Enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in the presence of chiral iridium (P,S) ligand catalysts

Abstract

The present invention relates to a method for producing optically active 4-substituted 1,2,3,4-tetrahydroquinolines, including the enantioselective hydrogenation of corresponding 4-substituted 1,2-dihydroquinolines in the presence of a chiral iridium (P,S) ligand catalyst.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines by enantioselectively hydrogenating the corresponding 4-substituted 1,2-dihydroquinolines in the presence of a chiral iridium complex having a specific chiral chelate ligand (hereinafter also referred to as "chiral (P,S)-ligand") containing at least one phosphorus atom and at least one sulfur atom (both bonded to an iridium atom). [Background technology]

[0002] 4-substituted 1,2,3,4-tetrahydroquinolines are versatile intermediates in the synthesis of N-indanyl heteroarylcarboxamide fungicides, including the recently marketed pyrazolecarboxamide fungicide impilfluxam (EP0654464, WO2015 / 141564, WO2019 / 185541, WO2021 / 058457, WO2021 / 058458). They can be obtained by hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines.

[0003] WO2015 / 141564 describes a process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines, which involves hydrogenating the corresponding 4-substituted 1,2-dihydroquinolines in the presence of a transition metal catalyst having an optically active ligand. The reported asymmetric hydrogenation of 4-substituted NH-dihydroquinolines proceeded with moderate conversion rates (up to 62.6%) and enantioselectivity (up to 71.3%ee), while the hydrogenation of N-acetyl-dihydroquinolines yielded even lower conversion rates (up to 14%) and enantioselectivity (up to 31%ee).

[0004] WO2019 / 185541, WO2021 / 058457, and WO2021 / 058458 disclose the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines in the presence of specific chiral iridium(P,N)-ligand catalysts that provide improved conversion rates and enantioselectivity. The chiral iridium(P,N)-ligand catalysts exhibit excellent catalytic activity. However, the synthesis of each chiral iridium(P,N)-ligand catalyst is complex, and the recovery and recycling of spent catalysts has proven difficult. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] European Patent Application Publication No. 0654464 [Patent Document 2] International Publication No. 2015 / 141564 Brochure [Patent Document 3] International Publication No. 2019 / 185541 brochure [Patent Document 4] International Publication No. 2021 / 058457 Brochure [Patent Document 5] International Publication No. 2021 / 058458 Brochure [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is a need for a method for the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines that offers advantages over methods known from the prior art. The object of the present invention is to provide a method that provides a desired product with high conversion rate and enantioselectivity, enables the use of readily available catalysts through less complex synthetic routes, and / or allows for easy recovery and recycling. [Means for solving the problem]

[0007] The above object is achieved by a method according to the invention, namely of the formula (Ia) or (Ib) [Chemical formula] [wherein, R 1 is selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C6-C 14 -aryl and C6-C 14 -aryl-C1-C4-alkyl, [[ID=1�]]where the C1-C6-alkoxy in the C1-C6-alkyl, C3-C6-cycloalkyl and C1-C6-alkoxy-C1-C6-alkyl moieties is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, phenyl is unsubstituted or substituted by 1 to 5 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy, and where 14 -aryl and C6-C 14 -aryl-C1-C4-alkyl moiety of C6-C 14 -aryl is in each case unsubstituted or substituted by 1 to 5 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, R 2 and R / 3 are identical and are selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxy-C1-C6-alkyl, or or R 2 and R 3 together with the carbon to which they are attached form a C3-C6-cycloalkyl ring, R 4C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9-fluorenylmethyleneoxy, C6-C 14 -Aryl, C6-C 14 -Aryloxy, C6-C 14 -Aryl-C1-C4-alkyloxy and C6-C 14 Selected from the group consisting of -aryl-C1-C4-alkyl, Here, C6-C 14 -The aryl group is either unsubstituted, either by itself or as part of a composite substituent, or substituted with 1 to 5 substituents independently selected from the group consisting of halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy. n is 0, 1, 2, 3, or 4. Each substituent R 5 If present, it is independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino, and -C(=O)-C1-C6-alkyl. A method for producing the compound, Formula (II) [ka] [In the formula, substituent R 1 , R 2 , R 3 , R 4 , R 5 And the integer n is as defined for the compound of formula (Ia) or (Ib), respectively. This includes the enantioselective hydrogenation of the compound in the presence of a chiral iridium catalyst. Chiral iridium catalysts are based on formula (IIIa) or (IIIb) [ka] [During the ceremony, R 6 C6-C is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-C4 alkyl groups. 14 -Aryl, R 7 It is selected from the group consisting of phenyl, naphthyl, and anthracenyl. Here, phenyl is substituted with 1 to 5 substituents independently selected from the group consisting of C1-C4-alkyl groups, and naphthyl and anthracenyl are each unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C1-C4-alkyl groups. Each R 8 C6-C is substituted with 1 to 5 substituents independently selected from the group consisting of C1-C4-alkyl groups. 14 -Aryl, R 9 These are C1-C6-alkyl, C3-C8-cycloalkyl and C6-C 14 - Selected from the group consisting of aryls, Here, C1-C6-alkyl and C3-C8-cycloalkyl are either unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogens, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, and phenyl, and phenyl is either unsubstituted or substituted with 1 to 5 substituents independently selected from halogens, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, and C1-C4-haloalkoxy, and Here, C6-C 14 -The aryl group is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogens, C1-C4-alkyl groups, C1-C4-haloalkyl groups, C1-C4-alkoxy groups, and C1-C4-haloalkoxy groups. or R 9 [The carrier material is selected from the group consisting of polyether, polystyrene, silica, and alumina.] This is achieved by a method characterized by containing a chiral ligand.

[0008] Surprisingly, the optically active 4-substituted 1,2,3,4-tetrahydroquinolines of formulas (Ia) and (Ib) can be prepared in high yield and enantioselectively by enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines of formula (II) in the presence of the specific chiral iridium (P,S) ligand catalysts described above. The synthesis of these catalysts requires fewer steps than catalysts known from WO2019 / 185541, WO2021 / 058457 and WO2021 / 058458, and they can provide heterogeneous catalytic systems that are bonded to a solid support via ether functional groups, allowing for easy separation from the product mixture and recycling.

