Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic Esters—An Experimental and Theoretical Study on Directing Group Chemoselectivity

Abstract

Herein we report a combined experimental and theoretical study on the deuterium labelling of benzoate ester derivatives, utilizing our developed iridium N-heterocyclic carbene/phosphine catalysts. A range of benzoate esters were screened, including derivatives with electron-donating and -withdrawing groups in the para-position. The substrate scope, in terms of the alkoxy group, was studied and the nature of the catalyst counter-ion was shown to have a profound effect on the efficiency of isotope exchange. Finally, the observed chemoselectivity was rationalized by rate studies and theoretical calculations, and this insight was applied to the selective labelling of benzoate esters bearing a second directing group.

Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange

“…Further studies from our laboratory have gone on to establish the efficient, directed labelling of indole and pyrrole heterocycles, frameworks which, until recently, remained relatively underexplored classes of labelling substrates . Utilising common N ‐protecting groups to selectively direct C―H activation, high levels of deuterium incorporation have been achieved for a range of substrates, including the industrially‐relevant sumatriptan 6 , a 5‐hydroxytryptamine‐receptor drug (Scheme 4).…”

A quantitative empirical directing group scale for selectivity in iridium-catalysed hydrogen isotope exchange reactions

“…Complexes of the type [Ir(COD)(IMes)(PR 3 )]PF 6 have been successfully applied to homogeneous, ortho-directed HIE processes using a range of O-and N-donor directing groups (COD = 1,5-cyclooctadiene; IMes = 2,6-bis(2,4,6-trimethylphenyl) imidazol-2-ylidene); these include ketones, amides, esters, and nitroarenes, as well as various heterocycles, such as pyridines, pyrimidines, pyrazoles, imidazole(in)es, thiazole(in)es, oxazole(in)es and their benzo-fused analogues. 11,[13][14][15] The PF 6 counterion was replaced with tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BArF 24 ) to produce a second generation of complexes, further improving reactivity and broadening the range of applicable solvents. 16,17 Additionally, neutral [IrCl(COD)(NHC)] complexes were shown to be effective catalysts in the HIE of aryl ketones and nitrogen-based heterocycles, 18 and excelled in the labeling of secondary sulfonamides, 19 and the formyl HIE of aldehydes.…”

Catalyst design in C–H activation: a case study in the use of binding free energies to rationalise intramolecular directing group selectivity in iridium catalysis

“…[10][11][12] Yet, relative to the number of synthetic developments, fundamental studies on site selectivity in complex molecules are rare. [13][14][15][16][17][18][19][20][21] In our laboratories, 18,[22][23][24][25] we have explored iridium-catalysed C-H activation and hydrogen isotope exchange (HIE) protocols [26][27][28][29][30][31] for application in pharmaceutically-relevant labelling studies. Importantly, such studies also serve as an insightful proxy for determining site selectivity in other C-H functionalisation processes.…”