The reactivities of phenyl benzenethiosulfonate, o-nitrophenyl benzenethiosulfonate and 1, 2-bis (benzenesulfonylthio) ethane toward several active methylene compounds were examined. Consequently, bis (phenylmercapto) malondiamide obtained by the reaction of phenyl benzenethiosulfonate with malondiamide at room temperature was found to eliminate readily one of carboxamide and phenylmercapto group by warming at the temperature above 35°. On the other hand, bis (phenylmercapto) malonate was similarly eliminated one of phenylmercapto group under the same condition, without elimination of carboxylate group. 1-Benzylmercapto-1-phenylmercaptomalondiamide and 1-ethyl-1-phenylmercaptomalondiamide were eliminated one of carboxamide group, without elimination of any mercapto group. Moreover, 1, 2-bis (benzenesulfonylthio) ethane was allowed to react with malondiamide and acetylacetone to give cyclic compound, ethylenedithiomalondiamide and ethylenedithioacetylacetone, respectively. With comparison of these reactions, the reaction of benzyl benzenesulfonate with cyanoacetamide was carried out to result in the benzylation of cyanoacetamide.

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A ring-chain tautomerism between 3-hydroxy-6-(3'-oxoalkyl)-2(1H)-pyridone (VIII) and the alternative ring-form, 3, 6-dihydroxy-1, 2-dihydro-2-alkylindolizin-5 (3H)-one (IX), was studied by means of infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. The IR spectra of VIII show the presence of a lactam-NH at 3100-3150 cm^-1, a lactam-CO at 1620-1650 cm^-1 and a ketone at 1700-1750 cm^-1. However, the IR spectra of the ring-form (IX) lack a lactam-NH band and show only a lactam-CO band at 1620-1650 cm^-1. The structures obtained from their IR spectra were also supported by their NMR spectra, in which the signal at ca. 1.45τ, due to a lactam-NH, indicates the predominance of a chain-form and also the signals at 3-4τ, due to two aliphatic OH (cis and trans), do the predominance of a ring-form. From these results, the following conclusions were made. (1) When R³=H, a ringform is the prefered, and, when R³= an alkyl, a chain-form is the prefered. However, when R² becomes bigger than n-C₅, some steric hinderance appears to keep a chain-form. (2) When R², R³=-(CH₂)_n^-, i.e. cyclic ketone, a chain-form is the prefered except in the case of n=4. (3) These results indicate that the ring-chain tautomerism of this type is an intramolecular, nucleophilic addition reaction of a lactam-NH to a carbonyl function.

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In order to examine the pharmacological activity, some derivatives of 1, 2, 3, 4, 5, 6-hexahydro-2, 6-methano-3-benzazocine, 1, 2, 3, 4, 5, 6-hexahydro-1, 5-methano-3-benzazocine, 1, 2, 3, 4, 5, 6-hexahydro-1, 5-methano-2-benzazocine, 3, 4, 5, 6-tetrahydro-2H-1, 5-methano-1-benzazocine, 1, 2, 3, 4, 5, 6-hexahydro-1, 5-iminobenzocyclooctene, 3, 4, 5, 6-tetrahydro-1 H-2, 6-methano-2-benzazocine, 2, 3, 4, 5-tetrahydro-1, 4-methano-1H-3-benzazepine, 2, 3, 4, 5-tetrahydro-1, 4-methano-1H-2-benzazepine, 2, 3, 4, 5-tetrahydro-1, 4-methano-1H-1-benzazepine, 2, 3, 4, 5, -tetrahydro-1, 4-imino-1H-benzocycloheptene and 4, 5-dihydro-3H-2, 5-methano-1H-2-benzazepine were synthesized.

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A new yellow pigment named torachrysone was isolated from the seeds of Cassia tora L. (Leguminosae). The structure of torachrysone was established as I.

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A new rubrofusarin glycoside was isolated from the seeds of Cassia tora L. (Leguminosae) and its structure was established as rubrofusarin-6-β-gentiobioside (III).

