were converted into 4-(2-O-acetyl-3-bromo-3-deoxy- -threo-glycerol-l-yl)-2-aryl-1,2,3-triazole-5-carboxylic acid 5,4¹-lactones on treatment with acetic anhydride-pyridine.     

Studies on dehydro-l-ascorbic acid 2-arylhydrazone 3-oximes: Conversion into substituted triazoles and isoxazolines

l-threo-2,3-Hexodiulosono-1,4-lactone 2-(arylhydrazones) (2) were prepared by condensation of dehydro-l-ascorbic acid with various arylhydrazines. Reaction of 2 with hydroxylamine gave the 2-(arylhydrazone) 3-oximes (3). On boiling with acetic anhydride, 3 gave 2-aryl-4-(2,3-di-O-acetyl-l-threo-glycerol-l-yl)-1,2,3-triazole-5-carboxylic acid 5,4¹-lactones (4). On treatment of 4 with liquid ammonia, 2-aryl-4-(l-threo-glycerol-l-yl)-1,2,3-triazole-5-carboxamides (5) were obtained. Acetylation of 5 with acetic anhydride-pyridine gave the triacetates, and vigorous acetylation with boiling acetic anhydride gave the tetraacetyl derivatives. Periodate oxidation of 5 gave the 2-aryl-4-formyl-1,2,3-triazole-5-carboxamides (8), and, on reduction, 8 gave the 2-aryl-4-(hydroxymethyl)-1,2,3-triazole-5-carboxamides, characterized as the monoacetates and diacetates. Controlled reaction of 2 with sodium hydroxide, followed by neutralization, gave 3-(l-threo-glycerol-l-yl)-4,5-isoxazolinedione 4-(arylhydrazones), characterized by their triacetates. Reaction of 2 with HBr-HOAc gave 5-O-acetyl-6-bromo-6-deoxy-l-threo-2,3-hexodiulosono-1,4-lactone 2-(arylhydrazones); these were converted into 4-(2-O-acetyl-3-bromo-3-deoxy-l-threo-glycerol-l-yl)-2-aryl-1,2,3-triazole-5-carboxylic acid 5,4¹-lactones on treatment with acetic anhydride-pyridine.     

Some studies on dehydro-d-ascorbic acid 2-(phenylhydrazone)

Reaction of hydroxylamine with d-erythro-2,3-hexodiulosono-1, 4-lactone 2-(phenylhydrazone) (2) gave the 3-oxime 2-(phenylhydrazone) (3). On boiling with acetic anhydride, 3 gave 4-(d-erythro-2,3-diacetoxy-l-hydroxypropyl)-2-phenyl-1,2, 3-triazoIe-5-carboxylic acid 5,1′-lactone. Compound 3 was also converted into the related, unacetylated 2-(p-bromophenyl)triazole with bromine. Treatment of 2 with boiling acetic anhydride gave an optically inactive, olefinic compound, assigned the structure 4-(2-acetoxyethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(phenylhydrazone). The 2-(phenylhydrazone) 2 gave the corresponding 2,3-bis(phenylhydrazone) on condensation with phenylhydrazine.     

Studies on dehydro-l-ascorbic acid 3-oxime 2-phenylhydrazone: Conversion into substituted triazoles

l-threo-2,3-Hexodiulosono-1,4-lactone 3-oxime 2-(phenylhydrazone) (1) gave 2-(p-bromophenyl)-4-(l-threo-1,2,3-trihydroxypropyl)-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone (2), and this gave a diacetyl and a dibenzoyl derivative. On treatment of 2 with liquid ammonia, methylamine, or dimethylamine, the corresponding triazole-5-carboxamides (5–7) were obtained. Periodate oxidation of 5 gave 2-(p-bromophenyl)-4-formyl-1,2,3-triazole-5-carboxamide (10), and, on reduction, 10 gave 2-(p-bromophenyl)-4-(hydroxymethyl)-1,2,3-triazole-5-carboxamide, characterized as its monoacetate. Condensation of 10 with phenylhydrazine gave the triazole hydrazone. Acetonation of 2 gave the isopropylidene derivative. Reaction of 2 with HBr-HOAc gave 4-(l-threo-2-O-acetyl-3-bromo-1,2-dihydroxypropyl)-2-(p-bromophenyl)-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone. Similar treatment of 1 with HBr-HOAc gave 5-O-acetyl-5-bromo-6-deoxy-l-threo-2,3-hexodiulosono-1,4-lactone 3-oxime 2-(phenylhydrazone). This was converted into 4-(l-threo-2-O-acetyl-3-bromo-1,2-dihydroxypropyl)-2-phenyl-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone on treatment with boiling acetic anhydride. On reaction of 1 with benzoyl chloride in pyridine, dehydrative cyclization occurred, with the formation of 4-(l-threo-2,3-dibenzoyloxy-1-hydroxypropyl)-2-phenyl-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone, which was converted into the amide on treatment with ammonia.     

