US 2015 003 1920A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0031920 A1 KATAYAMA et al. (43) Pub. Date: Jan. 29, 2015
(54) PROCESS FOR PRODUCING OPTICALLY (52) U.S. Cl. ACTIVE SECONDARY ALCOHOL CPC ...... C07C29/20 (2013.01); C07C4I/20 (2013.01); C07C 253 I/28 (2013.01) (71) Applicants: KANTO KAGAKU KABUSHIKI USPC ...... 568/648: 568/814 KAISHA, Tokyo (JP); NATIONAL UNIVERSITY CORPORATION (57) ABSTRACT HOKKAIDO UNIVERSITY, Object Sapporo-Shi (JP) The object of this invention is to provide a method for pro (72) Inventors: TAKEAKI KATAYAMA, Soka-Shi ducing an optically active secondary alcohol at a high optical (JP); KUNIHIKOTSUTSUMI, purity by hydrogenating a Substrate carbonyl compound at a Soka-Shi (JP); KUNIHIKO MURATA, high efficiency using as a catalyst a ruthenium complex bear Soka-Shi (JP); TAKESHIOHKUMA, ing as a ligand certain optically active diphosphine compound Sapporo-Shi (JP): NORIYOSHI ARAI, and a readily synthesized amine compound. Sapporo-Shi (JP) Solution The method of producing an optically active secondary alco hol according to the present invention is characterized in that (21) Appl. No.: 14/340,790 a Substrate carbonyl compound (provided that 3-quinuclidi none, 3-quinuclidinone derivative having a Substituent, and a (22) Filed: Jul. 25, 2014 ketone having an aromatic hydrocarbon group and a hetero (30) Foreign Application Priority Data cycle are excluded) is reacted with hydrogen and/or a hydro gen donating compound in the presence of a ruthenium com Jul. 26, 2013 (JP) ...... 2013-156036 plex selected from the compounds expressed by following general formula (1) RuXYAB (1) in the general formula (1), Publication Classification X and Y are the same or different from each other and denote a hydrogen atom or an anionic group. A denotes an optically (51) Int. Cl. active diphosphine expressed by the general formula (2), B C07C 29/20 (2006.01) denotes an amine compound expressed by following general C07C4I/20 (2006.01) formula (3). US 2015/003 1920 A1 Jan. 29, 2015
PROCESS FOR PRODUCING OPTICALLY after 17 hours, although the optical purity was markedly ACTIVE SECONDARY ALCOHOL decreased to 39%, indicating that the addition of hydrogen did not effectively function. Moreover, said literature does FIELD OF INVENTION not mentionatallabout that the optical purity of the generated alcohol would be improved by introducing a substituent onto 0001. The present invention relates to a method of produc PICA. ing optically active secondary alcohols, in particular optically 0006. As an example of the use of a ruthenium complex active bioactive compounds that are used for medicaments, bearing an optically active diphosphine and 2-picolylamine agrochemicals, and the like, or optically active secondary (PICA) as ligands for hydrogenation, the hydrogenation of alcohols that are useful as intermediates for synthesizing a tert-alkylketone using anruthenium complex bearing an opti liquid crystal. cally active diphosphine compound such as BINAP and 2-pi colylamine has been reported (Patent Literature 4). However, BACKGROUND ARTS the only diphosphine ligand exemplified in this literature is 0002 An optically active alcohol is useful as a chiral the diphosphine having an asymmetric structure to the axis building block for synthesizing various optically active com such as BINAP. Said literature does not describe any reaction pounds. In general, an optically active alcohol is produced by using as a catalyst a complex of diphosphine ligand having optical resolution of a racemate, oranasymmetrical synthesis SKEWPHOS skeleton combined with 2-picolylamine, nor it using a biological catalyst, asymmetric organocatalyst or refers to improving the optical purity of the generated alcohol asymmetric organometallic catalyst. The synthesis of an opti by introducing a substituent onto PICA. cally active alcohol by these asymmetric syntheses is consid 0007 As an example of using a complex of diphosphine ered to be an essential technique for production of optically having SKEWPHOS skeleton with 2-picolylamine, the active alcohol in a large scale. hydrogenation of 3-quinuclidinone (Patent Literature 5) and 0003. Among the means for obtaining a optically active the hydrogenation of a heterocycle having a benzoyl group alcohol at a high efficiency, a method of asymmetric hydro (Patent Literature 6) have been reported. However, the ketone genation of a carbonyl compound in the presence of a ruthe substrates described in these literatures are only 3-quinucli nium metal complex bearing a optically active diphosphine dinone, 3-quinuclidinone having a substituent or a hetero compound Such as 2,2'-bis(diphenylphosphino)-1,1'-binaph cycle having a benzoyl group, and there is no reference to thyl (BINAP), a optically active diamine compound in a eth reactions of simple ketones such as acetophenone. Further ylenediamine form, and a base such as a hydroxide of an more, they do not refer to or Suggest the likelihood of improv alkaline metal or alkaline earth metal (Patent Literature 1), as ing the optical purity of the generated alcohol compound by well as a method of asymmetric hydrogenation of a carbonyl adding a substituent onto PICA. compound in the presence of an optically active diphosphine 0008. As mentioned above, there has been no reports on an compound such as BINAP, a ruthenium metal complex bear example whereina ruthenium complex bearing a diphosphine ing an ethylenediamine-type optically active diamine com having SKEWPHOS skeleton and a PICA ligand having pound as a ligand, and a base Such as a hydroxide of an more than one substituents on the pyridinering or a ruthenium alkaline metal or alkaline earth metal are disclosed (Patent complex bearing as a ligand a heterocycle having more than Literature 2). However, in order to improve optical purity of one nitrogen atoms Such as pyradine and pyrimidine effec the product of these method, i.e., the optically active alcohol, tively acts in the asymmetric hydrogenation of a carbonyl both diphosphine and diamine ligands have to be made opti compound. Moreover, it has not been known the optical cally active. Most of such optically active compounds used as purity of the generated optically active alcohol can be ligands are expensive for their long synthetic pathways. Con improved as compared to using an unsubstituted PICA. sequently, the complex is also expensive, producing a prob lem in its industrial use. PRIOR ART LITERATURES 0004. On the other hand, ruthenium complexes that have Patent Literatures an achiral amine and an optically active diphosphine as ligands has also been known. Patent Literature 1 JPA 8-225466 0005. A ruthenium complex that has an optically active diphosphine and 2-picolylamine (PICA) as ligands can be Patent Literature 2 JPA 11-189600 synthesized at low cost because PICA is not an optically active compound. This complex is known to act as a catalyst Patent Literature 3.JPA 2007-536338 for asymmetric transfar hydrogenation using 2-propanol as hydrogen Source, reducing a ketone at a high efficiency Patent Literature 4 WO 2006/046508 (Patent Literature 3). In this literature, acetophenone is reacted under pressurized hydrogen condition using the Patent Literature 5 WO 2006/103756 ruthenium complex bearing an optically active 2.4-bis(diphe nylphosphino)pentane (SKEWPHOS) and PICA as ligands, Patent Literature 6 JPA 2011-51929 showing the results of 96% of conversion rate and 86% ee optical purity in only 2 hours under the condition of substrate SUMMARY OF THE INVENTION concentration diluted at 0.1 mol/L, although a significant decrease in the optical purity is observed as compared to the Problems to be Solved by the Invention same condition without pressurization of hydrogen (conver 0009. An object of the present invention is to provide a sion rate 91%, optical purity 91% ee). In addition, when the method for producing an optically active secondary alcohol in Substrate concentration was increased to 1.0 mol/L under a high optical purity by hydrogenating a carbonyl compound pressurized hydrogen, 100% of conversion rate was reached at a high efficiency using as a catalyst a ruthenium complex US 2015/003 1920 A1 Jan. 29, 2015 bearing as ligands certain optically active diphosphine com hydrocarbon group which may have a substituent, and/or, R' pound and a readily synthesized amine compound. and R'' are connected to each other to form a saturated or unsaturated hydrocarbon ring or heterocycle which may have Means for Solving Problems a Substituent, 0010. On the course of intensively investigating the hydro (0020 each R" is the same or different from each other, genating reaction of a carbonyl compound as Substrate, the denote a C1-20 chained or cyclic hydrocarbon group which inventors found that a ruthenium complex catalyst bearing an may have a substituent, and/or, the adjacent R'' are connected