ENANTIOSELECTIVE HYDROGENATION OF 4-SUBSTITUTED 1,2-DIHYDROQUINOLINES IN PRESENCE OF A CHIRAL IRIDIUM CATALYST
20260015326 · 2026-01-15
Assignee
Inventors
Cpc classification
B01J31/2447
PERFORMING OPERATIONS; TRANSPORTING
B01J31/2295
PERFORMING OPERATIONS; TRANSPORTING
B01J31/189
PERFORMING OPERATIONS; TRANSPORTING
B01J31/2404
PERFORMING OPERATIONS; TRANSPORTING
International classification
B01J31/18
PERFORMING OPERATIONS; TRANSPORTING
Abstract
The invention relates to a process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines comprising enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in presence of a chiral iridium (P,N)-ligand catalyst.
Claims
1. A process for preparing a compound of the formula (Ia) or (Ib), ##STR00022## wherein R.sup.1 is C.sub.1-C.sub.6-alkyl, R.sup.2 and R.sup.3 are the same and are selected from the group consisting of C.sub.1-C.sub.6-alkyl, R.sup.4 is C.sub.1-C.sub.6-alkyl, n is 0 or 1, each substituent R.sup.5, if present, is independently selected from the group consisting of halogen, comprising enantioselective hydrogenation of a compound of the formula (II) ##STR00023## wherein the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and the integer n are each as defined for the compound of the formula (Ia) or (Ib), in presence of a chiral iridium catalyst, characterized in that the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa) or (IIIb) ##STR00024## wherein R.sup.6 and R.sup.7 are independently from one another selected from consisting of hydrogen, C.sub.1-C.sub.6-alkyl, and C.sub.6-C.sub.14-aryl, wherein the C.sub.6-C.sub.14-aryl is optionally substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-alkoxy, R.sup.8 is methyl, R.sup.9 and R.sup.10 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.12-cycloalkyl, and m is 1 or 2.
2. The process according to claim 1, wherein R.sup.2 and R.sup.3 are the same and are selected from C.sub.1-C.sub.4-alkyl, and R.sup.4 is C.sub.1-C.sub.4-alkyl.
3. The process according to claim 1, wherein R.sup.1 is methyl, ethyl or n-propyl, R.sup.2 and R.sup.3 are methyl, and R.sup.4 is C.sub.1-C.sub.4-alkyl.
4. The process according to claim 1, wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa) or (IIIb), wherein R.sup.6 is C.sub.6-C.sub.14-aryl, wherein the C.sub.6-C.sub.14-aryl is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-alkoxy, R.sup.7 is selected from the group consisting of hydrogen, and C.sub.1-C.sub.6-alkyl, and R.sup.9 and R.sup.10 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.12-cycloalkyl.
5. The process according to claim 1, wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa) or (IIIb), wherein R.sup.6 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl or phenyl, which is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-haloalkyl, R.sup.7 is hydrogen or C.sub.1-C.sub.6-alkyl, and R.sup.9 and R.sup.10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, and adamantyl.
6. The process according to claim 1, wherein the hydrogenation is conducted using hydrogen gas at a pressure of from 1 to 300 bar.
7. The process according to claim 1, wherein the amount of iridium catalyst used is within the range of from 0.001 mol % to 5 mol %, based on the amount of the compound of the formula (II).
8. The process according to claim 1, wherein the hydrogenation is conducted at a temperature within the range of from 20 C. to 130 C.
9. The process according to claim 1, wherein the hydrogenation is conducted in presence of a solvent selected from the group consisting of 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof.
10. The process according to claim 1, wherein the chiral iridium catalyst has the formula (Va), or (Vb): ##STR00025## wherein R.sup.6 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl or phenyl, wherein 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl and phenyl are unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-haloalkyl, R.sup.7 is hydrogen or C.sub.1-C.sub.6-alkyl, R.sup.8 is methyl, R.sup.9 and R.sup.10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, and adamantyl, and R.sup.18 is phenyl, which is unsubstituted or substituted with one to five substituents selected from group consisting of fluorine and C.sub.1-C.sub.4-haloalkyl.
11. The process according to claim 10, wherein R.sup.6 is selected from the group consisting of phenyl, 2,6- or 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3,5-bis-tert-butyl-4-methoxyphenyl, 4-tert-butyl-2,6-dimethylphenyl, 4-fluorophenyl, 4-trifluoromehtylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl or 2,6-diethyl-4-methylphenyl, R.sup.7 is hydrogen, and R.sup.9 and R.sup.10 are each the same and tert-butyl, adamantly, cyclopentyl or cyclohexyl.
12. The process according to claim 1, wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa) or (IIIb), wherein R.sup.6 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl or phenyl, which is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C.sub.1-C.sub.6-alkyl substituents, is hydrogen or C.sub.1-C.sub.6-alkyl, and R7 R.sup.9 and R.sup.10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, and adamantyl.
13. The process according to claim 12, wherein R.sup.6 is selected from the group consisting of phenyl, 2,6- or 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3,5-bis-tert-butyl-4-methoxyphenyl, 4-tert-butyl-2,6-dimethylphenyl, 4-fluorophenyl, 4-trifluoromehtylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl or 2,6-diethyl-4-methylphenyl, R.sup.7 is hydrogen R.sup.9 and R.sup.10 are each the same and tert-butyl, cyclopentyl or cyclohexyl, and m is 1.