Reaction of dehydro-d-erythorbic acid and its aryl analogs with ortho-diamines

Condensation of 3-(d-erythro -2,3,4-trihydroxy-l-oxobutyl)-2-quinoxalinone and its 6-chloro derivative (obtained by the reaction of d-erythro-2,3-hexodiulosono-1,4-lactone with ortho-diamines) with aryl- or aroyl-hydrazines gave 3-[l-(phenylhydrazono)-d-erythro-2,3,4-trihydroxybutyl]-2-quinoxalinone (5) and relatives. Whereas boiling acetic anhydride causes the loss of two molecules of water per molecule of such hydrazones, affording, the 3-[5-(acetoxymethyl)-l-arylpyrazol-3-yl]-2-quinoxalinones, identical with those obtained from the l-threo isomer, alkali causes the loss of only one molecule, affording, the corresponding flavazoles. Periodate oxidation of 5 gave 3-[l-(phenylhydrazono)glyoxal-l-yl]-2-quinoxalinone, which afforded the corresponding mixed bis(hydrazones). A similar sequence of reactions was conducted with the aryl analogs, 4-phenyl-2,3-dioxobutano-1,4-lactone and its p-chlorophenyl derivative, whereby the 3-[2-aryl-l-(arylhydrazono)-2-hydroxyethyl]2-quinoxalinones, were prepared; these were transformed into 3-(α-hydroxybenzyl)-flavazoles that gave monoacetyl derivatives.     

Cooperative aspects of hydrogen bonding in carbohydrates

Various compounds related to the antibacterial, sulfanilamide drugs have been prepared from dehydro-l-ascorbic acid or its d-erythro analog by reaction with hydrazines related to sulfanilamide, sulfadiazine, sulfamerazine, sulfamethazine, and sulfamethoxydiazine, whereby the 2-mono- and 2,3-bis-(hydrazone) were isolated. After opening of the lactone ring in the bis(hydrazones) with alkali, nucleophilic attack, on the carbonyl group, of the imino nitrogen atom of the 3-hydrazone residue afforded 3-(l-threo-glycerol-1-yl)-1-phenyl- and -1-(p-sulfamylphenyl)-4,5-pyrazole-dione 4-(p-sulfamylphenlhydrazone) and the related 3-(d-erythro-glycerol-1-yl)compounds. Whereas acetylation of l-threo-2,3-hexodiulosono-1,4-lactone 2,3-bis(p-sulfamylphenylhydrazone) (9) and 3-(l-threo-glycerol-1-yl)-1-(p-sulfamylphenyl)-4,5-pyrazoledione 4-(p-sulfamylphenylhydrazone) (15) gave the O-acetyl derivatives, benzoylation of 15 gave the di-N-benzoy ltri-O-benzoyl compound. Reaction of 9 with cupric chloride gave 3,6-anhydro-3-(p-suIfamylphenylazo) -l-xylo-2-hexulosono-1,4-lactone 2-(p-sulfamylphenylhydrazone). The 3-(l-threo-glycerol-1-yl)-1-(p-sulfamylphenyl)flavazole (35) was prepared by the rearrangement of 3-[(1-p-sulfamylphenyl)hydrazono-l-threo-trihydroxybutyl]-2-quinoxalinont (33). Periodate oxidation of 15,33, and 35 gave 3-formyl-1-(p-sulfamylphenyl)-4,5-pyrazoledione 4-(p-sulfamylphenylhydrazone), 3-1-[(p-sulfamylphenyl)hydrazono]glyoxal-1-yl]-2-quinoxalinone, and 3-formyl-1-(p-sulfamylphenyl)flavazole, respectively. The i.r. and n.m.r. spectral data for some of these derivatives are reported.     

The conversion of d-glucono-1,5-lactone into an α-pyrone derivative

Treatment of d-glucono-1,5-lactone (3) with excess of acetic anhydride in anhydrous pyridine at room temperature afforded the tetra-acetate and 2,4,6-tri-O-acetyl-3-deoxy-d-erythro-hex-2-enono-1,5-lactone (1). On prolonged reaction or at 80°, 3-acetoxy-6-acetoxymethylpyran-2-one (5) was the unexpected main product. The mechanistic implications of the conversion of 1 → 5 are discussed.     