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Thiamine (I) reacted with ethyl isocyanate to give three moles adduct (II) and four moles adduct (III). N-Ethylcarbamoylthiamine (VIII) reacted with ethyl isocyanate to afford a mixture of three moles adducts, and separation of these isomers revealed the formation of perhydrofurothiazole derivatives (IX, X). NaBH₄ reduction of these diastereomers gave dihydro (XIII) and tetrahydro (XV) compounds, respectively.

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Some 2-piperidones (IX and X) bearing β-keto ester groups were synthesized from the methyl esters (V) of alanine and phenylalanine according to a route similar to that described in our previous paper. Spectral studies (infrared, ultraviolet and nuclear magnetic resonance) revealed that these β-keto esters (IX and X) mainly exist in the chelated enolic tautomer (E) both in the solid state and in solution. The NMR spectra of some indole derivatives (XI-XVI) were also investigated.

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Camelliagenin A was oxidized by chromium trioxide to 28-nor-olean-12-ene-3, 16, 22-trione (VIII). From the data of the nuclear magnetic resonance (NMR) spectra, configuration of the C-3 hydroxyl group was decided as β. Formation of the acetonide and the NMR data also proved the configurations of other hydroxyl groups to be 16α, 22α. The structures of the other two genins were also elucidated systematically in relation to camelliagenin A. Thus camelliagenin A, B and C were decided as 3β, 16α, 22α, 28-tetrahydroxy-(I), 23-oxo-3β, 16α, 22α, 28-tetrahydroxy-(II) and 3β, 16α, 22α, 23, 28-pentahydroxy-olean-12-one (III) respectively.

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The Diels-Alder reactions of N-acetyl-3-phenacylidene-2-indolinone (VII) with dienes are reported. VII reacts with cyclohexadiene, cyclopentadiene and butadiene to afford VIII and IX, XIV and XV, and XIX, respectively. Mass spectra of VIII, IX, X and XII are recorded and discussed on their cleavages.

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N, N-Dialkyl-N'-substituted-N'-[3 (4-substituted-2-methyl-5-oxo-1-phenyl-3-pyrazolin-3-yl) methyl] ethylenediamines (IIIa-IIIe) were prepared by reacting 3-bromomethyl-3-pyrazolin-5-ones (Ia and Ib) with ethylenediamines (IIa-IIc). Reaction of 4-(N-4-ethoxyphenyl) aminomethyl-3-pyrazolin-5-one (V) with dialkylaminoethylchloride afforded N, N-dialkyl-N'-(4-ethoxyphenyl) ethylenediamines (IIa and VII) or 4-ethoxy-N, N-bis [(2, 3-dimethyl-1-phenyl-5-oxo-3-pyrazolin-4-yl) methyl] aniline (VIII).

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Wilzbach tritiation in ortho-, meta- and para-aminobenzoic acids was compared with acid catalysed hydrogen exchange reaction and bromination. The acid catalysed hydrogen exchange reaction of the acids in 4 N DCl occurred at ortho and para to amino group of the acids and it was confirmed that the reaction was a typical electrophilic substitution. Tritium incorporation in the acids by Wilzbach labelling was high at ortho and para to amino group of the acids although the order of reactivity on Wilzbach labelling did not completely agreed with that in acid hydrogen exchange reaction. This seems to suggest that HeT⁺ ion would participate in the labelling predominantly.

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A model was proposed to analyze the dissolution phenomena involving simultaneous phase changes and its experimental demonstration was done with p-hydroxybenzoic acid and phenobarbital which change to the respective hydrates during dissolution. The mathematical expression for the dissolution according to this model was given by equation (3) or (4). Conbining the rotating disk method with the above equations, it was possible to determine the rate constant of crystallization process, kr, and the saturated concentration of anhydrate, C_SA, which are hardly obtainable by other usual methods. At the same time, the rate constant of transport process, kt, and the saturated concentration of hydrate, C_SH, were obtained. Analyzing the values of kt, kr, C_SA, and C_SH obtained at various temperatures, the activation energies of transport and crystallization process and the thermodynamic functions of the transition from anhydrate were determined, being reasonable compared with the past data reported on organic medicinals. The transition temperatures obtained from the intersections of the van't Hoff plots regarding anhydrate and hydrate were 84°for p-hydroxybenzoic acid and 37°for phenobarbital. In the case of p-hydroxybenzoic acid, (C_SA-C_SH) increased with temperature in the experimental temperature region.

