A method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime

Abstract

The present invention provides a method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime. The method comprises the following steps: adding a nickel chiral catalyst to a solvent under a certain hydrogen pressure and temperature to hydrogenate the oxime to a chiral hydroxylamine compound, wherein the general formula of the oxime is: The general formula of the chiral hydroxylamine compound is: The method of the present invention has mild reaction conditions, simple operation, and can achieve good reaction yield and reaction efficiency, and has good application effect.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical engineering, and in particular to a method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime. Background Art

[0002] Chiral hydroxylamines and their derivatives are a class of structurally unique compounds containing two linked, highly electronegative nitrogen and oxygen atoms (NO). The repulsive force between the lone pairs of electrons on these nitrogen and oxygen atoms makes these compounds highly chemically reactive, enabling them to participate in numerous chemical reactions, such as nucleophilic substitution to form other chiral hydroxylamine derivatives, oxidation to form oximes and nitro compounds, and reduction to form chiral amines. These reactive properties have led to their widespread application in chemical, biological, and medicinal chemistry research.

[0003] The existing methods for obtaining such chiral compounds generally involve extraction, resolution, biological methods, or methods of synthesis from chiral raw materials, which have significant limitations and are uneconomical. Meanwhile, various attempts are underway to develop chemical asymmetric synthesis methods. Currently, only one example has been obtained using the asymmetric hydrogenation of iridium-catalyzed oximes. However, the expensive metal salts and difficult-to-remove heavy metal ions in the catalytic system have greatly hindered the industrial application of this type of catalyst.

[0004] In summary, chiral hydroxylamine compounds are a class of chiral substances with a wide range of applications. Developing green and efficient synthesis methods has become a current research focus. To date, there has been no report on the use of efficient nickel-catalyzed asymmetric hydrogenation of oximes to synthesize such compounds with high yield and high enantioselectivity. Summary of the Invention

[0005] To address the shortcomings of the prior art, this invention, for the first time, efficiently prepares chiral hydroxylamine compounds using an inexpensive transition metal asymmetric catalytic hydrogenation of oximes. The reaction method is mild, simple to operate, and achieves good yields and efficiencies, demonstrating promising application results. The present invention also provides a method for preparing chiral hydroxylamines using asymmetric nickel-catalyzed hydrogenation of oximes.

[0006] The object of the present invention is achieved through the following solutions:

[0007] The present invention provides a method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime, characterized in that the method comprises the following steps: adding a nickel chiral catalyst to a solvent under a certain hydrogen pressure and temperature to hydrogenate the oxime to a chiral hydroxylamine compound, wherein the oxime has the general formula: The chiral hydroxylamine compound has the general formula: in:

[0008] R 1is one of an aryl group which may have a substituent, an alkyl group which may have a substituent and has 1 to 8 carbon atoms, or an unsaturated group which may have a substituent and has 1 to 8 carbon atoms; R 2 is one of an aryl group which may have a substituent, an alkyl group which may have a substituent and has 1 to 8 carbon atoms, or an unsaturated group which may have a substituent and has 1 to 8 carbon atoms; R 3 It is one of hydrogen and an alkyl group having 1 to 8 carbon atoms which may have a substituent.

[0009] Preferably, the nickel chiral catalyst is formed by complexing nickel salts with different anions and chiral ligands.

[0010] Preferably, the nickel salt having different anions is a nickel salt whose anion is any one of chloride, bromide, acetate, tetrafluoroborate, trifluoroacetate, trifluoromethanesulfonate and perchlorate.

[0011] Preferably, the chiral ligand is any one ligand selected from L1 to L17, and the structural formulas of the ligands L1 to L17 are as follows:

[0012]

[0013] in:

[0014] In L1-L6, Ar is one of C6H5, 4-CH3OC6H4, 4-CF3C6H4, and 3,5-di-tBu-4-MeOC6H2.

[0015] Preferably, the solvent is one or more of a non-polar solvent, a polar solvent, and a protic solvent.

[0016] Preferably, the non-polar solvent is one or more of toluene, ether, and tetrahydrofuran; the polar solvent is one or more of dichloromethane, 1,2-dichloroethane, DMF, acetone, and acetonitrile; and the protic solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, formic acid, acetic acid, propionic acid, butyric acid, and isobutyric acid.

[0017] Preferably, the R 1 、R 2 、R 3methyl, ethyl, benzyl, isopropyl, n-propyl, n-butyl, tert-butyl, cyclohexyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-phenylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl phenyl, 3-nitrophenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-ditrifluoromethylphenyl, 3,5-difluorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2,4-dimethoxyphenyl 2-furyl, dibenzhydryl, cyclopropyl, cyclopentyl, chloromethylene, hydroxymethylene, methoxymethylene, 2-bromobenzyl, 4-bromobenzyl, 2,6-dichlorobenzyl, phenoxymethylene, wherein R 1 、R 2 and R 3 Can be connected to form a ring, where R 3 It may also be hydrogen.

[0018] Preferably, the hydrogen pressure is 1 to 80 bar, the temperature is -78°C to 80°C, and the reaction time is 1 to 72 hours.

[0019] Preferably, the hydrogen pressure is preferably 30 to 50 bar, the temperature is preferably 50° C. to 60° C., and the reaction time is preferably 24 to 48 hours.

[0020] Preferably, the molar ratio of the nickel chiral catalyst to the oxime is 1:20 to 100,000.

[0021] Preferably, the molar ratio of the nickel chiral catalyst to the oxime is preferably 1:50 to 1000.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The reaction method of the present invention has mild conditions, simple operation, and can achieve good reaction yield and reaction efficiency, and has good application effect;

[0024] (2) The present invention uses a cheap transition metal asymmetric catalytic hydrogenation method to efficiently prepare chiral hydroxylamine compounds, which is low in cost and suitable for large-scale promotion. DETAILED DESCRIPTION

[0025] The present invention will be described in detail below with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several changes and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0026] The method of preparing chiral amines by asymmetric nickel-catalyzed hydrogenation of oximes of the present invention can be represented by the following reaction formula:

[0027]

[0028] In the above reaction formula, general formula (1) represents an oxime, and general formula (2) represents a chiral hydroxylamine compound.

[0029] In general formulas (1) and (2), R 1 or R 2 Each represents: an aryl group which may have a substituent, or an alkyl group which may have a substituent and has 1 to 8 carbon atoms, or an unsaturated substituent such as an alkenyl or alkynyl group which may have a substituent and has 1 to 8 carbon atoms, wherein the aryl group which may have a substituent may be a substituted or polysubstituted aryl group such as a methyl group, a methoxy group, a chlorine group, a bromine group, a fluorine group or a trifluoromethyl group, a naphthalene group or a heterocyclic aryl group; the alkyl group which may have a carbon number of 1 to 8 may be a methyl group, an ethyl group, an isopropyl group, an n-butyl group, a tert-butyl group or a cyclohexyl group.

[0030] R 3 represents hydrogen or an alkyl group having 1 to 8 carbon atoms which may have a substituent.

[0031] In the above reaction formula, L*·Ni·X represents a nickel chiral catalyst, that is, an ionic compound of a complex of nickel, a chiral ligand, and an anion. L* represents a chiral ligand, which is any one selected from L1 to L17. X represents any one of chloride, bromide, acetate, tetrafluoroborate, trifluoroacetate, trifluoromethanesulfonate, and perchlorate.

