Technical Field
The present invention relates to novel ruthenium-diamine complexes, and methods for
selectively producing an optically active alcohol and an optically active amine, which are important as
precursors for the syntheses of pharmaceutical products and functional materials, by using the
10 complexes as catalysts.
Background Art
Numerous asymmetric reactions including asymmetric reduction have been developed, and
there have been many reports on asymmetric reactions which use an asymmetric metal complex having
15 an optically active phosphine ligand as a catalyst that is used in those asymmetric reactions. On the
other hand, it has been frequently reported that, for example, a complex in which an optically active
nitrogen compound is coordinated to a transition metal such as ruthenium, rhodium or iridium, has
excellent performance as a catalyst for asymmetric synthesis reactions. Thus, a wide variety of
optically active nitrogen compounds have been hitherto developed in order to enhance the performance
20 of this catalyst (Non-Patent Literatures 1,2, 3 and 4).
Among others, M. Wills et al. have reported complexes in which a diamine moiety and an
aromatic compound (arene) portion coordinating a ruthenium complex are linked via a carbon chain, and
these complexes are known to exhibit a higher activity as compared with conventional catalysts
(Non-Patent Literatures 5, 6, 7, 8, 9 and 10).
25
Citation List
Non Patent Literature
NPL 1: Chem Rev. (1992) p. 1051
NPL 2: J. Am. Chem. Soc. 117 (1995) p. 7562
30 NPL3: J.Am. Chem. Soc. 118 (1996) p. 2521
NPL4: J.Am. Chem. Soc. 118 (1996)p. 4916
NPL 5: J.Am. Chem. Soc. 127 (2005) p. 7318
NPL 6: J. Org. Chem. 71 (2006) p. 7035
NPL 7: Org. Biomol. Chem. 5 (2007) p. 1093
35 NPL 8: Org. Lett. 9 (2007) p. 4659
NPL 9: J. Organometallic. Chem. 693 (2008) p. 3527
NPL 10: Dalton. Trans. 39 (2010) p. 1395
Summary of Invention
40 Technical Problem
However, in the conventional methods using these complexes, the catalytic activity and the
enantiomeric excess may be insufficient depending on the subject reaction or the reaction substrate, and
development of new complexes is desired. Furthermore, even the methods for synthesizing those
complexes are complicated, or are of low yield, so that many of the methods cause problems in
45 industrial applications and the like.
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WO 2012/026201 PCT/JP2011/064490
The present invention was made to solve such problems.
Solution to Problem
In order to solve the problems described above, the inventors of the present invention paid
5 attention to the chain-like moiety that links the aromatic compound (arene) portion and the diamine
moiety that are coordinated to a ruthenium complex having an optically active diamine, and the
inventors found that when the chain-like moiety is constructed as a chain-like moiety having a
heteroatom, there is obtained a novel ruthenium-diamine complex which has a high catalytic activity and
a satisfactory enantiomeric excess, and which can be produced by a simple method and is appropriate
10 for industrial use.
That is, the present invention relates to a ruthenium complex represented by the formula (1)
shown below, a method for producing the ruthenium complex, a catalyst for asymmetric reduction
formed from the ruthenium complex, and methods for selectively producing an optically active alcohol
and an optically active amine using the catalyst for asymmetric reduction.
15 The present invention includes the following matters.
[1] Aruthenium complex represented by the following formula (1):
[Chem. 1]
(1)
wherein symbol * represents an asymmetric carbon atom;
20 R1 represents an alkyl group having 1 to 10 carbon atoms; a halogenated alkyl group having 1
to 10 carbon atoms; 10-camphoryl group; an amino group which may be substituted with one or two
alkyl group having 1 to 10 carbon atoms; an aryl group which may be substituted with an alkyl group
having 1 to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon atoms, a halogen atom, a
cyano group (-CN), an amino group, an alkylated amino group (-NR20R21), a five or six membered
25 cyclic amino group, an acylated amino group (-NH-CO-R20), a hydroxyl group, an alkoxy group (-OR20),
an acyl group (-CO-R20), a carboxyl group, an alkoxycarbonyl group (-COOR20), a phenoxy carbonyl
group, a mercapto group, an alkylthio group (-SR20), a silyl group (-SiR2^2^22), or a nitro group
(-N02); R20, R21 and R22 each independently represent a hydrogen atom , an alkyl group having 1 to 10
carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms;
30 Y represents a hydrogen atom;
X represents a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, a
methanesulfonyloxy group, a benzenesulfonyloxy group, a hydrogen atom, or a halogen atom;
j and k each represent 0 or 1, but j+k is not 1;
R2 and R3 each independently represent a hydrogen atom; an alkyl group having 1 to 10 carbon
35 atoms; a phenyl group which may be substituted with an alkyl group having 1 to 10 carbon atoms, an
alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8
carbon atoms, or R2 and R3 may be joined together to form a ring;
Rn, R12, R13, R14 and R15 each independently represent a hydrogen atom, an alkyl group having
2
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WO 2012/026201 PCT/JP2011/064490
1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms;
R16, R17, R18 and R19 each independently represent a hydrogen atom, a hydroxyl group, an alkyl
group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms, or R16 and R17 with
the carbon atom which is substituted with R16 and R17, and/or R18 and R19 with the carbon atom which is
substituted with R18 and R19 may form a carbonyl group(s);
Z represents an oxygen atom or a sulfur atom; and
ni represents 1 or 2, and n2 represents an integer from 1 to 3.
[2] A ruthenium complex represented by the following formula (2):
[Chem. 2]
( Q 0 ) (2)
R3 R181
wherein symbol * represents an asymmetric carbon atom;
R1 represents an alkyl group having 1 to 10 carbon atoms; a halogenated alkyl group having 1
to 10 carbon atoms; 10-camphoryl group; an amino group which may be substituted with one or two
alkyl group having 1 to 10 carbon atoms; an aryl group which may be substituted with an alkyl group
15 having 1 to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon atoms, a halogen atom, a
cyano group (-CN), an amino group, an alkylated amino group (-NR20R21), a five or six membered
cyclic amino group, an acylated amino group (-NH-CO-R20), a hydroxyl group, an alkoxy group (-OR20),
an acyl group (-CO-R20), a carboxyl group, an alkoxycarbonyl group (-COOR20), a phenoxy carbonyl
group, a mercapto group, an alkylthio group (-SR20), a silyl group (-SiR2^2^22), or a nitro group
20 (-NO2); R20, R21 and R22 each independently represent a hydrogen atom, an alkyl group having 1 to 10
carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms;
Y represents a hydrogen atom;
R2 and R3 each independently represent a hydrogen atom; an alkyl group having 1 to 10 carbon
atoms; a phenyl group which may be substituted with an alkyl group having 1 to 10 carbon atoms, an
25 alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8
carbon atoms, or R2 and R3 may be joined together to form a ring;
Rn, R12, R13, R14 and R15 each independently represent a hydrogen atom, an alkyl group having
1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms;
R16, R17, R18 and R19 each independently represent a hydrogen atom, a hydroxyl group, an alkyl
30 group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms, or R16 and R17 with
the carbon atom which is substituted with R16 and R17, and/or R18 and R19 with the carbon atom which is
substituted with R18 and R19 may form a carbonyl group(s);
Z represents an oxygen atom or a sulfur atom;
Q represents a counter anion; and
35 ni represents 1 or 2, and n2 represents an integer from 1 to 3.
[3] A ruthenium complex represented by the following formula (3):
[Chem. 3]
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(3)
R18 R19
wherein symbol * represents an asymmetric carbon atom;
R1 represents an alkyl group having 1 to 10 carbon atoms; a halogenated alkyl group having 1
to 10 carbon atoms; 10-camphoryl group; an amino group which may be substituted with one or two
5 alkyl group having 1 to 10 carbon atoms; an aryl group which may be substituted with an alkyl group
having 1 to 10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon atoms, a halogen atom, a
cyano group (-CN), an amino group, an alkylated amino group (-NR20R21), a five or six membered
cyclic amino group, an acylated amino group (-NH-CO-R20), a hydroxyl group, an alkoxy group (-OR20),
an acyl group (-CO-R20), a carboxyl group, an alkoxycarbonyl group (-COOR20), a phenoxy carbonyl
10 group, a mercapto group, an alkylthio group (-SR20), a silyl group (-SiR^R^R22), or a nitro group
(-N02); R , R and R each independently represent a hydrogen atom, an alkyl group having 1 to 10
carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms;
Y represents a hydrogen atom;
R2 and R3 each independently represent a hydrogen atom; an alkyl group having 1 to 10 carbon
15 atoms; a phenyl group which may be substituted with an alkyl group having 1 to 10 carbon atoms, an
alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8
carbon atoms, or R2 and R3 may be joined together to form a ring;
R11, R12, R13, R14 and R15 each independently represent a hydrogen atom, an alkyl group having
1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms;
20 R16, R17, R18 and R19 each independently represent a hydrogen atom, a hydroxyl group, an alkyl
group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms, or R16 and R17 with
the carbon atom which is substituted with R16 and R17, and/or R18 and R19 with the carbon atom which is
substituted with R18 and R19 may form a carbonyl group(s);
Z represents an oxygen atom or a sulfur atom;
25 V represents a halogen atom; and
n! represents 1 or 2, and n2 represents an integer from 1 to 3.
[4] A method for producing a reduction product by reducing an organic compound in the presence of the
ruthenium complex as set forth in any one of [1] to [3] and a hydrogen donor.
[5] A method for producing an optically active alcohol, the method comprising reducing a carbonyl
30 group of a carbonyl compound in the presence of the ruthenium complex according to any one of [1] to
[3] and a hydrogen donor.
[6] A method for producing an optically active amine, the method comprising reducing an imino group
of an imine compound in the presence of the ruthenium complex according to any one of [1] to [3] and a
hydrogen donor.
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[7] The method according to any one of [4] to [6], wherein the hydrogen donor is selected from formic
acid, a formic acid alkali metal salt, and an alcohol having a hydrogen atom on the a-position carbon
atom substituted with a hydroxyl group.
[8] The method according to any one of [4] to [6], wherein the hydrogen donor is hydrogen.
5 [9] A catalyst for reduction, comprising the ruthenium complex according to any one of [1] to [3].
[10] The catalyst for reduction according to [9], wherein the catalyst for reduction is a catalyst for
asymmetric reduction.
Advantageous Effects of Invention
10 The present invention is to provide a novel ruthenium-diamine complexes having a heteroatom
introduced into the chain-like moiety that links the aromatic compound (arene) portion and the diamine
moiety that are coordinated to ruthenium. The ruthenium-diamine complexes of the present invention
have highly catalytic activities, can be used for the reduction of the portion of carbonyl group, imino
group and ester group are useful as catalysts for various hydrogenation reactions. Also, the complexes
15 of the present invention, in which the ligand is an optically active substance, are excellent in
stereoselectivity and give high enantiomeric excess values. Conventional complexes, in which the
arene portion and the diamine portion are linked via a carbon chain only, are highly active; however, the
conventional complexes have problems that the methods for synthesis of the complexes are complicated;
that the synthesis of the complexes utilizes the Birch reduction, by which the use of toxic ammonia gas
20 or cryogenic apparatuses is unavoidable; that the Swera oxidation must be used, in which the stench
odor of dimethyl sulfide that is produced as a side product, harmfulness of carbon monoxide, the
necessity of cryogenic apparatuses, and the like cause a problem in the application of the oxidation
process in an industrial scale; and that the complexes give low yield in some of the reactions. However,
when a heteroatom is introduced into the chain-like moiety according to the present invention, a
25 complex having a side chain that links an arene portion and a diamine portion can be synthesized more
conveniently and efficiently by using an appropriate ruthenium-arene dimer and an appropriate diamine,
and by performing a thioetherification or etherification reaction simultaneously with the formation of the
complex.
Furthermore, the ruthenium complexes of the present invention having a heteroatom
30 introduced into the chain-like moiety have higher catalytic activities as compared with the conventional
complexes which do not have a heteroatom in the corresponding chain-like moiety, and in which the
chain-like moiety is composed of a carbon chain only. When the ruthenium complexes of the present
invention are used, target substances can be obtained with high optical purity and high yield by a
hydrogen transfer reaction or a hydrogenation reaction. Particularly, the complexes of the present
35 invention in which the ligand is an optically active substance are useful as catalysts for asymmetric
reduction.
When the ruthenium-diamine complexes of the present invention are used, an optically active
alcohol or an optically active amine, which are both useful as raw materials for pharmaceutical products
and functional materials, can be selectively produced.
40
Description of Embodiments
The ruthenium complexes of the present invention represented by the formulas (1), (2), and (3)
are ruthenium complexes characterized in that an aromatic compound (arene) portion is coordinated to a
ruthenium atom, and the chain-like moiety which links the aromatic compound (arene) portion and a
45 diamine moiety has a heteroatom such as an oxygen atom or a sulfur atom introduced therein.
Furthermore, the ruthenium complexes represented by the formulas (1) and (2) are
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WO 2012/026201 PCT/JP2011/064490
characterized in that two nitrogen atoms of a diamine ligand are bonded to a ruthenium atom via
covalent bonding or coordination bonding, an aromatic compound (arene) portion that is bonded to the
diamine also has a tridentate ligand which is coordinated to the ruthenium atom, and the chain-like
moiety that links the aromatic compound (arene) portion and the diamine moiety has a heteroatom such
5 as an oxygen atom or a sulfur atom introduced therein.
The symbol * in the formulas (1), (2) and (3) represents that the carbon atom to which the
symbol * is attached may optionally become an asymmetric carbon atom. When the carbon atom
becomes an asymmetric carbon atom, the resultant products may be optically active substances of the
ruthenium complexes, may be mixtures of optically active substances, or may be racemates (including
10 racemic compounds). In a preferred embodiment of the present invention, when these carbon atoms
become asymmetric carbon atoms, the resultant products may be optically active substances of the
ruthenium complexes.
Furthermore, the ruthenium complexes represented by the formula (2) is ruthenium complexes
in the case where the Ru-X bond in the ruthenium complexes represented by the formula (1) become an
15 ionic bond of Ru+-Q".
The ruthenium complex represented by the formula (3) is a dimer interrupted by a halogen
atom V, and is a complex in which an aromatic compound (arene) portion is coordinated to a ruthenium
atom. The ruthenium complex represented by the formula (3) is a ruthenium complex which is not
only useful as an intermediate in the production of a ruthenium complex represented by the formula (1)
20 or (2), but also has an activity as a reducing catalyst per se.
In regard to the formulas (1), (2), and (3) of the present invention, the alkyl group having 1 to
10 carbon atoms represented by R1 may be a linear or branched alkyl group having 1 to 10 carbon atoms,
and preferably 1 to 5 carbon atoms. Specific examples of the alkyl group include a methyl group, an
ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl
25 group, a t-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an
n-nonyl group, and an n-decyl group.
In regard to the formulas (1), (2), and (3) of the present invention, the halogenated alkyl group
having 1 to 10 carbon atoms represented by R1 is an alkyl group having 1 to 10 carbon atoms, in which a
linear or branched alkyl group described above such as, for example, a methyl group, an ethyl group, an
30 n-propyl group, an isopropyl group, an n-butyl group or an n-hexyl group, is substituted with one or
more of halogen atoms such as a fluorine atom, a chlorine atom and a bromine atom. Examples the
halogenated alkyl group include perfluoroalkyl groups such as a trifluoromethyl group, a
pentafluoromethyl group, and a heptafluoropropyl group.
In regard to the formulas (1), (2), and (3) of the present invention, the aryl group of the aryl
35 group which is optionally substituted with an alkyl group having 1 to 10 carbon atoms, a halogenated
alkyl group having 1 to 10 carbon atoms, a halogen atom, a cyano group (-CN), an amino group, an
alkylated amino group (-NR20R21), a five or six membered cyclic amino group, an acylated amino group
(-NH-CO-R20), a hydroxyl group, an alkoxy group (-OR20), an acyl group (-CO-R20), a carboxyl group,
an alkoxycarbonyl group (-COOR20), a phenoxy carbonyl group, a mercapto group, an alkylthio group
40 (-SR20), a silyl group (-SiR2^2^22), or a nitro group (-N02), as represented by R1, may be a
monocyclic, polycyclic or fused-ring aryl group having 1 to 20 carbon atoms, and preferably 6 to 12
carbon atoms, such as a phenyl group or a naphthyl group. The alkyl group having 1 to 10 carbon
atoms may be the same alkyl group as defined above. The halogenated alkyl group having 1 to 10
carbon atoms may be the same halogenated alkyl group as defined above, for example, a perfluoroakyl
45 group. The halogen atom may be a fluorine atom, a chlorine atom or the like.
The alkylated amino group is represented by the formula -NR20R21, wherein R20 and R21 each
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independently represent a hydrogen atom,an alkyl group having 1 to 10 carbon atoms or cycloalkyl
group having 3 to 10 carbon atoms. Examples of the alkylated amino group, include mono- or
di-alkylamino groups such as N-methylamino, N,N-dimethylamino, N,N-diethylamino,
N,N-diisopropylamino or N-cyclohexylamino groups, or the like.
5 The five- or six-membered cyclic amino group is a 5 or 6-membered saturated or unsaturated
heterocyclic group having one or two basic nitrogen atoms. Examples of the five- or six-membered
cyclic amino group include a pyrrolidino group, piperidino group or a morpholino group, or the like.
The acyl group is represented by the formula -CO-R20, wherein R20 represent a hydrogen atom,
an alkyl group having 1 to 10 carbon atoms or cycloalkyl group having 3 to 10 carbon atoms. Examples
10 of the acyl group, include formyl, acetyl, propionyl, butyryl, pivaloyl, pentanoyl or hexanoyl, or the like.
The acylated amino group is represented by the formula -NH-CO-R20, wherein R20 represent a
hydrogen atom, an alkyl group having 1 to 10 carbon atoms or cycloalkyl group having 3 to 10 carbon
atoms. Examples of the acylated amino group, include formylamino, acetylamino, propionylamino,
pivaloylamino, pentanoylamino or hexanoylamino, or the like.
15 The alkoxy group is represented by the fomula -OR20, wherein R20 represent a hydrogen atom, an
alkyl group having 1 to 10 carbon atoms or cycloalkyl group having 3 to 10 carbon atoms, for example,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, t-butoxy, n-pentyloxy,
2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropyloxy, n-hexyloxy, 2-methylpentyloxy,
3-methylpentyloxy, 4-methylpentyloxy, 5-methylpentyloxy or cyclohexyloxy groups, or the like.
20 The alkoxycarbonyl group is represented by the formula -COOR20, wherein R20 represent a
hydrogen atom, an alkyl group having 1 to 10 carbon atoms or cycloalkyl group having 3 to 10 carbon
atoms, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,
n-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl or 2-ethylhexyloxycarbonyl,
or the like.
25 The alkylthio group is represented by the formula -SR20, wherein R20 represent a hydrogen atom,
an alkyl group having 1 to 10 carbon atoms or cycloalkyl group having 3 to 10 carbon atoms, for
example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, s-butylthio, isobutylthio,
t-butylthio, pentylthio, hexylthio or cyclohexylthio groups, or the like.
The silyl group is represented by the formula -SiR20R21R22, wherein R20, R21 and R22 each
30 independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or cycloalkyl
group having 3 to 10 carbon atoms, for example, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl or triphenylsilyl groups, or the like.
The cycloalkyl group having 3 to 10 carbon atoms is a monocyclic, polycyclic or fused-ring,
and saturated or unsaturated 3 to 7-membered cycloalkyl group having 3 to 10 carbon atoms.
35 Examples of such an aryl group include a phenyl group, an o-, m- or p-tolyl group, an o-, m- or
p-ethylphenyl group, an o-, m- or p-isopropylphenyl group, an o-, m- or p-t-butylphenyl group, a
2,4,6-trimethylphenyl group, a 3,5-xylyl group, a 2,4,6-triisopropylphenyl group, an o-, m- or
p-trifluoromethylphenyl group, an o-, m- or p-fluorophenyl group, an o-, m- or p-chlorophenyl group,
and a pentafluorophenyl group.
40 In regard to the formulas (1), (2), and (3) of the present invention, the alkyl group having 1 to
10 carbon atoms represented by R2 and R3 may be a linear or branched alkyl group having 1 to 10
carbon atoms, and preferably 1 to 5 carbon atoms. Specific examples of the alkyl group include a
methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl
group, an s-butyl group, a t-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an
45 n-octyl group, an n-nonyl group, and an n-decyl group.
In regard to the formulas (1), (2), and (3) of the present invention, the alkyl group of the phenyl
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group which may be substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group
having 1 to 10 carbon atoms, or a halogen atom, as represented by R2 and R3, may be, for example, the
same alkyl group as defined above. Examples of the halogen atom include a fluorine atom, a chlorine
atom, and a bromine atom.
5 The alkoxy group having 1 to 10 carbon atoms may be a linear or branched alkoxy group
having 1 to 10 carbon atoms, and preferably 1 to 5 carbon atoms. Specific examples of the alkoxy
group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an
n-butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, an n-pentyloxy group, an
n-hexyloxy group, an n-heptyloxy group, an n-octyloxy group, an n-nonyloxy group, and an n-decyloxy
10 group.
In regard to the formulas (1), (2), and (3) of the present invention, the cycloalkyl group having
3 to 8 carbon atoms as represented by R2 and R3 may be a monocyclic, polycyclic or bridged cycloalkyl
group having 3 to 8 carbon atoms, and preferably 5 to 8 carbon atoms. Specific examples of the
cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl
15 group, a cycloheptyl group, and a cyclooctyl group. These cycloalkyl groups may be substituted with
an alkyl group such as a methyl group, an isopropyl group or a t-butyl group, or the like.
Furthermore, when R2 and R3 are joined together to form a ring, R2 and R3 are joined to form a
linear or branched alkylene group having 2 to 10 carbon atoms, and preferably 3 to 10 carbon atoms, and
the resulting alkylene group forms, together with adjacent carbon atoms, a 4- to 8-membered, and
20 preferably 5- to 8-membered, cycloalkane ring. Preferred examples of the cycloalkane ring include a
cyclopentane ring, a cyclohexane ring, and a cycloheptane ring, and these rings may each have an alkyl
group such as a methyl group, an isopropyl group or a t-butyl group as a substituent.
In regard to the arene moiety represented by the formulas (1), (2), and (3) of the present
invention, R11, R12, R13, R14 and R15 each independently represent a hydrogen atom, an alkyl group
25 having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms. The alkyl group may be
the same alkyl group as defined above, and specific examples of the alkyl group include a methyl group,
an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl
group, a t-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an
n-nonyl group, and an n-decyl group.
30 The alkoxy group may be the same linear or branched alkoxy group as defined above, and
specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group,
an isopropoxy group, an n-butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, an
n-pentyloxy group, an n-hexyloxy group, an n-heptyloxy group, an n-octyloxy group, an n-nonyloxy
group, and an n-decyloxy group.
35 R16, R17, R18 and R19 representing the substituents substituted on the carbon atoms of the
chain-like moiety that links the arene portion and the diamine moiety represented by the formulas (1),
(2), and (3), each independently represent a hydrogen atom, a hydroxyl group, an alkyl group having 1
to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms. The alkyl group may be the same
alkyl group as defined above, and specific examples thereof include a methyl group, an ethyl group, an
40 n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl
group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, and
an n-decyl group.
The alkoxy group may be the same linear or branched alkoxy group as defined above, and
specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group,
45 an isopropoxy group, an n-butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, an
n-pentyloxy group, an n-hexyloxy group, an n-heptyloxy group, an n-octyloxy group, an n-nonyloxy
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group, and an n-decyloxy group.
Preferred examples of the -(-C(R16)R17-)ni- group include a -CH2- group, a -CH(CH3)- group,
and a -CO- group, but the -(-C(R16)R,7-)ni- group is not intended to be limited to these.
Z in the formulas (1), (2), and (3) represents an oxygen atom (-O-) or a sulfur atom (-S-).
5 k and j in the formula (1) each represent an integer of 0 or 1, and the sum j+k is not equal to 1.
That is, when k is 1, j is also 1, and when k is 0, j is also 0. When k is 1, Y represents a hydrogen atom.
When j in the formula (1) is 1, X may be a hydrogen atom or a halogen atom, but X is
preferably a halogen atom. Specifically, a preferred example of X is a chlorine atom.
The hydrogen atom of Y in the formulas (1), (2) and (3) and of X in the formula (1) may be an
10 ordinary hydrogen atom, and may also be an isotope of a hydrogen atom. A preferred example of the
isotope is a deuterium atom.
Qe in the formula (2) represents a counter anion. Specific examples of the counter anion
include alkyl- or arenesulfonyloxy ions such as a trifluoromethanesulfonyloxy ion (TfO"), a
p-toluenesulfonyloxy ion (TsO"), a methanesulfonyloxy ion (MsO), and a benzenesulfonyloxy ion
15 (BsO); and ions such as BF4\ SbF6", CF3COO\ CH3COO", PF6", N03", C104", SCN", OCN", Re04",
Mo04", BPlu", BCCeFsV, and B(3,5-(CF3)2C6F3)4The halogen atom represented by V in the formula (3) represents a chlorine atom, a bromine
atom or an iodine atom, and all V's may represent an identical halogen atom, or may represent a
combination of different halogen atoms.
20 The complex of the present invention can be synthesized by, for example, the method of the
following Scheme (1).
[Chem. 4]
Scheme 1
(d) (9)
In the Scheme (1), R1, R2, R3, Rn to R15, and R16 to R19 respectively represent the same
25 substituents as defined above; Y represents a hydrogen atom or a deuterium atom; and Z represents an
oxygen atom or a sulfur atom. W in the ruthenium-arene dimer (a) represents a halogen atom, or an
9
WO 2012/026201 PCT/JP2011/064490
alkanesulfonyloxy or optionally substituted arenesulfonyloxy group; and V represents a halogen atom.
nj represents an integer of 1 or 2, and n2 represents an integer from 1 to 3.
As shown in the Scheme (1), when a ruthenium-arene dimer (a) having a halogen atom or the
like at a terminal of the substituent of the arene, is reacted with a diamine (b) having a hydroxy 1 group or
5 a thiol group at a terminal of the chain-like portion substituted with a nitrogen atom that is other than the
nitrogen atom substituted with a sulfonyl group, in the presence of an appropriate base, and thereby a
thioetherification or etherification reaction is carried out simultaneously with complexation, a
ruthenium-diamine complex (d), which is the target complex, can be synthesized directly or via an
amido complex (c) as an intermediate. When the amide complex (c) is employed as an intermediate,
10 the amido complex can be converted to a diamine complex (d) or a cationic diamine complex (g) by
adding an appropriate acid to the complex (c).
Examples of the halogen atom or the alkanesulfonyloxy or optionally substituted
arenesulfonyloxy group, which is represented by W in the ruthenium-arene dimer (a), include a chlorine
atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a
15 benzenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. Furthermore, the halogen atom
represented by V may be a chlorine atom, a bromine atom or an iodine atom, and all V's may represent
an identical halogen atom, or may represent a combination of different halogen atoms.
Z in the diamine (b) represents an oxygen atom or a sulfur atom. Furthermore, Y represents a
hydrogen atom.
20 Examples of the base that is used in case of synthesizing the amido complex (c) include
inorganic bases such as LiOH, NaOH, KOH, K2C03, and Cs2C03; and metal alkoxides such as sodium
methoxide and potassium methoxide. The amount of addition of the base is 2 moles or more relative to
the amount of ruthenium atoms. There are no particular limitations on the solvent used in this case, but
ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons such as toluene and xylene;
25 halogen-containing hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; aprotic polar
solvents such as acetonitrile and N,N-dimethylformamido; and the like are preferred, while
dichloromethane and toluene are particularly preferred. Furthermore, this reaction can be carried out as
a two-layer system reaction by using water as another solvent in addition to an organic solvent. In this
case, the reaction may be carried out using a phase transfer catalyst. Examples of the phase transfer
30 catalyst used in this case include tetrabutylammonium chloride, tetrabutylammonium bromide,
tetrabutylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide,
tetraethylammonium iodide, triethylbenzylammonium chloride, triethylbenzylammonium bromide, and
triethylbenzylammonium iodide.
Examples of the acid (X-Y) used when the amido complex (c) is converted to a diamine
35 complex (d) include hydrochloric acid, hydrobromic acid, and hydriodic acid.
Similarly, the amido complex (c) can also be converted to a cationic diamine complex (g).
Examples of the acid (Q-H) used in this case include trifluoromethanesulfonic acid (TfOH),
methanesulfonic acid (MsOU), p-toluenesulfonic acid (TsOFT), benzenesulfonic acid (BsOH), HBF4,
HSbF6, CF3COOH, CH3COOH, HPF6, HNO3, HCIO4, HSCN, HOCN, HRe04, and HM0O4.
40 There are no particular limitations on the solvent used to carry out this reaction; however, after
the synthesis of the amido complex (c) described above, the amido complex (c) may be directly
subjected to a reaction, without isolating the complex, in the presence of the same solvent within the
system to be converted to the diamine complex (d) or (g), or alternatively, the amido complex (c) may be
isolated and then subjected to a reaction using an appropriate, different solvent to be converted to the
45 diamine complex (d) or the cationic diamine complex (g).
As the base used in the case of directly synthesizing the diamine complex (d), organic tertiary
10
WO 2012/026201 PCT/JP2011/064490
amines such as trimethylamine, triethylamine, triisopropylamine, and diisopropylethylamine are
preferred, and particularly, triethylamine and diisopropylethylamine are suitable. The amount of
addition of the base in this case is equimolar or greater relative to the amount of the ruthenium atoms.
There are no particular limitations on the solvent used in this case, but ethers such as diethyl
ether and tetrahydrofuran; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons
such as toluene and xylene; halogenic solvents such as dichloromethane and 1,2-dichloroehtane; aprotic
polar solvents such as acetonitrile and N,N-dimethylformamide; and the like are preferred, while
dichloromethane and isopropanol are particularly preferred.
Furthermore, as a method for synthesizing the complex of the present invention, a
ruthenium-arene dimer (e) having a hydroxyl group or a thiol group at a terminal of the substituent of
the arene, and a diamine (f) having a halogen atom or the like at a terminal of the chain-like portion
substituted at a nitrogen atom that is other than the nitrogen atom substituted with a sulfonyl group, can
also be used as raw materials, as shown in the following Scheme (2).
[Chem. 5]
Scheme 2
»»1
>13
R R "
"1
15 Z-H
1/2
R^Kii,
Ru—V
v_--ftu
17 R1
>ts
J l*
3*3
H-2' R" R"
R/ - NH
k R , 8
(f)
Q-H
Rt2
R13
RU-PR1*
R16
0
R* -4 1 W"2
R1Z
R13
R1^PR1 4
T Y f p is
R3
R«R
(Q°)
(d) (9)
(The respective symbols in Scheme (2) have the same meanings as defined in Scheme (1)).
In the Scheme (2), the positions of the hydroxyl group or thiol group and the leaving group
such as a halogen atom are the reverse of the combination used in the Scheme (1). However, the
ruthenium-diamine complex (d) or the cationic diamine complex (g), which are both target complexes,
can be similarly synthesized directly or via the amido complex (c), by allowing the hydroxyl group or
thiol group and the leaving group to react in the presence of an appropriate base, and performing a
thioetherification or etherification reaction simultaneously with complexation. When the amido
complex (c) is employed as an intermediate, the amido complex can be converted to a diamine complex
11
WO 2012/026201 PCT/JP2011/064490
(d) or a cationic diamine complex (g) by adding an appropriate acid to the complex (c). The base,
solvent and the like used in the reaction respectively have the same meanings as defined above.
Furthermore, the complex of the present invention can also be produced by a method such as
shown in the following Scheme (3).
[Chem. 6]
Scheme 3
^ V ^ . / v ^ x v ^ O H Diels-Alder reaction > s v ^S
(h) (i)
TsHN NH2
( h )
Y\ PrfVh > P j | HCI f h
( ' ) HCI (j) H NHTs
<*> X X o Jlc
N'I^Ph _ ^ _ ^ L o J*^Ph
H MHTS """ Rj -C~I H' NHTS ^ /rCA*U"k
( j) V^ (*) ^ H
(I) A compound (h) having a 1,4-cyclohexadiene skeleton is synthesized by using the
Diels-Alder reaction.
(H) The compound (h) obtained in the item (I) is subjected to tosylation or the like, and thereby
10 a compound (i) having a leaving group at a terminal is synthesized.
(HI) The compound (i) is made to react with TsDPEN
(N-(p-toluensulfonyl)-l,2-diphenylethylenediamine), and thereby a diamine (j) having cyclohexadiene is
synthesized.
(TV) The diamine (j) thus obtained is made to react with ruthenium trichloride to obtain a
15 ruthenium dimer (k) as an intermediate, and thereby the target monomer complex is obtained.
Through this method, the ruthenium complex represented by the formula (1) and (3) of the
present invention can be produced.
Furthermore, the ruthenium complexes represented by the formula (2) of the present invention
can also be produced by a method such as shown in the following Scheme (4).
20 [Chem. 7]
12
WO 2012/026201 PCT/JP2011/064490
RVPR14
M-Q R1^PRM
R3 ( Y )P R18'
(Q0 ) m
00 Cg)
As shown in the Scheme (4), the cationic diamine complex (g) can also be obtained by
allowing a diamine complex (d) in which X is a halogen atom, to react with a metal salt represented by
the formula M-Q. Examples of the metal M in the formula: M-Q include silver (Ag), sodium (Na),
5 potassium (K), and lithium (Li). Examples of the moiety Q include alkanesulfonyloxy or
arenesulfonyloxy compounds such as trifluoromethanesulfonyloxy (TfO), p-toluenesulfonyloxy (TsO),
methanesulfonyloxy (MsO), and benzenesulfonyloxy (BsO); as well as BF4, SbF6, CF3COO, CH3COO,
PF6, NO3, CIO4, SCN, OCN, Re04, M0O4, BPI14, B(C6F5)4, and B(3,5-(CF3)2C6F3)4.
Examples of the metal salt represented by the formula: M-Q include AgOTf, AgOTs, AgOMs,
10 AgOBs, AgBF4, AgSbF6, CF3COOAg, CH3COOAg, AgPF6, AgN03, AgC104, AgSCN, AgOCN,
AgRe04, AgMo04, NaOTf, NaBF4, NaSbF6, CF3COONa, CH3COONa, NaPF6, NaN03, NaC104,
NaSCN, KOTf, KBF4, KSbF6, CF3COOK, CH3COOK, KPF6, KN03, KC104, KSCN, KBPlu, KB(C6F5)4,
KB(3,5-(CF3)2C6F3)4, LiOTf, LiBF4, LiSbF6, CF3COOLi, CH3COOLi, LiPF6, LiN03, LiC104, LiSCN,
LiBPlu, LiB(C6F5)4, and LiB(3,5-(CF3)2C6F3)4.
15 The amount of the metal salt M-Q that is used in the case of synthesizing the cationic diamine
complex (g) is equimolar or greater relative to the amount of ruthenium atoms. There are no particular
limitations on the solvent used in this case, but examples of the solvent include alcohols such as
methanol, ethanol, and isopropanol; aromatic hydrocarbons such as toluene and xylene; halogenated
hydrocarbons such as dichloromethane and 1,2-dichloroethane; aprotic polar solvents such as
20 acetonitrile and N,N-dimethylformamido; and ethers such as diethyl ether and tetrahydrofuran. Among
these, methanol is preferred.
As such, the ruthenium complex of the present invention having a heteroatom introduced into
the chain-like moiety can be synthesized using an appropriate ruthenium-arene dimer and an appropriate
diamine, by carrying out a thioetherification or etherification reaction simultaneously with the formation
25 of the complex, and thereby a complex having a side chain that links the arene portion and the diamine
portion can be synthesized. Theoretically, in this reaction, the complex can be produced by allowing
the ruthenium-arene dimer to react in an equimolar amount, in terms of ruthenium, based on the diamine,
and therefore, the reaction is very efficient. Also, since the reactions used in this synthesis method are
all reaction that are carried out under the conditions ranging from normal temperature to a heating
30 condition, it is not necessary to use cryogenic apparatuses, and harmful gases and the like are not
generated. Thus, this method is a synthesis method which is very simple, safe and expedient when
synthesis is carried out in an industrial scale.
The ruthenium complex of the present invention in which X is a halogen atom can be readily
converted to a complex in which X is a hydrogen atom by bringing the ruthenium complex into contact
35 with a hydrogen donor.
13
WO 2012/026201 PCT/JP2011/064490
Here, as the hydrogen donor, those generally used as hydrogen donors in hydrogen transfer
type reduction reactions of a metal hydride such as a borohydride compound, formic acid or a salt
thereof, isopropanol and the like, can be used. The amount of use of the hydrogen donor may be an
equimolar amount or greater, in terms of hydride, relative to the amount of the catalyst. Furthermore,
5 hydrogen gas can also be used as a hydrogen donor.
Furthermore, examples of the base that is used to obtain basic conditions include organic
tertiary amines such as trimethylamine, triethylamine, and triisopropylamine; inorganic bases such as
LiOH, NaOH, KOH, and K2C03; and metal alkoxides such as sodium methoxide, and potassium
methoxide.
10 Furthermore, conversion of a halogen atom to a hydrogen atom for X in the ruthenium
complex of the present invention may be carried out in advance before the reaction system is subjected
to the asymmetric reduction reaction, or may also be carried out in the middle of the asymmetric
reduction reaction.
The production of the ruthenium complex of the present invention is usually carried out at
15 120°C or below, and preferably at 100°C or below.
The asymmetric reduction reaction may be carried out by using a compound obtained by
isolating the amido complex (c), the diamine complex (d), the cationic diamine complex (g), or the
ruthenium dimer(k) as a catalyst, or may also be carried out without isolating the complex, by directly
using the reaction liquid resulting from the production of a complex (in situ method).
20 After completion of the reaction, the intended ruthenium complex can be separated by a
general precipitation technique such as concentration of the reaction liquid or addition of a poor solvent.
Furthermore, if a hydrogen halide salt is produced as a side product during the production described
above, an operation of water washing may be performed as necessary.
The asymmetric reduction reaction of the present invention is carried out by allowing a
25 ruthenium complex represented by the formula (1) to react with a carbonyl compound or an imine in the
co-presence of a hydrogen donor. There are no particular limitations on the hydrogen donor, as long as
it is a hydrogen donor that is generally used in hydrogen transfer reduction reactions of formic acid or a
salt thereof, isopropanol which is an alcohol having a hydrogen atom on the a-position carbon atom
substituted with a hydroxyl group, and the like. Furthermore, hydrogen gas can also be used as the
30 hydrogen donor. Also, it is preferable that the asymmetric reduction reaction be carried out in the
presence of a base. Examples of the base include organic tertiary amines such as trimethylamine,
triethylamine, triisopropylamine, l,4-diazabicyclo[2,2,2]octane (DABCO), and
l,8-diazabicyclo[5,4,0]undec-7-ene (DBU); and inorganic bases such as LiOH, NaOH, KOH, and
K2CO3. A suitable base is triethylamine. The base is used in an excess amount, for example, in an
35 amount of 1 to 100,000 times on a molar basis, relative to the amount of the ruthenium complex. In the
case of using triethylamine, it is preferable to use the base in an amount of 1 to 10,000 times relative to
the amount of the catalyst.
In the combination of a hydrogen donor and a base, when the hydrogen donor is formic acid, it
is preferable to use an amine as the base. In this case, formic acid and the amine may be added
40 separately to the reaction system, but an azeotropic mixture of formic acid and an amine may be
prepared in advance and used. A preferred example of the azeotropic mixture of formic acid and an
amine may be a formic acid-triethylamine (5:2) azeotropic mixture, or the like.
The reaction is usually carried out such that when the hydrogen donor is a liquid, the hydrogen
donor can be utilized as a reaction solvent. However, in order to dissolve the raw materials, a
45 non-hydrogen-donating solvent such as toluene, tetrahydrofuran, acetonitrile, dimethylformamide,
dimethyl sulfoxide, acetone, or methylene chloride can also be used singly or in mixture as an auxiliary
14
WO 2012/026201 PCT/JP2011/064490
solvent. In the case of using a formic acid salt or the like, water is used as an auxiliary solvent,
together with an organic solvent, in order to dissolve the formic acid salt, and the reaction may be
carried out in a two-layer system. In this case, a phase transfer catalyst may be used together in order
to accelerate the reaction. Furthermore, in the case of using hydrogen gas, an alcohol solvent such as
5 methanol, ethanol, isopropanol, trifluoroethanol, or hexafluoro-2-propanol is preferred.
The amount of use of the ruthenium complex as a catalyst is selected such that the molar ratio
(S/C) of the substrate (a carbonyl compound or an imine) (S) with respect to ruthenium metal atoms (C)
is in the range of 10 to 1,000,000, and preferably 100 to 15,000.
In regard to the amount of the hydrogen donor relative to the amount of the carbonyl
10 compound or the imine, usually an equimolar amount or greater is used, and inter alia, when the
hydrogen donor is formic acid or a salt thereof, the amount of the hydrogen donor is preferably a
1.5-fold molar amount or greater. Furthermore, the hydrogen donor is used in an amount in the range
of a 20-fold molar amount or less, and preferably a 10-fold molar amount or less. On the other hand,
when the hydrogen donor is isopropanol or the like, the hydrogen donor is used in a large excess based
15 on the substrate from the viewpoint of reaction equilibrium, and the hydrogen donor is usually used in
an amount in the range of a 1000-fold molar amount or less.
The reaction temperature is selected in the range of -20°C to 100°C, and preferably 0°C to
70°C.
The reaction pressure is not particularly limited, and the reaction is usually carried out at 0.05
20 to 0.2MPa, and preferably at normal pressure.
Furthermore, in the case of using hydrogen gas, the pressure is usually 5 MPa or less.
The reaction time may vary depending on the catalyst ratio, but the reaction time is 1 to 100
hours, and usually 2 to 50 hours.
After the reaction, the optically active substance thus produced can be separated and purified
25 by general operations such as distillation, extraction, chromatography, and recrystallization.
Examples
Hereinafter, the present invention will be described in detail by way of Examples, but the
present invention is not intended to be limited thereto.
30 The NMR spectra used in the identification of complexes and the determination of purity in the
following Examples were measured using a Mercury Plus 300 4N type apparatus manufactured by
Varian Technologies Japan, Ltd., or a Bruker BioSpin Avance EQ 500 System. Furthermore, the GC
analysis was carried out using Chirasil-DEX CB (0.25 mm x 25 m, 0.25 um) (manufactured by Varian,
Inc.), InertCapPure-WAX(0.25mmX30m, 0.25/zm) (GL Sciences Inc.) and the HPLC analysis was
35 carried out using CHIRALCEL OJ-H (0.46 mm x 25 cm) (manufactured by Daieel Chemical Industries,
Ltd.).
The symbols in the Examples have the following meanings.
MsDPEN: N-methanesulfonyl-1,2-diphenylethylenediamine
TsDPEN: N-(p-toluensulfonyl)-1,2-diphenylethylenediamine
40 o-TFTsDPEN: N-(2-trifluorotoluenesulfonyl)-1,2-diphenylethylenediamine
TJJPPsDPEN: N-(2,4,6-triisopropylbenzenesulfonyl)-1,2-diphenylethylenediamine
MESsDPEN: N-(2,4,6-trimethylbenzenesulfonyl)-1,2-diphenylethylenediamine
TsCYDN: N-(p-toluenesulfonyl)-1,2-cyclohexanediamine
MIBK: Methyl isobutyl ketone
45 dppe: Diphenylphosphinoethane
DEPEA: Diisopropylethylamine
15
WO 2012/026201 PCT/JP2011/064490
However, the diamine in the complex represents that one or two hydrogen atoms of the
diamine have been detached.
The term S/C represents the value of the ratio (mole number of substrate /mole number of
catalyst).
5

