Chiji Yamazaki

Cyclization of isothiosemicarbazones. Part 10. A novel route to 2-amino[1,2,4]triazolo[1,5-a]pyridine derivatives

2-Alkylamino[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile and 8-carboxylate derivatives 3 are obtained directly in moderate yields by the reaction of ketone isothiosemicarbazones 1, carrying a bulky alkyl group on the terminal nitrogen and at least one α-methylene group, with an active ethoxymethylene compound with elimination of a thiol. Butanone isothiosemicarbazone 1e gives an isomeric pair of 5-ethyl- and 5,6-dimethyl-triazolopyridines 3e and 3f depending upon which of the α-carbons is incorporated into the ring system, with the 5,6-dimethyl compound being the major product. When the substituent on the terminal nitrogen is less bulky, the reaction gives both [1,2,4]triazolo[1,5-a]pyridines 3 and penta-substituted 2-triazolines 4 or the latter compounds only. A plausible reaction mechanism is proposed.

Synthesis of Trichloromethyl-1, 3, 5-triazines and Their Nitrification-Inhibitory Activity

It is well known that upland soil has capacity to bind ammonium nitrogen (NH4+-N), thus preventing an excessive loss of nitrogen through leaching, but the ammonium nitrogen is gradually oxidized to form nitrate (N03-N). The formed nitrate is soluble in water and not adsorbed onto the soil to the same degree as ammonium nitrogen. As a result a considerable amount of nitrogen is lost through leaching. Nitrogen is therefore supplied as a fertilizer during the growing season of plants. Nitrification inhibitors such as 2-chloro -6trichloromethylpyridine (N-Serve) and 2-amino-4-methyl-6-trichloromethyll, 3, 5-triazine and others, 1-31 were developed to prove availability of fertilizers by plant. These chemicals are capable of controlling generation of nitrate from ammonium nitrogen in upland soil. The nitrificationinhibitory activity caused by 1, 3, 5-triazines has beenn reported already by one of the authors, 3-s1 however, mechanism of inhibitory action, fate of the inhibitors in soil, structureactivity correlations study among 1, 3, 5triazine inhibitors and others have still to be studied. In this paper, we discuss effects of trichloromethyl-1, 3, 5-triazines on the nitrification process [NH4+-N-(NH2OH)-NO2-NN03-N] in upland soil to confirm the primary inhibition step by the inhibitors and furthermore to study the aspect of structure-activity relationships among 1, 3, 5-triazine inhibitors.

[4+2]Cycloaddition of monocyclic imidazole derivatives with electron-deficient acetylenes

1-Alkylidene- and 1-arylmethylene-amino-4-aryl-2-mercapto-1H-imidazole derivatives 2–11 react with dimethyl acetylenedicarboxylate (DMAD) in hot chlorobenzene to give the corresponding retro-Diels–Alder products 1-alkylidene- and 1-arylmethylene-amino-2-mercapto-lH-pyrrole-3,4-dicarboxylate derivatives 19–26 and benzonitriles 27 in high yield. No intermediate Diels–Alder adducts could be isolated from these substrates. 1 -Amino-2-methylthio-4-phenyl-lH-imidazole 1 gives dimethyl 1-[1,2-bis(methoxycarbonyl)vinylamino]-2-methylthio-4-phenyl-1H-1,3-diazepine-5,6-dicarboxylate 28 in addition to dimethyl 1-amino-2-methylthio-1H-pyrrole-3,4-dicarboxylate 18, with the ratio 18:28 ranging from 2:1 to 3:1 under the same reaction conditions. At lower temperature, however, the former cycloadduct is obtained as the sole product in acetonitrile. No cycloaddition to these imidazole derivatives is observed with ethyl propiolate or with bis(trimethylsilyl)acetylene even under forced conditions. Any changes in the substituents or their positions on the imidazoles 2–11 that otherwise successfully give rise to the cycloaddition decidedly inhibited the reaction. Among a number of di- and tri-substituted imidazole derivatives employed as substrates, only a limited number bearing an amino or alkylidene- or arylmethylene-amino, a substituted mercapto, and an aryl group at the 1-, 2- and 4-position, respectively, can produce the corresponding pyrroledicarboxylates through the retro-Diels–Alder reaction.

Cyclization of isothiosemicarbazones. Part 8. Formation and structure of gem-bis(3-alkylthio-1H-1,2,4-triazol-1-yl)alkanes and related compounds

Symmetrical gem-bis(3-alkylthio-1H-1,2,4-triazol-1-yl)alkanes (6) are directly obtained by the reaction of aliphatic ketone isothiosemicarbazones (1) with ethyl ethoxymethylenenitroacetate (2) as a methine donor in aqueous formic acid. Aldehyde isothiosemicarbazones indirectly give both symmetrical and unsymmetrical terminal gem-bis(triazolyl)alkanes, after conversion into the 4-[2,2-bis(ethoxycarbonyl)vinyl]-3-alkylisothiosemicarbazones (5) and exposure to aqueous acidic media, with the former being the major product. Electronic and steric factors in the starting isothiosemicarbazones exert a marked influence on the yield of bis(triazolyl)alkanes. Two unsymmetrical bis(azole)s are obtained through these reactions, one in which the two triazole rings are linked together by the different nitrogens, and the other, which carries a different substituent on each sulphur in two azole rings, the latter being obtained through the cross-reaction between differently substituted isothiosemicarbazones. The gem-bis(azole) formation may involve nucleophilic attack of 4-(substituted vinyl)isothiosemicarbazone (4) or (5) on an intermedially formed iminium cation (14) as the key step, followed by intramolecular cyclization of the resulting oxonium ion.

Cyclization of isothiosemicarbazones. Part 7. Synthesis of N-alkenyl-1,2,4-triazoles with anti-Saytzeff orientation

Aliphatic ketone 4-[2-cyano-2-(ethoxycarbonyl)vinyl]-3-methylisothiosemicarbazones (4) give N-alkenyl-1,2,4-triazoles (6) in moderate yields with elimination of ethyl cyanoacetate in hot acetic acid. When the carbonyl component is an unsymmetrical ketone, the reaction proceeds predominantly to afford the less substituted terminal alkenes, and little or no formation of the more substituted internal alkenes was observed, even though the internal alkene would be thermodynamically more favourable. Without an intervening isolation of the N(4)-(substituted vinyl) isothiosemicarbazones, these alkenes are obtained in much higher yields through a direct ‘cycloalkenylation’ of N(4)-unsubstituted isothiosemicarbazones (1) with ethyl β-ethoxy-α-nitroacrylate (3) along with a minor amount of 2(3)-(3-alkylthio-1,2,4-triazol-1-yl)alkan-2 (3)-yl acetates (7). The proposed mechanism involves preferential abstraction of a proton at the less crowded alpha-carbon of the potentially formed iminium ion.