Asymmetric Hydrogenation of Enamines and Indoles

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]. 

Steric interaction was also clearly an issue for all of the systems investigated. Most notable is the large difference in the reactivity between ThrePHOX 6b- and PHOX 5c-based catalysts with respect to the substituents bound to the nitrogen atom. ThrePHOX consistently performed best with A-methyl-A-benzyl enamines while PHOX preferred a W-methyl-A-phenyl derivative. Lowering the temperature had a favorable outcome on enantioselectivity but slowed the reaction and caused drops in conversion for 5c and 6b. 

Baeza and Pfaltz also investigated indoles which reacted very sluggishly but excellent enantioselectivity could be obtained (Table 15) [78]. 

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