optically active SKEWPHOS (2,4-bis(diphenylphosphino) to each other to form a Saturated or unsaturated hydrocarbon pentane) derivative compound, a readily-synthesized diphos ring or heterocycle which may have a Substituent, phine compound having an asymmetric carbon atom, and a (0021) R' may at least partly be bound to ruthenium as an PICA-type ligand having more than one Substituents on the anionic group X, pyridinering or a PICA-type ligand in which the pyridine ring 0022 n is an integer of 0 to (4-(the number of D that are has been Substituted with a heterocycle having more than one nitrogen atoms)), provided that n is an integer of 2 to 4 when nitrogen atoms shows an excellent performance as a catalyst the number of D that are nitrogen atoms is 0), for asymmetric hydrogenation of a carbonyl compound, a Substrate carbonyl compound (provided that 3-quinuclidi thereby completed the invention. none, 3-quinuclidinone derivative having a Substituent, and a Namely, the invention relates to: ketone having an aromatic hydrocarbon group and a hetero 1 A method for producing optically active secondary alco cycle are excluded) is reacted with hydrogen and/or a hydro hols, wherein in the presence of one or more ruthenium com gen donating compound. plexes selected from the compound expressed by following 2 The method described in 1, wherein, in the reaction general formula (1): system, a ruthenium complex expressed by the general for mula (1) is prepared in situ in the presence of: RXYAB (1) 0023 one or more complexes selected from the com in the general formula (1), pounds expressed by following general formula (4) 0.011 X and Y are the same or different from each other RuxYA (4) and denote a hydrogen atom or an anionic group, 0012. A denotes an optically active diphosphine expressed in the general formula (4), X, Y and A each independently by following general formula (2): have the meaning as defined in the general formula (1), and 0024 one or more amine compound selected from the compounds expressed by the above described general for (2) mula (3). R5R6P PR7R8 3 The method described in 1 or 2, wherein n is 2 or more than 2. RI R2 4 The method described in 3, wherein (0025) the adjacent R'' are connected to each other to form R3 R4 a Saturated or unsaturated hydrocarbon ring or heterocycle which may have a substituent, and 0013 (in general formula (2), I0026 a ring system formed by the ring formed by R'' and 0014) R' and Rare the same or different from each other, a ring constituted by comprising D is a quinoline or isoquino denote a C1-20 chained or cyclic hydrocarbon group which line ring system. may have a Substituent, 5The method described in any one of 1 to 4, wherein, in 0015 Rand Rare the same or different from each other, the general formula (3), one or more of four D are nitrogen denote hydrogen atoms or C1-3 hydrocarbon groups, atOmS. 0016 R. R. R7 and Rare the same ordifferent from each 6. The method described in any one of 1 to 5, wherein A other, denote hydrocarbon groups which may have a substitu is 2.4-bis(diphenylphosphino)pentane, 2.4-bis(di-4- ent, tolylphosphino)pentane, 2.4-bis(di-3,5-xylylphosphino)pen * expresses an asymmetric carbon atom); and tane, 2.4-bis(di-4-tert-butylphenylphosphino)pentane, 2,4- 0017 B denotes an amine compound expressed by follow bis(di-4-isopropylphenylphosphino)pentane, 2.4-bis(di-3,5- ing general formula (3): diethylphenylphosphino)pentane, 2.4-bis(di-3,5- diisopropylphenylphosphino)pentane, 2,4-bis (diphenylphosphino)-3-methylpentane, 2.4-bis(di-4- (3) tolylphosphino)-3-methylpentane, 2.4-bis(di-3,5- R11 R10 Xylylphosphino)-3-methylpentane, 2.4-bis(di-4-tert D butylphenylphosphino)-3-methylpentane, 2.4-bis(di-3,5- D1N NHR9 diethylphenylphosphino)-3-methylpentane, 2,4-bis(di-3,5- (RP-1 N diisopropylphenylphosphino)-3-methylpentane, 1,3-bis na2 (diphenylphosphino)-1,3-diphenylpropane, 1,3-bis(di-4- tolylphosphino)-1,3-diphenylpropane, 1,3-bis(di-3,5- Xylylphosphino)-1,3-diphenylpropane, 1,3-bis(di-4-tert (in the general formula (3), butylphenylphosphino)-1,3-diphenylpropane, 1,3-bis(di-3, 0018 each D is independently the same or different, 5-diethylphenylphosphino)-1,3-diphenylpropane, 1,3-bis denotes a carbon atom or nitrogen atom, (di-3,5-diisopropylphenylphosphino)-1,3-diphenylpropane, 0019 R. R'' and R'' are the same or different from each 1,3-bis(diphenylphosphino)-1,3-diphenyl-2-methylpropane, other, a hydrogen atom or denote a C1-20 chained or cyclic 1,3-bis(di-4-tolylphosphino)-1,3-diphenyl-2-methylpro
US 2015/003 1920 A1 Jan. 29, 2015
RandR are the same or different from each other, denote a Embodiments for Practicing the Invention hydrogen atom or a C1-3 hydrocarbon group, R. R. R7 and Rare the same or different from each other, 0035. Hereinbelow, the present invention is described in denote a hydrocarbon group which may have a Substituent, detail based on preferred embodiments. * expresses an asymmetric carbon atom), and 0030 one or more amine compounds selected from the 0036. The present invention is a method for producing an compounds expressed by the following general formula (3): optically active secondary alcohol comprising reacting a Sub strate carbonyl compound (providing that the instances of 3-quinuclidinone, 3-quinuclidinone derivative having a Sub (3) stituent, and a ketone having an aromatic hydrocarbon group R11 R10 and a heterocycle are excluded) is reacted with hydrogen or a compound donating hydrogen in the presence of one or more D D1N NHR9 ruthenium complexes selected from compounds expressed by (R12)-- N the general formula (1) described below. D na2 0037 Hereinbelow, the ruthenium complex used in this method is described in detail and then suitable embodiments of such method are described in detail. In the general formula (3), 0031 each D is independently the same or different, denotes a carbon atom or nitrogen atom,
0051 Examples of the optically active diphosphine (2) expressed by the general formula (2) include such as a pen R5R6P PR7R8 tane derivative having diphenylphosphino groups at 2- and 4-positions, a pentane derivative having di-4-tolylphosphino RI R2 groups at 2- and 4-positions, a pentane derivative having R3 R4 di-4-t-butylphenylphosphino groups at 2- and 4-positions, a pentane derivative having di-3,5-xylylphosphino groups at 2 and 4-positions, a pentane derivative having di-3,5-dieth 0042. In the general formula (2), RandR are the same or ylphenylphosphino groups at 2- and 4-positions, a 1,3-diphe different from each other and denote a C1-20 chained or nylpropane derivative having diphenylphosphino groups at 1 cyclic hydrocarbon group which may have a substituent, R and 3-positions, a 1,3-diphenylpropane derivative having and Rare the same or different from each other and denote di-4-tolylphosphino groups at 1- and 3-positions, a 1,3-diphe hydrogen or a C1-3 hydrocarbon group, R. R. RandR are nylpropane derivative having di-4-t-butylphenylphosphino the same or different from each other and denote a hydrocar bon group which may have a Substituent, and * denotes an groups at 1- and 3-positions, a 1,3-diphenylpropane deriva asymmetric carbon atom. tive having di-3,5-xylylphosphino groups at 1- and 3-posi 0043. Here, R' and R include, without limitation, for tions, a 1,3-diphenylpropane derivative having di-3,5-dieth example, a saturated or unsaturated chained aliphatic hydro ylphenylphosphino groups at 1- and 3-positions. carbon group, a saturated or unsaturated, monocyclic or poly 0.052 More specifically, the optically active diphosphine cyclic, cyclic aliphatic hydrocarbon group, monocyclic or compound A is SKEWPHOS:2.4-bis(diphenylphosphino) polycyclic aromatic hydrocarbon group and a combined pentane, TolSKEWPHOS:2.4-bis(di-4-tolylphosphino)pen group of these various hydrocarbon groups, etc., and these tane, XylSKEWPHOS:2,4-bis(di-3,5-xylylphosphino)pen hydrocarbon groups may further have Substituents. tane, 4-t-BuSKEWPHOS:2,4-bis(di-4-tert 0044) Examples of RandR include hydrocarbon groups butylphenylphosphino)pentane, 4-i-PrSKEWPHOS:2,4-bis Such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, e.g., (di-4-isopropylphenylphosphino)pentane, 3,5- phenyl and naphthyl, aralkyl, e.g., phenylalkyl, as well as diEtSKEWPHOS:24-bis(di-3,5-diethylphenylphosphino) hydrocarbon groups in which said hydrocarbon groups fur pentane, 2.4-bis(di-3,5-diisopropylphenylphosphino) ther have an acceptable Substituents such as alkyl, alkenyl, pentane, 2.4-bis(diphenylphosphino)-3-methylpentane, 2,4- cycloalkyl, aryl, alkoxy, ester, acyloxy, a halogenatom, nitro bis(di-4-tolylphosphino)-3-methylpentane, 2.4-bis(di-3,5- group and cyano group. Xylylphosphino)-3-methylpentane, 2.4-bis(di-4-tert I0045. Among these, R' and Rare preferably a saturated butylphenylphosphino)-3-methylpentane, 2.4-bis(di-3,5- chained aliphatic hydrocarbon group or a monocyclic aro diethylphenylphosphino)-3-methylpentane, 2,4-bis(di-3,5- matic hydrocarbon group, more preferably, a methyl group, diisopropylphenylphosphino)-3-methylpentane, 1,3-bis ethyl group, propyl group or a Substituted or unsubstituted (diphenylphosphino)-1,3-diphenylpropane, 1,3-bis(di-4- phenyl group, particularly preferably a methyl group and tolylphosphino)-1,3-diphenylpropane, 1,3-bis(di-3,5- phenyl group. Xylylphosphino)-1,3-diphenylpropane, 1,3-bis(di-4-tert I0046 RandR area hydrogenatom or C1-3 hydrocarbon butylphenylphosphino)-1,3-diphenylpropane, 1,3-bis(di-3, group, preferably an aliphatic Saturated hydrocarbon group. 