Design and synthesis of novel quinoline derivatives bearing oxadiazole, isoxazoline, triazolothiadiazole, triazolothiadiazine, and piperazine moieties

Abstract A new series of 2,3‐disubstituted quinoline derivatives were synthesized from 2‐chloroquinoline‐3‐carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2‐chloroquinoline‐3‐carbaldehyde 1 , which was transformed to 2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐carbaldehyde 2 by reaction with 4‐phenylpiperazine in DMF‐containing anhydrous K 2 CO 3 ; then, compound 2 was oxidized by iodine in methanol, and methyl 2‐(4‐phenylpiperazin‐1‐yl)quinoline‐3‐carboxylate 3 was synthesized. The key intermediate 4 , 4‐amino‐5‐[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]‐4 H ‐1,2,4‐triazole‐3‐thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4‐triazolo[3,4‐ b ][1,3,4]thiadiazoles 5a‐c and 1,2,4‐triazolo[3,4‐ b ][1,3,4]thiadiazines 6a‐c , respectively. Moreover, compound 2 condensed with o ‐phenylenediamine to give 2‐[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]‐1 H ‐benzimidazole 7 . Interaction of 7 and 2‐chloromethyl‐5‐aryl‐1,3,4‐oxadiazoles in the presence of K 2 CO 3 led to the title compounds 8a‐c . Furthermore, 4,5‐dihydroisoxazoline derivatives 9a‐c were obtained by the reaction of readily accessible starting materials including 2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐carbaldehyde 2 , 1‐phenyl‐2‐(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et 3 N. The hydrazone intermediates 10a‐c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3‐acetyl‐5‐aryl‐2‐[2‐(4‐phenylpiperazin‐1‐yl)quinolin‐3‐yl]‐2,3‐dihydro‐1,3,4‐oxadiazoles 11a‐c . Structures of these compounds were established by their elemental analysis, IR, 1 H NMR, and mass spectral data.

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