Pyridones alkyl halides

O-Alkylation is also favored using more sterically hindered electrophiles such as secondary alkyl halides thus, alkylation of 2-pyridone with isopropyl iodide under mild conditions in the presence of cesium fluoride at room temperature leads to the formation of a mixture of N- and O-alkylated products in a 11 89 ratio <1995SL845>. 

Taking into account that the properties of methiodides obtained from bases 1-methyl-IcP 86 and 3-methyl IcP 288 differ greatly not only from each other but also from the imidazolium salt 242, their structures were assumed to be those of pyridinium salts 235, 236 and 238. On the other hand, iodide 235 and quaternary salts 215 and 235 have similar UV spectra and this suggests their structures are that of A -5-alkyl halides. Samples of chloride 237 obtained by quaternization of 86 and by an alternative procedure from pyridone 243 proved to be identical (78MI4). 

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. ... 

The course of alkylation of 2- and 6-substituted-3-pyridinols is subject 10 a steric effect. Sodium salts of 3-pyridinol in ethanol are N-alkylated by methyl bromo- or iodoacetate. However, 2-bromo-3-pyridinol is N-alkylated by methyl and ethyl iodide in dimethylformamide but is 0-alkylated by haloacetates to XII-563 (Rj = Br, R = H). 2-Bromo-6-methyl-3-pyridinol (XH-562, Rj = Br, R = CH3) is A-alkylated by methyl and ethyl iodide and 6>-alkylated by diazomethane, but reacts with bromoacetic acid in chlorobenzene to give 3-hydroxy-6-methyl-2-pyridone (XII-565), possibly via 2-(a-bromoacetoxy)-6-methyl-3-pyridinol (XII-S64). With 6-methyl-2-methylthio-3-pyridinol (XII-562 Rj = CH3S, R = CH3), A-alkylation should be favored electronically, particularly by electron release by the 2-methylthio group. However, quaternization is difficult even with the simple alkyl halides and only 0-alkylation is observed when methyl iodoacetate is used. ... 

The alkyl halide-catalyzed rearrangement can be extended to reactions where R R and provides a convenient route to A -alkylpyridones as an alternative to direct alkylation. For example, although alkylations of 2-pyridone salts with iS-(6-methoxy-l-naphthyl)ethyl halides (MI-746, R = 6-methoxy-l-naphthyl) appear to be unsuccessfiil, 2-ethoxypyridine and XI-746 [X = Br, R = 1<6-CH30CioH6),C6H5] give the A -arylethyl derivativein good yield. ... 

The chemical reactions of nicotinamide at the ring nitrogen site are t3q>ical, combining with alkyl halides and acids to form quaternary ammonium compounds. Knox and Grossman have reported that ring carbon 6 is the reactive position of the quaternary nicotinamide ring, as evidenced by studies in which oxidation of iVi-methylnicotinamide chloride by a quinine-oxidizing enzyme resulted in i-methyl-3-carboxylamide-6-pyridone. 

The behaviour of 2-alkoxypyridines resembles that of 2-hydroxypyridine when heated with an alkyl halide, they give l-alkyl-2-pyridones, with the loss of the original 0-alkyl group349, 537, 742, 835, 899,... 

Alkylation of the silver salt of pyrid-2-ones usually gives exclusive O-alkylation, whereas alkylation of the sodium or potassium salt gives predominantly TV-alkylation, e.g. Scheme 98. However, the course of such reactions is strongly dependent on conditions. Not only is the nature of the metal salt important but also the structure of the halide, the substituents on the pyridone ring and the solvent used (770PP5,70JOC2517,67JOC4040). 

The carbonyl tautomers deprotonate at N-H, generating ambident anions that can react at either oxygen or nitrogen, depending on the exact conditions for example 0-alkylation can be achieved with silver carbonate. They are converted, as with the pyridones, into halo-quinolines and halo-isoquinolines by reaction with phosphorus halides. 

Diazinones, like pyridones, react with phosphorus halides with overall conversion into halides. Anions produced by A-deprotonation of diazinones are ambident, with phenolate-like resonance contributors, but they generally react with electrophilic alkylating agents at nitrogen, rather than oxygen, giving A-alkyl diazinones. 

As base. The 0-alkylation of tetronic acids and the alkylation of 2-pyridone (at O with primary halides and at N with secondary halides) are mediated by CsF. In each case the displacement of secondary mesylates with carboxylic acids and malonic esters proceeds stereoselectively using CsF as the base, thereby permitting the preparation of chiral substances. 

Similarly, in the reaction of 2-pyridone (31) with benzyl halides 32 in the absence of solvent [52], the classical route gives N-alkylation whereas microwave irradiation... 

MSubstituted-2-pyridones can be used as substrates for ring closure to a number of polyheterocyclic systems, as an alternate to the Pschorr cycliza-tion Of to the cyclizations of the corresponding At-alkyl-2-halopyridinium halides. 2-Substituted pyridines (MI-625 X =C1, Br, OC Hj) and 3-(2-bromo-ethyl)indole give -[2-(3-indolyl)ethyl]-2-substituted pyridinium bromide... 

The most important modification of the reaction between phosphorus halides and 2- or 4-hydroxypyridines is that in which 1-alkyl- or l-aryl-2-or -4-pyridones are used. The reaction is especially valuable in its application to l-alkyl-2-pyridones because of the ready availability of these compounds. Introduced by Fischer 42 it has often been applied ... 

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