Catalytic functionalization of unactivated primary C-H bonds directed by an alcohol

Abstract

New synthetic methods for the catalytic functionalization of C-H bonds have the potential to revolutionize the synthesis of complex molecules. However, the realization of this synthetic potential requires the ability to functionalize selectively one C-H bond in a compound containing many such bonds and an array of functional groups. The site-selective functionalization of aliphatic C-H bonds is one of the greatest challenges that must be met for C-H bond functionalization to be used widely in complex-molecule synthesis, and processes catalysed by transition-metals provide the opportunity to control selectivity. Current methods for catalytic, aliphatic C-H bond functionalization typically rely on the presence of one inherently reactive C-H bond, or on installation and subsequent removal of directing groups that are not components of the desired molecule. To overcome these limitations, we sought catalysts and reagents that would facilitate aliphatic C-H bond functionalization at a single site, with chemoselectivity derived from the properties of the catalyst and site-selectivity directed by common functional groups contained in both the reactant and the desired product. Here we show that the combination of an iridium-phenanthroline catalyst and a dihydridosilane reagent leads to the site-selective γ-functionalization of primary C-H bonds controlled by a hydroxyl group, the most common functional group in natural products. The scope of the reaction encompasses alcohols and ketones bearing many substitution patterns and auxiliary functional groups; this broad scope suggests that this methodology will be suitable for the site-selective and diastereoselective functionalization of complex natural products.

Figure 1 ∣. Hydroxyl-directed γ-oxygenation of secondary and tertiary alcohols and ketones.

Overall isolated yields for reactions conducted on a 1.0-mmol scale following purification by silica-gel chromatography. Reagents and conditions: a, 7 (to give products marked *) or 8 (products marked **) (1.0 equiv.), Et₂SiH₂ (1.2 equiv.), [Ir(cod)OMe]₂ (0.05 mol %), THF, room temperature (rt); removal of volatiles, then [Ir(cod)OMe]₂ (0.5 mol %), Me₄phen (1.2 mol %), nbe (1.2 equiv.), THF, 80–100 °C. b, KHCO₃ (2.5 equiv.), 30% aqueous H₂O₂ (10 equiv.), THF/MeOH, 50 °C. c, Ac₂O (1.5–3.0 equiv.), DMAP (0–0.05 equiv.), CH₂Cl₂/Et₃N, room temperature. Ac₂O, acetic anhydride; DMAP, 4-dimethylaminopyridine; Et₃N, triethylamine. For full experimental details, see the Supplementary Information.

Figure 2 ∣. Functional-group tolerance of hydroxyl-directed γ-oxygenation.

Overall isolated yields for reactions conducted on a 1.0-mmol scale following purification by silica-gel chromatography. Reagents and conditions: a, 7 (to give products marked *)or 8 (products marked **) (1.0 equiv.), Et₂SiH₂ (1.2 equiv.), [Ir(cod)OMe]₂ (0.05 mol %), THF, room temperature; removal of volatiles, then [Ir(cod)OMe]₂ (0.5 mol %), Me₄phen (1.2 mol %), nbe (1.2 equiv.), THF, 100–120 °C. b, KHCO₃ (2.5 equiv.), 30% aqueous H₂O₂ (10 equiv.), THF/MeOH, 50 °C. c, Ac₂O (1.5–3.0 equiv.), DMAP (0–0.05 equiv.), CH₂Cl₂/Et₃N, room temperature. For compounds 9t, 9u, 9v and 9w, step a (first half) used Ru(PPh₃)₃Cl₂ (0.2 mol %) in benzene or toluene at 50 °C. For compound 9u, step a (second half) used 2 mol % [Ir]/Me₄phen. For full experimental details, see the Supplementary Information.

Figure 3 ∣. Directed aliphatic C─H functionalization of natural products.

a, Directed γ-functionalization of the monoterpenes fenchol (10) and camphor (12). b, Hydroxyl-directed γ-functionalization of the triterpenoid saponins methyl oleanate (14b) and methyl glycyrrhetinate (16). For full experimental details, see the Supplementary Information.