[0032] In the method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime of the present invention, the hydrogen atmosphere pressure is 1 to 80 bar, more preferably 30 to 50 bar, from the viewpoint of reaction yield and reaction efficiency.

[0033] In the method of preparing chiral hydroxylamine by asymmetric palladium-catalyzed hydrogenation of oxime of the present invention, the molar ratio of the nickel chiral catalyst to the oxime represented by the general formula (1) is 1:20 to 10,000, preferably 1:50 to 1000, from the viewpoint of reaction yield and reaction efficiency.

[0034] The method of preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime of the present invention has the following characteristics: from the viewpoints of reaction yield and reaction efficiency, the reaction temperature is -78°C to 80°C, preferably -40°C to 70°C, more preferably 20°C to 60°C, and further preferably 50°C to 60°C; the reaction time is 1 to 72 hours, preferably 5 to 60 hours, more preferably 12 to 48 hours, further preferably 18 to 48 hours, and particularly preferably 24 to 48 hours.

[0035] The present invention uses an oxime represented by general formula (1) as a substrate and performs asymmetric catalytic hydrogenation over a nickel chiral catalyst to obtain a chiral hydroxylamine compound represented by general formula (2). The method of the present invention has mild reaction conditions, simple operation, and can achieve good reaction yield and reaction efficiency, thus having good application effects.

[0036] In the following examples, according to R 1-3 Depending on the substituent, 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1o, 1p, 1q, 1r, 1s, 1t, 1u, 1v, 1w, 1x, 1y, 1z, 1aa, 1ab, 1ac, 1ad, 1ae, 1af, 1ag, 1ah, 1ai, 1aj, 1ak, 1al, 1am, 1an, 1ao, 1ap, 1aq, 1ar, 1as, 1at, 1au, 1av, 1aw, 1ax, 1ay, 1az, 1aaa, 1aab, 1aac, 1aad, 1aae, 1aaf represent various oximes represented by the general formula (1), and In addition, various chiral hydroxylamine compounds represented by the general formula (2) are represented by 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2J, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2ab, 2ac, 2ad, 2ae, 2af, 2ag, 2ah, 2ai, 2aj, 2ak, 2al, 2am, 2an, 2ao, 2ap, 2aq, 2ar, 2as, 2at, 2au, 2av, 2aw, 2ax, 2ay, 2az, 2aaa, 2aab, 2aac, 2aad, 2aae, and 2aaf.

[0037] It goes without saying that, according to the reaction method of the present invention, 1a is asymmetrically hydrogenated to produce 2a, 1b is asymmetrically hydrogenated to produce 2b, 1c is asymmetrically hydrogenated to produce 2c, 1d is asymmetrically hydrogenated to produce 2d, 1e is asymmetrically hydrogenated to produce 2e, 1f is asymmetrically hydrogenated to produce 2f, 1g is asymmetrically hydrogenated to produce 2g, 1h is asymmetrically hydrogenated to produce 2h, 1i is asymmetrically hydrogenated to produce 2i, 1J is asymmetrically hydrogenated to produce 2J, 1k is asymmetrically hydrogenated to produce 2k, 1l is asymmetrically hydrogenated to produce 2l, 1m is asymmetrically hydrogenated to produce 2m, 1n is asymmetrically hydrogenated to produce 2n, and 1o is asymmetrically hydrogenated to produce 2 o, 2p is generated by asymmetric hydrogenation of 1p, 2q is generated by asymmetric hydrogenation of 1q, 2r is generated by asymmetric hydrogenation of 1r, 2s is generated by asymmetric hydrogenation of 1s, 2t is generated by asymmetric hydrogenation of 1t, 2u is generated by asymmetric hydrogenation of 1u, 2v is generated by asymmetric hydrogenation of 1w, 2x is generated by asymmetric hydrogenation of 1x, 2y is generated by asymmetric hydrogenation of 1y, 2z is generated by asymmetric hydrogenation of 1z, 2aa is generated by asymmetric hydrogenation of 1aa, 2ab is generated by asymmetric hydrogenation of 1ab, 2ac is generated by asymmetric hydrogenation of 1ac, 2ad is generated by asymmetric hydrogenation of 1ae Hydrogenation to 2ae, asymmetric hydrogenation of 1af to 2af, asymmetric hydrogenation of 1ag to 2ag, asymmetric hydrogenation of 1ah to 2ah, asymmetric hydrogenation of 1ai to 2ai, asymmetric hydrogenation of 1aj to 2aj, asymmetric hydrogenation of 1ak to 2ak, asymmetric hydrogenation of 1al to 2al, asymmetric hydrogenation of 1am to 2am, asymmetric hydrogenation of 1an to 2an, asymmetric hydrogenation of 1ao to 2ao, asymmetric hydrogenation of 1ap to 2ap, asymmetric hydrogenation of 1aq to 2aq, asymmetric hydrogenation of 1ar to 2ar, asymmetric hydrogenation of 1as 2as is generated by asymmetric hydrogenation of 1at to generate 2at, 1au is asymmetric hydrogenated to generate 2au, 1av is asymmetric hydrogenated to generate 2av, 1aw is asymmetric hydrogenated to generate 2aw, 1ax is asymmetric hydrogenated to generate 2ax, 1ay is asymmetric hydrogenated to generate 2ay, 1az is asymmetric hydrogenated to generate 2az, 1aaa is asymmetric hydrogenated to generate 2aaa, 1aab is asymmetric hydrogenated to generate 2aab, 1aac is asymmetric hydrogenated to generate 2aac, 1aad is asymmetric hydrogenated to generate 2aad, 1aae is asymmetric hydrogenated to generate 2aae, and 1aaf is asymmetric hydrogenated to generate 2aaf.

[0038] Furthermore, in the following examples, as described above, L*·Ni·X represents a chiral nickel catalyst, for example, L1·Ni·Cl represents a chiral catalyst composed of nickel, a chiral ligand L1, and chloride ions.

[0039] In the following embodiments, according to the different substituents of Ar, L1a, L2a, L3a, L4a, L5a, and L6a are used to represent L1-L6 whose Ar is C6H5; L1b, L2b, L3b, L4b, L5b, and L6b are used to represent L1-L6 whose Ar is 4-CH3OC6H4; L1c, L2c, L3c, L4c, L5c, and L6c are used to represent L1-L6 whose Ar is 4-CF3C6H4; and L1d, L2d, L3d, L4d, L5d, and L6d are used to represent L1-L6 whose Ar is 3,5-di-tBu-4-MeOC6H2.

