ENANTIOSELECTIVE HYDROGENATION OF 4-SUBSTITUTED 1,2-DIHYDROQUINOLINES IN PRESENCE OF A CHIRAL IRIDIUM CATALYST

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.

##STR00001##

Claims

1: A process for preparing a compound of the formula (Ia) or (b), ##STR00023## wherein R.sup.1 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.6-C.sub.14-aryl, or C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and the C.sub.1-C.sub.6-alkoxy in the C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl moiety, are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-haloalkoxy, and wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, R.sup.2 and R.sup.3 are the same and are selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl and C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, or R.sup.2 and R.sup.3 together with the carbon to which they are bonded, form a C.sub.3-C.sub.6-cycloalkyl ring, R.sup.4 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.6-alkenyloxy, 9-flurorenylmethyleneoxy, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryloxy, C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyloxy or C.sub.6-C.sub.4-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl as such or as part of a composite substituent 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, n is 0, 1, 2, 3 or 4, each substituent R.sup.5, if present, is independently selected from the group consisting of halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, hydroxyl, amino and C(O)C.sub.1-C.sub.6-alkyl, comprising enantioselective hydrogenation of a compound of the formula (II) ##STR00024## 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 (a) or (b), in presence of a chiral iridium catalyst, characterized in that the chiral iridium catalyst comprises a chiral ligand of the formula (IIIa), (IIIb), (IVa) or (IVb), ##STR00025## wherein R.sup.6, R.sup.7 and R.sup.8 are independently from one another selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl, C.sub.3-C.sub.7-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.14-aryl and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl and the C.sub.3-C.sub.7-cycloalkyl in the C.sub.3-C.sub.7-cycloalkyl-C.sub.1-C.sub.4-alkyl moiety are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkyl and C.sub.1-C.sub.4-haloalkoxy, and wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety are 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, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C.sub.1-C.sub.6-alkyl substituents, 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, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, di(C.sub.1-C.sub.6-alkyl)amino, C.sub.3-C.sub.12-cycloalkyl, C.sub.3-C.sub.12-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryloxy and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy and di(C.sub.1-C.sub.6-alkyl)amino are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-haloalkoxy, and wherein the C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryloxy and C.sub.3-C.sub.12-cycloalkyl, in each case as such or as part of a composite substituent, are 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, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C.sub.1-C.sub.6-alkyl substituents or R.sup.9 and R.sup.10 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C.sub.1-C.sub.6-alkyl groups, or R.sup.9 and R.sup.10 together form ##STR00026## where the bonds identified by x and y are both bonded directly to the phosphorus atom, p and q are independently from one another selected from 0, 1 and 2, R.sup.11 and R.sup.12 are independently selected from C.sub.1-C.sub.6-alkyl and phenyl, which may be 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-alkoxy and phenyl, which may be substituted by one or two C.sub.1-C.sub.4-alkyl substituents, m is 1 or 2, A is ##STR00027## where the bond identified by * is bonded directly to the phosphorus atom and where the bond identified by # is bonded directly to the oxazoline moiety, R.sup.13 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.2-cycloalkyl, C.sub.3-C.sub.2-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.7-cycloalkyl, C.sub.6-C.sub.14-aryl or C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, R.sup.14 and R.sup.15 are independently from one another selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.12-cycloalkyl, C.sub.3-C.sub.7-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.7-cycloalkyl, C.sub.6-C.sub.14-aryl and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, or R.sup.14 and R.sup.15 together with the carbon to which they are bonded, form a C.sub.5-C.sub.6-cycloalkyl ring, R.sup.16 and R.sup.17 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, di(C.sub.1-C.sub.6-alkyl)amino, C.sub.3-C.sub.12-cycloalkyl, C.sub.3-C.sub.12-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryloxy and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-cycloalkyl and di(C.sub.1-C.sub.6-alkyl)amino are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C.sub.1-C.sub.4-alkyl, phenyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-haloalkoxy, and wherein the C.sub.6-C.sub.14-aryl, the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, the C.sub.6-C.sub.14-aryloxy and C.sub.3-C.sub.12-cycloalkyl, in each case as such or as part of a composite substituent, are optionally substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, phenyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, or R.sup.16 and R.sup.17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C.sub.1-C.sub.6-alkyl groups or R.sup.16 and R.sup.17 together form G.sup.1 or G.sup.2, wherein G.sup.1 and G.sup.2 are as defined for the substituents R.sup.9 and R.sup.10 of the ligands of the formulae (IIIa) and (IIIb).