14. The process according to claim 1, wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa) or (IIIb), wherein R.sup.6 is selected from the group consisting of phenyl, 2,6- or 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3,5-bis-tert-butyl-4-methoxyphenyl, 4-tert-butyl-2,6-dimethylphenyl, 4-fluorophenyl, 4-trifluoromehtylphenyl, 1-naphtyl, 9-antracenyl, 2,4,6-triisopropylphenyl, 9-phenantryl and 2,6-diethyl-4-methylphenyl, R.sup.7 is hydrogen, R.sup.9 and R.sup.10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, and adamantyl, and m is 1.
Description
Preparation of Iridium Catalysts
##STR00015##
[0243] The ligand precursors (enantiomerically enriched secondary alcohols) were prepared according to known literature procedures like to the method disclosed in S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197 or in D. H. Woodmansee Chem. Sci 2010, 1, 72. The ligands and Iridium complexes were prepared by a modified procedure based on the same literature precedents:
[0244] Procedure of ligand synthesis (under Ar): A solution of alcohol precursor in THF (0.25 mmol, in 5.0 mL THF) was cooled to 78 C. and n-BuLi (0.1 mL of a 2.5 M n-BuLi solution in hexane; 0.25 mmol; 1 eq.) was added dropwise to the continuously stirred solution. After completion of the addition the solution was allowed to warm to room temperature and was stirred at this temperature for further 30 min. The solution was cooled to 78 C. again and R.sub.2PCl (0.25 mmol, 1 eq.) was added to the continuously stirred solution. The mixture was allowed to warm to room temperature and subsequently heated to 50 C. and kept at this temperature overnight. The theoretical yield of ligand was calculated using .sup.31P-NMR and the ligand was used for the next step without further purification.
[0245] Procedure of complexation (under Ar): To the crude ligand solution was added [Ir(COD).sub.2]BARF (BARF=Tetrakis[3,5-bis(trifluoromethyl)phenyl]-borate) (as a solid, 1 eq. based on the theoretical yield). The resulting mixture was heated to 50 C. and kept at this temperature for 3 h.
[0246] Work-up (under air): After cooling to room temperature the reaction solution is rotary evaporated onto silica, loaded onto a column of silica. Side components were eluted using pentane/diethylether and the desired complexes subsequently with DCM. The solvent was then evaporated under reduced pressure.
[0247] The following specified catalysts were synthesized and characterized:
##STR00016##
[0248] with m=1 and R.sup.18=3.5-bis(trifluoromethyl)phenyl
TABLE-US-00001 Catalyst R.sup.6 R.sup.7 R.sup.8 R.sup.9, R.sup.10 Va-1 phenyl H H tert-butyl Va-2 phenyl H methyl tert-butyl Vb-3 phenyl H H cyclohexyl Va-4 phenyl H methyl cyclohexyl Vb-5 4-tert-butylphenyl H H cyclohexyl Va-6 4-tert-butylphenyl H methyl cyclohexyl Vb-7 9-antracenyl H H cyclohexyl Va-8 9-antracenyl H methyl cyclohexyl Va-9 2,6-dimethylphenyl H methyl cyclohexyl Va-10 2,4,6-trimethylphenyl H methyl cyclohexyl Va-11 3,5-dimethylphenyl H methyl cyclohexyl Va-12 1-naphtyl H methyl cyclohexyl Va-13 4-methoxyphenyl H methyl tert-butyl Va-14 4-fluorophenyl H methyl tert-butyl Va-15 4-(trifluoromethyl)phenyl H methyl tert-butyl Va-16 phenyl H methyl cyclopentyl Vb-17 phenyl H H ethyl Va-18 phenyl H methyl isopropyl Va-19 methyl H methyl cyclohexyl Va-20 3,5-bis-tert.-butyl,-4- H methyl cyclohexyl methoxyphenyl Va-21 2,4,6-triisopropylphenyl H methyl cyclohexyl Va-22 4-tert-butyl-2,6- H methyl cyclohexyl dimethylphenyl Va-23 phenyl H H adamantyl
Va-2
[0249] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (89.5 mg; 53% based on [Ir(COD).sub.2]BARF).
[0250] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.26 (dd, J=7.9, 1.7 Hz, 2H), 7.81-7.36 (m, 16H), 5.75 (dt, J=8.0, 5.2 Hz, 1H), 5.34-5.29 (m, 1H), 4.51 (q, J=5.3, 3.2 Hz, 1H), 4.11 (dq, J=12.5, 7.6, 5.9 Hz, 1H), 3.08 (ddd, J=16.6, 10.3, 3.8 Hz, 1H), 2.99-2.70 (m, 2H), 2.61-2.00 (m, 8H), 1.92-1.79 (m, 1H), 1.69 (dd, J=14.8, 8.1 Hz, 1H), 1.51 (s, 9H), 1.29-1.24 (m, 3H), 1.06 (d, J=14.4 Hz, 9H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=142.09. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.85. HR-MS (ESI) m/z calcd for C.sub.31H.sub.44NOPIr [M]+670.2790 found 670.2798.
Va-4
[0251] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (241 mg; 71% based on [Ir(COD).sub.2]BARF).
