Ruthenium-catalysed hydrogenation of aromatic ketones using monodentate phosphoramidite ligands

Article abstract of DOI:10.1002/adsc.201000425

A ruthenium pre-catalyst containing two equivalents of the bulky monodentate phosphoramidite 3,3′-dimethyl-PipPhos and one equivalent of a chiral diamine such as 1,2-diphenylethylenediamine or 1,2-diaminocyclohexane was used for the asymmetric hydrogenation of aromatic ketones. A range of substituted and unsubstituted aryl alkyl ketones was hydrogenated using only 0.1 mol% of this catalyst with full conversions and enantioselectivities up to 97%. The phosphoramidite and diamine ligands matched when both had the same configuration, i.e., S-phosphoramidite with S,S-diamine. In that case the product was obtained with high enantioselectivity and the R-configuration. The mismatched case produced the product in lower ee. The product configuration was determined by the configuration of the diamine ligand. A mechanistic proposal was made.

Full text of DOI:10.1002/adsc.201000425

FULL PAPERS
DOI: 10.1002/adsc.201000425
Ruthenium-Catalysed Hydrogenation of Aromatic Ketones using
Monodentate Phosphoramidite Ligands
Bart Stegink,a Lonneke van Boxtel,b Laurent Lefort,b Adriaan J. Minnaard,a,*
Ben L. Feringa,a,* and Johannes G. de Vriesa,b,*
a
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Fax : (+31)-50-363-4296; e-mail: a.j.minnaard@rug.nl, b.l.feringa@rug.nl
DSM Innovative Synthesis BV, A unit of DSM Pharma Chemicals, P.O. Box 18, 6160 MD Geleen, The Netherlands
b
Fax : (+31)-46-476-1572; e-mail: Hans-JG.Vries-de@dsm.com
Received: May 30, 2010; Published online: October 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000425.
Abstract: A ruthenium pre-catalyst containing two matched when both had the same configuration, i.e.,
equivalents of the bulky monodentate phosphorami- S-phosphoramidite with S,S-diamine. In that case the
dite 3,3’-dimethyl-PipPhos and one equivalent of a product was obtained with high enantioselectivity
chiral diamine such as 1,2-diphenylethylenediamine and the R-configuration. The mismatched case pro-
or 1,2-diaminocyclohexane was used for the asym- duced the product in lower ee. The product configu-
metric hydrogenation of aromatic ketones. A range ration was determined by the configuration of the di-
of substituted and unsubstituted aryl alkyl ketones amine ligand. A mechanistic proposal was made.
was hydrogenated using only 0.1 mol% of this cata-
lyst with full conversions and enantioselectivities up Keywords: asymmetric hydrogenation; homogeneous
to 97%. The phosphoramidite and diamine ligands catalysis; ketones; phosphoramidites; ruthenium
Introduction
drogenation reactions. In that year three groups sepa-
rately introduced the first examples of the use of
Asymmetric hydrogenation has blossomed into a chiral monodentate phosphorus ligands in rhodium-
mature technology, both on the laboratory scale as catalysed asymmetric hydrogenation. Pringle and co-
well as in production.[1] For the reduction of aromatic workers developed the use of monodentate phos-
ketones, the [Ru(PP)(NN)Cl2] catalyst (PP=chiral phonites,[6] Reetz and co-workers developed the use
bis-phosphine such as BINAP, NN=chiral diamine of monodentate phosphites[7] and we have developed
such as 1,2-cyclohexanediamine) developed by Noyori the use of monodentate phosphoramidites.[8] These li-
and co-workers remains the golden standard.[2] It is a gands were all used in the hydrogenation of C=C
highly enantioselective catalyst, which in addition is double bonds, obtaining very good results (fast reac-
very fast, allowing its economic use in production. tions and ees>99%). By now these ligands are well
After Noyoriꢀs seminal publications a range of similar accepted and have proven their usefulness on a range
catalysts were developed in which BINAP was re- of different substrates.[9] In our patent on the use of
placed by other bisphosphines.[3,4] The asymmetric hy- rhodium and ruthenium phosphoramidite complexes
drogenation of aliphatic ketones has remained more for asymmetric hydrogenation we have shown the
problematic, with most ketones being reduced with first examples of the use of
a
ruthenium(bis-
low to medium enantioselectivities.[3] The use of alco- MonoPhos)
AHCTUNGTERNN(GUN diamine) dichloride complex as a ketone
hol dehydrogenases (ADH) for the enantioselective hydrogenation catalyst with moderate ees.[10] Better
reduction of ketones has made remarkable progress results were obtained by Wills and co-workers who
in the last decade, and now can be considered the tested a range of BINOL-based monodentate ligands
method of choice for the enantioselective reduction in ruthenium-catalysed aromatic ketone hydrogena-
of aliphatic ketones.[5]
tion.[11] Full conversion and exellent ees (up to 99%)
Until the year 2000 the use of bidentate ligands was were reached in the hydrogenation of acetophenones,
considered a conditio sine qua non in asymmetric hy- using the monodentate phosphonite ligand BrXuPhos
Adv. Synth. Catal. 2010, 352, 2621 – 2628
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2621

Bart Stegink et al.
