Xyliphos ligand

The benchmark ligand for this reaction, which is also the one used for the industrial-scale reaction, is the Xyliphos ligand, a ferrocene-based diphosphine bearing the same stereochemical features and substitution pattern as ligand... 

Figure 6.28 Structural formulas of the DiPAMP, BINAP, and Xyliphos ligands.

Another useful reduction process is asymmetric transfer hydrogenation (ATH) where the hydrogen is transferred from the solvent, often isopropanol, to the ketone or imine function to produce the enantiopure alcohol or amine. For example, Baratta et alP made ruthenium complexes containing the (/ ,S)-Xyliphos ligand to reduce a simple ketone to (5)-l-(3-trifluoromethylphenyl)ethanol, used in the synthesis of the fungicide (5)-MA20565 (Scheme 3). 

The following three separation methods of product from the Ir-catalyst were evaluated distillation, extraction and filtration. For the last two options the preparation of new modified extractable or immobilized xyliphos ligands was necessary. However, lower activity and selectivity of these xyliphos derivatives and the additional development work that would have been required led to the decision to stay with the already well optimized soluble xyliphos system. After the hydrogenation step, a continuous aqueous extraction is performed to neutralize and eliminate the acid from the crude product. After flash distillation to remove residual water the catalyst is separated from (S)-NAA in a subsequent distillation on a thin film evaporator (see Fig. 13). From the organic distillation residue, Ir could in principle be recovered whereas the chiral ligand decomposes. Owing to the very low catalyst concentrations, Ir recovery is not economical. 

Scheme 12 Iridium (iodo) and (hydrido) (iodo) complexes containing the xyliphos ligand.

The optimized process operates at 80 bar hydrogen and 50 °C with a catalyst generated in situ from [Ir(cod)Cl]2 and the Josiphos ligand PPF-PXyl2 (short name Xyliphos) at a SCR of >1000000. Complete conversion is reached within 3—4h, the initial TOFs exceed 1 800 000 h 1, and the ee is about 80%. This process is now operated by Syngenta on a scale of >10000 ty-1 [127]. 

Figure 3.36 a The original Josiphos ligand b the Ir-xyliphos complex used in the Ciba-Geigy metolachlor process. 

Fig. 3.24 Lonza s biotin process using Rh-Xyliphos-type ligands.

As described above, the Ir-xyliphos catalysts showed extremely high catalyst activities and productivities. On the other hand, the enantioselectivity to the desired S-enantiomer just barely met the requirements. Therefore, we tried to improve the ee values by tuning of the electronic and steric properties of the new ferrocenyl ligands. As shown in Tab. 2, it was indeed possible to increase the selectivity of the catalyst, however, as observed earlier with other ligands, any gain in selectivity was always offset by a loss in catalyst activity and often productivity. In the end, xyliphos was the best compromise as regards activity and selectivity for a technical process. 

At the moment, the production process made possible by the extraordinarily active and productive Ir-xyliphos catalyst is the exception, but there are indications that other technical applications might be feasible. For preparative apph-cations in the laboratory some catalytic know-how" is required to make these catalysts work. The scope of the various catalyst types is sometimes still rather narrow, but will most likely improve with time. However, in most cases activity and productivity must be improved decisively. As more and more types of ligands are becoming commercially available a broader catalyst screening will become possible. This means that progress regarding both enantioselectivity and activity is quite likely. 

In recent years an amazing number and variety of chiral ferrocene ligands have been used in asymmetric catalysis. A quite remarkable example of the great utility of chiral ferrocene hgands is the synthesis of a precursor of the herbicide (IX)-metolachlor by an Ir-Xyliphos-catalysed asymmetric imine hydrogenation reaction (Scheme 3.19). 

Particularly interesting are the industrial applications of catalytic systems based on these ligands. Thus, as the most illustrative example an enantioselective catalytic process for the large-scale production of the herbicide (S)-metolachlor has been developed (173,174). The key step is the asymmetric hydrogenation of an imine using an Ir/Xyliphos complex (Fig. 46). 

Studies of imine binding to iridium employed a slightly simpler 2,6-dimethylphenyl-substituted imine rather than the 2-methyl-6-ethylphenyl-substituted imine of the commercial process. Treatment of [Ir(cod)(xyliphos)]BF4 with the imine under H2 resulted in displacement of 1,5-cyclooetadiene, oxidative addition of H2, and binding of the imine in a chelate manner. The Ir(lll) dihydride adduct, [Ir(xyliphos)(MeOCH2-C(Me)=N(2,6-Me2C6H3)H2]BF4, was shown by NMR spectroscopy to exist as a mixture of foru stereoisomers, each having m-hydride ligands, with the methyl ether function always trans to hydride and the imine N trans to P. The two major isomers, shown in Scheme 13, are formed in almost equal amounts. 

Reactions of the cationic Ir(l) complexes [Ir(cod)(xyliphos)]BF4 and [Ir(cod)(K -ArN=C(Me)CH20Me)]BF4 with I2 resulted in transformations involving C-H activation of the 1,5-cyclooctadiene ligand. Although the current evidence does not allow precise formulation of all the species which participate in the catalytic cycle, the results summarized above provide some important observations concerning ligand-coordination modes and interconversions. 

Nowadays enantioselective synthesis of the herbicide (5)-metolachlor (Dual Magnum) is, to our knowledge, one of the most successful commercial applications of asymmetric C=N bond hydrogenation. Developed by Blaser and Spindler as a key step in the technical synthesis of (5)-metolachlor, the enantioselective hydrogenation of an imine intermediate 193 proceeds in the presence of an iridium ferrocenyl-diphosphine catalyst bearing a Solvias Josiphos-type chiral ligand (/ )-Xyliphos to give... 

The chelating phosphine 2.56 is called DIPAMP. It was found to be effective for the industrial manufacture of l-DOPA by Knowles. The ligand 2.57 is also a chiral chelating phosphine, but it is made from ferrocene. It is called Josiphos or Xyliphos depending on the R and R groups. It is used for the industrial manufacture of (S)-metolachlor (see Section 5.1.2). 

Apart from the manufacture of l-DOPA, there are many other appU-cations of asymmetric hydrogenation reactions. Two important examples are the industrial manufacture of intermediates for the herbi-cide(S)-metolachlorandthepharmaceuticalcandoxatril.(S)-metolachlor is manufactured at a >10,000 ton/year scale. In the first step of reaction 5.1.2.4, the imine is hydrogenated using an Ir analogue of 5.1 and Xyliphos (see 2.57) as the chiral ligand. 

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