Catalytic Asymmetric Hydrogenation Of β-acetylamino Acrylonitriles

Chiralβ-amino nitriles are valuable structural units in the synthesis of many drugs. Their derivatives, alkylnitrile quinoline compounds, are reportedly useful in the prevention and management of central nervous system and peripheral diseases or disorder. Moreover, the nitrile group is one of the most versatile functional groups and can be readily transformed into a variety of valuable functionalities, such as carbonyl, aldehyde, amino and carboxyl groups, which enable a facile approach toβ-lactams,β-amino amides,β-amino acids, aldehydes and 1,3-diamines, respectively. Due to their significance in chemical synthesis, much effort has been devoted to pursuit of practical asymmetric routes to produce chiralβ-amino nitriles. Herein, we report the firstly direct asymmetric hydrogenation of prochiral substrateβ-acetylamino acrylonitriles (17 compounds) with transition metal-phosphine ligand catalysts which provide the correspondingβ-acetylamino nitriles in excellent enantioselectivities. Following is the main results:(1) The coupling of benzonitrile and substituted benzonitrile with acetonitrile was carried out at room temperature for 4 h in the solvent of toluene by using of ultrasound to give 6-95% yield of a series ofβ-enaminonitriles 1a-p, r with E-selectivity (1a-f, i-p, r), Z/E-mixture 1g (E/Z=8.3:1) and 1h (E/Z=9.6:1). Furthermore, 3-acetylamino-2-butenenitrile 1q, 2-acety1amino-cyclopentenecarbonitrile 1t and 2-acety1amino-cyclohexenecarbonitrile 1u were prepared via intermolecular dimerization of nitriles and intramolecular cyclization of dinitriles under solvent-free condition in 42%,93% and 80% yield, respectively.(2)β-Acetylamino acrylonitriles 2a-n, q were prepared fromβ-amino acrylonitriles and acetic anhydride using the base-catalyst Et3N in the solvent of toluene, the yield from 24% to 84%. Using dry pyridine as solvent and base-catalyst, we also prepared 2-acety1amino -cyclopentenecarbonitrile and 2-acety1amino -cyclohexenecarbonitrile in 52% and 78% yield, respectively.(3) Under the optimal reaction conditions (all reactions were carried out with a substrate/catalyst ratio of 100:1 in MeOH at 40 oC under 10 atm hydrogen pressure for 24 h), substrates 2a-n, q were examined using catalyst [Rh(COD)TangPhos]BF₄ to produce the correspondingβ-acetylamino nitriles 3. In most cases, all the substrates could be hydrogenated with excellent enantioselectivities (82-98% ee) and conversions (100%) except 2b, 2g, 2j, 2l. Further studies indicated that the hydrogenation of 2b, 2g, 2l proceeded smoothly with 100% conversions and 20%, 33% and 20% ee respectively when the reactions were performed under 50 atm for 72 h. However, 2j afforded products with 100% conversions and 92% ee under the same hydrogen pressure for 48 h.During our effort to study the reactivity and turnover number (TON) limit of the hydrogenation of 2a, 2i, 2f, 2k, 2n even more with [Rh(COD)TangPhos] BF₄ in MeOH at 40 oC for 24 h, we got the following results: S/C_2a = 1000 (P_H2 = 10 atm, 93% ee), S/C_2i = 500 (P_H2 = 50 atm, 89% ee), S/C_2f = 500 (P_H2 = 50 atm, 93% ee), S/C_2k = 500 (P_H2 = 50 atm, 97 % ee), S/C_2n = 500 (P_H2 = 10 atm, 97% ee).(4) Under the optimal reaction conditions (all reactions were carried out with a substrate/catalyst ratio of 100:1 in MeOH at 40 oC under 100 atm hydrogen pressure for 24 h), all the substrates could be hydrogenated by [Rh(COD)QuinoxP*]BF₄ with high enantiosele -ctivities (77-92% ee) and conversions (100 %) except 2b, 2g, 2j, 2l which could not be hydrogenated incompletedly. Although the hydrogenation of 2q showed completely conversion, we obtainted very poor enantioselectivity.(5) 2-Acety1amino-cyclopentenecarbonitrile was hydrogenated by [Rh(COD)DuanPhos] BF₄ in MeOH at 40 oC under 50 atm hydrogen pressure for 24 h. However moderate enantioselectivity (60%) and convertion (61%) were achieved.(6) As the above results, we expanded the screening scope of Rh-phosphine complexes in order to improve the enantioselectivity of hydrogeration product. To our delight, the [Rh(COD)Josiphos CyPF-t-Bu]BF₄ catalyst proved to be full convertions and good enantioselectivities to 2-acety1amino-cyclocarbonitrile. Under the optimal reaction conditions (all reactions were carried out with a substrate/catalyst ratio of 100:1 in MeOH at 25 oC under 70 atm hydrogen pressure for 24 h), 2-acety1amino-cyclopentenecarbonitrile and 2-acety1amino-cyclohexene carbonitrile were found to give cis-2-acety1amino-cyclopentane carbonitrile and cis-2-acety1amino-cyclohaxenecarbonitrile with 64% ee and 83% ee, respevtively.