[0252] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.38-8.14 (m, 2H), 7.83-7.43 (m, 16H), 5.76 (dt, J=7.7, 4.9 Hz, 1H), 4.81 (t, J=7.6 Hz, 1H), 4.70-4.46 (m, 1H), 3.56-3.39 (m, 1H), 3.06 (ddd, J=16.7, 10.3, 3.6 Hz, 1H), 2.98-2.73 (m, 2H), 2.71-2.57 (m, 1H), 2.44 (s, 3H), 2.41-2.02 (m, 6H), 2.00-1.75 (m, 7H), 1.72-1.54 (m, 4H), 1.46-0.94 (m, 13H), 0.72-0.50 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=121.27. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.86. HR-MS (ESI) m/z calcd for C.sub.35H.sub.48NOPIr [M]+722.3103 found 722.3116.
Vb-5
[0253] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated as an orange solid (261 mg; 74% based on [Ir(COD).sub.2]BARF).
[0254] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.25 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.1 Hz, 1H), 7.81-7.64 (m, 11H), 7.56 (s, 4H), 5.74 (dt, J=8.2, 4.6 Hz, 1H), 4.95-4.74 (m, 1H), 4.74-4.51 (m, 1H), 3.60-3.45 (m, 1H), 3.23-2.91 (m, 2H), 2.90-2.70 (m, 1H), 2.67-2.50 (m, 1H), 2.52-2.23 (m, 4H), 2.28-2.04 (m, 3H), 2.04-1.77 (m, 7H), 1.69-1.58 (m, 4H), 1.45-1.26 (m, 17H), 1.17-0.95 (m, 4H), 0.68-0.42 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=121.12. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.85. HR-MS (ESI) m/z calcd for C.sub.38H.sub.54NOPIr [M]+764.3572 found 764.3586.
Va-6
[0255] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (286 mg; 64% based on [Ir(COD).sub.2]BARF).
[0256] .sup.1H-NMR (300 MHz, CDCl.sub.3): (ppm)=8.20 (d, J=8.2 Hz, 2H), 7.77-7.69 (m, 8H), 7.66 (d, J=8.4 Hz, 2H), 7.53 (d, J=4.9 Hz, 5H), 5.77-5.67 (m, 1H), 4.78 (d, J=7.6 Hz, 1H), 4.57 (s, 1H), 3.47 (s, 1H), 3.08-2.89 (m, 1H), 2.89-2.66 (m, 2H), 2.59 (p, J=7.4 Hz, 1H), 2.47-1.74 (m, 15H), 1.42 (s, 17H), 1.18-0.78 (m, 5H), 0.72-0.48 (m, 1H). .sup.31P-NMR (122 MHz, CDCl.sub.3) 121.31. .sup.19F-NMR (282 MHz, CDCl.sub.3) =62.42. HR-MS (ESI): m/z calculated for [C.sub.39H.sub.56NOP193Ir]+:778.3729 found 778.3732.
Vb-7
[0257] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated after two time purification as an orange solid (151 mg; 36% based on [Ir(COD).sub.2]BARF).
[0258] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.84 (s, 1H), 8.38-8.27 (m, 1H), 8.21 (ddt, J=8.5, 1.3, 0.7 Hz, 1H), 8.18-8.02 (m, 2H), 7.83-7.72 (m, 10H), 7.72-7.54 (m, 6H), 7.49 (ddd, J=8.8, 6.6, 1.4 Hz, 1H), 7.23-6.96 (m, 1H), 5.74-5.54 (m, 1H), 5.26-5.12 (m, 1H), 4.41-4.18 (m, 1H), 3.53-3.15 (m, 3H), 2.75-2.61 (m, 2H), 2.59-2.32 (m, 2H), 2.18-1.91 (m, 6H), 1.92-1.74 (m, 5H), 1.74-1.56 (m, 2H), 1.48-1.21 (m, 10H), 1.18-0.99 (m, 1H), 0.96-0.59 (m, 2H), 0.39-0.15 (m, 1H), 0.06--0.11 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=120.30. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.87. HR-MS (ESI) m/z calcd for C.sub.42H.sub.50NOPIr [M]+808.3259 found 808.3278.
Va-8
[0259] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated using DCM (100%) to afford an orange solid (296 mg; 78% based on [Ir(COD).sub.2]BARF).
[0260] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.68 (s, 1H), 8.23-7.85 (m, 3H), 7.75-7.23 (m, 17H), 7.05 (dq, J=8.8, 1.0 Hz, 1H), 5.61-5.40 (m, 2H), 5.12-4.88 (m, 1H), 4.24-4.00 (m, 1H), 3.25-2.88 (m, 3H), 2.58-2.46 (m, 2H), 2.44-2.14 (m, 7H), 2.08-1.61 (m, 11H), 1.61-1.37 (m, 5H), 1.37-1.07 (m, 6H), 1.03-0.85 (m, 1H), 0.65-0.45 (m, 1H), 0.16 (dtd, J=15.8, 10.4, 5.6 Hz, 1H), 0.16 (dt, J=13.2, 9.1 Hz, 1H). .sup.31P-NMR (122 MHz, CD2Cl2) =120.57. .sup.19F-NMR (282 MHz, CD2Cl2) =62.86. HR-MS (ESI) m/z calcd for C.sub.43H.sub.52NOPIr [M]+822.3416 found 822.3416.
Va-9
[0261] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated as an orange solid (298 mg; 82% based on [Ir(COD).sub.2]BARF).
