Heating of 1, 5-bis (5-nitro-2-furyl)-1, 4-pentadien-3-one amidinohydrazone hydrochloride (I) with sodium dihydrogenphosphate in dimethylformamide (DMFA) resulted in the reaction of the guanidine group with the double bond in I to form cyclized products, the α-form (II) and β-form (III) of 3-amino-5-(5-nitrofurfuryl)-6-[2-(5-nitro-2-furyl)-vinyl]-4, 5-dihydro-1, 2, 4-triazine. These compounds which have such electron-attracting group like nitrothiophene and nitrobenzene in place of nitrofuran ring, also formed analogous cyclized products with sodium dihydrogenphosphate but, the compound which lacks the nitro group did not give the reaction product.
1, 5-Bis (5-nitro-2-furyl)-1, 4-pentadien-3-one amidinohydrazone hydrochloride (I) or 3-amino-5-(5-nitrofurfuryl)-6-[2-(5-nitro-2-furyl) vinyl]-4, 5-dihydro-1, 2, 4-triazine (II) was heated with equimolar amount of sodium hydrogencarbonate in dimethylformamide (DMFA) to give an orange base (III), m.p. 270° (decomp.), which had a strong antibacterial activity. III was found to be 3-amino-6-[2-(5-nitro-2-furyl) vinyl]-1, 2, 4-triazine from its UV and IR absorption spectra, and the fact that oxidation product of III was identified as 3-amino-6-[2-(5-nitro-2-furyl) vinyl]-1, 2, 4-triazine-5 (4H)-one, which was synthesized as the cyclized product of ethyl (5-nitrofurfurylidene) pyruvate amidinohydrazone with sodium dihydrogenphosphate or sulfuric acid. III-hydrochloride (VI) has 1 mole of water and seems to be a hydrate; in this hydrate molecule the position of the water addition was determined as C(4)-C(5) of the 1, 2, 4-triazine by means of IR and UV spectra, and pKa.
6-(p-Nitrostyryl), 6-[2-(5-nitro-2-thienyl) vinyl], and 6-[2-(5-nitro-2-furyl) vinyl]-derivatives of 3-amino-1, 2, 4-triazine shown in Table I were prepared by heating 1, 5-disubstituted 1, 4-pentadien-3-one amidinohydrazones in dimethylformamide. Reaction of 3-amino-6-[2-(5-nitro-2-furyl) vinyl]-1, 2, 4-triazine (III) with formaldehyde and secondary amine hydrochloride afforded 3-dialkylaminomethylamino-6-[2-(5-nitro-2-furyl) vinyl]-1, 2, 4-triazine hydrochloride (X) which was converted into 3-methyleneamino-6-[2-(5-nitro-2-furyl) vinyl]-1, 2, 4-triazine (XII) on heating. The latter compound was also obtained by treatment of III with slight excess of formaldehyde or by prolonged heating of 3-bis (hydroxymethyl) amino-6-[2-(5-nitro-2-furyl) vinyl]-1, 2, 4-triazine (XIII). Antibacterial activity of the above and related compounds is shown in Table II.
Application of tosyl chloride to 2- or 4-chloropyridine 1-oxide in the presence of pyridine results in the formation of 1-(2-chloro-4-pyridyl) pyridinium or 1-(4-chloro-2-pyridyl) pyridinium salt, respectively, without any change to the chlorine. In the case of 2-hydroxypyridine 1-oxide, the reaction stops merely with formation of 1-tosyloxy-2 (1H)-pyridone, while in the case of 4-hydroxypyridine 1-oxide, pyridinium group is introduced into the 2-position to form 1-(4-hydroxy-2-pyridyl) pyridinium salt in a good yield.
Application of tosyl chloride to 4-chloroquinoline 1-oxide in the presence of pyridine gives 1-(4-chloro-2-quinolyl) pyridinium chloride (II). The same reaction with 2-quinolinol 1-oxide (III) produces 89.5% of 8-toxyloxycarbostyril (IV) and 8.5% of 1-(2-hydroxy-6-quinolyl) pyridinium chloride (V) when 1 equivalent of tosyl chloride is used, and 81.9% of 2, 8-ditosyloxyquinoline (IV′) and 15.5% of V when 2 equivalents of tosyl chloride is used. The same reaction of 4-quinolinol 1-oxide (VIII) produces 46-61% of 3-tosyloxy-4-quinolone (IX) and 31-45% of 1-(4-hydroxy-6-quinolyl) pyridinium salt (X), 1-Isoquinolinol 2-oxide produced only 4-tosyloxyisocarbostyril (XIII) by the same reaction. Considerations were made on the reaction mechanism of III, VIII, and XII and general characteristics of this reaction was clarified.
Reaction between quinoline 1-oxide (I) and various amines in the presence of acylating agent was examined and following results were obtained. (1) Heating of I with primary or secondary amine in the presence of tosyl chloride gives 2-aminoquinoline derivative as the main product with 4-aminoquinoline derivative as the by-product. (2) Reaction with N, N-dlmethylaniline (VI) gives different products according to the kind of acylating agent used. The use of benzoyl or acetyl chloride gives 2-(4-dimethyl-aminophenyl)-quinoline (VII) and the use of tosyl chloride gives VII with 2- and 4-chloroquinoline, and 3-tosyloxyquinoline. (3) Shaking of I and tosyl chloride in chloroform solution with 10% ammonia water at room temperature for 2 hours produces 2-aminoquinoline in 71% yield.