5-diethylphenylphosphino)-1,3-diphenylpropane, 1,3-bis In specific, a hydrogen atom, methyl group, ethyl group, (di-3,5-diisopropylphenylphosphino)-1,3-diphenylpropane, propyl group, isopropyl group and the like are preferred. 1,3-bis(diphenylphosphino)-1,3-diphenyl-2-methylpropane, 0047 R. R. R7 and R include, without limitation, for 1,3-bis(di-4-tolylphosphino)-1,3-diphenyl-2-methylpro example, a saturated or unsaturated chained aliphatic hydro pane, 1,3-bis(di-3,5-xylylphosphino)-1,3-diphenyl-2-meth carbon group, a saturated or unsaturated, monocyclic or poly ylpropane, 1,3-bis(di-4-tert-butylphenylphosphino)-1,3- cyclic, cyclic aliphatic hydrocarbon group, a monocyclic or diphenyl-2-methylpropane, 1,3-bis(di-3,5- polycyclic aromatic hydrocarbon group and the like, and diethylphenylphosphino)-1,3-diphenyl-2-methylpropane or these hydrocarbon groups may further have substituents. 1,3-bis(di-3,5-diisopropylphenylphosphino)-1,3-diphenyl 0048 Examples of R. R. RandR includehydrocarbon 2-methylpropane. groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, 0053. The optically active diphosphine compound A is, e.g., phenyl and naphthyl, aralkyl, e.g., phenylalkyl as well as more preferably, SKEWPHOS:2,4-bis(diphenylphosphino) hydrocarbon groups in which said hydrocarbon groups fur pentane, TolSKEWPHOS:2.4-bis(di-4-tolylphosphino)pen ther have an acceptable Substituents such as alkyl, alkenyl, tane, XylSKEWPHOS:2,4-bis(di-3,5-xylylphosphino)pen cycloalkyl, aryl, alkoxy, ester, acyloxy, a halogen atom, tane, 4-i-PrSKEWPHOS:24-bis(di-4- dialkyl amino group, nitro group and cyano group. isopropylphenylphosphino)pentane, 4-t-BuSKEWPHOS:2. 0049 Among these, R. R. R7 and Rare preferably a 4-bis(di-4-tert-butylphenylphosphino)pentane, 4-i- Substituted or unsubstituted monocyclic aromatic hydrocar PrSKEWPHOS:2.4-bis(di-4-isopropylphenylphosphino) bon group, more preferably a phenyl group and Substituted pentane, 3,5-dietSKEWPHOS:24-bis(di-3,5- phenyl group, and especially preferably a phenyl group, as diethylphenylphosphino)pentane, O 2,4-bis well as a Substituted phenyl group that has at least one Sub (diphenylphosphino)-3-methylpentane. stituent selected from a methyl group, ethyl group, isopropyl 0054 Among these, SKEWPHOS, TolSKEWPHOS, 3.5- group, propyl group and tert-butyl group. diEtSKEWPHOS, t-BuSKEWPHOS, and XylSKEWPHOS 0050. The number of carbons in each of R. R. RandR are particularly suitable. However, naturally, the optically may be, though not particularly limited to, for example, 1 to active diphosphine compounds that can be used in the present 20, preferably, 5 to 10. invention are by no means limited to these compounds. US 2015/003 1920 A1 Jan. 29, 2015
0055 Besides, as the amine compound B in the optically I0067. The above mentioned R is preferably a hydrogen active ruthenium complex expressed by the general formula atom, alkyl group, phenyl group and phenylalkyl group, more (1), a compound may be used which is expressed by following preferably, a hydrogen atom, benzyl group, and particularly formula (3): preferably a hydrogen atom. 0068. The abovementioned R'' and R'' is preferably such as a hydrogenatom, alkyl group, phenyl group orphenylalkyl (3) group, particularly preferably both are hydrogen atoms, or R11 R10 either R' or R'' is a methyl group. D 0069. Moreover, R'' and R'' may be connected to each D1N NHR9 other to form a saturated or unsaturated hydrocarbon ring or (RP-1 N heterocycle which may have a substituent. Such hydrocarbon na ring includes a cycloalkane ring, cycloalkene ring or cycloalkyne ring having 3 to 10, preferably 4 to 8 ring mem bers. Rings formed by R'' and R' include, more specifically, 0056. In the general formula (3), e.g., cyclopropylidene, cyclobutylidene, cyclopentylidene, 0057 each D is independently the same or different, cyclohexylidene and pyperidylidene, either with or without denotes a carbon atom or nitrogen atom, further Substituents. Among those described above, a mono 0.058 R. R'' and R'' are the same or different from each cyclic hydrocarbon group, in particular, cyclopentylidene and other, denote a hydrogen atom or a C1-20 chained or cyclic cyclohexylidene are preferred. hydrocarbon group which may have a substituent, and/or R' 0070 Furthermore, R' includes, without limitation, for and R'' are connected to each other to form a saturated or example, such as a saturated or unsaturated chained aliphatic unsaturated hydrocarbon ring or heterocycle which may have hydrocarbon group, a saturated or unsaturated, monocyclic or a Substituent, polycyclic, cyclic aliphatic hydrocarbon group, a monocyclic 0059 each R' is the same ordifferent from each other and or polycyclic aromatic hydrocarbon group, and these hydro denotes a C1-20 chained or cyclic hydrocarbon group which carbon groups may further have substituents. may have a substituent, and/or, the adjacent R'' are connected (0071. Examples for R' include hydrocarbon groups such to each other to form a Saturated or unsaturated hydrocarbon as an alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, e.g., phe ring or heterocycle which may have a Substituent, nyl, naphthyl, and aralkyl, e.g., phenylalkyl, as well as said hydrocarbon group having various acceptable substituents 0060) R' may at least partly be bound to ruthenium as an Such as an alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acy anionic group X, loxy, a halogen atom, nitro group or cyano group. 0061 n is an integer of 0 to (4-(the number of D that are 0072. The above mentioned R' is preferably an alkyl nitrogen atoms)), provided that n is an integer of 2 to 4 when group or aryl group, more preferably a methyl group, ethyl the number of D that are nitrogen atoms is 0. group, isopropyl group, tert-butyl group, a Substituted or 0062 Here, as mentioned above, in the formula each Dis unsubstituted phenyl group, especially preferably a methyl independently the same or different and denotes a nitrogen group, phenyl group, or o-, m- or p-tolyl group. atom or carbon atom. (0073. The adjacent R' may be connected to each other to 0063) Nitrogen atoms which exist in the ring constituted form a saturated or unsaturated hydrocarbon ring or hetero by comprising D can be for example 1 to 3, preferably 1 to 2. cycle that may have a substituent. A ring formed by R' Thus, in this case, of four D in the formula, 0 to 2, preferably, includes a saturated or unsaturated hydrocarbon ring or het 0 or 1 D is nitrogen atom, and the other D are carbon atoms. erocycle having 3 to 10, preferably 4 to 8 ring members, and In addition, when one or more of four D in the formula is (are) more specifically, for example, a benzene ring, naphthalene nitrogen atom(s), the optical purity of the optically active ring, pyridine ring, pyradine ring, pyrimidine ring, pyridazine secondary alcohol obtained in after-mentioned the method of ring, triazine ring, tetrazine ring, imidazoline ring, pyrrole the present invention will be high. ring, imidazole ring, pyrazole ring, either with or without 0064. A ring constituted by comprising D can be, without further Substituents. Among those described above, a mono limitation, for example, a pyridine ring, pyradine ring, pyri cyclic hydrocarbon aromatic group, in particular benzene midine ring, pyridazine ring, triazine ring or tetrazine ring. ring is preferred. Among these, the ring constituted by comprising D is, pref 10074) A ring system formed witharing formed by R'' and erably, a pyridine ring, pyradine ring or pyrimidine ring. a ring constituted by comprising D includes, such as, for 0065. In the formula, R to R' include, without limitation, example, quinoline, isoquinoline, purine, quinoxaline, for example, Such as a hydrogen atom, a saturated or unsat quinazoline, cinnoline, phthalazine, phenanthridine ring sys urated chained aliphatic hydrocarbon group, a saturated or tems, and among these, quinoline or isoquinoline ring sys unsaturated, monocyclic or polycyclic, cyclic aliphatic tems are preferred. hydrocarbon group, monocyclic or polycyclic aromatic 0075. As mentioned above, in the formula, n is an integer hydrocarbon group, and these hydrocarbon groups may fur of Oto (4-(the number of D that are nitrogenatoms)), provided ther have substituents. that n is an integer of 2 to 4 when the number of D that are 0066. Examples for R to R' include a hydrogen atom, nitrogenatoms is 0. Namely, n is from 2 to 4 when the number hydrocarbon groups such as an alkyl, alkenyl, cycloalkyl, of D that are nitrogen atoms is 0; n is from 0 to 3 when the cycloalkenyl, aryl, e.g., phenyl, naphthyl, aralkyl, e.g., phe number of D that are nitrogenatoms is 1: n is from 0 to 2 when nylalkyl, as well as said hydrocarbon groups having various the number of D that are nitrogen atoms is 2; n is from 0 to 1 acceptable Substituents such as an alkyl, alkenyl, cycloalkyl, when the number of D that are nitrogenatoms is 3; and n is 0 aryl, alkoxy, ester, acyloxy, a halogen atom, nitro group or when the number of D that are nitrogen atoms is 4. Further cyano group. more, in the method discussed below according to the present US 2015/003 1920 A1 Jan. 29, 2015
