Synthesis of nitriles by the reaction of pyridinecarboxylic acids with p-toluenesulfonamide was examined. The carboxyl group in the 2-position is eliminated and picolinic acid forms pyridine but nicotinic and isonicotinic acids, having carboxyl group in the 3- and 4-positions, respectively form nicotinonitrile and isonicotinonitrile. The carboxyl group in the 2-position of pyridinepolycarboxylic acids is also eliminated but those in 3- and 4-positions form nitriles, 2, 6-pyridinedicarboxylic acid forming pyridine, quinolinic and isocinchomeronic acids forming nicotinonitrile, and lutidinic acid and 2, 4, 6-pyridinetricarboxylic acid forming isonicotinonitrile. Isonicotinonitrile was derived to the acid amide by the application of hydrogen peroxide and sodium hydroxide, and reacted with hydrazine hydrate to form isonicotinic acid hydrazide.
Condensation of 4-chloro-2, 6-lutidine with carboxylic acids was examined. By heating the lutidine with silver salt of benzoic, phenylacetic, or diphenylacetic acid with stirring, ester-type compounds, 4-benzoyloxy- (I), 4-phenylacetoxy- (II), and 4-diphenylacetoxy-2, 6-lutidine (III), were successfully prepared. They are liable to hydrolyze into the corresponding carboxylic acids and 4-hydroxy-2, 6-lutidine, especially (II) and (III). Some colorless plates, m.p. 80°C, were obtained as a byproduct in the preparation of (II) and (III), and the substance was proved to be bis-(2, 6-dimethyl-4-pyridyl) ether (IV). Nine kinds of new alkoxy- and phenoxylutidines were prepared from 4-chloro-2, 6-lutidine and sodium alkoxide or phenoxide by the application of the method of Conrad.
Reduction product of desoxynupharidine was submitted to repeated exhaustive methylation and reduction and the nitrogen-free product (I), C15H30O, was named anhydronupharanediol. Oxidation of (I) with chromium trioxide yielded a lactone compound, C15H28O2, and the same oxidation of the methyl ester (VI) of hydroxy acid yielded isocaproic acid and a dibasic acid (IX), C15H28O4. The anhydride (X) of (IX) gave the diol (VII) by the action of lithium aluminum hydride and (VII) was derived to (I) with sulfuric acid. The zinc dust distillation product of the imide of (X) gave positive Ehrlich reaction. It was concluded from the foregoing results that the ether ring in (I) is five-membered and that the carbon atoms on both sides of ether oxygen are methylenes. On these basis, the structural formula for desoxynupharidine proposed earlier by the writers is withdrawn.
The composition of the products, C15H25ON, and C15H27ON, obtained by the catalytic reduction under heating of desoxynupharidine, are corrected respectively to C15H27ON (tetrahydrodesoxynupharidine) and C15H29ON (hexahydrodesoxynupharidine). Repeated exhaustive methylation of the hexahydro compound and ozonolysis of its product (VIII), C15H26O, afforded a monobasic acid (X), C10H18O3, and a methyl ketone compound (IX), C9H16O. (X) was derived to (IX) through the methyl ester, alcohol (XI), anhydro compound. Desoxynupharidine contains two C-CH3 groups and one of them has already been clarified. The position of the remaining one C-CH3 group was now clarified as shown by (A) or (B).
Ozonic oxidation of des-N-methyl-tetrahydrodesoxynupharidine (I) afforded 3-tetrahydrofurylformaldehyde (II) and 3-tetrahydrofuroic acid (III). On the other hand, the bis-ammonium salt (V), obtained by heating diiodonupharane (IV) with trimethylamine, was treated with silver oxide and heated to give nupharadiene (VI). Oxidation of the ozonolytic product of (VI) with potassium permanganate or with lead dioxide respectively afforded 4, 8-dimethylnonanoic acid (X) or 5, 9-dimethyldeca-noic acid (XIII). Based on these reaction products, the formula (XIV) is forwarded for anhydronupharanediol.
