Martin Studer

Enantioselective hydrogenation of α-ketoesters using cinchona modified platinum catalysts and related systems: A review

Abstract The state of the art for the heterogeneous enantioselective hydrogenation of α-ketoesters using cinchona modified Pt catalysts and related systems is reviewed. The effect of the following elements of the catalytic system are well known: Catalyst. Supported Pt catalysts with relatively low dispersion (particle diameter >2 nm) are preferred for the hydrogenation of α-ketoacid derivatives, Pd catalysts for functionalized olefins. Most support materials are suitable. Substrate. The reacting function is preferentially a ketone or a C=C bond, a carbonyl group in a-position is necessary for good optical yields. Modifier. The minimal requirements for an efficient modifier for the hydrogenation of α-ketoesters is the presence of a basic nitrogen atom close to one or more stereogenic centers and connected to an extended aromatic system (preferentially quinolyl or naphthyl). The presence of an alcohol or ether in β-position to the basic nitrogen often gives better enantioselectivities. Solvent. Solvents with adielectric constant between 2 and 10 give best selectivities for a-ketoesters with best e.e.s in acetic acid. For the hydrogenation of substrates with a free acid function aqueous polar solvents are preferred. The highest optical yields for the different substrate types: 95% e.e. for α-ketoesters, 85% for a-ketoacids and 70% for α,)-unsaturated acids. Practical problems for the use of the catalytic system are low e.e.s at the start of the reaction, the instability of the modifier and some side reactions as well as the purity of the ethyl pyruvate. Mechanistic investigations have established interactions between substrate and modifier in solution and adsorption of the ethyl pyruvate and cinchonidine on the catalyst. The dependence of rate and e.e. on catalyst, cinchonidine, ethyl pyruvate and hydrogen concentration has been established for ethyl pyruvate hydrogenation using Pt/Al 2 O 3 -cinchona. A Langmuir-Hinshelwood scheme is well suited for explaining the observed kinetic results. Based on the kinetic results, the effect of modifier and substrate structure, and molecular modeling studies, the following mechanistic model has been developed: On the unmodified catalyst, the a-ketoester and hydrogen are reversibly adsorbed and the addition of the first hydrogen atom is rate determining. A modified active site is formed by adsorption of one cinchona molecule. It is postulated that a protonated adsorbed modifier interacts with the α-ketoester and forms a stabilized half hydrogenated intermediate. The rate determining step for the preferred enantiomer is the addition of the second hydrogen. The rate acceleration and the enantiodiscrimination is therefore due to the preferential stabilization of one of the two diastereomeric intermediates. Alternative mechanisms are discussed but considered to be less satisfying.

Supported palladium catalysts for fine chemicals synthesis

Abstract The contribution reviews the application of heterogeneous Pd catalysts for the manufacture of fine chemicals with special emphasis of their organic synthetic potential. In a first part, some background is given on the scope and limitations of homogeneous and heterogeneous catalysis and on significant parameters and the various types of supported Pd catalysts. Then, the application of supported Pd catalysts for important classes of transformations are reviewed organized according to reaction type. The general statements are illustrated with relevant examples from the literature and from our own laboratories. Hydrogenation, hydrogenolysis, and dehydrogenation reactions are considered to be mature technologies with an extremely broad scope both for small-scale laboratory applications and large to very large-scale manufacturing processes. Oxidation reactions and CC coupling reactions usually have a rather narrow scope and only relatively few have been developed to the technical stage. Especially for CC coupling reactions, the nature of the active Pd species is under debate because it is not clear whether the reaction takes place on the metallic surface or whether leached soluble Pd complexes are the active catalysts.

Enantioselective catalysis in fine chemicals production

The application of enantioselective catalysis to the fine chemicals industry has great potential both from economic and ecological points of view, but to date has not been widely implemented on a technical scale. The author hopes that the award of the 2001 Chemistry Nobel Prize in this field will give the necessary impetus to future applications.

Solvias Josiphos ligands: from discovery to technical applications

The various stages from the invention of a ligand class to its technical application are described and illustrated by the case history of the Solvias Josiphos ligands. First, the prerequisites for a so-called “privileged ligand” are discussed, followed by a description of the Josiphos ligand family and their technical synthesis. Then, the catalytic performance of various Josiphos metal complexes in model reactions and in “real world” synthetic applications are summarized in the next two chapters. In the last part, three technical processes using Josiphos ligands are described: (i) The Ir-PPF-P(Xyl)2-catalyzed hydrogenation of MEA imine for the large scale production of the herbicide (S)-metolachlor; (ii) the application of a Rh-PPF-P(tBu)2 complex for the hydrogenation of a biotin intermediate; (iii) the Ru-PPF-P(Cy)2-catalyzed hydrogenation of a tetrasubstituted C=C bond for the production of cis-methyl dihydrojasmonate.