[0040] Example 1

[0041] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0042] To a 10mL Schlenck tube, phosphine ligand L1 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol) were added. The system was vacuum-purged with nitrogen three times, and 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added. The system was placed in an autoclave and, after six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 61% and the enantiomeric excess was 57%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0043] Example 2

[0044] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0045] To a 10mL Schlenck tube, add phosphine ligand L2 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 65% and the enantiomeric excess was 51%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0046] Example 3

[0047] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0048] A 10mL Schlenck tube was charged with phosphine ligand L3 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 63% and the enantiomeric excess was 47%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0049] Example 4

[0050] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0051] To a 10mL Schlenck tube, phosphine ligand L4 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 52% and the enantiomeric excess was 48%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0052] Example 5

[0053] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0054] A 10mL Schlenck tube was charged with phosphine ligand L5 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then flushed with nitrogen three times through a vacuum line. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen flushes, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 69% and the enantiomeric excess was 50%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0055] Example 6

[0056] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0057] A 10mL Schlenck tube was charged with phosphine ligand L6 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 67% and the enantiomeric excess was 47%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0058] Example 7

[0059] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0060] A 10mL Schlenck tube was charged with phosphine ligand L7 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 51% and the enantiomeric excess was 87%. 2a: white solid. 1H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0061] Example 8

[0062] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0063] A 10mL Schlenck tube was charged with phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 67% and the enantiomeric excess was 84%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0064] Embodiment 9

[0065] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0066] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 94% and the enantiomeric excess was 97%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0067] Example 10

[0068] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0069] A 10mL Schlenck tube was charged with phosphine ligand L10 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 59% and the enantiomeric excess was 52%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0070] Example 11

[0071] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0072] A 10mL Schlenck tube was charged with phosphine ligand L11 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 74% and the enantiomeric excess was 8%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0073] Example 12

[0074] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0075] A 10mL Schlenck tube was charged with phosphine ligand L12 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 81% and the enantiomeric excess was 11%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0076] Example 13

[0077] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0078] A 10mL Schlenck tube was charged with phosphine ligand L13 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then flushed with nitrogen three times through a vacuum line. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen flushes, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 54% and the enantiomeric excess was 3%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0079] Example 14

[0080] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0081] A 10mL Schlenck tube was charged with phosphine ligand L14 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then flushed with nitrogen three times through a vacuum line. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen flushes, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 55% and the enantiomeric excess was 11%. 2a: white solid. 1H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0082] Example 15

[0083] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0084] To a 10mL Schlenck tube, add phosphine ligand L15 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 64% and the enantiomeric excess was 6%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0085] Example 16

[0086] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0087] A 10mL Schlenck tube was charged with phosphine ligand L16 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 52% and the enantiomeric excess was 9%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0088] Example 17

[0089] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0090] A 10mL Schlenck tube was charged with phosphine ligand L17 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 57% and the enantiomeric excess was 10%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0091] Embodiment 18

[0092] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0093] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 30°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 54% and the enantiomeric excess was 98%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0094] Example 19

[0095] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0096] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 60°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 95%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0097] Example 20

[0098] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0099] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then flushed with nitrogen three times through a vacuum line. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen flushes, the initial hydrogen pressure was 30 bar. The reaction was stirred at 50°C for 24 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 90% and the enantiomeric excess was 97%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0100] Example 21

[0101] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0102] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was then flushed with nitrogen three times through a vacuum line. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen flushes, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 12 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 83% and the enantiomeric excess was 97%. 2a: white solid. 1H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0103] Example 22

[0104] 2a(R 1 =Ph,R 2 =CH3,R 3 =H)

[0105] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1a (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 97%, and the enantiomeric excess was 97%. 2a: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.28 (m, 5H), 4.13 (q, J = 6.8Hz, 1H), 1.43 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 142.17, 128.56, 127.66, 127.23, 61.78, 19.35.

[0106] Example 23

[0107] 2b(R 1 =4-Me-C6H4,R 2 =CH3,R 3 =H)

[0108] To a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1b (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 92% and the enantiomeric excess was 97%. 2b: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.24(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),4.10(q,J=6.4Hz,1H),2.37(s,3H),1.41(d,J=6.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ 139.34, 137.54, 129.46, 127.36, 61.70, 21.33, 19.52.

[0109] Example 24

[0110] 2c(R 1 =4-MeO-C6H4,R 2 =CH3,R 3 =H)

[0111] To a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1c (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 92% and the enantiomeric excess was 94%. 2c: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.26(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),4.08(q,J=6.8Hz,1H),3.81(s,3H),1.41(d,J=6.8Hz,3H); 13C NMR (101MHz, Chloroform-d) δ159.07,134.12,128.37,113.90,61.09,55.27,19.28.

[0112] Example 25

[0113] 2d(R 1 =4-F-C6H4,R 2 =CH3,R 3 =H)

[0114] To a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1d (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 97% and the enantiomeric excess was 99%. 2d: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.33-7.28(m,2H),7.07-7.00(m,2H),4.11(q,J=6.8Hz,1H),1.39(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ 162.22 (d, J = 246.6Hz), 137.92 (d, J = 3.2Hz), 128.79 (d, J = 8.0Hz), 115.35 (d, J = 21.3Hz), 61.04, 19.39; 19 F NMR (376MHz, Chloroform-d) δ-114.98.

[0115] Example 26

[0116] 2e(R 1 =4-Cl-C6H4,R 2 =CH3,R 3 =H)

[0117] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1e (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 92% and the enantiomeric excess was 96%. 2e: white solid, 1 H NMR (400MHz, Chloroform-d) δ7.32 (d, J = 8.4Hz, 2H), 7.26 (d, J = 8.4Hz, 2H), 4.08 (q, J = 6.8Hz, 1H), 1.37 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ 140.70, 133.32, 128.69, 128.61, 61.10, 19.27.

[0118] Example 27

[0119] 2f(R 1 =4-Br-C6H4,R 2 =CH3,R 3 =H)

[0120] To a 10mL Schlenck tube, add the phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1f (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 93% and the enantiomeric excess was 97%. 2f: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.48 (d, J = 8.4Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 5.62 (br.s, 2H), 4.07 (q, J = 6.8Hz, 1H), 1.35 (d, J = 6.8Hz, 3H); 13C NMR (101MHz, Chloroform-d) δ141.55,131.87,129.18,121.64,61.39,19.48.

[0121] Example 28

[0122] 2g(R 1 =4-NO2-C6H4,R 2 =CH3,R 3 =H)

[0123] To a 10mL Schlenck tube, add the phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and 1g of oxime (0.2mmol). The system was vacuumed and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 93% and the enantiomeric excess was 95%. 2g: white solid. 1 H NMR (400MHz, Chloroform-d) δ8.19(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),4.24(q,J=6.8Hz,1H),1.36(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ150.55,147.58,128.17,124.01,61.47,19.69.

[0124] Example 29

[0125] 2h(R 1 =4-CF3-C6H4,R 2 =CH3,R 3 =H)

[0126] To a 10mL Schlenck tube, add the phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1h (0.2mmol). The system was vacuumed and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 96% and the enantiomeric excess was 95%. 2h: White solid. 1 H NMR (400MHz, Chloroform-d) δ7.59 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.0Hz, 2H), 4.17 (q, J = 6.8Hz, 1H), 1.36 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ146.80, 127.70, 125.71 (d, J = 3.8Hz), 61.62, 19.59, the carbon peaks near F atom is obscure; 19 F NMR (376MHz, Chloroform-d) δ-62.94.

[0127] Example 30

[0128] 2i(R 1 =3-Me-C6H4,R 2 =CH3,R 3 =H)

[0129] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1i (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 97% and the enantiomeric excess was 96%. 2i: white solid. 1H NMR (600MHz, Chloroform-d) δ7.23-7.18(m,1H),7.12-7.06(m,3H),4.03(q,J=6.6Hz,1H),2.33(s,3H),1.36(d,J=6.6Hz,3H); 13 C NMR (151MHz, Chloroform-d) δ142.06,138.10,128.44,128.38,127.94,124.20,61.74,21.42,19.26.

