Bioisosteric sulfoxonium ylides as building blocks for accessing thiazole derivatives using flow chemistry

Replacement of aromatic motifs with saturated bioisosteres is a proven tactic for improving the pharmacokinetic profiles of lead compounds. We present a modular continuous-flow methodology for the rapid generation of structurally diverse benzene bioisosteres, specifically targeting sp³-rich architectures such as bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, and cubane. By implementing a packed-bed flow strategy for the generation of α-keto sulfoxonium ylides as key intermediates, we developed an efficient flow-based protocol for the synthesis of 2-aminothiazoles that tolerates a wide range of thioureas and thioamides. This approach enables the rapid construction of scaffold-diverse libraries, facilitating the fine-tuning of molecular properties. Comparative analysis reveals that these bioisosteric substitutions markedly improve aqueous solubility and reduce lipophilicity relative to their phenyl counterparts, while offering a tunable scaffold to modulate molecular properties without significantly altering polar surface area or topology. This work establishes a practical synthetic framework for the systematic bioisosteric optimization of drug candidates in medicinal chemistry campaigns.