By heating aromatic amino acids in aqueous solution of potassium persulfate, corresponding carbonyl compounds were obtained (Table I). In the case of DL-phenylglycine, benzaldehyde was obtained in a good yield of 77%, indicating that the reaction proceeded easily through the same route as with carbinols. The same reaction carried out with phenylacetic acid was found to form a dimter, diphenylethane, apart from the carbonyl compound. These results are interesting in that they suggest a kind of radical reaction taking place in an aqueous solution.
Synthesis of N-alkylphenothiazines by the rearrangement-cyclization of o-alkylaminophenyl o-nitrophenyl sulfides was studied and it was found that phenothiazines are not obtained by the so-called Smiles rearrangement with alkali hydroxide. The phenothiazines were obtained by heating to above 170° and the reaction was accelerated by the use of organic bases as a solvent, especially quinoline and aniline, and by the addition of sodium phenoxide, resulting in an increased yield. The reaction proceeded the most smoothly when the alkyl was methyl, became somewhat difficult with ethyl, and further with propyl, and the starting material was recovered in the case of N-benzyl derivative.
The Diels-Alder reactions reported to date chiefly used C=C-C=C system as the diene component and the use of C=C-C=N or N=C-C=N system was extremely rare. The present series of experiments were carrid out in order to see how far the nitrogen-containing conjugated diene system would submit to this reaction and, becuase, if C=C-C=N system diene synthesis was possible in 1-vinyl-3, 4-dihydroisoquinoline derivatives, it would contribute much to the synthesis of benzoquinolizine compounds, important as the basic structure of numerous alkaloids. The synthesis of 1-vinyl derivative of isoquinoline seemed somewhat difficult that 1-styryl derivative, which can be prepared easily, was chosen. Its reaction with maleic anhydride was carried out and the reduction and decarboxylation of its reaction product afforded 1, 2, 3, 4, 6, 7-hexahydro-9, 10-dimethoxy-2-phenyl-11bH-benzo[α]-quinolizine, whose structure was confirmed by the identity of its infrared absorption spectrum with that of the authentic specimen synthesized by another route. Although the yield of this product is still not satisfactory as yet, it is certain that the desired objective had been attained.
A few 2-pyridinealdehydes, with nitro, methoxy, and chlorine in the 4-position of the pyridine ring were prepared from 2-picoline or 2, 6-lutidline through its 1-oxides. Tests on their thiosemicarbazides in inhibiting the growth of tubercle bacilli were described.
As allithiamine homologs, disulfide derivatives of thiamine and 2-benzamidoethanethiol, ethoxycarbonylmethanethiol, 2-alkoxyethanethiol, 2-alkylthioethanethiol, and 3-alkylthiopropanethiol, and oxythiamine alkyl disulfide derivatives were prepared.
Thermal decomposition of disulfide-type thiamine always afforded thiothiamine (VIII). Separatory determination of thiochrome (II), thiamine-thiazolone (III), and thiothiamine (VIII) was carried out by the combination of paper partition chromatography and measurement of optical density of ultraviolet absorption spctrum.
Thiamine alkyl disulfide derivatives all behave like thiamine propyl disulfide (IV) in decomposition reaction but thiamine disulfide (IX) and thiamine 2-hydroxyethyl disulfide (X) afford thiamine-thiazolone (II) as the chief reaction product, and show different behavior from that of (IV). Fluorescent substances formed by this reaction, besides thiochrome (I), was found to be vitachrome (XIII). The formation of thiothiamine (III) is the largest when ethylene glycol is used as the solvent and the amount increases generally under drastic conditions.
In the thermal decomposition of disulfide-type thiamine derivatives in isobutanol, the addition of dialkyl disulfide, sulfur, or bis (2-hydroxyethyl) disulfide resulted in the increased formation of thiochrome (I), thiothiamine (III), or thiamine-thiazolone (II), respectively. The formation of thiamine butyl disulfide (VIII) as an intermediate was observed by the addition of dibutyl disulfide to thiamine disulfide (IV). Therefore, it is assumed that the addition of dialkyl disulfide has effected change of the usual decomposition route of (IV) to the decomposition of thiamine alkyl disulfide and resulted in the formation of a different product.
