Quinoline reaction with phosphorus oxychloride

Pyridine and quinoline /V-oxides react with phosphorus oxychloride or sulfuryl chloride to form mixtures of the corresponding a- and y-chloropyridines. The reaction sequence involves first formation of a nucleophilic complex (e.g. 270), then attack of chloride ions on this, followed by rearomatization (see also Section 3.2.3.12.5) involving the loss of the /V-oxide oxygen. Treatment of pyridazine 1-oxides with phosphorus oxychloride also results in an a-chlorination with respect to the /V-oxide groups with simultaneous deoxygenation. If the a-position is blocked substitution occurs at the y-position. Thionyl chloride chlorinates the nucleus of certain pyridine carboxylic acids, e.g. picolinic acid — (271), probably by a similar mechanism. 

The isoquinoline ring, although common in natural products, is not as important among pharmaceuticals as is the quinoline ring. Several synthetic methods are available, but we will discuss only the most commonly used one, the Bischler-Napieralski synthesis that was reported in 1893. With some modifications, it is stiU of great value today for the synthesis of isoquinolines. The process is simple and involves the reaction of an acyl derivative (an amide) of a 2-arylethylamine with phosphorus oxychloride or phosphorus pentoxide (Scheme 9.54). The... 

By chlorinating kynurenic acid with phosphorus pentachloride and oxychloride and by successive addition of quinoline to the reaction product, the authors obtained a colored substance, soluble in ethanol and giving a brilliant red-violet color with maximum absorption at 556-557 mp, of remarkable stability. 

This plant yielded the first 1-phenyltetrahydroisoquinoline alkaloid to be found in nature. Spectral data indicated that it was l-(3,4-methylenedioxyphenyl) -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso -quinoline, C19H29O4N (mp 101° [ajj) -t-54°) and a synthesis of the diform confirmed this structure (XLVI). The amide resulting from the reaction of piperonoyl chloride with 3,4-dimethoxyphenethylamine was cyclized by means of phosphorus oxychloride. The resulting dihydro-isoquinoline was converted to methiodide and the latter reduced with sodium borohydride. The resulting dZ-base (mp 117°) was identical in spectral properties with the natural alkaloid 66). 

Reaction between two moles of wj-chloroaniline and a mole of formic acid yields an imidine which on treatment with ethyl malonate at 100° undergoes exchange and results into a diester. This further imdergoes cyclization through condensation to yield the corresponding ethyl ester of 7-chloro-4-hydroxy-quinoline-3-carboxylie acid which on hydrolysis gives 7-chloro-4-hydroxy quinoline. Finally, on chlorination with either phosphorus oxychloride or thionyl chloride yields the nueleus 4, 7-diehloro quinoline. 

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