It has already been shown that desoxynupharidine (A) possesses a partial structure indicated by (I) and that anhydronupharanediol is indicated by formula (II). Consequently, formula (III) is forwarded for hexahydrodesoxynupharidine. Ozonic or permanganate oxidation of des-N-methyl-apotetrahydrodesoxynupharidine (F) and apotetrahydrodesoxynupharidine methohydroxide (E) afforded, in both cases, d-2-methylbutyric acid (anilide: mp 105-106°, [α]D10+15.4°). Since catalytic reduction of desoxynupharidine under heating affords tetrahydro- as well as hexahydrodesoxynupharidine and that the furan ring in desoxynupharidine is hydrogenated to hydrofuran ring at the same time, forming optically active asymmetric carbon in the hydrofuran ring, the formula (IV) is forwarded for tetrahydrodesoxynupharidine and formula (VI) for desoxynupharidine. Nupharidine would then be indicated as the N-oxide of formula (VI).
Structure of isochondodendrine had been studied by Scholtz, Faltis, King, and Dutcher, and a tentative structural formula (I) was proposed. The positions of the two phenolic hydroxyls were assumed merely from biosynthesis of the alkaloids in plants and no definite proof has yet been offered. Cleavage reaction of its O, O-diethyl ether (III) with metallic sodium in liquid ammonia was newly carried out and the examination of the bisected phenolic base revealed it to be l-1-(4-hydroxy-benzyl)-2-methyl-6-methoxy-7-ethoxy-1, 2, 3, 4-tetrahydroisoquinoline (VI), affirming the positions of the two phenolic hydroxyls. This has made it possible to prove definitely that the formula (I) assumed by Faltis, et al. is correct for the structure of isochondodendrine.
There are three isomers, normal, iso, and pseudo forms, of dihydrothiamine, but its difference has not been clarified. The infrared absorption spectra of normaland iso-dihydrothiamines were compared with those of the newly synthesized (VI) and (VIII) and all these compounds were proved to have perhydrofurothiazole structure. It follows, therefore, that the structure of normal- and iso-dihydrothiamine would best be represented by (IX), and not by (II) as heretofore assumed, and it is assumed that the ring fusion is trans in the normal compound and cis in the iso compound.
In connection with the proposed three isomers of dihydrothiamine, the structure of pseudo-dihydrothiamine was examined. Condensation of 2-methyl-4-amino-5-aminomethylpyrimidine, formaldehyde, and 3-acetyl-3-mercaptopropanol affords normal-dihydrothiamine but the use of a mercaptoketone compound with hydroxyl substituted with other groups, such as 3-acetyl-3-mercaptopropyl benzoate (III) or 3-acetyl-3-mercaptopropyl methyl ether (IV), affords homologs of the pseudo compound. The same result is obtained on the use of 3-acetyl-3-mercaptobutyl acetate (V). From these experimental results and infrared absorption spectral measurements of these reaction products, it is assumed that pseudo-dihydrothiamine and its homologs all possess the skeleton of pyrimido [4, 5-d] thiazolo [3, 4-a] pyrimidine.
α-Methyl-2-methoxyphenethylamines known as excellent stimulant of sympathetic nerves, were prepared with 2-(2-halopropyl) anisole as intermediate. Allyl phenyl ether, obtained from phenol and allyl halide, was submitted to Claisen rearrangement, methylated to 2-allylanisole, and reacted with hydrogen bromide or iodide to form 2-(2-halopropyl) anisole. Its reaction with ammonia or amines by heating under high pressure afforded the objective α-methyl-2-methoxyphenethylamines.
1-(2-Methoxyphenyl)-2-propanone was prepared by several methods for a starting material for α-methyl-2-methoxyphenethylanine and comparative examinations were made on the following three methods. (1) Hydrolysis and decarboxylation of 2-(2-methoxyphenyl)-2-acetylacetonitrile (2) condensation of (2-methoxyphenyl) acetyl chloride and ethyl ethoxymagnesiomalonate, followed by hydrolysis and decarboxylation, or a reaction of the acid chloride and dimethylcadmium, and (3) reaction of 2-propenylanisole and peracetic or performic acid and hydrolysis of its product with dilute acid, or alkali treatment of acetoxyl derivative of 2-propenylanisole pseudonitrosite to form 1-(2-methoxyphenyl)-2-nitropropene and its reductive hydrolysis with iron and hydrochloric acid.