Quercetagetin had been isolated as the flavonoid from the flowers of Tagetes erecta L. (Compositae) and its glycoside was obtained this time, designated as tagetiin. It was obtained in 0.1% yield as yellow needles, m.p. 203° (decomp.), [α]D10:-109.64°, C21H20O13⋅3 H2O. Hydrolysis of tagetiin affords 1 mole of querecetagetin and 1 mole of glucose. The aglycone obtained by the hydrolysis of completely methylated tagetiin comes as almost colorless needles, m.p. 220°, corresponding to quercetagetin-pentamethyl ether, but not identical with 3, 6, 7, 3′, 4′-pentamethyl ether m.p. 158-159° It is assumed that the glucose is bonded at the 3-position. Some pale yellow needles, m.p. 180-181°, were obtained in 0.7% yield from its leaves. The hydrolysis of this substance afforded 1 mole of kaempferol and 2 moles of rhamnose and was identified as kaempferitrin (lespedin or kaempferol-3, 7-dirhamnoside).
It had been shown earlier that hydroxoaluminum ions are present in various ratios in the solution of basic aluminum chloride (Al2+n(OH)3nCl6) and, in order to confirm this point, paper electrophoresis was carried out and following facts were observed. 1) Electrophoresis carried out with buffer solutions of pH 3-7 indicated that ion migrates better in a solution with larger n at above pH 5, and vice versa in a solution below pH 5. 2) Electrophoresis of the solution with n above 4 is not affected in migration velocity if carried out for a long period at above pH 5 but the solution with n=1 becomes harder to migrate. This fact indicates the presence of aluminum ion with higher basicity in the solution with n above 4, as described in Part II of this series. 3) The migration value of the ion is affected by endosmosis by the electrolyte present. 4) The migration band is elongated but more closely collected in the peak portion. This indicates that various basic aluminum ions are present in equilibrium. 5) Migration distance is affected by temperature and solutions of different basicity show the same tendency.
The condensation of the hydroxoaluminum ion (Alx(OH)y(OH2)z)(3x-y)+byμ-ol bridge is affected not only by temperature and time but also by the concentration. The condensation proceeds when the concentration is larger in a solution with large basicity and when the concentration is smaller in a solution with low basicity. In this connection, it is assumed that the increase of y by ligandolysis of the ligand, H2O, is more influential, the lower the concentration in solutions with low basicity, while the approach of ions is the requisite condition in solutions with higher basicity. In other words, the increase of y is the primary condition. Together with these considerations, electrophoresis of solutions containing ions of different degree of condensation, with the same basicity, was carried out. The migration distance of the ions was found to be smaller in a solution containing ions of larger degree of condensation than in that of ions with smaller degree of condensation.
The composition of basic aluminum sulfate formed by the combination of various hydroxo-aluminum ion and sulfate ion differs according to the kind of hydroxo-aluminum ion. The composition of the salt obtained by combination with ions with high degree of condensation shows the ratio of Al:SO4 is 3-4:1 but that obtained by combination with ions with extremely low degree of condensation is about 1.5:1. The solution of comparatively high concentration, obtained by the addition of alkali to aqueous solution of aluminum chloride containing a sulfate, when diluted with water, precipitates basic aluminum sulfate. The relationship between the amount of solution and temperature during this hydrolysis reaction was examined by precipitation curve. Hydrolysis of such a solution gradually from a low temperature affords a substance with composition of Al:SO4=3:1, irrespective of basicity of the solution and an example of a formation mechanism of such a substance is shown.
The properties of basic aluminum sulfate, formed by the combination of hydroxoaluminum ion and sulfate ion in the basic aluminum chloride solution, differs according to the degree of ionic condensation. The substances formed by combination with ions of greater degree of corsdensation are in globular form in the majority, generally possess smooth appearance, rapidly dissolve in dilute hydrochloric acid, and easily liberate the sulfate ion with alkali to form aluminum hydroxide. On the other hand, the substances formed by combination with ions of lower degree of condensation do not show such properties. Titration of basic aluminum sulfate in paste form with alkali showed that the pH curve does not show almost any jump but the solution obtained by separation of that paste does. Therefore, there is a great difference in the pH of a solution containing the paste and that of a solution separated from it. The pH of the solution, during the formation of basic aluminum sulfate in the solution, lowers irrespective of the manner of its preparation and n.
