Picolines lithiation

Carbon-linked sugar-heterocycles were also obtained by reaction of the lithiated derivatives obtained from 2-bromopyridine, a-picoline, and ben-zothiazole with 4-0-benzyl-2,3 6,7-di-0-cydohexylidene-D-g(ycero-D-gulo-htplono-1,5-lactone (55). The corresponding o-glycero-D-gulo-hepto-pyranose-substituted compounds 56a-c were isolated in 35-43.5% yields. With other heterocycles (for example furan), 1-disubstituted guloheptitols were obtained (59). 

More powerful directing groups such as those based on amides and sulphonamides are successful with pyridines as with carboxylic rings, and will not be discussed separately. The enhanced acidity of pyridine ring protons makes the simple carboxylate substituent an ideal director of lithiation in pyridine systems . The pyridinecarboxylic acids 232-234 are deprotonated with BuLi and then lithiated with an excess of LiTMP all the substitution patterns are lithiated nicotinic acid 233 is lithiated in the 4-position (Scheme 113). The method provides a valuable way of introducing substituents into the picolinic, nicotinic and isonicotinic acid series. 

Kaminski, T. Gros, P. Fort, Y. Side-chain retention during lithiation of 4-picoline and 3,4-lutidine easy access to molecular diversity in pyridine series. Eur. J. Org. Chem. 2003, 3855-3860. 

In a recently reported synthesis of pyridines, lithiated methoxyallenes react with nitriles in the presence of trifluoroacetic acid (Scheme 107) <2004CEJ4283>. The mechanism is postulated to proceed via initial protonation followed by nucleophilic addition of the trifluoroacetate ion with subsequent intramolecular acyl transfer and aldol condensation to give the pyridine. An additional pyridine formation starting from azaenyne allenes forms a-5-didehydro-3-picoline diradicals, which can be trapped by 1,4-cyclohexadiene, chloroform, and methanol to produce various pyridines <20040L2059>. 

Our synthesis began with the diisopropyl amide of picolinic acid (39, Scheme 11). Introduction of an iodine at the 3-position was accomplished in 80% yield by lithiation with LDA and trapping with iodine. A second metalation with LDA and trapping with iodine provided the 3,4-diiodo species 41, probably via the 3-lithio-4-iodo compound (40) that is produced by a 1,2-halogen-dance. Unfortunately, attempted preparation of 36 by treatment of 41 with LDA and quenching with water... 

Our synthesis began with picolinic acid, which was treated with thionyl chloride in the presence of LiBr according to the procedure of Sundberg to provide the 4-chloro acid chloride, which was then treated with diisopropylamine to provide diisopropyl amide 45 (Scheme 12). Ortho-lithiation of this species with LDA and trapping with iodine provided compound 46. Unfortunately, this compound also proved to be... 

In the classical lithiation of triazolopyridines at —40 °C with LDA in THF, the 7-lithio derivatives 71 formed are trapped by electrophiles giving 7-substituted triazolopyridines 138a-d. When the starting material was 3-(2-pyridyl)-triazolopyridine 33,19a was formed (Scheme 32), using as electrophiles 2-pyridine carbaldehyde (98T15287), 2-cyanopyridine, and in better yield, ethyl picolinate (04T5785). 

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