Iridium catalyzed imine hydrogenation asymmetric

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. 

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

Compared to the rhodium-catalyzed stereoselective reactions, studies on the iridium-catalyzed reactions have been limited until recently. Usually lower selectivities have been observed in the Ir(i)-catalyzed reactions.459,460 The asymmetric hydrosilylation of imines affords optically active secondary amines. These are very valuable compounds, but the studies on that reaction are quite limited.461 Close examinations of these reactions revealed that they proceed via a transfer hydrogenation. Other conditions such as the 2-propanol/base system in the presence of an appropriate metal complex have been employed as well, but only low selectivities were obtained.462... 

One of the emerging applications of 4,5-dihydroimidazole-based compounds is as chiral auxiliaries in metal complexes used for asymmetric synthesis for example, 457 in ruthenium-catalyzed DielsAlder reactions <2001 J(P 1)1500, 2006JOM(691)3445> 458 in diethylzinc addition to aldehydes <2003SL102> 459 in asymmetric intramolecular Heck reactions <20030L595> and 460 in ruthenium-catalyzed epoxidation <2005OL3393> and iridium-catalyzed hydrogenation of imines <2004TA3365>. 

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.

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. 

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

Only one paper has reported on catalytic asymmetric hydrogenation. In this study by Corma et al., the neutral dimeric duphos-gold(I)complex 332 was used to catalyze the asymmetric hydrogenation of alkenes and imines. The use of the gold complex increased the enantioselectivity achieved with other platinum or iridium catalysts and activity was very high in the reaction tested [195] (Figure 8.5). 

Alkyl and aryl substituted imines have received the most attention as substrates for asymmetric hydrogenation, and the development of the field can therefore be outlined by examining their reductions. These are usually catalyzed by chiral complexes of titanium, ruthenium, rhodium, or iridium, though gold catalysts have also recently proven useful for this purpose [31]. New catalysts are generally tested for the reductions of substrates A-D (Scheme 6.1). 

There have been multiple efforts toward supported catalysts for asymmetric transfer hydrogenation, and the 4 position on the aryl sulfonate group of 26 has proven a convenient site for functionalization. Thus far, this ligand has been supported on dendrimers [181,182], polystyrenes [183], silica gel [184], mesoporous siliceous foam [185], and mesoporous siliceous foam modified with magnetic particles [186]. The resulting modified ligands have been used in combination with ruthenium, rhodium, and iridium to catalyze the asymmetric transfer of imines and, more commonly, ketones. 

Asymmetric Transfer Hydrogenation of Ketones. The first reports on asymmetric transfer hydrogenation (ATH) reactions catalyzed by chiral metallic compounds were published at the end of the seventies. Prochiral ketones were reduced using alcohols as the hydrogen source, and Ru (274,275) or Ir (276) complexes were used as catalysts. Since then, many chiral catalytic systems for homogeneous ATH of ketones, imines, and olefins have been developed (37,38,256,257,277-289). The catalytic systems are usually based on ruthenium, rhodium, or iridium, and the ATH of aryl ketones is by far the most studied. Because of the reversibility of this reaction, at high conversions, a gradual erosion of the ee of the product has been frequently reported. An azeotropic 5 2 mixture of formic acid/triethylamine can be used to overcome this limitation. 

The Novartis process for the synthesis of the optically active herbicide(s)-metachlor (Blaser and Spindler, 1998) involves a chiral metal complex as a catalyst (see Fig. 3.11). An iridium(l) complex of a chiral ferrocenyldiphosphine catalyzes the asymmetric hydrogenation of a prochiral imine, a key step in the process. The sub-strate/catalyst ratio for this step is 750,000, tvith high turnover, thus making the process industrially viable. 

Another commercial success, this time for Novartis, was the Ir-catalyzed asymmetric synthesis of the herbicide, (5)-metolachlor, from an imine precursor. The key advantage of iridium is the extremely high rate (>200,000 TOP h ) and catalyst lifetime ( 10 TON) despite a substantially lower e.e. than with Rh. This shows both that C=N bonds can be hydrogenated, and that in commercial applications, it is not just high e.e. that counts but also productivity per unit reactor volume per unit time. 

Morimoto and co-workers reported on the total synthesis of the optically active 1-hydroxymethyl-substituted tetrahydroisoquinoUne alkaloid (S)-calycotoinine employing the Ir-catalyzed asymmetric hydrogenation of cyclic imine 197 (Scheme 30.38). Iridium(I)-(/ )-BINAP-F4-phthaUmide complex (0.5 mol%) has been used as a chiral catalyst, and hydrogenation was accomplished in tolue-ne/MeOH mixture under 100 atm at 2°C to 5°C to furnish (5)-198 in 85% yield and 86% ee. 

Mrsic N, Minnaard A, Feringa B, De Vries J. Iridium/mono-dentate phosphoramidite catalyzed asymmetric hydrogenation of AT-aryl imines. J. Am. Chem. Soc. 2009 131 8358 359. 

Recently, Lyubimov et al. [35] reported the asymmetric hydrogenation of imines catalyzed by the iridium compounds with a series of chiral phosphite-type ligands in SCCO2 (Scheme 13.8). The results showed that, in contrast to amidophosphite, diamidophosphite gave low enantioselectivity and conversion. The use of SCCO2... 

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