Thermal decomposition of various basic aluminum sulfate was measured with a thermal balance and at the same time, determination of Al and SO42- was carried out, thereby establishing the molar ratio of Al, SO4, OH, and H2O. The same analyses of numerous thermal decomposition products established their composition. The pyrolysis curves were found to be classified into three kinds. Basic aluminum sulfates possessing a composition of Al:SO4=1.5:1 show different behavior to decomposition from other substances and the decomposition temperature of SO4 was about 200° lower than that of other substances. This substance possesses two kinds of H2O with different type of bonding and H2O that liberates at around 500° shows a clear decomposition curve. In this substance, OH was found to still remain at above 700° while it is decomposed in other substances by 500°.
Infrared absorption spectra of various basic aluminum sulfates and their thermal decomposition products were determined and some new observations were gained. The broad absorption of SO4 generally appears at 1100cm-1 but in the substance with a composition of Al: SO4=1.5:1, absorptions appear at 1200 (w) and 1025 (w, sh) cm-1 besides the above, and these are assumed to be due to the coordination of SO4 to Al. In order to find analogous phenomenon, infrared spectra of ZnSO4⋅H2O, FeSO4⋅H2O, CoSO4⋅H2O, Li2SO4⋅H2O, CaSO4⋅2H2O, CuSO4⋅H2O, and NiSO4⋅H2O were measured and all showed a sharp absorption at around 1020cm-1. The same tendency was found with the absorption of VOH, this substance showing a sharp absorption while other substances show a broad absorption. This was assumed to be due to H2O that decomposes at around 500°C.
X-Ray diffraction pattern of various basic aluminum sulfates and their thermal decomposition products were measured with the Norelco X-ray diffraction apparatus. This has enabled clear discrimination of crystalline and non-crystalline substances. The substance having the composition of Al3(OH)5(SO4)2⋅5H2O is a perfect crystal compared to the other substances. The process of the formation of this substance in a solution until completion of crystallization was examined and conditions for the crystal formation were established. It was found that five moles of water in this substance can be divided into 3 moles of zeolite-type water and 2 moles of crystal-type, water and that a crystalline substance is formed again at high temperature after partial decomposition of SO4. On the contrary, thermal decomposition of other substances at above 900° was assumed to result in the final formation of α-Al2O3. The foregoing facts are related to the series of pyrolysis curves and infrared absorption spectra.
Detailed studies have already been made on the tertiary nonphenolic bases, insularine (I) and cycleanine (II), in Cyclea insularis (MAKINO) DIELS and their structures have been established. Further systematic isolation of alkaloidal components of this plant afforded isochondodendrine (III) as the tertiary phenolic base, and magnoflorine (IV) and a new kind of crystalline base as water-soluble quaternary bases. The new quaternary base was named cyclanoline. Insularine had not been obtained in crystalline form, either as a free base or as salts, but in the present series of experiments, insularine picrate was isolated as crystals.
Structure of the new quaternary base from Cyclea insularis (MAKINO) DIELS, cyclanoline, was examined and it was found that O, O-dimethylcyclanoline iodide was identical with l-tetrahydropalmatine α-methiodide. The methine base obtained by the Hofmann degradation of cyclanoline was proved to be none other than rac-7, 8-dimethoxy-3-(4′, 5′-dimethoxy-2′-vinyl-phenyl)-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (IV).
Positions of the two phenolic hydroxyls in cyclanoline were examined. Permanganate oxidation of O, O-diethylcyclanoline afforded 5-ethoxy-4-methoxyphthalic acid (I), 3-ethoxy-4-methoxyphthalic acid (II), and 7-ethoxy-6-methoxy-1-oxo-1, 2, 3, 4-tetrahydroisoquinoline (IV). It was found that the N-demethyl compound derived from O, O-diethylcyclanoline iodide was identical with l-O, O-diethylscoulerine, and therefore, cyclanoline was proved to be l-α-N-methylscoulerine (V).
