Alkylated 3 -ethylpyridine

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

The alkyl pyridines (6) and (7) can be transformed either to nicotinic acid or nicotinonitrile. In the case of nicotinic acid, these transformations can occur by either chemical or biological means. From an industrial standpoint, the majority of nicotinic acid is produced by the nitric acid oxidation of 2-meth5i-5-ethylpyridine. Although not of industrial significance, the air oxidation has also been reported. Isocinchomeronic acid (10) (Fig. 2) is formed as an intermediate. 

Various alkyl-substituted pyridine derivatives are formed from the condensation of butyraldehyde with ammonia at high temperatures. For example, cocondensation of //-butyraldehyde with acroleia [107-02-8] and ammonia at 400°C over a borosiUcate 2eohte gives 3-ethylpyridine [536-78-7] ia 70% yield... 

Alkylation of 1-indanone with 2-dimethylaminoethyl chloride affords the substituted ketone (1). Condensation with the lithium reagent obtained from 2-ethylpyridine affords the alcohol (2). Dehydration under acidic conditions gives dimethyl-pyrindene (3). ... 

C-Alkylation of weakly activated methylpyridines to yield the isopropyl and tert-butyl derivatives (35-40%), which normally requires the use of strong bases, such alkyl lithiums, is earned out effectively using a phase-transfer catalyst and aqueous sodium hydroxide on the /V-methylpyridinium salts. The pyridines are regenerated by reaction with sodium acetate or sodium 4-toluenethiolate [134]. 3-Methylpyridine fails to react under these conditions and the synthesis of 2-ethylpyridines by this procedure is also unsuccessful. 

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). 

Additive effects again are not observed when interchanging the position of an alkyl group on a pyridine ring and on an alkylating agent. 2-Methylpyridine reacts 18 times slower with ethyl iodide than does 2-ethylpyridine with Mel at 25°.4... 

In all the above cases, C-2 is activated toward attack by phenyllithium compared with the same position in pyridine, while C-6 is about six- to sevenfold deactivated by the 3-methyl or 3-ethyl group compared with the oc-position of pyridine. Also, the 2,3- 2,5-isomer ratios remained unchanged in all cases. A 3-methyl group activates C-2 more than does a 3-ethyl, the activation in the former case being sufficient to overcome the deactivation of C-6 and resulting in an over-all activation of the 3-picoline nucleus compared with that of pyridine and a value of the total rate ratio greater than unity. In the case of 3-ethylpyridine, the activation is insufficient to overcome the normal deactivation of the position para to the alkyl group. 

As mentioned earlier (see Section 7.12.4.5.3), tautomeric oxohydroxyazolopyrimidines exists mainly in the oxo form. Several 0-alkylation reactions have been reported. The reaction of the derivatives (274) with a-bromo-3-ethylpyridine hydrochloride in the presence of potassium carbonate gives compounds (275) (Equation (34)) <88JAP63246377>. Reaction of compound (276 X = O) with methyl iodide or diazomethane gives 0-alkylated products together with some N-l and N-4 alkylated products (277-279) (82AJC2299). 

In contrast to / - and y-alkyl-substituted pyridines, in their a isomers (65), the rupture of a bond between C-2 and a hydrogen (as in the case of a-ethylpyridine) or C-3 (as in the case of higher homologs), (65)—>[66], occurs with much higher probability than that between C-l and C-2, (65)->[67]. 

Alkylated pyridines such as 3-picoline, 3(5)-ethylpyridine and 2-methyl-5-ethyl-pyridine (MEP) are the natural choice as starting materials for the nicotinates. The choice of alkyl pyridine is governed by their availability and the process being used. 

The influence of acid on these additions is considerable. In ethanol, for example, ethyl nicotinate is converted into the corresponding 6a-hydroxyethylpyridine, whereas in acidified solution the 6-ethylpyridine derivative is obtained.147 The function of the acid may, of course, simply be to promote dehydration of the intermediate 6a-hydroxyethyldihydropyridine. Phthalazine and quinoxaline are converted by irradiation in acidified methanol into 1-methylphthalazine and 2-methylquinoxaline, respectively.148 In this case, however, there is evidence to suggest that the alkylations proceed by way of electron transfer from the solvent to an excited state of the protonated diazines in neutral solution, a hydrogen... 

Real-world data for other more ubiquitous alkyl-substituted pyridines are even more scarce. From data reported by Heavner et al. (1992) of a survey in eight homes, mean values are 2-picoline (0.2pg/m ) 3-picoline (0.3pg/m ) 3-ethylpyridine (O.lpg/m ) and pyridine (1.7pg/m ). 

This method has been validated for the determination of vapor-phase nicotine (Ogden 1989, 1992) and 3-ethenylpyridine (Nelson and Ogden 1990 Ogden 1991) in ambient air. Indications are that the methodology can be extended to the determination of vapor-phase myosmine however, the methodology is not suited for the collection or determination of pyridine. Suitability for determining alkyl pyridines (picolines, lutidines, ethylpyridine, etc.) is not known. 

Soum and Fontanille report that di-s-butyl magnesium generates living polymer from 2-vinylpyridine without the involvement of the side-reactions that afflict the polymerization initiated by alkali metal alkyls the resulting polymer has an isotacticity index of 0.9. Arai et al. have synthesized styrene-butadiene-4-vinylpyridine triblock copolymers. Hogen-Esch et a/. have continued their study of the stereochemistry of the anionic polymerization of 2-vinylpyridine in THF solution. Oligomers were synthesized by addition of alkali salts of 2-ethylpyridine to 2-vinylpyridine termination was effected by reaction with methyl iodide. Highly isotactic products were obtained with U and Na as counterions but with K or Rb there was no stereoselection. Epimerization resulted in the expected statistical mixtures of stereoisomers and it was concluded that stereoselection is kinetically controlled. 

Alkylation and Substituted Alkylation—Reactions in this group (other than hydroxyalkylations and benzylations effected by carbonyl compounds, dealt with below) are not numerous. Mannich aminomethylations have been carried out with 2- and 4-picoline and 2-ethylpyridine, formaldehyde and a number of amines , but yields are poor . 

The sodium derivatives of 2- and 4-picoline and of their 1-oxides react with alkyl nitrites to give good yields of the pyridine aldoximes247a, 6i3 but the 3-isomers fail or give traces of products. The oxides are more reactive than the parent bases. 4-Ethylpyridine performed satisfactorily in the reaction, 2,6-lutidine gave a good yield of the monoxime, and 2,4-lutidine reacted at the 4-methyl group247a. 

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