MEA imine hydrogenation

The next breakthrough was obtained when iridium was used instead of rhodium. This idea was inspired by results from Crabtree who had described an extraordinarily active Ir-tricyclohexylphosphine-pyridine catalyst that was able to hydrogenate even tetra-substituted C=C bonds. For the MEA imine hydrogenation very good ee values were obtained with an Ir-bdpp catalyst in the presence of iodide ions (ee 84% at 0°C) but the activity was disappointing. Turnover numbers (ton) of up to 10000 and tof numbers of 250/h (100 bar and 25 °C) but somewhat lower ee values were obtained with Ir-diop-iodide catalysts [10, 11], A major problem with these new Ir-diphosphine catalysts was an irreversible catalyst deactivation. 

Tab. 2 MEA imine hydrogenation with selected Ir-ferrocenyl diphosphine complexes (formulas see Fig. 8)...

Discovery of new Iridium diphosphine catalysts that are more active and selective than Rh cata s for MEA imine hydrogenation 1987 Ca-Sn-Pt catalyst for direct alkylation of MEA in the gas phase developed... 

Table3. MEA imine hydrogenation with Ir-ferrocenyldiphoshine complexes Comparison of catalyst performances of (a) homogeneous catalysts, (b) immobilized on silica gel, and (c) for reductive alkylation in a two-phase system (formulas see Fig. 7)...

Salzer et al. prepared a set of planar-chiral diphosphine ligands based on the arene chromium tricarbonyl backbone (Fig. 36.3) [21]. The straightforward four-step synthetic route allowed the preparation of 20 ligands of this family. These ligands were tested in Ru- and Rh-catalyzed enantioselective hydrogenation of various substrates, including the standard C=C substrates (dimethyl itaconate, methyl-2-acetamidocinnamate, methyl-2-acetamidoacrylate) as well as MEA-imine (l-(methoxymethyl)ethylidene-methylethylaniline) and ethyl pyruvate. Moderate conversions and ee-values were obtained. 

Another striking example of this principle came from the former Ciba-Geigy central research services.1141 During investigation into the discovery of a feasible protocol for the enantioselective hydrogenation of MEA-imine 20, variation of the steric and electronic influences of each phosphine unit in the... 

Scheme 5. Ciba-Geigy s Ir-catalyzed hydrogenation of MEA-imine 20.

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. 

Table 1.2 The most successful Josiphos ligands for the hydrogenation of MEA imine (for ligand structures, see Figure 1.2).

Two alternatives to the homogeneous hydrogenation of the isolated MEA imine have been investigated (see Figure 1.4). The first method involved the direct ami-nation of MEA with methoxyacetone in order to avoid isolation of the MEA imine [27] the second method involved the use of immobihzed josiphos Hgands in order to avoid product distillation [28], While both variants led to the desired product with similar ee-values as the homogeneous process, both the TON and TOF were insufficient for a technical application. 

I 1.4 The "Daniphos Ligands Synthesis and Catalytic Applications Table 1.4.2 Results of the hydrogenation of the MEA imine. 

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... 

Table 12.3 Hydrogenation of MEA imine using Ir-xyliphos catalysts.

The functionalized ligands were tested for various hydrogenation reactions (see Scheme 12.17). Ir-Josiphos bound to silica gel as well as to a water-soluble complex produced TONs in excess of 100000 and TOFs up to 20000h for the Ir-catalyzed hydrogenation of 2-methyl-6-ethyl aniline (MEA) imine to give an intermediate for (SJ-metolachlor [45a]. The polymer-bound Ir complex was much less active, and in all cases the ee-values were comparable to those for the homogeneous catalyst Selected results are summarized in Table 12.3. However, no immobilized system could compete with the homogeneous catalyst which is used to produce >10000 tonsy of enantioenriched (. S J-metolachlor and which, under optimized condi-... 

A Representative Synthesis It would be inappropriate, and near impossi ble, to review asymmetric imine hydrogenation without discussing (S) metolachlor. A great deal of progress in the iridium catalyzed asymmetric hydrogenation of imines has been inspired by the industrial synthesis of (S) metolachlor and by the extremely well documented development of this synthesis [28 30]. The key step in the commercial synthesis of (S) metolachlor is the hydrogenation of MEA imine, E (Scheme 6.2) [67]. 

Scheme 6.2 The iridium catalyzed asymmetric hydrogenation of MEA imine, E, is part of the industrial synthesis of (S) metolachlor.

Fig. 5 Imine hydrogenation structures of MEA imine and (S)-N-alkylated aniline.

Because the racemic metolachlor was produced via a reductive alkylation, it was obvious that hydrogenating the MEA imine intermediate should be tried (Fig. 5), either isolated or formed in situ. Unfortunately, at that time only one single imine hydrogenation had been described in the literature with an ee of only 22% [6]. 

The results of the route screening left the hydrogenation of the MEA imine as the only realistic possibility. 

The history of the development of a technically feasible catalyst for the enantioselec-tive hydrogenation of MEA imine has been described [3]. Collaborations, initially with a research team from the University of British Columbia at Vancouver and later with the group of J. A. Osborn of the University of Strasbourg were very important. 

After intensive development work, first in the laboratory (conqjrising >1500 ejq)eriments) and later in the pilot plant (also used for the production of the first commercial quantities), the following production process was established in early 1978 (see Figure 3) MOIP is dehydrogenated in the gas phase and MOA is isolated by azeotropic distillation vrith water. The MEA imine formed in situ fi-om MOA and MEA is hydrogenated in a batch process at 5 bar... 

Figure 10. Milestones of progress for the enantioselective hydrogenation of MEA imine (requirements ee 80%, tof >10 000 h, s/c >50 000)...

Keywords Imine hydrogenation, Ir diphosphine complexes, Ir ferrocenyldiphosphine complexes, Rh diphosphine complexes. Technical process. Industrial application, MEA imine, Ir ferrocenyldiphosphine complexes, (S)-Metolachlor, Chiral switch... 

Hydrogenation of MEA imine (Fig.4). Because the racemic metolachlor is produced via a reductive alkylation, it was obvious to try to hydrogenate the imine... 

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