Stability of various thiamine salts, possessing different solubility in water and different acidity, was examined by preparing into powders compounded with wheat starch, precipitated calcium carbonate, ascorbic acid, or calcium ascorbate. It was thereby found that the stability of thiamine in powder preparations is chiefly dependent on the solubility of thiamine salts, the sparingly soluble salts being stable in principle. In the combination with calcium carbonate, which is a weakly acid salt, the neutral (mono) salts of thiamine were not affected but the acidic (di) salts seem to undergo reaction in the presence of water and the stability decreased in some of the sparingly soluble salts. In combination with ascorbic acid, due to its acidity, monosalts of thiamine underwent change and their stability decreased, but the acidic salts, especially their sparingly soluble salts, were stable. The use of calcium ascorbate in place of ascorbic acid makes sparingly soluble thiamine monosalts markedly stable.
Among the various compounds of 4-chloro-3-(2-chloroethyl) quinaldine series, 8-hydroxy compounds possesses strong antibacterial action against dysentery (Shigella flexneri 2a) and typhoid (Salmonella typhi H 901 W) bacilli. In order to examine the relationship between the substituents in 2, 3, or 4-position in the foregoing quinaldine compounds and antibacterial activity, various compounds of such quinaldine series fused with pyrrole ring in 3-4 position were prepared by the application of various amines to the 8-hydroxy compound. The condensation-cyclization of the 8-hydroxy compound with amines occurs with more difficulty than that of the original quinaldine compound. This activity was examined with various amines and it was found that the reactivity of chlorine in the 4-position of the 8-hydroxy compound was markedly reduced by chelation than that of chlorine in the 4-position of the original quinaldine compound.
Antibacterial activity against Shigella flexneri 2a and Salmonella typhi H 901 W was tested by the serial dilution method with 51 kinds of quinaldine series compounds (I) prepared from 2-acetyl-γ-butyrolactone, 2, 3-dihydro-4-methyl-1H-pyrrolo[3, 2-c]-quinoline series, 2, 3-dihydro-4-methylfuro[3, 2-c]quinoline series, and 2, 3-dihydro-1H-cyclopenta[b]quinoline series. The compounds possessing strong activity against typhoid bacilli all possess hydroxyl in the 8-position of quinoline ring and the ability to form chelation, as oxine, was thought to be the main cause of antibacterial activity.
Relationship between chemical structure and antibacterial activity was examined with the dehydroacetic acid-type and 3-acyl-4-hydroxycoumarin-type compounds, which are pyrone derivatives. It is known that the introduction of an acyl group in the 3-position of triacetic acid lactone and 4-hydroxycoumarin results in marked increase of antibacterial action. In the present series of experiments, the effect of change in acyl side chain into 3-position of pyrone derivatives, which possess all the requisite conditions thought to be necessary for the appearance of antibacterial activity, on antibacterial activity was examined. The compounds synthesized and submitted for antibacterial tests were 12 kinds of substances possessing ethoxycarbonyl group or carboxyl group at the terminal end of the acyl group in 3-position of triacetic acid lactone and 4-hydroxycoumarin. It was thereby found that these pyrone derivatives possessed lower antibacterial activity than that of corresponding acyl compounds and the degree of such lowering was the more marked in the carboxyl series.
4-Hydroxycoumarin derivatives possessing an acid amide group in the terminal end of acyl side chain in 3-position were prepared and submitted to antibacterial tests. These derivatives were prepared by the amination of 3-(ω-carboxyacyl)- and 3-(ω-ethoxycarbonylacyl)-4-hydroxycoumarins to the objective 3-(ω-carbamoylacyl)-4-hydroxycoumarins. The interesting phenomenon observed during this amination is that the oxygen atom of the carbonyl in α-position of 3-acyl group is extremely active and is easily substituted with an imino group when 3-(ω-ethoxycarbonylacyl)-4-hydroxycoumarin is reacted with conc. ammonia water to form 3-(α-imino-ω-ethoxy-carbonylalkyl) derivative, followed by the reaction of the terminal ethoxycarbonyl group, affording 3-(α-imino-ω-carbamoylalkyl)-4-hydroxycoumarin. However, none of these α-imino and acid amide derivatives showed any marked antibacterial activity.