Production of
N-(( 1 R,2R)-1,2-diphenyl-2-(2-(tetrahydro-2H-pyran-2-yloxy)emylamino)ethyl)-4-methylbenzenesulfon
amide
10 The target compound (B) was produced by the reaction shown below.
[Chem. 8]
Ph* /»» S-d m, Ph V-cf
TsH/i,H, + .^r* —• H^r^
TSHN NHj Br—' A TsHN HN—' B
In a 50-ml Schlenk tube, 5.0 g (13.65 mmol) of (R,R>TsDPEN and 2.85 g (2.07 ml) (13.65
mmol) of an alkyl bromide (A) were mixed with 10 ml of DMSO, and the mixture was allowed to react
15 for 29 hours at 60°C. Subsequently, 50 ml of dichloromethane and 50 ml of a saturated aqueous
solution of NaHCOs were introduced into the reaction mixture, and the resulting mixture was stirred.
Subsequently, the organic layer was separated and was washed two more times with 50 ml of a saturated
aqueous NaHCC>3. Dichloromethane was recovered, and the residue was purified by silica gel column
chromatography. Thus, 4.94 g (72% yield) of the desired compound (B) was obtained.
20
'H-NMR^DCls, 300MHz)8:
1.43-1.80(m, 6H), 2.32(s, 3H), 2.42-2.70(m, 2H), 3.40-3.55(m, 2H), 3.70-3.85(m, 2H), 3.77(d, 1H),
4.30(m, 1H), 4.45 (d, 1H), 6.93-7.38(m, 14H)
25
Production of
N-(( 1 R,2R)-2-(2-hydroxyethylamino)-1,2-diphenylethy l)-4-methylbenzenesulfonamide
The target diamine (C) was produced by the reaction shown below.
[Chem. 9]
p V / h y~° ph* /h
TSH|/HM-^' B TsHl^lV^0" c
30
135 ml of ethanol and 34.5 ml of a 1 M aqueous solution of HC1 were added to 5.69 g of the
compound (B) obtained in Example 1 as described above, and the mixture was allowed to react for 2
hours at 40°C. Subsequently, 3.45 g of NaHCOs was added to the reaction mixture to neutralize the
solution, and then 75 ml of water and 150 ml of diethyl ether were added thereto. The reaction mixture
35 was separated. Subsequently, 50 ml of water was added, and the ether was removed with an evaporator.
Thus, white crystals were precipitated. The reaction mixture was ice-cooled and filtered. The filter
16
WO 2012/026201 PCT/JP2011/064490
cake was washed with water, and then was dried at 70°C under reduced pressure. Thus, 4.33 g (92%
yield) of the desired diamine (C) was obtained.
^-NMI^CDCla, 300MHz)5:
5 2.3l(s, 3H), 2.50-2.62(m, 2H), 3.58-3.75(m, 2H), 3.79(d, 1H), 4.40(d, 1H), 6.82-7.41(m, 14H)

