Iridium-Catalyzed C–H Activation and Deuteration of Primary Sulfonamides: An Experimental and Computational Study

Abstract

Iridium-catalyzed C−H activation and orthohydrogen isotope exchange is an important technology for allowing access to labeled organic substrates and aromatic drug molecules and for the development of further C−H activation processes in organic synthesis. The use of [(COD)Ir(NHC)Cl] complexes (NHC = N-heterocyclic carbene) in the orthodeuteration of primary sulfonamides under ambient conditions is reported. This methodology has been applied to the deuteration of a series of substrates, including the COX-2 inhibitors Celecoxib and Mavacoxib, demonstrating selective complexation of the primary sulfonamide over a competing pyrazole moiety. The observed chemoselectivity can be reversed by employing more encumbered catalyst derivatives of the type [(COD)Ir(NHC)(PPh 3 )]PF 6 . Computational studies have revealed that, although C−H activation is rate-determining, substrate complexation or subsequent C−H activation can be product-determining depending on the catalyst employed.

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

“…In previous C-H activation studies, we rationalised observed directing group chemoselectivity using density functional theory (DFT) calculations (see Supplementary Materials for details) to model the relative energies of the binding conformers and subsequent C-H activation pathways [20]. We have now extended this approach to the analysis of the labelling reactions of 12 and 14 (Scheme 7).…”

“…Thin layer chromatography was carried out using Camlab silica plates coated with fluorescent indicator UV254 (Sigma-Aldrich), and were visualized using a Mineralight UVGL-25 lamp (Fisher Scientific UK Ltd., Loughborough, UK) or developed using vanillin solution. Catalysts 1a [20], 1b [16], and 1d [18] were prepared according to literature procedures. Esters 6c [32], 10a [33], 10b [34], 10c [35], 10d [36], 10e [37], and 13 [38] were prepared according to the corresponding literature procedures.…”

“…The reaction mixture was then stirred for the allotted reaction time. An aliquot (1 mL) of the reaction mixture was removed at intervals throughout the reaction (10,20,30,40,50, 60 min, 2 h, and 18 h). Each aliquot was transferred to a vial containing diethyl ether.…”

“…Over recent years, research in our laboratory has focused on the development of iridium(I) N-heterocyclic carbene (NHC)-ligated precatalysts of the type 1, and their application in HIE via ortho-directed C-H activation protocols (2→4 via 3, Scheme 1) [6,[16][17][18][19][20][21][22]. Despite the growing list of compatible directing groups, we [23] and others [24][25][26][27] have found these developed C-H activation methods less applicable in the labelling of aromatic esters under ambient conditions.…”

Isotopic Labelling of Functionalised Arenes Catalysed by Iridium(I) Species of the [(cod)Ir(NHC)(py)]PF6 Complex Class

“…Whilst we believe that the encumbered nature of the iridium centre within this wider catalyst series is key to the high levels of activity shown, 6 we were conscious that these same steric constraints may disfavour the initial coordination of larger and more tetrahedral directing functional units such as sulfonamides. 7 Having stated this, we were able to induce high levels of incorporation within compound 5i, albeit by moving to a much higher catalyst loading of 50 mol%.…”