Method for preparing chiral succinimide through asymmetric hydrogenation of alpha-alkylene succinimide under catalysis of nickel

Abstract

The invention discloses a method for preparing chiral succinimide through asymmetric hydrogenation of alpha-alkylene succinimide under the catalysis of nickel. The method comprises the following steps: in a solvent, under certain hydrogen pressure and temperature, alpha-alkylene succinimide represented by a general formula (1) is hydrogenated into a chiral succinimide compound represented by a general formula (2) by a nickel chiral catalyst; the structural formulas of the general formulas (1) and (2) are shown in the specification. The method is mild in reaction condition, simple and convenient to operate, capable of achieving good yield and efficiency and wide in application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical technology, and relates to a preparation method of chiral succinimide, in particular to a method for preparing chiral succinimide by nickel-catalyzed asymmetric hydrogenation of alpha-alkylidene succinimide. BACKGROUND

[0002] As an advantageous structural motif in drug molecules, chiral succinimide and its derivatives are widely present in various compounds with biological activity, and have good pharmacological activity and selectivity, for example, specific antagonists of alpha 7 neuronal nicotinic acetylcholine receptors (alpha 7 nAChR) and human leukocyte elastase inhibitors.

[0003] Through literature search of the prior art, it is found that the general method for obtaining such chiral compounds is extraction, resolution, biological or synthesis from chiral raw materials, which has great limitations and is not economical.

[0004] At the same time, different attempts are being made on chemical asymmetric synthesis methods. At present, they are mostly obtained by addition and cycloaddition reaction of nucleophilic reagents to maleimide, or by asymmetric hydrogenation of maleimide or succinimide catalyzed by noble metals. The expensive metal salt and difficult-to-remove heavy metal ions in the catalytic system greatly hinder the industrial application of such catalysts. The method for obtaining such compounds by using inexpensive transition metal catalyzed asymmetric hydrogenation has not been reported. SUMMARY

[0005] The present application provides a method for preparing chiral succinimide by nickel-catalyzed asymmetric hydrogenation of alpha-alkylidene succinimide, which first uses the method for obtaining chiral succinimide compounds by inexpensive transition metal catalyzed asymmetric hydrogenation, and has the advantages of greenness, safety, high efficiency and good enantioselectivity.

[0006] The present application is realized by the following technical solutions.

[0007] The present application provides a method for preparing chiral succinimide by nickel-catalyzed asymmetric hydrogenation of alpha-alkylidene succinimide, which first uses the method for obtaining chiral succinimide compounds by inexpensive transition metal catalyzed asymmetric hydrogenation, and has the advantages of greenness, safety, high efficiency and good enantioselectivity. ; In the formula, R 1 represents an aryl group with or without a substituent, or an alkyl group with or without a substituent, and the number of carbon atoms is 1-10, R 2represents an aryl group with or without a substituent, or an alkyl group with or without a substituent having 1 to 6 carbon atoms.

[0008] Preferably, the chiral catalyst of nickel is complexed from a nickel salt with different anions and a chiral ligand.

[0009] Preferably, the nickel salt with different anions refers to a nickel salt with any one of acetate, triflate, perchlorate, tetrafluoroborate, chloride and formate as anion. Preferably, the anion is acetate.

[0010] Preferably, the chiral ligand is selected from any one of L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14 and L15, and the structural formulae of L1-L15 are as follows: ; In L1-L15, Ar is selected from C6H5, 4-CH3OC6H4, 4-CF3C6H4, 3,5-di- t Bu-4-MeOC6H2or 3,5-di- t BuC6H3, and n = 7-12.

[0011] Preferably, the solvent is a non-polar solvent, a polar solvent or a protic solvent, and specifically, can be any one or more selected from trifluoroethanol, methanol, ethanol, dichloromethane or toluene.

[0012] Preferably, in the general formula (1) and (2), R 1 represents any one selected from phenyl, benzyl, methyl, ethyl, n-propyl, i-propyl, t-butyl, cyclohexyl, diethylmethyl, adamantyl, R 2 represents any one selected from phenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-naphthyl, ethyl, n-propyl, cyclohexyl.

[0013] Preferably, the hydrogen pressure is 1-80 bar.

[0014] Preferably, the temperature is 20-60°C.

