Pyridines Ladenburg

Piperideines unsubstituted at the nitrogen atom may be prepared from the corresponding pyridine compounds by partial reduction with sodium and boiling alcohols (the Ladenburg reduction), by electrolytic reduction, or, preferably, by reduction with aluminum hydride. l-Alkyl-3-piperideines are prepared by reduction of quaternary pyridinium salts with formic acid (the Lukes reduction) or with complex hydrides. 

The Ladenburg reduction of 3-methylpyridine,47 4-methyl-pyridine,47 4-ethylpyridine,48 and 2-methyl-5-ethylpyridine48 was... 

Two 3-piperideines (63 and 64) and two piperidines (cis and trans isomers) are obtained by the Ladenburg reduction of 4-ethyl-3-methyl-pyridine, whereas only one tetrahydro base, namely, 4,6-dimethyl-3-piperideine (65), results from 2,4-dimethylpyridine, in addition to the piperidines.48... 

The aluminum hydride reduction of pyridine bases is very advantageous in the preparation of 3-piperideines since the amount of the corresponding accompanying hexahydro bases is small. The resulting tetrahydropyridines possess the same constitution as those obtained by the electrolytic or Ladenburg reduction (see Table III). 

Reduction of quaternary pyridinium halides (or, more precisely, formates) with formic acid in the presence of potassium formate at about 150°C is usually referred to as the Lukes reduction.80-95 Instead of potassium formate, triethylamine may be used, especially with quaternary pyridinium iodides.85,86 Mixtures of l-alkyl-3-piperideines (77) and 1-alkylpiperidines (78) are usually obtained. Formation of piperideines (77) might be explained by analogy with the Ladenburg reduction of pyridine bases the double bond at position 3 is resistant toward further reduction by formic acid or by... 

Conine is also of especial interest because it is the first natural alkaloid to have been made synthetically. In 1886 Ladenburg prepared it from a//>/fa-picoline which is alpha-m hy pyridine. By condensing this with acetaldehyde he obtained alpha-dXLy pyridine and by reduction this yielded the corresponding saturated compound, viz., alpha-yroyyl piperidine. This proved to be inactive conine and from it the dextro and levo isomers were obtained. The dextro conine thus prepared is identical with the natural alkaloid of hemlock. The reactions are as follows ... 

Ladenburg s preparation of piperidine from pyridine14 will be described as an example Pyridine (20 g) in anhydrous ethanol (150 g) is placed in a round-bottomed flask under a reflux condenser and warmed on the water-bath. Then sodium pieces (75 g) are added not too slowly. As soon as the reaction slackens or sodium ethoxide separates, more ethanol is added and the reaction is brought to conclusion as fast as possible. When all the sodium has been consumed, the mixture is allowed to cool, treated with an equal volume of water, and distilled in steam. The distillate is neutralized with hydrochloric acid and evaporated to dryness. Piperidine hydrochloride is obtained as residue in almost quantitative yield and can be recrystallized from ethanol. 

LADENBURG Pyridine Benzylation Cu catalyzed a- and y-benzylation of pyridine. 

Finally, pyridine derivatives can be reduced by metals. Piperidine is obtained from pyridine with sodium in alcohols Ladenburg reaction) piperidines, as well as tetrahydropyridines, are obtained from 4-alkylpyridines. A -Alkylpyridinium ions are converted into 7V-alkylpiperidines by metals such as Zn or Sn in an acidic medium, or by electrochemical reduction (122 - 125, see p 293). 

Reduction of pyridine derivatives can be accomphshed by metals. Sodium in alcohol solvents reduces pyridine to piperidine (Ladenburg reaction), and N-alkylpyridinium ions are converted to N-alkylpiperidines by metals (such as Sn or Zn) in acidic medium or by electrochemical reduction. 

Ladenburg reaction, of pyridine 367 Larock synthesis (isoquinoline) 416 Lautens synthesis (indole) 141... 

Ladenburg 38 described the reduction of pyridine and some of its homologues to piperidines by sodium and alcohol, and the method has occasionally been used for this purpose it is useful with pyridine-carboxylic acids and their side-chain vinylogues which give piperidine-carboxylic acidsi 40 Esters of pyridine-carboxylic and vinylogous side-chain acids give the fully saturated alcohols. ... 

Carbonyl reactions— Their aldol reactions with carbonyl compounds are perhaps the most important undergone by primary or secondary alkyl groups attached to the pyridine ring. Ladenburg first observed the reaction of 2-picoline with paraldehyde, which gave, at 250 -260 , 2-propenylpyridine. At lower temperatures, a-(2-picolyl)ethanol is formed, but in low yield 3a, 6-4, Formaldehyde is more reactive. jS-(2-Pyridyl)ethanol has been prepared by heating 2-picoline and formalin or formaldehyde under pressure and this reaction and that with 4-picoline has... 

The use of pyrido[2,3-fc]pyrazin-3(47/)-ones 95 instead of quinoxalinones 37 in the rearrangement considered here makes it possible to synthesize aza-analogues of benzimidazoles-lT7-imidazo[4,5-Z7]pyridines 96 which are not easily accessible by classical Phillips-Ladenburg (Ladenburg 1875 Phillips 1928a, b Ogg and Bergstrom 1931 Preston 1974 Hudkins 1995 White et al. 2000) and Weidenhagen (1936) (Tollari et al. 1994 White et al. 2000 Beaulieu et al. 2003 Kim et al. 2002 ... 

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