Ir-catalyzed hydrogenation of imines

The hydrogenation reaction was applied in the synthesis of the chiral antidepressant drug sertraline. 

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Scheme 3 Summary of the best results obtained in the Ir-catalyzed hydrogenation of imines using the combination of ligand 23 and triphenylphosphine...

Ligand Design in Metal Chemistry 4.2.9 Ir-catalyzed hydrogenation of imines... 

In the initial mechanistic studies of the Ir-catalyzed hydrogenation of imines catalytic cycles involving imine coordination to the metallic center have been considered. - However, in the recent computational study of Hopmann and Bayer it has been shown that in the case of asymmetric hydrogenation with [lr(PHOX)(cod)]+BArF" 9 various catalytic cycles containing coordinated imine are characterized with unreasonably high activation barriers (35-50 kcal/mol). On the other hand, a catalyhc cycle resembling that outlined in 2006 by Oro et al. (Figure 1.30) - has been found kinetically feasible. 

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

Scheme 1 Proposed mechanism for the Ir-f-binaphane-catalyzed hydrogenation of imines. S = substrate or solvent...

Application of the known iridium-catalyzed hydrogenation of imines to the pyridine system results in excellent yields and good enantiomeric excess when reaction conditions, catalysts, and activated pyridines are optimized. Among the findings are the use of molecular iodine to oxidize the Ir(l) to Ir(lll) in situ, choice of ligand, and that of a variety of 2-methylpyridines, activated and unactivated, only the A -acyliminopyridinium ylide 193 was hydrogenated (Equation 101) <2005JA8966>. The conditions shown for synthesis of 194 are optimal. 

Selected Results for Ir-f-Binaphane (lr-11)-Catalyzed Hydrogenation of Imines 27... 

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 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-... 

Scheme 6.17 Ir-catalyzed hydrogenation of allyl alcohols and imines...

A very recent example on the application of phosphinines in homogeneous catalysis was reported by Neumann [69]. The chiral oxazoline-functionalized phosphinine 8 (Fig. 6.5), first reported by Breit et al., was applied in the Ir-catalyzed hydrogenation of several highly substituted unfunctionalized and functionalized alkenes and imines (Scheme 6.17). 

The direct reductive amination (DRA) is a useful method for the synthesis of amino derivatives from carbonyl compounds, amines, and H2. Precious-metal (Ru [130-132], Rh [133-137], Ir [138-142], Pd [143]) catalyzed reactions are well known to date. The first Fe-catalyzed DRA reaction was reported by Bhanage and coworkers in 2008 (Scheme 42) [144]. Although the reaction conditions are not mild (high temperature, moderate H2 pressure), the hydrogenation of imines and/or enam-ines, which are generated by reaction of organic carbonyl compounds with amines, produces various substituted aryl and/or alkyl amines. A dihydrogen or dihydride iron complex was proposed as a reactive intermediate within the catalytic cycle. 

Enantiopure phosphinodihydrooxazoles were used in the Ir-catalyzed enantioselective hydrogenation of imines in CH2C12. Leitner reported that it is possible to replace the organic solvents with scC02 without loss of enantioselectivity, if these Ir catalysts are suitably tailored to the specific properties of the reaction medium by careful choice of the substituents on the chiral ligands and in the anion 365... 

Fig. 34.14 Schematic catalytic cycle postulated for the Ir diphosphine-catalyzed hydrogenation of N-aryl imines. For clarity, the halide ligands are not shown.

The asyininetric hydrogenation of imines provides an efficient and direct route for the synthesis of chiral amines. Zhu et al. [27a] reported a highly efficient asymmetric hydrogenation of acyclic A -aryl ketimines catalyzed by lr-(5 5)-25a under ambient pressure with excellent enantioselectivities (up to 91% ee) (Scheme 24). The high rigidity and bulkiness of the ligands 25 efficiently prevents the trimerization of the catalysts Ir-25 and maintains the stability of the catalysts under hydrogen atmosphere. 

A remarkable increase in catalyst efficiency in SCCO2 as compared to conventional solvents was observed for the Ir-catalyzed enantioselective hydrogenation of imines shown in Scheme 12.12 [34]. Imine hydrogenation is a key step in the commercial synthesis of (S)-metolachlor, a commercial herbicide produced by Novartis in Switzerland. The reaction is approximately zero-order with respect to substrate in CO2 whereas it slows down dramatically at higher conversion in the organic solvent (Fig. 12.8). Thus, the time required for quantitative conversion is reduced by a factor of 20 when changing from the conventional to the supercritical solvent ... 

In comparison to Rh and Ru catalysis, Ir-catalyzed hydrogenation developed much later and still is used much less in industry. The discovery by a Ciba-Geigy team [107] that Ir catalysts are superior to Rh and Ru for the hydrogenation of N-aryl imines, culminating in the development of the (5)-metolachlor process (see below) gave Ir catalysis a strong boost. 

After this success, Ir catalysts were employed more often, and it was shown that besides imines, C=0 as well as C=C btmds could be hydrogenated with good success. The hydrogenation depicted in Scheme 47 was developed by Lonza [38] for an intermediate of dextromethorphan and carried out on >100-kg scale. Important success factors were the ligand fine tuning and the use of a biphasic system. Chemoselectivity is high but catalyst productivity rather low for an economical technical application. Bristol-Meyers Squibb [111] achieved the first case of Ir diphosphine-catalyzed hydrogenation of a C=C bond to prepare a lactam pharmacaphore on a 20-kg scale (Scheme 48). DSM [112] in collaboration with Solvias developed a new route for biotin, based on the unprecedented reduction of... 

Figure 1.30 Catalytic cycle for the Ir-catalyzed asymmetric hydrogenation of imines. Dihydrogen replaces coordinated imine in A yielding molecular hydrogen complex B with a molecule of imine in the outer sphere. Then imine is pro-tonated by one of the hydrogen atoms from the H2 molecule to give neutral Ir complex C. The following hydride transfer of the hydride trans- to phosphorus gives the catalyst-product complex D. Replacement of the product with a new substrate molecule finishes the catalytic cycle recovering A.

Zhu, G. Zhang, X. Additive effects in Ir-BlCP catalyzed asymmetric hydrogenation of imines. Tetrahedron Asymmetry 1998, 9,2415-2418. 

Binol-derived phosphoroamidite PipPhos (19) has been successfully used as a ligand for the Ir-catalyzed asymmetric hydrogenation of 2- and 2,6-substituted quinolines [39], 2- and 2,6-substituted quinoxalines [40], and IV-aryl imines [41] (Fig. 16). 

Figure 1.33. Industiral asymmetric hydrogenation of a functionalized imine catalyzed by XYLIPHOS-Ir complex.

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... 

Most recently, these BlNAP-cored dendrimers were further employed in the Ir-catalyzed asymmetric hydrogenation of quinolines by Fan et al. (Scheme 4.3) [33]. Unlike the asymmetric hydrogenation of prochiral olefins, ketones and imines, the hydrogenation of heteroaroniatic compounds proved to be rather difficult [34—37]. All four generations of dendrimer catalysts generated in situ from BlNAP-cored dendrimers and [lr(COD)Cl]2 were found to be effective, even at an extremely high substrate catalyst ratio in the asymmetric hydrogenation of quinaldine with... 

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