[0262] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=7.80-7.52 (m, 12H), 7.42-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 5.65 (td, J=5.6, 2.6 Hz, 1H), 5.48-5.42 (m, 1H), 4.43-4.37 (m, 1H), 3.38-3.30 (m, 1H), 3.21-2.89 (m, 3H), 2.67 (s, 3H), 2.58-2.45 (m, 2H), 2.42 (s, 3H), 2.38-2.16 (m, 2H), 2.13-2.05 (m, 3H), 2.02-1.89 (m, 4H), 1.84 (s, 3H), 1.81-1.72 (m, 2H), 1.64-1.49 (m, 3H), 1.39-1.19 (m, 8H), 1.12-0.99 (m, 4H), 0.68-0.56 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) =118.80. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) =62.88. HR-MS (ESI) m/z calcd for C.sub.37H.sub.52NOPIr [M]+750.3416 found 750.3420.
Va-10
[0263] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated as an orange solid (148 mg; 40% based on [Ir(COD).sub.2]BARF).
[0264] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=7.91-7.46 (m, 12H), 7.21 (s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 5.67-5.63 (m, 1H), 5.46-5.41 (m, 1H), 4.38-4.36 (m, 1H), 3.36-3.32 (m, 1H), 3.19-2.85 (m, 3H), 2.64 (s, 3H), 2.53-2.46 (m, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.31-2.18 (m, 2H), 2.19-1.83 (m, 14H), 1.68-1.54 (m, 6H), 1.38-1.20 (m, 5H), 1.14-0.97 (m, 5H), 0.68-0.56 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) =118.64. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) =62.87. HR-MS (ESI) m/z calcd for C.sub.38H.sub.54NOPIr [M]+764.3572 found 764.3577.
Va-11
[0265] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated using DCM (100%) to afford an orange solid (310 mg; 85% based on [Ir(COD).sub.2]BARF).
[0266] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=7.86 (s, 2H), 7.79-7.47 (m, 13H), 7.36 (s, 1H), 5.79-5.62 (m, 1H), 4.78-4.74 (m, 1H), 4.57-4.53 (m, 1H), 3.56-3.48 (m, 1H), 3.13-2.95 (m, 1H), 2.95-2.61 (m, 3H), 2.51 (s, 6H), 2.47-2.36 (m, 5H), 2.34-2.03 (m, 5H), 2.03-1.77 (m, 7H), 1.71-1.47 (m, 7H), 1.45-1.19 (m, 5H), 1.19-0.98 (m, 4H), 0.70-0.62 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) =121.65. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) =62.88. HR-MS (ESI) m/z calcd for C.sub.37H.sub.52NOPIr [M]+750.3416 found 750.3406.
Va-12
[0267] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated as an orange solid (286 mg; 78% based on [Ir(COD).sub.2]BARF).
[0268] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.61-8.48 (m, 1H), 8.28-8.15 (m, 1H), 8.11-7.98 (m, 1H), 7.98-7.81 (m, 1H), 7.79-7.50 (m, 16H), 5.70 (ddd, J=8.1, 4.9, 3.2 Hz, 1H), 5.37-5.25 (m, 1H), 4.79 (d, J=10.4 Hz, 1H), 3.53-3.41 (m, 1H), 3.13 (ddd, J=17.2, 9.5, 4.9 Hz, 1H), 2.96 (ddd, J=17.1, 9.4, 4.9 Hz, 1H), 2.88-2.66 (m, 1H), 2.49-2.34 (m, 7H), 2.27-2.14 (m, 1H), 2.09-1.56 (m, 15H), 1.43-1.12 (m, 9H), 1.06-0.92 (m, 1H), 0.78-0.59 (m, 1H), 0.42-0.25 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) =121.69. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) =62.87. HR-MS (ESI) m/z calcd for C.sub.39H.sub.50NOPIr [M]+722.3259 found 722.3262.
Va-13
[0269] The reaction was performed according to the above described procedure. The theoretical yield of the ligand was 51%. The complex could be isolated as an orange solid (78.0 mg; 39% based on [Ir(COD).sub.2]BARF).
[0270] .sup.1H-NMR (300 MHz, CDCl.sub.3): (ppm)=8.22 (d, J=8.7 Hz, 2H), 7.80-7.63 (m, 8H), 7.63-7.43 (m, 5H), 7.16 (d, J=8.8 Hz, 2H), 5.82-5.66 (m, 1H), 5.37-5.22 (m, 1H), 4.56-4.41 (m, 1H), 4.18-4.00 (m, 1H), 3.93 (s, 3H), 3.12-2.97 (m, 1H), 2.96-2.74 (m, 2H), 2.70-2.56 (m, 1H), 2.43 (s, 3H), 2.41-2.03 (m, 4H), 1.96-1.84 (m, 1H), 1.72 (dd, J=14.6, 7.9 Hz, 1H), 1.51 (d, J=15.0 Hz, 9H), 1.34-1.23 (m, 3H), 1.05 (d, J=14.4 Hz, 9H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=141.86. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.85. HR-MS (ESI) m/z calcd for C.sub.32H.sub.46NO.sub.2PIr [M]+700.2895 found 700.2899.
Va-14
[0271] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated as an orange solid (245 mg; 70% based on [Ir(COD).sub.2]BARF).
