Kinetic and thermodynamic control of C(sp2)-H activation enables site-selective borylation

Abstract

Catalysts that distinguish between electronically distinct carbon-hydrogen (C-H) bonds without relying on steric effects or directing groups are challenging to design. In this work, cobalt precatalysts supported by N-alkyl-imidazole-substituted pyridine dicarbene (ACNC) pincer ligands are described that enable undirected, remote borylation of fluoroaromatics and expansion of scope to include electron-rich arenes, pyridines, and tri- and difluoromethoxylated arenes, thereby addressing one of the major limitations of first-row transition metal C-H functionalization catalysts. Mechanistic studies established a kinetic preference for C-H bond activation at the meta-position despite cobalt-aryl complexes resulting from ortho C-H activation being thermodynamically preferred. Switchable site selectivity in C-H borylation as a function of the boron reagent was thereby preliminarily demonstrated using a single precatalyst.

Figure 1.. Background and catalyst development.

A) Transition-metal catalyzed regioselective arene borylation. B) This work: Electronically controlled remote C(sp²)–H borylation.

Figure 2.. Precatalyst synthesis and characterization.

A) Activation of benzene by 3-Me. B) Steric maps of [(^iPrCNC)Co] and [3,5-Me₂-(^iPrACNC)Co] from the solid-state structures of the corresponding cobalt-methyl complexes generated in SambVca2.1. See supplementary materials for experimental details.

Figure 3.

C(sp²)–H borylation of (hetero)arenes. Yields and selectivities were determined by ¹⁹F NMR spectroscopy using a 4-fluorotoluene internal standard. *Isolated yield. ^†3 equiv. of B₂Pin_2. ^‡0.3 mol% of 3-Me. ^§50 °C. ^¶ 80 °C.^# 3 equiv. of arene

Figure 4.. Mechanistic considerations and kinetic vs. thermodynamic selectivity.

A) Reaction of 3-Me with 8 and probing isomerization of 3-Ar^F upon treatment with HBPin. B) Thermodynamic and kinetic preferences of C–H activation. C) Switchable C–H borylation. See supplementary materials for experimental details.* 4 equiv. of 5a.^†3 equiv. of 5c.