[0015] Preferably, the molar ratio of the chiral catalyst of nickel to the α-alkylenesuccinimide represented by the general formula (1) is 1:20-20000.

[0016] Preferably, the hydrogenation time is 1-120 hours.

[0017] Compared with the prior art, the present invention has the following beneficial effects: This invention is the first to utilize an inexpensive transition metal asymmetric catalytic hydrogenation method for the efficient preparation of chiral succinimide compounds. The reaction method is mild, simple to operate, and achieves good reaction yield and efficiency, demonstrating good application potential. Attached Figure Description

[0018] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings: Figure 1 For 2a(R) 1 =Ad,R 2 =Ph) hydrogen spectrum; Figure 2 For 2a(R) 1 =Ad,R 2 =Ph) carbon spectrum; Figure 3 For 2a(R) 1 =Ad,R 2 =Ph) HPLC chromatogram, HPLC [DIACEL CHIRALPAK IA, hexane / i PrOH = 90 / 10, 210 nm, 0.5 mL / min.t R1 =10.260 (main peak), t R2 =11.959 (secondary peak)]; ee=97%. Detailed Implementation

[0019] The present invention will be described in detail below with reference to embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0020] The method for preparing chiral succinimide by nickel-catalyzed asymmetric hydrogenation of α-alkylene succinimide according to the present invention can be represented by the following reaction formula: ; In the above reaction formulas, general formula (1) represents α-alkylene succinimide, and general formula (2) represents chiral succinimide.

[0021] In general formulas (1) and (2), R 1represents an aryl group with or without a substituent, or an alkyl group with or without a substituent and having 1 to 10 carbon atoms. The aryl group with or without a substituent can be a phenyl group. The alkyl group with or without a substituent and having 1 to 10 carbon atoms can be a benzyl group, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a t-butyl group, a cyclohexyl group, a diethylmethyl group, or an adamantyl group. 2 represents an aryl group with or without a substituent, or an alkyl group with or without a substituent and having 1 to 6 carbon atoms. The aryl group with or without a substituent can be a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, or a trifluoromethyl group. The alkyl group with or without a substituent and having 1 to 6 carbon atoms can be an ethyl group, a n-propyl group, or a cyclohexyl group.

[0022] In the above reaction formula, L * Ni·X represents a chiral catalyst of nickel, i.e., an ionic compound of a complex of nickel and a chiral ligand and an anion. L * represents a chiral ligand, and is any one of L1 to L15. Y represents any one of acetate, triflate, perchlorate, tetrafluoroborate, chloride, and formate.

[0023] In the method for preparing a chiral succinimide by nickel-catalyzed asymmetric hydrogenation of an α-alkylidene succinimide according to the present application, the hydrogen pressure of the hydrogen atmosphere is 1 to 80 bar, and further preferably 20 to 80 bar from the viewpoint of reaction yield and efficiency.

[0024] In the method for preparing a chiral succinimide by nickel-catalyzed asymmetric hydrogenation of an α-alkylidene succinimide according to the present application, the molar ratio of the chiral catalyst of nickel to the α-alkylidene succinimide represented by General Formula (1) is 1:20 to 20,000, and preferably 1:50 to 5,000 from the viewpoint of reaction yield and efficiency.

[0025] In the method for preparing a chiral succinimide by nickel-catalyzed asymmetric hydrogenation of an α-alkylidene succinimide according to the present application, the reaction temperature is 20°C to 60°C, and preferably 40°C to 60°C, and further preferably 50°C to 60°C from the viewpoint of reaction yield and efficiency. The reaction time is 1 to 120 hours, and preferably 6 to 72 hours, and more preferably 12 to 48 hours, and further preferably 24 to 48 hours.

[0026] In the method for preparing a chiral succinimide by nickel-catalyzed asymmetric hydrogenation of an α-alkylidene succinimide according to the present application, the reaction conditions are mild and the operation is simple, and a good yield and efficiency can be achieved, and thus the method has a wide application prospect.

[0027] In the following examples, 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1r, 1s represent various different a-alkylenesuccinimides (i.e., substrates) represented by general formula (1), and 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s represent the corresponding reaction products (i.e., chiral succinimides represented by general formula (2)) obtained by nickel-catalyzed asymmetric hydrogenation of these substrates a-alkylenesuccinimides.