Production of
N-(( 1 S,2S)-1,2-diphenyl-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethylamino)ethyl)methanesulfonamide
10 The target compound (D) was produced by the reaction shown below.
[Chem. 10]
N MsHN NH2 Br-J . " MsH, HI*-7 n
A
In a 50-ml Schlenk tube, 7.0 g (24.1 mmol) of (S,S)-MsDPEN and 5.04 g (3.64 ml, 24.1
mmol) of an alkyl bromide (A) were mixed with 17.6 ml of DMSO, and the mixture was allowed to
15 react for 30 hours at 60°C. Subsequently, 50 ml of dichloromethane and 50 ml of a saturated aqueous
solution of NaHCC>3 were introduced into the reaction mixture, and the resulting mixture was stirred.
Subsequently, the organic layer was separated and was washed two more times with 50 ml of a saturated
aqueous NaHCOa. Dichloromethane was recovered, and the residue was purified by silica gel column
chromatography. Thus, 5.06 g (50% yield) of the desired compound (D) was obtained.
20
^-NMR^DCla, 300MHz)5:
1.42-1.90(m, 6H), 2.20(d, 3H), 2.50-2.75(m, 2H), 3.40-3.50(m, 2H), 3.70-3.83(m, 2H), 3.90(d, 1H) ,
4.45(m, 1H), 4.50(d, 1H), 7.10-7.30(m, 10H)
25
Production of N-((lS,2S)-2-(2-hydroxyethylamino)-l,2-diphenylethyl)methanesulfonamide
The target diamine (E) was produced by the reaction shown below.
[Chem. 11]
P hM"h
MsHN H
30 142 ml of ethanol and 38.7 ml of a 1 M aqueous solution of HC1 were added to 5.06 g of the
compound (D) obtained in Example 3 as described above, and the mixture was allowed to react for 2
hours at 40°C. Subsequently, 3.63 g of NaHCC>3 was added to the reaction mixture to neutralize the
solution, and then 147 ml of water and 200 ml of diethyl ether were added thereto. The ether layer was
separated. The aqueous layer was extracted two times with ether, and the ether layers thus obtained
17
WO 2012/026201 PCT/JP2011/064490
were combined, dried over Na2SC"4, and then concentrated in an evaporator. Thus, 3.62 g (90% yield)
of the desired diamine (E) was obtained.
!H-NMR(CDCl3, 300MHz)8:
5 2.40(s, 3H), 2.50-2.72(m, 2H), 3.60-3.75(m, 2H), 3.93(d, 1H), 4.57(d, 1H), 7.10-7.24(m, 10H)

