Hydrogenation of imines

Enantioselective hydrogenation of imines to produce optically active amines is an important synthetic reaction. The imine of acetophenone is hydrogenated in the presence of chiral phosphine-Rh(I) complexes in 

SCHEME 76. Asymmetric hydrogenation of imines catalyzed by [IrHI3(diphosphme)]2. 

SCHEME 78. Titanocene-catalyzed asymmetric hydrogenation of imines. 

Addition of Hydrogen and Hydrogen Cyanide to Carbon-Carbon Double and Triple Bonds, in G. Wilkinson, F. G. A. Stone, and E. W. Abel, eds., Comprehensive Organometallic Chemistry, Vol. 8, Chap. 51, Pergamon Press, Oxford, 1982. 

The hydrogenation of C=N double bonds is an important synthetic strategy for the synthesis of secondary amines. Chiral iridium catalysts allow the hydrogenation of prochiral imines to be carried out with high enantioselectivity in conventional liquid solvents. Such a process has already found industrial application in the preparation of (S)-metolaclor, a herbicide produced by Novartis in Switzerland [40]. Recent research at the Max Planck Institute for Coal Research has demonstrated that reactions of this type can be carried out in SCCO2 with the same level of enantioselectivity and with enhanced catalyst efficiency [12]. 

With substrate 8a, the use of SCCO2 leads to a significant improvement of the performance of the catalyst compared to the reaction in CH2CI2. Hence, significantly lower amounts of iridium complex are required for efficient catalysis in the supercritical medium and turnover frequencies (TOF, mole product per mole metal center per hour) above 2,000 h were achieved at catalysts loadings as low as 0.014 mol%. It is important to note that this effect is not related to a simple increase in reaction rate, but rather to a change in the overall kinetic behavior of the catalytic system. 

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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. 

Ir(cod)Cl]2 + bcpm + (a) nBu4NI or Nil3 2,3,3-trimethylindolenine Asymmetric hydrogenation of imines 722... 

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 ... 

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... 

Iridium(III) hydride forms complexes with DIOP, BDPP (2,4-bis(diphenyl-phosphino)pentane), NORPHOS, and BINAP ligands to produce amines in 11 -80% ee.679 Similar modest results are obtained in the reduction of N-arylketimines with an iridium(HI) complex with (2S,3 S) -C HIRA PHOS as the chiral ligand.680 The indium complexes with chiral phosphinodihydrooxazoles catalyze the enantioselective hydrogenation of imines in supercritical carbon dioxide with up to 80% ee, but generally lower ee values are observed in... 

Scheme 8.4. Catalytic hydrogenation of imines using cationic iridium catalysts with the C02-philic BARF anion...

Scheme 3. Chemoselective hydrogenation of imine 8 in a hydrogenation reactor...

Hydrogenation of Imines with Croup III and Lanthanide Complexes... 

The hydrogenation of imines is typically carried out with 1 mol% of the lantha-nocene catalyst under an H2 pressure of 13 bar at 90°C [127]. The best catalysts are based on Sm having Cp ligands, the ansa systems being unreactive. The rate and the total conversion are improved by the addition of PhSiH3, probably because it stabilizes the system (Table 6.16), and both are very sensitive to the... 

Table 6.16 Hydrogenation of imines catalyzed by Croup III and lanthanide complexes.

Samec and Backvall found that the dinuclear Shvo complex catalyzes the transfer hydrogenation of imines using benzene as solvent and isopropanol as the hydrogen source (Eq. (45)) [76]. These catalytic hydrogenations were typically carried out at 70 °C, and gave >90% yields of the amine in 4 h or less. 

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]. 

A trons-[RuCl2(diphosphine)(l,2-diamine)] complex with (R,R)-Et-DuPhos and (R,R)-l,2-diaminocyclohexane as the ligand combination has been found to be effective for the hydrogenation of imine 143, with up to 94% ee being obtained under the standard basic conditions employed for this catalytic system [198]. Unfortunately, the optimum combination of chiral diphosphine and diamine was found to be substrate-dependent, with only 40% ee being obtained for 2-methylquinoxaline 144 with Et-DuPhos. 

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. 

In contrast to the hydrogenation of imines, where addition of acids and/or iodine often has a beneficial effect, here additives of this type were found to deactivate the catalyst. 

Ru-diphosphine-diamine complexes developed originally by Noyori for the hydrogenation of aryl ketones are also suitable for the hydrogenation of imines. The best results are obtained for N-aryl imines where a Ru-duphos-diamine complex achieved up to 94% ee, albeit with relatively low activity and productivity (entry 3.7) (for data relating to cyclic imines, see Table 34.5). 

Only a few detailed studies of the reaction mechanism of the homogeneous hydrogenation of imines have been published until now. A generalization seems to be very difficult for two reasons. First, rather different catalyst types are effective and probably act by different mechanisms. Second, the effect of certain additives (especially iodide or iodine and acid/base) is often decisive for ee and rate, but a promoter in one case can be a deactivator in another case. 

Among the various catalyst types investigated in recent years for the hydrogenation of imines, Ir-diphosphine complexes have proved to be most versatile catalysts. The first catalyst of this type generated in situ from [Ir(cod)Cl]2, a chiral diphosphine and iodide was developed by the Ciba-Geigy catalysis group in 1985. Ir ferrocenyl diphosphines (josiphos) complexes in presence of iodide and acid... 

Rhodium diphosphine catalysts can be easily prepared from [Rh(nbd)Cl]2 and a chiral diphosphine, and are suitable for the hydrogenation of imines and N-acyl hydrazones. However, with most imine substrates they exhibit lower activities than the analogous Ir catalysts. The most selective diphosphine ligand is bdppsuif, which is not easily available. Rh-duphos is very selective for the hydrogenation of N-acyl hydrazones and with TOFs up to 1000 h-1 would be active enough for a technical application. Rh-josiphos complexes are the catalysts of choice for the hydrogenation of phosphinyl imines. Recently developed (penta-methylcyclopentyl) Rh-tosylated diamine or amino alcohol complexes are active for the transfer hydrogenation for a variety of C = N functions, and can be an attractive alternative for specific applications. 

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