Application of tethered ruthenium catalysts to asymmetric hydrogenation of ketones, and the selective hydrogenation of aldehydes

Article abstract of DOI:10.1002/adsc.201200362

An improved method for the synthesis of tethered ruthenium(II) complexes of monosulfonylated diamines is described, together with their application to the hydrogenation of ketones and aldehydes. The complexes were applied directly, in their chloride form, to asymmetric ketone hydrogenation, to give products in excess of 99% ee in the best cases, using 30 bar of hydrogen at 60 °C, and to the selective reduction of aldehydes over other functional groups. Copyright

Full text of DOI:10.1002/adsc.201200362

UPDATES
DOI: 10.1002/adsc.201200362
Application of Tethered Ruthenium Catalysts to Asymmetric
Hydrogenation of Ketones, and the Selective Hydrogenation
of Aldehydes
Katherine E. Jolley,a Antonio Zanotti-Gerosa,b Fred Hancock,b Alan Dyke,b
Damian M. Grainger,b Jonathan A. Medlock,b Hans G. Nedden,b
Jacques J. M. Le Paih,b Stephen J. Roseblade,b Andreas Seger,c
Vilvanathan Sivakumar,c Ivan Prokes,a David J. Morris,a and Martin Willsa,*
a
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, U.K.
Fax : (+44)-24-7652-4112; phone (+44)-24-7652-3260; e-mail: m.wills@warwick.ac.uk
Johnson Matthey Chiral Technologies, Johnson Matthey Catalysts, 28 Cambridge Science Park, Milton Road, Cambridge,
b
CB4 0FP, U.K.
c
Johnson Matthey Chemicals India Pvt. Ltd., Plot No. 6, MIDC Industrial Estate, Taloja Dist. Raigad, Maharashtra –
410208, India
Received: April 25, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200362.
Abstract: An improved method for the synthesis of
tethered ruthenium(II) complexes of monosulfony-
lated diamines is described, together with their ap-
plication to the hydrogenation of ketones and alde-
hydes. The complexes were applied directly, in their
chloride form, to asymmetric ketone hydrogenation,
to give products in excess of 99% ee in the best
cases, using 30 bar of hydrogen at 608C, and to the
selective reduction of aldehydes over other func-
tional groups.
derived from chiral amines have recently been report-
ed.[5,6]
An important breakthrough in this area was provid-
ed by complex 1,[6] the OTf derivative of the well-es-
tablished asymmetric transfer hydrogenation catalyst
2,[7] itself an organometallic complex of the ligand N-
tosyl-1,2-diphenylethane-1,2-diamine (TsDPEN). Al-
though complex 2 is reported to be a poor catalyst for
ketone hydrogenation, replacement of its chloride
with triflate, and conducting the hydrogenation in
methanol rather than 2-propanol, results in the forma-
tion of a much more active hydrogenation system
(Scheme 1) which was first tested on a series of chro-
manone substrates.[3a] The increased activity is due to
the ionisation of 1 to form 3, which then reacts with
dihydrogen to form the hydride 4. It is hydride 4
which then performs the reduction of ketones,
through the well-established outer-sphere six-centred
transition state mechanism already established in the
closely related transfer hydrogenation process.[7]
The mechanism of hydrogen activation by 1 has
Keywords: alcohols; aldehydes; asymmetric cataly-
sis; enantioselectivity; ketones; ruthenium; tethered
catalysts
Introduction
Asymmetric hydrogenation of ketones using organo-
metallic catalysts provides a convenient access to now been extended,[6b,c] and related Ru(II) complexes
enantiomerically pure alcohols.[1–6] The majority of containing TsDPEN ligands have been reported, in-
catalysts for asymmetric hydrogenation contain either cluding examples in which additional functionalities
phosphorus/nitrogen donor ligands or a combination assist the hydrogen dissociation step.[6e,f] Following the
of each type.[2] Asymmetric hydrogenation catalysts initial disclosure by Noyori et al.,[6a] it was found that
which lack phosphine-based ligands are relatively the closely related Ir complex 5 was also active in the
rare.[3–6] Catalysts of this type[3] can be prepared in asymmetric reduction of a-hydroxy acetophenone de-
(III) com- rivatives.[6d] Complexes 1 and 5, and the related Rh
situ by combining Ru(II), RhACTHNUTRGNENG(U III) and IrCAHTUNGTRENNUGN
plexes with chiral diamine ligands,[4] however, complex 6 have found application in the asymmetric
a number of very efficient, well-defined complexes hydrogenation of cyclic and acyclic imines[8] and in
the asymmetric reduction of quinoline derivatives.[9]
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plications to the asymmetric hydrogenation of a range
of ketones and the selective reduction of aldehydes.
Results and Discussion
In our previous approach to the synthesis of 7 and its
derivatives,[10b] the reaction between the aldehyde de-
rived from alcohol 13 and (R,R)-TsDPEN was em-
ployed in order to form intermediate 14a, which was
then converted to dimer 15a upon reaction with
ruthenium trichloride. During attempts to scale-up
the synthesis, it proved to be inconsistent on a larger
scale (10s of grams). In response to this, the direct at-
tachment of alcohol 13 was investigated. It was found
that in situ formation of the triflate of 13, with 2,6-lu-
tidine as base, followed by addition of (R,R)-TsDPEN
with careful control of the temperature, gave 14a in
70% yield on a 35-g scale. Formation of dimer 15a
was completed through a controlled addition of an
aqueous solution of ruthenium chloride to the HCl
salt of 14a at 758C. The solution of 15a was then con-
verted to 7 using diisopropylethylamine in DCM at
08C, and purified by direct recrystallisation of the
celite-filtered product (Scheme 2). From the precursor
15a, monomer 7 was formed in yields of 67–83%.
Both steps could additionally be ꢁtelescopedꢂ to pro-
duce 7 directly from diamine 14a in a one pot process
in 63–79% yield. Using this sequence, complexes 11
and 12 (12 via the mesylated alcohol in the first step)
were also produced (Scheme 2), although the yield of
12 over two steps was lower due to a low conversion
to the dimer.
