Direct asymmetric hydrogenation of n-alkylimines catalyzed by JACS: IR (III) H

Chiral n-alkylamines are common pharmacophores in drugs, including sertraline (treatment of depression), dextromethylamine (treatment of attention deficit hyperactivity disorder and narcolepsy), kabalatin (treatment of Alzheimer's disease and Parkinson's disease), sinacasai (treatment of hyperparathyroidism), etc (Figure 1) Therefore, asymmetric synthesis of optically pure n-alkylamines has become an important research topic At present, n-alkylamines are mainly synthesized by catalytic reduction of corresponding imines; however, the high alkalinity and nucleophilic nature of n-alkylamines usually lead to deactivation of catalysts (photo source: J am Chem SOC.) from an industrial point of view, the preparation of optically pure n-alkylamines by direct asymmetric hydrogenation of imines is the most ideal method Pfaltz and his colleagues reported a scheme 1 method for hydrogenation of n-methylimine with IR phox catalyst, but the EE value was only 58%, and high pressure hydrogen (100 bar) and high catalyst dosage (4 mol%) were needed Recently, Xavier Verdaguer and Antoni Riera of the University of Barcelona and Agust í led ó s of the Autonomous University of Barcelona reported a new IR (III) pre catalyst on J am Chem SOC., and applied it to the direct asymmetric hydrogenation of n-alkylimines (scheme 1) (DOI: 10.1021 / JACS 8b11547) (photo source: J am Chem SOC.) previously, the author found that the catalyst IR (I) - maxphox has high activity and selectivity in the hydrogenation of n-aryleneamines In this study, the activity of IR (I) - maxphox catalyst (1-4) was tested with n-methylimine as model substrate (Table 1), but the preliminary results were disappointing Next, the author tried to increase the reduction ability of n-methylimine by adding appropriate ring metallization reagent After screening a large number of cyclometallization reagents, the author determined that acetophenone n-phenylimine (A5) is the best additive, which can improve the conversion and selectivity of the reaction The screening results of catalyst 1 - 4 show that 1 is the best catalyst, which can increase EE value to 90% (photo source: J am Chem SOC.) in order to obtain a method suitable for industrial production, the author tried to prepare a more stable cation IR (III) H catalyst Therefore, in the presence of hydrogen, the author reacted 1 with A5 and treated the resulting complexes with several ligand stabilizers (Table 2) Finally, IR (III) complex 5-7 was obtained by using CH3CN, ph3p and me3p as ligands, and the complex 8 was obtained by pressurizing with ethylene gas All four complexes are stable solids, which can be used in air and stored in nitrogen (photo source: J am Chem SOC.) then, the catalytic activity of 5-8 was tested by the hydrogenation of Acetophenone n-methylimine as a model reaction (Table 3) It was found that the CH3CN, PME3 and THF coordinated catalysts can all catalyze at room temperature to achieve 100% conversion, while PPh3 complex has no activity The selectivity of catalyst 7 and catalyst 8 is the best, 90% and 91% ee, respectively When the reaction temperature drops to 0 ℃, catalyst 8 can keep its activity, while catalyst 7 is inactive In the presence of hydrogen, the THF solvent molecules in 8 can be released rapidly, which makes the activation process faster (photo source: J am Chem SOC.) next, the author used catalyst 8 to hydrogenate several n-alkylimines (Figure 2), and found that all substrates can be completely converted At low temperature (0-10 ℃), the reaction has higher selectivity For the substrate containing electron withdrawing group, the reaction selectivity (93-94% ee) can be increased when the temperature is reduced to - 10 ℃ In addition, N-methyl, n-propyl and n-isobutylimide all have good reaction effect, which shows that the hydrogenation of n-alkylimides has high selectivity (photo source: J am Chem SOC.) conclusion: Xavier Verdaguer, antonioriera and Agust í led ó s have developed a new cationic IR (III) H catalyst (8), which can realize the direct asymmetric hydrogenation of n-alkylimines under mild conditions The catalyst contains maxphox ligand, cyclized imine and THF solvent molecules, which are stable in solid form and can be stored in nitrogen.