Asymmetric Transfer Hydrogenation of Ketones with Modified Grubbs Metathesis Catalysts: On the Way to a Tandem Process

Article abstract of DOI:10.1002/adsc.201500933

Herein, we report the successful transformation of a 1^st generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation (ATH) catalyst. Upon addition of a chiral amine ligand, an alcohol and a base, the 1^st generation Hoveyda-Grubbs catalyst (HG-I) was found to promote the enantioselective reduction of acetophenone to 1-phenylethanol. After optimizing the order of addition and the reaction conditions, the substrate scope was assessed leading to enantiomeric excesses up to 97% ee. NMR experiments were run in order to get information about the in situ-generated ATH catalyst. Furthermore, the possibility to perform olefin metathesis and ketone transfer hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis-ketone asymmetric transfer hydrogenation was carried out.

Full text of DOI:10.1002/adsc.201500933

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DOI: 10.1002/adsc.201500933
Asymmetric Transfer Hydrogenation of Ketones with Modified
Grubbs Metathesis Catalysts: On the Way to a Tandem Process
a,b
a,b
b
Marc Renom-Carrasco, Piotr Gajewski, Luca Pignataro,
c
d
b
a,
Johannes G. de Vries, Umberto Piarulli, Cesare Gennari, and Laurent Lefort *
DSM Ahead R&D B.V. – Innovative Synthesis, P. O. Box 18, 6160 MD Geleen, The Netherlands
a
E-mail: laurent.lefort@dsm.com
Università degli Studi di Milano, Dipartimento di Chimica, via C. Golgi 19, 20133 Milan, Italy
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Università degli Studi dell’Insubria, Dipartimento di Scienza e Alta Tecnologia, via Valleggio 11, 22100 Como, Italy
b
c
d
Received: October 2, 2015; Revised: November 16, 2015; Published online: January 26, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500933.
[
3]
Abstract: Herein, we report the successful transfor-
mation of a 1 generation Grubbs metathesis cata-
and organic synthesis. It has been frequently incor-
st
[4]
porated in tandem processes among which the
lyst into an asymmetric transfer hydrogenation
tandem metathesis–hydrogenation is probably the
(
ATH) catalyst. Upon addition of a chiral amine
most studied example. First applied in the field of
st
[5]
ligand, an alcohol and a base, the 1 generation
Hoveyda–Grubbs catalyst (HG-I) was found to pro-
mote the enantioselective reduction of acetophe-
none to 1-phenylethanol. After optimizing the
order of addition and the reaction conditions, the
substrate scope was assessed leading to enantiomer-
ic excesses up to 97% ee. NMR experiments were
run in order to get information about the in situ-
generated ATH catalyst. Furthermore, the possibili-
ty to perform olefin metathesis and ketone transfer
hydrogenation sequentially in one pot was demon-
strated, and the first tandem olefin metathesis–
ketone asymmetric transfer hydrogenation was car-
ried out.
polymers,
the tandem metathesis–hydrogenation
was later extended to the synthesis of small mole-
[6]
cules. Very recently, we reported the first asymmet-
ric version of this tandem protocol, that is, a metathe-
sis–asymmetric hydrogenation (AH) of C=C bonds,
where – after the metathesis step – the ruthenium cat-
alyst is converted into an olefin AH catalyst upon ad-
[7]
dition of a chiral ligand.
Herein, we describe our efforts to expand this con-
cept to ATH, i.e., to achieve a tandem metathesis–
ATH. The non-asymmetric tandem metathesis–TH
has been previously described leading either to the re-
duction of the C=C double bond formed by metathe-
[8]
[6,9]
sis or of an adjacent carbonyl group.
However,
the enantioselective version of this tandem protocol
towards the formation of an enantiopure alcohol is
not known. Based on our previous work, we foresaw
that the addition of a chiral ligand after the metathe-
sis could lead to such an enantioselective transforma-
tion.
Keywords: asymmetric catalysis; metathesis; ruthe-
nium; tandem catalysis; transfer hydrogenation
In preliminary experiments, we tested whether
Asymmetric transfer hydrogenation (ATH) of ke- a Ru metathesis catalyst could be turned into an
tones is an important methodology for the production ATH catalyst. For this purpose, the Hoveyda–Grubbs
st
of chiral alcohols with applications in the synthesis of 1 generation catalyst (HG-I) and the Noyori chiral
[
1]
fine chemicals and pharmaceuticals. Contrary to the ligand (R,R)-Ts-DPEN (L1) were dissolved in THF
direct hydrogenation with H , it employs easy to or in DCM in the presence of acetophenone (1a) as
2
handle and cheap reagents as the hydrogen source a model substrate (Scheme 1). t-BuOK (a necessary
and does not require pressure vessels. Since the semi- component to activate the Noyori catalysts) and i-
[
2]
nal discovery of the Noyori catalysts, ruthenium is PrOH (the hydrogen donor) were added to the solu-
the metal that has been used most extensively in tions, and the obtained mixtures were stirred at 308C
metal-catalyzed ATH.
for 18 h. Gratifyingly, GC analysis revealed the pres-
Ru-based olefin metathesis is an equally important ence of the desired product, (R)-1-phenylethanol (2a),
reaction with numerous applications both in polymers with a significant enantiomeric excess in both reac-
Adv. Synth. Catal. 2016, 358, 515 – 519
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515

Marc Renom-Carrasco et al.
