Engineering Catalysts for Selective Ester Hydrogenation

Abstract

The development of efficient catalysts and processes for synthesizing functionalized (olefinic and/or chiral) primary alcohols and fluoral hemiacetals is currently needed. These are valuable building blocks for pharmaceuticals, agrochemicals, perfumes, and so forth. From an economic standpoint, bench-stable Takasago Int. Corp.’s Ru-PNP, more commonly known as Ru-MACHO, and Gusev’s Ru-SNS complexes are arguably the most appealing molecular catalysts to access primary alcohols from esters and H2 (Waser, M. et al. Org. Proc. Res. Dev. 2018, 22, 862). This work introduces economically competitive Ru-SNP­(O) z complexes (z = 0, 1), which combine key structural elements of both of these catalysts. In particular, the incorporation of SNP heteroatoms into the ligand skeleton was found to be crucial for the design of a more product-selective catalyst in the synthesis of fluoral hemiacetals under kinetically controlled conditions. Based on experimental observations and computational analysis, this paper further extends the current state-of-the-art understanding of the accelerative role of KO-t-C4H9 in ester hydrogenation. It attempts to explain why a maximum turnover is seen to occur starting at ∼25 mol % base, in contrast to only ∼10 mol % with ketones as substrates.

Alkali Metal Alkoxides in Noyori‐Type Hydrogenations

“…In summary, intrinsic catalytic abilities of KO t Bu and other bases are, for the most part, kinetically silent when Noyori‐type molecular catalysts are involved in the hydrogenations of ketones and esters. The base/catalyst concentration does not seem to have an effect on the reaction [7a,21] …”

“…To date, I am unaware of any report on alkali metal alkoxides‐catalyzed ester hydrogenation. Computational studies suggest that the activation barrier of such a reaction with KO t Bu is ∼2 kcal mol −1 above that of ketones, [17] and ∼15 kcal mol −1 above the typical barrier with Noyori‐type catalysts [7a] . However, the practical realization of alkali metal alkoxides‐catalyzed ester hydrogenation could be challenging due to the need for harsher conditions, which might trigger side reactions involving aldehydes as intermediates.…”

“…As a last point, physical activation via polarization of a catalyst within the catalyst‐substrate complex through noncovalent cation−π interactions, [25] where the M a + bonds to a phenyl (or similar) moiety of a ligand, may also play an important role in catalyst activation (Figure 5). Computational analysis suggests that such interaction might actually increase the activation barriers [7a] . Therefore, catalyst deactivation could be an important factor when extremely large base concentrations are employed.…”

Ruthenium-Catalyzed Ester Reductions Applied to Pharmaceutical Intermediates

“…24 A simplified mechanistic cycle is illustrated below (Figure 2). For more in depth mechanistic discussions, see work by Dub 25,26 and Schaub. Adoption of this technology within the pharmaceutical industry in contrast has been significantly slower, and metal hydride reagents are more typically employed.…”

Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist

“…A lower activity of Ru-SNS, with higher selectivity towards the hemiacetal intermediate 4 when compared to using Ru-MACHO as catalyst, has been reported by Dub and co-workers. 32 A long run experiment was performed over a total operation time of nearly 6 hours to demonstrate the stability of the process (entry 6b). A gas-liquid separator was incorporated into the flow setup after the BPR to enable inline analysis (Fig.…”