FULL PAPERS
Figure 1. Ruthenium catalysts based on monodentate ligands for asymmetric ketone hydrogenation.
(Figure 1) in combination with 1,2-diphenylethylene- tion of a complex, which displayed a single peak in
1,2-diamine (DPEN) (denoted as NN in Figure 1).
the 31P NMR at 148.8 ppm which we tentatively assign
Morris replaced the BINAP in Noyoriꢀs Ru-com- the structure [Ru(1)2A(DMF)nCl2]. After three hours, a
CTHUNGTRENNUNG
plex by two monodentate triphenylphosphine ligands. chiral 1,2-diamine or another auxiliary ligand was
With this catalyst he obtained 60% ee in the asym- added and this mixture was left stirring at room tem-
metric hydrogenation of acetophenone.[12] Ding sub- perature overnight. The structure of the resulting
stantially improved this catalyst by using very bulky complex will be discussed later. After removal of the
triarylphosphines.[13] Using tris(3,5-dixylylphenyl)- solvent the complex was used directly without further
phosphine in combination with the chiral diamine purification in the hydrogenation reactions. In initial
DPEN they reached up to 95% ee in the Ru-catalysed experiments, we screened a limited number of ligands
hydrogenation of acetophenone. Beller tested a range 1a–d and 2 (Figure 2), a limited number of auxiliary
of monodentate phosphorus ligands in the Ru-cata- ligands (Figure 3), bases and solvents.
lysed asymmetric hydrogenation of b-keto esters. Best
results were obtained with the bis-naphthyl-based scale in well-stirred vials in an autoclave at 50 bar H2.
phosphepine ligands they had developed earlier.[14]
Some experiments were performed on 10-mmol scale
These experiments were carried out on a 1-mmol
Here we report on the use of monodentate phos- directly in the autoclave. The first experiments used
phoramidites in the Ru-catalysed asymmetric hydro-
genation of acetophenones. A clear advantage of the
use of phosphoramidite ligands is their easy accessi-
bility. They can be made from the BINOLs in a very
simple two-step procedure and virtually any amine or
aniline can be used to make a ligand.[15] In contrast, li-
gands like BINAP or the monodentate ligands de-
scribed by the groups of Ding and Beller all require a
difficult multi-step synthesis. The ease of synthesis of
the phosphoramidites has allowed the development of
a protocol for their parallel synthesis in the robot.
This enabled the synthesis of 96 ligands in a single
day followed by their testing in hydrogenation the
next day.[16] Finally, because of their monodentate
nature, it is possible to synthesise catalysts that con-
tain two different ligands. This tremendously increas-
es the available diversity.[17,18] A mixed phosphorami-
dite/phosphine rhodium catalyst is used by DSM in a
ton-scale process.[19]
Results
For the preparation of the phosphoramidite-based
catalysts we followed the procedure of Noyori.[2]
Thus, the pre-catalyst was made by heating [RuCl2
ACHTUNGTRENNUNG
Figure 2. Monodentate and bidentate phosphoramidite li-
2622
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2621 – 2628

Ruthenium-Catalysed Hydrogenation of Aromatic Ketones
portance. The catalyst was not very soluble in non-
polar solvents such as dichloromethane and EtOAc
leading to neglible conversions (entries 4, 5).
To rule out the possibility that the solubility of the
base also plays a role, we also tested Cs2CO3 as base;
this did not improve matters (entry 5). Surprisingly,
use of NMP also led to poor conversions; in this case
the coordinative nature of the solvent may be the cul-
prit. Thus, protic solvents such as methanol and 2-
propanol (entries 7, 8) turn out to be the best for
these hydrogenations. Potassium bases seem best; rate
and ee were lower when Cs2CO3 was used (entry 7).
KO-t-Bu also is an excellent base for this reaction
(entry 8). Although only two equivalents of base are
needed to convert the dichloride into the dihydride,
Noyori and co-workers have shown that an excess
Figure 3. Diamines and other auxiliary ligands.
the catalyst based on MonoPhos 1a and were per- may lead to increased rate; hence the 5- to 20-fold
formed in MeOH as solvent using K2CO3 as base.