Heating of 1-(4-quinolyl)- or 1-(2-quinolyl)-pyridinium salt with various nucleophilic reagents (amine hydrochloride, hydroxyamine hydrochloride, phenols, thiophenols, phosphorus pentachloride, etc.) generally results in exchange reaction between the pyridinium group and the reagent in a considerably good yield. Some side reaction also occurs but this reaction can be used fairly extensively for the synthesis of 4- or 2-substituted quinolines.
The pale yellow crystals obtained from the tree bark of pecan (Carya pecan ENGL. et GRAEBN.) formed needle crystals of m.p. 299-301° from hydrous methanol and corresponded to C17H14O7⋅3H2O. When recrystallized from dehyd. methanol, the product formed prismatic crystals of m.p. 299-301°, corresponding to C17H14O7⋅CH3OH. This substance colors dark green with ferric chloride, deep scarlet with magnesium and hydrochloric acid, is soluble in potassium hydroxide, sodium hydroxide, and sodium carbonate solution, and insoluble in sodium hydrogencarbonate solution. UV λmaxEtOHmμ (logε): 253 (4.39), 347 (4.37). Acetate, m.p. 141-142°, C17H11O7(COCH3)3. It has two methoxyl groups. It shows strong fluorescent on irradiation of ultraviolet rays. Demethylation of this substance with hydrogen iodide (sp. gr. 1.7) gave quercetin, m.p. 313°, and methylation with dimethyl sulfate gave quercetin pentamethyl ether, m.p. 149-150°, which is also formed on methylation with diazomethane. Reduction with sodium amalgam followed by acidification with hydrochloric acid produces a scarlet color. It is negative to the “zirconium-citric acid test.” The absorption maximum of its ultraviolet spectrum does not show any marked change in the presence of aluminum chloride. These evidences suggested that the substance is quercetin 3, 5-dimethyl ether and the fact was proved by the formation of protocatechuic acid and phloroglucinol monomethyl ether by decomposition with potassium hydroxide solution, protocatechuic acid and 4, 6-dihydroxy-2, ω-dimethoxy-acetophenone, m.p. 207°, by decomposition with alcoholic potassium hydroxide solution, and substance corresponding to protocatechuic acid diethyl ether and 6-hydroxy-4-ethoxy-2, ω-dimethoxy-acetophenone, m.p. 109-110°, by decomposition of its ethyl ether, C17H11O4(OC3H5)3 (anhyhrate, m.p. 123-124°) with alcoholic potassium hydroxide. This flavonol is a new substance and was named caryatin.
In the reaction of phenol with xanthydrol in the presence of acid, formation of xanthenylphenol is thought to be the ratedetermining step and, as the effect of a substituent on phenol, the electron-donor group is likely to accelerate the reaction and the electron-acceptor group, retard the reaction. In glacial acetic acid, phenol is thought to participate in this reaction as the phenoxide anion and the effect of a substituent in anionic activity is thought to be the same as in the case of phenol but a reverse effect may be expected for its concentration. Consequently, effect of the substituent would be offset to a certain extent and would not be as great as in the presence of an acid. These assumptions were tested with cresol having an electron-donating group and with hydroxybenzoic acid having an electron-withdrawing group. In the case of phenols having a substituent in the meta-position, difference between ortho and para substitution in the formation of xanthenyl derivative and pigment was found to become less due to the steric hindrance of the substituent in meta position.
In the reaction of resorcinol with xanthydrol in glacial acetic acid, 4-xanthenyl and 4, 6-dixanthenyl derivatives are obtained in about an equal yield, and 2, 4, 6-trixanthenyl derivative is obtained when xanthydrol is present in excess. The position of xanthenyl groups in the dixanthenyl derivative was assumed to be at 4- and 6-positions instead of that reported (2-and 4-positions) and this assumption was supported by the NMR spectra. Dixanthenyl derivative is formed as the pigment in the color reaction of resorcinol with xanthydrol in the presence of an acid and this is considered to be due to the fact that the formation of 4, 6-dixanthenyl derivative is much faster than that of the pigment of 4-xanthenyl derivative by the effect of 1, 3-dihydroxyl group. Decomposition of xanthenyl derivative becomes faster in the presence of an acid and xanthylium ion is thought to be formed by the action of xanthylium ion formed by this decomposition. In such a case, the pigment formed was found to be chiefly 4-xanthenyl derivative.
