Regiocontrolled and Stereoselective Syntheses of Tetrahydrophthalazine Derivatives using Radical Cyclizations

Abstract

Tetrahydrophthalazine derivatives have found important applications in pharmaceutical research, but existing synthetic methods are unable to access them regio‐ and stereoselectively. Here, a new approach is presented that addresses these challenges by utilizing a 6‐endo‐trig radical cyclization in the key step. The desired tetrahydrophthalazines can be accessed in high yields (55–98 %) and high diastereoselectivities for the trans‐product (>95:5) starting either from readily accessible hydrazones, or from the corresponding aldehydes and substituted Boc‐hydrazides in a one‐pot process. The synthetic versatility of the tetrahydrophthalazine core was demonstrated by its straightforward conversion to dihydro‐phthalazines, phthalazines, or pyrazolo dione derivatives. Furthermore, the N−N bond was reduced to afford a new route to 1,4‐diamines.