Iridium-catalyzed hydrogenation imines

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 ... 

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. 

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. 

Scheme 44.11 Iridium-catalyzed enantioselective imine hydrogenation.

Under the conditions of iridium-catalyzed hydrogenation, alkyne-carbonyl and alkyne-imine reductive coupling occurs in the absence of stoichiometric byproducts. For example, iridium-catalyzed hydrogenation of nonconjugated alkynes in the presence of ot-ketoesters delivers the corresponding a-hydroxy esters in... 

Scheme 5 Enantioselective iridium-catalyzed hydrogenation of alkynes in the presence of N-arylsulfonyl imines to furnish trisubstituted allylic amines...

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. 

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>. 

Scheme 11 Schematic catalytic cycle for iridium-catalyzed aryl imine hydrogenation.

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]. 

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]. 

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... 

L = P(CH3)3 or CO, oxidatively add arene and alkane carbon—hydrogen bonds (181,182). Catalytic dehydrogenation of alkanes (183) and carbonylation of benzene (184) has also been observed. Iridium compounds have also been shown to catalyze hydrogenation (185) and isomerization of unsaturated alkanes (186), hydrogen-transfer reactions, and enantioselective hydrogenation of ketones (187) and imines (188). 

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. 

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... 

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.

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