α-Methyl-2-methoxyphenethylamine was obtained by various methods from 1-(2-methoxyphenyl)-2-propanone such as reductive amination in the presence of methylamine by (1) hydrogen and platinum oxide or Raney nickel, (2) activated aluminum or (3) sodium borohydride. They were also obtained by the Leuckart reaction (4) N-methylformamide and formic acid, or (5) dimethylurea and formic acid. N-Substituted derivatives were prepared from primary amines obtained by similar methods.
The formation mechanism of thiothiamine (II) during pyrolysis of disulfide-type thiamine derivatives is thought to be the (C) or (D) formula by the reaction of thiamine and sulfur. The use of selenium in place of sulfur in this reaction affords seleno-thiamine (XVI) and the reaction of dihydrothiamine (XXII) and sulfur affords thiothiamine (II) in a good yield.
The formation of thiochrome (VII) during the decomposition of thiamine-disulfide (I) is thought not to pass through dihydrothiochrome (VI). The hydroxyl group attached to the ethyl group bonded to the β-position of N-vinylene in symmetrical disulfide derivatives and the hydroxyl group in the alkyl bonded to the disulfide in asymmetrical disulfide derivatives bear important significance in the formation of thiaminethiazolone (IV) and thiochrome (VII), since the presence of the hydroxyl effects progress of the decomposition reaction towards the formation of (IV), while the absence of hydroxyl group or the substitution of the hydrogen with alkyl group effects progress of the reaction towards formation of (VII).
Several partially hydrogenated phenanthridines were prepared by the methods of Bischler-Napieralsky's dihydroisoquinoline synthesis and of Pictet-Spengler's tetrahydroisoquinoline synthesis, and comparison between them was made. 5-Methyl-11-methoxy-1, 2, 3, 4, 4a, 6, 7, 8, 9, 13b-decahydro-9aH-dibenzo [ac] quinolizinium iodide was also prepared.
Examinations were made on quaternary bases in Stephania japonica MIERS (Japanese name “Hasunoha-kazura”) and a new crystalline base was isolated. This base, named steponine, agrees with the molecular formula C20H24O4N+, possessing two methoxyls, two phenolic hydroxyls, and one N-methyl group. Its chloride, C20H24O4NCl⋅H2O, m.p. 235° (decomp.), shows following constants: [α]D21-129.89°(H2O); U.V. λmaxMeOH mμ (logε): 234 (4.12), 282 (3.85); λminMeOH 256mμ (logε 2.76). It colors slightly greenish with ferric chloride and deep blue with the Gibbs reagent. Recently, Tomita and Kikuchi isolated a new quaternary base, cyclanoline, from Cyclea insularis (MAKINO) DIELS and determined its structure as l-α-N-methylscoulerine (IV). Cyclanoline chloride, C20H24O4NCl⋅H2O, m.p. 214-215°(decomp.); [α]D8-115.8° (MeOH); U.V. λmaxMeOH mμ (log ε): 233 (4.13), 286 (3.88); λminMeOH 255mμ (log ε 2.79). It was described as giving almost no change with ferric chloride and coloring deep blue with Gibbs reagent. Although steponine and cyclanoline (IV) are extremely alike, the infrared spectra of the two chlorides were not identical. Since the infrared spectra of their respective O, O-dimethyl-methine (VI) were completely identical, it was assumed that steponine might be α, β-steric isomer of the N-methyl group in cyclanoline or position isomers of the substituents (two methoxyls and two phenolic hydroxyls) in the protoberberine skeleton.
