Late-stage functionalization offers the discovery chemist the promise of preparing many relevant analogues of a lead compound with maximum synthetic efficiency. We aimed to realize this promise by setting up an automation-compatible platform for preparing multiple useful derivatives from a lead compound using a lynchpin functionalization strategy. First, we identified thianthrenation and borylation as attractive C-H functionalization methods to install a versatile reactive handle on a late-stage intermediate. We demonstrate the applicability of these reactions in the context of several representative drugs and agrochemicals [1] and, for borylation, developed a reaction screen to identify catalysts capable of regiodivergent functionalization [2]. We next identified suitable reaction conditions to convert the thianthrene and boronate intermediates into 6-12 diverse derivatives useful for structure-activity relationship studies and optimized the conditions such that the reactions could be run in parallel on an automated synthesis platform. We demonstrate that a systematic late-stage functionalization and derivatization approach can be a useful tool in optimization campaigns and share some of our experience in applying this challenging chemistry as a platform.

[1] D. Ahmadli, S. Müller, Y. Xie, T. Smejkal, S. Jaeckh, A. V. Iosub, S. R. Williams, T. Ritter, J. Am. Chem. Soc. 2025, 147, 5, 4268–4283

[2] J. M. Zakis, R. A. Lipina, S. Bell, S. R. Williams, M. Mathis, M. J. Johansson, J. Wencel-Delord, T. Smejkal, ACS Catal. 2025, 15, 4, 3525–3534