Metal-Free Synthesis of 1,3,5-Trisubstituted 1,2,4-Triazoles

Significance

Reported is the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles from sequential reaction of carboxylic acids with primary amidines followed by treatment with monosubstituted hydrazines. For the first step, a range of different coupling agents were screened, of which HATU was determined to be the best. PyBOP gave comparable yields, whereas EDCI afforded no product and EDCI/HOBt furnished the product in clearly lower yield. The acylamidine intermediates were not isolated but directly treated with the hydrazine counterpart. The substrate scope was widely studied and the yields of obtained products range from poor to very good. The reaction was also shown to be tolerant of chiral compounds; thus, the use of a proline derivative gave non-­racemized product.