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 K2CO3; 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]‐4H‐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]‐1H‐benzimidazole 7. Interaction of 7 and 2‐chloromethyl‐5‐aryl‐1,3,4‐oxadiazoles in the presence of K2CO3 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 Et3N. 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, 1H NMR, and mass spectral data.
