Quinolines, carbanions from methyl

Preparation of a somewhat more complex leukotriene antagonist begins by aldol condensation of the methyl carbanion from quinoline (29-1) with meta-phthalalde-hyde (29-2) to give the stilbene-like derivative (29-3) dimer formation is presumably inhibited by the use of excess aldehyde. Reaction of that product with A,A-dimethyl-3-mercaptopropionamide in the presence of hexa-methylsilazane affords the silyl ether (29-4) of the hemimercaptal. Treatment of that intermediate with ethyl 3-mercaptopropionate leads to the replacement of the silyl ether by sulfur and the formation of the corresponding thioacetal (29-5). Saponification of the ester group leads to the carboxylic acid and thus to verlukast (29-6) [33]. 

Steric hindrance from substituents at the 8-position of a 2-methyl-quinoline inhibits reactions of the nitrogen atom. The quinoline 323 only reacts with DMAD at 200° and yields 324 as sole product.375 In the case of 2,4,6,8-tetramethylquinoline, the analog of 324 and also its presumed precursor (325) formed by proton addition to an intermediate carbanion (cf. Scheme 6) were isolated along with 328.379 This last could be formed via an intermediate (cf. Scheme 6) undergoing proton transfer to 326, cyclization to a phenol (327), and addition to another mole of DMAD.379 2,8-Dimethylquinoline in tetrahydrofuran with DMAD yielded some of the phenol corresponding to 327 379... 

The reaction of benzo[f]quinoline with methylsulphinyl carbanion prepared from dimetl lsulphoxide and sodium hydride leads to the 5-methyl and the 6-methyl derivatives in a 1 4 ratio. Although benzo[flquinoline-4-oxide gives a high yield of phenanthrene under these conditions, the carbanion generated using potassium t-butoxide as the base leads to alkylation at C-3 and to simultaneous deoxygenation (Y. Hamada and I. Takeuchi. J. org. Chem.. 1977. fa, 4209). 

Phenanthroline-l-oxide loses the /7-oxide function on brief treatment with the carbanion derived from dimethylsulphoxide and sodium hydride to give benzo[h]quinoline in 48% yield. Prolonged reaction results in methylation of the benzoquinoline at the 5-and the 6-position (Y. Hamada et al, Chem. pharm. Bull. Japan, 1979, 1535). 

Alternatively, a SchifTs base (53), obtained from condensation of 2-aminobenzonitrile 49 and an aryl or heteroaryl methyl ketone 52, was deprotonated with LDA, and the resulting carbanion underwent cyclization to form a 4-aminoquinoline product 54 in high yield. It is interesting that when this reaction was carried out with the ethyl ketone analog of 52 it did not produce the analogous quinoline product. Instead, it was determined that rather than undergoing deprotonation, the more sterically hindered ethyl ketone derivative underwent an addition reaction with LDA to form 55. ... 

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