Reduction of pyridine

Colourless liquid with a characteristic ammo-niacal smell m.p. 9 C, b.p. 106°C. Miscible with water. It is present in pepper as the alkaloid piperine from which it can be obtained by healing with alkali. It can also be prepared by the reduction of pyridine, either electrolytically or by other means. Piperidine is a strong base, behaving like the aliphatic amines. 

The 1,2-dihydro derivative is formed by reduction of pyridine with LiAlH4 (85). Analogous reduction with sodium in 95 % alcohol affords the 1,4-dihydro derivative. Monomeric N-trimethylsilyl-l,2,3,4-tetrahydro (28)... 

Cyclic enamines can also be obtained by the reduction of pyridine and isoquinoline with lithium aluminum hydride (163-165), and the latter reduction has also been accomplished with sodium in liquid ammonia (166). 

Kubota and Miyazaki studied the polarographic reduction of pyridine N-oxides and found a satisfactory correlation with the <7-values. The values increase with increasing pH. 

Figure 4 summarizes the direct oxidative pathway with its relations to (a) the gycolytic route of G-6-P utilization, (b) the reduction of pyridine nucleotides, and (c) the influences on some reactions depending on reduced pyridine nucleotides. 

More detailed reduction of pyridine and its derivatives is given in Schemes 31 and 32 (pp. 55,... 

Electron transfer reduction of pyridines in both acid and alkaline solution generates the protonated radical-anion. This rapidly accepts a further electron and a proton to give a mixture of dihydropyridines. Enamine structures in these dihydro-pyridines can tautomerise to the imine, which is more readily reduced than the original pyridine molecule. Further reaction of the 1,4-dihydropyridine leads to piperidine while reduction of the t, 2-dihydropyridine leads to a tetrahydropyridine in which the alkene group cannot tautomerise to the imine and which is not therefore reduced to the piperidine stage. The reaction sequence is illustrated for 2,6-dimethyl-pyridine 18 which yields the thermodynamically favoured cis-2,6-dimethylpiperidine in which the two alkyl substituents occupy equatorial conformations. 

As in the case of 2,2 -bipyridine, the most important synthetic routes to 4,4 -bipyridine use pyridine as starting material. One method of synthesizing 4,4 -bipyridine from pyridine was discovered by Dimroth in 1921. If pyridine in acetic anhydride is treated with zinc dust, l,l -diacetyl-l,r,4,4 -tetrahydro-4,4 -bipyridine is formed. This compound is readily oxidized and hydrolyzed by moist air to 4,4 -bipyridine. Various oxidizing agents assist in the conversion to 4,4 -bipyridine. By-products from the reaction include 1,1 -diacetyl-l,T-dihydro-4,4 -bipyridine. This method of synthesizing 4,4 -bi-pyridine has frequently been used. ° The reduction of pyridine in acetic anhydride by catalytic hydrogenation instead of by zinc dust is less satisfactory because of the formation of other reduction products. Several variations and improvements in the Dimroth reaction have subsequently... 

Free radical attack at the pyridine ring is noted for its low selectivity and substituents have little effect. Arylation takes place at all three positions, but halogen atoms preferentially attack the a-, and alkyl radicals the a- and y-positions. Metals such as sodium and zinc transfer a single electron to pyridine to form anion radicals. These can dimerize by reaction at the a- or y-position to yield dipyridyls by loss of hydride ion. Thus, reduction of pyridine by chemical and catalytic means is easier than reduction of benzene. 

The reduction of pyridine is known to give a mixture of 1,2- and 1,4-dihydroaIuminate derivatives. Alkylation of this mixture has provided a simple entry into 3-substituted pyridines (Scheme 22) (71JA1294). 

Pyridines are more susceptible to reduction than benzenes. Sodium in ethanol or in liquid ammonia evidently reduces pyridine to 1,4-dihydropyridine (or a tautomer) because hydrolysis of the reaction mixture affords glutaric dialdehyde (318 — 317 — 316). Reduction of pyridines with sodium and ethanol can proceed past the dihydro stages to A3-tetrahydropyridines and piperidines (318 — 319 and 320). 

Electrochemical reduction of pyridines to piperidines can be achieved using various methods. Piperidines can be obtained in high yield by the electrochemical reduction of pyridine on a lead cathode in the presence of carbon dioxide and Pd — Ni or Cu — Ni catalysts (89KFZ1120). In the absence of catalyst, 4,4 -bipyridine was produced as the major product. 

The reduction of ( )-2-, ( )-3- and ( )-4-cinnamoylpyridines by 1,4-dihydropyridines to give dihydro ketones has also been shown to be catalyzed by zinc(II) and magnesium(II).527 Kinetic measurements show that the rate of reduction is fastest in the case of the 2-isomer where the metal is simultaneously complexed with the nitrogen and oxygen donors. A very fast zinc-catalyzed reduction of pyridine-2-carbaldehyde by the alcohol dehydrogenase coenzyme model JV,JV -diethyl-N-benzyl-l,4-dihydronicotinamide (170) has also been described.528... 