invention, n is preferred to be 2 or higher Such that an amine diisopropylpyridine, 2-(1-aminoethyl)-3,6- compound B has more than one substituents R' in order to diisopropylpyridine, 2-(1-aminoethyl)-4,5- obtain an optically active secondary alcohol at a high optical diisopropylpyridine, 2-(1-aminoethyl)-4,6- purity. diisopropylpyridine, 2-(1-aminoethyl)-5,6- diisopropylpyridine, 2-(1-aminoethyl)-3,4-di 0076 More specifically, an amine compound B preferably n-butylpyridine, 2-(1-aminoethyl)-3,5-di n-butylpyridine, is, for example, 3.4-MePICA:2-(aminomethyl)-3,4-dimeth 2-(1-aminoethyl)-3,6-din-butylpyridine, 2-(1-aminoethyl)- ylpyridine, 3.5-MePICA:2-(aminomethyl)-3,5-dimethylpy 4,5-din-butylpyridine, 2-(1-aminoethyl)-4,6-din-butylpyri ridine, 2-(aminomethyl)-3,6-dimethylpyridine, 2-(aminom dine, 2-(1-aminoethyl)-5,6-din-butylpyridine, 2-(1-aminoet ethyl)-4,5-dimethylpyridine, 2-(aminomethyl)-4,6- hyl)-3,4-diisobutylpyridine, 2-(1-aminoethyl)-3,5- dimethylpyridine, 2-(aminomethyl)-5,6-dimethylpyridine, disobutylpyridine, 2-(1-aminoethyl)-3,6-diisobutylpyridine, 2-(aminomethyl)-3,4,5-trimethylpyridine, 2-(aminomethyl)- 2-(1-aminoethyl)-4,5-diisobutylpyridine, 2-(1-aminoethyl)- 3,5,6-trimethylpyridine, 2-(aminomethyl)-4,5,6-trimeth 4,6-diisobutylpyridine, 2-(1-aminoethyl)-5,6-diisobutylpyri ylpyridine, 2-(aminomethyl)-3,4,5,6-tetramethylpyridine, dine, 2-(1-aminoethyl)-3,4-di tert-butylpyridine, 2-(1-ami 2-(aminomethyl)-3,4-diethylpyridine, 2-(aminomethyl)-3,5- noethyl)-3,5-di tert-butylpyridine, 2-(1-aminoethyl)-3,6-di diethylpyridine, 2-(aminomethyl)-3,6-diethylpyridine, tert-butylpyridine, 2-(1-aminoethyl)-4,5-di tert-butylpyri 2-(aminomethyl)-4,5-diethylpyridine, 2-(aminomethyl)-4,6- dine, 2-(1-aminoethyl)-4,6-di tert-butylpyridine, 2-(1-ami diethylpyridine, 2-(aminomethyl)-5,6-diethylpyridine, noethyl)-5,6-di tert-butylpyridine, 2-(1-aminoethyl)-3,4- 2-(aminomethyl)-3,4-din-propylpyridine, 2-(aminomethyl)- diphenylpyridine, 2-(1-aminoethyl)-3,5-diphenylpyridine, 3,5-di n-propylpyridine, 2-(aminomethyl)-3,6-di n-propy 2-(1-aminoethyl)-3,6-diphenylpyridine, 2-(1-aminoethyl)-4, lpyridine, 2-(aminomethyl)-4,5-din-propylpyridine, 2-(ami 5-diphenylpyridine, 2-(1-aminoethyl)-4,6-diphenylpyridine, nomethyl)-4,6-din-propylpyridine, 2-(aminomethyl)-5,6-di 2-(1-aminoethyl)-5,6-diphenylpyridine, 2-(1-aminoethyl) n-propylpyridine, 2-(aminomethyl)-3,4-diisopropylpyridine, quinoline, 1-(1-aminoethyl)isoquinoline, 3-(1-aminoethyl) 2-(aminomethyl)-3,5-diisopropylpyridine, 2-(aminom ethyl)-3,6-diisopropylpyridine, 2-(aminomethyl)-4,5-diiso isoquinoline, 2-(1-aminoethyl)pyradine, 2-(1-aminoethyl) propylpyridine, 2-(aminomethyl)-4,6-diisopropylpyridine, pyrimidine or 6-(1-aminoethyl)phenanthridine. Among 2-(aminomethyl)-5,6-diisopropylpyridine, 2-(aminom these, in particular, 2-AMQ, 1-AMIQ, 3-AMIQ, 3,4- ethyl)-3,4-din-butylpyridine, 2-(aminomethyl)-3,5-din-bu MePICA, 3.5-MePICA, 2-AMPZ, 2-AMPR are suitable. tylpyridine, 2-(aminomethyl)-3,6-din-butylpyridine, 2-(ami 0077. The ruthenium complex expressed by the general nomethyl)-4,5-di n-butylpyridine, 2-(aminomethyl)-4,6-di formula (1) described hereinabove bears as an amine ligand n-butylpyridine, 2-(aminomethyl)-5,6-di n-butylpyridine, an amine compound B expressed by the general formula (3), 2-(aminomethyl)-3,4-diisobutylpyridine, 2-(aminomethyl)- which either comprises more than one substituents on its 3,5-diisobutylpyridine, 2-(aminomethyl)-3,6-diisobutylpyri contained nitrogen or comprises a nitrogen-containing ring dine, 2-(aminomethyl)-4,5-diisobutylpyridine, 2-(aminom with more than one nitrogen atoms. When a Substrate carbo ethyl)-4,6-diisobutylpyridine, 2-(aminomethyl)-5,6- nyl compound is hydrogenated using a ruthenium complex disobutylpyridine, 2-(aminomethyl)-3,4-di tert bearing Such an amine compound B and an optically active butylpyridine, 2-(aminomethyl)-3,5-di tert-butylpyridine, diphosphine compound A expressed by the general formula 2-(aminomethyl)-3,6-di tert-butylpyridine, 2-(aminom (2), one can obtain an optically active secondary alcohol at ethyl)-4,5-ditert-butylpyridine, 2-(aminomethyl)-4,6-ditert much higher optical purity as compared to the case using a butylpyridine, 2-(aminomethyl)-5,6-di tert-butylpyridine, ruthenium complex bearing known conventional achiral 2-(aminomethyl)-3,4-diphenylpyridine, 2-(aminomethyl)-3, ligand. 5-diphenylpyridine, 2-(aminomethyl)-3,6-diphenylpyridine, 0078 Moreover, the ruthenium complex expressed by the 2-(aminomethyl)-4,5-diphenylpyridine, 2-(aminomethyl)-4, general formula (1) used in the present invention may also be 6-diphenylpyridine, 2-(aminomethyl)-5,6-diphenylpyridine, prepared in the reaction system (in situ) upon reacting the 2-AMQ:2-(aminomethyl)guinoline, 1-AMIQ:1-(aminom Substrate carbonyl compound with hydrogen in the presence ethyl)isoquinoline, 3-AMIQ:3-(aminomethyl)isoquinoline, ofa base. Although Such method is not limited, as an example, 2-AMPZ:2-(aminomethyl)pyradine, 2-AMPR:2-(aminom in the reaction system, the ruthenium complex expressed by ethyl)pyrimidine, 6-(aminomethyl)phenanthridine, 2-(1- the general formula (1) can be prepared in situ in the presence aminoethyl)-3,4-dimethylpyridine, 2-(1-aminoethyl)-3,5- of one or more complexes selected from the precursor com dimethylpyridine, 2-(1-aminoethyl)-3,6-dimethylpyridine, pound expressed by following general formula (4): 2-(1-aminoethyl)-4,5-dimethylpyridine, 2-(1-aminoethyl)-4, RuxYA (4) 6-dimethylpyridine, 2-(1-aminoethyl)-5,6-dimethylpyridine, 2-(1-aminoethyl)-3,4,5-trimethylpyridine, 2-(1-aminoet in the general formula (4), X, Y and A each independently hyl)-3,5,6-trimethylpyridine, 2-(1-aminoethyl)-4,5,6-trim have the meaning as defined in the general formula (1); and ethylpyridine, 2-(1-aminoethyl)-3,4,5,6-tetramethylpyri one or more amine compound selected from the compounds dine, 2-(1-aminoethyl)-3,4-diethylpyridine, 2-(1- expressed by the above described general formula (3). aminoethyl)-3,5-diethylpyridine, 2-(1-aminoethyl)-3,6- 0079 Molar ratio of a complex expressed by the general diethylpyridine, 2-(1-aminoethyl)-4,5-diethylpyridine, 2-(1- formula (4) and an amine compound expressed by the general aminoethyl)-4,6-diethylpyridine, 2-(1-aminoethyl)-5,6- formula (3) is not particularly limited. However, since the diethylpyridine, 2-(1-aminoethyl)-3,4-di n-propylpyridine, complex expressed by the general formula (4) and an amine 2-(1-aminoethyl)-3,5-din-propylpyridine, 2-(1-aminoethyl)- compound expressed by the general formula (3) are reacted to 3,6-di n-propylpyridine, 2-(1-aminoethyl)-4,5-di n-propy generate a catalyst precursor expressed by the general for lpyridine, 2-(1-aminoethyl)-4,6-di n-propylpyridine, 2-(1- mula (1), if the amount of the amine compound expressed by aminoethyl)-5,6-din-propylpyridine, 2-(1-aminoethyl)-3,4- the general formula (3) is insufficient relative to that of the diisopropylpyridine, 2-(1-aminoethyl)-3,5- complex expressed by the general formula (4), the later US 2015/003 1920 A1 Jan. 29, 2015 remains without changing into the catalyst precursor polynuclear ruthenium(benzene) bichloride, polynuclear expressed by the general formula (1), being disadvantageous ruthenium(p-cymene) bichloride, polynuclear ruthenium from the viewpoint of reaction economy. Therefore, a com (trimethyl benzene) bichloride or polynuclear ruthenium plex expressed by the general formula (4) and an amine (hexamethylbenzene) bichloride; and a phosphine-coordi compound expressed by the general formula (3) may exist nated complex Such as dichlorotris(triphenyl phosphine) preferably at 1:1 to 1:50 molar ratio, more preferably at 1:1 to ruthenium, etc. may be employed. Any other ruthenium 1:20 molar ratio, in the vessel in which a substrate carbonyl complexes may be used without limitation as long as it has a compound will be reacted with hydrogen and/or a hydrogen ligand which is capable of being Substituted with an optically donating compound. Even if the amount of the amine com active diphosphine compound or an optically active diamine pound expressed by the general formula (3) is insufficient compound. For example, various ruthenium complexes relative to that of the complex expressed by the general for described in COMPREHENSIVE ORGANOMETALLIC mula (4), they can be used without any problem, except that CHEMISTRY II (Vol. 7) p. 294-296 (PERGAMON) can be the reactivity would be reduced. used as a starting material. 