Use of ethylenediamine as auxiliary ligand gave
excess in most experiments.[20] Gratifyingly, the bis-
AHCTUNGTREG(NNUN isopropyl)amine-based phosphoramidite 1b in combi-
near complete conversion in 4 h but the product 1- nation with (S,S)-DPEN led to an improved ee of
phenylethanol was obtained in disappointingly low ee 67% (entry 9). Here we see a clear match/mismatch
(Table 1, entry 1). Better results were obtained using effect with respect to the ee (entries 9, 10). Again, the
(S,S)-1,2-diphenylethylenediamine. Not only is the re- configuration of the product changed with the config-
action much faster, but the ee also increased to 58%. uration of the diamine used. Use of ligand 1c contain-
Using the diamine with the reversed configuration ing 6,6’-dibromo substituents on the BINOL gave sim-
leads to a similar ee, however, the configuration of ilar results as with ligand 1a (entries 11, 12). Use of
the product has also reversed. These 3 experiments the octahydro-BINOL-based ligand 2 led to 60% ee
suggest that the diamine plays a dominant role in the in the case of the matched ligands; the mismatched
determination of the enantioselectivity and that the combination led to only 39% ee (entries 13, 14). Use
chirality of the phosphoramidite is only of minor im- of ethylene glycol or BINOL as auxiliary ligand in
Table 1. Initial screening of ligands and conditions in the Ru-phosphoramidite-catalysed hydrogenation of acetophenone.[a]
Entry
Ligand
Auxiliary Ligand
Base
Solvent
t (h)
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
2
ethylenediamine
S,S-DPEN
R,R-DPEN
S,S-DPEN
S,S-DPEN
S,S-DPEN
S,S-DPEN
S,S-DPEN
S,S-DPEN
R,R-DPEN
S,S-DPEN
R,R-DPEN
S,S-DPEN
R,R-DPEN
ethylene glycol
S-BINOL
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
KO-t-Bu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeOH
MeOH
MeOH
CH2Cl2
EtOAc
NMP
i-PrOH
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
4
95
93
95
0
2
3
18
100
98
53
49
50
94
39
59
16
9 (S)
58 (R)
56 (R)
–
–
–
47 (R)
52 (R)
67 (R)
52 (S)
57 (R)
55 (S)
60 (R)
39 (S)
1
0.75
2.5
2.5
22
16
22
16
2.5
0.5
1
9
10
11
12
13
14
15
16
1
3.8
0.5
16
2.5
2
1a
1a
15
[a]
Conditions: reaction on 1-mmol scale in 5 mL of solvent, S/C=100.
All ligands were made from BINOLs with the S-configuration.
10 mol% of KO-t-Bu, S/C=1000 was used.
[b]
[c]
Adv. Synth. Catal. 2010, 352, 2621 – 2628
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2623

Bart Stegink et al.
FULL PAPERS
Table 2. Ligand screening in the asymmetric hydrogenation
stituent could be beneficial we tested ligand 1d con-
taining the bulky bis-1-phenylethylamino group. Grat-
ifyingly, full conversion was obtained, although the
enantioselectivity was a disappointing 41% (entry 5).
PipPhos (1e) has been an extraordinary successful
ligand in the Rh-catalysed hydrogenation of enam-
ides.[22] In the hydrogenation of acetophenone using
DPEN or DACH as auxiliary ligand full conversion
was achieved with a product ee of 51% (entries 6, 7).
Use of ethylenediamine instead of DPEN did not im-
prove matters, and the product was obtained with
34% ee (entry 8). Next, we examined ligands in which
the cone angle has been substantially increased by the
presence of methyl substituents in the 3 and 3’ posi-
tions. Use of 3,3’-dimethyl-MonoPhos 1f in combina-
tion with DPEN led to full conversion and we ob-
tained the product in 90% ee (entry 9). Although this
is already very good, by using 3,3’-dimethyl-PipPhos
1g we could further improve upon this result. This
ligand has been used with great success in the asym-
metric hydrogenation of a-alkylated cinnamic acids
culminating in its application in a ton-scale produc-
tion process of an intermediate for the blood pres-
of acetophenone.[a]
Entry Ligand Diamine
Conv.[e] [%] ee[e] [%]
1
2
3
4
5
6
7
8
3
DPEN
DPEN
DPEN
DPEN
DPEN
DPEN
DACH
40
20
50
13
100
100
100
rac
10
12
41
41
52
55
34
90
97
97
–
4a
4b
4c
1d[c]
1e
1e
1e
1f
ethylenediamine 100
9
DPEN
DPEN
DACH
DACH
100
100
100
0
10
11
12[d]
13
1g
1g
1g
BINAP DPEN
100
87
[a]
Experiments were performed in the Endeavor apparatus
on 2-mmol scale in 4 mL solvent.
All experiments were performed with (R)-BINOL-based
ligands and (R,R)-diamine, unless noted otherwise. This
combination leads to the product with the S-configura-
tion.
(S,RR)-1d was used in combination with (S,S)-DPEN.
Transfer hydrogenation experiment.
Conversion and ee were determined by chiral GC.
[b]
sure-lowering agent AliskirenTM [19]
In the present
.
study this ligand also turned out to be the key to suc-
cess as the product, 2-phenylethanol, could be ob-
tained in 97% ee with both DPEN or DACH as auxil-
iary ligands (entries 10, 11). Considering that the use
of 2-propanol could lead to product formation via
transfer hydrogenation we performed a control ex-
periment without hydrogen to verify this (entry 12).
