Methylation of pyridine

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

Ol. Okuda, Y., Studies on the methylation of pyridine compounds in animal organisms. J. Biochem. (Tokyo) 48, 13-17 (1960). 

Ni-Co ferrites with the general formula Nii cCoxFe204 were tested for the methylation of pyridine [110]. It was observed that the systems possessing x values >0.5 are selective for 3-picoline formation, whereas the ones with x values 0 and 0.2 give a mixture of 2- and 3-picolines. Pyridine conversion increased with the progressive substitution of Ni ions by Co ions. The cation distribution in the spinel lattice influences their acidic and basic properties, and these factors have been considered as helpful to evaluate the activity of the systems. 

Kinetic studies of the 5-methyl analogs 5-methyldibenzothiophenium tetrafluoroborate (72) and 5-methyldiphenylsulfonium tetrafluoroborate (73) were reported. The difference in AS between heterocyclic S —CH3 salt 72 AS = -13.4 eu for ethanolysis) (91JOC1845) and nonheterocyclic S —CH3 salt 73 (A5 = -10.3 eu at 25°C for A-methylation of pyridine-ds) (83TL4859) was small. This is in accord with the conventional 5n2 attack mechanism of a nucleophile on the CH3 carbon along the S—CH3 bond. Thus, the great difference in AS found between heterocyclic S—CF3 salt 17 and nonheterocyclic S —CF3 salt 29 suggests a different reaction mechanism, probably an attack on the S — CF3 bond. 

Free radical substitution of pyridines usually occurs principally at position 2 (Table 25), which is in agreement with theoretical calculations (69CCC1110). 2-Substitution is more favored in methylation than in phenylation of pyridine. This suggests that the methyl has more nucleophilic character than the phenyl radical. Furthermore, methylation of pyridine in acidic solution gives 13-fold excess of 2- over 4-substitution, although the overall yield is low. Alkyl and aryl radicals have been generated from diverse sources (Table 25). 

Substrates 1-3 are readily prepared with a few steps as illustrated in Scheme 4. After methylation of pyridine with dimethyl sulfate, oxidation with potassium ferricyanide in the presence of sodium hydroxide leads... 

A detailed correlation analysis of the N-methylation of pyridines was later carried out by Schaper on a complete series of 83 azines (22-24) (Scheme 16) and diazines (78AP641 78AP650) 3-, 4-, and (or) 5-substituted pyridines 22 give ... 

A new scale of ortho-steric parameters S° was determined by Berg et al, from the N-methylation of pyridines (80JCS(P2)1350). It is based on the fact that all ortho-substituted pyridines fall below the Bronsted line obtained under the same conditions with non-ortho-substituted pyridines (Fig. 4). 

Substituent Rate Factors (Logarithmic Values) from /V-Methylation of Pyridine Derivatives by Methyl Iodide in DMSO to be Used for Predicting the Regioselectivity in Polyazines Quaternization... 

The ortho-steric parameters given in this paragraph are derived from N-methylation of pyridines. The basic set was calculated by the general equation... 

Figure 2. Methylation of pyridines (Numbers on arrows denote conver on percents ...

The major reaction paths in the methylation of pyridine may be depicted as in Figure 3-... 

G. Grins "Catalytic o -Methylation of Pyridines", Unlv. Microfilms, Ann Arbor, Mich., (1970) ... 

Reactions of methoxy tellurium pentafluoride with alcohols also produced unsymmetrical methoxy alkoxy tellurium tetrafluorides but in lower yields than those achieved in reactions with methanol. Methoxy tellurium pentafluoride is partly lost through methylation of pyridine. ... 

Although the direct iV-methylation of pyridine compounds by diazomethane is not normal except in the presence of HBF4, it has now been shown that treatment of pyridin-2-ylphosphonic monoesters, e.g. (99 R=H), with diazomethane does result in direct A-methylation followed by rearrangement. ... 

N-Methylation of pyridine-type nitrogen atoms (reaction 4, Fig. 13.15) seems to be of greater in vivo pharmacological significance than reactions 2 and 3 for two reasons. First, the resulting metabolites, being quaternary amines, are more stable than tertiary or secondary amines toward N-demethylation. And second these metabolites are also more polar... 

As noted earlier, the replacement of halogen by an amino group (a substitution reaction at carbon and at nitrogen [ ]) is generally not useful for the preparation of primary (RNH2) or secondary (R2NH) amines since the alkylamines are stronger bases than ammonia. However, the substitution reaction is useful for tertiary (R3N) amines, for example, the A-methylation of pyridine with methyl iodide (Equation 10.48) and the formation of other quaternary ammonium salts (cf. the Menschutkin reaction. Table 7.7, item h). 

The methylation of pyridine by passage with methanol over a heated catalysti026 i y be a radical substitution. 

The methylation of pyridine, quinoline, and isoquinoline N-oxides to afford A-methoxy salts has also been investigated. For example, treatment of quinoline A-oxide with dimethyl sulfate provides the N-methoxy methylsulfate salt in excellent yield (eq 9). The resulting salts were subsequently treated... 

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