Steponine isolated from Stephania japonica MIERS possessed properties extremely similar to those of cyclanoline (II) isolated from Cyclea insularis (MAKINO) DIELS that their respective derivatives were comparatively examined (cf. Table I). From the identity of the infrared spectra of the iodide (III), methine (V), and N-demethyl base (VI) of the O, O-demethyl derivatives of the two bases, it was found that Steponine is an l-α-N-methyl-tetrahydroprotoberberine-type base and is an isomer of cyclanoline. In order to determine the position of substituents (two methoxyls and two hydroxyls) in steponine, its O, O-diethyl iodide and O, O-diethyl-N-demethyl base (X) were oxidized with potassium permanganate. The iodide afforded two kinds of acid, 4-methoxy-5-ethoxyphthalic acid (XI) and 3-ethoxy-4-methoxyphthalic acid (XII), while the latter (X) afforded 6-ethoxy-7-methoxy-1, 2, 3, 4-tetrahydro-1-isoquinolinone (XIV). It was thereby confirmed that steponine would be represented by the structural formula (XV).
Acetone-dried cells of Escherichia coli and Lactobacillus arabinosus were prepared and the formation of arginosuccinic acid (ASA) and canavanosuccinic acid (CSA) from arginine or canavanine and fumarate was followed by paper electrophoresis and paper chromatography. ASA was found to be formed by the parent strain of E. coli but it was not detected with its arginine-requiring mutant (cannot be compensated with ornithine or citrulline). Even with the parent strain, its culture in a medium containing arginine causes disappearance of arginosuccinase activity and ASA formation does not take place. The formation of CSA was identical with the case of ASA. With Lact. arabinosus, ASA was formed from citrulline and aspartic acid, as well as from arginine and fumarate. CSA itself inhibits proliferation of Lact. arabinosus and this inhibition is easily recovered with arginine. Considerations were made on the action mechanism of canavanine from these experimental results.
There has been no example of a Diels-Alder type reaction taking place in conjugated diene system containing anil nitrogen and the present series of experiments were carried out in order to examine the behavior of such compounds, especially N=C-C=N type dianils, in such a reaction. Reaction of the known, glyoxal bis-(4-dimethylaminoanil) with maleic anhydride was first carried out. While this substance itself is stable when alone, it was found to undergo hydrolysis with a minute amount of water in the solvent, in the presence of maleic anhydride, resulting in the severance of anil bonding. It was thereby learned that p-dimethylaminoaniline thereby formed reacted with maleic anhydride to form maleic acid mono-p-dimethylaminoanilide, and that the minute amount of free maleic acid present in the anhydride acted catalytically. Reaction of the same starting material with p-quinone did not materialize at the reflux temperature of benzene or xylene, but on heating a benzene solution of the two in a sealed tube at 160-170°, a crystalline compound, whose analytical values agreed with those for an equimolar adduct of the two, was obtained. From its infrared absorption spectrum, the adduct was thought to be a product of the anticipated reaction.
dl-1- (2-Methoxybenzyl)-2-methyl-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (XVI) and dl-1-methoxy-5, 6-methylenedioxyaporphine (I) were synthesized and it was confirmed that the racemic compound (I) is identical with. l-stephanine, contained in Stephania capitata SPRENG. and Stephania japonica MIERS., through comparison of the ultraviolet absorption spectra and Rf values of the methiodides of both. This has shown by synthesis that structure of stephanine would be represented by the formula (I).
2′, 4′-Dihydroxy-4, 6′-dimethoxychalcone and its 3′-methyl derivative afforded 4′, 5-dimethoxy-7-hydroxy-flavanone and its 8-methyl derivative in a good yield on heating with conc. phosphoric acid for a few minutes on a water bath. However, condensation of 2, 6-dihydroxy-3-methyl-4-methoxyacetophenone and anisaldehyde did not afford 2′, 6′-dihydroxy-3′-methyl-4, 4′-dimethoxychalcone but formed 4′, 7-dimethoxy-5-hydroxy-8-methylflavanone, that it was not possible to examine the action of conc. phosphoric acid on this chalcone. The methylation of the flavanones hereby obtained with dimethyl sulfate did not afford the completely methylated compound but gave 2′-hydroxy-3′-methyl-4, 4′, 6′-trimethoxychalcone and its completely methylated compound.