Transformation of the hydrazones of 6-chloro-3-(l-threo-2,3,4-trihydroxy-1-oxobutyl)-2-quinoxalinone into other heterocyclic compounds

The difference in reactivity of the two amino groups in 4-chloro-o-phenylene-diamine allowed it to react with l-threo-2,3-hexodiulosono-1,4-lactone to give, after further reaction with various hydrazines, 6-chloro-3-(1-substituted-hydrazono-l-threo-2,3,4-trihydroxybutyl)-2-quinoxalinones (5-14), whose structures were deduced from their reactions, as well as from mass spectrometry of the (p-nitrophenyl)-hydrazone. Elimination of one mole of water per mole from these hydrazones gave the 1-aryl-6-chloro-3-(l-threo-glycerol-1-yl)flavazoles; the mass spectrum of one of these flavazoles is discussed. Elimination of two moles of water per mole from the hydrazones (5, 7, and 8) occurred with simultaneous cyclization to give 3-[l-aryl-5- (hydroxymethyl)pyrazol-3-yl]-6-chloro-2-quinoxalinones. whose acetylation gave the corresponding- monoacetyl derivatives (that could also be obtained by the action of boiling acetic anhydride on the starting hydrazones). Periodate oxidation of the hydrazones and the flavazole derivatives afforded the corresponding aldehydes (that could react with hydrazines).     

On the ring transformation of hydrazine derivatives of l-ascorbic acid into nitrogen heterocyclic derivatives

l-hreo-2,3-hexodiulosono-1,4-lactone 2-(p-methoxyphenylhydrazone) (1) was condensed with arylhydrazines to give mixed bishydrazones, whose acetylation gave the corresponding di-O-acetyl derivatives. The hydrazone 1 undergoes elimination of one molecule of water per molecule during, the acetylation, and gives 4-(2-acetoxy- ethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(p-methoxyphenylhydrazone), which reacts with methylhydrazine, via a ring transformation process, to give 1-methyl-3-(L-methylpyrazolin-3-yl)-4,5-pyrazoledione 4-(p-methoxyphenylhydrazone). Alkali rearranged the mixed bishydrazones to 1-aryl-3-(l-threo-glycerol-1-yl)-4,5- pyrazoledione 4-(p-methoxyphenylhydrazones), which gave triacetyl and tribenzoyl derivatives, and, upon periodate oxidation, afforded 1-aryl-3-formyl-4,5- pyrazolediones 4-(p-methoxyphenylhydrazones) that gave the corresponding phenylhydrazones. The n.m.r. and mass spectra of some of these derivatives have been investigated.     

Reactions of the 3-oxime 2-phenylhydrazone and mixed bishydrazones of dehydro-L-ascorbic acid: Conversion into substituted triazoles and pyrazolinediones

L-threo-2,3-Hexodiulosono-1,4-lactone 2-phenylhydrazone(1) reacted with hydroxylamine to give the 3-oxime 2-phenylhydrazone(2). On boiling with acetic anhydride,2 was dehydrated to 4-[L-threo-2,3-diacetoxy-(1-hydroxypropyl)]-2-phenyl-1,2,3-triazole-5-car?ylic acid lactone(3), which was converted into 2-phenyl-4-(L-threo-1,2,3-trihydroxypropyl)-1,2,3-triazole-5-car?amide(4) with liquid ammonia. The structure of compound4 was confirmed by acetylation to 2-phenyl-4-(L-threo-1,2,3-triacetoxypropyl)-1,2,3-triazole-5-car?amide(5), and by periodate oxidation followed by reduction, to give 4-(hydroxymethyl)-2-phenyl-1,2,3-triazole-5-car?amide(6). Treatment of compound1 with aryl- or aroyl-hydrazines afforded mixed bishydrazones(7–14), which were acetylated to15–21, and treated with hydrazine to give pyrazolinediones22 and23     

Facile synthesis and rearrangement of L-threo-2,3-hexodiulosono-1,4-lactone 2-(2-arylhydrazones)

Controlled reaction of L-threo-2,3-hexodiulosono-1,4-lactone with substituted phenylhydrazines gave the 2-(monoarylhydrazones) (2), which underwent dehydrative acetylation to 4-(2-acetoxyethylidene)-4-hydroxy-2,3-dioxohutyro-1,4-lactone 2-(2-arylhydrazones) (3). The latter reacted with methylhydrazine to give 1-methyl-3-(1-methylpyrazolin-3-yl)-4,5-pyrazoledione 4-(2-arylhydrazones) (4). Reaction of the monoarythydrazones (2) with phenylhydrazine gave the mixed bishydrazones (5), which were rearranged by alkali and acidification to the pyrazolediones (6). Compounds 6 gave triacetyl (7) and tribenzoyl derivatives (8), and, on periodite oxidation, the aldehydes (9), which afforded the monohydrazones (10). The i.r.. n.m.r.. and mass-spectral data of some of the compounds were investigated.     

