Improved Preparation of the Clathrate Host Compound Tri-o-thymotide and Related Trisalicylide Derivatives

In order to improve the relatively low yield (ca. 35%) previously observed in the synthesis of tri-o-thymotide (TOT, 1) from o-thymotic acid (2), the cyclodehydration was studied using a variety of conditions. The low yield is due to the formation of di-o-thymotide (DOT, 3), previously reported, and at least three other products (4-6), which apparently result from the acid-catalyzed decarboxylation of 2 and subsequent condensation with thymol (7). Using pyridine as a solvent, side-product formation is inhibited. Under appropriate conditions, namely, neat POCl₃ at 50 °C, the yield of 1 is 93%. Other salicylic acid derivatives also give high yields of the corresponding “trimers” under these conditions, thus providing a general, improved preparation of a family of potential clathrate host substances.