Scheme 1. Asymmetric hydrogenation of ketones using Ru/
TsDPEN catalysts.
The spectroscopic analysis of catalyst 7 thus gener-
1
ated was found to be facilitated by running H and
13C NMR spectra in CD3NO2 rather than in CDCl3.
Recently, we reported the synthesis and applica- The spectra in CDCl3 appeared to contain a substan-
tions to asymmetric transfer hydrogenation of a series tial amount of an ꢁimpurityꢂ, which has been observed
of complexes which contain a linking group (ꢁtetherꢂ) in previous syntheses,[10b] however the spectra record-
between the TsDPEN unit and the arene ring on the ed in CD3NO2, of an identical sample, revealed no
ruthenium atom.[10] Complexes 7 (3C tether) and 8 evidence of a similar impurity (see Supporting Infor-
(4C tether) are the most widely used examples of this mation) and were clean other than for a small quanti-
series[10] and are highly active for ketone transfer hy- ty of residual (i-Pr)2NEt. The observed ꢁimpurityꢂ
drogenation when used in formic acid/triethylamine may be due to another diastereoisomer of the com-
as the hydrogen source and solvent.[10] In our early plex, i.e., at the metal or through the conformation of
studies, complex 7 was found to be active at the asym- the linking chain, the ratio of which is solvent depen-
metric hydrogenation of a-chloroacetophene.[10j] Ikar- dent. The ratio of the ꢁimpurityꢂ found in the CHCl3
iya et al. recently reported the synthesis of both the spectra did not, however, change over a range of
(CH2)4 (4C) tethered complex 9 and the O-tethered 213 K to 333 K during
a variable temperature
derivative 10, and their application to asymmetric 1H NMR study.
ketone transfer and pressure hydrogenation.[6h] Com-
Having established a suitable route for the practical
plex 10, which was found to be active as a pressure synthesis of catalysts 7, 11 and 12, their application to
hydrogenation catalyst without modification,[6h] was the asymmetric hydrogenation of ketones was investi-
also prepared by ourselves in contemporaneous stud- gated (Scheme 1, Figure 1, Table 1). The application
ies, although our studies focussed on transfer hydro- of the unmodified complexes 7, 11 and 12 to hydroge-
genation.[10i] In this paper we describe an improved nation would have the advantage of eliminating the
synthesis of 7, new catalysts 11 and 12, and their ap- requirement to preform, or form in situ, either the tri-
2
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Application of Tethered Ruthenium Catalysts to Asymmetric Hydrogenation of Ketones
Scheme 2. Synthesis of catalysts 7, 11 and 12.
flate complex or the 16 electron unsaturated species silver salts led to a sharp reduction of catalyst activity
prior to the reaction. In the event, this proved to be (Table 1 entries 3, 10, and 12), which is in contrast to
the case, and in initial tests at S/C=100 (Table 1 en- the findings of related studies using the untethered
tries 1 and 2), acetophenone was fully reduced in 94% catalysts.[8a,f] Increasing the S/C to 500 resulted in a de-
ee using catalyst 7. Unexpectedly, the addition of crease in conversion at 508C although this could be
restored to >99% within 16 h by raising the tempera-
ture to 608C (entries 5 and 6). The ee, at a substrate
concentration of 0.5M, was 94.5% (S/C 500) and 93%
(S/C 1000) and lower conversions were observed at
higher substrate concentrations (entry 9). Reducing
the hydrogen pressure gave a slightly inferior result
with respect to conversion (entry 7), and at S/C of
2000 the reaction became significantly slower, even at
608C (entry 14).
The N-mesylated complex 11 was also efficient in
the reaction, although the conversions were lower
than for 7, and again the addition of silver triflate
gave an inferior result (entries 15–18). An achiral
tethered catalyst can also be employed for racemic
ketone hydrogenation; use of complex 12 resulted in
efficient reduction of acetophenone in 16 h at 408C at
S/C of 250 (Table 1, entries 19 and 20).
Having established optimal conditions for the hy-
drogenation reactions, a further series of ketones was
evaluated as substrates, with a focus on catalyst 7, in
order to establish its versatility; alcohols 16–31 and 33
were formed in these studies (Figure 1, Table 2). Ace-
tophenone derivatives worked well, including elec-
tron-rich and electron-poor substrates, cyclic sub-
strates and those bearing a heteroatom substituent at
the a-position. An a-hydroxy ketone worked excep-
tionally well (21 formed in >99.5% ee), as did tetra-
lone and chromanone. Given the close similarity of
the results, in terms of absolute configuration and
enantioselectivity, to those obtained using transfer hy-
drogenation, we anticipate that the asymmetric reduc-
tion step is common to both reduction systems. The
process by which the resulting ꢁ16eꢂ Ru species is con-
Figure 1. Products of reduction of ketones using catalyst 7;
configuration illustrated matches that obtained using (R,R)-
catalyst.
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Table 1. Hydrogenation of acetophenone using catalysts 7, 11 and 12, with optional additives.[a]
Entry
Catalyst
S/C
Scale [S]/M, additives
Temperature [8C]
Conversion [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
U
100
100
100
250
500
500
500
500
1000
1000
1000
1000
1000
2000
200
200
500
1000
100
250
2 mmol [0.5]
1 mmol [1]
1 mmol [1]+1 mol% AgOTf
2 mmol [0.5]
2 mmol [0.5]
2 mmol [0.5]
10 mmol [1]
2 mmol [0.5]
5 mmol [1.4]
5 mmol [1.4]+1 mol% AgBF4
3 mmol [1.0]
3 mmol [1.0]+1 mol% AgOTf
2 mmol [0.5]
4 mmol [1]
3 mmol [1]
3 mmol [1]+1 mol% AgOTf
3 mmol [1]
3 mmol [1]
3 mmol [1]
3 mmol [1]
40
60
60
50
50
60
60
60
60
60
60
60
60
60
60
60
60
60
30
40
100
100
9
100
67
>99
97e
100
71
94 (S)
96 (S)
Nd[c,d]
94 (S)
92.5 (R)
94.5 (R)
91.5 (R)
93.5 (S)
94 (S)
nd[c,f]
9
10
11
12
13
14
15
16
17
18
19
20
7
>99
1
100
49
>99
<1
62
33
100
100
94 (S)
nd[c,g]
93 (S)
93 (S)
88 (R)
nd[c,f]
88 (R)
88 (R)[h]
–
–
[a]
16 h, MeOH, 30 bar H2.