0080. The ruthenium complex expressed by the general I0084. When a trivalent ruthenium complex is used as a formula (1) or the general formula (4) may include one or starting material, a phosphine-ruthenium halide complex can more than one organic compound that is a reaction reagent be synthesized by reacting, for example, a halogenated ruthe used in its synthesis. Here, the organic compound denotes a nium (III) with excess amount of phosphine. Thus obtained coordinating organic compound exemplified by Such as, for phosphine-ruthenium halide complex with amine can then be example, an aromatic hydrocarbon solvent such as toluene or reacted with amine to obtain the intended amine-phosphine Xylene, an aliphatic hydrocarbon Solvent Such as pentane or ruthenium halide complex expressed by the general formula hexane, a halogen-containing hydrocarbon Solvent Such as (1). This type of synthesis is described, for example, in the methylene dichloride, an ether solvent such as an ether or literatures such as J. Mol. Cat., 15, 297(1982). tetrahydrofuran, an alcoholic solvent such as methanol, etha I0085 Namely, RuCl(PPh), synthesized by a method nol, 2-propanol, butanol or benzyl alcohol, a ketone solvent Such as those described in e.g., Inorg. Synth., Vol 12, 237 Such as acetone, methylethylketone and cyclohexylketone, a (1970) is reacted in benzene with ethylenediamine to obtain heteroatom-containing organic solvent Such as acetonitrile, RuCl(PPh),(en) (note that there is no description about the DMF, N-methylpyrrolidone, DMSO or triethylamine. yield). However, in this method, the reaction system is het 0081. The synthesis of a ruthenium complex expressed by erogeneous condition and tends to leave unreacted ingredi the general formula (1) can be carried out, as an example, by ents. On the other hand, the reaction can be carried out uni reacting an optically active ruthenium complex expressed by formly to improve the operability when the reaction solvent is the general formula (4) with an amine compound or, alterna changed to a solvent Such as methylene dichloride or chloro tively, an optically active amine compound. The synthesis of form. an optically active ruthenium complex expressed by the gen I0086. The reaction of a halogenated ruthenium and phos eral formula (4) can be carried out by reacting an optically phine ligand can be carried out in a solvent such as: an active diphosphine compound with the source ruthenium aromatic hydrocarbon Solvent such as toluene or Xylene; an complex. The complex expressed by the general formula (1) aliphatic hydrocarbon solvent such as pentane or hexane; a to be used may preliminarily be prepared as mentioned above, halogen-containing hydrocarbon Solvent Such as methylene or may be prepared in situ during the reaction of hydrogena dichloride; an ether solvent such as an ether or tetrahydrofu tion. Any method that has been reported so far can be used for ran; an alcoholic solvent such as methanol, ethanol. 2-pro preparation of the ruthenium complex expressed by the gen panol, butanol or benzyl alcohol; a heteroatom-containing eral formula (1), including chemical structures of the Source organic solvent such as acetonitrile, DMF, N-methylpyrroli ingredients. Although not limited thereto, one of the embodi done or DMSO, at a reaction temperature from -100° C. to ments is shown below. 200° C. to give an phosphine-ruthenium halide complex 0082. A ruthenium complex as a starting material for syn expressed by the general formula (4). thesizing the complex that can be used may be a non-valent, I0087. The reaction of thus obtained phosphine-ruthenium monovalent, divalent or trivalent ruthenium complex, orthose halide complex expressed by the general formula (4) and an with higher valencies. When a non-valent or monovalent amine ligand expressed by the general formula (3) can be ruthenium complex is used, ruthenium needs to be oxidized carried out in a solvent such as: an aromatic hydrocarbon by the final step. When a divalent complex is used, the syn Solvent such as toluene or Xylene; an aliphatic hydrocarbon thesis can be carried out by reacting the ruthenium complex, Solvent Such as pentane or hexane; a halogen-containing an optically active diphosphine compound and optically hydrocarbon solvent such as methylene dichloride; an ether active diamine compound in this order or in the reverse order, Solvent such as an ether or tetrahydrofuran; an alcoholic or by reacting these ingredients all together. When a trivalent Solvent Such as methanol, ethanol. 2-propanol, butanol or ruthenium complex or a ruthenium complex of higher benzyl alcohol; a heteroatom-containing organic solvent Such Valency is used as the starting material, ruthenium needs to be as acetonitrile, DMF, N-methylpyrrolidone or DMSO at a reduced by the final step. reaction temperature from -100° C. to 200° C. to give an 0083. As a ruthenium complex to be starting material, an amine-phosphine-ruthenium halide complex expressed by inorganic ruthenium compound Such as ruthenium (III) chlo the general formula (1). ride hydrate, ruthenium(III) bromide hydrate, ruthenium(III) I0088. On the other hand, a divalent ruthenium complex iodide hydrate; a diene-coordinated ruthenium compound may also be used from the beginning, reacting it with phos Such as polynuclear ruthenium(norbornadiene) bichloride. phine compound and amine compound in this order or in the polynuclear ruthenium(cycloocta-1,5-diene) bichloride or reverse order. As an example, a diene-coordinated ruthenium bis(methyl allyl)ruthenium(cycloocta-1,5-diene); an aro compound such as polynuclear ruthenium(norbornadiene) matic compound-coordinated ruthenium complex such as bichloride, polynuclear ruthenium(cyclooct-1,5-diene) US 2015/003 1920 A1 Jan. 29, 2015
bichloride or bis(methyl allyl)ruthenium(cyclooctadiene); may be a mixture of several complexes with different coor an aromatic compound-coordinated ruthenium complex Such dination manner, it can directly be used for the hydrogenating as binuclearruthenium(benzene) bichloride, binuclear ru reaction without purifying to obtain single structure complex. thenium(p-cymene) bichloride, binuclearruthenium(trim ethyl benzene) bichloride or binuclearruthenium(hexam
(CH) and quaternary ammonium salts, and one or more Substrate. Therefore, upon carrying out the present invention, from these may be used in combination. Among these, the there is no need to constantly monitor the progress of the base preferably is KOH or KOCH (CH), and particularly reaction, nor any need to stop the reaction immediately after preferably KOCH(CH). the completion of the reaction. Accordingly, the reaction time 0116. The amount of base to be added is, without limita may be set longer than the Substantial reaction time, provid tion, for example, an amount Such that the base concentration ing the method with an advantage in industrial practice. will be 0.001 to 0.2 moles/L in the reaction system, preferably 0.125 By hydrogenating substrate carbonyl compounds an amount such that the base concentration will be 0.005 to according to the method described above, corresponding 0.1 moles/L, more preferably an amount such that the base optically active alcohols can be obtained. concentration will be 0.01 to 0.05 moles/L. I0126. However, even by the method of the present inven 0117. As discussed above, the ruthenium complex indi tion, the product of the hydrogenating reaction might contain cated by the general formula (1) to be used as the catalyst and the source material ketone, added base or a salt generated by the base are essential ingredients in order to Smoothly con the reaction of the complex and the base. These can be duct the reaction of asymmetric hydrogenation to achieve a removed by generally known purification operation Such as high asymmetric yield, and the reaction activity will not be distillation, washing, recrystallization and chromatography. Sufficient to obtain an optically active alcohol at a high optical 0127. The reaction manner of the above mentioned reac purity if either one ingredient is insufficient. tion is not particularly limited and the reaction can be carried 0118. However, when X and Y in the ruthenium complex out in any of a batch method, a continuous method or in a expressed by the general formula (1) are hydrogen atoms, or micro-flow reactor. alternatively when X is a hydrogen atom and Y is tetrahy I0128. According to the present invention as discussed droborate anion, the ruthenium complex and Substrate carbo above, a readily synthesized diphosphine compound having nyl compound may be mixed and then, without adding a base, an asymmetric carbon, i.e., an optically active SKEWPHOS the reaction may be conducted by applying pressurized (2,4-bis(diphenylphosphino)pentane) derivative compound, hydrogen and stirring. In Such case, still the Substrate carbo and a ruthenium complex catalyst bearing a PICA-type ligand nyl compound may be hydrogenated. having more than one substituents on the pyridine ring or a 0119) A solvent may also be present in the reaction sys PICA-type ligand substituted with a heterocycle in which the tem. pyridine ring has more than one nitrogen atoms act as a 0120. The solvents which can be used are not particularly hydrogenating catalyst with a high efficiency. This complex is limited, but those which solubilize the substrate and the cata not the optically active amine which has conventionally been lyst system are preferred. Examples include lower alcohols employed, and inexpensive because it can employ a readily Such as methanol, ethanol, n-propanol. 