[0130] Example 31

[0131] 2j(R 1 =3-MeO-C6H4,R 2 =CH3,R 3 =H)

[0132] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1j (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 93% and the enantiomeric excess was 96%. 2j: A colorless oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.32-7.20(m,1H),6.96-6.86(m,2H),6.82(dd,J=8.0,2 .4Hz,1H),5.50(br.s,2H),4.10(q,J=6.4Hz,1H),3.80(s,3H),1.37(d,J=6.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ159.99,144.31,129.81,119.63,113.13,112.99,62.05,55.43,19.76.

[0133] Example 32

[0134] 2k(R 1 =3-F-C6H4,R 2 =CH3,R 3 =H)

[0135] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1k (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 96% and the enantiomeric excess was 97%. 2k: white solid. 1 H NMR(400MHz,Chloroform-d)δ7.32(td,J=8.0,6.0Hz,1H),7.11(d,J=7.6Hz,1H),7.07( dt,J=10.0,2.0Hz,1H),7.01-6.96(m,1H),4.12(q,J=6.8Hz,1H),1.38(d,J=6.8Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ162.97(d,J=246.8Hz),145.06(d,J=6.8Hz),130.02(d,J=8.3Hz) ,122.82(d,J=2.8Hz),114.46(d,J=21.1Hz),114.02(d,J=21.7Hz),61.34(d,J=1.8Hz),19.35; 19 F NMR (376MHz, Chloroform-d) δ-112.95.

[0136] Example 33

[0137] 2l(R 1 =3-Cl-C6H4,R 2 =CH3,R 3 =H)

[0138] To a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1l (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 96% and the enantiomeric excess was 97%. 2l: White solid.1 H NMR (600MHz, Chloroform-d) δ7.34 (s, 1H), 7.27-7.24 (m, 2H), 7.22-7.20 (m, 1H), 4.09 (q, J = 6.6Hz, 1H), 1.34 (d, J = 6.6Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ144.48,134.61,130.08,128.04,127.62,125.66,61.53,19.39.

[0139] Example 34

[0140] 2m(R 1 =3-Br-C6H4,R 2 =CH3,R 3 =H)

[0141] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1m (0.2mmol). The system was vacuum-purged with nitrogen three times, and 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added. The system was then placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 93% and the enantiomeric excess was 98%. 2m: white solid, 1 H NMR(600MHz,Chloroform-d)δ7.48(t,J=1.8Hz,1H),7.42-7.38(m,1H),7.24(dt,J= 7.8,1.2Hz,1H),7.20(t,J=7.8Hz,1H),4.04(q,J=6.6Hz,1H),1.32(d,J=6.6Hz,3H); 13 C NMR (151MHz, Chloroform-d) δ 144.79, 130.66, 130.28, 130.11, 125.88, 122.60, 61.29, 19.27.

[0142] Example 35

[0143] 2n(R 1 =3-NO2-C6H4,R 2 =CH3,R 3 =H)

[0144] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1n (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 90% and the enantiomeric excess was 95%. 2n: white solid, 1 H NMR(400MHz,Chloroform-d)δ8.22(s,1H),8.15-8.07(m,1H),7.66(d,J=8.0Hz,1H), 7.50(t,J=8.0Hz,1H),5.57(br.s,2H),4.23(q,J=6.8Hz,1H),1.37(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ148.65,145.11,133.75,129.68,122.79,122.34,61.29,19.59.

[0145] Example 36

[0146] 2o(R 1 =2-Me-C6H4,R 2 =CH3,R 3 =H)

[0147] A 10mL Schlenck tube was charged with phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1o (0.2mmol). The system was then flushed with nitrogen three times through a vacuum line. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen flushes, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 81% and the enantiomeric excess was 97%. 2o: A colorless oily liquid. 1 H NMR (400MHz, Chloroform-d) δ7.35(d,J=7.2Hz,1H),7.21-7.16(m,3H),5.28(br.s,2H),4.43(q,J=6.4Hz,1H),2.38(s,3H),1.38(d,J=6.4Hz,3H);13 C NMR (101MHz, Chloroform-d) δ140.37,136.05,130.79,127.46,126.59,125.70,57.34,19.51,19.09.

[0148] Example 37

[0149] 2p(R 1 =2-MeO-C6H4,R 2 =CH3,R 3 =H)

[0150] A 10mL Schlenck tube was charged with phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1p (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 90% and the enantiomeric excess was 92%. 2p: a colorless oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.30(d,J=7.6Hz,1H),7.24(d,J=8.0Hz,1H),6.95(t,J=7.6Hz,1H), 6.88(d,J=8.0Hz,1H),5.54(br.s,2H),4.48(q,J=6.8Hz,1H),3.84(s,3H),1.43(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ157.42,130.00,128.64,128.02,120.91,110.82,56.56,55.53,17.77.

[0151] Example 38

[0152] 2q(R 1 =2-F-C6H4,R 2 =CH3,R 3 =H)

[0153] To a 10mL Schlenck tube, add the phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1q (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 95% and the enantiomeric excess was 98%. 2q: a colorless oily liquid. 1 H NMR (400MHz, Chloroform-d) δ7.43-7.31(m,1H),7.29-7.20(m,1H),7.17-7.08(m,1H),7.09-6.96(m,1H),4.46(q,J=6.8Hz,1H),1.41(d,J=6.8Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ161.09(d,J=246.9Hz),129.36(d,J=13.3Hz),129.12(d,J =8.5Hz), 128.40 (d, J = 4.7Hz), 124.46 (d, J = 3.6Hz), 115.82 (d, J = 22.5Hz), 55.57, 18.40; 19 F NMR (376MHz, Chloroform-d) δ-119.73.

[0154] Example 39

[0155] 2r(R 1 =3,4-DiMeO-C6H3,R 2 =CH3,R 3 =H)

[0156] To a 10mL Schlenck tube, add the phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1r (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 92% and the enantiomeric excess was 95%. 2r: A colorless oily liquid. 1H NMR (400MHz, Chloroform-d) δ6.86-6.79 (m, 3H), 4.02 (q, J = 6.4Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 1.34 (d, J = 6.4Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ149.00,148.48,134.74,119.37,111.12,110.27,61.53,55.91,55.86,19.39.

[0157] Example 40

[0158] 2s(R 1 =3,4-Methylenedioxygen-C6H3,R 2 =CH3,R 3 =H)

[0159] To a 10mL Schlenck tube, add the phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1s (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50 bar. The reaction is stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product is obtained by column chromatography. The yield is 93% and the enantiomeric excess is 99%. 2s: A colorless oily liquid. 1 H NMR (400MHz, Chloroform-d) δ6.80 (s, 1H), 6.77-6.72 (m, 2H), 5.91 (s, 2H), 3.99 (q, J = 6.8Hz, 1H), 1.32 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ147.75,146.95,136.14,120.61,108.23,107.49,100.99,61.50,19.38.

[0160] Example 41

[0161] 2t(R 1 =3,5-DiCF3-C6H3,R 2 =CH3,R 3 =H)

[0162] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1t (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 89% and the enantiomeric excess was 92%. 2t: white solid, 1 H NMR (400MHz, Chloroform-d) δ7.81-7.80 (m, 3H), 4.25 (q, J = 6.8Hz, 1H), 1.37 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ145.86, 132.00 (q, J = 33.4Hz), 127.62, 123.57 (q, J = 274.0Hz), 121.70 (t, J = 3.5Hz), 61.29, 19.67; 19 F NMR (376MHz, Chloroform-d) δ-63.25.