[0009] The chiral iridium (P,S) ligand catalysts used in the method according to the present invention and their synthesis are those described by J. Margalef et al., Chem. Eur. J. 2014, 20, 12201-12214, or closely related analogs thereof. Formula (IIIa) or (IIIb) (wherein R 7 is tert-butyl or unsubstituted phenyl, and / or R 8 Chiral iridium (P,S)-ligand catalysts known from the aforementioned references, which include a (P,S)-ligand of (an unsubstituted phenyl), provide insufficient conversion rate and / or enantioselectivity in the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines of formula (II), but surprisingly, good conversion rate and enantioselectivity are found in formula (IIIa) or (IIIb) (wherein R 7 R is a substituted phenyl, naphthyl, or anthracenyl, 8 is the substitution C6-C 14 -It is aryl, that is, R 7 and R 8 This is achieved by hydrogenation in the presence of a chiral iridium (P,S)-ligand catalyst containing a (P,S)-ligand (both residues are sterically highly required). J. Margalef et al. have not pointed out this particular substitution pattern.

[0010] definition In the definitions of the symbols given in the above formulas, the following generic terms representing substituents were generally used.

[0011] Halogen: Fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine.

[0012] Alkyl: Saturated, linear, or branched hydrocarbyl substituents having 1 to 6, preferably 1 to 4, carbon atoms, for example (but not limited to) C1-C6 alkyl, for example methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethyl propyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. In particular, the group is a C1-C4 alkyl group, for example, methyl, ethyl, propyl, 1-methylethyl(isopropyl), butyl, 1-methylpropyl(sec-butyl), 2-methylpropyl(isobutyl) or 1,1-dimethylethyl(tert-butyl) group. This definition is, unless otherwise defined, a compound substituent, for example, C3-C6-cycloalkyl-C1-C4-alkyl, C6-C 14 This also applies to alkyl groups as part of aryl-C1-C4-alkyl groups.

[0013] Alkenyl: Unsaturated linear or branched hydrocarbyl substituents having 2 to 6, preferably 2 to 4, carbon atoms and one double bond at any position, for example (but not limited to) C2-C6 alkenyls, such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-buta-2-enyl, (Z)-buta-2-enyl, (E)-buta-1-enyl, (Z)-buta-1-enyl, 2-methylpropa-2-enyl, 1-methylpropa-2-enyl, 2-methylpropa-1-enyl, (E)- 1-methylpropa-1-enyl, (Z)-1-methylpropa-1-enyl, penta-4-enyl, (E)-penta-3-enyl, (Z)-penta-3-enyl, (E)-penta-2-enyl, (Z)-penta-2-enyl, (E)-penta-1-enyl, (Z)-penta-1-enyl, 3-methylbuta-3-enyl, 2-methylbuta-3-enyl, 1-methylbuta-3-enyl, 3-methylbuta-2-enyl, (E)-2-methylbuta-2-enyl, (Z)-2-methylbuta-2-enyl, (E)-1-methylbuta-2-enyl, (Z)-1- Methylbuta-2-enyl, (E)-3-methylbuta-1-enyl, (Z)-3-methylbuta-1-enyl, (E)-2-methylbuta-1-enyl, (Z)-2-methylbuta-1-enyl, (E)-1-methylbuta-1-enyl, (Z)-1-methylbuta-1-enyl, 1,1-dimethylpropa-2-enyl, 1-ethylpropa-1-enyl, 1-propylvinyl, 1-isopropylvinyl, (E)-3,3-dimethylpropa-1-enyl, (Z)-3,3-dimethylpropa-1-enyl, hexa-5-enyl, (E)-hexa-4-enyl, (Z)-hexa-4-enyl (E)-Hexa-3-enyl, (Z)-Hexa-3-enyl, (E)-Hexa-2-enyl, (Z)-Hexa-2-enyl, (E)-Hexa-1-enyl, (Z)-Hexa-1-enyl, 4-Methylpenta-4-enyl, 3-Methylpenta-4-enyl, 2-Methylpenta-4-enyl, 1-Methylpenta-4-enyl, 4-Methylpenta-3-enyl, (E)-3-Methylpenta-3-enyl, (Z)-3-Methylpenta-3-enyl, (E)-2-Methylpenta-3-enyl, (Z)-2-Methylpenta-3-enyl, (E)-1-Methylpenta-3-enyl,(Z)-1-methylpenta-3-enyl, (E)-4-methylpenta-2-enyl, (Z)-4-methylpenta-2-enyl, (E)-3-methylpenta-2-enyl, (Z)-3-methylpenta-2-enyl, (E)-2-methylpenta-2-enyl, (Z)-2-methylpenta-2-enyl, (E)-1-methylpenta-2-enyl, (Z)-1-methylpenta-2-enyl, (E)-4-methylpenta-1-enyl, (Z)-4-methylpenta-1-enyl, (E)-3-methylpenta-2-enyl Tylpent-1-enyl, (Z)-3-methylpenta-1-enyl, (E)-2-methylpenta-1-enyl, (Z)-2-methylpenta-1-enyl, (E)-1-methylpenta-1-enyl, (Z)-1-methylpenta-1-enyl, 3-ethylbuta-3-enyl, 2-ethylbuta-3-enyl, 1-ethylbuta-3-enyl, (E)-3-ethylbuta-2-enyl, (Z)-3-ethylbuta-2-enyl, (E)-2-ethylbuta-2-enyl, (Z)-2-ethylbuta-2 - Enyl, (E)-1-ethylbuta-2-enyl, (Z)-1-ethylbuta-2-enyl, (E)-3-ethylbuta-1-enyl, (Z)-3-ethylbuta-1-enyl, 2-ethylbuta-1-enyl, (E)-1-ethylbuta-1-enyl, (Z)-1-ethylbuta-1-enyl, 2-propylpropa-2-enyl, 1-propylpropa-2-enyl, 2-isopropylpropa-2-enyl, 1-isopropylpropa-2-enyl, (E)-2-propylpropa-1-enyl, ( Z)-2-propylpropa-1-enyl, (E)-1-propylpropa-1-enyl, (Z)-1-propylpropa-1-enyl, (E)-2-isopropylpropa-1-enyl, (Z)-2-isopropylpropa-1-enyl, (E)-1-isopropylpropa-1-enyl, (Z)-1-isopropylpropa-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl. In particular, the group is vinyl or allyl. This definition also applies to alkenyls as part of a composite substituent, unless otherwise defined.

