Alkylpyridines side chain

Steric effects apparently become important with higher alkylpyridines, especially with the isobutylpyridines, which react only about one-eighth as fast as n-propylpyridines. A side chain having /3-methyl groups may hinder the approach of the ethylene with its jt electrons towards the electrons of the anion (as shown in the diagram, below). 

Pyridinecarboxylic acids also result from the oxidation of alkylpyridines with potassium permanganate (55OS(3)740), nitric acid, and chromium trioxide in sulfuric acid (Scheme 60) (71S31). Alkylquinolines can be oxidized at the side chain with potassium dichromate and sulfuric acid. 

The acidic hydrogen atoms in the side chain of alkylpyridines may interfere with the formation of o-adducts. Thus 4-isopropylpyridine reacts with phenyllithium in THF to yield a mixture of the 2-adduct 90 and l-lithio-4-(2-propyliden)-l,4-dihydropyridine (91). However, alkyllithiums, such as BuLi, (-BuLi, and MeLi, mainly yield the related 2-adducts 92.136... 

The typical reactions of alkyl groups attached to benzenoid rings involve benzyl-type radical intermediates. An azine ring can stabilize a side-chain radical just as can a phenyl ring, and thus most alkylpyridines and azines show these reactions. 

If the side chain is long enough for a McLafferty rearrangement this is the predominant cleavage process (cf. the a-alkylpyridines, (69)—>[70]). 

The mass spectra of only a few 1-alkyl-substituted /J-carbolines have been investigated (Biemann, loc. cit., p. 302). If the side chain is longer than two carbon atoms, the McLafferty rearrangement is the most important degradation process, as for the appropriately substituted a-alkylpyridines and alkylpyrazines, (90)—>-[91]. If the first... 

The picolyl hydrogens of 2- and 4-alkylpyridines are more acidic than the corresponding benzylic hydrogens. For that reason, the reactions of alkylpyridines with olefins occur under mild ccHiditions, and with conjugated dienes, styrenes, and vinylpyridines at below room temperatures. The mechanism of side-chain addition of alkylpyridines to olefins is very similar to that described for alkylbenzenes. 

The general process begins with Cr(CO)3L3, in which the L unit can be CO (most common),MeCN, " o-alkylpyridine, ammonia, and other donor ligands (equation 91). The rate (reaction temperature) is related to the nature of L the most reactive readily available source of Cr(CO)3 is ( ] -naphthalene)Cr(CO)3, which undergoes favorable arene exchange under mild conditions with many substituted arenes. " The most general and convenient procedure employs a mixture of THF and di-n-butyl ether at reflux. " A variety of polar and nonpolar aprotic solvents has been used and, for some purposes such as complexation of a-amino acids with aromatic side chains, water-THF mixtures are effective. 

Chromic acid and potassium permanganate are more powerful oxidizing agents than nitric acid they usually convert all side chains into carboxyl groups. Like benzene homologs, alkylpyridines can also be oxidized, yielding pyridinecarboxylic acids, e.g., isonicotinic acid from 4-ethylpyridine ... 

Alkylpyridines undergo reactions analogous to benzene such as side-chain halogenation and oxidative functionalization (cf. p 291). In addition, C-H bonds directly attached to the heterocycle display a kinetic acidity which is greater by a factor of > 10 compared to the corresponding benzene derivatives. This is more pronounced in the 2- and 4-positions than in the 3-position. H/D-Exchange experiments of 2-, 3- and 4-picoline with a relative exchange rate of 130 1 1810 (MeOD/MeONa at 20°C, cf toluene 10" ) demonstrate this point. 

A-Oxides of 2- and 4-alkylpyridines are functionalized in the side-chain by acylating agents (acid anhydrides, sulfonyl chloride, POCI3). For instance, 2- or 4-picoline-l-oxide with acetic anhydride yields a mixture of acetoxy compounds in which the methyl-substituted products, namely 2- and 4-acetoxymethylpyridine, dominate (87 and 90). Some nuclear-substituted products (88, 89, 91) are also formed ... 

