Solid‐Phase Parallel Synthesis of a Tetrahydroindazolone Library Containing Three Unique Core Skeletons

Abstract

We have developed a practical strategy for the regioselective synthesis of a 1-(hetero)aryl-3-substituted tetrahydroindazolone library. The condensation of in situ generated arylhydrazine on solid supports with 2-acylcyclohexane-1,3-diones ensured the efficiency of solid-phase parallel synthesis. In addition, we introduced three unique core skeletons containing nitrophenyl, anilyl, and pyridyl groups to maximize the molecular diversity through a diverse display of polar surface area in 3D chemical space. A 162-membered drug-like tetrahydroindazolone library was constructed in an average purity of 92% without further purification.

Regioselective Construction and Screening of 1,3-Disubstituted Tetrahydroindazolones in Enantiomerically Pure Pairs

“…To address this problem, we recently reported a regioselective pathway for the synthesis of complementary regioisomers of 1,2- and 1,3-disubstituted tetrahydroindazolones by the sequential protection and deprotection of substituted hydrazines . We also reported a practical solid-phase synthetic pathway for 1,3-disubstituted tetrahydroindazolones …”

Synthetic and Mechanistic Investigation of an Unexpected ­Intramolecular 1-5 Nitrogen to Carbon Tosyl Migration

“…[6][7][8][9][10] Consequently, their biological utility has seen the development of several synthetic procedures to access the core tetrahydroindazolone scaffold. [11][12][13][14][15] The most commonly reported procedures typically involve introducing a hydrazine source to a suitably functionalized dimedone derivative. (3) with hydrazine hydrate in THF in the absence of acid or base to generate a 3-methyltetrahydroindazolone analogue (4).…”