4- Hydroxypyridine, reaction with

Displacement reactions with oxygen nucleophiles are of potential commercial interest. Alkaline hydrolysis provides 2-fluoro-6-hydroxypyridine [55758-32-2], a precursor to 6-fluoropyridyl phosphoms ester insecticides (410—412). Other oxygen nucleophiles such as bisphenol A and hydroquinone have been used to form aryl—pyridine copolymers (413). 

Hydroxypyridine (86, R = H) and its derivatives also belong to the class of heterocyclic enols. In benzene and dioxane, 3-hydroxy-pyridine occurs as the neutral molecule (and not as a betaine).Its reaction with diazomethane, in heterogeneous media, gives a mixture of 3-methoxypyridine (86, R = Me) (10%) and l-methyl-3-hydroxy-pyridinium betaine (87) (30%If tert-butanol is used as a... 

Mixed O, N donor molecules are truly extensive and structurally diverse, and only a few selected examples will be presented. In line with other 2-substituted pyridine analogs reported in this chapter, it is worthwhile noting the chemistry of 2-pyridone (or 2-hydroxypyridine, Hopy), which can form O-bonded monodentate complexes such as Co(Hopy)4(N03)2, but as the monoanion is an effective chelate ligand, forming Co(opy)2 and Co(bpy)(opy)2 compounds.454 An unusual solid state melt reaction with Co(OAc)2 yields the dodecanuclear cluster Co12 (OH)6(OAc)6(opy )12.455... 

Other interesting data in these reactions concern the H/D isotopic effect of the nucleophile/catalyst, for example when [2-hydroxypyridine] = [2 — 02H] = 0.08, fcobsH/ obsD = 1-5. Since a very poor H/D effect is usual in SjvAr reactions with neutral nucleophiles (amines) in apolar solvents10, the authors conclude that the unusually high H/D effect should be due to a difference in the Xh/Xd = 1.75 of the molecular complex. Nevertheless, the same effect could be explained on the basis of an autoassociation of... 

Pyridin-2-one undergoes the Kolbe reaction with carbon dioxide under pressure to give a good yield of the 5-carboxylic acid (60%). Pyridin-4-one also reacts readily to give 3-mono- or 3,5-di-carboxylic acids. The nature of the products derived from a Kolbe reaction with 3-hydroxypyridine is very susceptible to the reaction conditions. This is illustrated by the difference in behaviour of the sodium and potassium salts (equation 56). When the sodium salt is heated rapidly to 280 °C with carbon dioxide at atmospheric pressure the 2-carboxylic acid (8%) is the only product. Under the same conditions the potassium salt gives a mixture of 2- (3%) and 6- (24%) carboxylic acids (75RCR823). 

The palladium/copper-catalyzed coupling reaction of 2-iodo-3-methoxy-6-methylpyridine and terminal alkynes leads to the formation of o-methoxyalkynylpyridines which undergo electrophilic cyclization reactions to afford furo[3,2-3]pyridines in moderate yields <2005JOC10292>. A similar Pd/Cu-catalyzed reaction with hydroxypyridines and trimethylsilyl (TMS)-acetylene leads to the formation of alkynyl pyridines which cyclize to form furo[2,3- ]-pyridines in good yields <1998JME1357>. 

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-... 

Hydroxypyridine undergoes the Kolbe reaction (with carbon dioxide to give the carboxylic acid) the Na salt reacts mainly at the 2-, and the K salt at the 6-position. Uracil undergoes the Reimer-Tiemann reaction with sodium hydroxide/chloroform to give 5-formyluracil. 

A new synthesis leading to a previously unknown 8-substituted indolizine involves initially the formation of the dihydropyridopyranyl ether (81) by reaction between a vinyl ether and a Mannich base obtained from 3-hydroxypyridine treatment with dilute hydrochloric acid... 

Shaver, A., J.B. Ng, D.A. Hall, B. Soo Lum, and B.I. Posner. 1993. Insulin-mimetic peroxo vanadium complexes Preparation and structure of potassium oxodiper-oxo(pyridine-2-carboxylato)vanadate(V), K2[V0(02)2(C5H4NC00)]-2H20, and potassium oxodiperoxo(3-hydroxypyridine-2-carboxylato)vanadate(V), K2[V0(02)2 (0HC4H3NC00)]3H20, and their reactions with cysteine. Inorg. Chem. 32 3109-3113. 

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>. 

Hydroxypyridines are readily alkylated under a variety of conditions. Mitsunobu reaction with alcohols occurs selectively at oxygen in the presence of PPh3 and DEAD in THF at room temperature <2003TL725>. The 3-hydroxy group may be selectively alkylated in the presence of aliphatic hydroxyl groups. Pyridine 104 is alkylated at the aromatic position with dodecyl bromide in the presence of potassium carbonate in DMF at 95 °C <20030BC644> (Equation 70). 

Hydroxypyridine may be allylated by Pd(0)-catalyzed nucleophilic attack of oxygen onto allene <2001T7965>. Reaction with 2 equiv of allene in THF in the presence of Pd(OAc)2 and tris-(2-furyl)phosphine gives 1,3-dienyl ether 105 in 34% yield (Equation 71). This process occurs in similar yield when performed on 3-hydroxyisoquinoline. 

Chlorination of the pyridone (436 R = 4-pyridinyl) with phosphorus oxychloride followed by a reaction with hydrazine gave a low yield of the corresponding 2-amino-3-hydroxypyridine (437). Cyclization of this product was carried out by a reaction with l,r-carbonyldiimidazole in DMF at room temperature to give the oxazolo[4,5-6]pyridine (438 R = 4-pyridinyl) (Scheme 51) <94JMC248>. 

The reaction of 2-acetyl-3-hydroxypyridine (441) with hydroxylamine 0-sulfonic acid afforded a 1 1 mixture of compound (442) and 2-methylisoxazolo[4,5-6]pyridine (443) (Equation (35)) <87H(26)292i). The formation of the oxazolo[4,5-6]pyridine (442) results from a Beckmann rearrangement. The reaction of the oxime (444) with hydroxylamine O-sulfonic acid also gave Beckmann rearrangement products, such as (445) and (446) as a 1 1 mixture (Equation (36)). 

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