Asymmetric Hydrogenation Catalysts

s-PICA cat.

Optically active alcohols, which couldn't be obtained withprevious catalysts, are obtainable with the s-PICA cat.!
R1O

R3 +R2R1s-PICA

H21 MPa

BrRu

P H N
Ar2 2*

R3

R2Ar2PAr2POH

Br
Ru

P H N
Ar2 2BrAr2PBrRu

P H N
Ar2 2BrNBr
N
Ns-PICA cat.

N

2 Diphosphines × (S,S),(R,R) × 3 Diamines ＝ 12 type catalysts
Ar = 3,5-iPr2C6H3 [dipskewphos]
Ar = 3,5-Me2C6H3 [xylskewphos]

3-(aminomethyl)isoquinoline [3-AMIQ]
3,5-Dimethyl-2-picolylamine [3,5-DMPICA]
2-Aminomethylpyrazine [AMPZ]

The s-PICA cat. can hydrogenate ketones, which have not been reduced eﬃciently by theprevious catalysts, to aﬀord optically active alcohols in excellent enantiomeric excess.
The s-PICA cat. can be applied to industrial scale synthesis.

Improved substrate scope
Polysubstituted acetophenones, acetylbenzimidazole, ketoesters and alsosimple ketones are hydrogenated in excellent enatioselectivity.
OOHs-PICAcat.

HN*Os-PICAcat.

HNNOSOOEts-PICAcat.

*OEt

∗

NOOH OSOH

Ot-BuPhs-PICAcat.

OHPhO

*OH

Examples are illustrated at next page.

Industrial scale production
Multi kg-scale synthesis has been achieved.
The reaction proceeds at a substrate-to-catalyst molar ratio(S/C) of >10,000.
ClO

F+Cl
S/C = 10,000

s-PICA cat.

H2
t-BuOK, IPA, 40°C, 20 h
1 MPa

distillation

ClFOH
*

Cl
27 kg
96％ isolated yield
98% ees-PICA cat.: The Feature of Ligands
iPr

iPrPiPr

iPr

PPiPr

iPr

Ar2 BrPRuP
Ar2 N
H2iPr
iPr iPr

iPr iPr(S,S)-DIPSKEWPHOS

P

iPr

iPr

iPr

s-PICA Cat.

P

iPr

iPr

(R,R)-DIPSKEWPHOS

PPPN
H2N

Br

3-AMIQNN

H2N
3,5-DMPICA

RnNN

H 2N
(S,S)-XylSKEWPHOS

AMPZ(R,R)-XylSKEWPHOS

Diphosphine ligands
ligands

Diamine ligands
featureligands

DIPSKEWPHOS

better enantioselectivity

XylSKEWPHOS

better reactivity

feature3-AMIQ

better enatioselectivity
good enatioselectivity and reactivity

3,5-DMPICA

suitable at higher temp.(60–70℃)
suitable for heteroarenesAMPZ

Examples of reaction
Asymmetric hydrogenation of polysubstituted aromatic ketones1) and other aromatic ketones
R1R2OAr

H2+R3[ketone]0 = 0.5–2.0 M[t-BuOK] = 20–30 mM

1 MPa

R1

RuBr2[(S,S)-dipskewphos](3-amiq)

R3

Ar

R2

t-BuOK, IPA or EtOH, 40°C, 8–36 hOH

Examples : Reaction of polysubstituted aromatic ketones
OHClOHOMe OHOHOHOCl

S/C = 500
95% isolated yield
99% eeMeO

S/C = 2,000
99% isolated yield
99% eeOMeOMeS/C = 1,000
97% isolated yield99% ee

S/C = 1,000
93% isolated yield
95% eeS/C = 1,000
99% isolated yield
99% eeExamples : Reaction of other aromatic ketones
OHHN

HO

S/C = 1,000
99% yield
95% ee*[t-BuOK/ketone = 1]*[RuBr2[(S,S)-dipskewphos](ampz)]

Cl

O

S/C = 10,000
99% yield
96% ee+Cl

s-PICA cat.

H2
1 MPa

Ru cat.

ON

S/C = 2,000
99% yield
99% eeComparison of catalysts for the hydrogenation of polysubstituted acetophenone
FOHOPhN

S/C = 1,000
99% yield
97% eei-Pr OHOHOHFt-BuOK, IPA, 40°C, 21 h

ClOHClRu cat.

