Lukes reduction

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. 

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... 

The LukeS reduction of 1-methylpyridinium bromide affords a 76% yield of a 1 1 mixture of l-methyl-3-piperideine (79) and 1-methyl-piperidine.81... 

In Lukes reductions of quaternary salts of pyridine homologs, the ratio of the tetrahydro to the hexahydro product is strongly dependent of the position and bulkiness of the substituent on the pyridine ring. Only the tetrahydro base is obtained from 4-methylpyridine metho-bromide.83 On the other hand, both the tetrahydro and hexahydro bases (in the ratio 1 1) result from the reduction of 3-methylpyridine methobromide.82 The LukeS reductions of 2-methylpyridine metho-bromide and 2,6-dimethylpyridine methobromide (80) are accompanied by formation of by-products (81-83) due to reductive cleavage... 

Only hexahydro bases were isolated in the LukeS reduction of l-methyl-3,2 -dipyridylium bromide90 (84) and l-phenyl-3-hydroxy-pyridinium chloride (85).89... 

The Lukes reduction of l-(ethoxycarbonylmethyl)pyridinium bromide (86, R = H) and l-(l-ethoxycarbonylethyl)pyridinium bromide (86, R = Me) was accompanied by decarboxylation mixtures of the appropriate 1-methyl- or 1-ethyl-piperidine and 3-piperideine were obtained.92... 

Decarboxylations occurred also in the LukeS reduction of the methyl betaines of picolinic and nicotinic acids. Thus, both homarine (87) and trigonelline (88) afforded a mixture of l-methyl-3-piperideine and 1-methylpiperidine.91... 

In contrast, the LukeS reduction of isonicotinic acid methyl betaine (89) afforded 1-methylisonipecotinic acid.91... 

The methyl betaines of 3-(2-pyridyl)acrylic acid (90) and 3-(4-pyridyl)acrylic acid (91) behave slightly differently on Lukes reduction. A piperidine derivative results in the former case (90), and a... 

Cervinka and Kriz95 investigated the mechanism of the Luke reduction with the use of deuteriated formic acid. 1-Methylpyridinium iodide afforded a mixture of l-methyl-5-deuterio-3-piperideine (92, R = H) and l-methyl-3,5-dideuteriopiperidine (93, R = H). A mixture containing l,3-dimethyl-3,5-dideuteriopiperidine (93, R = Me) was obtained from 1,3-dimethylpyridinium iodide. 

The reduction of pyridinium species with formic acid in the presence of its salts at elevated temperatures is often referred to as Lukes reduction and has been reviewed. Mixtures of tetrahydropyridines (98) and piperidines (99 Scheme 20) commonly result. The isolated double bond is resistant to further reduction under these conditions. Reductive cleavage and subsequent cyclization have also been observed, producing ketones as by-products. ... 

The remaining major method for the reduction of the C=N+ functionality is the reaction with formic acid. The first report was that of Luke , who found (95) that thermal cleavage of l,l-dimethyl-2-methylenepyrrolidinium formate was accompanied by reduction. Lukes then explored the generality... 

That the reduction with formic acid proceeds by a hydride transfer reaction was proposed by Lukes and Ji2ba 100) and finally proven by Leonard and Sauers 63). The use of variously deuterated formic acid allowed Leonard and Sauers to determine that (1) protonation or... 

This method has been used for the reduction of l-methyl-2-alkyl-.d -pyrrolinium and l-methyl-2-alkyl-.d -piperideinium salts by Lukes et al. (42,249-251) and for the reduction of more complex bases containing the dehydroquinolizidine skeleton by Leonard et al. (252). The formic add reduction may be satisfactorily explained by addition of a hydride ion, or an equivalent particle formed from the formate anion, to the -carbon atom of the enamine (253), as shown in Scheme 13. 

By analogy with the reduction of nickel salts with borohydride ion, a mechanism involving hydride, or H, ions as the purported reducing species was advanced by Hersch [41] and elaborated on by Lukes [42], and is shown here in part for acidic solutions ... 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

Reduction of both the free bases and their quaternary salts proceeds by similar mechanisms. In pyridine and its quaternary salts, a hydride ion, or its equivalent, attacks a position of a low electron density, i.e. the 2- or 4-position. The mechanism of the reduction of quaternary salts of pyridine and its homologs (LukeS and Ferles414) has been elucidated using deuterated formic acid.415 The hydride ion attack in position 2 is followed by addition of a proton to the enamine grouping with the formation of A 3-piperideines (124). If the reduction commences with attack in the 4-position, a saturated base (125) is the final product. In agreement, a-picoline methobromide yields 1,2-dimethyl-... 

Substitutions of amino acid residues in two positions of this contact, a-92-Arg and a-95-Pro, have been observed in five variants. Four of these variants (Hb-St. Luke s has not been analyzed) have an increased affinity for molecular oxygen which is particularly evident for the variants Hb-Chesapeake and Hb-J-Capetown. Erythrocytosis is a common feature in carriers of these abnormalities. The oxy derivatives of the hemoglobins G-Georgia and Rampa are completely dissociated into dimers, and association into tetramers is observed when the oxygen is removed (S53). Such a phenomenon is not as evident for the Hb-St. Luke s variant (H38). Reduction in the heme-heme interaction, a common finding in these variants, can be explained by an increased dissociation of the oxy derivatives. 

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