A Convenient Ruthenium‐Catalysed α‐Methylation of Carbonyl Compounds using Methanol

Abstract

An efficient ruthenium catalyst is reported, for the first time, to catalyse the α‐methylation of ketones and esters using methanol as a green methylating agent. The in situ generated catalyst from the complexes [RuCp*Cl2]2 or [RuCp*Cl2]n with dpePhos provided up to quantitative yields in the presence of only 20 mol% of lithium tert‐butoxide (LiO‐t‐Bu) as a base. Regioselective mono‐ or multi‐methylation could be effectively controlled by temperature. This catalyst system was also effective for the one‐pot sequential α‐alkylation–α‐methylation of methyl ketones and conjugate reduction–α‐methylation of α,β‐unsaturated ketones to synthesise α‐branched ketones. An application of the α‐methylation of esters using the ruthenium catalyst was demonstrated for an alternative catalytic synthesis of Ketoprofen.magnified image

α‐Methylation of Ketones with Methanol Catalyzed by Ni/SiO2‐Al2O3

“…The reactions between acetophenone 1b , methanol and either benzyl alcohol 5a or 4‐methoxybenzyl alcohol 5b successfully gave 6a and 6b in good yields (56 % and 58 %, respectively). Such reactions have already been studied by other groups with expensive noble metal catalyst only, such as Ru,[13b] Ir[12a] and Pd. [19b] Therefore, the promising results in this work constitute the first example of a three‐component cross‐alkylation‐methylation of ketones with methanol and higher alcohols catalyzed by a supported non‐noble metal.…”

“…In the past decade, methanol has been successfully used for the α‐methylation of ketones through the borrowing hydrogen methodology (Scheme ). This reaction has been mainly reported with homogeneous Ir, Ru and Rh complexes (Scheme a). More recently, it has been shown that non‐noble metal complexes of Co, Mn, Ni and Fe could efficiently catalyze this reaction (Scheme b).…”

Base Metal‐Catalyzed C‐Methylation Reactions Using Methanol

“…Applying optimized conditions, a series of functionalized ketones including heterocyclic and aliphatic ones are converted into their corresponding methylated or dimethylated products in low to high yields (23–95%) (Scheme 21A). This procedure also allowed for the catalytic α ‐methylation of challenging ester derivatives, which have been less explored [19b] . Several aryl acetic esters were methylated with methanol in moderate to good isolated yields (20–95%) (Scheme 21B).…”

Transition‐Metal‐Catalyzed Utilization of Methanol as a C1 Source in Organic Synthesis

“…Very recently,S eayad and co-workers [20] developed an elegant procedure for the a-methylation of ketones with ruthenium catalysts (Figure 3a). Key to success was the use of RuCp*(dpePhos)Cl as the catalyst along with as ubstoichiometric amount of LiOtBu as the base.A side from ketones, this catalyst system enabled the methylation of alcohols ( Figure 3b…”