Directed C–H borylation: From metal catalysis to metal free

Abstract

<p indent="0mm">Organoborons play a highly important role in many science fields, range from synthetic chemistry to materials science to medicinal chemistry. The C−H borylation strategy has made significant development in recent decades, and its reaction system is changing from noble-metal catalysis to more environmentally friendly metal-free systems. Typically, an organic molecule contains multiple C−H bonds with subtle difference in activation barrier. Therefore, controlling the positional selectivity represents a key challenge in complex molecules. To override this intrinsic selectivity, introducing a directing group in molecules can exhibit different site-selectivity. This review focuses on the development of ortho-selective borylation of (hetero)arenes by various directing groups, including: (1) Metal-catalyzed directed C−H borylation; and (2) metal-free directed C−H borylation. The directed C−H borylation is shifting from noble metals to metal-free systems, breaking through the dependence of traditional means on metal catalysts and broadening the concept of C–H functionalization. In the first section, the development of transition metal catalysts for directed C−H<italic> </italic>borylation is summarized. Among various catalysts, the iridium complexes have proven to be most active toward C−H borylation. The 16e intermediate <sc>[Ir(dtbpy)(Bpin)₃] </sc>(dtbpy=4,4′-di-tert-butyl-2,2′-bipyridine, Bpin = 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) has been proved to be the catalytically active species in the [Ir(X)(cod)]₂/dtbpy (X=OMe or Cl, cod=1,5-cyclooctadiene) catalyzed directed C−H borylation. Three different strategies have been developed for the direct regioselective C−H bond borylation: Chelate directed, relay directed, and outer-sphere directed. Notably, dimethylsilyl can be employed as the directing group in Ir-catalyzed ortho-borylation of arenes. In addition to iridium, the use of other transition metal catalysts including rhodium and palladium has met some success as well. The second section first analyses the disadvantages of traditional C−H<italic> </italic>borylation by transition metal catalysts. The requirement of precious metals and metal residues in the final product will limit the application of these processes, especially in large-scale synthesis. Alternatively, some novel metal-free electrophilic borylations of arenes have been reported which proceed via borenium or boronium species, but stoichiometric quantities of by-products are formed at the same time. Therefore, the development of simpler and efficient metal-free C−H bond borylation is highly desirable. Then we show our discovery on the development of a talent approach for the C−H bond borylation of (hetero)arenes including indoles, pyrroles and amides using the readily available BBr₃ without any additive. Other groups also reported some similar examples after our discovery. The concluding section of this review discusses the significance of the directed C−H<italic> </italic>borylation under metal-free conditions, and limitations of the known approaches in this field. The additional breakthroughs required to further advance the metal-free C−H functionalization are described in the concluding section of this review. We hope that this review will not only present the most exciting new discoveries for the C–H borylation of feedstock chemicals into valuable organoboron products, but also provide valuable guidance for researchers, especially in drug and natural product research, facilitating the continued development of synthetic chemistry.