Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C-H Borylation of Aromatic Quaternary Ammonium Salts

The use of noncovalent interactions to direct transition-metal catalysis is a potentially powerful yet relatively underexplored strategy, with most investigations thus far focusing on using hydrogen bonds as the controlling element. We have developed an ion pair-directed approach to controlling regioselectivity in the iridium-catalyzed borylation of two classes of aromatic quaternary ammonium salts, leading to versatile meta-borylated products. By examining a range of substituted substrates, this provides complex, functionalized aromatic scaffolds amenable to rapid diversification and more broadly demonstrates the viability of ion-pairing for control of regiochemistry in transition-metal catalysis.Engineering and Physical Sciences Research Council and Pfizer (CASE studentship), AstraZeneca (AZ-Cambridge Ph.D. Program studentship), Royal Society (University Research Fellowship), Engineering and Physical Sciences Research Council and Engineering and Physical Sciences Research Council U.K. National Mass Spectrometry Facility (Swansea University

Palladium-Catalyzed Cross Coupling of Benzylammonium Salts with Boronic Acids under Mild Conditions

Herein, we give a full account of the development of the palladium­-catalysed cross-coupling of benzylammonium salts with boronic acids. A range of benzylamine-derived quaternary ammonium salts can be coupled with boronic acids under relatively mild conditions. Our optimization has identified ligands that can be used to chemoselectively cross-couple at the ammonium in the presence of chlorides. We demonstrate that intramolecular palladium-catalysed C–H activation is also a viable pathway for the putative benzyl-Pd(II) intermediate obtained upon oxidative addition and have optimised this to obtain fluorene in good yield.We are grateful to the Engineering and Physical Sciences Research Council (EPSRC, Grant Number EP/N005422/1) and Pfizer for a CASE studentship (H.J.D.), the EPSRC and the Royal Society for a University Research Fellowship (R.J.P.). P.L.T. thanks the Swiss-European Mobility Programme for Traineeships for funding his stay in Cambridge

meta-Selective C−H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand

Selective functionalization at the meta position of arenes remains a significant challenge. In this work, we demonstrate that a single anionic bipyridine ligand bearing a remote sulfonate group enables selective iridium-catalyzed borylation of a range of common amine-containing aromatic molecules at the arene meta position. We propose that this selectivity is the result of a key hydrogen bonding interaction between the substrate and catalyst. The scope of this meta-selective borylation is demonstrated on amides derived from benzylamines, phenethylamines and phenylpropylamines; amine-containing building blocks of great utility in many applications.We are grateful to the EPSRC and Pfizer for a CASE studentship (H.J.D.), the EPSRC (EP/N005422/1, G.R.G.) and the Royal Society for a University Research Fellowship (R.J.P.)

Site-Selective Cross-Coupling of Remote Chlorides Enabled by Electrostatically-Directed Palladium Catalysis

Control of site-selectivity in chemical reactions that occur remote from existing functionality remains a major challenge in synthetic chemistry. We describe a strategy that enables three of the most commonly used cross-coupling processes to occur with high site-selectivity on dichloroarenes which bear acidic functional groups. We have achieved this by repurposing an established sulfonylated phosphine ligand to exploit its inherent bifunctionality. Mechanistic studies suggest that the sulfonate group engages in attractive electrostatic interactions with the associated cation of deprotonated substrate, guiding cross-coupling to the chloride at the arene meta-position. This counterintuitive combination of anionic ligand and anionic substrate demonstrates an alternative design principle when considering applying non-covalent interactions to direct catalysis.We are grateful to AstraZeneca for PhD studentships through the AZ‐Cambridge PhD program (W.A.G. and R.P.), the Royal Society for a University Research Fellowship (R.J.P.), the EPSRC (EP/N005422/1) and the ERC (StG 757381)

Ion Pair-Directed C-H Activation on Flexible Ammonium Salts: Meta-Selective Borylation of Quaternized Phenethylamines and Phenylpropylamines

Ion pairing has unexplored potential as a key catalyst-substrate interaction for controlling regioselectivity and site-selectivity in transition metal catalysis, particularly in the area of C-H activation. However, there is a significant perceived challenge that has meant that few have investigated this approach to date – that of the low directionality, which could present an insurmountable challenge if seeking positional selectivity on flexible substrates. Herein, we demonstrate that even flexible substrates with several freely rotatable bonds undergo ion pair-directed CH borylation with good to excellent levels of regiocontrol for the arene meta position. Furthermore, we demonstrate that in specially designed competition substrates, ion pair direction prevails over competing hydrogen bond direction. We anticipate that these findings will inspire the greater incorporation of ion-pairing into site-selective catalytic strategies

Ion-Pair-Directed meta -Selective C-H Borylation of Aromatic Quaternary Ammonium Salts

We recently reported the use of ion pairing as a key noncovalent interaction to control regioselectivity in the iridium-catalyzed C–H borylation of aromatic quaternary ammonium salts. Two classes of substrates, benzylamine- and aniline-derived ammonium salts were selectively borylated at the meta position by employing a newly developed anionic ligand for the iridium. It was proposed that the ligand interacts with the cationic substrate via an ion-pairing interaction, positioning the substrate in the optimal orientation for selective activation of the $\textit{meta}$ C–H bond.We are grateful to AstraZeneca for a studentship (M.T.M.) through the AZ-Cambridge PhD Program and the Royal Society for a University Research Fellowship (R.J.P.)