Alkylpyridines alkylation

The effect of alkyl groups in the 5-position on the reactivity of the thiazole nitrogen is analogous to that found for 3-alkylpyridines, in other words, a simple inductive effect. In passing from the unsubstituted heterocycle to the methyl derivative, the rate constant doubles a further increase in substitution produces a much less pronounced variation. 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

Methylpyridines (picolines) and dimethylpyridines (lutidines) have prominent m/z 65 and m/z 66 ions in their mass spectra. Aniline can be distinguished from picolines by the m/z 78 ion in the mass spectra of picolines. If the alkyl group. R. is attached to the carbon atom adjacent to the nitrogen atom. RCN can be lost easily. Alkylpyridines are characterized by ions at m/z 65, 66, 78, 92, 106, and so forth. 

A solution of sodamicle in liquid ammonia (essentially the amide NHj ion) is a very powerful alkylation catalyst, enabling condensations to be carried out with ease and in good yield which are otherwise either impossible or pro ceed with difficulty and are accompanied by considerable by-products. Thus 3-alkylpyridines, otherwise inaccessible, are easily prepared from 3-picoline (see 3- -amylpyridine in Section V,20). Also benzyl cyanide (I) and cycZohexyl bromide give a- r/ohexylphenylacetonitrile (II) ... 

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. 

Alkylpyridines have been shown to undergo base-catalyzed alkylations similar to those of alkylbenzenes These compounds are included in... 

The position of the alkyl group on the pyridine ring is very important. 4-Alkylpyridines react readily and much like alkylbenzenes, whereas... 

Competitive ethylations were carried out by using 2- and 4-alkyl-pyridines to study inductive effects. Results of a study on this subject made by Notari and Pines 52) are reported in Table V along with results for alkylbenzenes. The 4-alkylpyridines closely parallel the alkylbenzenes in their relative reaction rates, whereas the 2-alkylpyridines have a different order. A solvation effect of the nitrogen may be the reason. 

Maximum activity in both cases is found with the salts of 2-pentadecyl pyridine (51JCS1263). 2-Alkylpyridines having Cio-Ci8-alkyl chains have attracted some industrial interest as starting materials for further derivation experimental details may be found in Bonnemann and Brijoux (84MI4). 

Nitrosation of 2- and 4-alkylpyridines, their quaternary salts and N-oxides, can be effected with an alkyl nitrite and sodamide in liquid ammonia the product is an oxime (Scheme 54) (69AP494, 65YZ451). 

In a reactivity study conducted by competitive methods, the influence of 3-alkyl groups (Me and Et) has been found to be rather peculiar.135 3-Alkylpyridines are attacked at the adjacent 2-position more easily than pyridine itself in spite of the weak adverse electronic effect of the substituent. However, at the 6-position the attack occurs more slowly, as expected. Of the several possible reasons for this behavior, probably the most likely is the establishment of a weak attractive interaction between the a carbon of the 3-alkyl group and phenyllithium, which would favor orientation for attack at the 2- rather than the 6-position and overcome the small electronic effect of the group. 

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

The above reactions have been illustrated for 2- and 4-alkylpyridines. They generally fail if no heteroatom is a or 7, as in 3-alkylpyridines and 5-alkylpyrimidines. a- and [3-Alkyl groups in pyridine A-oxides are somewhat more reactive than those on the corresponding pyridines. In addition to the reactions already mentioned, 2-picoline 1-oxide undergoes Claisen condensation with ethyl oxalate to yield the pyruvic ester (630) (for the conversion of alkyl substituents in A-oxides into CH,OAc groups see Section 3.2.3.12.5.iv). 

Alkylpyridinium halides give mixtures of alkylpyridines on heating, e.g. (964) gives 2- and 4-picoline, with other minor products. This reaction is known as the Ladenburg rearrangement, and involves /V-alkyl bond homolysis. 

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 products of coupling of alkylpyridines with ketones follows the same course as for pyridine itself except that the relative position of substitution is now of interest.37,39,398 Coupling seemed to take place preferentially in the 2-or 6-position but would also occur in the 4-position, especially when both the 2- and 6-positions were blocked with alkyl groups (Scheme 7) (Table III). Hydrocoupling with aldehydes was also studied.39,398... 

The amide ions are powerful bases and may be used (i) to dehydrohalogenate halo-compounds to alkenes and alkynes, and (ii) to generate reactive anions from terminal acetylenes, and compounds having reactive a-hydrogens (e.g. carbonyl compounds, nitriles, 2-alkylpyridines, etc.) these anions may then be used in a variety of synthetic procedures, e.g. alkylations, reactions with carbonyl components, etc. A further use of the metal amides in liquid ammonia is the formation of other important bases such as sodium triphenylmethide (from sodamide and triphenylmethane). 

Alkylpyridines.3 Highly selective alkylation of pyridine at C4 is possible by quatemization with this triflate followed by reaction with a Grignard reagent. Substitution occurs with almost complete regiospecificity ( > 99%) to give 4-alkyl-l, 4-dihydropyridines, which are oxidized by oxygen to 4-substituted pyridines (equation 1). 

The study of pyridine-piperidine reactions under high pressure conditions has given much information concerning the kinetics of HDN, but these results are however complicated by alkyl transfer (disproportionation) reactions, and thus the possibility of using such reactions as an easy test for determination of mechanism and as a catalyst probe is partly excluded. The study of polycyclic amines (quinoline, etc.) for the same purpose is limited by the complexity and the number of different possible routes, but is a very interesting test reaction for an overall study of catalytic activity or selectivity toward HDN in industrial conditions. Because no disproportionation occurs and the numbers of products and routes are reasonable, the studies of pyridine-piperidine and alkylpyridine-alkylpiperidine HDN under normal H2 pressure and low amine pressure (< lOTorr) are very powerful test reactions both for mechanism determination and catalyst study, although these conditions are far removed from those of industrial practice. 

Under dioxygen-deficient conditions, pyridinium cations can compete with dioxygen in capturing alkyl radicals (Scheme 3). The resulting alkylpyridinium radical cations rapidly rearomatize by means of Fe(III)-induced oxidation to afford alkylpyridines and replenish the pool of Fe(II) sites. Other potential traps of alkyl radicals are Fe(III)—Cl moieties, which are known to effect oxidative chlorination (Eq. 8). 

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