[0163] Example 42

[0164] 2u(R 1 =3,5-DiF-C6H3,R 2 =CH3,R 3 =H)

[0165] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1u (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 97% and the enantiomeric excess was 95%. 2u: white solid, 1 H NMR (400MHz, Chloroform-d) δ6.87 (d, J = 6.0 Hz, 2H), 6.71 (tt, J = 8.8, 2.0 Hz, 1H), 4.09 (q, J = 6.8 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H);13 C NMR (101MHz, Chloroform-d) δ 163.34 (dd, J = 249.1, 12.9Hz), 147.05 (t, J = 8.9Hz), 110.11 (dd, J = 18.6, 6.9Hz), 103.06 (t, J = 25.6Hz), 61.41, 19.57; 19 F NMR (376MHz, Chloroform-d) δ-110.12 (t, J=8.09Hz).

[0166] Example 43

[0167] 2v(R 1 =2,4-DiF-C6H3,R 2 =CH3,R 3 =H)

[0168] A 10mL Schlenck tube was charged with phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1v (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 92% and the enantiomeric excess was 96%. 2v: A colorless oily liquid. 1 H NMR (400MHz, Chloroform-d) δ7.32(q,J=7.6,1H),6.95-6.69(m,2H),5.93(br.s,2H),4.39(q,J=6.8,1H),1.37(d,J=6.8Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ162.39(dd,J=249.4,12.3Hz),161.09(dd,J=249.6,11.8Hz),129.33(dd, J=9.7, 6.2Hz), 125.23 (d, J=13.2Hz), 111.52 (dd, J=21.0, 3.8Hz), 104.15 (t, J=26.1Hz), 55.00, 18.24; 19 F NMR (376MHz, Chloroform-d) δ -111.99 (p, J = 7.9Hz), -115.56 (q, J = 8.7Hz).

[0169] Example 44

[0170] 2w(R 1 =2-Naphthyl(2-naphthyl), R 2 =CH3,R 3 =H)

[0171] To a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1w (0.2mmol). The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 91% and the enantiomeric excess was 93%. 2w: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.88-7.71 (m, 4H), 7.49-7.44 (m, 3H), 4.29 (q, J = 6.4Hz, 1H), 1.46 (d, J = 6.4Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ139.84,133.62,133.26,128.55,128.13,127.89,126.41,126.35,126.09,125.34,62.15,19.59.

[0172] Example 45

[0173] 2x(R 1 =1-Naphthyl(1-naphthyl)R 2 =CH3,R 3 =H)

[0174] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1x (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 57% and the enantiomeric excess was 92%. 2x: Colorless oily liquid. 1H NMR(400MHz,Chloroform-d)δ8.17(d,J=8.0Hz,1H),7.88(d,J=8.4Hz,1H),7.79(d,J=8.0Hz ,1H),7.60(d,J=7.2Hz,1H),7.55-7.45(m,3H),5.01(q,J=6.4Hz,1H),1.56(d,J=6.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ138.04,134.20,131.52,129.23,128.20,126.43,125.81,125.75,123.58,123.06,57.27,19.55.

[0175] Example 46

[0176] 2y(R 1 =Ph,R 2 =Et,R 3 =H)

[0177] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1y (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was allowed to cool, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 96% and the enantiomeric excess was 99%. 2y: white solid. 1 H NMR (400MHz, Chloroform-d) δ7.39-7.22(m,5H),3.83(dd,J=8.8,5.2Hz,1H),1.96-1.86(m,1H),1.69-1.58(m,1H),0.82(t,J=7.6Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ141.12,128.69,128.05,127.85,68.92,26.41,10.83.

[0178] Example 47

[0179] 2z(R 1 =Ph,R 2 =nPr(n-propyl), R 3 =H)

[0180] A 10mL Schlenck tube was charged with phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1z (0.2mmol). The system was then passed through a vacuum line and replaced with nitrogen three times. 2mL of a 20:1 trifluoroethanol / acetic acid mixture was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 50°C for 24 hours. The reaction was cooled, the gas was carefully released, the autoclave was opened, the vial removed, and the solvent was drained. The conversion was determined by NMR, and the product was obtained by column chromatography. The yield was 98%, and the enantiomeric excess was 98%. 2z: white solid. 1 H NMR(400MHz,Chloroform-d)δ7.42-7.19(m,5H),3.92(dd,J=8.8,5.6Hz,1H),1 .88-1.80(m,1H),1.65-1.56(m,1H),1.29-1.14(m,2H),0.89(t,J=7.2Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ141.47,128.70,127.98,127.83,67.20,35.70,19.63,14.34.

[0181] Example 48

[0182] 2aa(R 1 =Ph,R 2 =Bn,R 3 =H)

[0183] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1aa (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 20:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product was obtained by column chromatography. The yield was 92% and the enantiomeric excess was 98%. 2aa: white solid, 1H NMR (400MHz, Chloroform-d) δ7.65-6.69(m,10H),5.52(br.s,2H),4.17(t,J=7.2Hz,1H),3.09(dd,J=13.6,8.0Hz,1H),2.93(dd,J=13.6,6.4Hz,1H); 13 C NMR (101MHz, Chloroform-d) δ141.10,138.29,129.53,128.73,128.69,128.03,127.94,126.75,68.34,40.37.

[0184] Example 49

[0185] 2ab(R 1 =Diphenylmethylene, R 2 =CH3,R 3 =H)

[0186] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ab (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product was obtained by column chromatography. The yield was 77% and the enantiomeric excess was 90%. 2ab: white solid, 1 H NMR (400MHz, Chloroform-d) δ7.46-7.09 (m, 10H), 3.91 (d, J = 10.8Hz, 1H), 3.77 (dt, J = 10.8, 6.4Hz, 1H), 1.15 (d, J = 6.4Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ142.64,142.22,129.23,128.91,128.51,128.23,127.14,126.79,59.90,55.50,17.18.

[0187] Embodiment 50

[0188] 2ac(R 1 =2-Cl-C6H4,R 2 =CH3,R 3 =H)

[0189] In a 10mL Schlenck tube, phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ac (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 96% and the enantiomeric excess was 94%. 2ac: colorless oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.45(dd,J=7.6,1.6Hz,1H),7.36(dd,J=8.0,1.6Hz,1H),7.31-7.23 (m,1H),7.20(td,J=7.6,1.6Hz,1H),5.22(br.s,2H),4.66(q,J=6.8Hz,1H),1.39(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ139.64,133.79,129.99,128.74,127.77,127.32,57.85,18.33.

[0190] Example 51

[0191] 2ad(R 1 =Ph,R 2 =Cyclopropyl,R 3 =H)

[0192] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ad (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 90% and the enantiomeric excess was 95%. 2ad: colorless oily liquid, 1H NMR(400MHz,Chloroform-d)δ7.40-7.21(m,5H),5.20(br.s,2H),3.15(d,J=9.2Hz ,1H),1.12-1.03(m,1H),0.69-0.57(m,1H),0.49-0.38(m,2H),0.25-0.19(m,1H); 13 C NMR (101MHz, Chloroform-d) δ141.63,128.64,127.84,127.73,72.11,14.80,4.99,2.68.

[0193] Example 52

[0194] 2ae(R 1 =Ph,R 2 =Cyclopentyl, R 3 =H)

[0195] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ae (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 50°C for 24 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product was obtained by column chromatography. The yield was 91% and the enantiomeric excess was 85%. 2ae: colorless oily liquid, 1 H NMR (400MHz, Chloroform-d) δ7.43-7.16(m,5H),3.65(d,J=9.6Hz,1H),2.1-2.0(m,1H),1.92-1.80(m,1H),1.73-1.22(m,6H),1.13-0.98(m,1H); 13 C NMR (101MHz, Chloroform-d) δ142.19,128.49,128.21,127.54,72.79,43.39,30.84,30.69,25.71,24.87.