[0272] .sup.1H-NMR (300 MHz, CDCl.sub.3): (ppm)=8.38-8.12 (m, 2H), 7.82-7.63 (m, 8H), 7.51 (s, 5H), 7.44-7.17 (m, 2H), 5.81-5.63 (m, 1H), 4.81-4.67 (m, 1H), 4.67-4.49 (m, 1H), 3.57-3.35 (m, 1H), 3.05-2.90 (m, 1H), 2.88-2.61 (m, 3H), 2.36 (s, 3H), 2.31-2.04 (m, 7H), 2.01-1.73 (m, 7H), 1.70-1.48 (m, 6H), 1.42-1.20 (m, 6H), 1.16-0.97 (m, 4H), 0.63-0.40 (m, 1H). .sup.31P-NMR (122 MHz, CDCl.sub.3) (ppm)=121.31. .sup.19F-NMR (282 MHz, CDCl.sub.3) (ppm)=62.43,106.61. HR-MS (ESI) m/z calcd for C.sub.35H.sub.47NOFPIr [M]+740.3009 found 740.3013.
Va-15
[0273] The reaction was performed according to the above described procedure using 287 mg of [Ir(COD).sub.2]BARF (0.225 mmol). The complex could be isolated as an orange solid (180.0 mg; 48% based on [Ir(COD).sub.2]BARF).
[0274] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.46 (d, J=7.9 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H), 7.82-7.38 (m, 13H), 5.83-5.69 (m, 1H), 4.94-4.78 (m, 1H), 4.73-4.54 (m, 1H), 3.65-3.38 (m, 1H), 3.15-2.72 (m, 3H), 2.61-2.27 (m, 7H), 2.25-2.04 (m, 4H), 2.04-1.72 (m, 8H), 1.75-1.58 (m, 3H), 1.43-1.22 (m, 8H), 1.19-0.93 (m, 1H), 0.63-0.44 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=121.74. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.88,63.40. HR-MS (ESI) m/z calcd for C.sub.36H.sub.47NOF.sub.3PIr [M]+790.2977 found 790.2990.
Va-16
[0275] The reaction was performed according to the above described procedure. The theoretical yield of the ligand was 90%. The complex could be isolated as an orange solid (261 mg; 75% based on [Ir(COD).sub.2]BARF).
[0276] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=8.28-8.11 (m, 2H), 7.93-7.45 (m, 16H), 5.81 (dt, J=9.3, 5.0 Hz, 1H), 4.89 (t, J=6.9 Hz, 1H), 4.72-4.51 (m, 1H), 3.86-3.66 (m, 1H), 3.18-3.04 (m, 1H), 3.04-2.57 (m, 4H), 2.49 (s, 3H), 2.46-1.61 (m, 18H), 1.56-1.36 (m, 5H), 1.36-1.14 (m, 1H), 1.13-0.93 (m, 1H), 0.77-0.66 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=129.37. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.88. HR-MS (ESI) m/z calcd for C.sub.33H.sub.44NOPIr [M]+694.2790 found 694.2789.
Vb-17
[0277] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (134 mg; 95% purity based on 31P-NMR; 39% based on [Ir(COD).sub.2]BARF).
[0278] .sup.1H-NMR (300 MHz, CDCl.sub.3): (ppm) 8.00-7.92 (m, 2H), 7.81-7.76 (m, 1H), 7.75-7.64 (m, 10H), 7.62-7.55 (m, 2H), 7.52 (d, J=1.9 Hz, 4H), 5.88 (dt, J=8.3, 4.9 Hz, 1H), 4.52 (dt, J=8.3, 4.2 Hz, 1H), 4.37 (ddt, J=7.4, 5.0, 2.5 Hz, 1H), 3.61 (td, J=8.0, 3.8 Hz, 1H), 3.17-2.64 (m, 4H), 2.34-1.79 (m, 9H), 1.68-1.55 (m, 1H), 1.36-0.90 (m, 9H). .sup.31P-NMR (122 MHz, CDCl.sub.3) =116.36 (mayor product: 95%), 111.79 (minor species; 5%). .sup.19F-NMR (282 MHz, CDCl.sub.3) =62.41. HR-MS (ESI) m/z calcd for C.sub.26H.sub.34NOPIr [M]+600.2006 found 600.2006.
Va-18
[0279] The reaction was performed (0.5 mmol scale) according to the above described procedure, but after the addition of CIP(iPr).sub.2 was completed, the reaction mixture was stirred at RT for 16 h. The complex could be isolated as an orange solid (605 mg; 85% based on [Ir(COD).sub.2]BARF).
[0280] .sup.1H-NMR (300 MHz, CDCl.sub.3): (ppm)=8.17 (dd, J=7.1, 1.8 Hz, 2H), 7.78-7.40 (m, 16H), 5.74 (dt, J=9.0, 4.7 Hz, 1H), 4.83 (t, J=6.9 Hz, 1H), 4.61 (dt, J=8.7, 4.1 Hz, 1H), 3.62-3.53 (m, 1H), 3.11-2.94 (m, 1H), 2.91-2.67 (m, 2H), 2.67-2.44 (m, 2H), 2.39 (s, 3H), 2.36-1.93 (m, 6H), 1.85 (dd, J=14.5, 7.3 Hz, 1H), 1.46 (dd, J=15.2, 7.1 Hz, 3H), 1.39-1.31 (m, 1H), 1.23 (dd, J=13.3, 6.9 Hz, 4H), 1.08 (dd, J=19.4, 7.1 Hz, 3H), 0.52 (dd, J=15.5, 7.1 Hz, 3H). .sup.31P-NMR (122 MHz, CDCl.sub.3) (ppm)=129.53. .sup.19F-NMR (282 MHz, CDCl.sub.3) (ppm)=62.42. HR-MS (ESI) m/z calcd for C.sub.29H.sub.40NOPIr [M]+642.2477 found 642.2480.