[c]
[d]
[e]
combination with MonoPhos 1a resulted in low enan- No conversion ensued after overnight reaction at
tioselectivities (entries 15, 16). room temperature, establishing that this is a true hy-
Having thus established that protic solvents, potas- drogenation reaction. These results compare well with
sium bases and diamine auxiliary ligands are the best the experiment in which BINAP was used as a ligand
we continued screening more monodentate and bi- and in which only 87% ee was obtained (entry 13). It
dentate phosphoramidite ligands and this time also in- should be noted of course that using other BINAP an-
cluded enantiopure 1,2-cyclohexanediamine as auxili- alogues or other bidentate bisphosphines can also
ary ligand. (Table 2). These screening experiments lead to very high enantioselectivities.[3]
were all performed at ambient temperature with a
substrate/catalyst ratio (S/C) of 1000 in i-PrOH using the ruthenium catalyst based on 1g with DACH or
KO-t-Bu as base. DPEN as auxiliary ligands we established the scope
Having thus established the good performance of
Use of ligand 3, in which the chirality stems solely of its application by screening a range of substituted
from the amine part and in which the BINOL has and unsubstituted aromatic ketones (Table 3). We
been replaced by catechol, in combination with found that especially the para- and ortho-substituted
(R,R)-DPEN led to a relatively slow reaction; the acetophenones are hydrogenated very well using this
product alcohol was obtained in racemic form system (entries 2, 4). No conversion was obtained
(entry 1).[21] Next, we tested three bidentate phosphor- with o-hydroxyacetophenone (entry 3). The acidic
amidite ligands (entries 2–4). Again, slow reactions functionality presumably protonates the amido ligand
ensued and the enantioselectivities ranged from low of the active catalyst. Both electron-withdrawing as
to moderate. This is comparable to the results in the well as electron-donating substituents were well toler-
rhodium-catalysed asymmetric hydrogenation of N- ated at the para-position and p-chloro- and p-me-
acylated dehydroamino acids, where use of these li- thoxy-substituted 1-phenylethanol were obtained with
gands also led to slow rates and very low enantiose- excellent ees (entries 5, 6).
lectivities.[8a]
meta-Substituted acetophenones were hydrogenat-
As the improvement obtained going from ligand 1a ed in good yield, although the enantioselectivity of
to ligand 1b suggested that bulk on the amino sub- the product alcohols was somewhat lower (en-
2624
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2621 – 2628

Ruthenium-Catalysed Hydrogenation of Aromatic Ketones
Table 3. Results of hydrogenation reactions using different
ture could be obtained. After three hours, a chiral
1,2-diamine or another auxiliary ligand was added
and this mixture was left stirring at room temperature
overnight. The resulting product shows two signals in
the 31P NMR at 147.7 (free 1a) and at 172.2. This
latter peak presumably belongs to the ruthenium
complex. Similar results were obtained when using
3,3’-dimethyl-PipPhos (1g). We observe a single peak
substrates.[a]
Entry R1
R2
Alcohol Conv.[b] [%] ee[c] [%]
for [Ru(1g)2ACTHUNTRGNEUNG(DMF)nCl2] at 149 ppm and two peaks
after reaction with DACH, one of which is from 1g at
147.2 ppm and the other at 173.4 ppm, which we as-
cribe to the ruthenium complex. As the presence of a
rather large residual ligand peak suggests that the
complex contains only a single phosphoramidite
ligand per ruthenium, we repeated the entire proce-
dure with only 1 equivalent of 1g per ruthenium and
indeed, in this case a product was obtained which
showed mostly the peak in the 31P NMR at 173.4 ppm
with only small amounts of 1g showing up. Unfortu-
nately, extensive attempts to establish the exact struc-
ture of this complex failed on account of its instability
upon attempted isolation. In several crystallisation at-
tempts, products were obtained that, surprisingly, had
lost large amounts of the phosphoramidite. Several at-
tempts to obtain electrospray mass spectra also failed
to give meaningful results, although several peaks
were observed that clearly belong to a dimeric ruthe-
nium species. From the stoichiometry of the experi-
ments only a limited number of structures would
seem to be possible. These could be either dimeric or
monomeric [Ru(P)(NN)Cl2] (structures A and B in
Scheme 1). Previously, we have shown that reaction
1
2
3
4
5
6
7
8
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
6a
6b
6c
6d
6e
6f
6g
6h
6i
100
100
0
97
97
–
96
97
95
65
83
–
95
93
94
91
93
–
2-Me
2-OH
2-OMe
4-OMe
4-Cl
3-Br
3-Cl
3-OMe
3,5-CF3 Me
1-acetonaphthone 8a
2-acetonaphthone 8b
H
H
H
H
H
100
100
100
100
100
<10
100
100
100
100
100
<10
<10
<10
9
10
11
12
13
14
15
16
17
6k
C2H5
n-Pr
i-Pr
CH2Cl 6o
CF3 6p
6l
6m
6n
–
–
[a]
For conditions see Table 2. All hydrogenations were per-
formed using (R)-1g in combination with (R,R)-DACH
leading to the S-products.
