Alkylpyridines acidity

Preston, J. S. du Preez, A. C. Separation of nickel and calcium by solvent extraction using mixtures of carboxylic acids and alkylpyridines. Hydrometallurgy 2000, 58, 239-250. 

The cyclization of diethyl iV-substituted N-(6-alkyl-2-pyridyl)amino-methylenemalonates (265, R2 = Et) in polyphosphoric acid at 200-230°C for 10 min gave 1-substituted 7-alkyl- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acids (1022, R = Me, Et R1 = alkyl R2 = H) in 17-56% yields (71GEP2108046). From the mother liquor, 2-(substituted amino)-6-alkylpyridines could be recovered. 

Hydroxymethylpyridines are reduced directly to alkylpyridines in the presence of samarium diiodide <99TL8823>. The electroreduction of pyridinedicarboxylic acid derivatives to 1 -and 1,4-dihydropyridines has been achieved in good yield <99TL8587>. 

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. 

In the absence of the strong acid a different course ensues. The acetate ion attacks the A-acyloxypyridinium cation (127) at the a-position and elimination of acetic acid gives the product, 2-acetoxypyridine (128 Scheme 116) (65T1971,63JA958). The course of the reaction under these conditions with 2- and 4-alkylpyridine A-oxides has been discussed earlier (Section 2.06.3.1). 

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... 

Selective o/t/io-acylation and orrfio-formylation of 2-alkyl pyridines is possible by [2,3] sigmatropic rearrangement (Sommelet-Hauser) of a-pyrrolidinyl-2-alkylpyridine sulfonates (268), prepared by treating the parent base with cyanomethyl benzenesulfonate (76JOC2658). Acid hydrolysis of the rearranged product (269 R = H) yields 3-formyl-2-methylpyridine (270). Methylation of (269 R = H) using NaH-Mel and acid hydrolysis of the reaction mixture gives 3-acetyl-2-methylpyridine (270 R = Me). 

The larger part of the work on ketones concerns the reduction of the isomeric acetylpyridines (48). The products were the carbinols (49) and pina-cols (50) (Scheme 17) there are no reports of alkylpyridine products, as were seen in carbinol reductions (see Section II,D). In acidic media, reduction of 2-(48) gave almost exclusively 2-(49) and little dimer.69 What dimer was formed was mostly meso and the proportion of it increased as pH increased. 

Anodic oxidation of alkylpyridines to pyridinecarboxylic acids is an old but viable synthetic procedure, usually giving the desired product in reasonable yield. In contrast to catalytic air oxidation, which works best for making... 

Isocinchomeronic (135) and lutidinic (136) acids have also been prepared by similar methods.203-205 One of the earliest attempts to oxidize alkylpyridines... 

A recent patent describes selective oxidations on certain alkylpyridines.206 For instance, oxidation of the isomeric ethylpyridines gave the isomeric acetylpyridines (137) in reasonable yields (Scheme 45). The carboxylic acid was always a co-product. Certain of the dimethylpyridines (138,20) were oxidized... 

Stamicarbon217> claims the use of anion exchange membranes in divided cells for the electrochemical oxidation of alkylpyridines to the corresponding pyridinecarboxylic acids. Finally, Takeda 218) has used the principle of paired synthesis in a divided cell for the simultaneous generation of synthetic intermediates. 

Fig. 6. Relative strengths of pyridine and 2-alkylpyridines with reference acids of increasing steric requirements.

The gas phase acid-catalyzed synthesis of pyridines from formaldehyde, ammonia and an alkanal is a complex reaction sequence, comprising at least two aldol condensations, an imine formation, a cyclization and a dehydrogenation (9). With acetaldehyde as the alkanal, a mixture of pyridine and picolines (methylpyridines) is formed. In comparison with amorphous catalysts, zeolites display superior performance, particularly those with MFI or BEA topology. Because formation of higher alkylpyridines is impeded in the shape-selective environment, the lifetime of zeolites is much improved in comparison with that of amorphous materials. Moreover, the catalytic performance can be enhanced by doping the structure with metals such as Pb, Co or Tl, which assist in the dehydrogenation. 

In an analogous manner, the generation of alkyl radicals in benzene solution by the O-acyl oxime method results in the formation of alkylbenzenes with moderate to good yields for simple acids (equation 55). Use of pyridine as solvent leads to the formation of alkylpyridines as mixtures of ortho, meta and para isomers in which the para isomer predominates. The 0-acyI benzophenone oxime chemistry can also be applied to aryl acids in benzene or pyridine, resulting in the formation of mixed biaryls. A closely related method involves photolysis of mixed anhydrides of arenecarboxylic acids with the hydrox-amic acid A -hydroxy-Z-pyridone in benzene solution (equation 56). 

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. 

And 4-alkylpyridines undergo reaction with ethylene under pressure at 140-1500 in the presence of sodium to form the corresponding 2-n-propyl- and (3-pentyl)-2- and 4-pyridines. Yields of 6-94 of monoethylated products are obtained from higher 2- and 4-alkylpyridines (28). The relative ethylation of 4-alkylpyridines is 3. 5 to 7.0 times greater than that of 2-alkylpyridines, and is associated with greater acidity of the 4 over the 2 isomers. 

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. 

A unique method for preparing 4-alkylpyridines consists in treatment of pyridine with aliphatic anhydrides in the presence of zinc dust. The intermediate l,4-diacyl-l,4-dihydropyridines are not isolated but are further reduced to the 4-alkylpyridlnes by the action of zinc dust and acetic acid. The procedure is illustrated by the synthesis of 4-ethyl-pyridine (38% over-all). ... 

Pyrazole rings are formed from 2-alkylpyridine-Af-imines and acid chlorides under basic conditions. For example, the 1-aminopyridinium salt (336) gives first (337) but this is very reactive and is acetylated under the reaction conditions to (338 Scheme 95) (68JOC3766). The 2-hydroxymethylpyridine (339) shows similar reactions (Scheme 96) (73CPB2146). 

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