[b]
Determined by GC [ChromPack CP-Chirasil-Dex-CB 25 mꢃ0.25 mmꢃ0.25 mm. 1008C for 10 min, then to 2008C @
108CminÀ1, 10 psi He flow, injector: 2008C; detector (FID): 2108C].
ND=not determined.
7% side product also formed. Using 2 mol% AgOTf the conversion was 4%.
15 bar H2 pressure.
3% side product formed.
4% side product formed.
Lower conversions were observed using 5 mmol at [S]=1.4 and 2 mmol at [S]=0.5M.
[c]
[d]
[e]
[f]
[g]
[h]
verted back to the hydride is probably identical to to form self-condensation side-products.[12] This result
that of the untethered complexes.[10b] On this basis, it highlights the potential for using an asymmetric cata-
was not surprising that acetylcyclohexane gave a prod- lyst that works under completely neutral conditions.
uct of just 66.8% ee, and in the opposite sense to the The low ee for the formation of 29 would suggest that
acetophenone reduction; under transfer hydrogena- the Ph and CF3 groups have similar affinity for the
tion conditions, a product of 69% ee (S) is formed ruthenium-bound h6-arene within the accepted transi-
using (R,R)-7.[10b]
tion states for ketone reductions by these com-
The reduction of a-chloroacetophenone using 7 re- pounds,[7] whilst the high ee and sense of reduction to
quired 75 bar H2 pressure. Under these conditions, re- give 30 indicates that the CF3 has a higher affinity
duction to (R)-28 in 95% conversion and 94% ee was than the methyl group, as would be anticipated.[11]
achieved after 16 h (508C, MeOH). Reduction of the During the reduction of 1,1,1-trifluoroacetone, a side
unsaturated ketone 32 resulted in formation of an in- product, which may be the product of addition of
separable mixture of products of C=O and C=C re- methanol to the substrate, was observed along with
duction. Reduction of this mixture gave almost race- incomplete conversion. Addition of ca 10 mol% of
mic saturated alcohol 33, which indirectly indicated water resulted in full reduction to 30, possibly due to
that there was no enantioselectivity in the reduction. reversal of formation of the observed side product.
The reduction of trifluoromethylated substrates re- The reduction of 1,1,1-trifluoroacetone in EtOH and
turned some interesting results. Alcohol 29 was i-PrOH was also successful, at 608C, giving products
formed in very low ee of only 8% (>99% conversion) of 92 and 90% ee, respectively (unchanged configura-
at S/C 500, although this could be raised to 20% ee tion).
[(R) using (S,S)-7] at S/C 50.[11] In contrast the reduc-
The tethered catalysts also proved to be effective at
tion of 1,1,1-trifluoroacetone resulted in formation of catalysis of reduction of a series of aldehydes 35–39
30 in 94% ee [(S)-product formed using (S,S)-7]. (Table 3). Although the chiral catalyst (S,S)-7 worked
1,1,1-Trifluoro-2-propanol 30 is an important chiral well, it is preferable to use the non-chiral analogue
building block difficult to access due to its tendency 12. During initial studies on benzaldehyde (35) in
4
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Application of Tethered Ruthenium Catalysts to Asymmetric Hydrogenation of Ketones
Table 2. Hydrogenation of ketones with catalyst 7.[a]
Product
Catalyst
Time
Temperature [8C]
Conversion [%][b]
ee [%][b]
16
17
18
19
20
21
22
23
24
25
26
27
N
24 h
16 h
16 h
48 h
24 h
24 h
48 h
48 h
48 h
24 h
48 h
48 h
16 h
18 h
18 h
18 h
24 h
60
60
60
60
60
60
60
60
60
60
60
60
50
60
50
50
60
>99%
99.3
>99.9
99.9
99.9
>99
73.7
70 (R)
91.1 (R)
88.2 (R)
89.7 (R)
84.4 (S)
>99.5 (S)
68.8 (R)
99.3 (R)
97.5 (R)
99.0 (R)
>95% (S)[e]
66.8 (S)
94 (R)
99.9
99.5
99.9
87.7[d]
99.95
95
28[f]
29[g]
30[h]
30[i]
31, 33
>99
94
8 (R)
92 (S)
94 (S)
4.7% (S)
>99
80.3[c]
[a]
MeOH, S/C=500, 30 bar H2, 1 mmol scale, [S]=0.5Mm except where indicated.
For details of the methods used for determination of the ee of the products, see the Supporting Information.
[b]
[c]
37.3% unsaturated alcohol 31, 30.9% saturated alcohol 33, 12.1% saturated ketone 34, reduction of the mixture gave the
saturated alcohol 33 in 4.7% ee.
[d]
[e]
[f]
1
Conversion determined by H NMR.
1
Only one enantiomer is visible in H NMR using Mosherꢂs method.
S/C=200, 1.3 mmol, [S]=0.13M, 75 bar H2.
[g]
[h]
[i]
2 mmol, [S]=0.7M, product of 20% ee obtained at S/C=50.
Ca. 6% side product also formed under these conditions (see the Supporting Information).
10 mol% H2O added, <1% side product formed.
Table 3. Hydrogenation of aldehydes with catalysts 7 and 12.[a]
Substrate.
