Abstract
Herein, we report the rational, computationally-guided design of an iridium(I) catalyst system capable of enabling directed hydrogen isotope exchange (HIE) with the challenging sulfone directing group. Substrate binding energy was used as a parameter to guide rational ligand design via an in silico catalyst screen, resulting in a lead series of chelated iridium(I) NHC-phosphine complexes. Subsequent preparative studies show that the optimal catalyst system displays high levels of activity in HIE, and we demonstrate the labeling of a broad scope of substituted aryl sulfones. We also show that the activity of the catalyst is maintained at low pressures of deuterium gas and apply these conditions to tritium radiolabeling, including the expedient synthesis of a tritium-labeled drug molecule.
Highlights
We report the rational, computationallyguided design of an iridium(I) catalyst system capable of enabling directed hydrogen isotope exchange (HIE) with the challenging sulfone directing group
One of the most utilized methods in this area is directed hydrogen isotope exchange (HIE, Scheme 1), wherein hydrogen atoms ortho to a Lewis basic directing group (DG) are replaced with deuterium or tritium
Studies within our own laboratory have led to the development of a series of catalytically active iridium(I) NHC/phosphine complexes 1−2 (Figure 1), which deliver heavy isotopes of hydrogen to aryl and alkenyl substrates via a directed C−H activation process with a broad range of directing groups.3d,5 iridium(I) NHC chloride complexes of type 3 have shown utility in the labeling of primary aryl sulfonamides and aryl aldehydes
Summary
We report the rational, computationallyguided design of an iridium(I) catalyst system capable of enabling directed hydrogen isotope exchange (HIE) with the challenging sulfone directing group. When these catalyst systems were applied to the labeling of phenyl methyl sulfone 4a, low levels of incorporation were observed (Figure 3a).6a We hypothesized that, in this case, substrate binding was unusually the turnover-limiting step, in contrast to less hindered directing groups where C−H activation is turnover limiting.5c
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