HCl/DMF for enhanced chemoselectivity in catalytic hydrogenolysis reactions

Optimized Conditions for the Palladium‐Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

“…Ley et al found competitive hydrogenation of benzyl ethers in the synthesis of a high mannose type nonasaccharide but were unable to eliminate this side reaction and ultimately had to accept a 35 % yield in the final step . While Ellervik et al described partial and total saturation of naphthoxylosides during hydrogenolysis in their efforts towards developing anti‐tumor drugs, ultimately using solvent effects to tune the selectivity of the catalyst …”

“…Inspired by the work of Morooka et al and Ellervik et al,, we explored the role of solvents in influencing palladiums selectivity, with an emphasis on our desire to eliminate the saturation of the benzyl and naphthylmethyl groups. Aqueous solvent mixtures containing tetrahydrofuran, acetone, and N,N ‐dimethylformamide (DMF) mixtures all reduced the level of saturation compared to ethyl acetate and 1,4‐dioxane aqueous mixtures (organic/aqueous, 80:20, v/v).…”

Optimised Conditions for the Palladium-Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

“…We reasoned that a pre-conditioned catalyst could improve the selectivity of the reaction by tuning the catalyst to the 'correct' reactivity prior to being exposed to our substrate. [14] Pre-conditioned aqueous mixtures of tetrahydrofuran and acetone still led to quantities of the saturated ethers (confirmed by 1 H NMR). Acetone containing solvent systems also had to be abandoned due to the reaction of the amino group of 8 with the carbonyl carbon of the acetone.…”

“…Catalyst pre-treatment strategy Initially, we presumed the aqueous DMF solvent system suppressed the formation of saturation side-products due to solvent effects, e.g., intermolecular interactions or dielectric constants. [14,17,18] However, conflicting observations including the requirement of stoichiometric quantities of catalyst in batch, the loss of our acetylation pattern when samples were stored in crude mixtures, and the loss of activity of catalyst-cartridges in flow led us to investigate further. In literature, it is known that in acidic or basic aqueous systems DMF can undergo a gradual decomposition to dimethylamine and carbon monoxide.…”

Optimised Conditions for the Palladium-Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

“…Inspired by the work of Morooka et al and Ellervik et al, [14,17] we explored the role of solvents in influencing palladiums selectivity, with an emphasis on our desire to eliminate the saturation of the benzyl and naphthylmethyl groups. Aqueous solvent mixtures containing tetrahydrofuran, acetone, and N,N-dimethylformamide (DMF) mixtures all reduced the level of saturation compared to ethyl acetate and 1,4-dioxane aqueous mixtures (organic:aqueous, 80:20, v/v).…”