Catalyst
Solvent
Time [h]
Temperature [8C]
Conversion [%][b]
Alcohol:acetal[b]
35
35
35
35
35
35
35
35
35
35
35
35
36
37
38
39
39
39
N
MeOH
24
8
60
60
60
60
60
60
60
60
60
40
60
60
60
60
60
40
60
60
100
99.97
100
62:38
MeOH:H2O 95:5
MeOH:H2O 90:10
MeOH:H2O 75:25
MeOH:H2O 50:50
MeOH:H2O 25:75
MeOH
MeOH:H2O 95:5
MeOH:H2O 95:5
MeOH:H2O 95:5
MeOH:H2O 95:5
MeOH:H2O 90:10
MeOH:H2O 90:10
MeOH:H2O 90:10
MeOH:H2O 90:10
MeOH
99.94:0.03
99.9:<0.01
99.8:<0.01
99.8:<0.01
71.8:0.4
33.7:66.1
12.3:32.3
98.7:0.9
16
24
24
24
24
4
8
16
8
16
16
16
16
24
24
16
99.8
99.8
72.2
99.8
44.6
99.6
59.1
51.4
99.6
99.6
99.9
99.2
83.95
99.95
67.6
7.4:51.7
2.7:47.2
99.5:0.1
99.6:0
99.8:0.1[g]
94.8:4.4[c]
59.2:22.8[d]
96.1:0.3[e]
62.4:2.6[f]
MeOH:H2O 90:10
MeOH:H2O 90:10
[a]
MeOH, 30 bar H2, S/C 500, 1 mmol scale [S]=0.5M except where indicated.
Conversion and alcohol:dimethoxy acetal ratio determined by GC.
4.4% is sum of 4-aminobenzylalcohol (2.8%) and 3 unidentified impurities in GC.
Also +1.2% saturated alcohol+0.75% saturated aldehyde.
[b]
[c]
[d]
[e]
[f]
Also 3.5% saturated alcohol+0.06% saturated aldehyde.
Also 1.3% saturated alcohol+0.6% saturated aldehyde+0.7% other unidentified products.
Also <0.1% impurity at room temperature, 8.1 in GC.
S/C=1000.
[g]
[h]
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methanol, using 7, dimethyl acetal 40a was formed in vation by additives. The tethered catalysts are also ef-
high yield alongside the desired alcohol. This could fective for highly chomoselective aldehyde reduction.
be eliminated by the addition of at least 5% (volume)
of water to the solvent; even within 8 h at 608C,
almost complete reduction was observed, with only Experimental Section
a trace of the acetal in the product. This parallels the
General experimental details are given in the Supporting In-
formation.
observation made in the reduction to 30, that is, water
may be assisting the conversion of the unwanted
acetal to aldehyde substrate. The water content could
be increased to 10% without detriment to the rate,
however at >25% water loading the rate was seen to
decrease, and longer reaction times were required for
full reduction. In neat water, 26.2% conversion to al-
Synthesis of Tethered Ligand (R,R)-14a
A
solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol 13
(22.1 g, 0.16 mol, 1.6 equiv.) and 2,6-lutidine (d: 0.92 g/mL;
24.5 mL, 0.21 mol, 2.10 equiv.) in anhydrous CH2Cl2
(500 mL) was cooled to 08C under N2. A solution of
trifluoroACTHNUTRGNEUGmN ethanesulfonic anhydride (d: 1.677; 29.1 mL,
0.17 mol, 1.7 equiv) in anhydrous CH2Cl2 (100 mL) was
added slowly, keeping the internal temperature below 58C.
The resulting amber solution was stirred for 30 min at 08C,
60 min room temperature, and cooled back to 08C. A solu-
tion of (R,R)-TsDPEN (36.6 g, 0.10 mol) and triethylamine
(d: 0.726; 33.5 mL, 0.24 mol, 2.4 equiv.) in anhydrous
CH2Cl2 (100 mL) was added slowly, keeping the internal
temperature below 58C. At the end of the addition, stirring
was continued for 30 min at 08C, and then at room tempera-
ture overnight (17.5 h). The reaction mixture was diluted
with CH2Cl2 (500 mL), washed with saturated aqueous
NaHCO3 (2ꢃ500 mL, 1ꢃ250 mL), water (2ꢃ300 mL), brine
(250 mL), dried over MgSO4, and concentrated under re-
duced pressure to give a highly viscous, amber oil. Ethanol
(250 mL) was added, and the mixture was stirred until
a solid formed. Additional ethanol (450 mL) was added, and
the mixture was heated to 708C until a clear solution was
obtained, which was allowed to cool to room temperature
overnight. The thick suspension (solvent not visible, volumi-
nous product) was filtered, and the off-white precipitate was
washed with ethanol, hexane, and dried under high vacuum
to give 14a; yield: 34.10 g (0.0702 mol, 70%), NMR purity:
>98% (1H NMR). The spectroscopic data match those al-
ready reported for this known compound.[10b]
cohol was achieved under the standard conditions.
Solvents other than methanol, including i-PrOH,
DCM, toluene, cyclohexanol, dioxane and DMF, were
significantly inferior, affording less than 5% alcohol
within 24 h at 608C and 30 bar. Using achiral catalyst
12, a 90:10 MeOH:H2O ratio of solvents gave the op-
timal selectivity, with 99.5% of the desired alcohol
product formed. These conditions were applied to the
reduction of aldehydes 36–39, and were found to
work well, with minimal reduction of either the bro-
mide (none visible) or the nitro (2.8% 4-aminobenzyl
alcohol identified) group, or formation of the corre-
sponding acetals 40 or 41 under the conditions used.
Aldehyde 39 provided a very difficult test of selectivi-
ty, however using catalyst 12, 96.1% of the unsaturat-
Synthesis of Tethered Ligand (S,S)-14b·HCl
A
solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol 13
(8.3 g, 60.0 mmol, 1.20 equiv.) and 2,6-lutidine (8.3 mL,
70.0 mmol, 1.40 equiv.) in anhydrous CH2Cl2 (250 mL) was
cooled to 08C under N2. A solution of triflic anhydride
(10.7 mL, 62.5 mmol, 1.25 equiv.) in anhydrous CH2Cl2
(40 mL) was added slowly, keeping the internal temperature
below 58C. The resulting amber solution was stirred for
ed alcohol product was formed alongside products of 30 min at 08C, 90 min at room temperature, and cooled to
08C. A solution of (S,S)-MsDPEN (14.52 g, 50.0 mmol) and
triethylamine (11.2 mL, 80.0 mmol, 1.6 equiv.) in anhydrous
CH2Cl2 (90 mL) was added slowly, keeping the internal tem-
perature below 58C. At the end of the addition, stirring was
continued for 30 min at 08C and then at room temperature
overnight (20.5 h). The reaction mixture was diluted with
CH2Cl2 (total volume: ca. 500 mL), washed with saturated
aqueous NaHCO3 (2ꢃ250 mL, 1ꢃ150 mL), water (2ꢃ
200 mL), brine (200 mL), dried over MgSO4, and concen-
trated under reduced pressure to give a highly viscous,
amber oil (yield: 26.5 g). The crude product was filtered
reduction of the C=C bond.
