Continuous‐Flow Asymmetric Hydrogenation of the β‐Keto Ester Methyl Propionylacetate in Ionic Liquid–Supercritical Carbon Dioxide Biphasic Systems

Abstract

A continuous-flow process for the asymmetric hydrogenation of methyl propionylacetate as a prototypical b-keto ester in a biphasic system of ionic liquid and supercritical carbon dioxide (scCO 2 ) is presented. An established ruthenium/2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) catalyst was immobilised in an imidazolium-based ionic liquid while scCO 2 was used as mobile phase transporting reactants in and products out of the reactor. The use of acidic additives led to significantly higher reaction rates and enhanced catalyst stability albeit at slightly reduced enantioselectivity. High single pass conversions (> 90%) and good enantioselectivity (80-82% ee) were achieved in the first 80 h. The initial catalyst activity was retained to 91% after 100 h and to 69% after 150 h time-on-stream, where-as the enantioselectivity remained practically constant during the entire process. A total turnover number of~21,000 and an averaged space-time yield (STY av ) of 149 g L À1 h À1 were reached in a long-term experiment. No ruthenium and phosphorus contaminants could be detected via inductively coupled plasma optical emission spectrometry (ICP-OES) in the product stream and almost quantitative retention by the analysis of the stationary phase was confirmed. A comparison between batch-wise and continuous-flow operation on the basis of these data is provided.

Continuous‐Flow Asymmetric Hydrogenation of an Enol Ester by using Supercritical Carbon Dioxide: Ionic Liquids versus Supported Ionic Liquids as the Catalyst Matrix

“…[11,3] The liquid substrate was introduced through an HPLC pump, the H 2 gas was added through am ass-flow controller,a nd the CO 2 was dosed as compressed liquid via ap neumatic actuated needle valve controlled by am ass-flow meter.T he three streams passedt hrough as tatic mixer before entering the reactor.T he reactionc onditions were set at T = 60 8Ca nd at otal pressure p tot of 120 bar,b ecause this provided as uitable compromise between activity, selectivity,a nd extraction efficiency.Awindow autoclave (volume % 13 mL) equipped with am agnetic stirring bar was used as ac ontinuouss tirred tank reactor and [EMIM][NTf 2 ] (2.5 mL) as the IL phase. Behind the back-pressure regulator, the product mixture wascollected in cold traps filled with toluene and was analyzed (see the Supporting Information for details).…”

“…In previous work, we showedt hat continuous-flow asymmetric hydrogenationc an be carried out successfully with IL/ scCO 2 [3] andS ILP/scCO 2 [4] strategies. Herein, we describe the asymmetricc ontinuoush ydrogenation of the enol ester 1-(trifluoromethyl)vinyla cetate (1)t o1 -(trifluoromethyl)ethyl acetate (2;s ee Scheme 1), au seful chiral synthon for the preparation of active ingredients for the treatmento fn eurological and neuropsychiatric disorders.…”

Research Advances of the Chiral Binap-Ru(II) Catalysts in Asymmetric Hydrogenation Reactions

“…[45] 和乙醇-bmimPF 6 (41) [46] 混合相 中催化乙酰乙酸甲酯加氢, 发现这两种催化体系均表现 出非常优秀的对映体选择性. 2013 年, Leitner 课题组 [47] 2016 年, Baratta 课题组 [48] 在三乙胺存在下, 使用…”

Unlocking the potential of supported liquid phase catalysts with supercritical fluids: low temperature continuous flow catalysis with integrated product separation

“…A number of examples have successfully exploited these properties in liquid/SCF biphasic systems [ 174 ]. For example, high long-term productivity and enantioselectivity could be achieved for the asymmetric hydrogenation of β-keto esters in our group immobilizing the Ru-BINAP catalyst in bulk IL and using scCO 2 as mobile phase [ 175 ]. In contrast to the SILP/gas-phase system reported by Wasserscheid and co-workers [ 148 ], substrates of low volatility could be used at milder temperatures contributing at least partly to higher stability and enantioselectivity with scCO 2 as flow medium.…”