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Scheme 1. ATH of acetophenone 1a using a catalyst formed
in situ from HG-I and Ts-DPEN.
tions (Scheme 1). Use of THF/i-PrOH led to a higher
conversion and was chosen as solvent for the follow-
up experiments.
When monitoring the reaction 1a!2a vs. time, we
observed that the enantiomeric excess increased
during the first 20 h (Figure 1A). This suggests that an
active catalytic species more enantioselective than the
initial one(s) was forming during the course of the re-
action. Stirring HG-I/Ts-DPEN (L1) with t-BuOK in
THF for 3 h before the addition of i-PrOH did not
have any effect (Figure 1B). From this experiment,
we reasoned that the formation of the more enantio-
selective catalytic species was triggered by the addi-
tion of i-PrOH. Additionally, reacting t-BuOK with
HG-I alone in THF before addition of the ligand had
a negative effect both on the activity and enantiose-
lectivity (Figure 1C). This confirmed the crucial role
of i-PrOH which must quickly convert t-BuOK into i-
PrOK. Consequently, we performed the ATH of 1a
by first adding i-PrOH to the mixture of HG-I/Ts- Figure 1. 1a and HG-I were mixed in THF and the other
DPEN in THF followed by t-BuOK. In this case, the components were subsequently added in the order shown on
top of each graph (stirring 5 min between each addition
ee remained constant during the course of the reac-
unless otherwise stated). Conversion and ee vs time for the
tion and 1-phenylethanol (2a) was obtained with 96%
ATH of 1a under different conditions (molar ratio: 1a/HG-
conversion and 90% ee after 18 h (Figure 1D). Re-
I/L1/base=100:1:1.1:20, 0.1 mmol 1a, 1:1 THF/i-PrOH
markably, no erosion of ee was observed even after
(2.0 mL), 308C).
42 h, in contrast to what is known from other ATHs
as a result of the reversible nature of this transforma-
[
10]
tion.
When t-BuOK was replaced by KOMe, the NMR and GC-MS (see the Supporting Information).
same behavior related to the order of addition of In agreement with the catalytic test, no change was
base and i-PrOH was observed (Figure 1E and F). In observed by NMR when HG-I and Ts-DPEN were
contrast, when i-PrONa was used as a base, a high ee dissolved in THF-d :i-PrOH-d . Upon stirring this
8
8
was observed from the beginning of the reaction, no mixture in the presence of t-BuOK for 5 h at room
matter what the order of addition (Figure 1G and H). temperature, we noticed the complete disappearance
Altogether, this set of experiments points towards of the benzylidene proton (d=17.2 ppm, doublet) and
a Ru-isopropoxide species as the most enantioselec- the formation of o-isopropoxytoluene-d by GC-MS
2
tive catalyst or as an intermediate towards it. Notably, (m/z=152), arising from the hydrogenation of the
3
1
the reactions carried out with i-PrONa showed a slow benzylidene moiety. In the P NMR spectrum four
erosion of the ee during time, possibly due to a cation main peaks were observed: a singlet at 6 ppm (free
effect (Na vs. K) already evidenced in some previous PCy ), a singlet at 47 ppm (O=PCy ), and two triplets
3
3
[
11]
studies.
The optimal procedure towards the most enantiose-
(d=56.8 ppm and 56.2 ppm, in a 3:1 ratio, both with
JP, D =7.7 Hz). These NMR signals are consistent with
2
lective catalyst (D, Figure 1) was further studied by Ru species containing both D and PCy as ligands. In
3
5
16
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Asymmetric Transfer Hydrogenation of Ketones
1
the H NMR spectra, two doublets at À7.4 and Table 1. Optimization of the ATH of acetophenone (1a) to
[
a]
2
1-phenylethanol (2a).
À7.5 ppm (both with J =52 Hz, also in 3:1 ratio)
H,P
1
could be observed, probably belonging to the H ana-
logs of these latter species formed from residual un-
deuterated i-PrOH. Two other smaller singlets were
present in the hydride zone (at À5.0 and À6.2 ppm),
which were assigned to RuH species without any li-
gated PCy (for more details on the qualitative iden-
3
tification of the active species, see the Supporting In-
formation, pp 9–12). These observations are consis-
tent with previous reports related to the alcoholysis of
Grubbs catalysts and the concomitant formation of
[
12]
Ru hydrides. What is remarkable in our case is the
high ee obtained from such a mixture of potentially
active Ru complexes. This suggests the presence of
one enantioselective Ru species bearing the chiral Ts-
DPEN ligand whose activity is superior to those of
the other species present.