Conclusions
In conclusion, tethered Ru(II) catalysts 7, 11 and 12
can be prepared in high yield and purity, and can be
used effectively in asymmetric pressure hydrogenation
of ketones, as the chlorides, without the need for acti-
6
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Application of Tethered Ruthenium Catalysts to Asymmetric Hydrogenation of Ketones
through a layer of silica gel (7 cm thick, 9 cm in diameter)
with EtOAc/hexane 2/1 as eluent. The product was obtained
with the first two fractions (200 mL each) but still contained
30 min. The resulting suspension was then heated to 758C
and to this was added RuCl3 in H2O (assay 19.23% in Ru,
d=1.628, 1.62 mL, 5 mmol) in isopropyl acohol (IPA)
(20 mL) dropwise over 1 hour. The solution was then stirred
at 758C overnight. The solution was then cooled, hexane
(100 mL) added with vigorous stirring and the solution was
filtered. The solids obtained were then washed with hexane,
collected and dried under high vacuum to give a light brown
solid (~6 g, carried forward). The dimer 15a was isolated as
a crude solid and shown to be >90% pure by 1H NMR
(CDCl3).[10b]
Procedure 3: To a stirred suspension of (R,R)-diamine
14a (2.9 g, 6.0 mmol) in toluene (20 mL) was added HCl
(3 mL, 37%, 36 mmol) at 508C and the solution was stirred
for 30 min. The resulting suspension was then heated to
758C and to this was added RuCl3 in H2O (assay 19.23% in
Ru, d=1.628, 1.62 mL, 5 mmol) in IPA (20 mL) dropwise
over 1 hour. The solution was then stirred at 758C over-
night. The solution was then cooled, hexane (100 mL) added
with vigorous stirring and solution filtered. The solids ob-
tained were then washed with hexane, collected and dried
under high vacuum to give a light brown solid (~6 g, carried
forward). The dimer 15a was isolated as a crude solid and
shown to be >90% pure by 1H NMR (CDCl3).
an impurity, which eluted first [TLC in EtOAc, RfACTHNUGRTENUNG(impurity):
0.76, Rf(tethered MsDPEN): 0.66; visualised with UV @
254 nm or with basic KMnO4]. Evaporation of the solvents
under reduced pressure furnished the crude product as
a
yellow-to-orange oil, which slowly solidified (yield:
20.2 g). The solid was dissolved in methyl t-butyl ether
(MTBE) (500 mL) and the solution was cooled to ca. 08C.
A 1.25M solution of HCl in MeOH (120 mL, 150 mmol)
was added with vigorous stirring. After 45 min at 08C the
thick suspension was filtered, the solid was washed with
MTBE, and dried under high vacuum to give 14b; yield:
17.13 g (0.0384 mol, 77%), NMR purity: >98% (1H NMR).
A second batch of product was obtained by working up the
mother liquor: The combined filtrate and washings were
evaporated to dryness under reduced pressure until a solid
was obtained, which was triturated with ethyl acetate
(40 mL) at 708C for 1 hour. After cooling to room tempera-
ture, the mixture was filtered and the filter cake was washed
with EtOAc. The off-white solid was then dried under high
vacuum; yield: 1.66 g (3.72 mmol, 7%), NMR purity: >98%
(1H NMR): mp 1868C; [a]D26: À20.25 (c 1 in CHCl3); MS
(ESI):
m/z=411.2099
[M+ +HÀHCl],
calcd.
for
C24H31N2O2S [M]: 411.2101; IR: nmax =3676, 2972, 2901,
Synthesis of [Ts-teth-DPEN Ru Cl] (Monomer) 7
1590, 1455, 1395, 1329, 1157, 1066, 985, 756, 698, 664 cmÀ1
;
1H NMR (400 MHz, CDCl3): dH =10.08 (1H, br s, HN+H),
8.81 (1H, d, J=9.1 Hz, NHMs), 8.61 (1H, br s, HN+H),
7.52–7.51 (2H, m, CHAr), 7.38–7.36 (2H, m, CHAr), 7.25–
7.24 (3H, m, CHAr), 7.20–7.14 (3H, m, CHAr), 5.57 (2H, s,
HC=CHꢃ2), 5.26 (1H, s, C=CH), 5.23 (1H, d, J=10.0 Hz,
CHPh), 4.91 (1H, d, J=10.4 Hz, CHPh), 2.97–2.94 (1H, m,
NH2CHaHb), 2.85–2.83 (1H, m, NH2CHaHb), 2.65 (3H, s,
CH3), 2.50–2.48 (2H, m, =C-CH2-C=), 2.44–2.40 (2H, m, =
C-CH2-C=), 2.16–1.82 (4H, m, 2ꢃCH2); 13C NMR
(100 MHz, CDCl3): dC =137.1, 132.7, 130.9, 129.6, 129.5,
129.1, 128.8, 128.4, 128.2, 124.01 (ꢃ2), 119.5, 65.5, 61.1, 45.7,
42.1, 34.1, 28.6, 26.6, 22.9; MS (ESI): m/z=411.1 (M+ +
18À36).
Procedure 1: To a stirred solution of the (R,R)-dimer 15a
(14 g carried forward, ~10.1 mmol) in DCM (300 mL) at
08C was added N,N-diisopropylethylamine (20.9 mL,
120 mmol) and the solution was stirred at room temperature
for 1 hour. The solution was then filtered over celite, IPA
(300 mL) and the DCM removed by rotary evaporation.