Conversions were determined via H NMR.
The ees were determined via chiral GC.
[b]
[c]
1
tries 7,8). Surprisingly, m-methoxyacetophenone was a of bulky 3,3’-disubstituted phosphoramidites with di-
poor substrate and only 10% conversion was obtained meric [Ir(COD)Cl]2 leads to formation of
(COD)(P)Cl], irrespective of the amount of phos-
AHCTUNGTRENNUNG
after overnight reaction (entry 9). Gratifyingly, the [IrACHTUNGTRENNUNG
hydrogenation of 3,5-bis(trifluoromethyl)acetophe- phoramidite ligand.[24] This iridium catalyst was highly
none yielded the alcohol in 100% conversion and active and enantioselective for the asymmetric hydro-
95% ee. This alcohol is an intermediate for the anti- genation of N-acylated dehydroamino esters.
emetic AprepitantTM (entry 10).[23] Both 1- and 2-ace-
To gain more information about the true nature of
tonaphthones were hydrogenated with excellent ee the catalytically active species, we performed a range
(entries 11, 12). Although propiophenone (entry 13) of experiments (Table 4). First, hydrogenation of o-
and butyrophenone (entry 14) were hydrogenated methylacetophenone using the precatalyst with Ru/
with very high enantioselectivity, surprisingly, 2-meth- 1g=1 led to formation of the alcohol in 75% ee
ylpropiophenone was a sluggish substrate (entry 15). (entry 1). Addition of an additional 0.5 equivalents of
Also electron-withdrawing substituents on the 2 posi- 1g to the 1: 1 complex gave the product in 90% ee
tion of acetophenone led to poor conversions (en- and finally addition of 1.0 equivalent of 1g led to full
tries 16, 17).
restoration of the ee to 97% as in the original proce-
dure (entries 2, 3). Addition of more than one equiva-
lent of 1g led to a reduction of ee again (entry 4).
It is also possible to add a different ligand, which
we illustrated by the addition of 0.5 and 1.0 equiv-
Mechanistic Aspects
Reaction of [RuCl2ACHTNUGTRENUNG(cymene)]2 with four equivalents alent of PPh3 (entries 5,6). Surprisingly, this led to
of MonoPhos (1a) for 3 h in DMF at 908C results in lower rates and enantioselectivities, which is in stark
the formation of a complex which displayed a single contrast to our results with rhodium where the rate
peak in the 31P NMR at 148.8 ppm which we tenta- increased in all cases.[18b] These experiments suggest
tively assign the structure [Ru(1)
2ACHTUNGTREN(UNGN DMF)nCl2]. The that although in the precatalyst the ruthenium com-
1H NMR shows broad absorptions and no X-ray struc- plex contains only a single phosphoramidite ligand, in
Adv. Synth. Catal. 2010, 352, 2621 – 2628
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2625

Bart Stegink et al.
FULL PAPERS
Scheme 1. Proposed mechanism for the asymmetric hydrogenation of ketones
Table 4. Hydrogenation
[RuCl2(1g)ACHTUNGTRENNUNG(DACH)]n as catalyst precursor.
results
using
the
putative
the dihydride C. Thus, once the precatalyst has been
converted into the dihydride by the action of KO-t-
Bu and H2, the second phosphoramidite can bind to
the ruthenium. The resulting dihydride C reacts with
the ketone in a six-membered transition state (TS),
similar to the Morris mechanism. The resulting 16
electron complex D reacts with hydrogen to form the
dihydrogen complex E which reconverts to the dihy-
dride C.
A preliminary examination of the reaction kinetics
seems to confirm the reaction is zero order in sub-
strate as in the Morris mechanism (Figure 4). In this
experiment a turnover frequency of 50 hÀ1 was
reached. Higher rates can probably be obtained at
508C.