Production of (4-methylcyclohexa-1,4-dienyl)methanol
The target compound (F) was produced by the reaction shown below.
10 [Chem. 12]
TDH
F
In a 500-ml four-necked flask, 1.73 g (7.93 mmol) of CoBr2, 8.4 g (26.3 mmol) of Znl2, 3.47 g
(8.8 mmol) of dppe, and 370 ml of dichloromethane were introduced, the flask was then purged with
nitrogen, and the mixture was stirred for 30 minutes at 30°C. Subsequently, 78 ml (53.1 g, 780 mmol)
15 of isoprene, 41 ml (39.3 g, 701 mmol) of propargyl alcohol, and 2.2 g (8.53 mmol) of BU4NBH4 were
fed to the flask, and the resulting mixture was allowed to react for 7 hours at 30°C. Subsequently, the
dichloromethane solution was recovered and was distilled under reduced pressure at 160°C. Thus, 27.7
g (32% yield) of the desired diene mixture (F) was obtained. The purity of the target diene in this
mixture as determined by gas chromatography (GC) was approximately 98%.
20
'H-NMR^DCls, 300MHz)5:
1.67(s,z, 3H), 2.55-2.70(m, 4H), 4.02 (s, 2H), 5.44(m, 1H), 5.68(m, 1H)

25 Production of [RuCl2(l-(bromomethyl)-4-methylbenzene)]2
The target complex compound (G) was produced by the reaction shown below.
[Chem. 13]
T)u« RuCb^HjO , \>H HBr-H2S04
>-
4.75 g (38.2 mmol) of the diene (F) obtained in Example 5 as described above, 2.0 g (7.65
30 mmol) of ruthenium trichloride trihydrate, and 0.643 g (7.65 mmol) of NaHC03 were dissolved in 40 ml
of 2-methoxyethanol and 4 ml of water, and the solution was allowed to react for 1.5 hours at 130°C.
Subsequently, the solvent was distilled off in an evaporator, and 52 ml of a concentrated aqueous
solution of hydrobromic acid and 4 ml of concentrated sulfuric acid were added to the residue. The
resulting mixture was stirred for 4 hours at 100°C. The solution obtained after the reaction was mixed
35 with dichloromethane, water, and 2-methoxyethanol, and the mixture was stirred and left to stand still.
Crystals precipitated therefrom were filtered, and thus 1.9 g (79% yield) of the desired complex (G) was
18
WO 2012/026201 PCT/JP2011/064490
obtained.
'H-NMRO^MSO-de, 300MHz)8:
2.23(s, 3H), 4.40(s, 2H), 5.84(d, 2H), 6.15(d, 2H)

Production of RuCl((R,R)-0-HT-Tsdpen)
The target complex, RuCl((R,R)-0-HT-Tsdpen), was produced by the reaction shown below.
[Chem. 14]
10
1.6 g (2.24 mmol) of the arene dimer (G) obtained in Example 6 as described above, 1.53 g
(3.73 mmol) of the diamine (C) produced in Example 2, 1.19 g (3.73 mmol) of triethylbenzylammonium
iodide (EtsBnNT), 52.8 ml of dichloromethane, and 52.8 ml of water were mixed, and the mixture was
stirred at 35°C. 1.78 g (26.9 mmol) of KOH was added to the mixture, and the resulting mixture was
15 allowed to react for 3 hours. The organic layer turned into a purple solution. The reaction mixture
was left to stand, and then the aqueous layer was removed. 50 ml of water was added to the organic
layer, the mixture was stirred and then left to stand, and the aqueous layer was removed. This
operation was repeated three times, and then 65 ml of a 0.1 M aqueous solution of HC1 was added to the
organic layer. The mixture was stirred for 30 minutes. Thereafter, 0.034 g of NaHCOs was added
20 thereto to neutralize the solution, and then the mixture was left to stand. Only the dichloromethane
layer was collected and dried to solid. This solid was purified with a silica gel column (eluent:
CHClj/MeOH = 20/1), and thus 1.1 g (45% yield) of the desired complex, RuCl((R,R)-0-HT-Tsdpen),
was obtained (the purity determined by liquid chromatography (HPLC) was approximately 95%).
25 'H-NMR^DzCb, 300MHz)8:
2.25(s,3H), 2.52(s,3H), 3.13(m,lH), 3.60(m,lH), 3.80-4.00(m,4H), 4.48(d,J=l 5.0Hz, 1H), 4.52(brs,lH),
4.95(d,J=15.0 Hz, 1H), 5.45(d,J=5.2Hz,lH), 5.75(d,J = 6.2 Hz,lH), 6.05(d,J=5.2 Hz,lH), 6.60 (d,J=6.9
Hz,2H), 6.65-6.70(m,4H), 6.88(d,J = 8.0 Hz,2H), 7.08-7.18(m,4H), 7.23(d,J=8.0 Hz,2H)
HRMS (ESI):
30 As C3iH33N203RuS,
Calculated value: [M-C1]+ 615.1258
Found value: 615.1258

35 Asymmetric hydrogen transfer reaction of acetophenone using the complex
RuCl((R,R)-0-HT-Tsdpen) (S/C = 2000)
19
WO 2012/026201 PCT/JP2011/064490
In 50-ml Schlenk tube, 6.5 mg (0.01 mmol) of the complex RuCl((R,R)-0-HT-Tsdpen)
produced in Example 7 as described above, 2.32 ml (2.40 g, 20 mmol) of acetophenone, and 10 ml of a
formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the Schlenk tube was purged with
nitrogen. Subsequently, the mixture was allowed to react for 24 hours at 60°C. An analysis of the
5 reaction liquid was carried out by GC, and it was found that (R)-l-phenylethanol with 96.3% ee was
produced at a conversion rate of 97.5%.

Production of RuCl((S,S)-0-HT-Msdpen)
10 The target complex, RuCl((S,S)-0-HT-Msdpen), was produced by the reaction shown below.
[Chem. 15]
> -
" V _ / h
(3"
Production of Ru((R,R)-0-HT-Tsdpen) and hydrogen transfer reaction (in situ method) of
acetophenone using the complex
The complex Ru((R,R)-0-HT-Tsdpen) was produced by the reaction shown below, and a
hydrogen transfer reaction of acetophenone was carried out in situ using the complex (in situ method).
15 [Chem. 16]
o1 OH
O"
18.0 mg (0.025 mmol) of the arene dimer (G) produced in example 6, 17.2 mg (0.042 mmol)
of the diamine (C) produced in Example 2, 13.4 mg (0.042 mmol) of triethylbenzylammonium iodide
(Et3BnNr), 0.6 ml of dichloromethane, and 0.6 ml of water were mixed, and while the mixture was
20 stirred at 35°C, 0.02 g (0.3 mmol) of KOH was added to the mixture. The resulting mixture was
allowed to react for 6 hours. The organic layer turned into a purple solution. The reaction liquid was
left to stand, and 36 ul of the reaction liquid was evacuated from the organic layer to apply to the
reduction for the catalyst ratio was S/C = 2000. The catalyst solution was added to a 15-ml Schlenk
tube, and 0.58 ml (0.6 g, 5.0 mmol) of acetophenone and 2.5 ml of a formic acid-triethylamine (5:2)
25 azeotropic mixture were incorporated therein. The Schlenk tube was purged with nitrogen, and then
the mixture was allowed to react for 24 hours at 60°C. An analysis of the reaction liquid was carried
out by GC, and it was found that (R)-l-phenylethanol with 96.2% ee was produced at a conversion ratio
of 96.5%.
30
Production of
N-(( 1 R,2R)-2-(2-mercaptoethylamino)-1,2-diphenylethyl)-4-methylbenzenesulfonamide
21
WO 2012/026201 PCT/JP2011/064490
The target mercaptodiamine (H) was produced by the reaction shown below.
[Chem. 17]
TsHN NH2 TsHN HN—/
H
In a 50-ml glass autoclave, 5.0 g (13.6 mmol) of (R, R)-TsDPEN, 0.758 g (0.75 ml) (13.6
5 mmol) of ethylene sulfide, and 25 ml of toluene were mixed, and the mixture was allowed to react for 48
hours at 120°C. Subsequently, toluene was recovered, and the residue was purified by silica gel
column chromatography. Thus, 3.2 g (55% yield) of the desired mercaptodiamine (H) was obtained.
'H-NMR^DzCU, 300MHz)5:
10 0.58(br, 2H), 1.94(s, 3H), 2.10-2.33(m, 4H), 3.53(d, IH), 4.59(d, IH), 6.36(br, IH), 6.69(d, 2H), 6.79(m,
8H), 6.93-7.00(m, 8H), 7.64(d, 2H)

Production of the complex RuCl((R,R)-S-HT-Tsdpen)
15 The target complex RuCl((R,R)-S-HT-Tsdpen) was produced by the reaction shown below.
[Chem. 18]
TsNH NH
H
0.1 g (0.234 mmol) of the arene dimer (G) produced in Example 6, 0.1 g (0.14 mmol) of the
mercaptodiamine (H) produced in Example 12, 0.121 g (163 ul, 0.936 mmol) of DIPEA (Hunig's Base),
20 and 2 ml of dichloromethane were mixed, and the mixture was allowed to react at 45 °C. Subsequently,
three times operation of adding water, stirring the mixture, subsequently leaving the mixture to stand,
washing the organic layer was carried out, and the organic layer was dried to solid. Thus, a solid
mixture containing the desired complex, RuCl((R,R)-S-HT-Tsdpen), was obtained.
HRMS (ESI):
25 As C31HS3N2O2RUS2,
Calculated value: [M-C1]+ 631.1028
Found value: 631.1012

Asymmetric hydrogen transfer reaction of acetophenone using a complex
30 RuCl((R,R)-S-HT-Tsdpen)
22
WO 2012/026201 PCT/JP2011/064490
A hydrogen transfer reaction of acetophenone was carried out in a formic acid-triethylamine
(5:2) azeotrope with S/C = 600 at 60°C. After the reaction was carried out for 16 hours, an analysis of
the reaction liquid was carried out by GC, and it was found that (R)-l-phenylethanol with 77.9% ee was
produced at a conversion ratio of 67.0%.
5

Asymmetric hydrogen transfer reaction of propiophneone using a complex
RuCl((R,R>0-HT-Tsdpen)
In a 15-ml Schlenk tube, 3.3 mg (0.005 mmol) of RuCl((R,R)-0-HT-Tsdpen), 0.67 ml (0.67 g,
10 5.0 mmol) of propiophenone, and 2.5 ml of a formic acid-triethylamine (5:2) azeotropic mixture were
mixed, and the Schlenk tube was purged with nitrogen. Subsequently, the mixture was allowed to react
for 24 hours at 60°C. An analysis of the reaction liquid was carried out by GC, and it was found that
(R)-l-phenylpropan-l-ol with 93.7% ee was produced at a conversion rate of 99.7%.
15
Asymmetric hydrogen transfer reaction of propiophenone using a complex
RuCl((S,S)-0-HT-Msdpen)
In a 15-ml Schlenk tube, 2.9 mg (0.005 mmol) of RuCl((S,S)-0-Ht-Msdpen), 0.67 ml (0.67 g,
5.0 mmol) of propiophenone, and 2.5 ml of a formic acid-triethylamine (5:2) azeotropic mixture were
20 mixed, and the Schlenk tube was purged with nitrogen. Subsequently, the mixture was allowed to react
for 24 hours at 60°C. An analysis of the reaction liquid was carried out by GC, and it was found that
(S)-l-phenylpropan-l-ol with 92.1% ee was produced at a conversion rate of 95.9%.

25 Asymmetric hydrogen transfer reaction of propiophenone using a known complex
RuCl((R,R)-Tsdpen)(mesitylene)
In a 15-ml Schlenk tube, 6.2 mg (0.01 mmol) of RuCl((R,R)-Tsdpen)(mesitylene), 0.67 ml
(0.67 g, 5.0 mmol) of propiophenone, and 2.5 ml of a formic acid-triethylamine (5:2) azeotropic mixture
were mixed, and the Schlenk tube was purged with nitrogen. Subsequently, the mixture was allowed to
30 react for 24 hours at 60°C. An analysis of the reaction liquid was carried out by GC, and it was found
that (R)-l-phenylpropan-l-ol with 93.0% ee was produced at a conversion rate of 52.3%.

Asymmetric hydrogen transfer reactions of the ketones (1) to (14) presented in the following
35 Tables 1 and 2 were respectively carried out in the same manner as in Example 15 using
RuCl((R,R)-0-HT-Tsdpen), or in the same manner as in Example 10 using RuCl((S,S)-0-HT-Msdpen).
Each reaction was carried out at the catalyst ratio (S/C) and temperature indicated in the tables, using a
formic acid-triethylamine (5:2) azeotropic mixture as a hydrogen source in an amount such that the
substrate concentration was 2 mol/L. After a lapse of a predetermined time, an analysis of the reaction
40 liquid was carried out by GC, and thereby the conversion rate and the optical purity were determined.
Furthermore, as a comparison, the reaction results obtained in the same manner as in Reference
Example 1 using the known complex RuCl((R,R)-Tsdpen)(mesitylene) are also presented in the right
columns of the respective tables. In the tables that will be presented hereinafter, the abbreviation
"conv." means the conversion rate of the substrate ketone; "selc." means the selectivity ratio to the target
45 product; "% ee" represents the optical purity; and "S/C" represents the value of the ratio (mole number
of substrate ketone/mole number of catalyst).
23
WO 2012/026201 PCT/JP2011/064490
[Table 1]
Substrate Ketone
^ CD
Reaction
Temperature - 60 Me (2)
Reaction . ^
Temperature • DU v_>
UU(3)
Reaction . _
Temperature • DU V^
O
UCJ (4)
Reaction . <^
Temperature • DU w
0^
^ (5)
Reaction . /»*><*-•
Temperature " *>U Vs
N < r ^ ^ (6)
Reaction . ^fyy-*
Temperature • 4UX^
^ (7)
Reaction _
Temperature • 40 *C
^ (8)
Reaction . AfVY^
Temperature" 4U ^
RuCI(O-HT-Tsdpen)
(S/C=1000)
5h; 100%conv.
93.6%ee
(S/C=1000)
5h; 99.4%conv.
93.2%ee
(S/C=1000)
5h; 93.6%conv.
83.6%ee
(S/C=1000)
5h; 98.5%conv.
93.3%ee
(S/C=1000)
5h; 100%conv.
97.7%ee
(S/C=1000)
24h; 98.5%conv.
86.2%ee
(S/C=1000)
5h; 97.6%conv.
96.0%ee
(S/C=1000)
5h; 100%conv.
94.7%ee
RuCI(O-HT-Msdpen)
(S/C=1000)
5h; 99.4%conv.
93.2%ee
(S/C=1000)
5h; 99.3%conv.
92.0%ee
(S/C=1000)
5h; 97.8%conv.
96.5%ee
(S/C=1000)
5h; 98.8%conv.
90.5%ee
(S/C=1000)
5h; 99.5%conv.
96.8%ee
(S/O1000)
24h; 98.6%conv.
87.0%ee
(S/C=1000)
5h; 97.1%conv.
96.1%ee
(S/C=1000)
5h; 100%conv.
94.9%ee
RuCI(Tsdpen)
(mesitylene)
(S/C=500)
24h.* 53.2%conv.
93.0%ee
(S/C=500)
24h; 20.8%conv.
86.6%ee
(S/C=500)
24h; 15.0%conv.
65.8%ee
(S/C=500)
24h; 28.1%conv.
90.6%ee
(S/C=500)
24h; 25.0%conv.
94.5%ee
(S/C=500)
24h; 59.0%conv.
88.0%ee
(S/C=500)
5h; 3.8%conv.
0%ee
(S/C=500)
5h; 65.0%conv.
96.2%ee
24
WO 2012/026201 PCT/JP2011/064490
[Table 2]
Substrate Ketone
06 ,„
Reaction
Temperature! 6 0 t
c6 a*
Reaction . -^
Temperature • Oil \^
Reaction nn
c6«-
Reaction . en
Temperature" 4Uv>
^ (14)
Reaction . e/>
Temperature • bU\s
RuCI(O-HT-Tsdpen)
(S/C=1000)
5h; 99.0%conv.
>99.9%ee
(S/C=1000)
5h; 99.1%conv.
99.8%ee
(S/C=1000)
5h; 97.1%conv.
98.4%ee
(S/C=1000)
24h; 77.1%couv.
94.8%ee
(S/O500)
24h»* 71.3%conv.
(96.0%selc.)
63.0%ee
(S/C=1000)
5h; 100%conv.
(>95%selc.)
97.3%ee
RuCI(O-HT-Msdpen)
(S/C=1000)
5h; 99.4%conv.
99.8%ee
(S/C=1000)
5h; 98.5%conv.
99.5%ee
(S/C=1000)
5h; 96.5%conv.
98.5%ee
(S/C=1000)
24h; 69.0%conv.
96.7%ee
(S/C=500)
24h; 71.1%conv.
(95.3%selc.)
63.7%ee
(S/C=1000)
5h; 100%conv.
(>95%selc.)
96.4%ee
RuCI(Tsdpen)
(mesitylene)
(S/C=500)
24h; 99.0%conv.
98.5%ee
(S/C=500)
24h; 61.9%conv.
97.8%ee
(S/C=500)
24h; 17.4%conv.
90.1%ee
(S/C=500)
24h; 1.9%conv.
51.5%ee
(S/C=200)
24h; 38.3%conv.
(93.7%selc.)
52.3%ee
(S/O500)
5h; 97.7%conv.
(66%selc.)
90.9%ee
The leftmost columns of Table 1 and Table 2 indicate the kind of ketones used as the substrate,
and the next right columns indicate the results obtained when the complex RuCl((R,R)-0-HT-Tsdpen) of
the present invention was used. The next right columns indicate the results obtained when the complex
RuCl((S,S)-0-HT-Msdpen) of the present invention was used, and the rightmost columns indicate the
results obtained when the known complex RuCl((R,R)-Tsdpen)(mesitylene) was used as a Comparative
Example.
As such, the ruthenium complexes of the present invention having a heteroatom introduced
into the chain-like moiety exhibit very high activities and selectivities, and the ruthenium complexes can
produce optically active cyclic alcohols by reducing cyclic ketones, such as the ketones (9) to (12)
which could not be hitherto efficiently reduced with hydrogenation catalysts or the like, or can produce
25
WO 2012/026201 PCT/JP2011/064490
optically active diols by reducing ketones having a hydroxyl group, such as the ketone (7). Similarly,
the ruthenium complexes can produce optically active alcohols having a halogen substituent by
hydrogenating ketones having a halogen substituent (particularly, ketones having a halogen substituent
at the oc-position), such as the ketone (14), which are unstable to bases and are therefore not easily
5 reducible with conventional hydrogenation catalysts or the like. Thus, the ruthenium complexes
according to the present invention are highly useful.