2-propanol, butanol synthesized achiral amine as a ligand. Such characteristics and benzyl alcohol; aliphatic hydrocarbon solvents such as can be considered industrially and economically excellent as pentane and hexane; halogen-containing hydrocarbon Sol compared to conventional methods. In addition, the optically vents such as methylene dichloride; ether solvents such as active secondary alcohol obtained by the method of the ether, methyl-tert-butyl ether, cyclopentylmethyl ether and present invention has a higher optical purity than that tetrahydrofuran; and heteroatom-containing organic solvents obtained by a conventional method. such as acetonitrile, N,N-dimethylformamide (DMF), N-me I0129. According to another embodiment of the present thylpyrrolidone and dimethylsulfoxide (DMSO), and one or invention, the method of producing an optically active sec more from these may be used in combination. ondary alcohols is characterized in that a Substrate carbonyl 0121 The amount of the solvent is determined according compound (provided that 3-quinuclidinone, 3-quinuclidi to the solubilities of the reaction substrates and economies. none derivative having a Substituent, and a ketone having an For instance, although some Substrates can be reacted at low aromatic hydrocarbon group and a heterocycle are excluded) concentration of 0.1 moles/L or below in the reaction system is reacted with hydrogen and/or a hydrogen donating com to almost without solvent depending on the types of the Sub pound in the presence of: strates, it is preferred to use the Substrate at the concentration in a range from 0.3 to 5 moles/L. 0.130 one or more complexes selected from the com 0122) The higher limit of the reaction temperature is pounds expressed by following general formula (4): needed to be set in a range Such that the decomposition of the RuxYA (4) catalytic ruthenium complex will not occur, and the lower limit is needed to be set in consideration of the activity. For in the general formula (4), X and Y are the same or different instance, the reaction is preferably carried out at 0 to 60°C., from each other and have the meaning as defined in the preferably at 25 to 40°C., and such temperature range can be general formula (1), and considered good from economic point of view. I0131 one or more amine compounds expressed by the 0123. The reaction time varies depending on the reaction above mentioned general formula (3). condition Such as the reaction solvent, the concentration of 0.132. The complex expressed by the general formula (4) the reaction Substrate, the temperature, the pressure and the and the amine compound expressed by the general formula Substrate/catalyst ratio, though it can optionally be set from (3) may be placed preferably at a molar ratio from 1:1 to 1:50, several minutes to several dozen hours, e.g., 10 minutes to 96 more preferably at a molar ratio from 1:1 to 1:20 in a vessel in hours, preferably 2 hours to 48 hours such that the reaction which the substrate carbonyl compound is reacted with will be completed within that time, in consideration of the hydrogen and/or a hydrogen donating compound. ease of reaction operation and economic efficiency. 0133. The aforementioned other conditions can be used in 0.124. In addition, no problem will be observed even if the this embodiment. reaction operation is continuously carried on after the I0134. A similar result can be obtained by a method accord completion of the reduction of the carbonyl groups of the ing to Such embodiment. US 2015/003 1920 A1 Jan. 29, 2015 12
WORKING EXAMPLES 0146 Firstly, under an argon gas atmosphere, 27.3 g of 0135. Hereinafter, the present invention will be further 3,4-dimethylpyridine (Aldrich) (255 mmol) in 150 mL acetic explained in detail by the way of Working Examples, acid solution was cooled on ice, and 25 mL of 35% hydrogen although the present invention is not to be limited by follow peroxide aqueous solution was added thereto, stirred at 75°C. ing Working Examples. In following Working Examples, all for 3 hours. Then additional 17.5 mL of 35% hydrogen per reactions were carried out under an inert gas atmosphere Such oxide aqueous solution was added and stirred at 75° C. for 3 as argon gas or nitrogen gas. The solvent used in the reaction hours. The reaction solution was neutralized by adding an had been dehydrated and degassed unless otherwise aqueous solution of Sodium hydrogen carbonate, extracted described. The hydrogenating reaction of the carbonyl com with methylene dichloride. The extract was dried on salt cake pound was carried out in an autoclave with pressurized hydro and concentrated to give a solid. The obtained solid was gen. washed with ethyl acetate to give 29.55g of 3,4-dimethylpy 0136. The ketone substrates described in Working ridine-N-oxide (94% yield). Examples and Comparative Examples were purchased as reagents and directly used, unless otherwise described. The 0147 17.8g of the obtained 3,4-dimethylpyridine-N-ox solvents used in the reactions were the dehydrated solvent ide (144.5 mmol) was dissolved under an argon gas atmo from KANTO CHEMICAL CO., INC., which were directly sphere in 250 mL of methylene dichloride, added thereto 13.2 used. Other chemicals were the reagents from KANTO mL of dimethyl carbamoyl chloride (144 mmol), then 19.0 CHEMICAL CO., INC. which were directly used, unless mL of trimethylsilyl cyanide (152 mmol), and stirred over otherwise described. night at room temperature. The reaction solution was 0.137 In Working Examples and Comparative Examples quenched with 10%-KCO aqueous solution, the methylene described below, S/C denotes the substrate/catalyst molar dichloride layer was separated, dried on salt cake and con ratio. centrated to give 3.40 g of 6-cyano-3,4-dimethylpyridine 0.138. Following apparatuses were used for measurement (18% yield). below: NMR: JNM-ECX400P (400 MHz) (JEOL Ltd.) 0.148. In an autoclave, 3.40 g of 6-cyano-3,4-dimethylpy 0139 Internal standard substance: 'H-NMR tetramethyl ridine (25.7 mmol), 0.15g of Pd/C (water-content—50%), 200 silane mL methanol and 3.0 mL concentrated hydrochloric acid are 0140) External standard substance: 'P-NMR 85% phos placed, stirred at room temperature for 3 hours while pressur phoric acid izing with hydrogen to 3 atm. The reaction Solution was The optical purity measurement by GC filtered through Celite and the filtrate was concentrated to 0141 Measuring apparatus: GC-17A (FID detector, dryness. This was washed with methanol to give 2.41 g of Simadzu Corporation) 2-aminomethyl-3,4-dimethylpyridine (3.4-MePICA) 0142 Column: CPChirasil-DEXCB (0.25 mml. Dx25m, hydrochloride (93% yield). This 2-aminomethyl-3,4-dimeth DF=0.25 um) (from VARIAN) ylpyridine hydrochloride was treated with an aqueous solu The optical purity measurement by HPLC tion of potassium carbonate to give 2-aminomethyl-3,4-dim 0143 Measuring apparatus: LC-20A (UV detector, ethylpyridine (3.4-MePICA) quantitatively. Simadzu Corporation) 0149 2-aminomethyl-3,5-dimethylpyridine (3,5- 0144) Column: CHIRALPAK AD-RH (4.6 mm)x150 MePICA) was synthesized in a similar way. As for 1-ami mm) (DAICEL Corporation) nomethyl isoquinoline (1-AMIQ), 3-aminomethyl isoquino 1. Synthesis of Ruthenium Complexes line (3-AMIQ), 2-aminomethyl quinoline (2-AMQ) and Synthetic Examples 1 to 6 2-aminomethyl pyrimidine (2-AMPR), corresponding nitrile intermediates are in market from Sigma-Aldrich Co. LLC. Syntheses of Various PICA-Type Amine Ligands and these were used as source materials. The yields of the 0145 A synthetic method for 2-aminomethyl-3,4-dimeth synthesized compounds, etc., are summarized in the Table ylpyridine (3.4-MePICA) is described below as an example. below.
