Enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in presence of a chiral iridium catalyst and an additive

1 . A process for preparing a compound of formula (Ia) or (Ib),

wherein

R 1 is C 1 -C 6 -alkyl,

R 2 and R 3 are the same and are selected from C 1 -C 4 alkyl,

R 4 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenyl or benzyl,

n is 0, 1, or 2,

each substituent R 5 , if present, is independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl,

comprising enantioselective hydrogenation of a compound of formula (II)

wherein the substituents R 1 , R 2 , R 3 , R 4 , R 5 and the integer n are each as defined for the compound of formula (Ia) or (Ib),

in presence of a chiral iridium catalyst, wherein

the chiral iridium catalyst comprises a chiral ligand of formula (IIIa), (IIIb), (IXa) or (IXb),

wherein

R 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 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C 1 -C 6 -alkyl substituents,

R 7 and R 8 are independently from one another hydrogen or C 1 -C 6 -alkyl,

R 9 and R 10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl, and

m is 1 or 2,

R 19 is phenyl or t-butyl,

R 20 is hydrogen or methyl,

each R 21 is independently selected from benzyl and methyl,

each R 22 is cyclohexyl,

and

in the presence of an additive,

wherein the additive is selected from the group consisting of hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris(2,3,4,5,6-pentafluoro-phenyl)borane, aluminum (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, aluminum (III) fluoride, titanium (IV) isopropoxide, trimethyl aluminum, boron trifluoride, boron trifluoride diethylether, boron trifluoride acetic acid and boron trifluoride n-propanol, and mixtures thereof.

2 . The process according to claim 1 , wherein

R 1 is C 1 -C 4 -alkyl,

R 2 and R 3 are methyl,

R 4 is C 1 -C 4 -alkyl,

n is 0 or 1,

R 5 if present, is fluorine,

and wherein the chiral iridium catalyst comprises a chiral ligand of formula (IIIa), (IIIb), (IXa), or (IXb),

wherein

R 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-trifluoromethylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl and 2,6-diethyl-4-methylphenyl,

R 7 is hydrogen,

R 8 is hydrogen or methyl,

R 9 and R 10 are each the same and selected from the group consisting of ethyl, iso-propyl, tert-butyl, cyclopentyl, adamantyl and cyclohexyl,

m is 1,

R 19 is phenyl,

R 20 is methyl,

R 21 is benzyl,

R 22 is cyclohexyl,

and wherein

the additive is selected from the group consisting of aluminum (III) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, tris(2,3,4,5,6-pentafluorophenyl)borane, hexafluorophosphoric acid, boron trifluoride, boron trifluoride-diethylether, boron trifluoride acetic acid and boron trifluoride n-propanol.

3 . The process according to claim 1 , wherein

R 1 is methyl, ethyl or n-propyl,

R 2 and R 3 are methyl,

R 4 is C 1 -C 4 -alkyl,

n is 0, 1 or 2,

each substituent R 5 , if present, is independently selected from the group consisting of halogen and C 1 -C 6 -alkyl.

4 . The process according to claim 1 , wherein the hydrogenation is conducted using hydrogen gas at a pressure of from 1 to 300 bar.

5 . The process according to claim 1 , wherein the amount of chiral iridium catalyst used is within a range of from 0.001 mol % to 5 mol %, based on the amount of the compound of formula (II).

6 . The process according to claim 1 , wherein the hydrogenation is conducted at a temperature within a range of from 20° C. to 130° C.

7 . 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.

8 . The process according claim 1 , wherein the chiral iridium catalyst has formula (Va) or (Vb):

wherein

R 6 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl and 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 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C 1 -C 6 -alkyl substituents,

R 7 and R 8 are independently from one another hydrogen or C 1 -C 6 -alkyl,

R 9 and R 10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl,

m is 1 or 2,

R 18 is phenyl, which is unsubstituted or substituted with one to five substituents selected from fluorine and C 1 -C 4 -haloalkyl.

9 . The process according to claim 8 , wherein

R 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-trifluoromethylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl and 2,6-diethyl-4-methylphenyl,

R 7 is hydrogen,

R 8 is hydrogen or methyl,

R 9 and R 10 are each the same and selected from the group consisting of tert-butyl, adamantyl, cyclopentyl or and cyclohexyl,

m is 1 or 2, and

R 18 is 3,5-bis(trifluoromethyl)phenyl.

10 . The process according to claim 1 , wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa) or (IIIb), wherein

R 6 is selected from the group consisting of 1-naphtyl, 2-naphtyl, 9-antracenyl, 9-phenantryl and phenyl, which is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C 1 -C 6 -alkyl substituents,

R 7 and R 8 are independently from one another hydrogen or C 1 -C 6 -alkyl,

R 9 and R 10 are independently from one another selected from the group consisting of ethyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, cyclohexyl, cyclopentyl, adamantyl and benzyl, and

m is 1 or 2.

11 . The process according to claim 10 , wherein

R 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-trifluoromethylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl and 2,6-diethyl-4-methylphenyl,

R 7 is hydrogen,

R 8 is hydrogen or methyl,

R 9 and R 10 are each the same and selected from the group consisting of tert-butyl, cyclopentyl or and cyclohexyl, and

m is 1.

12 . The process according claim 1 , wherein the amount of additive used is within a range of from 0.1 to 10 mol %, based on the amount of the compound of formula (II).