The resulting suspension was then filtered and product col-
lected as a dark orange solid. The solid was then further
dried under high vacuum over night to give 7 as a fine
orange powder; yield: 10.6 g (0.0171 mol, 83% from 14a).
The isolated product was shown to be >95% pure by
1
1H NMR (CDCl3). A detailed H NMR study was conducted
on a 700 MHz instrument fitted with a cryoprobe in CDCl3
and CD3NO2 (see the Supporting Information). The data
matched those previously reported for this known com-
pound.[10b]
Procedure 2: To a stirred solution of the (R,R)-dimer 15a
(14 g, ~10.1 mmol) in IPA (1 L) at 508C was added N,N-di-
AHCTUNGTREGiNNNU sopropylethylamine (20.9 mL, 120 mmol) and the solution
Synthesis of TsDPEN Ru Dimer (R,R)-15a
Procedure 1: To a stirred suspension of (R,R)-tethered di-
ACHTUNGTRENNUNGamine 14a (11.68 g, 24 mmol) in EtOH (500 mL) was added
concentrated HCl (3 mL, 37%, 36 mmol) at 608C and the
solution was stirred for 30 min. The solution was then
heated to 758C and to this was added RuCl3 in H2O (assay
19.23% in Ru, d=1.628, 6.46 mL, 20 mmol) in EtOH
(50 mL) dropwise over 1 hour. The solution was then stirred
at 758C overnight. The solution was then cooled, hexane
(600 mL) added with vigorous stirring and solution filtered.
The solids obtained were then washed with hexane, collect-
ed and dried under high vacuum to give a light brown solid
(~15 g, carried forward). The isolated product 15a was
was stirred at 858C for 2 h. The solution was then cooled,
evaporated to a third of its original volume and then filtered
to give a dark orange solid. The solid was then further dried
under high vacuum over night to give 7 as a fine orange
powder; yield: 8.5 g (13.7 mmol, 67%). The isolated product
1
was shown to be >95% pure by H NMR (CDCl3).
Synthesis of (R,R)-7 in One-Pot from Diamine 14a
Procedure 1: To a stirred suspension of (R,R)-diamine 14a
(2.9 g, 6.0 mmol) in toluene (20 mL) was added HCl
(0.75 mL, 37%, 9 mmol) at 508C and the solution was
stirred for 30 min. The resulting suspension was then heated
to 758C and to this was added RuCl3 in H2O (assay 19.23%
in Ru, d=1.628, 1.62 mL, 5 mmol) in IPA (10 mL) dropwise
over 1 hour. The solution was then stirred at 758C overnight
(16 h). The solution was then cooled to 08C, toluene
1
shown to be >95% pure by H NMR (CDCl3). No further
purification was attempted and this material was carried for-
ward to the next step. The spectroscopic data matched those
previously reported for this known compound.[10b]
Procedure 2: To a stirred suspension of (R,R)-diamine
14a (2.9 g, 6.0 mmol) in DCE (20 mL) was added HCl
(3 mL, 37%, 36 mmol) at 508C and solution was stirred for
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Katherine E. Jolley et al.
UPDATES
(30 mL) added and N,N-diisopropylethylamine (4.35 mL,
25 mmol) added dropwise with stirring. The solution was
then allowed to warm to room temperature and then heated
to 808C for 30 min. The solution was cooled, diluted with
DCM (50 mL), filtered over neutral alumina (1 g/mmol) and
the pad was washed with further portions of DCM (2ꢃ
20 mL). The filtrate was evaporated to remove the solvent,
IPA (50 mL) added and solution stirred at room tempera-
ture for 1 h. The resulting slurry was then filtered to give an
orange solid, which was dried under high vacuum for 2 h to
give 7; yield: 2.3 g (3.71 mmol, 63%). After the initial heat-
ing phase a thick precipitate formed which resulted in the
stirring of the solution failing. Addition of the toluene and
N,N-diisopropylethylamine however resulted in re-dissolu-
tion of the solids as the monomer formation proceeded. Iso-
lated product was shown to be >95% pure by 1H NMR
(CDCl3).
509.0836 [M+ÀCl], calcd. for C24H27N2O2RuS [M]: 509.0837;
IR: nmax =2972, 1730, 1452, 1261, 1109, 1058, 958, 905, 805,
1
699 cmÀ1; H NMR (400 MHz, CDCl3): dH =7.17–7.15 (3H,
m, CHAr), 7.04–7.01 (3H, m, CHAr), 6.95–6.93 (2H, m,
CHAr), 6.85–6.83 (2H, m, CHAr), 6.24 (1H, t, J=5.5 Hz,
CHAr), 6.06 (1H, t, J=5.7 Hz, CHAr), 5.99 (1H, t, J=
5.7 Hz, CHAr), 5.19 (1H, d, J=5.6 Hz, CHAr), 5.03 (1H, d,
J=5.6 Hz, CHAr), 4.46–4.43 (1H, m, NH), 4.05 (1H, d, J=
10.7 Hz, MsNCH), 3.67 (1H, t, J=11.4 Hz, HNCH), 2.90–
2.83 (1H, m, CHH), 2.71–2.65 (4H, s overlapping m, CH3
with CHH overlapping), 2.55–2.49 (1H, m, CHH), 2.35–2.29
(1H, m, CHH), 2.27–2.17 (1H, m, CHH), 2.02–1.93 (1H, m,
CHH); 13C NMR (100 MHz, CDCl3): dC =142.4, 136.7,
128.8, 128.5, 128.0, 127.63, 127.58, 126.7, 99.7, 93.6, 92.8,
81.9, 79.2, 77.8, 72.8, 69.8, 48.8, 41.3, 29.7, 26.8; MS (ESI):
m/z=509.0 (M+ +1À35).