[0014] Alkynyl: A linear or branched hydrocarbyl substituent having 2 to 8 carbon atoms, preferably 2 to 6, more preferably 2 to 4 carbon atoms and one triple bond at any position, for example (but not limited to), C2-C6 alkynyl, e.g., ethinyl, propa-1-inyl, propa-2-inyl, buta-1-inyl, buta-2-inyl, buta-3-inyl, 1-methylpropa-2-inyl, penta-1-inyl, penta-2-inyl, penta-3-inyl, penta-4-inyl, 2-methylbuta-3-inyl, 1-methylbuta-3-inyl, 1-methylbuta-2-inyl, 3-methylbuta-1-inyl, 1-ethylpropa-2-inyl, hexa-1-inyl, hexa-2-inyl, hexa -3-inyl, hexa-4-inyl, hexa-5-inyl, 3-methylpenta-4-inyl, 2-methylpenta-4-inyl, 1-methylpenta-4-inyl, 2-methylpenta-3-inyl, 1-methylpenta-3-inyl, 4-methylpenta-2-inyl, 1-methylpenta-2-inyl, 4-methylpenta-1-inyl, 3-methylpenta-1-inyl, 2-ethylbuta-3-inyl, 1-ethylbuta-3-inyl, 1-ethylbuta-2-inyl, 1-propylpropa-2-inyl, 1-isopropylpropa-2-inyl, 2,2-dimethylbuta-3-inyl, 1,1-dimethylbuta-3-inyl, 1,1-dimethylbuta-2-inyl, or 3,3-dimethylbuta-1-inyl group. In particular, the alkynyl group is ethynyl, propa-1-inyl, or propa-2-inyl. This definition also applies to alkynyls as part of a compound substituent, unless otherwise defined.

[0015] Alkylamino: Monoalkylamino or dialkylamino, where monoalkylamino represents an amino group having one alkyl residue having 1 to 6 carbon atoms bonded to the nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, and dialkylamino represents an amino group having two independently selected alkyl residues, each having 1 to 6 carbon atoms bonded to the nitrogen atom. Non-limiting examples include N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, and N-tert-butyl-N-methylamino.

[0016] Alkoxy: Saturated linear or branched alkoxy substituents having 1 to 6, more preferably 1 to 4, carbon atoms, for example (but not limited to), C1-C6 alkoxys, e.g., methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy Methylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, and 1-ethyl-2-methylpropoxy. This definition also applies to alkoxys as part of a complex substituent unless otherwise defined.

[0017] Cycloalkyl: monocyclic or polycyclic saturated hydrocarbyl substituents having 3 to 12, preferably 3 to 8, more preferably 3 to 6 carbon ring members, such as (but not limited to) cyclopropyl, cyclopentyl, cyclohexyl, and adamantyl. This definition also applies to cycloalkyls as part of complex substituents (e.g., C3-C6-cycloalkyl-C1-C4-alkyl) unless otherwise defined.

[0018] Haloalkyl: A linear or branched alkyl substituent (as specified above) having 1 to 6, preferably 1 to 4, carbon atoms, wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to), C1-C3 haloalkyls, e.g., chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoropropane-2-yl. This definition also applies to haloalkyls as part of a composite substituent unless otherwise defined.

[0019] Haloalkenyls and haloalkynyls are defined similarly to haloalkyls, except that alkenyl and alkynyl groups are present as substituents instead of alkyl groups.

[0020] Haloalkoxy: A linear or branched alkoxy substituent (as specified above) having 1 to 6, preferably 1 to 4, carbon atoms, wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to), C1-C3 haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoropropa-2-oxy. This definition also applies to haloalkoxys as part of a composite substituent, unless otherwise defined.

[0021] Aryl: Monocyclic, bicyclic, or tricyclic aromatic or partially aromatic substituents having 6 to 14 carbon atoms, such as (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indenyl, and indanyl. Attachment to the superstructure can be made via any possible ring member of the aryl residue. The aryl is preferably selected from phenyl, 1-naphthyl, 2-naphthyl, 9-phenanthryl, and 9-anthracenyl. Phenyl is particularly preferred unless otherwise specified.

[0022] As used herein, the term “enantioselective” means that one of the two possible enantiomers of the hydrogenation product, namely the enantiomer of formula (Ia) or the enantiomer of formula (Ib), is preferably formed. “Enantiomeric excess” or “ee” indicates the degree of enantioselectivity:

number

[0023] The method according to the present invention is used to prepare compounds of formula (Ia) or (Ib), preferably (Ia).

[0024] Preferred are compounds of formula (Ia) or (Ib), particularly (Ia), in which substituents are defined as follows: R 1 C1-C6-alkyl or C6-C 14 -aryl-C1-C4-alkyl, Here, C6-C 14 -C6-C in the aryl-C1-C4-alkyl moiety 14 -The aryl group is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogens, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy. R 2 and R 3 These are identical and selected from C1-C4-alkyl groups. R 4 These are C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl, or benzyl. n is 0, 1 or 2, and Each substituent R 5 If present, it is independently selected from the group consisting of halogens, C1-C6-alkyls, and C1-C6-haloalkyls.

[0025] More preferable are compounds of formula (Ia) or (Ib), particularly (Ia), in which the substituents are defined as follows: R 1 It is a C1-C6-alkyl group, R 2 and R 3They are identical and selected from C1-C4-alkyl groups, or R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a C3-C6-cycloalkyl ring. R 4 These are C1-C4-alkyl, C1-C4-haloalkyl, phenyl, or benzyl. n is 0, 1 or 2, and Each substituent R 5 If present, it is independently selected from the group consisting of halogens and C1-C6-alkyl groups.

[0026] Even more preferable are compounds of formula (Ia) or (Ib), particularly (Ia), in which the substituents are defined as follows: R 1 This is a C1-C4 alkyl group, preferably methyl, ethyl, or n-propyl. R 2 and R 3 These each represent methyl, R 4 It is a C1-C4 alkyl group, n is 0, 1 or 2, and Each substituent R 5 If present, it is independently selected from the group consisting of halogens and C1-C6-alkyl groups, and is preferably fluorine.

[0027] Even more preferable are compounds of formula (Ia) or (Ib), particularly (Ia), in which the substituents are defined as follows: R 1 is methyl or n-propyl, R 2 and R 3 Each of these represents methyl, R 4 It is methyl, n is 0 or 1, and R 5 If present, it is fluorine.

[0028] Most preferred are compounds of formula (Ia) or (Ib), particularly (Ia), in which substituents are defined as follows: R 1 It is methyl, R 2 and R 3 Each of these represents methyl, R 4 is methyl, and n is 0.

[0029] The method according to the present invention comprises the enantioselective hydrogenation of a compound of formula (II). Substituent R in the compound of formula (II) 1 , R 2 , R 3 , R 4 , R 5 And the integer n are as defined for the compound of formula (Ia) or (Ib), respectively. Substituent R is as outlined above for the compound of formula (Ia) or (Ib). 1 , R 2 , R 3 , R 4 , R 5 The meanings of preferred, more preferred, even more preferred, and most preferred for integer n are applied mutatis mutandis to the compound of formula (II).

[0030] The enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst containing the chiral ligand of formula (IIIa) or (IIIb).