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First, N-oxidation of trifluoromethylated pyridines was carried out. The three isomers of trifluoromethylpyridine were successfully N-oxidized using acetic acid and hydrogen peroxide, but with 2, 4- and 2, 6-bis (trifluoromethyl) isomers of bis (trifluoromethyl) pyridine, N-oxidation was successful only when trifluoroacetic acid and hydrogen peroxide were used. Next, the reaction of the N-oxides of the three isomers of (trifluoromethyl) pyridine with acetic anhydride and their Reissert reaction were carried out ; the effect of trifluoromethyl group was very marked. The success in the Reissert reaction with pyridine series is only second to that with 4-chloropyridine 1-oxide.

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Treatment of β-anhydrodigitoxigenin acetate (I) with osmium tetroxide gave two cis-glycols (β- and α-), 15β-hydroxydigitoxigenin 3-monoacetate (II) and 15α-hydroxy-14α-digitoxigenin 3-monoacetate (IV) in the ratio of approximately 1 : 9. Acid hydrolysis of II and IV yielded 15β-hydroxydigitoxigenin (III) and 15α-hydroxy-14α-digitoxigenin (V). On the other hand, treatment of β-anhydro-17α-digitoxigenin (β-anhydromenabegenin) (X) as well as its acetate (IX) with the reagent resulted exclusively in the formation of the β-glycol, 15β-hydroxy-17α-digitoxigenin (15β-hydroxymenabegenin) (XII) and its 3-monoacetate (XI) respectively.

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The reactions of tetrahydrofuran with N, N-dibromobenzenesulfonamide, N-bromosuccinimide, or bromine were investigated and the same major product, trans-2-(4'-bromobutoxy)-3-bromotetrahydrofuran (3), was obtained.

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Reaction of N-bromo-N-benzylbenzenesulfonamide (2), N, N-dibromobenzenesulfonamide, and bromine with benzylamines were studied. Tertiary benzylamine degraded to secondary benzylamine hydrobromide and benzaldehyde, secondary benzylamine to primary benzylamine hydrobromide and benzaldehyde, and primary benzylamine to ammonia, benzaldehyde, and primary benzylamine hydrobromide in moist benzene. When the reaction was carried out in dried medium, several intermediates such as salts of benzalbenzylamine (8, 9) and benzalbenzenesulfonamide were identified. The structure of an intermediate, benzalbenzylamine hydrobromide perbromide (9) was established.

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Janovsky reaction of 2, 4, 6-trinitroanisole (TNA) and acetone in the presence of sodium methoxide was studied. By comparing the ratios of intensity of the peak at shorter wave length to that at longer one in the different solvents, the initial peaks at 418 and 488 mμ that observed three seconds after start of the reaction were assigned to be due to the Meisenheimer complex IVa and not to IIIa. That the final spectrum having maxima at 443 and 531 mμ in the reaction mixture coincides with the formation of Janovsky complex IVb, were clarified by NMR spectroscopy (Fig. 8) of IVb and by chemical way such as transferring it to 3-acetonyl-2, 4, 6-trinitroanisole. Contrary to the observation by Foster, et al. in the state of higher concentration, in the diluted acetone solution of IIIb extra sodium methoxide was necessary for transferring IIIb to IIIc. When TNA was added to the mixture prepared beforehand with acetone and sodium methoxide, the initial rate of increase in the absorbances at 443 and 531 mμ became higher than that in the simultaneous mixture of these three reactants. These would indicate that there was no solvolysis of IVa by acetone but the initial step was the deprotonation of solvent by the methoxide ion dissociated from IVa and the acetonate ion thus generated then attacked the dissociated TNA forming IVa. The rate of color development varied with the different interval between the addition of sodium methoxide and of TNA (Fig. 9) ; the reaction mixture of TNA, diacetone alcohol and sodium methoxide gave gradually the similar pattern having maxima at 445 and 526 mμ. The process of this reaction may thus be represented in Eq. (1), (3), (4), (5), and (6) ; Eq. (2) being excluded. The logarithmic equilibrium constant of the overall reaction was obtained as 5.4.

