3-Alkylpyridines

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. 

A further consequence of the stabilisation of carbanionic centres at pyridine a- and 7-positions is the facility with which vinylpyridines, and alkynylpyridines, add nucleophiles, in Michael-like processes (mercury-catalysed hydration goes in the opposite sense ). Complimentarily, pyridin-2-yl- and 4-ylethyl esters, sulfides or sulfones can serve as protecting groups, being readily and mildly removed by pyridine nitrogen quaternisation (iodomethane), causing elimination of the vinylpyridinium salt.  

In considering reactions of side-chain halides, it is significant that calculations, supported by mass spectroscopic measurements, showed that pyridyl-2-cations are stabilised significantly by overlap with the coplanar nitrogen lone pair.  

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 

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The value of d obtained by linear regression is 0.96 with a correlation coefficient of 0.9985. For 2 alkylpyridines 8 is 2.030 (256), which leads to the conclusion that 2-alkylpyridines are twice as sensitive to steric effects as their thiazole analogs. 

C-Acylation imidazoles in, 1, 463 ortiio-Acylation 2-alkylpyridines, 1, 436 Acylimines... 

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. 

By gas-liquid chromatography analysis. In all reactions, 2-alkylpyridine was not obtained. 

The hydrochlorides and methiodides of a number of 2-alkylpyridines [Eq.(ll), where R = C H2n+i] have been examined for their effect on aqueous surface tension and for their antibacterial properties. 

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). 

The results of some of the many aminations of pyridine and its derivatives that have been carried out appear in Table 14. Yields are quoted where possible but these should not be used for quantitative comparisons as reaction and work up conditions vary widely. 2-Alkylpyridines aminate at the vacant a-position, except when the substituent is very large. 2-f-Butylpyridine does not undergo the Chichibabin reaction, probably because the bulky 2-f-butyl group prevents adsorption on to the sodamide surface. In contrast, 2-phenylpyridine undergoes amination in very good yield. Aminations of 2- and 4-methyl-pyridines do not involve attack on the anhydrobases in aprotic solvents, but some ionization does take place in liquid ammonia. 4-Benzylpyridine forms a carbanion (148) which is only aminated with difficulty by a second mole of sodamide (equation 103). 

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 general process is shown in equation (3). The L unit in the [Cr(CO)3L3] can be CO (most common),15"20 MeCN,21 22 2-alkylpyridine,23 ammonia24-27 and other donor ligands. The rate (reaction temperature) is related to the nature of L the most reactive readily available source of Cr(CO)3 is [(q6-naphthalene)Cr(CO)3], which undergoes favorable arene exchange under mild conditions with many... 

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. RLi and RMgX both add selectively to pyridines to form 1,2-dihydro-2-alkylpyridines. A number of organometallic reagents add to N-ethoxycar-bonylpyridinium chloride (1) to give a mixture of 1,4- and 1,2-dihydropyridine derivatives (equation I). The most efficient and also selective reactions are shown by n-BuCu and n-BuCu BF3. The products are oxidized to the desired 4-alkylpyridines in 40 70% yield when stirred undcra stream of oxygen.17... 

Many 2-alkylpyridines were isolated and identified in roasted lamb fat (45). 2-Alkylpyridines were proposed to form from the corresponding unsaturated n-fatty aldehyde reacting with ammonia upon heat treatment. Ammonia, arising from glycine, can react with nonanal, arising from beef fat, produced 2-butylpyridine in a beef fat/glycine browning model system (6). The same phenomenon was observed in the formation of 2-pentylpyridine from 1-decanal. Maltol produced 2-ethyl-3-hydroxy-6-methylpyridine as a major product in a reaction with ammonia (12). 

R)-l-(3-pyridyl)propan-l-ol in 70% yield and greater than 99% ee (Equation 33). 2-Alkylpyridines undergo some ring hydroxylation and this mode of oxidation predominates with 4-alkylpyridines. 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

These quaternization rate constants of 2-alkylpyridines (Me—r-butyl) were correlated by Taft (53JA4538) with the steric parameters Es. 

For describing the nucleophilicity of 2-alkylpyridines, Popov and Gelbina (770R145) proposed ortho-steric parameters N, but values given were limited to the a-alkyl series where good correlations are usually observed. 

Fig. 3. Plot of log (fe/JfcMe) in quaternization of 2-alkylpyridines in MeOH vs, , (78AP650).

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

When R2 is a tetrahedral substituent, the situation is more diverse but can be analyzed simply. In Section II, the steric effect of an alkyl group was analyzed by the quaternization reactions of 2-alkylpyridines. The conformational state of an isopropyl group attached to a planar framework was depicted in Section III. 

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. 

And 2-Alkylpyridine with Diolefins, Styrenes, and Vinylpyridines. The reaction of alkylpyridines with isoprene, styrenes, and vinylpyridines occurs at 0-25°. The yields of adducts are high, and the compounds formed are those predicted from similar reactions made with alkylbenzenes (30). 

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). 

Optically active 0-benzoylatrolactic acid and its methyl ester were reduced to 2-phenylpropionic acids with almost complete loss of optical activity [392]. On the other hand, Nonaka and coworkers [393] found that l-(2-pyridyl)alkanols were reduced to 2-alkylpyridines with configurational retention in acidic medium l-(4-pyridyl)alkanols gave racemic 4-alkylpyridines. The stereochemical course was discussed considering perpendicular adsorption of pyridylalkanol molecules on the cathode and the configurational stability of carbanion intermediates. 

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