Microdroplet Accelerating C(sp2)–H Halogenation in Organic, Pharmaceutical, Analytical, and Environmental Use

Microdroplet chemistry is continuously attracting extensive interest from scientific communities because of striking properties (acceleration, redox, extreme pHs, etc.). Despite the vast majority contributing to reactions of polar compounds, there are scarce reports concerning weakly polar and nonpolar compounds-involved reactions. In this study, we showed good applicability of microdroplet chemistry to weakly polar compounds. As a typical class of weakly polar compounds, halogenation of heteroarenes and arenes with N-halosuccinimide was accelerated by microdroplet chemistry with considerable applications in organic, pharmaceutical, analytical, and environmental use. A total of 19 halogenated (hetero)arenes with a gram scale of 3.22 g h^–1, 6 late-stage halogenated/arylated drugs with a gram scale of 1.26 g h^–1, and 5 mono/polyhalogenated carbazoles was synthesized. Additionally, we proposed an online derivatization strategy for precharged tagging of (hetero)arenes by integrating bromination with Suzuki coupling in two successive steps, addressing the bottleneck of mass spectrometric analysis. Overall, the microdroplet method is attractive not only to organic synthesis and pharmaceutical design for creating halogenated compounds in a green and sustainable manner but also to analytical and environmental studies because of the advantages including high efficiency, mild conditions, wide scope, and gram-scalability.