Directed C(sp2)–H functionalisation has emerged as a powerful and economical method for the synthesis of complex aromatic systems. Despite the broad range of directing groups (DGs) developed, those bound by boronic acid functional groups remain limited in number, despite the ubiquity and versatility of aryl boronic acids in organic synthesis. Issues with the reactivity of the functionalities to transition metal catalysts and instability under forcing reaction conditions have hampered their development.
Herein is described the modification of N-methyliminodiacetic acid (MIDA) with the tethering of directing motifs for the protection and C–H functionalisation of aryl boronic acids. Initial designs focused on strongly co-ordinating heterocyclic DGs in attempts to achieve ortho-C–H functionalisation of phenylboronic acid. Though ultimately unsuccessful, the first generation designs provided valuable information used in the development of a different, second approach.
Changing focus to meta-C–H functionalisations and embracing the design principles elucidated during initial investigations allowed the development of a successful, nitrile based, MIDA tethered DG (MIDA-DG).
The MIDA-DG proved simple to install and remove by condensation and hydrolysis respectively, with full recovery of the DG after C–H functionalisation. The development of alkenylation and acetoxylation reactions are described, as is initial work towards the development of C–H arylations.
The benefits of using a boronic acid tethered DG are exemplified, by the removal of the MIDA-DG and diverse derivatisation of the functionalised boronic acid. Using established transformations of boronic acids, a range of functional groups were accessed, including those difficult to prepare using previously available DGs.
Finally, the development of an iterative C–H functionalisation/cross-coupling pathway is outlined, with the expedient synthesis of a 1,3,4,5,-tetrasubstituted aromatic system in just 3 catalytic steps and with one chromatographic purification.