TABLE 1
Substituted N-oxide Nitrile Synthesized "H-NMR spectrum pyridine intermediate intermediate compound (399.78 MHz, CDOD)
Synthetic N O N CN N 88.18 ppm (d. 1H), 7.09 Example n n n NH2 (d. 1H), 3.90 (s, 2H), 1 N 2.32 (s, 3H), 2.25 (s.3H) 21 2 2 21 SOUCE 18% yield 93% yield material 94% yield US 2015/003 1920 A1 Jan. 29, 2015
TABLE 1-continued Substituted N-oxide Nitrile Synthesized H-NMR spectrum pyridine intermediate intermediate compound (399.78 MHz, CDOD) Synthetic N O N CN N 88.16 ppm (s, 1H), 7.41 Example n n n NH2 (s, 1H), 3.84 (s, 2H), 2.30 2 s (s, 3H), 2.28 (s, 3H)
SOUCE 2 47% yield 25% yield material 62% yield Synthetic 88.39 ppm (d. 1H), 8.23 Example N N (s, 1H), 7.92 (s, 1H), 3 7.77-7.66 (m, 3H), 4.42 2N 2N (s, 2H)
CN
SOUCE NH2 material 43% yield
Synthetic CN 89.23 ppm (s, 1H), 8.06 Example N N NH2 (d. 1H), 7.90 (d. 1H), 4 7.78-7.74 (m, 2H), 7.68 2N 2N (s, 1H), 4.03 (s, 2H) SOUCE 21% yield material
Synthetic N CN N 88.29 ppm (d. 1H), 8.00 Example n n NH. (s, 1H), 7.89 (s, 1H), 5 7.73 (m, 1H), 7.56 (m, 21 21 2H)4.07 (s, 2H SOUCE 21% yield material
Synthetic N CN N 88.75 ppm (d. 2H), 7.35 Example N n NH2 (t, 1H), 7.90 (d. 1H), 4.00 6 (s, 2H) 2N 2N SOUCE 29% yield material
Synthetic Example 7 diene)(methylallyl), (64 mg. 0.2 mmol) were placed. Then 5 The synthesis of 2-aminomethyl pyradine (2-AMPZ) mL of hexane was added and stirred at 70° C. for 6 hours. 0150. The synthesis of 2-aminomethyl pyradine Insoluble matter was filtered off through a glass filter, the (2-AMPZ) was carried out by a method shown below, by filtrate was concentrated to give the intended material. This reference to the method described in literature (JPA 2001 was used for the next reaction without purification in particu 894594). 2-cyanopyradine used was from Sigma-Aldrich Co. lar. LLC. 0151. 1.05 g of 2-cyanopyradine (10 mmol) and 100 mg of (2) The synthesis of RuBr(S,S)-xylskewphos 60 wt %-Ni/SiO, were placed in an autoclave (SUS316) with 20 mL of toluene and replaced with argon gas. This was (O155 RuBr(S.S)-xylskewphos (methylallyl), complex pressurized with hydrogen gas to 50 atm, stirred at 140°C. for (153 mg, 0.2 mmol) was dissolved in 15 mL of acetone, 47% 4 hours. The reaction solution was filtered and concentrated HBr methanol solution (0.046 mL, 0.4 mmol) was added, to give 2-aminomethyl pyradine (2-AMPZ) quantitatively. degassed and stirred at room temperature for 30 minutes. 0152 'H-NMR spectrum (399.78 MHz, CDC1): 88.60-8. After removing the solvent, the residue was used for next 45 (m, 3H), 4.07 (s. 2H), 1.79 (br, 2H) reaction without purification. Synthetic Example 8 (3) The synthesis of RuBr(S.S)-xylskewphos(3,4- Synthetic Example of RuBr(S.S)-xylskewphos Mepica) (3.4-Me pica) 0156. In a 50 mL Schlenk tube RuBr(S,S)-xylskewphos 0153 (1) The synthesis of RuBr(S.S)-xylskewphos complex (163 mg. 0.2 mmol) and 2-aminomethyl-3,4-dim (methyl allyl) ethylpyridine (27.3 mg. 0.2 mmol) were placed, and replaced 0154) To an argon-replaced 50 mL Schlenk tube (S,S)- with argon gas. Then dimethylformamide (5 mL) was added, XylSKEWPHOS (110 mg, 0.2 mol) and Ru(cycloocta-1,5- degassed and stirred overnight at room temperature. The reac US 2015/003 1920 A1 Jan. 29, 2015
tion solution was filtered through a glass filter filled with while measuring by a Syringe, pressurized with hydrogen to silica gel, then the solvent was removed to give 184 mg of 10 atm, stirred at 40°C. for 19 hours, then the reduction of the RuBr(S,S)-xylskewphos (3.4-Me-pica) (97% yield). hydrogen pressure was confirmed and phenylethanol was (O157 P-NMR spectrum (161.7 MHz, CD):863.7 (d. obtained at 100% yield. The optical purity was 88.0% ee as J=44 Hz), 45.7 (d. J=43 Hz) measured by GC (CP-Chirasil-DEXCB (0.25 mml. Dx25m, DF=0.25um, from VARIAN), constant at 110°C., pressure: Synthetic Examples 9 to 14 102.0 kPa, column flow: 1.18 mL/min, vaporizing chamber temperature: 250° C., detector temperature: 275° C., the The Synthesis of Ruthenium XylSKEWPHOS retention time of each enantiomer was: (R): 11.7 min, (S): Complexes with Various PICA Ligands 12.4 min), and (S) isomer has predominantly been generated. 0158. The ruthenium complexes with other amine ligands were synthesized in similar way as Synthetic Example 8 (3) Comparative Example 1 except that amine ligands synthesized in Synthetic Examples 1 to 7 were used instead of 3.4-MePICA. The yield was 0.161 The reaction was carried out in similar way as Work almost quantitative. The results are summarized in the Table ing Example 1 except that the complex was changed to RuBra below. (S,S)-xylskewphos (pica). After the reaction, the reduction TABLE 2 P-NMR spectrum Complexes Amine ligands (161.83 MHz, CD) Synthetic RuBr(S,S)-skewphos N 8 63.6 ppm (d, J = 39 Hz), Example (3,5-Me-pica) n NH2 43.3 ppm (d, J = 44 Hz) 9 2 Synthetic RuBr(S,S)-skewphos N 8 62.9 ppm (d, J = 44 Hz), Example (1-amiq) 43.4 ppm (d, J = 44 Hz) 10 2N
NH2 Synthetic RuBr(S,S)-skewphos 8 63.4 ppm (d, J = 44 Hz), Example (3-amiq) N NH2 43.8 ppm (d, J = 44 Hz) 1 2N Synthetic RuBr(S,S)-skewphos N 8 60.2 ppm (d, J = 48 Hz), Example (2-amq) N NH2 45.3 ppm (d, J = 44 Hz) 2 21 Synthetic RuBr(S,S)-skewphos N 8 61.0 ppm (d, J = 44 Hz), Example (2-ampz) n NH2 42.5 ppm (d, J = 44 Hz) 3 2 N Synthetic RuBr(S,S)-skewphos N 8 62.5 ppm (d, J = 44 Hz), Example (2-ampr) N 44.3 ppm (d, J = 44 Hz) 4 N^n, 2 N
Working Example 1 in hydrogen pressure was confirmed, and phenylethanol was obtained at 100% yield. The optical purity was 80.3% ee as The Hydrogenating Reaction of Acetophenone measured under the analysis condition described in Working Example 1, and (S) isomer has predominantly been gener 0159. Acetophenone used was the guaranteed reagent ated. from KANTO CHEMICAL CO., INC., which was used directly. Working Examples 2 to 6 (0160. In an autoclave, 1.32 mg of RuBr(S.S)-xylskew 0162 The experiment was carried out in similar way as phos (3.5-Me-pica) (1.29x10 mmol, S/C=10000) and 5.79 Working Example 1 except that the reaction solvent and sub mg of potassium tert-butoxide (5.16x10 mmol) are placed, strate were changed as indicated in the Table below. The and replaced with argon gas. Under argon gas flow, 1.5 mL of results are summarized in the Table below, which also acetophenone (12.9 mmol) and 2.9 mL of ethanol was added describes the results from Working Example 1. US 2015/003 1920 A1 Jan. 29, 2015 15
TABLE 3 Ketone Reaction Yield Optical purity Absolute Analysis substrate solvate (%) (% ee) configuration condition Working O ethanol 100 88.0 S Example 1
Working C O ethanol 100 96.2 Example 2
Working C O 2-propanol 100 95.8 Example 3
Working O ethanol 100 82.5 Example 4
C
Working F O ethanol 100 91.4 Example 5
Working OMe O 2-propanol 93 98.9 Example 6
(Analysis Condition A) retention time of each enantiomer was: (R): 8.1 min, (S): 8.5 1. (0163 GC (CP-Chirasil-DEX CB (0.25 mml. Dx25 m, DF=0.25um, from VARIAN)), constant at 140°C., pressure: (Analysis Condition D) 102.0 kPa, column flow: 1.04 mL/min, vaporizing chamber (0166 GC(CP-Chirasil-DEX CB (0.25 mml. Dx25 m, temperature: 250° C., detector temperature: 275° C., the DF=0.25 um, from VARIAN)), 110° C. (50 min hold)-(2° retention time of each enantiomer was: (R): 9.1 min, (S): 10.3 C./min)-140°C. (5 min hold), pressure: 102.0 kPa, column 1. flow: 1.18 mL/min, vaporizing chamber temperature: 250° C., detector temperature: 275°C., the retention time of each (Analysis Condition B) enantiomer was: (S): 39.5 min, (R): 44.1 min. (0164 GC (CP-Chirasil-DEX CB (0.25 mml. Dx25 m, Comparative Examples 2 to 7 DF=0.25um, from VARIAN)), constant at 140°C., pressure: 0167. The reaction was carried out in similar way as Work 102.0 kPa, column flow: 1.04 mL/min, vaporizing chamber ing Example 1 except that the complex was changed to RuBra temperature: 250° C., detector temperature: 275° C., the (S,S)-Xylskewphos (pica), and the reaction solvent and Sub retention time of each enantiomer was: (R): 9.9 min, (S): 10.6 strate were changed as indicated in the Table below. The 1. results are summarized in the Table below, which also describes the results from Comparative Example 1. Analysis (Analysis Condition C) conditions indicated in the Table is the same as the Table (0165 GC (CP-Chirasil-DEX CB (0.25 mml. Dx25 m, provided from Working Examples 1 to 6. From the results, it DF=0.25um, from VARIAN)), constant at 120°C., pressure: is clear that RuBr(S.S)-xylskewphos (3.5-Me-pica) has a 102.0 kPa, column flow: 1.13 mL/min, vaporizing chamber better enantioselectivity as compared to RuBr(S.S)-xyl temperature: 250° C., detector temperature: 275° C., the skewphos (pica) complex. US 2015/003 1920 A1 Jan. 29, 2015 16
TABLE 4 Ketone Reaction Yield Optical purity Absolute Analysis Substrate solvate (%) (% ee) configuration condition Comparative O ethanol 100 80.3 S Example 2
Comparative C O ethanol 100 92.3 S A. Example 3
Comparative C O 2-propanol 100 912 S A. Example 4
Comparative O ethanol 100 70.O S B Example 5
C
Comparative F O ethanol 100 83.6 S C Example 6
Comparative OMe O 2-propanol 69 96.6 S D Example 7
Working Example 7 mL/min, 25°C., 220 nm, the retention time of each enanti omer: (S): 56.1 min, (R): 64.5 min) was 98.5% ee. The hydrogenating reaction of 2,6'-dichloro-3'-fluo roacetophenone Working Examples 8 to 13, Comparative Examples (0168 In an autoclave, 3.22 mg of RuBr(S.S)-xylskew 8, 9 phos)(3.5-Me-pica) (3.39x10 mmol, S/C=1000) and 7.62 mg of potassium tert-butoxide (6.79x10 mmol) are placed, (0169. The reaction was carried out under similar condition replaced with argon gas. Under argon gas flow, 0.5 mL of as Working Example 7 except that the type of the complex 2,6'-dichloro-3'-fluoroacetophenone (3.39 mmol, from was changed. Also, an example in which the complex was Jiangxi Jixiang Pharmachemical) and 2.9 mL of 2-propanol changed to RuBr(S.S)-Xylskewphos (pica) under the same are added while measuring with syringe, pressurized with condition is shown in Comparative Example 8, and an hydrogen to 10 atm., stirred at 40°C. for 21 hours, and the example in which the complex was changed to RuBr(S.S)- reduction of hydrogen pressure was confirmed and (S)-1-(2, skewphos (pica) is shown in Comparative Example 9. It was 6-dichloro-3-fluorophenyl)ethanol was obtained at 100% elucidated that the use of the ligand described in the general yield. The optical purity measured by HPLC (DAICEL formula (3) improves the enantioselectivity as compared to CHRALPAK AD-RH, acetonitrile/water=25/75, 0.5 the ruthenium complex with known PICA-type ligand.