Va-19
[0281] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (249 mg; 73% based on [Ir(COD).sub.2]BARF).
[0282] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=7.81-7.61 (m, 9H), 7.56 (d, J=2.0 Hz, 4H), 7.34 (d, J=8.0 Hz, 1H), 5.76 (dt, J=8.7, 4.5 Hz, 1H), 5.05-4.84 (m, 2H), 3.74-3.57 (m, 1H), 3.56-3.36 (m, 1H), 3.07 (s, 3H), 3.01-1.49 (m, 23H), 1.42-1.01 (m, 9H), 0.85-0.70 (m, 1H), 0.51-0.25 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=126.20. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.88. HR-MS (ESI) m/z calcd for C.sub.29H.sub.44NOPIr [M]+644.2766 found 644.2762.
Va-20
[0283] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (164 mg; 42% based on [Ir(COD).sub.2]BARF).
[0284] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): (ppm)=7.86-7.62 (m, 10H), 7.56 (s, 4H), 7.38 (s, 1H), 5.72 (dt, J=8.1, 5.2 Hz, 1H), 4.85-4.63 (m, 2H), 3.80 (s, 3H), 3.49-3.30 (m, 1H), 3.18-2.60 (m, 4H), 2.54-2.23 (m, 6H), 2.23-1.57 (m, 16H), 1.53-1.49 (m, 20H), 1.46-0.93 (m, 10H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=123.26. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.87. HR-MS (ESI) m/z calcd for C.sub.44H.sub.66NO.sub.2PIr [M]+864.4460 found 864.4448.
Va-21
[0285] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (51 mg; 14% based on [Ir(COD).sub.2]BARF).
[0286] .sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): (ppm)=7.80-7.64 (m, 8H), 7.56 (s, 4H), 7.23 (s, 2H), 7.04 (s, 1H), 5.65 (dt, J=5.9, 3.7 Hz, 1H), 5.45-5.35 (m, 1H), 4.04 (ddd, J=8.2, 5.4, 3.6 Hz, 1H), 3.34 (dd, J=11.2, 6.4 Hz, 1H), 3.19-3.08 (m, 3H), 3.06-2.89 (m, 2H), 2.56-2.44 (m, 2H), 2.41 (s, 3H), 2.33-1.84 (m, 9H), 1.84-1.43 (m, 15H), 1.35-1.24 (m, 12H), 1.23-1.14 (m, 5H), 1.09 (dd, J=10.0, 6.8 Hz, 6H), 0.95 (d, J=6.6 Hz, 3H), 0.60-0.46 (m, 1H). .sup.31P-NMR (162 MHz, CD.sub.2Cl.sub.2) (ppm)=119.43. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.86. HR-MS (ESI) m/z calcd for C.sub.44H.sub.66NOPIr [M]+848.4511 found 848.4512.
Va-22
[0287] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (274 mg; 73% based on [Ir(COD).sub.2]BARF).
[0288] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 8 (ppm) =7.79-7.66 (m, 8H), 7.56 (s, 4H), 7.29 (s, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 5.65 (td, J=5.9, 2.2 Hz, 1H), 5.46-5.40 (m, 1H), 4.42-4.36 (m, 1H), 3.38-3.30 (m, 1H), 3.19-2.86 (m, 3H), 2.65 (s, 3H), 2.59-2.44 (m, 2H), 2.42 (s, 3H), 2.38-1.54 (m, 20H), 1.46-0.98 (m, 21H), 0.70-0.58 (m, 1H). .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) (ppm)=118.67. .sup.19F-NMR (282 MHz, CD.sub.2Cl.sub.2) (ppm)=62.86. HR-MS (ESI) m/z calcd for C.sub.41H.sub.60NOPIr [M]+806.4042 found 806.4053.
Va-23
[0289] The reaction was performed according to the above described procedure. The complex could be isolated as an orange solid (15.6 mg; 20% based on [Ir(COD).sub.2]BARF).
[0290] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2) =8.43-8.36 (m, 2H), 7.92-7.85 (m, 1H), 7.81-7.69 (m, 12H), 7.68-7.53 (m, 4H), 5.73-5.65 (m, 1H), 5.50-5.43 (m, 1H), 4.58-4.43 (m, 2H), 3.25-3.12 (m, 1H), 3.08-2.94 (m, 1H), 2.92-2.77 (m, 1H), 2.72-1.45 (m, 40H). .sup.19F-NMR (282 MHz, CDCl.sub.3) =62.42. .sup.31P-NMR (122 MHz, CD.sub.2Cl.sub.2) =134.32. HR-MS (TOF) m/z calcd for C.sub.42H.sub.54NOPIr [M]+812.3572 found 812.3578.