[0031] Preferably, the substituents of formula (IIIa) and (IIIb) are defined as follows: R 6 Preferably, the phenyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

[0032] R 6The more preferably selected from the group consisting of phenyl, 2-methylphenyl(o-tolyl), 3-methylphenyl(m-tolyl), 4-methylphenyl(p-tolyl), 2,6-dimethylphenyl, 3,5-dimethylphenyl, and 2,4,6-trimethylphenyl(mesityl).

[0033] R 6 Most preferably, it is selected from the group consisting of phenyl and 2,4,6-trimethylphenyl (mesityl).

[0034] R 7 Preferably, it is selected from the group consisting of phenyl and naphthyl. Here, phenyl is substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl, and naphthyl is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

[0035] R 7 It is more preferably selected from the group consisting of phenyl and naphthyl. Here, phenyl is substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl, while naphthyl is unsubstituted.

[0036] R 7 More preferably, the substance is selected from the group consisting of 2-methylphenyl(o-tolyl), 3-methylphenyl(m-tolyl), 4-methylphenyl(p-tolyl), 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl(mesityl), 1-naphthyl, and 2-naphthyl.

[0037] R 7is more preferably selected from the group consisting of 2,6-dimethyl-phenyl, 3,5-dimethyl-phenyl and 2,4,6-trimethyl-phenyl (mesityl).

[0038] R 7 is most preferably 2,6-dimethyl-phenyl.

[0039] R 8 is preferably phenyl substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl.

[0040] R 8 is more preferably phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl.

[0041] R 8 is even more preferably phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of methyl and ethyl.

[0042] R 8 is even more preferably selected from the group consisting of o-tolyl, m-tolyl, p-tolyl and mesityl.

[0043] R 8 is most preferably o-tolyl or mesityl.

[0044] R 9 is preferably selected from the group consisting of C1-C6-alkyl, C3-C8-cycloalkyl and C6-C 14 -aryl, Here, C1-C6-alkyl and C3-C8-cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, phenyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy, and Here, C6-C 14 -aryl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0045] R 9 is more preferably selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, here, phenyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0046] R 9 is even more preferably selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, here, phenyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl.

[0047] R 9More preferably, the compound is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.

[0048] R 9 More preferably, it is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.

[0049] R 9 It is most preferably methyl.

[0050] Preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst containing a chiral ligand of formula (IIIa) or (IIIb), where, R 6 It is selected from the group consisting of phenyl, 2-methylphenyl(o-tolyl), 3-methylphenyl(m-tolyl), 4-methylphenyl(p-tolyl), 2,6-dimethylphenyl, 3,5-dimethylphenyl, and 2,4,6-trimethylphenyl(mesityl), R 7 It is selected from the group consisting of 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl (mesityl), 1-naphthyl, and 2-naphthyl. R 8 This is a phenyl compound substituted with one, two, or three substituents independently selected from the group consisting of methyl and ethyl. R 9 The compound is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.

[0051] More preferably, the enantioselective hydrogenation of the compound of formula (II) is carried out in the presence of a chiral iridium catalyst containing a chiral ligand of formula (IIIa) or (IIIb), in which R 6 It is phenyl or mesityl, R 7 It is 2,6-dimethylphenyl, R 8 is o-tril or mesityl, and R 9 It is methyl.

[0052] More preferably, the enantioselective hydrogenation of the compound of formula (II) is performed by formula (IV) [ka] [During the ceremony, L * is a chiral ligand of formula (IIIa) or (IIIb) as defined above, L (I) is 1,5-cyclooctadiene or norbornadiene, and Y is [B(R 10 )4] - PF6 - SbF6 - CF3SO3 - [Al{OC(CF3)3}4] - (VI) and Δ-TRISPHAT(VII) [ka] [In the formula, R 10 [The substituent is selected from fluorine and phenyl, and is either unsubstituted or substituted with 1 to 5 substituents independently selected from C1-C4-alkyl, C1-C4-haloalkyl, and halogen.] [A non-coordinating anion selected from the group consisting of the following:] This is carried out in the presence of a chiral iridium catalyst.

[0053] L * With respect to the chiral chelate ligand of formula (IIIa) or (IIIb), the above definitions of preferred, more preferred, even more preferred, and most preferred apply mutatis mutandis.

[0054] L (I) The compound is preferably 1,5-cyclooctadiene.

[0055] Y is preferably [B(R 10 )4] - PF6 - and [Al{OC(CF3)3}4] - (VI) [ka] [In the formula, R 10 [The phenyl is either unsubstituted or substituted with 1 to 5 substituents selected from C1-C4-alkyl, C1-C4-haloalkyl, and halogen compounds.] It is a non-coordinating anion selected from the group consisting of the following.

[0056] Y is more preferably [B(R 10 )4] - and [Al{OC(CF3)3}4] - (VI) [ka] [In the formula, R 10 [This is phenyl, which is either unsubstituted or substituted with 1 to 5 substituents selected from fluorine and trifluoromethyl.] It is a non-coordinating anion selected from the group consisting of the following.

[0057] Y is most preferably [B(R 10 )4] - (In the formula, R 10 (is a non-coordinating anion selected from the group consisting of 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.)

[0058] More preferably, the enantioselective hydrogenation of the compound of formula (II) is performed by formula (IV) [ka] [During the ceremony, L* is a chiral ligand of formula (IIIa) or (IIIb), Here, R 6 It is phenyl or mesityl, R 7 It is 2,6-dimethylphenyl, R 8 is o-tril or mesityl, and R 9 It is methyl, L (I) is 1,5-cyclooctadiene, and Y is [B(R) in equation (VI) 10 )4] - and [Al{OC(CF3)3}4] - (In the formula, R 10 (This is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl.) [A non-coordinating anion selected from the group consisting of the following] This is carried out in the presence of a chiral iridium catalyst.

[0059] More preferably, the enantioselective hydrogenation of the compound of formula (II) is performed by formula (IV) [ka] [During the ceremony, L * is a chiral ligand of formula (IIIa) or (IIIb), Here, R 6 It is phenyl, R 7 It is 2,6-dimethylphenyl, R 8 is mesityl, and R 9 Is it methyl? or R 6 is mesityl, R 7 It is 2,6-dimethylphenyl, R 8 is an o-trill, and R 9It is methyl, L (I) is 1,5-cyclooctadiene, and Y is a non-coordinating anion [B(R 10 )4] - (In the formula, R 10 (This is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl, preferably 3,5-bis(trifluoromethyl)phenyl.) This is carried out in the presence of a chiral iridium catalyst.

[0060] More preferably, the enantioselective hydrogenation of the compound of formula (II) is performed using formula (Va) or (Vb) [ka] [During the ceremony, R 6 It is phenyl or mesityl, R 7 It is 2,6-dimethylphenyl, R 8 It is o-tril or mesityl, R 9 is methyl, and Y is a non-coordinating anion [B(R 10 )4] - (In the formula, R 10 (This is 3,5-bis(trifluoromethyl)phenyl.) This is carried out in the presence of a chiral iridium catalyst.

