Now, Antonio Misale, Dmitriy M. Volochnyuk and John F. Hartwig report the iridium-catalysed borylation of the bridgehead tertiary C–H bonds of bicyclo[1.1.1]pentanes (BCPs), bicyclo[2.1.1]hexanes (BCHs) and oxa- and aza-bicyclo[2.1.1]hexanes (XBCHs).The researchers initiated their study by testing several iridium catalysts that had been previously applied for the borylation of alkyl C–H bonds. In these experiments, the catalytic systems formed from the ligand 2-methylphenanthrolin (2-mphen) and the precatalysts (mesitylene)Ir(Bpin)3 (where Bpin is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) or [Ir(COD)(OMe)]2 (where COD is cycloocta-1,5-diene) were the most efficient for the borylation of the bridgehead tertiary C–H bond in the presence of the boron source bis(pinacolato)diboron (B2pin2) (pictured). The proposed catalytic mechanism involves a reversible oxidative addition of the bridgehead C–H bond to the catalyst, a turnover-limiting isomerization step and reductive elimination. Testing different substrates revealed a broad functional-group compatibility. Further, the authors demonstrated downstream reactions of the borylated products and showed the applicability of this method for late-stage modification of pharmaceuticals. However, the tertiary C–H bond of the less strained BCH could not be borylated with this catalytic system, exemplifying the limitation of the current approach to highly strained substrates. Mechanistic investigations revealed that the sp2 character of the tertiary C–H bonds in the highly strained BCPs, BCHs and XBCHs was mainly responsible for the observed reactivity. Consequently, a broadly applicable catalytic method for borylation of tertiary C–H bonds, particularly unstrained ones, remains to be developed. Nevertheless, the present work is a useful addition to the functionalization of BCPs and BCHs. This is important as these substructures are sought after as bioisosteres to improve properties such as water solubility and metabolic stability of drug candidates.
Original reference: Nat. Chem. https://doi.org/10.1038/s41557-023-01159-4 (2023)
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