Diverse functionalization of strong alkyl C–H bonds by undirected borylation

Abstract

The selective functionalization of strong, typically inert carbon-hydrogen (C–H) bonds in organic molecules is changing synthetic chemistry. However, the undirected functionalization of primary C–H bonds without competing functionalization of secondary C–H bonds is rare. The borylation of alkyl C–H bonds has occurred previously with this selectivity, but slow rates required the substrate to be the solvent or in large excess. We report an iridium catalyst ligated by 2-methylphenanthroline with activity that enables, with the substrate as limiting reagent, undirected borylation of primary C–H bonds and, when primary C–H bonds are absent or blocked, borylation of strong secondary C–H bonds. Reactions at the resulting carbon-boron bond show how these borylations can lead to the installation of a wide range of carbon-carbon and carbon-heteroatom bonds at previously inaccessible positions of organic molecules.

Ligand-Driven Advances in Iridium-Catalyzed sp3 C–H Borylation: 2,2′-Dipyridylarylmethane

“…The substantial improvement in catalyst performance we observed with L2 versus L1 is evocative of recent observations by the Hartwig group on phenanthroline derivatives. 16,18 An exploration of substituent effects resulted in the identification of 2-methylphenanthroline as a particularly effective ligand. 2-methylphenanthroline provides a substantial rate increase over Me4Phen, which allows for sp 3 borylation under conditions of limiting alkane in cyclooctane solvent.…”

“…2-methylphenanthroline provides a substantial rate increase over Me4Phen, which allows for sp 3 borylation under conditions of limiting alkane in cyclooctane solvent. 18 Subtle perturbations of the phenanthroline core have been shown to have a profound impact on transition state energies and therefore catalyst activity, 16 and it would appear that dipyridylarylmethane derivatives share this remarkable sensitivity to substitution.…”

“…Traditional alkane borylation systems including both Cp*Rh/Ir 7,12,26 and (diimine)Ir 13,27 perform quite poorly in solvent. Catalysts have been developed for the sp 3 borylation of activated (including benzylic, cyclopropane, and alkylsilane substrates) [27][28][29][30] or directed substrates, 29,[31][32][33][34][35] however, the C-H borylation of unactivated alkyl substrates in solvent was largely unaddressed prior to recent work by Hartwig 18 and ourselves. 15 The success of the [(cod)IrOMe]2/L2 system in neat n-octane ( Figure 4) inspired us to survey potential conditions for borylation in solvent.…”

“…While our group was successful in reducing the required substrate excess to 5 equivalents and carrying out borylation in cyclohexane solvent, a coincident report by the Hartwig group showed that the 2-methylphenanthroline ligand enables sp 3 borylation of unactivated substrates in stoichiometric quantities in cyclooctane. 18 In both cases, the success of cycloalkane solvents reflects the intrinsic selectivity of iridium sp 3 C-H borylation catalysts for methyl C-H bonds over methylene C-H bonds. Substantial limitations remain for both systems however, leaving space for the development of improved catalysts for sp 3 C-H borylation chemistry in solvent.…”

Direct Synthesis of Cyclopropanes from Gem-Dialkyl Groups Through Double C–H Activation

“…9 This mechanism allows cleavage of two primary C-H bonds within the same reaction, despite the fact that these are theoretically the strongest types of C-H bonds in organic molecules. 10…”