Synthesis of novel benzo-substituted macrocyclic ligands containing thienothiophene subunits

Abstract

A facile synthetic approach was adopted toward the synthesis of benzo-fused macrocyclic ligands with thienothiophene group incorporated into the ring system. Thus, treatment of bis(bromomethyl) compound 2 with the K salt of the appropriate bis(phenol)s 3a, 3b, 3c, 3d in boiling DMF led to the formation of the novel macrocyclic diamides 4a, 4b, 4c, 4d in 39-58% yield. Reaction of 2 with the potassium salt (obtained upon treatment of salicylaldehyde 5 with ethanolic potassium hydroxide) in refluxing DMF afforded the novel bis(aldehyde) 6 in 73% yield. Cyclocondensation of 6 with the appropriate bis(N-substituted) cyanoacetamide derivatives 7a and 7b afforded the target macrocycles 8a and 8b in 48 and 55% yields, respectively. Reaction of the bis(aldehyde) 6 with 1,3- and 1,4-diaminopropane 9a and 9b in refluxing ethanol under high-dilution conditions afforded the corresponding macrocyclic Schiff bases 10a and 10b in 41 and 37% yields, respectively. Cyclocondensation of 6 with 1,3-bis(4-amino-5- phenyl-3-ylsulfanylmethyl)propane (15) in glacial acetic acid under high-dilution conditions gave the macrocyclic Schiff base 14 in 46% yield. On the other hand, cyclocondensation of bis(aldehydes) 17 and 20 with 3,4-bis(4-amino-5-phenyl-3-ylsulfanylmethyl)thienothiophene 16 in refluxing acetic acid under high-dilution conditions afforded unexpectedly the novel condensed heteromacrocycles 18 and 21 in 33 and 28%, respectively. The novel bis(amine) 16 was obtained in 50% yield upon treatment of 2 with 4-amino-1,2,4-triazol-3-thione 11 in ethanol/water mixture containing potassium hydroxide. © 2014 HeteroCorporation.