Ir-Catalyzed ortho-Borylation of Phenols Directed by Substrate–Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions

Abstract

A strategy for affecting ortho versus meta/para selectivity in Ir-catalyzed C–H borylations (CHBs) of phenols is described. From selectivity observations with ArylOBpin (pin = pinacolate), it is hypothesized that an electrostatic interaction between the partial negatively charged OBpin group and the partial positively charged bipyridine ligand of the catalyst favors ortho selectivity. Experimental and computational studies designed to test this hypothesis support it. From further computational work a second generation, in silico designed catalyst emerged, where replacing Bpin with Beg (eg = ethylene glycolate) was predicted to significantly improve ortho selectivity. Experimentally, reactions employing B2eg2 gave ortho selectivities > 99%. Adding triethylamine significantly improved conversions. This ligand– substrate electrostatic interaction provides a unique control element for selective C–H functionalization.

Achieving High Ortho Selectivity in Aniline C–H Borylations by Modifying Boron Substituents

“…The syn PhOBeg TS has short (~3.0 Å) contacts between the Beg group and the bipyridine ligand that are reminiscent of π stacking. 38 The analogous TS was not found for PhN(H)Beg. Instead, the N(H)Beg group rotated about the N–C ipso bond to engage in hydrogen bonding between the aniline proton and an Ir–Beg oxygen.…”

“…However, it is not unreasonable to expect that the calculated steric destabilization from changing Beg to Bpin in phenol ortho CHB transition states would translate to aniline CHBs. 38 The experiments in Scheme 3 demonstrate that the B substituents on the boryl ligands, and thus the CHB reagent, have the greater influence on the ortho selectivity.…”

Ligand–Substrate Dispersion Facilitates the Copper-Catalyzed Hydroamination of Unactivated Olefins

“…2–5 Additionally, the through-space non-covalent interactions between the ligand and the substrate also play a key role in influencing the reactivity of a catalyst. 6–11 Classical transition state models usually describe these through-space interactions as steric repulsion. 12–16 London dispersion, an essential type of van der Waals forces arising from the attraction between instantaneous dipoles, also contributes to the ligand-substrate interactions.…”

Hydrogen Bond Directed ortho‐Selective C−H Borylation of Secondary Aromatic Amides

“…[2] Crucial for the application is that the selectivity of the reaction can be controlled, and this is particularly challenging for CÀHbonds that are sterically and electronically deactivated. [4] However, ortho-selective CÀH borylation has only been reported for electronically activated arenes,s uch as an amine-, [5] alcohol-, [6] or thioether-substituted [7] arenes.Secondary aromatic amides are very common structural motifs in pharmaceuticals,a grochemicals,a nd fine chemicals, [8] and the ortho-selective C À Hb orylation of this class of compounds would therefore be highly interesting. [4] However, ortho-selective CÀH borylation has only been reported for electronically activated arenes,s uch as an amine-, [5] alcohol-, [6] or thioether-substituted [7] arenes.Secondary aromatic amides are very common structural motifs in pharmaceuticals,a grochemicals,a nd fine chemicals, [8] and the ortho-selective C À Hb orylation of this class of compounds would therefore be highly interesting.…”