Alkylpyridines can be oxidized to give pyridine carboxylic acids by a number of methods. For instance, nicotinic acid 114 is produced commercially by oxidation of 5-ethyl-2-methylpyridine 115 with HNO3, followed by selective thermal decarboxylation of the dicarboxylic acid 116 [60]. Selective side-chain oxidation is also possible, as shown in the examples 117 and 118 ... 

The oxidation of pyridines to pyridones and the selective oxidation of a side-chain in alkylpyridines and other azines, have been well studied. 

The special properties associated with pyridine a- and 7-positions show again in the reactions of alkylpyridines the protons on alkyl groups at those positions are particularly acidified because the enaminate anions formed are delocalised. The ability to form side-chain anions provides an extremely useful means for the manipulation of a- and 7-side-chains. 

Pyridinium salts show the properties which have been discussed above, but in extreme they are highly resistant to electrophilic substitution but, conversely, nucleophiles add very easily. The hydrogens of a- and 7-alkyl side-chains on pyridinium salts are further acidified compared with the uncharged alkylpyridine. 

More vigorous conditions are required for the amination of 2- or 4-alkylpyridines since proton abstraction from the side-chain by the amide occurs first and ring attack must therefore involve a dianionic intermediate. " Amination of 3-alkylpyridines is regioselective for the 2-position. ... 

The main feature of the reactivity of alkylpyridines is deprotonation of the alkyl group at the carbon adjacent to the ring. Measurements of side-chain-exchange in methanolic sodium methoxide, 4 2 3, 1800 130 1, and of pK values in tetrahydrofuran each have the 7-isomer more acidic than the a-isomer, both being much more acidic than the / -isomer, though the actual carbanion produced in competitive situations can depend on both the counterion and the solvent. Alkyllithiums selectively deprotonate an a-methyl where amide bases produce the... 

The enaminate anions produced by deprotonating a- and 7-alkylpyridines can participate in a wide range of reactions, " being closely analogous to enolate anions. Similar side-chain carbanion formation is seen in ortho- but not me/a-nitrotoluene. Side-chain metallation of 2-/-butylcarbonylamino-4-methylpyridine proceeds at room temperature. ... 

In the quaternary salts of alkylpyridines, the side-chain hydrogens are considerably more acidic and condensations can be brought about under quite mild conditions, the reactive species being an enamine " side-chain deprotonation of 7V-oxides can also be achieved, though it can be complicated by ring deprotonation at C-2. 

The main feature of the reactivity of alkylpyridines is deprotonation of the alkyl group at the carbon adjacent to the ring. Measurements of side-chain-exchange in methanolic sodium methoxide, 4 2 3, 1800 130 and of pK values... 

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. ... 

Pyridine and alkylpyridines are found in coal tar. The monomethyl pyridines (called picolines) undergo side-chain oxidation to carboxylic acids (review Sec. 10.7.b). For example, 3-picoline gives nicotinic acid (or niacin), a vitamin essential in the human diet to prevent the disease pellagra. 

Reductions—Gases of the reduction of pyridine nuclei in which side chains are also saturated have been mentioned. It is possible, however, to saturate the double bonds of alkylpyridines without modifying the nucleus. For this purpose have been used hydriodic acid a also widi phosphorus , sodium amalgam , Raney alloy and alkali , and various forms of catalytic hydrogenation . Benzyl alcoholic potash can evidently reduce stilbazoles (p. 336). 

Dimerization is well known to be a side reaction in the Chichibabin reaction (78RCR1042). In fact, dimerization can be the only product with certain alkylpyridines (79USP4177349 81USP4267335). Under normal Chichibabin conditions, heating a heterogeneous mixture of sodium amide in a hydrocarbon at atmospheric pressure with a branched chain alkylpyridine leads to... 

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