Monomethyl pyridines

Pyridine and its simple derivatives are stable and relatively unreactive liquids, with strong penetrating odours that are unpleasant to some people. They are much used as solvents and bases, especially pyridine itself, in reactions snch as N- and 0-acylation and -tosylation. Pyridine and the three monomethyl pyridines (picolines) are completely miscible with water. 

Pyridine and alkylpyridines are found in coal tar. The monomethyl pyridines (called picolines) undergo side-chain oxidation to carboxylic acids (review Sec. 10.7.b). For example, 3-picoline gives nicotinic acid (or niacin), a vitamin essential in the human diet to prevent the disease pellagra. 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

Pyridine, and its monomethyl and 3,5-dimethyl derivatives " combine exothermically with dimethyl acetylenedicarboxylate in ether yielding some ether soluble materials, including trimethyl pyrrocoline-1,2,3-tricarboxylate (Section III,F,3) and deep red ether-insoluble gums. A number of crystalline compounds have been isolated from these gums by fractional crystallizations and will now be considered in detail. In the case of pyridine, Diels et al. ° isolated a red labile 1 2 molar adduct, which they formulated as (75), which isomerized rapidly on standing to a yellow stable adduct (76). These formulations are no longer accepted. Diels and Alder also suggested that the acetylenic ester first dimerized to the diradical (74) which then combined with the pyridine. 

Turanose Phenylosazone. A mixture of 4 g. of turanose, 2 ec. of water, and 1 co. of phenylhydrazine was warmed on the steam-bath until solution was complete. To the cooled solution was added 3.5 cc. of phenylhydrazine and 4 cc. of glacial acetic acid, and the mixture returned to the steam-bath for one hour. At the expiration of this time, 40 cc. of warm 60% alcohol was added and, upon cooling, a rapid crystallization of the osazone occurred. The osazone was recovered by filtration and washed with absolute alcohol followed by ether to yield 4.2 g. (69%) of lemon-yellow needles. The osazone is soluble in hot water and separates on cooling as jelly-like particles, but water is not a satisfactory solvent for its purification. It was recrystallized from 15 parts of 95% alcohol with good recovery, as needles which melted with decomposition at 200-205° and rotated [ ]d +24.5° - +33.0° (24 hours, constant value c, 0.82) in a mixture of 4 parts of pyridine, by volume, and 6 parts of absolute ethyl alcohol. In methyl cellosolve (ethylene glycol monomethyl ether) solution it rotated C< 3d" + 44.3°— + 48.5° (24 hours, constant value c, 0.80). 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

In a recent publication from our laboratory (87), the substitution behavior of the Cu(II) complex of the trimethylated tren (Me3tren, each amino-terminal nitrogen is monomethylated) was studied. The substitution of the coordinated water molecule by pyridine was only slightly slower than in the tren case. The activation volumes of -8.7 4.7 cm3 mol-1 for the forward reaction and -6.2 1.1 cm3 mol-1 for the reverse aquation reaction (see the volume profile in Fig. 7) indicate that substitution occurs via an associative pathway and that the steric influence is not as significant as in the case of Me6tren. 

Pyridine-based ligands which have been used for dendrimers are 2,2-bipyridine (bpy) 17,2,3-bis(2-pyridyl)pyrazine (2,3-dpp) 18 and its monomethylated salt 19, and 2,2 6, 2"-terpyridine 20. Their transition metal complexes possessing dendritic structures were first reported in the collaborative work of Denti, Campagne, and Balzani whose divergent synthetic strategy has led to systems containing 22 ruthenium centers. - The core unit is [Ru(2,3-dpp)3] 21 which contains three... 

Limitations and interferences. The Karl Fischer reagent is composed of pyridine, sulfur dioxide, and iodine dissolved in either methyl alcohol or ethylene glycol monomethyl ether. Substances which react with any of these components will interfere. For example, Karl Fischer reagent will react with aldehydes or ketones in the presence of Methyl alcohol. 

Reductive amination of benzaldehyde with (R)-81 provided the corresponding benzyl amine, which was reductively alkylated with formaldehyde to give 82 (Scheme H) " Compound 82 was debenzylated by hydrogenation in the presence of Pearlman s catalyst to afford frovatriptan ((/J)-6). Alternatively, monomethylation of amine (/ )-81 was affected by treatment with carbon disulfide and dicyclohexylcarbodiimide in pyridine to provide isothiocyanate 83, which was reduced with sodium borohydride to give (l )-6. 

The first example of the use of a chiral-core dendrimer as enantioselective receptor in molecular recognition processes was reported by Diederich (see Fig. 4.70). This dendrimer, designated as a dendrocleff, acts as enantioselective receptor for monosaccharides. It bears a central axially chiral 9,9 -spirobi[9H-fluorene] unit which is linked via two 2,6-bis(carbonylamino)pyridine spacer groups, each in 2,2 position, with triethylene glycol monomethyl ether dendrons [14b]. Both... 

In benzofuroxanes the nature and position of the substituents have a marked effect on the equilibrium position. In the pyridine analogue the influence of the aza group overrides the effects of the methyl substituents at —45 °C 80-90% of the equilibrium pair from monomethyl and dimethyl derivatives consists of the 1-oxide isomer (553) (70JCS(B)636). 

Hydration of aryl-substituted epoxides. Treatment of aryl-substituted oxiranes with copper(II) sulfate and pyridine in an aqueous phosphate buffer (pH 7) affords cis-diols by reaction of water at the benzylic position. Less than 15% of trans cleavage products obtain. In the absence of pyridine, the oxides are rapidly destroyed. Triethylamine cannot be substituted for pyridine. cis-Chlorohydrins are obtained when aryl-substituted oxides are treated with copper(II) sulfate, pyridine, and kiCl in THF, When methanol is used as solvent, the corresponding cis-glycol monomethyl ether is obtained. In all cases substitution occurs at the benzylic position. Alkyl oxiranes do not react under these conditions. ... 

Radical alkylation of 1-methyl-, 3-methyl- and 2,3-dimethyl-imidazo[4,5-c]pyridine (147) takes place at C-4 giving (148) with some dimethylation of monomethyl compounds occurring, the second methylation being at C-2 (77KGS933, 78MI41006). 

Pyridine is found in coal tar. Along with it are found a number of methyl-pyridines, the most important of which are the monomethyl compounds, known as picoUnes. 

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