2: The process according to claim 1, wherein R.sup.1 is C.sub.1-C.sub.6-alkyl or C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy R.sup.2 and R.sup.3 are the same and are selected from C.sub.1-C.sub.4-alkyl, R.sup.4 is C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, phenyl or benzyl, n is 0, 1 or 2, and each substituent R.sup.5, if present, is independently selected from the group consisting of halogen, C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-haloalkyl.

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, R.sup.4 is C.sub.1-C.sub.4-alkyl, n is 0, 1 or 2, and each substituent R.sup.5, if present, is independently selected from the group consisting of halogen and C.sub.1-C.sub.6-alkyl.

4: The process according to claim 1, wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIa) or (IIIb), wherein R.sup.6 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.7-cycloalkyl or 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, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl again is unsubstituted or substituted by one to five C.sub.1-C.sub.6-alkyl substituents, R.sup.7 and R.sup.8 are independently from one another selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.14-aryl or C.sub.1-C.sub.6-haloalkyl, wherein the C.sub.6-C.sub.14-aryl is unsubstituted or substituted by one to five C.sub.1-C.sub.4-alkyl substituents, 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, C.sub.1-C.sub.6-alkoxy, di(C.sub.1-C.sub.6-alkyl)amino, C.sub.3-C.sub.12-cycloalkyl, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryloxy and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and di(C.sub.1-C.sub.6-alkyl)amino moieties are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-haloalkoxy, and wherein the C.sub.6-C.sub.14-aryloxy, C.sub.3-C.sub.12-cycloalkyl and C.sub.6-C.sub.14-aryl, as such or as part of a composite substituent, in each case 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, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl is unsubstituted or substituted by one to five C.sub.1-C.sub.6-alkyl substituents, or R.sup.9 and R.sup.10 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C.sub.1-C.sub.6-alkyl groups, m is 1 or 2, or the chiral iridium catalyst comprises a chiral ligand of the formula (IVa) or (IVb), wherein A is ##STR00028## where the bond identified by * is bonded directly to the phosphorus atom and where the bond identified by # is bonded directly to the oxazoline moiety, R.sup.13 is C.sub.3-C.sub.6-alkyl, C.sub.3-C.sub.12-cycloalkyl, C.sub.6-C.sub.14-aryl or C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, R.sup.14 and R.sup.15 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, C.sub.3-C.sub.12-cycloalkyl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety 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, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, or R.sup.14 and R.sup.15 together with the carbon to which they are bonded, form a C.sub.5-C.sub.6-cycloalkyl ring, and R.sup.16 and R.sup.17 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.12-cycloalkyl, C.sub.6-C.sub.14-aryl and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.1-C.sub.6-alkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy and phenyl, wherein the phenyl may be substituted by one to five substituents selected independently from each other from halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, and C.sub.1-C.sub.4-haloalkoxy, and wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, phenyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, or R.sup.16 and R.sup.17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C.sub.1-C.sub.6-alkyl groups.

5: The process according to claim 1, wherein the chiral iridium catalyst comprises a chiral ligand of the formula (IIa) 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, R.sup.7 and R.sup.8 are independently from one another hydrogen or C.sub.1-C.sub.6-alkyl, 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, adamantyl and benzyl, and m is 1 or 2, or the chiral iridium catalyst comprises a chiral ligand of the formula (IVa) or (IVb), wherein A is ##STR00029## where the bond identified by * is bonded directly to the phosphorus atom and where the bond identified by # is bonded directly to the oxazoline moiety, R.sup.13 is selected from the group consisting of C.sub.3-C.sub.6-alkyl, C.sub.3-C.sub.2-cycloalkyl, C.sub.6-C.sub.14-aryl or C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen or C.sub.1-C.sub.4-alkyl, R.sup.14 and R.sup.15 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen and C.sub.1-C.sub.4-alkyl, and R.sup.16 and R.sup.17 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.12-cycloalkyl, C.sub.6-C.sub.14-aryl and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl and the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, phenyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy, or R.sup.16 and R.sup.17 together with the phosphorus atom to which they are bonded, form a phospholane ring, which may be substituted with one or two C.sub.1-C.sub.6-alkyl groups.

