Alkoxypyridines

Deuterium-labeling and mass spectrometry prove that the mechanism of the thermal O to N rearrangement of 4-alkoxypyridines to N-alkyl-4-pyridones is intermolecular (88CS347). 

While the aforementioned reaction works well for aminopyridines and alkoxypyridines, it is not operative for most electron-deficient pyridines as well as 2- and 4-bromopyridines. One of the possible reasons for its failure with 2-halopyridines is the formation of an unreactive dimer complex from the oxidative addition intermediate [130]. 

The presence of substituents on the pyridine ring, which reduce the basicity of the annular nitrogen atom, not only shifts the pyridone-hydroxypyridine equilibrium towards the hydroxy form [62], but they also inhibit A-alkylation. Thus, for example, 3,5,6-trichloro-2-hydroxypyridine is alkylated preferentially on the oxygen atom. Predictably, alkylation of 3-hydroxypyridine and of 2-amino-3-hydroxypyridine leads to the 3-alkoxypyridines in high yield under basic conditions [63] (see Chapter 3). 

The presence of the enamino moiety in 2-amino-4H-pyrans accoimts for their ability to undergo recyclizations into various pyridones, 1,4-dihy-dropyridines, and 2H-pyrones-2. To some extent, properties of 2-amino-4H-pyrans in reactions with nucleophiles can be compared to those of pyrillium salts (68T5059,80T697) because they also tend to form recyclized products. Reactions proceed in the presence of bases or acids. Naphthopyrans 133 form 2-alkoxypyridines 261 on the action of sodium alcoholates or ethanolic NaOH (79M115) (Scheme 101). 

Very recently, chiral 6-DPPon derivatives, the phospholanes 4b and 5b and the phosphepine 6b, have been prepared and studied as ligands in asymmetric hydrogenation (Figure 2.4) [14]. For comparison, the corresponding 2-alkoxypyridine systems 4a-6a were studied, too. The latter should behave as truly monodentate ligands while the pyridine systems 4b-6b should allow for complementary hydrogenbonding. 

Pyridine (25) readily reacts with cesium fiuoroxysulfate in various solvents at room temperature producing a mixture of up to three products (2-fluoropyridinc, 2-pyridyl fluorosul-fonate and 2-chloro- or 2-alkoxypyridine). whose distribution strongly depends on the solvent used.33... 

Clearly, coordination effects are significant in alkoxypyridine metalation, and the significance of coordination and electron attracting effects are inverted compared to the halopyridines. Using the optimum n-BuLi/ TMEDA/THF/-40°C conditions, a variety of 3-alkoxypyridine derivatives were tested for the synthesis of 2-substituted pyridines. The results of treatment of 291 with a variety of electrophiles to give products 302-305 are summarized in Scheme 91 (82S235). The best case 3-ethoxypyridine, was converted into derivatives 303—305. 

The demonstration that 3-alkoxypyridines are metalated in the 2-position (Scheme 91) (82S235) allowed the preparation of a series of ribo-furanosyl pyridines 565 as potential deazapyrimidine nucleosides for evaluation as thymidylate synthetase inhibitors (Scheme 170) (86MI2). Thus, metalation of the 3-alkoxypyridines 291 followed by condesation at lower temperatures with a protected D-ribose aldehyde afforded diaster-eoisomeric mixtures of compounds 564 which, upon mesylation and acid-catalyzed cyclization, delivered the ribofuranosyl pyridines 565 in high yields. Purification by affinity chromatography afforded the a- and /3-anomers, which showed insignificant antileukemic activity. 

Later Bristol et al.139 have described an improved synthesis of 2-amino-3-alkoxypyridines using PTC, which yielded selectively an O-alkylated derivative without traces of any N-alkylation. 

The sp3 C-H bond adjacent to oxygen in 2-alkoxypyridines undergoes selective oxidation in moderate yield in the presence of catalytic Pd(OAc)2 and stoichiometric amounts of PhI(OAc)2 in dichloromethane <2004JA9542>. Selectivity in this process arises from chelation of Pd(ll) to the pyridine nitrogen. 2-Methoxypyridine undergoes regioselective oxidation to acetal 109 in 66% yield on treatment with 5 mol% Pd(OAc)2 and 1.1 equiv of PhI(OAc)2 in dichloromethane at 100 °C (Equation 74) while -butoxypyridine is oxidized in 44% yield and isopropyloxypyridine is oxidized in 42% yield. 

Alkoxypyridines such as 110 undergo thermally induced rearrangement to /V-alkylpyridones such as 111 under flash vacuum pyrolysis <2003AJC913> (Equation 75). 2-Methoxy-4-methylquinoline and 1-methoxyisoquinoline also undergo rearrangement in 35% and 70% yield, respectively. 

Yields in nitrations of a range of hydroxy- and alkoxypyridine A-oxides have been tabulated (70RCR627) as have the activation parameters for various substituted pyridine N-oxides [67JCS(B)1213, 67JCS(B)1235]. 

Alkoxypyridines appear to be less labile to hydrogenolysis than do 2-alkoxypyridines.50,51 3-Methoxypyridine was hydrogenated to 3-methoxypiperidine in good yield over Raney Ni at 150°C and 15 MPa H2.50 The hydrogenation of... 

Reactions of A/-alkoxypyridines and -azines. Two distinct types of reaction are common ... 

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