The role of catalysis for the clean production of fine chemicals

Abstract The role of catalysis for the production of fine chemicals is reviewed. The following topics are discussed on a general level: characteristics of the manufacture of fine chemicals, opportunities opened up by catalysis, critical factors for the application of catalysts and the tools that are available to the catalytic chemist. The general part is illustrated by specific examples from the catalysis group of Ciba-Geigy/Novartis such as chemoselective hydrogenations of aromatic nitro groups, the combination of a homogeneous and heterogeneous Pd catalyzed reaction for the alkylation of aromatic systems, catalytic systems for the enantioselective reduction of an α-keto ester, different routes to an N -alkylated hindered aniline including the (S)-metolachlor process, and the use of on-line monitoring of catalytic hydrogenations with ATR-probes. A short outlook on future developments is also presented.

Enantioselective synthesis of ethyl nipecotinate using cinchona modified heterogeneous catalysts

Ethyl nicotinate was hydrogenated to ethyl nipecotinate in two steps. In the first step, the starting material was converted to the 1,4,5,6-tetrahydro derivative with PdrC and hydrogen in 76% yield. The hydrogenation of this intermediate was investigated with both unmodified and 10,11-dihydrocinchonidine modified noble metal catalysts and the influence of the catalyst metal, support, solvent and modifier concentration was tested. Catalyst activity was low in all cases, probably because the C5C double bond is part of a vinylogeous carbamate. The highest activity was observed with Rh and RhrPt .

First Application of Secondary Phosphines as Supporting Ligands for the Palladium-Catalyzed Heck Reaction: Efficient Activation of Aryl Chlorides

Secondary dialkylphosphines were successfully used for the first time as efficient supporting ligands for the palladium-catalyzed Heck reaction of electron-rich and electron-poor aryl chlorides with olefins such as acrylate, ethylene, styrene, and n-butyl vinyl ether. The yields with HP(t-butyl)2 and HP(adamantyl)2 were comparable or better than those obtained with known systems of tertiary phosphines such as P(cyclohexyl)3 and P(t-butyl)3, especially at a catalyst loading of <1 mol %. In comparison with tertiary phosphines, the secondary phosphines have the advantage of being readily available at low cost on a technical scale, and are comparable with respect to handling and oxygen sensitivity.

Modulating the hydroxylamine accumulation in the hydrogenation of substituted nitroarenes using vanadium-promoted RNi catalysts

The effect of vanadium promotion of Raney nickel on aryl hydroxylamine accumulation in the catalytic hydrogenation of electron deficient aromatic nitro compounds was investigated. High accumulation of 70–80% was observed with unmodified Raney nickel. Vanadium promoters were able to modulate the accumulation and depending on the modifier used, an increase (up to 86%) or a decrease (down to 11%) was found. Higher rates were obtained in the former (up to a factor 1.3), lower ones in the latter case (down to a factor 0.1) compared to the unmodified system. Supported or unsupported NH4VO3 was usually the most efficient modifier for obtaining low accumulation and reasonable rates, but the optimum concentration and modification procedure had to be determined for every substrate separately. In cases of low accumulation, the vanadium promoters worked as disproportionation catalysts. Dehalogenation was not significantly influenced by the presence of promoters: in all cases dehalogenation took only place after both the nitro arene and aryl hydroxylamine compound had been consumed completely.

Influence of catalyst type, solvent, acid and base on the selectivity and rate in the catalytic debenzylation of 4-chloro-N,N-dibenzyl aniline with PdC and H2

Abstract The influence of catalyst type, solvent, and acid/base modifiers on the catalytic debenzylation of 4-chloro-N,N-dibenzyl aniline with Pd C and H2 was studied. Under the reaction conditions investigated, the catalyst-type had no significant effect. Solvents: In neutral apolar solvents, the over-all reaction was slow and the main product isolated after 1.9 mol H2-uptake was always 4-chloroaniline. No high intermediary concentration of 4-chloro-N-benzyl aniline (monodebenzylation product) was found. In polar solvents, both debenzylation and dehalogenation were much faster. After 1.9 mol H2-uptake, significant amounts of the dehalogenation product aniline were found. Catalytic amounts of strong acids significantly increased the rate for debenzylation and dehalogenation was suppressed. With equimolar amounts of strong acid, the debenzylation was slower, but high intermediary amounts (> 80%) of the monodebenzylation product could be isolated. A kinetic model to rationalize these effects was developed.

Critical issues for using enantioselective catalysis for fine chemicals production

This review describes the requirements for using enantioselective catalysis in the synthesis of fine chemicals. The most important issues are the catalyst performance (ee, activity, and productivity), the availability and cost of the catalysts, the sensitivity of the catalytic system, and the substrate price and quality. With the help of selected examples (synthesis of l-DOPA, (−)-menthol, S-metolachor, and an intermediate for ACE inhibitors), these points are illustrated. The most important tools for the optimization of a catalytic system (e.g., ligand, metal, additives, solvents, substrate quality, etc.) are also discussed. Chirality 11:459–464, 1999.