Although the flavanone cyclization was not effected by heating only with conc. phosphoric acid, 2′-hydroxy-4-methoxychalcone (II), and 4′-methoxyl (V:R=H) and 6′-methoxyl (IV) derivatives of (II) underwent cyclization to the corresponding flavanones in a good yield on heating with a mixture of glacial acetic acid and conc. phosphoric acid for 5-10 minutes. Chalcones with methyl group introduced into the ring, i.e. 6′-methyl (VIII), 3′-methyl (VI), and 5′-methyl (V:R=CH3) derivatives of (V:R=H), and 3′-methyl compound (VII) of (IV), also underwent similar cyclization. The reaction was especially facile in the case of (VIII), in which methyl group is present in the position meta to the hydroxyl, the heating of 1 minute being sufficient. The 5-nitro (R=NO2), 5-bromo (R=Br), and 5-(4-methoxy-cinnamoyl) (R=CH3O-C6H4-CH=CH-CO) compounds of (V) also underwent cyclization to the corresponding flavanones, although the heating required 30-60 minutes and the respective yield was poor.
By benzylation of 3-methylphloroacetophenone (I), its O4, O6-dibenzyl ether (II) and O6-monobenzyl ether (III) were obtained. The chalcones obtained from the catalytic reduction product of the methylated compound (IV) of (II), 2-methoxy-3-methyl-4, 6-dihydroxyacetophenone, and its O4-methyl ether, underwent cyclization to the corresponding flavanones in 40% yield by heating for 5 minutes with glacial acetic acid and conc. phoshoric acid. The cyclization of the chalcones (XII, XIV, XXI, and XXIII) possessing benzyl group, derived from 2-methoxy-3-methyl-4-benzyloxy-6-hydroxyacetophenone, obtained by hydrolysis of (IV) with hydrochloric acid, (II), (III), and O4-methyl ether of (III), required longer time. Although (XII) afforded the corresponding flavanone, (XIV), possessing 6-benzyloxy group, (XXI), and (XXIII) afforded flavanones with the benzyl group next to the carbonyl liberated, 4′-methoxy-5-hydroxy-7-benzyloxy-8-methyl-, 4′-methoxy-5, 7-dihydroxy-8-methyl-, and 4′, 7-dimethoxy-5-hydroxy-6-methylflavanones (XXVI) in a low yield. (XXVI) was also formed by the methylation of 4′-methoxy-5, 7-dihydroxy-6-methyl-flavanone, the Friedel-Crafts reaction product of 2-methylphloroglucinol and 4-methoxycinnamoyl chloride.
Antibacterial action against Sarcina lutea and antifungal action against Candida albicans M10 were examined with 128 kinds of lichen components and their derivatives and 73 kinds of decomposition products of lichen components and their derivatives. Growth inhibition against Sarcina lutea was shown by anziac acid and olivetoric acid in 160, 000-320, 000 dilutions, by methyl anziate, evernic acid, rangiformic acid, and isopropyl olivetolcarboxylate in 160, 000 dilution, and by collatolone dimethyl ether, isoamyl triacetyllecanorate, squamatic acid, tenuiorin, and isoamyl, hexyl, octyl, and benzyl orsellate in 80, 000 dilution. On the other hand, all 201 compounds tested were ineffective in inhibiting the growth of Candida albicans M10 except methyl squamatate in 80, 000 dilution.
Oxidation of 2-propenylanisole, derived from phenol, with Pb3O4 and glacial acetic acid affords 1-(2-methoxyphenyl)-2-propanone. Condensation of nitromethane to this propanone with aluminum amalgam as the reducing agent and ethanol as a solvent, gave N, α-dimethyl-2-methoxyphenethylamine in a good yield.
In order to find industrial process for the synthesis of 4-methylsulfonylbenzylamine, the following synthetic route was examined. 4-Toluenesulfonyl chloride was derived to 4-tolyl methyl sulfone by the usual method and chlorine gas was passed through its fused liquid under irradiation of ultraviolet light at 125°. The chlorine in 4-chloromethylphenyl methyl sulfone so obtained was substituted with an amino group with hexamethylenetetramine and derived to the objective compound.