Asymmetric hydrogen transfer reaction of benzil using complex RuCl((R,R)-0-HT-Tsdpen)
10 (S/C = 2000)
Benzil was asymmetrically reduced according to the following reaction formula.
[Chem. 19]
{S,S) (K,R) (meso)
In a 50-ml Schlenk tube, 3.5 mg (0.005 mmol) of RuCl((R,R)-0-HT-Tsdpen), 2.1 g (10 mmol)
15 of benzil, 5 ml of a formic acid-triethylamine (5:2) azeotropic mixture, and 10 ml of DMF were mixed,
and the Schlenk tube was purged with nitrogen. Subsequently, the mixture was allowed to react for 5
hours at 60°C. An analysis of the reaction liquid was carried out by GC and HPLC, and it was found
that hydrobenzoin was produced at the ratio of ((S,S) form:(R,R) form:meso form = 88.1:0.9:11.0) at a
conversion rate of 90.0%. The enantiomeric excess of the (S,S) form and the (R,R) form in this case is
20 98.0% ee.

Asymmetric hydrogen transfer reaction of
(E)-N-(3,4-dihydronaphthalen-1 (2H)-ylidene)-1 -phenylmethanamine
25 In a 50-ml Schlenk tube, 3.3 mg (0.005 mmol) (S/C = 300) of RuCl((R,R)-0-HT-Tsdpen), 0.35
g (1.5 mmol) of the indicated imine, 3 ml of dichloromethane, and 0.75 ml of a formic
acid-triethylamine (5:2) azeotropic mixture were mixed, and the mixture was allowed to react for 24
hours at 30°C. The yield and optical purity of the product were measured by a GC analysis, and as a
result, optically active N-benzyl-l-(l,2,3,4-tetrahydronaphthyl)amine, which was the target amine, was
30 obtained with a yield of 70.0% and an optical purity of 70% ee.

Asymmetric hydrogenation of 4-chromanone
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl((R,R)-0-HT-Tsdpen) was
35 placed, and the autoclave was purged with nitrogen. Subsequently, 0.74 g (5.0 mmol) of 4-chromanone
and 4.4 ml of methanol were added thereto, and the pressure was raised with hydrogen up to 3.0 MPa.
Subsequently, the mixture was stirred for 18 hours at 60°C. The reaction liquid was subjected to a GC
analysis, and as a result, (R)-4-chromanol was obtained at a conversion rate of 98.6% with an optical
purity of 99. l%ee.
40

Asymmetric hydrogenation of a-tetralone
26
WO 2012/026201 PCT/JP2011/064490
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl((R,R>0-HT-Tsdpen) was
placed, and the autoclave was purged with nitrogen. Subsequently, 0.73 g (5.0 mmol) of a-tetralone
and 4.4 ml of methanol were added thereto, then hydrogen gas was charged to 3.0 MPa. Subsequently,
the mixture was stirred for 20 hours at 60°C. The reaction liquid was subjected to a GC analysis, and
5 as a result, (R)-l-tetralol was obtained at a conversion rate of 52.0% with an optical purity of 99.3% ee.

Asymmetric hydrogenation of 1-indanone
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl((R,R)-0-HT-Tsdpen) was
10 placed, and the autoclave was purged with nitrogen. Subsequently, 0.66 g (5.0 mmol) of 1-indanone
and 4.4 ml of methanol were added thereto, then hydrogen gas was chraged to 3.0 MPa. Subsequently,
the mixture was stirred for 20 hours at 60°C. The reaction liquid was subjected to a GC analysis, and
as a result, (R)-l-indanol was obtained at a conversion rate of 58.6% with an optical purity of 97.8% ee.
15
The hydrogenation of methyl benzoate using RuCl ((R,R)-0-HT-Tsdpen)
In a 50-ml autoclave, 13.5 mg (0.020 mmol, S/C=50) of RuCl((R,R)-0-HT-Tsdpen) was placed, and
the autoclave was purged with nitrogen. Subsequently, 1.8ml of tetrahydrofuran and 0.14g
(l.Ommol) of methyl benzoate, 0.2ml (0.20mmol) of the 1.0M tetrahydrofuran solution of potassium
20 tert-Butoxide were added thereto, then hydrogen gas was charged to 5.0 MPa. Subsequently, the
mixture was stirred for 15 hours at 60°C. The reaction liquid was subjected to a GC analysis, and as a
result, benzyl alcohol was obtained at a conversion rate of 90.4% with an selectivity of 78.9%.

25 In order to investigate the effects of the heteroatom in the novel ruthenium-diamine complexes
having a heteroatom introduced into the chain-like moiety that links the aromatic compound (arene)
portion and the diamine moiety that are coordinated to ruthenium, which has been newly discovered in
this invention, the following complex which does not have any heteroatom, and in which the chain-like
moiety is composed only of carbon atoms, was separately synthesized, and a comparison of activity was
30 made.
[Chem. 20]
The complex was produced by making reference to the production method described in the
Non-Patent Literature 5 (J. Am. Chem. Soc. 127 (2005), p. 7318). This newly produced complex will
35 be hereinafter referred to as RuCl(p-Tol-C4-teth-Tsdpen).
27
WO 2012/026201 PCT/JP2011/064490
'H-NMRCCDCfe, 300MHz)8:
1.82-2.04 (m, 2H), 2.04-2.31 (m, 5H), 2.26(s, 3H), 2.53(s, 3H), 2.89-2.71(m, 2H), 3.10-3.16(m, 1H),
3.47-3.56(m, 1H), 3.80(dd, J = l l . l , 12.1Hz, 1H), 3.99(d, J=ll.lHz, 1H), 4.77(m, 1H), 5.32(d, J=5.5Hz,
2H), 5.38(d, J=6.3Hz, 2H), 5.55(d, J=6.3Hz, 1H), 6.20(d, J=5.5Hz, 1H), 6.61(d, J=7.2Hz, 1H), 6.59-6.62
5 (m, 2H), 6.71-6.81 (m, 4H), 6.83-6.91 (m, 3H), 7.03-7.12 (m, 3H), 7.18(d, J=8.4Hz, 2H);
HRMS (ESI):
As C32H35N202SRu,
Calculated value: [M-C1]+ 613.1457
Found value: 613.1473
10

In order to investigate the activities of the complex RuCl((R,R)-0-HT-Tsdpen) having a
heteroatom in the side chain moiety and of the complex RuCl(p-Tol-C4-teth-Tsdpen) produced in
Reference Example 2, in which the side chain moiety is composed only of carbon atoms, hydrogen
15 transfer reactions of acetophenone were carried out at catalyst ratios such as indicated in the following
table. The reactions were carried out at the catalyst ratios indicated in the following Table 3 and at
60°C, using a formic acid-triethylamine (5:2) azeotropic mixture as a hydrogen source in an amount
such that the substrate concentration was 2 mol/L. After a lapse of a predetermined time, an analysis of
the reaction liquids was carried out by GC, and thereby the conversion rate and the optical purity were
20 determined.
The results are presented in the following Table 3.
[Table 3]
Catalytic Ratio
( S / C )
1 0 0 0
5 0 0 0
1 0 0 0 0
1 5 0 0 0
RuCI(O-HT-Tsdpen)
(20h) 99. 0%conv. 96.3%ee
(24h) 94. 8%conv. 96. 2%ee
(24h) 71.5%conv. 96.l*ee
(48h) 91.5%conv. 96. 2%ee
(72h) 95. 2%conv. 96. 2%ee
(24h) 61.0%conv. 96. lfcee
(48h) 87. 3%conv. 96.3%ee
(72h) 94. l%conv. 96. 3%ee
RuCI(p-Tol-C«-teth-Tsdpen)
(20h) 99. 0%conv. 96. 3%ee
(24h) 94. 6%conv. 96.3%ee
(24h) 40. 0%conv. 94. 9%ee
(48h) 43. l%conv. 94. 4%ee
(72h) -
(24h) 6. 5%conv. 79. 7%ee
(48h) -
As such, the complex RuCl(O-HT-Tsdpen) having a heteroatom in the side chain moiety, and
25 the complex RuCl(p-Tol-C4-teth-Tsdpen) in which the side chain moiety is composed only of carbon
atoms, both exhibit high activities in the acetophenone reduction reaction as compared with the
conventional hydrogen transfer type complexes, and both of the complexes gave equally satisfactory
results in the reactions at catalyst ratios of up to S/C = 5000. However, when the catalyst ratio was
increased to S/C = 10,000, the reaction carried out using the complex RuCl(O-HT-Tsdpen) of the present
30 invention was almost completed, but in the reaction using the complex RuCl(p-Tol-C4-teth-Tsdpen), the
conversion rate was only around 40%, while the reaction was stopped due to deactivation of the catalyst.
Furthermore, when the catalyst ratio was increased to S/C = 15,000, the reaction carried out using the
complex RuCl(O-HT-Tsdpen) of the present invention was likewise almost completed, but the reaction
hardly proceeded when the complex RuCl(p-Tol-C4-teth-Tsdpen) was used. Therefore, when a
35 comparison was made between these two complexes which respectively have an equal length of the side
chain that links the skeleton on the arene or links the arene and diamine portions, but different elements
28
WO 2012/026201 PCT/JP2011/064490
constituting the side chain, such as oxygen atoms and carbon atoms, it was found that the complex
RuCl(O-HT-Tsdpen) of the present invention having an oxygen atom among the atoms constituting the
side chain exhibits a very high catalytic activity even when used in a very small amount.
5
Production of Ru(BF4)((R,R)-0-HT-Tsdpen)
In a 150-ml Schlenktube, 0.52 g (0.8 mmol, 1 eq) of RuCl((R,R)-0-HT-Tsdpen), 0.187 g (0.96
mmol, 1.2 eq) of AgBF4, 15 ml of dichloromethane, and 15 ml of methanol were mixed, and the mixture
was stirred for one hour at room temperature. The reaction solution was filtered through Celite, and
10 the filtrate was dried to solid. Thus, 0.55 g (98% yield) of the desired complex,
RuBF4((R,R)-0-HT-Tsdpen), was obtained.
1H-NMR(CD3OD, 300MHz)8:
2.12(s, 3H), 2.46(s, 3H), 3.35-3.60(m, 4H), 3.60-3.80(m, 1H), 3.95-4.10(m, 3H),
15 4.70-4.80(m, 1H), 5.84(d, 1H), 5.89(d, 1H), 5.99(d, 1H), 6.20(d, lH),6.46-7.50(m, 14H)
HRMS (ESI):
As C31H33BF4N2O3RUS,
Calculated value: [M-BF4]+ 615.1250
Found value: 615.1271
20

Production of Ru(OTf)((R^)-0-HT-Tsdpen)
In a 150-ml Schlenk tube, 0.52 g (0.8 mmol, 1 eq) of RuCl((R,R)-0-HT-Tsdpen), 0.247 g (0.96
mmol, 1.2 eq) of AgOTf, 15 ml of dichloromethane, and 15 ml of methanol were mixed, and the mixture
25 was stirred for one hour at room temperature. The reaction solution was filtered through Celite, and
the filtrate was dried to solid. Thus, 0.59 g (96% yield) of the desired complex,
RuOTf((R,R)-0-HT-Tsdpen), was obtained.
1H-NMR(CD3OD 300MHz)8:
30 2.13(s, 3H), 2.47(s, 3H), 3.35-3.60(m, 4H), 3.60-3.80(m, 1H), 3.95-4.10(m, 3H),
4.70-4.80(m, 1H), 5.84(d, 1H), 5.89(d, 1H), 5.99(d, 1H), 6.20(d, 1H),
6.46-7.50(m, 14H)
HRMS (ESI):
AS C32H33F3N206RUS2,
35 Calculated value: Positive side [M-TfO]+ 615.1250
Negative side [TfO]" 148.9526
Found value: Positive side [M-TfO]+ 615.1258
Negative side [TfO]- 148.9521
40
Production of Ru(SbF6)((R,R)-0-HT-Tsdpen)
In a 150-ml Schlenk tube, 0.52 g (0.8 mmol, 1 eq) of RuCl((R,R)-0-HT-Tsdpen), 0.330 g (0.96
mmol, 1.2 eq) of AgSbFe, 15 ml of dichloromethane, and 15 ml of methanol were mixed, and the
mixture was stirred for one hour at room temperature. The reaction solution was filtered through Celite,
45 and the filtrate was dried to solid. Thus, 0.65 g (95% yield) of the desired complex,
RuSbF6((R,R)-0-HT-Tsdpen), was obtained.
29
WO 2012/026201 PCT/JP2011/064490
'H-NMR(CD3OD, 300MHZ)5:
2.16(s, 3H), 2.42(s, 3H), 3.30-3.60(m, 4H), 3.60-3.80(m, 1H), 4.00-4.15(m, 3H),
4.70-4.80(m, 1H), 5.83(d, 1H), 5.91(d, 1H), 5.97(d, 1H), 6.19(d, lH),6.48-7.25(m, 14H)
5 HRMS (ESI):
As C31H33F6N2O3RUSSD
Calculated value: [M-SbF6]+ 615.1250
Found value: 615.1251
10
Production of Ru(CF3COO)((R,R)-0-HT-Tsdpen)
In a 150-ml Schlenk tube, 0.52 g (0.8 mmol, 1 eq) of RuCl((R,R)-0-HT-Tsdpen), 0.212 g (0.96
mmol, 1.2 eq) of CF3COOAg, 15 ml of dichloromethane, and 15 ml of methanol were mixed, and the
mixture was stirred for one hour at room temperature. The reaction solution was filtered through Celite,
15 and the filtrate was dried to solid. Thus, 0.58 g (99% yield) of the desired complex,
Ru(CF3COO)((R,R)-0-HT-Tsdpen), was obtained.
HRMS (ESI):
As C33H33F3N206RuS
Calculated value: [M-CF3COO]+ 615.1250
20 Found value: 615.1243

