4-Picoline, 3-bromo

Attempts to get more information on this interesting meta-rearrangement by choosing derivatives of 2-bromopyridine containing various substituents in the 6-position for the starting material led to a remarkable result. Whereas 2-bromo-6-picoline gave a mixture of 2-and 4-amino-6-picoline (in a ratio of 60 1) in 25% total yield together with a resinous mass, 2,6-dibromopyridine (79) was converted into a pyrimidine, i.e. 4-amino-2-methylpyrimidine (80), in 20% yield. The same pyrimidine was obtained from 2,6-dichloropyridine and, in small amount, also from 2,4-dibromopyridine (81). The course of the... 

Reaction of -picoline over degassed Raney nickel was found to give 5,5 -dimethyl-2,2 -bipyridine (5), the structure of which was established by its synthesis from 2-bromo-5-methylpyridine. Oxidation of this dimethyl-2,2 -bipyridine, and similar oxidation of the diethyl-2,2 -bipyridine derived from 3-ethylpyridinc, gave the corresponding dicarboxylic acid and the same acid was produced by the action of degassed Raney nickel on sodium nicotinate (in water) or on ethyl nicotinate. These transformations established the 5,5 -substitution pattern for three 2,2 -bipyridines derived from 3-substituted pyridines but such evidence is not available for the biaryls... 

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. 

Lithium dibutylisopropylmagnesate proved to be quite efficient for the bromine-magnesium exchange of 5-bromo-2-picoline at —10 °C (Table 14) . The resulting picolyl-magnesium reagent reacted with electrophiles including thiuram disulfide (last entry). 

The coupling of halopyridines was also extended to chiral amines. 2-Bromo-4-picoline was coupled with a series of enantiopure amines in the presence of Buchwald s palladium-BINAP catalyst system (7.71.).91... 

Condensation of y-picoline with mesoxalic ester yielded 4-(j8,j8-diethoxycarbonylvinyl)pyridine (35). The unsaturated ester (35) was hydrogenated with platinum catalyst to form 36 which was treated with bromine. 4-(j8-Bromo-j8,j8-diethoxycarbonylethyl)-piperidine (37) was obtained and was cyclized with pyridine to 2,2-die th 0 xycarbony 1 quinuclidine (38). Hydrolysis of 38 and partial decarboxylation gave quinuclidine-2-carboxylic acid (39). 

Racemic baikiain can be obtained by an electrolytic reduction of picolinic acid60 (see Section II, B, 2), by an eight-step synthesis from l-benzoyloxy-4-bromo-2-butyne163 or, more simply, from cis-1,4-dichloro-2-butene (175).164... 

Fischer attempted the bromination of apoharmine in dilute sulfuric acid at room temperature and obtained a tetrabromo compound, which he did not characterize further. Treatment of l-benzoyl-2,5-dimethyl-4-azaindole with bromine in acetic acid at 25° gave the 3-bromo-l-benzoyl compound in 60% yield. On oxidation with permanganate it gave the same picolinic acid obtained before. Alkaline hydrolysis gave 3-bromo-2,5-dimethyl-4-azaindole (90%), also obtained by direct bromination of 2,5-dimethyl-4-azaindole in 60 % yield. 

Displacement of the chloro substituent from pyrazines by the cyano group has not been satisfactorily accomplished (866), but many cyanopyrazines have been prepared from the bromo analogues. Karmas and Spoerri (866) prepared 11 cyanopyrazines with mono-, di-, or trialkyl or phenyl substituents from the corresponding bromo compounds and cuprous cyanide in refluxing dry 4-picoline, but the procedure was not suitable for the preparation of 2-cyanopyrazine (866). It was prepared in 29% yield when the reaction was performed in pyridine (866). Another preparation of 2-cyano-3-phenylpyrazine from the bromo analogue has also been reported (1024). 

Acetylamino-3-chloroanthraquinone (2) is an intermediate to an important solubilized vat dye, but is available only by a lengthy synthesis. The corresponding 3-bromo compound (1), however, is available in high yield by bromination of 2-aminoanthraquinone and acetylation. Hardy and Fortenbaugh found that (1) reacts with cuprous chloride in a-picoline at 130° to give (2) in almost quantitative yield. 

The checkers prepared 2-bromo-6-picoline from inexpensive 2-amino-6-picoline R. Adams and S. Miyano, J. Am. Chem. Soc. 76, 3168-3171 (1954). 

Picoline (2-methylpyridine) gives a lithio derivative that with 5-bromo-2-pentanone ethylene ketal affords 6-(2-pyridyl)-2-hexanone ethylene ketal in 80% yield 421... 

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