The conversion of d-glucono-1,5-lactone into an α-pyrone derivative

Treatment of d-glucono-1,5-lactone (3) with excess of acetic anhydride in anhydrous pyridine at room temperature afforded the tetra-acetate and 2,4,6-tri-O-acetyl-3-deoxy-d-erythro-hex-2-enono-1,5-lactone (1). On prolonged reaction or at 80°, 3-acetoxy-6-acetoxymethylpyran-2-one (5) was the unexpected main product. The mechanistic implications of the conversion of 1 → 5 are discussed.     

The reactions of 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) in dilute acid

On heating in dilute acid, 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) is converted into 2,7-anhydro-3-deoxy-α-d-manno-2-octulofuranosonic acid and 5-(d-erythro-1,2,3-trihydropropyl)-2-furoic acid. The former is unreactive to periodic acid-thiobarbituric acid and to semicarbazide, and its formation explains the depressed estimates of KDO in lipopolysaccharides. Formation of the furoic acid can lead to high estimates using the semicarbazide assay. Neither product can be formed from 5-O-glycosyl-KDO.     

Homo-C-nucleoside analogs III. Studies on the base-catalyzed dehydrative cyclization of 4-(d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole

Treatment of 4-(d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole with one molar equivalent of 2,4,6-triisopropylbenzenesulfonyl chloride (TIBSCl) in pyridine solution afforded the homo-C-nucleoside analog; 4-(2,5-anhydro-d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole in 54% yield and 4-(α-d-arabinopyranosyl)-2-phenyl-2H1,2,3-triazole analog in 3% yield. The 4-(5-O-triisopropylbenzenesulfonyl)-d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole analog was isolated as an intermediate and identified as its tetra-O-acetyl derivative. The 4-(5-chloro-5-deoxy-d-manno-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole analog was isolated as a byproduct. The structure and anomeric configuration of the products were determined by acylation, NMR spectroscopy, and mass spectrometry.     

Improved preparation and synthetic uses of 3-deoxy-d-arabino-hexonolactone: an efficient synthesis of Leptosphaerin

Acetylation of d-glucono-1,5-lactone and subsequent treatment with triethylamine gave 2,4,6-tri-O-acetyl-d-erythro-hex-2-enono-1,5-lactone. Hydrogenation of the latter in the presence of palladium on carbon yielded 2,4,6-tri-O-acetyl-3-deoxy-d-arabino-hexono-1,5-lactone (5) in almost quantitative yield calculated from gluconolactone. Catalytic hydrogenation of 5 with platinum on carbon in the presence of triethylamine gave 2,4,6-tri-O-acetyl-3-deoxy-d-arabino-hexopyranose in quantitative yield. Deacetylation of 5 gave 3-deoxy-d-arabino-hexono-1,4-lactone, which was converted into 3-deoxy-5,6-O-isopropylidene-2-O-methanesulfonyl-d-arabino-hexono-1,4-lactone (10). The latter was converted into 2-acetamido-2,3-dideoxy-d-erythro-hex-2-enono-1,4-lactone (Leptosphaerin). When 10 was boiled in water in the presence of acid, it gave a high yield of 2,5-anhydro-3-deoxy-d-ribo-hexonic acid.     

The preparation of some bromodeoxy- and dibromodideoxy-pentonolactones

Brief reaction of d-lyxono-1,4-lactone (1) with hydrogen bromide in acetic acid (HBA) yields 2-bromo-2-deoxy-d-xylono-1,4-lactone (2), and a similar treatment of d-ribono-1,4-lactone (8) gives 2-bromo-2-deoxy-d-arabinono-1,4-lactone (12). On longer reaction with HBA, 1 is converted into 2,5-dibromo-2,5-dideoxy-d-xylono-1,4-lactone, whereas 8 forms a mixture of 2,5-dibromolactones. Reduction of 2 and 12 gives 2-bromo-2-deoxy-d-xylose and -d-arabinose, respectively. On hydrogenolysis, 2 and 12 are converted into 2-deoxy-d-threo- and 2-deoxy-d-erythro-pentono-1,4-lactone, respectively. The 2,5-dibromolactones can be selectively hydrogenolysed to 5-bromo-2,5-dideoxy-d-pentono-1,4-lactones.     

