Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp3 Chemical Space Exploration

From a retrosynthetic standpoint, functionalization or synthesis of heterocyclic cores are fundamental disconnections that chemists make. This manuscript highlights heterocycle synthesis as the strategic bond disconnection by leveraging ubiquitous building blocks, carboxylic acids and amines, for preparation of heterocyclic cores in a library-friendly format. This heterocyclic formation strategy allows medicinal chemists to access much wider chemical space, especially for analogs with higher Fsp³ vs state-of-the-art heterocycle functionalization methods. The direct impact on medicinal chemistry programs is underscored by adapting and miniaturizing the synthesis of N2-indazoles and C2-benzimidazoles to μ-scale parallel medicinal chemistry (PMC) libraries, affording a similar success rate (80%) as venerable Suzuki and Buchwald-Hartwig libraries.