Alkylpyridines aldehydes

Mills and Smith (504) were the first, in 1922, to develop a systematic study of the reactivity of methyl groups fixed on nitrogen-containing heterocycles. While in alkylpyridines the 2- (or 6) and 4-positions are activated, only the 2-position in thiazole corresponds to an enhanced reactivity of the methyl groups in condensation with aldehydes 4- and 5-methylthiazoles bear inert methyl groups. Quatemization of the thiazole nitrogen enhances still further the reactivity of the methyl in the 2-position (cf. Chapter IX), but it does not increase the reactivity of a methyl group in the 4-position (504). The authors invoke the possibility for 2- (and 6) methylpyridine and 2-methylthiazole to pass, to some extent, into the reactive enamine form (245), while 4-methylthiazole could adopt such a structure only with the participation of an unusual formula such as 247 (Scheme 112). 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

The products of coupling of alkylpyridines with ketones follows the same course as for pyridine itself except that the relative position of substitution is now of interest.37,39,398 Coupling seemed to take place preferentially in the 2-or 6-position but would also occur in the 4-position, especially when both the 2- and 6-positions were blocked with alkyl groups (Scheme 7) (Table III). Hydrocoupling with aldehydes was also studied.39,398... 

Very little work has been done on selectivity in anodic reactions of pyridines. Selective methoxylation and acetoxylation are known for al-kylbenzenes, but such reactions have not been reported for alkylpyridines. Also, reports on the oxidation of pyridines having aldehyde, ketone, halogen, hydroxyalkyl, or aminoalkyl functionalities are sparse. 

Reaction of dihydropyridine 378 with aldehydes like 379 involves C(3) atom [322], but the treatment is more complicated and can lead to further transformations resulting in the formation of 3-alkylpyridines 380 (Scheme 3.100). 

Many 2-alkylpyridines were isolated and identified in roasted lamb fat (45). 2-Alkylpyridines were proposed to form from the corresponding unsaturated n-fatty aldehyde reacting with ammonia upon heat treatment. Ammonia, arising from glycine, can react with nonanal, arising from beef fat, produced 2-butylpyridine in a beef fat/glycine browning model system (6). The same phenomenon was observed in the formation of 2-pentylpyridine from 1-decanal. Maltol produced 2-ethyl-3-hydroxy-6-methylpyridine as a major product in a reaction with ammonia (12). 

A novel method for the synthesis of 2-alkylpyridines and 2-pyridine-carbinols starts from pyridine and involves the pyridine Reissert analog 175. Anion formation with sodium hydride and alkylation with alkyl halides afford the 2-alkyl-l-ethoxycarbonyl-2-cyano-1,2-dihydropyridines 176, which on heating with HMPT/Nal (HMPT = hexamethylphosphorous triamide) give 2-alkylpyridines 177. Condensation of the anion with benzaldehyde or o-tolualdehyde leads to 2-pyridinecarbinols (85CI(L)125). The reaction of 1,4-bis(trimethylsilyl)-1,4-dihydropyridine (178) with aldehydes (and ketones) in... 

A pathway leading to the formation of pyridines by aldolization of aldehydes, reaction with ammonia and intramolecular cyclization has been proposed by Vernin (1981). Mottram (1991) explained the formation of 2-alkylpyridines by reaction of ammonia on dienals. 

A number of publications also describe the air oxidation of the same pyridine substrates in the presence of cupric nitrate. Extensive work has also been reported on the fixed or fluidized bed vapor phase of alkylpyridines using vanadium catalysts. " The intermediate aldehydes can be isolated, but usually the conditions are set to minimize this side reaction. Vanadates, molybdates, and tin salts of these two oxyacids are also described as efTective catalysts in the high temperature oxidation of quinolines and isoquinolines. " ... 

In the laboratory, selenium dioxide in organic solvents is a good reagent for the oxidation of alkylpyridines to carboxylic acids. " The intermediate aldehydes can be obtained depending on the position of the alkyl side-chain and the substrate/Se02 ratio. The reaction is selective in the case of 5-ethynyl-2-methylpyridine (X-S9) yielding 5-ethynyl-2-picolinic acid in 40% yield. ... 

Oxidation and dehydrogenation— The oxidation of alkylpyridines has been extensively studied for two main purposes. Early workers used oxidation in proving the structures of both alkylpyridines and the pyridine-carboxylic acids. Oxidation for the purpose of producing pyridine-carboxylic acids remains a major aim, particularly because of the importance of nicotinic acid. Only recently have methods been devised for oxidizing alkylpyridines to pyridine aldehydes. 

The introduction of vapour-phase oxidation of alkylpyridines over vanadium and molybdenum oxides in 1951 made pyridine aldehydes and dialdehydes technically available 2< 278d, With a deficiency of air, pyridoins result 4 > 278e, 294 with a sufficiency, aldehydes result (3-methyl groups are oxidized, but pyridine-3-aldehyde does not appear to have been made by this method 278e, 295) and with an excess, the carboxylic acids, including nicotinic acid, and pyridines are formed by decarboxylation , 296-7, Vapour-phase oxidation in presence of ammonia gives nitriles and pyridine-carboxylic acid amides278/, 296,... 

An alternate route to styrylpyridinium polymers [30] uses sulfonate esters of polyvinyl alcohol which are quaternized with alkylpyridines. The quaternary salts are then caused to react with various aldehydes. 

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