Ovokeratin possesses approximately the same chemical composition as other keratins but behaves very differently from them towards neutral and alkaline reducing agents, which is assumed to be due to the structure of proteins, especially in the manner of bonding of sulfur atom. Alkali treatment of ovokeratin followed by hydrolysis afforded meso-lanthionine and rac-lanthionine in a good yield. It is assumed that one of the causes for the difference in the properties of keratins is the number of monosulfide bond in keratin and, from the characteristics of ovokeratin, the presence of lanthionine could be presumed.
2-Benzothiazolethiol is a powerful molluscicide against Onchomelania nosophora but inhibits the potato tyrosinase far more strongly than other thiol compounds. This effect is assumed to occur also against the functions of copper-proteins, such as hemocyanin.
The majority of organic mercury compounds easily undergo decomposition when heated in hydrochloric acid or hydrochloric and nitric acids to liberate mercury ion. Direct titration of this mercury ion with EDTA in such a case results in indefinite color change of the indicator due to the presence of the organic residue. Therefore, titration was carried out after extracting organic residue with solvent or saturating such a solution with hydrogen sulfide, collected mercuric sulfide dissolved in aqua regia, and converted again to mercuric chloride. The titration was carried out on mercury salicylate, phenylmercuric acetate, and sodium ethylmercurithiosalicylate. Compared to the assay methods in the formularies, the difference was found to be within about 0.5%.
Some pale yellow needles, m.p. 185-186°, were obtained in 0.8% yield from the leaves of Trichosanthes cucumeroides MAXIM., and pale yellow microneedles, m.p. 240-241°, in 0.65-0.8% yield, from the leaves of T. japonica REGEL. Both are glycosides and their respective hydrolysis revealed the former substance to be kaempferitrin (lespedin or kaempferol-3, 7-dirhamnoside), giving 1 mole of kaempferol and 2 moles of rhamnose, and the latter to be luteolin-7-glucoside, giving 1 mole each of luteolin and glucose.
Some pale yellow microneedles, m.p. 175-176°, were obtained in 0.8% yield from the leaves of Aleurites cordata STEUD. (Euphorbiaceae) and the hydrolysis of this glycoside afforded 1 mole each of quercetin and rhamnose, identifying it as quercitrin (quercetin-3-rhamnoside). The leaves of Firmiana simplex W. F. WIGHT (Sterculia-ceae), Ficus carica L. (Moraceae), and Humulus-lupulus L. var. cordifolius MAXIM. (Moraceae) afforded the same glycoside as pale yellow needles, m.p. 176°, in 0.15, 0.1, and 2.0% respective yields. This was identified as rutin, affording 1 mole each of quercetin, glucose, and rhamnose by hydrolysis.
Some pale yellow microneedles, m.p. 200° (decomp.), were obtained in 0.7% yield from the leaves of Boehmeria nivea GAUD (Urticaceae) and were identified as rhoifolin (apigenin-7-rhamnoglucoside), affording 1 mole each of apigenin, glucose, and rhamnose by hydrolysis. The leaves of B. japonica MTQ., B. holoserisea BLUME, and B. biloba WEED. afforded the same glycoside as pale yellow microneedles, m.p. 175-176°, in respective yields of 0.1, 0.15, and 0.15%. This was identified as rutin.
The root and rhizome of Epimedium rugosum NAKAT (Berberidaceae family) were found to contain a fairly large amount of magnoflorine (I), an aporphine-type quaternary base, but not any tertiary bases. The same base was found in the leaves and stems but in extremely minute amount. The root and rhizomes were found to contain a flavone glucoside, des-O-methylicariin.
An alkaloid, gentianine, was isolated from the domestic Gentianaceous plants, the root of Gentiana axillariflora LEV. ET VNT., root of G. scabra BUNGE, and the whole herb of Swertia japonica MAKINO, in respective yields of 0.15, 0.05, and 0.76%. By the use of paper partition chromatography, the presence of gentianine was detected in 9 out of 14 kinds of herbarium specimens of plants of this family (Table II).
Heating of β-dialkylglutaric acid (or anhydride) with formamide or methylformamide for a few hours in an oil bath results in the liberation of formic acid and formation of β-dialkyl- or β-dialkyl-N-methyl-glutarimide in a good yield. The product is of high purity even in a crude state.