S/Cyield (%)

ee (%)

RuBr2[(S,S)-xylskewphos](3,5-dmpica)

20,00099

98

RuBr2[(S,S)-dipskewphos](3-amiq)

1,000

9999

RuCl2[(R)-binap][(R,R)-dpen)

1,000

2115

S/C = 2,000
99% yield
98% eeAsymmetric hydrogenation of α-aminoketones with DKR
O

RAr

H2+OH

RuBr2[(S,S)-dipskewphos](3-amiq)

N
0.8 MPaS/C = 500
[substrate]0 = 0.2 M[t-BuOK] = 30 mM

RAr

t-BuOK, IPA, 30°C, 2 hN

Examples : Reaction of α-aminoketones
OHPhOHOHNPhO
97% isolated yield
syn:anti = 96:4
99% eeNHBz
95% isolated yield
syn:anti = 87:1397% ee

OHOHN

NHBoc
BnO
80% isolated yield
syn:anti = 85:15
97% ee

Ph

NPhth

NPhth
82% isolated yield
syn:anti = 99:1
99% ee82% isolated yield
syn:anti = 99:1
>99% ee*[RuBr2[(S,S)-dipskewphos](ampz)]

Asymmetric hydrogenation of β-ketoesters, amides and analogues
OO

Ar+Y

[substrate] = 0.5–1.0 M[t-BuOK] = 20–50 mM

OHRuBr2[(S,S)-dipskewphos](3-amiq)

H21 MPaO

Ar

t-BuOK, IPA or EtOH, 40°C, 17 hY

Examples : Reaction of β-ketoesters, amides and analogues
OH O
PhOH OSOEt

S/C = 5,000
97% yield
99% eeOH O
PhOEt

S/C = 1,000
95% yield
97% ee

NHMe

OH O
P OEt
PhOEt

S/C = 500
97% yield
96% ee*[60°C]*[RuBr2[(S,S)-dipskewphos](ampz)]

S/C = 500
98% yield
98% eeAsymmetric hydrogenation of γ-, δ- and ε-ketoesters2)
OOH
OR'nR+n = 1–3 O

RuBr2[(S,S)-dipskewphos](3-amiq)

H2t-BuOK, EtOH, 25°C, 2–5 h

0.8 MPa

t-BuOK/Ru = 3.5

OR'nRO

Examples : Reaction of γ-, δ- and ε-ketoesters
OOOOOHPh

Ph

S/C = 5,000
97% isolated yield
97% eeS/C = 5,000
97% isolated yield
99% eeOHOOt-Bu

PhOEt

OS/C = 500
99% yield>99% ee

S/C = 500
99% yield
99% eeAsymmetric hydrogenation of γ- and δ-ketoesters to diols2)
OOH
OR'n

Rn = 1–2 O[t-BuOK] = 50 mM+RuBr2[(S,S)-dipskewphos](3-amiq)

H22–5 MPat-BuOK, EtOH, 40°C, 24–40 hn

ROH

Examples : Reaction of γ- and δ-ketoesters to diols
OHPhOHOH

S/C = 5,000
97% isolated yield
96% eeOH
OH

S/C = 5,000
97% isolated yield
98% eeOH
OH

Cl

S/C = 500
96% isolated yield
95% eePh

OH

S/C = 500
96% isolated yield
98% eeProduct list
Product Name
Dibromo[(S,S)-DIPSKEWPHOS](3-AMIQ)ruthenium(II)Dibromo[(2S,4S)-2,4-bis[bis(3,5-diisopropylphenyl)phosphino]pentane](3-aminomethylisoquinoline)ruthenium(II)CAS︓2170985-21-2

FW︓1196.24

Dibromo[(R,R)-DIPSKEWPHOS](3-AMIQ)ruthenium(II)Dibromo[(2R,4R)-2,4-bis[bis(3,5-diisopropylphenyl)phosphino]pentane](3-aminomethylisoquinoline)ruthenium(II)

CAS︓-

FW︓1196.24

Dibromo[(S,S)-DIPSKEWPHOS](3,5-DMPICA)ruthenium(II)Dibromo[(2S,4S)-2,4-bis[bis(3,5-diisopropylphenyl)phosphino]pentane](2-aminomethyl-3,5-dimethylpyridine)ruthenium(II)CAS︓2241509-73-7

FW︓1174.23

Dibromo[(R,R)-DIPSKEWPHOS](3,5-DMPICA)ruthenium(II)Dibromo[(2R,4R)-2,4-bis[bis(3,5-diisopropylphenyl)phosphino]pentane](2-aminomethyl-3,5-dimethylpyridine)ruthenium(II)