Entry
Extra equiv. of ligand
Conv. [%]
ee [%]
1
2
3
4
5
6
0
100 (18 h)
100 (17 h)
100 (16 h)
100 (14 h)
50 (24 h)
50 (24 h)
75
90
97
89
31
38
0.5 of 1g
1.0 of 1g
1.5 of 1g
0.5 of PPh3
1.0 of PPh3
the active and enantioselective catalyst 2 equivalents Conclusions
of 1g are bound to ruthenium. We propose a mecha-
nism, similar to the mechanism described by Morris In conclusion, we have developed a catalyst that is
and co-workers for asymmetric hydrogenations with able to hydrogenate a wide range of aryl alkyl ke-
[Ru
that reacts with the ketone is a ruthenium dihydride mol% in methanol or 2-propanol. The precatalyst is
(structure C in Scheme 1).[25]
in essence a ruthenium dichloride complex containing
It is conceivable that although the dichloride (A or one 3,3’-dimethyl-PipPhos ligand and one chiral di-
B) is too sterically encumbered to accommodate two amine or possibly a dimer thereof. It is proposed that
bulky phosphoramidites this is less problematic for during treatment with KO-t-Bu, an extra equivalent
ACHTUNGTRENNUNG(PPh3)2ACHTUNGTRENNUNG(DPEN)Cl2], in which the ultimate catalyst tones with high enantioselectivities using only 0.1
AHCTUNGTRENNUNG
2626
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2621 – 2628

Ruthenium-Catalysed Hydrogenation of Aromatic Ketones
PrOH. To this 3.7 mL i-PrOH were added. The liner was
put into one of the parallel autoclaves and subjected to
three vacuum/nitrogen cycles. Then, while stirring, 25 bars
of hydrogen pressure were applied. After 24 h the autoclave
was carefully vented and the glass liner taken out. From the
reaction mixture a sample was taken and filtered over a
silica plug to prepare a GC sample. The sample containing
the product alcohol was analysed by chiral GC.
Acknowledgements
T. Tiemersma-Wegman is acknowledged for assistance with
chromatography, and E. P. Schudde for technical assistance.
Figure 4. Hydrogen uptake curve of the hydrogenation of
acetophenone with [Ru(1g)2ACHTNUGRTNEUNG(DPEN)Cl2]n plus 1 equivalent
of 1g (S/C=218, room temperature, 25 bar H2).
References
[1] a) The Handbook of Homogeneous Hydrogenation,
(Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH, Wein-
heim, 2007, Chapters 23–37; b) Acc. Chem. Res. special
issue on hydrogenation and transfer hydrogenation,
2007, 12, 1237–1419; c) Asymmetric Catalysis on Indus-
trial Scale, (Eds.: H.-U. Blaser, E. Schmidt), Wiley-
VCH, Weinheim, 2004; d) Asymmetric Catalysis on In-
dustrial Scale, 2nd edn., (Eds.: H.-U. Blaser, H.-J. Feder-
sel), Wiley-VCH, Weinheim, 2010; e) J. G. de Vries, in:
Encyclopedia of Catalysis, (Ed.: I. Horvath), John
Wiley & Sons, New York, 2003, Vol. 3, pp 295–347.
[2] a) H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M.
Kozawa, E. Katayama, A. F. England, T. Ikariya, R.
Noyori, Angew. Chem. 1998, 110, 1792–1796; Angew.
Chem. Int. Ed. 1998, 37, 1703–1707; b) R. Noyori, T.
Ohkuma, Angew. Chem. 2001, 113, 40–75; Angew.
Chem. Int. Ed. 2001, 40, 40–73; c) R. Noyori, Angew.
Chem. Int. Ed. 2002, 41, 2005–2022.
of 1g and hydrogen this precatalyst is transformed
into a ruthenium complex that contains two phosphor-
amidite ligands and one chiral diamine; presumably
this is a dihydride.
Experimental Section
Ligands 1a,[26] 1b,[27] 1c,[28] 1d–f,[27] 1g,[29] 2,[28] 3,[30] 4a[27] and
4b[31] were synthesised according to previously reported pro-
cedures from the literature.
Synthesis of the Pre-Catalyst Comprising Ru, (R)-
3,3’-Dimethyl-PipPhos and (R,R)-DACH)
A
Schlenk flask was flame-dried and 62 mg [RuCl2
[3] T. Ohkuma, R. Noyori, in: The Handbook of Homoge-
ACHTUNGTRENNUNG(cymene)]2 (0.1 mmol) and 160 mg of (R)-3,3’-dimethyl-Pip-
neous Hydrogenation, (Eds.: J. G. de Vries, C. J. Else-
AHCTUNGTREGUNvNN ier), Wiley-VCH, Weinheim, 2007, Vol. 2, pp 1105–
1163.
Phos (0.4 mmol) were added. The Schlenk tube was de-
gassed by three cycles of vacuum/N2 and then kept under N2
and the solids were dissolved in 5 mL of dry DMF. This mix-
ture was heated for 3 h at 908C. After three hours the mix-
ture was allowed to cool down to room temperature. Subse-
quently, 23 mg (R,R)-DACH (0.2 mmol) was added. After
overnight stirring, DMF was evaporated under reduced
pressure. The resulting solid was subjected to azeotropic dis-
tillation with toluene (2ꢂ5 mL) and washed twice with
5 mL hexane. The obtained solid was used in hydrogenation
reactions without further purification. 31P NMR (162 MHz,
[4] W, Tang, X. Zhang, Chem. Rev. 2003, 103, 3029–3069.
[5] a) S. M. A. de Wildeman, T. Sonke, H. E. Schoemaker,
O. May, Acc. Chem. Res. 2007, 40, 1260–1266; b) T.
Matsuda, R. Yamanaka, K. Nakamura, Tetrahedron:
Asymmetry 2009, 20, 513–557.