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The antitumor activity of 8-AG was potentiated by its administration with AICA or Aza-AICA to Ehrlich ascites carcinoma in mice. AICA or Aza-AICA alone had no carcinostatic actions, but Monomethyl-TICA alone was found to be slightly carcinostatic at the concentration used in these experiments. AICA and Monomethyl-TICA inhibited liver 8-AG deaminase activity of normal mice, but Aza-AICA did not. Neither AICA nor Aza-AICA affected the activity of the liver xanthine oxidase of normal mice. Therefore, the potentiating actions of AICA and Monomethyl-TICA on 8-AG may be to their inhibitory effects on 8-AG deaminase activity. That of Aza-AICA could be due to a different action from those of the former two compounds.

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The twenty-three compounds related to 4-nitro- and 4-hydroxyamino-quinoline 1-oxides, in addition to forty quinoline derivatives already tested, were tested for carcinogenic activity by the subcutaneous injection in mice. The results were tried to be correlated with chemical and physical properties of the compounds.

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The thiation of methyl substituted oxindoles (I) with phosphorous pentasulfide gave the corresponding 2-indolinethiones (II). The 2-indolinethione (II) having more than one hydrogen at 3-position, however, were sensitive towards phosphorous pentasulfide to produce the indolic compounds such as III, IV, V and VI. On the other hand the 2-indolinethione (VIII) prepared from VII with phosphorous pentasulfide, was stable towards the reagent. Reactivity of 2-indolinthione (IIb) was compared with the oxindole (Ib) in some reactions including the deuteration at 3-position in deuterochloroform-acetic acid-d₄.

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Alkyl 3-aryl-5-methyl-4-pyrrolecarboxylate (IIIa-j) and alkyl 2, 5-dimethyl-3-aryl-4-pyrrolecarboxylate (IIIk-m), two kinds of key intermediates for synthesizing pyrrolnitrin (I), were obtained from 2-aminoacetophenones (IV) and alkyl acetoacetate by Knorr's pyrrole synthesis. The mechanism of the pyrrole ringclosure of the above compounds was proposed since alkyl 3-substituted benzoylmethylaminocrotonates (VIII) could be isolated as intermediates presumably because of their difficult cyclization to the corresponding pyrroles ; for which the infrared spectra of nitro and carbonyl group of VIII were discussed.

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Ethyl 3-aryl-5-methyl-2-pyrrolecarboxylate (XXIII), a desirable intermediate for chlorination to prepare pyrrolnitrin, was derived from ethyl 3-aryl-5-methyl-4-pyrrolecarboxylate (I) by following two routes. At first, it was undertaken to introduce a second ester group to the 2-position of I before the first ester group at the 4-position of I was eliminated. Then the first ester group was hydrolysed selectively and the resulting carboxyl group was removed by decarboxylation. Secondly, the ester group of I was eliminated at first, affording 3-aryl-5-methylpyrrole (XIV). Introduction of an ester group to 2-position of XIV was carried out successively by two methods via a cyano group or a carbonyl chloride group.

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Cyclization of diethyl N-[1-methyl-3-(2-nitro-3- chlorophenyl)-3-oxopropylidene]-aminomalonate (XV) with polyphosphoric acid ethyl ester (PPE) gave ethyl 3-(2-nitro-3-chlorophenyl-5-methyl-2-pyrrolecarboxylate (XVI) in good yield. In such reaction, diethyl 3-(3-chlorophenyl)-5-methyl-2, 2-(2H)-pyrroledicarboxylate (XX) was obtained easily by ring-close of diethyl N-[1-methyl-3-(3-chlorophenyl)-3-oxopropylidene] aminomalonate (XVIII) with PPE. It may be concluded from this result that ethyl 3-aryl-5-methyl-2-pyrrolecarboxylate was prepared via the 2H-pyrrole compound from the corresponding enamine.

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Treatment of the crude-enamine (IV), prepared from 1-(3-chlorophenyl)-1, 3-butanedione (II) and diethyl aminomalonate (III), with sodium ethoxide gave ethyl 3-(3-chlorophenyl)-5-methyl-2-pyrrolecarboxylate (VI) and ethyl 2-(3-chlorophenyl)-4-methyl-5-pyrrolecarboxylate (VII'), whose structures were confirmed by other synthetic methods. Mechanism of above reaction and ultraviolet absorption spectra of these pyrrole derivatives were discussed.