[0196] Example 53

[0197] 2af(R 1 =Ph,R 2 =CH3,R 3 =CH3)

[0198] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1af (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 95% and the enantiomeric excess was 94%. 2af: colorless oily liquid, 1 H NMR (400MHz, Chloroform-d) δ7.46-7.17(m,5H),4.14(q,J=6.8Hz,1H),3.48(s,3H),1.37(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ 143.08, 128.63, 127.63, 127.28, 62.68, 60.69, 20.08.

[0199] Example 54

[0200] 2ag(R 1 =Ph,R 2 =CH3,R 3 Preparation of =Et)

[0201] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ag (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product is obtained by column chromatography. The yield is 84% ​​and the enantiomeric excess is 97%. 2ag: colorless oily liquid, 1 H NMR (400MHz, Chloroform-d) δ7.57-6.98(m,5H),5.49(br.s,1H),4.14(q,J=6.8Hz,1H),3.81-3.52(m,2H),1.38(d,J=6.8Hz,3H),1.11(t,J=7.2Hz,3H); 13C NMR (101MHz, Chloroform-d) δ143.11,128.58,127.60,127.41,70.03,60.80,20.08,14.36.

[0202] Example 55

[0203] 2ah(R 1 =Ph,R 2 =CH3,R 3 =nPr)

[0204] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ah (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product is obtained by column chromatography. The yield is 86% and the enantiomeric excess is 96%. 2ah: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.55-7.12(m,5H),5.47(br.s,1H),4.15(q,J=6.8Hz,1H) ,3.65-3.52(m,2H),1.52(h,J=7.2Hz,2H),1.38(d,J=6.8Hz,3H),0.84(t,J=7.2Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ143.11,128.58,127.61,127.45,76.50,60.82,22.12,20.09,10.74.

[0205] Example 56

[0206] 2ai(R 1 =4-MeO-C6H4,R 2 =CH3,R 3 =CH3)

[0207] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ai (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 95% and the enantiomeric excess was 89%. 2ai: colorless oily liquid, 1 H NMR (400MHz, Chloroform-d) δ7.28(d,J=8.8Hz,2H),6.87(d,J=8.8Hz,2H),4.10(q,J=6.8Hz,1H),3.80(s,3H),3.48(s,3H),1.35(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ159.14,135.05,128.41,114.00,62.68,60.03,55.46,20.01.

[0208] Example 57

[0209] 2aj(R 1 =4-MeO-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0210] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1aj (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 91% and the enantiomeric excess was 94%. 2aj: colorless oily liquid, 1H NMR(400MHz,Chloroform-d)δ7.30(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),5.48(br.s,1H),4.1 1(q,J=6.4Hz,1H),3.82(s,3H),3.77-3.59(m,2H),1.38(d,J=6.4Hz,3H),1.13(t,J=7.2Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ159.11,135.07,128.53,113.94,70.03,60.13,55.47,20.00,14.38.

[0211] Example 58

[0212] 2ak(R 1 =4-MeO-C6H4,R 2 =CH3,R 3 =iPr)

[0213] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ak (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 50% and the enantiomeric excess was 96%. 2ak: colorless oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.27(d,J=8.8Hz,2H),6.86(d,J=8.8Hz,2H),5.28(br.s,1H),4.06(q, J=6.8Hz,1H),3.88-3.66(m,4H),1.36(d,J=6.8Hz,3H),1.14(d,J=6.4Hz,3H),1.05(d,J=6.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ159.09,135.14,128.67,113.87,75.25,60.17,55.45,21.50,21.46,20.02.

[0214] Example 59

[0215] 2al(R1 =4-MeO-C6H4,R 2 =CH3,R 3 =iPr)

[0216] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1al (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 91% and the enantiomeric excess was 91%. 2al: colorless oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.39-7.29(m,7H),6.92(d,J=8.8Hz,2H),5.61(br.s ,1H),4.75-4.57(m,2H),4.17(q,J=6.8Hz,1H),3.84(s,3H),1.40(d,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ158.96,137.94,134.92,128.48,128.36,128.33,127.76,113.78,76.80,59.97,55.28,19.88.

[0217] Example 60

[0218] 2am(R 1 =3-MeO-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0219] In a 10mL Schlenck tube, add the phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1am (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol and acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50 bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product is obtained by column chromatography. The yield is 89% and the enantiomeric excess is 95%. 2am: colorless oily liquid, 1H NMR(400MHz,Chloroform-d)δ7.31-7.17(m,1H),7.02-6.87(m,2H),6.86-6.73(m,1H),5.47(br.s,1H) ),4.11(q,J=6.8Hz,1H),3.81(s,3H),3.75-3.62(m,2H),1.36(d,J=6.8Hz,3H),1.11(t,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ159.85,144.89,129.57,119.73,113.00,112.92,70.04,60.79,55.41,20.16,14.38.

[0220] Example 61

[0221] 2an(R 1 =2-MeO-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0222] In a 10mL Schlenck tube, add the phosphine ligand L8 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1an (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product is obtained by column chromatography. The yield is 97% and the enantiomeric excess is 80%. 2an: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.35(dd,J=7.6,1.6Hz,1H),7.29-7.16(m,1H),6.95(td,J=7.6,1.2Hz,1H),6.91-6.77(m, 1H),5.86(br.s,1H),4.51(q,J=6.8Hz,1H),3.84(s,3H),3.79-3.71(m,2H),1.40(d,J=6.8Hz,3H),1.16(t,J=6.8Hz,3H); 13C NMR (101MHz, Chloroform-d) δ157.29,130.63,128.41,127.87,120.84,110.74,69.90,55.55,54.95,18.34,14.49.

[0223] Example 62

[0224] 2ao(R 1 =4-Me-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0225] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1ao (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, detect the conversion rate by NMR, and obtain the product by column chromatography. The yield is 91% and the enantiomeric excess is 91%. 2ao: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.25(d,J=7.6Hz,2H),7.15(d,J=7.6Hz,2H),5.45(br.s,1H),4.1 1(q,J=6.4Hz,1H),3.81-3.55(m,2H),2.34(s,3H),1.37(d,J=6.4Hz,3H),1.12(t,J=6.8Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ140.03,137.22,129.29,127.32,70.03,60.50,21.35,20.10,14.40.

[0226] Example 63

[0227] 2ap(R 1 =4-Ph-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0228] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ap (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol and acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 97% and the enantiomeric excess was 97%. 2ap: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.64-7.60(m,4H),7.49-7.45(m,4H),7.37(t,J=7.2Hz,1H),5.56( br.s,1H),4.22(q,J=6.8Hz,1H),3.89-3.63(m,2H),1.45(d,J=6.8Hz,3H),1.17(t,J=7.2Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ142.26,141.22,140.56,129.02,127.88,127.47,127.39,127.35,70.12,60.53,20.16,14.46.

[0229] Example 64

[0230] 2aq(R 1 =4-Br-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0231] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1aq (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, detect the conversion rate by NMR, and obtain the product by column chromatography. The yield is 85% and the enantiomeric excess is 94%. 2aq: colorless oily liquid, 1H NMR(400MHz,Chloroform-d)δ7.44(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),5.44(br. s,1H),4.09(q,J=6.8Hz,1H),3.74-3.49(m,2H),1.32(s,3H),1.07(t,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ142.39,131.64,129.16,121.29,70.07,60.19,20.06,14.34.