Adsorption of 1-ethylpiperidine from aqueous solution by various compositions of SiO2-Al2O3 and SiO2 was examined at variety of pH. Using the data obtained therefrom and adsorption capacity at pH 7 was calculated from the Langmuir plot and this value agreed well with the value directly obtained by the Kjehldahl method. These values represent the acid content of acid center on the gel surface, above a certain strength. Diagram was drawn for the relationship between differential coefficient of adsorption at the equilibrium concentration, c=1.0 meq./L., relative to pH, d(x/g)c=1.0/pH, and pH. The pH value at the peak of the curve can be regarded as the index showing acid strength of the gel. From these results, the following facts became known. 1) Acid content of the gel reaches the maximum when alumina content is around 10%. 2) Acid strength becomes the greatest at below few percent of alumina.
Effects of anesthetics, sympathomirnetic amines, reserpine, phenethylhydrazine, and cocaine on hypotensive action of guanethidine and [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate were examined in rats. Guanethidine possessed a lasting hypotensive action in urethane anesthetized rats, whereas only temporary depression was observed in rats anesthetized with pentobarbital sodium, thiopental sodium, secobarbital sodium, or chloralose. The hypotensive action of guanethidine decreased after previous administration of reserpine and cocaine. Furthermore, guanethidine and [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate showed hypertensive action after pretreatment with phenethylhydrazine in rats anesthetized with urethane. The pressor action of adrenaline and noradrenaline were potentiated, but effect of tyramine was inhibited by guanethidine and [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate. These were also observed after section of the spinal cord at C1-C2. It was concluded that hypotensive action of [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate and guanethidine was mainly due to the depletion of endogeneous catecholamines from peripheral stores.
Examinations were made on the anticonvulsant action and toxicity of corydalis tuber, using excised small intestine and uterus of mice, tests being made on eight kinds of main alkaloids contained in the corydalis tuber, and three kinds of extract from commercial crude drugs from China, Southern Asia, and Korea, and of a tuber of Corydalis ambigua var. amurensis MAXIM., which is morphologically close to the Chinese product. All the alkaloids showed antiacetylcholine action against the small intestine, the action being strong in dl-tetrahydrocoptisine but weak in its dehydro form. The quaternary base and protopine showed contraction of uterus and the tertiary bases showed only a weak contraction or rather slackening. Antagonism against acetylcholine was found in d- and dl-corydaline, and l-tetrahydrocolumbamine. Anticonvulsant action of various extracts of corydalis tuber was proportional to the amount of alkaloids contained, being strong in the Chinese and South Asian products. Their action on the uterus was weak in the Chinese product and strong in South Asian product. Strong toxicity was found in the Chinese and South Asian products. However, when calculated on the weight of the crude drug, the action is weak in the South Asian product and strong in Chinese product because the yield of the extract is small from South Asian crude drug.
The two anhydro isomers, m. p. 204° and 259-261°, formed by heating gamabufotalin with alcoholic hydrochloric acid or with sulfuric acid were examined by measurement of their infrared, ultraviolet, and NMR spectra, and optical rotation. These examinations confirmed that the former is Δ14-anhydrogamabufotalin and the latter, Δ8(14)-anhydrogamabufotalin.
In the preceding paper of this series, we have reported that furfural gave a specific blue color with anthrone when the reaction mixture was cooled sufficiently to avoid evolution of heat. When pentose was previously heated in concentrated acid in the absence of anthrone, it also gave the same blue color with anthrone, though pentose itself gave no color without heating. In the present work, the specific colored substance was isolated and its structure was investigated. The colored substance of this reaction was separated on CaHPO4 column with petroleum ether or benzene, and one of main dyes was obtained as a yellow syrup (F). (F) and synthesized 10-furfurylideneanthrone (I) have the same formula of C19H12O2 and also give a blue color in cocentrated sulfuric acid. UV λmax70%H2SO4 600mμ (log ε 4.13). The absorption spectra of (F) and I in the infrared and ultraviolet region are respectively identical. Pentose also gave I in the same reaction with anthrone after it was previously heated in concentrated acid in the absence of anthrone, but another carbohydrate did not give I. Thus, the main colored substance formed from the new color reaction is considered as a new substance having the structure of 10-furfurylideneanthrone.
Terpene and aromatic alcohols (geraniol, nerol, citronellol, l-menthol, l-borneol, benzyl alcohol and benzhydrol), in which the corresponding carbonyl compounds were proved to be absent by gas chromatography and from infrared spectra, were found not to be oxidized to the corresponding carbonyl compounds by the action of 2, 4-dinitrophenylhydrazine reagents by reaction at 60-70° for 1-2 hours and proved by paper and thin-layer chromatography. This fact suggests that Braude's theory does not apply universally.
Dissociation constants (pKa) of 12 commercial sulfanilamides were determined precisely by the spectrophotometric method at 27±1° and the ionic strength of 0.2. The compounds and their pKa values are: sulfapyridine 3.56, sulfisomidine 7.49, sulfathiazole 7.23, sulfamethoxypyridazine 7.17, sulfamerazine 6.85, sulfadiazine 6.37, sulfadimethoxine 5.98, sulfaphenazole 5.89, sulfisomezole 5.72, sulfamethizole 5.22, sulfisoxazole 4.79 and N-sulfanilyl-3, 4-xylamide 4.37. Effect of a substituent in the heterocyclic ring of sulfanilamides on pKa is discussed by correlating it with Hammett's sigma constant, σ.