Alkylated 3-picoline

A solution of sodamide 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 proceed with difficulty and are accompanied by considerable by-products. Thus 3-alkylpjTidines, otherwise inaccessible, are easily prepared from 3-picoline (see 3-n-amylpyridine in Section V,20). Also benzyl cyanide (I) and cyclohexyX bromide give a- r/ohexylphenylacetonitrile (II) ... 

Commercial Manufacture of Pyridine. There are two vapor-phase processes used in the industry for the synthesis of pyridines. The first process (eq. 21) uti1i2es formaldehyde and acetaldehyde as a co-feed with ammonia, and the principal products are pyridine (1) and 3-picoline (3). The second process produces only alkylated pyridines as products. 

The most thoroughly investigated compounds are the alkyl-pyridines. Coleman and Fuoss compared the reactions of pyridine, 4-picoline, and 4-isopropylpyridine with n-butyl bromide and found a steady increase in the rate in the order given the activation energies are 16.0,15.95, and 15.6 kcal per mole, respectively. Brown and Cahn carried out a detailed study of the reactions of 2-, 3-, and 4-alkyl-pyridines with methyl, ethyl, and isopropyl iodides in nitrobenzene the results are given in Table II. These data show the higher activation... 

The reactivity of the 1-methyl group and of corresponding positions (i.e., a-carbon atoms) in other l-alkyl-j8-carbolines, analogous to that in a-picoline, quinaldine, and isoquinaldine, is due to the acidity of this center. Deprotonation yields a resonance-stabilized anion (288) which reacts readily with electrophilic reagents. Metallation with phenyl-lithium of the 1-methyl group of a l-methyl-j8-carboline derivative in which the indole nitrogen is protected, first described by Woodward... 

A characteristic feature of picolines and many azoles is the well-known ability of methyl (and corresponding methylene) groups to undergo condensation of the aldol, crotonic, and Michael type. This is especially pronounced in the quaternary salts of these heterocycles where it occurs under comparatively mild conditions. Such condensations are not unknown for alkylisoxazoles. Lampe and Smolinska were the first to describe the condensation of the quaternary alkyl iodides of 3,5-dimethyl- (96) and 3-methyl-5-phenylisoxazole with... 

A rather simple pyridine derivative shows activity as an immunoregulator. Alkylation of 4-chlo-romethylpyridine (2), available from 4-picoline (1), with l-hydroxyethane-2-thiol affords ristianol (3)[1]. 

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. 

The three picolines react with alkyl halides in liquid ammonia solution in the presence of sodamide to yield the corresponding monoalkylpyridines. a-Picoline also reacts with alkyl chlorides in the presence of sodamide either alone or in the presence of xylene to give a fair yield of monoalkylpyridine CjH N.CHjR. With y-picoliue under similar experimental conditions disubstitution of the alkyl group (CjHjN.CHRj) occurs to an appreciable extent. The preparation of tile three n-amylpyridines is described the 3- and 4-compounds by the liquid ammonia - sodamide method and the 2-compound by the sodamide-3 ene procedure. 

Aromatic N-containing heterocycles (pyridine, imidazole etc.,) and their alkyl derivatives represent an important group of products and they have received considerable attention because of their various applications. For instance, methyl pyridines (picolines) and dimethyl pyridines (lutidines) are a class of industrially valuable compounds for the production of dyes and fine chemicals [108]. Sreekumar et al [109] reported pyridine methylation to 3-picolines over Zni xCoxFe204 spinel systems at reaction temperature between 325 and 425°C. The... 

Subsequently, Kato and Goto have reported the synthesis of 2- and 4-pyridinecarbox-aldoximes from 2- and 4-picoline with potassium amide and amyl nitrite in liquid ammonia at — 33°C, although they failed to obtain either of these oximes when the reaction was carried ont with sodium amide in liquid ammonia at room temperature in a sealed tube. Finally, in 1964, aUcyl-substituted heteroaromatic compounds and allyl-substituted benzenes were oximated in liquid ammonia at —33 °C with sodamide and an alkyl nitrite . 

Substantially fewer studies have been published for the reactions of alkyl-substituted heteroaromatics, although these compounds also have implications for coal combustion. Several references discussed in the previous section contain information on methylated heteroaromatic rings. Mackie and coworkers completed experimental and theoretical studies of the pyrolytic decomposition of 2-picoline (2-methylpyridine). They concluded that decomposition proceeded mainly through o-pyridinyl and 2-picolinyl radicals. The former tended to decompose predominantly to yield cyanoacetylene, while the latter favored decomposition to a cyano-functionalized cyclopentadiene (Fig. 16). 

Despite the authors assertion that alkylated heteroaromatic compounds provide a better model for fuel-bound nitrogen than do the unsubstituted heterocycles, their pyrolytic study remains the most comprehensive look at substituted heteroaromatic chemistry, even several years later/ Kinetic studies are more common in the literature Frerichs et al. examined the reaction of the picolines with oxygen atom, while Yeung and Elrod studied reactions of HO with pyridine and its methyl- and ethyl-substituted derivatives.Both groups noted that the presence of nitrogen did not demonstrably affect the species chemistry generally, reactivity is comparable to toluene. 

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive de-cyanation (596) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH4 in MeOH led to predominant (8 2) formation of the trans isomer (232) which was then debenzylated to ( )-solenopsin A (Id). The cis product (Ic) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by de-benzylation (Scheme 10). 

Picoline and 4-picoline are easily deprotonated as the conjugate car-banions are resonance stabilized. These anions can be used in alkylations and other reactions with electrophiles (Scheme 2.20). 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

Myadera and Iwai (64CPB1338) have devised a convenient route to the bromide (139 R1 = R2 = R3 = H) starting with commercially available materials (Scheme 84). The anion formed from -y-butyrolactone by the action of sodium hydride was allowed to react with ethyl picolinate to yield the keto lactone (141) which, when heated with hydrobromic acid, undergoes decarboxylation as well as bromination, yielding the bromo ketone (139). Several substituted ethyl picolinates have been used successfully, and it has also been found that the anion of the keto lactone (141) may be alkylated. 

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