Production of Ru(CH3COO)((R,R)-0-HT-Tsdpen)
In a 150-ml Schlenk tube, 0.52 g (0.8 mmol, 1 eq) of RuCl((R,R)-0-HT-Tsdpen), 0.16 g (0.96
25 mmol, 1.2 eq) of CH3COOAg, 15 ml of dichloromethane, and 15 ml of methanol were mixed, and the
mixture was stirred for one hour at room temperature. The reaction solution was filtered through Celite,
and the filtrate was dried to solid. Thus, 0.50 g (92% yield) of the desired complex,
Ru(CH3COO)((R,R)-0-HT-Tsdpen), was obtained.
30 1H-NMR(d6-DMSO, 300MHz)5:
1.89(s, 3H), 2.18(s, 3H), 2.26(s, 3H), 3.00-4.00(m, 4H), 3.85(d, 1H), 4.03(t, 1H),
4.62(d, 1H), 4.85(d, 1H), 4.03(t, 1H), 5.53(m, 2H), 5.97(m, 2H), 6.48-7.60(m, 14H), 10.07(m, 1H),
HRMS (ESI):
As Cas^gNaOsRuS
3 5 Calculated value: [M-CH3COO]+ 615.1250
Found value: 615.1240

Production of Ru(B(C6F5)4)((R,R)-0-HT-Tsdpen)
40 In a 150-ml Schlenk tube, 0.40 g (0.61 mmol, 1 eq) of RuCl((R,R)-0-HT-Tsdpen), 0.5 g (0.74
mmol, 1.2 eq) of LiB(C6F5)4, 11 ml of dichloromethane, and 11 ml of methanol were mixed, and the
mixture was stirred for one hour at room temperature. The reaction solution was filtered through Celite,
and the filtrate was dried to solid. Thus, 0.74 g (93% yield) of the desired complex,
Ru(B(C6F5)4)((R,R)-0-HT-Tsdpen), was obtained.
45
1H-NMR(CD3OD, 300MHz)5:
30
WO 2012/026201 PCT/JP2011/064490
2.15(s, 3H), 2.39(s, 3H), 3.10-3.23(m, 2H), 3.40-3.58(m, 2H), 3.70-4.00(m, 2H),
3.90(t, 1H), 4.15(d, 1H), 4.62(m, 1H), 5.60-5.95(m, 4H),6.52-7.25(m, 14H)
19F-NMR(CD30D)8:
-168.8,-164.9,-133.0
5 HRMS (ESI):
As C55H33BF20N2O3RUS
Calculated value: Positive side [M-B(C6F5)4]+ 615.1250
Negative side [B(C6F5)4]" 678.9776
Found value: Positive side [M-B(C6F5)4]+ 615.1254
10 Negative side [ B ^ s F ^ I 678.9774

Asymmetric hydrogen transfer reaction of acetophenone using complex
Ru(BF4)((R,R)-0-HT-Tsdpen) (S/C = 1000)
15 In 15-ml Schlenk tube, 3.5 mg (0.005 mmol) of the complex Ru(BF4)((R,R)-0-HT-Tsdpen)
produced in Example 25 as described above, 0.58 ml (0.6 g, 5 mmol) of acetophenone, and 2.5 ml of a
formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the Schlenk tube was purged with
nitrogen. Subsequently, the mixture was allowed to react for 5 hours at 60°C. An analysis of the
reaction liquid was carried out by GC, and it was found that (R)-l-phenylethanol with 96.2% ee was
20 produced at a conversion rate of 96.5%.

Asymmetric hydrogenation reaction of 2-methylquinoline using complex
Ru(BF4)((R,R)-0-HT-Tsdpen)
25 In a 100-ml autoclave, 17.5 mg (0.025 mmol) of Ru(BF4)((R,R)-0-HT-Tsdpen) was placed,
and the autoclave was purged with nitrogen. Subsequently, 0.34 ml (0.36 g, 2.5 mmol) of
2-methylquinoline and 1.4 ml of HFIP (hexafluoro-2-propanol) were added thereto, then hydrogen gas
was charged to 5.0 MPa. Subsequently, the mixture was stirred for 19 hours at 40°C. The reaction
liquid was subjected to a GC analysis, and as a result, it was found that 1,2,3,4-tetrahydroquinaldine,
30 which is a reduced form, was produced at a conversion rate of 93.8%, with an optical purity of 86% ee.

[Chem. 21]
OX OCX
H
35 Asymmetric hydrogenation reactions were carried out in the same manner as in Example 32,
by respectively using Ru(BF4)((R,R)-0-HT-Tsdpen), Ru(OTf)((R,R)-0-HT-Tsdpen),
Ru(SbF6)((R,R)-0-HT-Tsdpen), Ru(CF3COO)((R,R)-0-HT-Tsdpen),
Ru(CH3COO)((R,R)-0-HT-Tsdpen) or Ru(B(C6F5)4)((R,R)-0-HT-Tsdpen) as the catalyst, and using
HFIP or methanol as the solvent. 2-Methylquinoline was used as the substrate for the reactions, and
40 the reactions were respectively carried out for 19 hours. The results are presented in the following
Table 4.
31
WO 2012/026201 PCT/JP2011/064490
[Table 4]
Catalyst
(S/C=100)
Ru(BF4)(0-HT-Tsdpen)
Ru(OTf)(0-HT-Tsdpen)
Ru(SbF6)(0-HT-Tsdpen)
Ru(CF3COO)(0-HT-Tsdpen)
Ru(CH3COO)(0-HT-Tsdpen)
Ru(B(C6F5)4)(0-HT-Tsdpen)
Solvent
HFIP
MeOH
HFIP
MeOH
HFIP
MeOH
HFIP
MeOH
HFIP
MeOH
HFIP
MeOH
Conversion rate
(%conv.)
93.8
95.7
98.1
84.3
97.2
85.8
98.4
79.1
98.8
56.2
92.1
51.4
Assymetric yield
(%ee)
86
58
90
42
86
46
90
35
91
16
90
28

Asymmetrichydrogenation reaction of 2-methylquinoxaline using complex
5 Ru(BF4)((R,R)-0-HT-Tsdpen)
In a 100-ml autoclave, 17.5 mg (0.025 mmol) of Ru(BF4)((R,R)-0-HT-Tsdpen) was placed,
and the autoclave was purged with nitrogen. Subsequently, 0.32 ml (0.36 g, 2.5 mmol) of
2-methylquinoxaline and 1.4 ml of HFIP (hexafluoro-2-propanol) were added thereto, then hydrogen gas
was charged to 5.0 MPa. Subsequently, the mixture was stirred for 20 hours at 50°C. The reaction
10 liquid was subjected to a GC analysis, and as a result, it was found that
2-methyl-l,2,3,4-tetrahydroquinoxaline, which is a reduced form, was produced at a conversion rate of
68.5%, with an optical purity of 48% ee.

15 [Chem. 22]
ax cc!H
Asymmetrichydrogenation reactions were carried out in the same manner as in Example 34, by
respectively using Ru(BF4)((R,R)-0-HT-Tsdpen), Ru(OTf)((R,R)-0-HT-Tsdpen),
Ru(SbF6)((R,R)-0-HT-Tsdpen) as the catalyst, in the HFIP solvent. 2-Methylquinoxaline was used as
20 the substrate for the reactions, and the reactions were respectively carried out for 20 hours. The results
are presented in the following Table 5.
32
WO 2012/026201
[Table 5]
PCT/JP2011/064490
Catalyst
(S/C=100)
Ru(BF4)(0-HT-Tsdpen)
Ru(OTf)(0-HT-Tsdpen)
Ru(SbF6)(0-HT-Tsdpen)
Solvent
HFIP
HFIP
HFIP
Conversion rate
(%conv.)
68.5
66.0
65.2
Assymetric yield
(%ee)
48
46
46

Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethanol and
2-((5-methylcyclohexa-1,4-dienyl)methoxy)ethanol
[Chem. 23]
(1,4type)
II ll
X ,^\/°H OH
XX»J^
7.74 g (0.019 mol) of l,2-bis(diphenylphosphino)ethane, 4.05 g (0.019 mol) of cobalt bromide,
11.82 g (0.037 mol) of zinc iodide, and 2.42 g (0.037 mol) of zinc were added to 460 ml of THF, and the
10 solution was stirred for 15 minutes at 70°C. The solution was cooled to room temperature, and 74.89 g
(1.10 mol) of isoprene was added thereto. Subsequently, 92.70 g (0.93 mol) of alkynyl alcohol was
slowly added dropwise to the mixture in a water bath. The resulting mixture was stirred for one hour at
35°C, and then the solvent was distilled off under a reduced pressure. To the residue thus obtained, 460
ml of toluene and 460 ml of water were added (stirred for 10 minutes, and left to stand for 10 minutes).
15 The mixture was filtered through Celite in a nitrogen atmosphere, and then the organic layer of solution
thus obtained was separated. The solvent was distilled off under reduced pressure, and the crude
product thus obtained was purified by Claisen distillation (101°C-113°C, at 3 torr). Thus, 106.6 g of
diene alcohol was obtained as a colorless oil. Yield 68.5% (l,4-type/l,5-type = 91/9).
20 'H-NMR^DCb, 300MHz)5:
1.68 (s, 3H) , 2.31 (brs, 1H), 2.64 (brs, 4H), 3.48 - 3.52 (m, 2H), 3.70 - 3.75 (m, 2H), 3.93 (s, 2H), 5.43 -
5.45 (m, 1H), 5.70 - 5.71 (m, 1H);
HRMS (ESI):
As CioHi602
25 Calculated value: [M+H]+ 167.1430
Found value: 167.1432
30

Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethyl 4-methylbenzenesulfonate and
2-((5 -methylcyclohexa-1,4-dienyl)methoxy)ethyl 4-methylbenzenesulfonate
[Chem. 24]
33
WO 2012/026201 PCT/JP2011/064490
(1,4type) (1,4type)
OTs
(1,5type)
10
15
100.00 g (0.59 mol) of the diene alcohol obtained in Example 36, 90.29 g (0.89 mol) of
triethylamine, and 73.20 g (0.89 mol) of 1-methylimidazole were dissolved in 400 ml of toluene. In an
ice bath, a toluene solution (400 ml) of 130.33 g (0.68 mol) of p-toluenesulfonyl chloride was slowly
added dropwise to the solution, and then the resulting mixture was stirred for one hour at room
temperature. Water was added thereto, and the organic layer was separated. The obtained organic
layer was washed sequentially with 15% sulfuric acid, water, and a saturated aqueous sodium hydrogen
carbonate. The solvent was distilled off under reduced pressure, and thus 188.01 g of the desired
tosylate was obtained as a colorless oil. Yield 98.1% (l,4-type/l,5-type = 91/9).
'H-NMR^DCIB, 300MHZ)5:
1.67 (s, 3H), 2.44 (s, 3H), 2.58 (brs, 4H), 3.58 - 3.55 (m, 2H), 3.84 (s, 2H), 4.18 - 4.14 (m, 2H), 5.41 -
5.40 (m, 1H), 5.64 - 5.63 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H);
HRMS (ESI):
As C17H22O4S
Calculated value: [M+H]+ 323.1312
Found value: 323.1325

20 Production of
4-methyl-N-(( 1 R,2R)-2-(2-((4-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylethyl)ben
zenesulfonamide hydrochloride and
4-methyl-N-(( 1 R,2R)-2-(2-((5-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylethyl)ben
zenesulfonamide hydrochloride
25 [Chem. 25]
(1,4type)
OTs
(I) (1,4type)
TsHN NH2
Ph Ph
NHTs
(1,5type) (ii)
OTs
HCI XX, HCI Ph
H J..,
(1,5type)
Ph
NHTs
2.2 g (6.9 mmol) of the tosylate obtained in Example 37 was dissolved in 10 ml of toluene, and
0.90 g (6.9 mmol) of DEPEA and 2.53 g (6.9 mmol) of (R,R)-TsDPEN were added to the solution. The
resulting mixture was stirred for 27 hours at 135°C. Water was added thereto, and the organic layer
34
WO 2012/026201 PCT/JP2011/064490
was separated. The obtained organic layer was washed with water, then 20% hydrochloric acid was
added thereto. The resulting mixture was stirred for one hour at room temperature, and then was
precipitated under ice cooling. Crystals precipitated therefrom were collected by filtration, and thus
3.14 g of the desired diamine hydrochloride was obtained as a white solid. Yield 82.3%.
10
'H-NMI^CDCla, 300MHz)8:
1.43-1.80(m, 6H), 2.32(s, 3H), 2.42-2.70(m, 2H), 3.40-3.55(m, 2H), 3.70-3.85(m, 2H) ,3.77(d, IH),
4.30(m, IH), 4.45 (d, IH), 6.93-7.38(m, 14H);
HRMS (ESI):
As C31H37N2O3S
Calculated value: [M-C1]+ 517.2519
Found value: 517.2523
15
20
25

Production of RuCl((R,R)-0-HT-Tsdpen)
[Chem. 26]
(1,4type)
HCI Ph
TsN-Ru-fTc,
JL Mi—'
H
(1,4type)
I HCI Ph
H J,.,
(1,5type)
Ph
NHTs
TsN^Ru^fil
J ,N:—'
H
(1,3type)
25.15 g (45.20 mmol) of the diamine hydrochloride produced in Example 38 was dissolved in
375 ml of 3-methoxypropanol and 75 ml of water. 10.74 g (41.09 mmol) of ruthenium trichloride
trihydrate and 3.45 g (41.09 mmol) of sodium hydrogen carbonate were added to the solution, and the
resulting mixture was stirred for 45 minutes at 120°C. 3-methoxypropanol was recovered, and then
425 ml of MIBK and 16.63 g (164.4 mmol) of triethylamine were added to the reaction liquid, and the
mixture was stirred for one hour at 60°C. Heptane was added to the residue which washed by 0.3 M
hydrochloric acid, and the residue was subjected to crystallization. And thus 22.26 g of the desired Ru
complex was obtained. Yield 83.3%.
30
'H-NMR^DCls, 500MHz)8:
2.26 (s, 3H), 2.52 (s, 3H), 3.14 - 3.10 (m, IH), 3.60 - 3.56 (m, IH), 3.98 - 3.91 (m, 4H), 4.58 - 4.45 (m,
2H), 4.96 - 4.92 (m, IH), 5.46 (brd, J = 3.6 Hz, IH), 5.62 (d, J = 6.3 Hz, IH), 5.75 (d, J = 6.3 Hz, IH),
6.05 (brd, J = 3.6 Hz, IH), 6.60 (d, J = 7.3 Hz, 2H), 6.75 - 6.69 (m, 4H),7.21 (d, J = 8.0 Hz, 2H), 6.84 (d,
J = 7.3 Hz, IH), 6.88 (d, J = 8.0 Hz, 2H), 7.17 - 7.08 (m, 4H);
HRMS (ESI):
35
WO 2012/026201 PCT/JP2011/064490
As C31H34CIN2O3RUS
Calculated value: [M+H]+ 651.1057
Found value: 651.1008
5
Production of RuCl((R,R>0-HT-Tsdpen)-dimer
[Chem. 27]
15
20
NHTs
HCI
0.50 g (0.904 mmol) of the diamine hydrochloride produced in Example 38 was dissolved in
10 7.5 ml of 2-methoxypropanol and 1.5 ml of water. 0.23 g (0.86 mmol) of ruthenium trichloride
trihydrate and 0.072 g (0.86 mmol) of sodium hydrogen carbonate were added to the solution, and the
resulting mixture was stirred for 90 minutes at 120°C. 2-Methoxypropanol was recovered, and then 15
ml of diethyl ether was added to the residue. Crystals precipitated therefrom were collected by
filtration, and thus 0.60 g of the desired Ru complex was obtained. Yield 96.5%.
'H-NMRpMSO-do, 300MHz)8:
2.10-2.15 (m, 3H), 2.20 (s, 3H), 2.70-3.00 (m, 2H), 3.60-3.90 (m, 2H), 4.35 - 4.42 (m, 2H), 4.70 (m,lH),
4.85 (m, 1H), 5.75-6.10 (m, 4H), 6.88-7.35 (m, 14H), 8.90 (brd, 1H), 8.95-9.15 (m, 2H), 10.00 (brd,
1H);

Asymmetric hydrogen transfer reaction of acetophenone using complex
RuCl((R,R)-C--HT-Tsdpen)-dimer (S/C = 1000)
In a 50-ml Schlenk tube, 3.6 mg (0.005 mmol) of the complex
25 RuCl((R,R)-0-HT-Tsdpen)-dimer produced in Example 40 as described above, 0.58 ml (0.60 g, 5 mmol)
of acetophenone, and 2.5 ml of a formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the
Schlenk tube was purged with nitrogen. Subsequently, the mixture was allowed to react for 5 hours at
60°C. An analysis of the reaction liquid was carried out by GC, and it was found that
(R)-l-phenylethanol with 96.2% ee was produced at a conversion rate of 97.5%.
30