CAS︓-

FW︓1174.23

Dibromo[(S,S)-DIPSKEWPHOS](AMPZ)ruthenium(II)Dibromo[(2S,4S)-2,4-bis[bis(3,5-diisopropylphenyl)phosphino]pentane](2-aminomethypyrazine)ruthenium(II)

CAS︓-

FW︓1147.16

Dibromo[(R,R)-DIPSKEWPHOS](AMPZ)ruthenium(II)Dibromo[(2R,4R)-2,4-bis[bis(3,5-diisopropylphenyl)phosphino]pentane](2-aminomethypyrazine)ruthenium(II)

CAS︓-

FW︓1147.16

Dibromo[(S,S)-XylSKEWPHOS](3-AMIQ)ruthenium(II)Dibromo[(2S,4S)-2,4-bis[di(3,5-xylyl)phosphino]pentane](3-aminomethylisoquinoline)ruthenium(II)CAS︓1646350-83-5

FW︓971.80

Dibromo[(R,R)-XylSKEWPHOS](3-AMIQ)ruthenium(II)Dibromo[(2R,4R)-2,4-bis[di(3,5-xylyl)phosphino]pentane](3-aminomethylisoquinoline)ruthenium(II)

CAS︓-

FW︓971.80

Dibromo[(S,S)-XylSKEWPHOS](3,5-DMPICA)ruthenium(II)Dibromo[(2S,4S)-2,4-bis[di(3,5-xylyl)phosphino]pentane](2-aminomethyl-3,5-dimethylpyridine)ruthenium(II)CAS︓1646350-81-3

FW︓949.80

Dibromo[(R,R)-XylSKEWPHOS](3,5-DMPICA)ruthenium(II)Dibromo[(2R,4R)-2,4-bis[di(3,5-xylyl)phosphino]pentane](2-aminomethyl-3,5-dimethylpyridine)ruthenium(II)

CAS︓-

FW︓949.80

Dibromo[(S,S)-XylSKEWPHOS](AMPZ)ruthenium(II)Dibromo[(2S,4S)-2,4-bis[di(3,5-xylyl)phosphino]pentane](2-aminomethylpyrazine)ruthenium(II)CAS︓1646350-84-6

FW︓922.73

Dibromo[(R,R)-XylSKEWPHOS](AMPZ)ruthenium(II)Dibromo[(2R,4R)-2,4-bis[di(3,5-xylyl)phosphino]pentane](2-aminomethylpyrazine)ruthenium(II)

CAS︓-

FW︓922.73

Ar2 BrPRuP
Ar2 N
H2Product No.

Package

10163-68

100 mg10164-68

100 mg10173-68

100 mg10181-68

100 mg10165-68

100 mg10166-68

100 mg11214-68

100 mg11215-68

100 mg11218-68

100 mg11219-68

100 mg11216-68

100 mg11217-68

100 mgBr
N

Ar = 3,5-iPr2C6H3Ar2 Br
PRu
P
Ar2 N
H2BrN

Ar = 3,5-iPr2C6H3Ar2 Br
PRu
P
Ar2 N
H2BrN

Ar = 3,5-iPr2C6H3Ar2 Br
PRu
P
Ar2 N
H2Br
N

Ar = 3,5-iPr2C6H3Ar2 Br
PRu
P
Ar2 N
H2Br
NN

Ar = 3,5-iPr2C6H3Ar2 Br
PRu
P
Ar2 N
H2BrN
N

Ar = 3,5-iPr2C6H3Ar2 BrPRu
P
Ar2 N
H2Br
N

Ar = 3,5-Me2C6H3Ar2 Br
PRu
P
Ar2 N
H2Br
N

Ar = 3,5-Me2C6H3Ar2 Br
PRu
P
Ar2 N
H2Br
N

Ar = 3,5-Me2C6H3Ar2 BrPRu
P
Ar2 N
H2Br
N

Ar = 3,5-Me2C6H3Ar2 Br
PRu
P
Ar2 N
H2BrN
N

Ar = 3,5-Me2C6H3Ar2 BrPRu
P
Ar2 N
H2BrNN

Ar = 3,5-Me2C6H3

We can supply other catalysts for asymmetric hydrogenation or asymmetric transfer hydogenation,and optically active alcohols that are produced by these asymmetric catalysts.
The ligands such as DIPSKEWPHOS, XylSKEWPHOS and SKEWPHOS are also suppliable.
Please contact us for more information.

Reference

1) ChemCatChem 2018, 10, 1.
2) Angew. Chem. Int. Ed. 2018, 57, 1386

OEA-07(201910)