On the Mechanism of the Ruthenium‐catalyzed β‐methylation of Alcohols with Methanol

Abstract

Selective β-methylation of alcohols with methanol has been recently described using a catalytic system comprising the ruthenium pincer complex [RuH(CO)(BH 4 )(HN(C 2 H 4 PPh 2 ) 2 )]-(Ru-MACHO-BH) 1 and alcoholate bases as co-catalysts. [1] Here we present a detailed mechanistic analysis for the mono-methylation of 1-phenyl-propane-1-ol 2 a as prototypical example. Several experimentally observed intermediates were localized as stable minima on the DFT-derived energy surface of the entire reaction network. The ruthenium complex [Ru(H) 2 (CO) (HN(C 2 H 4 PPh 2 ) 2 )] I was inferred as the active species catalyzing the de-hydrogenation/re-hydrogenation of substrates and intermediates ("hydrogen borrowing"). The hydrogen-bonded alcohol adduct of this complex was identified as the lowest lying intermediate (TDI). The CÀ C bond formation results from a base-catalyzed aldol reaction comprising the transition state with the highest energy (TDTS). Experimentally determined Gibbs free activation barriers of 26.1 kcal/mol and 26.0 kcal/mol in methanol and toluene as solvents, respectively, are reflected well by the computed energy span of the complex reaction network (29.2 kcal/mol).Catalytic methods for the introduction of methyl groups into organic substrates using methanol as C1 building block offer attractive synthetic pathways in line with the principles of Green Chemistry. In particular the synthesis of methyl branches in aliphatic carbon chains using methanol remains a significant challenge, however. [2] Most recently we showed that ruthenium pincer complex [RuH(CO)(BH 4 )(HN(C 2 H 4 PPh 2 ) 2 )]-(Ru-MACHO-BH) 1 is a versatile pre-catalyst for this reaction. [1] For a broad range of primary and secondary alcohols as substrates, the methyl group is introduced selectively in βposition providing the branched products in good to very high yields with water as the only byproduct (Scheme 1). The synthetic methodology has been transferred and largely extended by the use of Mn(I)-MACHO complex most recently. [3] In this work we present a mechanistic analysis of this transformation with the original ruthenium catalyst based on experimentally and theoretically compiled data.From the results of the synthetic studies, we postulated a working hypothesis for the catalytic process exemplified in Scheme 2 for the mono-methylation of 1-phenyl-propane-1-ol 2 a to 1-phenyl-2-methyl-propane-1-ol 3 a. The overall trans-formation involves five individual cycles A-E forming a complex reaction network. Initially both alcohol and methanol are dehydrogenated by the transition metal catalyst to form ketone and formaldehyde, respectively. [4] Subsequently, a base-catalyzed aldol condensation generates the CÀ C bond [5] and finally the unsaturated intermediate is step-wise re-hydrogenated at the ruthenium catalyst.The involvement of the de-and re-hydrogenation cycles is corroborated with a series of control experiments summarized in scheme 3. 1-phenyl-propane-1-ol 2 a reacts with 13 CH 3 OH to the mono-methylated product containing the 13 ...

Carbon monoxide and hydrogen (syngas) as a C1-building block for selective catalytic methylation

“…Formaldehyde is formed as the C1 building block in situ by de-hydrogenation of methanol in these systems. [21][22][23] Starting from syngas as the C1 source would thus require to provide sufficient concentrations of formaldehyde to enter this sequence. Notably, examples for catalytic generation of formaldehyde from syngas using homogeneous catalysis are very scarce.…”

Manganese(I)‐Catalyzed β‐Methylation of Alcohols Using Methanol as C1 Source

“…Heterogeneous catalyst reports based on Ir and Pt metals also showed promising activity for this transformation . We demonstrated that the reaction can be achieved by a single Ru II pincer complex bearing the MACHO ligand . Mechanistic studies suggest that the Ru II catalyst affects the dehydrogenation of alcohol and MeOH to the corresponding aldehyde/ketone and formaldehyde.…”

“…A base mediates the aldol condensation between the carbonyl compounds. Subsequently the catalyst re‐hydrogenates the carbonyl bond and C−C coupled bond to provide the final β‐methylated product and complete the catalytic cycle . The metal–ligand cooperativity is of vital importance for the dehydrogenation/rehydrogenation steps in the complex reaction network.…”

“…Then, the selectivity starts to catch up until conversion and yield are both close to 90 % after 24 h. This can be rationalized assuming that 2‐phenyl ethanol ( 6 a ) and methanol are both converted relatively fast to phenylacetaldehyde ( 6 a′ ) and formaldehyde with the liberation of H 2 . With the base‐catalyzed aldol condensation being the slowest step in the catalytic network, the formation of the final product is delayed relative to substrate conversion . Consequently, the use of (over‐)stoichiometric amounts of base is beneficial to achieve practical reaction rates.…”

The Guerbet Reaction Network – a Ball‐in‐a‐Maze‐Game or: Why Ru‐MACHO‐BH is Poor in Coupling two Ethanol to n‐Butanol

“…[25] Thus, it appears as a suitable catalyst for the Guerbet reaction at first sight and was already applied for Guerbet reactions starting from methanol. [26,27] However, Wass et al [8] reported that Ru-MACHO is an inferior catalyst for the Guerbet reaction, but they could not find an explanation based on the structure of the catalyst. A recent study shows that Ru-MACHO degrades to a mixture of several catalytically active complexes in alkaline media.…”