[0028] Further, it goes without saying that by the reaction method of the present application, 2a is produced by asymmetric hydrogenation of 1a, 2b is produced by asymmetric hydrogenation of 1b, 2c is produced by asymmetric hydrogenation of 1c, 2d is produced by asymmetric hydrogenation of 1d, 2e is produced by asymmetric hydrogenation of 1e, 2f is produced by asymmetric hydrogenation of 1f, 2g is produced by asymmetric hydrogenation of 1g, 2h is produced by asymmetric hydrogenation of 1h, 2i is produced by asymmetric hydrogenation of 1i, 2j is produced by asymmetric hydrogenation of 1j, 2k is produced by asymmetric hydrogenation of 1k, 2l is produced by asymmetric hydrogenation of 1l, 2m is produced by asymmetric hydrogenation of 1m, 2n is produced by asymmetric hydrogenation of 1n, 2o is produced by asymmetric hydrogenation of 1o, 2p is produced by asymmetric hydrogenation of 1p, 2q is produced by asymmetric hydrogenation of 1q, 2r is produced by asymmetric hydrogenation of 1r, and 2s is produced by asymmetric hydrogenation of 1s.

[0029] Further, in the following examples, L * • Ni• X represents a chiral catalyst of nickel, for example, L1• Ni• OAc represents a chiral catalyst composed of nickel, chiral ligand L1, and acetate ion.

[0030] Example 1 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube, chiral ligand L1b (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol), and a-alkylenesuccinimide 1a (0.2 mmol) were added, respectively, and then transferred to a glove box to add trifluoroethanol (1.0 mL). The reaction tube was placed in a hydrogenation cell, and after three hydrogen gas replacements, the initial hydrogen gas pressure was made to be 30 bar, and the reaction was stirred at 50°C for 24 hours. After cooling to room temperature, the gas was carefully released, the high-pressure cell was opened, the reaction tube was taken out, the solvent was concentrated and evaporated, the conversion rate was detected by NMR, and the product was obtained by column chromatography. The yield was 36%, and the enantiomeric excess value was 58% (ee) (2R, 3R) (2S, 3S) = 58% (2R, 3S) (2S, 3R) = 42%). Figure 1 , 2 ).

[0031] Example 2 2a (R 1 = Ad, R 2 = Ph) A 10 mL reaction tube was charged with chiral ligand L1c (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 46% and the enantiomeric excess was 51%.

[0032] Example 3 2a (R 1 = Ad, R 2 = Ph) A 10 mL reaction tube was charged with chiral ligand L1d (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 63% and the enantiomeric excess was 70%.

[0033] Example 4 2a (R 1 = Ad, R 2 = Ph) A 10 mL reaction tube was charged with chiral ligand L2b (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 39% and the enantiomeric excess was 77%.

[0034] Example 5 2a (R 1 = Ad, R2 Preparation of 2a (R = Ph, R = Ad) In a 10 mL reaction tube were added chiral ligand L2c (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 42% and the enantiomeric excess was 78%.

[0035] Example 6 2a (R = Ph, R = Ad) 1 Preparation of 2a (R = Ph, R = Ad) 2 Preparation of 2a (R = Ph, R = Ad) In a 10 mL reaction tube were added chiral ligand L3a (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 35% and the enantiomeric excess was 70%.

[0036] Example 7 2a (R = Ph, R = Ad) 1 Preparation of 2a (R = Ph, R = Ad) 2 Preparation of 2a (R = Ph, R = Ad) In a 10 mL reaction tube were added chiral ligand L3b (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 30% and the enantiomeric excess was 73%.

[0037] Example 8 2a (R = Ph, R = Ad) 1 Preparation of 2a (R = Ph, R = Ad) 2 Preparation of 2a (R = Ph, R = Ad) A 10 mL reaction tube was charged with chiral ligand L3c (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 41% and the enantiomeric excess was 78%.

[0038] Example 9 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L3d (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 52% and the enantiomeric excess was 85%.

[0039] Example 10 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L4a (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 25% and the enantiomeric excess was 67%.

[0040] Example 11 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L4b (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 39% and the enantiomeric excess was 58%.

[0041] Example 12 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L4c (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 35% and the enantiomeric excess was 66%.