In the Dumas method of nitrogen determination, oxidation of the sample is made in anaerobic state that two types of incomplete combustion are known to take place. It was confirmed from present series of experiments that the sample vapor is likely to enter the azotometer without combustion when the fixed furnace temperature is at 600°, while such can be prevented at 750°. It was also found that the majority of substances with ring-nitrogen can be burned with addition of copper oxide, with the temperature of the sample heater at 850-900°, while the addition of cobalt oxide is necessary with some substances, and that such combustion supplement should be added directly to the sample.
Determination of nitrogen gas volume in azotometer requires various corrections of its reading. It was found that the effect of capillary phenomenon by alkali solution inside the azotometer could be disregarded in milligram scale but big enough to require some considerations in decimilligram scale. A nozzle-type, without ground joints, was designed as an improvement of azotometer.
It has already been shown that a quaternary aporphine-type base, magnoflorine, is present in a fairly large amount in the root and rhizome of Epimedium rugosum NAKAI and Epimedium grandiflorum MORREN var. Thunbergianum NAKAI (Berberidaceae family), which do not contain any tertiary alkaloids. Examination of alkaloids in the root and rhizome of Epimedium cremeum NAKAI et F. MAEKAWA also revealed that it did not contain any tertiary bases but contained a large amount of the watersoluble, quaternary base, magnoflorine. The root and rhizome were also found to contain a flavone glycoside, des-O-methyl-icariin.
From the measurement of infrared absorption spectra, the presence of furan ring in desoxynupharidine was assumed from its absorption bands at 3135, 1499, and 874cm-1, and a tetrahydrofuran ring in the decomposition product of tetrahydro-desoxynupharidine from its absorption bands at around 1060 and 905 cm-1.
Since N-methyl derivatives of tetrahydroberberine possess hypotensive action, tetrahydroprotoberberine, with such skeleton, and its allied compounds were prepared in order to compare their hypotensive action. The compounds so synthesized were the N-methyl derivatives of 1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo [a]quinolizine, octahydro-2H-quinolizine, and 1, 3, 4, 6, 11, 11a-hexahydro-2H-benzo[b]quinolizine.
In order to examine the presence of hypotensive action in the N-methyl derivatives of berberine-type alkaloids, other than that of tetrahydroberberine, palmatine, coptisine, jatrorrhizine, and berberrubine were derived to the tetrahydro compounds and thence to N-methyl derivatives.
2′, 5′-Dihydroxy-3′, 4, 4′, 6′-tetramethoxychalcone and 2′-hydroxy-3′, 4, 4′, 5′, 6′-penta-methoxychalcone underwent cyclization by short heating with glacial acetic acid and conc. phosphoric acid to give in a good yield the corresponding 4′, 5, 7, 8-tetrame-thoxy-6-hydroxyflavanone and 4′, 5, 6, 7, 8-pentarnethoxyflavanone, mp 108.5-109.5°. The latter compound was also obtained by methylation of the former with dimethyl sulfate and potassium carbonate and it was found to have a far different melting point from that (mp 152°) of poncanetin. 4′, 5, 6, 7, 8-Pentamethoxyflavone, obtained by the bromination-dehydrobromination of 4′, 5, 6, 7, 8-pentamethoxyflavanone was also obtained by the Baker-Venkataraman method from 2-hydroxy-3, 4, 5, 6-tetrame-thoxyacetophenone and melted at 152.5-153.5°. It follows, therefore, that poncane-tin is not a flavanone but a flavone compound.
The Friedel-Crafts reaction of 2′-hydroxy-4, 4′-dimethoxychalcone (I) and acetyl chloride was found to give 3′-acetyl compound (III) of (I) when the reaction temperature was about 30°, and 5′-acetyl compound of (I) when at about 15°C. (III) was also formed by the Fries rearrangement of the acetate of (I), but there was no difference in the products with different reaction temperatures in the case of the Fries rearrangement.