[6] a) C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J.
Hyett, A. Martorell, A. G. Orpen, P. G. Pringle, Chem.
Commun. 2000, 961–962; b) D. W. Norman, C. A.
Carraz, D. J. Hyett, P. G. Pringle, J. B. Sweeney, A. G.
Orpen, H. Phetmung, R. L. Wingad, J. Am. Chem. Soc.
2008, 130, 6840–6847.
[7] a) M. T. Reetz, G. Mehler, Angew. Chem. 2000, 112,
4047–4049; Angew. Chem. Int. Ed. 2000, 39, 3889–
3890; b) M. T. Reetz, A. Meiswinkel, G. Mehler, K.
Angermund, M. Graf, W. Thiel, R. Mynott, D. G.
Blackmond, J. Am. Chem. Soc. 2005, 127, 10305–
10313.
[8] a) M. van den Berg, A. J. Minnaard, E. P. Schudde, J.
van Esch, A. H. M. de Vries, J. G. de Vries, B. L. Ferin-
ga, J. Am. Chem. Soc. 2000, 122, 11539–11540; b) A. J.
1
CDCl3): d=173.4; H NMR (400 MHz, CDCl3) : d=8.05 (d,
1H, J=36 Hz), 7.90–7.70 (m, 6H), 7.39–7.11 (m, 13H), 5.87
(dd, 2H, J=22 Hz, J=120 Hz), 5.85 (d, 2H, J=22 Hz),
2.95–2.51 (m, 15H), 2.37–2.36 (m, 6H) 1.99–0.79 (m, 50H).
Hydrogenation Procedure
Most experiments were performed in small autoclaves in an
Endeavor apparatus that can be pressurised to 25 bar. To a
glass liner for an autoclave 2 mmol of substrate was added.
To the substrate was added 0.1 mol% of preformed catalyst
of example 3 and 10 mL of a 1M solution of KO-t-Bu in i-
Adv. Synth. Catal. 2010, 352, 2621 – 2628
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2627

Bart Stegink et al.
FULL PAPERS
Minnaard, B. L. Feringa, L. Lefort, J. G. de Vries, Acc.
Chem. Res. 2007, 40, 1267–1277.
gers, H. Bernsmann, A. J. Minnaard, A. Meetsma, T. D.
Tiemersma-Wegman, A. H. M. de Vries, J. G. de Vries,
B. L. Feringa, Angew. Chem. 2005, 117, 4281–4284;
Angew. Chem. Int. Ed. 2005, 44, 4209–4212.
[9] a) T. Jerphagnon, J.-L. Renaud, C. Bruneau, Tetrahe-
dron: Asymmetry 2004, 15, 2101–2111; b) J. G. de
Vries, in: Handbook of Chiral Chemicals, 2nd edn.,
(Ed.: D. J. Ager), CRC Press, Boca Raton, 2005,
pp 269–286; c) M. van den Berg, B. L. Feringa, A. J.
Minnaard, in: The Handbook of Homogenous Hydro-
genation, (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-
VCH, Weinheim, 2007, Vol. 2, pp 995–1028.
[10] M. van den Berg, A. J. Minnaard, B. L. Feringa, J. G.
de Vries, (to DSM n.v.), Catalyst for asymmetric (trans-
fer)hydrogenation, WO 02 04466, 2002.
[11] a) Y. Xu, N. W. Alcock, G. C. Clarkson, G.; Docherty,
G. Woodward, M. Wills, Org. Lett. 2004, 6, 4105–4107;
b) Y. Xu, G. C. Clarkson, G. Docherty, C. L. North, G.
Woodward, M. Wills, J. Org. Chem. 2005, 70, 8079–
8087.
[19] J. A. F. Boogers, U. Felfer, M. Kotthaus, L. Lefort, G.
Steinbauer, A. H. M. de Vries, J. G. de Vries. Org.
Proc. Res. Dev. 2007, 11, 585–591.
[20] C. A. Sandoval, T. Ohkuma, K. MuÇiz, R. Noyori, J.
Am. Chem. Soc. 2003, 125, 13490–13503.
[21] R. Hoen, M. van den Berg, H. Bernsmann, A. J. Min-
naard, J. G. de Vries, B. L. Feringa, Org. Lett. 2004, 6,
1433–1436.
[22] H. Bernsmann, M. van den Berg, R. Hoen, A. J. Min-
naard, G. Mehler, M. T. Reetz, J. G. de Vries, B. L. Fer-
inga, J. Org. Chem. 2005, 70, 943–951.
[23] K. M. J. Brands, J. F. Payack, J. D. Rosen, T. D. Nelson,
A. Candelario, M. A. Huffman, M. M. Zhao, J. Li, B.
Craig, Z. J. Song, D. M. Tschaen, K. Hansen, P. N.
Devine, P. J. Pye, K. Rossen, P. G. Dormer, R. A.
Reamer, C. J. Welch, D. J. Mathre, N. N. Tsou, J. M.
