Iridium catalyzed imine hydrogenation

A catalytic cycle indicating the key steps thought to occur in iridium-catalyzed imine hydrogenation is shown in Scheme 11. Coordination of the imine and insertion into an Ir-H bond gives an amido intermediate, which activates H2 to give a hydrido-amine complex. This liberates the amine product and binds another substrate molecule to complete the cycle. 

Another interesting application of high-pressure tubes is the in-situ investigation of reactions in supercritical solvents such as carbon dioxide. For example, the iridium-catalyzed enantioselective hydrogenation of imines was investigated in a sapphire tube at 313 K [32]. 

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. 

S. Kainz, A. Brinkmann, W. Leitner, A. Pfaltz, Iridium-Catalyzed Enantioselective Hydrogenation of Imines in Supercritical Carbon Dioxide , J. Am Chem Soc 1999, 121, 6421-6429. 

Iridium-Catalyzed Asymmetric Hydrogenation of Olefins with Chiral N,P and C,N Ligands 73 Table 19 Asymmetric hydrogenation of imines... 

Kainz, S., Brinkmann, A., Leitner, W. and Pfaltz, A. (1999) Iridium-catalyzed enantioselective hydrogenation of imines in supercritical carbon dioxide. /. Am. Chem. Soc., 121, 6421. 

Phosphines ligands that have chirality from ferrocenes have been implemented in the iridium-catalyzed asymmetric hydrogenation of imine with moderate enantioselectivities for Novartis s manufacture of metolachlor. Electronic modifications of these ferrocenyl ligands have increased the enantioselectivity and catalyst reactivity for Lonza s asymmetric hydrogenation processes of biotin and 2-substituted piperazines, intermediates for several pharmaceutical drugs. 

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. 10.3-11 Reductive alkylation of proteins using iridium catalyzed transfer hydrogenation, (a) The iridium(lll) catalyst shown reacts with formate ion to form a water-stable hydride. This species reduces imines formed in situ, (b) This reduction process proceeds readily on proteins, affording multiple alkylated products.

High concentrations of CO2 in the IL may enhance the solubility of reactant gases and this may explain, at least partly, observations that the presence of CO2 appears to overcome mass-transport limitations [25], The solubility of hydrogen as a reactant gas in ILs has been determined in the presence of compressed CO2 very recently [26], Indeed, a remarkable increase in concentration of the hydrogen at constant H2 partial pressure has been observed with increasing CO2 pressure. These data could be correlated with an increase in hydrogenation efEciency for the iridium-catalyzed asymmetric hydrogenation of imines. 

Hopmann, K. H. Bayer, A. On the mechanism of iridium-catalyzed asymmetric hydrogenation of imines and alkenes A theoretical study. OrganometalUcs 2011, 30,2483-2497. 

Figure 5 Catalyst recycling in the iridium-catalyzed enantioselective hydrogenation of imines in SCCO2. (Reprinted with permission from Ref. 188. Copyright 1999 American Chemical Society.)...

Baeza A, Pfaltz A. Iridium-catalyzed asymmetric hydrogenation of imines. Chemistry 2010 16(13) 4003-4009. 

The iridium-catalyzed enantioselective hydrogenation of imines in scCOj (Scheme 13.7) was reported by Leitner and Pfaltz [34]. They investigated the effects of the structures of the cation and anion on the activity and selectivity of the catalyst in detail. It was shown that the anion had a dramatic effect on the enantioselectivity, and BARF led to the highest asymmetric induction. Performing the reaction in SCCO2 allowed lower catalyst loading as weU as eflicient product isolation and catalyst recycling. 

Scheme 13.7 Iridium-catalyzed enantioselective hydrogenation of imines in scCOj.

In a study by Leitner of the iridium-catalyzed hydrogenation of imines, a nearly 20-fold increase in catalytic efficiency was observed due to a different kinetic profile in scC02 as compared to methylene chloride.358 The change in rate and selectivity found in scC02 with respect to the other solvents can be related to the following major points ... 

At the same time, however, the iridium-catalyzed hydrogenation of 80 was reported using chiral phosphoric acid diester 17be based on BINOL [47a]. Full conversion and a maximum e.e. of 50% was observed, again in a slow reaction. Interestingly, a catalyst based on palladium and 17be afforded 39% e.e. and full conversion in the hydrogenation of aryl imine 87. 

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.

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