[0061] Most preferably, the enantioselective hydrogenation of the compound of formula (II) is performed on compounds of formula (Va-1), (Vb-1), (Va-2), or (Vb-2). [ka] [During the ceremony, R 6 It is phenyl, R 7 It is 2,6-dimethylphenyl, R 8is mesityl, R 9 is methyl, and Y is a non-coordinating anion [B(R 10 )4] - (In the formula, R 10 (This is 3,5-bis(trifluoromethyl)phenyl.) [ka] [During the ceremony, R 6 is mesityl, R 7 It is 2,6-dimethylphenyl, R 8 is an o-trill, R 9 is methyl, and Y is a non-coordinating anion [B(R 10 )4] - (In the formula, R 10 (This is 3,5-bis(trifluoromethyl)phenyl.) This is carried out in the presence of a chiral iridium catalyst.

[0062] Depending on whether compound (Ia) or (Ib) is the desired product, the ligand of formula (IIIa) or (IIIb) is selected.

[0063] As described above, the chiral iridium (P,S) ligand catalysts used in the method according to the present invention are those described by J. Margalef et al., Chem. Eur. J. 2014, 20, 12201-12214, or closely related analogs thereof. They can be prepared by or similarly to the synthetic routes disclosed in the aforementioned reference.

[0064] The amount of chiral iridium(P,S) ligand catalyst used is preferably in the range of 0.001 mol% to 5 mol%, more preferably 0.001 mol% to 4 mol%, most preferably 0.002 mol% to 3 mol%, and particularly 0.005 mol% to 1.0 mol%, based on the amount of compound of formula (II).

[0065] Preferably, hydrogenation is carried out using hydrogen gas at a pressure of 1 to 300 bar, preferably 3 to 200 bar, and most preferably 20 to 150 bar.

[0066] Hydrogenation is preferably carried out at a temperature in the range of 20°C to 130°C, more preferably 30°C to 100°C.

[0067] The method according to the present invention is preferably carried out in the presence of a solvent.

[0068] Suitable solvents include halogenated alcohols such as 2,2,2-trifluoroethanol, hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol), and tetrafluoropropanol (2,2,3,3-tetrafluoro-1-propanol); halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, and trichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, and anisole; and esters such as ethyl acetate and isopropyl acetate, as well as mixtures thereof.

[0069] Preferred solvents are selected from the group consisting of 2,2,2-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, 1,4-dioxane, isopropyl acetate, toluene, and mixtures thereof.

[0070] A more preferred solvent is selected from the group consisting of 2,2,2-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof.

[0071] 2,2,2-trifluoroethanol and hexafluoroisopropanol are particularly preferred.

[0072] Hexafluoroisopropanol, specifically 1,1,1,3,3,3-hexafluoro-2-propanol, is most preferred.

[0073] The amount of solvent, if present, is preferably in the range of 0.5 to 20 mass equivalents, more preferably 1 to 10 mass equivalents, most preferably 2 to 7 mass equivalents, and particularly 4 to 6 mass equivalents, based on the amount of compound of formula (II).

[0074] The method according to the present invention is preferably carried out in the presence of an additive selected from the group consisting of Brønsted acids and Lewis acids.

[0075] The additive is preferably selected from the group consisting of hexafluorophosphate, acetic acid, trifluoromethylsulfonic acid, water, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroboric acid, diethyl ether tetrafluoroborate complex, Nafion, Amberlist, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, boranetetrahydrofuran complex, boric acid, aluminum(III) trifluoromethanesulfonate, zinc(II) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, boron trifluoride complexes, and mixtures thereof.

[0076] Preferred complexes of boron trifluoride include complexes of boron trifluoride with organic solvents, such as dialkyl ethers or alcohols, and complexes of boron trifluoride with organic acids, such as carboxylic acids. Preferred boron trifluoride complexes are selected from the group consisting of boron trifluoride-diethyl ether complexes, boron trifluoride-acetic acid complexes, and boron trifluoride-n-propanol complexes.

[0077] More preferably, the additive is selected from the group consisting of hexafluorophosphate, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, diethyl ether tetrafluoroborate complex, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof, wherein the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride-diethyl ether complex, boron trifluoride-acetic acid complex, and boron trifluoride-n-propanol complex.

[0078] More preferably, the additive is selected from the group consisting of hexafluorophosphate, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof, where the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride-diethyl ether complexes, boron trifluoride-acetic acid complexes, and boron trifluoride-n-propanol complexes.

[0079] Most preferably, the additive is selected from the group consisting of aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, tris(2,3,4,5,6-pentafluorophenyl)borane, hexafluorophosphate, boron trifluoride, and boron trifluoride complexes, where the boron trifluoride complex is preferably selected from the group consisting of boron trifluoride-diethyl ether complex, boron trifluoride-acetic acid complex, and boron trifluoride-n-propanol complex.

[0080] If present, the amount of additive selected from the group consisting of Brønsted acids and Lewis acids used is preferably in the range of 0.1 mol% to 10 mol%, more preferably 0.2 mol% to 5 mol%, most preferably 0.3 mol% to 2 mol%, and particularly 0.4 mol% to 1 mol%, based on the amount of the compound of formula (II).

[0081] Abbreviations and acronyms: [Table 1] [Examples]

[0082] Examples Preparation of chiral iridium (P,S) ligand catalysts: The chiral ligands of formulas (IIIa) and (IIIb), and their respective chiral iridium (P,S)-ligand catalysts, such as the chiral iridium (P,S)-ligand catalysts of formulas (Va) and (Vb), can be prepared as described by J. Margalef et al., Chem. Eur. J. 2014, 20, 12201-12214, or similarly.

[0083] General procedure for the synthesis of chiral iridium (P,S) ligand catalysts: The corresponding ligand (IIIa) or (IIIb) (0.074 mmol) was dissolved in CH2Cl2 (5 mL), and [Ir(μ-Cl)(cod)]2 (25.0 mg, 0.037 mmol) was added. The reaction mixture was heated under reflux at 50 °C for 1 hour. After 5 minutes at room temperature, NaBArF (77.2 mg, 0.080 mmol) and water (5 mL) were added, and the reaction mixture was vigorously stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4, filtered through a Celite plug, and the solvent was evaporated to obtain the product as an orange solid.