Production of
N-(( 1 R,2R)-2-(2-((4-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylethyl)-2-(trifluoro
methyl)benzenesulfonamide hydrochloride
35 [Chem. 28]
36
WO 2012/026201 PCT/JP2011/064490
10
(0
I V <
5-NH NH2
XX^>™ - - \ XX,- Ph
°^^w^vph
F3C
(ii) HCI ^ T \ I ^
"S H N t P K
F3C
8.07 g (26.1 mmol) of the tosylate obtained in Example 37 was dissolved in 31.6 ml of toluene,
and 3.38 g (26.2 mmol) of DIPEA, 10.00 g (23.8 mmol) of (R,R)-o-TFTsDPEN, and 4.34 g (26.2 mmol)
of potassium iodide were added to the solution. The resulting mixture was stirred for 6 hours at 135°C.
The reaction liquid was concentrated, and was purified by silica gel column chromatography. Thus,
10.1 g of diamine J was obtained. Yield 74.5%. Subsequently, 110 ml of dichloromethane and 65.3
ml of an HCl-methanol solution (1 N) were added to 10.1 g (17.7 mmol) of the diamine J, and the
resulting mixture was stirred for 0.5 hours. Subsequently, the solvent was removed, and thus 11.1 g of
the desired diamine hydrochloride K was obtained. Yield 93.9%.
'H-NMRpMSO-dfi, 300MHz)5:
1.62(m, 3H), 2.60(s, 3H), 2.78-3.12(m, 2H), 3.52-3.70(m, 2H), 3.86(s, 2H) ,4.75(m, IH), 4.92(m, IH),
5.40(m, IH), 5.68(m, IH), 6.75-7.35(m, 10H), 7.40(t, IH), 7.50(t, IH), 7.60(d, IH), 7.75(d, IH), 8.90(m,
IH), 8.98(brd, IH), 9.92(brd, IH);
15 19F-NMR(DMSO-d6) 8:
-57.16
HRMS (ESI):
As C31H33N2O3F3SHCI
Calculated value: [M-C1]+ 571.2237
20 Found value: 571.2244

Production of RuCl((R,R)-0-HT-o-TFTsdpen)
[Chem. 29]
37
WO 2012/026201 PCT/JP2011/064490
6"
5.0 g (8.25 mmol) of the diamine hydrochloride produced in Example 42 was dissolved in 66
ml of 3-methoxypropanol and 22 ml of water. 1.79 g (6.86 mmol) of ruthenium trichloride trihydrate
and 0.58 g (6.86 mmol) of sodium hydrogen carbonate were added to the solution, and the resulting
5 mixture was stirred for 2 hours at 120°C. 50 ml of 3-methoxypropanol was recovered, and then 75 ml
of MD3K and 2.78 g (27.45 mmol) of triethylamine were added to the residue. The mixture was stirred
for one hour at 60°C. 0.3 M hydrochloric acid was added thereto, and the organic layer was separated.
The obtained organic layer was washed two times with water. After washing, about 60 ml of the solvent
was recovered, and 85 ml of heptane was added to the residue. The mixture was subjected to
10 crystallization. Crystals precipitated therefrom were collected by filtration, and thus 4.60 g of the
desired Ru complex was obtained. Yield 95.2%.
'H-NMR^DaClj, 300MHz)8:
2.50 (s, 3H), 3.15 - 3.20 (m, 1H), 3.70 - 3.82 (m, 2H), 4.00 (m, 2H), 4.15 (m, 1H), 4.40 (m, 1H), 4.80 (m,
15 1H), 5.10 (d, 1H), 5.45 (d, 1H), 5.62 (d, 1H), 5.70 (d, 1H), 6.38 (d, 1H), 6.50-7.50(m, 14H);
19F-NMR(DMSO-d6)8:
-58.45
HRMS(ESI)
As CsiHsoC^OaFsRuS
20 Calculated value: [M+H]+ 705.7034
Found value: 705.0758

Asymmetrichydrogen transfer reaction of acetophenone using complex
25 RuCl((R,R)-0-HT-o-TFTsdpen) (S/C=1000)
In a 50-ml Schlenk tube, 3.5 mg (0.005 mmol) of the complex RuCl((R,R)-0-HT-o-TFTsdpen)
produced in Example 43 as described above, 0.58 ml (0.60 g, 5 mmol) of acetophenone, and 2.5 ml of a
formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the Schlenk tube was purged with
nitrogen. Subsequently, the mixture was allowed to react for 5 hours at 60°C. An analysis of the
30 reaction liquid was carried out by GC, and it was found that (R)-l-phenylethanol with 97.5% ee was
produced at a conversion rate of 98.9%.

Production of
3 5 2,4,6-triisopropyl-N-(( 1 S,2S)-2-(2-((4-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylet
38
10
15
WO 2012/026201
hyl)benzenesulfonamide
[Chem. 30]
PCT/JP2011/064490
XX, ° ^
«v^v
OTs
6.03 g (18.82 mmol) of the tosylate obtained in Example 37 as described above was dissolved
in 25 ml of toluene, and 2.43 g (18.82 mmol) of DEPEA and 9.00 g (18.80 mmol) of (S,S)-TD?PsDPEN
were added to the solution. The mixture was stirred for 13 hours at 135°C. Subsequently, the solvent
was distilled off under reduced pressure, and the residue thus obtained was purified by silica gel column
chromatography (toluene/ethyl acetate = 20/1 -> 15/1). Thus, 10.53 g of the title compound was
obtained as a colorless oil. Yield 89.0%.
^-NMR^DCU, 300MHz)5:
1.06(d, J = 6.9Hz, 3H), 1.21(d, J = 6.9Hz, 3H), 1.87(brs, 1H), 1.68(s, 3H), 2.60(brs, 4H), 2.71-2.48(m,
2H), 3.52-3.34(m, 2H), 3.55(d, J = 8.9Hz, 1H), 3.77(s, 2H), 3.95(septet, J = 6.7Hz, 3H), 4.40(d, J =
8.9Hz,lH), 5.44(m, 1H), 5.64(m, lH),6.52(brs, 1H), 6.74-7.28 (m, 12H);
HRMS (ESI):
As C39H53N2O3S
Calculated value: [M+H]+ 629.3 771
Found value: 629.3771
20
25
30

Production of RuCl((S,S)-0-HT-TD?Psdpen)
[Chem. 31]
2.02 g (3.21 mmol) of the sulfonamide obtained in Example 45 as described above was
dissolved in 8 ml of methanol. Under ice cooling, 0.67 g (6.42 mmol) of a 1 M methanol solution of
hydrochloric acid was added to the solution, and the mixture was stirred for 20 minutes at room
temperature. Subsequently, the solvent was distilled off under reduced pressure, and the residue thus
obtained was dissolved in 30 ml of 3-methoxypropanol and 18 ml of water. 0.72 g (2.75 mmol) of
ruthenium trichloride trihydrate was added to the solution, and the mixture was stirred for one hour at
120°C. The solvent was distilled off under reduced pressure, and to the residue thus obtained, 35 ml of
B?A and 0.72 g (7.15 mmol) of triethylamine were added. The resulting mixture was stirred for one
hour at 60°C. The solvent was distilled off under reduced pressure, and the residue thus obtained was
39
WO 2012/026201 PCT/JP2011/064490
purified by silica gel column chromatography (chloroform/methanol = 97/3 -> 20/1). Thus, 1.28 g of
the desired Ru complex was obtained. Yield 52.3%.
'H-NMRCCDaClz 500MHz)8:
5 1.0-1.2(m, 18H), 1.70(m, IH), 2.41(s, 3H), 2.60(m, IH), 3.05(m, IH), 3.35(m, IH), 3.68(m, IH), 3.75(t,
IH), 3.85(m, 2H), 4.18(d, IH), 4.25(d, IH), 4.85(brs, IH), 5.02(d, IH), 5.30(d, IH), 5.48(d, IH), 5.63(d,
IH), 6.35(d, IH), 6.40-6.70(m, 10H), 6.90-7.05(m, 3H);
HRMS (ESI):
As C39H50N2O3SCIRU
10 Calculated value: [M+H]+ 763.2269
Found value: 763.2257

Asymmetric hydrogen transfer reaction of acetophenone using complex
15 RuCl((S,S)-O-HT-TIPPsdpen)(S/C = 1000)
In a 50-ml Schlenk tube, 2.8 mg (0.005 mmol) of the complex RuCl((S,S)-0-HT-TIPPsDPEN)
produced in Example 46 as described above, 0.58 ml (0.60 g, 5 mmol) of acetophenone, and 2.5 ml of a
formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the Schlenk tube was purged with
nitrogen. Subsequently, the mixture was allowed to react for 10 hours at 60°C. An analysis of the
20 reaction liquid was carried out by GC, and it was found that (S)-l-phenylethanol with 95.8% ee was
produced at a conversion rate of 38.5%.

Production of 4-(4,5-dimethylcyclohexa-1,4-dienyl)butan-1 -ol
25 [Chem. 32]
- II II .
OH
800 mg (2.00 mmol) of l,2-bis(diphenylphosphino)ethane, 437 mg (2.00 mmol) of cobalt
bromide, 1.28 g (4.00 mmol) of zinc iodide, and 260 mg (4.00 mmol) of zinc were added to 40 ml of
THE, and the solution was stirred for 15 minutes at 70°C. The solution was cooled to room
30 temperature, and 9.86 g (120 mmol) of 2,3-dimethyl-l,3-butadiene was added thereto. Subsequently,
9.8 g (100 mmol) of 5-hexyn-l-ol was slowly added dropwise to the mixture in a water bath. The
resulting mixture was stirred for one hour at 35°C, and then the solvent was distilled off under reduced
pressure. The residue thus obtained was purified by silica gel column chromatography (hexane/ethyl
acetate = 3/1), and thus 11.5 g of the title compound alcohol was obtained as a colorless oil. Yield
35 63.4%.
!H-NMR(CDCl3, 300MHz)5:
1.28(bs, IH), 1.79-1.46(m, 4H), 1.63(s, 6H), 1.98-2.11(m, 3H), 2.48-2.61(m, 2H), 3.63 -3.67(m, 2H),
40
5.41-5.56(m, IH);

Production of 4-(4,5-dimethylcyclohexa-l,4-dienyl)butyl4-methylbenzenesulfonate
[Chem. 33]
40
WO 2012/026201 PCT/JP2011/064490
15
II II ^ II l|
OH ^ ^ - ^ ^ -OTs
11.0 g (61.0 mmol) of 4-(4,5-dimethylcyclo-l,4-diene)butan-l-ol, 7.40 g (73.08 mmol) of
triethylamine, and 6.0 g (73.0 mmol) of 1-methylimidazole were dissolved in 55 ml of toluene. In an
ice bath, 40 ml of a toluene solution of 13.9 g (73.1 mmol) of p-toluenesulfonyl chloride was slowly
5 added dropwise to the solution, and then the resulting mixture was stirred for one hour at room
temperature. Water was added to the mixture, and the organic layer was separated. The obtained
organic layer was washed with 2 M hydrochloric acid and water. The solvent was distilled off under
reduced pressure, and the residue thus obtained was purified by silica gel column chromatography
(hexane/ethyl acetate = 20/1 -» 4/1). Thus, 16.3 g of tosylate of the title compound was obtained.
10 Yield 80%.
'H-NMR^DCla, 300MHz)8:
1.60-1.41(m, 2H), 1.67(s, 6H), 1.79-1.74(m, 3H), 1.89-2.05(m, 3H), 2.45(s, 3H ), 2.53 (brs, 2H),
4.00-4.05(m, 2H), 5.28-5.40(m, IH), 7.33-7.36(d, 2H ), 7.77-7.80(d, 2H );

Production of
N-(( 1 R,2R)-2-(2-((4,5-dimethylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylethyl)methanes
ulfonamide
20 [Chem. 34]
MsHN NH2 X
Ph Ph ~XX< OTs
Ph
NHMs
8.00 g (23.78 mmol) of the tosylate obtained in Example 49 was dissolved in 35 ml of toluene,
and 3.07 g (23.78 mmol) of DDPEA and 6.90 g (23.78 mmol) of (R,R)-MsDPEN were added to the
solution. The mixture was stirred for 12.5 hours at 135°C. Subsequently, the solvent was distilled off
25 under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography
(hexane/ethyl acetate = 2/1). Thus, 9.83 g of the title compound was obtained as a colorless solid.
Yield 90.9%.
^-NMI^CDCls, 300MHz)8:
30 1.65(s, 3H), 1.68(s, 3H), 1.89-1.75(m, IH), 2.33(s, 3H), 2.46-2.54(m, 3H), 2.60-2.71(m, 3H),
3.35-3.48(m, 2H), 3.77(s, 2H), 3.81(d, J=7.8Hz, IH), 4.47(d, J=7.8Hz,lH), 5.60(m, IH), 6.21(brs, IH),
7.10-7.27(m, 10H);
HRMS (ESI):
As C26H35N2O3S
35 Calculated value: [M+H]+ 455.2363
Found value: 455.2358

Production of RuCl((R,R)-xyl-0-HT-Msdpen)
40 [Chem. 35]
41
WO 2012/026201 PCT/JP2011/064490
NHMs n ^ Y H
2.00 g (4.40 mmol) of the diamine compound obtained in Example 50 was dissolved in 8 ml of
dichloromethane. Under ice cooling, 0.92 g (8.80 mmol) of a 1 M methanol solution of hydrochloric
acid was added to the solution, and the mixture was stirred for 20 minutes at room temperature.
5 Subsequently, the solvent was distilled off under reduced pressure, and the residue thus obtained was
dissolved in 30 ml of 3-methoxypropanol and 18 ml of water. 0.97 g (3.71 mmol) of ruthenium
trichloride trihydrate was added to the solution, and the resulting mixture was stirred for one hour at
120°C. The solvent was distilled off under reduced pressure, and to the residue thus obtained, 35 ml of
EPA and 0.80 g (7.87 mmol) of triethylamine were added. The resulting mixture was stirred for one
10 hour at 60°C. The solvent was distilled off under reduced pressure, and the residue thus obtained was
purified by silica gel column chromatography (chloroform/methanol = 97/3 —> 20/1). Thus, 1.48 g of
the desired Ru complex was obtained. Yield 57.2%.
1H-NMR(CDCl3,300MHz)5:
15 2.27(s, 3H), 2.30(s, 3H), 2.39(s, 3H), 3.15-3.35(m, 2H), 3.75-3.85(m, 2H), 4.00-4.10 (m, 2H),
3.95-4.05(brs, 1H), 4.42(d, 1H), 4.85(d, 1H), 5.50(d, 1H), 5.76(s, 1H), 5.85 (d, 1H), 6.82-7.22(m, 10H);
HRMS (ESI):
As C26H32N203SClRu
Calculated value: [M+H]+ 589.0860
20 Found value: 589.0863

Asymmetric hydrogen transfer reaction of acetophenone using complex
RuCl((R,R)-xyl-0-HT-Msdpen) (S/C = 1000)
25 In a 50-ml Schlenk tube, 2.8 mg (0.005 mmol) of the complex RuCl((R,R)-xyl-0-HT-Msdpen)
produced in Example 51 as described above, 0.58 ml (0.60 g, 5 mmol) of acetophenone, and 2.5 ml of a
formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the Schlenk tube was purged with
nitrogen. Subsequently, the mixture was reacted for 10 hours at 60°C. An analysis of the reaction
liquid was carried out by GC, and it was found that (R)-l-phenylethanol with 95.9% ee was produced at
30 a conversion rate of 95.4%.