New C-nucleoside analogs by dehydration of 1-benzyl-4,5,6,7-tetrahydro-6,6-dimethyl-2-(d-galacto-pentitol-1-yl)-indol-4-one

The reaction between 2-(benzylamino)-2-deoxy-d-glycero-l-gluco-heptose and 5,5-dimethyl-1,3-cyclohexanedione yields 1-benzyl-4,5,6,7-tetrahydro-6,6-dimethyl-2-(d-galacto-pentitol-1-yl)-indol-4-one (2). Acid-catalyzed, intramolecular dehydration of 2 under kinetically controlled conditions gives 1-benzyl-4,5,6,7-tetrahydro-2-α-d-lyxofuranosyl-6,6-dimethylindol-4-one; the anomeric configuration of this compound is only suggested. When the dehydration reaction is conducted under thermodynamically controlled conditions, it produces a 1:1 mixture of the α- and β-d-lyxopyranosyl compounds. The structures of the new compounds were elucidated by chemical and physical methods.     

Preparation of 1-aryl-2-(benzylthio)-(1,2-dideoxy-d-glycero-β-l-gluco-heptofurano)[1,2-d]-2-imidazolines,and new,acyclic C-nucleosides of the imidazole

The reaction of 1-aryl-(1,2-dideoxy-d-glycero-β-l-gluco-heptofurano)[1,2-d]imidazolidine-2-thiones with benzyl chloride and an equivalent amount of sodium hydrogencarbonate yields 1-aryl-2-(benzylthio)-(1,2-dideoxy-d-glycero-β-l-gluco-heptofurano)[1,2-d]-2-imidazolines (2). If the reaction is carried out in the absence of sodium hydrogencarbonate, the 1-aryl-2-(benzylthio)-4-(d-galacto-pentitol-1-yl)imidazoles are obtained. These compounds are also obtained by acid-catalyzed isomerization of compounds 2.     

Synthesis and reactions of some hydrazones of dehydro-l-ascorbic acid

l-threo-2,3-Hexodiulosono-1,4-lactone 2-(3-chlorophenylhydrazone) and 4- (2-acetoxyethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(3-chlorophenylhydrazone) were prepared. The two geometric isomers of the corresponding bis(hydrazone) underwent an intramolecular rearrangement to 1-(3-chlorophenyl)- 3-(l-threo-glycerol-1-yl)-4,5-pyrazoledione 4-(3-chlorophenylhydrazone), which gave a tri-O-acetyl derivative upon acetylation and the anticipated formyl derivative upon periodate oxidation. Oxidation of the bis(hydrazone) with cupric chloride afforded the bicyclic compound 3,6-anhydro-3-C-(3-chlorophenylazo)-l- xylo-2-hexulosono-1,4-lactone 2-(3-chlorophenylhydrazone), whose acetylation afforded the mono-O-acetyl derivative.     

Equilibria of the anomeric and ring forms of ammonium 3-deoxy-d-manno-octulosonate in deuterium oxide

The tautomeric composition of a solution of ammonium 3-deoxy-d-manno-octulosonate (KDO, 1a) in D₂O at 28° was assessed by means of ¹³ C-F.t.-n.m.r. spectroscopy. The results revealed the presence of 6?0 and 11 % of the α and β anomers of the pyranose, and 20 and 9 % of the two furanoses, and suggested, but did not unequivocally prove, that the major furanose form is the α anomer. To facilitate interpretation of the spectral results for 1, ammonium 3,5-dideoxy-d-arabino(or ribo)-octulosonate (3a) was prepared by the reaction of 5-deoxy-d-erythro-pentose with sodium oxalacetate at pH 11. A chromatographically homogeneous, noncrystalline sample of 3 was obtained by lyophilization, and characterized as its (4-nitrophenyl)hydrazone (m.p. 162-163°). The ¹³C-n.m.r. spectrum of a solution of 3a in D₂O revealed it to be substantially all in the α-pyranose form. No signals were obtained for the possible 1,4-lactone of 3. As the 1,5-lactone and furanose forms are impossible for 3, it exhibited no signals analogous to those attributed to furanoid 1. On the basis of these results for 3, the two lactone forms of 1 were excluded from consideration, and the three pairs of ¹³C-n.m.r. signals observed at ≈45, 86, and 104 p.p.m. were assigned to the furanose forms of 1.