[0084] Example 1, Synthesis of chiral iridium (P,S)-ligand catalyst of formula (Va-1): Formula (IIIa-1) [ka] [In the formula, Mes is mesityl.] The ligands were prepared as follows: Bis(2,4,6-trimethylphenyl)phosphorus chloride (0.55 mmol) was dissolved in toluene (2.5 mL), and pyridine (0.15 mL, 2.9 mmol) was added. Free alcohol (1R,2S)-1-((2,6-dimethylphenyl)thio)-3-methoxy-1-phenylpropan-2-ol (0.5 mmol) was azeotropically dried using toluene, then dissolved in dry toluene (2.5 mL), to which pyridine (0.15 mL, 2.9 mmol) was added. The alcohol solution was then slowly transferred to the bis(2,4,6-trimethylphenyl)phosphorus chloride / pyridine solution. The reaction mixture was stirred at 80°C for 90 minutes, and the pyridine salt was removed by filtration. The solvent was evaporated to obtain a white foam, which was purified by flash chromatography on alumina (toluene / NEt3 = 100:1) to produce the corresponding ligand (IIIa-1) as a white solid.

[0085] Equation (Va-1) [ka] [During the ceremony, R 6 It is phenyl, R 7 It is 2,6-dimethylphenyl, R 8 is mesityl, R 9 is methyl, and Y is a non-coordinating anion [B(R 10 )4] - And here, R 10 This is 3,5-bis(trifluoromethyl)phenyl. The chiral iridium(P,S)-ligand catalyst was prepared from the ligand of formula (IIIa-1) according to the general procedure outlined above.

[0086] Yield: 114 mg (89%). 31 P NMR (162 MHz, C6D6, 25oC, H3PO4): δ= 98.3 ppm (s). 1 H NMR (400 MHz, C6D6, 25oC, TMS): δ= 7.1-8.0 (m, 24H; CH= aromatic), 4.82 (b, 1H; CH=, cod), 4.78 (s, 1H; CH-S), 4.62 (b, 1H; CH=, cod), 4.40 (m, 1H; CH-O), 3.64 (m, 1H; CH=, cod), 3.37 (m, 1H; CH2), 3.16 (m, 1H; CH2), 3.11 (s, 3H; CH3-O), 2.94 (b, 1H; CH=, cod), 2.41 (m, 2H; CH2cod), 2.82 (s, 3H; CH3), 2.1-2.4 (m, 9H; CH2cod and CH3), 2.08 (s, 3H; CH3), 2.00 (s, 3H; CH3), 1.79 (s, 6H; CH3), 1.71 (s, 3H; CH3), 1.67 ppm (s, 3H; CH3). 13 C NMR (126 MHz, C6D6, 25oC, TMS): δ= 161.9 (q, 1J(C,B) = 49.9 Hz; CB, BArF), 117.6-143.0 (aromatic carbons (multiple)), 101.3 (d, J(C,P) = 12.4 Hz; CH=, cod), 98.4 (d, J(C,P)= 9.2 Hz; CH=, cod), 79.8 (d, 2 J(C,P) = 3.6 Hz; CH-O), 75.9 (s; CH=, cod), 70.9 (s; CH=, cod), 64.9 (d, 3 J(C,P) = 4.0 Hz; CH2), 59.3 (s; CH3-O), 58.4 (s; CH-S), 33.0 (s; CH2,cod), 32.1 (s; CH2,cod), 30.1 (s; CH2,cod), 29.1 (b; CH2,cod), 23.2 (s; CH3), 22.5 (s; CH3), 22.3 (s; CH3), 22.1 (s; CH3), 22.0 (s; CH3), 21.9 (s; CH3), 20.6 ppm (s; CH3). MS HR-ESI [Actual value 871.3272,C 44 H 55 IrO2PS (M-BarF) + [Calculated value: 871.3284]

[0087] Example 2, Synthesis of chiral iridium (P,S)-ligand catalyst of formula (Va-2): Formula (IIIa-2) [ka] [In the formula, Tol is an o-trill.] The ligands were prepared in the same manner as described above for the ligands of equation (IIIa-1).

[0088] Equation (Va-2) [ka] [During the ceremony, R 6 is mesityl, R 7It is 2,6-dimethylphenyl, R 8 This is an o-trill, R 9 is methyl, and Y is a non-coordinating anion [B(R 10 )4] - And here, R 10 This is 3,5-bis(trifluoromethyl)phenyl. The chiral iridium(P,S)-ligand catalyst was prepared from the ligand of formula (IIIa-2) according to the general procedure outlined above.

[0089] Yield: 115 mg (92%). 31 P NMR (162 MHz, CDCl3, 25oC, H3PO4): δ= 105.2 ppm (s). 1 H NMR (400 MHz, CDCl3, 25oC, TMS): δ= 6.62-7.93 (m, 25 H; CH= aromatic), 4.79 (m, 1 H; CH-O), 4.61 (m, 1 H; CH= cod), 4.17 (b, 2 H; CH-S, CH=, cod), 3.91 (b, 1 H; CH=, cod), 3.12 (m, 2 H; CH2, CH= cod), 2.99 (s, 3 H; CH3-O), 2.96 (b, 1 H; CH2), 2.93 (s, 3 H; CH3), 2.67 (s, 3 H; CH3), 2.54 (b, 1 H; CH2, cod), 2.52 (s, 3 H; CH3), 2.13 (s, 6 H; CH3), 1.9-2.4 (b, 7 H; CH2, cod), 1.72 (s, 3 H; CH3), 1.12 ppm (s, 3 H; CH3). 13 C NMR (126 MHz, CDCl3, 25oC, TMS): δ= 161.8 (q, 1J(C,B) = 49.8 Hz; CB, BArF), 117.6-144.5 (aromatic carbons (multiple)), 101.2 (d, J(C,P) = 12.5 Hz; CH=, cod), 99.1 (d, J(C,P)= 12.1 Hz; CH=, cod), 73.4 (s; CH=, cod), 79.5 (s; CH-O), 72.4 (d, 3 J(C,P)= 6.9 Hz; CH2), 70.2 (s; CH=, cod), 58.9 (s; CH3-O), 50.1 (s; CH-S), 34.0 (b; CH2,cod), 30.3 (d, J(C,P) = 3.2 Hz; CH 2, cod), 30.1 (s; CH2,cod), 27.0 (s; CH2,cod), 23.6 (s; CH3), 22.9 (s; CH3), 22.4 (s; CH2), 21.6 (s; CH3), 21.3 (s; CH2), 20.7 (s; CH3), 19.3 ppm (s; CH3). MS HR-ESI [Actual value 855.3103,C 43 H 53 IrO2PS (M-BArF) + [Calculated value: 855.3104]

[0090] Comparative Examples 3-5: Synthesis of comparative chiral iridium (P,S) ligand catalysts of formulas (Va-3), (Va-4), and (Va-5): Equations (IIIa-3), (IIIa-4), and (IIIa-5) [ka] [In the formula, Ph is phenyl and Tol is o-tolyl] The comparative ligand was prepared in the same manner as described in Examples 1 and 2.

