2-Hydroxy-6-chloro-2-hydroxypyridines

The direct bromination of 2-hydroxypyridine is regioselective at C-3 whereas chlorination is not. Qu6guiner has developed a halide exchange reaction. Heating 3-bromo-2-hydroxypyridine in pyridine hydrochloride at reflux gives 3-chloro-2-hydroxypyridine in good yield <96TL(37)6695>. The directed aminomethylation of 3-hydroxy-2(lH)-pyridones and 3-hydroxy-4(lfl)-pyridones has been studied <96T(52)1835>. 

Reaction of anthranilic acid and 2-chloro-5-cyano-4-hydroxypyridin-6(l//)-one in glacial acetic acid for 18 h gave 8-cyano-7-hydroxy-5,9-dihydro-11 //-pyrido[2,l-6]quinazoline-9,l 1-dione (45). When the reaction was carried out in dimethylformamide under Ullmann conditions, 5-cyano-2-dimethylamino-4-hydroxypyridin-6-one also formed as a by-product... 

Isoxazolo[4,5-c]pyridines have been converted into thiazolo[5,4-(>]pyridines by three methods. Catalytic hydrogenation of compound (616) using palladium on carbon (10%) in aqueous sodium hydroxide at 50 psi followed by neutralization with HC1 to selectively cleave the isoxazole ring afforded 6-chloro-3-(l-iminoethyl)-4-hydroxypyridine-2-thione (617) (57%) <90JCS(P1)1477>. Animation of the thione moiety of the imine (617) with hydroxyamine-Osulfonic acid and subsequent cyclization affords 6-chloro-4-hydroxy-3-methylisothiazolo[5,4-<5 pyridine (618) (57%) (Scheme 78). 

The concentration dependence of FTIR and UV spectra of 2-hydroxypyridine and its 6-chloro analog was measured in chloroform and CCI4 in order to elucidate their tautomeric equilibrium and determine the association constants (96MI1). For unsubstituted 2-hydroxypyridine, the hydroxy monomer or dimer was not detected in both solvents, and the equilibrium existed exclusively between oxo monomer and dimer. In contrast, for 6-chloro-2-pyridone both monomeric hydroxy (about 72%) and oxo (about 28%) forms were observed in chloroform. Increase in the substrate concentration led to decrease in the content of the monomeric species in favor of relevant dimers. In CC14, 6-chloro-2-hydroxypyridine was found to exist mainly in hydroxy monomer hydroxy dimer equilibrium. 

The substituent effect on the equilibrium of 3-hydroxypyridines has been investigated by 3H and 13C NMR spectroscopy (90JST(221)299) and UV spectroscopy (89KG1094). It was shown that the equilibrium in 2-halo-substituted 3-hydroxypyridines is shifted toward the zwitterionic form 15b, whereas 6-methyl- and 5-chloro-substituted derivatives exist exclusively in the enol form 15a. No bipolar form was detected for 2-benzyl- or 2-tert-butyl-substituted 3-hydroxypyridines in CHC13, DMSO, or alcohols. In neutral aqueous solution, all 3-hydroxypyridines studied existed as mixtures of hydroxy and zwitterionic forms, the ratio being dependent on the nature and the position of the substituent. 

Fuss, A. Koch, V. Chemistry of 3-hydroxypyridine. Part 4. Synthesis of 2- and 2,3-sub-stituted 5[fluoro(chloro)alkoxy]p3Tidines via 5-hydroxy-2-(4-nitrophenylazo)pyridines. Synthesis 1990, 8, 681-685. 

Next, the substituent effect on the tautomeric preference should be considered. For example, ortho-derivatives of pyridine with substituents which have an acidic proton may participate in prototropic tautomerism (Scheme 12 2002A(11)198). Stabihty of the particular tautomeric form depends on an additional substituent and intermolecular H-bonding (Scheme 13). Moreover, tautomeric preferences can be changed by a solvent. For 6-X substituted 2-hydroxypyridines, the tautomeric equihbrium is stron y affected by substituents which can change the Tt-electron structure of fragments involved in the prototropy. For example, it was found that 2-hydroxy-6-chloro-and 2-hydroxy-6-methoxy-pyridines exist mainly in the aromatic form a... 

In several examples referred to above, halogen atoms at C(3) remain unaffected during the hydrolysis of 2- or 4-substituents. 3-Bromopyridine is converted into 3-hydroxypyridine by caustic soda and a copper catalyst i at 200 , and boiling 50 per cent caustic potash converts 3-chloro- into 3-hydroxy-isonicotinic acid . 

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