Iridium-Catalyzed Silylation of Unactivated C-H Bonds

Abstract

The functionalization of primary C-H bonds has been a longstanding challenge in catalysis. Our group has developed a series of silylations of primary C-H bonds that occur with site selectivity and diastereoselectivity resulting from an approach to run the reactions as intramolecular processes. These reactions have become practical by using an alcohol or amine as a docking site for a hydrosilyl group, thereby leading to intramolecular silylations of C-H bonds at positions dictated by the presence common functional groups in the reactants. Oxidation of the C-Si bond leads to the introduction of alcohol functionality at the position of the primary C-H bond of the reactant. The development, scope, and applications of these functionalization reactions is described in this minireview.

Fig. 1

Proposed mechanism for hydrosilyl-directed borylations of aromatic C-H bonds.

Fig. 2

Relative computed transition-state energies for the C-H bond-cleavage and C-Si bond-forming elementary reaction steps of rhodium-catalyzed silylation of primary and secondary C-H bonds.

Scheme 1

Platinum catalyzed intramolecular silylation of a methyl C-H bond.

Scheme 2

Iridium-catalyzed borylation of ortho C-H bonds of phenols directed by a hydrosilyl ether.

Scheme 3

Borylation of indoles at the 7-position of the heterocycle likely proceeds through a pathway directed by the hydrosilyl group.

Scheme 4

Silylation of methyl C-H bonds of hydrosilyl ethers affords 1,3-diols after Tamao-Fleming oxidation of the intermediate 5-membered oxasilolanes (top). Scope of the reaction (bottom).

Scheme 5

Regioselective one-pot hydroxylation of a methyl C-H bond of methyl oleanate to afford methyl hederagenate in high yield.

Scheme 6

Hydrosilyl ether-directed γ-C-H bond silylation efficiently yields 1,3-diols after oxidation.

Scheme 7

Competition experiments prove the preferential activation of methyl C-H bonds over methylene C-H bonds.

Scheme 8

δ-C-H bond silylation of hydrosilyl ethers catalyzed by the combination of rhodium and xantphos generates 1,4-diols after oxidation and can be applied to the hydroxylation of complex architectures.

Scheme 9

The strategy to access β-C-H bond silylation comprises the installation of a hydrosilyl acetal directing group and C-H bond silylation. The resulting dioxasilinanes have been oxidized to the corresponding 1,2-diols

Scheme 10

Hydrosilylation of alkenes affords precursors for Ir-catalyzed δ-C-H bond silylation to yield acetyl-protected 1,4-diols after oxidation.

Scheme 11

Hydrosilyl-directed silylation of β-C-H bonds of tertiary amines followed by oxidation and protection of the resulting silapyrrolidines affords N-boc-1,2-amino alcohols.

Scheme 12

Ir-catalyzed hydrosilyl-directed silylation of enantiotopic methyl C-H bonds yields enantiopure products and can be applied to complex molecule scaffolds.

Scheme 13

Use of a chiral ancillary ligand enables the enantioselective β-C-H bond silylation reaction to occur in high yields and moderate enantioselectivities.

Scheme 14

4-step, 1-pot reaction sequence affording fully protected sugars in good yields.^–

Scheme 15

C-H bond silylation of betulinic acid occurs in modest yield.

Scheme 16

Summary of the strategic C-H bond silylations of (+)-pleuromutilin.

Scheme 17

Pd-catalyzed directed-silylation of primary C-H bonds located beta or gamma to the directing group.^–,

Scheme 18

Application of Pd-catalyzed C-H bond silylation to polypeptide substrates in modest to good yields.

Scheme 19

Ru-catalyzed silylation of the primary alkyl C(sp³)-H bond of pyridines.