[0042] Example 13 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L4d (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 40% and the enantiomeric excess was 75%.

[0043] Example 14 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5a7(L5a, n = 7) (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 91%.

[0044] Example 15 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5b8(L5b, n = 8) (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 90%.

[0045] Example 16 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5c9(L5c, n = 9) (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 91%.

[0046] Example 17 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5d10(L5d, n = 10) (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 96%.

[0047] Example 18 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10(L5e, n = 10) (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 97% ( Figure 3 ).

[0048] Example 19 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e12(L5e, n = 12) (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 91%.

[0049] Example 20 2a (R 1 = Ad, R 2Preparation of (R)-2-(4-methoxyphenyl)-4-oxo-3-(piperidin-4-yl)thiazolidine-5-carboxylic acid methyl ester In a 10 mL reaction tube were added chiral ligand L6 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas carefully released and the bomb opened. The reaction tube was removed and the solvent evaporated. The conversion was checked by NMR and the product purified by column chromatography. The yield was 30% and the enantiomeric excess was 91%.

[0050] Example 21 2a (R 1 = Ad, R 2 = Ph) Preparation of (R)-2-(4-methoxyphenyl)-4-oxo-3-(piperidin-4-yl)thiazolidine-5-carboxylic acid methyl ester In a 10 mL reaction tube were added chiral ligand L7 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas carefully released and the bomb opened. The reaction tube was removed and the solvent evaporated. The conversion was checked by NMR and the product purified by column chromatography. The yield was 80% and the enantiomeric excess was 97%.

[0051] Example 22 2a (R 1 = Ad, R 2 = Ph) Preparation of (R)-2-(4-methoxyphenyl)-4-oxo-3-(piperidin-4-yl)thiazolidine-5-carboxylic acid methyl ester In a 10 mL reaction tube were added chiral ligand L8 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas carefully released and the bomb opened. The reaction tube was removed and the solvent evaporated. The conversion was checked by NMR and the product purified by column chromatography. The yield was <5%.

[0052] Example 23 2a (R 1 = Ad, R 2 = Ph) Preparation of (R)-2-(4-methoxyphenyl)-4-oxo-3-(piperidin-4-yl)thiazolidine-5-carboxylic acid methyl ester In a 10 mL reaction tube were added chiral ligand L9 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 44%.

[0053] Example 24 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube were added chiral ligand L10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 71%.

[0054] Example 25 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube were added chiral ligand L11 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was <5%.

[0055] Example 26 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L12 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 25% and the enantiomeric excess was 29%.

[0056] Example 27 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L13 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 41% and the enantiomeric excess was 60%.

[0057] Example 28 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L14 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 35% and the enantiomeric excess was 56%.

[0058] Example 29 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), anhydrous nickel acetate (0.36 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas carefully released and the bomb opened. The reaction tube was removed and the solvent evaporated. The conversion was checked by NMR and the product purified by column chromatography. The yield was 85% with an enantiomeric excess of 97%.

[0059] Example 30 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), anhydrous nickel acetate (0.36 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas carefully released and the bomb opened. The reaction tube was removed and the solvent evaporated. The conversion was checked by NMR and the product purified by column chromatography. The yield was 85% with an enantiomeric excess of 97%.

[0060] Example 31 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), anhydrous nickel acetate (0.36 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 hours. The reaction was cooled to room temperature, the gas carefully released and the bomb opened. The reaction tube was removed and the solvent evaporated. The conversion was checked by NMR and the product purified by column chromatography. The yield was 85% with an enantiomeric excess of 97%.

[0061] Example 32 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), nickel perchlorate hexahydrate (0.74 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 25% and the enantiomeric excess was 97%.

[0062] Example 33 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), nickel perchlorate hexahydrate (0.74 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 25% and the enantiomeric excess was 97%.

[0063] Example 34 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), nickel perchlorate hexahydrate (0.74 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 25% and the enantiomeric excess was 97%.

[0064] Example 35 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel formate (0.30 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and charged with trifluoroethanol (1.0 mL). The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was <5%.

[0065] Example 36 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel formate (0.30 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and charged with trifluoroethanol (1.0 mL). The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was <5%.

