Iridium Catalyst Hydrogenation, enantioselective

As expected initial examination of the hydrogenation of this substrate revealed its relatively low activity compared to dehydroamino acids that provide 3-aryl-a-amino acids. By carrying out the hydrogenation at an elevated temperature, however, the inherent low activity could be overcome. A screen of the Dowpharma catalyst collection at S/C 100 revealed that several rhodium catalysts provided good conversion and enantioselectivity while low activity and selectivity was observed with several ruthenium and iridium catalysts. Examination of rate data identified [(l )-PhanePhos Rh (COD)]Bp4 as the most active catalyst with a rate approximately... 

Fig. 5.5. Suggested basis of enantioselectivity in hydrogenation of a-methylstilbene by a phosphinoaryl oxazoline-iridium catalyst. Reproduced from Chem. Eur. J., 9, 339 (2003), by permission of Wiley-VCH.

Asymmetric hydrogenation of nitrones in an iridium catalyst system, prepared from [IrCl(cod)]2, (S)-BINAP, NBu 4 BH4, gives with high enantioselectivity the corresponding A-hydroxylamines which are important biologically active compounds and precursors of amines (480). Further reduction of hydroxylamines to secondary amines or imines can be realized upon treatment with Fe/AcOH (479), or anhydrous titanium trichloride in tetrahydrofuran (THF) at room temperature (481). 

A wide variety of iridium-based hydrogenation catalysts are currently under development, notably for organic syntheses including enantioselective synthesis. Hydrogenation by hydrogen transfer is well known [15], and the reduction of C=0 and C=N double bonds is also possible [16, 17]. 

Tetrasubstituted alkenes are challenging substrates for enantioselective hydrogenation because of their inherently low reactivity. Crabtree showed that it was possible to hydrogenate unfunctionalized tetrasubstituted alkenes with iridium catalysts [46]. Among the iridium catalysts described in the previous section, several were found to be sufficiently reactive to achieve full conversion with al-kene 77 (Table 30.14). However, the enantioselectivities were significantly lower than with trisubstituted olefins, and higher catalyst loadings were necessary. 

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]. 

P. Schnider, G. Koch, R. Pr etot, G. Wang, F. M. Bohnen, C. Kruger, A. Pfaltz, Enantioselective Hydrogenation of Imines with Chiral (Phospanodihydrooxazole)iridium Catalysts, Chem. Eur. J. 1997, 3, 887-892. 

Much like the enol systems discussed in Sect. 6.1, enamines are predictably difficult substrates for most iridium asymmetric hydrogenation catalysts. Both substrate and product contain basic functionahties which may act as inhibitors to the catalyst. Extended aromatic enamines such as indoles may be even more difficult substrates for asymmetric hydrogenation with an additional energetic barrier to overcome. Initial reports by Andersson indicated a very difficult reaction indeed (Table 14) [75]. Higher enantioselectivities were later reported by Baeza and Pfaltz (Table 14) [76]. 

In spite of the success of asymmetric iridium catalysts for the direct hydrogenation of alkenes, there has been very limited research into the use of alternative hydrogen donors. Carreira and coworkers have reported an enantioselective reduction of nitroalkenes in water using formic acid and the iridium aqua complex 69 [66]. For example, the reduction of nitroalkene 70 led to the formation of the product 71 in good yield and enantioselectivity (Scheme 17). The use of other aryl substrates afforded similar levels of enantioselectivity. 

Mononuclear oxazolines are among the most effective ligands for enantioselective hydrogenation of nonfunctionalized alkenes." " The styrene substrate 597 is one of the most studied nonfunctionahzed alkenes used to evaluate the efficiency of new chiral ligands (Scheme 8.185). Selected examples of enatioselective hydrogenation of 597 using iridium catalysts are shown in Table g jg 359,425,426,457-459... 

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). 

In the past, this field has been dominated by ruthenium, rhodium and iridium catalysts with extraordinary activities and furthermore superior enantioselectivities however, some investigations were carried out with iron catalysts. Early efforts were reported on the successful use of hydridocarbonyliron complexes HFcm(CO) as reducing reagent for a, P-unsaturated carbonyl compounds, dienes and C=N double bonds, albeit complexes were used in stoichiometric amounts [7]. The first catalytic approach was presented by Marko et al. on the reduction of acetone in the presence of Fe3(CO)12 or Fe(CO)5 [8]. In this reaction, the hydrogen is delivered by water under more drastic reaction conditions (100 bar, 100 °C). Addition of NEt3 as co-catalyst was necessary to obtain reasonable yields. The authors assumed a reaction of Fe(CO)5 with hydroxide ions to yield H Fe(CO)4 with liberation of carbon dioxide since basic conditions are present and exclude the formation of molecular hydrogen via the water gas shift reaction. H Fe(CO)4 is believed to be the active catalyst, which transfers the hydride to the acceptor. The catalyst presented displayed activity in the reduction of several ketones and aldehydes (Scheme 4.1) [9]. 

In the work with asymmetric hydrogenation in SC-CO2, Kainz et al. used modified iridium catalysts to hydrogenate imines. The presence of BARF as a counterion provided the best results in CO2. In comparison to dichloromethane, CO2 gave up to double the turnover frequency (TOF = TON/time) but enantioselectivities were lower by 10%. Again yield and selectivity were substrate specific. Lange et al. developed a chiral rhodium diphosphinite catalyst... 

In 2008, Fan and Xu developed an air stable and phosphine free Ir catalyst for the asymmetric hydrogenation of quinolines [20]. They used chiral cationic Cp Ir(OTf) (CF3TSDPEN) complex as catalyst ]21]. The reaction proceeded smoothly in unde gassed methanol with no need for inert gas protection and afforded the 1,2,3,4 tetrahydroquinoline derivatives in up to 99% ee (Table 10.3). The counterion of iridium catalyst is very important, OTf gave high reactivity and enantioselectivity, and no reactivity was observed for chloride. It is noted that it is one ofthe best results of asymmetric hydrogenation of quinolines. 

The above catalytic systems for the asymmetric hydrogenation of quinolines are mainly iridium catalysts. In 2008, Fan and coworkers developed recyclable phos phine free chiral cationic ruthenium catalyzed asymmetric hydrogenation of qui nolines [23]. They found that the phosphine free cationic Ru/TsDPEN catalyst exhibited unprecedented reactivity and high enantioselectivity in the hydrogenation of quinolines in neat ionic liquid. The results were very excellent and enantioselec... 

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