McNamara, P. J. Reider, J. Am. Chem. Soc. 2003, 125,
2129–2135.
[12] K. Abdur-Rashid, A. J. Lough, R. H. Morris, Organo-
metallics 2000, 19, 2655–2657.
[13] Q. Jing, X. Zhang, J. Sun, K. Ding, Adv. Synth. Catal.
2005, 347, 1193–1197.
[14] a) B. Hagemann, K. Junge, S. Enthaler, M. Michalik, T.
Riermeier, A. Monsees, M. Beller, M. Adv. Synth.
Catal. 2005, 347, 1978–1986; b) K. Junge, B. Hage-
mann, S. Enthaler, G. Oehme, M. Michalik, A. Mon-
sees, T. Riermeier, U. Dingerdissen, M. Beller, Angew.
Chem. 2004, 116, 5176–5179; Angew. Chem. Int. Ed.
2004, 43, 5066–5069.
[15] a) Houben Weyl, Methoden der Organischen Chemie,
(Ed.: E. Mꢃller), Georg Thieme Verlag, Stuttgart,
1964, Vol. XII/2, p 99; b) R. S. Edmundson, in: Com-
prehensive Organic Chemistry, (Eds.: D. Barton, W. D.
Ollis), Pergamon Press, Oxford, 1979, Vol. 2, part 10.3;
c) A. van Rooy, D. Burgers, P. C. J. Kamer, P. W. N. M.
van Leeuwen, Recl. Trav. Chim. Pays-Bas 1996, 115,
492–498; d) A. H. M. de Vries, A. Meetsma, B. L. Fer-
inga, Angew. Chem. 1996, 108, 2526–2528; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2374–2376; e) . H. Choi,
J. Y. Choi, H. Y. Yang and Y. H. Kim, Tetrahedron:
Asymmetry 2002, 13, 801–804; f) R. Hulst, N. K. de
Vries, B. L. Feringa, Tetrahedron: Asymmetry 1994, 5,
699–708.
[24] F. Giacomina, A. Meetsma, L. Panella, L. Lefort,
A. H. M. de Vries, J. G. de Vries, Angew. Chem. 2007,
119, 1519–1522; Angew. Chem. Int. Ed. 2007, 46, 1497–
1500.
[25] a) K Abdur-Rashid, S. E. Clapham, A. Hadzovic, J. N.
Harvey, A. J. Lough, R. H. Morris, J. Am. Chem. Soc.
2002, 124, 15104–15118; b) R. Abbel, K Abdur-Rashid,
M. Faatz, A. Hadzovic, A. J. Lough, R. H. Morris, J.
Am. Chem. Soc. 2005, 127, 1870–1882; c) M. Zimmer-
De Iuliis, R. H. Morris, J. Am. Chem. Soc. 2009, 131,
11263–11269.
[26] R. Hulst, N. K. de Vries, B. L. Feringa, Tetrahedron:
Asymmetry 1994, 5, 699–708.
[27] L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries,
R. Naasz, B. L. Feringa, Tetrahedron 2000, 56, 2865–
2878.
[28] M. van den Berg, A. J. Minnaard, R. M. Haak, M.
Leeman, E. P. Schudde, A. Meetsma, B. L. Feringa,
A. H. M. de Vries, C. E. P. Maljaars, C. E. Willans, D.
Hyett, J. A. F. Boogers, H. J. W. Hendrickx, J. G. de
Vries, Adv. Synth. Catal. 2003, 345, 308–323.
[29] R. Hoen, J. A. F. Boogers, H. Bernsmann, A. J. Min-
naard, A. Meetsma, T. D. Tiemersma-Wegman,
A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Angew.
Chem. 2005, 117, 4281–4284; Angew. Chem. Int. Ed.
2005, 44, 4209–4212.
[16] L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G.
de Vries, Org. Lett. 2004, 6, 1733–1735.
[17] a) M. T. Reetz, T. Sell, A. Meiswinkel, G. Mehler,
Angew. Chem. 2003, 115, 814–817; Angew. Chem. Int.
Ed. 2003, 42, 790–793; b) M. T. Reetz, Angew. Chem.
2008, 120, 2592–2626; Angew. Chem. Int. Ed. 2008, 47,
2556–2588.
[30] A. W. van Zijl, L. A. Arnold, A. J. Minnaard, B. L. Fer-
inga, Adv. Synth. Catal. 2004, 346, 413–420.
[18] a) D. PeÇa, A. J. Minnaard, J. A. F. Boogers, A. H. M.
de Vries, J. G. de Vries, B. L. Feringa, Org. Biomol.
Chem. 2003, 1, 1087–1089; b) R. Hoen, J. A. F. Boo-
[31] R. B. C. Jagt, P. Y. Toullec, E. P. Schudde, J. G. de Vries,
B. L. Feringa, A. J. Minnaard, J. Comb. Chem. 2007, 9,
407–414.
2628
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2621 – 2628