US 2015/003 1920 A1 Jan. 29, 2015 ethyl)-4,5-di n-propylpyridine, 2-(aminomethyl)-4,6-di 5-diphenylpyridine, 2-(1-aminoethyl)-4,6-diphenylpyridine, n-propylpyridine, 2-(aminomethyl)-5,6-din-propylpyridine, 2-(1-aminoethyl)-5,6-diphenylpyridine, 2-(1-aminoethyl) 2-(aminomethyl)-3,4-diisopropylpyridine, 2-(aminom quinoline, 1-(1-aminoethyl)isoquinoline, 3-(1-aminoethyl) ethyl)-3,5-diisopropylpyridine, 2-(aminomethyl)-3,6-diiso isoquinoline, 2-(1-aminoethyl)pyradine, 2-(1-aminoethyl) propylpyridine, 2-(aminomethyl)-4,5-diisopropylpyridine, pyrimidine and 6-(1-aminoethyl)phenanthridine. 2-(aminomethyl)-4,6-diisopropylpyridine, 2-(aminom 9. A method for producing optically active secondary alco ethyl)-5,6-diisopropylpyridine, 2-(aminomethyl)-3,4-di hols, the method comprising: n-butylpyridine, 2-(aminomethyl)-3,5-di n-butylpyridine, reacting a substrate carbonyl compound, provided that 2-(aminomethyl)-3,6-di n-butylpyridine, 2-(aminomethyl)- 3-quinuclidinone, 3-quinuclidinone derivative having a 4,5-din-butylpyridine, 2-(aminomethyl)-4,6-din-butylpyri Substituent, and a ketone having an aromatic hydrocar dine, 2-(aminomethyl)-5,6-di n-butylpyridine, 2-(aminom bon group and a heterocycle are excluded, with hydro ethyl)-3,4-diisobutylpyridine, 2-(aminomethyl)-3,5- gen and/or a hydrogen donating compound in the pres disobutylpyridine, 2-(aminomethyl)-3,6-diisobutylpyridine, ence of one or more complexes selected from the 2-(aminomethyl)-4,5-diisobutylpyridine, 2-(aminomethyl)- compounds expressed by following general formula (4): 4,6-diisobutylpyridine, 2-(aminomethyl)-5,6-diisobutylpyri RuxYA (4); dine, 2-(aminomethyl)-3,4-ditert-butylpyridine, 2-(aminom where, ethyl)-3,5-ditert-butylpyridine, 2-(aminomethyl)-3,6-ditert X and Y are the same or different from each other and butylpyridine, 2-(aminomethyl)-4,5-di tert-butylpyridine, denote a hydrogen or an anionic group, 2-(aminomethyl)-4,6-di tert-butylpyridine, 2-(aminom A denotes an optically active diphosphine expressed by ethyl)-5,6-di tert-butylpyridine, 2-(aminomethyl)-3,4-diphe following general formula (2): nylpyridine, 2-(aminomethyl)-3,5-diphenylpyridine, 2-(ami nomethyl)-3,6-diphenylpyridine, 2-(aminomethyl)-4,5- diphenylpyridine, 2-(aminomethyl)-4,6-diphenylpyridine, (2) 2-(aminomethyl)-5,6-diphenylpyridine, 2-(aminomethyl) quinoline, 1-(aminomethyl)isoquinoline, 3-(aminomethyl) isoquinoline, 2-2-(aminomethyl)pyradine, 2-(aminomethyl) pyrimidine, 6-aminomethylphenanthridine, 2-(1- aminoethyl)-3,4-dimethylpyridine, 2-(1-aminoethyl)-3,5- dimethylpyridine, 2-(1-aminoethyl)-3,6-dimethylpyridine, 2-(1-aminoethyl)-4,5-dimethylpyridine, 2-(1-aminoethyl)-4, 6-dimethylpyridine, 2-(1-aminoethyl)-5,6-dimethylpyridine, R" and Rare the same or different from each other and 2-(1-aminoethyl)-3,4,5-trimethylpyridine, 2-(1-aminoet denotes a C1-20 chained or cyclic hydrocarbon group hyl)-3,5,6-trimethylpyridine, 2-(1-aminoethyl)-4,5,6-trim which may have a substituent; ethylpyridine, 2-(1-aminoethyl)-3,4,5,6-tetramethylpyri Rand Rare the same or different from each other and dine, 2-(1-aminoethyl)-3,4-diethylpyridine, 2-(1- denote a hydrogen atom or a C1-3 hydrocarbon aminoethyl)-3,5-diethylpyridine, 2-(1-aminoethyl)-3,6- group; diethylpyridine, 2-(1-aminoethyl)-4,5-diethylpyridine, 2-(1- R. R. R7 and Rare the same or different from each aminoethyl)-4,6-diethylpyridine, 2-(1-aminoethyl)-5,6- other and denote a hydrocarbon group which may diethylpyridine, 2-(1-aminoethyl)-3,4-di n-propylpyridine, have a Substituent; 2-(1-aminoethyl)-3,5-din-propylpyridine, 2-(1-aminoethyl)- * expresses an asymmetric carbon atom; and, 3,6-di n-propylpyridine, 2-(1-aminoethyl)-4,5-di n-propy one or more amine compound selected from the com lpyridine, 2-(1-aminoethyl)-4,6-di n-propylpyridine, 2-(1- pounds expressed by following general formula (3): aminoethyl)-5,6-din-propylpyridine, 2-(1-aminoethyl)-3,4- diisopropylpyridine, 2-(1-aminoethyl)-3,5- diisopropylpyridine, 2-(1-aminoethyl)-3,6- (3) diisopropylpyridine, 2-(1-aminoethyl)-4,5- R11 R10 diisopropylpyridine, 2-(1-aminoethyl)-4,6- D diisopropylpyridine, 2-(1-aminoethyl)-5,6- D1N NHR'. diisopropylpyridine, 2-(1-aminoethyl)-3,4-di n-butylpyridine, 2-(1-aminoethyl)-3,5-di n-butylpyridine, (R)- 2 N 2-(1-aminoethyl)-3,6-din-butylpyridine, 2-(1-aminoethyl)- na 4,5-din-butylpyridine, 2-(1-aminoethyl)-4,6-din-butylpyri dine, 2-(1-aminoethyl)-5,6-din-butylpyridine, 2-(1-aminoet where hyl)-3,4-diisobutylpyridine, 2-(1-aminoethyl)-3,5- each D is independently selected as a carbon atom or disobutylpyridine, 2-(1-aminoethyl)-3,6-diisobutylpyridine, nitrogen atom; 2-(1-aminoethyl)-4,5-diisobutylpyridine, 2-(1-aminoethyl)- R. R'' and R'' are the same or different from each 4,6-diisobutylpyridine, 2-(1-aminoethyl)-5,6-diisobutylpyri other, denote a hydrogen atom or a C1-20 chained or dine, 2-(1-aminoethyl)-3,4-di tert-butylpyridine, 2-(1-ami cyclic hydrocarbon group which may have a substitu noethyl)-3,5-di tert-butylpyridine, 2-(1-aminoethyl)-3,6-di ent, and/or, R'' and R'' are connected to each other to tert-butylpyridine, 2-(1-aminoethyl)-4,5-di tert-butylpyri form a saturated or unsaturated hydrocarbon ring or dine, 2-(1-aminoethyl)-4,6-di tert-butylpyridine, 2-(1-ami heterocycle which may have a substituent; noethyl)-5,6-di tert-butylpyridine, 2-(1-aminoethyl)-3,4- each R' is the same or different from each other and diphenylpyridine, 2-(1-aminoethyl)-3,5-diphenylpyridine, denotes a C1-20 chained or cyclic hydrocarbon group 2-(1-aminoethyl)-3,6-diphenylpyridine, 2-(1-aminoethyl)-4, which may have a Substituent, and/or, the adjacent US 2015/003 1920 A1 Jan. 29, 2015 20
R" are connected to each other to form a saturated or unsaturated hydrocarbon ring or heterocycle which may have a Substituent; R' may at least partly be bound to ruthenium as an anionic group X; and, n is an integerranging from 0 to (4-(the number of D that are nitrogen atoms)), provided that n is an integer ranging from 2 to 4 when the number of D that are nitrogen atoms is 0. 10. The method of claim 1, wherein the reacting includes reacting the Substrate carbonyl compound with hydrogen. 11. The method of claim 1, wherein the reacting includes reacting the Substrate carbonyl compound with hydrogen in the presence of a base. k k k k k