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The structure for pyrrolnitrin by chemical degradation was established. Pyrrolnitrin, 3-(2-nitro-3-chlorophenyl)-4-chloropyrrole (XIIIa), and several 3-aryl-4-chloropyrroles (XIII) were derived from ethyl 3-aryl-5-trichloromethyl-4-chloro-2-pyrrolecarboxylates (VII) via 3-aryl-4-chloro-2, 5-pyrroledicarboxylic acids (X). VII could be obtained by exhaustive chlorination of three kinds of starting materials, ethyl 3-aryl-5-methyl-2-pyrrolecarboxylates (I), 2-ethoxycarbonyl-3-aryl-5-methyl-4-pyrrolecarboxylic acids (III) and ethyl 3-(2-nitro-3-chlorophenyl)-4-chloro-5-methyl-2-pyrrolecarboxylate (IVa).

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Synthetic methods of nitro-chloro-2-aminoacetophenones (XV) and 1-(nitro-chlorophenyl)-1, 3-butanediones (XXIII : R=H), starting materials for the synthesis of pyrrolnitrin (I) and its related compounds, were investigated. Neber rearrangement was shown to be suitable for the preparation of XV. Cleavage of ethyl 2-(nitro-chlorobenzoyl)-acetoacetate (XXI) and 2, 4-pentanedione (XXII) led to XXIII (R=H).

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Preparation of 2, 5-dimethyl-3-arylpyrrole (IX) was accomplished by three different routes : at first alkyl 3-aryl-5-methyl-4-pyrrolecarboxylate (IV) was converted to IX by the series of reactions containing Mannich reaction, reduction and decarboxylation, and secondly IX was also prepared by the ringclosure of 3-aryl-2, 5-hexanedione (XIV) with ammonium acetate and thirdly the methiodide of a bis-Mannich base (XVIII) prepared by Mannich reaction of 3-arylpyrrole (XVII) was reduced with sodium borohydride to IX.

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A new method of pyrrole ringclosure using an aminoacetal (V) was investigated. Condensation of 2-nitro-3-chlorophenylpyruvic acid (VIII) and 2-nitro-3-chlorophenylacetone (XVI) with V afforded 3-(2-nitro-3-chlorophenyl) pyrrole (XII) and 1-acetyl-2-methyl-3-(2-nitro-3-chlorophenyl) pyrrole (XX) respectively in an AcOH-AcONa·3H₂O mixture. Cyclization of an enamine (XIV), prepared from ethyl 2-nitro-3-chlorophenylpyruvate (XIII) and V, under anhydrous condition afforded ethyl 3-(2-nitro-3-chlorophenyl)-2-pyrrolecarboxylate (XV). Hantzsch reaction was applied to VIII, which gave lastly XII. The reaction mechanism of these reactions was proposed.

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Synthetic methods of dialkyl 3-aryl-2, 5-pyrroledicarboxylates (VI) and alkyl β-aryl-5-methyl-2-pyrrolecarboxylates, intermediates to pyrrolnitrin (I), were investigated. VI were prepared by introduction of an ethoxycarbonyl group to ethyl 3-aryl-2-pyrrolecarboxylate (III) and by condensation of arylglyoxals with dimethyl acetyliminodiacetate. Alkyl β-aryl-5-methyl-2-pyrrolecarboxylates were prepared by methylation of alkyl β-aryl-2-pyrrolecarboxylates and by introduction of a methoxycarbonyl group to 2-methyl-3-arylpyrrole.

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Conversion of 2, 5-disubstituted-3-arylpyrrole (II) to pyrrolnitrin (Ia) and the related compounds (I) was investigated. II was transformed by chlorination followed by hydrolysis and oxidation to 3-aryl-4-chloro-2, 5-pyrroledicarboxylic acids (IV), which were decarboxylated to I in sulfuric acid. Dialkyl 3-aryl-4-chloro-2, 5-pyrroledicarboxylate (XI), alkyl β-aryl-4-chloropyrrolecarboxylates and halfesters of IV afforded Ia directly, when heated in sulfuric acid.

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