The ATH using HG-I as Ru precursor was further
optimized by varying the amount of t-BuOK (Table 1,
entries 1–4) and solvent ratio (entries 5 and 6). The
best result was obtained with 20 equivalents of t-
BuOK and a 1:3 THF/i-PrOH ratio leading to 97%
conversion and 93% ee (entry 5). Other commercially
available Ru-alkylidene complexes were investigated
#
Ru
Lig.
t-BuOK
(mol%)
THF/
i-PrOH
Conv.
[%]
ee
[%]
[
b]
[b]
1
2
3
4
5
6
7
8
9
10
HG-I
HG-I
HG-I
HG-I
HG-I
HG-I
G-I
HG-II
G-II
G-III
HG-I
HG-I
HG-I
HG-I
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
5
1:1
1:1
1:1
1:1
1:3
3:1
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
0
0
–
–
10
20
40
20
20
20
20
20
20
20
20
20
20
20
20
86
95
97
56
96
4
93
92
93
96
95
10
86
30
62
88
94
78
64
À5
(
entries 7–10). While G-I showed comparable results
to HG-I, all complexes containing an NHC ligand
showed very little activity. These differences between
PCy and the IMes-containing Ru complexes can be
3
explained by their different rates of reaction with alk-
oxides to form the active species, as demonstrated by
8
4
[
12d]
Fogg and co-workers.
Finally, a screening of chiral
1
1
1
1
1
2
3
4
53
96
92
97
67
34
ligands (entries 12–16) showed that Ts-DPEN (L1),
camphorsulfonyl-DPEN (L4) and to a lesser extent,
methanesulfonyl-DPEN (L3) were the best perform-
ing. Mesitylenesulfonyl-DPEN (L2) performed nota- 15 HG-I
bly worse than L1, illustrating the high dependence of 16 HG-I
catalyst performance on the ligand structure.
To explore the substrate scope of this transforma-
tion, several ketones were tested under the optimized
reaction conditions (Table 2). Both conversion and
enantiomeric excess were negatively affected when
the steric hindrance of the alkyl group increased (en-
tries 2–4). Similarly, o-substituted acetophenone
[
a]
The reactions were conducted with 0.1 mmol of 1a in
THF/i-PrOH (2.0 mL) at 308C for 18 h. 1a/Ru/Lig=
00:1:1.1.
Conversion and ee were determined by GC analysis with
a Chiralsil DEX CB column.
1
[b]
(
entry 8) was not reduced at all. Electron-deficient thesis–ATH protocol. To this purpose, two tests were
acetophenone derivatives (entries 5 and 6) proved performed under the optimized reaction conditions
more reactive than the electron-rich ones (entry 7). 2- (Scheme 2A and B). Ring-closing metathesis of dieth-
Acetonaphthone as well as aromatic cyclic ketones yl diallylmalonate (3, Scheme 2A) and homometathe-
(
entries 9–11) were reduced with high ees up to 97%. sis of 1-octene (5, Scheme 2B) were performed with
More challenging substrates like alkyl ketones (en- HG-I in the presence of acetophenone (1a) in THF,
tries 12 and 13) and 3-acetylpyridine (entry 14) led to followed by the addition of Ts-DPEN, i-PrOH and t-
poor or no conversion with low ee. Overall, these re- BuOK to perform the ketone ATH. In both cases 1-
sults are very similar to the ones obtained with the phenylethanol (2a) was formed with an ee comparable
[
2]
Noyori catalyst.
to the one obtained without previously performing
Having shown that HG-I catalyst can be converted the metathesis step (Table 2, entry 1), thus proving
to an efficient ketone ATH catalyst, our next goal that an ATH catalyst can be generated after the meta-
was to expand the concept towards a tandem meta- thesis reaction from a mixture of Ru precursors (un-
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Marc Renom-Carrasco et al.
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[
a]
Table 2. Substrate scope under the optimized conditions.
Scheme 2. Proof of concept for the tandem olefin metathe-
sis–ATH. All reactions were performed using 0.05 mmol of
the ketone. Reaction conditions: a) olefin (1 equiv.), HG-I
(
(
5 mol%), THF (0.5 mL), 4 h, 408C; b) addition of i-PrOH
1.5 mL), (R,R)-Ts-DPEN (5.5 mol%), t-BuOK (0.5 equiv.),
20 h, 308C; c) 1-octene (3 equiv.), HG-I (10 mol%), di-
chloroethane (0.3 mL), 5 h, 508C; d) addition of dichloro-
ethane (0.2 mL), i-PrOH (1.5 mL), (R,R)-Ts-DPEN
(11 mol%), t-BuOK (1 equiv.), 18 h, 308C. Conversion and
ee determined by GC analysis with a Chiralsil DEX CB
column.
