6-Chloro-2-hydroxypyridine

Guitian et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves... 

Chloro-3-hydroxypyridine is a readily available starting point for the synthesis of furo[2,3- ]pyridines via iodina-tion followed by a palladium cross-coupling reaction with alkynes to afford alkynylpyridines, 107. Cyclization of compound 107 leads to furo[2,3- ]pyridine products <1998JME1357, 1998JOC7851 Similarly, reaction of 5-bromo-... 

Pyrido[2,3-b] [l,4]oxazin-2-ones 88 were prepared [55] from 2-chloro-3-hydroxypyridine 84 and 2-chloroacetamide derivatives 85 (Scheme 32). hi principle, the intermediate anion 86 could cyclize through the pyridine C-2 or C-3 carbon atoms (the Smiles rearrangement). The best results were obtained when cesium or rubidium carbonate in boiling MeCN or cesium carbonate in DMF at 90-100 °C were used as the base (Table 4). 

Figure 3.2 Schematic diagram of (a) 2-chloro-3-quinolinyl methanol (VCLl) (b) 2-chloro-3-hydroxypyridine (VCL2) and (c) 2-chloro-3-chloromethyl-8-methylquinoline CL3).

In alkali, acid and carboxylic acid anion reactions, 2,4-dichloropyridines have been converted into chloro-hydroxypyridines 79a, 7756, 840< usually of uncertain orientation. 2-Iodopyridine methiodide reacts with carboxylic acids in presence of triethylamine, giving 2-acyloxy-l-methylpyridinium ions 20 379). 

Treatment of 2-amino-3-hydroxypyridine (185) with 2-chloro-3-nitropyridine (193) easily provided intermediate 194. Attempts to cyclize 194 with potassium hydroxide in aqueous ethanolic solutions failed, probably due to strong H-bonding. Similarly as with phenoxazines, the cyclization smoothly proceeded in DMSO to give low yield (31%) of 1,9-diazaphenoxazine (195) (Scheme 30) (74CC878, 76JHC107, 77H391). 

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>. 

Chloro-2-hydroxypyridine-3-carboxylate is a terminal metabolite in the degradation of 3-chloroquinoline-8-carboxylate, but can be degraded by Mycobacterium sp. strain BA to chlorofumarate by reactions analogous to those described above for pyridine carboxylates (Figure 10.18) (Tibbies et al. 1989a). 

Condensation of aminopyrazole 116 with ethoxy-methylene malonic ester gives the product of addition-elimination (117), which is then cyclized to the piperidone by heating in diphenyl ether. The product tautomerizes spontaneously to the hydroxypyridine 118. The hydroxyl group is then converted to the chloro derivative by means of phosphorus oxychloride (119). Displacement of halogen by n-butylamine gives... 

From pyridin-2-one-6-chloro-2-hydroxypyridine complex. b <72AX(B)3405>. c<7iAX(B)i20i). d(53AX59i). 

Beak has measured the UV spectra of 2- (0.4) and 4-hydroxypyridine (<0.1), 6-chloro-2-hydroxypyridine (0.05), 2- (<0.1) and 4-mercaptopyridine (<0.1) and acridin-5-one (>10) (73JA1700, 76JA171). A heated cell was employed with vacuum jacketed windows, over the temperature range 120-140 °C. It was thus demonstrated that these compounds exist predominantly in the form named above (the figure in brackets after each name gives the value of Kt = [NH]/[OH], or [NH]/[SH]), using the methylated compounds as model chromophores. 

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... 

Similar general procedures have been used to prepare azetidines. For instance, the sulfamidate 156 on treatment with 2-chloro-5-hydroxypyridine in the presence of sodium hydride gave the azetidine 157 <2005BML1637>. 

The hydroxymethyl derivative of 2-azabicyclo[2.2.0]hexane 199 (R = H) has been converted into the 2-chloropyr-idin-5-yl ether 199 (R = 2-CIG5H3N) by Mitsunobu reaction with 2-chloro-5-hydroxypyridine <2000T9227>. 

Conversion of 2-hydroxypyridines to 2-chloropyridines has been effected using triphenylphosphine and NCS <1999TL7477, 2001HCA1112>. Interestingly, 5-nitropyridine-2-sulfonic acid is converted to 2-chloro-5-nitropyr-idine in 87% yield when treated with phosphorus pentachloride (Equation 41). This reaction provides a new pathway to chloronitropyridines <20030BC2710>. 

The intermediacy of a cation, formed by electron transfer within a photochemically created radical pair, was also invoked to explain the results obtained upon photolysis of 2-bromo-, 2-chloro- and 2-iodopyridine in methanol, ethanol and acetonitrile-water376. The major products are 2-methoxypyridine, 2-ethoxypyridine and 2-acetamidopyridine + 2-hydroxypyridine. In all cases pyridine was the minor reaction product, in contrast with the 3- and 4-halopyridines which produce pyridine exclusively, via a radical process. It is proposed that the unshared electron pair on the nitrogen atom assists in the formation of the 2-pyridyl cation. The presence of cupric salts increases the relative amounts of products formed via ionic reactions because Cu2+ can accept an electron from the 2-pyridyl radical. 

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). 

Azine approach. The parent cation and substituted derivatives are available by acid-catalyzed cyclization of 2-/3-oxoalkylthiopyridines (401) using an acid such as sulfuric, phosphoric or PPA. Chloro or nitro substituents in the pyridine ring do not seriously interfere (66JHC27). The cyclization of 3-hydroxypyridine analogues (402) is also at the nitrogen to yield the thiazole derivatives. The cyclization, however, is sensitive to the peri interaction between 3- and 5-substituents. In 3,5-dimethyl derivatives (403 R2 = R3 = Me) the steric repulsion is apparent by the unusually low field signals for the methyl protons <81H(15)1349>. 

Different tautomeric species (e.g., 6-chloro-2-pyridone/6-chloro-2-hydroxypyridine). 

Yields in nitration of alkoxy- and hydroxypyridines have been tabulated (70RCR627). Nitration of 3-hydroxypyridine (9.74) gives 74% 2- and only 1% 6-substitution with no 4-substitution detected (68JOC478) this result was confirmed and shown to be qualitatively consistent with charge densities (69BAU1452). If, however, the 2-position is blocked with a methyl or chloro substituent (9.75), then both 4- and 6-substitution occur,... 

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