Enantioselective imine hydrogenation

The formation of dimers and trimers is a major issue in hydrogenations with iridium catalysts. In the context of developing an industrial process to produce (S)-metolachlor via an enantioselective imine hydrogenation (see Chapters 34 and 37), Blaser et al. investigated the causes of catalyst deactivation in the iri-dium/bisphosphine-catalyzed hydrogenation of DMA imine (Scheme 44.11) [84]. 

Scheme 44.11 Iridium-catalyzed enantioselective imine hydrogenation.

Figure 18 Schematic catalytic cycle proposed for the enantioselective imine hydrogenation.

Tab. 3 gives an overview of the timetable and the milestones for the development of a technical process for the production of enriched (S)-metolachlor. It took so many years to reach the ambitious goal because the efforts to find a suitable catalyst system for the enantioselective imine hydrogenation had to start almost from zero. The final result of our efforts can be seen in Fig. 14 which depicts a partial view of the production unit. 

The selection of the catalytic system was especially difficult because the required catalyst performance was very ambitious and very little was known about enantioselective imine hydrogenation. 

For recent overviews on enantioselective imine hydrogenations see H. U. Blaser and F. Spindler, ChimicaOggi, 1995, June, p. 11 H. U. Blaser and F. Spindler, Proceedings of Chiral Europe 94 Synq)osium, Spring Innovations, Stoclqx)rt, UK, 1994, p. 69. 

The time for process development obviously depends very much on the state of the art of a given catalytic technology. When one has to start almost at point zero as for the enantioselective imine hydrogenation, it may take many years to reach the goal. In our experience, an empirical approach is the fastest... 

Blaser H-U, Pugin B, Spinder F, Togni A. Enantioselective imine hydrogenation with Ir diphosphine catalysts fighting deactivation. C. R. Chim. 2002 5 379-385. 

Secondary phosphine oxides are known to be excellent ligands in palladium-catalyzed coupling reactions and platinum-catalyzed nitrile hydrolysis. A series of chiral enantiopure secondary phosphine oxides 49 and 50 has been prepared and studied in the iridium-catalyzed enantioselective hydrogenation of imines [48] and in the rhodium- and iridium-catalyzed hydrogenation functionalized olefins [86]. Especially in benzyl substituted imine-hydrogenation, 49a ranks among the best ligands available in terms of ex. 

Substituents on imino nitrogen influence both reactivity and enantioselectivity in hydrogenation of imino compounds. Figure 1.32 shows two successful examples. An f-BINAPHANE-Ir complex effects asymmetric hydrogenation of A-aryl aromatic imines.On the other hand, an Et-DuPHOS-Rh complex (see Figure 1.2) is effective for hydrogenation of A-acyUiydrazones. ... 

The enantiopure aldehyde 116 could easily be obtained from ester 123 via an enantioselective transfer hydrogenation of the dihydrocarboline 121 with triethyl ammonium formate in the presence of the chiral Ru-catalyst (S,S)-122 developed by Noyori [35] imine 121 is accessible by oxidation of rac-120 (Scheme 5.21) [36]. 

As an aside, decades of work have gone into the study of enantioselective homogeneous hydrogenation processes in both organic and aqueous systems. There is increasing commercial interest in this field spurred by the spectacular, time-encrusted development of a complex catalyst for the enantioselective hydrogenation of an imine to a chiral amine needed for manufacture of the important herbicide, (,S )-Metolaclor. The technical success of this program (Scheme l)25 owed much to the perserverance... 

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