4-Alkoxypyridine

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). 

In spite of the low nucleofiigal tendency of the NO2 group, nucleophilic substitution can be carried out on 78, e.g. alcoholates give rise to 4-alkoxypyridine-l-oxide 80. Deoxygenation of 78 with PCI3 furnishes 4-nitropyridine 81, and its catalytic reduction with H2/Pd-C yields first 4-aminopyridine-l-oxide and finally 4-aminopyridine 79. The pyridines 79 and 81 are not accessible by direct substitution reactions of pyridine. 

Alkoxypyridines rearrange at elevated temperatures to A -alkyl.4-pyndones. Isomerizations of this kind are catalyzed by acids and alkyl halides. Spinner and White, however, have prepared 4-methoxypyridine from 4-chloropyridine and sodium methoxide in 86% yield through temperature control and by neutralization of the reaction mixture with solid carbon dioxide. 2-(3,5-Dinitro-2-pyridyl)pyridinium chloride (XII-367), formed from 3,5-di-nitro-2-chloropyridine and pyridine in benzene or ether, is readily hydrolyzed in an alkaline medium to 3,5-dinitro-2-pyridone. ... 

Regardless of the low nucleofugal potential of the NO2 group, S Ar reactions can be carried out on 86 for example, alcoholates give 4-alkoxypyridine-N-oxides 89. Deoxygenation of 86 with PCI3 furnishes 4-nitropyridine, and catalytic reduction with H2/Pd-C in EtOH yields 4-aminopyridine-N-oxide (88), in H2O/HCI 4-aminopyridine (87). 

Many 4-alkoxypyridines, e.g. (410), and their corresponding iV-methyl-4-alkoxypyridinium iodides (411) have been prepared and pyrolysed at temperatures less than 185 °C to give olefins derived from the alkyl moiety. The alkoxypyridines are obtained by reaction of the alkoxide with 4-chloro-pyridine. However, synthetically, the reaction suffers from a lack of stereospecificity and carbonium ion rearrangement products may be obtained. ... 

For 3- and 4-substituted pyridines there is a linear relationship between pKa (in water) and log Aj2 for the quaternization reaction in nitrobenzene or nitromethane. In the second case, 4-alkoxypyridines deviate from the relationship, probably because of the weakly basic ether function and the acidic character of the solvent. The linear relationship enables approximate activation energies for 2-substituted pyridines to be calculated. The difference between the measured activation energy and that calculated AE in-creases 54 with the size of the 2-substituent and of the alkyl halide molecule Table 5.18). 

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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