[0232] Example 65

[0233] 2ar(R 1 =4-NO2-C6H4,R 2 =CH3,R 3 Preparation of =Et)

[0234] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1ar (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 99% and the enantiomeric excess was 92%. 2ar: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J=8.8Hz,2H),7.54(d,J=8.8Hz,2H),5.52(br.s,1H ),4.24(q,J=6.8Hz,1H),3.73-3.48(m,2H),1.33(d,J=6.8Hz,3H),1.05(t,J=7.2Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ151.43,147.44,128.17,123.82,70.07,60.23,20.06,14.25.

[0235] Example 66

[0236] 2as(R 1 =2-Naphthyl(2-naphthyl), R 2 =CH3,R3 Preparation of =Et)

[0237] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1as (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product is obtained by column chromatography. The yield is 90% and the enantiomeric excess is 94%. 2as: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ8.02-7.68(m,4H),7.63-7.36(m,3H),5.51(br.s,1H),4 .32(q,J=6.8Hz,1H),3.88-3.50(m,2H),1.46(d,J=6.8Hz,3H),1.11(t,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ140.69,133.62,133.19,128.27,128.12,127.89,126.20,125.91,125.61,70.13,60.96,20.21,14.42.

[0238] Example 67

[0239] 2at(R 1 =Ph,R 2 =Et,R 3 Preparation of =Et)

[0240] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1at (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol and acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 83% and the enantiomeric excess was 97%. 2at: colorless oily liquid, 1H NMR(400MHz,Chloroform-d)δ7.42-7.17(m,5H),5.54(br.s,1H),3.86(dd,J=8.8,5.2Hz,1H),3.7 5-3.54(m,2H),1.93-1.83(m,1H),1.72-1.57(m,1H),1.09(t,J=7.2Hz,3H),0.82(t,J=7.6Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ141.80,128.48,128.06,127.59,70.03,67.76,26.84,14.37,10.83.

[0241] Example 68

[0242] 2au(R 1 =Ph,R 2 =Chloromethylene(chloromethylene), R 3 Preparation of =Et)

[0243] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1au (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 71% and the enantiomeric excess was 83%. 2au: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.49-7.26(m,5H),5.98(br.s,1H),4.24(dd,J=7.2,5.6Hz,1H),3.90-3.57(m,4H),1.11(t,J=7.2Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ138.58,128.76,128.51,128.05,70.22,66.38,45.85,14.30.

[0244] Example 69

[0245] 2av(R 1 =Ph,R 2=Hydroxymethylene, R 3 Preparation of =Et)

[0246] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1av (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 50bar. Stir and react at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, detect the conversion rate by NMR, and obtain the product by column chromatography. The yield is 99% and the enantiomeric excess is 95%. 2av: colorless oily liquid, 1 H NMR (400MHz, Chloroform-d) δ7.45-7.20(m,5H),4.16(dd,J=6.8,5.2Hz,1H),3.87-3.62(m,4H),1.13(t,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ138.82,128.76,128.16,127.97,70.13,66.78,64.92,14.34.

[0247] Embodiment 70

[0248] 2aw(R 1 =Ph,R 2 =CH3OCOCH2(methoxycarbonylmethylene), R 3 Preparation of =Et)

[0249] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1aw (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a 10:1 trifluoroethanol / acetic acid mixed solvent was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 50 bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and analyze the conversion by NMR. The product was obtained by column chromatography. The yield was 98%, and the enantiomeric excess was 98%. 2aw: colorless oily liquid, 1H NMR (400MHz, Chloroform-d) δ7.41-7.20 (m, 5H), 6.29 (br.s, 1H), 4.20 (s, 3H), 3.74 (s, 3H), 1.35 (d, J = 6.8Hz, 3H); 13 C NMR (101MHz, Chloroform-d) δ171.64,142.83,128.68,127.71,127.27,71.94,60.67,51.96,20.06.

[0250] Example 71

[0251] 2ax(R 1 =2-Br-C6H4-CH2(2-bromophenylmethylene), R 2 =CH3,R 3 =H)

[0252] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1ax (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure is 60bar. Stir and react at 50°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, detect the conversion rate by NMR, and obtain the product by column chromatography. The yield is 81% and the enantiomeric excess is 77%. 2ax: white solid, 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J=7.6Hz,1H),7.30-7.25(m,2H),7.14-7.08(m,1H),3.36(h) ,J=6.4Hz,1H),3.05(dd,J=13.6,7.2Hz,1H),2.79(dd,J=13.6,6.4Hz,1H),1.18(d,J=6.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ138.41,133.06,131.54,128.12,127.42,124.95,57.08,39.99,17.68.

[0253] Example 72

[0254] 2ay(R 1 =4-Br-C6H4-CH2(4-bromophenylmethylene), R 2 =CH3,R3 =H)

[0255] In a 10mL Schlenck tube, add phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1ay (0.2mmol). The system is passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 is added and placed in an autoclave. After 6 hydrogen replacements, the initial hydrogen pressure is 60bar. Stir and react at 50°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, detect the conversion rate by NMR, and obtain the product by column chromatography. The yield is 92% and the enantiomeric excess is 75%. 2ay: white solid, 1 H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.4Hz,2H),7.06(d,J=8.4Hz,2H),3.16(h,J=6.4 Hz,1H),2.85(dd,J=13.6,6.8Hz,1H),2.56(dd,J=13.6,6.8Hz,1H),1.06(d,J=6.4Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ137.79,131.81,131.34,120.46,58.50,39.50,17.60.

[0256] Example 73

[0257] 2az(R 1 =2,6-DiCl-C6H3-CH2(2,6-dichlorophenylmethylene), R 2 =CH3,R 3 =H)

[0258] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1az (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 60bar. The reaction was stirred at 50°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product was obtained by column chromatography. The yield was 61% and the enantiomeric excess was 73%. 2az: white solid, 1H NMR(400MHz,Chloroform-d)δ7.28(t,J=6.8Hz,2H),7.09(t,J=8.0Hz,1H),3.44(h,J=6.8 Hz,1H),3.16(dd,J=13.6,7.2Hz,1H),2.97(dd,J=13.6,6.8Hz,1H),1.16(d,J=6.4Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ136.16,135.62,128.59,128.27,57.23,35.49,18.03.

[0259] Example 74

[0260] 2ba(R 1 =2,6-DiCl-C6H3-CH2(2,6-dichlorophenylmethylene), R 2 =CH3,R 3 =CH3)

[0261] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1aaa (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 60bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion rate by NMR. The product was obtained by column chromatography. The yield was 80% and the enantiomeric excess was 58%. 2aaa: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.35-7.20(m,2H),7.07(t,J=8.0Hz,1H),5.49(br.s,1H),3.56(s,2H),3.47 (dt,J=8.0,6.0Hz,1H),3.18(dd,J=13.2,6.0Hz,1H),2.95(dd,J=13.2,8.0Hz,1H),1.10(d,J=6.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ136.19,135.78,128.55,128.14,62.73,55.87,35.72,17.91.

