Alkylation of pyridines

The alkylation of pyridine [110-86-1] takes place through nucleophiUc or homolytic substitution because the TT-electron-deficient pyridine nucleus does not allow electrophiUc substitution, eg, Friedel-Crafts alkylation. NucleophiUc substitution, which occurs with alkah or alkaline metal compounds, and free-radical processes are not attractive for commercial appHcations. Commercially, catalytic alkylation processes via homolytic substitution of pyridine rings are important. The catalysts effective for this reaction include boron phosphate, alumina, siHca—alurnina, and Raney nickel (122). 

Few other reactions of series of substituted pyridines have been investigated extensively. Dondoni, Modena, and Todesco have measured the rate of N-oxidation of a limited series of pyridines and found a good correlation with normal u-values with a p-value of — 2.23. The A-alkylation of pyridines with alkyl iodides in nitrobenzene has been studied by Brown and Cahn and by Clarke and Rothwell. Unfortunately, the only data available are for the parent compound and for alkyl derivatives, and, since the a-values for the various alkyl groups in a given position are substantially constant, this leaves a correlation of only three independent points. However, the rates of A-alkylation of the j8- and y-alkyl derivatives are so nearly equal that it appears as if no correlation existed. Clarke and Rothwell have also studied the alkylation with allyl bromide in nitromethane at various temperatures, and in this case a more extensive series is available. The authors state that no overall Hammett correlation is obtained however, the j8-substituted derivatives fall on one straight line and the y-derivatives on another one with a different slope. The data are shown in Fig. 2. The line for the j8-compounds, p = — 2.53 0.31, r = 0.95, is seen not to be very good the line for the y-derivatives, p = — 1.42 0.06, r = 0.99, is much more satisfactory. It does not seem likely that the discrepancy is due to the intervention of resonance effects, since in this case one would expect the correlation for the y-derivatives to be poorer than that for the j8-analogs. More extensive studies with a wider variety of substituents would seem very desirable. 

Naphthalene and other fused ring compounds are so reactive that they react with the catalyst, and therefore tend to give poor yields in Friedel-Crafts alkylation. Heterocyclic rings are also tend to be poor substrates for the reaction. Although some furans and thiophenes have been alkylated, a true alkylation of a pyridine or a quinoline has never been described.However, alkylation of pyridine and other nitrogen heterocycles can be accomplished by a free radical (14-23) and by a nucleophilic method (13-15). 

The rigid, planar pyridine analog 111 was isolated in low yield by first hydrolyzing the known (67) pyridine diethyl phosphonate 109 to the corresponding free acid 110 followed by permanganate oxidation (2). An alternative synthesis of 111 has recently been reported (68). Alkylation of pyridine-2-carboxylate -oxide with dimethylsulfate and subsequent reaction with the sodium salt of diethyl phosphite gave the triester 112, which was readily converted to 111. 

Sometimes the reaction medium is not sufficiently oxidizing to allow the complete rearomatization of the a-complex, which can dimerize. This was observed in the alkylation of pyridine and pyrazine by oxaziri-dines the products (1 and 2) of the dimerization of the a-complex and subsequent oxidation were also formed. ... 

Table 5 Relative Rates of Alkylation of Pyridine Compared with Quinoline and 2-Methyl-...

The Wibaut-Arens procedure (41RTC119) is a useful, but seldom used, method for the 4-alkylation of pyridines. 3,4-Diethylpyridine can be obtained (55% yield) by heating 3-ethylpyridine with iron and acetic anhydride for several hours (Scheme 176) (65JOC3229). 

An indirect 3-alkylation of pyridine [15] is based on accentuation of the donor character of C-3 by reductive dearomatization. 

Pyridyl alkanol [41], diol [42], and ferrocenyl alcohol [43] were the first asymmetric autocatalysts found by Soai and co-workers in the enantioselective alkylation of pyridine-3-carbaldehyde, dialdehyde, and ferrocenecarbaldehyde, respectively, with dialkylzincs. 

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). 

Radical alkylations of pyridines and quinolines preferentially occur at positions 2 and 4. Protonation of the ring nitrogen influences the regioselectivity by favoring C-4 substitution. 

The free radical substitution reactions, other than phenylation, of pyridine and its derivatives have received but scant attention. Alkylation of pyridine itself has been studied briefly, the alkyl radicals being generated either by the thermolysis of diacyl peroxides or of lead tetraacetate in acetic acid, or by electrolysis of the carboxylic acid precursor (for summary, see Norman and Radda369). Most of the available results are summarized in Table XIV. These figures on isomer ratios are not very reliable since the analyses were carried out by... 

Evaluation of steric effects can also be made by separating electronic from steric effects with the help of linear free energy relationship and appropriate parameters. Applications of the Hammett equation to heterocycles have been reviewed (64AHC(3)209 76AHC(20)1) and the influence of substituent effects on the basicity and N-alkylation of pyridines, which have been by far the most widely studied, shows the difficulties in this approach. Jaffe and Jones (64AHC(3)209) reported a good correlation between pKA of 3- and 4-substituted pyridines and Hammett a parameters ([Pg.179]

Fig. 4. Relative rate constants for alkylation of pyridines by ICH3 in CH3CN vs. pK.. O, ortho substituents +, nonortho substituents...

The iV-alkylation which accompanies the hydrogenation of pyridines in alcohols can be utilized for the preparation of iV-alkylpiperidines.22,23 Sawa et al. studied the iV-alkylation of pyridine with alcohols in the presence of... 

Chiral pyridinium-based ionic liquids can be prepared by N-alkylation of pyridines with chloromethyl ()-menthyl ether <2006TA1728>. A room temperature ionic liquid brominating agent is obtained when A- -pcntylpyridinium bromide is reacted with bromine <2004SL1318>. 

Thus many compounds arc obtained (250, Table 24), which may be considered to be derived from C-alkylation of the nucleophilic reagent by the Mannich base. Alkyl ketonic and phenolic bases arc mostly involved in this reaction, which exhibits many analogies with aminomethylation, particularly concerning chemo- and regioselectivity on aromatic and heteroaromatic derivatives. Ring activation by means of hydroxy and amino substituents in the alkylation of pyridine and pyrimidine derivatives is also required. 

Some Aspects of the Direct Alkylation of Pyridine and Methyl Pyridines... 

As a typical example of Method 1, Nishide el al. cross-linked poly(4-vinyl-pyridine) (PVP) with 1,4-dibromobutane (DB) in the presence of metal ions as templates [2-4], The adsorption behaviour of Cu(II), Co(II), Zn(II), Ni(II), Hg(II) and Cd(II) on the obtained resins was studied. The resins preferentially adsorbed the metal ion which had been used as template. PVP was cross-linked by alkylation of pyridine groups in PVP with DB to yield insoluble PVP resins, of which free pyridines were utilised to coordinate metal ions (Scheme 9.2). The stability constant of the Cu(II) complex of the resin was largest for the resin prepared with Cu(II) as template, being due to its large entropy change for the complexation. 

Minisci, F., Gain, R., Malatesta, V., Caronna, T. Nucleophilic character of alkyl radicals. II. Selective alkylation of pyridine, quinoline, and acridine by hydroperoxides and oxaziranes. Tetrahedron 1970, 26,4083-4091. 

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