Procedure 2: To a stirred suspension of (S,S)-diamine·HCl
14b (8.03 g, 18 mmol) in toluene (60 mL) at 758C under ni-
trogen RuCl3 in H2O (assay 19.23% in Ru, d=1.628,
4.86 mL, 15 mmol) in IPA (30 mL) was added dropwise over
1 hour. The solution was then stirred at 758C overnight
(16 h). The solution was then cooled to 08C, DCM (100 mL)
and N,N-diisopropylethylamine (15.66 mL, 90 mmol) were
added dropwise with stirring. The solution was allowed to
warm to room temperature and was stirred for 2 h. The so-
lution was filtered over neutral alumina (1 g/mmol) and pad
washed with further portions of 10/90 IPA/DCM (2ꢃ
50 mL). The combined filtrate was evaporated to remove
the solvent, IPA (200 mL) added and the solution was
stirred at room temperature for 2 h. The resulting slurry was
filtered to give 11 as an orange solid, which was washed
with cold IPA (30 mL) and dried under high vacuum for
2 h; yield: 5.0 g (9.2 mmol, 51%). The crude isolated prod-
uct was shown to be >95% pure by 1H NMR (CDCl3).
Procedure 2: To a stirred suspension of (S,S)-diamine 14a
(14.5 g, 30 mmol) in toluene (100 mL) under nitrogen was
added HCl (3.75 mL, 37%, 45 mmol) at 508C and the solu-
tion was stirred for 30 min. The resulting suspension was
then heated to 758C and to this RuCl3 in H2O (assay
19.23% in Ru, d=1.628, 8.1 mL, 25 mmol) in IPA (50 mL)
was added dropwise over 1 hour. The solution was then
stirred at 758C overnight (16 h). The solution was cooled to
08C, DCM (100 mL) and N,N-diisopropylethylamine
(21.75 mL, 125 mmol) were added dropwise with stirring.
The solution was then allowed to warm to room tempera-
taure and stirred for 2 h. The solution was then filtered over
neutral alumina (1 g/mmol) and pad washed with further
portions of 10/90 IPA/DCM (2ꢃ50 mL). The combined fil-
trate was evaporated to remove the solvent, IPA (200 mL)
was added and solution stirred at room temperature for 2 h.
The resulting slurry was then filtered to give an orange
solid, which was washed with cold IPA (30 mL) and dried
under high vacuum for 2 h to give 7; yield: 12.3 g
(19.8 mmol, 79%). The same observations were made as for
procedure 1. Crude isolated product was shown to be >95%
Synthesis of Achiral Tethered Catalyst 12
1
Synthesis of ligand 14c: To a stirred solution of 3-(1,4-cyclo-
hexadien-1-yl)-1-propanol 13 (1.21 g, 9.18 mmol) in DCM
(25 mL), NEt3 (2.7 mL, 19.28 mmol) was added and the re-
sulting solution was cooled to 08C. A solution of methane-
sulfonyl chloride (1.1 mL, 13.8 mmol) was added over
a period of 20 min by keeping the internal temperature
below 58C. After 30 min the reaction mixture was allowed
to warm up to room temperature and stirred overnight. The
reaction was quenched with saturated NaHCO3 solution.
The reaction was worked up with water, brine and dried
over Na2SO4. The mesylate derivative (96% yield) was car-
ried forward directly to the next step.
pure by H NMR (CDCl3).
Synthesis of (S,S)-11 in One Pot from 14b
Procedure 1: To a stirred suspension of (S,S)-diamine·HCl
14b (2.67 g, 6.0 mmol) in toluene (20 mL) at 758C under ni-
trogen RuCl3 in H2O (assay 19.23% in Ru, d=1.628,
1.62 mL, 5 mmol) in IPA (10 mL) was added dropwise over
1 hour. The solution was then stirred at 758C overnight
(16 h). The solution was cooled to 08C, DCM (30 mL)
added and N,N-diisopropylethylamine (4.35 mL, 25 mmol)
was added dropwise with stirring. The solution was allowed
to warm to room temperature and stirred for 2 h. The solu-
tion was diluted with DCM (50 mL), filtered over neutral
alumina (1 g/mmol) and pad washed with further portions of
DCM (2ꢃ20 mL). The combined filtrate was evaporated to
remove solvent, IPA (50 mL) was added and the solution
stirred at room temperature for 1 h. The resulting slurry was
then filtered to give 11 as an orange solid, which was dried
under high vacuum for 2 h; yield: 1.8 g (3.31 mmol, 55%);
mp 1878C; [a]2D6: À460 (c 0.05 in CHCl3). After the initial
heating phase a thick precipitate was not observed in com-
parison to the Ts example. The isolated product was shown
A solution of the mesylate derivative in 10 mL of DME
was added slowly over a period of 5 min to a stirred solution
of monotosylated ethylenediamine (1.98 g, 9.25 mmol) in
1,2-dimethoxyethane
(20 mL)
and
NEt3
(2.7 mL,
19.43 mmol) at 608C. The resulting solution was heated to
808C and stirred overnight. The reaction was quenched with
saturated NaHCO3 solution. The reaction was worked up
with water, brine and dried over Na2SO4. The desired ligand
14c was isolated, as a yellow oil by column chromatography
with EtOAc as eluent (Rf value 0.1 in EtOAc; visualised
with UV @ 254 nm or with basic KMnO4); yield: 1.0 g
(3.0 mmol, 33% yield based on the starting alcohol). MS
(ESI): m/z=335.1798 [M+ +H], calcd. for C18H27N2O2S [M]:
1
to be >95% pure by H NMR (CDCl3). MS (ESI): m/z=
8
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Application of Tethered Ruthenium Catalysts to Asymmetric Hydrogenation of Ketones
335.1788); IR: nmax =2925, 2362, 2325, 1597, 1448, 1322,
1155, 1092, 1034, 814, 752, 659 cmÀ1 1H NMR (400 MHz,
Hydrogenation of Ketones and Aldehydes with
(R,R)- and (S,S)-7, 11 and 12
;
CDCl3): dH =7.76–7.74 (2H, m, ArH), 7.31–7.28 (2H, m,
ArH), 5.70 (2H, br s, CH=CH), 5.38 (1H, br s, =CH), 2.99–
2.97 (2H, m, CH2NH), 2.68–2.65 (4H, m, -CH2-C=and=
CH-CH2-CH=), 2.57–2.53 (2H, m, CH2-NH), 2.46–2.42
(5H, m, CH2 and CH3 overlapping), 1.96–1.90 (2H, m, -NH-
CH2-), 1.54–1.45 (2H, m, -CH2-CH2-CH2); 13C NMR
(100 MHz, CDCl3): dC =143.3, 136.9, 134.4, 129.7, 127.1,
124.3, 118.6, 48.9, 48.0, 42.4, 35.0, 28.9, 27.5, 26.8, 21.5; MS
(ESI): m/z=335.2 (M+ +1), 357.1 (M+ +23).
