Size-selective synthesis of calix[n]furan[2n]thiazoles bearing <i>meso</i>-CH₂ bridges

Size-selective synthesis of calixpyrrole-related macrocycles remains challenging, particularly for ring-contracted and expanded analogues, although calix[4]-type macrocycles are often obtained as major products via conventional acid-catalyzed condensation reactions of aryl monomers. Here, we found that the strain-based design of thiazole-containing macrocycles enables the size-selective synthesis of calix[[Formula: see text]]furan[2[Formula: see text]]thiazoles ([Formula: see text] = 1 or 2) in which two thiazole units are linked by a methylene bridge. The DFT calculation through StrainViz analysis revealed that calix[1]furan[2]thiazole bearing a methylene bridge had a total strain of 11.2 kcal/mol, which was smaller than that of calix[3]pyrrole (13.4 kcal/mol). The target calix[1]furan[2]thiazole was almost exclusively formed in 45% yield by a Hantzsch reaction between the corresponding bis([Formula: see text]-bromoketone) and bis(thioamide) at 0.50 mM concentration. When the substrate concentration was increased above 10 mM, the calix[6]-type product, calix[2]furan[4]thiazole, was formed as the major product. Despite the existence of the meso-CH 2 -bridge, the obtained macrocycles were stable to air oxidation. Acid-catalyzed hydrolysis of the furan rings in calix[1]furan[2]thiazole and subsequent Paal–Knorr reaction afforded calix[1]pyrrole[2]thiazole. We also found that the deformation angles [Formula: see text] determined from the single crystal X-ray structures show a good correlation with the total strain and synthetic yield of calix[3]-type compounds via direct macrocyclization.