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.

Fig. 1.. Profiles of the Ir-catalyzed reactions of THF and dibutyl ether with B₂pin₂ with variously substituted phenanthrolines as ligands.

The reactions are catalyzed by the combination of 5 mol % [Ir(mesitylene)(Bpin)₃] and 5 mol % 2-mphen (red), tmphen (blue), or 2,9-dmphen (green). The relative rates were estimated from the slope of the curves for the initial rates of reactions with 2-mphen (red) versus those for the reactions with the other two ligands after the induction period. n-Bu₂O, n-dibutyl ether; Me, methyl.

Fig. 2.. Borylation of the primary C–H bonds of alkyl groups and secondary C–H bonds of cyclic compounds.

(A) Borylation of primary C–H bonds of acyclic alkanes, ethers, silyl ethers, and protected amines. (B) Borylation of the methyl C–H bonds of alcohols, including the natural terpene menthol. (C) Borylation of the secondary C–H bonds of carbocycles. tBu, tert-butyl; d.r., diastereomeric ratio. (D) Borylation of the methylene C–H bonds beta to oxygen in tetrahydrofurans and tetrahydropyrans and beta to nitrogen in azetidine, pyrrolidine, piperidine, and azepine derivatives. Assay yields were measured by ¹H NMR spectroscopy, with isolated yields in every example given in parentheses. The difference in yields determined by NMR spectroscopy and by isolation typically resulted from the difficulty of separating the products from the alkyl reactants, unreacted diboron reagent, and boron-containing side products owing to their similar polarities. In no case did a reaction form >5% of any other product from reaction with the substrate. Yields marked with an asterisk refer to the yield of the corresponding alcohol isolated after oxidation in cases for which the alkylboronate could not be separated from other reaction components. Piv, pivaloyl.

Fig. 3.. Derivatization of the products from C–H borylation at alkyl C–H bonds.

Borylation of an alkylarene at the aryl and primary alkyl C–H bonds, followed by derivatization specifically at the aryl C–B bond or C–Br bond, and then at the alkyl C–B bond. brs, based on recovered starting material; NBS, N-bromosuccinimide.

Fig. 4.. Derivatization of the B–C bond of an N-Boc 3-borylpyrrolidine.

DAST, diethylaminosulfur trifluoride.

Fig. 5.

Borylation and derivatization of tert-butyl ester of dehydroabietic acid.