[0262] Example 75

[0263] 2bc(R1 =2,6-DiCl-C6H3-CH2(2,6-dichlorophenylmethylene), R 2 =CH3,R 3 Preparation of =Et)

[0264] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1aac (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was set to 60bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 82% and the enantiomeric excess was 70%. 2aac: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J=8.0Hz,2H),7.07(t,J=8.0Hz,1H),5.38(br.s,1H),3.74(q,J=7.2 Hz,2H),3.50-3.42(m,1H),3.19(dd,J=13.2,6.0Hz,1H),2.94(dd,J=13.2,8.0Hz,1H),1.22-0.96(m,6H); 13 C NMR (101MHz, Chloroform-d) δ136.20,135.89,128.52,128.09,70.09,56.02,35.82,18.01,14.38.

[0265] Example 76

[0266] 2bd(R 1 =Cyclopropyl, R 2 =CH3,R 3 =Bn)

[0267] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1aad (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 60bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product was obtained by column chromatography. The yield was 75% and the enantiomeric excess was 53%. 2aad: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.46-7.27(m,5H),4.76(s,2H),2.26(dq,J=9.2,6.4Hz,1H),1.2 1(d,J=6.4Hz,3H),0.79-0.70(m,1H),0.52-0.44(m,2H),0.33-0.20(m,1H),0.18-0.10(m,1H); 13 C NMR (101MHz, Chloroform-d) δ138.16,128.60,128.00,62.06,18.43,15.12,4.01,2.36.

[0268] Example 77

[0269] 2be(R 1 =tBu,R 2 =PhOCH2(phenoxymethylene), R 3 =CH3)

[0270] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol) and oxime 1aae (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 60bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 65% and the enantiomeric excess was 62%. 2aae: colorless oily liquid, 1H NMR(400MHz,Chloroform-d)δ7.33-7.22(m,2H),6.94(d,J=6.8Hz,3H),5.98(br.s,1H) ),4.18-4.14(m,1H),4.07-4.03(m,1H),3.52(s,3H),2.90-2.81(m,1H),1.04(s,9H); 13 C NMR (101MHz, Chloroform-d) δ 159.08, 129.65, 120.99, 114.85, 67.89, 65.00, 61.51, 33.41, 28.00.

[0271] Example 78

[0272] 2bf(R 1 =tBu,R 2 =PhOCH2(phenoxymethylene), R 3 Preparation of =Et)

[0273] In a 10mL Schlenck tube, phosphine ligand L9 (0.004mmol), nickel acetate tetrahydrate (1.0mg, 0.004mmol), and oxime 1aaf (0.2mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 2mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 10:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 60bar. The reaction was stirred at 55°C for 48 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and detect the conversion by NMR. The product was obtained by column chromatography. The yield was 67% and the enantiomeric excess was 71%. 2aaf: colorless oily liquid, 1 H NMR(400MHz,Chloroform-d)δ7.38-7.21(m,2H),7.07-6.75(m,3H),5.86(br.s,1H),4.20-4.17(m,1H ),4.10-4.06(m,1H),3.73(q,J=7.2Hz,2H),2.87(t,J=4.8Hz,1H),1.17(t,J=7.2Hz,3H),1.05(s,8H); 13 C NMR (101MHz, Chloroform-d) δ159.14,129.63,120.92,114.86,69.02,67.97,65.14,33.49,28.02,14.44.

[0274] Embodiment 79

[0275] 2av(R 1=Ph,R 2 =HOCH2,(hydroxymethylene)R 3 Preparation of =Et)

[0276] In a 10mL Schlenck tube, phosphine ligand L9 (0.01mmol), nickel acetate tetrahydrate (49.77mg, 0.2mmol), and oxime 1av (10mmol) were added. The system was passed through a vacuum line and replaced with nitrogen three times. 17mL of a mixed solvent of trifluoroethanol / acetic acid with a volume ratio of 7.5:1 was added and placed in an autoclave. After six hydrogen replacements, the initial hydrogen pressure was 60bar. The reaction was stirred at 60°C for 72 hours. Cool, carefully release the gas, open the autoclave, remove the vial, drain the solvent, and measure the conversion by NMR. The product was obtained by column chromatography. The yield was 95% and the enantiomeric excess was 96%. 2av: colorless oily liquid, 1 H NMR (400MHz, Chloroform-d) δ7.45-7.20(m,5H),4.16(dd,J=6.8,5.2Hz,1H),3.87-3.62(m,4H),1.13(t,J=6.8Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ138.82,128.76,128.16,127.97,70.13,66.78,64.92,14.34.

[0277] In summary, the reaction method of the present invention has mild conditions and is easy to operate. In addition, it can achieve good reaction yield and reaction efficiency when the preferred hydrogen atmosphere pressure is 30 to 50 bar, the reaction temperature is 50° C. to 60° C., and the reaction time is 24 to 48 h, and has good application effect.

[0278] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art may make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. The embodiments of this application and the features in the embodiments may be combined with each other in any manner unless there is a conflict.

Claims

1. A method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime, characterized in that: The method comprises the following steps: adding a nickel chiral catalyst to a solvent under a certain hydrogen pressure and temperature to hydrogenate an oxime into a chiral hydroxylamine compound. The oxime has the general formula: The chiral hydroxylamine compound has the general formula: The hydrogen pressure is 30-80 bar and the temperature is 30-80° C., wherein: R 1 、R 2 methyl, ethyl, benzyl, isopropyl, n-propyl, n-butyl, tert-butyl, cyclohexyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-phenylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 4-nitrophenyl, 4-trifluoromethyl One of phenyl, 3-nitrophenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-ditrifluoromethylphenyl, 3,5-difluorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2,4-dimethoxyphenyl, 2-furyl, dibenzhydryl, cyclopropyl, cyclopentyl, chloromethylene, hydroxymethylene, methoxymethylene, 2-bromobenzyl, 4-bromobenzyl, 2,6-dichlorobenzyl, and phenoxymethylene; R 3 is one of methyl, ethyl, benzyl, isopropyl, n-propyl, n-butyl, tert-butyl, cyclohexyl, and hydrogen; The nickel chiral catalyst is formed by complexing nickel salts with different anions and chiral ligands; The chiral ligand is any one of the ligands selected from L1 to L17, and the structural formulas of the ligands L1 to L17 are as follows: in: In L1-L6, Ar is one of C6H5, 4-CH3OC6H4, 4-CF3C6H4, and 3,5-di-tBu-4-MeOC6H2.

2. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 1, characterized in that: The nickel salts with different anions are nickel salts whose anions are any one of chloride, bromide, acetate, tetrafluoroborate, trifluoroacetate, trifluoromethanesulfonate and perchlorate.

3. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 1, characterized in that: The solvent is one or more of a non-polar solvent, a polar solvent, and a protic solvent.

4. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 3, characterized in that: The non-polar solvent is one or more of toluene, ether, and tetrahydrofuran; the polar solvent is one or more of dichloromethane, 1,2-dichloroethane, DMF, acetone, and acetonitrile; and the protic solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, formic acid, acetic acid, propionic acid, butyric acid, and isobutyric acid.

5. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 1, characterized in that: The reaction time is 1 to 72 hours.

6. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 1, characterized in that: The molar ratio of the nickel chiral catalyst to the oxime is 1:20 to 100,000.

7. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to any one of claims 1 to 6, characterized in that: The chiral ligand is any one selected from L1, L2, L5, L7, L8, L9, and L10.

8. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 7, characterized in that: The chiral ligand is selected from L8 or L9.

9. The method for preparing chiral hydroxylamine by asymmetric nickel-catalyzed hydrogenation of oxime according to claim 8, characterized in that: The chiral ligand is selected from L9.

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