Examples
[0291] Reactions were performed in metal autoclaves. Reaction mixtures were analyzed without workup via HPLC (Chiralpak IC column, 95/5 heptane/ethanol, 1 mL/min) or SFC (OZ-H column, 2.5% MeOH in supercritical CO.sub.2, 3 mL/min) chromatography.
Example 1
[0292] A 600 mL autoclave was filled with 21 g of 1-(2,2,4-trimethyl-1-quinolyl) ethanone (97.5 mmol, 1 equiv), 0.74 g of catalyst (Va-1) (0.48 mmol, 0.5 mol %) and 450 mL of 2,2,2-trifluoroethanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85 C. and the reaction mixture was stirred at that temperature for 72 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed complete conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone (97% a/a purity according to SFC analysis) with an enantioselectivity of >98% ee.
Example 2
[0293] A 16 mL autoclave was filled with 0.7 g of 1-(2,2,4-trimethyl-1-quinolyl) ethanone (3.3 mmol, 1 equiv), 4.9 mg of catalyst (Va-1) (3.3 mol, 0.1 mol %) and 4.2 mL of 1,1,1,3,3,3-hexafluor-2-propanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85 C. and the reaction mixture was stirred at that temperature for 16 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 99.3% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 97.5% ee.
[0294] .sup.1H-NMR (400 MHz, CDCl.sub.3) (ppm)=7.12-7.21 (m, 3H), 6.90-6.97 (m, 1H), 2.7-2.83 (m, 1H), 2.09 (s, 3H), 1.83 (d, 1H), 1.72 (s, 3H), 1.49 (s, 3H), 1.35 (d, 2H), 1.22 (t, 1H). UPLC-MS: R.sub.t: 1.26 min, UV (210 nm): 100%, m/z (ES+) 218.3. GC-MS: R.sub.t: 4.78 min, m/z (RInt, %): 217 (15), 202 (10), 175 (5), 160 (100).
Example 3
[0295] A 16 mL autoclave was filled with 0.52 g of 1-(2,2,4-trimethyl-1-quinolyl) ethanone (2.41 mmol, 1 equiv), 9.2 mg of catalyst (Va-1) (6 mol, 0.25 mol %) and 6 mL of 1,1,1,3,3,3-hexafluoro-2-propanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85 C. and the reaction mixture was stirred at that temperature for 15 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 99.8% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 96.5% ee.
Example 4
[0296] A 100 mL autoclave was filled with 5 g of 1-(6-fluoro-2,2,4-trimethyl-1-quinolyl) ethanone (21.4 mmol, 1 equiv), 65 mg of catalyst (Va-1) (40 mol, 0.2 mol %) and 50 mL of 1,1,1,3,3,3-hexafluoro-2-propanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85 C. and the reaction mixture was stirred at that temperature for 36 h. From the cooled and de-pressurized reaction mixture the solvent was evaporated to dryness under reduced pressure giving 5.6 g of the hydrogenated product 1-(6-fluoro-2,2,4-trimethyl-3,4-dihydroquinolin-1-yl) ethanone (88.9% w/w purity, 98.7% yield) with an enantioselectivity of 98% ee.
Example 5
[0297] A 16 mL autoclave was filled with 0.25 g of 1-(2,2-dimethyl-4-propyl-1-quinolyl) ethanone (88.7% a/a HPLC, 1.02 mmol, 1 equiv), 7.8 mg of catalyst (Va-1) (5 mol, 0.5 mol %) and 5 mL of 1,1,1,3,3,3-hexafluoro-2-propanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85 C. and the reaction mixture was stirred at that temperature for 15 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 92.4% a/a HPLC conversion of starting material to the hydrogenated product 1-(2,2-dimethyl-4-propyl-3,4-dihydroquinolin-1-yl) ethanone with an enantioselectivity of 81.2% ee.
Example 6: Comparison Using Reaction Conditions from Example 6 of DE112015001290 T5
[0298] A 25 mL autoclave was filled with 0.5 g of 1-(2,2,4-trimethyl-1-quinolyl) ethanone (2.3 mmol, 1 equiv), 43.9 mg of catalyst (Va-1) (29 mol, 1.2 mol %) and 12.2 mL of 2,2,2-trifluoroethanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 70 bar of hydrogen, heated to 90 C. and the reaction mixture was stirred at that temperature for 9 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 70% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 95.5% ee.
Example 7: Comparison Using Catalyst from Example 6 of DE112015001290 T5
[0299] In the comparative example 7 the following commercially available Cy-UbaPHOX (CAS 583844-38-6) catalyst was used:
##STR00017##
[0300] A 16 mL autoclave was filled with 0.7 g of 1-(2,2,4-trimethyl-1-quinolyl) ethanone (3.3 mmol, 1 equiv), 5.6 mg of catalyst (Cy-UbaPHOX, CAS 880262-14-6) (3.3 mol, 0.1 mol %) and 4.2 mL of 1,1,1,3,3,3-hexafluor-2-propanol. The autoclave was pressurized with argon three times, followed by pressurization with hydrogen twice. Subsequently, the autoclave was pressurized with 60 bar of hydrogen, heated to 85 C. and the reaction mixture was stirred at that temperature for 16 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed 84% a/a HPLC conversion of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone with an enantioselectivity of 81.7% ee.