Catalyst (0.005 mol) and any required additive were weigh-
ed into a glass reaction tube. The tubes were placed in a Bi-
otage Endeavour (at JM) or a Parr hydrogenator (at War-
wick) and flushed with nitrogen. Acetophenone was added,
followed by MeOH. The reaction was purged with hydrogen
gas, heated and pressurised. The reaction was heated and
pressurised with H2 for 16 h then analysed by GC (full re-
sults are given in the Tables, spectroscopic and chromato-
graphic data are given in the Supporting Information).
Synthesis of monomer 12: To a stirred solution of teth-
ered ethylenediamine ligand 14c (0.270 g, 0.808 mmol) in
EtOH (15 mL) was added concentrated HCl (0.12 mL, 35%,
1.212 mmol) at 08C. The solution was heated at 608C for
30 min. After this time the solution was heated to 758C and
a solution of RuCl3 (0.110 g, 0.533 mmol) in EtOH (15 mL)
and water (0.5 mL) was added dropwise over 20 min. The
solution was stirred at 758C overnight. The solution was
cooled, hexane (60 mL) was added with vigorous stirring
and the resulting solid collected by filtration. The solid was
then washed with hexane and dried under high vacuum to
give 15c as a dark brown solid (yield: 0.006 g, 0.0055 mmol,
1.3%). The filtrate was concentrated to give an orange
powder (yield: 0.040 g, 0.037 mmol, 9.2%). Both these solids
were combined with those from other reactions and used di-
rectly in the next reaction. The isolated product was >95%
Acknowledgements
We thank EPSRC for financial support through a project stu-
dentship (to KEJ). We acknowledge the use of the EPSRC
Chemical Database Service.[13]
References
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1
pure by H NMR: H NMR (300 MHz, DMSO-d6): dH =8.74
(4H, br s, NH2), 7.91 (2H, br s, NH), 7.74–7.72 (4H, m,
ArH), 7.46–7.44 (4H, m, ArH), 6.05–6.02 (4H, m, Ru-ArH),
5.84–5.80 (6H, m, Ru-ArH), 3.01 (12H, br s, CH2), 2.57–
2.54 (4H, m, CH2), 2.42 (8H, m, CH3 +CH overlapping),
1.95 (4H, br s, -CH2-).
To a stirred solution of dimer 15c (0.238 g, 0.220 mmol) in
DCM (50 mL) at 08C was added N,N-diisopropylethylamine
(3.0 mL, 1.696 mmol) and the solution was stirred at room
temperature for 2 h. The solution was then filtered over
celite and the DCM was removed by rotary evaporation.
EtOH was added to the resulting paste which was stored in
the freezer for 3 h before the cold solution was filtered and
an orange precipitate collected. The dark precipitate was
washed with further portions of cold EtOH. The desired
ruthenium complex was isolated by column chromatography
with EtOAc (Rf value 0.2 in EtOAc; visualised with UV @
254 nm and phosphomolybdic acid); yield: 205 mg
(0.44 mmol, quant); mp 1258C (decomposed); MS (ESI): m/
z=433.0525 [M+ÀCl], calcd. for C18H23N2O2RuS [M]:
433.0522; IR: nmax =3675, 3169, 2970, 2901, 1447, 1406, 1266,
1105, 1075, 1049, 984, 864, 850, 810, 661 cmÀ1 1H NMR
;
(400 MHz, CDCl3): dH =7.73 (2H, d, J=8.2 Hz, CHAr),
7.15 (2H, d, J=8.2 Hz, CHAr), 6.36 (1H, t, J=5.6 Hz,
CHAr), 5.96 (1H, t, J=5.6 Hz, CHAr), 5.83 (1H, t, J=
5.8 Hz, CHAr), 5.01 (1H, d, J=5.6 Hz, CHAr), 4.91 (1H, d,
J=5.8 Hz, CHAr), 3.79 (1H, br s NH), 3.30–3.23 (1H, m,
CHH), 3.03 (1H, dd, J=11.5 and 4.2 Hz, CHH), 2.79–2.71
(1H, m, CHH), 2.66–2.62 (1H, m, CHH), 2.43–2.36 (3H, m,
CH2 +CHH), 2.34 (3H, s, CH3), 2.27–2.19 (2H, m, CH2),
2.08–1.99 (1H, m, CHH); 13C NMR (100 MHz, CDCl3): dC =
140.5, 140.2, 128.7, 127.4, 98.8, 92.8, 91.3, 78.6, 78.1, 73.5,
57.7, 52.2, 47.5, 29.5, 28.6, 21.4; MS (ESI): m/z=432.9 (M+ +
1À35).
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UPDATES
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9598–9601; n) D. H. Woodmansee. A. Pfaltz, Chem.
Commun. 2011, 7912–7916; o) M. T. Reetz, X. Li,
Chem. Commun. 2006, 2159–2160; p) R. Noyori, T.
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These are not the final page numbers!

UPDATES
12 Application of Tethered Ruthenium Catalysts to
Asymmetric Hydrogenation of Ketones, and the Selective
Hydrogenation of Aldehydes
Adv. Synth. Catal. 2012, 354, 1 – 12
Katherine E. Jolley, Antonio Zanotti-Gerosa,
Fred Hancock, Alan Dyke, Damian M. Grainger,
Jonathan A. Medlock, Hans G. Nedden,
Jacques J. M. Le Paih, Stephen J. Roseblade, Andreas Seger,
Vilvanathan Sivakumar, Ivan Prokes, David J. Morris,
Martin Wills*
12
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!