Metolachlor synthesis

Figure 2.55 Preparation and structure of ferrocenyl diphosphine ligands for enantioselective Metolachlor synthesis and dependence of performance on the substituents in the ligand.

This chapter summarizes some of the most characteristic results obtained with the use of mainly homogeneous metal complex eatalysts either in the industry or in processes recommended for practical use. These are large seale processes of asymmetric synthesis of the herbicide metolachlor, synthesis of optically pure menthol with the use of chiral iridium and rhodium phosphine complexes, consideration of the synthesis of ethyl 2-hydroxybutyrate as a monomer for the preparation of biodegradable polyesters with use of heterogeneous ehiral modified nickel catalyst, the manufacturing of (fJ)-pantolactone by means of a possible eata-IjTic systems for enantioselective hydrogenation of ketopantolactone, and catalytic systems for the preparation of other pharmaceuticals. 

An even more impressive example of catalytic efficiency has recently been disclosed by Novartis (Bader and Bla.ser, 1997). The key step in a proce.ss for the synthesis of the optically active herbicide, (S)-metolachlor involves asymmetric hydrogenation of a prochiral imine catalysed by an iridium-ferrocenyldipho-sphine complex (see Fig. 2.36). 

Optically active drugs now occupy centre stage status and some agrochemicals like (S)-metolachlor, have also been introduced as optically pure isomers, so that the ballast of the unwanted isomer is avoided. Asymmetric synthesis is a topic of great interest in current research, and there is a steady flow of articles, reviews and books on almost every aspect of this subject. Table 4.8 lists examples of industrially important asymmetric synthesis. 

Kumada s use of a ferrocene moved away from the C2-symmetrical motive, as planar chirality can result from the two ferrocene rings having different substituents. The development of this class of ligand is well documented [5, 125-127]. The best-known uses of these ligands are for reductions of carbon-heteroatom multiple bonds, as in the synthesis of the herbicide, Metolachlor [128, 129]. 

Enantiomerically pure amines are extremely important building blocks for biologically active molecules, and whilst numerous methods are available for their preparation, the catalytic enantioselective hydrogenation of a C=N bond potentially offers a cheap and industrially viable process. The multi-ton synthesis of (S)-metolachlor fully demonstrates this [108]. Although phospholane-based ligands have not proven to be the ligands of choice for this substrate class, several examples of their effective use have been reported. 

Indeed, the imine intermediate 142 in the synthesis of metolachlor has been reduced in 97% ee using an iridium complex of the phospholane-containing ligand 55 [80]. 

Metolachlor is the active ingredient of Dual , one of the most important grass herbicides for use in maize and a number of other crops. In 1997, after years of intensive research. Dual Magnum, with a content of approximately 90% (I S)-diastereomers and with the same biological effect at about 65% of the use rate, was introduced into the market. This chiral switch was made possible by the new technical process that is briefly described below. The key step of this new synthesis is the enantioselective hydrogenation of the isolated MEA imine, as depicted in Figure 1.3. 

Togni and Spindler introduced non-C2-symmetric ferrocene-based Josiphos-type ligands [47], which are effective for rhodium-catalyzed hydrogenation of a-(acetami-do)cinnamate, dimethyl itaconate, and / -keto esters. The Josiphos-type hgands have been applied as the stereodefming step in a number of industrial processes, as exemplified the use of PPF- Bu2 for the commercial synthesis of (-i-)-biotin [48], and Xyli-Phos for the preparation of the herbicide (S)-metolachlor [49]. 

Quite a wide range of substrates 100 could be converted into products 101 with high ee values since it is known that the N-protecting group of 101 can easily be cleaved, the approach represents a formal synthesis of optically active amines. It remains to be seen if this iridium/sulfoximine combination also opens up an alternative access to industrially relevant products such as the herbicide (S)-metolachlor produced by Syngenta [80]. 

Source Advanced Synthesis Catalysis, H.-U. Blaser (Solvias) personal communication Fig. 13.8 Metolachlor story - activity-selectivity labyrinth. 

The raw materials used in the commercial synthesis of metolachlor include 2-ethyl 6-methyl-aniline, which can be built up from... 

Enantioselective Hydrogenation of A -Arylimines in the Synthesis of the Chiral Herbicide, ( S)-Metolachlor... 

The synthesis of racemic metolachlor was accomplished by condensation of 2-methyl-6-ethyl-aniline (MEA) with methoxyacetone, followed by Pt/C reduction and chloroacetylation according to Figure 16. 

The chiral switch of the metolachlor was achieved in 1997. It was put on the market with a content of approximately 90% of the Sc active diastereomers. The key step of the large-scale enantioselective synthesis is the catalytic hydrogenation of the MEA imine shown in Figure 17. A mixture of [IrCl(l,5-cyclooctadiene)]2, the chiral diphosphine (i ,5)-xylyphos, iodide (as tetrabutylammonium or sodium salts) and acetic (30%) or sulfuric (at low... 

Scheme 9.20 illustrates the last key steps in the synthesis of (S)-metolachlor. Early on, researchers at Novartis turned their attention to creating conditions for an asymmetric, homogeneous, metal-catalyzed hydrogenation of imine 83 to... 

For a rendition of the story behind the research and development of the asymmetric hydrogenation in the synthesis of (S)-metolachlor, see H.-U. Blaser, Adv. Synth. Catal., 2002, 344, 17. 

The syntheses of ibuprofen, (S)-metolachlor, and (-)-menthol represent only three of the numerous uses of soluble transition metal complexes to catalyze, often stereoselectively, key steps in the production of biologically important compounds in the laboratory or on an industrial scale. Discussions in Chapter 12, especially with regard to asymmetric conditions, will explore more fully the use of these catalysts in the synthesis of other organic compounds. 

In Section 9-4-3, we mentioned that cationic Ir catalysts (sometimes called Crabtree catalysts) are quite active for hydrogenation of highly substituted C=C bonds. Moreover, asymmetric Ir-catalyzed hydrogenation of an imine is a key step in the industrial-scale synthesis of the herbicide (S)-metolachlor (Section 9-7-2). In addition to these applications, relatively recent work has shown that cationic Ir(I) complexes bonded to chiral ligands can catalyze asymmetric hydrogenation of unfunctionalized C=C bonds (i.e., C=C bonds to which no polar functional groups, such as C=0, are attached). 

The synthesis of metolachlor (17) is described in detail elsewhere (Chapter 9). This compound is sold as an enantioenriched compound (—80% ee) rather than the pure enantiomer due to economic constraints. 

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