[0066] Example 37 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel formate (0.30 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and charged with trifluoroethanol (1.0 mL). The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was <5%.

[0067] Example 38 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and charged with dichloromethane (1.0 mL). The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened, and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was <5%.

[0068] Example 39 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and charged with toluene (1.0 mL). The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened, and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was <5%.

[0069] Example 40 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and charged with trifluoroethanol (1.0 mL). The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 20 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened, and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 90% and the enantiomeric excess was 97%.

[0070] Example 41 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 40 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0071] Example 42 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 60 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 94%.

[0072] Example 43 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 40 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 77% and the enantiomeric excess was 98%.

[0073] Example 44 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 12 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 87% and the enantiomeric excess was 97%.

[0074] Example 45 2a (R 1 = Ad, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1a (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 48 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0075] Example 46 2b (R 1 = Ad, R 2 = 2-F-Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1b (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0076] Example 47 2c (R 1 = Ad, R 2 = 2-OMe-Ph) Preparation In a 10 mL reaction tube were added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1c (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 96%.

[0077] Example 48 2d (R 1 = Ad, R 2 = 3-F-Ph) Preparation In a 10 mL reaction tube were added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1d (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0078] Example 49 2e (R 1 = Ad, R 2 = 3-Cl-Ph) Preparation In a 10 mL reaction tube were added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1e (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 95% and the enantiomeric excess was 98%.

[0079] Example 50 2f (R 1 = Ad, R 2 = 3-Br-Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1e (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 48 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 96% and the enantiomeric excess was 97%.

[0080] Example 51 2g (R 1 = Ad, R 2 = 3-Me-Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1g (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 98%.

[0081] Example 52 2h (R 1 = Ad, R 2 = 3-OMe-Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1h (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was evaporated and the conversion was checked by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0082] Example 53 2i (R 1 = Ad, R 2 = 4-F-Ph) Preparation In a 10 mL reaction tube were added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1i (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0083] Example 54 2j (R 1 = Ad, R 2 = 4-Cl-Ph) Preparation In a 10 mL reaction tube were added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1j (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 95% and the enantiomeric excess was 97%.

[0084] Example 55 2k (R 1 = Ad, R 2 = 4-Br-Ph) Preparation In a 10 mL reaction tube were added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1k (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 48 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 85% and the enantiomeric excess was 97%.

[0085] Example 56 2l (R 1 = Ad, R 2 = 4-Me-Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1k (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 98% and the enantiomeric excess was 98%.

[0086] Example 57 2m (R 1 = Ad, R 2 = 4-OMe-Ph) was prepared A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and α-alkylenesuccinimide 1m (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 95%.

[0087] Example 58 2n (R 1 = Ad, R 2 = 2-naphthyl) was prepared A 10 mL reaction tube was charged with chiral ligand L5e10 (0.01 mmol), nickel acetate tetrahydrate (2.49 mg, 0.01 mmol) and α-alkylenesuccinimide 1n (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 60 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 92% and the enantiomeric excess was 99%.

[0088] Example 59 2o (R 1 = Ad, R 2 = Et) was prepared A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1o (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 98%.

[0089] Example 60 2p (R 1 = Ad, R 2 = n Pr) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1p (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 98%.

[0090] Example 61 2q (R 1 = CHEt2, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1q (0.2 mmol), then transferred to a glovebox and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released, the bomb was opened and the reaction tube was removed. The solvent was concentrated and dried under vacuum. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 97%.

[0091] Example 62 2r (R 1 = Cy, R 2 = Ph) Preparation A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1r (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 93% and the enantiomeric excess was 97%.

[0092] Example 63 2s (R 1 = Ph) was prepared t Bu, R 2 = Ph) was prepared A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1s (0.2 mmol), then transferred to a glove box and trifluoroethanol (1.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 30 bar. The reaction was stirred at 50 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 97% and the enantiomeric excess was 97%.

[0093] Example 64 2a (R 1 = Ad, R 2 = Ph) was prepared A 10 mL reaction tube was charged with chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (0.50 mg, 0.002 mmol) and a-alkylenesuccinimide 1a (1.0 mmol), then transferred to a glove box and trifluoroethanol (2.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 80 bar. The reaction was stirred at 60 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 96%.