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 general formula (Va), (Vb), (VIa) or (VIb): ##STR00030## 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, 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, R.sup.7 and R.sup.8 are independently from one another hydrogen or C.sub.1-C.sub.6-alkyl, 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, adamantyl and benzyl, m is 1 or 2, R.sup.13 is iso-propyl, sec-butyl, iso-butyl, tert-butyl, phenyl or benzyl, R.sup.14 and R.sup.15 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen and C.sub.1-C.sub.4-alkyl, R.sup.16 and R.sup.17 are independently from one another phenyl, 1-naphthyl or 2-naphthyl, which in each case is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-haloalkyl, and R.sup.18 is phenyl, which is unsubstituted or substituted with one to five substituents selected from 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-trifluoromethylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl or 2,6-diethyl-4-methylphenyl, R.sup.7 is hydrogen, R.sup.8 is hydrogen or methyl, R.sup.9 and R.sup.10 are each the same and tert-butyl, adamantly, cyclopentyl or cyclohexyl, m is 1 or 2, R.sup.13 is tert-butyl, R.sup.14 and R.sup.15 are methyl, R.sup.16 and R.sup.17 are independently from one another phenyl, which is substituted by one or two methyl, in particular R.sup.16 and R.sup.17 are each the same and 2-methylphenyl or 3,5-dimethylphenyl, and R.sup.18 is 3,5-bis(trifluoromethyl)phenyl.

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, R.sup.7 and R.sup.8 are independently from one another hydrogen or C.sub.1-C.sub.6-alkyl, 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, adamantyl and benzyl, and m is 1 or 2.

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-trifluoromethylphenyl, 1-naphtyl, 9-antracenyl 2,4,6-triisopropylphenyl, 9-phenantryl or 2,6-diethyl-4-methylphenyl, R.sup.7 is hydrogen R.sup.8 is hydrogen or methyl, 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 (IVa) or (IVb), wherein A is ##STR00031## where the bond identified by * is bonded directly to the phosphorus atom and where the bond identified by # is bonded directly to the oxazoline moiety, R.sup.13 is iso-propyl, sec-butyl, iso-butyl, tert-butyl, phenyl or benzyl, R.sup.14 and R.sup.15 are independently from one another selected from the group consisting of C.sub.1-C.sub.6-alkyl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, wherein the C.sub.6-C.sub.14-aryl in the C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl moiety is unsubstituted or substituted by one to five substituents selected from the group consisting of halogen and C.sub.1-C.sub.4-alkyl, R.sup.16 and R.sup.17 are independently from one another phenyl, 1-naphthyl or 2-naphthyl, which in each case is unsubstituted or substituted by one to five C.sub.1-C.sub.4-alkyl substituents.

15: The process according to claim 14, wherein R.sup.13 is tert-butyl, R.sup.14 and R.sup.15 are methyl, and R.sup.16 and R.sup.17 are independently from one another phenyl, which is substituted by one or two methyl groups.

16: 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-trifluoromethylphenyl, 1-naphtyl, 9-antracenyl, 2,4,6-triisopropylphenyl, 9-phenantryl and 2,6-diethyl-4-methylphenyl, R.sup.7 is hydrogen, R.sup.8 is C.sub.1-C.sub.6-alkoxy, 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, adamantyl and benzyl, and m is 1.

Description

EXAMPLES

[0323] 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

[0324] 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

[0325] 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.

[0326] .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: Re: 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

[0327] 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

[0328] 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

[0329] 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

[0330] 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

[0331] In the comparative example 7 the following commercially available Cy-UbaPHOX (CAS 583844-38-6) catalyst was used:

##STR00018##

[0332] 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.

Conclusion from Comparative Examples 6 and 7

[0333] 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.

[0334] 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

[0335] 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

[0336] 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).

[0337] 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

[0338] 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 [00019] BARF.sup.2) 47 89 9 [IrL*(COD)]Y [00020] BARF.sup.2) 47 93 10 [IrL*(COD)]Y [00021] BARF.sup.2) 55 91 11 [IrL*(COD)]Y [00022] BARF.sup.2) 44 51 .sup.1)The catalyst used in example 8 was prepared according to the method disclosed in S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197; the catalysts used in examples 9 and 10 were prepared according to the method disclosed in W. J. Drury III et al., Angew. Chem. Int. Ed. 2004, 43, 70-74; the catalyst used in example 11 was formed in situ from [Ir(COD).sub.2]BARF and the depicted ligand. .sup.2)BARF = Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate

Examples 12-39

[0339] 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 (diluted 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