Azine-carboxylic acids

Pyridine- and azine-carboxylic acids, as amino acids, exist partly as betaines (e.g. 679) in aqueous solution, but very dominantly as neutral molecules in ethanol which has a lower dielectric constant. 

In most of their reactions, the pyridine- and azine-carboxylic acids and their derivatives behave as expected (cf. Scheme 61). However, some acid chlorides can be obtained only as hydrochlorides, and we must also consider decarboxylation. 

Amino-6-cyano-5-methoxy-2-pyr azine-carboxylic acid... 

Depending upon the reaction conditions, 2-ethoxy-3,4,5,6-tetrahydropy-ridine and isopropylidene 2-acetylmalonate afforded either perhydropy-rido[2,l-h][l,3]oxazine-2,4-dione (162) or hexahydropyrido[2,l-b][l,3]ox-azine-3-carboxylic acid (163) (86MI1). Reaction of 2-methoxy-3,4,5, 6-tetrahydropyridine with diketene without a solvent gave a mixture of 4H-quinazolin-4-one (164) and hexahydropyrido[2,l-h][l,3]oxazin-4-one (165) [75H(3)927]. 

Table 15.10 presents a summary of the applications of gas chromatography to the determinations of other organic compounds, including chlorofluoroparalfins, carboxylic acids, monosaccharides, organosulphur compounds, polychlorobiphenols and azine herbicides in seawater. 

Pyrazolotroponehydrazones like 580a, on treatment with carboxylic acid derivatives or aliphatic carbonyl compounds, are cyclized to fused [l,2,4]tri-azine derivatives (e.g., 580b,c) with aromatic carbonyl compounds, they form azines (79BCJ1972 80JHC1057, 80S331). 

Optically active pipecolic acid and its derivatives can be prepared via 4-phenylpyrido[2,l-c][l,4]oxazin-l-one derivatives. Representatives of the third generation of quinoline-3-carboxylic acid antibacterial agents ofloxacin (19), its levorotatory enantiomer, levofloxacin (20), and rufloxacin (21) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (22) is under development. Other 10-aryl-9-fluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzox-azine-6-carboxylic acids and 7//-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylic acids exhibit mammalian topoisomerase II inhibitory activity. 

Cyclization of methyl 4-(c/s-3,5-H-2-oxomorpholin-5-yl)butyrate in boiling toluene provided c/s-4,9a-H-4-phenylperhydropyrido[2,l-c][l,4]ox-azine-3,6-dione [95H(41)1931], Heating l,4-oxazin-2-one 163 afforded [l,4]oxazino[4,3-a]quinoline-4,6-dione 164 (94IZV299, 94JFC119). The reaction of carboxylic acid 165 with l.l -carbonyldiimidazole in the presence of 4-methylmorpholine afforded pyrido[2,l-c][l,4]oxazin-4-one (61)... 

Azine approach. Cyclocondensation between 3-amino-4-hydroxypyridines and carboxylic acids leads to oxazole fusion as in (233) (77CR(C)(284)73>. The 2-phenyl derivative (235) has been obtained via a pyridyne-type reaction 3-benzamido-5-bromopyridine reacts with lithium piperidide via an intermediate which can be visualized as the pyridyne enolate (234) (73CB220). 

Azine approach. Condensation of 4-amino-3-hydroxypyridines with carboxylic acids yields 2-substituted oxazolo[5,4-c]pyridines (245) (74GEP2330109). 

Azine approach. 8,8a-Dihydro-l-oxo-l//,3//-oxazolo[4,3-c][l,4]thiazines (265) are available from the corresponding l,4-thiazine-3-carboxylic acids and aldehydes or ketones 2,2-dimethoxypropane with acid catalysis yields the 3,3-dimethyl derivative (265 R=Me), and acetaldehyde with a water absorbent yields the monomethyl derivative as a diastereoisomeric mixture (76JCS(P1)584>. 

Azine approach. With the heteroatoms in the appropriate vicinal positions in the pyridine nucleus, cyclization with the missing one-carbon unit is by analogy to the preparation of benzothiazoles effected by using a carboxylic acid or its equivalents as for example in the preparation of (437) (77USP4038496). The use of a carbonate ester or its equivalents will yield 2-oxy, 2-amino or 2-thio substituted derivatives. 2-Amino derivatives are also available by cyclization of vicinal aminothiocyanates such as (438) (66CJC2465). 

Subsequent investigations have reinforced earlier evidence for the wide occurrence of hydrogen bonding of azines. Bonding of all the monocyclic azines,many substituted azines, and azinones with water, alcohols, and dilute acids has been studied by electronic absorption spectra and the variation of the effect with changes in the position of the substituent noted. Quinolines and acridines with chloroform, alcohols, phenols, carboxylic acids, aniline, and pyrrole show the influence of hydrogen bonding on... 

The pronounced electron-withdrawing nature of the 1,2,5-thia-diazole ring is evidenced by the fact that its carboxylic acid derivatives are highly acidic. The titration curve of the dicarboxylic acid exhibits two breaks with and Kai, equal to 1.59 and 4.14, respectively. The monocarboxylic acid is also strongly acidic and has a piTa of 2.47, comparable to that of ornitrobenzoic acid 2.18) and pyrazine-2-carboxylic acid (pifa 2.80). In general the piTa values for the thiadiazole carboxylic acids are in fair agreement with the pica s of the corresponding p3U azine acids (see Table II). 

This hydrazine is available by catalytic reduction of acetone azine.1 Protection of carboxylic acids.2 The reagent reacts with carboxylic acid derivatives (the acyl chloride or mixed anhydride) to give a monoacylhydrazide, RCON(CHMe2)-NH(CHMe2). The derivatives are stable to both acids and bases. They are reconverted into carboxylic acids by selective oxidation, preferably with lead tetraacetate. The new method of protection has been used for penicillins. 

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