[0094] Example 65 2a (R 1 = Ad, R 2 = Ph) was prepared In a 10 mL reaction tube was added chiral ligand L5e10 (0.002 mmol), nickel acetate tetrahydrate (5.0 mg, 0.02 mmol) and a-alkylenesuccinimide 1a (2.0 mmol), then transferred to a glove box and trifluoroethanol (5.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 80 bar. The reaction was stirred at 60 °C for 24 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 96%.

[0095] Example 66 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.004 mmol), nickel acetate tetrahydrate (10.0 mg, 0.04 mmol) and a-alkylenesuccinimide 1a (20.0 mmol), then transferred to a glove box and trifluoroethanol (20.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 80 bar. The reaction was stirred at 60 °C for 72 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 96%.

[0096] Example 67 2a (R 1 = Ad, R 2 = Ph) Preparation In a 10 mL reaction tube was added chiral ligand L5e10 (0.004 mmol), nickel acetate tetrahydrate (10.0 mg, 0.04 mmol) and a-alkylenesuccinimide 1a (40.0 mmol), then transferred to a glove box and trifluoroethanol (30.0 mL) was added. The reaction tube was placed in a hydrogenation bomb and purged with hydrogen three times to give an initial hydrogen pressure of 80 bar. The reaction was stirred at 70 °C for 120 h. The reaction was cooled to room temperature, the gas was carefully released and the bomb was opened. The reaction tube was removed and the solvent was evaporated. The conversion was checked by NMR and the product was purified by column chromatography. The yield was 99% and the enantiomeric excess was 95%.

[0097] The specific embodiments of the present application have been described. It is to be understood that the application is not limited to the specific devices, methods, or conditions described, but include any and all embodiments falling within the scope of the appended claims.

Claims

1. A process for the preparation of chiral succinimides by nickel-catalyzed asymmetric hydrogenation of α-alkylidene succinimides, characterized in that, The method comprises: hydrogenating an α-alkylidene succinimide represented by general formula (1) into a chiral succinimide compound represented by general formula (2) in a solvent under a certain hydrogen pressure and temperature with a chiral catalyst of nickel as a catalyst; ； wherein R 1 represents an aryl group with or without a substituent, or an alkyl group with or without a substituent having a carbon number of 1 to 10; R 2 represents an aryl group with or without a substituent, or an alkyl group with or without a substituent having a carbon number of 1 to 6.

2. The method of preparing a chiral succinimide according to claim 1, characterized in that, the substituent group comprises at least one of methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl; and the aryl group comprises phenyl and naphthyl.

3. The method of claim 1, wherein the method is characterized by, The chiral catalyst of nickel is complexed by a nickel salt with different anions and a chiral ligand.

4. The method of preparing a chiral succinimide according to claim 3, characterized in that, The nickel salt with different anions refers to a nickel salt with any one of acetate, triflate, perchlorate, tetrafluoroborate, chloride and formate as an anion.

5. The method of claim 3, wherein the compound of formula (II) is prepared by the reaction of the compound of formula (III) with the compound of formula (IV) in the presence of a base. The chiral ligand is any one selected from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14 and L15. ； wherein Ar is selected from C6H5, 4-CH3OC6H4, 4-CF3C6H4, 3,5-di- t Bu-4-MeOC6H2or 3,5-di- t BuC6H3, n = 7-12.

6. The method of claim 1, wherein the method is characterized by, The solvent is a non-polar solvent, a polar solvent or a protic solvent.

7. The method for preparing chiral succinimide according to claim 6, characterized in that, The solvent is any one or more selected from trifluoroethanol, methanol, ethanol, dichloromethane and toluene.

8. The method of claim 1, wherein the method is characterized by, In the general formula (1) and (2), R 1 represents any one selected from the group consisting of phenyl, benzyl, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclohexyl, diethylmethyl, and adamantyl, R 2 represents any one selected from the group consisting of phenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-naphthyl, ethyl, n-propyl, and cyclohexyl.

9. The method of claim 1, wherein the method is characterized by, The hydrogen pressure is 1-80 bar; and the temperature is 20-60℃.

10. The method of claim 1, wherein the method is characterized by, The molar ratio of the chiral catalyst of nickel to the α-alkylidene succinimide represented by general formula (1) is 1:20-20000; and the hydrogenation time is 1-120 hours.

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