[0091] Comparative chiral iridium (P,S) ligand catalysts of formulas (Va-3), (Va-4), and (Va-5) [ka] [During the ceremony, R 6 , R 7 , R 8 and R 9 This has the meanings described in Table 1, and Y is a non-coordinating anion [B(R 10 ) 4 ] - And here, R 10 This is 3,5-bis(trifluoromethyl)phenyl. These were prepared from each ligand of equations (IIIa-3) to (IIIa-5) according to the general procedure outlined above.

[0092] Table 1: [Table 2] Hydrogenation of 4-substituted 1,2-dihydroquinolines: Examples 6 and 7 and Comparative Examples 8-10: A 20 ml glass vial equipped with a cruciform stirring rod was packed with TMQA (300 mg, 1.4 mmol) and 2.8 μmol of Ir catalyst (Va-1), (Va-2), or one of the comparative catalysts (Va-3) to (Va-5), as shown in Table 2. The vial was closed with a septum and purged under 1.2 bar of Ar for 10 minutes. Then, HFIP (2.8 mL) was added and the mixture was stirred for 1 minute. Next, a needle was inserted into the glass vial and immediately transferred to an autoclave and sealed under a positive Ar atmosphere (1.2 bar). The reactor was then pressurized with 20 bar of hydrogen, released (3 times), and finally pressurized with 40 bar of hydrogen. The reactor was then heated to 45°C and stirred at 690 rpm. After 2.5 hours, the reactor was cooled to room temperature and the pressure was carefully released. The solution was analyzed by GC. The results and further details of the reactions are shown in Table 2.

[0093] Table 2: [Table 3] Comparative Example 8 has a tert-butyl substituent (R) on the sulfur atom. 7 ) and a phenyl substituent (R 8This shows that catalyst (Va-3) containing a phosphorus atom (R) provides an insufficient conversion rate (4%) and an enantiomer excess rate (<2%) in the desired hydrogenation reaction. 8 When only the substituent of ) is replaced with a bulkier residue o-tolyl, no improvement is observed (see Comparative Example 9). 7 When only the substituent of ) is replaced with the bulkier residue 2,6-dimethylphenyl, some but still insufficient improvement is observed (see Comparative Example 10; conversion rate = 12%, enantiomer excess rate = 40%). Surprisingly, R 7 and R 8 Both are catalysts (Va-1)(R 7 =2,6-dimethylphenyl, R 8 In the case of sterically demanding residues, such as in (=mesityl), significant improvements are observed in both the conversion rate and the enantiomer excess (see Example 6; conversion rate = 95%, enantiomer excess = 64%).

[0094] Furthermore, in Example 7, which uses catalyst (Va-2), the catalyst contains a sulfur atom (R 7 (where is 2,6-dimethylphenyl) and phosphorus atom (R 8 We demonstrate that improved conversion rates and enantiomer excess rates are achieved when both (where is o-tryl) have bulky substituents.

[0095] Examples 11 and 12: Hydrogenation in the presence of additive BF3·OEt2 A 20 ml glass vial equipped with a reaction cruciform stirring rod was packed with TMQA (300 mg, 1.4 mmol) and 2.8 μmol of Ir catalyst (Va-1) or (Va-2) as shown in Table 3. The vial was closed with a septum and purged under 1.2 bar of Ar for 10 minutes. Then, HFIP (2.8 mL) was added and the mixture was stirred for 1 minute. Then, BF3·OEt2 (1 μL) was added, a needle was inserted into the glass vial, and it was quickly transferred to an autoclave and closed under a positive Ar atmosphere (1.2 bar). The reactor was then pressurized with 20 bar of hydrogen, released (3 times), and finally pressurized with 40 bar of hydrogen. The reactor was then heated to 45°C and stirred at 690 rpm. After 2.5 hours, the reactor was cooled to room temperature and the pressure was carefully released. The solution was analyzed by GC. The results and further details of the reactions are shown in Table 3.

[0096] Table 3: [Table 4] A comparison of the results from Examples 11 and 12 with those from Examples 6 and 7 indicates that the presence of the additive BF3·OEt2 further increases the conversion rate and / or enantiomer excess rate, and therefore promotes the desired reaction.

