Para-Selective C–H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation

Abstract

The selective functionalization of C–H bonds at the arene para position is highly challenging using transition metal catalysis. Iridium-catalyzed borylation has emerged as a leading technique for arene functionalization, but there are only a handful of strategies for para-selective borylation, which operate on specific substrate classes and use bespoke ligands or catalysts. We describe a remarkably general protocol which results in para-selectivity on some of the most common arene building blocks (anilines, benzylamines, phenols, benzyl alcohols) and uses standard borylation ligands. Our strategy hinges upon the facile conversion of the substrates into sulfate or sulfamate salts, wherein the anionic arene component is paired with a tetrabutylammonium cation. We hypothesize that the bulk of this cation disfavors meta-C–H borylation, thereby promoting the challenging para-selective reaction.

Iridium‐Catalysed C−H Borylation of Heteroarenes: Balancing Steric and Electronic Regiocontrol

“…[87] Enhanced para selectivity is similarly observed in the borylation of sulfamate and sulfate salts in which a tetraalkylammonium counterion shields nominally active meta CÀH sites (Scheme 7 b,c). [88,89] In a ligand-based approach, the use of the bulky phosphine ligand L3 creates a flexible reaction pocket at the active catalyst which inhibits the access to meta aryl CÀH bonds (Scheme 7 d). [90,91] Finally, whilst most ligands are based on a simple bipyridine template, Smith and Maleczka have excitingly shown that alternative motifs have considerable potential to enhance selectivity, with hindered electron-rich ligands dipyridylmethane (dpm, L4) and 4,4'-bis(dimethylamino)-2,2'dipyridyl)methane (dmadpm, L5) favouring steric control, and unhindered electron-poor ligands 2,2'-bis-2-oxazoline (bozo, L6) and 2,2'-bis[(4S)-4-benzyl-2-oxazoline] (bnbozo, L7), favouring greater degrees of electronic control (Scheme 7 e).…”

“… [87] Enhanced para selectivity is similarly observed in the borylation of sulfamate and sulfate salts in which a tetraalkylammonium counterion shields nominally active meta C−H sites (Scheme 7 b,c). [88, 89] In a ligand‐based approach, the use of the bulky phosphine ligand L3 creates a flexible reaction pocket at the active catalyst which inhibits the access to meta aryl C−H bonds (Scheme 7 d). [90, 91] …”

Iridium‐katalysierte C‐H‐Borylierung von Heteroarenen: Eine Balance zwischen sterischer and elektronischer Regiokontrolle

“… [87] Erhöhte para ‐Selektivität kann auch bei der Borylierung von Sulfamaten und Sulfaten beobachtet werden, wo ein Tetraalkylammonium‐Gegenion die nominal aktive meta ‐C‐H‐Bindung abschirmt (Schema 7 b,c). [88, 89] Bei einem Ansatz auf Ligandenbasis wird durch die Verwendung eines sperrigen Phosphanliganden L3 eine flexible Reaktionstasche am aktiven Katalysator erzeugt, die den Zugang zur meta ‐C‐H‐Bindung inhibiert (Schema 7 d). [90, 91] …”

“…[87] Erhçhte para-Selektivitätk ann auch bei der Borylierung von Sulfamaten und Sulfaten beobachtet werden, wo ein Tetraalkylammonium-Gegenion die nominal aktive meta-C-H-Bindung abschirmt (Schema 7b,c). [88,89] Bei einem Ansatz auf Ligandenbasis wird durch die Verwendung eines sperrigen Phosphanliganden L3 eine flexible Reaktionstasche am aktiven Katalysator erzeugt, die den Zugang zur meta-C-H-Bindung inhibiert (Schema 7d). [90,91] Während die meisten Liganden auf einfachen Bipyridin-Vorlagen beruhen, haben Smith und Maleczka außerdem gezeigt, dass alternative Motive ein beträchtliches Potenzial haben, die Selektivitätz ue rhçhen, wobei die gehinderten elektronenreichen Liganden Dipyridylmethan (dpm, L4)und 4,4'-Bis(dimethylamino)2,2'-dipyridyl)methan (dmadpm, L5) eine sterische Kontrolle begünstigen und die ungehinderten elektronenarmen Liganden 2,2'-Bis-2-oxazolin (bozo, L6) und 2,2'-Bis[(4S)-4-Benzyl-2-oxazolin] (bnbozo, L7)e in hçheres Maß an elektronischer Kontrolle begünstigen (Schema 7e).…”

A novel exchange method to access sulfated molecules

“…Methods to accomplish a lipophilic cation-exchange of highly polar sulfated molecules include the process route to Avibactam reported by Ball et al 12 . Recent work by Montero Bastidas et al 21 , and Mihai et al 22 have shown the importance of routes to sulfated molecules with a sterically bulky tetrabutylammonium cation for iridium catalysed para -selective C–H borylations. An alternate approach is to design an all-in-one reagent with a sulfating agent combined with a lipophilic counterion, such as our own work 19 , 20 and the work of Kowalska et al 23 .…”