[0301] Conclusion from comparative examples 6 and 7: Both the catalyst VI-a used in this invention (e.g. example 2) and the reaction conditions are superior to the benchmark catalyst and conditions from DE112015001290 T5 (example 6). For optimal results, the reaction conditions and the catalysts (e.g. Va-1) of this invention have to be used in combination (e.g. example 2). Other catalysts from this invention like Va-4, Va-6, Va-8, Va-10 and Va-22 show even superior activity to both Va-1 and Cy-UbaPHOX.
[0302] Detailed Comparison of experiments with DE112015001290 T5:
TABLE-US-00002 Catalyst Conv. ee Example Catalyst [mol %] Solvent [%] [%] DE112015001290 T5, Ir 1.2 Trifluoro- 14.3 31.3 example 6 catalyst (I) ethanol Present invention, Va-1 1.2 Trifluoro- 70 95.5 example 6 ethanol
[0303] The comparison shows that catalyst Va-1 of this invention is superior conversion and enantiomeric excess (ee) to Ir catalyst (I) from DE112015001290 T5 (example 6) under the conditions used in DE112015001290 T5, example 6 (1.2 mol % of catalyst in trifluoroethanol).
TABLE-US-00003 Catalyst Conv. ee Example Catalyst [mol %] Solvent [%] [%] Present invention, Ir 0.1 Hexafluoroiso- 84 81.7 example 7 catalyst (I) propanol Present invention, Va-1 0.1 Hexafluoroiso- 100 97.5 example 2 propanol
[0304] The comparison shows that catalyst Va-1 of this invention is superior in conversion and enantiomeric excess (ee) to Ir catalyst (I) from DE112015001290 T5, example 6 under the conditions used in the present patent application (0.1 mol % of catalyst in hexafluoroisopropanol).
[0305] Additionally, the conditions used in the present patent application (0.1 mol % of catalyst in hexafluoroisopropanol) are superior in conversion, enantiomeric excess (ee) and catalyst amount to the conditions used in DE112015001290 T5, example 6 (1.2 mol % of catalyst in trifluoroethanol).
Examples 8-11
[0306] Under an inert gas atmosphere, one well of a 96 well-plate autoclave was filled with 9.8 mg of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (45.5 mol, 1 equiv) and 1.82 mol of catalyst (4 mol %, see table 1) in 0.49 mL of 2,2,2-trifluoroethanol. The autoclave was pressurized with 30 bar of hydrogen, heated to 40 C. and the reaction mixture was shaken at that temperature for 16 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed the % a/a HPLC conversion rates of starting material to the hydrogenated product 1-[2,2,4-trimethyl-3,4-dihydroquinolin-1-yl]ethanone. The % a/a HPLC conversion rates and enantioselectivities are depicted in table 1 below.
TABLE-US-00004 Conversion Ex. Catalyst.sup.1) Ligand L* Anion Y (% a/a HPLC) % ee 8 [IrL*(COD)]Y
Examples 12-39
[0307] The Ir-complex (catalyst loading given) and 0.64 g 1-(2,2,4-trimethyl-1-quinolyl) ethanone (3 mmol) were placed in an 8-mL autoclave vial containing a PTFE-coated stirring bar. The autoclave vial was closed using a screw cap with septum and flushed with argon (10 min). Hexafluoroisopropanol (HFIP, 4 mL) was added via the septum to the vial. The vial was placed in an argon containing autoclave and the autoclave was flushed with argon (10 min). The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this the autoclave was pressurized to 60 bar hydrogen pressure and was placed in a suitable alumina block. After heating to 85 C. the reaction was kept at this temperature for the given time. After cooling to room temperature and depressurizing, the vial was taken out of the autoclave and the reactions outcome was determined by GC-FID analysis (deluted with EtOH) and the enantiomeric excess by HPLC analysis.
TABLE-US-00005 Reaction catalyst Conversion Enantiomeric time loading GC excess Example Catalyst (h) (mol %) (% a/a) (% ee) 12 Va-1 16 0.1 99.2 98.0 13 Va-1 6 0.1 81.5 97.5 14 Va-2 6 0.1 94.5 97.5 15 Vb-3 6 0.05 88.2 97.6 16 Va-4 16.5 0.05 94.4 97.3 17 Va-4 16 0.1 99.4 96.0 18 Va-4 16.5 0.1 92.0 97.0 19 Vb-5 16 0.05 98.4 96.8 20 Vb-5 6 0.025 67.2 97.3 21 Va-6 6 0.025 91.6 97.3 22 Vb-7 16.5 0.05 98.9 95.8 23 Vb-7 16.5 0.025 79.5 97.5 24 Va-8 16 0.025 94.1 97.5 25 Va-9 16.5 0.025 81.7 97.9 26 Va-10 16.5 0.025 98.0 98.1 27 Va-11 16.5 0.025 42.2 94.5 28 Va-12 16 0.05 92.4 96.9 29 Va-13 16.5 0.1 91.2 97.0 30 Va-14 16 0.05 64.7 92.4 31 Va-15 16 0.05 34.6 83.2 32 Va-16 16 0.05 87.9 95.8 33 Vb-17 16 0.1 30 90.0 34 Va-18 16 0.1 76.0 96.0 35 Va-19 16 0.025 7.2 70.8 36 Va-20 16 0.025 60 92.1 37 Va-21 16 0.025 74 98.0 38 Va-22 1 0.025 97.5 97.3 39 Va-23 16 0.1 30 94