Claims

1. Formula (Ia) or (Ib) 【Chemistry 1】 [wherein, R １ is C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkoxy-C １ -C ６ -alkyl, C ３ -C ６ -cycloalkyl, C ６ -C １４ -aryl and C ６ -C １４ -aryl-C １ -C ４ -alkyl, and is selected from the group consisting of Here, C １ -C ６ - Alkyl, C ３ -C ６ - Cycloalkyl and C １ -C ６ -Alkoxy-C １ -C ６ - C in the alkyl portion １ -C ６ - alkoxy is either unsubstituted or contains halogens, C １ -C ４ - Alkoxy, C １ -C ４ - Haloalkyl, C １ -C ４ - Substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and phenyl, wherein the phenyl is unsubstituted or a halogen, C １ -C ４ - Alkyl, C １ -C ４ - Alkoxy, C １ -C ４ - Haloalkyl and C １ -C ４ - Substituted with 1 to 5 substituents independently selected from haloalkoxys, and Here, C ６ -C １４ - Aryl and C ６ -C １４ -Aryl-C １ -C ４ - C in the alkyl portion ６ -C １４ - In all cases, the aryl is either unsubstituted or a halogen, C １ -C ４ - Alkyl, C １ -C ４ - Haloalkyl, C １ -C ４ - Alkoxy and C １ -C ４ - Substituted with 1 to 5 substituents independently selected from the group consisting of haloalkoxys, R ２ and R ３ They are identical, and hydrogen and C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl and C １ -C ６ -Alkoxy-C １ -C ６ - Selected from the group consisting of alkyl groups, or R ２ and R ３ Together with the carbon atoms to which they are bonded, C ３ -C ６ - Forms a cycloalkyl ring, R ４ is selected from the group consisting of hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkoxy, C １ -C ６ -haloalkoxy, C １ -C ６ -alkylamino, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C ３ -C ６ -cycloalkyl, C ３ -C ６ -cycloalkyl-C １ -C ４ -alkyl, C ２ -C ６ -alkenyloxy, 9-fluorenylmethyleneoxy, C ６ -C １４ -aryl, C ６ -C １４ -aryloxy, C ６ -C １４ -aryl-C １ -C ４ -alkyloxy and C ６ -C １４ -aryl-C １ -C ４ -alkyl, and is selected from the group consisting of Here, C ６ -C １４ - Aryls, either by themselves or as part of a complex substituent, are unsubstituted or halogens, C １ -C ４ - Alkyl, C １ -C ４ - Haloalkyl, C １ -C ４ - Alkoxy and C １ -C ４ - Substituted with 1 to 5 substituents independently selected from the group consisting of haloalkoxys, n is 0, 1, 2, 3, or 4. Each substituent R ５ If present, halogen, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, C １ -C ６ -alkoxy, hydroxyl, amino and -C(=O)-C １ -C ６ - Independently selected from the group consisting of alkyl groups. A method for producing the compound, Formula (II) 【Chemistry 2】 [In the formula, substituent R １ , R ２ , R ３ , R ４ , R ５ And the integer n is as defined for the compound of formula (Ia) or (Ib), respectively. This includes the enantioselective hydrogenation of the compound in the presence of a chiral iridium catalyst. The chiral iridium catalyst is of formula (IIIa) or (IIIb) 【Transformation 3】 [During the ceremony, R ６ is either non-substituted or C １ -C ４ - A C atom substituted with 1 to 5 substituents independently selected from the group consisting of alkyl groups. ６ -C １４ - It is an allele, R ７ It is selected from the group consisting of phenyl, naphthyl, and anthracenyl. Here, phenyl is C １ -C ４ - Substituted with 1 to 5 substituents independently selected from the group consisting of alkyl groups, where naphthyl and anthracenyl are either unsubstituted or C １ ~C ４ - Substituted with 1 to 5 substituents independently selected from the group consisting of alkyl groups, Each R ８ C １ -C ４ - A C atom substituted with 1 to 5 substituents independently selected from the group consisting of alkyl groups. ６ -C １４ - It is an aryl, and R ９ C １ -C ６ - Alkyl, C ３ -C ８ - Cycloalkyl and C ６ -C １４ - Selected from the group consisting of aryls, Here, C １ -C ６ - Alkyl and C ３ -C ８ - The cycloalkyl group is either unsubstituted or contains a halogen, C １ -C ４ - Alkoxy, C １ -C ４ - Haloalkyl, C １ -C ４ - Substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and phenyl, where phenyl is unsubstituted or a halogen, C １ -C ４ - Alkyl, C １ -C ４ - Alkoxy, C １ -C ４ - Haloalkyl and C １ -C ４ - Substituted with 1 to 5 substituents independently selected from haloalkoxys, and Here, C ６ -C １４ - The aryl group is either unsubstituted or contains halogens, C １ -C ４ - Alkyl, C １ -C ４ - Haloalkyl, C １ -C ４ - Alkoxy and C １ -C ４ - Substituted with 1 to 5 substituents independently selected from the group consisting of haloalkoxys, or R ９ [The carrier material is selected from the group consisting of polyether, polystyrene, silica, and alumina.] The method, characterized by containing a chiral ligand.

2. R １ However, C １ -C ６ - Alkyl or C ６ -C １４ -Aryl-C １ -C ４ -It is alkyl, Here, C ６ -C １４ -Aryl-C １ -C ４ - C in the alkyl portion ６ -C １４ - The aryl group is either unsubstituted or contains halogens, C １ -C ４ - Alkyl, C １ -C ４ - Haloalkyl, C １ -C ４ - Alkoxy and C １ -C ４ - Substituted with 1 to 5 substituents independently selected from the group consisting of haloalkoxys, R ２ and R ３ However, they are identical, C １ -C ４ - Selected from alkyl groups, R ４ However, 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, and Each substituent R ５ However, if present, halogen, C １ -C ６ - Alkyl and C １ -C ６ - Independently selected from the group consisting of haloalkyls, The method according to claim 1.

3. R １ However, C １ -C ４ -It is alkyl, R ２ and R ３ However, it is methyl, R ４ However, C １ -C ４ -It is alkyl, n is 0 or 1, and R ５ However, if present, it is fluorine. The method according to claim 1.

4. R ６ However, the phenyl is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. The method according to any one of claims 1 to 3.

5. R ６ The method according to any one of claims 1 to 3, wherein is phenyl or mesityl.

6. R ７ However, selected from the group consisting of phenyl and naphthyl, Here, phenyl is substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl, and naphthyl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. The method according to any one of claims 1 to 3.

7. R ７ The method according to any one of claims 1 to 3, wherein is 2,6-dimethylphenyl.

8. R ８ The method according to any one of claims 1 to 3, wherein the phenyl is substituted with 1 to 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

9. R ８ The method according to any one of claims 1 to 3, wherein is o-tolyl or mesityl.

10. R ９ The method according to any one of claims 1 to 3, wherein the agent is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and phenyl.

11. R ９ The method according to any one of claims 1 to 3, wherein is methyl.

12. The chiral iridium catalyst is given by formula (IV) 【Chemistry 4】 [During the ceremony, L ＊ is a chiral ligand of formula (IIIa) or (IIIb) as described in any of claims 1 and 4 to 11, L （Ｉ） is 1,5-cyclooctadiene or norbornadiene, and Y is [B(R １０ ), PF ６ － － , SbF ６ － , CF ６ － , [Al{OC(CF ３ ), SO ３ － , [Al{OC(CF ３ ), ３} ４ ４ , － (VI) and Δ-TRISPHAT(VII) 【Transformation 5】 [In the formula, R １０ It is selected from fluorine and phenyl, and it is either unsubstituted or C １ -C ４ - Alkyl, C １ -C ４ - A non-coordinating anion selected from the group consisting of 1 to 5 substituents independently selected from haloalkyls and halogens. The method according to any one of claims 1 to 3, wherein the catalyst is...

13. L ＊ However, it is a chiral ligand of formula (IIIa) or (IIIb), Here, R ６ It is phenyl or mesityl, R ７ It is 2,6-dimethylphenyl, R ８ is o-trill or mesityl, and R ９ It is methyl, L （Ｉ） However, it is 1,5-cyclooctadiene, and Y is [B(R １０ ) ４ ] － and the formula (VI) [Al{OC(CF ３ ) ３ } ４ ] － A non-coordinating anion selected from the group consisting of, Here, R １０ This is 3,5-bis(trifluoromethyl)phenyl or 2,3,4,5,6-pentafluorophenyl. The method according to claim 12.

14. Chiral iridium catalysts are based on formula (Va) or (Vb) 【Transformation 6】 [During the ceremony, R ６ It is phenyl or mesityl, R ７ It is 2,6-dimethylphenyl, R ８ It is o-tril or mesityl, R ９ is methyl, and Y is a non-coordinating anion [B(R １０ ) ４ ] － (In the formula, R １０ (This is 3,5-bis(trifluoromethyl)phenyl.) The catalyst for The method according to any one of claims 1 to 3.

15. The method according to any one of claims 1 to 14, carried out in the presence of an additive selected from the group consisting of hexafluorophosphate, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof.

Images