The effect of process conditions (temperature, partial pressures of CO and H 2 ) on the product selectivity and ee of the palladium-catalysed asymmetric hydro-acylation of 1-pentene in dichloromethane with the chiral Josiphos ligand (SL-J008-1, L1) was investigated. The highest ee value (73%) for the desired product 4-methyl-5-decanone (1) was obtained at the lowest temperature in the range (30°C). The selectivity for 1 was between 12 and 20 mol % at 30°C, though considerably higher at 90°C (59 mol %). Statistical modeling was applied to quantify the influence of the process conditions on the product selectivity and ee.
■ INTRODUCTIONThe enantioselective production of linear α-substituted ketones is of particular interest as this structure element is present in many drugs and pheromones. 1,2 A known method for the asymmetric synthesis of α-methyl substituted ketones is the reduction of α-methylene ketones by the use of Baker's yeast (Scheme 1). 3−5 Good results were obtained in, for example, the reduction of α-methyleneketone with R 1 = Me and R 2 = n-hexyl at 30°C. A conversion of 70% was obtained after 2 h with a product ee > 99%. 5 An attractive alternative for the synthesis of α-methylsubstituted ketones is the hydro-acylation of 1-alkenes with Syngas (Scheme 2). Recently, Drent and Budzelaar reported a nonasymmetrical version of this reaction, using palladium diphosphine catalysts of the type L 2 PdX 2 (in which X is a noncoordinating anion) for the selective production of monoketones (Scheme 2). 6,7 Very promising results were obtained with a catalyst prepared in situ from Pd(OAc) 2 , an alkyldiphosphine like DnBPP (1,3-bis(di-n-butylphosphino)-propane), and trifluoromethanesulphonic acid (HOTf). For 1-octene, a chemoselectivity of 98 mol % was obtained when the reactions were performed in diglyme at 125°C with a P CO = P H 2 = 30 bar. 6,7 Our research activities concern the development of an asymmetric version of the hydro-acylation reaction given in Scheme 2. We have performed an extensive catalyst screening study with homogeneous palladium catalyst of the type (L 2 )Pd-(OTf) 2 . 8 A total of 16 diphosphine ligands belonging to four different chiral ligand classes (Josiphos, DuPhos, Walphos, and ferroTANE) were studied (Figure 1). The reactions were carried out in dichloromethane at reaction temperatures between 60 and 125°C and at initial H 2 and CO pressures of 30 bar each. The enantio-, chemo-, and regioselectivity of the reaction are a clear function of the diphosphine ligand (Table 1). Low ee values (<20%) were obtained for the Duphos ligands, albeit at a product selectivity >66 mol %. The highest ee for 1 was 39% for a Josiphos type ligand (L1) (Figure 1) at 60°C, though the product selectivity was low (6 mol %). Other products were enones, higher CO−olefin oligomers resulting from alternating CO−olefin copolymerisation aldehydes/ alcohols resulting from hydroformylation and olefin oligomerisation products (Scheme 3).In this paper, we have investigated the effects of process conditions such as tempe...