Pyridines lithio derivatives

Tetrahydro[l,5-tf]pyridine 52 was also subjected to lithiation by reaction with butyllithium and gave the 1-lithio derivative 56. This compound when treated with methyl iodide afforded the 4-methyl derivative 57. Further interesting transformations of 56 have also been carried out reaction with 1,3-dibromopropane gave first the... 

Ethyl pyridine-2-acetate and ethyl 6-methylpyridine-2-acetate have previously been prepared by carboxylation of the lithio derivatives of a-picoline and lutidine, respectively. Use of ethyl carbonate to acylate the organometallic derivative avoids the intermediacy of the (unstable) carboxylic acid, and the yields are better. In the present procedure potassium amide is used as the metalating agent the submitters report that the same esters may be formed by metalation with sodium amide (43% yield) or with w-butyllithium (39% yield). The latter conditions also yield an appreciable amount of the acid (which decarboxylates). 

Metalation can also occur adjacent to the bridgehead 5p -nitrogen in six-membered rings, and examples include the lithio derivatives of 3-ethylthioimidazo[l,5-fl]pyridine 67 (80TL2I95, 80TL4193), 1,2,3-triaz-... 

Direct metalation of 2,6-disubstituted pyridines has also been reported to occur at the 4-position under certain conditions. Thus the 2,6-bistrimeth-ylsilyl chromium tricarbonyl compound 96 gave the 4-lithio derivative 102 [91JCS(P1)501], and 2,6-dichloropyridine gave mainly the 4-lithio derivative 103 under kinetic deprotonation conditions, in contrast to the thermodynamic situation where 3-lithiation was preferred (91JOC4793). 

There are several bicyclic compounds with five-membered heterocycles fused to pyridine rings, where metalation occurs in the smaller ring due to activation by the heteroatom. The ring-A lithiation of imidazopyridines and pyrimidines was discussed in Section II,E,6, but in addition, the a-lithio derivatives of thieno[2,3-6]pyridine 119 (74JHC355), thieno[3,2-... 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

Bromo substituents in the 6- and 6 -positions of 2,2 -bipyridines are particularly reactive, being readily converted to amino,cyano, ° al-koxyl, hydrazino, chloro, and hydrogen groups and by way of the corresponding lithio derivatives to carboxyl, methyl, aldehyde or alkylcarbonyl, and other groupings. 6,6 -Dibromo-2,2 -bi-pyridine also reacts with the disodium derivatives of polyethylene glycols to give crown ethers akin to 100, and 6,6 -bis(chloromethyl)-2,2 -bi-pyridine " and the derived 6,6 -bis(mercaptomethyl)-2,2 -bipyridine... 

The bromine group in 4-bromo-5-methoxy-2-trifluoromethyl-l,10-phenanthroline has been replaced by lithium with w-butyllithium and the lithio derivative reacted with pyridine 2-aldehyde.215... 

Ring metallation generally succeeds with /V-oxides. a-Lithio derivatives (348) can be generated in non-protic conditions by treating pyridine 1-oxides with n-butyllithium. These may be intercepted by various electrophiles such as cyclohexanone (Scheme 35). Reaction of substituted lithio /V-oxides with carbon dioxide gives carboxylic acids with elementary 02 and S8 (347, X = 0, S) are produced. 

Furan is resinified by sulfuric acid but it can be sulfonated with the complex of sulfur trioxide with pyridine or dioxane. Depending on conditions the 2-sulfonic or the 2,5-disulfonic acid may be obtained. Furan-2-carboxylic acid can be sulfonated with oleum. Benzo[6]furan is polymerized by sulfuric acid. The 2-sulfonic acid has been obtained by oxidation of the sulfinic acid available in turn by treatment of the lithio derivative with sulfur dioxide. Benzo[6]furan with the sulfur trioxide-pyridine complex allegedly affords the 3-sulfonic acid. 

Reaction of the lithio derivative of ferrocene with pyridine gave a-pyridylferrocene (86) together with a small amount of 87 (from dilithioferrocene formed during the preparation of lithioferro-cene).80,81 A small yield of 86 was also obtained80 when l,l -ferro-... 

Pyridine A-oxides are readily deprotonated at C(2) using LDA or -butyllithium as base in THF and the reagents thus produced react in the usual way in high yields with a variety of electrophiles including iodine, alkyl halides, aldehydes, and ketones < 1995J(P 1 )2503>. For example, -lithio derivative 361 can be generated and intercepted by various electrophiles, e.g., carbon dioxide, elementary sulfur, or cyclohexanone giving 362 note that the lithiation prefers the carbon to the oxide rather than that ortho to the chlorine. 

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