Reduction of pyridine by electrolytic methods is the oldest reported industrial process involving pyridine compounds. Merck patented this process in 1896 however, catalytic hydrogenation has supplanted this process for virtually every piperidine manufacturer.8,14,13 The earliest report was by Ahrens, who described a process that others could not repeat.16 Up to 1934 the technology was to use an aqueous sulfuric acid electrolyte and a lead cathode. Many of these reports are conflicting.17-19 The interacting nature of electrochemical variables may be responsible in part for these discrepancies. Thus experimentation by an approach that attempts to hold all but one variable constant is bound to lead to different results depending on where the starting point was chosen or whether an important variable was, or was not,... 

The production of bipyridyls (1) and bipiperidyls (2) was observed on reduction of pyridine. Schering AG has a patent on a process for producing 4,4 -dipyridyls at the cathode of a divided or undivided cell using liquid ammonia as the solvent.26 The same bipyridyl was also formed during electrolysis of bromobenzene in pyridine solvent, using Mg electrodes.27 Bipiperidyls (2) were observed as products of pyridine reduction as early as... 

Only the 2,2 - and 4,4 -bipiperidyl (2) were reported at that time however, later studies report the 2,4 -isomer as one of the products.29 Recent work suggests that acidic reduction of pyridine gives not only 4,4 -bipyridine (1) as well as 2,2 -(l) and bipiperidyl (2), but also the diketone (3).30 The structure of this product is apparently in error because the authors report a carbonyl stretching frequency (1400-1590 cm-1) that is inconsistent with a cyclic ketone. The calculated m/e peaks are incorrect, and the reported fragmentation pattern is unexpected. A better formulation of this material would perhaps be an open-chain structure. 

Few reports on the electrolytic reduction of pyridine mention the isolation of partially reduced products. The only one observed to date has been the 3-piperideine (5). Ferles attributed the presence of 5 to concurrent reduction mechanisms, one which led to this product and the other to piperidine (Scheme 2).3S Thus, if the first-formed intermediate was a 1,4-dihydro product, then full reduction to piperidine occurred, but if the intermediate was a 1,2-dihydro product, then the olefin was formed. The 3-piperideine (5) would not be further reduced under the conditions. The concept of competing pathways at an initial step in the reduction mechanism is probably sound, but the proposal of 1,2- versus 1,4-dihydro intermediates has not been fully substantiated. 

Carboxamides can be cathodically reduced to amines or alcohols, depending on the reaction conditions the reaction is carried out industrially. One example is the reduction of pyridine carboxamides at Reilly 543) ... 

In the reduction of pyridine and quinoline compounds, hydrogenation generally occurs.2... 

The bipyridyl herbicide Paraquat is made by reduction of pyridine to radical ions, which couple at the para positions. Oxidation and reaction with methyl bromide gives paraquat. Diquat is formed by dehydrogenation of pyridine and quaternization with ethylene dibromide. 

Chemical reduction of pyridines can be achieved with hydride, dithionite, dissolving metal reagents, or hydrogenation. The pyridine nucleus can be activated to reduction by conversion to a pyridinium species <1984CHEC(2)165, 1996CHEC-II(5)80>. 

A common and often efficient method for the preparation of saturated piperidines is the catalytic reduction of pyridines, pyridine Ar-oxides, or pyridinium salts <2001CHE797, 2003T2953>. Reduction of the naphthylpyridyl alcohol 188... 

An efficient procedure for the reduction of pyridine iV-oxides to piperidines using ammonium formate and palladium on carbon has been developed (Equation 98) <2001JOC5264>. The reaction conditions are mild and can also be applied to the iV-oxides of quinoline and isoquinoline. 

A variety of new methods for the selective reduction of pyridine Ar-oxides to the corresponding pyridine have been developed. A procedure that is limited to the reduction of relatively electron-rich pyridine Ar-oxides utilizes hexamethyldisilane in the presence of methyllithium in THF/HMPA <1999JOC2211>. This reduction can also be performed on quinoline and isoquinoline Ar-oxides. Tris(2-carboxyethyl)phosphine (TCEP) can be used to... 

Dihydropyridine dianion 42, generated from the Birch reduction of pyridine 41, was found to undergo alkylation only at the 2-position with no 5-substituted products being isolated (Scheme 11) <2001J(P 1)1435, 20000L3861>. 

Dihydropyridines are far more stable than the previously mentioned dihydropyridine isomers and have been used in numerous synthetic transformations. In particular, iV-alkoxycarbonyl-l,2-dihydropyridines, which can be obtained from the Fowler reduction of pyridines, are widely used. The use of phenyl chloroformate rather than ethyl or benzyl chloroformate in the Fowler reduction of 3-substituted pyridines, where the substituent is an electron-withdrawing group, was found to increase the yield and selectivity of the 3-substituted-l,2-dihydropyridine (Scheme 15) <20010L201>. 

B. Reduction of Pyridines and Pyridinium Salts with Lithium... 

The formation of piperidines from the borohydride reduction of pyridine and picoline methiodides has been reported by Ferles.17 He assumed that this complete reduction arose from initial formation of the 1,4-dihydropyridine, and that the ratio of tetrahydropyridine to piperidine represented the ratio of attack of hydride at the 2-position to that at the 4-position. 

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