[
[
a]
b]
Reactions were conducted with 0.1 mmol of 1a in 1:3
THF/i-PrOH (2.0 mL) at 308C for 20 h. 1a/HG-I/L1/t-
BuOK=100:1:1.1:20.
Conversion and ee (including absolute configuration, see
the Supporting Information) were determined by GC or
HPLC analysis. n.d.=not determined.
[15]
Chatterjee/Grubbs nomenclature.
Without any
work-up or isolation, i-PrOH, (R,R)-Ts-DPEN and t-
BuOK were then added to the reaction mixture.
After 18 h, the desired alcohol (8) resulting from a se-
quential cross metathesis–ATH was obtained with
[
[
[
c]
d]
e]
[16]
40 equivalents of base compared to the catalyst.
87% ee (Scheme 2C) and an overall yield of 28%.
Reaction run for 44 h.
Reaction run for 90 h.
In this experiment, dichloroethane was used instead
of THF, as it proved beneficial for the sluggish meta-
thesis reaction without affecting the ATH step. It is
also noteworthy that in all cases the ketone was re-
[
13]
reacted or regenerated HG-I and the new Ru spe- duced selectively, and the C=C bond did not react.
cies formed during the metathesis reaction). Remark-
st
In summary, we have shown that 1 generation
ably, no reduction nor isomerization of the C=C ruthenium catalysts for olefin metathesis can be con-
[
14]
double bond was observed in this case.
verted into highly enantioselective catalysts for
Although electron-poor styrenes are known to be ketone ATH by addition of a chiral ligand, a base and
st
sluggish substrates with 1 generation Grubbs cata- i-PrOH. Owing to the orthogonal reactivity of the C=
[
15]
lysts,
4-vinylacetophenone (7) (Scheme 2C) ap- C and C=O bond, the first example of a tandem cross
peared to be a straightforward choice to demonstrate metathesis–ATH was realized with model substrate 7.
our concept of tandem metathesis–ATH. In the first Remarkably, in this tandem process, by addition of
step, we carried out the cross-metathesis of 7 with 1- a chiral ligand to the Ru species present at the end of
octene (5) using HG-I as catalyst.
the metathesis step, a number of new Ru-hydride
Although the reaction did not reach completion, complexes were formed (as shown by NMR), among
we observed good selectivity towards the desired which the most enantioselective one appears to be the
cross-metathesized product due to the fact that 7 is most active. We believe that this simple methodology
a type II olefin relative to HG-I according to the could be of broad use for the synthetic community.
5
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COMMUNICATIONS
Asymmetric Transfer Hydrogenation of Ketones
Additionally, it allows for multiple use of ruthenium
in different catalytic processes and therefore discloses
new prospects towards a more efficient and sustaina-
ble use of this precious metal.
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[
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de Vries, U. Piarulli, C. Gennari, L. Lefort, Adv. Synth.
Catal. 2015, 357, 2223–2228.
Experimental Section
[
[
Procedure for the Tandem Cross Metathesis–ATH
In a nitrogen-filled mBraun glovebox, a solution of HG-I
(3.0 mg, 0.005 mmol) in dichloroethane (0.3 mL) was added
to 1-octene (16.8 mg, 0.15 mmol) and 1-(4-vinylphenyl)etha-
none (7.3 mg, 0.05 mmol). The reaction mixture was stirred
in an open glass vial for 5 h at 508C. After this time, (R,R)-
Ts-DPEN (2.0 mg, 0.0055 mmol), dichloroethane (0.2 mL),
i-PrOH (1.5 mL) and t-BuOK (5.6 mg, 0.05 mmol) were
added in this order. The vial was closed and the mixture
stirred for 18 h at 308C. Chiral GC analysis showed a conver-
sion of 28% and 87% ee.
[8] a) T. Connolly, Z. Wang, M. A. Walker, I. M. McDo-
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Acknowledgements
3817–3818.
We thank the European Commission [ITN-EID “REDUC-
TO” PITN-GA-2012-316371] for financial support and for
predoctoral fellowships (to M. R.-C. and P. G.).
11] For the effect of other cations in asymmetric reduction
of ketones, see, for example: a) R. Hartmann, P. Chen,
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[
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[
[
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[16] Upon hydrogenation, the remaining 1-(4-vinylphenyl)-
ethanone was hydrogenated to 1-(4-vinylphenyl)ethan-
1-ol with 79% conversion and 90% ee.
[4] For reviews about non-metathetic reactions using
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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519