Production of
4-methyl-N-(( 1 R,2R)-2-(2-((4-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)cyclohexyl)benzenesul
35 fonamide hydrochloride
[Chem. 36]
42
WO 2012/026201 PCT/JP2011/064490
(') TsHN NH2
10
XXo^TS ^_ XX,
HN-Ts
(ii) HCI ~^a, M
5.06 g (16.4 mmol) of the tosylate obtained in Example 37 was dissolved in 26 ml of toluene,
and 2.12 g (16.4 mmol) of DIPEA, 4.00 g (14.9 mmol) of (R,R)-TsCYDN, and 2.72 g (16.4 mmol) of
potassium iodide were added to the solution. The resulting mixture was stirred for 20 hours at 135°C.
The reaction liquid was concentrated and purified by silica gel column chromatography. Thereby, 2.92
g of diamine L was obtained. Yield 46.9%. Subsequently, 42 ml of dichloromethane and 24.6 ml of
an HCl-methanol solution (1 N) were added to 2.8 g (6.69 mmol) of the diamine L, and the resulting
mixture was stirred for 0.5 hours. Subsequently, the solvent was removed, and thus 2.9 g of the desired
diamine hydrochloride M was obtained. Yield 94.7%.
^-NMR^MSO-de, 300MHz)8:
0.95-1.30(m, 4H), 1.50(m, 2H), 1.63(s, 3H), 2.10(m, 2H), 2.40(s, 3H), 2.60(m, 2H), 2.95(brd, 1H),
3.18(m, 2H), 3.60(m, 2H), 3.90(s, 2H), 5.40(m, 1H), 5.70(m, 1H), 7.40(d, 1H), 7.75(d, 1H), 8.15(d, 1H),
8.23(brd, 1H), 9.10(brd, 1H)
15 HRMS (ESI):
As C23H34N203S
Calculated value: [M-C1]+ 419.2363
Found value: 419.2365
20
Production of RuCl((R,R)-0-HT-Tscydn)
[Chem. 37]
XX, H
HCI HN" TS
0.5 g (1.1 mmol) of the diamine hydrochloride produced in Example 53 was dissolved in 15 ml
25 of 3-methoxypropanol and 3 ml of water. 0.25 g (0.96 mmol) of ruthenium trichloride trihydrate and
43
WO 2012/026201 PCT/JP2011/064490
0.08 g (0.96 mmol) of sodium hydrogen carbonate were added to the solution, and the resulting mixture
was stirred for one hour at 120°C. 12 ml of 3-methoxypropanol was recovered, and then 13 ml of
MEBK and 0.39 g(3.82 mmol) of triethylamine were added to the residue. The resulting mixture was
stirred for one hour at 60°C. 0.3 M hydrochloric acid was added thereto, and the organic layer was
5 separated. The obtained organic layer was washed two times with water. After washing,
approximately 10 ml of the solvent was recovered, 15 ml of heptane was added to the residue, and the
resulting mixture was subjected to crystallization. Crystals precipitated therefrom were collected by
filtration, and thus 0.24 g of the desired Ru complex was obtained. Yield 45.5%.
10 'H-NMRCCDzCl, 500MHz)5:
0.65-1.05(m, 4H), 1.90(m, 1H), 1.15(m, 1H), 2.08(m, 1H), 2.70(m, 1H), 2.75(s, 1H), 2.77(s, 1H),
2.60(m, 1H), 3.60-3.70(m, 2H), 3.80(m, 1H), 4.00(m, 1H), 4.25(m, 1H), 4.35(d, 1H), 4.92(d, 1H),
5.25(d, 1H), 5.50(d, 1H), 5.67(d, lH),5.83(d, 1H), 7.20 (d, 1H), 7.80(d, 1H);
HRMS (ESI):
15 As C23H3iN203RuS
Calculated value: [M-C1]+ 517.1093
Found value: 517.1101

20 Asymmetric hydrogen transfer reaction of acetophenone using complex
RuCl((R,R)-0-HT-Tscydn) (S/C = 1000)
In a 50-ml Schlenk tube, 2.8 mg (0.005 mmol) of the complex RuCl((R,R)-0-HT-Tscydn)
produced in Example 54 as described above, 0.58 ml (0.60 g, 5 mmol) of acetophenone, and 2.5 ml of a
formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the Schlenk tube was purged with
25 nitrogen. Subsequently, the mixture was allowed to react for 10 hours at 60°C. An analysis of the
reaction liquid was carried out by GC, and it was found that (R)-l-phenylethanol with 95.5% ee was
produced at a conversion rate of 73.7%.

30 Production of
2,4,6-trimethyl-N-(( 1 R,2R)-2-(2-((4-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenyleth
yl)benzenesulfonamide
[Chem. 38]
XL, ° ^ O T s
35 1.0 g(3.0 mmol) of the tosylate obtained in Example 37 was dissolved in 5 ml of toluene, and
0.39 g (3.0 mmol) of DIPEA and 1.3 g (3.3 mmol) of (R,R)-MESsDPEN were added to the solution.
The mixture was stirred for 8 hours at 120°C. Subsequently, the solvent was distilled off under reduced
pressure, and the residue thus obtained was purified by silica gel column chromatography (toluene/ethyl
acetate = 4/1). Thus, 0.71 g of the title compound was obtained as a colorless oil. Yield 44.7%.
40
44
WO 2012/026201 PCT/JP2011/064490
10
15
20
25
30
35
Production of RuCl((R,R)-0-HT-MESsDPEN)
[Chem. 39]
Bh XX. H „,
0.67 g (1.2 mmol) of the sulfonamide obtained in Example 56 was dissolved in 5 ml of
methanol. Under ice cooling, 0.25 g (2.4 mmol) of a 1 M methanol solution of hydrochloric acid was
added to the solution, and the resulting mixture was stirred for 20 minutes at room temperature.
Subsequently, the solvent was distilled off under reduced pressure, and the residue thus obtained was
dissolved in 20 ml of 2-methoxyethanol, 2 ml of water, and 0.09 g (1.2 mmol) of sodium hydrogen
carbonate. 0.36 g (1.35 mmol) of ruthenium trichloride trihydrate was added to the solution, and the
resulting mixture was stirred for 3 hours at 120°C. The solvent was distilled off under reduced
pressure, and to the residue thus obtained, 40 ml of ethanol and 0.5 g (4.94 mmol) of triethylamine were
added. The resulting mixture was stirred for 2 hours at 80°C. The solvent was distilled off under
reduced pressure, and the residue thus obtained was purified by silica gel column chromatography
(chloroform/methanol = 20/1). Thus, 0.13 g of the desired Ru complex was obtained. Yield 16.0%.
'H-NMR(CD2C1, 500MHZ)5:
1.95 (s, 3H), 2.45(s, 6H), 2.46(s, 3H), 3.05(m, 1H), 3.70(m, 1H), 3.80(d, 1H), 3.85(m, 2H), 3.95(d, 1H),
4.25(d, 1H), 4.75(m, 1H), 5.00(d, 1H), 5.40(d, 1H), 5.50(d, 1H), 5.60(d, 1H), 6.30(s, 2H), 6.53(d, 1H),
6.40-7.00(m, 10H);
HRMS (ESI):
As C33H37ClN203RuS
Calculated value: [M+H]+ 679.1335
Found value: 679.1327

Production of Ru((R,R>0-HT-TsDPEN)
[Chem. 40]
// vs
O
Ts
'/ ^y
CI
KOH
H20, CH2CI2
Ph Ph
To a suspension of RuCl((R,R)-0-HT-TsDPEN) 140 mg (0.215 mmol) and potassium hydroxide 84 mg
(1.28 mmol) in dichloromethane (10 mL) was added water (1 mL). The reaction mixture was stirred at
room temperature for 20min. Then the organic solution was washed with water three times (10 mL><3).
The organic layer was concentrated under reduced pressure to give the desired product as purple solid.
Yield 125 mg (95%)
lH NMR (500 MHz, CD2C12) 5 7.48 (d, J= 7.3 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.30-6.85 (m, 8H), 6.98
45
WO 2012/026201 PCT/JP2011/064490
(d, J= 8.0 Hz, 2H), 6.15 (d, J= 6.3 Hz, IH), 5.55 (d, J= 6.0 Hz, IH), 5.45 (dd, J= 6.3, 6.0 Hz, 2H), 4.95
(d, J= 14.4 Hz, IH), 4.35 (d, J= 14.4 Hz, IH), 4.13 (s, IH), 3.55-3.42 (m, 2H), 3.36-3.28 (m, IH), 3.35
(s, IH), 3.08-3.00 (m, IH), 2.60 (s, 3H), 2.32 (s, 3H);
HRMS (ESI):
5 As C31H33N2O3S
Calculated value: [M+H]+ 615.1250
Found value: 615.1231

10 Production of RuH((R,R)-0-HT-TsDPEN)
[Chem. 41]
plf^S "H H20,CH2CI2
T s ^ . . > R J ' \ c | KOH
Ph
To a suspension of RuCl((R,R)-0-HT-TsDPEN) 140 mg (0.215 mmol) and potassium hydroxide 84 rng
(1.28 mmol) in dichloromethane (10 mL) was added water (1 mL). The reaction mixture was stirred at
15 room temperature for 20min. Then the organic solution was washed with water three times (10 mL><3).
The organic layer was separated to another Schlenk tube and this solution was added formic acid (2 mL).
The reaction mixture was stirred at room temperature for 5min. Then the organic solution was washed
with water three times (10 mL><3). The organic layer was concentrated under reduced pressure to give the
desired product as light brown solid. Yield 120 mg (90%)
20
'HNMR (300 MHz, CD2C12) 8 7.50-6.60 (m, 14H), 6.30 (d, J= 4.5 Hz, IH), 6.05 (m, 2H), 5.45 (m, IH),
4.85 (d, J= 13.5 Hz, IH), 4.78 (d, J= 4.5 Hz, IH), 4.25-3.90 (m, 4H), 3.85 (d, J= 13.5 Hz, IH),
3.20-3.15 (m, IH), 2.80-2.70 (m, IH), 2.22 (s, 3H), 2.20 (s, IH), -5.10 (s, IH);
HRMS (ESI):
25 As C3iH33N203S
Calculated value: [M-H]+ 615.1250
Found value: 615.1243

3 0 Production of Ru (BF4)((R,R)-0-HT-TsDPEN)
[Chem. 42]
f~~\— / r-$ ^ — \ r-#~^
P K /V ^H H2O.CH2CI2 \ Ph^V / PirV H
pfi \ PR / ps
To a suspension of RuCl((R,R)-0-HT-TsDPEN) 140 mg (0.215 mmol) and potassium hydroxide 84 mg
(1.28 mmol) in dichloromethane (10 mL) was added water (1 mL). The reaction mixture was stirred at
35 room temperature for 20min. Then the organic solution was washed with water three times (10 mL><3).
The organic layer was separated to another Schlenk tube and this solution was added 42% aqueous HBF4
46
WO 2012/026201 PCT/JP2011/064490
solution (0.5 mL). The reaction mixture was stirred at room temperature for 5min. Then the organic
solution was washed with water three times (10 mL><3). The organic layer was concentrated under
reduced pressure to give the desired product as brown solid. Yield 136 mg (90%)
5 ]H-NMR(CD30D, 300MHz)5:
2.12(s, 3H), 2.46(s, 3H), 3.35-3.60(m, 4H), 3.60-3.80(m, 1H), 3.95-4.10(m, 3H),
4.70-4.80(m, 1H), 5.84(d, 1H), 5.89(d, 1H), 5.99(d, 1H), 6.20(d, lH),6.46-7.50(m, 14H)
HRMS (ESI):
As C31H33BF4N203RuS,
10 Calculated value: [M-BF4]+ 615.1250
Found value: 615.1271
Industrial Applicability
The present invention provides a novel ruthenium complex which can be produced
15 conveniently and safely. The ruthenium complex of the present invention is a ruthenium complex
which has a very strong catalytic activity, is useful as a catalyst for various hydrogenation reactions, is
also useful as a catalyst for asymmetric reduction having excellent stereoselectivity and capable of
giving a high enantiomeric excess, and is useful in the field of industrial chemistry.

We Claim
1. A ruthenium complex represented by the following formula
(2):
[Chem. 44]
Ri//°R14
( Q 0 ) (2)
wherein symbol * represents an asymmetric carbon atom;
R1 represents an alkyl group having 1 to 10 carbon atoms;
a halogenated alkyl group having 1 to 10 carbon atoms; 10-
camphoryl group; an amino group which may be substituted with
one or two alkyl group having 1 to 10 carbon atoms; an aryl
group which may be substituted with an alkyl group having 1 to
10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon
atoms, a halogen atom, a cyano group (-CN), an amino group, an
alkylated amino group (-NR20R21), a five or six membered cyclic
amino group, an acylated amino group (-NH-CO-R20), a hydroxyl
group, an alkoxy group (-OR20), an acyl group (-CO-R20), a
carboxyl group, an alkoxycarbonyl group (-COOR20), a phenoxy
carbonyl group, a mercapto group, an alkylthio group (-SR20), a
silyl group (-SiR20R21R22), or a nitro group (-NO2); R20, R21 and
R22 each independently represent a hydrogen atom, an alkyl group
having 1 to 10 carbon atoms or a cycloalkyl group having 3 to
10 carbon atoms;
Y represents a hydrogen atom;
R2 and R3 each independently represent a hydrogen atom; an
alkyl group having 1 to 10 carbon atoms; a phenyl group which
may be substituted with an alkyl group having 1 to 10 carbon
atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen
atom; or a cycloalkyl group having 3 to 8 carbon atoms, or R2
and R3 may be joined together to form a ring;
R11, R12, R13, R14 and R15 each independently represent a
hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or
an alkoxy group having 1 to 10 carbon atoms;
R16, R17, R18 and R19 each independently represent a hydrogen
atom, a hydroxyl group, an alkyl group having 1 to 10 carbon
atoms, or an alkoxy group having 1 to 10 carbon atoms, or R16
and R17 with the carbon atom which is substituted with R16 and
R17, and/or R18 and R19 with the carbon atom which is substituted
with R18 and R19 may form a carbonyl group(s);
Z represents an oxygen atom or a sulfur atom;
Q- represents a counter anion; and
n1 represents 1 or 2, and n2 represents an integer from 1
to 3.
2. A ruthenium complex represented by the following formula
(3):
[Chem. 45]
R
R" 12 ^ oR1n?6,.1 7
R 1 / R19R18
(3)
wherein symbol * represents an asymmetric carbon atom;
R1 represents an alkyl group having 1 to 10 carbon atoms;
a halogenated alkyl group having 1 to 10 carbon atoms; 10-
camphoryl group; an amino group which may be substituted with
one or two alkyl group having 1 to 10 carbon atoms; an aryl
group which may be substituted with an alkyl group having 1 to
10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon
atoms, a halogen atom, a cyano group (-CN), an amino group, an
alkylated amino group (-NR20R21), a five or six membered cyclic
amino group, an acylated amino group (-NH-CO-R20), a hydroxyl
group, an alkoxy group (-OR20), an acyl group (-CO-R20), a
carboxyl group, an alkoxycarbonyl group (-COOR20), a phenoxy
carbonyl group, a mercapto group, an alkylthio group (-SR20), a
silyl group (-SiR20R21R22), or a nitro group (-NO2); R20, R21 and
R22 each independently represent a hydrogen atom, an alkyl group
having 1 to 10 carbon atoms or a cycloalkyl group having 3 to
10 carbon atoms;
Y represents a hydrogen atom;
R2 and R3 each independently represent a hydrogen atom; an
alkyl group having 1 to 10 carbon atoms; a phenyl group which
may be substituted with an alkyl group having 1 to 10 carbon
atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen
atom; or a cycloalkyl group having 3 to 8 carbon atoms, or R2
and R3 may be joined together to form a ring;
R11, R12, R13, R14 and R15 each independently represent a
hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or
an alkoxy group having 1 to 10 carbon atoms;
R16, R17, R18 and R19 each independently represent a hydrogen
atom, a hydroxyl group, an alkyl group having 1 to 10 carbon
atoms, or an alkoxy group having 1 to 10 carbon atoms, or R16
and R17 with the carbon atom which is substituted with R16 and
R17, and/or R18 and R19 with the carbon atom which is substituted
with R18 and R19 may form a carbonyl group(s);
Z represents an oxygen atom or a sulfur atom;
V represents a halogen atom; and
n1 represents 1 or 2, and n2 represents an integer from 1
to 3.
3. A method for producing a reduction product by reducing an
organic compound in the presence of the ruthenium complex as
claimed in claim 1 or 2 and a hydrogen donor.
4. A method for producing an optically active alcohol, the
method comprising reducing a carbonyl group of a carbonyl
compound in the presence of the ruthenium complex as claimed in
claim 1 or 2 and a hydrogen donor.
5. A method for producing an optically active amine, the
method comprising reducing an imino group of an imine compound
in the presence of the ruthenium complex as claimed in claim 1
or 2 and a hydrogen donor.
6. The method as claimed in any one of claims 3 to 5, wherein
the hydrogen donor is selected from formic acid, a formic acid
alkali metal salt, and an alcohol having a hydrogen atom on the
a-position carbon atom substituted with a hydroxyl group.
7. The method as claimed in any one of claims 3 to 5, wherein
the hydrogen donor is hydrogen.
8. A catalyst for reduction, comprising the ruthenium complex
as claimed in claim 1 or 2.
9. The catalyst as claimed in claim 8, wherein the catalyst
is a catalyst for asymmetric reduction.